WO2019222509A1 - Pyrazolopyrimidines servant d'inhibiteurs de mertk et leur utilisation dans le traitement du cancer - Google Patents

Pyrazolopyrimidines servant d'inhibiteurs de mertk et leur utilisation dans le traitement du cancer Download PDF

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Publication number
WO2019222509A1
WO2019222509A1 PCT/US2019/032680 US2019032680W WO2019222509A1 WO 2019222509 A1 WO2019222509 A1 WO 2019222509A1 US 2019032680 W US2019032680 W US 2019032680W WO 2019222509 A1 WO2019222509 A1 WO 2019222509A1
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compound
cancer
alkyl
substituted
disorder
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PCT/US2019/032680
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English (en)
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Xiaodong Wang
Stephen Frye
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The University Of North Carolina At Chapel Hill
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the presently disclosed subject matter relates generally to pyrazolopyrimidine containing compounds that inhibit one or more of Mer tyrosine kinase (MerTK), Tyro3 tyrosine kinase, and Axl tyrosine kinase activity. Additionally disclosed are methods of synthesis and use of the pyrazolopyrimidine containing compounds as anti-cancer agents, immunostimulatory and immunomodulatory agents, anti-platelet agents, anti-infective agents, and as adjunctive agents.
  • MerTK Mer tyrosine kinase
  • Tyro3 tyrosine kinase Tyro3 tyrosine kinase
  • Axl tyrosine kinase activity Axl tyrosine kinase activity.
  • MerTK is a member of a receptor tyrosine kinase (RTK) family known as TAM, which also includes Axl and Tyro3. Each member of the TAM family contains an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The TAM family members undergo ligand-induced homodimerization, followed by catalytic tyrosine kinase activation and intracellular signaling. Cross-phosphorylation has been demonstrated within this RTK family, suggesting heterodimerization can also occur. These RTKs are widely expressed in many epithelial tissues and in cells of the immune, nervous, and reproductive systems. Specifically, MerTK has been found to be expressed in monocytes and in tissues of epithelial and reproductive tissue.
  • RTK receptor tyrosine kinase
  • TAM receptor and ligand overexpression have been shown in a wide range of solid and hematological tumors, and correlate with poor prognosis in a variety of tumor types and their signals and promote survival, chemoresistance, motility and invasion.
  • their role in diminishing the innate immune response makes their inhibition a novel mechanism for reversing the immunosuppressive tumor microenvironment.
  • the subject matter described herein is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may further comprise one or more additional active agents.
  • the subject matter described herein is directed to a method of treating a disease or disorder associated with one or more of Mer, Tyro3, and Axl tyrosine kinase.
  • the disease or disorder is cancer.
  • the disease or disorder is an infection.
  • the disease or disorder is associated with Mer tyrosine kinase.
  • the subject matter described herein is directed to a method of using a compound of Formula I in immunostimmulatory therapy. In other embodiments, the subject matter described herein is directed to a method of using a compound of Formula I in immunomodulatory therapy.
  • the subject matter described herein is directed to methods of making the compounds of Formula I.
  • the subject matter described herein is directed to a kit for treating a condition mediated by one or more of Mer, Tyro3, and Axl tyrosine kinase, comprising: a) a first pharmaceutical composition comprising a Formula I compound; and b) instructions for use.
  • compounds of Formula I and pharmaceutical compositions thereof that are inhibitors or modulators of one or more of Mer tyrosine kinase (MerTK), Tyro3 tyrosine kinase, and Axl tyrosine kinase activity.
  • the compounds of Formula I are selective inhibitors of Mer tyrosine kinase.
  • the compounds and compositions disclosed herein are useful in treating diseases and disorders mediated by one or more of Mer tyrosine kinase (MerTK), Tyro3 tyrosine kinase, and Axl tyrosine kinase activity.
  • An example of a method of treating is in the case of a subject who is suffering from cancer.
  • the compounds can be used not only to combat cancer, but can also advantageously be used as immunostimulatory and immunomodulatory agents, anti-platelet agents, anti-infective agents, and as adjunctive agents.
  • the term“about,” when referring to a measurable value such as an amount of a compound or agent of the current subject matter, dose, time, temperature, and the like, is meant to encompass variations of ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of the specified amount.
  • “approximately”,“about”, and“substantially” may refer to an amount that is within less than or equal to 10% of the stated amount.
  • the term“generally” as used herein represents a value, amount, or characteristic that predominantly includes or tends toward a particular value, amount, or characteristic. Ranges can be expressed herein as from“about” one particular value, and/or to “about” another particular value. When such a range is expressed, some embodiments includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms some embodiments.
  • each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. For example, if the value“10” is disclosed, then“about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • the terms“optional” or“optionally” mean that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • the term“subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • the subject is a human.
  • a patient refers to a subject afflicted with a viral infection.
  • the term“patient” includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment of one or more viral infections prior to the administering step.
  • the one or more disorders is selected from chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the term covers any treatment of a subject, including a mammal (e.g ., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in some embodiments, the subject is a human.
  • the term“prevent” or“preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • diagnosisd means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
  • the subject has been diagnosed with a need for treatment of a viral infection prior to the administering step.
  • the phrase “identified to be in need of treatment for a disorder,” or the like refers to selection of a subject based upon need for treatment of the disorder. It is contemplated that the
  • identification can, in some embodiments, be performed by a person different from the person making the diagnosis. It is also contemplated, in some embodiments, that the administration can be performed by one who subsequently performed the administration.
  • administering and“administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration,
  • intracerebral administration rectal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration.
  • Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • contacting in a biological context, refers to bringing a disclosed compound and a cell, target receptor, or other biological entity together in such a manner that the compound can affect the activity of the target (e.g ., receptor, cell, etc.), either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.
  • the target e.g ., receptor, cell, etc.
  • the term“effective amount” refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is 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 specific compound employed and like factors well known in the medical arts.
  • the effective daily dose can be divided into multiple doses for purposes of administration.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. 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.
  • a preparation can be administered in a“prophylactically effective amount”; that is, an effective amount for prevention of a disease or condition.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion.
  • a compound of Formula I can be in the form of a“prodrug,” which includes compounds with moieties which can be metabolized in vivo.
  • the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977)
  • prodrugs “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19). Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
  • prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxym ethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl ester moieties, (e.g., propionoic acid esters
  • “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • the compounds of this disclosure form acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this disclosure.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric acid, and the like.
  • Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate,
  • the term“substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or“substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g ., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain embodiments, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • “A 1 ,”“A 2 ,”“A 3 ,” and“A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, s- butyl, /-butyl, «-pentyl, isopentyl, 5-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • A“lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • alkylamino specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like.
  • alkyl is used in one instance and a specific term such as“alkylalcohol” is used in another, it is not meant to imply that the term“alkyl” does not also refer to specific terms such as “alkylalcohol” and the like.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g, an“alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g, a“halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g, an“alkenylalcohol,” and the like.
  • cycloalkyl is a non-aromatic carbon-based ring, which may be single or multi -cyclic, composed of at least three carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, and the like.
  • Cycloalkyl can include any number of carbons, non-limiting examples of which are C3-C6, C4-C6, C5-C6, C3-C8, C4-C8, C5-C8, and C6-C8. In some embodiments, cycloalkyl is C3-C8.
  • heterocycloalkyl refers to single and multi-cyclic non aromatic ring systems in which at least one of the ring members is other than carbon.
  • Heterocycloalkyl can include any number of carbons, non-limiting examples of which are C2-C9, C2-C8, C2-C7, C3-C6, C4-C6, C5-C6, C3-C8, C4-C8, C5-C8, and C6-C8.
  • heterocycloalkyl is C2-C7.
  • Non-limiting examples of heterocycloalkyl groups include piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkoxy refers to an -O-alkyl or -O-cycloalkyl radical bonded through an ether linkage. Alkoxy groups may be optionally substituted with one or more substituents.
  • haloalkoxy refers to an -O-alkyl group that is substituted by one or more halo substituents.
  • haloalkoxy groups include trifluoromethoxy, and 2,2,2- trifluoroethoxy.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbomenyl, and the like.
  • Cycloalkenyl can include any number of carbons, non-limiting examples of which are C3-C6, C4-C6, C5-C6, C3-C8, C4-C8, C5-C8, and C6-C8. In some embodiments, cycloalkenyl is C3-C8.
  • Heterocycloalkenyl can include any number of carbons, non-limiting examples of which are C3-C6, C4-C6, C5-C6, C3-C8, C4-C8, C5-C8, and C6-C8.
  • heterocycloalkenyl is C3-C8.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkynyl is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • aryl as used herein is a single or multi-cyclic group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like.
  • the term“biaryl” is a specific type of aryl group and is included in the definition of“aryl.” Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon- carbon bonds, as in biphenyl.
  • heteroaryl as used herein is a single or multi-cyclic group that contains any aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
  • the heteroaryl can include any number of carbons, non-limiting examples of which are C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C5, C4-C6, C5-C6, C4-C8, C5-C8, and C6-C8.
  • heteroaryl is C4-C5.
  • Non-limiting examples of such heteroaryl groups include imidazolyl, quinolyl, isoquinolyl, indolyl, indazolyl, pyridazyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, quinoxolyl, pyranyl, pyrimidinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, benzofuranyl, thiamorpholinyl sulfone, oxazolyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, oxopiperidinyl,
  • oxopyrrolidinyl oxoazepinyl, azepinyl
  • isoxazolyl isothiazolyl, furazanyl, thiadiazyl, oxathiolyl, acridinyl, phenanthridinyl, and benzocinnolinyl, and the like.
  • the aryl or heteroaryl group can be substituted or unsubstituted.
  • the aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aldehyde as used herein is represented by the formula— C(0)H.
  • NA 1 A 2 where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • alkylamino as used herein is represented by the formula— NH(-alkyl) where alkyl is a described herein.
  • Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.
  • dialkylamino as used herein is represented by the formula— N(-alkyl) 2 where alkyl is a described herein.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group,
  • esters as used herein is represented by the formula— OC(0)A 1 or— C(0)OA 1 , where A 1 can be an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polystyrene resin as used herein is represented by the formula— (A 1 0(0)C-A 2 -C(0)0) a— or— (A 1 0(0)C-A 2 - 0C(0)) a— , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A'OA 2 , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula— (A 1 0-A 2 0) a— , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halide refers to the halogens fluorine, chlorine, bromine, and iodine.
  • hydroxyl as used herein is represented by the formula— OH.
  • ketone as used herein is represented by the formula A 1 C(0)A 2 , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • nitrile as used herein is represented by the formula— CN.
  • silica as used herein is represented by the formula— SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo as used herein is represented by the formulas— S(0)A',— S(0) 2 A 1 , — OS(0) 2 A 1 , or— OS(0) 2 OA 1 , where A 1 can be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 can be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula— S(0) 2 A', where A 1 can be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • the term“sulfone” as used herein is represented by the formula A ' S(0) 2 A 2 , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • the term“sulfoxide” as used herein is represented by the formula A 1 S(0)A 2 , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • R 1 ,”“R 2 ,”“R 3 ,”“R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or,
  • the first group can be pendant (z.e., attached) to the second group.
  • the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the subject matter described herein may contain “optionally substituted” moieties.
  • the term“substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by the subject matter described herein are those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, - (CH 2 ) O-2 R ⁇ , -(haloR*), -(CH 2 ) 0-2 OH, -(CH 2 )o- 2 OR e , -(CH 2 ) 0-2 CH(OR*) 2 ; -0(haloR*), -CN, -N 3 , -(CH 2 ) O-2 C(0)R ⁇ , -(CH 2 ) O-2 C(0)OH, -(CH 2 ) O-2 C(0)OR ⁇ , -(CH 2 ) O-2 SR*, -(CH 2 ) O-2 SH, -(CH 2 ) O-2 NH 2 , -(CH 2 ) O-2 NHR ⁇ , -(CH 2 ) O-2 NR* 2 , -N0 2 , -SiR* 3 , -OSiR*
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: -0(CR * 2 ) 2-3 0-, wherein each independent occurrence of R * is selected from hydrogen, Ci- 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, - R*, -(haloR*), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH 2 , NHR*, -NR* 2, or -N0 2 , wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently Ci- 4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , - S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci- 6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s)
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R*, -(haloR*), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2, or -N0 2 , wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently Ci- 4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
  • Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di- substituted amino, amide groups, etc.
  • Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms
  • a very close synonym of the term“residue” is the term“radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • a 2,4- thiazolidinedione radical in a particular compound has the structure:
  • radical for example an alkyl
  • substituted alkyl can be further modified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.”
  • the number of atoms in a given radical is not critical to the presently described subject matter unless it is indicated to the contrary elsewhere herein.
  • Organic radicals contain one or more carbon atoms.
  • An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1- 12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
  • an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfmyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that
  • Inorganic radicals contain no carbon atoms and therefore comprise only atoms other than carbon.
  • Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations.
  • Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
  • the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
  • Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture.
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via
  • Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step can liberate the desired enantiomeric form.
  • specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.).
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%.
  • the designated enantiomer is substantially free from the other enantiomer.
  • the“R” forms of the compounds can be substantially free from the“S” forms of the compounds and are, thus, in enantiomeric excess of the“S” forms.
  • “S” forms of the compounds can be substantially free of“R” forms of the compounds and are, thus, in enantiomeric excess of the“R” forms.
  • a disclosed compound When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
  • the pairs of enantiomers e.g., (S,S)/(R,R)
  • the stereoisomers that are not mirror-images e.g., (S,S) and (R,S) are diastereomers.
  • diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.
  • a compound may have two chiral carbons on a cycloalkyl ring, such as a cyclohexyl ring.
  • the substituents on the chiral carbons may be labeled as in the“cis” or“trans” configuration.
  • the substituents on the cyclohexyl may, in some embodiments, labeled as such:
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the subject matter described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 ⁇ 4, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F and 36 Cl, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the subject matter described herein.
  • Certain isotopically-labeled compounds of the presently described subject matter for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 ⁇ 4, and carbon-l4, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds of the presently described subject matter and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • A“solvate” refers to an association or complex of one or more solvent molecules and a compound of Formula I.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • the term“hydrate” refers to the complex where the solvent molecule is water. Unless stated to the contrary, the subject matter described herein includes all such possible solvates.
  • polymorphic forms or modifications It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the subject matter described herein can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the subject matter described herein includes all such possible polymorphic forms.
  • 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.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • Formula I is a compound of Formula I or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof. These compounds are useful inhibitors of one or more of Mer, Tyro3, and Axl tyrosine kinase.
  • Formula I has the following general structure:
  • Cy 1 is selected from C3-C8 cycloalkyl and C2-C7 heterocycloalkyl, and substituted with 0, 1,
  • R la is selected from hydrogen, deuterium, C1-C8 alkyl, and Cy 2 , and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, Cl- C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, and (Cl-C4)(Cl-C4) dialkylamino;
  • R la is selected from hydrogen, deuterium, C1-C8 alkyl, and Cy 2 , and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, nitrile, -C(0)N(R 17 )R 18 , and (Cl-C4)(Cl-C4) dialkylamino;
  • R 17 is selected from hydrogen and C1-C4 alkyl
  • R 18 is selected C3-C8 cycloalkyl
  • Cy 2 is selected from C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, aryl, and C3- C5 heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Cl- C4 hydroxyalkyl, C1-C4 alkylamino, and (Cl-C4)(Cl-C4) dialkylamino;
  • Cy 2 is selected from C3-C8 cycloalkyl, C2-C7
  • heterocycloalkyl aryl, and C3-C9 heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, nitrile, -C(0)N(R 22 )R 20 , and (Cl-C4)(Cl-C4) dialkylamino;
  • R lb is selected from C1-C8 alkyl, Cy 2 , and (C1-C4 alkyl)Cy 2 , and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, and (Cl-C4)(Cl-C4) dialkylamino; wherein
  • R lb is selected from C1-C8 alkyl, Cy 2 , and (C1-C4 alkyl)Cy 2 , and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, nitrile, -C(0)N(R 22 )R 2 °, and (Cl-C4)(Cl-C4) dialkylamino;
  • R 2 is selected from hydrogen, C1-C4 alkyl, -C(0)R 20 , -C(0)N(R 22 )R 2 °, -N(R 22 )C(0)R 2 °, - S0 2 N(R 22 )R 21 , -N(R 22 )S0 2 R 21 , -S0 2 R 21 , and -(CH 2 ) n Cy 3 ; wherein
  • n is selected from 0, 1, 2, 3, and 4;
  • R 20 and R 21 is each independently selected from C1-C4 alkyl, -(CH 2 ) q OR 30 , and -(CH 2 ) q Cy 4 ; wherein q is selected from 0, 1, 2, 3, and 4;
  • R 30 is selected from hydrogen and C1-C4 alkyl
  • Cy 4 is selected from C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, aryl, and C3-C5 heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -C(0)-(Cl-C4 alkyl), C1-C4
  • R 20 is as defined above;
  • R 40a and R 40b is each independently selected from hydrogen and C1-C4 alkyl
  • R 22 is selected from hydrogen and C1-C4 alkyl
  • Cy 3 is selected from C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, aryl, and C3- C5 heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, -C(0)R 2 °, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, and (Cl-C4)(Cl-C4) dialkylamino; wherein
  • R 20 is as defined above;
  • R 3 is selected from -(CH 2 ) p OH and -(CH 2 ) P NHR 23 ;
  • p is selected from 0, 1, and 2;
  • R 23 is selected from hydrogen and C1-C4 alkyl
  • X is either present or absent, and when present is C1-C3 alkyl
  • a compound wherein the optionally substituted C2-C7 heterocycloalkyl is an optionally substituted piperidine.
  • R lb is selected from C1-C8 alkyl and Cy 2 .
  • R lb is C1-C8 alkyl substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl.
  • R lb is C3-C5 alkyl substituted with 1 or 2 groups independently selected from C1-C4 alkyl.
  • R 2 is selected from the group consisting of hydrogen, -C(0)R 2 °, and -(CH 2 ) n Cy 3 .
  • a compound wherein n is 1 and Cy 3 is C3-C5 heteroaryl.
  • a compound wherein the C3-C5 heteroaryl is pyridine substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl.
  • a compound wherein the substituents on the carbons marked“a” and“b” are in a trans configuration.
  • a compound wherein the compound has a structure:
  • R lb and R 2 are defined as herein.
  • a compound wherein the compound is selected from the group consisting of:
  • a compound wherein the compound is selected from the group consisting of:
  • the subject matter described herein relates to pharmaceutical compositions comprising at least one compound of Formula I and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition can be provided comprising a therapeutically effective amount of at least one disclosed compound.
  • a pharmaceutical composition can be provided comprising a prophylactically effective amount of at least one disclosed compound.
  • the subject matter described herein relates to pharmaceutical compositions comprising a
  • Pharmaceutically acceptable salts of the compounds are conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p- toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • Example base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetram ethyl ammonium hydroxide.
  • Chemical modification of a pharmaceutical compound into a salt is a known technique to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. ah, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
  • compositions comprise the compounds in a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • the compounds can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, l9th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
  • the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants.
  • the instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous)
  • compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granule; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water, cyclodextrin, dimethyl sulfoxide and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols including polyethylene glycol, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water, cyclodextrin, dimethyl sulfoxide and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols including polyethylene glycol, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphat
  • Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, the addition to the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • an inert base such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present disclosure alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be formulated as
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2- dimethyl- 1, 3-dioxolane-4-methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcelluslose, or emulsifying agents and other pharmaceutical adju
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl b-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • compositions of the present disclosure are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present disclosure. The following methods and excipients are merely exemplary and are in no way limiting.
  • the pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not cause adverse side-effects.
  • Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice , J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs , Toissel, 4 th ed., 622-630 (1986).
  • Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • administering a compound of the present disclosure to an animal are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route.
  • the present methods include the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of one or more of Mer, Tyro3, and Axl tyrosine kinase.
  • the compound of Formula I administered to an animal is a Mer tyrosine kinase selective inhibitor.
  • the methods also include the administration of a therapeutically effect amount of the compound for the treatment of patient having a predisposition for being afflicted by a disorder associated with one or more of Mer, Tyro3, and Axl tyrosine kinase dysfunction, or an infectious disease.
  • the patient is afflicted by a disorder associated with Mer tyrosine kinase.
  • the dose administered to an animal, particularly a human, in the context of the presently described subject matter should be sufficient to affect a therapeutic response in the animal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the disorder or infectious disease.
  • the total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg/kg and about 1000 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose.
  • This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
  • a method is provided to treat a host by administering a daily amount of a Mer TKI including active compounds of the present invention, which may be provided in dosages once or more a day.
  • the Mer TKI dose is between about .5 mg and about 200 mg.
  • the dose is at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 125 mg, about 140 mg, about 150, about 175, or about 200 mg. In another embodiment, the dose is between about 200 mg and 1250 mg.
  • the dose is about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg or more.
  • the compounds described herein are combined with an additional anti-tumor agent, anti -neoplastic agent, anti-cancer agent, immunomodulatory agent, immunostimulatory agent, anti-infective agents, anti -thrombotic, and/or anti-clotting agent.
  • the dosage administered to the host can be similar to that as administered during monotherapy treatment, or may be lower, for example, between about 0.5 mg and about 150 mg.
  • the dose is at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 125 mg, about 140 mg, or about 150 mg.
  • the amount of the compound of Formula I to be administered ranges from about 0.01 mg/kg of the patient to about 50 mg/kg or more of the patient or considerably more, depending upon the second compound to be co administered, the condition of the patient, severity of the disease to be treated, and the route of administration.
  • the additional anti-tumor agent, anti -neoplastic agent, anti-cancer agent, immunomodulatory agent, immunostimulatory agent, anti -infective agents, anti -thrombotic, and/or anti -clotting agent may, for example, be administered in amounts ranging from about 0.01 mg/kg to about 500 mg/kg.
  • suitable daily dosages are, for example, between about 0.1-4000 mg administered orally once-daily, twice-daily, or three times-daily, continuous (every day) or intermittently (e.g., 3- 5 days a week).
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
  • the composition further comprises at least one or more of an agent known to treat a viral infection, a bacterial infection, a thrombotic disorder or a clotting disorder, or a disorder of uncontrolled cellular proliferation.
  • an agent known to treat a viral infection, a bacterial infection, a thrombotic disorder or a clotting disorder, or a disorder of uncontrolled cellular proliferation The agents are described in detail herein. D. METHODS OF MAKING THE COMPOUNDS
  • a compound of Formula I in some embodiments, disclosed are methods of making a compound of Formula I.
  • Compounds according to the present disclosure can, for example, be prepared by the methods described herein.
  • a practitioner skilled in the art will understand the appropriate use of protecting groups [see: Greene and Wuts, Protective Groups in Organic Synthesis ] and the preparation of known compounds found in the literature using the standard methods of organic synthesis. There may come from time to time the need to rearrange the order of the recommended synthetic steps, however this will be apparent to the judgment of a chemist skilled in the art of organic synthesis.
  • the following examples are provided so that the subject matter described herein might be more fully understood, are illustrative only, and should not be construed as limiting.
  • the disclosed compounds comprise the products of the synthetic methods described herein. In some embodiments, the disclosed compounds comprise a compound produced by a synthetic method described herein. In some
  • the subject matter described herein comprises a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier.
  • the subject matter described herein comprises a method for manufacturing a medicament comprising combining at least one compound of any of disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.
  • the compounds and pharmaceutical compositions of the subject matter described herein are useful in treating or controlling a variety of disorders including, but not limited to, disorders of uncontrolled cellular proliferation such as, for example, cancer, infections such as, for example, a viral infection and a bacterial infection, and thrombotic disorders.
  • ligand-bound MerTK can complex with phosphatidyl serine and bind apoptotic cells, which triggers ingestion and suppression of inflammatory cytokines. It is aberrantly expressed in certain cancers (e.g., acute leukemia (ALL and AML)) and some solid tumors (e.g., breast cancer, colon cancer, non-small cell lung carcinoma, glioblastoma, and others).
  • ALL and AML acute leukemia
  • solid tumors e.g., breast cancer, colon cancer, non-small cell lung carcinoma, glioblastoma, and others.
  • the MerTK ligands include growth arrest-specific 6 protein (GAS6; Chen, et al; Oncogene (1997) 14, 2033-2039), protein-S, tubby and tubby-like protein- 1 (TULP1), and galectin-3.
  • GAS6 growth arrest-specific 6 protein
  • TULP1 tubby and tubby-like protein- 1
  • galectin-3 Several of these ligands are present in serum and expressed locally in a number of tissues. These ligands bind to the extracellular domain of MerTK, resulting in tyrosine kinase activation.
  • MerTK -/- knock-out mice are less susceptible to tumor growth than normal mice (Cook et al. (2013) J. Clin. Invest. 123: 3231-3242).
  • MerTK is normally expressed in myeloid lineage cells where it acts to suppress pro-inflammatory cytokines following ingestion of apoptotic material. It was found that MerTK -/- leukocytes exhibit lower tumor cell-induced expression of wound healing cytokines (IL-10 and GAS6) and enhanced expression of acute inflammatory cytokines (IL-12 and IL-6). Further, intratumoral CD8+ lymphocytes are increased. The loss of MerTK in the tumor
  • TAM receptor tyrosine kinases have been investigated for their involvement in certain infectious diseases. For example, Shimojima et al. reported the involvement of members of the Tyro3 receptor tyrosine kinase family, Axl, Dkt and MerTK, in the cell entry of filoviruses Ebola virus and Marburg virus, and concluded that each Tyro3 family member is likely a cell entry factor in the infection (Shimokima et al. (2006) Journal of Virology p. 10109- 10116). Additional diseases for which TAM receptor tyrosine kinases have been studied include, but are not limited to, microbial infections (U.S.
