Helicase inhibitors

Abstract

The present disclosure provides 3,7-disubstituted 2-oxo-2H-chromenyl compounds of Formula I or Formula II as inhibitors of helicases, such as SF3 and / or SF6 helicases, and more particularly, for example, CMG helicase and HPV El helicase, useful in treating medical disorders such as cancers or papilloma virus infections, as well as methods of making and using said compounds.

Description

[0001] HELICASE INHIBITORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 675,928 filed July 26, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR

[0005] DEVELOPMENT

[0006] This invention was made with government support under Grant Nos. GM140140 and CA211447 awarded by the National Institutes of Health. The Government has certain rights in the invention.

[0007] BACKGROUND

[0008] Helicases are a class of enzymes that unpack an organism’s genes. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy from ATP hydrolysis. There are many helicases representing the great variety of processes in which strand separation must be catalyzed, such as DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis. Helicases are classified into six superfamilies based on their shared sequence motifs; helicases not forming a ring structure are in superfamilies 1 and 2, and ring-forming helicases form part of superfamilies 3 to 6. In particular, superfamily 3 (SF3) consists of AAA+ helicases encoded mainly by small DNA viruses and some large nucleocytoplasmic DNA viruses, with the most known being the papilloma virus El helicase. Superfamily 6 (SF6) contains the core AAA+ that are not included in the SF3 classification; some proteins in this group are mini chromosome maintenance MCM, CMG, RuvB, RuvA, and RuvC.

[0009] The human replicative helicase functions during DNA replication to melt double-stranded DNA (dsDNA), allowing the polymerases and other replisome components access to single- stranded DNA (ssDNA) for synthesis of daughter strands of DNA. The human replicative helicase is referred to as the CMG helicase, which is derived from the names of its core subunits: Cdc45-MCM complex-GINS complex. MCM subunits are the six Mcm2-7 proteins, and GINS subunits are the four proteins named Go-Ichi-Ni-San (Japanese for 5-1-2-3). The entire CMG holoenzyme is thus composed of 11 subunits, Cdc45, 6 MCM monomers, and 4 GINS subunits, producing a very large ~750-800 kDa enzyme. Enzymatic activity of the CMG helicase is derived from ATP binding and hydrolysis within the regions between each pair of MCM dimers that make up the MCM hexamer. There are six pairs of MCMs that form six distinct ATP hydrolysis clefts, which work in a non-symmetrical and combinatorial manner to hydrolyze ATP and alter MCM subunit structures to achieve movement along DNA during the melting steps. ATP hydrolysis alters a staircase structure within the central channel of the MCM hexamer through which ssDNA moves in response to changes to this staircase structure during inter-coordinated ATP hydrolysis steps between MCM subunits.

[0010] The CMG helicase is an attractive target for cancer drug development due to unique features of its assembly, utilization in cells, and oncogene-induced errors in CMG management that lead to replication dysfunction during tumorigenesis and chemotherapeutic intervention. During the cell cycle, mammalian cells are ‘smart* and predict that they will likely encounter problems during the replicative S-phase, when DNA is being duplicated. For this reason, mammahan cells assemble more CMG helicase precursors, the MCM hexamer, than will be required to complete a normal unperturbed S-phase. An excess of reserve MCM hexamers (~ 5X needed) is pre-loaded onto DNA prior to S-phase beginning. Only a subset of these MCM hexamers is chosen, apparently stochastically, to become full CMG helicases upon recruitment of Cdc45 and GINS subunits. Those CMG helicases that form are active during DNA replication. However, if the cell encounters problems such as fork stalling events due to heterochromatin resistance or chemotherapeutic drug exposure that stall forks, then the excess (reserve) MCM hexamers become converted to functional CMG helicases to recover from the fork stalling events. The previous CMG helicases that had been functioning stop unwinding DNA, and these new CMGs become necessary to complete S-phase and the cell cycle. Herein lies the problem in cancers: tumor cells have been found to lack a proper number of unused reserve MCM hexamers and cannot easily create new CMG helicases as needed, for example, in recovering from chemotherapy drugs.

[0011] There are two currently known mechanisms by which tumor cells mismanage MCM / CMG helicases and thus fail to contain enough reserve helicases. First, overexpression of Cyclin E, which is oncogenic for a number of tumor types, leads to a reduction in MCM hexamer loading onto DNA in tumor cells. This results in a lower yield of total MCM hexamers that could become CMGs for replication or recovery (relative to non-tumor cells that load normal levels of MCMs). Second, Myc overexpression, which is known to occur in 70% or more of human malignancies, produces a related but different effect. Myc is known to be involved in stimulating the assembly and activation of CMG helicases (from MCM hexamers), but too much Myc causes this process to become deregulated and leads to excessive CMG helicase activation. This extra activation of CMG helicases by Myc leads to a loss of unused reserve MCMs, as they have already been turned on by the excess Myc proteins. When a tumor cell with excessive Myc and overactive CMGs is exposed to fork stalling chemotherapy, there are not enough unused reserve MCMs available to mount a healthy response to allow survival of the tumor cells. Again, non-tumor cells do not have elevated Myc expression and CMG activation. Therefore, these two known mechanisms by which oncogenes (Cyclin E or Myc) can mismanage MCM / CMG complexes produce a tumor-selective weakness in CMG levels and recovery from replicative stresses such as fork stalling chemotherapy. These findings also argue that a therapeutic window exists between tumor cells and non-tumor cells in a likely poor response of tumor cells to chemotherapy drugs (for example, as combination approaches using a future CMG inhibitor and chemotherapy). It is predicted from these findings that future CMG inhibitors could provide a unique means of cancer intervention for a variety of cancer types since the CMG helicase presents an exploitable tumor-specific vulnerability. Note also that other oncogenes besides Myc and Cyclin E could be found to mismanage CMG dynamics in tumor cells, so this concept could extend beyond just these two examples.

[0012] Papillomaviridae is a family of non-enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses have been identified, infecting all carefully inspected mammals, as well as other vertebrates, including birds, snakes, turtles, and fish. Infection by most papillomavirus types is either asymptomatic or causes small benign tumors, known as papillomas or warts. Papillomas caused by some papillomavirus types carry a risk of becoming cancerous. Papillomaviruses replicate exclusively in the basal layer of the body surface tissues, with all known papillomavirus types infecting a particular body surface, typically the skin or mucosal epithelium of the genitals, anus, mouth, or airways. Papillomaviruses replicate exclusively in keratinocytes, with less-differentiated keratinocyte stem cells thought to be the initial target of productive papillomavirus infections. Subsequent steps in the viral life cycle are strictly dependent on the process of keratinocyte differentiation.

[0013] El, an ATP-dependent DNA helicase, is the only enzyme encoded by papillomaviruses. It is essential for replication and amplification of the viral episome in the nucleus of infected cells. It forms a complex with the viral E2 protein, which is a site-specific DNA-binding transcriptional activator. The E1-E2 complex binds to the replication origin, which contains binding sites for both proteins. In addition to E2, it also interacts with DNA polymerase alpha and replication protein A to affect DNA replication. In solution, El is a monomer but binds DNA as a dimer. Recruitment of more El subunits to the complex leads to melting of the origin and ultimately to the formation of an El hexamer with helicase activity.

[0014] Human papillomavirus (HPV) infection is caused by HPV, a DNA virus of the Papillomaviridae family. About 90% of HPV infections cause no symptoms and resolve spontaneously within two years. In some cases, an HPV infection persists and results in either warts or precancerous lesions. These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, or throat. Over 170 HPV types have been described, with more than 40 able to be spread through sexual contact and infect the anus and genitals. Nearly every individual is infected by HPV at some point in their lives, leading it to be the most common sexually transmitted infection globally.

[0015] SUMMARY

[0016] The present disclosure provides compounds which may be useful in treating medical disorders, as well as methods of making and using said compounds. In particular, the present disclosure provides compounds that are helicase inhibitors, which may be useful in treating such disorders as cancers and papilloma viral infections.

[0017] In some aspects, a compound is provided of Formula I or Formula II or a pharmaceutically acceptable salt or derivative thereof; wherein all variables are as defined herein.

[0018] In some further aspects, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

[0019] In some even further aspects, a method is provided for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition described herein.

[0020] In some further aspects, a method is provided for treating an infection with a papillomavirus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound 5, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition described herein.

[0021] The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description, the drawings, and the claims.

[0022] DESCRIPTION OF DRAWINGS

[0023] FIG. 1 provides an X-ray crystal structure of compound KCC-01-097, a representative compound of the disclosure as described in the examples. The trans isomer (major isomer) is shown.

[0024] FIG. 2 provides data showing that KCC-01 (corresponding to KCC-09 in the examples) can inhibit CMG helicase as determined in a fork unwinding assay.

[0025] FIGs. 3A-3E provides data showing that CMGi induce DN A damage and selectively reduce tumor cell viability. (FIG. 3A) Cell Titer Gio viability assays for CAl / CMGi sensitivity were performed on 143B (OS), Psnl (PDAC), and H460 (NSCLC) tumor lines, and on primary human keratinocytes and HaCaT immortalized keratinocytes. Novobiocin was tested against 143B cells as a comparison, and against primary cells, which were not sensitive (ICso was not determined, ND). (FIG. 3B) Cell growth rate calculations, with approximate times for each to double on the right (in hours). Cells from equally plated initial cultures were counted at 12 or 24 hr intervals. (FIG. 3C) Immunoblot of chromatin-bound proteins (as indicated) from asynchronous 143B, H460, or Psnl tumor cells treated with 5 μM novobiocin or increasing concentrations of CAI for 24 hrs. (FIG. 3D) Immunoblot of total proteins from Psnl, H460, 143B, and HaCaT cells treated with 5 μM CAl / CMGi or DMSO / novobiocin controls, or HaCaT treated with 15 μM CAl / CMGi (right side). The Psnl and H460 cells were treated for 24 hrs, and 143B and HaCaT cells were treated for 48 hrs. Probing of blots was done with anti-gamma-H2AX (DNA damage signal) or anti-cleaved-Parp (apoptotic indicator). Anti- GAPDH is a loading control. (FIG. 3E) HaCaT cells were infected with a lentivirus expressing regulatable HA-tagged H-Ras-61L under control of the Tet-On promoter. An experiment was designed as shown in the left panel to assess effects of mutant Ras induction / expression on proliferation (cell count average / plate, + / - 1 SD), and on DNA damage (gamma-H2AX) and Parp cleavage using immunoblotting with indicated antibodies or anti-HA for ectopic H-Ras61L (right panel). Doxycycline inducer alone (with no Ras induction) was verified in a separate analysis to have no effect on HaCaT proliferation or CMGi effectiveness.

[0026] FIGs. 4A-4B depict and provide data regarding a representative medical chemistry approach to develop small CMGi with drug-like features that hit CMG enzyme in cells. FIG.4A depicts compounds synthesized using representative synthetic routes described herein, which are significantly smaller than coumennycin Al (CAI) and have head groups attached to either side of the core. FIG. 4B depicts and provides data regarding the ability of each compound to inhibit CMG helicase activity in vitro (biochemical) or to disrupt CMG in cells (in vivo using HaCat Gl-synchronized cells, which require higher CMGi levels relative to mut-Ras tumor cells). Each compound is compared to CAI, a DMSO control, or novobiocin (a negative control). Some compounds are effective in vitro, but not in vivo, while some are effective in both assays (i.e., are cell-permeable and hit CMG at μM levels close to those of CAI; a dot in FIG. 4A depicts such compounds). In cells, CMGi cause inactivation by disrupting CMG from DNA / chromatin. CMG assembly and helicase function are dependent on different ATP clefts in the MCM ring, and compounds can hit clefts required for one or both functions.

[0027] DETAILED DESCRIPTION

[0028] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known aspects. Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, benefiting from the teachings presented in the descriptions herein and the associated drawings. Therefore, it is understood that the disclosures are not limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0029] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0030] As apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure.

[0031] Any recited method can be carried out in the order of events recited or any other order that is logically possible. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not explicitly state in the claims or descriptions that the steps are to be limited to a particular order, it is in no way intended that an order be inferred in any respect. This holds for any possible non-express basis for interpretation, including logic concerning the arrangement of steps or operational flow, meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0032] All publications mentioned herein are incorporated by reference to disclose and describe the methods or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure before the filing date of the present application. Furthermore, the dates of publication provided herein may differ from the actual publication dates, which may require independent confirmation.

[0033] It is also to be understood that the terminology herein describes particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms herein have tire same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0034] Before describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

[0035] Definitions

[0036] As used herein, “comprising” is interpreted as specifying the presence of the stated features, integers, steps, or components but does not preclude the presence or addition of one or more features, integers, steps, components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves," “involved," and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, “consisting essentially of* is intended to include examples encompassed by the term “consisting of.”

[0037] As used in the specification and the appended claims, the singular forms “a,” ‘an,” and “the” include plural referents unless the context dictates otherwise.

[0038] Ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. Further, the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. There are many values disclosed herein, and each value is also disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value and to “about” another particular value. Similarly, when values are expressed as approximations, using the antecedent “about,” the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0039] When a range is expressed, a further aspect includes from the one particular value and to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y*. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less* and should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z* as well as the ranges of ‘less than x,’ ‘less than y.’ and ‘less than z.’ Likewise, the phrase ‘about x, y, z, or greater* should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z* as well as the ranges of ‘greater than x,’ greater than y,’ and ‘greater than z.’ In addition, the phrase “about ‘x* to ‘y’,” where ‘x* and ‘y* are numerical values, includes “about ‘x* to about ‘y’.”

[0040] Such a range format is used for convenience and brevity and thus, should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitiy recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0041] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate, larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about,” whether or not expressly stated to be such. Where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless expressly stated otherwise.

[0042] As used herein, the term “therapeutically effective amount” refers to an amount sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset.

[0043] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to increase the dosage gradually until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The individual physician can adjust the dosage in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. However, a patient may insist on a lower or tolerable dose for medical reasons, psychological reasons, or virtually any other reason.

[0044] A response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following the administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound or pharmaceutical composition, changing the disclosed compound or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. Dosage can vary and can be administered in one or more dose administrations daily for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0045] As used herein, the term “prophy tactically effective amount" refers to an amount effective for preventing the onset or initiation of a disease or condition.

[0046] As used herein, “prevent” or “preventing" refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. Where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0047] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur. The description includes instances where said event or circumstance occurs and those where it does not.

[0048] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g., human). “Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof.

[0049] As used herein, “treating” and “treatment" generally refer to obtaining a desired pharmacological or physiological effect. The effect can be but does not necessarily have to be prophylactic in preventing or partially preventing a disease, symptom, or condition. The effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder in a subject, particularly a human. It can include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease or its symptoms or conditions. The term “treatment," as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder or those in whom the disorder is to be prevented. As used herein, the term “treating" can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Heating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0050] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0051] As used herein, “therapeutic” can refer to treating, healing, or ameliorating a disease, disorder, condition, or side effect or decreasing the rate of advancement of a disease, disorder, condition, or side effect.

