Methods and compositions for inhibiting dihydroorotate dehydrogenase

Abstract

This invention discloses 6-substituted 2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analogs, which are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds can be used to treat a variety of disorders and diseases where inhibition of DHODH may be clinically useful, including cancers such as hematologic cancers, including acute myeloid leukemia (AML), graft-versus-host disease, autoimmune disorders, and disorders associated with T-cell proliferation. When administered orally, the disclosed compounds exhibit flipped kinetics, i.e., pharmacokinetics in which the absorption rate, rather than the elimination rate, dominates the pharmacokinetic profile. The disclosed compounds exhibit sustained pharmacokinetic characteristics rather than immediate release characteristics. This summary is intended as a scanning tool for searching in a specific field and is not intended to limit this disclosure.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 953,708, filed on December 26, 2019, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Proliferating cells require nucleotides for DNA replication and transcription of genes into RNA, as well as for various other metabolic processes. Cells can provide these nucleotides through de novo nucleotide synthesis pathways. A crucial step in the de novo pyrimidine nucleotide synthesis pathway is the oxidation of dihydroorotic acid to orotic acid. This reaction is catalyzed by dihydroorotic acid dehydrogenase (DHODH), and this step is one of the rate-limiting steps in the pyrimidine nucleotide synthesis pathway. DHODH has a subcellular location in the mitochondrial membrane and uses cytochrome C as an electron acceptor in the electron transport chain to oxidize dihydroorotic acid to orotic acid.

[0004] Under normal circumstances, the intracellular pool of pyrimidine nucleotides can be replenished via a rescue pathway, in which pyrimidine nucleotides are recycled. Although this DHODH-independent mechanism is sufficient for resting lymphocytes, “activated” and proliferating lymphocytes require a significant increase in available pyrimidines and therefore rely on de novo pyrimidine synthesis. Since orotic acid is an essential intermediate in pyrimidine nucleotide synthesis, and since pyrimidine nucleotides are essential for DNA replication, gene expression, and carbohydrate metabolism, inhibition of the DHODH enzyme inhibits cell growth.

[0005] Furthermore, rapidly proliferating cells require pyrimidines not only for cell growth but also for protein glycosylation, membrane lipid biosynthesis, and chain break repair (e.g., see Fairbanks et al., J. Biol. Chem., Vol. 270, pp. 29682-29689, 1995). Under these conditions, to meet the increased demand, large amounts of pyrimidine nucleotides must be produced in rapidly proliferating cells. Therefore, DHODH inhibitors are attractive candidates for treating proliferative disorders (e.g., see Liu, S. et al., Structure, Vol. 8: pp. 25-31 (2000)), and various studies have shown that DHODH inhibitors can inhibit the proliferation of tumor cells under certain conditions (e.g., see Loffler, Eur. J. Biochem., Vol. 107: pp. 207-215 (1980)).

[0006] Other cases 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 agents. Examples of DHODH inhibitors used or being developed for proliferative disorders include buquina, leflunomide, and teriflunomide. Further disclosures of DHODH inhibitors for the treatment or prevention of autoimmune diseases, immune and inflammatory diseases, angiogenesis-related disorders, and viral, bacterial, and protozoan diseases have also been made public.

[0007] While DHODH is an attractive target for therapeutic intervention in a variety of clinical conditions, including cancer, the compounds currently described still present significant challenges. For example, many of these compounds (including buquina) suffer from poor bioavailability, partly due to their poor water solubility and gastrointestinal absorption. Therefore, due to these bioavailability issues, the currently described DHODH inhibitors may have limited pharmacological efficacy.

[0008] Despite progress in research on effective and therapeutically useful DHODH inhibitors, compounds with both efficacy and appropriate bioavailability remain scarce. This disclosure addresses these and other needs. Summary of the Invention

[0009] In accordance with the purposes of this disclosure, as embodied and broadly described herein, this disclosure relates in one aspect to compounds as inhibitors of dihydroorotate dehydrogenase (DHODH), and the disclosed compounds possess improved pharmacokinetic properties, making them extremely useful for therapeutic interventions in a variety of disorders and diseases (e.g., cancer) where inhibition of DHODH may be clinically useful. In each aspect, the disclosed compounds are 6-substituted -2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analogs. In another aspect, the disclosed compounds can be used in methods of treating cancers, such as hematologic cancers, including acute myeloid leukemia (AML), graft-versus-host disease, and disorders associated with T-cell proliferation. In some aspects, when administered orally, the disclosed compounds may exhibit flip-flop kinetics, i.e., pharmacokinetics in which the absorption rate rather than the elimination rate dominates the pharmacokinetic profile. Furthermore, the disclosed compounds may exhibit sustained pharmacokinetic characteristics rather than immediate release characteristics.

[0010] This article discloses compounds having the following structural formulas:

[0011]

[0012] Where R 1 Selected from hydrogen, halogens, −SF5, −CN, −N3, −OH, −NH2, −CF3, and −CF2CF3; where R 5a R5b R 5c R 5d and R 5e One of them is selected from groups having the following structural formula: -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 ;where A 1 Selected from -O- and -NR 50 —; where R 50 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 2 Selected from -O- and -NR 60 —; where R 60 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 3 Selected from -O- and -NR 70 —; where R 70 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein R 20 Selected from halogens, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, and -(CH2). n Cy 1 and ─(CH2) n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Cy 1 It is a C3-C10 cycloalkyl or C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; wherein Ar 1It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 independently selected groups from the following: 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; wherein R 30 and R 31 Each of them is independently selected from -C1-C10 alkyldiyl, -C1-C10 haloalkyldiyl, -C1-C10 aminoalkyldiyl, and -C1-C10 hydroxyalkyldiyl; and R 40 Selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 and ─(CH2) n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Cy 1 It is a C3-C10 cycloalkyl or C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; wherein Ar 1 It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; and wherein R 5a R 5b R 5c R 5d and R 5e The four elements are independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; among which R 6a R 6b R 6c and R 6dEach of these elements is 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, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen; or a pharmaceutically acceptable salt thereof.

[0013] This article discloses compounds having the following structural formulas:

[0014]

[0015] Where R 1 Selected from hydrogen, halogens, −SF5, −CN, −N3, −OH, −NH2, −CF3, and −CF2CF3; where R 5a R 5b R 5c R 5d and R 5e One of them is selected from groups having the following structural formula: -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 ;where A 1 Selected from -O- and -NR 50 —; where R 50 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 2 Selected from -O- and -NR 60 —; where R 60 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 3 Selected from -O- and -NR 70 —; where R 70 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein R 20Selected from halogens, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, and -C1-C10 alkoxy; wherein R 30 and R 31 Each of them is independently selected from -C1-C10 alkyldiyl, -C1-C10 haloalkyldiyl, -C1-C10 aminoalkyldiyl, and -C1-C10 hydroxyalkyldiyl; and R 40 Selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl and -(CH2). n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Ar 1 It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; and wherein R 5a R 5b R 5c R 5d and R 5e The four elements are independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; among which R 6a R 6b R 6c and R 6d Each of these elements is 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, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen; or a pharmaceutically acceptable salt thereof.

[0016] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0017] A method for treating diseases or disorders in mammals is also disclosed, comprising the steps of 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.

[0018] A method for treating cancer in mammals is also disclosed, comprising the steps of 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.

[0019] A method for treating graft-versus-host disease in mammals is also disclosed, comprising the steps of 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.

[0020] A method for treating T-cell proliferation-related diseases or disorders in mammals is also disclosed, comprising the steps of 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.

[0021] Also disclosed is a kit comprising: a therapeutically effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof or a disclosed pharmaceutical composition; and: (a) at least one agent known to treat cancer, host resistance to graft disease and / or disorders associated with T cell proliferation; and (b) instructions for use in treating cancer, host resistance to graft disease and / or disorders associated with T cell proliferation.

[0022] A method for preparing a drug is also disclosed, comprising mixing at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0023] The use of the disclosed compounds or products in the preparation of medicaments for treating diseases or disorders in mammals, such as cancer, disorders related to T-cell proliferation, or graft-versus-host disease, is also disclosed.

[0024] Other systems, methods, features, and advantages of this disclosure will become apparent to those skilled in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features, and advantages be included in this specification, within the scope of this disclosure, and protected by the appended claims. Furthermore, all optional and preferred features and modifications of the described embodiments are applicable to all aspects of the disclosure taught herein. Moreover, the various features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments, are combinable and interchangeable. Attached Figure Description

[0025] Many aspects of this disclosure can be better understood with reference to the following figures. The components in the figures are not necessarily drawn to scale, but the emphasis is on clearly illustrating the principles of this disclosure. Furthermore, in the figures, the same reference numerals denote corresponding parts in multiple views.

[0026] Figure 1 Representative data on the effect of the disclosed compound Cpd1 on p53 expression in AML cell lines are shown, as determined by immunoblotting analysis.

[0027] Figures 2A to 2D Representative data on the activities of the disclosed compounds in cell proliferation assays performed using the MTS assay described below, and data on the determination of IC50 in the same manner, are presented. 50 The suppression curve of the value. Figure 2A Representative data on the activities of the disclosed compounds in cell proliferation assays performed using the MTS assay described below, and IC50 values ​​for determining the compounds Cpd1-Cpd6 in the same manner, are shown. 50 The suppression curve of the value. Figure 2B Representative data on the activities of the disclosed compounds in cell proliferation assays performed using the MTS assay described below are shown, along with IC50 values ​​for determining, in the same manner, the activities of the compounds Cpd7, Cpd8, Cpd10, and Cpd12-Cpd15. 50 The suppression curve of the value. Figure 2C Representative data on the activities of the disclosed compounds in cell proliferation assays performed using the MTS assay described below, and IC50 values ​​for determining the compounds Cpd16-Cpd21 in the same manner, are shown. 50 The suppression curve of the value. Figure 2D Representative data on the activities of the disclosed compounds in cell proliferation assays performed using the MTS assay described below, and IC50 values ​​for determining the compounds Cpd22-Cpd27 in the same manner, are shown. 50 The suppression curve of the value.

[0028] Other advantages of the invention will be set forth in part in the description which follows, and will be apparent in part from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only, and not intended to limit the scope of the claimed invention. Detailed Implementation

[0029] With the aid of the teachings given in the foregoing description and the accompanying drawings, those skilled in the art will conceive of numerous modifications and other embodiments of the disclosed compositions and methods. Therefore, it should be understood that this disclosure is not limited to the specific 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 numerous variations and modifications to the aspects described herein. These variations and modifications are intended to be included within the teachings of this disclosure and are covered by the claims herein.

[0030] Although certain terms are used in this article, they are used only in a general and descriptive sense, and not for limiting purposes.

[0031] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features, which can be readily separated from or combined with features of any aspect of other embodiments without departing from the scope or substance of this disclosure.

[0032] Any of the methods may be performed in the order of the events stated or in any other logically possible order. That is, unless expressly stated otherwise, it is never intended to interpret any method or aspect set forth herein as requiring its steps to be performed in a particular order. Therefore, unless a method claim specifically states in the claims or specification that the steps are limited to a particular order, it is never intended to refer to any particular order. This applies to any possible non-express basis of interpretation, including logical questions relating to the arrangement of steps or operational procedures, explicit meanings derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0033] All publications mentioned herein are incorporated by reference to disclose and describe methods and / or materials relating to those publications. The publications discussed herein are provided only because they predate the filing date of this application. Nothing herein should be construed as an admission that the invention is not entitled to any prior publication due to prior inventiveness. Furthermore, the publication dates provided herein may differ from the actual publication dates, which may require independent verification.

[0034] While various aspects of this disclosure may be described and claimed in specific statutory categories such as the systems statutory category, this is only for convenience, and those skilled in the art will understand that each aspect of this disclosure may be described and claimed in any statutory category.

[0035] It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods pertain. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having the same meaning as they have in the context of the specification and related art, and should not be interpreted as idealized or overly formal unless expressly defined herein.

[0036] Before describing various aspects of this disclosure, the following definitions should be provided and used unless otherwise stated. Additional terms may be defined elsewhere in this disclosure.

[0037] definition

[0038] As used herein, “comprising” will be interpreted as specifying the presence of the features, integers, steps, or components mentioned, but does not preclude the presence or addition of one or more features, integers, steps, or components or groups thereof. Furthermore, each of the terms “by,” “comprising,” “including,” “involving,” and “such as” is used in its open, non-limiting sense and may be used interchangeably. Additionally, the term “comprising” is intended to include examples and aspects covered by the terms “substantially constitutes” and “consistent with.” Similarly, the term “substantially constitutes” is intended to include examples covered by the term “consistent with.”

[0039] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “described” include plural references. Thus, for example, references to “DHODH inhibitor,” “cancer,” or “pyrimidine nucleotide” include, but are not limited to, combinations of two or more such DHODH inhibitors, cancers, or pyrimidine nucleotides.

[0040] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in range format herein. It should also be understood that the endpoints of each range are significant, both relative to and independent of the other endpoint. It should also be understood that multiple values ​​are disclosed herein, and each value is disclosed not only as the value itself but also as “about” that particular value. For example, if the value “10” is disclosed, then “about 10” is also disclosed. A range may be expressed herein as from “about” one particular value and / or to “about” another particular value. Similarly, when a value is expressed as an approximation using the antecedent “about”, it should be understood that the particular value forms another aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0041] When indicating a range, on the other hand, it includes from one specific value and / or to another specific value. For example, where the specified range includes one or two limits, the range excluding any one or two of the included limits is also included in this disclosure; for example, the phrase "x to y" includes the range from "x" to "y" as well as the range greater than "x" and less than "y". The range can also be expressed as an upper limit, such as "about x, y, z or less", and should be interpreted as including the specific ranges of "about x", "about y", and "about z" as well as the ranges of "less than x", "less than y", and "less than z". Similarly, the phrase "about x, y, z or greater" should be interpreted as including the specific ranges of "about x", "about y", and "about z" as well as the ranges of "greater than x", "greater than y", and "greater than z". Furthermore, the phrase "about 'x' to 'y'" includes "about 'x' to about 'y'", where 'x' and 'y' are numerical values.

[0042] It should be understood that this range format is used for convenience and brevity, and therefore should be interpreted flexibly to include not only the explicitly listed values ​​as limits to the range, but also all individual values ​​or subranges covered within that range, as if each value and subrange were explicitly listed. For example, the range “about 0.1% to 5%” should be interpreted to include not only the explicitly listed values ​​of about 0.1% to about 5%, but also individual values ​​(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%, and other possible subranges) within the specified range.

[0043] As used herein, the terms “about,” “approximately,” “equal to or about,” and “substantially” mean that the quantity or value in question may be an exact value or a value that provides an equivalent result or effect to that listed in the claims and taught herein. That is, it should be understood that quantities, dimensions, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller as required, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art to obtain an equivalent result or effect. In some cases, it is not reasonable to determine a value that provides an equivalent result or effect. In such cases, unless otherwise specified or implied, it should generally be understood that, as used herein, “about” and “equal to or about” indicate a nominal value indicating a variation of ±10%. Generally speaking, quantities, dimensions, formulations, parameters, or other quantities or characteristics are “about,” “approximately,” or “equal to or about,” whether explicitly stated or not. It should be understood that where “about,” “approximately,” or “equal to or about” is used before a quantitative value, unless otherwise specifically stated, the parameter also includes the specific quantitative value itself.

[0044] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, and the description includes instances where the event or situation occurs as well as instances where it does not occur.

[0045] As used herein, “dihydroorotate dehydrogenase” and “DHODH” are used interchangeably. DHODH is an enzyme encoded by the human genome, located at 16q22.2, molecularly at base pairs 72,008,744 to 72,025,417 on chromosome 16 (Homo sapiens Annotation Release 109, GRCh38.p12). The human genome contains nine exons. DHODH has an EC classification of 1.3.1.1, an intracellular location within mitochondria, and catalyzes the fourth enzymatic step in de novo pyrimidine biosynthesis. DHODH is also known as DHO dehydrogenase; dihydroorotate dehydrogenase, mitochondria; dihydroorotate dehydrogenase, mitochondrial precursor; dihydroorotate oxidase; human complement of yeast URA1; POADS; PYRD_HUMAN; and URA1.

[0046] Unless otherwise specified, the term “inhibition” or “inhibitor” of DHODH as used herein refers to the inhibition of the enzyme DHODH.

