Methods and compositions for the inhibition of dihydroorotate dehydrogenase

Abstract

Disclosed herein are compounds, i.e., 6-substituted-2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds can be used in the treatment of various disorders and diseases in which inhibition of DHODH is clinically useful, including cancers such as hematological cancers, including acute myeloid leukemia (AML), graft-versus-host disease, autoimmune disorders, and disorders associated with T-cell proliferation. The disclosed compounds may exhibit flip-flop kinetics when orally administered, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of excretion, governs the pharmacokinetics. The disclosed compounds may exhibit a sustained pharmacokinetic profile instead of an immediate-release profile. This Abstract is intended as a scanning tool for purposes of searching within a particular technical field and is not intended to limit the disclosure.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 953,708, filed December 26, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Proliferating cells require a supply of nucleotides for DNA replication and gene transcription into RNA, as well as for various other metabolic processes. Cells can supply such nucleotides through the de novo nucleotide synthesis pathway. A key step in the de novo synthesis pathway of pyrimidine nucleotides is the oxidation of dihydroorotate to form orotate. This reaction is catalyzed by dihydroorotate dehydrogenase (DHODH), which is one of the rate-limiting steps in the pyrimidine nucleotide synthesis pathway. DHODH has a subcellular location within the mitochondrial membrane and uses cytochrome C in the electron transport chain as an electron acceptor for the oxidation of dihydroorotate to orotate.

[0003] Under normal circumstances, intracellular pools of pyrimidine nucleotides can be replenished by salvage pathways in which pyrimidine nucleotides are recycled. This DHODH-independent mechanism is sufficient for resting lymphocytes, but "activated" and proliferating lymphocytes require a substantial increase in available pyrimidines and therefore become dependent on de novo pyrimidine synthesis. Because orotic acid is a necessary intermediate for pyrimidine nucleotide synthesis, and pyrimidine nucleotides are required for DNA replication, gene expression, and carbohydrate metabolism, inhibition of the DHODH enzyme can inhibit cell proliferation.

[0004] Furthermore, rapidly proliferating cells require pyrimidines not only for cell growth but also for protein glycosylation, membrane lipid biosynthesis, and strand break repair (see, e.g., Fairbanks, et al., J. Biol. Chem. 270:29682-29689 (1995)). Under such conditions, a substantial amount of pyrimidine nucleotides must be produced in rapidly proliferating cells to meet the increased demand. Therefore, DHODH inhibitors are attractive candidates for treating proliferative disorders (see, e.g., Liu, S., et al., Structure 8:25-31 (2000)). Various studies have shown that DHODH inhibitors can stop tumor cell proliferation in some situations (see, e.g., Loffler, Eur. J. Biochem. 107:207-215 (1980)).

[0005] Other situations in which DHODH inhibitors have been identified as candidates for clinical control of rapid cell division include activated immune cells, diseased skin cells, cancer, and infectious pathogens. Examples of DHODH inhibitors that have been used or developed for proliferative disorders include brequinar, leflunomide, and teriflunomide. DHODH inhibitors have also been disclosed for the treatment or prevention of autoimmune diseases, immune and inflammatory diseases, angiogenesis-related disorders, viral, bacterial, and protozoal diseases.

[0006] Although DHODH is an attractive target for therapeutic intervention in various clinical conditions, including cancer, serious problems remain for currently described compounds.For example, many of these compounds, including brequinar, suffer from poor bioavailability, partly due to poor water solubility and GI uptake.Therefore, the currently described DHODH inhibitors may have limited pharmaceutical effectiveness due to such bioavailability problems.

[0007] Despite progress in research into effective and therapeutically useful DHODH inhibitors, there remains a lack of compounds that are both effective and have suitable bioavailability characteristics. These and other needs are met by the present disclosure. Summary of the Invention

[0008] In accordance with the purpose of this disclosure, as embodied and broadly described herein, the present disclosure relates, in one aspect, to compounds that are inhibitors of dihydroorotate dehydrogenase (DHODH). The disclosed compounds have improved pharmacokinetic properties, making them highly useful for therapeutic intervention in a variety of disorders and diseases in which inhibition of DHODH may be clinically useful, such as cancer. In various aspects, the disclosed compounds are 6-substituted-2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analogs. In further aspects, the disclosed compounds can be used in methods for treating cancer, such as hematological cancers including acute myeloid leukemia (AML), graft-versus-host disease, and disorders associated with T-cell proliferation. In some aspects, the disclosed compounds can exhibit flip-flop kinetics when orally administered, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of excretion, governs the pharmacokinetics. Furthermore, the disclosed compounds can exhibit a sustained pharmacokinetic profile instead of an immediate-release profile.

[0009] Disclosed herein are compounds having a formula represented by the structure: TIFF0007800865000001.tif40170, R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is halogen, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1 is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1 is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d are each independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0010] Disclosed herein are compounds having a formula represented by the structure: TIFF0007800865000002.tif39170, R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of them has the structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 A is selected from the group having the formula 1 -O- and -NR50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5efour of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d are each independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0011] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] Also disclosed are methods for treating a disease or disorder in a mammal comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition.

[0013] Also disclosed are methods for treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition.

[0014] Also disclosed is a method for treating graft-versus-host disease in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition.

[0015] Also disclosed is a method for treating a disease or disorder associated with T-cell proliferation in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition.

[0016] Also disclosed are kits comprising a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition; (a) at least one agent known to treat cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation; and (b) instructions for treating cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation.

[0017] Also disclosed are methods for producing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0018] Also disclosed is the use of a disclosed compound or disclosed product in the manufacture of a medicament for the treatment of a disease or disorder in a mammal, such as cancer, a disorder associated with T-cell proliferation, or graft-versus-host disease.

[0019] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included herein, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments can be used in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, and all optional and preferred features and modifications of the described embodiments, are combinable and interchangeable with each other. [Brief explanation of the drawings]

[0020] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals indicate corresponding parts throughout the several views.

[0021] [Figure 1] 1 shows representative data of the effect of a representative disclosed compound, Cpd1, on the expression of p53 in AML cell lines as determined by immunoblot analysis. [Figure 2A] Figures 2A-2D show representative data for the activity of representative disclosed compounds in cell proliferation assays performed using the MTS assay described herein below, and the inhibition curves used to determine IC50 values ​​therein. Figure 2A shows representative data for the activity of representative disclosed compounds in cell proliferation assays performed using the MTS assay described herein below, and the inhibition curves used to determine IC50 values ​​therein for compounds Cpd1-Cpd6 as shown. [Figure 2B] FIG. 2B shows representative data for the activity of representative disclosed compounds in a cell proliferation assay performed using the MTS assay described herein below, and the inhibition curves used to determine IC50 values ​​therein for compounds Cpd7, Cpd8, Cpd10, and Cpd12-Cpd15 as indicated. [Figure 2C] Figure 2C shows representative data for the activity of representative disclosed compounds in a cell proliferation assay performed using the MTS assay described herein below, and the inhibition curves used to determine IC50 values ​​therein for compounds Cpd16-Cpd21 as indicated. [Figure 2D] Figure 2D shows representative data for the activity of representative disclosed compounds in a cell proliferation assay performed using the MTS assay described herein below, and the inhibition curves used to determine IC50 values ​​therein for compounds Cpd22-Cpd27 as indicated.

[0022] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0023] Many modifications and other embodiments of what is disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosure is not limited to the particular embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the aspects described herein. These variations and adaptations are intended to be included within the teachings of the present disclosure and are intended to be encompassed by the scope of the claims herein.

[0024] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0025] As will be apparent to those skilled in the art upon reading this disclosure, the individual embodiments described and illustrated herein have separate components and features that may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0026] Any recited method may be carried out in the order of events recited or in any other order that is logically possible. That is, unless expressly stated otherwise, it is in no way intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Accordingly, method claims are not specifically recited in the claims or the specification to be limited to a particular order of steps, and no order is intended to be inferred in any respect. This also applies to any possible implicit basis for interpretation, including logical considerations regarding the arrangement of steps or operational flow, the plain meaning derived from grammatical structure or punctuation, or the number or type of aspects described within the specification.

[0027] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which they are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publications by virtue of prior invention. Furthermore, the dates of publications provided herein may be different from the actual publication dates, which may require independent confirmation.

[0028] Although aspects of the present disclosure may be described and claimed in particular statutory classifications, such as systems statutory classifications, this is for convenience only, and those skilled in the art will understand that aspects of the present disclosure may be described and claimed in any statutory classification.

[0029] It should also be understood that the terms used herein are merely for describing particular embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the disclosed compositions and methods belong. Furthermore, it should be understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with the meaning in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0030] Before describing the various aspects of this disclosure, the following definitions are provided and shall be used unless otherwise indicated: Some terms may be defined elsewhere in this disclosure.

[0031] definition As used herein, "comprising" should be interpreted as specifying the presence of the stated feature, integer, step, or component as referenced, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Furthermore, the terms "by," "comprising," "comprises," "composed of," "including," "includes," "included," "involving," "involves," "involved," and "such as" are each used in an open, non-limiting sense and may be used interchangeably. Furthermore, the term "comprising" is intended to include examples and embodiments encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of."

[0032] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "DHODH inhibitor," "cancer," or "pyrimidine nucleotide" includes, but is not limited to, combinations of two or more such DHODH inhibitors, cancers, or pyrimidine nucleotides, and the like.

[0033] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It should be further understood that the endpoints of each range are significant both in relation to the other endpoint, and independently of the other endpoint. It should also be understood that there are multiple values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if a value of "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. Similarly, when values ​​are expressed as approximations, by the use of "about," it should be understood that the particular value forms a further aspect. For example, if a value of "about 10" is disclosed, then "10" is also disclosed.

[0034] When a range is expressed, a further embodiment includes one particular value and / or the other particular value. For example, when the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, the phrase "from x to y" includes ranges from "x" to "y," as well as ranges from greater than "x" to less than "y." Ranges can also be expressed as upper limits, e.g., "about x, about y, about z, or less," and should be interpreted to encompass the specific ranges of "about x," "about y," and "about z," as well as the ranges "less than x," "less than y," and "less than z." Similarly, the phrase "about x, y, z, or more" should be interpreted to encompass the specific ranges of "about x," "about y," and "about z," as well as the ranges "greater than x," "greater than y," and "greater than z." Additionally, the phrase "about 'x' to 'y'" (where 'x' and 'y' are numerical values) includes "about 'x' to about 'y'."

[0035] It should be understood that such range formats are used for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as range limits, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. By way of example, a numerical range of "about 0.1% to 5%" should be interpreted to include not only the explicitly recited values ​​of about 0.1% to about 5%, but also individual values ​​within the stated range (e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, and about 0.5% to about 4.4%, as well as other possible subranges).

[0036] As used herein, the terms "about," "approximately," "at or about," and "substantially" mean that the amount or value in question may be an exact value or a value that will produce the same results or effects as those recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not, and need not be, exact, but can be approximated and / or made larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement error, and the like, as well as other factors known to those skilled in the art, so as to produce the same results or effects. In some circumstances, a value that will produce the same results or effects cannot be reasonably determined. In such cases, as used herein, "about" and "at or about" are generally understood to mean the nominal value, expressed with a ±10% variance, unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is "about," "approximately," or "at or about," whether or not expressly stated as such. When "about," "approximately," or "around" is used before a quantitative value, unless otherwise specified, it is to be understood that the parameter also includes the particular quantitative value itself.

[0037] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0038] As used herein, "dihydroorotate dehydrogenase" and "DHODH" can be used interchangeably and refer to an enzyme encoded by a human gene with a cytogenetic location of 16q22.2 and a molecular location of base pairs 72,008,744 to 72,025,417 on chromosome 16 (Homo sapiens Annotation Release 109, GRCh38.p12). The human gene structure contains nine exons. DHODH is classified as EC 1.3.1.1 and is located intracellularly within mitochondria, where it catalyzes the fourth enzymatic step in de novo pyrimidine biosynthesis. DHODH has also been referred to as DHOdehase, mitochondrial dihydroorotate dehydrogenase, mitochondrial precursor dihydroorotate dehydrogenase, dihydroorotate oxidase, human complement of yeast URA1, POADS, PYRD_HUMAN, and URA1.

[0039] As used herein, unless otherwise specified, the terms "inhibit" or "inhibiting" DHODH or "inhibitor" of DHODH refer to the inhibition of the enzyme DHODH.

[0040] As used herein, "IC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process, an enzymatic reaction, or a component of a biological or enzymatic process. For example, IC 50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. For example, IC for DHODH activity 50DHODH activity can be determined in an in vitro enzyme assay using the methods described herein. Alternatively, activity can be determined in a cell-based assay, including measuring activity or function associated with the inhibition of a target process or enzyme. That is, DHODH activity can be indirectly determined in a cell-based assay of cell proliferation. It is believed that DHODH inhibition can result in growth arrest or inhibition in a suitable cell type. DHODH activity can be determined in suitable cells, such as primary AML cells or AML cell lines, using a cell proliferation assay, such as the MTS assay described herein, or the cell colony formation assay described herein. Suitable cell lines are described later in this specification.

[0041] As used herein, the term "immune" includes cells of the immune system and cells that perform a function or activity in an immune response, such as, but not limited to, T cells, B cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, leukocytes, antigen-presenting cells, and natural killer cells.

[0042] As used herein, "brequinar" and "BQR" may be used interchangeably and refer to a compound having a structure represented by the following formula: TIFF0007800865000003.tif33170 Brequinar can also be referred to by its IUPAC chemical name, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid. Common salt forms are brequinar potassium and brequinar sodium (also referred to herein as BQR Na), which are alkali metal salts of the conjugate base of the carboxylic acid. Brequinar is sometimes referred to as DuP-785 or NSC-368390.

[0043] As used herein, "graft-versus-host disease," "graft versus host disease," and GVHD can be used interchangeably to refer to a clinical complication following allogeneic tissue transplantation. It is commonly associated with stem cell or bone marrow transplantation, but the term also applies to other forms of tissue transplantation. Immune cells (white blood cells) in the tissue (graft) recognize the recipient (host) as "foreign." The transplanted immune cells then attack the host's somatic cells. GVHD can also occur after blood transfusions if the blood products used are not irradiated or treated with an approved pathogen reduction system.

[0044] As used herein, "administering" can refer to oral, topical, intravenous, subcutaneous, transdermal, transcutaneous, intramuscular, intraarticular, parenteral, intraarterial, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernosal, intrathecal, intravitreal, intracerebral, intraventricular, intratympanic, intracochlear, rectal, intravaginal, by inhalation, by catheter, by stent, or via an implanted reservoir or other device that actively or passively (e.g., by diffusion) administers the composition to the perivascular space and adventitia. For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or otherwise distribute to surrounding tissues and cells. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Administration can be continuous or intermittent. In various embodiments, the preparations can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparations can be administered prophylactically, i.e., administered for the prevention of a disease or condition.

[0045] As used herein, "therapeutic agent" refers to any substance, compound, molecule, and the like that may be biologically active or otherwise capable of inducing a pharmacological, immunogenic, biological, and / or physiological effect in a subject to which it is administered by local and / or systemic action. A "therapeutic agent" may be a primary active agent, or in other words, a component of a composition that contributes all or part of the composition's effect. A "therapeutic agent" may be a secondary active agent, or in other words, a component of a composition that contributes an additional portion of the composition and / or other effect. As such, the term encompasses compounds or chemicals traditionally considered to be drugs, vaccines, and biopharmaceuticals (including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, and the like). Examples of therapeutic agents are described in well-known references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and include, but are not limited to, pharmaceuticals, vitamins, mineral supplements, substances used in the treatment, prevention, diagnosis, cure, or mitigation of disease or illness, substances that affect the structure or function of the body, or prodrugs, which become biologically active or more active after being placed in a physiological environment.For example, the term "therapeutic agent" includes, but is not limited to, adjuvants, anti-infectives such as antibiotics and antivirals, analgesics and analgesic combinations, appetite suppressants, anti-inflammatory agents, antiepileptics, local and general anesthetics, hypnotics, sedatives, antipsychotics, neuroleptics, antidepressants, anxiolytics, antagonists, neuroleptics, anticholinergics and cholinomimetics, antimuscarinics and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensives, hormones, and nutrients, antiarthritics, antiasthmatics, anticonvulsants, antihistamines, antiemetics, antineoplastics, antipruritics, antipyretics, antispasmodics, cardiovascular preparations (including calcium channel blockers, beta blockers, beta agonists, and antiarrhythmics), antihypertensives, diuretics, vasodilators, These include compounds or compositions for use in all major therapeutic areas, including central nervous system stimulants, cough and cold preparations, decongestants, diagnostic agents, hormones, bone growth stimulants and bone resorption inhibitors, immunosuppressants, muscle relaxants, psychostimulants, sedatives; tranquilizers, proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized, or recombinantly produced), as well as nucleic acid molecules (either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including polymeric forms of two or more nucleotides, both double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, and the like), small molecules (e.g., doxorubicin), and other biologically active macromolecules such as proteins and enzymes. The drugs may be biologically active agents used in medical applications, including veterinary medicine, and in agriculture, such as with plants, as well as in other fields. The term therapeutic agent also includes, but is not limited to, pharmaceuticals, vitamins, mineral supplements, substances used to treat, prevent, diagnose, cure, or mitigate a disease or illness, or substances that affect the structure or function of the body, or prodrugs that become biologically active or more active after being placed in a defined physiological environment.

[0046] As used herein, a "kit" refers to a collection of at least two components that make up the kit. These components together constitute a functional unit for a given purpose. The individual components may be physically packaged together or separately. For example, a kit that includes instructions for using the kit may or may not physically include the instructions with the other individual components. Alternatively, the instructions may be provided as separate components, either in paper form or in electronic form, which may be provided on a computer-readable memory device, downloaded from an internet website, or provided as a recorded presentation.

[0047] As used herein, "instructions" means documents describing the relevant materials or methodologies associated with the kit. These materials may include any combination of the following: background information, a list of components and their availability (such as purchasing information), brief or detailed protocols for using the kit, troubleshooting, reference materials, technical support, and other related documentation. The instructions can be supplied with the kit or as a separate component, either in paper form or in electronic form, which may be provided on a computer-readable memory device, downloaded from an internet website, or provided as a recorded presentation. The instructions may include one or more documents and are intended to include future revisions.

[0048] As used herein, "bonded" can refer to a covalent bond or a non-covalent interaction between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Waals forces, dipole-dipole interactions, dipole-induced dipole interactions, London dispersion forces, hydrogen bonds, halogen bonds, electromagnetic interactions, π-π interactions, cation-π interactions, anion-π interactions, polar π interactions, and hydrophobic effects.

[0049] As used interchangeably herein, "subject," "individual," or "patient" can refer to a vertebrate organism, such as a mammal (e.g., a human). "Subject" can also refer to a cell, a cell population, a tissue, an organ, or an organism, preferably a human and its components. It is understood that a vertebrate can be a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the methods disclosed herein can be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The term does not denote a particular age or sex. Furthermore, adult and newborn subjects and fetuses, regardless of male or female, are intended to be encompassed. A patient refers to a subject suffering from a clinical condition, disease, or disorder. The term "patient" includes human and veterinary subjects.

[0050] As used herein, the terms "treating" and "treatment" may generally refer to obtaining a desired pharmacological and / or physiological effect. The effect may be, but is not necessarily, prophylactic in terms of preventing or partially preventing a disease, such as cancer, a T-cell proliferation-related disorder or disease, or graft-versus-host disease, or a symptom or condition thereof. The effect may be therapeutic in terms of partially or completely curing a disease, condition, symptom, or adverse effects resulting from the disease, disorder, or condition. As used herein, the term "treatment" may include any treatment of cancer, a T-cell proliferation-related disorder or disease, or graft-versus-host disease in a subject, particularly a human, and may include any one or more of the following: (a) preventing the occurrence of the disease in a subject predisposed to the disease but not yet diagnosed as having it, (b) inhibiting the disease, i.e., arresting its development, and (c) palliating the disease, i.e., reducing or ameliorating the disease and / or its symptoms or condition. As used herein, the term "treatment" may refer to therapeutic treatment only, prophylactic treatment only, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those who already have a disorder and / or those in whom a disorder is to be prevented. As used herein, the term "treating" can include inhibiting a disease, disorder, or condition, e.g., preventing its progression, and alleviating a disease, disorder, or condition, e.g., resulting in the alleviation of a disease, disorder, and / or condition. Treating a disease, disorder, or condition can include improving at least one symptom of a particular disease, disorder, or condition even if the underlying pathophysiology is unaffected, such as, for example, treating a subject's pain by administering an analgesic, even though the analgesic does not treat the cause of the pain.