[0052] As used herein, the term or phrase “effective,” “effective amount,” or “conditions effective to” refers to such amount or condition that is capable of performing the function or property for which an effective amount or condition is expressed. As will be pointed out below, the exact amount or particular condition required will vary from one aspect to another, depending on recognized variables such as the materials employed and the processing conditions observed. Thus, it is not always possible to specify an exact “effective amount” or “condition effective to.” However, it should be understood that an appropriate effective amount will be readily determined by one of ordinary skill in the art using only routine experimentation.

[0053] Chemical Definitions

[0054] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0055] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration. The compounds provided herein may either be enantiomerically pure or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein may contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, all such possible isomers are contemplated, as well as mixtures of such isomers. Compounds described herein may also be present as an equilibrium of tautomers. For example, ketones with an .-hydrogen can exist in an equilibrium of the keto form and the enol form. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, all possible tautomers of the compounds described herein are contemplated. A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2is attached through the carbon of the keto (C=O) group. The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =O) then two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and / or can be formulated into a form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art. Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to: halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, AxO-(C0-C6 alkyl)-, AxS-(C0-C6 alkyl)-, (AxAyN)-(C0-C6 alkyl)-, AzC(O)-(C0-C6 alkyl)-, AzC(N)-(C0-C6 alkyl)-, and AzS(O)-(C0-C6alkyl)-, and AzS(O)2-(C0-C6alkyl)-, wherein Axand Ayare independently selected at each occurrence from Aa, AzC(O)-, AzC(N)-, AzS(O)-, and AzS(O)2-, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein Azis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -OAa, -SAa, and -NAaAb, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein Aaand Abare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0- C3 alkyl)-, (4- to 6-membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0- C3 alkyl)-, each of which may be optionally substituted by one or more B groups as allowed by valency, and,wherien B is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, ApO-, ApS-, ApAqN-, AoC(O)-, AoC(O)-O- , AoC(O)-NAq-, AoS(O)2-, AoS(O)2-O-, and AoS(O)2-NAq-, wherein Aois independently selected at each occurrence from Ap, halo, ApO-, and ApAqN-, and wherein Apand Aqare independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2- C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0- C6 alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-. The terms for various functional groups as used herein are not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent groups, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person in the context in which said functional groups are recited. As used herein, the symbol (which hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, “ indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound

[0056] CH3-R3, wherein R3is H or infers that when R3is “XY”, the point of attachment bond is the same bond as the bond by which R3is depicted as being bonded to CH3.

[0057] “Halo” or “halogen” indicates, independently, any of fluoro, chloro, bromo or iodo.

[0058] The term “nitro” as used herein is represented by the formula — NO2.

[0059] The term “cyano” as used herein is represented by the formula — CN

[0060] The term “azido" as used herein is represented by the formula -N3.

[0061] The term “oxo” as used herein is represented by the formula =0.

[0062] “Alkyl” is a straight chain or branched saturated aliphatic hydrocarbon group. In certain aspects, the alkyl is C1-C2, C1-C3, or C1-C6(i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). The specified ranges as used herein indicate an alkyl group with length of each member of the range described as an indqpendent species. For example, C1-C6alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and C1-C4alkyl as used herein indicates an alkyl group having from 1 , 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When Co-Cnalkyl is used herein in conjunction with another group, for example (C3-C7cycloalkyl)Co-C4alkyl, or -Co- C4(C3-C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (Coalkyl), or attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms, as in -O-Co- C4alkyl(C3-C7cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3- dimethylbutane. In some aspects, the alkyl group is optionally substituted as described herein. “Haloalkyl” refers to an alkyl group that is substituted with one or more halo groups, e.g., fluoro, chloro, bromo, iodo, or combinations thereof. “Cycloalkyl” is a saturated or partially unsaturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some aspects, the cycloalkyl group is optionally substituted as described herein. “Alkenyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain. Non-limiting examples include C2-C4alkenyl and C2- C6alkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one aspect, the alkenyl group is optionally substituted as described herein. “Alkynyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4alkynyl or C2-C6alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5- hexynyl. In one aspect, the alkynyl group is optionally substituted as described herein. “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one aspect, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one aspect, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one aspect, the aryl group is optionally substituted as described herein.

[0063] The term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions. Examples of saturated heterocycle groups including saturated 4- to 7 -membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited, dihydrothienyl, dihydropyranyl, dihydrofiiryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2, 3, 4, 4a, 9,9a- hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydro-l ,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro- 2H-benzo[l,4]oxazinyl, benzofl, 4]dioxanyl, 2,3,-dihydro-lH-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofiiryl, and dihydrothiazolyl. Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical. Representative examples include, but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms. In one aspect, the heterocycle group is optionally substituted as described herein.

[0064] “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 4, or in some aspects 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some aspects from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon. In one aspect, the only heteroatom is nitrogen. In one aspect, the only heteroatom is oxygen. In one aspect, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 to 6 ring atoms. In some aspects, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring which contains from 1 to 4 heteroatoms selected from N, O, S, B, or P is fused to a second aromatic or non-aromadc ring, wherein the point of attachment is an aromatic ring. When the total number of S and O atoms in the heteroaryl ring exceeds 1 , these heteroatoms are not adjacent to one another within the ring. In one aspect, the total number of S and O atoms in the heteroaryl ring is not more than 2. In another aspect, the total number of S and O atoms in the heteroaryl ring is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In one aspect, the heteroaryl group is optionally substituted as described herein.

[0065] A “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts which are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts. Example of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, H00C-(CH2)1-4- COOH, and the like, or using a different acid that produced the same counterion. Suitable counterions found in pharmaceutically acceptable salts described herein include, but are not limited to, cations such as calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, potassium, procaine, sodium, triethylamine, and zinc, and anions such as acetate, aspartate, benzenesulfonate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, teoclate, and tosylate. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, PA., p. 1418 (1985).

[0066] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compound. Exemplary derivatives include, but are not limited to, salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0067] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gas- chromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not delectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Both traditional and modem methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers.

[0068] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers, such as Sigma- Aldrich (formally MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc. (Waltham, MA), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons, 2007); Organic Reactions (John Wiley and Sons, 2004); March's Advanced Organic Chemistry, (John Wiley and Sons, 8thEdition); and Larock's Comprehensive Organic Transformations (John Wiley and Sons, 3rdedition, 2017).

[0069] Compounds

[0070] The present disclosure provides compounds that may be useful as inhibitors of helicases, such as SF3 and / or SF6 helicases, and more particularly, for example, CMG helicase and HPV El helicase. The present compounds are useful in the treatment of medical disorders mediated by a helicase, such as cancer.

[0071] In one aspect, a compound is provided of Formula I or Formula II

[0072] or a pharmaceutically acceptable salt or derivative thereof; wherein:

[0073] R1is selected from 3- to 8-membered monocyclic or bicyclic heterocycle and 5- to 10- membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted by one or more groups selected from R3as allowed by valency;

[0074] R2is selected from C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6 cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co-Cc alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted by one or more groups selected from R3as allowed by valency;

[0075] R3is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6 cycloalkyl)(Co-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(Co-C6alkyl)-, (RxRyN)-(Co-C6alkyl)-, RzC(O)-(C0-C6alkyl)-, RzC(N)C-0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)z-(C0-C6alkyl)-, each of which may be optionally substituted by one or more groups selected from Y as allowed by valency;

[0076] Rxand Ryare independently selected at each occurrence from Ra, RzC(O)-, Rz(N)-, RzS(O)- , and RzS(O)z-, each of which may be optionally substituted with one or more Y groups as allowed by valency;

[0077] Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more Y groups as allowed by valeny; and Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-, wherein Rois independently selected at each occurrence from Rp, halo, RpO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-. In some aspects of Formula I or Formula II is selected from In some aspects of Formula I or Formula II, R1is 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula II, R1is 3- to 8- membered monocyclic or bicyclic heterocycle optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, independently selected from halo, C1- C6alkyl, C1-C6haloalkyl, and -ORx. In some aspects of Formula I or Formula II, R1is 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, independently selected from fluoro, chloro, bromo methyl, ethyl, isopropyl, trifluoromethyl, propargyl, cyclopropyl, -OCH3, phenyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3), and benzyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3). In some aspects of Formula I or Formula II, R1is 3- to 6-membered monocyclic heterocycle optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R1as allowed by valency. In some aspects of Formula I or Formula II, R1is 3- to 6-membered monocyclic heterocycle optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, and -ORx. In some aspects of Formula I or Formula II, R1is 3- to 6-membered monocyclic heterocycle optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from fluoro, chloro, bromo methyl, ethyl, isopropyl, trifluoromethyl, propargyl, cyclopropyl, -OCH3, phenyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3), and benzyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3). In some aspects of Formula I or Formula II, R1is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl, each of which may be optionallysubstituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3 as allowedby valency. In some aspects of Formula I or Formula II, R1is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from halo, C1-C6alkyl, C1-C6haloalkyl, and -ORx. In some aspects of Formula I or Formula n, R1is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indo liny 1, and isoindolinyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from fluoro, chloro, bromo methyl, ethyl, isopropyl, trifluoromethyl, propargyl, cyclopropyl, -OCH3, phenyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3), and benzyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3).

[0078] In some aspects of Formula I or Formula II, R1is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula n, R1is 5- to 10- membered monocyclic or bicyclic heteroaryl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX. In some aspects of Formula I or Formula n, R1is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from fluoro, chloro, bromo methyl, ethyl, isopropyl, trifluoromethyl, propargyl, cyclopropyl, -OCH3, phenyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3), and benzyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3).

[0079] In some aspects of Formula I or Formula II, R1is 5- to 6-membered monocyclic heteroaryl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula n, R1is 5- to 6-membered monocyclic heteroaryl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX. In some aspects of Formula I or Formula n, R1is 5- to 6-membered monocyclic heteroaryl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from fluoro, chloro, bromo methyl, ethyl, isopropyl, trifluoromethyl, propargyl, cyclopropyl, -OCH3, phenyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3), and benzyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3). In some aspects of Formula I or Formula II, R1is selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofiiranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula n, R1is selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofiiranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from halo, C1-C6alkyl, C1-C6halo alkyl, and -OR*. In some aspects of Formula I or Formula II, R1is selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from fluoro, chloro, bromo methyl, ethyl, isopropyl, trifluoromethyl, propargyl, cyclopropyl, -OCH3, phenyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3), and benzyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3).

[0080] In some aspects of Formula I or Formula II, R1is selected from pyrrolyl, pyrazolyl, and furanyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula n, R1is selected from pyrrolyl, pyrazolyl, and furanyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from halo, C1-C6alkyl, Ci-Cs haloalkyl, and -OR*. In some aspects of Formula I or Formula H, R1is selected from pyrrolyl, pyrazolyl, and furanyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups, as allowed by valency, selected from fluoro, chloro, bromo methyl, ethyl, isopropyl, trifluoromethyl, propargyl, cyclopropyl, -OCH3, phenyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3), and benzyl (optionally substituted with 1 to 3 groups selected from fluoro, chloro, bromo, methyl, trifluoromethyl, and -OCH3).

[0081] In some aspects of Formula I or Formula II, R1is selected from:

[0082] In some aspects of Formula I or Formula II, R1is selected from:

[0083] In some aspects of Formula I or Formula II, R2is selected from C1-C6 alkyl, C1-C6haloalkyl, C3-C6 cycloalkyl, and 6- to 10-membered monocyclic or bicyclic aryl, each of which may be optionally substituted by one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula II, R2is selected from methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.

[0084] In some aspects of Formula I or Formula II, R2is C1-C6alkyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula II, R2is selected from R2is selected from methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3- dimethylbutane, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from R3as allowed by valency. In some aspects of Formula I or Formula II, R2is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3- methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some aspects of Formula I or Formula n, R2is isopropyl.

[0085] Representative examples of compounds described herein include, but are not limited to: or a pharmaceutically acceptable salt or derivative thereof.

[0086] Further representative examples of compounds described herein include, but are not limited to: or a pharmaceutically acceptable salt or derivative thereof.

[0087] The present disclosure also includes compounds described herein with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.

[0088] Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as2H,3H,nC,13C,15N,17O,18O,18F,31p-32p,35S,36Cl, and125I, respectively. In one aspect, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an,8F-labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0089] By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H), may optionally be used anywhere in described structures that achieve the desired result. Alternatively, or in addition, isotopes of carbon, e.g.,13C and14C, may be used. In one aspect, the isotopic substitution is replacing hydrogen with a deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a beta-deuterium kinetic isotope effect). Isotopic substitutions, such as deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain aspects, the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest. In some aspects, deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance, and in an aspect, is enough to alter a detectable property of the compounds as a drug in a human.

[0090] The compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one aspect, the disclosure includes a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, or de-DMSO. A solvate can be in a liquid or solid form.

[0091] It is known that chemical substances may form solids present in different states of order, termed polymorphic forms or modifications. The different forms of a polymorphic substance can differ greatly in their physical properties. The compounds disclosed herein can be present in different polymorphic forms, with it possible for particular forms to be metastable. Unless stated to the contrary, the present disclosure includes all such polymorphic forms.

[0092] A “prodrug" as used herein means a compound which, when administered to a host in vivo, is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described compounds herein. Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including to increase the half-life of the drug in vivo. Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug. Non-limiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to, acylating, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides, among others. In certain aspects, the prodrug renders the parent compound more lipophilic. In certain aspects, a prodrug can be provided that has several prodrug moieties in a linear, branched, or cyclic manner. For example, nonlimiting aspects include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compound that has at least two functional groups that can link the parent compound with another prodrug moiety and is typically biodegradable in vivo. In some aspects, 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound. Non-limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and a hydroxylated prodrug moiety to form a phosphate ester; a hydroxyl on the parent drug and a phosphonate on the prodrug to form a phosphonate ester; a hydroxyl on the parent drug and a phosphoric acid prodrug moiety to form a phosphate ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2- 24 alkyl) to form an ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-S-(C2-24 alkyl) to form a thioester; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an ether; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an thioether; and a carboxylic acid, oxime, hydrazide, hydrazine, amine or hydroxyl on the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer including but not limited to polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyanhydride, polyester, polyamide, or a peptide.

[0093] In some aspects, a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug. The amino acid can be used alone or covalently linked (straight, branched or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties. The amino acid can be any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid.

[0094] Pharmaceutical Compositions

[0095] The compounds described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the active components described herein can be formulated in a physiologically- or pharmaceutically- acceptable form and administered by any suitable route known in the art including, for example, oral and parenteral routes of administering. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrastemal administration, such as by injection. Administration of the active components of their compositions can be a single administration, or at continuous and distinct intervals as can be readily determined by a person skilled in the art.

[0096] Compositions, as described herein, comprising an active compound and a pharmaceutically acceptable carrier or excipient of some sort may be useful in a variety of medical and nonmedical applications.

[0097] "Pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate-buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion), and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.

[0098] “Excipients” include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. General considerations in formulation and / or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0099] Exemplary excipients include, but are not limited to, any non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium cafboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. As would be appreciated by one skilled in this art, the excipients may be chosen based on the composition’s intended use. For example, with a pharmaceutical composition or cosmetic composition, the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and / or to animals, orally, rectally, parenterally, intracistemally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray. In some aspects, the active compounds disclosed herein are administered topically.