[0047] As used in this article, "IC" 50 "Intended to refer to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process, enzymatic reaction, or component of a biological or enzymatic process by 50%. For example, IC50..." 50 The IC50 refers to the maximum half-maximal (50%) inhibitory concentration of a substance, determined using an appropriate assay. For example, the IC50 for DHODH activity. 50 The activity can be determined in an in vitro enzymatic assay using the methods described herein. Alternatively, the activity can be determined in a cell-based assay, including measuring the activity or function associated with the inhibition of the target process or enzyme. That is, DHODH activity can be determined indirectly in a cell-based cell proliferation assay. DHODH inhibition is believed to lead to growth arrest or inhibition in suitable cell types. DHODH activity can be determined in suitable cells, such as primary AML cells or AML cell lines, using cell proliferation assays, such as the MTS assay described herein, or the colony formation assay described herein. Suitable cell lines are described below.

[0048] As used herein, the term “immunity” includes cells of the immune system and cells that perform functions or play an active role in the 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.

[0049] As used herein, the interchangeable terms "buquina" and "BQR" refer to compounds having the structure represented by the following formula:

[0050]

[0051] Buquina can also be referred to by the IUPAC chemical name or 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid. Common salt forms are potassium and sodium bukequina (also referred to herein as BQR Na), which are alkali metal salts of the conjugate bases of carboxylic acids. Buquina is sometimes called DuP-785 or NSC-368390.

[0052] As used herein, “graft-versus-host disease” and GVHD are used interchangeably and refer to a clinical complication following allogeneic tissue transplantation. It is commonly associated with stem cell or bone marrow grafts, but the term also applies to other forms of tissue grafts. Immune cells (white blood cells) in the tissue (graft) recognize the recipient (host) as a “foreign object.” The transplanted immune cells then attack the host’s body cells. GVHD can also occur after transfusion if the blood product used has not been irradiated or treated with an unapproved pathogen reduction system.

[0053] As used herein, “application” can mean oral, local, intravenous, subcutaneous, percutaneous, transdermal, intramuscular, intra-articular, parenteral, intra-arterial, intradermal, intravenous, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intra-articular, intracavitary, intralesional, intravascular, intravitreal, intracerebral, intraventricular, intratympanic, intracochlear, rectal, intravaginal, by inhalation, by catheter, stent, or by implanted cartridge or other means of actively or passively administering (e.g., by diffusion) a composition to the perivascular space and adventitia. For example, medical devices such as stents may contain a composition or formulation disposed on their surface, which may then dissolve or otherwise distribute to the surrounding tissues and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Application can be continuous or intermittent. In various respects, the formulation may be administered therapeutically; that is, administered to treat an existing disease or condition. In other respects, the preparation can be administered preventively; that is, it can be administered to prevent disease or illness.

[0054] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, etc., that is biologically active or can induce pharmacological, immunogenic, biological, and / or physiological effects on the subject to which it is administered, through local and / or systemic action. A therapeutic agent can be the primary active agent, or in other words, the component of the composition to which all or part of the effect of the composition is attributed. A therapeutic agent can be an adjunctive therapeutic agent, or in other words, an additional portion and / or additional effect of the composition to which the component of the composition is attributed. Therefore, the term encompasses those compounds or chemical substances traditionally considered as drugs, vaccines, and biological drugs, including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the American Medical Association's Handbook of Medications (64th edition), and the Fundamentals of Pharmacology (12th edition), and therapeutic agents include, but are not limited to: drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or alleviate disease; substances that affect the structure or function of the body; or prodrugs that become biologically active or more active when placed in a physiological environment. For example, the term "therapeutic agent" includes compounds or compositions used in all major therapeutic areas, including but not limited to: adjuvants; anti-infectives, such as antibiotics and antivirals; analgesics and combinations of analgesics, anorexia nervosa, anti-inflammatory drugs, antiepileptic drugs, local and general anesthetics, hypnotics, sedatives, antipsychotics, psychotropics, antidepressants, anxiolytics, antagonists, neuronal blocking agents, anticholinergics and cholinergics, antimuscarinic and muscarinic drugs, antiadrenergics, antiarrhythmics, antihypertensives, hormones and nutrients, antiarthritis drugs, antiasthmatics, anticonvulsants, antihistamines, antinausea drugs, antitumor drugs, antipruritics, antipyretics; anticonvulsants, cardiovascular agents (including calcium channel blockers, beta-blockers, etc.). - Blockers, beta-agonists, and antiarrhythmics; antihypertensives, diuretics, vasodilators; 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 recombinant); and nucleic acid molecules (polymers of two or more nucleotides, ribonucleotides (RNA) or deoxyribonucleotides (DNA), including double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, etc.), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as proteins and enzymes. The agent can be a bioactive agent for medical (including veterinary) applications and agricultural (e.g., for plants) and other fields. The term therapeutic agent also includes, but is not limited to: drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or alleviate disease; substances that affect the structure or function of the body; or prodrugs that become biologically active or more active when placed in a physiological environment.

[0055] As used herein, a “kit” refers to a collection of at least two components that constitute a kit. These components together form a functional unit for a given purpose. Individual component members may be physically packaged together or individually packaged. For example, a kit that includes instructions for using the kit may or may not physically include those instructions along with other individual component members. Instead, the instructions may be provided as a separate component, either in print or electronic form. The electronic form may be available on a computer-readable storage device or downloadable from an internet website, or as a recorded presentation.

[0056] As used herein, “instructions for use” refers to a document describing the relevant materials or methods associated with the kit. These materials may include any combination of the following: background information, a list of components and their availability (purchase information, etc.), a brief or detailed protocol for using the kit, troubleshooting, references, technical support, and any other relevant documentation. Instructions for use may be provided with the kit or as a separate component, and may be provided in print or electronic form. Electronic versions may be available on computer-readable storage devices or downloadable from the internet, or as a recorded presentation. Instructions for use may contain one or more documents and should include future updates.

[0057] As used herein, “connected” can refer to covalent or non-covalent interactions 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 interactions.

[0058] As used interchangeably herein, “subject,” “individual,” or “patient” may refer to a vertebrate organism, such as a mammal (e.g., a human). “Subject” may also refer to a cell, cell population, tissue, organ, or organism, preferably a human or its components. It should be understood that vertebrates can be mammals, fish, birds, reptiles, or amphibians. Therefore, the subject of the methods disclosed herein may be a human, a non-human primate, a horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. This term does not indicate a specific age or sex. Furthermore, adult and newborn subjects, as well as fetuses, whether male or female, are included. A patient is a subject suffering from a clinical condition, disease, or disorder. The term “patient” includes both human and veterinary subjects.

[0059] As used herein, the term "treatment" can generally refer to achieving a desired pharmacological and / or physiological effect. This effect may be prophylactic, but not necessarily prophylactic, in relation to the prevention or partial prevention of a disease, symptom, or condition, such as cancer, a disorder or disease associated with T-cell proliferation, or graft-versus-host disease. This effect may be therapeutic in relation to the partial or complete cure of a disease, condition, symptom, or side effects caused by that disease, disorder, or condition. As used herein, the term "treatment" can include any treatment of cancer, a disorder or disease associated with T-cell proliferation, or graft-versus-host disease in subjects, particularly humans, and can include any one or more of the following: (a) prevention of the disease in subjects who may be susceptible to the disease but have not yet been diagnosed with it; (b) suppression of the disease, i.e., prevention of its development; and (c) alleviation of the disease, i.e., reduction or improvement of the disease and / or its symptoms or condition. As used herein, the term "treatment" can mean therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Subjects who require treatment (subjects for whom the need exists) may include those who already have the disorder and / or those who wish to prevent the disorder. As used herein, the term "treatment" may include suppressing a disease, disorder, or condition, for example, hindering its progression; and alleviating a disease, disorder, or condition, for example, causing its remission. Treating a disease, disorder, or condition may include improving at least one symptom of a particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, for example, treating a subject's pain by administering an analgesic, even if such an agent does not treat the cause of the pain.

[0060] As used herein, “dose” or “dosage” can refer to a physically discrete unit suitable for use by a subject, each unit containing a predetermined amount of the disclosed compound and / or its pharmaceutical composition, which is calculated to produce one or more desired responses in relation to its administration.

[0061] As used in this article, "therapeutic" can mean treating, curing, and / or improving a disease, disorder, symptom, or side effect, or slowing the progression of that disease, disorder, symptom, or side effect.

[0062] As used herein, "effective amount" can refer to an amount of the disclosed compound or pharmaceutical composition provided herein that is sufficient to achieve a beneficial or desired biological, emotional, medical, or clinical response in cells, tissues, systems, animals, or humans. An effective amount may be administered, applied, or dosed once or multiple times. Within its scope, the term may also include amounts that effectively enhance or restore substantially normal physiological function.

[0063] As used herein, the term "therapeutic effective dose" refers to an amount sufficient to achieve the desired therapeutic outcome or to have an effect on undesirable symptoms, but generally insufficient to cause adverse side effects. The specific therapeutic effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and its severity; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the time of administration; the route of administration; the excretion rate of the specific compound used; the duration of treatment; the medications used in combination with or concurrently with the specific compound used; and similar factors within the knowledge and expertise of a healthcare practitioner, which are well known in the medical field. In the treatment of a particular disease or condition, in some cases, the desired response may inhibit the progression of the disease or condition. This may only involve temporarily slowing the progression of the disease. However, in other cases, it may be desired to permanently stop the progression of the disease. This can be monitored using routine diagnostic methods known to those skilled in the art for any particular disease. A desired response to the treatment of a disease or condition may also delay or even prevent the onset of the disease or condition.

[0064] For example, administration of the compound may be initiated at a level below that required to achieve the desired therapeutic effect, and the dose may be gradually increased until the desired effect is achieved, which is within the scope of the art. If necessary, the effective daily dose may be divided into multiple doses for administration purposes. Thus, a single-dose composition may contain such an amount or an approximation thereof to constitute the daily dose. In the event of any contraindications, the dose may be adjusted by the individual physician. Generally, the maximum dose of the disclosed drug (alone or in combination with other therapeutic agents) is preferred, i.e., the highest safe dose based on reasonable medical judgment. However, those skilled in the art will understand that patients may adhere to a lower or tolerated dose for medical, psychological, or virtually any other reason.

[0065] For example, the response to a therapeutically effective dose of the disclosed compound and / or pharmaceutical composition can be measured by determining the physiological effect of the treatment or drug, such as the reduction or disappearance of disease symptoms after administration of the treatment or drug. Other assays are known to those skilled in the art and can be used to measure response levels. The dosage can be varied, for example, by increasing or decreasing the amount of the disclosed compound and / or pharmaceutical composition, by changing the administered disclosed compound and / or pharmaceutical composition, by changing the route of administration, by changing the time of administration, etc. Dosage can be varied and can be administered once or multiple times daily for one or several days. Guidelines for appropriate dosages of given classes of pharmaceuticals can be found in the literature.

[0066] In this disclosure, it should be understood that, in some cases, an effective amount or dose of the disclosed compound is an amount of composition capable of inhibiting DHODH, thereby providing clinically meaningful relief from signs, symptoms, or causes of disease or any other desired biological systemic alteration due to the inhibition of DHODH. For example, an "effective amount" for therapeutic use. In some aspects, in any individual case, an appropriate "effective" amount is determined using techniques such as dose escalation studies.

[0067] As used in this article, the term "preventive effective dose" refers to the amount that is effective in preventing the onset or onset of a disease or symptom.

[0068] As used herein, the term "prevent" means to eliminate, prevent, avoid, preemptively stop, cease, or hinder the occurrence of something, especially through preemptive action. It should be understood that the use of "reduce," "suppress," or "prevent" herein explicitly discloses the use of the other two terms unless otherwise specified herein.

[0069] The term "pharmaceutically acceptable" describes materials that are not biologically or otherwise undesirable, that is, materials that do not cause undesirable biological effects at unacceptable levels or interact in a harmful manner.

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of an active pharmaceutical ingredient prepared with an acid or base, which, when administered in a therapeutically effective amount, is tolerated by the biological system or by the subject, or is tolerated by both the biological system and the subject. When the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amino, magnesium, lithium, strontium, or similar salts. When the compounds of this disclosure contain relatively basic functional groups, an acid addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired acid, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, 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, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts of amino acids, such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid are also included.

[0071] The term "pharmaceutically acceptable ester" refers to an ester of the compounds of this disclosure that hydrolyzes in vivo, including those that readily decompose in the human body, leaving behind the parent compound or its salts. Examples of pharmaceutically acceptable, non-toxic esters of this disclosure include C1 to C6 alkyl esters and C5 to C7 cycloalkyl esters, although C1 to C4 alkyl esters are preferred. Esters of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be attached to the hydroxyl group by reacting a compound containing a hydroxyl group with an acid and an alkyl carboxylic acid such as acetic acid, or with an acid and an aryl carboxylic acid such as benzoic acid. In the case of compounds containing a carboxylic acid group, pharmaceutically acceptable esters are prepared from compounds containing a carboxylic acid group, specifically by reacting the compound with a base such as triethylamine and an alkyl halide, for example with methyl iodine, benzyl iodine, cyclopentyl iodine, or an alkyl ester of trifluoromethanesulfonate. They can also be prepared by reacting the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0072] The term "pharmaceutically acceptable amide" refers to the non-toxic amides of this disclosure derived from ammonia, primary C1 to C6 alkylamines, and secondary C1 to C6 dialkylamines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amides derived from ammonia, C1 to C3 alkyl primary amides, and C1 to C2 dialkyl secondary amides are preferred. The 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, specifically by reacting the compound containing an amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aryl acyl halide. In the case of compounds containing a carboxylic acid group, pharmaceutically acceptable amides are prepared from compounds containing a carboxylic acid group, specifically by reacting the compound with a base such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkylamine, a dialkylamine (e.g., with methylamine, diethylamine), and piperidine. They can also be prepared by reacting the compound with acids such as sulfuric acid and alkyl carboxylic acids such as acetic acid, or with acids and aryl carboxylic acids such as benzoic acid, under dehydration conditions, such as using an added molecular sieve. The composition may comprise a pharmaceutically acceptable prodrug form of the disclosed compound.

[0073] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to those prodrugs of the compounds disclosed herein that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., commensurate with a reasonable cost-benefit ratio, and effective for their intended use. The prodrugs of this disclosure can, for example, be rapidly converted in vivo into a parent compound having the structure of the disclosed compound by hydrolysis in the blood. They are discussed in detail in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," ACSSymposium Series, Volume 14, and in Edward B. Roche, ed., "Bioreversible Carriers in Drug Design," American Pharmaceutical Association and Pergamon Press, 1987.

[0074] As used herein, the term "contact" means bringing the disclosed compound or pharmaceutical composition into contact with a cell, target protein, or other biological entity in such a way that the disclosed compound or pharmaceutical composition can directly (i.e., through interaction with the cell, target protein, or other biological entity itself) or indirectly (i.e., through interaction with another molecule, cofactor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself depends) affect the activity of the cell, target protein, or other biological entity.

[0075] It should be understood that, unless otherwise stated, the temperatures referred to herein are based on atmospheric pressure (i.e., one atmosphere).

[0076] As used herein, the nomenclature of compounds (including organic compounds) may be given using common names, IUPAC, IUBMB, or CAS recommended nomenclature. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rule of stereochemistry may be used to specify stereochemical priority, E / Z specification, etc. If a name is given, those skilled in the art can systematically simplify the compound structure using nomenclature conventions, or using commercially available software such as CHEMDRAW. TM (Cambridgesoft Corporation, USA) can easily determine the structure of compounds.

[0077] As used herein, the term “substituted” is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described below. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compound described herein that satisfy the heteroatom valence. This disclosure is not intended to be limited in any way by the permissible substituents of an organic compound. Additionally, the terms “substituted” or “replaced” include the implicit limitation that such substitution is consistent with the permissible valence of the substituted atom and substituent, and that the substitution produces a stable compound, such as a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. It is also contemplated that, in some respects, unless expressly indicated otherwise, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0078] When defining various terms, "A" 1 “A” 2 “A” 3 "and "A 4 "In this article, it is used as a general symbol to represent various specific substituents. Similarly, "Ar" 1 “Ar” 2 “Ar” 3 "and "Ar 4 "These symbols are used herein as general symbols to represent various specific aryl substituents. These symbols can be any substituents, not limited to those disclosed herein, and while they may be defined as some substituents in one instance, they may be defined as others in another instance."