[0051] As used herein, "dose," "unit dose," or "dosage" may refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or pharmaceutical composition thereof calculated to produce one or more desired responses in association with its administration.

[0052] As used herein, "therapeutic" may mean treating, curing, and / or ameliorating a disease, disorder, condition, or side effect, or slowing the rate of progression of a disease, disorder, condition, or side effect.

[0053] As used herein, "effective amount" can refer to an amount of a compound or pharmaceutical composition disclosed herein that is sufficient to produce a beneficial or desired biological, emotional, medical, or clinical response in a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope an amount effective to enhance or restore substantially normal physiological function.

[0054] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to have an effect on undesired symptoms, but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder, the specific composition used, the patient's age, weight, overall health, sex, and diet, the time of administration, the route of administration, the excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or simultaneously with the specific compound used, and similar factors within the knowledge and skill of health professionals and well known in the medical field. When treating a particular disease or condition, in some cases, the desired response may be to inhibit the progression of the disease or condition. This may simply involve temporarily slowing the progression of the disease. However, in other cases, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to those skilled in the art for any particular disease. The desired response to the treatment of a disease or condition may be to delay or even prevent the onset of the disease or condition.

[0055] For example, it is well within the skill of those skilled in the art to start with a dose of the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Consequently, a single dose of the composition can contain such an amount or a sub-amount to constitute a daily dose. The dosage can be adjusted by an individual physician if any contraindications arise. Generally, it is preferred to use the maximum dose of the pharmacological agent of the present disclosure (alone or in combination with other therapeutic agents), i.e., the maximum safe dose according to sound medical judgment. However, it will be understood by those skilled in the art that a patient may require a lower or tolerable dose for medical reasons, psychological reasons, or almost any other reason.

[0056] Response to a therapeutically effective dose of the disclosed compounds and / or pharmaceutical compositions can be measured, for example, by determining the physiological effect of the treatment or administration, such as a reduction or absence of disease symptoms after administration of the treatment or pharmacological agent. Other assays are known to those skilled in the art and can be used to measure the level of response. The amount of treatment can be varied, for example, by increasing or decreasing the amount of the disclosed compounds and / or pharmaceutical compositions, by changing the disclosed compounds and / or pharmaceutical compositions administered, by changing the route of administration, by changing the timing of administration, etc. Dosages can vary and can be administered in one or more doses per day for one or several days. Guidance on appropriate dosages for a given class of pharmaceutical products can be found in the literature.

[0057] In this disclosure, it should be understood that in some cases, an effective amount or dose of the disclosed compound is the amount of the composition capable of inhibiting DHODH and providing a clinically meaningful reduction in the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system, as a result of DHODH inhibition. For example, an "effective amount" for therapeutic use. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study.

[0058] As used herein, the term "prophylactically effective amount" refers to an amount effective to prevent the development or onset of a disease or condition.

[0059] As used herein, the term "prevent" or "preventing" refers to preventing, avoiding, avoiding, forestalling, deterring, or impeding something from occurring, especially by prior action. Where reduce, inhibit, or hinder is used herein, it should be understood that the use of the other two words is also expressly disclosed unless specifically indicated otherwise.

[0060] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, i.e., does not cause unacceptable levels of undesirable biological effects or interact in a deleterious manner.

[0061] As used herein, the term " pharmaceutically acceptable salt " refers to the salt of an active main drug prepared with an acid or base that is tolerated by biological systems or tolerated by subjects when administered in a therapeutically effective amount, or that is tolerated by biological systems and tolerated by subjects.When a compound of the present disclosure contains a relatively acidic functional group, the neutral form of such a compound can be contacted with a sufficient amount of a desired base, either directly or in a suitable inert solvent, to obtain a base addition salt.Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium salt, potassium salt, calcium salt, ammonium salt, organic amino salt, magnesium salt, lithium salt, strontium salt, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, the neutral form of such a compound can be contacted with a sufficient amount of a desired acid, either directly or in a suitable inert solvent, to obtain an acid addition salt. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginic acid and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like.

[0062] The term "pharmaceutically acceptable ester" refers to an ester of a compound of the present disclosure that hydrolyzes in vivo, including those that readily decompose in the human body to leave the parent compound or its salt. Examples of pharmaceutically acceptable, non-toxic esters of the present disclosure include C1-C6 alkyl esters and C5-C7 cycloalkyl esters, with C1-C4 alkyl esters being preferred. Esters of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be added to a hydroxy group by reacting the compound with acid and an alkyl carboxylic acid, such as acetic acid, or acid and an aryl carboxylic acid, such as benzoic acid. For compounds containing a carboxylic acid group, pharmaceutically acceptable esters can be prepared from the compound by reacting the compound with triethylamine and a base such as an alkyl halide, e.g., methyl iodide, benzyl iodide, cyclopentyl iodide, or an alkyl triflate. They can also be prepared by reacting the compound with an acid, such as hydrochloric acid, and an alcohol, such as ethanol or methanol.

[0063] The term "pharmaceutically acceptable amide" refers to the non-toxic amides of the present disclosure derived from ammonia, primary C1-C6 alkylamines, and secondary C1-C6 dialkylamines. In the case of secondary amines, the amine can also take the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amides, and C1-C2 dialkyl secondary amides are preferred. Amides of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reacting the amino group-containing compound with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable amides can be prepared from compounds containing carboxylic acid groups by reacting the compound with a base such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole, and an alkylamine, dialkylamine, e.g., methylamine, diethylamine, and piperidine. They can also be prepared by reacting the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or an arylcarboxylic acid such as benzoic acid, under dehydrating conditions, such as with the addition of molecular sieves. The compositions can contain the compounds of the present disclosure in the form of pharmaceutically acceptable prodrugs.

[0064] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to a prodrug of a compound of the present disclosure that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and is effective for its intended use. The prodrugs of the present disclosure can be rapidly converted in vivo, for example, by hydrolysis in blood, to the parent compound having the structure of the disclosed compound. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0065] As used herein, the term "contacting" refers to bringing the disclosed compounds or pharmaceutical compositions into proximity with a cell, target protein, or other biological entity in such a way that the disclosed compounds or pharmaceutical compositions can affect the activity of the cell, target protein, or other biological entity, either directly, i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly, i.e., by interacting with another molecule, cofactor, or protein on which the activity of the cell, target protein, or other biological entity itself depends.

[0066] Unless otherwise specified, temperatures referred to herein should be understood to be based on atmospheric pressure (ie, 1 atmosphere).

[0067] As used herein, the names of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, the Cahn-Inglod-Prelg rules for stereochemistry may be used to specify stereochemical priority, E / Z designation, and equivalents. Those skilled in the art can easily verify the structure of a compound when a name is given by either using the naming rules to systematically reduce the compound structure or by using commercially available software such as CHEMDRAW™ (Cambridgesoft Corporation, USA).

[0068] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, 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. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent and results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, it is also contemplated that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted), unless expressly indicated to the contrary.

[0069] In defining various terms, 1 ","A 2 ","A 3 ", and "A4 " is used herein as a generic symbol to represent various specific substituents. Similarly, "Ar 1 ", "Ar 2 ", "Ar 3 " and "Ar 4 " is used herein as a generic symbol to represent various specific aryl substituents. These symbols can be any substituent, not limited to those disclosed herein, and when in some cases they are defined to be a specific substituent, in other cases they can be defined as some other substituent.

[0070] As used herein, the terms "aliphatic" or "aliphatic group" refer to a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclics) and may be fully saturated or contain one or more unsaturated (but not aromatic) units. Unless otherwise specified, aliphatic groups contain 1 to 20 carbon atoms. Aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, as well as hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0071] As used herein, the term "alkyl" refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. An alkyl group can be cyclic or acyclic. An alkyl group can be branched or unbranched. An alkyl group can also be substituted or unsubstituted. For example, an alkyl group can be substituted with one or more groups, including, but not limited to, 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 1 to 6 (e.g., 1 to 4) carbon atoms. Also, the term alkyl group can be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like, up to and including C1-C24 alkyl.

[0072] Throughout this specification, the term "alkyl" is used generally to refer to both unsubstituted and substituted alkyl groups, although substituted alkyl groups are also specifically referred to herein by identifying the particular substituents on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halide, such as fluorine, chlorine, bromine, or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group independently substituted with two or more halides; i.e., each halide substituent need not be the same halide as another halide substituent, nor do multiple instances of halide substituents need not be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxy groups. When "alkyl" is used in one instance and a specific term such as "hydroxyalkyl" is used in another, it is not intended to imply that the term "alkyl" does not also refer to specific terms such as "hydroxyalkyl" and the like.

[0073] As used herein, "aminoalkyl" refers to a straight or branched chain alkyl group in which at least one hydrogen is replaced with an amino group, typically one to three amino groups. Non-limiting examples of aminoalkyl groups include -CH2NH2, -(CH2)2NH2, -CHCH3NH2, -(CH2)2CHCH3NH2, -(CH2)2CHNH2CH2CH3, -CHCH3(CH2)2NH2, and the like.

[0074] As used herein, "alkylamino" refers to an amino group having at least one hydrogen replaced with an alkyl group. Thus, alkylamino refers to the group -NR a R a refers to R a and R b are independently a or R b is selected from H and alkyl, provided that at least one of is alkyl. Non-limiting examples of alkylamino groups include -NHCH, -NHCHCH, -NH(CH), -N(CH), -N(CH)CHCH, -N(CH)CH, and the like.

[0075] As used herein, "hydroxyalkyl" refers to a straight or branched chain alkyl group in which at least one hydrogen has been replaced with a hydroxy group, typically one to three hydroxy groups. Non-limiting examples of hydroxyalkyl groups include -CHOH, -(CH)OH, -CHCHOH, -(CH)CHCHOH, -(CH)CHOHCHCH, -CHCH(CH)OH, and the like.

[0076] As used herein, the term "alkanediyl" refers to a divalent, straight- and branched-chain saturated hydrocarbon radical having 1 to 6 carbon atoms, unless otherwise specified. For example, "C1-C6 alkanediyl" refers to a divalent, straight- and branched-chain saturated hydrocarbon radical having 1 to 6 carbon atoms, such as methylene, 1,2-ethanediyl (-CH2CH2-), propanediyl or 1,3-propanediyl (-(CH2)3-), butanediyl or 1,4-butanediyl (-(CH2)4-), pentanediyl or 1,5-pentanediyl (-(CH2)5-), hexanediyl or 1,6-hexanediyl (-(CH2)6-), and their branched isomers (e.g., isopropanediyl (-CHCH3CH2-)). Alkanediyl groups can be further substituted, for example, aminoalkanediyl or hydroxyalkanediyl.

[0077] As used herein, "aminoalkanediyl" refers to a straight or branched chain alkanediyl group in which at least one hydrogen is replaced with an amino group, typically one to three amino groups. Non-limiting examples of aminoalkanediyl groups include -CHNH-, -(CH)NH-, -CHCHNH-, -(CH)CHCHNH-, -(CH)CHNH(CH)-, -CHCHNH(CH)-, -CHNH(CH)-, -(CH)NH(CH)-, -CHCH(CH)NH-, and the like.

[0078] As used herein, "hydroxyalkanediyl" refers to a straight or branched chain alkanediyl group in which at least one hydrogen has been replaced with a hydroxy group, typically one to three hydroxy groups. Non-limiting examples of hydroxyalkanediyl groups include -CHOH-, -CHCHOH-, -CCHOH-, -(CH)CCHOH-, -(CH)CHOH(CH)-, -CHCHOH(CH)-, -CHOH(CH)-, -CHCHOH(CH)-, -CHCHCHCHOH-, and the like.

[0079] As used herein, the terms "alkoxy" and "alkoxyl" refer to an alkyl or cycloalkyl group bonded through an ether linkage; i.e., an "alkoxy" group is an A 1 is alkyl or cycloalkyl as defined above; 1 "Alkoxy" also includes polymers of the alkoxy groups described above, i.e., alkoxy is defined as "a" is an integer from 1 to 200, and A 1 , A 2 , and A 3 is an alkyl and / or cycloalkyl group; 1 -OA 2 or -OA 1 -(OA 2 ) a -OA 3The polyether may be a polyether such as

[0080] As used herein, the term "aromatic group" refers to a ring structure having a cyclic cloud of delocalized π electrons above and below the plane of the molecule, the π cloud containing (4n+2) π electrons. Further discussion of aromaticity is found in Chapter 13 (entitled "Aromaticity"), pages 477-497 of Morrison and Boyd, Organic Chemistry (5th Ed., 1987), which is incorporated herein by reference. The term "aromatic group" includes both aryl and heteroaryl groups.

[0081] As used herein, the term "aryl" refers to a group containing any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. Aryl groups can also be substituted or unsubstituted. Aryl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl." Additionally, aryl groups can include multiple ring structures, which can be single ring structures, fused ring structures, or linked via one or more bridging groups, such as carbon-carbon bonds. For example, a biaryl refers to two aryl groups that are linked together through a fused ring structure, as in naphthalene, or through one or more carbon-carbon bonds, as in biphenyl.

[0082] As used herein, the term "cycloalkyl" refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term "heterocycloalkyl" refers to a type of cycloalkyl group defined above, but is included in the meaning of the term "cycloalkyl" in which at least one of the ring carbon atoms is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0083] As used herein, the term "heteroalkyl" refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, where nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroalkyl can be substituted as defined above for alkyl groups.

[0084] As used herein, the term "heteroaryl" refers to an aromatic group having at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, with N-oxides, sulfur oxides, and dioxides being acceptable heteroatom substitutions. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. Heteroaryl groups can be monocyclic or, alternatively, fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0085] As used herein, the term "heterocycle" can be used interchangeably and refers to mono- and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term includes, but is not limited to, "heterocycloalkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle." Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole including 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, thiadiazole including 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole including 1,2,3-triazole and 1,3,4-triazole, tetrazole including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine including 1,2,4-triazine and 1,3,5-triazine, tetrazine including 1,2,4-tetrazine, pyrrolidine, piperidine, piperazine, morpholidine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be C2-heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like, up to and including C2-C18 heterocyclyl. For example, C2 heterocyclyl includes groups having two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, C5 heterocyclyl includes groups having five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.It is understood that a heterocyclyl group may be attached, if chemically possible, through either a heteroatom within the ring or through one of the carbons comprising the heterocyclyl ring.

[0086] As used herein, the term "bicyclic heterocycle" refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl includes ring systems in which an aromatic ring is fused to another aromatic ring, or an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclyl includes ring systems in which a benzene ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, or a pyridine ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0087] As used herein, the term "heterocycloalkyl" refers to an aliphatic, partially unsaturated or fully saturated 3- to 14-membered ring system, including monocyclic and bicyclic and tricyclic ring systems of 3 to 8 atoms. Heterocycloalkyl ring systems contain 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0088] As used herein, the term "amine" or "amino" refers to a group of the formula -NA 1 A 2 and A 1 and A 2 can independently be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A particular example of amino is -NH2.

[0089] The term "carboxylic acid" as used herein is represented by the formula --C(O)OH.

[0090] As used herein, the terms "halo," "halogen," or "halide" can be used interchangeably and refer to F, Cl, Br, or I.

[0091] The terms "hydroxyl" or "hydroxy" as used herein are represented by the formula --OH.

[0092] The term "nitro" as used herein is represented by the formula --NO.sub.2.

[0093] The term "nitrile" or "cyano" as used herein is represented by the formula --CN.

[0094] As used herein, "R" refers to a group of compounds where n is an integer. 1 "," "R 2 "," "R 3 ",..."R n " can independently possess one or more of the groups listed above. For example, R 1When is a straight-chain alkyl group, one of the hydrogen atoms of the alkyl group can be optionally substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending on the group selected, the first group can be incorporated into the second group, or alternatively, the first group can be a pendant group (i.e., attached) to the second group. For example, when using the phrase "an alkyl group comprising an amino group," the amino group can be incorporated into the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is embedded in or attached to the second group.

[0095] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, 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 substituents may be either the same or different at every position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. It is also contemplated that, in certain embodiments, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted), unless explicitly stated to the contrary.

[0096] As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0097] The term "organic residue" defines a carbon-containing residue, i.e., a residue containing at least one carbon atom, and includes, but is not limited to, the carbon-containing groups, residues, or radicals defined above. Organic residues may contain various heteroatoms or be bonded to another molecule through heteroatoms, including oxygen, nitrogen, sulfur, phosphorus, and the like. Examples of organic residues include, but are not limited to, alkyl or substituted alkyl, alkoxy-substituted alkoxy, mono- or di-substituted amino, amido groups, and the like. Organic residues may preferably contain 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. In further embodiments, organic residues may contain 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.

[0098] A close synonym for the term "residue" is the term "radical," which, as used in the specification and final claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure: TIFF0007800865000004.tif18170. In some embodiments, a radical (e.g., alkyl) can be further modified by having one or more "substituent radicals" attached thereto (i.e., substituted alkyl). The number of atoms in a given radical is not critical to the present disclosure unless indicated to the contrary elsewhere herein.

[0099] As defined and used herein, the term "organic radical" contains one or more carbon atoms. An organic radical can have, for example, 1 to 26 carbon atoms, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In further aspects, an organic radical can have 2 to 26 carbon atoms, 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Organic radicals often have hydrogen bonded to at least some of the carbon atoms of the organic radical. One example of an organic radical that does not contain inorganic atoms is the 5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1 to 10 inorganic heteroatoms bonded to or within it, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, disubstituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfonyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, as these terms are defined elsewhere herein. Some non-limiting examples of organic radicals containing heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals, and the like.

[0100] As defined and used herein, an "inorganic radical" does not contain carbon atoms and therefore includes only atoms other than carbon. Inorganic radicals include bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which may exist individually or be bonded together in chemically stable combinations. Inorganic radicals have up to 10, or preferably 1 to 6 or 1 to 4, inorganic atoms such as those listed above bonded together. Examples of inorganic radicals include, but are not limited to, amino, hydroxy, halogen, nitro, thiol, sulfate, phosphate, and commonly known equivalents. Inorganic radicals do not have metal elements of the periodic table (e.g., alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals) bonded thereto, although such metal ions can sometimes serve as pharmaceutically acceptable cations for anionic inorganic radicals, such as sulfate, phosphate, or similar anionic inorganic radicals. Inorganic radicals do not include metalloid elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or noble gas elements, unless specifically indicated otherwise elsewhere herein.

[0101] As used herein, the term "derivative" means a compound derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to the structures disclosed herein that, based on that similarity, one skilled in the art would expect to exhibit the same or similar activity and utility as the claimed compound, or, as a precursor, to induce the same or similar activity and utility as the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0102] The compounds described herein contain one or more double bonds and can therefore potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the present disclosure includes all such possible isomers, as well as mixtures of such isomers.

[0103] Unless otherwise stated, formulas with chemical bonds shown only with solid lines and not with wedges or dashed lines contemplate each possible isomer, for example, each enantiomer and diastereomer, as well as mixtures of isomers, such as racemic or scalemic mixtures. The compounds described herein contain one or more asymmetric centers and can therefore potentially give rise to diastereomers and optical isomers. Unless otherwise stated, the present disclosure includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0104] Many organic compounds exist in optically active forms, possessing the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture. Many of the compounds described herein may have one or more chiral centers and therefore may exist in different enantiomeric forms. Where desired, chiral carbons may be indicated with an asterisk (*). When a bond to a chiral carbon is shown as a straight line in a disclosed formula, both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are encompassed by the formula. As used in the art, when it is desired to specify the absolute configuration around a chiral carbon, one of the bonds to the chiral carbon can be shown as a wedge (a bond to an atom above the plane), and the other can be shown as a series of short parallel lines or a wedge (a bond to an atom below the plane). The Cahn-Ingold-Prelog system can be used to assign an (R) or (S) configuration to a chiral carbon.

[0105] The compounds described herein comprise atoms of both their natural isotopic abundance and non-natural abundance.The disclosed compounds may be identical to their isotopically labeled or isotopically substituted compounds, but one or more atoms may be replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is typically found in nature.The examples of isotopes that can be incorporated into the compounds of the present disclosure include: 2 H, 3 H, 13C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 Included within the scope of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as Cl. Compounds further include prodrugs thereof, and pharmaceutically acceptable salts of such compounds or such prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled compounds of the present disclosure, such as 3 H and 14 Those in which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavier isotopes such as H can offer certain therapeutic advantages due to added metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the following procedures by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0106] The compounds described in the present disclosure can exist as solvates.In some cases, the solvent used to prepare solvates is an aqueous solution, and then the solvates are often referred to as hydrates.The compounds can exist as hydrates, which can be obtained, for example, by crystallization from a solvent or aqueous solution.In this regard, one, two, three, or any number of solvents or water molecules can be combined with the compounds according to the present disclosure to form solvates and hydrates.Unless stated to the contrary, the present disclosure includes all such possible solvates.