[0100] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.

[0101] Exemplary granulating and / or dispersing agents include potato starch, com starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.

[0102] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Plutonic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and / or combinations thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0103] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0104] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0105] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0106] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0107] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl. In certain aspects, the preservative is an antioxidant. In other aspects, the preservative is a chelating agent.

[0108] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and combinations thereof.

[0109] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.

[0110] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0111] Additionally, the composition may further comprise a polymer. Exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.-caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid / acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxidepropylene oxide), and a Plutonic polymer, polyoxy ethylene (polyethylene glycol), polyanhydrides, polyvinylalcohol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N- [Methoxy(Polyethylene glycol)- 1000] , 1 ,2-Distearoyl-sn-glycero- 3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000], and 1,2-Distearoyl-sn- glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000]), copolymers and salts thereof.

[0112] Additionally, the composition may further comprise an emulsifying agent. Exemplary emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Plutonic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. In certain aspects, the emulsifying agent is cholesterol.

[0113] Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0114] Injectable compositions, for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In certain aspects, the particles are suspended in a carrier fluid comprising 1% (w / v) sodium carboxymethyl cellulose and 0.1% (v / v) Tween 80. The injectable composition can be sterilized, for example, by filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0115] Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.

[0116] Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, the particles are mixed with at least one excipient and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0117] Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0118] Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is admixed with an excipient and any needed preservatives or buffers as may be required. The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0119] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0120] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the particles in a polymer matrix or gel.

[0121] Methods of Use

[0122] The present disclosure also provides methods for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. The methods can further comprise administering one or more additional therapeutic agents, such as anti-cancer agents or anti-inflammatory agents. Additionally, the method can further comprise administering a therapeutically effective amount of ionizing radiation to the subject.

[0123] Methods of killing a cancer or tumor cell are also provided comprising contacting the cancer or tumor cell with an effective amount of a compound or composition as described herein. The methods can further include administering one or more additional therapeutic agents or administering an effective amount of ionizing radiation.

[0124] The disclosed methods can optionally include identifying a patient who is or can be in need of treatment of an oncological disorder. The patient can be a human or other mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog, cat, cow, pig, or horse, or other animals having an oncological disorder. In some aspects, the subject can receive the therapeutic compositions prior to, during, or after surgical intervention to remove part or all of a tumor.

[0125] The term “neoplasia” or “cancer” is used throughout this disclosure to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant, hematogenous, ascitic and solid tumors. The cancers which may be treated by the compounds or compositions disclosed herein may comprise carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, or blastomas.

[0126] Carcinomas which may be treated by the compounds or compositions of the present disclosure include, but are not limited to, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky- cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, and carcinoma vilosum.

[0127] Representative sarcomas which may be treated by the compounds or compositions of the present disclosure include, but are not limited to, liposarcomas (including myxoid liposarcomas and pleomorphic liposarcomas), leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors (including Ewing's sarcoma of bone, extraskeletal or non-bone) and primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST) and osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, and chondrosarcoma.

[0128] The compounds or compositions of the present disclosure may be used in the treatment of a lymphoma. Lymphomas which may be treated include mature B cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, precursor lymphoid neoplasms, Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders. Representative mature B cell neoplasms include, but are not limited to, B-cell chronic lymphocytic leukemia / small cell lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (such as Waldenstrom macroglobulinemia), splenic marginal zone lymphoma, hairy cell leukemia, plasma cell neoplasms (such as plasma cell myeloma / multiple myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, and heavy chain diseases), extranodal marginal zone B cell lymphoma (MALT lymphoma), nodal marginal zone B cell lymphoma, follicular lymphoma, primary cutaneous follicular center lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, diffuse large B-cell lymphoma associated with chronic inflammation, Epstein-Barr virus-positive DLBCL of the elderly, lyphomatoid granulomatosis, primary mediastinal (thymic) large B- cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman’s disease, and Burkitt lymphoma / leukemia. Representative mature T cell and NK cell neoplasms include, but are not limited to, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, lycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders (such as primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis), peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma. Representative precursor lymphoid neoplasms include B-lymphoblastic leukemia / lymphoma not otherwise specified, B-lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities, or T- lymphoblastic leukemia / lymphoma. Representative Hodgkin lymphomas include classical Hodgkin lymphomas, mixed cellularity Hodgkin lymphoma, lymphocyte-rich Hodgkin lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma.

[0129] The compounds or compositions of the present disclosure may be used in the treatment of a leukemia. Representative examples of leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia, adult T-cell leukemia, clonal eosinophilias, and transient myeloproliferative disease.

[0130] The compounds or compositions of the present disclosure may be used in the treatment of a germ cell tumor, for example, germinomatous (such as germinoma, dysgerminoma, and seminoma), non-germinomatous (such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma), and mixed tumors.

[0131] The compounds compositions of the present disclosure may be used in the treatment of blastomas, for example, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme.

[0132] Representative cancers which may be treated include, but are not limited to: bone and muscle sarcomas such as chondrosarcoma, Ewing’s sarcoma, malignant fibrous histiocytoma of bone / osteosarcoma, osteosarcoma, rhabdomyosarcoma, and heart cancer; brain and nervous system cancers such as astrocytoma, brainstem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioma, medulloblastoma, neuroblastoma, oligodendroglioma, pineal astrocytoma, pituitary adenoma, and visual pathway and hypothalamic glioma; breast cancers including invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medullary carcinoma, male breast cancer, Phyllodes tumor, and inflammatory breast cancer; endocrine system cancers such as adrenocortical carcinoma, islet cell carcinoma, multiple endocrine neoplasia syndrome, parathyroid cancer, phemochromocytoma, thyroid cancer, and Merkel cell carcinoma; eye cancers including uveal melanoma and retinoblastoma; gastrointestinal cancers such as anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal carcinoid tumors, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, hepatocellular cancer, pancreatic cancer, and rectal cancer; genitourinary and gynecologic cancers such as bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumor, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, penile cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, prostate cancer, testicular cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor; head and neck cancers such as esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, and hypopharyngeal cancer; hematopoietic cancers such as acute biphenotypic leukemia, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid dendritic cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, intravascular large B-cell lymphoma, large granular lymphocytic leukemia, lymphoplasmacytic lymphoma, lymphomatoid granulomatosis, mantle cell lymphoma, marginal zone B-cell lymphoma, Mast cell leukemia, mediastinal large B cell lymphoma, multiple myeloma / plasma cell neoplasm, myelodysplastic syndroms, mucosa-associated lymphoid tissue lymphoma, mycosis fungoides, nodal marginal zone B cell lymphoma, nonHodgkin lymphoma, precursor B lymphoblastic leukemia, primary central nervous system lymphoma, primary cutaneous follicular lymphoma, primary cutaneous immunocytoma, primary effusion lymphoma, plasmablastic lymphoma, Sezary syndrome, splenic marginal zone lymphoma, and T-cell prolymphocytic leukemia; skin cancers such as basal cell carcinoma, squamous cell carcinoma, skin adnexal tumors (such as sebaceous carcinoma), melanoma, Merkel cell carcinoma, sarcomas of primary cutaneous origin (such as dermatoflbrosarcoma protuberans), and lymphomas of primary cutaneous origin (such as mycosis fungoides); thoracic and respiratory cancers such as bronchial adenomas / carcinoids, small cell lung cancer, mesothelioma, non-small cell lung cancer, pleuropulmonary blastoma, laryngeal cancer, and thymoma or thymic carcinoma; HTV / AIDs-related cancers such as Kaposi sarcoma; epithelioid hemangioendothelioma; desmoplastic small round cell tumor; and liposarcoma.

[0133] Compounds and compositions disclosed herein can be locally administered at one or more anatomical sites, such as sites of unwanted cell growth (such as a tumor site or benign skin growth, e.g., injected or topically applied to the tumor or skin growth), optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent. Compounds and compositions disclosed herein can also be systemically administered, such as intravenously or orally, optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent, or an assimilable edible carrier for oral delivery. In addition, the active compound can be incorporated into sustained release preparations and / or devices.

[0134] For the treatment of oncological disorders, compounds, agents, and compositions disclosed herein can be administered to a patient in need of treatment prior to, subsequent to, or in combination with other antitumor or anticancer agents or substances (e.g., chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cytotoxic agents, etc.) and / or with radiation therapy and / or with surgical treatment to remove a tumor. For example, compounds, agents, and compositions disclosed herein can be used in methods of treating cancer wherein the patient is to be treated or is or has been treated with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosphamide or ifosfamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, antiestrogens such as tamoxifen, and / or other anti-cancer drugs or antibodies, such as, for example, imatinid or trastuzumab. These other substances or radiation treatments can be given at the same time as or at different times from the compounds disclosed herein. Examples of other suitable chemotherapeutic agents include, but are not limited to, altretamine, bleomycin, bortezomib, busulphan, calcium folinate, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, liposomal doxorubicin, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pentostatin, procarbazine, raltitrexed, streptozocin, tegafur-uraxil, temozolomide, thiotepa, tioguanine / thioguanine, topotexan, treosulfan, vinblastine, vincristine, vindesine, and vinorelbine. Examples of suitable immunotherapeutic agents include, but are not limited to, alemtuzumab, cetuximab, gemtuzumab, iodine 131 tositumomab, rituximab, and trastuzumab. Cytotoxic agents include, for example, radioactive isotopes and toxins of bacterial, fungal, plant, or animal origin. Also disclosed are methods of treating an oncological disorder comprising administering an effective amount of a compound described herein prior to, subsequent to, and / or in combination with administration of a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, or radiotherapy.

[0135] In another aspect, methods are provided for the treatment of medical disorders associated with a helicase, for example, an SF3 and / or SF6 helicase, by administering a compound of Formula I, or pharmaceutically acceptable salts or derivatives thereof. In particular aspects, the compounds described herein may be used in the treatment of cancer, either alone or in combination with one or more additional therapeutic agents, for example, a chemotherapeutic agent. In some aspects, the helicase comprises CMG helicase. In other aspects, the helicase comprises HPV El helicase.

[0136] Thus, in one aspect, a method is provided for treating a cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition as further described herein. In some aspects, the subject is a human. In some aspects, the cancer is associated with dysregulation of a helicase, for example, an SF3 and / or SF6 helicase. In some aspects, the cancer is associated with CMG helicase. In some aspects, the cancer is associated with HPV El helicase.

[0137] In another aspect, a method is provided for treating cancers associated with elevated expression levels of Myc and / or elevated expression levels of Cyclin E. Elevated levels of Myc and Cyclin E have been associated with overactivation of CMG helicases, leading to diminished reserve MCMs available to allow the cancer cell to successfully complete the S- phase of the cell cycle. Upon exposure of the cancer cell to a CMG helicase inhibitor such as those described herein, the cancer cell faces diminished survival and potentially cell death. Thus, in one aspect, a method is provided for treating a cancer in a subject in need thereof, the method comprising:

[0138] (a) determining whether the cancer is characterized by elevated Myc expression and / or elevated Cyclin E expression; and

[0139] (b) if the cancer is determined to be characterized by elevated Myc expression and / or elevated Cyclin E expression in (a), administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof, either alone or in combination with one or more additional therapeutic agents (such as a chemotherapeutic or cytotoxic agent).

[0140] In another aspect, a method of treating a cancer associated with elevated Myc expression and / or elevated Cyclin E expression is provided comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof, either alone or in combination with one or more additional therapeutic agents (such as a chemotherapeutic or cytotoxic agent).

[0141] In another aspect, a method of treating a cancer associated with a mutant Ras protein or gene is provided, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof, either alone or in combination with one or more additional therapeutic agents (such as a chemotherapeutic or cytotoxic agent). In some aspects, the mutant Ras protein or gene is K-Ras. In some aspects, the mutant Ras protein or gene is H-Ras. In some aspects, the mutant Ras protein or gene is N-Ras.

[0142] In yet another aspect, a method is provided for inhibiting CMG helicase in a eukaryotic cell comprising contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof. In some aspects, the eukaryotic cell is a human cell.

[0143] In yet another aspect, a method for treating cancer in a subject in need thereof is provided, the method comprising:

[0144] (a) determining whether the cancer is associated with one or more signs of replicative stress; and (b) if the cancer is determined to be associated with one or more signs of replicative stress, administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof.

[0145] In another aspect, a method is provided for treating cancer in a subject in need thereof, wherein the cancer has been previously determined to be associated with one or more signs of replicative stress, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof.

[0146] In some aspects, the one or more signs of replicative stress may comprise Myc overexpression, CyclinE overexpression, Rb loss, p53 loss, PolQ overexpression, or combinations thereof. In some aspects, the one or more signs or replicative stress comprises Myc overexpression. In some aspects, the one or more signs or replicative stress comprises CyclinE overexpression. In some aspects, the one or more signs or replicative stress comprises Rb loss. In some aspects, the one or more signs or replicative stress comprises p53 loss. In some aspects, the one or more signs or replicative stress comprises PolQ overexpression.

[0147] In yet another aspect, a method for treating cancer in a subject in need thereof is provided, the method comprising:

[0148] (a) determining whether the cancer harbors one or more inherited or acquired germ-line mutations; and

[0149] (b) if the cancer is determined to harbor one or more inherited or acquired germ-line mutations in (a), administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof.

[0150] In another aspect, a method for treating cancer in a subject in need thereof is provided, wherein the cancer has been previously determined to harbor one or more inherited or acquired germ-line mutations, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof.

[0151] In some aspects, the one or more inherited or acquired germ-line mutations may comprise loss of: p53, Rb, BRCA1, BRCA2, ATM, a xeroderma pigmentosum gene (such as XPA, XPB, XPC, XPD, XPE, XPF, or XPG), a mismatch repair gene (such as MSH2, MLH1, MSH6, PMS2), WRN, BLM, a Fanconi anemia gene (such as FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCT, FANCU, FANCY, or FANCW), NBS, Chek2, RecqL4, MYH, PALB2, BACH1, RAC51C, or combinations thereof.

[0152] In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of p53. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of Rb. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BRCA1. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BRCA2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of ATM. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPA. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPB. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPC. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPD. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPE. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPE In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPG. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of MSH2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of MLH1. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of MSH6. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of PMS2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of WRN. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BLM. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCA. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCB. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCC. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCD2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCE. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCE In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCG. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCI. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCI. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCL. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCM. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCN. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCO. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCP. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCQ. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCT. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCU. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCY. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCW. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of NBS. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of Chek2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of RecqL4. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of MYH. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of PALB2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BACH1. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of RAC51C.

[0153] In another aspect, a method is provided for treating an infection resulting from a papillomavirus in a subject in need thereof comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof, to the subject.

[0154] In some aspects, the papillomavirus is human papillomavirus (HPV). In some aspects, the HPV is an HPV strain selected from a strain including, but not limited to, HPV1, HPV2, HPV3, HPV4, HPV6, HPV7, HPV10, HPV11, HPV13, HPV16, HPV18, HPV22, HPV26,

[0155] HPV28, HPV31, HPV32, HPV33, HPV35, HPV39, HPV42, HPV44, HPV45, HPV51,

[0156] HPV52, HPV53, HPV56, HPV58, HPV59, HPV60, HPV63, HPV66, HPV68, HPV73,

[0157] HPV82, or any other HPV strain which is known to result in an infection associated with a medical disorder.