[0079] As used herein, the term "aliphatic" or "aliphatic group" means a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spirofused polycyclic) and may be fully saturated or contain one or more unsaturated units but not aromatic units. Unless otherwise stated, an aliphatic group comprises 1-20 carbon atoms. Aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, and their hybrids such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl groups.

[0080] As used herein, the term "alkyl" is a branched or unbranched saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetradecyl, etc. Alkyl groups can be cyclic or acyclic. Alkyl groups can be branched or unbranched. Alkyl groups 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, halogroup, hydroxyl, nitro, silyl, sulfo-oxo, or thiol, as described herein. "Lower alkyl" is an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl can also 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, etc., up to and including C1-C24 alkyl.

[0081] Throughout this specification, "alkyl" is generally used to refer to both unsubstituted and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying a particular substituent on the alkyl group. For example, the term "haloalkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halogroups (e.g., fluorine, chlorine, bromine, or iodine). Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halogroup (e.g., fluorine, chlorine, bromine, or iodine). The term "polyhaloalkyl" specifically refers to an alkyl group independently substituted with two or more halogroups, i.e., each halosubstituent need not be the same halogroup as another halosubstituent, and multiple instances of halosubstituents need not be on the same carbon atom. 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 hydroxyl groups. When “alkyl” is used in one context and a specific term such as “hydroxyalkyl” is used in another context, it does not imply that the term “alkyl” does not refer to the specific term such as “hydroxyalkyl”.

[0082] As used herein, “aminoalkyl” refers to a straight-chain or branched alkyl group in which at least one hydrogen atom is replaced by an amino group (usually 1-3 amino groups). Non-limiting examples of aminoalkyl groups include ─CH2NH2, ─(CH2)2NH2, ─CHCH3NH2, ─(CH2)2CHCH3NH2, ─(CH2)2CHNH2CH2CH3, ─CHCH3(CH2)2NH2, etc.

[0083] As used herein, "alkylamino" refers to an amino group having at least one hydrogen atom substituted with an alkyl group. Therefore, alkylamino refers to the group —NR a R a , where R a and R b Independently selected from H and alkyl groups, provided that R a or R b At least one of them is an alkyl group. Non-limiting examples of alkylamino groups include -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)(CH2)2CH3, etc.

[0084] As used herein, “hydroxyalkyl” refers to a straight-chain or branched alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group (usually 1-3 hydroxyl groups). Non-limiting examples of hydroxyalkyl groups include ─CH2OH, ─(CH2)2OH, ─CHCH3OH, ─(CH2)2CHCH3OH, ─(CH2)2CHOHCH2CH3, ─CHCH3(CH2)2OH, etc.

[0085] Unless otherwise stated, the term "alkadiyl" as used herein refers to a divalent straight-chain and branched saturated hydrocarbon group having a carbon atom. For example, "C1-C6 alkadiyl" refers to a divalent straight-chain and branched saturated hydrocarbon group having one to six carbon atoms, such as methylene, 1,2-ethylenediyl (─CH2CH2─), propylenediyl or 1,3-propylenediyl (─(CH2)3─), butadiyl or 1,4-butadiyl (─(CH2)4─), pentadiyl or 1,5-pentadiyl (─(CH2)5─), hexadiyl or 1,6-hexadiyl (─(CH2)6─), and their branched isomers (e.g., isopropyldiyl (─CHCH3CH2─)). Alkadiyl groups may be further substituted, for example, with aminoalkadiyl or hydroxyalkadiyl groups.

[0086] As used herein, “aminoalkyldiyl” refers to a straight-chain or branched alkyldiyl group in which at least one hydrogen atom is replaced by an amino group (usually one to three amino groups). Non-limiting examples of aminoalkyldiyl groups include ─CH2NH─, ─(CH2)2NH─, ─CHCH3NH─, ─(CH2)2CHCH3NH─, ─(CH2)2CHNH2(CH2)2─, ─CH2CHNH2(CH2)2─, ─CH2NH(CH2)2─, ─(CH2)2NH(CH2)2─, ─CHCH3(CH2)2NH─, etc.

[0087] As used herein, “hydroxyalkyldiyl” refers to a straight-chain or branched alkyldiyl group in which at least one hydrogen atom is replaced by a hydroxyl group (usually one to three hydroxyl groups). Non-limiting examples of hydroxyalkyldiyl groups include ─CHOH─, ─CH2CHOH─, ─CCH3OH─, ─(CH2)2CCH3OH─, ─(CH2)2CHOH(CH2)2─, ─CH2CHOH(CH2)2─, ─CHOH(CH2)2─, ─CH2CHOH(CH2)2─, ─CHCH3CH2CHOH─, etc.

[0088] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl group bonded by an ether bond; that is, "alkoxy" can be defined as -OA. 1 A 1 It is an alkyl or cycloalkyl group as defined above. "Alkoxy" also includes polymers of alkoxy groups just described; that is, alkoxy groups can be polyethers, such as -OA. 1 ─OA 2 Or OA 1 —(OA) 2 ) a ─OA 3 Where "a" is an integer from 1 to 200, and A 1 A 2 and A 3 It is an alkyl and / or cycloalkyl group.

[0089] As used herein, the term "aromatic group" refers to a ring structure having a ring cloud of delocalized π electrons above and below the molecular plane, wherein the π cloud contains (4n+2) π electrons. Further discussion of aromaticity can be found in Morrison and Boyd, Organic Chemistry (5th ed., 1987), Chapter 13, entitled "Aromaticity," pp. 477–497, which is incorporated herein by reference. The term "aromatic group" includes aryl and heteroaryl groups.

[0090] As used herein, the term "aryl" is a group comprising any carbonyl aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, anthracene, etc. Aryl groups can be substituted or unsubstituted. Aryl groups can be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halogroup, hydroxyl, ketone, azide, nitro, silyl, sulfonyl-oxo, or thiol, as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl". Furthermore, an aryl group can be a monocyclic structure or comprise multiple ring structures, which are either fused ring structures or linked by one or more bridging groups such as carbon-carbon bonds. For example, a biaryl group refers to two aryl groups bonded together by fused ring structures, as in naphthalene, or two aryl groups linked by one or more carbon-carbon bonds, as in biphenyl.

[0091] As used herein, the term "cycloalkyl" is a non-aromatic carbonyl ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc. The term "heterocyclic alkyl" is a cycloalkyl group as defined above and is included within the meaning of the term "cycloalkyl" in which at least one carbon atom of the ring is substituted with a heteroatom (such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus). Cycloalkyl and heterocyclic alkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocyclic alkyl groups can be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halogroup, hydroxyl, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0092] 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, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyl groups may be substituted as defined above for alkyl groups.

[0093] As used herein, the term "heteroaryl" refers to an aromatic group having at least one heteroatom incorporated into a ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, wherein N-oxides, sulfur oxides, and dioxides are permitted heteroatom substitutes. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups may be substituted by one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halogroup, hydroxyl, nitro, silyl, sulfo-oxo, or thiol groups, as described herein. Heteroaryl groups may be monocyclic or alternatively fused-ring systems. Heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrimidinyl, tetrazolyl, thiophene, pyridinyl, pyrroleyl, N-methylpyrroleyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazinyl, benzofuranyl, benzodioxolane, benzothiophene, indolyl, inazolyl, benzimidazolyl, imidazopyridyl, pyrazolopyridyl, and pyrazolopyrimidinyl. Other non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thiopheneyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazole, imidazo[1,2-b]pyridinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0094] As used herein, the term "heterocyclic" is used interchangeably and refers to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is not carbon. Thus, the term includes, but is not limited to, "heterocyclic alkyl," "heteroaryl," "bicyclic heterocyclic," and "polycyclic heterocyclic." Heterocyclic compounds 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, 1,3,4-triazole), tetrazolium (including 1,2,3,4-tetrazolium and 1,2,4,5-tetrazolium), pyridazine, pyrazine, triazine (including 1,2,4-triazine and 1,3,5-triazine), tetrazine (including 1,2,4,5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azacyclobutane, tetrahydropyran, tetrahydrofuran, dioxane, etc. The term "heterocyclic group" can also refer to C2 heterocyclic group, C2-C3 heterocyclic group, C2-C4 heterocyclic group, C2-C5 heterocyclic group, C2-C6 heterocyclic group, C2-C7 heterocyclic group, C2-C8 heterocyclic group, C2-C9 heterocyclic group, C2-C10 heterocyclic group, C2-C11 heterocyclic group, etc., up to and including C2-C18 heterocyclic group. For example, a C2 heterocyclic group includes a group having two carbon atoms and at least one heteroatom, including but not limited to aziridinyl, diazacyclobutyl, dihydrodiazacyclobutyl, ethylene oxide, thiaranyl, etc. Alternatively, for example, a C5 heterocyclic group includes a group having five carbon atoms and at least one heteroatom, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, diazacycloheptyl, pyridinyl, etc. It should be understood that heterocyclic groups can be bonded by a heteroatom in the ring (where chemically possible) or by a carbon atom in the carbon containing the heterocyclic group ring.

[0095] As used herein, the term "bicyclic heterocycle" refers to a ring system in which at least one ring member is not carbon. Bicyclic heterocyclic groups encompass ring systems in which one aromatic ring is fused to another aromatic ring, or in which an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclic groups encompass ring systems in which a benzene ring is fused to a 5- or 6-membered ring containing one, two, or three heteroatoms, or in which a pyridine ring is fused to a 5- or 6-membered ring containing one, two, or three heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indole, indazole, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxane, 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.

[0096] As used herein, the term "heterocyclic alkyl" refers to aliphatic, partially unsaturated, or fully saturated 3- to 14-membered ring systems, including monocyclic, bicyclic, and tricyclic systems with 3 to 8 atoms. Heterocyclic alkyl ring systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be substituted. Representative heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolinyl, isothiazolyl, and tetrahydrofuranyl.

[0097] As used herein, the term "amine" or "amino" is derived from the formula —NA 1 A 2 It means that A 1 and A 2 It can be hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl, as described herein. A specific example of an amino group is ─NH2.

[0098] As used herein, the term “carboxylic acid” is represented by the formula ─C(O)OH.

[0099] As used herein, the terms “halogenated,” “halogen,” or “halogenated group” are used interchangeably to refer to F, Cl, Br, or I.

[0100] As used herein, the terms “hydroxyl” or “hydroxyl group” are represented by the formula —OH.

[0101] As used in this article, the term "nitro" is represented by the formula -NO2.

[0102] As used herein, the terms “nitrile” or “cyano” are represented by the formula ─CN.

[0103] Where n is an integer "R" 1 “R” 2 “R” 3 ",...“R n "As used herein, it may independently have one or more of the groups listed above. For example, if R..." 1 If it is a straight-chain alkyl group, one of the hydrogen atoms of the alkyl group may optionally be substituted with a hydroxyl, alkoxy, alkyl, halogroup, etc. Depending on the chosen group, the first group may be incorporated into the second group, or alternatively, the first group may be side-attached (i.e., connected) to the second group. For example, for the phrase "alkyl group containing an amino group," the amino group may be incorporated into the backbone of the alkyl group. Alternatively, the amino group may be attached to the backbone of the alkyl group. The nature of the chosen group will determine whether the first group is inserted into or attached to the second group.

[0104] As described herein, compounds of this disclosure may comprise "optionally substituted" portions. Generally, the term "substituted," whether or not preceding the term "optionally," refers to one or more hydrogen atoms of the specified portion being substituted by suitable substituents. Unless otherwise stated, the "optionally substituted" group may have suitable substituents at each substituted position of the group, and when more than one position in any given structure is substituted by more than one substituent selected from a particular group, the substituents may be the same or different at each position. The combinations of substituents contemplated in this disclosure are preferably those that result in the formation of stable or chemically viable compounds. It is also contemplated that, in some respects, unless explicitly stated otherwise, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0105] As used herein, the term “stable” means a compound that remains substantially unchanged when subjected to conditions that allow it to be produced, detected, and in some respects to be recovered, purified, and used for one or more purposes disclosed herein.

[0106] The term "organic residue" defines a carbon-containing residue, that is, a residue containing at least one carbon atom, and includes, but is not limited to, carbon-containing groups, residues, or radicals as defined above. Organic residues may contain various heteroatoms or be bonded to another molecule via heteroatoms, including oxygen, nitrogen, sulfur, phosphorus, etc. Examples of organic residues include, but are not limited to, alkyl or substituted alkyl groups, alkoxy or substituted alkoxy groups, monosubstituted or disubstituted amino groups, amide groups, etc. 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. Alternatively, 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.

[0107] A very close synonym for the term "residue" is the term "base," as used in the specification and concluding claims, which refers to a fragment, group, or substructure of the molecule described herein, regardless of how the molecule is prepared. For example, the 2,4-thiazolidinedione group in a particular compound has the following structure:

[0108]

[0109] Regardless of whether a thiazolidinedione is used to prepare the compound. In some embodiments, the group (e.g., alkyl) may be further modified by bonding with one or more "substituents" (i.e., substituted alkyl groups). The number of atoms in a given radical is not critical to this disclosure unless otherwise indicated elsewhere herein.

[0110] As defined and used herein, the term "organogroup" contains one or more carbon atoms. An organic group may 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. Alternatively, an organic group may 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. An organic group typically has hydrogen atoms bonded to at least some of the carbon atoms of the organic group. An example of an organic group that does not contain inorganic atoms is 5,6,7,8-tetrahydro-2-naphthyl. In some embodiments, the organic group may contain 1 to 10 inorganic heteroatoms bonded thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, etc. Examples of organogroups include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, disubstituted amino, acyloxy, cyano, carboxyl, carbamoalkoxy, alkylformamide, substituted alkylformamide, dialkylformamide, substituted dialkylformamide, alkylsulfonyl, alkylsulfonyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic, wherein the terms are defined elsewhere herein. Some non-limiting examples of organogroups that include heteroatoms include alkoxy, trifluoromethoxy, acetoxy, dimethylamino, etc.

[0111] As defined and used herein, the term "inorganic group" contains no carbon atoms and therefore includes only atoms other than carbon. Inorganic groups comprise 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 bonded together in chemically stable combinations. An inorganic group has 10 or fewer, or preferably 1 to 6 or 1 to 4 inorganic atoms bonded together as listed above. Examples of inorganic groups include, but are not limited to, amino, hydroxyl, halogen, nitro, thiol, sulfate, phosphate, and similar commonly known inorganic groups. Inorganic groups do not contain bonded periodic table metal elements (such as alkali metals, alkaline earth metals, transition metals, lanthanides, or actinides), although such metal ions can sometimes be used as pharmaceutically acceptable cations for anionic inorganic groups such as sulfate, phosphate, or similar anionic inorganic groups. Inorganic bases do not contain metalloid elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead or tellurium, or rare gas elements, unless otherwise specified elsewhere herein.

[0112] As used herein, the term "derivative" refers to a compound whose structure is derived from that of a parent compound (e.g., compounds disclosed herein), and whose structure is sufficiently similar to those disclosed herein, and based on that similarity, those skilled in the art would expect it to exhibit the same or similar activity and utility as the claimed compound, or to induce the same or similar activity and utility as the claimed compound as a precursor. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of parent compounds.

[0113] The compounds described herein may contain one or more double bonds, thus potentially yielding cis / trans (E / Z) isomers and other conformational isomers. Unless otherwise specified, this disclosure includes all such possible isomers and mixtures thereof.

[0114] Unless otherwise specified, formulas having chemical bonds shown only with solid lines and not with wedges or dashed lines consider every possible isomer, e.g., every enantiomer and diastereomer, and mixtures of isomers such as racemic or scalemic mixtures. The compounds described herein may contain one or more asymmetric centers, thus potentially producing diastereomers and optical isomers. Unless otherwise specified, this disclosure includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Mixtures of stereoisomers and isolated specific stereoisomers are also included. In synthetic steps used to prepare such compounds, or in the use of racemic or epimerization steps known to those skilled in the art, the products of such steps may be mixtures of stereoisomers.