[0107] The term "cocrystal" refers to a physical association of two or more molecules that achieves stability through non-covalent interactions. One or more components of this molecular complex provide a stable framework within the crystal lattice. In certain cases, the guest molecule is incorporated into the crystal lattice as an anhydrate or solvate. See, for example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. An example of a cocrystal is p-toluenesulfonic acid and benzenesulfonic acid.

[0108] Chemical substances are known to form solids that exist in different ordered states, called polymorphic forms or modifications. Different modifications of polymorphic substances can have significantly different physical properties. Compounds according to the present disclosure can exist in different polymorphic forms, and certain modifications may be metastable. Unless otherwise stated, the present disclosure includes all such possible polymorphic forms.

[0109] Certain materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques well known to those skilled in the art. For example, starting materials and reagents used in preparing the disclosed compounds and compositions are available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or can be synthesized by methods known to those skilled in the art, as described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers, These compounds are either prepared according to procedures described in references such as (Inc., 1989).

[0110] Unless otherwise expressly stated, no method described herein is intended to be construed in any way as requiring that its steps be performed in a particular order. Thus, a method claim does not actually recite an order to be followed by its steps or otherwise specifically state in the claim or description that the steps are limited to a particular order, and no order is intended to be inferred in any way. This also applies to any possible implicit basis for interpretation, including logical considerations regarding the arrangement of steps or operational flow, plain meaning derived from grammatical construction or punctuation, and the number or type of embodiments described within the specification.

[0111] Disclosed are components used to prepare the disclosed compositions, as well as the compositions themselves used within the methods disclosed herein. These and other materials are disclosed herein, and when combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that specific reference to each of the various individual and collective combinations and permutations of these compounds cannot be explicitly disclosed, but each is specifically contemplated and described herein. For example, when a particular compound is disclosed and discussed, and multiple modifications that can be made to multiple molecules comprising the compound are discussed, what is specifically contemplated is any and all combinations and permutations of the compounds and modifications that are possible, unless stated to the contrary. Thus, when classes of molecules A, B, and C, and classes of molecules D, E, and F are disclosed, and example combined molecules A-D are disclosed, each is individually and collectively contemplated, even if not individually listed, meaning that combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the subgroups A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application, including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, where there are various additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

[0112] It is understood that the compositions disclosed herein have certain functions, and that certain structural requirements for performing the disclosed functions are disclosed herein, and that there are a variety of structures that can perform the same function associated with the disclosed structures, and that these structures will typically achieve the same result.

[0113] Described herein are compounds that inhibit dihydroorotate dehydrogenase (DHODH) and may have therapeutic or clinical utility for diseases or disorders that can be treated by inhibiting DHODH. Also described herein are methods for synthesizing the disclosed compounds. Also described herein are methods for administering the disclosed compounds to a subject in need thereof. In some embodiments, the subject may have a disease or disorder associated with DHODH activity, such as cancer, a disorder or disease associated with T-cell proliferation, or graft-versus-host disease. Other compositions, compounds, methods, features, and advantages of the present disclosure will be, or become, apparent to those skilled in the art upon review of the following figures and detailed description, and examples. All such additional compositions, compounds, features, and advantages are intended to be included within this description and within the scope of the present disclosure.

[0114] compound. In various embodiments, the disclosed compounds are 6-substituted-2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analogs useful as inhibitors of dihydroorotate dehydrogenase, which have applications as therapeutic agents in a variety of clinical conditions, such as cancer, graft-versus-host disease, and disorders associated with T-cell proliferation.

[0115] Disclosed herein are compounds having a formula represented by the structure: TIFF0007800865000005.tif39170, R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is halogen, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1 is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1 is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d are each independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0116] Disclosed herein are compounds having a formula represented by the structure: TIFF0007800865000006.tif38170, R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5efour of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d are each independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0117] Disclosed herein are compounds having a formula represented by the structure: TIFF0007800865000007.tif38170, R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of them has the structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5efour of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d are each independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, R 6a , R 6b , R 6c , and R 6d can be independently selected from hydrogen, halogen, C-C alkyl, C-C alkoxy, and C-C haloalkyl. 6a and R 6b is independently selected from hydrogen and halogen. 6a is fluoro or R 6b is fluoro, or a combination thereof. 6c and R 6d can be hydrogen.

[0119] In other aspects, disclosed herein is a compound having the structure: TIFF0007800865000008.tif61170TIFF0007800865000009.tif188170TIFF0007800865000010.tif183170 or a combination thereof.

[0120] In other aspects, disclosed herein is a compound having the structure: TIFF0007800865000011.tif164170TIFF0007800865000012.tif173170TIFF0007800865000013.tif193170TIFF0007800865000014.tif171170TIFF0007800865000015.tif84170 or a subgroup thereof.

[0121] In other aspects, disclosed herein is a compound having the structure: TIFF0007800865000016.tif64170 or a combination thereof.

[0122] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0123] In various aspects, the disclosed compounds are also intended to include their biological equivalents. The term "bioequivalent" refers to a compound or group that possesses approximately the same molecular shape and volume, approximately the same electron distribution, and exhibits similar physical and biological properties. Examples of such equivalents include (i) fluorine to hydrogen, (ii) oxo to thia, (iii) hydroxyl to amide, (iv) carbonyl to oxime, and (v) carboxylate to tetrazole. Examples of such bioisosteric substitutions can be found in the literature, including (i) Burger A, Relation of chemical structure and biological activity (Medicinal Chemistry Third ed., Burger A, ed.; Wiley-Interscience; New York, 1970, 64-80); (ii) Burger, A.; "Isosterism and bioisosterism in drug design"; Prog. Drug Res. 1991, 37, 287-371; (iii) Burger A, "Isosterism and bioanalogy in drug design", Med. Chem. Res. 1994, 4, 89-92; (iv) Clark RD, Ferguson AM, Cramer RD, "Bioisosterism and molecular diversity", Perspect. Drug Discovery Des. 1998, 9 / 10 / 11, 213-224; (v) Koyanagi T, Haga T, "Bioisosterism in agrochemicals”, ACS Symp. Ser. 1995, 584, 15-24, (vi) Kubinyi H, “Molecular similarities. Part 1.Chemical structure and biological activity”, Pharm. Unserer Zeit 1998, 27, 92-106, (vii) Lipinski C A.; “Bioisosterism in drug design”; Annu. Rep. Med. Chem.1986, 21, 283-91, (viii) Patani GA, LaVoie EJ, “Bioisosterism: A rational approach in drug design”, Chem.Rev. (Washington, DC) 1996, 96, 3147-3176, (ix) Soskic V, Joksimovic J, “Bioisosteric approach in the design of new dopaminergic / serotonergic (x) Thornber CW, “Isosterism and molecular modification in drug design”, Chem. Soc. Rev. 1979, 8, 563-80. .

[0124] In a further aspect, a bioisostere is an atom, ion, or molecule whose electron periphery can be considered substantially identical. The term bioisostere is typically used to refer to a portion of an entire molecule, as opposed to the entire molecule itself. Bioisosteric substitution involves using one bioisostere to replace another, with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. Thus, the bioisostere in this case is an atom or group of atoms with similar size, shape, and electron density. Preferred bioisosteres of esters, amides, or carboxylic acids are compounds containing two sites for hydrogen-bonding tolerance. In one embodiment, the bioisostere of an ester, amide, or carboxylic acid is a five-membered monocyclic heteroaryl ring, such as optionally substituted 1H-imidazolyl, optionally substituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or optionally substituted [1,2,4]oxadiazolyl.

[0125] In various embodiments, the disclosed compounds are also intended to include isotopically labeled or isotopically substituted variants thereof, i.e., compounds identical to the described compounds, but in which one or more atoms have been replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 Included within the scope of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl. Compounds further include prodrugs thereof, and pharmaceutically acceptable salts of such compounds or such prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled compounds of the present disclosure, such as 3 H and 14 Those in which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavier isotopes such as H can offer certain therapeutic advantages due to added metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the following procedures by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0126] In various embodiments, the disclosed compounds may possess at least one asymmetric center and may exist in the form of their racemates, in the form of pure enantiomers and / or diastereomers, or in the form of mixtures of these enantiomers and / or diastereomers. Stereoisomers may exist in any proportion of mixtures. In some embodiments, where this is possible, the disclosed compounds may exist in the form of tautomers.

[0127] Thus, for example, the disclosed compounds that possess one or more chiral centers and occur as racemates can be separated into optical isomers, i.e., enantiomers or diastereomers, using methods known per se. This separation can be brought about by column separation on a chiral phase, or by recrystallization from an optically active solvent, or by derivatization with an optically active acid or base, or with an optically active reagent such as an optically active alcohol, followed by cleavage of the residue.

[0128] In various embodiments, the disclosed compounds may be in the form of cocrystals. The term "cocrystal" refers to a physical association of two or more molecules that achieves stability through non-covalent interactions. One or more components of the molecular complex provide a stable framework within the crystal lattice. In certain cases, the guest molecule is incorporated into the crystal lattice as an anhydride or solvate. See, for example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Preferred cocrystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0129] The term "pharmaceutically acceptable co-crystal" means one that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0130] In a further aspect, the disclosed compounds can be isolated as solvates, particularly hydrates of the disclosed compounds, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In this regard, one, two, three, or any number of solvate or water molecules can combine with a compound according to the present disclosure to form solvates and hydrates.

[0131] The disclosed compounds can be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, and salts formed with suitable organic ligands, for example, quaternary ammonium salts, which can be prepared by reacting drug compounds with suitable pharmaceutically acceptable bases. Salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or after final isolation, by reacting free base functions, such as secondary or tertiary amines, of the disclosed compounds with suitable inorganic or organic acids, or by reacting free acid functions, such as carboxylic acids, of the disclosed compounds with suitable inorganic or organic bases.

[0132] Acid addition salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or by reacting a moiety containing one or more nitrogen groups with a suitable acid. In various embodiments, acids that can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. In a further embodiment, salts further include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate), nicotinic acid The basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfides such as dimethyl, diethyl, dibutyl, and diamyl; long chain halides such as decyl chlorides, bromides, and iodides; lauryl, myristyl, and stearyl; aralkyl halides such as benzyl bromide and phenethyl bromide; and others.

[0133] Base addition salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or separately, by reacting the carboxylic acid moiety with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia, or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. In a further aspect, bases that can be used in the preparation of pharmaceutically acceptable salts include ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

[0134] The disclosed compounds can be advantageously utilized as building blocks of degradation molecules. Thus, in various embodiments, the disclosed compounds can be used as ligands, linkers, or adjacent chemical structures within proteolysis targeting complexes or targeted proteolysis complexes. For example, proteolysis targeting chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome (see, for example, Bondeson and Crews, Annu Rev Pharmacol Toxicol. 2017 Jan 6; 57: 107-123; Lai et al. Angew Chem Int Ed Engl. 2016 Jan 11; 55(2): 807-810; and PCT Application No. PCT / US2018 / 061573).

[0135] In a further embodiment, the disclosed compounds further comprise a conjugate with a proteolytic targeting chimera (PROTAC), thereby providing interaction with the intracellular ubiquitin-proteasome system and selectively degrading the target protein. For example, in some cases, any one or more compounds can be used to form a composition, chimera, fusion, or complex with proteolytic function. Some exemplary complexes can include a protein targeting chimera (PROTAC) or degronimide. As will be understood by those skilled in the art, such complexes can combine or link cellular processes related to protein degradation to a specific target protein, and the cellular machinery and the target protein are conjugated by a ligand, a linker, or a neighboring chemical structure.

[0136] Methods for making compounds. In one aspect, the disclosure relates to methods of making compounds useful as inhibitors of dihydroorotate dehydrogenase (DHODH), which may be useful in treating clinical conditions, diseases, and disorders associated with DHODH dysfunction, as well as other diseases in which DHODH is implicated. In one aspect, the disclosure relates to the disclosed synthetic procedures. In a further aspect, the disclosed compounds include products of the synthetic methods described herein. In a further aspect, the disclosed compounds include compounds produced by the synthetic methods described herein. In still a further aspect, the disclosure includes pharmaceutical compositions comprising a therapeutically effective amount of a product of the disclosed methods and a pharmaceutically acceptable carrier. In still a further aspect, the disclosure includes a method for manufacturing a medicament comprising combining at least one compound of any of the disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.

[0137] The compounds of the present disclosure can be prepared by using the reactions shown in the disclosed schemes, in addition to other standard operations known in the literature, illustrated in the experimental section, or apparent to those skilled in the art. The following examples are provided so that the present disclosure may be more fully understood and are merely illustrative and should not be construed as limiting. For clarity, when multiple substituents are permitted under the definitions disclosed herein, examples with fewer substituents may be shown.

[0138] It is contemplated that each disclosed method may further include additional steps, operations, and / or components. It is also contemplated that any one or more steps, operations, and / or components may optionally be omitted from the present disclosure. It is understood that the disclosed methods can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be used in the disclosed compositions, kits, and uses.

[0139] In one aspect, the substituted 6-substituted-2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analogs of the present disclosure can be generally prepared by the synthetic scheme as shown below. TIFF0007800865000017.tif34170Step 1 (Suzuki-Miyaura reaction). TIFF0007800865000018.tif38170 Step 2 (Pfitzinger reaction).

[0140] The compounds are depicted in generic form, with substituents as described in the compound descriptions elsewhere herein. More specific examples are described below. TIFF0007800865000019.tif27170Step 1 (Suzuki-Miyaura reaction). TIFF0007800865000020.tif27170Step 2 (Pfitzinger reaction).

[0141] In one embodiment, compounds of the present disclosure, such as compounds of formula 5, can be prepared in a two-step reaction as shown above. Briefly, the synthesis of compounds of formula 5 begins in step 1 with the reaction of compounds of formula 1 and 2 to produce compounds of formula 3. Compounds of formula 1, i.e., 4-halo-substituted phenone analogs, such as 3-fluoro-4-bromoacetophenone, and compounds of formula 2, i.e., appropriately substituted phenylboronic acids, such as 4-ethoxyphenylboronic acid, can be obtained from commercial sources or can be easily prepared by those skilled in the art according to methods described in the literature. For example, both 3-fluoro-4-bromophenone and 4-ethoxyphenylboronic acid are commercially available. The reaction of the compounds of Formulas 1 and 2 is typically carried out in a suitable solvent, such as 1-propanol, in the presence of palladium acetate and triphenylphosphine in a molar ratio of the compound of Formula 1 to the compound of Formula 2 of about 25:1 to about 1:1, at a suitable temperature, such as about 75°C to about 200°C, for a suitable period of time, such as about 10 minutes to about 2 hours, to ensure the reaction is complete. The reaction is then cooled to a suitable temperature, such as room temperature, and then further cooled, such as to about 0°C, to obtain suitable crystals that can be collected by filtration. Other suitable methods for isolating the product will be apparent to those skilled in the art.

[0142] In Step 2, the compound of Formula 3 isolated from Step 1 is reacted with a compound of Formula 4 to produce the desired disclosed compound of Formula 5, as shown above. Briefly, a mixture of an appropriate isatin, i.e., a compound of Formula 4, e.g., 5-fluoroisatin (5-fluoroindoline-2,3-dione), and a suitable base, e.g., aqueous potassium hydroxide (33%), is gently stirred and heated. To this solution, a roughly equimolar amount of a compound of Formula 3, e.g., 1-(4'-ethoxy-[1,1'-biphenyl]-4-yl)ethan-1-one, relative to the compound of Formula 4, and a suitable solvent, e.g., ethanol, are added to form a slurry. The reaction mixture is then heated to a suitable temperature, e.g., reflux or about 70°C to about 200°C, for a suitable period of time, e.g., about 10 minutes to about 3 hours, to ensure completion of the reaction. The reaction is then cooled to a suitable temperature, for example, room temperature, and then further cooled, for example, to about 0°C, to obtain suitable crystals that can be collected by filtration. Other suitable methods for isolating the product will be apparent to those skilled in the art. The product can also be further purified, if residual solvent is present, for example, by methods known in the art.

[0143] Pharmaceutical compositions. In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of the disclosed method, or a pharmaceutically acceptable salt thereof.As used herein, " pharmaceutically acceptable carrier " refers to one or more of pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, release agents, coating agents, sweeteners, flavorings and fragrances, and adjuvants.The disclosed pharmaceutical compositions are conveniently presented in unit dosage form and can be prepared by any method well known in the fields of pharmacy and pharmaceutical science.

[0144] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of the disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agents, and optionally one or more adjuvants. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. In a further aspect, the disclosed pharmaceutical compositions can be formulated to allow for oral, nasal, inhalation, parenteral, peri-cancer, transmucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intraventricular, intracranial, and intratumoral administration.

[0145] As used herein, "parenteral administration" includes administration by bolus injection or infusion, as well as intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0146] In various aspects, the present disclosure also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a therapeutically effective amount of the disclosed compounds, products of the disclosed methods of making, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or stereochemically isomeric forms thereof. In further aspects, the disclosed compounds, products of the disclosed methods of making, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or stereochemically isomeric forms thereof, or any subgroups or combinations thereof, can be formulated into various pharmaceutical forms for administration purposes.

[0147] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable non-toxic bases or acids. For therapeutic use, the salts of the disclosed compounds are salts in which the counterions are pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are contemplated by the present disclosure. Pharmaceutically acceptable acid and base addition salts are intended to include the therapeutically active non-toxic acid and base addition salt forms that the disclosed compounds can form.

[0148] In various aspects, the disclosed compounds containing acidic groups or moieties, such as carboxylic acid groups, can be used to prepare pharmaceutically acceptable salts. For example, such disclosed compounds can include an isolation step, including treatment with a suitable inorganic or organic base. In some cases, it may be practical to first isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and then convert the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be easily prepared using conventional techniques, for example, by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanolic solutions of the acidic compound and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as described above.

[0149] Bases that can be used to prepare pharmaceutically acceptable base addition salts of basic compounds are those that can form non-toxic base addition salts, i.e., salts containing alkali metal cations (e.g., lithium, potassium, and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium, or other water-soluble amine addition salts, such as N-methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines. In a further embodiment, those derived from pharmaceutically acceptable non-toxic organic bases include cyclic amines and substituted amines, such as primary, secondary, and tertiary amines, and naturally occurring and synthetic substituted amines. In various embodiments, such pharmaceutically acceptable organic non-toxic bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any of the four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, N,N'-dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, thiazolinone ... Included are methamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine, quinoline, and isoquinoline, benzathine, N-methyl-D-glucamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, methylglucurcamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, hydrabamine salts, and salts with amino acids such as histidine, arginine, lysine, and the like. The aforementioned salt forms can be converted back to the free acid forms by treatment with acid.

[0150] In various aspects, the disclosed compounds containing protonatable groups or moieties, such as amino groups, can be used to prepare pharmaceutically acceptable salts. For example, such disclosed compounds can include an isolation step involving treatment with a suitable inorganic or organic acid. In some cases, it may be practical to first isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to the free base compound by treatment with a basic reagent, and then convert the free base to a pharmaceutically acceptable acid addition salt. These acid addition salts can be readily prepared using conventional techniques, for example, by treating the corresponding basic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by treating the free base form of the disclosed compounds with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0151] Acids that can be used to prepare pharmaceutically acceptable acid addition salts are those that can form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions formed from the corresponding inorganic and organic acids. Exemplary, but non-limiting, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Exemplary, but non-limiting, organic acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, and the like. In a further embodiment, the acid addition salts contain anions formed from hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0152] In practice, the compounds of the present disclosure or pharmaceutically acceptable salts thereof can be combined as active ingredients in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. The carriers can take a wide variety of forms depending on the preparation desired for administration, e.g., oral or parenteral (including intravenous) administration. Thus, pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be presented as a powder, granules, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. In addition to the common dosage forms listed above, the compounds of the present disclosure and / or pharmaceutically acceptable salts thereof can also be administered by controlled-release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, The product can then be conveniently shaped into the desired presentation.