  • TAM (Tyro3-Axl-Mer) receptor tyrosine kinases have also been investigated for their involvement in platelet aggregation.
  • MerTK presumably through activation by its ligand Gas6, participates in the regulation of platelet function in vitro and platelet-dependent thrombosis in vivo (Chen et al. (2004 ) Arterioscler. Thrombosis Vase. Biol. 1118-1123). Chen reported that PtdSer on aggregating platelets activates MerTK, helping to stabilize clot formation.
  • MerTK knockout mice have decreased platelet
  • mice appear to be protected from thrombosis without concomitant increased spontaneous bleeding. See also, Angelillo-Scherrer et al. (2005) J. Clin. Invest. 115(2): 237-246).
  • MERTK and Axl dual inhibitors the normal roles of MERTK and AXL in preventing or terminating innate immune-mediated inflammation and natural killer (NK) cell responses are subverted in the tumor microenvironment. MERTK and AXL decrease NK cell antitumor activity, which paradoxically allows increased metastases.
  • AXL chemoresistance. Therefore, targeting AXL allowed for increased potency of small molecule MerTK inhibitors, both on its ability to decrease the activation of MERTK and downstream effectors, as well its ability to decrease proliferation and colony formation.
  • the cooperative relationship between MERTK and AXL, and coordinated regulation of expression has been demonstrated. Specifically, inhibition of either receptor increases expression of the other receptor. Additionally, MERTK and AXL are capable of physical interaction, suggesting that heterodimerization between MERTK and AXL may be a relevant mechanism of dual receptor activation. Targeting these two receptors concurrently provided synergistic decreases in oncogenic signaling, cell proliferation and colony formation.
  • Dual inhibition of MERTK and AXL may be a rational combination strategy that may have clinical utility against NSCLC and other solid tumors.
  • the compounds disclosed herein are useful for treating or controlling disorders of uncontrolled cellular proliferation, infections, and/or thrombotic or clotting disorders.
  • methods comprising administering a therapeutically effective amount of a disclosed compound or a composition comprising a disclosed compound to a subject.
  • the compounds disclosed herein are also useful as immunomodulatory or
  • a disorder associated with one or more of Mer tyrosine kinase, Tyro3 tyrosine kinase, and Axl tyrosine kinase comprising the step of
  • the method is treatment of a disorder associated with Mer tyrosine kinase.
  • a method wherein the disorder is a cancer, an infection, a fibrosis, a thrombotic disorder, a clotting disorder, or a disorder associated with an immunosuppressed microenvironment surrounding diseased tissue.
  • a method wherein the disorder is a cancer.
  • a method wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
  • a method wherein the tumor or cancer is MerTK +/+.
  • a method wherein the tumor or cancer is MerTK -/-.
  • a method wherein the dsorder is an infection.
  • a method wherein the infection is viral.
  • a method wherein the infection is bacterial.
  • a method wherein the disorder is a fibrosis.
  • the fibrosis is a liver fibrosis.
  • a method further comprising administering an additional active agent.
  • a method for inhibiting one or more of Mer tyrosine kinase, Tyro3 tyrosine kinase, and Axl tyrosine kinase, in at least one cell comprising the step of contacting the at least one cell with an effective amount of at least one compound of Formula I.
  • the method is a method for inhibiting Mer tyrosine kinase, in at least one cell, the method comprising the step of contacting the at least one cell with an effective amount of at least one compound of Formula I.
  • the mammal has been diagnosed with a need for treatement of a disorder related to Mer tyrosine kinase.
  • a disclosed compound or composition is capable of direct anti cancer effects by inhibiting Mer tyrosine kinase within tumor cells.
  • the cancer treated overexpresses MerTK.
  • the cancer which is a disclosed compound or composition is capable of direct anti cancer effects by inhibiting Mer tyrosine kinase within tumor cells.
  • the cancer treated overexpresses MerTK.
  • the cancer which is a disclosed compound or composition is capable of direct anti cancer effects by inhibiting Mer tyrosine kinase within tumor cells.
  • the cancer treated overexpresses MerTK.
  • MerTK is selected from the group consisting of acute myeloid leukemia, T-cell acute lymphoid leukemia, B-cell acute lymphoid leukemia, lung cancer, glioma, melanoma, prostate cancer, schwannoma, mantle cell lymphoma, and rhabdomyosarcoma.
  • the cancer ectopically expresses MerTK.
  • the cancer treated has a mutation in the amino acid sequence of the MerTK extracellular or transmembrane domain selected from P40S (melanoma),
  • the cancer treated has a mutation in the amino acid sequence of the MerTK cytosolic domain mutation selected from L586F (urinary tract), G594R (breast), S626C (urinary tract), P672S (lung), L688M (colon), A708S (head and neck), N718Y (lung), R722stop (colon), M790V (lung), P802S (melanoma), V873I Giver), S905F (lung), K923R (melanoma), P958L (kidney), D983N (liver), and D990N (colon).
  • a disclosed compound or composition is administered to a host with a cancer in combination with one or more additional chemotherapeutic agents, resulting in a synergistic anti-cancer effect and the prolonged survival of a host compared to treatment with either a compound described herein or chemotherapeutic agent alone.
  • the use of a Mer TKI compound described herein in combination with a chemotherapeutic agent provides for increased antitumor effects without an increase in the standard of care dosage of the chemotherapeutic agent.
  • the use of a Mer TKI compound described herein in combination with a chemotherapeutic provides for equivalent or increased anti-tumor effects utilizing a lower dosage of a chemotherapeutic agent than the standard of care dosage.
  • a disclosed compound or composition is provided for use in treating a non-small cell lung carcinoma (NSCLC).
  • a method is provided to treat a host with non-small cell lung carcinoma (NSCLC) comprising
  • a method is provided to treat a host with cancer comprising administering to the host an effective amount of a Mer TKI including active compounds of the presently described subject matter in combination with another tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is a fibroblast growth factor receptor (FGFR) inhibitor.
  • the FGFR inhibitor is AZD-4547.
  • the cancer is non-small cell lung carcinoma (NSCLC).
  • a method is provided to treat a host with non-small cell lung carcinoma (NSCLC) comprising administering to the host an effective amount of a Mer TKI including active compounds of the presently described subject matter in combination with an additional tyrosine kinase inhibitor, wherein the additional tyrosine kinase inhibitor is selected from the group consisting of gefitinib and crizotinib.
  • NSCLC non-small cell lung carcinoma
  • a disclosed compound or composition is provided for use in treating a melanoma.
  • the administration of the Mer TKI compound described herein is combined with a chemotherapeutic agent.
  • the chemotherapeutic agent is an anti-programmed cell death -1 (PD-l) agent.
  • the chemotherapeutic agent is a B-RAF inhibitor.
  • the B-RAF inhibitor is vemurafenib.
  • the host does not have a melanoma with a B-RAF mutation.
  • the host has a melanoma with a B-RAF mutation.
  • the host has a melanoma with a RAS mutation.
  • the melanoma over-expresses MerT.
  • the melanoma has metastasized.
  • a disclosed compound or composition is provided for use in treating Acute Lymphoblastic Leukemia (ALL).
  • a method is provided to, treat a host with ALL comprising administering to the host an effective amount of a disclosed compound or composition in combination with methotrexate.
  • a disclosed compound or composition is provided for use in treating Acute Myeloid Leukemia (AML).
  • AML contains a wild type FLT3 protein.
  • the replication of the AML cells are dependent on FLT3 expression.
  • the AML contains a FLT3-ITD mutation.
  • the AML contains a FLT3-TKD mutation.
  • the AML contains both a FLT3-ITD and FLT3-TKD mutation.
  • a FLT3 or dual MER/FLT3 inhibitor described herein is administered to a host suffering from AML, wherein the AML contains a mutation within the FLT3-TKD at amino acid F691 or D835.
  • a tumor survival-signal inhibiting amount for example 0.5 to 150 mg dose
  • a tumor survival-signal inhibiting amount for example 0.5 to 150 mg dose
  • a tumor survival-signal inhibiting amount for example, at least 150 mg/dose, and in some embodiments, at least 200, 250, 300, 350, 400, 450, or 500 mg/dosage or more
  • a tumor survival-signal inhibiting amount for example, at least 150 mg/dose, and in some embodiments, at least 200, 250, 300, 350, 400, 450, or 500 mg/dosage or more
  • the Mer TKI and the chemotherapeutic agent act synergistically.
  • the use of a Mer TKI in combination with a chemotherapeutic agent provides for increased anti-tumor effects without an increase in the standard of care dosage of the chemotherapeutic agent.
  • the use of a Mer TKI including compounds of the presently described subject matter in combination with a chemotherapeutic provides for equivalent or increased antitumor effects utilizing a lower dosage of a chemotherapeutic agent than the standard of care dosage.
  • the Mer TKI including compounds of the presently described subject matter can be administered to a host with a cancer prior to, during, or after administration with a chemotherapeutic agent or exposure to ionizing radiation.
  • a host is administered an effective amount of a chemotherapeutic agent or ionizing radiation and subsequently administered a Mer TKI.
  • a method is provided to treat a host with cancer comprising administering to the host an effective amount of a disclosed compound or composition in combination with an immunomodulatory agent.
  • the host an effective amount of a disclosed compound or composition in combination with an immunomodulatory agent.
  • immunomodulatory agent is selected from the group consisting of a CTLA-4 inhibitor, PD-l or anti -PD-l ligand, IFN-alpha, IFN-beta, and a vaccine, for example, a cancer vaccine.
  • a method is provided to treat a host with cancer comprising
  • a method is provided to treat a host with cancer comprising
  • a method is provided to treat a host with cancer comprising administering to the host an effective amount of a Mer TKI including active compounds of the presently described subject matter in combination with Yervoy® (ipilimumab).
  • a method is provided to treat a host with cancer comprising administering to the host an effective amount of a Mer TKI including active compounds of the presently described subject matter in combination with an immunomodulatory agent selected from the group consisting of pembrolizumab and ipilimumab, wherein the cancer is melanoma.
  • the Mer TK is useful in the presently described subject matter, including active compounds of the presently described subject matter, are dual MER/Tyro3 TKIs.
  • the Mer TKIs are dual Mer/Axl TKIs.
  • the Mer TKIs are dual Mer/Tyro3 TKIs.
  • the Mer TKIs are MER-specific TKIs.
  • the Mer TKIs are Tyro3 -specific TKIs.
  • the cancer treated can be a primary tumor or a metastatic tumor.
  • the methods described herein are used to treat a solid tumor, for example, melanoma, lung cancer (including lung adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, bronchiogenic carcinoma, non-small-cell carcinoma, small cell carcinoma, mesothelioma); breast cancer (including ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma, serosal cavities breast carcinoma); colorectal cancer (colon cancer, rectal cancer, colorectal adenocarcinoma); anal cancer; pancreatic cancer (including pancreatic adenocarcinoma, islet cell carcinoma, neuroendocrine tumors); prostate cancer; prostate adenocarcinoma; ovarian carcinoma (ovarian epithelial carcinoma
  • oropharyngeal squamous cell carcinoma salivary gland adenoid cystic carcinoma; bladder cancer; gastric cancer; bladder carcinoma; carcinoma of the uterus (including endometrial adenocarcinoma, ocular, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas, mixed mullerian tumors); glioma, glioblastoma, medulloblastotna, and other tumors of the brain; kidney cancers (including renal cell carcinoma, clear cell carcinoma, Wilm's tumor); cancer of the head and neck (including squamous cell carcinomas); cancer of the stomach (gastric cancers, stomach adenocarcinoma, gastrointestinal stromal tumor); testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumors including s
  • myofibroblastoma myofibroblastoma, fibromatosis, inflammatory myofibroblastic rumor, lipoma, angiolipoma, granular cell tumor, neurofibroma, schwannoma, angiosarcoma, liposarcoma,
  • rhabdomyosarcoma osteosarcoma, leiomyoma, leiomysarcoma, skin, including melanoma, cervical, retinoblastoma, head and neck cancer, pancreatic, brain, thyroid, testicular, renal, bladder, soft tissue, adenal gland, urethra, cancers of the penis, myxosarcoma,
  • lymphangiosarcoma mesothelioma, squamous cell carcinoma; epidermoid carcinoma, malignant skin adnexal tumors, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, hypernephroma, cholangiocarcinoma, transitional cell carcinoma,
  • choriocarcinoma seminoma, embryonal cell carcinoma, glioma anaplastic; glioblastoma multiforme,, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, pheochromocytoma, Islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell neoplasm, cystosarcoma phylloide, salivary cancers, thymic carcinomas, and cancers of the vagina among others.
  • a method is provided to treat a host with a glioblastoma comprising administering to the host an effective amount of a Mer TKI including active compounds of the presently described subject matter in combination with temozolomide. In some embodiments, a method is provided to treat a host with a breast cancer comprising administering to the host an effective amount of a Mer TKI including active compounds of the presently described subject matter in combination with trastuzumab.