[0115] Many organic compounds exist in an optically active form, possessing the ability to rotate the plane of polarized light. In 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 that the compound rotates plane-polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-overlapping mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture. Many compounds described herein may have one or more chiral centers and therefore may exist in different enantiomeric forms. An asterisk (*) may be used to denote a chiral carbon if desired. When bonds to chiral carbons are depicted as straight lines in the disclosed formulas, it should be understood that both the (R) and (S) configurations of the chiral carbon, and thus enantiomers and mixtures thereof, are included in the formulas. As used in the art, when it is desired to specify an absolute configuration with respect to chiral carbons, one bond of the chiral carbon may be depicted as a wedge (bonded to an atom above the plane), while another may be depicted as a series or wedge-shaped short parallel lines (bonded to an atom below the plane). The Cahn-Ingold-Prelog system can be used to assign either the (R) or (S) configuration to chiral carbons.

[0116] The compounds described herein contain atoms of both natural and non-natural abundance. The disclosed compounds may be compounds labeled with the same isotopes as those described herein or compounds with isotopic substitutions, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F and 36 Cl. The compound also contains its prodrug, and other isotopes of the compound or the prodrug containing the aforementioned isotopes and / or other atoms are pharmaceutically acceptable salts within the scope of this disclosure. Certain isotope-labeled compounds of this disclosure, for example, those doped with radioactive isotopes such as 3 H and 14 Compounds of C can be used for drug and / or substrate tissue distribution assays. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14C) Isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0117] The compounds described in this disclosure may exist in the form of solvates. In some cases, the solvent used to prepare the solvate is an aqueous solution, and therefore the solvate is often referred to as a hydrate. The compound may exist in the form of a hydrate, 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 may combine with the compound according to this disclosure to form a solvate and a hydrate. Unless otherwise specified, this disclosure includes all such possible solvates.

[0118] The term "cocrystal" refers to a physical association of two or more molecules that is stable through non-covalent interactions. One or more components of this molecular complex provide a stable framework within a crystal lattice. In some cases, the guest molecule is incorporated into the lattice as an anhydrous form or a 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, pp. 1889–1896, 2004. Examples of cocrystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0119] Chemical substances are known to form solids existing in different ordered states, which are referred to as polymorphic forms or modifications. Different modifications to polymorphs can result in significant differences in their physical properties. Compounds according to this disclosure can exist in different polymorphic forms, wherein a particular modification may be metastable. Unless otherwise specified, this disclosure includes all such possible polymorphic forms.

[0120] Some of the materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques generally known to those skilled in the art. For example, the starting materials and reagents used to prepare 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 prepared by methods known to those skilled in the art according to the procedures described in the following references: such as 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 Supplements (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). Inc. (1989).

[0121] Unless otherwise expressly stated, it is by no means intended to interpret any method set forth herein as requiring its steps to be performed in a particular order. Therefore, in any instance where a method claim does not actually state the order in which its steps are followed, or where the claims or description do not otherwise specify that the steps are limited to a particular order, it is by no means intended to imply an order. This applies to any non-expressive basis of interpretation, including logical questions relating to the arrangement of steps or operational procedures, explicit meanings derived from grammatical organization or punctuation, or the number or type of embodiments described in the specification.

[0122] The components used to prepare the compositions of this disclosure, as well as the compositions themselves used in the methods disclosed herein, are disclosed herein. These and other materials are disclosed herein, and it should be understood that while specific references to various individual and collective combinations and arrangements of these materials are not explicitly disclosed when combinations, subsets, interactions, groups, etc., of these materials are disclosed, each material is specifically considered and described herein. For example, if a particular compound is disclosed and discussed, and numerous modifications that can be made to a number of molecules including that compound are discussed, then every combination and arrangement of that compound and possible modifications are specifically considered, unless otherwise specified. Thus, if a class of molecules A, B, and C and a class of molecules D, E, and F are disclosed, and an example of a combination molecule AD is disclosed, then each is a combination of meanings individually and collectively considered, even if each is not individually enumerated; that is, AE, AF, BD, BE, BF, CD, CE, and CF are considered disclosed. Similarly, any subsets or combinations of these are also disclosed. Thus, for example, a subset of AE, BF, and CE would be considered disclosed. This concept applies to all aspects of this application, including but not limited to the steps in methods for preparing and using the compositions of this disclosure. Therefore, if there are multiple executable additional steps, it should be understood that each of these additional steps can be performed using any particular implementation or combination of implementations of the methods disclosed herein.

[0123] It should be understood that the compositions disclosed herein have certain functions. This document discloses certain structural requirements for performing the disclosed functions, and it should be understood that multiple structures can perform the same functions associated with the disclosed structures, and these structures will generally achieve the same results.

[0124] This document describes compounds that can inhibit dihydroorotate dehydrogenase (DHODH) and have therapeutic or clinical utility for diseases or disorders that can be treated by inhibiting DHODH. Methods for synthesizing the disclosed compounds are also described. Methods for administering the disclosed compounds to a subject in need are also described. In some aspects, the subject may suffer from a disease or disorder associated with DHODH activity, such as cancer, disorders or diseases related to T-cell proliferation, or graft-versus-host disease. Other compositions, compounds, methods, features, and advantages of this disclosure will be apparent or become apparent to those skilled in the art upon review of the following figures, detailed description, and examples. All such additional compositions, compounds, methods, features, and advantages are intended to be included in this specification and within the scope of this disclosure.

[0125] Compounds.

[0126] In all respects, the disclosed compound is a 6-substituted 2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analog that can be used as an inhibitor of dihydroorotate dehydrogenase and is used as a therapeutic agent in various clinical conditions such as cancer, graft-versus-host disease, and disorders associated with T-cell proliferation.

[0127] This article discloses compounds having the following structural formulas:

[0128]

[0129] Where R 1 Selected from hydrogen, halogens, −SF5, −CN, −N3, −OH, −NH2, −CF3, and −CF2CF3; where R 5a R 5b R 5c R 5d and R 5 One of e is selected from groups having the following structural formula: ─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 ;where A 1 Selected from -O- and -NR 50 —; where R 50 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 2 Selected from -O- and -NR 60 —; where R 60 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 3 Selected from -O- and -NR 70 —; where R 70 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein R 20 Selected from halogens, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, and -(CH2). n Cy1 and ─(CH2) n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Cy 1 It is a C3-C10 cycloalkyl or C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; wherein Ar 1 It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 independently selected groups from the following: 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; wherein R 30 and R 31 Each of them is independently selected from -C1-C10 alkyldiyl, -C1-C10 haloalkyldiyl, -C1-C10 aminoalkyldiyl, and -C1-C10 hydroxyalkyldiyl; and R 40 Selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 and ─(CH2) n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Cy 1 It is a C3-C10 cycloalkyl or C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; wherein Ar 1It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; and wherein R 5a R 5b R 5c R 5d and R 5e The four elements are independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; among which R 6a R 6b R 6c and R 6d Each of these elements is 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, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen; or a pharmaceutically acceptable salt thereof.

[0130] This article discloses compounds having the following structural formulas:

[0131]

[0132] Where R 1 Selected from hydrogen, halogens, −SF5, −CN, −N3, −OH, −NH2, −CF3, and −CF2CF3; where R 5a R 5b R 5c R 5d and R 5e One of them is selected from groups having the following structural formula: -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 —A3 —R 40 ;where A 1 Selected from -O- and -NR 50 —; where R 50 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 2 Selected from -O- and -NR 60 —; where R 60 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 3 Selected from -O- and -NR 70 —; where R 70 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein R 20 Selected from halogens, -C1-C10 alkyl groups, -C1-C10 alkylamino groups, and -C1-C10 alkoxy groups; wherein R 30 and R 31 Each of them is independently selected from -C1-C10 alkyldiyl, -C1-C10 aminoalkyldiyl, and -C1-C10 hydroxyalkyldiyl; and R 40 Selected from -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl and -(CH2). n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Ar 1 It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; and wherein R 5a R 5b R 5c R 5d and R 5e The four elements are independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; among which R 6a R 6b R 6c and R 6d Each of these elements is 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, provided that R6a R 6b R 6c and R 6d At least one of them is not hydrogen; or a pharmaceutically acceptable salt thereof.

[0133] This article discloses compounds having the following structural formulas:

[0134]

[0135] Where R 1 Selected from hydrogen, halogens, −SF5, −CN, −N3, −OH, −NH2, −CF3, and −CF2CF3; where R 5a R 5b R 5c R 5d and R 5e One of them is selected from groups having the following structural formula: -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 ;where A 1 Selected from -O- and -NR 50 —; where R 50 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 2 Selected from -O- and -NR 60 —; where R 60 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 3 Selected from -O- and -NR 70 —; where R 70 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein R 20 Selected from halogens, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, and -C1-C10 alkoxy; wherein R 30 and R 31Each of them is independently selected from -C1-C10 alkyldiyl, -C1-C10 haloalkyldiyl, -C1-C10 aminoalkyldiyl, and -C1-C10 hydroxyalkyldiyl; and R 40 Selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl and -(CH2). n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Ar 1 It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; and wherein R 5a R 5b R 5c R 5d and R 5e The four elements are independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; among which R 6a R 6b R 6c and R 6d Each of these elements is 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, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen; or a pharmaceutically acceptable salt thereof.

[0136] In some respects, R 6a R 6b R 6c and R 6d Each of these can be independently selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkoxy, and C1-C10 haloalkyl. On the other hand, R 6a and R 6b It is independently selected from hydrogen and halogens. On the other hand, R... 6a It's fluorine, or R. 6b It is fluorine, or a combination thereof. On the other hand, R 6c and R 6d It could be hydrogen.

[0137] In other respects, this paper discloses compounds represented by the formula having the following structure:

[0138]

[0139]

[0140]

[0141] Or a combination thereof.

[0142] In other respects, this paper discloses compounds represented by the formula having the following structure:

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] Or their subgroups.

[0150] In other respects, this paper discloses compounds represented by the formula having the following structure:

[0151] Or a combination thereof.

[0152] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0153] In all respects, the compounds disclosed herein are expected to also include their bioisosteric equivalents. The term “bioisosteric equivalent” refers to a compound or group having approximately equal molecular shape and volume, approximately the same electron distribution, and exhibiting similar physical and biological properties. Examples of such equivalents are: (i) fluorine to hydrogen, (ii) oxo to thiazolyl, (iii) hydroxyl to amide, (iv) carbonyl to oxime, and (v) carboxylic acid ester to tetrazolium. Examples of such bioisosteric substitution can be found in the literature, and examples of such literature are as follows: (i) Burger A, “Relation of chemical structure and biological activity”, Medicinal Chemistry, 3rd edition, edited by Burger A, Wiley-Interscience, New York, 1970, pp. 64-80; (ii) Burger, A., “Isosterism and bioisosterism in drug design”, Prog. Drug Res., 1991, Vol. 37, pp. 287-371; (iii) Burger A, “Isosterism and bioanalogy in drug design”, Med. Chem. Res., 1994, Vol. 4, pp. 89-92; (iv) Clark RD, Ferguson AM, Cramer RD, “Bioisosterism and molecular diversity”, Perspect. Drug Discovery. Des., 1998, 9 / 10 / 11, pp. 213-224; (v) Koyanagi T, Haga T, “Bioisosterism in agrochemicals”, ACS Symp. Ser., 1995, Vol. 584, pp. 15-24; (vi) Kubinyi H, “Molecular similarities. Part 1. Chemical structure and biological activity”, Pharm. Unserer Zeit, 1998, Vol. 27, pp. 92-106; (vii) Lipinski C A., “Bioisosterism in drug design”, Annu. Rep. Med. Chem.(viii) Patani GA, LaVoie EJ, “Bioisosterism: A rational approach in drug design”, Chem. Rev. (Washington, DC), 1996, Vol. 96, pp. 3147-3176; (ix) Soskic V, Joksimovic J, “Bioisosteric approach in the design of new dopaminergic / serotonergic ligands”, Curr. Med. Chem., 1998, Vol. 5, pp. 493-512; (x) Thornber CW, “Isosterism and molecular modification in drug design”, Chem. Soc. Rev., 1979, Vol. 8, pp. 563-580.

[0154] In another aspect, bioisosteres are atoms, ions, or molecules in which the outer electron shells can be considered substantially identical. The term "bioisostere" is generally used to refer to a portion of a whole molecule, rather than the entire molecule itself. Bioisostere substitution involves replacing one bioisostere with another, with the intention of maintaining or slightly altering the biological activity of the first bioisostere. Thus, in this case, bioisosteres are atoms or groups of atoms having similar size, shape, and electron density. Preferred bioisosteres of esters, amides, or carboxylic acids are compounds containing two hydrogen bond accepting sites. In one embodiment, the bioisostere of the ester, amide, or carboxylic acid is a 5-membered monocyclic heteroaryl ring, such as an optionally substituted 1H-imidazolyl, optionally substituted oxazolyl, 1H-tetrazole, [1,2,4]triazolyl, or optionally substituted [1,2,4]oxadiazolyl.

[0155] In all respects, the disclosed compounds are contemplated herein to also contain isotopically labeled or isotopically substituted variants, i.e., the same compounds but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、35 S, 18 F and 36 Cl. The compound also contains its prodrug, and other isotopes of the compound or the prodrug containing the aforementioned isotopes and / or other atoms are pharmaceutically acceptable salts within the scope of this disclosure. Certain isotope-labeled compounds of this disclosure, for example, those doped with radioactive isotopes such as 3 H and 14 Compounds of C can be used for drug and / or substrate tissue distribution assays. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0156] In all respects, the disclosed compounds may have at least one asymmetric center, and they may exist as racemic mixtures, pure enantiomers and / or diastereomers, or mixtures of these enantiomers and / or diastereomers. Stereoisomers may exist in the mixture in any proportion. In some respects, the disclosed compounds may exist as tautomers, whenever possible.

[0157] Therefore, methods known per se can be used to isolate the disclosed compounds, which have one or more chiral centers and exist in racemic form, into their optical isomers, i.e., enantiomers or diastereomers. Separation can be achieved by column separation of the chiral phase, by recrystallization from an optically active solvent, by using an optically active acid or base, or by derivatization with an optically active reagent such as an optically active alcohol followed by residue removal.

[0158] In all respects, the disclosed compounds may be in the form of cocrystals. The term "cocrystal" refers to a stable physical association of two or more molecules through non-covalent interactions. One or more components of the molecular complex provide a stable framework in a crystal lattice. In some cases, the guest molecule is incorporated into the crystal lattice in the form of anhydrous or solvated forms, 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, pp. 1889-1896, 2004. Preferred cocrystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0159] The term "pharmaceutically acceptable cocrystal" refers to a cocrystal that is compatible with other components of a formulation and is harmless to its recipients.

[0160] On the other hand, the disclosed compound can be separated as a solvate, particularly as a hydrate of the disclosed compound, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In this respect, one, two, three, or any number of solvent or water molecules can combine with the compound according to this disclosure to form a solvate and a hydrate.

[0161] The disclosed compounds may 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 such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts, which can be similarly prepared by reacting the pharmaceutical compound with a suitable pharmaceutically acceptable base. Salts may be prepared in situ during the final isolation and purification of the disclosed compounds; or after final isolation, by reacting the free basic functional group of the disclosed compounds, such as a secondary or tertiary amine, with a suitable inorganic or organic acid; or by reacting the free acid functional group of the disclosed compounds, such as a carboxylic acid, with a suitable inorganic or organic base.

[0162] Acid addition salts can be prepared in situ during the final isolation and purification of the disclosed compound, or prepared separately by reacting a portion containing one or more nitrogen groups with a suitable acid. In various aspects, acids that can be used 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 another aspect, salts also include, but are not limited to, the following substances: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronide, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, butyrate, etc. Camphorates, camphor sulfonates, digluconate, glyceryl phosphate, hemisulfate, heptanate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (hydroxyethanesulfonate), nicotinate, 2-naphthalenesulfonate, oxalate, pectate, persulfate, 3-phenylpropionate, picrate, neopentanoate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, undecanoate, and bis(hydroxynaphthalene) (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarboxylate)). Similarly, basic nitrogen-containing groups can be quaternized using, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and dipentyl sulfates; long-chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides, etc.

[0163] Base addition salts can be prepared in situ during the final separation and purification of the disclosed compounds, or they can be prepared alone by reacting the carboxylic acid moiety with a suitable base (such as a pharmaceutically acceptable hydroxide, carbonate, or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, magnesium, and aluminum salts, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Other representative organic amines that can be used to form base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. In another respect, bases that can be used to prepare pharmaceutically acceptable salts include the following substances: ammonia, L-arginine, phenethylbenzylamine, benzylamine, calcium hydroxide, choline, tannin, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hebamin, 1H-imidazolium, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, aminobutanetriol, and zinc hydroxide.