[0153] It is particularly advantageous to formulate the above-mentioned pharmaceutical composition into a unit dosage form for ease of administration and uniformity of dosage.As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit summary amount, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect together with the required pharmaceutical carrier.That is, "unit dosage form" is interpreted to mean a single dose in which all active and inactive ingredients are combined in a suitable system, so that a patient or a person administering a drug to a patient can open a single container or package containing the entire dose, and there is no need to mix any components from two or more containers or packages together.Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules, or pills for oral administration, single-dose vials for injectable solutions or suspensions, suppositories for rectal administration, powder packets, wafers, and segregated multiples thereof.This list of unit dosage forms is not intended to be limiting in any way, but is intended to simply represent typical examples of unit dosage forms.

[0154] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, one or more additional therapeutic agents. In various embodiments, the disclosed pharmaceutical compositions can comprise a pharmaceutically acceptable carrier and a disclosed compound or a pharmaceutically acceptable salt thereof. In further embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. Compositions of the present invention include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical compositions are conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy.

[0155] Techniques and compositions for making dosage forms useful in the materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7 (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989), Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993), Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; JGHardy, SSDavis, Clive G. Wilson, Eds.), Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).

[0156] The compounds described herein are typically administered in admixture with suitable pharmaceutical diluents, excipients, fillers, or carriers (herein referred to as pharmaceutically acceptable carriers, or carriers), which are appropriately selected according to the intended administration form and in accordance with conventional pharmaceutical practice.The deliverable compound may be in a form suitable for oral, rectal, topical, intravenous injection, or parenteral administration.Carriers include solid or liquid, and the type of carrier is selected based on the type of administration used.The compound may be administered as a dosage with a known amount of the compound.

[0157] For ease of administration, oral administration may be the preferred dosage form, with tablets and capsules representing the most advantageous oral dosage forms when solid pharmaceutical carriers are clearly employed. However, other dosage forms may be suitable depending on the clinical population (e.g., age and severity of clinical condition), the solubility characteristics of the particular disclosed compound used, and the like. Thus, the disclosed compounds may be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. When preparing compositions for oral dosage forms, any convenient pharmaceutical medium may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs, and solutions, while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules, and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units when solid pharmaceutical carriers are used. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0158] The disclosed pharmaceutical compositions in oral dosage form can include one or more pharmaceutical excipients and / or additives. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as sugar or lactose, lecithin, pectin, starch (e.g., corn starch or amylose), dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talc, lycopodium, silica gel (e.g., colloid), cellulose, cellulose derivatives (e.g., cellulose derivatives in which the cellulose hydroxy groups are bonded to low-saturated aliphatic alcohols and / or low-saturated aliphatic oxyalcohols, e.g., methyloxypropyl cellulose, methylcellulose, etc.), and the like. cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose ethers partially etherified with phthalic acid), fatty acids and magnesium, calcium or aluminum salts of fatty acids having 12 to 22 carbon atoms, in particular saturated ones (for example stearates), emulsifiers, fats and oils, in particular vegetable oils (for example peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, coconut liver oil, also optionally hydrated in each case), saturated fatty acids C 12 H 24 O2~C 18 H 36Glycerol and polyglycerol esters of O2 and mixtures thereof (wherein the glycerol hydroxy groups may be fully or partially esterified (e.g., mono-, di-, triglycerides)), pharmaceutically acceptable mono- or polyhydric alcohols such as polyethylene glycol and their derivatives, fatty acids with monohydric aliphatic alcohols (1-20 carbon atoms) or polyhydric alcohols such as glycol, glycerol, diethylene glycol, pentacryltriol, sorbitol, mannitol, and the like, which may also be esterified. Examples include esters of saturated or unsaturated aliphatic fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms), primary alcohols, acetic acid, urea, benzyl benzoate, dioxolane, glyceroform, esters of citric acid with tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C12 alcohols, dimethylacetamide, lactamide, lactate, ethyl carboxylate, silicones (especially medium viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, and the like.

[0159] Other auxiliary substances useful in preparing oral dosage forms are those that cause disintegration (so-called disintegrants), such as cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, or microcrystalline cellulose. Conventional coating substances can also be used to produce oral dosage forms. For example, coating substances that can be considered include polymers and copolymers of acrylic acid and / or methacrylic acid and / or their esters, copolymers of acrylic acid and methacrylic acid esters with a low ammonium group content (e.g., Eudragit® RS), copolymers of acrylic acid and methacrylic acid esters and trimethylammonium methacrylate (e.g., Eudragit® RS). RL), polyvinyl acetate, fats, oils, waxes, fatty alcohols, hydroxypropyl methylcellulose phthalate or acetate succinate, cellulose acetate phthalate, starch acetate phthalate and polyvinyl acetate phthalate, carboxymethylcellulose, methylcellulose phthalate, methylcellulose succinate, -phthalate succinate, and methylcellulose phthalic acid half ester, zein, ethylcellulose and ethylcellulose succinate, shellac, gluten, ethylcarboxyethylcellulose, ethacrylate-maleic anhydride copolymer, maleic anhydride-vinyl methyl ether copolymer, styrene-maleic acid copolymer, 2-ethyl-hexyl-acrylate maleic anhydride, crotonic acid-vinyl acetate copolymer, glutamic acid / glutamic acid ester copolymer, carboxymethylethylcellulose glycerol monooctanoate, cellulose acetate succinate, polyarginine, and the like.

[0160] Plasticizers that may be considered as coating materials in the disclosed oral dosage forms include citric and tartaric acid esters (acetyl-triethylcitrate, acetyltributyl-, tributyl-, triethyl-citrate), glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil), phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate, and butylphthalylethyl glycolate. The following are examples of suitable oleic acid surfactants: ethyl glycolate, alcohols (propylene glycol, polyethylene glycols of various chain lengths), adipates (diethyl adipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate, benzophenone, diethyl and dibutyl sebacate, dibutyl succinate, dibutyl tartrate, diethylene glycol dipropionate, ethylene glycol diacetate, dibutyrate, dipropionate, tributyl phosphate, tributyrin, polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbate 50), sorbitan monooleate, and the like.

[0161] In addition, suitable binder, lubricant, disintegrant, coloring agent, flavoring agent, flow inducer and melting agent can be included as carrier.The pharmaceutical carrier used can be, for example, solid, liquid or gas.The example of solid carrier includes but is not limited to lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, talc, starch, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.The example of liquid carrier includes sugar syrup, peanut oil, olive oil and water.The example of gas carrier includes carbon dioxide and nitrogen.

[0162] In various embodiments, binders can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. In further embodiments, disintegrants can include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

[0163] In various embodiments, oral dosage forms, such as solid dosage forms, can include the disclosed compounds linked to polymers as targetable drug carriers or prodrugs. Suitable biodegradable polymers useful in achieving controlled drug release include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0164] The tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients may be inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period.

[0165] The tablet containing the disclosed compound can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants.Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, a surfactant, or a dispersant, in a suitable machine.Molded tablets can be produced by molding a mixture of the powdered compound moistened with an inert diluent in a suitable machine.

[0166] In various embodiments, solid oral dosage forms such as tablets can be coated with an enteric coating to prevent them from disintegrating easily in the stomach. In various embodiments, enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate phthalate, and cellulose acetate phthalate. See Akihiko Hasegawa, "Application of solid dispersions of nifedipine with enteric coating agents to prepare a sustained-release dosage form," Chem. Pharm. Bull. 33:1615-1619 (1985). Various enteric coating materials can be selected based on testing to achieve enteric-coated dosage forms originally designed to have a desirable combination of dissolution time, coating thickness, and diametral crushing strength (see, e.g., S. Corter et al. "The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate," Pharmacol. 22:42p (1970)). In a further embodiment, the enteric coating can include hydroxypropyl-methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate, and cellulose acetate phthalate.

[0167] In various embodiments, the oral dosage form can be a solid dispersion containing a water-soluble or water-insoluble carrier. Examples of water-soluble or water-insoluble carriers include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylcellulose, or hydroxypropylmethylcellulose, ethylcellulose, or stearic acid.

[0168] In various aspects, oral dosage forms can be liquid dosage forms, including those that can be taken orally or alternatively administered as mouthwash or gargle.For example, liquid dosage forms can include aqueous suspensions containing active materials mixed with suitable excipients for the preparation of aqueous suspensions.In addition, oily suspensions can be prepared by suspending active ingredients in vegetable oils, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin.Oily suspensions can also contain various excipients.The pharmaceutical compositions of the present disclosure can also be in the form of oil-in-water emulsions, which can also contain excipients such as sweeteners and flavoring agents.

[0169] For the preparation of solutions or suspensions, it is possible to use, for example, water, in particular sterile water, or physiologically acceptable organic solvents, such as ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and derivatives thereof, fatty alcohols, alcohols such as partial esters of glycerol, oils (e.g., peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil, castor oil, bovine hoof oil), paraffin, dimethyl sulfoxide, triglycerides, and the like.

[0170] In the case of liquid dosage forms such as drinking solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- or polyhydric alcohols having 2 to 4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols having a molecular weight of 200 to 600 (e.g., 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, such as amides of aliphatic C1-C6 carboxylic acids with ammonia or primary, secondary, or tertiary C1-C4 amines or C1-C4 hydroxyamines, such as urea, urethane, acetamide, N-methylacetamide, N,N-diethylacetamide, N,N-dimethylacetamide, lower aliphatic amines and diamines having 2 to 6 carbon atoms, such as ethylenediamine, hydroxyethyltheophylline, tromethamine (e.g., as a 0.1 to 20% aqueous solution), and aliphatic amino acids.

[0171] Upon preparation, the disclosed liquid dosage forms can include solubilizers and emulsifiers, including, but not limited to, polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolized oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols, or fatty acids, and 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context, polyoxyethylated means that the substance in question contains polyoxyethylene chains, the degree of polymerization of which is generally 2 to 40, and particularly 10 to 20. Polyoxyethylated substances of this type can be obtained, for example, by reacting hydroxyl-containing compounds (e.g., mono- or diglycerides or unsaturated compounds, such as compounds containing an oleic acid radical) with ethylene oxide (e.g., 40 moles of ethylene oxide per mole of glyceride). Examples of oleotriglycerides include olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, and corn oil. See also Dr. HP Fiedler, "Lexikon der Hillsstoffe fur Pharmazie, Kostnetik und angrenzende Gebiete," 1971, pages 191-195.

[0172] In various embodiments, the liquid dosage form can further include preservatives, stabilizers, buffer substances, taste correctors, sweeteners, colorants, antioxidants, and complexing agents, and the like. For example, complexing agents that may be considered are chelating agents such as ethylenediaminetetraacetic acid, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, and salts thereof.

[0173] Optionally, it may be necessary to stabilize the liquid dosage form with a physiologically acceptable base or buffer to a pH range of approximately 6 to 9. A neutral or slightly basic pH value (maximum pH 8) is considered preferable whenever possible.

[0174] To improve the solubility and / or stability of the disclosed compounds in the disclosed liquid dosage forms, parenteral injection forms, or intravenous injectable forms, it may be advantageous to use α-, β-, or γ-cyclodextrin or derivatives thereof, particularly hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Cosolvents such as alcohols may also improve the solubility and / or stability of the compounds according to the present disclosure in pharmaceutical compositions.

[0175] In various aspects, the disclosed liquid dosage forms, parenteral injection forms, or intravenous injection forms can further comprise delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicle liposomes. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0176] The pharmaceutical composition of the present disclosure is suitable for parenteral administration, such as intravenous, intramuscular, or subcutaneous administration, by injection. Pharmaceutical compositions for injection can be prepared as a solution or suspension of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. In addition, preservatives can be included to prevent harmful growth of microorganisms.

[0177] Pharmaceutical compositions of the present disclosure suitable for parenteral administration can include sterile aqueous or oily solutions, suspensions, or dispersions. Moreover, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some embodiments, the final injectable form must be sterile and effectively fluid for use in syringes. The pharmaceutical composition should be stable under the conditions of manufacture and storage, and therefore preferably protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0178] For example, injectable solutions can be prepared in which the carrier comprises saline solution, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, and the like can be used. In some embodiments, the disclosed parenteral formulations can comprise about 0.01-0.1 M, e.g., about 0.05 M, phosphate buffer. In further embodiments, the disclosed parenteral formulations can comprise about 0.9% saline.

[0179] In various embodiments, the disclosed parenteral pharmaceutical compositions can include pharmaceutically acceptable carriers, such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include, but are not limited to, water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives, such as antimicrobials, antioxidants, collating agents, and inert gases, can also be present. In another aspect, the disclosed parenteral pharmaceutical composition can contain minor additives, such as substances that enhance isotonicity and chemical stability, for example, buffers and preservatives.Also contemplated are injectable pharmaceutical compositions of solid-form preparations, which are intended to be converted into liquid-form preparations immediately before use.In addition, other adjuvants can be included to make the formulation isotonic with the blood of the subject or patient.

[0180] In addition to the pharmaceutical compositions described herein above, the disclosed compounds can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.Therefore, for example, the compounds can be prepared using suitable polymeric or hydrophobic materials (for example, as emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0181] The pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration. As used herein, the phrase "topical application" refers to administration onto a biological surface, such as the skin (e.g., hands, forearms, elbows, legs, face, nails, anal, and genital areas) or mucous membranes. By selecting an appropriate carrier and, optionally, other ingredients that may be included in the composition as detailed herein below, the compositions of the present disclosure can be formulated into any form typically used for topical administration. Topical pharmaceutical compositions can take the form of creams, ointments, pastes, gels, lotions, milks, suspensions, aerosols, sprays, foams, dusting powders, pads, and patches. Furthermore, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared using the compounds of the present disclosure or pharmaceutically acceptable salts thereof via conventional processing methods. For example, a cream or ointment can be prepared by mixing about 5% to about 10% by weight of the compound, a hydrophilic material, and water together to produce a cream or ointment having the desired consistency.

[0182] In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable wetting agent, optionally combined with a small proportion of suitable additives of any nature that do not introduce significant adverse effects on the skin. Such additives may facilitate application to the skin and / or may be useful for preparing the desired composition. These compositions may be administered in various ways, for example, as a transdermal patch, as a spot-on, or as an ointment.

[0183] Ointments are semi-solid preparations typically based on petrolatum or petroleum derivatives.The specific ointment base used is one that provides optimal delivery for the active agent selected for a given formulation, and preferably also provides other desired characteristics (e.g., softening).Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.As described in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp.1399-1404, ointment bases can be grouped into four classes: oily bases, emulsifiable bases, emulsion bases, and water-soluble bases.Oil-based ointment bases include, for example, vegetable oils, fats obtained from animals, and semi-solid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of various molecular weights.

[0184] Lotion is a preparation that is applied to the skin surface without friction.Lotion is typically a liquid or semi-liquid preparation, and solid particles, including active agents, are present in a water or alcohol base.Lotion is typically preferred for treating large body areas because it is easier to apply a more fluid composition.Lotion is typically a suspension of solids, often containing a liquid oily emulsion of oil-in-water type.Generally, the insoluble material in lotion needs to be finely divided.Lotion typically contains a suspending agent to provide better dispersion, as well as a compound that is useful for localizing and retaining active agents in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.

[0185] Creams are viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, is generally composed of petrolatum and / or fatty alcohols such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. For further information, see Remington: The Science and Practice of Pharmacy (see above).

[0186] Pastes are semi-solid dosage forms in which bioactive agents are suspended in a suitable base. Depending on the nature of the base, pastes are divided into fatty pastes or those made from single-phase aqueous gels. The base in fatty pastes is generally petrolatum, hydrophilic petrolatum, and the like. Pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. For further information, please refer to Remington: The Science and Practice of Pharmacy.

[0187] Gel formulations are semi-solid suspension-type systems.Single-phase gels contain organic polymers distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but preferably also contains alcohol and optionally oil.Preferred organic polymers, i.e., gelling agents, are cross-linked acrylic acid polymers, such as the carbomer polymer family, for example, carboxypolyalkylene, which can be commercially obtained under the trade name Carbopol™.Other preferred types of polymers in this context are hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; modified celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin.To prepare a uniform gel, dispersants such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, or stirring, or a combination thereof.

[0188] Sprays generally provide active agents in aqueous and / or alcoholic solutions that can be sprayed onto the skin for delivery.Such sprays include those formulated to provide a concentrated active agent solution at the administration site after delivery; for example, the spray solution can be mainly composed of alcohol or other similar volatile liquids that can dissolve the active agent.Once delivered to the skin, the carrier evaporates, leaving the concentrated active agent at the administration site.

[0189] Foam compositions are typically formulated into a single-phase or multi-phase liquid form and housed in a suitable container, optionally with a propellant that facilitates the expulsion of the composition from the container, thereby converting it into a foam upon application. Other foam-forming techniques include, for example, the "bag-in-a-can" formulation technique. Compositions formulated in this manner typically contain a low-boiling hydrocarbon, such as isopropane. When such compositions are applied and stirred at body temperature, the isopropane evaporates, producing a foam in a manner similar to that of a pressurized aerosol foaming system. Foams can be water-based or aqueous alkanols, but are typically formulated with a high alcohol content, which evaporates quickly when applied to the user's skin, propelling the active ingredient through the upper skin layers to the treatment site.

[0190] Skin patches typically include a backing to which a reservoir containing an active agent is attached. The reservoir can be, for example, a pad into which the active agent or composition is dispersed or soaked, or a liquid reservoir. The patch typically also includes a water-permeable adhesive on the front surface that adheres and secures the device to the treatment area. Self-adhesive silicone rubber can alternatively be used. In either case, a protective permeable layer can be used to protect the adhesive surface of the patch before use. Skin patches can also include a removable cover, which serves the function of protecting it during storage.

[0191] Examples of patch configurations that can be used with the present disclosure include single-layer or multi-layer drug-in-adhesive systems, which feature the drug directly contained within the skin contact adhesive. In such transdermal patch designs, the adhesive not only serves to adhere the patch to the skin, but also serves as a formulation matrix containing the drug and all excipients under a single backing film. Multi-layer drug-in-adhesive patches either have a membrane placed between two separate drug-in-adhesive layers, or multiple drug-in-adhesive layers are incorporated under a single backing film.

[0192] Examples of pharmaceutically acceptable carriers suitable for topical pharmaceutical compositions include carrier materials well known for use in the cosmetic and medical fields, such as emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols, and the like, depending on the final form of the composition.Representative examples of suitable carriers according to the present disclosure include, but are not limited to, water, liquid alcohol, liquid glycol, liquid polyalkylene glycol, liquid ester, liquid amide, liquid protein hydrolysate, liquid alkylated protein hydrolysate, liquid lanolin and lanolin derivatives, and similar materials commonly used in cosmetic and pharmaceutical compositions. Other suitable carriers according to the present disclosure include, but are not limited to, alcohols such as monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexylene glycol, mannitol, and propylene glycol, ethers such as diethyl ether or dipropyl ether, polyethylene glycol and methoxypolyoxyethylene (carbowaxes with molecular weights ranging from 200 to 20,000), polyoxyethylene glycerol, polyoxyethylene sorbitol, stearoyl diacetin, and the like.

[0193] The topical composition of the present disclosure can be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient, if desired. The dispenser device may, for example, comprise a tube. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the composition form for human or veterinary administration. Such notice may include, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions comprising the topical composition of the present disclosure formulated with a pharmaceutically acceptable carrier can also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0194] Another patch system configuration that can be used according to the present disclosure is a reservoir transdermal system design, characterized by a liquid compartment containing a drug solution or suspension separated from a release liner by a semipermeable membrane and adhesive. The adhesive component of this patch system can be incorporated either as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Yet another patch system configuration that can be utilized according to the present disclosure is a matrix system design, characterized by a semisolid matrix containing the drug solution or suspension in direct contact with the release liner. The component responsible for skin adhesion is incorporated into an overlay, forming a concentric configuration around the semisolid matrix.

[0195] The pharmaceutical composition of the present disclosure can be in a form suitable for rectal administration, where the carrier is solid.Preferably, the mixture forms unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by first mixing the composition with softened or melted carrier, then cooling and shaping in molds.

[0196] Pharmaceutical compositions containing the compounds of the present disclosure and / or pharmaceutically acceptable salts thereof may also be in powder or liquid concentrate form.

[0197] Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Generally, an article for distribution includes a container that holds the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container typically has a label affixed thereto that describes the contents of the container and any appropriate warnings or instructions.