  • the cancer is NSCLC. In some embodiments, the cancer is a melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a bone cancer. In some embodiments, the cancer is a brain cancer. In some embodiments, the cancer is a colon cancer. In some embodiments, the cancer is a rectal cancer. In some embodiments, the cancer is an endometrial cancer. In some embodiments, the cancer is an esophageal cancer. In some embodiments, the cancer is a cancer of the gastrointestinal tract. In some embodiments, the cancer is a kidney cancer. In some embodiments, the cancer is a liver cancer.
  • the cancer is a lung cancer. In some embodiments, the cancer is a mantle cell lymphoma. In some embodiments, the cancer is an ovarian cancer. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a pituitary cancer. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a skeletal muscle cancer. In some embodiments, the cancer is a skin cancer. In some embodiments, the cancer is a stomach cancer. In some embodiments, the cancer is a thyroid cancer. In some embodiments, the cancer is a neuroendocrine cancer. In some embodiments, the cancer is a gastroesophageal cancer. In some embodiments, the cancer is a renal cell cancer. In some embodiments, the cancer is a head and neck cancer.
  • the methods described herein are useful for treating a host suffering from a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality.
  • the Mer TKIs as described herein can be administered to a subject suffering from a Hodgkin Lymphoma of a Non-Hodgkin Lymphoma.
  • the subject can be suffering from a Non-Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic
  • Lymphoma Blastic NK-Cell Lymphoma; Burkitf s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy- Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone
  • Lymphoma Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; or Waldenstrom's Macroglobulinemia.
  • the subject may be suffering from a Hodgkin Lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin's Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.
  • CHL Nodular Sclerosis Classical Hodgkin's Lymphoma
  • Mixed Cellularity CHL Lymphocyte-depletion CHL
  • Lymphocyte-rich CHL Lymphocyte Predominant Hodgkin Lymphoma
  • Lymphocyte Predominant Hodgkin Lymphoma or Nodular Lymphocyte Predominant HL.
  • the methods as described herein may be useful to treat a host suffering from a specific T-cell, a B-cell, or a NK-cell based lymphoma, proliferative disorder, or abnormality.
  • the subject can be suffering from a specific T-cell or NK-cell lymphoma, for example, but not limited to: Peripheral T-cell lymphoma, for example, peripheral T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS); anaplastic large cell lymphoma, for example anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides, S zary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoprolife
  • ALK an
  • Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma; or Subcutaneous panniculitis-like T-cell lymphoma.
  • the subject may be suffering from a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa- Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; Mantle cell lymphoma (MCL); Burkitt lymphoma; Mediastinal large B cell lymphoma; Waldenstrom macroglobulinemia; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL);
  • a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa- Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; Mantle cell lymphoma (
  • Intravascular large B-cell lymphoma Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; Chronic ' lymphocytic leukemia/small lymphocytic lymphoma; B-cell prolymphocyte leukemia; Hairy cell leukemia Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy cell leukemia-variant;
  • Lymphoplasmacytic lymphoma Heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease; Plasma cell myeloma; Solitary plas acyto a of bone; Extraosseous plasmacytoma; Primary cutaneous follicle center lymphoma; T cell/histiocyte rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of - the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma; Large B-cell lymphoma arising in HHV8 -associated multicentric; Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell
  • the methods described herein can be used to a subject suffering from a leukemia.
  • the subject may be suffering from an acute or chronic leukemia of a lymphocytic or myelogenous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (A L); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); T- cell prolymphocyte leukemia (TPLL); large granular lymphocytic leukemia; or Adult T-cell chronic leukemia; large granular lymphocytic leukemia (LGL).
  • ALL Acute lymphoblastic leukemia
  • a L Acute myelogenous leukemia
  • CLL Chronic lymphocytic leukemia
  • CML Chronic
  • the methods described herein can be used to treat a host suffering from Acute Myeloid Leukemia (AML).
  • AML contains a wild type FLT3 protein.
  • the replication of the AML cells are dependent on FLT3 expression.
  • the AML contains a FLT3-ITD mutation.
  • the AML contains a FLT3-T D mutation.
  • the AML contains both a FLT3-ITD and FLT3-TKD mutation.
  • FLT3-ITD mutations are well known in the art.
  • FLT3-TKD mutations are also well known in the art.
  • a FLT3 or dual MER/FLT3 inhibitor is administered to a host suffering from AML, wherein the AML contains a mutation within the FLT3-TKD at amino acid F691 or D835.
  • the FLT3-TKD mutation is selected from D835H, D835N, D835Y, D835A, D835V, D835V, D835E, I836F, I836L, I836V, I836D, I836H, I836M, and F691L.
  • the host is suffering from the FLT3-TKD mutation D835Y.
  • the host is suffering from the FLT3-TKD mutation F691L.
  • the host is suffering from acute promyelocytic leukemia (a subtype of AML); a minimally differentiated AML (MO); myeloblastic leukemia (Ml;
  • acute promyelocytic leukemia a subtype of AML
  • MO minimally differentiated AML
  • Ml myeloblastic leukemia
  • the host is suffering from AML that has relapsed or become refractory to previous treatments. In some embodiments, the host has previously been treated with a FLT3 inhibitor or other chemotherapeutic agent.
  • the FLT3 inhibitors are efficacious against AML having both FLT3-ITD and FLT3-TKD mutations, wherein resistance to other FLT3 inhibitors, for example, AC220, has been established.
  • the host has an Acute Myeloid Leukemia (AML) comprising a FLT3 mutation, wherein the mutation confers resistance to a FLT3 inhibitor other than the FLT3 inhibitors described herein.
  • AML Acute Myeloid Leukemia
  • the host has an AML comprising a FLT3 mutation, wherein the mutation has conferred resistance to quizartinib (AC220) or other FLT3 inhibitor selected from lestaurtinib, sunitinib, sorafenib, tandutinib, midostaurin, amuvatinib crenolanib, dovitinib, ENMD-2076 (EntreMed), or KW-2449 (Kyowa Hakko Kirin), or a combination thereof.
  • CHEMOTHERAPEUTIC AGENTS Acute Myeloid Leukemia
  • an active compound or Mer TKI as described herein is used in combination or alternation with a chemotherapeutic agent.
  • agents may include, but are not limited to, tamoxifen, midazolam, letrozole, bortezomib, anastrozole, goserelin, an mTOR inhibitor, a PI3 kinase inhibitors, dual mTOR-PBK inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors, HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or a combination thereof).
  • mTOR inhibitors include but are not limited to rapamycin and its analogs, everolimus (Afmitor), temsirolimus, ridaforolimus, sirolimus, and
  • P13 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, PX-866, IPI-145, BAY 80-6946, BEZ235, RP6503, TGR 1202 (RP5264), MLN1117 (GNK1117), Pictilisib, Buparlisib, SAR245408 (XL147), SAR245409 (XL765), Palomid 529, ZSTK474, PWT33597, RP6530, CUDC-907, and AEZS-136.
  • Examples of MEK inhibitors include but are not limited to Trametinib,
  • the chemotherapeutic agent is an anti -programmed cell death -1 (PD-l) agent, for example, nivolumab, pembrolizumab, BMS936559,
  • the chemotherapeutic agent is a B-RAF inhibitor, for example, vemurafenib or sorafenib.
  • the chemotherapeutic agent is a FGFR inhibitor, for example, but not limited to, AZD4547, dovitinib, BGJ398, LY2874455, and ponatinib.
  • an active compound or Mer TKI as described herein is used in combination with crizotinib.
  • the additional therapeutic agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent.
  • Suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds.
  • General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or
  • Cerubidine® or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (El spar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP- 16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (IclusigTM).
  • chemotherapeutic agents include but are not limited to 1 -dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6- thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), anti-mitotic agents, cis- dichlorodiamine platinum (GG) (DDP) cisplatin), diamino-dichloro-platinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucovorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (CCNU),
  • Cyclophosphamide Cyclophosphamide, Cyclophosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), Daunorubicin HC1, Daunorubicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HC1, dronabinol, E.
  • Additional therapeutic agents that can be administered in combination with a compound disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, fmasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI- 522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN90l-DMl, atiprimod, natalizumab, bortezomib, carfilzomi
  • a FLT3 or dual Mer/FLT3 inhibitor described herein is used in combination with a chemotherapeutic agent for the treatment of AML.
  • chemotherapeutic agents may include, but are not limited to, cytarabine (ara-C), anthracycline drugs including but not limited to, daunorubicin, idarubicin; cladribine, fludarabine, Gleevec® (imatinib), Sprycel® (dasatinib), adriamycin, arsenic trioxide, cerubidine, clafen, cyclophosphamide, cytarabine, daunorubicin, doxorubicin, vincristine, and topotecan.
  • cytarabine ara-C
  • anthracycline drugs including but not limited to, daunorubicin, idarubicin; cladribine, fludarabine, Gleevec® (imatin
  • a FLT3 or dual Mer/FLT3 inhibitor described herein is used in combination with cytarabine.
  • a FLT3 or dual Mer/FLT3 inhibitor described herein is used in combination with an additional FLT3 inhibitor to treat with a host suffering from AML.
  • Additional FLT3 inhibitors for use in combination with the FLT3 or dual Mer/FLT3 inhibitors described herein include lestaurtinib, sunitinib, sorafenib, tandutinib, midostaurin, crenolanib, dovitinib, ENMD-2076 (Entremed), amuvatinib, or KW- 2449 (Kyowa Hakko Kirin).
  • a FLT3 or dual Mer/FLT3 inhibitor described herein is used in combination with a Ras inhibitor.
  • Ras inhibitors include but are not limited to Reolysin, FusOn-H2, and siG 12D LODER.
  • a FLT3 or dual Mer/FLT3 inhibitor described herein is used in combination with a Phosphoinositide 3 -kinase inhibitor (PI3K inhibitor).
  • PI3K inhibitors that may be used in the presently described subject matter are well known.
  • PI3K inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, AEZS-136, PX-866, IPI-145, RP6503, SAR245408 (XL147), duvelisib, GS-9820, GDC-0032 (2-[4-[2-(2-Isopropyl-5- methyl-l,2,4- triazol-3-yl)-5,6-dmydroimidazo[l,2-d][l,4]benzoxazepin-9-yl]pyrazol-l-yl]-2- methylpropanamide), MLN-1 1 17 ((2R)-l-Phenoxy-2-butanyl hydrogen (S)- methylphosphonate; or Methyl(oxo) ⁇ [(2R)-l-l
  • KTN-193 ((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H- pyrido[l,2- a]pyrimidin-9-yl)ethyI)amino)benzoic acid), TGR-1202/RP5264, GS-9820 ((S)- 1- (4-((2-(2- aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan- 1 -one), GS-1101 (5-fluoro- 3-phenyl-
  • a FLT3 or dual Mer/FLT3 inhibitor described herein is used in combination with a modulator of the STAT5 pathway.
  • Compounds which modulate the Janus Kinase 2 (JAK2) - Signal Transducer and Activator of Transcription 5 (STAT5) pathway include but are not limited to Lestaurtinib, Ruxolitinib, SB1518, CYT387, LY3009104, INC424, LY2784544, BMS-91 1543, NS-018, and TG101348.
  • a FLT3 or dual Mer/FLT3 inhibitor described herein is used in combination with an AKT inhibitor, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine.
  • AKT inhibitor including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine.
  • Active compounds as described herein used in a dosage for direct effect on the diseased cell can be used in combination with one or more immunotherapy agents for additive or synergistic efficacy against solid tumors.
  • a tumor associated macrophage MerT inhibiting amount of a Mer T J is used in combination or alternation with the immunomodulatory agent.
  • a host tumor survival- signal inhibiting, antiviral or antibacterial amount of a Mer T I is used in combination or alternation with the immunomodulatory agent.
  • Immunomodulators are small molecules or biologic agents that treat a disease by inducing, enhancing or suppressing the host's immune system.
  • one or more immunomodulators are selected that induce or enhance the host's immune system.
  • Some immunomodulators boost the host's immune system and others help train the host's immune system to better attack tumor cells.
  • Other immunomodulators target proteins that help cancer grow.
  • Antibodies are typically administered as monoclonals, although that is not required.“Naked monoclonal antibodies” work by attaching to antigens on tumor cells. Some antibodies can act as a marker for the body's immune system to destroy the tumor cells. Others block signaling agents for tumor cells. Antibodies can generally be used to bind to any signaling or metabolic agent that directly or indirectly facilitates tumor growth. Examples are alemtuzumab (Campath) which binds to CD52 antigen, and
  • trastuzumab (Herceptin), which binds to the HER2 protein.
  • an antibody can be used that is conjugated to another moiety that increases it delivery or efficacy.
  • the antibody can be connected to a cytotoxic drug or a radiolabel.
  • Conjugated antibodies are sometimes referred to as“tagged, labeled or loaded”.