[0158] In another aspect, a method is provided for treating a medical disorder associated with infection with human papillomavirus comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof. In some aspects, the medical disorder associated infection with human papillomavirus is cancer. Representative examples of medical disorders resulting from infection with HPV include, but are not limited to, common warts (associated with HPV2, HPV7, and HPV22, for example), plantar warts (associated with HPV1, HPV2, HPV4, and HPV63, for example), flat warts (associated with HPV3, HPV10, and HPV28, for example), anogenital warts (associated with HPV6, HPV11, HPV42, and HPV42, for example), genital cancers (associated with HPV16, HPV18, HPV26 HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV53, HPV56, HPV58, HPV59, HPV66, HPV72, and HPV82, for example), epidermodysplasia verruciformis, focal epithelial hyperplasia (associated with HPV13 and HPV32, for example), mouth papillomas (associated with HPV6, HPV7, HPV11, HPV16, and HPV32, for example), oropharyngeal cancer (associated with HPV16, for example), verrucous cyst (associated with HPV60, for example), and laryngeal papillomatosis (associated with HPV6 and HPV11, for example).

[0159] In some aspects, the one or more additional therapeutic agents may comprise a Chkl inhibitor, an ATR inhibitor, a Cdc7 inhibitor, or a Parp inhibitor.

[0160] In another aspect, a method for treating cancer in a subject in need thereof is provided, the method comprising:

[0161] (a) administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof; and

[0162] (b) administering one or more additional therapeutic agents selected from a Chkl inhibitor, an ATR inhibitor, a Cdc7 inhibitor, and a Parp inhibitor.

[0163] Representative Chkl inhibitors which may be used in the above methods include, but are not limited to, AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF- 477736, prexasertib (LY2606368), GDC-0575, SAR-020106, CCT245737, and PD166285.

[0164] Representative ATR inhibitors which may be used in the above methods include, but are not limited to, VE-821, Berzosertib (VE-822), elimusertib (BAY-1895344), ETP-46464, CGK 733, AZ20, AZ31, ceralasertib (AZD6738), and VX-803 (M4344).

[0165] Representative examples of Cdc7 inhibitors which may be used in the above methods include, but are not limited to, XL-413, PHA-767491 (CAY10572), and LY3143921.

[0166] Representative examples of Parp inhibitors which may be used in the above methods include, but are not limited to, Olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib (BGB- 290), CEP 9722, E7016, 3-aminobenzamide,fluzoparib, AG-14361, A-966492, PJ34, UPF 1069, AZD2461, ME0328, BYK204165, BGP-15, RBN-2397, NU1025, E7449, 4- hydroxyquinazoline, NMS-P118, RBN012759, and picolinamide.

[0167] The active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether the active compound itself, or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0168] The active ingredient may be administered by any route. In some aspects, the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.

[0169] The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art.

[0170] The dosage ranges for the administration of the compositions are those laige enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary and can be administered in one or more dose administrations daily, for one or several days.

[0171] Additional Particular Aspects

[0172] In view of the described compounds, compositions, and methods, hereinbelow are described certain more particular aspects of the disclosure. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein, or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulae literally used therein.

[0173] Aspect 1. A compound of Formula I or Formula II

[0174] or a pharmaceutically acceptable salt or derivative thereof; wherein: R1is selected from 3- to 8-membered monocyclic or bicyclic heterocycle and 5- to 10- membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted by one or more groups selected from R3as allowed by valency; R2is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted by one or more groups selected from R3as allowed by valency; R3is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RzC(O)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted by one or more groups selected from Y as allowed by valency; Rxand Ryare independently selected at each occurrence from Ra, RzC(O)-, RzC(N)-, RzS(O)- , and RzS(O)2-, each of which may be optionally substituted with one or more Y groups as as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more Y groups as allowed by valeny; and Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally s ubstiuted by one or moreY groups as allowed by valeny; and Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-, wherein Rois independently selected at each occurrence from Rp, halo, RpO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-. Aspect 2. The compound of aspect 1, or a pharmaceutically acceptable salt or derivative thereof, wherein is selected from

[0175] Aspect 3. The compound of aspect 1 or aspect 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0176] Aspect 4. The compound of aspect 3, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 3- to 6-membered monocyclic heterocycle optionally substituted with 1, 2, 3, or 4 groups selected from R1as allowed by valency.

[0177] Aspect 5. The compound of aspect 3, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0178] Aspect 6. The compound of aspect 1 or aspect 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0179] Aspect 7. The compound of aspect 6, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 5- to 6-membered monocyclic heteroaryl optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0180] Aspect 8. The compound of aspect 6, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0181] Aspect 9. The compound of aspect 6, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from pyrrolyl, pyrazolyl, and furanyl, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0182] Aspect 10. The compound of aspect 1 or aspect 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from:

[0183] Aspect 11 . The compound of any one of aspects 1 -10, or a pharmaceutically acceptable salt or derivative thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0184] Aspect 12. The compound of aspect 11 , or a pharmaceutically acceptable salt or derivative thereof, wherein R2is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3- methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

[0185] Aspect 13. The compound of aspect 11 , or a pharmaceutically acceptable salt or derivative thereof, wherein R2is isopropyl.

[0186] Aspect 14. The compound of aspect 1, wherein the compound is selected from: or a pharmaceutically acceptable salt or derivative thereof.

[0187] Aspect 15. The compound of aspect 1, wherein the compound is selected from:

[0188] or a pharmaceutically acceptable salt or derivative thereof.

[0189] Aspect 16. A pharmaceutical composition comprising a compound of any one of aspects 1-15, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

[0190] Aspect 17. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-15, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of aspect 16.

[0191] Aspect 18. A method for treating an infection with a papillomavirus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-15, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of aspect 16.

[0192] Aspect 19. A method for inhibiting a helicase in a eukaryotic cell comprising contacting the cell with an effective amount of a compound of any one of aspects 1-15, or a pharmaceutically acceptable salt or derivative thereof.

[0193] Aspect 20. A method for inhibiting replication of a papillomavirus in a eukaryotic cell comprising contacting the cell with an effective amount of a compound of any one of aspects 1-15, or a pharmaceutically acceptable salt or derivative thereof.

[0194] A number of aspects of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other aspects are within the scope of the following claims.

[0195] By way of non-limiting illustration, examples of certain aspects of the present disclosure are given below.

[0196] EXAMPLES

[0197] The following examples are set forth below to illustrate the compounds, compositions, and methods claimed herein, along with associated methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present disclosure, which are apparent to one skilled in the art.

[0198] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

[0199] Example 1. Synthetic Strategy for Compounds of Formula I and Formula II

[0200] The below scheme provides a representative synthesis of a compound of Formula II - KC-

[0201] 01-099:

[0202] In the first step of the scheme involving the reaction of GM2-084 with isobutyric acid in the presence of HATU and DIPEA, the isopropyl amide product was initially expected to be obtained. However, the ester product GMS-110 was instead obtained. This was confirmed in the X-ray structure of KCC-01-097 (see FIG. 1). As shown in FIG. 2, this compound (labeled as KCC-01 / cpd-32 in FIG. 2) was capable of inhibiting CMG helicase.

[0203] The following compounds were synthesized according to a process similar to the above scheme:

[0204]

[0205] The below scheme provides a representative synthesic route for exemplary compounds of

[0206] Formula I: The below scheme provides an alternative synthetic route for exemplary compounds of Formula I: Example 2. Synthesis of Representative Compounds of Formula I and Formula II The route to CMG helicase inhibitors with a cyclohexyl based head group is shown in Scheme 1. The bis acetylated aminohydroxycoumarin 3 was prepared using a reported procedure1by condensation of 2,4-dihydroxybenzaldehye and 1 and N-acetyl glycine 2. Acid catalysed deacetylation of 3 was achieved by the reported2use of thionyl chloride to provide the aminohydroxycoumarin 4. The hydroxycoumarin 4 was protected as its tert- butyldimethylsilyl ether 5, which was N-acylated to provide amide 6. Deprotection of 6 with TBAF (tetrabutylammonium fluoride) gave the hydroxycoumarin 7 which was alkylated3with 3-bromocyclohex-1-ene to give the ether 8. Rhodium catalysed hydroboration- oxidation4of 8 gave the trans-1,3-cyclohexanediol derivative 9. Coupling of the alcohol 9 with a variety of carboxylic acids gave the examples 10-17.

[0207]

[0208] Scheme 1: (a) (CH3CO)2O2 NaOAc, 115 °C, 16 h; (b) SOC12, MeOH, reflux, 2 h; (c) TBSC1, Imidazole, THF, rt, 2 h; (d) Et3N, DCM, rt, 2h; (e) TBAF, THF, 0 °C, 30 min; HATU, DIPEA, DMF, rt,l h; (f) K2CO3, MeCN, rt, 16 h; (g) RhCl(PPh3)3, catecholborane, THF, rt, 2 h; (h) NaOAc, H2O2, rt, 2h; (i) DIG, DMAP, DCM, rt, 20 h oorr l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, DMAP, rt, 20 h; (j) HC1 (4M in dioxane), rt, 5 h.

[0209] 3-Acetamido-2-oxo-2H-chromen-7-yl aacceettaattee (3)1: AA mmiixxttuurere ooff 2,4- dihydroxybenzaldehyde (1, 5.00 g, 36.2 mmol), N-acetyl glycine (2, 5.04 g, 43.1 mmol), and anhydrous sodium acetate (5.93 g, 72.4 mmol) in acetic anhydride (27 mL) was refluxed under stirring for 16 hours. The reaction mixture was then poured into ice (600 mL) to obtain a yellow precipitate. The precipitate was filtered off, washed with ice water and diethyl ether, and dried under reduced pressure to afford the 3-acetamido-2-oxo-2 / / -chromen-7-yl acetate (3) as a yellow solid (4.61 g, 48.6 %). *H NMR (500 MHz, DMSO) 89.76 (s, 1H), 8.63 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.5, 2.2 Hz, 1H), 2.31 (s, 3H), 2.17 (s, 3H).I3C NMR (126 MHz, DMSO) 8 170.69, 169.41, 157.78, 151.43, 150.36, 128.97, 124.59, 123.61, 119.49, 117.91, 110.17, 24.40, 21.33. HPLC-MS (ESI+): m / z 261.9 (M+H)+.

[0210] 3-Amino-7-hydroxy-2H-chromen-2-one hydrochloride (4)2: To a suspension of 3- acetamido-2-oxo-2H-chromen-7-yl acetate (3, 620 mg, 2.37 mmol) in methanol (30 mL), thionyl chloride (0.17 mL, 2.44 mmol) was added and refluxed under stirring for 2 hours. The reaction mixture was then evaporated to dryness under reduced pressure and triturated with diethyl ether (20 mL). The precipitate was filtered off, washed with diethyl ether (10 mL), and dried under reduced pressure to afford 3-amino-7-hydroxy-2H-chromen-2-one hydrochloride (4) as a light brown solid (496 mg, 98.2 %). *H NMR (500 MHz, DMSO) 5 7.30 (d, J = 8.5 Hz, 1H), 6.93 (s, 1H), 6.72 (dd, J = 8.4, 2.3 Hz, 1H), 6.69 (d, J = 2.3 Hz, 1H), 4.25 (bs, 2H).I3C NMR (126 MHz, DMSO) 8 158.71, 157.69, 150.58, 126.93, 126.33, 116.27, 113.30, 112.57, 101.99. HPLC-MS (ESI+): m / z 178.1 (M+H)+. HRMS (ESI+): m / z calcd. for C9H8NO3(M+H)+178.0499, found 178.0495.