[0198] The disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. For example, the pack may comprise a metal or plastic foil, such as a blister bag. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may accompany the container with a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or veterinary administration. Such notice may, for example, be labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Pharmaceutical compositions containing the disclosed compounds formulated with a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0199] The exact dosage and frequency of administration will depend, as is well known to those skilled in the art, on the particular disclosed compound, product of the disclosed methods of making, pharmaceutically acceptable salt, solvate, or polymorph thereof, hydrate, solvate, polymorph, or stereochemically isomeric form thereof, the particular condition being treated and the severity of the condition being treated, various factors specific to the medical history of the subject to whom the dosage is being administered, such as the age, weight, sex, extent of disability, and general health of the particular subject, and other medications the individual may be taking. Furthermore, the effective daily amount may be reduced or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present disclosure.

[0200] Depending on the mode of administration, the pharmaceutical composition may contain 0.05 to 99% by weight, preferably 0.1 to 70% by weight, more preferably 0.1 to 50% by weight, of the active ingredient and 1 to 99.95% by weight, preferably 30 to 99.9% by weight, more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0201] For therapeutic conditions requiring inhibition of dihydroorotate dehydrogenase activity, appropriate dosage levels will generally be about 0.01 to 1000 mg / kg of patient body weight per day, which can be administered in single or multiple doses. In various embodiments, dosage levels will be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage may be 0.05-0.5, 0.5-5.0, or 5.0-50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 1.0-1000 mg of active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg, for symptomatic adjustment of the dosage to the patient being treated. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen may be adjusted to provide the optimal therapeutic response.

[0202] Such unit doses, as described hereinabove and below, can be administered two or more times per day, e.g., two, three, four, five, or six times per day. In various embodiments, such unit doses can be administered once or twice per day, resulting in a total dosage for a 70 kg adult ranging from 0.001 to about 15 mg per kg of subject body weight per administration. In further embodiments, the dosage is from 0.01 to about 1.5 mg per kg of subject body weight per administration, and such therapy can extend for weeks or months, or even years. However, it will be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, the age, weight, general health, sex, and diet of the individual being treated, the time and route of administration, the rate of excretion, other previously administered drugs, and the severity of the particular disease being treated, as will be well understood by those skilled in the art.

[0203] A typical dosage might be a single 1 mg to about 100 mg or 1 mg to about 300 mg tablet taken once daily or multiple times daily, or a single time-release capsule or tablet with a proportionally higher active ingredient content taken once daily. The time-release effect can be achieved by capsule materials that dissolve at different pH values, by capsules that slowly release by osmotic pressure, or by any other known means of controlled release.

[0204] It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art. Furthermore, it should be noted that the clinician or treating physician will know how and when to initiate, interrupt, adjust, or terminate therapy in conjunction with an individual patient's response.

[0205] The present disclosure is further directed to methods for the manufacture of a medicament for modulating dihydroorotate dehydrogenase activity in a mammal (e.g., a human) (e.g., treating one or more disorders, such as cancer or graft-versus-host disease, that can be treated through the inhibition of dihydroorotate dehydrogenase dysfunctional activity), comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Accordingly, in one aspect, the present disclosure further relates to a method for the manufacture of a medicament, comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0206] The disclosed pharmaceutical compositions may further comprise other therapeutically active compounds that are usually applied in the treatment of the above mentioned pathological or clinical conditions.

[0207] It is understood that the disclosed compositions can be prepared from the disclosed compounds, and that the disclosed compositions can be used in the disclosed methods of use.

[0208] As already mentioned, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds, products of the disclosed methods of making, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, and a pharmaceutically acceptable carrier. In addition, the present disclosure relates to processes for preparing such pharmaceutical compositions, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure.

[0209] As mentioned above, the present disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds, the products of the disclosed methods of preparation, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, and one or more other drugs in the treatment, prevention, control, improvement, or reduction of diseases or conditions for which the disclosed compounds or other drugs may be useful, and also relates to the use of such compositions for the manufacture of medicaments.The present disclosure also relates to the combination of the disclosed compounds, the products of the disclosed methods of preparation, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, and therapeutic agents that can be used to treat autoimmune diseases, immune and inflammatory diseases, destructive bone disorders, malignant neoplastic diseases, angiogenesis-related disorders, viral diseases, and infectious diseases.The present disclosure also relates to such combinations for use as medicines. The present disclosure also relates to products comprising (a) a disclosed compound, product of the disclosed method of making, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, and (b) an additional therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in the treatment or prevention of a condition in a mammal, including a human, whose treatment or prevention is affected or facilitated by the modulating effects of the disclosed compound and the additional therapeutic agent. The different agents of such combinations or products can be combined in a single preparation with a pharmaceutically acceptable carrier or diluent, or they can each be in separate preparations with a pharmaceutically acceptable carrier or diluent.

[0210] Methods of using the compounds. In a further aspect, the present disclosure provides a method of treatment, comprising administering a therapeutically effective amount of the disclosed compound or pharmaceutical composition as disclosed hereinabove to a subject in need thereof. Specifically, the disclosed compound and the disclosed pharmaceutical composition can be used in a method of treating a disease or disorder associated with increased, abnormal, or dysfunctional levels of dihydroorotate dehydrogenase (DHODH) activity in a cell, tissue, or organism. That is, the disclosed compound and the disclosed pharmaceutical composition can be used to inhibit DHODH in a cell, tissue, or organism to provide clinical or therapeutic benefits to a subject who has been determined or diagnosed to have increased, abnormal, or dysfunctional levels of dihydroorotate dehydrogenase (DHODH) activity.

[0211] In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment prior to the administering step. In some embodiments of the disclosed methods, the subject has been diagnosed with a disorder treatable by inhibition of DHODH and / or in need of DHODH inhibition prior to the administering step. In some embodiments of the disclosed methods, the subject may have been diagnosed with cancer, a disorder associated with T-cell proliferation, or may be at risk of post-transplant graft-versus-host disease or organ rejection prior to the administering step. In some embodiments of the disclosed methods, the subject has been identified as in need of treatment prior to the administering step.

[0212] The disclosed compounds can be used as a single agent or in combination with one or more other drugs when the combined use of drugs is safer or more effective than either drug alone in treating, preventing, controlling, ameliorating, or reducing the risk of the aforementioned diseases, disorders, and conditions for which the compounds of Formula I or other drugs are useful. The other drugs can be administered simultaneously or sequentially with the disclosed compounds by a route and in an amount commonly used for the other drugs. When the disclosed compounds are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compounds is preferred. However, the combination therapy can also be administered on an overlapping schedule. It is also anticipated that the combination of one or more active ingredients with the disclosed compounds will be more effective than either of them as a single drug.

[0213] DHODH is the enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidines. It converts dihydroorotic acid (DHO) to orotic acid (ORO). Human DHODH is a ubiquitous flavin mononucleotide (FMN) moiety flavoprotein. In mammalian cells, DHODH is tethered to the inner mitochondrial leaflet and catalyzes the conversion of DHO to ORO, which represents the rate-limiting step in de novo pyrimidine biosynthesis. Kinetic studies indicate a sequential ping-pong mechanism for the conversion of DHO to ORO (see, for example, Knecht et al., Chem. Biol. Interact. 2000, 124, 61-76). The first half-reaction involves the reduction of DHO to ORO. Electrons are transferred to FMN, which is oxidized to dihydroflavin mononucleotide (FMNH2). After ORO dissociates from the enzyme, FMNH2 is regenerated by a ubiquinone molecule recruited from the inner mitochondrial membrane. Kinetic and structural studies reveal two unique binding sites for DHO / ORO and ubiquinone, respectively.

[0214] Human DHODH consists of two domains: a large C-terminal domain (Met78-Arg396) and a small N-terminal domain (Met30-Leu68) connected by an extended loop. The large C-terminal domain is best described as an α / β barrel fold, with a central barrel of eight parallel β-strands surrounded by eight α-helices. The substrate-binding pocket and the redox site formed by the binding site for the cofactor FMN are located in this large C-terminal domain. Meanwhile, the small N-terminal domain consists of two α-helices (labeled α1 and α2) connected by a short loop. This small N-terminal domain contains the binding site for the cofactor ubiquinone. Helices α1 and α2 span a slot of approximately 10 × 20 Å in a so-called hydrophobic patch, with a short α1-α2 loop at the narrow end of the slot. The slot forms the entrance to a tunnel that terminates in the FMN cavity near the α1-α2 loop. This tunnel narrows toward the proximal redox site and terminates in several charged or polar side chains (Gln47, Tyr356, Thr360, and Arg136). Structural clues such as those discussed above, along with kinetic studies, suggest that ubiquinone, which can readily diffuse into the inner mitochondrial membrane, uses this tunnel to access the FMN cofactor for the redox reaction (see, e.g., Baumgartner et al., J. Med. Chem. 2006, 49, 1239-1247).

[0215] In vivo, DHODH catalyzes the synthesis of pyrimidines required for cell growth. Inhibition of DHODH inhibits the growth of (pathologically) rapidly proliferating cells, while cells growing at normal rates can obtain the necessary pyrimidine bases from normal metabolic cycles. Lymphocytes, the most important cell type for the immune response, use pyrimidine synthesis exclusively for their growth and are particularly sensitive to DHODH inhibition.

[0216] DHODH inhibition results in a decrease in cellular levels of the ribonucleotide uridine monophosphate (rUMP), thereby arresting proliferating cells in the G1 phase of the cell cycle. Inhibition of de novo pyrimidine nucleotide synthesis is of great interest in light of the observation that lymphocytes appear unable to undergo clonal expansion when this pathway is blocked. Substances that inhibit lymphocyte growth are important pharmaceutical agents for the treatment of autoimmune diseases.

[0217] During homeostatic proliferation, the DHODH-independent salvage pathway appears to be sufficient for cellular pyrimidine base replenishment. Cells with high turnover, particularly T and B lymphocytes, require the de novo pathway to proliferate. In these cells, DHODH inhibition halts cell cycle progression, suppresses DNA synthesis, and ultimately inhibits cell proliferation.

[0218] Therefore, inhibitors of DHODH exhibit beneficial immunosuppressive and antiproliferative effects in human diseases characterized by abnormal and uncontrolled cell proliferation that leads to chronic inflammation and tissue destruction.The human enzyme dihydroorotate dehydrogenase (DHODH) represents a well-characterized target for small molecular weight disease-modifying antirheumatic drugs (DMARDs).

[0219] Thus, in various aspects, the present disclosure relates to methods of treating a variety of diseases or disorders, including, but not limited to, autoimmune diseases, immune and inflammatory diseases, destructive bone disorders, cancer and malignant neoplastic diseases, angiogenesis-related disorders, viral diseases, and infectious diseases.

[0220] In a further aspect, the present disclosure relates to methods for treating immunological disorders, inflammatory disorders, cancer or other proliferative diseases through the inhibition of DHODH by administering to a subject in need of such treatment a therapeutically effective amount of at least one disclosed compound or at least one disclosed pharmaceutical composition.

[0221] In a further aspect, the present disclosure relates to methods for treating immunological disorders, inflammatory disorders, cancer or other proliferative diseases through the inhibition of DHODH by administering to a patient in need of such treatment a therapeutically effective amount of at least one disclosed compound or at least one disclosed pharmaceutical composition in combination (concurrently or sequentially) with at least one other anti-inflammatory, immunomodulatory, or anti-cancer agent.

[0222] In various aspects, autoimmune disorders or diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, lupus, rheumatoid arthritis, ankylosing spondylitis, glomerulonephritis, minimal change complex, ulcerative colitis, Crohn's disease, Addison's disease, adult Still's disease, alopecia areata, autoimmune hepatitis, autoimmune angioedema, Behcet's disease, bullous pemphigoid and variants, celiac disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, CREST syndrome, dermatomyositis, neuromyelitis optica, discoid lupus, fibromyalgia, giant cell arteritis, giant cell myocarditis, Glomerulonephritis, glaucoma ... and / or those selected from Adpasture's disease, Evans syndrome, autoimmune hemolytic anemia, immune thrombocytopenia, Henoch-Schönlein purpura, IgA nephropathy, IgG4-related sclerosing disease, juvenile arthritis, juvenile diabetes mellitus, Kawasaki disease, leukocytoclastic vasculitis, mixed connective tissue disease, multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, autoimmune neutropenia, optic neuritis, peripheral neuropathy, POEMS syndrome, polymyositis, primary biliary cirrhosis, nonalcoholic fatty liver and associated cirrhosis, psoriasis, scleroderma, sarcoidosis, temporal arteritis, vasculitis, and uveitis.

[0223] In a further aspect, autoimmune diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, Reiter's syndrome, fibromyalgia, and type 1 diabetes.

[0224] Immune and inflammatory diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, asthma, COPD, respiratory distress syndrome, acute or chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, Behcet's syndrome, inflammatory eye diseases such as conjunctivitis and uveitis.

[0225] In various aspects, the present disclosure relates to methods for treating organ rejection disorders or ameliorating and / or preventing organ rejection in patients predisposed to organ rejection by administering to a patient in need of such treatment a therapeutically effective amount of at least one disclosed compound or disclosed pharmaceutical composition. In a further aspect, the patient has undergone an organ transplant or has been diagnosed as being in need of an organ transplant. In still further aspects, the organ transplant can include, but is not limited to, kidney, liver, skin, heart, pancreas, lung, or a combination thereof.

[0226] In various aspects, the present disclosure relates to methods for treating EBV viral lymphoproliferation in the setting of tumor immunosuppression. In a further aspect, the method for treating EBV viral lymphoproliferation can provide both ongoing organ transplant maintenance and also treatment of the underlying EBV lymphoproliferation.

[0227] Destructive bone disorders that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, osteoporosis, osteoarthritis, and multiple myeloma-related bone disorder.

[0228] Cancers and malignant neoplasms that can be treated by the disclosed compounds or the disclosed pharmaceutical compositions include, but are not limited to, prostate cancer, ovarian cancer, and brain cancer. Cancers, including cancers of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic neoplasms of the lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; hematopoietic neoplasms of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannoma; and tumors of the central and peripheral nervous system, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum Other tumors, including thyroid carcinoma, thyroid carcinoma, thyroid cancer, and Kaposi's sarcoma.

[0229] Angiogenesis-related disorders that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, hemangiomas, ocular neovascularization, macular degeneration, or diabetic retinopathy.

[0230] Viral diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, HIV infection, hepatitis, and cytomegalovirus infection.

[0231] Infectious diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, shigellosis, and other protozoal infestations such as malaria.

[0232] In a further aspect, the disclosed compounds or disclosed pharmaceutical compositions can act as regulators of apoptosis, and thus can be used to treat cancer (including but not limited to the types of cancer described herein above), viral infections (including but not limited to herpes viruses, pox viruses, Epstein-Barr virus, Sindbis virus, and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes), neurodegenerative disorders ( They may be useful in the treatment of diseases including, but not limited to, Alzheimer's, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, cardiac arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood disorders (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive sinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

[0233] In a further aspect, the disclosed compounds or pharmaceutical compositions can act to modulate the level of cellular RNA and DNA synthesis. Thus, the disclosed compounds and pharmaceutical compositions can be used in the treatment of viral infections, including but not limited to, HIV, human papillomavirus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus, and adenovirus.

[0234] In another aspect, the disclosed compounds or disclosed pharmaceutical compositions can be used in cancer chemoprevention.Chemoprevention is understood as clinical intervention to inhibit the development of invasive cancer, either by blocking the onset of mutagenic events, or by blocking the progression of already damaged premalignant cells, or by inhibiting tumor recurrence.Therefore, the disclosed compounds and disclosed pharmaceutical compositions can be used in inhibiting tumor angiogenesis and metastasis.

[0235] In further embodiments, the disclosed compounds and disclosed pharmaceutical compositions can also be combined with other active compounds in the treatment of diseases in which inhibition of DHODH is known to have beneficial effects.

[0236] In various embodiments, diseases, conditions, or disorders that may benefit from inhibition of DHODH include, but are not limited to, immune system-related diseases (e.g., autoimmune diseases), diseases or disorders involving inflammation (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, and disorders of the immune system), cancer or other proliferative diseases, liver diseases or disorders, and kidney diseases or disorders.

[0237] In a further aspect, the disclosed compounds and disclosed pharmaceutical compositions can be used as immunosuppressants to prevent transplant graft rejection, allo- or xenograft rejection (organ, bone marrow, stem cell, other cell and tissue), and graft-versus-host disease. In other embodiments, transplant graft rejection results from tissue or organ transplantation. In a further embodiment, graft-versus-host disease results from bone marrow or stem cell transplantation.

[0238] In a further aspect, the disclosed compounds and disclosed pharmaceutical compositions can be used in the treatment of various inflammatory diseases, including, but not limited to, inflammation, glomerulonephritis, uveitis, liver disease or disorder, kidney disease or disorder, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory myopathy, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allo- or xenotransplantation, transplant rejection, graft-versus-host disease, corneal graft rejection, lupus erythematosus, systemic lupus erythematosus, proliferative lupus nephritis, type 1 diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, and Sjogren's syndrome.

[0239] In further aspects, the disclosed compounds and disclosed pharmaceutical compositions can be used in the treatment of a variety of diseases, including Felty's syndrome, Wegener's granulomatosis, Crohn's disease, sarcoidosis, Still's disease, pemphigoid, Takayasu's arteritis, systemic sclerosis, relapsing polychondritis, refractory IgA nephropathy, SAPHO2 syndrome (SAS), cytomegalovirus infections including rhinitis or cysts, psoriasis, IGG4 disease, and multiple myeloma.

[0240] In further aspects, the disclosed compounds and disclosed pharmaceutical compositions can be used in combination with known anti-cancer treatments, such as radiation therapy, or cytostatic or cytotoxic or anti-cancer agents, including, but not limited to, DNA-interacting agents such as cisplatin or doxorubicin, topoisomerase II inhibitors such as etoposide, topoisomerase I inhibitors such as CPT-11 or topotecan, tubulin-interacting agents such as paclitaxel, docetaxel, or epothilones (e.g., ixabepilone), either naturally occurring or synthetic, hormonal agents such as tamoxifen, thymidylate drugs such as 5-fluorouracil, and the like. These agents can also be used in combination (administered together or sequentially) with antimetabolites such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774, angiogenesis inhibitors, BTK inhibitors, SYK inhibitors, ITK inhibitors, PI3-kinase inhibitors, FLT3 inhibitors, EGF inhibitors, PAK inhibitors, VEGF inhibitors, CDK inhibitors, SRC inhibitors, c-Kit inhibitors, Her1 / 2 inhibitors, and monoclonal antibodies directed against growth factor receptors such as Erbitux (EGF) and Herceptin (Her2), and other protein kinase modulators. These agents can be used in combination with differentiation agents such as ATRA, EZH2 inhibitors, DNMT inhibitors, corticosteroids, IDH1 inhibitors, IDH2 inhibitors, and vitamin C. These agents can be used in combination with small molecules that enhance DNA damage killing of cancer cells, including PARP inhibitors, MDM2 inhibitors, NAMPT inhibitors, and HSP90 inhibitors. These agents can be used in combination with antibodies that target cell surface molecules on immune or cancer cells, including, but not limited to, CD33, CD37, CD19, CD20, CD3, CD123, CD70, BAFFR, CD4, CD8, CD56, and CD38. These agents can be used in combination with antibodies or peptides that neutralize cytokines, including, but not limited to, IL1 beta, IL6, IL10, IL21, TNFA, TNFB, and IFN.These agents can be used in combination with CAR-T cells to attenuate cell proliferation in situations of significant cytokine release syndrome and neurotoxicity. These agents can be combined with bispecific antibodies or peptide molecules that target T cell and immune / tumor cell antigens in a dual manner, such as, but not limited to, CD19, CD20, CD33, CD123, CD38, and CD37, to attenuate T cell proliferation, cytokine production, and neurotoxicity. These agents can be used to attenuate T cell proliferation and tissue damage caused by immune checkpoint inhibitor antibodies against targets such as, but not limited to, PD1, PDL1, CTLA4, and LAG3.

[0241] In a further aspect, the diseases, disorders, or conditions that can be treated or prevented using the disclosed compounds and disclosed pharmaceutical compositions are capable of inhibiting DHODH and are therefore useful for treating diseases, conditions, or disorders involving inflammation and / or the immune system, including, but not limited to, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases such as multiple sclerosis, and disorders of the immune system.