[0164] The disclosed compounds can be readily used as components of degradation molecules. Therefore, in various respects, the disclosed compounds can be used as ligands, linkers, or adjacent chemical structures within proteolytic targeting complexes or targeted protein degradation complexes. For example, proteolytic targeting chimeras (PROTACs) are a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTACs employ small molecules recruiting target proteins for ubiquitination and proteasome removal (see, for example, Bondeson and Crews, Annu Rev Pharmacol Toxicol., 6 January 2017, Vol. 57: pp. 107-123; Lai et al., Angew Chem Int Ed Engl., 11 January 2016, Vol. 55, No. 2: pp. 807-810; and PCT application number PCT / US2018 / 061573).

[0165] On the other hand, the disclosed compounds may also include a linker to a protein-degrading targeted chimera (PROTAC), thereby providing interaction with the intracellular ubiquitin-proteasome system to selectively degrade target proteins. For example, in some cases, any one or more compounds may be used to form compositions, chimeras, fusions, or complexes with protein degradation functions. Some exemplary complexes may include a protein-degrading targeted chimera (PROTAC) or degronimid. As those skilled in the art will understand, such complexes are capable of binding or assembling cellular processes associated with protein degradation to specific target proteins, wherein the cellular mechanisms and target proteins are complexed through ligands, linkers, or adjacent chemical structures.

[0166] Methods for preparing compounds.

[0167] In one aspect, this disclosure relates to a method for preparing a compound used as a dihydroorotate dehydrogenase (DHODH) inhibitor, which may be used to treat clinical symptoms, diseases, and disorders associated with DHODH dysfunction, as well as other diseases involving DHODH. In one aspect, this disclosure relates to the disclosed synthetic operations. In another aspect, the disclosed compounds include products of the synthetic methods described herein. In another aspect, the disclosed compounds include compounds produced by the synthetic methods described herein. In yet another aspect, this disclosure includes a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier. In yet another aspect, this disclosure includes a method for preparing a medicament comprising mixing at least one of the disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.

[0168] The compounds of this disclosure can be prepared by employing reactions as 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 to provide a more complete understanding of this disclosure; these examples are illustrative only and should not be construed as limiting. For clarity, examples with fewer substituents are shown, wherein multiple substituents are permitted according to the definition disclosed herein.

[0169] It is anticipated that each disclosed method may further include additional steps, operations, and / or components. It is also anticipated that any one or more steps, operations, and / or components may be optionally omitted from this disclosure. It should be understood that the disclosed methods can be used to provide the disclosed compounds. It should also be understood that the products of the disclosed methods can be used in the disclosed compositions, kits, and uses.

[0170] In one aspect, the substituted 6-substituted -2-([1,1'-biphenyl]-4-yl)quinoline-4-carboxylic acid analogs of this disclosure can generally be prepared by the synthetic scheme shown below.

[0171]

[0172] Step 1 (Suzuki-Miyaura reaction).

[0173]

[0174] Step 2 (Puffinger-Zinger reaction).

[0175] Compounds are represented in a general form, with substituents as described elsewhere in this document. A more specific example is given below.

[0176]

[0177] Step 1 (Suzuki-Miyaura reaction).

[0178]

[0179] Step 2 (Puffinger-Zinger reaction).

[0180] In one aspect, the compounds of this disclosure, such as those of Formula 5, can be prepared in a two-step reaction as shown above. Briefly, the synthesis of the compound of Formula 5 begins in step 1, wherein the compound of Formula 1 and the compound of Formula 2 react to produce the compound of Formula 3. The compound of Formula 1 (i.e., a 4-halobenzophenone analog, such as 3-fluoro-4-bromoacetophenone) and the compound of Formula 2 (i.e., a suitably substituted phenylboronic acid, such as 4-ethoxyphenylboronic acid) are available from commercial sources or can be readily prepared by those skilled in the art according to methods described in the literature. For example, both 3-fluoro-4-bromoacetophenone and 4-ethoxyphenylboronic acid are commercially available. The reaction of the compound of Formula 1 and the compound of Formula 2 is typically carried out in a suitable solvent (e.g., 1-propanol) in the presence of palladium acetate and triphenylphosphine, at a suitable temperature (e.g., from about 75°C to about 200°C), for a suitable time period (e.g., from about 10 minutes to about 2 hours), at a molar ratio of about 25:1 to about 1:1 for the compound of Formula 2 to ensure complete reaction. The reactants are then cooled to a suitable temperature (e.g., room temperature), and may be further cooled (e.g., to about 0°C) to obtain suitable crystals, which can be collected by filtration. Other suitable methods for separating the products will be apparent to those skilled in the art.

[0181] In step 2, the compound of formula 3 isolated from step 1 is reacted with the compound of formula 4 to produce the desired disclosed compound of formula 5, as shown above. Briefly, a mixture of suitable indigo (i.e., the compound of formula 4, such as 5-fluoroindigo (5-fluoroindoline-2,3-dione)) and a suitable base (e.g., an aqueous solution of potassium hydroxide (33%)) is gently stirred and heated. A slurry of the compound of formula 3 (e.g., 1-(4'-ethoxy-[1,1'-biphenyl]-4-yl)ethyl-1-one) is added to this solution in approximately an equimolar amount to the compound of formula 4, and this slurry is prepared using a suitable solvent (e.g., ethanol). The reaction mixture is then heated to a suitable temperature, e.g., refluxed at about 70°C to about 200°C, for a suitable period of time (e.g., about 10 minutes to about 3 hours) to ensure complete reaction. The reactants are then cooled to a suitable temperature (e.g., room temperature), and may then be further cooled (e.g., cooled to about 0°C) to obtain suitable crystals, which can be collected by filtration. Other suitable methods for separating the product will be apparent to those skilled in the art. If residual solvent is present, the product may also be further purified, for example by methods known in the art.

[0182] Pharmaceutical composition.

[0183] In all respects, this 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, a “pharmaceutically acceptable carrier” means one or more of a pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifier, colorant, release agent, coating agent, sweetener, flavoring agent, and adjuvant. The disclosed pharmaceutical compositions are readily available in unit dosage forms and can be prepared by any method well known in the fields of pharmacy and pharmaceutical science.

[0184] In another aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound as an active ingredient, at least one product of the disclosed method or a pharmaceutically acceptable salt thereof, 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 specific host and the nature and severity of the condition to which the active ingredient is applied. In another aspect, the disclosed pharmaceutical compositions can be formulated for administration via oral, nasal, inhalation, parenteral, adjacent to, mucosal, percutaneous, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intravenous, intracranial, and intratumoral administration.

[0185] As used in this article, “parenteral administration” includes administration by bolus or infusion, as well as administration by intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0186] In various aspects, this disclosure also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent, and a therapeutically effective amount of the disclosed compound, the product of the disclosed preparation method, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, or its stereochemical isomer as an active ingredient. In another aspect, the disclosed compound, the product of the disclosed preparation method, the pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, or its stereochemical isomer, or any subgroup or combination thereof, can be formulated into various pharmaceutical forms for administration purposes.

[0187] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable non-toxic bases or acids. For therapeutic uses, the salts of the disclosed compounds are those in which the counterion is pharmaceutically acceptable. However, salts of non-pharmaceutical acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds. This disclosure considers all salts, whether or not they are pharmaceutically acceptable. Pharmaceutically acceptable acid and base addition salts refer to non-toxic acid and base addition salt forms that can be formed from the disclosed compounds and possess therapeutic activity.

[0188] In various respects, the disclosed compounds containing an acidic group or portion (e.g., a carboxylic acid group) can be used to prepare pharmaceutically acceptable salts. For example, such disclosed compounds may include a separation step comprising treatment with a suitable inorganic or organic base. In some cases, it may be desirable in practice to first separate the compound from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert the compound back to a 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 readily prepared using conventional techniques, for example, by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then preferably evaporating the resulting solution to dryness under reduced pressure. Alternatively, they can also be prepared by mixing a lower alkanol solution of the acidic compound with the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as before.

[0189] A pharmaceutically acceptable base for preparing alkali compounds is a base that can form a non-toxic base addition salt, i.e., a salt containing a pharmacologically acceptable cation such as an alkali metal cation (e.g., lithium, potassium, and sodium ions), an alkaline earth metal cation (e.g., calcium and magnesium ions), an ammonium cation, or other water-soluble amine addition salts such as N-methylglucosamine-(glucosamine), lower alkanol ammonium cations, and other such organic amine bases. On the other hand, bases derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, as well as cyclic and substituted amines, such as naturally occurring and synthetic substituted amines. In all respects, this pharmaceutically acceptable non-toxic organic alkaloid includes, but is not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any one 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, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinine ring, pyridine, quinoline and isoquinoline; benzathine penicillin, N-methyl-D-glucosamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, heptaamine salts and salts containing amino acids (e.g., histidine, arginine, lysine, etc.). The aforementioned salt form can be converted back to the free acid form by acid treatment.

[0190] In various respects, the disclosed compounds containing a protonable group or portion (e.g., an amino group) can be used to prepare pharmaceutically acceptable salts. For example, such disclosed compounds may include a separation step comprising treatment with a suitable inorganic or organic acid. In some cases, it may be desirable in practice to first separate the compound from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert the compound back to a free base compound by treatment with a basic reagent, and then convert the free base into 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 anion, and then preferably evaporating the resulting solution to dryness under reduced pressure. Alternatively, they can also be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0191] 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 their corresponding inorganic and organic acids. Exemplary but non-limiting inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, methylene dihydroxynaphthyl acid, pantothenic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, etc. On the other hand, acid addition salts contain anions formed from hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0192] In practice, the compounds of this disclosure or their pharmaceutically acceptable salts can be tightly mixed with a drug carrier as active ingredients using conventional pharmaceutical mixing techniques. Depending on the desired formulation for administration, the carrier can take various forms, such as oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions of this disclosure can exist as discrete units suitable for oral administration, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can exist as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition to the commonly used dosage forms listed above, the compounds of this disclosure and / or their pharmaceutically acceptable salts can also be administered via controlled-release devices and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Typically, such methods involve the step of combining the active ingredient with a carrier constituting one or more essential components. Typically, the composition is prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a subdivided solid carrier, or both. The product can then be conveniently shaped into the desired appearance.

[0193] For ease of administration and consistent dosage, it is particularly advantageous to formulate the above-described pharmaceutical compositions into unit dosage forms. As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of the active ingredient, which is calculated to produce the desired therapeutic effect when combined with the desired drug carrier. In other words, a "unit dosage form" refers to a single dose in which all active and inactive ingredients are mixed in a suitable system so that the patient or the person administering the medication to the patient can open a single container or package containing the entire dose without having 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; rectal suppositories; sachet powders; crystals; and their separate multi-dose forms. This list of unit dosage forms is not intended to be limiting in any way, but merely represents typical examples of unit dosage forms.

[0194] The pharmaceutical compositions disclosed herein comprise, as an active ingredient, a compound of the present disclosure (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier, and optionally one or more other therapeutic agents. In various aspects, the disclosed pharmaceutical compositions may include a pharmaceutically acceptable carrier and the disclosed compound or a pharmaceutically acceptable salt thereof. In another aspect, the disclosed compound or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds. The compositions of the present invention comprise pharmaceutical 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 specific host and the nature and severity of the condition to which the active ingredient is applied. The pharmaceutical compositions are readily available in unit dosage forms and can be prepared by any method well known in the pharmaceutical field.

[0195] For example, techniques and compositions for preparing dosage forms that can be used with the materials and methods described herein are described in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, eds., 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd ed. (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, Volume 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)). McGinity, ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Volume 61 (Alain Rolland, ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences.Series in Pharmaceutical Technology; JG Hardy, SS Davis, Clive Edited by G. Wilson); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Volume 40 (Editors by Gilbert S. Banker and Christopher T. Rhodes).

[0196] The compounds described herein are typically administered in combination with suitable drug diluents, excipients, expanders, or carriers (referred to herein as pharmaceutically acceptable carriers, or carriers), which are appropriately selected according to the intended form of administration and in accordance with routine pharmaceutical practice. Deliverable compounds will be in forms suitable for oral, rectal, topical, intravenous, or parenteral administration. Carriers may be solid or liquid, and the type of carrier is selected based on the type of administration used. The compounds may be administered in doses with known amounts.

[0197] Oral administration is a preferred dosage form due to its ease of application, and tablets and capsules represent the most advantageous oral unit dosage forms, in which case a solid drug carrier is obviously used. However, other dosage forms may be suitable depending on the clinical population (e.g., age and severity of clinical condition), the solubility of the specific disclosed compound used, etc. Therefore, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Any convenient pharmaceutical medium can be used in the preparation of compositions for oral dosage forms. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid formulations such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., can be used to form oral solid dosage forms such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units using solid drug carriers due to their ease of application. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0198] The disclosed oral dosage form pharmaceutical composition may contain one or more pharmaceutical excipients and / or additives. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starch (e.g., corn starch or amylose), dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginate, Tyles, talc, phycocyanin, silica gel (e.g., colloids), cellulose, cellulose derivatives (e.g., cellulose ethers in which the cellulose hydroxyl groups are partially etherified by lower saturated aliphatic alcohols and / or lower saturated aliphatic hydroxyl alcohols, such as methyloxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate), fatty acids, and magnesium, calcium, or aluminum salts, especially saturated salts (e.g., stearates), of fatty acids having 12 to 22 carbon atoms; emulsifiers; oils, especially vegetable oils (e.g., peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower oil, cod liver oil, optionally hydrated in each case); saturated fatty acid C 12 H 24 O2 to C 18 H36 Glyceryl esters and polyglycerol esters and mixtures thereof, wherein the glycerol hydroxyl groups may be wholly or partially esterified (e.g., monoglycerides, diglycerides, and triglycerides); pharmaceutically acceptable monovalent or polyvalent alcohols and polydiols such as polyethylene glycol and its derivatives, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms) with monovalent fatty alcohols (1 to 20 carbon atoms) or polyvalent alcohols (such as ethylene glycol, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., which may also be optionally etherified), esters of citric acid and primary alcohols, acetic acid, urea, benzyl benzoate, dioxolane, glyceraldehyde, tetrahydrofurfuryl alcohol, polyethylene glycol ethers having C1-C12 alcohols, dimethylacetamide, lactamide, lactate esters, ethyl carbonate, silicones (especially medium viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, etc.

[0199] Other excipients that can be used in the preparation of oral dosage forms are those substances that cause disintegration (so-called disintegrants), such as cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, or microcrystalline cellulose. Conventional coating substances can also be used in the preparation of 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 acrylates and methacrylates with low ammonium content (e.g., Eudragit R RS); copolymers of acrylates and methacrylates and trimethylammonium methacrylate (e.g., Eudragit R 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, carboxymethyl cellulose; methylcellulose phthalate, methylcellulose succinate, methylcellulose phthalic acid succinate, and methylcellulose phthalic acid half ester; zein; ethyl cellulose and ethyl cellulose succinate; shellac, gluten; ethyl carboxyethyl cellulose; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethylhexyl acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamate copolymer; carboxymethyl ethyl cellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine, etc.

[0200] Plasticizers that can be considered coating substances in publicly available oral dosage forms include: citrates and tartrates (triethyl acetylglucosyl citrate, tributyl acetylglucosyl citrate, tributyl citrate, triethyl citrate); glycerols and glycerides (glyceryl diacetate, glyceryl triacetate, acetylated monoglycerides, castor oil); phthalates (dibutyl phthalate, diamyl phthalate, diethyl phthalate, dimethyl phthalate, dipropyl phthalate), di(2-methoxyethyl or 2-ethoxyethyl) phthalate, and ethyl phthaloyl glycolic acid. Esters, butyl phthaloyl ethyl glycolate and butyl glycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl adipate, di-(2-methoxy- or 2-ethoxyethyl) adipate); benzophenone; diethyl sebacate and dibutyl sebacate, dibutyl succinate, dibutyl tartrate; diethylene glycol dipropionate; ethylene glycol diacetate, dibutyrate, dipropionate; tributyl phosphate, glyceryl tartrate; polyethylene glycol sorbitan monooleate (polysorbate, such as polysorbate 50); sorbitan monooleate, etc.