[0211] 3-Amino-7-((tert-butyldimethylsilyl)oxy)-2H-chromen-2-one (5): Under an atmosphere of argon, phenol 4 (1.0 g, 4.68 mmol) was dissolved in anhydrous THF (12 mL). tert- Butyldimethylsilyl chloride (1.20 g, 7.96 mmol) and imidazole (0.954 g, 14.01 mmol) were added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (100 mL), dried with Na2SO4, filtered, and concentrated to give the TBS ether 5 (1.227 g, 90%) as a brown solid, which was used without further purification. *H NMR (500 MHz, DMSO) 5 7.31 (d, J = 9.2 Hz, 1H), 6.83 - 6.73 (m, 2H), 6.70 (s, 1H), 5.41 (s, 2H), 0.95 (s, 9H), 0.20 (s, 6H).13C NMR (126 MHz, DMSO) 5 158.80, 153.29, 148.82, 131.31, 125.64, 117.12, 115.87, 108.70, 106.67, 25.54, 25.51, -4.58. HPLC–MS (ESI+): m / z 292.0 (M+H)+. m / z calcd. for C15H22NO3Si (M+H)+292.1363, found 292.1362. N-(7-((tert-Butyldimethylsilyl)oxy)-2-oxo-2H-chromen-3-yl)iso-butyramide (6): Under an atmosphere of argon, 5 (1.00 g, 3.44 mmol) was dissolved in anhydrous DCM (6 mL). Triethylamine (0.960 mL, 6.89 mmol) was added to the flask and cooled to 0 °C. Isobutyryl chloride (0.44 mL, 4.20 mmol) added and allowed to stirred at room temperature for 2 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine (100 mL), dried with Na2SO4, filtered, and concentrated to give the amide 6 (99%, 1.251 g), as a pale yellow solid which was used without further purification.1H NMR (500 MHz, DMSO) J 9.49 (s, 1H), 8.56 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 6.88-6.84 (m, 2H), 2.90 (hept, J = 6.8 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H), 0.96 (s, 9H), 0.24 (s, 6H).13C NMR (126 MHz, DMSO) J 176.78, 157.74, 156.68, 151.00, 128.87, 125.15, 122.18, 117.60, 113.69, 106.78, 34.20, 25.48, 19.46, 17.99, -4.61. HPLC–MS (ESI+): m / z 384.0 (M+Na)+. HRMS (ESI+): m / z calcd. for C19H31N2O4Si (M+NH4)+379.2048, found 379.2025. N-(7-Hydroxy-2-oxo-2H-chromen-3-yl)iso-butyramide (7): Under an atmosphere of argon, 6 (1.740 g, 4.81 mmol) was dissolved in anhydrous THF (52 mL). The flask was cooled to 0 °C and a solution of TBAF (1M in THF, 5.28 mL, 5.28 mmol) was added. The mixture was stirred at 0 °C for 30 min. After completion, the mixture was warmed to room temperature and diluted with H2O. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with H2O (100 mL) and brine (100 mL). The organic layer was dried with Na2SO4, filtered, and concentrated. to give the phenol 7 (99%, 1.188 g) as a pale yellow solid, which was used without further purification.1H NMR (500 MHz, DMSO) J 10.35 (s, 1H), 9.41 (s, 1H), 8.50 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 6.79 (dd, J = 8.5, 2.3 Hz, 1H), 2.88 (hept, J = 6.8 Hz, 1H), 1.07 (d, J = 6.9 Hz, 7H).13C NMR (126 MHz, DMSO) J 176.63, 159.55, 157.98, 151.52, 128.96, 126.24, 120.94, 113.59, 111.43, 101.95, 34.20, 19.49. HPLC–MS (ESI+): m / z 248.0 (M+H)+. m / z calcd. for C13H13NO4Na (M+Na)+270.0737, found 270.0735. N-(7-(Cyclohex-2-en-1-yloxy)-2-oxo-2H-chromen-3-yl)iso-butyramide (8): Under an atmosphere of argon, hydroxycoumarin 7 (1.00 g, 4.04 mmol) was dissolved in anhydrous acetonitrile (15 mL). To the solution, K2CO3(1.090 g, 7.88 mmol) was added followed by 3- bromocyclohexene (0.70 mL, 6.08 mmol). The mixture was stirred at room temperature for 16 h and then diluted with water (100 mL). The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated to give the ether 8 (96%, 1.271 g) as a pale yellow solid, which was used without further purification.1H NMR (500 MHz, DMSO) J 9.47 (s, 1H), 8.55 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.7, 2.4 Hz, 1H), 6.00-5.94 (m, 1H), 5.85-5.81 (m, 1H), 5.03-4.98 ( m, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 2.15 – 1.86 (m, 4H), 1.78-1.66 (m, 2H), 1.66-1.57 (m, 1H), 1.08 (d, J = 6.8 Hz, 6H).13C NMR (126 MHz, DMSO) J 176.72, 159.00, 157.88, 151.40, 132.28, 128.86, 125.70, 125.57, 121.68, 113.87, 112.58, 101.93, 70.62, 34.21, 27.67, 24.53, 19.48, 19.43, 18.39. HPLC–MS (ESI+): m / z 328.0 (M+H)+ N-(7-([1RS,3RS]-3-Hydroxycyclohexyl)oxy)-2-oxo-2H-chromen-3-yl)iso-butyramide (9): Under an atmosphere of argon, the cyclohexenyl ether 8 (0.130 g, 0.40 mmol) was dissolved in anhydrous THF (3.9 mL). Wilkinson’s catalyst (0.036 g, 0.039 mmol) was added to the mixture and then catecholborane (1M in THF, 1.2 mL, 1.2 mmol) was added slowly at room temperature. The mixture was allowed to stir at room temperature for 3 hours. After that time, a 1:1 EtOH:THF mixture (0.8 mL) was added. When the bubbling stopped, sodium acetate (3M, 0.3 mL) was added followed by hydrogen peroxide (30% w / v in water, 0.1 mL) and allowed to stir at room temperature for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with 30% ethyl acetate in hexanes to give the alcohol 9 (0.053 g, 39%) as a white solid.1H NMR (500 MHz, DMSO) J 9.46 (s, 1H), 8.55 (s, 1H), 7.58 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 8.7, 2.4 Hz, 1H), 4.77 (m, 1H), 4.60 (d, J = 3.8 Hz, 1H), 3.93 – 3.85 (m, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 1.83-1.69 (m, 3H), 1.66 – 1.53 (m, 2H), 1.42-1.34 (m, 1H), 1.08 (d, J = 6.8 Hz, 6H).13C NMR (126 MHz, DMSO) J 176.72, 158.86, 157.88, 151.40, 128.85, 125.55, 121.68, 113.88, 112.54, 101.97, 73.20, 64.80, 38.34, 34.21, 33.33, 29.91, 19.48, 18.78. HPLC–MS (ESI+): m / z 346.0 (M+H)+. HRMS (ESI+): m / z calcd for C19H24NO5 (M+H)+346.1649, found 346.1640 (1RS,3RS)-3-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl 5- methylfuran-2-carboxylate (10, KCC-02-035): Under an atmosphere of argon, 9 (0.050 g, 0.144 mmol) was dissolved in anhydrous dichloromethane (0.36 mL). To the solution, 4- dimethylaminopyridine (0.003 g, 0.024 mmol, 0.17 equiv.) and diisopropylcarbodiimide (0.045 mL, 0.290 mmol, 2 equiv.) were added, followed by 5-methyl-2-furoic acid (0.020 g, 0.158 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 20 h, and the solvent evaporated in vacuo. The residue was purified via silica gel column chromatography eluting with 10% ethyl acetate in hexanes to give 10 (KCC-02-035) (0.061 g, 91%) as a white solid.1H NMR (500 MHz, DMSO) J 8.55 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.6, 2.4 Hz, 1H), 6.34 (d, J = 3.4 Hz, 1H), 5.27-5.16 (m, 1H), 4.90-4.81 (m, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 2.35 (s, 1H), 2.13 – 2.01 (m, 1H), 1.98 (m, 1H), 1.87 – 1.77 (m, 2H), 1.72-1.56 (m, 4H), 1.08 (d, J = 6.8 Hz 6H).13C NMR (126 MHz, DMSO) J 177.21, 158.98, 158.32, 157.71, 157.65, 151.82, 142.94, 129.37, 125.90, 122.30, 120.41, 114.49, 113.30, 109.30, 102.69, 73.35, 70.46, 35.45, 34.68, 30.35, 29.47, 19.94, 19.17, 14.05. HPLC-MS (ESI+): m / z 454.0 (M+H)+. m / z calculated for C25H28NO7+(M+H)+454.1860, found 454.1848. HPLC: 99.80% [tR = 16.85 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,3RS)-3-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl 5-methyl-1H- pyrrole-2-carboxylate (12, KCC-02-073): Under argon, 9 (0.040 g, 0.115 mmol) was dissolved in dry dimethylformamide (1 mL). To the mixture, 1-(tert-butoxycarbonyl)-5- methyl-1H-pyrrole-2-carboxylic acid (0.040 g, 0.177 mmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.044 g, 0.299 mmol) and 4- dimethylaminopyridine (0.028 g, 0.299 mmol) were added and stirred at room temperature for 20 h. The mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with 10-20% ethyl acetate and hexanes to give 11 (0.036 g, 56%). The protected pyrrole 11 (0.014 g, mmol) was dissolved in HCl (4M in dioxane, 0.5 mL) and stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate (25 mL) and washed with aqueous NaHCO3 (25 mL). The organic layer was subsequently washed with brine, dried with Na2SO4, filtered, and concentrated to give 12 (KCC-02-073) (10 mg, 90%) as a white solid, which required no further purification.1H NMR (500 MHz, DMSO) J 11.51 (s, 1H), 9.47 (s, 1H), 8.55 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.6, 2.4 Hz, 1H), 6.74-6.70 (m, 1H), 5.89-5.86 (m, 1H), 5.22-5.17 (m, 1H), 4.92-4.86 (m, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 2.22 (s, 3H), 1.92 – 1.84 (m, 1H), 1.83 – 1.58 (m, 2H), 1.07 (d, J = 6.9 Hz, 6H). HPLC- MS (ESI+): m / z 453.0 (M+H)+. m / z calculated for C25H29N2O6+(M+H)+453.2020, found 453.2005. HPLC: 96.66% [tR = 16.64 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,3RS)-3-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl 1,5-dimethyl- 1H-pyrrole-2-carboxylate (13, KCC-02-040): Under an atmosphere of argon, 9 (0.04 g, 0.116 mmol) was dissolved in anhydrous DMF (1.0 mL). To the mixture, 4- dimethylaminopyridine (0.017 g, 0.139 mmol) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.088 g, 0.460 mmol) was added. Subsequently, 1,5-dimethylpyrrole carboxylic acid (0.048 g, 0.345 mmol) was added to the mixture which was stirred at room temperature for 72 h. The mixture was then heated at 70 °C for 8 h. The mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with 10-20% ethyl acetate in hexanes to give 13 (KCC-02-040) (0.009 g, 17%) as a white solid.1H NMR (500 MHz, DMSO) J 9.47 (s, 1H), 8.55 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.6, 2.4 Hz, 1H), 6.88 (d, J = 3.9 Hz, 1H), 5.93 (d, J = 3.9 Hz, 1H), 5.20 (m, 1H), 4.83 (m, 1H), 2.89 (p, J = 6.8 Hz, 1H), 2.22 (s, 3H), 1.88 (m, 1H), 1.78 (m, 1H), 1.67 (m, 4H), 1.08 (s, 3H), 1.07 (s, 3H). HPLC-MS (ESI+): m / z 467.0 (M+H)+. m / z calculated for C26H31N2O6+(M+H)+467.2177, found 467.2161. HPLC: 99.40% [tR = 18.93 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,3RS)-3-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl 3-methyl-1H- pyrazole-5-carboxylate (14, KCC-02-041): Under an atmosphere of argon, 9 (0.04 g, 0.116 mmol) was dissolved in anhydrous DMF (1.0 mL). To the mixture, 4-dimethylaminopyridine (0.017 g, 0.139 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.088 g, 0.460 mmol) was added. Subsequently 3-methylpyrazole carboxylic acid (0.044 g, 0.350 mmol) was added to the mixture which was stirred at room temperature for 72 h. The mixture was then heated at 70 °C for 8 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography eluting with 50% ethyl acetate in hexanes to provide 14 (KCC-02- 041) (0.021 g, 40%) as a white solid.1H NMR (500 MHz, DMSO) J 13.15 (s, 1H), 9.47 (s, 1H), 8.55 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.6, 2.4 Hz, 1H), 6.52 (s, 1H), 5.23 (m, 1H), 4.86 (m, 1H), 2.89 (p, J = 6.8 Hz, 1H), 2.26 (s, 3H), 2.07 (m, 1H), 1.96 (m, 1H), 1.84 (m, 2H), 1.66 (m, 5H), 1.08 (s, 3H), 1.07 (s, 3H). HPLC-MS (ESI+): m / z 454.0 (M+H)+. m / z calculated for C24H27N3NaO6+(M+Na)+476.1792, found 476.1776. HPLC: 95.60% [tR = 14.93 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,3RS)-3-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl-1H-pyrazole- 3-carboxylate (15, KCC-02-043): Under an atmosphere of argon, 9 (0.038 g, 0.110 mmol) was dissolved in anhydrous DMF (1.0 mL). To the mixture, 4-dimethylaminopyridine (0.016 g, 0.131 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.045 g, 0.234 mmol) was added. Subsequently 1H-pyrazole-3-carboxylic acid (0.044 g, 0.393 mmol) was added to the mixture which was stirred at room temperature for 16 h. After this time, more 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.045 g) and 1H- pyrazole-3-carboxylic acid (0.02 g) were added. The mixture was then heated to 50 °C for 4 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography eluting with 40% ethyl acetate in hexanes to give 15 (KCC-02-043) (0.026 g, 51%)as a white solid.1H NMR (500 MHz, DMSO) J 13.47 (s, 1H), 9.47 (s, 1H), 8.55 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 8.6 Hz, 2H), 6.98 (dd, J = 8.6, 2.4 Hz, 1H), 6.81 – 6.77 (m, 1H), 5.26 (m, 1H), 4.87 (m, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 2.08 (m, 1H), 1.99 (m, 1H), 1.85 (m, 2H), 1.71 (m, 5H), 1.08 (s, 3H), 1.07 (s, 3H). HPLC-MS (ESI+): m / z 440.0 (M+H)+. m / z calculated for C23H25N3NaO6+(M+Na)+462.1636, found 462.1624. HPLC: 97.78% [tR = 13.87 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,3RS)-3-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl 5- (trifluoromethyl)furan-2-carboxylate (16, KCC-02-060): Under an atmosphere of argon, 5-trifluoromethyl-2-furoic acid (0.007g, 0.039 mmol), 4-dimethylaminopyridine (0.007 g, 0.057 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.011 g, 0.057 mmol) were dissolved in anhydrous DMF (0.15 mL). To the mixture, 9 (0.01 g, 0.029 mmol) was added and allowed to stir at room temperature for 72 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated in vacuo. The residue was purified via silica gel column chromatography eluting with 20% ethyl acetate in hexanes to give 16 (KCC-02-060) (0.011 g, 78%) as a white solid.1H NMR (500 MHz, DMSO) J 9.47 (s, 1H), 8.55 (s, 1H), 7.65 – 7.53 (m, 2H), 7.48 (m, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.6, 2.4 Hz, 1H), 5.36 – 5.21 (m, 1H), 4.90 (m, 1H), 2.89 (p, J = 6.8 Hz, 1H), 2.08 (m, 2H), 1.86 (m, 2H), 1.70 (m, 4H), 1.08 (s, 3H), 1.07 (s, 3H). HPLC-MS (ESI+): m / z 507.9 (M+H)+. m / z calculated for C25H25F3NO7+(M+H)+508.1578, found 508.1559. HPLC: 93.28% [tR = 18.08 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,3RS)3-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl 5- (trifluoromethyl)-1H-pyrrole-2-carboxylate (17, KCC-02-062): Under an atmosphere of argon, 5-trifluoromethyl-1H-pyrrole-2-carboxylic acid (0.008 g, 0.039 mmol), 4- dimethylaminopyridine (0.007 g, 0.057 mmol) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.012 g, 0.063 mmol) were dissolved in anhydrous DMF (0.15 mL). To the mixture, 9 (0.01 g, 0.029 mmol) was added and allowed to stir at room temperature for 24 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated in vacuo. The residue was purified via silica gel column chromatography eluting with 20% ethyl acetate in hexanes to give the ester 17 (KCC- 02-062) as a white solid (0.005 g, 35%).1H NMR (500 MHz, DMSO) J 13.09 (s, 1H), 9.47 (s, 1H), 8.55 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.7, 2.4 Hz, 1H), 6.93-6.90 (m, 1H), 6.71-6.68 (m, 1H), 5.27 (br s, 1H), 4.92 (br s, 1H), 2.89 (p, J = 6.8 Hz, 1H), 2.06-2.01 (m, 2H), 1.93 – 1.59 (m, 5H), 1.28-1.20 (m, 2H), 1.08 (d, J = 6.9 Hz, 7H). HPLC-MS (ESI+): m / z 506.9 (M+H)+. m / z calculated for C25H26F3N2O6+(M+H)+507.1737, found 507.1721. HPLC: 86.39% [tR = 18.20 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. The route to CMG helicase inhibitors with a cyclohexyl group attached to the amino group is shown in Scheme 2. The aminohydroxycoumarin 4 was O-acylated by the use of HATU (O- (7-azabenzotriazol-1-yl)-N,N,N^,N^-tetramethyluronium hexafluorophosphate) carboxylic acid coupling. Lithium catalysed epoxide ring-opening by the trans-aminocoumarin 19 gave the cyclohexyl alcohol 20. Coupling of the alcohol 9 with a variety of carboxylic acids gave the examples 21-27.