[0242] In further aspects, the disclosed compounds and disclosed pharmaceutical compositions can be used to treat immune and immune-related disorders, including, for example, chronic immune diseases / disorders, acute immune diseases / disorders, autoimmune and immunodeficiency diseases / disorders, diseases / disorders involving inflammation, organ transplant graft rejection and graft-versus-host disease, and altered immune responses (e.g., hyperactivity). In still further aspects, other exemplary immune disorders that can be treated using the disclosed compounds and disclosed pharmaceutical compositions include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory myopathies, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allo- or xenotransplantation (organ, bone marrow, hepatocyte, and other cell and tissue (transplant rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases), type 1 diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0243] Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT) (Baird K, Pavletic SZ. Curr Opin Hematol. 2006; 13(6):426-435, Lee SJ, Vogelsang G, Flowers ME. Biol Blood Marrow Transplant. 2003; 9(4):215-233, Pidala J, et al. Blood. 2011; 117(17):4651-4657, and Arai S, et al. Blood. 2011; 118(15):4242-4249). Drug therapy for cGVHD is primarily limited to steroids and calcineurin inhibitors, which are incompletely effective and associated with long-term risks of infection and toxicity (Holler, E. Best Pract Res Clin Haematol. 2007;20(2):281-294). The disclosed compounds can be used to treat cGVHD.

[0244] kit In various aspects, the present disclosure relates to a kit comprising a therapeutically effective amount of at least one disclosed compound, a disclosed product of a method of making a disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition; at least one agent known to treat cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation; and instructions for treating cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation.

[0245] The disclosed compounds and / or pharmaceutical compositions comprising the disclosed compounds can be conveniently presented as kits, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided along with instructions for the preparation of the actual dosage form by the patient or the person administering the drug to the patient. Such kits may be provided with all necessary materials and components contained therein, or may include instructions for using or making materials or components that must be obtained independently by the patient or the person administering the drug to the patient. In further embodiments, the kits can include any components that aid in the administration of a unit dose to a patient, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. In addition, the kits can contain instructions for the preparation and administration of the compositions. The kits can be manufactured as single-use unit doses for one patient, as multiple uses for a particular patient (at a fixed dose or where the potency of individual compounds may vary over the course of therapy), or the kits can contain multiple doses suitable for administration to multiple patients ("bulk packaging"). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0246] In further embodiments, the disclosed kits can be packaged with a daily dosing regimen (e.g., packaged on a card, with a dosing card, packaged on a blister or blow-molded plastic, etc.). Such packaging promotes the product and increases patient compliance with the drug regimen. Such packaging can also reduce patient confusion. The present disclosure also features such kits, which further contain instructions for use.

[0247] In a further aspect, the present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the present disclosure, which containers may be accompanied by a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, reflecting approval by the agency for the manufacture, use, or sale for human administration.

[0248] In various embodiments, the disclosed kits can also include compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug reseller, physician, compounding pharmacy, or pharmacist can provide a kit that includes the disclosed compounds and / or products and other components for delivery to a patient.

[0249] The disclosed kits can be used in conjunction with the disclosed methods of making, the disclosed methods of use or treatment, and / or the disclosed compositions.

[0250] Research Tools The disclosed compounds and pharmaceutical compositions have activity as inhibitors of DHODH activity or cell proliferation. Therefore, the disclosed compounds are also useful as research tools. Accordingly, one aspect of the present disclosure relates to a method of using the disclosed compounds as a research tool, comprising conducting a biological assay using the disclosed compounds. The disclosed compounds can also be used to evaluate novel chemical compounds. Accordingly, another aspect of the present disclosure relates to a method of evaluating a test compound in a biological assay, comprising: (a) conducting a biological assay with a test compound to provide a first assay value; (b) conducting a biological assay with a disclosed compound to provide a second assay value, wherein step (a) is performed either before, after, or simultaneously with step (b); and (c) comparing the first assay value from step (a) with the second assay value from step (b). Exemplary biological assays include measuring cell proliferation in an in vitro DHODH enzyme assay or a cell culture-based assay. Suitable methods for performing such assays are described herein. Yet another aspect of the present disclosure relates to a method of studying a biological system, e.g., a model animal, or a biological sample containing DHODH protein, for a clinical condition, comprising: (a) contacting the biological system or sample with a compound of the present disclosure; and (b) determining the effect of the compound on the biological system or sample.

[0251] Aspects The following list of exemplary embodiments supports and is supported by the disclosure provided herein.