  • Radiolabeled antibodies have small radioactive particles attached to them. Examples are Zevalin, which is an antibody against CD20 used to treat lymphoma.
  • Chemolabeled antibodies are antibodies that have cytotoxic agents attached to them.
  • Adcetris which targets CD30
  • Kadcyla which targets HER2.
  • Ontak while not an antibody, is similar in that it is interleukin-2 attached to a toxin from diphtheria.
  • cancer vaccine Another category of immunotherapy that can be used in the presently described subject matter is a cancer vaccine.
  • Most cancer vaccines are prepared from tumor cells, parts of tumor cells or pure antigens.
  • the vaccine can be used with an adjuvant to help boost the immune response.
  • An example is Provenge, which is the first cancer vaccine approved by the ETS FDA.
  • the vaccine can for example be a dendritic cell vaccine or a vector-based vaccine
  • Nonspecific tumor immunotherapies and adjuvants include compounds that stimulate the immune system to do a better job at attacking the tumor cells.
  • Such immunotherapies include cytokines, interleukins, interferons (a primarily but can be also b or g).
  • Specific agents include granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, IL-7, IL-21, drugs that target CTLA-4 (such as Yervoy, which is Ipilimumab) and drugs that target PD-l or PDL-l (such as for example, nivolumab (BMS), pembrolizumab (Merck), pidilizumab (CureTech/Teva), AMP -244 (Amplimmune/GSK), BMS-936559 (BMS), and MEDI4736 (Roche/Genentech)).
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-12 such as
  • thalidomide lenalidomide
  • Additional therapeutic agents that can be used in combination with the MerTK inhibitor include bispecific antibodies, chimeric antigen receptor (CAR) T-cell therapy and tumor-infiltrating
  • lymphocytes are lymphocytes.
  • a compound described herein can be combined with at least one immunosuppressive agent.
  • the immunosuppressive agent is preferably selected from the group consisting of a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
  • Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a SIP receptor modulator, e.g. fmgolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
  • Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, l5-deoxyspergualin, tresperimus,
  • Leflunomide ARAVA® CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3 lg, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti- LFA-l antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siphzumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, be
  • immunomodulatory agents that reverse the MerTK -induced suppression of proimflammatory cytokines such as wound healing cytokines (IL-10 and GAS6) and enhance the expression of acute inflammatory cytokines (IL-12 and IL-6).
  • IL-10 and GAS6 wound healing cytokines
  • IL-12 and IL-6 acute inflammatory cytokines
  • the pyrazolopyrimidine compounds can“re-normalize” or“re-program” the host microenvironment in the diseased tissue area to attack the diseased cells.
  • This immunostimulatory activity can be used therapeutically to treat a host with a tumor, cancer or other neoplasm, or alternatively, to treat a host with an infection, for example, a viral or bacterial infection.
  • a MERTK -negative (-/-) tumor or cancer may be used for the treatment of a MERTK -negative (-/-) tumor or cancer.
  • the cancer is a MERTK -negative (-/-) breast cancer. Therefore, as part of the subject matter described herein, one or more of the compounds disclosed herein can be used as adjunctive therapy for its immunostimulatory effect as a means to increase the efficacy of the antineoplastic standard of care therapies, such as chemotherapeutic compounds or radiation.
  • one or more of the compounds disclosed herein can be used as adjunctive therapy for its immunostimulatory effect as a means to increase the efficacy of the antiviral or antibacterial standard of care therapies.
  • a disclosed compound or composition is administered to a host in an immunomodulatory effective amount to inhibit Mer tyrosine kinase activity in the host's tumor associated macrophage to suppress tumor immunity.
  • the dosage of the Mer TKI administered as an immunomodulatory agent to stimulate innate anti-tumor immunity is lower than a dosage of a Mer TKI administered to a host as a direct anti-cancer agent.
  • the Mer TKI is administered at a dosage which exhibits immunomodulatory but not direct cytotoxic effect.
  • the cancer is a MERTK -negative (-/-) cancer.
  • chemotherapeutic agent results in the apoptosis of tumor cells, exposing antigenic tumor proteins.
  • the host's innate immune system is thus stimulated to recognize the antigenic apoptotic components from the tumor cells after chemotherapy or ionizing radiation and mount an immune response.
  • the administration of a chemotherapeutic agent results in the apoptosis of tumor cells, exposing antigenic tumor proteins.
  • the host's innate immune system is thus stimulated to recognize the antigenic apoptotic components from the tumor cells after chemotherapy or ionizing radiation and mount an immune response.
  • the administration of a chemotherapeutic agent results in the apoptosis of tumor cells, exposing antigenic tumor proteins.
  • the host's innate immune system is thus stimulated to recognize the antigenic apoptotic components from the tumor cells after chemotherapy or ionizing radiation and mount an immune response.
  • the administration of a chemotherapeutic agent results in the apoptosis of tumor cells, exposing antigenic tumor proteins.
  • chemotherapeutic agent or ionizing radiation before, with or subsequently followed by the administration of a Mer TKI is carried out using the normal standard of care
  • the standard of care protocol of the chemotherapeutic is changed in a manner that causes less toxicity to the host due to the adjunctive or synergistic activity of the Mer TKI.
  • a method for the treatment of a tumor includes administering an effective amount of a Mer TKI to inhibit TK signaling in a tumor associated macrophage, without inhibiting the survival signal in the tumor itself.
  • the Mer TKI can be used to ramp up the immune response to the tumor by inhibiting macrophage tumorogenic tolerance during normal tumor chemotherapeutic agent.
  • the immunomodulatory dosage of the Mer TKI can be given prior to, with or after chemotherapeutic therapy and can be used simultaneously with or intermittently with the chemotherapeutic therapy.
  • less chemotherapeutic therapy is needed than the normal standard of care defined for that chemotherapeutic agent, due to the increased efficacy of the immune response in the surrounding tumor microenvironment.
  • a dose of Mer TKI including active compounds of the presently described subject matter is given as a type of adjunctive therapy with the chemotherapeutic agent.
  • a Mer TKI is
  • the dosage of the Mer TKI administered as an immunomodulatory agent to stimulate innate anti-tumor immunity is lower than a dosage of a Mer TKI adniinistered to a host as a direct anti -cancer agent.
  • the Mer TKI is administered at a dosage which exhibits immunomodulatory but not direct cytotoxic effects on the cancer.
  • the dose associated with the immunomodulatory effect of an active compound of the presently described subject matter is about 2-fold, about 3 -fold, about 4-fold, about 5- fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10- fold or greater lower than the dose associated with a direct survival -signal inhibiting anti tumor or cytotoxic effect, or the direct antiviral or antibacterial effect.
  • the dose used to induce an immunomodulatory effect in a host is between about 0.5 mg and about 150 mg.
  • the dose is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 125 mg, about 140 mg, or about 150 mg.
  • an effective amount of a disclosed compound or composition can be administered as an immunomodulatory agent to stimulate the innate immune system.
  • This immunostimulatory activity can be used therapeutically to treat a host with an infection.
  • the infection is a viral infection.
  • the infection is a bacterial infection.
  • an effective amount of a disclosed compound or composition can be used to treat a host bearing any virus-related infection where the virus has a virion envelope phosphatidyl serine that complexes with MerTK to achieve viral entry or is otherwise facilitated by MerTK in the infectious process or maintenance.
  • the virus may be an enveloped virus or a non-enveloped virus.
  • the host is infected or threatened to become infected with a virus selected from, for example, Flaviviridae viruses, including Flavivirus (such as Yellow Fever, West Nile and Dengue), Hepacivirus (Hepatitis C virus,“HCV”), Pegivirus and Pestivirus (Bovine viral diarrhea virus); Filoviridae viruses, including Ebola viruses; Togaviridae viruses, including
  • Chikungunya virus Chikungunya virus; Coronaviruses, such as SARS (Severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome); Orthomyxoviridae viruses, for example influenza; Paramyxoviridae viruses, for example Respiratory syncytial virus (RSV), measles and mumps; and Caliciviridae viruses, including Lagovirus, Vesivirus, and Sapovirus and Norovirus (Norwalk-like virus), and Lentiviruses, for example, HIV.
  • an active compound disclosed herein is administered in combination or alternation with another anti-viral agent for combination therapy.
  • the host to be treated may be infected with an enveloped virus including, but not limited to, viruses of the following families: Bomaviridae, Bunyaviridae, Coronaviridae, Filoviridae, Flaviridae, Hepadnaviridae, Herpesviridae, Nyamiviridae, Orthomyxoviridae, Paramyxoviridae, Poxyiridae, Retroviridae, Rhabdoviridae, and
  • viruses form the Bunyaviridae family include, but are not limited to, bunya viruses such as La Crosse virus and Hantaan.
  • viruses from the Coronaviridae family include, but are not limited to, coronaviruses such as SARS virus or Toroviruses.
  • viruses from the Filoviradae family include, but are not limited to, Ebola and Marburg.
  • viruses from the Flaviridae family include, but are not limited to, dengue, encephalitis viruses including West Nile virus, Japanese encephalitis virus and yellow fever virus and Hepatitis C virus.
  • viruses from the Hepadnaviridae family include, but are not limited to, Hepatitis B. Examples of viruses from the
  • Herpesviridae family include, but are not limited to, cytomegalovirus, herpes simplex viruses 1 and 2, HHV-6, HHV-7, HHV-8, pseudorabies virus, and varicella zoster virus.
  • viruses from the Orthomyxoviridae family include, but are not limited to, influenza virus.
  • viruses from the Para yxoviridae family include, but are not limited to, measles, metapneumovirus, mumps, parainfluenza, respiratory syncytial virus, and sendai.
  • viruses from the Poxviridae family include, ' but are not limited to, pox viruses such as smallpox, monkey pox, and MoUuscum contagiosum virus, variola viruses, vaccinia virus, and yatapox viruses such as Tanapox and Yabapox.
  • viruses from the Retroviridae family include, but are not limited to, Coltiviruses such as CTFV and Banna virus, human immunodeficiency viruses such as HIV-l and HTV-2, murine leukemia virus, simian immunodeficiency virus, feline immunodeficiency virus, human T-cell leukemia viruses 1 and 2, and XMRV.
  • viruses from the Rhabdoviridae family include, but are not limited to, vesicular stomatitis and rabies.
  • viruses from the Togaviridae family include, but are not limited to, rubella viruses or alpha viruses such as Chikungunya virus, Eastern equine encephalitis virus, O'nyong'nyong virus, Ross River virus, Semliki Forest virus, Sindbis, Venezuelan equine encephalitis or Western equine encephalitis virus.
  • the host is infected with Chikungunya virus. In some embodiments, the host is infected with Ebola virus. In some embodiments, an active compound or Mer TKI as described herein is used in combination with brincidofovir
  • the host is infected with a non-enveloped virus, sch as, but not limited to, viruses of the following families: Adenoviridae, Arenaviridae, Bimaviridae, Calciviridae, Iridoviridae, Ophioviridae Parvoviradae, Papillomaviridae, Papovaviridae, Picornaviridae, and Reoviridae.
  • viruses from the Adenoviridae family include, but are not limited to adenoviruses.
  • viruses from the Arenaviradae family include, but are not limited to, hemorrhagic fever viruses such as Guanarito, LCMV, Lassa, Junin, and Machupo.
  • viruses from the Iridoviridae family include, but are not limited to, African swine fever virus.
  • viruses from the Papillomavirus family include, but are not limited to, papillomaviruses.
  • viruses from the Papovaviridae family include, but are not limited to, polyoma viruses such as BK virus and JC virus.
  • viruses from the Parvoviridae family include, but are not limited to,
  • parvoviruses such as human bocavirus and adeno-associated virus.
  • viruses from the Picornaviridae family include, but are not limited to, aptoviruses, cardioviruses, coxsackieviruses, echoviruses, enteric viruses, enteroviruses, foot and mouth disease virus, hepatitis A virus, hepatoviruses, Poliovirus, and rhinovirus.
  • viruses from the Reoviradae family include, but are not limited to, orbiviruses, reoviruses and rotaviruses.
  • a host is infected with a virus such as an astroviruses, caliciviruses including but not limited to, Norovirus and Norwalk, and Hepeviruses including, but not limited to, Hepatitis E.
  • a virus such as an astroviruses, caliciviruses including but not limited to, Norovirus and Norwalk, and Hepeviruses including, but not limited to, Hepatitis E.
  • a compound described herein can be administered to a host suffering from a viral infection in combination with another anti-viral or anti-infective compound.
  • Antiviral compounds that can be used in combination with the compounds described herein include, but are not limited to, abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbitol, atazanavir, balavir, boceprevir, boceprevirertet, cidofovir, dolutegravir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, epivir, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imi
  • a host is infected with a human immunodeficiency virus and is administered a compound described herein in combination with the anti-HIV combination drug, such as Atripla® or other drug that includes emtricitabine.
  • the patient with the human immunodeficiency virus can be treated with atazanavir, ritonavir, or Truvada® in combination with a compound described herein.