[0212]

[0213] Scheme 2: (a) HATU, DIPEA, DMF, rt,l h; (b) LiC104, neat ,100 °C, 3 h; (c) D1C, DMAP, DCM, rt, 3 h. 3-Amino-2-oxo-2H-chromen-7-yl isobutyrate (19): A mixture of 3-amino-7-hydroxy-2H- chromen-2-one hydrochloride (4, 4.00 g, 18.7 mmol), isobutyric acid (18, 2.47 g, 28.1 mmol), HATU (8.54 g, 22.4 mmol) and DIPEA (7.26 g, 56.2 mmol) in DMF (80 mL) was stirred at room temperature for 1 h. The reaction mixture was then poured into ice cold water to yield the 3-amino-2-oxo-2H-chromen-7-yl isobutyrate as a precipitate. The precipitate was filtered off, washed with ice water and hexane, and dried under reduced pressure to afford 3-amino- 2-oxo-2H-chromen-7-yl isobutyrate (19) as a pale brown solid (3.78 g, 81.6%).1H NMR (500 MHz, DMSO) ^ 7.44 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 2.3 Hz, 1H), 6.73 (s, 1H), 5.69 (s, 2H), 2.82 (p, J = 7.0 Hz, 1H), 1.23 (d, J = 7.0 Hz, 6H).13C NMR (126 MHz, DMSO) ^ 175.47, 158.94, 148.35, 148.33, 133.31, 125.66, 120.08, 118.87, 109.70, 107.83, 33.77, 19.10. HPLC-MS (ESI+): m / z 247.9 (M+H)+. HRMS (ESI+): m / z calcd. for C13H14NO4(M+H)+248.0917, found 248.0915. 3-(((1RS,2RS)-2-Hydroxycyclohexyl)amino)-2-oxo-2H-chromen-7-yl iso-butyrate (20): The amine 19 (0.400 g, 1.62 mmol) and cyclohexene oxide (0.494 mL, 4.88 mmol) were added to a vial. Lithium perchlorate (0.342 g, 3.21 mmol) was added to the mixture which was stirred at 50oC for 24 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and transferred to a round bottom flask evaporated in vacuo. The residue was purified via silica gel column eluting with 15% ethyl acetate in hexanes to afford 20 (0.404 g, 72%) as a white solid.1H NMR (500 MHz, CDCl3) J 7.28 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.95 (dd, J = 8.4, 2.3 Hz, 1H), 6.39 (s, 1H), 5.06 (d, J = 7.7 Hz, 1H), 4.16 – 4.05 (m, 1H), 3.39 (qd, J = 7.8, 3.2 Hz, 1H), 2.81 (hept, J = 7.0 Hz, 1H), 1.87 (m, 1H), 1.76 – 1.60 (m, 6H), 1.52 – 1.44 (m, 1H), 1.33 (s, 3H), 1.31 (s, 3H).13C NMR (126 MHz, CDCl3) J 175.49, 159.58, 148.64, 147.86, 131.76, 125.25, 119.40, 118.51, 109.65, 105.06, 67.58, 67.56, 54.52, 54.50, 34.21, 31.46, 31.42, 26.54, 26.51, 23.59, 23.57, 20.22, 20.20, 20.18, 20.17, 19.02, 18.98, 18.93, 18.87, 18.86, 18.84. HPLC-MS (ESI+): m / z 346.0 (M+H)+. HRMS (ESI+): m / z calcd. for C19H24NO5 (M+H)+346.1649, found 346.1641. (1RS,2RS)-2-((7-(iso-Butyryloxy)-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5-methyl- 1H-pyrrole-2-carboxylate (21, KCC-01-099): Under an atmosphere of argon, 20 (0.05 g, 0.145 mmol) and 5-methyl-1H-pyrrole-2-carboxylic acid, prepared according to the reported procedure,5(0.027 g, 0.22 mmol) were dissolved in anhydrous DCM (1 mL). Subsequently N,N'-diisopropylcarbodiimide (0.044 mL, 0.284 mmol) and 4-dimethylaminopyridine (0.008 g, 0.065 mmol) were added and allowed to stir at room temperature for 20 h. The solvent was evaporated in vacuo and the residue purified via silica gel column eluting with 20% ethyl acetate in hexanes to afford 21 (KCC-01-099) as a white solid (0.051 g, 78%).1H NMR (500 MHz, CDCl3) J 8.66 (s, 1H), 7.32 (dd, J = 8.3, 1.5 Hz, 1H), 7.02 – 6.97 (m, 1H), 6.94 (dd, J = 8.5, 2.3 Hz, 1H), 6.73 – 6.69 (m, 1H), 6.61 (s, 1H), 5.85 (m, 1H), 5.02 (d, J = 7.8 Hz, 1H), 4.96 (td, J = 8.9, 4.0 Hz, 1H), 3.51-3.41 (m, 1H), 2.91 – 2.65 (m, 1H), 2.20 (s, 3H), 2.18 – 2.10 (m, 1H), 1.87-1.74 (m, 2H), 1.66-1.57 (m, 1H), 1.46 (m, 3H), 1.33 (s, 3H), 1.32 (s, 3H).13C NMR (126 MHz, DMSO) J 175.44, 160.39, 158.83, 148.12, 147.33, 134.77, 132.35, 125.77, 120.81, 120.16, 118.96, 116.32, 109.58, 108.54, 104.77, 75.76, 55.12, 33.77, 31.47, 30.91, 24.52, 24.02, 19.10, 13.07. HPLC-MS (ESI+): m / z 453.0 (M+H)+m / z calculated for C25H28N2NaO6+(M+Na)+475.1840, found 475.1837. HPLC: 99.29% [tR = 17.09 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,2RS)-2-((7-(iso-Butyryloxy)-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 1H- pyrazole-3-carboxylate (22, KCC-01-156): Under an atmosphere of argon, alcohol 20 (0.05 g, 0.145 mmol) and 1H-pyrazole-3-carboxylic acid (0.024 g, 0.214 mmol) were dissolved in anhydrous DCM (1 mL). Subsequently, 4-dimethylaminopyridine (0.008 g, 0.065 mmol) and N,N'-diisopropylcarbodiimide (0.044 mL, 0.284 mmol) were added to the mixture which was then stirred at room temperature for 20 h. The solvent was evaporated and the residue purified via silica gel column eluting with 50% ethyl acetate in hexanes to afford 22 (KCC-01-156) (0.034 g, 56%) as a white solid.1H NMR (500 MHz, CDCl3) J 7.50 (d, J = 2.3 Hz, 1H), 7.38 – 7.29 (m, 1H), 6.97 – 6.89 (m, 2H), 6.74 (d, J = 2.3 Hz, 1H), 6.68 (s, 1H), 5.12 – 5.01 (m, 1H), 4.90 (d, J = 8.3 Hz, 1H), 3.57 – 3.49 (m, 1H), 2.81 (hept, J = 7.0 Hz, 1H), 2.18 (d, J = 8.2 Hz, 3H), 1.88 – 1.79 (m, 2H), 1.73 – 1.61 (m, 1H), 1.56 – 1.45 (m, 2H), 1.33 (s, 3H), 1.32 (s, 1H).13C NMR (126 MHz, DMSO) J 174.99, 158.35, 147.67, 146.88, 131.86, 125.35, 119.64, 118.51, 109.12, 33.30, 30.79, 30.76, 30.72, 30.42, 30.38, 24.01, 23.97, 23.54, 18.63. HPLC-MS (ESI+): m / z 440.0 (M+H)+m / z calculated for C23H26N3O6+(M+H)+440.1816, found 440.1806. HPLC: 89.05% [tR = 14.07 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min].

[0214] (1RS,2RS)-2-((7-(iso-Butyryloxy)-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 3-methyl- 1H-pyrazole-5-carboxylate (23, KCC-01-165): Under an atmosphere of argon, alcohol 20 (0.05 g, 0.14 mmol) and 3-methyl-pyrazole-5-carboxylic acid (0.026 g, 0.21 mmol) were dissolved in anhydrous dichloromethane (1 mL). Subsequently, 4-dimethylaminopyridine (0.008 g, 0.07 mmol) and N,N'-diisopropylcarbodiimide (0.044 mL, 0.28 mmol) were added to the mixture which was stirred at room temperature for 20 h. The solvent was evaporated in vacuo and the residue purified via silica gel column eluting with 30% ethyl acetate in hexanes to give 23 (KCC-01-165) (0.057 g, 87%), as a white solid.1H NMR (500 MHz, CDCl3) J 7.30 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 8.4, 2.3 Hz, 1H), 6.68 (m1H), 6.45 (m, 1H), 5.07 – 5.01 (m, 1H), 4.89 (d, J = 4.89 Hz, 1H), 3.52 (m, 1H), 2.81 (p, J = 7.0 Hz, 1H), 2.23 (s, 3H), 2.19 – 2.10 (m, 3H), 1.88 – 1.75 (m, 3H), 1.72 – 1.60 (m, 2H), 1.52-1.41 (m, 4H), 1.32 (d, J = 7.0 Hz, 6H). HPLC-MS (ESI+): m / z 454.0 (M+H)+. m / z calculated for C24H28N3O6+(M+H)+454.1973, found 454.1960. HPLC: 88.78% [tR = 15.15 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,2RS)-2-((7-(iso-Butyryloxy)-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5- methylfuran-2-carboxylate (24, KCC-01-168): Under an atmosphere of argon, alcohol 20 (0.05 g, 0.14 mmol) and 5-methyl-2-furoic-carboxylic acid (0.026 g, 0.21 mmol) were dissolved in anhydrous dichloromethane (1 mL). Subsequently, 4-dimethylaminopyridine (0.008 g, 0.07 mmol) and N,N'-diisopropylcarbodiimide (0.044 mL, 0.28 mmol) were added to the mixture which was then stirred at room temperature for 20 h. The solvent was evaporated in vacuo and the residue purified via silica gel column eluting with 20% ethyl acetate in hexanes to afford ester 24 (KCC-01-168) (0.063 g, 97%) as a yellow solid.1H NMR (500 MHz, CDCl3) J 7.33 (d, J = 8.4 Hz, 1H), 7.00 – 6.97 (m, 2H), 6.94 (dd, J = 8.4, 2.3 Hz, 1H), 6.71 (s, 1H), 6.02 (dd, J = 3.3, 1.0 Hz, 1H), 5.01 (td, J = 8.8, 4.0 Hz, 1H), 4.92 (d, J = 7.8 Hz, 1H), 3.53-3.46 (m, 1H), 2.80 (p, J = 7.0 Hz, 1H), 2.28 (s, 3H), 2.19 – 2.06 (m, 2H), 1.87-1.85 (m, 2H), 1.69 – 1.59 (m, 1H), 1.51 – 1.46 (m, 2H), 1.33 (s, 3H), 1.31 (s, 3H). 13C NMR (126 MHz, DMSO) J 174.98, 174.97, 158.32, 157.46, 157.03, 147.72, 146.88, 142.31, 131.92, 125.32, 119.73, 119.60, 118.50, 118.48, 109.13, 108.62, 104.58, 76.77, 54.44, 33.30, 30.80, 30.48, 24.03, 23.57, 18.63, 18.61, 18.56, 13.38. HPLC-MS (ESI+): m / z 454.0 (M+H)+m / z calculated for C25H28NO7+(M+H)+454.1860, found 454.1843. HPLC: 86.98% [tR = 17.33 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,2RS)-2-((7-(iso-Butyryloxy)-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 1,5- dimethyl-1H-pyrrole-2-carboxylate (25, KCC-01-175): Under an atmosphere of argon, alcohol 20 (0.05 g, 0.145 mmol) and 1,5-dimethyl-1H-pyrrole-2-carboxylic acid (0.030 g, 0.215 mmol) were dissolved in anhydrous dichloromethane (1 mL). Subsequently, 4- dimethylaminopyridine (0.008 g, 0.065 mmol) and N,N'-diisopropylcarbodiimide (0.044 mL, 0.284 mmol) were added to the mixture which was then stirred at room temperature for 20 h. The solvent was evaporated in vacuo and the residue purified via silica gel column eluting with 5% ethyl acetate in hexanes to afford ester 25 (KCC-01-175) (0.018 g, 27%) as a white solid.1H NMR (500 MHz, CDCl3) J 7.28 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 8.4, 2.3 Hz, 1H), 6.80 (d, J = 3.9 Hz, 1H), 6.59 (s, 1H), 5.81 (dd, J = 4.0, 0.9 Hz, 1H), 5.03 (d, J = 7.7 Hz, 1H), 4.97 (td, J = 8.9, 4.1 Hz, 1H), 3.77 (s, 3H), 2.80 (p, J = 7.0 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.08 (m, 1H), 1.88 – 1.74 (m, 2H), 1.66 – 1.52 (m, 2H), 1.52 – 1.41 (m, 3H), 1.32 (s, 3H), 1.31 (s, 3H). HPLC-MS (ESI+): m / z 467.0 (M+H)+. m / z calculated for C26H34N3O6+(M+NH4)+484.2442, found 484.2441. HPLC: 97.59% [tR = 19.55 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,2RS)-2-((7-(iso-Butyryloxy)-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5- (trifluoromethyl)-1H-pyrrole-2-carboxylate (26, KCC-01-174): Under an atmosphere of argon, alcohol 20 (0.05 g, 0.14 mmol) and 5-trifluoromethyl-1H-pyrrole-carboxylic acid (0.037 g, 0.21 mmol) were dissolved in anhydrous dichloromethane (1 mL). Subsequently, 4-dimethylaminopyridine (0.008 g, 0.07 mmol) and N,N'-diisopropylcarbodiimide (0.044 mL, 0.28 mmol) were added and the mixture stirred at room temperature for 20 h. The solvent was evaporated in vacuo and the residue purified via silica gel column eluting with 10% ethyl acetate in hexanes to afford ester 26 (KCC-01-174) (0.031 g, 42%) as a white solid.1H NMR (500 MHz, CDCl3) J 9.42 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.5, 2.3 Hz, 1H), 6.75 (m, 1H), 6.57 (s, 1H), 6.49 (m, 1H), 5.03 (ddd, J = 9.6, 8.4, 4.1 Hz, 1H), 4.98 (d, J = 8.1 Hz, 1H), 3.48 (td, J = 8.5, 4.2 Hz, 1H), 2.80 (p, J = 7.0 Hz, 1H), 2.17 (td, J = 18.3, 6.7 Hz, 3H), 1.88 – 1.77 (m, 3H), 1.70 – 1.60 (m, 1H), 1.53 – 1.42 (m, 3H), 1.32 (d, J = 7.0 Hz, 6H).13C NMR (126 MHz, DMSO) J 174.95, 159.41, 158.33, 147.71, 146.87, 131.88, 125.87, 125.86, 125.26, 123.81, 123.50, 121.60, 119.59, 119.47, 118.46, 114.50, 110.52, 110.49, 110.46, 110.44, 109.10, 104.37, 76.59, 59.76, 54.51, 33.30, 30.79, 30.44, 24.04, 23.50, 18.62. HPLC-MS (ESI+): m / z 506.9 (M+H)+. m / z calculated for C25H26F3N2O6+(M+H)+507.1737, found 507.1733. HPLC: 98.00% [tR = 18.25 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. (1RS,2RS)-2-((7-(iso-Butyryloxy)-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5- (trifluoromethyl)furan-2-carboxylate (27, KCC-01-176): Under an atmosphere of argon, alcohol 20 (0.05 g, 0.14 mmol) and 5-trifluoromethyl-1H-furoic acid (0.038 g, 0.21 mmol) were dissolved in anhydrous dichloromethane (1 mL). Subsequently, 4- dimethylaminopyridine (0.008 g, 0.07 mmol) and N,N'-diisopropylcarbodiimide (0.044 mL, 0.28 mmol) were added and the mixture stirred at room temperature for 20 h. The solvent was evaporated in vacuo and the residue purified via silica gel column eluting with 20% ethyl acetate in hexanes to give ester 27 (KCC-01-176) (0.059 g, 83%) as an off-white solid.1H NMR (500 MHz, CDCl3) J 7.30 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.93 (dd, J = 8.4, 2.3 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 6.66 (s, 1H), 5.05 (td, J = 9.1, 4.1 Hz, 1H), 4.89 (d, J = 8.1 Hz, 1H), 3.51 (m, 1H), 2.80 (hept, J = 6.9 Hz, 1H), 2.15 (m, 2H), 1.83 (m, 2H), 1.67 (m, 1H), 1.55 – 1.45 (m, 3H), 1.32 (s, 3H), 1.31 (s, 3H).13C NMR (126 MHz, DMSO) J 174.93, 158.27, 156.65, 147.75, 146.88, 146.09, 146.07, 142.65, 142.31, 131.87, 125.23, 119.46, 119.28, 118.44, 118.34, 118.26, 117.15, 114.59, 114.57, 114.54, 114.51, 109.07, 104.39, 77.90, 54.26, 54.21, 33.30, 30.56, 30.39, 23.93, 23.49, 18.61. HPLC-MS (ESI+): m / z 508.0 (M+H)+. m / z calculated for C23H25F3NO7+(M+H)+508.1578, found 508.1562. HPLC: 91.87% [tR = 18.48 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. Scheme 3 shows an alternative route to CMG helicase inhibitors with a cyclohexyl based head group. The key cyclohexanol derivative cis-28 and trans isomer 9 can be prepared from amidohydroxycoumarin 7 by reaction with the Tsunoda reagent (cyanomethylene)tributylphosphorane6and a mixture of cis and trans cyclohexane-1,3-diol. Reaction of amidohydroxycoumarin 7 with cyclohexene oxide provides the trans alcohol 29 from which ester can be made of the type 30. Scheme 3: (a) Tsunoda reagent (cyanomethylenetributylphosphorane), 1,4-dioxane, 150 °C, 2h; (b) cyclohexene oxide, K2CO3, 120 °C for 20 h; (c) 5 -methyl- lH-pyrrole-2-carboxylic acid, DIC, DMAP, DCM, rt, 20 h. N-(7-(((1RS,3SR)-3-Hydroxycyclohexyl)oxy)-2-oxo-2H-chromen-3-yl)iso-butyramide (28). In a microwave vial, phenol 7 (0.050 g, 0.202 mmol) and 1,3 cyclohexanediol (cis / trans mixture) (0.047 g, 0.404 mmol) were dissolved in dry 1,4-dioxane (1 mL). Tsunoda reagent (0.165 mL, 0.630 mmol) was added and argon bubbled through the solution for 5 minutes. The vial was capped and heated in a microwave reactor at 150 °C for 2 h. After completion, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was purified via silica gel column with 20% ethyl acetate in hexanes to give cis isomer 28 (0.015 g, 22%) as an off-white solid and trans isomer 9 (0.014 g, 20%) as an off white solid.1H NMR (500 MHz, DMSO) J 9.46 (s, 1H), 8.54 (s, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H), 4.71 (d, J = 4.6 Hz, 1H), 4.42 (tt, J = 10.8, 4.1 Hz, 1H), 3.55 (ddt, J = 15.2, 11.0, 4.3 Hz, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 2.28 (ddt, J = 10.2, 3.4, 1.8 Hz, 1H), 2.04 – 1.97 (m, 1H), 1.82 (dd, J = 11.9, 4.1 Hz, 1H), 1.71 (dp, J = 13.7, 3.4 Hz, 1H), 1.41 – 1.14 (m, 2H), 1.08 (s, 3H), 1.07 (s, 3H).13C NMR (126 MHz, DMSO) J 176.72, 158.85, 157.88, 151.40, 128.82, 125.58, 121.68, 113.85, 112.56, 101.93, 74.28, 66.85, 41.36, 34.62, 34.21, 30.86, 20.15, 19.48. N-(7-(((1RS,2RS)-2-Hydroxycyclohexyl)oxy)-2-oxo-2H-chromen-3-yl)iso-butyramide (KCC-03-112): The phenol 7 (0.500 g, 2.02 mmol) and cyclohexene oxide (0.620 mL, 6.13 mmol) were dissolved in dimethylformamide (10 mL). Potassium carbonate (0.560 g, 4.05 mmol) was added and the mixture was heated to 120 °C for 20 h. The mixture was cooled to room temperature and diluted with water (100 mL). The aqueous solution was extracted with ethyl acetate (3 x 100 mL), washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with 15% ethyl acetate in hexanes to give the alcohol 29 (0.417 g, 59%).1H NMR (500 MHz, DMSO) J 9.45 (s, 1H), 8.54 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.6, 2.4 Hz, 1H), 4.93 (d, J = 4.7 Hz, 1H), 4.23 – 4.09 (m, 1H), 3.56-3.49 (m, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 2.05-1.98 (m, 1H), 1.90-1.82 (m, 1H), 1.66-1.58 (m, 2H), 1.38 – 1.16 (m, 4H), 1.08 (d, J = 6.8 Hz, 6H). HPLC-MS (ESI+): m / z 346.1 (M+H)+. (1RS,2RS)-2-((3-iso-Butyramido-2-oxo-2H-chromen-7-yl)oxy)cyclohexyl 5-methyl-1H- pyrrole-2-carboxylate (30, KCC-03-12) Under argon, alcohol 29 (0.050 g, 0.145 mmol) and 5-methyl-1H-pyrrole-2-carboxylic acid, prepared according to the reported procedure,5(0.026 g, 0.208 mmol) were dissolved in dry dicholoromethane (1 mL). Subsequently, 4- dimethylaminopyridine (0.008 g, 0.065 mmol) and N,N'-diisopropylcarbodiimide (0.044 mL, 0.284 mmol) were added to the mixture which was then stirred at room temperature for 20 h. The solvents were evaporated in vacuo and the residue purified via silica gel column eluting with 20% ethyl acetate in hexanes to give the ester 30 (0.029 g, 45%) as an off-white solid.1H NMR (500 MHz, DMSO) J 11.51 (s, 1H), 9.46 (s, 1H), 8.52 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H), 6.50 (dd, J = 3.6, 2.5 Hz, 1H), 5.77 (ddd, J = 3.5, 2.4, 0.9 Hz, 1H), 4.99 (ddd, J = 9.6, 7.9, 4.4 Hz, 1H), 4.60 (td, J = 8.5, 4.2 Hz, 1H), 2.89 (p, J = 6.8 Hz, 1H), 2.16 (s, 3H), 2.14-2.08 (m, 1H), 2.01-1.95 (m, 1H), 1.76- 1.67 m, 1H), 1.60 – 1.36 (m, 2H), 1.07 (d, J = 6.8 Hz, 6H). HPLC-MS (ESI+): m / z 453.0 (M+H)+. m / z calculated for C25H29N2O6+(M+H)+453.2020, found 453.2020. HPLC: 99.36% [tR = 15.387 min, Grad. MeOH / Water (50% to 95% with 0.1% TFA), 20 min]. Scheme 4 illustrates the synthesis of aminocoumarins bearing substitution at the 8 position. The 3-amino-7-hydroxycoumarin 33 was prepared from 31 and intermediate 32 using a similar route described in Scheme 1. Esterification of 33 gives esters of type 34. Reaction of 34 with cyclohexene oxide provides alcohols 35 which can be further acylated to provide the esters 36.