[0252] Aspect 1. A compound having a formula represented by the structure: TIFF0007800865000021.tif39170, R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is halogen, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof. Aspect 2. A compound having a formula represented by the structure: TIFF0007800865000022.tif38170, R 1is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of them has the structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof. Aspect 3.R 1 A compound according to any one of embodiments 1 to 2, wherein is selected from halogen, —SF5, —CF3, and —CF2CF3. Aspect 4.R 1 The compound according to embodiment 3, wherein is halogen or —SF 5 . Aspect 5.R 1 The compound of embodiment 4, wherein is —F or —Cl. Aspect 6.R1 A compound according to embodiment 4, wherein is —F. Aspect 7.R 1 The compound of embodiment 4, wherein is —Cl. Aspect 8.R 1 The compound of embodiment 4, wherein is —SF5. Aspect 9.R 1 is selected from -SF5, -CF3, and -CF2CF3. Aspect 10.R 1 A compound according to embodiment 9, wherein is —SF5. Aspect 11.R 1 is selected from -CF3 and -CF2CF3. Aspect 12.R 5c The compound of any one of aspects 1-11, wherein is halogen, C1-C7 haloalkyl, or -O(C1-C7 haloalkyl). Aspect 13.R 5c 13. The compound according to embodiment 12, wherein is halogen. Aspect 14.R 5c is F. Aspect 15.R 5c is —OCF 3 , —OCH 2 CF 3 , or —OCF 2 CF 3 . Aspect 16.R 5c is —OH, —O(C1-C7 alkyl), —C1-C7 hydroxyalkyl, —O—(C1-C7 hydroxyalkyl), —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 17.R 5c is —O(C1-C7 alkyl), —(C1-C7 alkanediyl)-OH, —O(C1-C7 alkanediyl)-OH, —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 18.R 5c is —OCH 3 or —OCH 2 CH 3 . Aspect 19.R 5a , R5b , R 5d , and R 5e 19. The compound of any one of aspects 16-18, wherein each of is hydrogen. Aspect 20.R 5a But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 R is selected from the group having the formula 5b , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 21.R 5a But R 20 21. The compound of embodiment 20, wherein Aspect 22.R 20 22. The compound of any one of aspects 20 or 21, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 23.R 20 22. The compound according to any one of aspects 20 or 21, wherein is halogen. Aspect 24.R 5b , R 5c , R 5d , and R 5e Aspect 24. The compound of any one of aspects 1-23, wherein each of is selected from halogen and hydrogen. Aspect 25.R 5b , R 5c , R 5d , and R 5e 25. The compound according to embodiment 24, wherein each of is hydrogen. Aspect 26.R 5b But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 R is selected from the group having the formula 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 27.R 5b But R 20 27. The compound of embodiment 26, wherein Aspect 28.R 20 28. The compound according to any one of embodiments 26 to 27, wherein is selected from —C2-C7 alkylamino and —C2-C7 alkoxy. Aspect 29.R 20 28. The compound according to embodiment 26 or 27, wherein is halogen. Aspect 30.R 5a , R 5c , R 5d , and R 5e 30. The compound of any one of embodiments 26-29, wherein each of is selected from halogen and hydrogen. Aspect 31.R 5a , R 5c , R 5d , and R 5e 31. The compound according to embodiment 30, wherein each of is hydrogen. Aspect 32.R 5c But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 R is selected from the group having the formula 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 . Aspect 33.R 5c But R 20 33. The compound of embodiment 32, wherein Aspect 34.R 20 A compound according to any one of embodiments 32 to 33, wherein is selected from —C2-C7 alkylamino and —C2-C7 alkoxy. Aspect 35.R 20 A compound according to any one of embodiments 32 to 33, wherein is halogen. Aspect 36.R 5a , R 5b , R 5d , and R 5e A compound according to any one of embodiments 32 to 35, wherein each of is selected from halogen and hydrogen. Aspect 37.R 5a , R 5b , R 5d , and R 5e 37. The compound according to embodiment 36, wherein each of is hydrogen. Aspect 38.R 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6dis independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl. Aspect 39.R 6a and R 6b is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 40.R 6a and R 6b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 41.R 6a and R 6b is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 42.R 6a and R 6c is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 43.R 6a and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 44.R 6a and R 6c is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 45.R 6a and R 6d is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 46.R 6a and R 6d is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 47.R 6a and R 6d is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 48.R 6a is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 49.R 6a is selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 50.R 6b is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 51.R 6a is selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 52.R 6c and R 6d 52. The compound of any one of embodiments 1-51, wherein each of is hydrogen. Aspect 53.R 6a is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b , R 6c , and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 54.R 6a is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 55.R6a 55. The compound of embodiment 54, wherein is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 56.R 6a 56. The compound according to embodiment 55, wherein is —F. Aspect 57.R 6b is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a , R 6c , and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 58.R 6b 58. The compound of embodiment 57, wherein is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 59.R 6b is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 60.R 6b 60. The compound of embodiment 59, wherein is —F. Aspect 61.R 6a and R 6b are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6c and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 62.R 6a and R 6b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 63.R 6a and R 6bis independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 64.R 6a and R 6b 41. The compound according to embodiment 40, wherein each of Aspect 65.R 6a and R 6c are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 66.R 6a and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 67.R 6a and R 6c is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 68.R 6a and R 6c 41. The compound according to embodiment 40, wherein each of Aspect 69.R 6a and R 6d are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6c Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 70.R 6a and R 6dis independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 71.R 6a and R 6d is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 72.R 6a and R 6d 41. The compound according to embodiment 40, wherein each of Aspect 73.R 6b and R 6c are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 74.R 6b and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 75.R 6b and R 6c is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 76.R 6b and R 6c 41. The compound according to embodiment 40, wherein each of Aspect 77.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 78.R 20Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 79.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 80.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Aspect 81.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 82.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 83.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 84.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 85.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 86.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 87.R 20The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 88.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 89.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 90.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Aspect 91.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Aspect 92.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 93.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 94.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 95.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 96.R 20The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 97.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C6-C10 alkanediyl, —C6-C10 aminoalkanediyl, and —C6-C10 hydroxyalkanediyl. Aspect 98.R 30 and R 31 is independently selected from hydrogen, —C6-C8 alkanediyl, —C6-C8 aminoalkanediyl, and —C6-C8 hydroxyalkanediyl. Aspect 99.R 30 and R 31 The compound of any one of embodiments 1-76, wherein each of is independently selected from hydrogen, —C5-C10 alkanediyl, —C5-C10 aminoalkanediyl, and —C5-C10 hydroxyalkanediyl. Aspect 100.R 30 and R 31 The compound of any one of embodiments 1-76, wherein each of is independently selected from hydrogen, —C5-C8 alkanediyl, —C5-C8 aminoalkanediyl, and —C5-C8 hydroxyalkanediyl. Aspect 101.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C5-C6 alkanediyl, —C5-C6 aminoalkanediyl, and —C5-C6 hydroxyalkanediyl. Aspect 102.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C4-C10 alkanediyl, —C4-C10 aminoalkanediyl, and —C4-C10 hydroxyalkanediyl. Aspect 103.R 30 and R31 is independently selected from hydrogen, —C4-C8 alkanediyl, —C4-C8 aminoalkanediyl, and —C4-C8 hydroxyalkanediyl. Aspect 104.R 30 and R 31 is independently selected from hydrogen, —C4-C6 alkanediyl, —C4-C6 aminoalkanediyl, and —C4-C6 hydroxyalkanediyl. Aspect 105.R 30 and R 31 is independently selected from hydrogen, —C4-C5 alkanediyl, —C4-C5 aminoalkanediyl, and —C4-C5 hydroxyalkanediyl. Aspect 106.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C3-C10 alkanediyl, —C3-C10 aminoalkanediyl, and —C3-C10 hydroxyalkanediyl. Aspect 107.R 30 and R 31 is independently selected from hydrogen, —C3-C8 alkanediyl, —C3-C8 aminoalkanediyl, and —C3-C8 hydroxyalkanediyl. Aspect 108.R 30 and R 31 is independently selected from hydrogen, —C3-C6 alkanediyl, —C3-C6 aminoalkanediyl, and —C3-C6 hydroxyalkanediyl. Aspect 109.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C3-C5 alkanediyl, —C3-C5 aminoalkanediyl, and —C3-C5 hydroxyalkanediyl. Aspect 110.R 30 and R 31 is independently selected from hydrogen, —C3-C4 alkanediyl, —C3-C4 aminoalkanediyl, and —C3-C4 hydroxyalkanediyl. Aspect 111.R 30 and R 31 The compound of any one of embodiments 1-76, wherein each of is independently selected from hydrogen, —C2-C10 alkanediyl, —C2-C10 aminoalkanediyl, and —C2-C10 hydroxyalkanediyl. Aspect 112.R 30 and R 31 is independently selected from hydrogen, —C2-C8 alkanediyl, —C2-C8 aminoalkanediyl, and —C2-C8 hydroxyalkanediyl. Aspect 113.R 30 and R 31 is independently selected from hydrogen, —C2-C6 alkanediyl, —C3-C6 aminoalkanediyl, and —C2-C6 hydroxyalkanediyl. Aspect 114.R 30 and R 31 is independently selected from hydrogen, —C2-C5 alkanediyl, —C2-C5 aminoalkanediyl, and —C2-C5 hydroxyalkanediyl. Aspect 115.R 30 and R 31 is independently selected from hydrogen, —C2-C4 alkanediyl, —C2-C4 aminoalkanediyl, and —C2-C4 hydroxyalkanediyl. Aspect 116.R 30 and R 31is independently selected from hydrogen, —C2-C3 alkanediyl, —C2-C3 aminoalkanediyl, and —C2-C3 hydroxyalkanediyl. Aspect 117.R 40 Aspect 117. The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 118.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 119.R 40 The compound according to any one of embodiments 1-116, wherein is selected from hydrogen, —C5-C10 alkyl, —C5-C10 aminoalkyl, and —C5-C10 hydroxyalkyl. Aspect 120.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Manner 121.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 122.R 40 Aspect 117. The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 123.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 124.R 40 The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 125.R 40 The compound according to any one of aspects 1-116, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 126.R 40 The compound according to any one of aspects 1-116, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 127.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 128.R 40 The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Manner 129.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 130.R 40 The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Aspect 131.R 40 The compound according to any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C10 alkyl, —C2-C10 aminoalkyl, and —C2-C10 hydroxyalkyl. Aspect 132.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 133.R 40The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C6 alkyl, —C2-C3 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 134.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 135.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 136.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 137.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 138.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 139.R 50 Aspect 137. The compound according to any one of aspects 1-136, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 140.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Aspect 141.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 142.R50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 143.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 144.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 145.R 50 The compound according to any one of aspects 1-136, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 146.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 147.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 148.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 149.R 50 The compound according to any one of aspects 1-136, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 150.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Aspect 151.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Aspect 152.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 153.R 50 The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 154.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 155.R 50 The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 156.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 157.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 158.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 159.R 60 Aspect 157. The compound according to any one of aspects 1-156, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 160.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Aspect 161.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 162.R 60 Aspect 157. The compound according to any one of aspects 1-156, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 163.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 164.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 165.R 60 The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 166.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 167.R 60 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 168.R 60The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 169.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 170.R 60 The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Aspect 171.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Aspect 172.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 173.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 174.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 175.R 60 The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 176.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 177.R 70Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 178.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Manner 179.R 70 Aspect 177. The compound according to any one of aspects 1-176, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 180.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Aspect 181.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 182.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 183.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 184.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 185.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 186.R70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 187.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 188.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 189.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Manner 190.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Manner 191.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Manner 192.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Manner 193.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 194.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 195.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 196.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 197.A 1 is selected from —O—, —NH—, —NCH3—, —NCH2CH3—, —N(CH2)2CH3—, —NCH(CH3)2—, —N(CH2)3CH3—, and —N(CH2)4CH3—. Aspect 198.A 1 198. The compound according to embodiment 197, wherein is selected from —O—, —NH—, —NCH 3 —, and —NCH 2 CH 3 —. Aspect 199.A 1 198. The compound according to embodiment 197, wherein is —O—. Aspect 200.A 1 198. The compound according to embodiment 197, wherein is —NH—. Aspect 201.A 1 198. The compound according to embodiment 197, wherein is —NCH3—. Aspect 202.A 1 198. The compound according to embodiment 197, wherein is —NCH 2 CH 3 —. Aspect 203.A 2 The compound of any one of embodiments 1 to 202, wherein is selected from —O—, —NH—, —NCH3—, —NCH2CH3—, —N(CH2)2CH3—, —NCH(CH3)2—, —N(CH2)3CH3—, and —N(CH2)4CH3—. Aspect 204.A 2 204. The compound according to embodiment 203, wherein is selected from —O—, —NH—, —NCH 3 —, and —NCH 2 CH 3 —. Aspect 205.A 2 204. The compound according to embodiment 203, wherein is —O—. Aspect 206.A 2204. The compound according to embodiment 203, wherein is —NH—. Aspect 207.A 2 204. The compound according to embodiment 203, wherein is —NCH 3 —. Aspect 208.A 2 204. The compound according to embodiment 203, wherein is —NCH 2 CH 3 —. Aspect 209.A 3 The compound of any one of embodiments 1 to 208, wherein is selected from —O—, —NH—, —NCH 3 —, —NCH 2 CH 3 —, —N(CH 2 ) 2 CH 3 —, —NCH(CH 3 ) 2 —, —N(CH 2 ) 3 CH 3 —, and —N(CH 2 ) 4 CH 3 —. Aspect 210.A 3 210. The compound according to embodiment 209, wherein is selected from —O—, —NH—, —NCH 3 —, and —NCH 2 CH 3 —. Aspect 211.A 3 210. The compound according to embodiment 209, wherein is —O—. Aspect 212.A 3 209. The compound according to embodiment 209, wherein is —NH—. Aspect 213.A 3 209. The compound according to embodiment 209, wherein Aspect 214.A 3 209. The compound according to embodiment 209, wherein is —NCH 2 CH 3 —. Aspect 215.Ar 1 The compound according to any one of embodiments 1 to 214, wherein is an unsubstituted phenyl group. Aspect 216.Ar 1 is a phenyl group substituted with one group independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl. Aspect 217.Ar 1is a phenyl group substituted with one group selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —OCH3, —NHCH3, —N(CH3)2, —CH2OH, —CH3, —CH2Cl, —CHCl2, —CCl3, —CHF2, —CH2F, and —CF3. Aspect 218.Ar 1 217. The compound according to embodiment 216, wherein is a phenyl group substituted with one group selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 219.Ar 1 217. The compound according to embodiment 216, wherein is a phenyl group substituted with one group selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 220.Ar 1 is a phenyl group substituted with two groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl. Aspect 221.Ar 1 is a phenyl group substituted with two groups selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —OCH3, —NHCH3, —N(CH3)2, —CH2OH, —CH3, —CH2Cl, —CHCl2, —CCl3, —CHF2, —CH2F, and —CF3. Aspect 222.Ar 1 221. The compound according to embodiment 220, wherein is a phenyl group substituted with two groups selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 223.Ar 1is a phenyl group substituted with two groups independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 224.Ar 1 is a phenyl group substituted with three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl. Aspect 225.Ar 1 is a phenyl group substituted with three groups selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —OCH3, —NHCH3, —N(CH3)2, —CH2OH, —CH3, —CH2Cl, —CHCl2, —CCl3, —CHF2, —CH2F, and —CF3. Aspect 226.Ar 1 225. The compound according to embodiment 224, wherein is a phenyl group substituted with three groups selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 227.Ar 1 is a phenyl group substituted with three groups independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 228. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000023.tif161170, or a combination thereof. Aspect 229. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000024.tif95170, or a combination thereof. Aspect 230. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000025.tif85170, or a combination thereof. Aspect 231. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000026.tif87170, or a combination thereof. Aspect 232. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000027.tif184170, or a combination thereof. Aspect 233. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000028.tif177170, or a combination thereof. Aspect 234. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000029.tif98170, or a combination thereof. Aspect 235. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000030.tif118170, or a combination thereof. Aspect 236. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000031.tif65170, or a combination thereof. Aspect 237. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF0007800865000032.tif93170, or a combination thereof. Manner 238.R 1 The compound according to any one of embodiments 228-237, wherein is selected from halogen, —SF 5 , —CF 3 , and —CF 2 CF 3 . Manner 239.R 1 239. The compound according to embodiment 238, wherein is halogen or —SF 5 . Aspect 240.R 1239. The compound according to embodiment 238, wherein is —F or —Cl. Aspect 241.R 1 239. The compound according to embodiment 238, wherein is —F. Aspect 242.R 1 239. The compound according to embodiment 238, wherein is —Cl. Aspect 243.R 1 239. The compound according to embodiment 238, wherein is —SF5. Aspect 244.R 1 is selected from -CF3 and -CF2CF3. Aspect 245.R 6a , R 6b , R 6c , and R 6d R, provided that at least one of 6a , R 6b , R 6c , and R 6d is independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl. Aspect 246.R 6a and R 6b is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 247.R 6a and R 6b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 248.R 6a and R 6b is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 249.R 6a and R 6cis independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 250.R 6a and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 251.R 6a and R 6c is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 252.R 6a and R 6d is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 253.R 6a and R 6d is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 254.R 6a and R 6d is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 255.R 6a 246. The compound according to embodiment 245, wherein is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 256.R 6a is selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 257.R 6b 246. The compound according to embodiment 245, wherein is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 258.R 6ais selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 259.R 6c and R 6d 259. The compound of any one of embodiments 245 to 259, wherein each of is hydrogen. Manner 260.R 6a is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b , R 6c , and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 261.R 6a 261. The compound according to embodiment 260, wherein is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 262.R 6a 262. The compound according to embodiment 261, wherein is selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 263.R 6a 263. The compound according to embodiment 262, wherein Aspect 264.R 6b is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a , R 6c , and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Aspect 265.R 6b 265. The compound according to embodiment 264, wherein is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 266.R 6b266. The compound of embodiment 265, wherein is selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 267.R 6b 267. The compound according to embodiment 266, wherein is —F. Manner 268.R 6a and R 6b are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6c and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 269.R 6a and R 6b 269. The compound according to embodiment 268, wherein each of is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 270.R 6a and R 6b 270. The compound of embodiment 269, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 271.R 6a and R 6b 271. The compound according to embodiment 270, wherein each of Manner 272.R 6a and R 6c are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 273.R 6a and R 6c273. The compound according to embodiment 272, wherein each of is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 274.R 6a and R 6c 274. The compound of embodiment 273, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 275.R 6a and R 6c 275. The compound according to embodiment 274, wherein each of Manner 276.R 6a and R 6d are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6c The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 277.R 6a and R 6d 277. The compound according to embodiment 276, wherein each b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 278.R 6a and R 6d 278. The compound of embodiment 277, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 279.R 6a and R 6d 279. The compound according to embodiment 278, wherein each of Aspect 280.R 6b and R 6care each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 281.R 6b and R 6c 281. The compound according to embodiment 280, wherein each of is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 282.R 6b and R 6c 282. The compound of embodiment 281, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 283.R 6b and R 6c 283. The compound according to embodiment 282, wherein each of Aspect 284. Formula: 2. The compound of embodiment 1, having a structure represented by: TIFF0007800865000033.tif121170TIFF0007800865000034.tif184170TIFF0007800865000035.tif121170, or a combination thereof. Aspect 285. TIFF0007800865000036.tif32170TIFF0007800865000037.tif188170TIFF0007800865000038.tif177170TIFF0007800865000039.tif191170TIFF0007800865000040.tif173170TIFF0007800865000041.tif28170, or a subgroup thereof. Aspect 286. TIFF0007800865000042.tif64170, or a combination thereof. Aspect 287. The compound is a compound selected from the group consisting of a conjugate base form of the compound and Li+, K+, Na+, ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 and a counterion selected from: 288. The counter ion is Na + The compound of embodiment 0, wherein Embodiment 289. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 288, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 290. The pharmaceutical composition according to embodiment 289, further comprising at least one agent known to treat cancer. Embodiment 291. The pharmaceutical composition according to embodiment 290, wherein at least one agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof. Embodiment 292. The pharmaceutical composition according to embodiment 291, wherein the DNA methyltransferase inhibitor is 5-aza-2'-deoxycytidine, 5-azacytidine, zebularine, epigallocatechin-3-gallate, procaine, or a combination thereof. Aspect 293. The pharmaceutical composition of aspect 291, wherein the HDAC inhibitor is vorinostat, entinostat, pambinostat, trichostatin A, mocetinostat, belinostat, dacinostat, gibinostat, tubastatin A, pracinostat, droxinostat, xinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tacedinaline, rosirinostat, apicidin, or a combination thereof. Embodiment 294. The pharmaceutical composition according to embodiment 291, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof. Embodiment 295. The pharmaceutical composition according to embodiment 291, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination thereof. Embodiment 296. The pharmaceutical composition according to embodiment 291, wherein the cytotoxic agent is an alkylating agent, antimetabolite, antitumor antibiotic, antimitotic agent, mTor inhibitor, or other chemotherapeutic agent. Aspect 297. The pharmaceutical composition according to aspect 296, wherein the antitumor antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 298. The pharmaceutical composition of embodiment 296, wherein the antimetabolite is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 299. The pharmaceutical composition of embodiment 296, wherein the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 300. The pharmaceutical composition of embodiment 296, wherein the mitotic inhibitor is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 301. A pharmaceutical composition according to embodiment 296, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination thereof. Embodiment 302. The pharmaceutical composition according to embodiment 296, wherein the other chemotherapeutic agent is an anthracycline, cytarabine, a purine analog, sorafenib, gemtuzumab, ozogamicin, rituximab, or a combination thereof. Embodiment 303. A pharmaceutical composition according to embodiment 302, wherein the anthracycline is daunorubicin, idarubicin, or a combination thereof. Embodiment 304. A pharmaceutical composition according to embodiment 302, wherein the purine analog is cladribine, fludarabine, clofarabine, or a combination thereof. Embodiment 305. The pharmaceutical composition according to embodiment 289, further comprising at least one agent known to treat GVHD. Embodiment 306. The pharmaceutical composition according to embodiment 305, wherein the at least one agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or any other agent known to treat GVHD. Embodiment 307. The pharmaceutical composition according to embodiment 306, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof. Embodiment 308. A pharmaceutical composition according to embodiment 306, wherein the tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination thereof. Embodiment 309. A pharmaceutical composition according to embodiment 306, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination thereof. Aspect 310. The pharmaceutical composition according to aspect 306, wherein the other agent known to treat GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, halofuginone, hydroxychloroquine, or a combination thereof. Embodiment 311. The pharmaceutical composition of embodiment 289, further comprising administering a therapeutically effective amount of at least one agent known to treat an autoimmune disorder or disease. Embodiment 312. The pharmaceutical composition of embodiment 311, wherein the at least one agent known to treat an autoimmune disorder or disease is selected from the group consisting of (a) disease-modifying antirheumatic drugs, (b) nonsteroidal anti-inflammatory drugs, (c) COX-2 selective inhibitors, (d) COX-1 inhibitors, (e) immunosuppressants including p70S6 kinase inhibitors and inosine monophosphate dehydrogenase inhibitors, (f) steroids, (g) biological response modifiers, and (h) other agents useful for the treatment of autoimmune disorders. Embodiment 313. The pharmaceutical composition according to embodiment 312, wherein the disease-modifying antirheumatic drug is selected from methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auranofin, sulfasalazine, and combinations thereof. Embodiment 314. The pharmaceutical composition according to embodiment 312, wherein the nonsteroidal anti-inflammatory drug is selected from indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogues, acetaminophen, and combinations thereof. Embodiment 315. A pharmaceutical composition according to embodiment 312, wherein the COX-2 selective inhibitor is selected from celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib, and combinations thereof. Embodiment 316. The pharmaceutical composition according to embodiment 312, wherein the immunosuppressant is selected from calcineurin inhibitors such as cyclosporine and FK506, p70S6 kinase inhibitors such as sirolimus and rapamycin, inosine monophosphate dehydrogenase inhibitors such as mycophenolic acid, leflunomide, cyclophosphamide, azathioprine, and combinations thereof. Embodiment 317. The pharmaceutical composition according to embodiment 312, wherein the steroid is selected from prednisone, betamethasone, budesonide, and dexamethasone, and combinations thereof. Embodiment 318. The pharmaceutical composition according to embodiment 312, wherein the biological response modifier is selected from TNFα antagonists such as infliximab, adalimab, and etanercept, IL-1 receptor antagonists such as anakinra, humanized or chimeric antibodies or fusion proteins such as alefecept, efalizumab, daclizumab, anti-chemokine antibodies, anti-interleukin antibodies, and combinations thereof. Embodiment 319. The pharmaceutical composition according to embodiment 312, wherein the other agent useful for the treatment of an autoimmune disorder is selected from a hemokine receptor antagonist or modulator, a cannabinoid receptor antagonist or modulator, an inhibitor of matrix metalloproteinase, an inhibitor of TNFα converting enzyme, nitric oxide synthase or phosphodiesterase IV such as roflumilast or cilomilast, p38 MAP kinase, an inhibitor of NF-kappa beta, pathway or IL-1 receptor associated kinase, or an inhibitor of interactions involving adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, α4β7, MAdCAM-1, and αvβ3, and combinations thereof. Embodiment 320. A method for the treatment of a disease or disorder in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one compound according to any one of embodiments 1 to 288, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 289 to 319. Embodiment 321. The method of embodiment 320, wherein the mammal is a human. Embodiment 322 The method of embodiment 320, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. Embodiment 323. The method of embodiment 322, wherein the disorder or disease is associated with abnormal, increased, or aberrant dihydroorotate dehydrogenase (DHODH) activity. Embodiment 324. The method of embodiment 323, wherein the disorder or disease can be treated by inhibiting dihydroorotate dehydrogenase (DHODH) activity. Embodiment 325. The method of any one of embodiments 320 to 324, further comprising identifying a mammal in need of treatment for the disorder or disease. Embodiment 326. The method of embodiment 325, wherein the disorder or disease is associated with abnormal, increased, or aberrant dihydroorotate dehydrogenase (DHODH) activity. Embodiment 327. The method of embodiment 326, wherein the disorder or disease can be treated by inhibiting dihydroorotate dehydrogenase (DHODH) activity. Embodiment 328. The method of any one of embodiments 320 to 327, wherein the disorder is cancer. Embodiment 329. The method of embodiment 328, wherein the cancer is selected from breast cancer, kidney cancer, gastric cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, laryngeal cancer, lung cancer, pancreatic cancer, breast cancer, and malignant melanoma. Embodiment 330. The method of embodiment 328, wherein the cancer is a blood cancer. Embodiment 331. The method of embodiment 330, wherein the hematological cancer is leukemia, lymphoma, myeloma, myelodysplastic syndrome, or myeloproliferative neoplasm. Aspect 332. The method of aspect 331, wherein the hematological cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), Hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Hairy cell lymphoma, Burkett's lymphoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Embodiment 333. The method of embodiment 332, wherein the hematological cancer is chronic myeloid leukemia (CML) or acute myeloid leukemia (AML). Embodiment 334. The method of any one of embodiments 320 to 333, further comprising administering a therapeutically effective amount of at least one agent known to treat cancer. Embodiment 335. The method according to embodiment 335, wherein at least one agent is selected from the group consisting of uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, riboflavin, riboflavin, riboflavin, riboflavin-1, riboflavin-2, riboflavin-3, riboflavin-4, riboflavin-5, riboflavin-6, riboflavin-7, riboflavin-8, riboflavin-9, riboflavin-10, riboflavin-11, riboflavin-12, riboflavin-13, riboflavin-14, riboflavin-15, riboflavin-15, riboflavin-15, riboflavin-16, riboflavin-17, riboflavin-18, riboflavin-19, riboflavin-20, riboflavin-21, riboflavin-22, riboflavin-23, riboflavin-24, riboflavin-25, riboflavin-25, riboflavin-25, riboflavin-25, riboflavin-26, riboflavin-27, riboflavin-28, riboflavin-29, riboflavin-29, riboflavin-29, riboflavin-29, riboflavin-2 fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemetrexed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferon , etoposide, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flu 335. The method of embodiment 334, wherein the anticoagulant is selected from lutemide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, and vasostatin. Embodiment 336. The method of embodiment 334, wherein at least one agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof. Embodiment 337. The method of embodiment 336, wherein the DNA methyltransferase inhibitor is 5-aza-2′-deoxycytidine, 5-azacytidine, zebularine, epigallocatechin-3-gallate, procaine, or a combination thereof. Embodiment 338 The method of embodiment 336, wherein the HDAC inhibitor is vorinostat, entinostat, pambinostat, trichostatin A, mocetinostat, belinostat, dacinostat, gibinostat, tubastatin A, pracinostat, droxinostat, xinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tacediline, rosirinostat, apicidin, or a combination thereof. Embodiment 339. The method of embodiment 336, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination thereof. Embodiment 340. The method of embodiment 336, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination thereof. Embodiment 341. The method of embodiment 336, wherein the cytotoxic agent is an alkylating agent, antimetabolite, antitumor antibiotic, antimitotic, mTor inhibitor, or other chemotherapeutic agent. Aspect 342. The method of aspect 341, wherein the antitumor antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 343. The method of embodiment 341, wherein the antimetabolite is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 344. The method of embodiment 341, wherein the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 345. The method of embodiment 341, wherein the mitotic inhibitor is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Embodiment 346 The method of embodiment 341, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination thereof. Embodiment 347. The method of embodiment 341, wherein the other chemotherapeutic agent is an anthracycline, cytarabine, a purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or a combination thereof. Embodiment 348. The method of embodiment 347, wherein the anthracycline is daunorubicin, idarubicin, or a combination thereof. Embodiment 349. The method of embodiment 347, wherein the purine analog is cladribine, fludarabine, clofarabine, or a combination thereof. Embodiment 350. The method of any one of embodiments 334 to 349, wherein the at least one compound and the at least one agent are administered sequentially. Embodiment 351 The method of any one of embodiments 334 to 349, wherein the at least one compound and the at least one agent are administered simultaneously. Embodiment 352 The method of any one of embodiments 334 to 349, wherein the at least one compound and the at least one agent are co-formulated. Embodiment 353. The method of any one of embodiments 334 to 349, wherein the at least one compound and the at least one agent are co-packaged. Embodiment 354. The method of any one of embodiments 320 to 325, wherein the disorder is mediated by T cell proliferation. Embodiment 355. The method of embodiment 354, wherein the disorder is psoriasis. Embodiment 356. The method of embodiment 354, wherein the disorder is graft-versus-host disease (GVHD). Embodiment 357. The method of embodiment 356, wherein the GVHD is associated with organ transplantation, allograft, xenograft, or hematopoietic stem cell transplantation. Embodiment 358. The method of embodiment 356 or 357, wherein the GVHD is acute GVHD. Embodiment 359. The method of embodiment 356 or 357, wherein the GVHD is chronic GVHD. Embodiment 360. The method of any one of embodiments 356 to 359, further comprising administering a therapeutically effective amount of at least one agent known to treat GVHD. Embodiment 361 The method of embodiment 360, wherein the at least one agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other agent known to treat GVHD. Embodiment 362. The method of embodiment 361, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof. Embodiment 363. The method of embodiment 361, wherein the tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination thereof. Embodiment 364 The method of embodiment 361, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination thereof. Embodiment 365. The method of embodiment 361, wherein the other agent known to treat GVHD is tacrolimus, clofazimine, salalen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, halofuginone, hydroxychloroquine, or a combination thereof. Embodiment 366. A method according to any one of embodiments 320 to 325, wherein the disorder is associated with T cell proliferation. Embodiment 367. The method of any one of embodiments 320 to 325, wherein the disorder is an autoimmune disorder or disease. Aspect 368. The autoimmune disorder or disease is lupus, rheumatoid arthritis, ankylosing spondylitis, glomerulonephritis, minimal change disease, ulcerative colitis, Crohn's disease, Addison's disease, adult Still's disease, alopecia areata, autoimmune hepatitis, autoimmune angioedema, Bechet's disease, pemphigus and variants, celiac disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, CREST syndrome, dermatomyositis, neuromeningitis, optic nerve plaques, discoid lupus, fibromyalgia, giant cell arteritis, giant cell myocarditis, Goodpasteur's disease, Evan's syndrome, autoimmune hematopoietic anemia. 368. The method of embodiment 367, wherein the disease is selected from: hematopoietic stem cell transplantation, immune thrombocytopenia, Henoch-Schönlein purpura, IgA nephropathy, IgG4-related sclerosing disease, juvenile arthritis, juvenile diabetes mellitus, Kawasaki disease, leukocytoclastic vasculitis, mixed connective tissue disease, multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, autoimmune neutropenia, optic neuritis, peripheral neuropathy, POEMS syndrome, polymyositis, primary biliary cirrhosis, nonalcoholic fatty liver and associated cirrhosis, psoriasis, scleroderma, sarcoidosis, temporal arteritis, vasculitis, and uveitis. Embodiment 369 The method of embodiment 367 or 368, further comprising administering a therapeutically effective amount of at least one agent known to treat an autoimmune disorder or disease. Embodiment 370. The method of embodiment 369, wherein the at least one agent known to treat an autoimmune disorder or disease is selected from the group consisting of (a) disease-modifying antirheumatic drugs, (b) nonsteroidal anti-inflammatory drugs, (c) COX-2 selective inhibitors, (d) COX-1 inhibitors, (e) immunosuppressants including p70S6 kinase inhibitors and inosine monophosphate dehydrogenase inhibitors, (f) steroids, (g) biological response modifiers, and (h) other agents useful for the treatment of autoimmune disorders. Embodiment 371. The method of embodiment 370, wherein the disease-modifying antirheumatic drug is selected from methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auranofin, sulfasalazine, and combinations thereof. Embodiment 372. The method of embodiment 370, wherein the nonsteroidal anti-inflammatory drug is selected from indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogs, acetaminophen, and combinations thereof. Embodiment 373 The method of embodiment 370, wherein the COX-2 selective inhibitor is selected from celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib, and combinations thereof. Embodiment 374. The method of embodiment 370, wherein the immunosuppressant is selected from calcineurin inhibitors such as cyclosporine and FK506, p70S6 kinase inhibitors such as sirolimus and rapamycin, inosine monophosphate dehydrogenase inhibitors such as mycophenolic acid, leflunomide, cyclophosphamide, azathioprine, and combinations thereof. Embodiment 375. The method of embodiment 370, wherein the steroid is selected from prednisone, betamethasone, budesonide, and dexamethasone, and combinations thereof. Embodiment 376. The method of embodiment 370, wherein the biological response modifier is selected from TNFα antagonists such as infliximab, adalimab, and etanercept, IL-1 receptor antagonists such as anakinra, humanized or chimeric antibodies or fusion proteins such as alefecept, efalizumab, daclizumab, anti-chemokine antibodies, anti-interleukin antibodies, and combinations thereof. Embodiment 377. The method of embodiment 370, wherein the other agent useful for the treatment of an autoimmune disorder is selected from a hemokine receptor antagonist or modulator, a cannabinoid receptor antagonist or modulator, an inhibitor of matrix metalloproteinase, an inhibitor of TNFα converting enzyme, nitric oxide synthase or phosphodiesterase IV such as roflumilast or cilomilast, p38 MAP kinase, an inhibitor of NF-kappa beta, pathway or IL-1 receptor associated kinase, or an inhibitor of interactions involving adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, α4β7, MAdCAM-1, and αvβ3, and combinations thereof. Embodiment 378. A method for inhibiting dihydroorotate dehydrogenase activity in at least one cell, comprising contacting the at least one cell with an effective amount of at least one compound according to any of embodiments 1 to 288, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of embodiments 289 to 319. Embodiment 379. The method of embodiment 378, wherein the cell is mammalian. Embodiment 380. The method of embodiment 379, wherein the cell is human. Embodiment 381 The method of any of embodiments 378 to 380, wherein the cell is isolated from a mammal prior to the contacting step. Embodiment 382. The method of any one of embodiments 378 to 380, wherein the contacting is via administration to a mammal. Embodiment 383 The method of embodiment 382, ​​wherein the mammal has been diagnosed with a need for inhibition of dihydroorotate dehydrogenase activity prior to the administering step. Embodiment 384. The method of embodiment 383, wherein the mammal has been diagnosed as being in need of treatment for a disorder associated with dihydroorotate dehydrogenase activity prior to the administering step. Embodiment 385. The method of any one of embodiments 378 to 384, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 1,000 nM using a cell-free enzyme assay. Embodiment 386 The method of embodiment 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 500 nM. Embodiment 387. The method of embodiment 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 250 nM. Embodiment 388 The method of embodiment 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 100 nM. Embodiment 389. The method of embodiment 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 50 nM. Embodiment 390. A kit comprising a therapeutically effective amount of at least one compound according to any one of embodiments 1 to 288, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 289 to 319, (a) at least one agent known to treat cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation; (b) instructions for treating cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation. Embodiment 391. The kit according to embodiment 390, wherein the at least one compound or pharmaceutical composition and the at least one agent are co-formulated. Embodiment 392. The kit according to embodiment 390, wherein at least one compound or pharmaceutical composition and at least one agent are co-packaged. Embodiment 393. The kit of embodiment 390, further comprising instructions for providing the compound in connection with surgery. Embodiment 394. The kit of embodiment 393, wherein the instructions provide that surgery is performed prior to administration of the at least one compound. Embodiment 395. The kit of embodiment 393, wherein the instructions provide that surgery is performed after administration of the at least one compound. Embodiment 396. The kit of embodiment 393, wherein the instructions provide that administration of the at least one compound results in pre-surgical tumor debulking. Embodiment 397. The kit of embodiment 393, wherein the instructions provide that surgery is performed approximately simultaneously with the administration of the at least one compound. Embodiment 398. The kit according to embodiment 390, further comprising instructions for providing at least one compound or pharmaceutical composition in association with radiation therapy. Embodiment 399. The kit of embodiment 398, wherein the instructions provide that radiation therapy is administered prior to administration of the at least one compound. Embodiment 400. The kit of embodiment 398, wherein the instructions provide that radiation therapy is administered after administration of the at least one compound. Embodiment 401. The kit of embodiment 398, wherein the instructions provide that radiation therapy is administered substantially simultaneously with the administration of the at least one compound. Embodiment 402. The kit of embodiment 390, further comprising a plurality of dosage forms, the plurality of dosage forms comprising one or more doses, each dose comprising a therapeutically effective amount of at least one compound or pharmaceutical composition and at least one agent. Embodiment 403. The kit according to embodiment 402, wherein the respective doses of at least one compound or pharmaceutical composition and at least one agent are co-formulated. Embodiment 404. The kit according to embodiment 402, wherein each dose of at least one compound or pharmaceutical composition and at least one agent are co-packaged. Embodiment 405. The kit according to embodiment 402, wherein the dosage form is formulated for oral administration and / or intravenous administration. Embodiment 406. The kit of embodiment 402, wherein the dosage form is formulated for oral administration. Embodiment 407. The kit of embodiment 402, wherein the dosage form is formulated for intravenous administration. Embodiment 408. The kit according to embodiment 402, wherein the dosage form for at least one compound or pharmaceutical composition is formulated for oral administration and the dosage form for at least one agent is formulated for intravenous administration. Embodiment 409. The kit according to embodiment 402, wherein the dosage form for at least one compound or pharmaceutical composition is formulated for intravenous administration and the dosage form for at least one agent is formulated for oral administration.