  • the patient infected with human immunodeficiency virus can be treated with the combination of dolutegravir, Truvada® and a compound described herein.
  • human immunodeficiency virus can be treated with the combination dolutegravir, Epzicom® and a compound described herein.
  • a host infected with human immunodeficiency virus can be treated with atazanavir, ritonavir, or Truvada® in combination with a compound described herein.
  • the patient infected with human immunodeficiency virus can be treated with the combination of dolutegravir, Truvada® and a compound described herein
  • immunodeficiency virus can be treated with a combination of raltegravir, Truvada® and a compound described herein.
  • immunodeficiency virus can be treated with the combination of Complera® and a compound described herein. It will be appreciated by one skilled in the art that a host infected with HIV can be treated with a number of combinations of drugs depending on the mutation pattern of the virus. The patient can be treated with an appropriate combination of drugs in combination with a compound described herein.
  • the host is infected with a hepatitis C virus and is treated with an anti -hepatitis C drug in addition to the active compound described herein.
  • the patient can be treated with a combination of SovaldiTM, Harvoni®, ribavirin, and/or a pegylated interferon and a compound described herein.
  • the pegylated interferon is Peglntron®.
  • the pegylated interferon is Pegasys®.
  • the host infected with hepatitis C virus is treated with SovaldiTM, ribavirin and a compound described herein.
  • the host infected with hepatitis C virus is treated with Harvoni®, ribavirin and a compound described herein.
  • a host infected with hepatitis C virus is treated with a combination of OlysioTM, ribavirin, a pegylated interferon and a compound described herein.
  • the pegylated interferon is Peglntron®. In some embodiments, the pegylated interferon is Pegasys®.
  • the host is infected with a hepatitis C virus and is treated with a combination of ABT-267, ABT-333 and ABT-450/ritonavir, in addition to an active compound described herein. In some embodiments, the host is infected with a hepatitis C virus and is treated with a combination of MK-5172 and MK-8742, in addition to an active compound described herein.
  • a host infected with hepatitis C genotype 1 is treated with a combination of SovaldiTM, ribavirin, a pegylated interferon and a compound described herein for 12 weeks.
  • a host infected with hepatitis C genotype 1 is treated with SovaldiTM and a compound described herein for 12 weeks followed by ribavirin, pegylated interferon and a compound described herein for 24 weeks.
  • a host infected with hepatitis C genotype 2 is treated with SovaldiTM, ribavirin, and a compound described herein for 12 weeks.
  • a host infected with hepatitis C genotype 3 is treated with SovaldiTM, ribavirin, and a compound described herein for 24 weeks.
  • a host infected with hepatitis C genotype 3 is treated with SovaldiTM, ribavirin, pegylated interferon, and a compound described herein for 12 weeks.
  • a host infected with hepatitis C genotype 4 is treated with SovaldiTM, ribavirin, pegylated interferon, and a compound described herein for 12 weeks.
  • a host infected with hepatitis C genotype 4 is treated with a combination of OlysioTM, and a compound described herein for 12 weeks followed by ribavirin, pegylated interferon and a compound described herein for 24-28 weeks.
  • a host infected with hepatitis C genotype 5 is treated with SovaldiTM, ribavirin, pegylated interferon, and a compound described herein for 12 weeks.
  • a host infected with hepatitis C genotype 5 is treated with ribavirin, pegylated interferon, and a compound described herein for 48 weeks.
  • a host infected with hepatitis C genotype 6 is treated with SovaldiTM, ribavirin, pegylated interferon, and a compound described herein for 12 weeks. In some embodiments, a host infected with hepatitis C genotype 6 is treated with ribavirin, pegylated interferon, and a compound described herein for 48 weeks.
  • a host infected with hepatitis C genotype 1 is treated with Sovaldi , Olysio , ribavirin, and a compound described herein for 12 weeks.
  • a host infected with hepatitis C genotype 1 is treated with SovaldiTM, ribavirin, and a compound described herein for 24 weeks.
  • a host infected with hepatitis C genotype 2 is treated with SovaldiTM, ribavirin, and a compound described herein for 12 weeks.
  • a host infected with hepatitis C genotype 3 is treated with SovaldiTM, ribavirin, and a compound described herein for 24 weeks.
  • a patient infected with hepatitis C genotype 4 is treated with SovaldiTM, ribavirin, and a compound described herein for 24 weeks.
  • a host infected with papilloma virus is treated with imiquimod and a compound described herein.
  • a host infected with papilloma virus is treated with cryotherapy and a compound described herein.
  • papilloma virus is surgically removed from a host and the host is treated with a compound described herein. Jn some embodiments, the host receives a compound described herein prior to, during, and post-surgery. In some embodiments, the patient receives a compound described herein post-surgery.
  • a host infected with herpes simplex type 2 is treated with Famvir® and a compound described herein.
  • a host infected with herpes simplex type 1 is treated with acyclovir and a compound described herein.
  • a host infected with herpes simplex type 2 is treated with acyclovir and a compound described herein.
  • a host infected with herpes simplex type 1 is treated with Valtrex® and a compound described herein.
  • a host infected with herpes simplex type 2 is treated with Valtrex® and a compound described herein.
  • a host infected with herpes simplex type 1 virus receives a compound described herein for 7 days prior to'treatment with acyclovir.
  • a host infected with herpes simplex type 2 virus receives a compound described herein for 7 days prior to treatment with acyclovir. In some embodiments, a host infected with herpes simplex type 1 virus receives a compound described herein for 7 days prior to treatment with Valtrex®. In some embodiments, a host infected with herpes simplex type 2 virus receives a compound described herein for 7 days prior to treatment with
  • a host infected with varicella zoster virus, VZV is treated with acyclovir and a compound described herein. In some embodiments a host infected with varicella zoster virus, VZV, is treated with Valtrex® and a compound described herein. In some embodiments ahost infected with varicella zoster virus, VZV, is treated with famciclovir and a compound described herein. In some embodiments a host infected with varicella zoster virus, VZV, is treated with foscamet and a compound described herein.
  • a host infected with varicella zoster virus is treated with a compound described herein prior to vaccination with Zostavax®. In some embodiments, a host infected with varicella zoster virus is treated with a compound described herein prior to and post vaccination with Zostavax®.
  • a host infected with influenza virus is treated with Relenza® and a compound described herein. In some embodiments a host infected with influenza virus is treated with Tamiflu® and a compound described herein. In some embodiments a host is infected with influenza virus and is treated with amantadine and a compound described herein. In some embodiments, a host infected with influenza virus is treated with rimantadine and a compound described herein.
  • a hostinfected with cytomegalovirus is treated with valganciclovir and a compound described herein. In some embodiments, a host infected with cytomegalovirus is treated with ganciclovir and a compound described herein. In some embodiments, a host infected with cytomegalovirus is treated with foscarnet and a compound described herein. In some embodiments, a host infected with cytomegalovirus is treated with cidofovir and a compound described herein.
  • a host infected with hepatitis B virus is treated with lamivudine and a compound described herein. In some embodiments, a host infected with hepatitis B virus is treated with adefovir and a compound described herein.
  • a host infected with hepatitis B virus is treated with tenofovir and a compound described herein. In some embodiments, a host infected with hepatitis B virus is treated with telbivudine and a compound described herein.
  • a disclosed compound or composition is used in an effective amount to treat a host infected with a bacterial infection.
  • the bacteria treated is, for example, a Gram-negative bacilli (GNB), especially Escherichia coli, Gram positive cocci (GPC), Staphylococcus aureus, Enterococcus faecalis, or Streptococcus pneumoniae.
  • GNB Gram-negative bacilli
  • the bacterial infection may be caused, for example, by a Gram-negative bacteria, including, but not limited to Escherichia coli, Salmonella, and other Enterobacteriaceae, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas,
  • Bdellovibrio acetic acid bacteria, Legionella, Staphylococcus aureus, Hemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa, Vibrio cholerae, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens, Clostridium tetani, Helicobacter pylori, Salmonella enteritidis, Salmonella typhi, Shigella flexneri, or Acinetobacter baumanii.
  • the bacterial infection may be caused, for example, by a Gram-positive species from the following genera: Bacillus, Listeria, Staphylococcus, Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pedicoccus, Streptococcus, Acetobacterium, Clostridium, Eubacterium, Heliobacterium, Heliospirillum, Megasphaera, Pectinatus, Selenomonas, Zymophilus, Sporomusa, Mycoplasma, Spiroplasma, ETreaplasma, or Erysipelothrix.
  • a Gram-positive species from the following genera: Bacillus, Listeria, Staphylococcus, Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pedicoccus, Streptococcus, Acetobacterium, Clostridium, Eubacterium, Heliobacterium, Heliospirillum, Megasphaera, Pec
  • the bacterial infection is associated with liver failure.
  • an active compound disclosed herein is administered in combination with an antibiotic or another anti -bacterial agent.
  • the bacterial infection is associated with liver failure.
  • an active compound disclosed herein is administered in combination with an antibiotic or another anti -bacterial agent.
  • a patient is suffering from acute-on-chronic liver failure (ACLF).
  • ACLF acute-on-chronic liver failure
  • a patient is suffering from acute liver failure.
  • a patient is suffering from chronic liver failure.
  • the liver failure is caused by a disease or condition selected from alcoholic liver disease, chronic viral hepatitis type C, chronic viral hepatitis type B, chronic bile duct blockage, Wilson's disease, hemochromatosis, exposure to drug and toxins, autoimmune hepatitis, cystic fibrosis, alpha antitrypsin deficiency, obesity or schistosomiasis.
  • the fibrosis is a liver fibrosis.
  • an active compound disclosed herein is administered in combination with an antibiotic for the prevention or treatment of bacterial infections.
  • antibiotics include, but are not limited to, cefotaxime (Claforan), ofloxacin (Floxin), norfloxacin (Noroxin) or trimethoprim sulfamethoxazole (Bactrim, Septra). d. USE AS AN ANTI-PLATELET AGENT
  • a compound described herein is used in the treatment of blot clot (thrombus) formation in a host in need thereof.
  • the host is suffering from coronary artery disease, peripheral vascular disease, or cerebrovascular disease.
  • a compound described herein is administered to a host prior to any medical or surgical procedure in which diminished coagulation potential is desirable.
  • an active compound disclosed herein is administered in combination with another anti -thrombotic or anti -clotting agent.
  • a disclosed compound or composition as described herein is provided for use in treating blot clot (thrombus) formation in a subject in need thereof, comprising administering an active compound as described herein, or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
  • the treatment of blood clot formation is in, for example, a subject with coronary artery disease, peripheral vascular disease, or cerebrovascular disease, or the treatment is given prior to any medical or surgical procedure in which diminished coagulation potential is desirable.
  • Coronary artery disease includes, for example, any coronary dysfunction (pathological state) resulting from coronary artherosclerosis, i.e. partial or total occlusion of coronary vessels.
  • the term also includes a range of various acute and chronical pathological states comprising stable and unstable angina pectoris (SAP and UAP, respectively), left ventricular dysfunction LVD, (congestive) heart failure CHF, myocardial death.
  • Peripheral vascular disease includes, for example, occlusive or functional peripheral arterial disease (PAD).
  • occlusive PAD examples include peripheral arterial occlusion, which may be acute, and Buerger's disease (thomboangiitis obliterans).
  • functional PAD examples include Raynaud's disease, Raynaud's phenomenon, and acrocyanosis.
  • Cerebrovascular disease includes, for example, any abnormality of the brain resulting from a pathologic process of a blood vessel.
  • the cerebrovascular disease is selected from cerebral ischemia, cerebral hemorrhage, ischemic stroke, hemorrhagic stroke, or ischemic reperfusion injury resulting from reintroduction of blood flow following cerebral ischemia or ischemic stroke.
  • the medical or surgical procedure is pulmonary vein ablation.
  • the treatment of blood clot formation is in a host having thrombi in blood vessels from pathologies or treatments including, for example, myocardial infarction, unstable angina, atrial fibrillation, stroke, renal damage, percutaneous
  • the compounds described herein are administered to a host having blood clots on the surfaces of artificial organs, shunts and prostheses (for example, artificial heart valves that are implanted into a patient), and in patients that have received an intracoronary stent.
  • a host is administered an effective amount of a compound described herein due to the formation of clots resulting from some pathological conditions (for example, genetic mutation of VWF cleaving protease, ADAMT13), which may cause spontaneous binding of VWF to platelets resulting in formation of microthrombi in blood vessels leading to thrombotic
  • Microangiopathy is a disease of blood vessels in which the walls of very small blood vessels (capillaries) become so thick and weak that they bleed, leak protein, and slow the flow of blood.
  • the treatment is in a patient with hemolytic uremic syndrome.
  • an active compound disclosed herein is administered in combination with an additional anti-platelet agent.
  • anti-platelet agents include, but are not limited to, aspirin, tirofiban (Aggrastat), Aggrenox, Agrylin, triflusal (Disgren), Flolan, eptifibatide (Integrilin), dipyridamole (Presantine), cilostazol (Pletal), abciximab (ReoPro), and Terutroban.