[0201] Furthermore, suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow inducers, and melting agents may be included as carriers. The drug carrier used may be, for example, solid, liquid, or gaseous. Examples of solid carriers include, but are not limited to, lactose, gypsum powder, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, talc, starch, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrups, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0202] In various aspects, binders may include, for example, starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, astragalus gum or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. On the other hand, disintegrants may include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.

[0203] In various aspects, oral dosage forms, such as solid dosage forms, may contain the disclosed compounds linked to the polymer as targeted drug carriers or as prodrugs. Suitable biodegradable polymers for achieving controlled drug release include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and hydrogels, preferably covalently cross-linked hydrogels.

[0204] Tablets may contain an active ingredient mixed with non-toxic and pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action.

[0205] Tablets containing the disclosed compounds may be prepared by compression or molding, optionally together with one or more excipients or adjuvants. Compressed tablets may be prepared by compressing a free-flowing active ingredient, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets may be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0206] In various aspects, solid oral dosage forms such as tablets can be coated with enteric coatings to prevent easy decomposition in the stomach. Enteric coating agents include, but are not limited to, hydroxypropyl methylcellulose phthalate, methacrylate-methacrylate copolymer, polyvinyl acetate-phthalate, and cellulose acetate-phthalate. (Akihiko Hasegawa, “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form,” Chem. Pharm. Bull., Vol. 33: pp. 1615-1619 (1985).) Various enteric coating materials can be selected based on testing to achieve de novo design of enteric-coated dosage forms with an optimal combination of dissolution time, coating thickness, and radial compressive strength (e.g., see SCPorter et al., “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate,” J. Pharm. Pharmacol., Vol. 22: p. 42 (1970)). On the other hand, the enteric coating may contain hydroxypropyl methylcellulose phthalate, methacrylate-methacrylate copolymer, polyvinyl acetate-phthalate, and cellulose acetate phthalate.

[0207] In all respects, oral dosage forms can be solid dispersions with water-soluble or water-insoluble carriers. Examples of water-soluble or water-insoluble carriers include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropyl methylcellulose phthalate, carboxymethyl ethyl cellulose or hydroxypropyl methylcellulose, ethyl cellulose or stearic acid.

[0208] In various respects, oral dosage forms can be liquid dosage forms, including those that are ingested or administered in the form of mouthwash or gargles. For example, liquid dosage forms may include aqueous suspensions containing an active substance mixed with excipients suitable for preparing the aqueous suspension. Furthermore, oily suspensions can be formulated by suspending the active ingredient in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may also contain a variety of excipients. The pharmaceutical compositions disclosed herein may also be in the form of oil-in-water emulsions, which may further contain excipients such as sweeteners and flavoring agents.

[0209] For the preparation of solutions or suspensions, water, especially sterile water, or physiologically acceptable organic solvents can be used, such as alcohols (ethanol, propanol, isopropanol, 1,2-propanediol, polyethylene glycol and their derivatives, fatty alcohols, esters of glycerol), oils (e.g., peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil, castor oil, cow hoof oil), paraffin, dimethyl sulfoxide, triglycerides, etc.

[0210] In the case of liquid dosage forms such as drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic monovalent and polyvalent alcohols having 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycol with a molecular weight between 200 and 600 (e.g., 1%-40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propanediol, organic amides, such as amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary, or tertiary C1-C4 amines or C1-C4 hydroxylamines, such as urea, urethane, acetamide, N-methylacetamide, N,N-diethylacetamide, N,N-dimethylacetamide, lower aliphatic amines and diamines having 2-6 carbon atoms, such as ethylenediamine, hydroxyethyltheophylline, tromethamine (e.g., 0.1% to 20% aqueous solution), and aliphatic amino acids.

[0211] In preparing the disclosed liquid dosage form, a solubilizer and emulsifier may be included, such as the following non-limiting examples: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phospholipids such as lecithin, gum arabic, astragalus gum, polyoxyethylene-modified sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylene-modified fatty acids, polyoxyethylene-modified oleic acid triglycerides, linoleic acid-modified oleic acid triglycerides, polyoxyethylene condensation products of fatty alcohols, alkylphenols or fatty acids, or 1-methyl-3-(2-hydroxyethyl)imidazolinone-(2). In this context, polyoxyethyleneization means that the substance under discussion contains polyoxyethylene chains, typically with a degree of polymerization between 2 and 40, particularly between 10 and 20. This type of polyoxyethylene compound can be obtained, for example, by reacting a hydroxyl-containing compound (e.g., monoglycerides or diglycerides) or an unsaturated compound, such as those containing oleic acid groups, with ethylene oxide (e.g., 40 moles of ethylene oxide for every 1 mole of glyceride). Examples of oleic triglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, and corn oil. See also Dr. HP Fiedler, “Lexikon der Hillsstoffe für Pharmazie, Kostnetikund angrenzende Gebiete”, 1971, pp. 191-195.

[0212] In various aspects, liquid dosage forms may also include preservatives, stabilizers, buffers, flavoring agents, sweeteners, coloring agents, antioxidants, and complexing agents. Complexing agents that can be considered, for example, include chelating agents such as ethylenediaminetetraacetic acid, hypozinotriacetic acid, diethylenetriaminepentaacetic acid, and their salts.

[0213] Optionally, the liquid formulation may need to be stabilized at a pH range of approximately 6 to 9 using a physiologically acceptable base or buffer. Ideally, the pH should be as neutral or weakly alkaline as possible (up to pH 8).

[0214] To enhance the solubility and / or stability of the disclosed compounds in liquid, parenteral, or intravenous dosage forms, the use of α-, β-, or γ-cyclodextrins or their derivatives, particularly hydroxyalkyl-substituted cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin, may be advantageous. Cosolvents such as alcohols may also improve the solubility and / or stability of the compounds according to this disclosure in pharmaceutical compositions.

[0215] In various aspects, the disclosed liquid, parenteral, or intravenous injectable formulations may also include liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multiilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0216] The pharmaceutical compositions disclosed herein are suitable for injection, such as parenteral administration, intravenous administration, intramuscular administration, or subcutaneous administration. The injectable pharmaceutical compositions can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersants may also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0217] Pharmaceutical compositions of this disclosure suitable for parenteral administration may comprise sterile aqueous or oily solutions, suspensions, or dispersants. Furthermore, the composition may be in sterile powder form for ad hoc preparation of such sterile injectable solutions or dispersants. In some respects, the final injectable dosage form is sterile and must be an effective fluid when used in a syringe. The pharmaceutical composition should be stable under the conditions of preparation and storage; therefore, it should preferably be preserved against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0218] For example, injectable solutions can be prepared, wherein the carrier comprises an aqueous saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions can also be prepared, in which case a suitable liquid carrier, suspension, etc., can be used. In some aspects, the disclosed parenteral preparations may contain about 0.01 M to 0.1 M, for example about 0.05 M, phosphate buffer. In another aspect, the disclosed parenteral preparations may contain about 0.9% saline.

[0219] In various aspects, the disclosed parenteral pharmaceutical compositions may comprise pharmaceutically acceptable carriers, such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are 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, alcohol / aqueous solutions, emulsions, or suspensions, including saline and buffer media. Parenteral solvents may include mannitol, normal serum albumin, sodium chloride solution, Ringer's glucose, glucose and sodium chloride, lactated Ringer's solution, and fixed oils. Intravenous solvents include fluids and nutritional supplements, electrolyte supplements, such as Ringer's glucose-based supplements, etc. Preservatives and other additives, such as antimicrobial agents, antioxidants, finishing agents, inert gases, etc., may also be present. In another aspect, the disclosed parenteral pharmaceutical compositions may comprise small amounts of additives, such as substances that enhance isotonicity and chemical stability, such as buffers and preservatives. For injectable pharmaceutical compositions, solid formulations that will be converted into liquid form shortly before use are also considered. Additionally, other adjuvants may be included to make the formulation isotonic with the blood of the subject or patient.

[0220] In addition to the pharmaceutical compositions described above, the disclosed compounds can also be formulated into long-acting formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as as slightly soluble salts.

[0221] The pharmaceutical compositions disclosed herein can be in forms suitable for topical application. As used herein, the phrase "topical application" means application to a biological surface, including, for example, skin areas (e.g., hands, forearms, elbows, legs, face, nails, anus, and genital areas) or mucous membranes. By selecting suitable carriers and optional other ingredients that may be included in the composition, as detailed below, the compositions of this disclosure can be formulated into any form commonly used for topical application. Topical pharmaceutical compositions can be in the form of creams, ointments, pastes, gels, lotions, emulsions, suspensions, aerosols, sprays, foams, release agents, pads, and patches. Furthermore, the compositions can be in forms suitable for use in transdermal devices. These formulations can be prepared using conventional processing methods with the compounds of this disclosure or their pharmaceutically acceptable salts. For example, creams or ointments are prepared by mixing a hydrophilic material with water and about 5% to about 10% by weight of the compound to produce a cream or ointment having the desired consistency.

[0222] In compositions suitable for transdermal application, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally combined in small proportions with suitable additives of any nature that do not produce significant harmful effects on the skin. The additives may facilitate application to the skin and / or may aid in the preparation of the desired composition. These compositions can be applied in various ways, such as as transdermal patches, dabs, or ointments.

[0223] Ointments are semi-solid formulations, typically based on petrolatum or petroleum derivatives. The specific ointment matrix used is the matrix that provides optimal delivery of the active agent selected for a given formulation, and preferably, also provides other desired properties (e.g., emollient properties). Like other carriers or solvents, ointment matrices 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 matrices can be classified into four categories: oily matrices, emulsifiable matrices, emulsion matrices, and water-soluble matrices. Oily ointment matrices include, for example, vegetable oils, animal fats, and semi-solid hydrocarbons derived from petroleum. Emulsifiable ointment matrices, also known as absorbent ointment matrices, are virtually anhydrous or anhydrous and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. The emulsion ointment base is a water-in-oil (W / O) emulsion or an oil-in-water (O / W) emulsion, and includes, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weights.

[0224] Lotions are preparations that can be applied to the skin surface without friction. Lotions are typically liquid or semi-liquid preparations in which solid particles (including active agents) are present in water or alcohol. Lotions are generally preferred for treating larger areas of the body because they are easier to apply and offer a more fluid composition. Lotions are usually solid suspensions and often contain oil-in-water emulsions. It is often necessary to separate insoluble components in the lotion. Lotions typically contain suspending agents to produce a better dispersion, as well as compounds to position the active agents and maintain them in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, etc.

[0225] Creams are viscous liquid or semi-solid emulsions, which can be oil-in-water or water-in-oil. The cream base is typically washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, usually consists of petrolatum and / or fatty alcohols (such as cetyl alcohol or stearyl alcohol). Although not always the case, the aqueous phase usually exceeds the oil phase by volume and often contains a wetting agent. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. For more information, see Remington: The Science and Practice of Pharmacy, above.

[0226] Pastes are semi-solid dosage forms in which bioactive agents are suspended in a suitable matrix. Based on the nature of the matrix, pastes are classified into fatty pastes and pastes made from single-phase aqueous gels. The matrix in fatty pastes is typically petrolatum, hydrophilic petrolatum, etc. Pastes made from single-phase hydrogels usually incorporate carboxymethyl cellulose, etc., as a matrix. For more information, please refer to Remington: The Science and Practice of Pharmacy.

[0227] Gel formulations are semi-solid suspension systems. A single-phase gel contains organic macromolecules that are substantially uniformly distributed throughout a carrier liquid, which is typically aqueous but preferably contains alcohols and optionally oils. Preferred organic macromolecules, i.e., gelling agents, are cross-linked acrylic polymers, such as those from the carbomer polymer family, for example, branded Carbopol. TM Commercially available carboxylated polyalkylene compounds. In this context, other preferred types of polymers are hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; modified celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as astragalus gum and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, a dispersant such as alcohol or glycerol may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, stirring, or a combination thereof.

[0228] Sprays typically provide the active agent in the form of an aqueous and / or alcoholic solution, which can be sprayed onto the skin for delivery. Such sprays include those formulated as a concentrated solution of the active agent at the application site after delivery; for example, the spray solution may consist primarily of alcohol or other similar volatile liquids that dissolve the active agent. Upon delivery to the skin, the carrier evaporates, leaving a concentrated active agent at the application site.

[0229] Foam compositions are typically formulated as single-phase or multi-phase liquids and optionally contained in a suitable container along with a propellant that facilitates the expulsion of the composition from the container, thus transforming it into foam upon application. Other foam-forming techniques include, for example, "bag-in-a-can" formulations. Compositions thus formulated typically contain low-boiling-point hydrocarbons, such as isopropane. Application and agitation of this composition at body temperature causes isopropanol to evaporate and produce foam in a manner similar to a pressurized aerosol foaming system. The foam can be water-based or hydrous alkanols, but is typically formulated with a high alcohol content, which evaporates rapidly when applied to the user's skin, thus driving the active ingredient through the upper layers of skin to the treatment site.

[0230] Skin patches typically include a backing with a reservoir containing an active agent attached thereto. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or impregnated, or a liquid reservoir. The patch typically also includes a water-permeable adhesive on the front side, which adheres and secures the device to the treatment area. Self-adhesive silicone rubber may be used optionally. In both cases, a protective permeable layer may be used to protect the adhesive surface of the patch before application. Skin patches may also include a removable cover for protecting the skin patch during storage.

[0231] Examples of patch constructions that can be used in this disclosure include single-layer or multi-layer drug-in-adhesive systems, characterized in that the drug is directly contained within an adhesive that comes into contact with the skin. In this transdermal patch design, the adhesive serves not only to hold the patch to the skin but also as a formulation base, containing the drug and all excipients under a single backing membrane. In multi-layer drug-in-adhesive patches, the membrane is placed between two distinct adhesive dispersion layers, or multiple adhesive dispersion layers are combined under a single backing membrane.

[0232] Examples of pharmaceutically acceptable carriers suitable for topical application of pharmaceutical compositions include well-known carrier materials used in the cosmetic and medical fields as matrices for, for example, emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, emulsions, foams, suspensions, aerosols, etc., depending on the final form of the composition. Therefore, representative examples of suitable carriers according to this disclosure include, but are not limited to, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and similar materials commonly used in cosmetic and pharmaceutical compositions. Other suitable carriers according to this disclosure include, but are not limited to: alcohols, such as monohydric and polyhydric alcohols, such as ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexanediol, mannitol, and propylene glycol; ethers, such as diethyl ether or dipropyl ether; polyethylene glycol and methoxypolyoxyethylene (carbon waxes with a molecular weight of 200 to 20,000); polyoxyethylene glycerol, polyoxyethylene sorbitol, stearoyl glycerol diacetate, etc.

[0233] If desired, the topical compositions of this disclosure may be contained in a packaging or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, include a tube. The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser device may also be accompanied by a notification from a government agency regulating the form of manufacture, use, or sale of the drug, reflecting that agency’s approval of the form of the composition for human or veterinary use. For example, such notification may include a prescription drug label approved by the U.S. Food and Drug Administration (FDA) or an approved product label. Compositions containing the topical compositions of this disclosure formulated in a pharmaceutically acceptable carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0234] Another patch system configuration that can be used with this disclosure is a reservoir transdermal system design, characterized by including a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and an adhesive. The adhesive component of this patch system can be a continuous layer between the membrane and the release liner or bonded in a concentric configuration around the membrane. Yet another patch system configuration that can be used with this disclosure is a matrix system design, characterized by including a semi-solid matrix containing a drug solution or suspension in direct contact with the release liner. Components responsible for skin adhesion are incorporated into a cover layer and form a concentric configuration around the semi-solid matrix.

[0235] The pharmaceutical compositions disclosed herein can be in a form suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppository can be conveniently formed by first mixing the composition with a softened or molten carrier, and then cooling and shaping it in a mold.

[0236] Pharmaceutical compositions comprising compounds of this disclosure and / or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.

[0237] Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Typically, articles for dispensing include containers that contain the pharmaceutical composition in its appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, foil blister packs, etc. Containers may also include tamper-evident components to prevent accidental contact with the contents of the package. Additionally, containers are typically labeled with a description of the contents of the container, along with any appropriate warnings or instructions.