[0253] From the foregoing, it will be seen that the embodiments herein are well adapted to attain all ends and objectives hereinabove set forth, together with other advantages which are obvious and inherent in the structure.

[0254] Although certain elements and steps are discussed in relation to each other, it should be understood that any element and / or step provided herein, regardless of its express definition, may be combined with any other element and / or step while still being contemplated as being within the scope provided herein.

[0255] It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations, which are contemplated by and within the scope of the claims.

[0256] Although many possible embodiments may be made without departing from the scope thereof, it is to be understood that all matter set forth herein or shown in the accompanying drawings and detailed description is to be interpreted as illustrative and not in a limiting sense.

[0257] It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Those skilled in the art will recognize many variations and adaptations of the embodiments described herein. These variations and adaptations are intended to be included within the teachings of the present disclosure and encompassed by the claims herein. Having now described embodiments of the present disclosure, the following examples generally describe some additional aspects of the present disclosure. While embodiments of the present disclosure will be described in conjunction with the following examples and corresponding text and drawings, there is no intent to limit the embodiments of the present disclosure to this description. To the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. [Example]

[0258] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated, and are intended to be merely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is in ° C. or is ambient temperature, and pressure is near or at atmospheric pressure.

[0259] 1. Example 1: Synthesis of Representative Disclosed Compounds Synthesis of 2-(4'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd1): 2-(4'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd1) was prepared according to the synthetic procedure described below. TIFF0007800865000043.tif59170

[0260] Step 1—Suzuki Coupling. To a solution of 1-(4-bromo-3-fluorophenyl)ethan-1-one 1 (300 mg, 1.38 mmol), 4-ethoxyphenylboronic acid 2 (252 mg, 1.52 mmol), palladium acetate (1.5 mg, 0.007 mmol), XPhos (9 mg, 0.019 mmol), aqueous sodium carbonate (2 M, 1.50 mL), and then water (0.10 mL) were added in 1-propanol (3.2 mL, 0.43 M). The reaction mixture was stirred at 100° C. for 1 h (monitored by TLC), cooled to room temperature, diluted with EtOAc (40 mL) and water (30 mL), and the organic layer was separated and washed with brine (30 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude material. The resulting crude material was purified by flash column chromatography using methylene chloride / hexane to give 1-(4'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one (3) as a white solid (305 mg, 85% yield).

[0261] Step 2—Pfitzinger reaction. A mixture of 5-fluoroisatin 4 (174 mg, 1.06 mmol) and aqueous potassium hydroxide (33%, 4.8 mL, 0.22 M) was gently stirred and heated until a clear yellow solution was formed. To this solution was added a slurry of 1-(4'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one 3 (300 mg, 1.16 mmol) in ethanol (7.1 mL, 0.15 M). The reaction mixture was stirred and refluxed at 80 °C for 16 h (reaction progress was monitored by TLC), then cooled to room temperature, the ethanol was evaporated, and the aqueous layer was acidified to pH 2 with aqueous HCl (2 M).

[0262] Workup and purification procedure I: A yellow solid formed, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL). The organic layers were dried over anhydrous NaSO and concentrated to give the crude material, which was purified using flash column chromatography using methanol / dichloromethane as the eluent. The yellow solid was triturated with methanol, dichloromethane, and / or ethyl acetate to give 2-(4'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd1) as an off-white solid.

[0263] Workup and Purification Procedure II: An alternative workup procedure for the Pfitzinger reaction is as follows. The acidified mixture with the triturated product was stirred at room temperature for 2 hours to obtain a free-flowing solid, which was then filtered. The solid was washed with a small amount of methanol to remove trapped water and dried under vacuum. The resulting powder was triturated with dichloromethane, ethyl acetate, and / or methanol, filtered, and dried under vacuum to give 2-(4'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd 1) as an off-white solid (204 mg, 48% yield).

[0264] Synthesis of 2-(3'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd2). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(3'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd2) was prepared as follows. TIFF0007800865000044.tif59170

[0265] Step 1 was performed with 300 mg of 1-(4-bromo-3-fluorophenyl)ethan-1-one and 275 mg of (3-ethoxyphenyl)boronic acid to give 1-(3'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as a pale pink solid (327 mg, 90% yield). Step 2 (Workup / Purification Procedure I) was performed with 125 mg of 5-fluoroisatin and 200 mg of 1-(3'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(3'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd2) as an off-white solid (60 mg, 20% yield).

[0266] Synthesis of 2-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3). Following a synthetic procedure similar to that described for the preparation of Cpd1, the target compound 2-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3) was prepared as follows. TIFF0007800865000045.tif56170

[0267] Step 1 was carried out with 300 mg of 1-(4-bromo-3-fluorophenyl)ethan-1-one and 322 mg of (3-butoxyphenyl)boronic acid to give 1-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as a colorless oil (369 mg, 93% yield). Step 2 (workup / purification procedure I) was performed with 105 mg of 5-fluoroisatin and 200 mg of 1-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one, and only pure fractions were collected from column chromatography in ethyl acetate and hexane to give, after trituration with hexane, 2-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3) as an off-white solid (55 mg, 20% yield).

[0268] Synthesis of 2-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd4). Following a synthetic procedure similar to that described for the preparation of Cpd1, 2-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd4) was prepared as follows. TIFF0007800865000046.tif58170

[0269] Step 1 was performed with 300 mg of 1-(4-bromo-3-fluorophenyl)ethan-1-one and 185 mg of phenylboronic acid to give 1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as a white solid (265 mg, 89% yield). Step 2 was performed with 147 mg of 5-fluoroisatin and 200 mg of 1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 233 mg (approximately 90% purity) of 2-(3'-butoxy-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd4). Of the 233 mg, 110 mg was used for recrystallization using DMSO / water to give 54 mg as a white solid (19% yield).

[0270] Synthesis of 2-(2,2'-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd5). Following a synthetic procedure similar to that described for the preparation of Cpd1, the target compound 2-(2,2'-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd5) was prepared as follows. TIFF0007800865000047.tif57170

[0271] Step 1 was carried out with 300 mg of 1-(4-bromo-3-fluorophenyl)ethan-1-one and 185 mg of (2-fluorophenyl)boronic acid to give 1-(2,2'-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as a white solid (164 mg, 46% yield). Step 2 (Workup / Purification Procedure II) was carried out with 108 mg of 5-fluoroisatin and 160 mg of 1-(2,2'-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 236 mg (approximately 90% purity) of 2-(2,2'-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd5). To improve purity, this was triturated once with ethyl acetate and once with 10% methanol / dichloromethane to give 2-(2,2'-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd5) as an off-white solid (52 mg, 21% yield).

[0272] Synthesis of 2-(4'-(ethylamino)-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd6). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(4'-(ethylamino)-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd6) was prepared as follows. TIFF0007800865000048.tif57170

[0273] Step 1. To a solution of 1-(4-bromo-3-fluorophenyl)ethan-1-one 1 (50 mg, 2.30 mmol) in 1,4-dioxane (5 mL) was added bis(pinacolato)diborane (614 mg, 2.42 mmol) and potassium acetate (677 mg, 6.90 mmol). Argon was bubbled through the reaction mixture for 5 minutes, PdCl(dppf) (84 mg, 0.12 mmol) was added, and the reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude material. The crude material was purified using flash column chromatography with ethyl acetate / hexanes to give 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one as an off-white solid (460 mg, 76% yield). Step 2 (Workup / Purification Procedure II) was performed with 450 mg of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one and 375 mg of 4-bromo-N-ethylaniline to give 1-(4'-(ethylamino)-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as a white solid (310 mg, 71% yield). Workup / purification was performed with 88 mg of 5-fluoroisatin and 150 mg of 1-(4'-(ethylamino)-2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(4'-(ethylamino)-2-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd6) as a white solid (93 mg, 43% yield).

[0274] Synthesis of 2-(4'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd7). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(4'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd7) was prepared as follows. TIFF0007800865000049.tif53170

[0275] Step 1 was performed with 300 mg of 1-(4-chloro-2,5-difluorophenyl)ethan-1-one and 274 mg of (4-ethoxyphenyl)boronic acid to give 1-(4'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as an off-white solid (340 mg, 78% yield). Step 2 (Workup / Purification Procedure II) was performed with 120 mg of 5-fluoroisatin and 200 mg of 1-(4'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(4'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd7) as an off-white solid (240 mg, 78% yield).

[0276] Synthesis of 2-(3'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd8). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(3'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd8) was prepared as follows. TIFF0007800865000050.tif53170

[0277] Step 1 was performed with 300 mg of 1-(4-chloro-2,5-difluorophenyl)ethan-1-one and 274 mg of (3-ethoxyphenyl)boronic acid to give 1-(3'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as an off-white solid (338 mg, 78% yield). Step 2 (Workup / Purification Procedure II) was performed with 120 mg of 5-fluoroisatin and 200 mg of 1-(3'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(3'-ethoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd8) as an off-white solid (260 mg, 84% yield).

[0278] Synthesis of 2-(4'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd9). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(4'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd9) was prepared as follows. TIFF0007800865000051.tif54170

[0279] Step 1 was performed with 300 mg of 1-(4-bromo-2-fluorophenyl)ethan-1-one and 241 mg of (4-ethoxyphenyl)boronic acid to give 1-(4'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as an off-white solid (300 mg, 84% yield). Step 2 (Workup / Purification Procedure II) was performed with 127 mg of 5-fluoroisatin and 200 mg of 1-(4'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(4'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd9) as an off-white solid (150 mg, 48% yield).

[0280] Synthesis of 2-(3'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd10). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(3'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd10) was prepared as follows. TIFF0007800865000052.tif53170

[0281] Step 1 was performed with 300 mg of 1-(4-bromo-2-fluorophenyl)ethan-1-one and 241 mg of (3-ethoxyphenyl)boronic acid to give 1-(3'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as an off-white solid (313 mg, 88% yield). Step 2 (Workup / Purification Procedure II) was performed with 127 mg of 5-fluoroisatin and 200 mg of 1-(4'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 65 mg (21%) of 2-(3'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd10) as an off-white solid (65 mg, 21% yield).

[0282] Synthesis of 2-(3'-butoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd11). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(3'-butoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd11) was prepared as follows. TIFF0007800865000053.tif53170

[0283] Step 1 was carried out with 200 mg of 1-(4-chloro-2,5-difluorophenyl)ethan-1-one and 214 mg of (3-butoxyphenyl)boronic acid to give 1-(3'-butoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as an off-white solid (214 mg, 66% yield). Step 2 (workup / purification procedure II) was carried out with 114 mg of 5-fluoroisatin and 200 mg of 1-(3'-butoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 46 mg (15%) of 2-(3'-butoxy-2,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd11) as an off-white solid (46 mg, 15% yield).

[0284] Synthesis of 2-(3'-butoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd12). Following a synthetic procedure similar to that described for the preparation of Cpd1, the target compound 2-(3'-butoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd12) was prepared as follows. TIFF0007800865000054.tif52170

[0285] Step 1 was performed with 200 mg of 1-(4-bromo-2-fluorophenyl)ethan-1-one and 188 mg of (3-butoxyphenyl)boronic acid to give 1-(3'-butoxy-3-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as an off-white solid (230 mg, 66% yield). Step 2 (workup / purification procedure II) was performed with 114 mg of 5-fluoroisatin and 200 mg of 1-(3'-butoxy-3-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(3'-butoxy-3-fluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd12) as an off-white solid (89 mg, 29%).

[0286] Synthesis of 2-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd13). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd13) was prepared as follows. TIFF0007800865000055.tif53170

[0287] Step 1 was performed with 300 mg of 1-(4-bromo-3-methylphenyl)ethan-1-one and 245 mg of (4-ethoxyphenyl)boronic acid to give 1-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)ethan-1-one as an off-white solid (223 mg, 62% yield). Step 2 (Workup / Purification Procedure II) was performed with 130 mg of 5-fluoroisatin and 200 mg of 1-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd13) as a white solid (171 mg, 54%).

[0288] Synthesis of 2-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd14). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd14) was prepared as follows. TIFF0007800865000056.tif54170

[0289] Step 1 was performed with 300 mg of 1-(4-bromo-3-methylphenyl)ethan-1-one and 245 mg of (3-ethoxyphenyl)boronic acid to give 1-(3'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)ethan-1-one as a white solid (212 mg, 59% yield). Step 2 (Workup / Purification Procedure II) was performed with 130 mg of 5-fluoroisatin and 200 mg of 1-(3'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)ethan-1-one to give 70 mg (22%) of 2-(4'-ethoxy-2-methyl-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd14) as a white solid (70 mg, 22% yield).

[0290] Synthesis of 2-(4'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd15). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(4'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd15) was prepared as follows. TIFF0007800865000057.tif53170

[0291] Step 1 was performed with 300 mg of 1-(4-bromo-3-methoxyphenyl)ethan-1-one and 228 mg of (4-ethoxyphenyl)boron to give 1-(4'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-one as a white solid (157 mg, 44% yield). Step 2 (Workup / Purification Procedure II) was performed with 91 mg of 5-fluoroisatin and 150 mg of -(4'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(4'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd15) as a yellow solid (165 mg, 72% yield).

[0292] Synthesis of 2-(3'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd16). Following a similar synthetic procedure to that described for the preparation of Cpd1, the target compound 2-(3'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd16) was prepared as follows. TIFF0007800865000058.tif52170

[0293] Step 1 was performed with 300 mg of 1-(4-bromo-3-methoxyphenyl)ethan-1-one and 228 mg of (3-ethoxyphenyl)boronic acid to give 276 mg (78%) of 1-(3'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-one as a colorless oil (276 mg, 78% yield). Step 2 (Workup / Purification Procedure II) was performed with 122 mg of 5-fluoroisatin and 200 mg of 1-(3'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-one to give 2-(3'-ethoxy-2-methoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd16) as a yellow solid (100 mg, 32% yield).

[0294] Synthesis of 2-(4'-ethoxy-3,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd17). Following a synthetic procedure similar to that described for the preparation of Cpd1, the target compound 2-(4'-ethoxy-3,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd17) was prepared as follows. TIFF0007800865000059.tif53170

[0295] Step 1 was carried out with 300 mg of 1-(4-bromo-2,6-difluorophenyl)ethan-1-one and 222 mg of (4-ethoxyphenyl)boronic acid to give 1-(4'-ethoxy-3,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one as a white solid (291 mg, 83% yield). Step 2 (Workup / Purification Procedure II) was performed with 120 mg of 5-fluoroisatin and 200 mg of 1-(4'-ethoxy-3,5-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one to obtain 293 mg of 2-(4'-ethoxy-3,5-difluoro-[1,1'-biphenyl]-4-yl)-6-fluoroquino...

Claims

1. A compound having a formula represented by the structure: In the formula, R １ is a halogen, R ５ｂ and R ５ｃ One of them is -R ２０ and R ２０ is selected from —C1-C4 alkylamino and —C1-C4 alkoxy; R5a, R ５ｂ , R ５ｃ , R ５ｄ , and R ５ｅ four of which are hydrogen, R ６ａ , R ６ｂ , R ６ｃ , and R ６ｄ R, provided that at least one of ６ａ , R ６ｂ , R ６ｃ , and R ６ｄ are each independently selected from hydrogen, —F, —Cl, —CH 3 , and —OCH 3 ; or a pharmaceutically acceptable salt thereof.

2. R １ The compound of claim 1 , wherein is —F.

3. R ５ｂ But, R ２０ 2. The compound of claim 1, wherein:

4. R ５ｃ But, R ２０ 2. The compound of claim 1, wherein:

5. R ６ａ , R ６ｂ , R ６ｃ , and R ６ｄ R, provided that at least one of ６ａ , R ６ｂ , R ６ｃ , and R ６ｄ 2. The compound of claim 1, wherein each of is independently selected from hydrogen, —F, —CH 3 , and —OCH 3 .

6. R ６ａ and R ６ｂ The compound of claim 1, wherein is independently selected from -H, -F, -Cl, -CH 3 , and -OCH 3 .

7. R ６ａ and R ６ｃ The compound of claim 1 , wherein is independently selected from —H and —F.

8. R ６ａ and R ６ｄ The compound of claim 1 , wherein is independently selected from —H and —F.

9. A formula selected from the following:

10. The compound of claim 1 having a structure represented by:

10. the conjugate base form of the compound; and Li ＋ , K. ＋ , Na ＋ , ammonium, tetramethylammonium, tetraethylammonium, Fe ＋２ , Cu ＋２ , Zn ＋２ , Mg ＋２ , Ca ＋２ , Al ＋３ , Fe ＋３ 10. A pharmaceutically acceptable salt of the compound of claim 1, comprising a counterion selected from:

11. The counter ion is Na ＋ 11. A pharmaceutically acceptable salt of the compound of claim 10, wherein:

12. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. 13. The pharmaceutical composition of claim 12, further comprising at least one agent known to treat cancer.

14. 14. The pharmaceutical composition of claim 13, wherein the at least one agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof.

15. 13. The pharmaceutical composition of claim 12, further comprising at least one agent known to treat GVHD.

16. 16. The pharmaceutical composition of claim 15, wherein the at least one agent known to treat GVHD is a steroid, an mTOR inhibitor, a tyrosine kinase inhibitor, or another agent known to treat GVHD.

17. 13. The pharmaceutical composition of claim 12, further comprising at least one agent known to treat an autoimmune disorder or disease.

18. 18. The pharmaceutical composition of claim 17, wherein the at least one agent known to treat an autoimmune disorder or disease is selected from the group consisting of: (a) disease-modifying antirheumatic drugs, (b) nonsteroidal anti-inflammatory drugs, (c) COX-2 selective inhibitors, (d) COX-1 inhibitors, (e) immunosuppressants including p70S6 kinase inhibitors and inosine monophosphate dehydrogenase inhibitors, (f) steroids, (g) biological response modifiers, and (h) other agents useful for the treatment of autoimmune disorders.

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