  • the Mer TKI and the additional anti platelet agent act synergistically.
  • the use of a Mer TKI in combination with an additional anti-platelet agent provides for increased anti -thrombotic or anti-clotting effects without an increase in the standard of care dosage.
  • the additional anti-platelet agent is an adenosine diphosphate (ADP) receptor inhibitor.
  • ADP receptor inhibitors include, but are not limited to, clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), ticlopidine (Ticlid), N6- methyl-2'-deoxyadenosine-3',5'-bisphosphate (MRS2179; P 2 Yl inhibitor), and 2- methylthioadenosine 5 '-monophosphate triethylammonium salt (2-Me-SAMP; P 2 Yl2 inhibitor).
  • an active compound disclosed herein is administered in combination with multiple anti-platelet agents. In some embodiments, an active compound disclosed herein is administerd in combination with N6-methyl-2'- deoxyadenosine-3',5'- bisphosphate and 2-methylthioadenosine 5 '-monophosphate triethylammonium salt.
  • an active compound disclosed herein is administered in combination with an anti -coagulant.
  • the anti-coagulant is a heparin composition.
  • the heparin composition is a low molecular weight heparin composition.
  • Low molecular weight heparin compositions are well known to those of skill in the art and include, but are not limited to, tinzaparin, certoparin, pamaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, and fraxiparin. Additional examples of anticoagulants include, but are not limited to, warfarin (Coumadin), Fragmin, Hep-Lock, Lovenox, and Miradon. e. USE AS NANOPARTICLE COMPOSITIONS OR CARRIERS
  • an effective amount of an active compound as described herein is incorporated into nanoparticles, e.g. for convenience of delivery and/or extended release delivery.
  • the use of materials in nanoscale provides one the ability to modify fundamental physical properties such as solubility, diffusivity, blood circulation half- life, drug release characteristics, and immunogenicity.
  • nanoparticle-based therapeutic and diagnostic agents have been developed for the treatment of cancer, diabetes, pain, asthma, allergy, and infections. These nanoscale agents can provide more effective and/or more convenient routes of administration, lower therapeutic toxicity, extend the product life cycle, and ultimately reduce health-care costs.
  • nanoparticles allow targeted delivery and controlled release.
  • nanoparticle-based drug delivery can be used to release drugs at a sustained rate and thus lower the frequency of administration, deliver drugs in a target manner to minimize systemic side effects, or deliver two or more drugs simultaneously for combination therapy to generate a synergistic effect and suppress drug resistance.
  • nanotechnology -based therapeutic products have been approved for clinical use.
  • liposomal drugs and polymer-based conjugates account for more than 80% of the products. See, Zhang, L., et al., Nanoparticles in Medicine: Therapeutic
  • Optimal solid lipid nanoparticles can be produced in a controlled fashion when a fraction of lipid in the crystalline alpha form can be created and preserved.
  • the SLN carrier has a built in trigger mechanism as lipids transform from the alpha to beta form and consequently control drug release.
  • Drug release profiles can be modified according to the composition of the lipid matrix, surfactant concentration and production parameters. See, Muller, R.H., et al., Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art, Eur. H. Pharm. Biopharm., 50: 161-177, 2000. Consien et al.
  • lipid nanoparticles having novel amino-lipids that form lipid nanoparticles and their use for the intracellular delivery of biologically active compounds, e.g., nucleic acids. See, US 8,691,750 to Consien et al.
  • Kanwar has recently disclosed alginate adsorbed chitosan adsorbed lactoferrin adsorbed calcium phosphate nanoparticles and the controlled release of lactoferrin from the nanoparticles. See, WO 2012/145801 to Kanwar.
  • Armes et al. have recently disclosed polymer-templated core-shell nanoparticles adapted to facilitate controlled release of at least one active agent into a system in response to controlled changes in the pH of the system. See, US 8,580,311 to Armes, S. et al. incorporated by reference herein.
  • Nanoparticles may be prepared using a wide variety of methods known in the art.
  • nanoparticles can be formed by methods as nanoprecipitation, flow focusing fluidic channels, spray drying, single and double emulsion solvent evaporation, solvent extraction, phase separation, milling, microemulsion procedures, microfabrication, nanofabrication, sacrificial layers, simple and complex coacervation, and other methods well known to those of ordinary skill in the art.
  • aqueous and organic solvent syntheses for monodisperse semiconductor, conductive, magnetic, organic, and other nanomaterials have been described (Pellegrino et ah, 2005, Small, 1 :48; Murray et al., 2000, Ann. Rev. Mat.
  • Nanoparticles may comprise natural polymers, including but not limited to chitosan, alginate, dextran, gelatin, and albumin, and synthetic polymers such as, but not limited to, poly(lactide-co-glycolide) (PLGA), (3- hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(sebacic anhydride), poly(e- caprolactone), polystyrene, thermoresponsive (i.e., NIPAAm and CMCTS-g-PDEA) and pH- responsive (i.e., Eudragit LI 00, Eudragit S and AQOAT AS-MG) polymers.
  • PLGA poly(lactide-co-glycolide)
  • PHBV 3- hydroxybutyrate-co-3-hydroxyvalerate)
  • PHBV poly(sebacic anhydride)
  • poly(e- caprolactone) polystyrene
  • thermoresponsive i.e., NIPAAm and CMCTS-g
  • the polymeric particle is between about 0.1 nm to about 10000 nm, between about 1 nm to about 1000 nm, between about 10 nm and 1000 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm.
  • the micro-particles are about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm,
  • the compounds described herein are covalently coupled to a polystyrene particle, PLGA particle, PLA particle, or other nanoparticle.
  • the nanoparticle can be solid or hollow and can comprise one or more layers. In some embodiments, each layer has a unique composition and unique properties relative to the other layer(s).
  • the nanoparticle may have a core/shell structure, wherein the core is one layer (e.g. a polymeric core) and the shell is a second layer (e.g. a lipid bilayer or monolayer). In some embodiments, the nanoparticle may comprise a plurality of different layers. In some embodiments, the compounds described herein can be incorporated into or surrounded by one or more layers.
  • the nanoparticles comprising the compounds described herein may optionally comprise one or more lipids.
  • a nanoparticle may comprise a liposome.
  • a nanoparticle may comprise a lipid bilayer.
  • a nanoparticle may comprise a lipid monolayer.
  • a nanoparticle may comprise a micelle.
  • a nanoparticle may comprise a core comprising a polymeric matrix surrounded by a lipid layer (e.g., lipid bilayer, lipid monolayer, etc.).
  • a nanoparticle may comprise a non-polymeric core (e.g., metal particle, quantum dot, ceramic particle, bone particle, viral particle, proteins, nucleic acids, carbohydrates, etc.) surrounded by a lipid layer (e.g., lipid bilayer, lipid monolayer, etc.).
  • a non-polymeric core e.g., metal particle, quantum dot, ceramic particle, bone particle, viral particle, proteins, nucleic acids, carbohydrates, etc.
  • lipid layer e.g., lipid bilayer, lipid monolayer, etc.
  • the nanoparticle may comprise metal particles, quantum dots, ceramic particles, etc.
  • a non-polymeric nanoparticle is an aggregate of non-polymeric components, such as an aggregate of metal atoms (e.g., gold atoms).
  • nanoparticles may optionally comprise one or more
  • amphiphilic entities can promote the production of nanoparticles with increased stability, improved uniformity, or increased viscosity.
  • amphiphilic entities can be associated with the interior surface of a lipid membrane (e.g., lipid bilayer, lipid monolayer, etc.).
  • lipid membrane e.g., lipid bilayer, lipid monolayer, etc.
  • amphiphilic entities known in the art are suitable for use in making nanoparticles useful in the presently described subject matter. Such amphiphilic entities include, but are not limited to,
  • phosphoglycerides phosphatidylcholines; dipalmitoyl phosphatidylcholine (DPPC); dioleylphosphatidyl ethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol;
  • DPPC dipalmitoyl phosphatidylcholine
  • DOPE dioleylphosphatidyl ethanolamine
  • DOTMA dioleyloxypropyltriethylammonium
  • diacylglycerolsuccinate diphosphatidyl glycerol (DPPG); hexanedecanol
  • fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether
  • a surface active fatty acid such as palmitic acid or oleic acid
  • fatty acids fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate (Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60);
  • polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85 (Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol;
  • sphingomyelin phosphatidylethanolamine (cephalin); cardiolipin; phosphatide acid;
  • amphophilic entity component may be a mixture of different amphophilic entities. Those skilled in the art will recognize that this is an exemplary, not comprehensive, list of substances with surfactant activity. Any amphiphilic entity may be used in the production of nanoparticles to be used in accordance with the presently described subject matter.
  • a nanoparticle may optionally comprise one or more carbohydrates.
  • Carbohydrates may be natural or synthetic.
  • a carbohydrate may be a derivatized natural carbohydrate.
  • a carbohydrate comprises monosaccharide or disaccharide, including but not limited to glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose, xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid, glucosamine, galatosamine, and neuramic acid.
  • a carbohydrate is a polysaccharide, including but not limited to pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (C), dextran, cyclodextran, glycogen,
  • the nanoparticle does not comprise (or specifically exclude) carbohydrates, such as a polysaccharide.
  • the carbohydrate may comprise a carbohydrate derivative such as a sugar alcohol, including but not limited to mannitol, sorbitol, xylitol, erythritol, maltitol, and - lactitol.
  • a carbohydrate derivative such as a sugar alcohol, including but not limited to mannitol, sorbitol, xylitol, erythritol, maltitol, and - lactitol.
  • the associated nanoparticle can comprise one or more polymers.
  • the nanoparticle comprises one or more polymers that are a non-methoxy-terminated, pluronic polymer. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% (weight/weight) of the polymers that make up the
  • nanoparticles are non-methoxy-terminated, pluronic polymers.
  • all of the polymers that make up the nanoparticle are non-methoxy-terminated, pluronic polymers.
  • the nanoparticle comprises one or more polymers that are a non- methoxy-terminated polymer.
  • at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% (weight/weight) of the polymers that make up the nanoparticles are non- methoxy-terminated polymers.
  • all of the polymers that make up the nanoparticle are non-methoxy-terminated polymers.
  • the nanoparticle comprises one or more polymers that do not comprise pluronic polymer.
  • such a polymer can be surrounded by a coating layer (e.g., liposome, lipid monolayer, micelle, etc.).
  • various elements of the nanoparticle can be coupled with the polymer.
  • polymers include, but are not limited to polyethylenes,
  • polycarbonates e.g. poly(l,3-dioxan-2one)
  • polyanhydrides e.g. poly(sebacic anhydride)
  • polypropylfumerates e.g. polyamides (e.g. polycaprolactam), polyacetals, polyethers, polyesters (e.g., polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone,
  • polyhydroxyacid e.g. poly((P-hydroxyalkanoate))
  • poly(orthoesters) polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes, and polyamines, polylysine, polylysine-PEG copolymers, and poly(ethyleneimine), poly(ethylene imine)-PEG copolymers.
  • nanoparticles include polymers which have been approved for use in humans by the ET.S. Food and Drug Administration (FDA) under 21 C.F.R. ⁇ 177.2600, including but not limited to polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(l,3-dioxan-2one)); polyanhydrides (e.g., poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes;
  • FDA ET.S. Food and Drug Administration
  • polymethacrylates polyacrylates; and polycyanoacrylates.
  • polymers can be hydrophilic.
  • polymers may comprise anionic groups (e.g., phosphate group, sulphate group, carboxylate group); cationic groups (e.g., quaternary amine group); or polar groups (e.g., hydroxyl group, thiol group, amine group).
  • a nanoparticles comprising a hydrophilic polymeric matrix generates a hydrophilic environment within the nanoparticle.
  • polymers can be hydrophobic.
  • a nanoparticles comprising a hydrophobic polymeric matrix generates a hydrophobic environment within the nanoparticle. Selection of the hydrophilicity or hydrophobicity of the polymer may have an impact on the nature of materials that are incorporated (e.g., coupled) within the nanoparticle.
  • polymers may be modified with one or more moieties and/or functional groups.
  • moieties or functional groups can be used in accordance with the presently described subject matter.
  • polymers may be modified with polyethylene glycol (PEG), with a carbohydrate, and/or with acyclic polyacetals derived from polysaccharides (Papisov, 2001, ACS Symposium Series, 786:301).
  • embodiments may be made using the general teachings of U.S. Pat. No. 5,543,158 to Gref et al., or WO publication W02009/051837 by Von Andrian et al.
  • polymers may be modified with a lipid or fatty acid group.
  • a fatty acid group may be one or more of butyric, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, or lignoceric acid.
  • a fatty acid group may be one or more of palmitoleic, oleic, vaccenic, linoleic, alpha-linoleic, gamma-linoleic, arachidonic, gadoleic, arachidonic, eicosapentaenoic, docosahexaenoic, or erucic acid.