[0215]

[0216] Scheme 4: (a) (CH3CO)2O, NaOAc, 115 °C, 16 h; (b) SOCh, MeOH, reflux, 2 h; (c) HATU, DIPEA, DMF, rt, 1 h; (d) LiClO4, neat ,100 °C, 3 h; (e) 4M HC1 in dioxane, DCM, rt, 1 h; (f) DIG, DMAP, DCM, rt, 3 h.

[0217] 3-Acetamido-8-methyl-2-oxo-2H-chromen-7-yl acetate (32): A mixture of 2,4-dihydroxy- 3-methylbenzaldehyde (31, 4.00 g, 26.3 mmol), 7V-acetyl glycine (2, 3.66 g, 31.3 mmol), and anhydrous sodium acetate (4.26 g, 52.6 mmol) in acetic anhydride (35 mL) was refluxed under stirring for 16 hours. The reaction mixture was then poured into ice (500 mL) to yield a yellow precipitate. The precipitate was filtered off, washed with ice water and ethyl acetate, and dried under reduced pressure to afford 3-acetamido-8-me±yl-2-oxo-2H-chromen-7-yl acetate (32) as a yellow solid (2.48 g, 34.0%).1H NMR (500 MHz, DMSO) 89.77 (s, 1H), 8.61 (s, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H), 2.17 (d, J= 2.0 Hz, 6H).13C NMR (126 MHz, DMSO) 8 170.71, 169.34, 157.81, 150.00, 148.83, 125.99, 124.33, 124.03, 119.64, 118.23, 117.81, 24.41, 21.01, 9.15. HPLC-MS (ES1+): m / z 275.9 (M+H)+. HRMS (ESI+): nVz. calcd for C14H13NO5Na (M+Na)+298.0686, found 298.0687.

[0218] 3-Amino-7-hydroxy-8-methyl-2H-chromen-2-one hydrochloride (33): To a suspension of

[0219] 3-acetamido-8-methyl-2-oxo-2H-chromen-7-yl acetate (32, 2.48 g, 9.02 mmol) in methanol (120 mL), thionyl chloride (2.14 mL, 18.04 mmol) was added and refluxed under stirring for 2 hours. The reaction mixture was then evaporated to dryness under reduced pressure and triturated with diethyl ether (30 mL). The precipitate was filtered off, washed with diethyl ether (10 mL), and dried under reduced pressure to afford 3-amino-7-hydroxy-2H-chromen- 2-one hydrochloride (33) as a brown solid (496 mg, 98.2 %).1H NMR (500 MHz, DMSO) ^ 7.17 (d, J = 8.4 Hz, 1H), 7.07 (bs, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.33 (bs, 2H), 2.15 (s, 3H).13C NMR (126 MHz, DMSO) δ 159.00, 157.58, 150.45, 125.24, 124.37, 122.39, 113.07, 112.03, 111.09, 8.42. HPLC-MS (ESI+): m / z 192.2 (M+H)+. HRMS (ESI+): m / z calcd for C10H10NO3(M+H)+192.0655, found 192.0651. 3-Amino-8-methyl-2-oxo-2H-chromen-7-yl isobutyrate-7-oxabicyclo[4.1.0]heptane (34): A mixture of 3-amino-7-hydroxy-8-methyl-2H-chromen-2-one hydrochloride (33, 1.73 g, 7.60 mmol), iso-butyric acid (5, 1.00 g, 11.40 mmol), HATU (3.46 g, 9.12 mmol) and DIPEA (2.94 g, 22.80 mmol) in DMF (34.6 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine (15 mL). The organic layer was dried with sodium sulfate, filtered, and evaporated to afford the crude product. The crude product was purified by SiO2 chromatography using gradient elution of 0-30% ethyl acetate in hexanes to yield the corresponding product 3-amino-8-methyl-2-oxo-2H-chromen-7-yl iso-butyrate-7- oxabicyclo[4.1.0]heptane (34) as a yellow solid (1.23 g, 65.5%).1H NMR (500 MHz, DMSO) J 7.29 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 5.66 (s, 2H), 2.88 (p, J = 7.0 Hz, 1H), 2.12 (s, 3H), 1.26 (d, J = 7.0 Hz, 6H).13C NMR (126 MHz, DMSO) ^ 175.26, 158.97, 146.88, 146.80, 133.03, 122.84, 119.94, 118.92, 117.63, 108.28, 33.78, 19.19, 9.07. HPLC-MS (ESI+): m / z 262.0 (M+H)+. HRMS (ESI+): m / z calcd for C + 14H16NO4 (M+H) 262.1074, found 262.1071. 3-(((1RS,2RS)-2-Hydroxycyclohexyl)amino)-8-methyl-2-oxo-2H-chromen-7-yl iso- butyrate (35): To a mixture of 3-amino-8-methyl-2-oxo-2H-chromen-7-yl isobutyrate-7- oxabicyclo[4.1.0]heptane (34, 1.00 g), cyclohexene oxide (0.930 g, 9.53 mmol), lithium perchlorate (1.01 g, 9.53 mmol) was added in a pressure vial and stirred under neat conditions at 100 °C for 5 h. Caution! This reaction was carried behind a laboratory safety shield / screen. The resulting mixture was purified by SiO2chromatography using gradient elution of 0 to 20% ethyl acetate in hexanes to yield the corresponding product 3-((2- hydroxycyclohexyl)amino)-8-methyl-2-oxo-2H-chromen-7-yl iso-butyrate (35) as a yellow solid (0.75 g, 55.2%).1H NMR (500 MHz, DMSO) ^ 7.33 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 5.54 (d, J = 7.2 Hz, 1H), 4.81 (d, J = 5.1 Hz, 1H), 3.45 – 3.35 (m, 1H), 3.11 – 2.98 (m, 1H), 2.88 (p, J = 7.0 Hz, 1H), 2.13 (s, 3H), 2.05 – 1.97 (m, 1H), 1.93 – 1.83 (m, 1H), 1.71 – 1.58 (m, 2H), 1.34 – 1.28 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H), 1.23 – 1.13 (m, 2H).13C NMR (126 MHz, DMSO) ^ 175.27, 159.15, 146.58, 145.82, 132.58, 122.95, 120.17, 119.01, 117.56, 104.43, 72.56, 58.63, 34.79, 33.79, 30.39, 24.66, 24.52, 19.23, 9.07. HPLC-MS (ESI+): m / z 360.1 (M+H)+. HRMS (ESI+): m / z calcd for C20H26NO5 (M+H)+ 360.1805, found 360.1794. 2-(((1RS,2RS)-7-(iso-Butyryloxy)-8-methyl-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5-methylfuran-2-carboxylate (36a, GM5-078): A mixture of 3-((2- hydroxycyclohexyl)amino)-8-methyl-2-oxo-2H-chromen-7-yl iso-butyrate (35, 0.100 g, 0.27 mmol), 5-methylfuran-2-carboxylic acid (0.052 g, 0.41 mmol), DIC (0.070 g, 0.55 mmol), DMAP (0.016 g, 0.13 mmol) in DCM (1.5 mL) was stirred at room temperature for 16 h. The resulting mixture was purified by SiO2 chromatography using gradient elution of 0 to 12% ethyl acetate in hexanes to yield the corresponding product 2-((7-(iso-butyryloxy)-8-methyl- 2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5-methylfuran-2-carboxylate (36a, GM5-078) as a white solid (0.104 g, 80.0%).1H NMR (500 MHz, DMSO) ^ 7.35 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 3.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.13 (dd, J = 3.4, 1.1 Hz, 1H), 5.73 (d, J = 9.2 Hz, 1H), 4.97 - 4.91 (m, 1H), 3.61 – 3.54 (m, 1H), 2.88 (p, J = 7.0 Hz, 1H), 2.17 (s, 3H), 2.08 (s, 3H), 2.06 - 2.02 (m, 1H), 1.99 - 1.93 (m, 1H), 1.73 - 1.68 (m, 2H), 1.60 - 1.48 (m, 2H), 1.42 - 1.30 (m, 2H), 1.26 (d, J = 7.0 Hz, 6H).13C NMR (126 MHz, DMSO) δ 175.24, 158.83, 157.92, 157.49, 146.73, 145.80, 142.77, 132.15, 122.99, 120.20, 119.94, 119.01, 117.52, 109.09, 105.50, 77.29, 54.94, 33.78, 31.27, 31.00, 24.51, 24.04, 19.22, 13.84, 9.01. HPLC-MS (ESI+): m / z 468.1 (M+H)+; HPLC: 99.44% [te = 22.37 min., Grad. MeOH / water (50:95%, with 0.1% TFA) 25 min.; HRMS (ESI+): m / z calcd for C26H30NO7(M+H)+468.2017, found 468.2006.