[0238] If desired, the disclosed pharmaceutical composition may be contained in a packaging or dispenser device, which may comprise one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser may also be accompanied by a notification from a government agency relating to the container, regulating the form of manufacture, use, or sale of the pharmaceutical product, reflecting the agency’s approval of the form for human or veterinary use. For example, such notification may be a prescription drug label or approved product information sheet approved by the U.S. Food and Drug Administration. Pharmaceutical compositions comprising the disclosed compound formulated in a compatible drug carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0239] The exact dosage and frequency of administration depend on the specific disclosed compound, the product of the disclosed preparation method, its pharmaceutically acceptable salt, solvate, or polymorph, its hydrate, its solvate, its polymorph, or its stereochemical isomer; the specific condition being treated and its severity; various factors specific to the medical history of the subject taking the dose, such as the subject's age, weight, sex, degree of impairment, and general physical condition, and other medications the individual may be taking; as is well known to those skilled in the art. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the response of the treated subject and / or based on the assessment of the physician who prescribed the disclosed compound.

[0240] Depending on the method of administration, the pharmaceutical composition will contain 0.05% to 99% by weight, preferably 0.1% to 70% by weight, more preferably 0.1% to 50% by weight of an 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.

[0241] In therapeutic conditions requiring inhibition of dihydroorotate dehydrogenase activity, appropriate dosage levels will typically range from approximately 0.01 mg to 1000 mg per kg of patient body weight per day, and may be administered as a single or multiple doses. In various applications, dosage levels will be approximately 0.1 mg / kg to approximately 500 mg / kg per day, approximately 0.1 mg / kg to 250 mg / kg per day, or approximately 0.5 mg / kg to 100 mg / kg per day. Appropriate dosage levels may be approximately 0.01 mg / kg to 1000 mg / kg per day, approximately 0.01 mg / kg to 500 mg / kg per day, approximately 0.01 mg / kg to 250 mg / kg per day, approximately 0.05 mg / kg to 100 mg / kg per day, or approximately 0.1 mg / kg to 50 mg / kg per day. Within this range, the dosage may be 0.05 mg / kg to 0.5 mg / kg per day, 0.5 mg / kg to 5.0 mg / kg per day, or 5.0 mg / kg to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 1.0 mg to 1000 mg of the active ingredient, particularly 1.0 mg, 5.0 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 750 mg, 800 mg, 900 mg, and 1000 mg of the active ingredient, for dose adjustment to suit the symptoms of the patient being treated. The compound can be administered 1 to 4 times daily, preferably once or twice daily. This dosing regimen can be adjusted to provide the best therapeutic response.

[0242] The unit dose described above and below can be administered more than once daily, for example, two, three, four, five, or six times daily. In each respect, the unit dose can be administered once or twice daily, such that the total dose for a 70 kg adult is in the range of 0.001 mg to about 15 mg per kg of subject body weight per administration. In another respect, the dose is from 0.01 mg to about 1.5 mg per kg of subject body weight per administration, and this treatment can continue for weeks or months, and in some cases for years. However, it should be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound used; the individual's age, weight, general health condition, sex, and diet; the time and route of administration; the excretion rate; other medications previously taken; and the severity of the specific disease being treated, as is well known to those skilled in the art.

[0243] Typical dosages can be taken once daily or multiple times daily, in tablets ranging from 1 mg to approximately 100 mg or tablets ranging from 1 mg to approximately 300 mg, or once daily in a sustained-release capsule or tablet containing a higher proportion of the active ingredient. Sustained-release effects can be achieved through capsule materials dissolved at different pH values, capsules that release slowly via osmotic pressure, or any other known controlled-release mechanism.

[0244] It will be apparent to those skilled in the art that in certain situations it may be necessary to use doses outside this range. Furthermore, it should be noted that clinicians or attending physicians will know, and when to begin, interrupt, adjust, or terminate treatment, taking into account the individual patient's response.

[0245] This disclosure also relates to a method for preparing a medicament for modulating the activity of dihydroorotate dehydrogenase in mammals (e.g., humans) (e.g., for treating one or more disorders, such as cancer or graft-versus-host disease, which can be treated by inhibiting the dysfunctional activity of dihydroorotate dehydrogenase), comprising mixing one or more of the disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Therefore, in one aspect, this disclosure also relates to a method for preparing a medicament comprising mixing at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0246] The disclosed pharmaceutical compositions may also contain other therapeutically active compounds that are typically used to treat the aforementioned pathological or clinical conditions.

[0247] It should be understood that the disclosed compositions can be prepared from the disclosed compounds. It should also be understood that the disclosed compositions can be used in accordance with the disclosed methods of application.

[0248] As already mentioned, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound, a product of the disclosed preparation method, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and a pharmaceutically acceptable carrier. Furthermore, this disclosure relates to a method for preparing such a pharmaceutical composition, characterized by thoroughly mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound according to this disclosure.

[0249] As already mentioned, this disclosure also relates to pharmaceutical compositions comprising the disclosed compound, the product of the disclosed preparation method, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and one or more other drugs for the treatment, prevention, control, improvement of diseases or conditions in which the disclosed compound or other drugs may be effective, or reduction of their risk, and also relates to the use of such compositions in the preparation of medicaments. This disclosure also relates to combinations of the disclosed compound, the product of the disclosed preparation method, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and therapeutic agents, which can be used to treat autoimmune diseases, immune and inflammatory diseases, destructive bone disorders, malignant neoplasms, angiogenesis-related disorders, viral diseases, and infectious diseases. This disclosure also relates to such combinations used as medicaments. This disclosure also relates to products comprising (a) the disclosed compound, the product of the disclosed preparation method, a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, and (b) additional therapeutic agents, as a combination formulation for simultaneous, separate, or sequential use in the treatment or prevention of a disease in mammals (including humans), the treatment or prevention of which is influenced or promoted by the moderating effects of the disclosed compound and the additional therapeutic agent. Different pharmaceutical ingredients of such combinations or products may be combined with a pharmaceutically acceptable carrier or diluent in a single formulation, or they may each exist in a separate formulation with a pharmaceutically acceptable carrier or diluent.

[0250] Methods using compounds.

[0251] On the other hand, this disclosure provides a treatment method comprising administering a therapeutically effective amount of the disclosed compound or a pharmaceutical composition as disclosed above to a subject in need. Specifically, the disclosed compound and the disclosed pharmaceutical composition are methods for treating diseases or disorders associated with elevated, abnormal, or impaired levels of dihydroorotate dehydrogenase (DHODH) activity in cells, tissues, or organisms. That is, the disclosed compound and the disclosed pharmaceutical composition are methods for inhibiting DHODH activity in cells, tissues, or organisms to provide clinical or therapeutic benefit to a subject who has been identified or diagnosed with elevated, abnormal, or impaired levels of dihydroorotate dehydrogenase (DHODH) activity.

[0252] In some aspects of the disclosed methods, the subject has been diagnosed as needing treatment prior to the administration step. In some aspects of the disclosed methods, the subject has been diagnosed as having a disorder that can be addressed by suppressing DHODH and / or requires DHODH suppression treatment prior to the administration step. In some aspects of the disclosed methods, the subject has been diagnosed with cancer, a disorder related to T-cell proliferation, or a risk of graft-versus-host disease or organ rejection prior to the administration step, but after transplantation. In some aspects of the disclosed methods, the subject has been identified as needing treatment prior to the administration step.

[0253] The disclosed compound can be used as a single agent or in combination with one or more other drugs for the treatment, prevention, control, improvement, or reduction of the risk of the aforementioned diseases, disorders, and conditions, wherein the compound of formula I or other drugs is effective for these diseases, disorders, and conditions, and wherein the combination of drugs is safer or more effective than any single drug alone. Other drugs may be administered simultaneously or sequentially with the disclosed compound at the usual route and amount. When the disclosed compound is used simultaneously with one or more other drugs, a pharmaceutical composition comprising a unit dosage form of such drugs and the disclosed compound is preferred. However, combination therapy may also be administered on an overlapping schedule. It is also foreseeable that a combination of one or more active ingredients and the disclosed compound will be more effective than any single agent.

[0254] DHODH is an enzyme that catalyzes the fourth step of de novo pyrimidine biosynthesis. It converts dihydroorotic acid (DHO) to orotic acid (ORO). Human DHODH is a ubiquitous flavin mononucleotide (FMN) partial flavin protein. In mammalian cells, DHODH is anchored to the inner mitochondrial lobule and catalyzes the conversion of DHO to ORO, representing the rate-limiting step in de novo pyrimidine biosynthesis. Kinetic studies have shown a sequential ping-pong mechanism for the conversion of DHO to ORO (e.g., see Knecht et al., Chem. Biol. Interact., 2000, Vol. 124, pp. 61–76). The first half of the reaction involves the reduction of DHO to ORO. Electrons are transferred to FMN, which is then oxidized to dihydroflavin mononucleotide (FMNH2). After ORO dissociates from the enzyme, FMNH2 is regenerated by ubiquinone molecules recruited from the inner mitochondrial membrane. Kinetic and structural studies have shown that DHO / ORO and ubiquinone each have two distinct binding sites.

[0255] Human DHODH consists of two domains: a large C-terminal domain (Met78-Arg396) and a smaller N-terminal domain (Met30-Leu68), connected by an extended loop. The large C-terminal domain can be best described as an α / β barrel fold, where the central barrel consists of eight parallel β chains surrounded by eight α-helices. Redox sites, formed by the substrate-binding pocket and the binding site of the cofactor FMN, are located on this large C-terminal domain. The smaller N-terminal domain, on the other hand, consists of two α-helices (labeled α1 and α2), both connected by a short loop. This smaller N-terminal domain has a binding site for the cofactor ubiquinone. Helices α1 and α2 span approximately [missing information - likely a specific length] in the so-called hydrophobic patch. The slit, denoted by 2, has a short α1-α2 ring at its narrow end. This slit forms an entrance to a channel that terminates in the FMN cavity near the α1-α2 ring. The channel narrows towards the proximal redox site and terminates at several charged or polar side chains (Gln47, Tyr356, Thr360, and Arg136). As described above, structural clues and kinetic studies indicate that ubiquinone, which readily diffuses into the inner mitochondrial membrane, utilizes this channel to access FMN cofactors for redox reactions (see, for example, Baumgartner et al., J. Med. Chem., 2006, Vol. 49, pp. 1239-1247).

[0256] In organisms, DHODH catalyzes the synthesis of pyrimidines essential for cell growth. Inhibition of DHODH suppresses the growth of (pathologically) rapidly proliferating cells, while cells growing at a normal rate may obtain the pyrimidine bases they need from normal metabolic cycles. The most important cell type in the immune response is the lymphocyte, which specializes in the synthesis of pyrimidines for growth and is particularly sensitive to DHODH inhibition.

[0257] DHODH inhibition leads to a decrease in cellular levels of uridine monophosphate (rUMP), causing proliferating cells to arrest in the G1 phase of the cell cycle. Given that lymphocytes appear unable to undergo clonal expansion when this pathway is blocked, inhibition of de novo pyrimidine nucleotide synthesis is of great interest. Substances that inhibit lymphocyte growth are important drugs for the treatment of autoimmune diseases.

[0258] During steady-state proliferation, the DHODH-independent rescue pathway appears sufficient to provide pyrimidine bases to the cells. Only cells with high cell turnover rates, particularly T and B lymphocytes, require the de novo propagation pathway to proliferate. In these cells, DHODH inhibition halts cell cycle progression, thereby suppressing DNA synthesis and ultimately inhibiting cell proliferation.

[0259] Therefore, DHODH inhibitors have shown beneficial immunosuppressive and antiproliferative effects in human diseases characterized by chronic inflammation and tissue destruction caused by abnormal and uncontrolled cell proliferation. Human enzyme dihydroorotate dehydrogenase (DHODH) represents a well-defined target for low molecular weight disease-modifying antirheumatic drugs (DMARDs).

[0260] Therefore, in all respects, this disclosure relates to methods for treating a variety of diseases or disorders, including but not limited to autoimmune diseases, immune and inflammatory diseases, destructive bone disorders, cancer and malignant neoplasms, angiogenesis-related disorders, viral diseases and infectious diseases.

[0261] In another aspect, this disclosure relates to a method of treating immune disorders, inflammatory lesions, cancer, or other proliferative diseases by administering an effective amount of at least one disclosed compound or at least one disclosed pharmaceutical composition to a subject in need of such treatment to inhibit DHODH.

[0262] In another aspect, this disclosure relates to a method of treating immune disorders, inflammatory lesions, cancer or other proliferative diseases by administering an effective amount of at least one disclosed compound or at least one disclosed pharmaceutical composition in combination with at least one other anti-inflammatory agent, immunomodulatory agent or anticancer agent (simultaneously or sequentially) to a patient in need of such treatment to inhibit DHODH.

[0263] In various respects, autoimmune disorders or diseases that can be treated by the disclosed compounds or the disclosed pharmaceutical compositions include, but are not limited to, those selected from lupus, rheumatoid arthritis, ankylosing spondylitis, glomerulonephritis, minimal change disease, ulcerative colitis, Crohn's disease, Addison's disease, adult-onset Still's disease, alopecia areata, autoimmune hepatitis, autoimmune angioedema, Bechtel's disease, pemphigoid and its variants, celiac disease, chronic inflammatory demyelinating polyneuropathy, Chug-Strauss syndrome, CREST syndrome, dermatomyositis, neuromyelitis optica, discoid lupus, fibromyalgia, giant cell arteritis, giant cell myocarditis, and ancient... De Pasteur disease, Evan syndrome, autoimmune hemolytic anemia, immune thrombocytopenic purpura, allergic purpura, IgA nephropathy, IgG4-related sclerotic diseases, juvenile arthritis, juvenile diabetes, Kawasaki disease, leukocyte rupture vasculitis, mixed connective tissue disease, multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, autoimmune neutropenia, optic neuritis, peripheral neuropathy, POEMS syndrome, polymyositis, primary biliary cirrhosis, non-alcoholic liver disease and related cirrhosis, psoriasis, scleroderma, sarcoidosis, temporal arteritis, vasculitis, and uveitis are all autoimmune disorders or diseases.

[0264] On the other hand, autoimmune diseases that can be treated by the disclosed compounds or the 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 idiopathic arthritis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, Reiter's syndrome, fibromyalgia, and type 1 diabetes.

[0265] Immune and inflammatory diseases that can be treated by the disclosed compounds or the 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, Behçet's syndrome, and inflammatory eye diseases such as conjunctivitis and uveitis.

[0266] In various aspects, this disclosure relates to methods of treating or improving and / or preventing organ rejection disease by administering an effective amount of at least one disclosed compound or disclosed pharmaceutical composition to a patient in need of such treatment. In another aspect, the patient has received an organ transplant or has been diagnosed as needing an organ transplant. In yet another aspect, organ transplantation may include, but is not limited to, transplanted organs such as kidney, liver, skin, heart, pancreas, lung, or combinations thereof.

[0267] In various respects, this disclosure relates to methods for treating EBV viral lymphoproliferation under conditions of tumor immunosuppression. In another respect, methods for treating EBV viral lymphoproliferation can provide both continued organ transplant preservation and treatment for potential EBV lymphoproliferation.

[0268] Destructive bone disorders that can be treated with the disclosed compounds or the disclosed pharmaceutical compositions include, but are not limited to, osteoporosis, osteoarthritis, and multiple myeloma-related bone disorders.

[0269] Cancers and malignancies that can be treated with the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited to, prostate cancer, ovarian cancer, and brain cancer. Cancers, including those of the bladder, breast, colon, kidney, liver, and lungs, including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphatic spectrum, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pilocellular lymphoma, and Burkert's lymphoma; hematopoietic tumors of the bone marrow spectrum, including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; tumors of stromal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous systems, including astrocytoma, neuroblastoma, glioma, and schwannoma; and other tumors, including melanoma, seminoma, teratoma, osteosarcoma, and xenoderma pigmentosum. Pigmentosum, keratoacanthoma, thyroid follicular carcinoma, and Kaposi's sarcoma.

[0270] Angiogenesis-related disorders that can be treated with the disclosed compounds or the disclosed pharmaceutical compositions include, but are not limited to, hemangiomas, ocular neovascularization, macular degeneration, or diabetic retinopathy.

[0271] Viral diseases that can be treated with the disclosed compounds or the disclosed pharmaceutical compositions include, but are not limited to, HIV infection, hepatitis, and cytomegalovirus infection.

[0272] Infectious diseases that can be treated with the disclosed compounds or the disclosed pharmaceutical compositions include, but are not limited to, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome, Shigella infection, and other protozoan infections such as malaria.