  • polymers may be one or more acrylic polymers.
  • acrylic polymers include, for example, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, glycidyl methacrylate copolymers, polycyanoacrylates, and combinations comprising one or more of the foregoing polymers.
  • the acrylic polymer may comprise fully-polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammoni
  • polymers can be cationic polymers.
  • cationic polymers are able to condense and/or protect negatively charged strands of nucleic acids (e.g. DNA, or derivatives thereof).
  • Amine-containing polymers such as poly(lysine) (Zauner et al.,
  • the nanoparticles may not comprise (or may exclude) cationic polymers.
  • polymers can be degradable polyesters bearing cationic side chains (Putnam et al., 1999, acromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc, 115: 11010; Kwon et al., 1989, Macromolecules, 22:3250; Lim et al., 1999, J. Am. Chem.
  • polyesters examples include poly(L-lactide-co-L4ysine) (Barrera et al., 1993, J. Am. Chem. Soc, 115: 11010), poly(serine ester) (Zhou et al., 1990, Macromolecules, 23:3399), poly(4- hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al.,
  • Polymers can be linear or branched polymers. In some embodiments, polymers can be dendrimers. In some embodiments, polymers can be substantially cross-linked to one another. In some embodiments, polymers can be substantially free of cross-links. In some
  • polymers can be used without undergoing a cross-linking step. It is further to be understood that a nanoparticle may comprise block copolymers, graft copolymers, blends, mixtures, and/or adducts of any of the foregoing and other polymers. Those skilled in the art will recognize that the polymers listed herein represent an exemplary, not comprehensive, list of polymers that can be of use in accordance with the presently described subject matter.
  • the compounds of the presently described subject matter can be coupled to a nanoparticle by any of a number of methods.
  • the coupling can be a result of bonding between the compound and the nanoparticle. This bonding can result in the compound being attached to the surface of the nanoparticle and/or contained within
  • the compounds are encapsulated by the nanoparticle as a result of the structure of the nanoparticle rather than bonding to the nanoparticle.
  • the nanoparticle comprises a polymer as provided herein, and the compounds described herein are coupled to the nanoparticle.
  • the compounds described herein may be encapsulated into nanoparticles as desirable using a variety of methods including but not limited to C. Astete et ah,“Synthesis and
  • nanoparticles are prepared by a nanoprecipitation process or spray drying. Conditions used in preparing nanoparticles may be altered to yield particles of a desired size or property (e.g., hydrophobicity, hydrophilicity, external morphology, “stickiness,” shape, etc.).
  • the method of preparing the nanoparticles and the conditions (e.g., solvent, temperature, concentration, air flow rate, etc.) used may depend on the materials to be coupled to the nanoparticles and/or the composition of the polymer matrix. If particles prepared by any of the above methods have a size range outside of the desired range, particles can be sized, for example, using a sieve.
  • PRINT technology is used to manufacture nanoparticles comprising a compound described herein.
  • liposome based nanoparticles comprising a compound described herein.
  • a liposome based nanoparticle comprises a compound described herein formulated for controlled-release.
  • polymer based nanoparticles comprising a compound described herein. In some embodiments, provided herein are polymer based nanoparticles comprising a compound described herein formulated for controlled-release.
  • nanoparticles are comprised of albumin and a compound described herein. In some embodiments, nanoparticles are comprised of a polysaccharide and a compound described herein. In some embodiments, nanoparticles are comprised of a metal and a compound described herein. In some embodiments, nanoparticles are comprised of gold and a compound described herein. In some embodiments, nanoparticles are comprised of iron oxide and a compound described herein. In some embodiments, nanoparticles are comprised of silicon and a compound described herein.
  • nanoparticles are comprised of L-glutamic acid copolymers and a compound described herein. In some embodiments, nanoparticles are comprised of L- alanine copolymers and a compound described herein. In some embodiments, nanoparticles are comprised of L-lysine copolymers and a compound described herein. In some embodiments,
  • nanoparticles are comprised of L-tyrosine copolymers and a compound described herein. In other embodiments, nanoparticles are comprised of poly(lactic-co- glycolic acid) and a compound described herein. In some embodiments, nanoparticles are comprised of methoxy-PEG-poly(D,L-lactide) and a compound described herein. In some embodiments, nanoparticles are comprised of HPMA copolymer and a compound described herein. In some embodiments, nanoparticles are comprised of polycyclodextran and a compound described herein. In some embodiments, nanoparticles are comprised of polyglutamate and a compound described herein.
  • nanoparticles are comprised of poly(iso-hexyl-cyanoacrylate) and a compound described herein. In some embodiments, nanoparticles are comprised of poly-L-lysine and a compound described herein. In some embodiments, nanoparticles are comprised of PEG and a compound described herein. In some embodiments, nanoparticles are made of combinations of polymers and a compound described herein.
  • a compound described herein is released from a nanoparticle over a period of between about 1 and about 90 days. In some embodiments, the compound is released over a period of about 3 to 28 days. In some embodiments, the compound is released over a period of about 5 to 21 days.
  • the disorder is associated with Mer tyrosine kinase.
  • the subject has been diagnosed with a need for treatment of the tumor prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of the tumor.
  • the tumor is MerTK +/+. In other embodiments, the tumor is MerTK -/-.
  • the subject has been diagnosed with a need for treatment of the cancer prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of the cancer.
  • the cancer is MerTK +/+. In some embodiments, the cancer is MerTK -/-.
  • the subject has been diagnosed with a need for treatment of the immunosuppressed microenvironment prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of the immunosuppressed microenvironment.
  • Also disclosed are methods of treating a thrombotic disorder in a subject comprising administering to the subject an effective amount of a disclosed compound or composition.
  • the subject has been diagnosed with a need for anti thrombotic therapy prior to the administering step.
  • the method further comprises the step of identifying a subject in need of anti -thrombotic therapy.
  • the subject is a mammal. In some embodiments, the mammal is a human.
  • the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of the disorder.
  • the subject has been diagnosed with a need for treatment of an immunosuppressed microenvironment surrounding diseased tissue.
  • the method further comprises the step of identifying a subject in need of treatment of an immunosuppressed microenvironment surrounding diseased tissue.
  • the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.
  • the disorder is a cancer, an infection, a fibrosis, a thrombotic disorder, or a clotting disorder.
  • the disorder is an infection.
  • the infection is a bacterial infection.
  • the infection is a viral infection.
  • the viral infection has a virion envelope phosphatidyl serine.
  • the disorder is associated with an immunosuppressed microenvironment surrounding diseased tissue.
  • the disorder is a disorder of uncontrolled cellular proliferation.
  • the disorder of uncontrolled cellular proliferation is cancer.
  • the cancer is selected from breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome,
  • the cancer is MerTK +/+. In some embodiments, the cancer is MerTK -/-. In some embodiments, the disorder is a thrombotic disorder or a clotting disorder. Examples of thrombotic disorders include, but are not limited to, myocardial infarction, deep vein thrombosis, pulmonary embolism, and stroke.
  • the disorder is a liver disorder.
  • liver disorders include, but are not limited to, alcohol-related liver diseases, cirrhosis, non-alcoholic fatty liver disease, hepatitis, haemochromatosis, and primary biliary cirrhosis.
  • the disorder is associated with any one or more of Mer, Tyro3, and Axl tyrosine kinase. In some embodiments, the disorder is associated with any one or more of Mer, Tyro3, and Axl tyrosine kinase dysfunction. In further embodiments, the disorder is associated with Mer tyrosine kinase.
  • disclosed are methods for the treatment of an infection in a subject comprising the step of administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, thereby treating the infection.
  • the infection is a viral infection or a bacterial infection. In some embodiments, the infection is a bacterial infection. In some embodiments, the infection is a viral infection. In further embodiments, the viral infection has a virion envelope phosphatidyl serine.
  • the subject is a mammal. In some embodiments, the mammal is a human.
  • the subject has been diagnosed with a need for treatment of the infection prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of the infection.
  • the method further comprises administering an effective amount of an antiviral agent to the subject.
  • the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.
  • the infection is associated with any one or more of Mer,
  • the infection is associated with Mer tyrosine kinase dysfunction. In some embodiments, the infection is associated with Tyro3 tyrosine kinase dysfunction. In some embodiments, the infection is associated with Axl tyrosine kinase dysfunction.
  • TAM tyrosine kinase comprising one or more of Mer, Tyro3, and Axl
  • the method comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, thereby treating the infection.
  • the cell is mammalian. In some embodiments, the cell is human. In some embodiments, the cell has been isolated from a mammal prior to the contacting step.
  • contacting is via administration to a mammal.
  • the mammal has been diagnosed with a need for inhibiting a TAM tyrosine kinase prior to the administering step.
  • the mammal has been diagnosed with a need for treatment of a disorder related to dysfunction of a TAM tyrosine kinase prior to the administering step.
  • inhibiting Mer, Tyro3, and/or Axl tyrosine kinase is associated with treating a cancer. In further embodiments, inhibiting Mer tyrosine kinase is associated with treating a cancer.
  • the compound exhibits inhibition of Mer, Tyro3, and/or Axl tyrosine kinase with an IC50 of less than about 30 mM, less than about 25 pM, less than about 20 pM, less than about 15 pM, less than about 10 pM, less than about 5 pM, less than about 1 pM, or less than about 0.5 pM.
  • the subject matter described herein relates to a method for the manufacture of a medicament for treating a disorder in a subject, the method comprising combining an effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
  • the subject matter described herein relates to a method for the manufacture of a medicament for treating an infection in a subject, the method comprising combining an effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
  • the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of Mer, Tyro3, and/or Axl tyrosine kinase.
  • the dose administered to an animal, particularly a human, in the context of the presently described subject matter should be sufficient to affect a therapeutic response in the animal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.
  • the total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg/kg and about 1000 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose.
  • This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
  • the subject matter described herein relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.
  • kits comprising at least one compound of Formula I and one or more of: (a) at least one agent known to increase one or more of Mer, Tyro3, and/or Axl tyrosine kinase activity; (b) at least one agent known to treat a disorder of uncontrolled cellular proliferation; (c) at least one antibacterial agent; (d) at least one antiviral agent; (e) instructions for treating a disorder associated with one or more of Mer, Tyro3, and/or Axl tyrosine kinase dysfunction; (f) instructions for treating a disorder of uncontrolled cellular proliferation; or (g) instructions for treating an infection.
  • the at least one compound and the at least one agent are co- formulated. In some embodiments, the at least one compound and the at least one agent are co-packaged.
  • kits can also comprise compounds and/or products co-packaged, co-formulated, and/or co-delivered with other components.
  • a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient.
  • kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.
  • Microfluidic Capillary Electrophoresis (MCE) assays were performed in accordance with the procedure of Zhang et al. (J Med Chem 2013 56 (23), 9683-9692).
  • Activity assays were performed in a 384 well, polypropylene microplate in a final volume of 50 pL of 50 mM Hepes, pH 7.4 containing 10 mM MgCh , 1.0 mM DTT, 0.01% Triton X-100, 0.1% Bovine Serum Albumin (BSA), containing 1.0 mM fluorescent substrate and ATP at the Km for each enzyme. All reactions were terminated by addition of 20 pL of 70 mM EDTA.
  • nM Kinase Peptide Substrate Kinase (nM) ATP (uM)
  • reaction mixture was stirred at -70 °C. After complete conversion, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (3 x 10 mL), dried (Na 2 S0 4 ), and concentrated. The residue was purified by column chromatography with ethyl acetate/hexane and methanol/water to provide (2,6- dimethylpyridin-4-yl)(4-(l-(/ra «5-4-hydroxycyclohexyl)-6-(pyrimidin-5-ylamino)-liT- pyrazolo[3,4-i/]pyrimidin-3-yl)-5,6-dihydropyridin-l(2i7)-yl)methanone (13 mg, 12%) as a pale solid.
  • Table 2 The compounds below in Table 2 were prepared following general procedures described in Examples 1-5. The requisite starting materials were commercially available, described in the literature, or readily synthesized by one skilled in the art of organic synthesis. Table 2 also illustrates the effects of the disclosed compounds on Mer tyrosine kinase (Note: Mer IC50: ++++ means ⁇ 10 nM; +++ means between IO-IOOhM, ++ means between 100 nM-l mM; + means between 1-30 pM; - means inactive.)

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Abstract

L'invention concerne des composés contenant du pyrazolopyrimidine qui inhibent l'activité de la tyrosine kinase Mer, Tyro3 et Axl. L'invention concerne en outre des procédés de synthèse et d'utilisation des composés contenant du pyrazolopyrimidine en tant qu'agents anticancéreux, agents immunostimulateurs et immunomodulateurs, agents antiplaquettaires, agents anti-infectieux, et en tant qu'agents auxiliaires.
PCT/US2019/032680 2018-05-16 2019-05-16 Pyrazolopyrimidines servant d'inhibiteurs de mertk et leur utilisation dans le traitement du cancer WO2019222509A1 (fr)

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