[0220] 2-(((lR5,2RS)-7-(i$o-Butyryloxy)-8-methyl-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5-methyl-lH-pyrrole-2-carboxylate (36b, GM5-080): This compound was synthesized using the procedure described for 36a (35, 0.100 g, 0.27 mmol), and 5-methyl-lH-pyrrole-2- carboxylic acid (0.052 g, 0.41 mmol) was used as the starting material. The resulting mixture was purified by SiQz chromatography using gradient elution of 0 to 17% ethyl acetate in hexanes to yield corresponding product 2-((7-(wo-butyryloxy)-8-methyl-2-oxo-2H-chromen-

[0221] 3-yl)amino)cyclohexyl 5-methyl-l / / -pyrrole-2-carboxylate (36b, GM5-080) as a white solid (0.084 g, 64.7%).1H NMR (500 MHz, DMSO) δ 11.44 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.92 (s, 1H), 6.50 (dd, J = 3.6, 2.5 Hz, 1H), 5.71 - 5.67 (m, 2H), 4.92 - 4.86 (m, 1H), 3.55 - 3.47 (m, 1H), 2.88 (p, J = 1.0 Hz, 1H), 2.11 (s, 3H), 2.08 (s, 3H), 2.05 - 1.93 (m, 2H), 1.78 - 1.68 (m, 2H), 1 .62 - 1.45 (m, 2H), 1.43 - 1.32 (m, 2H), 1.26 (d, J = 7.0 Hz, 6H). HPLC-MS (ESI+): m / z 4613 (M+H)+; HPLC: 98.88% [tr = 22.21 min., Grad. MeOH / water (50:95%, with 0.1% TFA) 25 min.; HRMS (ESI+): m / z calcd for C26H31N2O6 (M+H)+467.2171, found 467.2166. (lR$',2RS)-2-((7-(iso-Butyryloxy)-8-methyl-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5-(trifluoromethyl)-lH-pyrrole-2-carboxylate (36c, GM5-092): This compound was synthesized using the procedure described for 36a (35, 0.050 g, 0.13 mmol), and 5- (trifluoromethyl)-l / / -pyrrole-2-carboxylic acid (lOd, 0.037 g, 0.41 mmol) was used as the starting material. The resulting mixture was purified by SiCh column chromatography using gradient elution of 0 to 14% ethyl acetate in hexanes to obtain the corresponding product 2- ((7-(iso-butyryloxy)-8-methyl-2-oxo-2H-chromen-3-yl)amino)cyclohexyl 5-methyl-1H- pyrrole-2-carboxylate (36c, GM5-092) as a white solid (0.053 g, 73.2%). *H NMR (500 MHz, DMSO) 5 13.04 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 6.65 - 6.63 (m, 1H), 6.50 - 6.47 (m, 1H), 5.74 (d, J = 9.0 Hz, 1H), 4.99 (ddd, J = 10.8, 9.3, 4.5 Hz, 1H), 3.61 - 3.52 (m, 1H), 2.87 (p, J = 7.0 Hz, 1H), 2.07 (s, 3H), 2.04 (s, 1H), 2.00 - 1.97 (m, 1H), 1.80 - 1.69 (m, 2H), 1.64 - 1.50 (m, 2H), 1.44 - 1.30 (m, 2H), 1.26 (d, J = 7.0 Hz, 6H). 19F NMR (471 MHz, DMSO) 5 -58.36. HPLC-MS (ESI+): m / z 521.2 (M+H)+; HPLC: 99.47% [fr = 23.41 min., Grad. MeOH / water (50:95%, with 0.1% TFA) 25 min.; HRMS (ESI+): m / z calcd for C26H28F3N2O6 (M+H)+521.1894, found 521.1880.

[0222] References for Example 2

[0223] (1) JΦlck, R. I.; Sim, H.; Berg, R. H.; Andresen, T. L. Catalyst-free conjugation and in situ quantification of nanoparticle ligand surface density using fluorogenic Cu-free Click chemistry. Chemistry 2011, 17 (12), 3326-3331.

[0224] (2) Krajnakova, J.; Joniak, J.; Putala, M.; Gorova, R.; Jurdakova, H.; Stankovidova, H. Mild and highly efficient deacetylation of acetamido and acetoxy coumarins: A convenient and expeditious synthesis of substituted 3-aminocoumarins. Synthetic Communications 2021, 51 (21), 3277-3291.

[0225] (3) tier, E.; Berthold, R.; Traxler, F. The stereospecific synthesis of all four stereoisomers of 2-amino-6-phenoxy-cyclohexanol. Helvetica Chimica Acta 1979, 62 (4), 932-940.

[0226] (4) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. Rhodium(I)-catalyzed hydroboration of olefins. The documentation of regio- and stereochemical control in cyclic and acyclic systems. Journal of the American Chemical Society 1988, 110 (20), 6917-6918.

[0227] (5) Farrar, M. A.; Olson, S. A.; Perlmutter, R. M.; Slossberg, L. H. Coumermycin analogs as chemical dimerizers of chimeric proteins. W001 / 87309 Al US20130252988, 2001.

[0228] (6) Mosallanejad, A.; Lorthioir, O. Application of Tsunoda reagent to the convenient synthesis of drug-like pyrazoles. Tetrahedron Letters 2018, 59 (18), 1708-1710; Sakamoto, I.; Kaku, H.; Tsunoda, T. Preparation of (Cyanomethylene)trimethylphosphorane as a New Mitsunobu- Type Reagent. Chemical and Pharmaceutical Bulletin 2003, 51 (4), 474-476. DOI: 10.1248 / cpb.51.474. Tsunoda, T; Ozaki, F.; Ito, S. Novel reactivity of stabilized methylenetributylphosphorane: Anew mitsunobu reagent. Tetrahedron Letters 1994, 35 (28), 5081-5082.

[0229] Example 3. K-Ras Mutated Tumor Cells Are Selectively Sensitive to CMGi-Induced DNA Damage / Apoptosis

[0230] Oncogenic signals (e.g., Myc or Cyclin E overexpression) cause replicative stress (RS) and reduce MCM / CMG reserve functionality ( Xiang S, Reed DR, Alexandrow MG. The CMG helicase and cancer: a tumor "engine" and weakness with missing mutations. Oncogene 2023;42(7):473-90). Since MCM / CMGs are required to recover from RS, but are debilitated at the same time, vulnerabilities to CMGi likely exist in solid tumor cells driven by certain oncogenes. K-Ras-driven tumor cells contain RS (e.g., replication fork stalling) and have been shown genetically to be selectively sensitive to reduction of MCM licensing, which is synthetically lethal ( Al Zubaidi T, Gehrisch OHF, Genois MM, Liu Q, Lu S, Kung J, et al. Targeting the DNA replication stress phenotype of KRAS mutant cancer cells. Sci Rep 2021;ll(l):3656; Maya-Mendoza A, Ostrakova J, Kosar M, Hall A, Duskova P, Mistrik M, et aL Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress. Mol Oncol 2015;9(3):601 -16; and Gastl B, Klotz-Noack K, Klinger B, Ispasanie S, Salib KHF, Zuber J, et al. Reduced replication origin licensing selectively kills KRAS-mutant colorectal cancer cells via mitotic catastrophe. Cell Death Dis 2020;l 1(7):499). This predicts that K-Ras-driven tumor cells will be selectively sensitive to pharmacologic treatment with CMGi. We assessed the CMGi / CAl effects on three tumor lines from malignancies that are K-Ras-driven and have limited treatment options or few effective targeted therapies [Psnl pancreatic ductal adenocarcinoma (PDAC; K-Ras-G12R, also Myc amplified); H460 non-small cell lung carcinoma (NSCLC; K-Ras-Q61H); 143B osteosarcoma (OS; K-Ras-G12S / A59T)]. CMGi effects were compared to responses seen in immortalized non-tumor HaCaT keratinocytes and primary human keratinocytes. In viability assays, all three tumor lines are -4-15 times more sensitive to CAI exposure relative to HaCaT and primary cells, with tumor cell IC50 estimates of -1-4 μM (FIG. 3A). Novobiocin has little effect until higher concentrations are tested. Using a larger cohort of tumor cells, the National Cancer Institute (NCI; NCI-60 tumor cell analyses) also found similar tumor cell sensitivities to CA1, but not novobiocin, using proliferation assays (CA1 GI500.5-5 µM). We assessed doubling times of the three tumor lines to that of HaCaT and primary cells (FIG. 3B). Two of the lines display faster growth rates than HaCaT (143B and Psn1), while H460 NSCLC cells are similar to HaCaT, and primary cells display the longest doubling times. This indicates that while a shorter doubling time, and perhaps reduced G1 and / or S-phase lengths that are known to reduce MCM loading ( Mei L, Kedziora KM, Song EA, Purvis JE, Cook JG. The consequences of differential origin licensing dynamics in distinct chromatin environments. Nucleic Acids Res 2022;50(17):9601-20), might explain in part the selective sensitivity of certain tumor cells to CA1 / CMGi, differences in doubling times are not the single reason. As we discuss below, it is more likely that these K-Ras-driven tumor cells are sensitive to CA1 / CMGi for numerous reasons, including the presence of RS, which requires efficient MCM / CMG functionality for recovery, or changes to the CMG helicase similar to that elicited by Myc or Cyclin E overexpression. We next verified that, at these effective CA1 / CMGi concentrations for viability loss, the CMG helicase was indeed targeted in asynchronous tumor cells. Results show that in each cell type the CMG helicase components (MCM subunits, Cdc45, GINS / Psf1,3) were displaced from chromatin at concentrations between 1-2.5 µM, with MCMs in some analyses being slightly more resistant (FIG. 3C). RPA was also lost from chromatin, indicating that CMG enzyme function was inhibited at these concentrations. In contrast, the ORC complex (assessed via Orc4 subunit), which contains multiple ATPase domains necessary for chromatin association, was not similarly sensitive to CA1. Exposure of all three tumor lines and HaCaT cells to a slightly higher 5 µM concentration of CA1 shows a tumor cell-specific increase in DNA damage signals (gamma-H2AX surrogate) and Parp cleavage indicative of apoptosis (FIG. 3D). Increasing the CA1 dose to 15 µM shows that HaCaT cells will eventually incur DNA damage and Parp cleavage at higher doses. We next tested whether ectopic expression of a mutant Ras protein could acutely sensitize cells to CMGi. For other ongoing studies, we had generated a lentiviral construct that allowed regulatable expression of HA-tagged oncogenic H-Ras-61L (using the Tet-On promoter). HaCaT cells containing wt-Ras were infected with these lentiviruses, pooled, and tested + / - H-Ras61L expression for effects on cell proliferation, DNA damage, and Parp cleavage in the absence or presence of CMGi (FIG. 3E). Ectopic expression of H-Ras61L alone has a small suppressive effect on proliferation of non-tumor HaCaT cells. However, while proliferation of uninduced HaCaT cells (with wt-Ras) is reduced at two tested CMGi concentrations, expression of H-Ras61L causes a significant increase in sensitivity of HaCaT cells to CMGi, reducing proliferation by almost 70% compared to cells without H-Ras61L expression. Consistent with this, immunoblotting (FIG.3E, right) shows that H-Ras61L expression in the presence of CMGi causes a dose-dependent increase in DNA damage, and at the higher CMGi concentration (15 µM, the HaCaT IC50for CMGi) Parp cleavage is elevated. The references cited herein are hereby incorporated by reference to disclose and describe the methods or materials in connection with which the publications are cited or to provide background for the present disclosure. Any incorporation by reference of documents herein is limited such that no subject matter is incorporated by reference that is contrary to the explicit disclosure herein. In the event of inconsistent usages between this document and those documents so incorporated by reference herein, the use in the incorporated references should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls. The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I or Formula IIor a pharmaceutically acceptable salt or derivative thereof; wherein:R1is selected from 3- to 8-membered monocyclic or bicyclic heterocycle and 5- to 10- membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted by one or more groups selected from R3as allowed by valency;R2is selected from C1-C6alkyl, C1-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted by one or more groups selected from R3as allowed by valency;R3is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6 alkynyl, (C1-C6cycloalkyl)(Co-C3 alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-,RzC(O)-(C0-C6 alkyl)-, RzC(N)-(C0-C6 alkyl)-, RzS(O)-(C0-C6 alkyl)-, and RzS(O)2-(C0-C6 alkyl)-, each of which may be optionally substituted by one or more groups selected from Y as allowed by valency; Rxand Ryare independently selected at each occurrence from Ra, RzC(O)-, RzC(N)-, RzS(O)-, and RzS(O)2-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more Y groups as allowed by valeny; and Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O- , RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-, wherein Rois independently selected at each occurrence from Rp, halo, RpO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2- C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0- C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0C6alkyl)-.

2. The compound of claim 1, or a pharmaceutically acceptable salt or derivative thereof,3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

4. The compound of claim 3, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 3- to 6-membered monocyclic heterocycle optionally substituted with 1, 2, 3, or 4 groups selected from R1as allowed by valency.

5. The compound of claim 3, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

7. The compound of claim 6, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is 5- to 6-membered monocyclic heteroaryl optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

8. The compound of claim 6, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

9. The compound of claim 6, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from pyrrolyl, pyrazolyl, and furanyl, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

10. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from:

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or derivative thereof, wherein R2is C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

12. The compound of claim 11, or a pharmaceutically acceptable salt or derivative thereof, wherein R2is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane, each of which may be optionally substituted with 1, 2, 3, or 4 groups selected from R3as allowed by valency.

13. The compound of claim 11, or a pharmaceutically acceptable salt or derivative thereof, wherein R2is isopropyl.

14. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt or derivative thereof.

15. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt or derivative thereof.

16. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

17. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of claim 16.

18. A method for treating an infection with a papillomavirus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of claim 16.

19. A method for inhibiting a helicase in a eukaryotic cell comprising contacting the cell with an effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt or derivative thereof.

20. A method for inhibiting replication of a papillomavirus in a eukaryotic cell comprising contacting the cell with an effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt or derivative thereof.

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