[0273] In another aspect, the disclosed compounds or pharmaceutical compositions can act as regulators of apoptosis and are therefore suitable for treating cancers (including, but not limited to, those described above herein), viral infections (including, but not limited to, herpesviruses, poxviruses, EBV, Sinderby virus, and adenoviruses), preventing the development of AIDS 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), and neurodegenerative disorders (including, but not limited to, Alzheimer's disease). Diseases, 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, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, hematologic disorders (including but not limited to chronic anemia and aplastic anemia), musculoskeletal degenerative diseases (including but not limited to osteoporosis and arthritis), aspirin-sensitive sinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

[0274] In another aspect, the disclosed compounds or pharmaceutical compositions can be used to regulate the levels of cellular RNA and DNA synthesis. Therefore, the disclosed compounds and pharmaceutical compositions can be used to treat viral infections (including, but not limited to, HIV, human papillomavirus, herpesvirus, poxvirus, EBV, Sinderby virus, and adenovirus).

[0275] In another aspect, the disclosed compounds or pharmaceutical compositions can be used for the chemoprevention of cancer. Chemoprophylaxis is considered a clinical intervention that inhibits the development of aggressive cancer by blocking initiation mutagenesis events or by blocking the progression of already damaged malignant procells or inhibiting tumor recurrence. Therefore, the disclosed compounds and pharmaceutical compositions can be used to inhibit tumor angiogenesis and metastasis.

[0276] In another respect, the disclosed compounds and the disclosed pharmaceutical compositions may also be combined with other active compounds for the treatment of diseases in which inhibition of DHODH is known to show beneficial effects.

[0277] In all respects, diseases, conditions, or disorders that may benefit from the suppression of DHODH include, but are not limited to, diseases related to the immune system (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 immune system disorders), cancer or other proliferative diseases, liver diseases or disorders, and kidney diseases or disorders.

[0278] On the other hand, the disclosed compounds and pharmaceutical compositions can be used as immunosuppressants to prevent graft rejection, allogeneic or xenograft rejection (organ, bone marrow, stem cells, other cells and tissues), and graft-versus-host disease. In other embodiments, graft rejection is caused by tissue or organ transplantation. In yet another embodiment, graft-versus-host disease is caused by bone marrow or stem cell transplantation.

[0279] On the other hand, the disclosed compounds and the disclosed pharmaceutical compositions can be used to treat a variety of 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 muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenograft, transplant rejection, graft-versus-host disease, corneal transplant rejection, lupus erythematosus, systemic lupus erythematosus, proliferative lupus nephritis, type I 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 Sjögren's syndrome.

[0280] On the other hand, the disclosed compounds and the disclosed pharmaceutical compositions can be used to treat a variety of diseases, including Felty syndrome, Wegener's granulomatosis, Crohn's disease, sarcoidosis, Still's disease, pemphigoid, aortitis, systemic sclerosis, relapsing polychondritis, refractory IgA nephropathy, SAPHO2 syndrome (SAS), cytomegalovirus infection (including rhinitis or cysts), psoriasis, IGG4 disease, and multiple myeloma.

[0281] On the other hand, the disclosed compounds and the disclosed pharmaceutical compositions may be used with known anticancer therapies such as radiotherapy or with cell growth inhibitors or cytotoxic agents or anticancer agents (e.g., but not limited to DNA interactors, such as cisplatin or doxorubicin); topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors, such as CPT-11 or topotecan; naturally occurring or synthetic microtubule interactors, such as paclitaxel, docetaxel, or epokine (e.g., ixaprone); hormonal drugs, such as tamoxifen; thymidylate synthase inhibitors, such as 5-fluorouracil. And antimetabolites, such as methotrexate; other tyrosine kinase inhibitors, such as gefitinib 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 against growth factor receptors (such as erbitux (EGF) and herceptin (Her2)) and other protein kinase modulators (administered together or sequentially). 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 in 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 cells 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 IL1Beta, IL6, IL10, IL21, TNFA, TNFB, and IFN. These agents can be used in combination with CAR-T cells to reduce cell proliferation in cases of significant cytokine release syndrome and neurotoxicity. These agents can be used in combination with bispecific antibodies or peptides that target both T cells and immune / tumor cell antigens (such as, but not limited to, CD19, CD20, CD33, CD123, CD38, and CD37) in a dual manner to reduce T cell proliferation, cytokine production, and neurotoxicity. These agents can be used to reduce T cell proliferation and tissue damage caused by immune checkpoint inhibitor antibodies targeting, but not limited to, PD1, PDL1, CTLA4, and LAG3.

[0282] On the other hand, diseases, disorders, or conditions that can be treated or prevented using the disclosed compounds and pharmaceutical compositions can inhibit DHODH, and therefore can be used to treat diseases, disorders, or conditions involving inflammation and / or related to the immune system. These diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases such as multiple sclerosis, and immune system disorders.

[0283] On the other hand, the disclosed compounds and the 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 rejection and graft-versus-host disease, and altered (e.g., overactive) immune responses. In another aspect, other exemplary immune disorders that can be treated with the disclosed compounds and the disclosed pharmaceutical compositions include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenograft (organ, bone marrow, stem cells and other cells and tissues) transplant rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0284] Chronic graft-versus-host disease (cGVHD) is a leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT) (Baird K, Pavletic SZ., Curr Opin Hematol., 2006, Vol. 13, No. 6: 426–435; Lee SJ, Vogelsang G, Flowers ME. Biol Blood Marrow Transplant., 2003, Vol. 9, No. 4: 215–233; Pidala J et al., Blood., 2011, Vol. 117, No. 17: 4651–4657; and Arai S et al., Blood., 2011, Vol. 118, No. 15: 4242–4249). Drug treatment for cGVHD is primarily limited to steroids and calcineurin inhibitors, which are not entirely effective and are associated with risks of infection and long-term toxicity (Holler, E., Best Pract Res Clin Haematol., 2007, Vol. 20, No. 2: pp. 281–294). The disclosed compounds may be used to treat cGVHD.

[0285] Reagent test kit.

[0286] In all respects, this disclosure relates to a kit comprising a therapeutically effective amount of at least one disclosed compound, a disclosed product of a method for preparing the disclosed compound, a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition; and: at least one known agent for treating cancer, host resistance to graft disease, and / or disorders related to T cell proliferation; and a specification for treating cancer, host resistance to graft disease, and / or disorders related to T cell proliferation.

[0287] The disclosed compounds and / or pharmaceutical compositions comprising the disclosed compounds are conveniently provided in the form of a kit, wherein two or more components (which may be active or inactive ingredients, carriers, diluents, etc.) are provided with instructions for the preparation of an actual dosage form by a patient or person administering the drug to a patient. Such kits may provide all necessary materials and components contained therein, or they may include instructions for the use or preparation of materials or components that must be obtained independently by the patient or person administering the drug to a patient. In another aspect, the kit may include optional components to facilitate the administration of a unit dose to a patient, such as vials for reconstituted powder form, syringes for injection, custom IV delivery systems, inhalers, etc. Additionally, the kit may include instructions for the preparation and administration of the composition. The kit may be prepared as a single-use unit dose for one patient, for multiple uses for a specific patient (prepared at a constant dose, or where the potency of individual compounds may change as treatment progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk”). The components of the kit may be assembled in cartons, blister packs, bottles, tubes, etc.

[0288] On the other hand, the disclosed kit can be packaged according to a daily dosing regimen (e.g., packaged on a card, packaged with a dosing card, packaged in a blister pack or blow-molded plastic, etc.). This packaging facilitates product development and improves patient adherence to medication therapy. Such packaging also reduces patient confusion. A further feature of this disclosure is that the kit also includes instructions for use.

[0289] In another aspect, this disclosure also provides a pharmaceutical package or kit comprising one or more containers containing one or more components of a pharmaceutical composition of this disclosure. Associated with such containers may be a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, reflecting that agency's approval for the manufacture, use, or sale for human administration.

[0290] In various respects, the disclosed kits may also contain compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, pharmaceutical manufacturers, drug distributors, physicians, pharmacies, or pharmacists may offer kits containing the disclosed compounds and / or products, as well as another component to be delivered to a patient.

[0291] It is anticipated that the disclosed kit can be used in conjunction with the disclosed preparation method, the disclosed use or treatment method, and / or the disclosed composition.

[0292] Research tools.

[0293] The disclosed compounds and pharmaceutical compositions have activity as inhibitors of DHODH activity or inhibitors of cell proliferation. Thus, the disclosed compounds can also be used as research tools. Therefore, one aspect of this disclosure relates to a method of using the disclosed compounds as a research tool, the method comprising performing a bioassay using the disclosed compounds. The disclosed compounds can also be used to evaluate novel chemical compounds. Therefore, another aspect of this disclosure relates to a method of evaluating a test compound in a bioassay, the method comprising: (a) performing a bioassay with the test compound to provide a first assay value; (b) performing a bioassay with the disclosed compounds to provide a second assay value; wherein step (a) is performed 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 bioassays include in vitro DHODH enzymatic assays or cell culture-based assays measuring cell proliferation. Methods suitable for performing such assays are described herein. Another aspect of this disclosure relates to a method for studying biological systems, such as animal models of clinical conditions or biological samples containing DHODH proteins, the method 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.

[0294] aspect.

[0295] The following list of exemplary aspects supports and is supported by the disclosures provided herein.

[0296] Aspect 1. A compound having a formula represented by the following structure:

[0297]

[0298] Where R 1 Selected from hydrogen, halogens, −SF5, −CN, −N3, −OH, −NH2, −CF3, and −CF2CF3; where R 5a R 5b R 5c R 5d and R 5e One of them is selected from groups having the following structural formula: -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 —R31 —A 3 —R 40 ;where A 1 Selected from -O- and -NR 50 —; where R 50 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 2 Selected from -O- and -NR 60 —; where R 60 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 3 Selected from -O- and -NR 70 —; where R 70 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein R 20 Selected from halogens, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, and -(CH2). n Cy 1 and ─(CH2) n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Cy 1 It is a C3-C10 cycloalkyl or C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; wherein Ar 1 It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 independently selected groups from the following: 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; wherein R 30 and R 31 Each of them is independently selected from -C1-C10 alkyldiyl, -C1-C10 haloalkyldiyl, -C1-C10 aminoalkyldiyl, and -C1-C10 hydroxyalkyldiyl; and R 40Selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 and ─(CH2) n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Cy 1 It is a C3-C10 cycloalkyl or C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; wherein Ar 1 It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; and wherein R 5a R 5b R 5c R 5d and R 5e The four elements are independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; among which R 6a R 6b R 6c and R 6d Each of these elements is 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, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen; or a pharmaceutically acceptable salt thereof.

[0299] Aspect 2. A compound having a formula represented by the following structure:

[0300]

[0301] Where R 1Selected from hydrogen, halogens, −SF5, −CN, −N3, −OH, −NH2, −CF3, and −CF2CF3; where R 5a R 5b R 5c R 5d and R 5e One of them is selected from groups having the following structural formula: -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 ;where A 1 Selected from -O- and -NR 50 —; where R 50 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 2 Selected from -O- and -NR 60 —; where R 60 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein A 3 Selected from -O- and -NR 70 —; where R 70 Selected from hydrogen, -C1-C10 alkyl, -C1-C10 aminoalkyl, and -C1-C10 hydroxyalkyl; wherein R 20 Selected from halogens, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, and -C1-C10 alkoxy; wherein R 30 and R 31 Each of them is independently selected from -C1-C10 alkyldiyl, -C1-C10 haloalkyldiyl, -C1-C10 aminoalkyldiyl, and -C1-C10 hydroxyalkyldiyl; and R 40 Selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl and -(CH2). n Ar 1 ; where n is an integer selected from 1, 2, and 3; and where Ar 1It is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from the following: 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; and wherein R 5a R 5b R 5c R 5d and R 5e The four elements are independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; among which R 6a R 6b R 6c and R 6d Each of these elements is 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, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen; or a pharmaceutically acceptable salt thereof.

[0302] Aspect 3. The compound according to aspect 1 or aspect 2, wherein R 1 Selected from halogens, -SF5, -CF3 and -CF2CF3.

[0303] Aspect 4. The compound according to aspect 3, wherein R 1 It is a halogen or -SF5.

[0304] Aspect 5. The compound according to aspect 4, wherein R 1 It can be either -F or -Cl.

[0305] Aspect 6. The compound according to aspect 4, wherein R 1 It is -F.

[0306] Aspect 7. The compound according to aspect 4, wherein R 1 It is ─Cl.

[0307] Aspect 8. The compound according to aspect 4, wherein R 1 It is SF5.

[0308] Aspect 9. The compound according to aspect 2, wherein R 1Selected from -SF5, -CF3 and -CF2CF3.

[0309] Aspect 10. The compound according to aspect 9, wherein R 1 It is SF5.

[0310] Aspect 11. The compound according to aspect 9, wherein R 1 Selected from -CF3 and -CF2CF3.

[0311] Aspect 12. The compound according to any one of Aspects 1 to 11, wherein R 5c It is a halogen, a C1-C7 haloalkyl, or an O (C1-C7 haloalkyl).

[0312] Aspect 13. The compound according to aspect 12, wherein R 5c It is a halogen.

[0313] Aspect 14. The compound according to aspect 13, wherein R 5c It is F.

[0314] Aspect 15. The compound according to aspect 12, wherein R 5c It can be -OCF3, -OCH2CF3, or -OCF2CF3.

[0315] Aspect 16. The compound according to any one of Aspects 1 to 15, wherein R 5c It can be ─OH, ─O(C1-C7 alkyl), ─C1-C7 hydroxyalkyl, ─O─(C1-C7 hydroxyalkyl), ─CH2O(C1-C7 alkyl) or ─(CH2)2O(C1-C7 alkyl).

[0316] Aspect 17. The compound according to aspect 16, wherein R 5c It can be ─O(C1-C7 alkyl), ─(C1-C7 alkyldiyl)─OH, ─O(C1-C7 alkyldiyl)─OH, ─CH2O(C1-C7 alkyl), or ─(CH2)2O(C1-C7 alkyl).

[0317] Aspect 18. The compound according to aspect 17, wherein R 5c It is either -OCH3 or -OCH2CH3.

[0318] Aspect 19. The compound according to any one of Aspects 16 to 18, wherein R 5a R 5b R 5d and R 5e Each of them is hydrogen.

[0319] Aspect 20. The compound according to any one of Aspects 1 to 19, wherein R5a Selected from groups having the following structural formula: ─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 ; and R 5b R 5c R 5d and R 5e Each of them is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3 and -CF2CF3.

[0320] Aspect 21. The compound according to aspect 20, wherein R 5a For R 20 .

[0321] Aspect 22. The compound according to any one of Aspect 20 or Aspect 21, wherein R 20 Selected from -C2-C7 alkylamino and -C2-C7 alkoxy.

[0322] Aspect 23. The compound according to any one of Aspect 20 or Aspect 21, wherein R 20 It is a halogen.

[0323] Aspect 24. The compound according to any one of Aspects 1 to 23, wherein R 5b R 5c R 5d and R 5e Each of them is selected from halogens and hydrogen.

[0324] Aspect 25. The compound according to aspect 24, wherein R 5b R 5c R 5d and R 5e Each of them is hydrogen.

[0325] Aspect 26. The compound according to any one of Aspects 1 to 25, wherein R 5b Selected from groups having the following structural formula: ─R 20 、─R 30 —A 1 —R40 、─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 ; and R 5a R 5c R 5d and R 5e Each of them is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3 and -CF2CF3.

[0326] Aspect 27. The compound according to aspect 26, wherein R 5b For R 20 .

[0327] Aspect 28. The compound according to aspect 26 or aspect 27, wherein R 20 Selected from -C2-C7 alkylamino and -C2-C7 alkoxy.

[0328] Aspect 29. The compound according to aspect 26 or aspect 27, wherein R 20 It is a halogen.

[0329] Aspect 30. The compound according to any one of Aspects 26 to 29, wherein R 5a R 5c R 5d and R 5e Each of them is selected from halogens and hydrogen.

[0330] Aspect 31. The compound according to aspect 30, wherein R 5a R 5c R 5d and R 5e Each of them is hydrogen.

[0331] Aspect 32. The compound according to any one of Aspects 1 to 31, wherein R 5c Selected from groups having the following structural formula: ─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 ; and R 5a R 5b R 5d and R 5e Each of them is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3 and -CF2CF3.

[0332] Aspect 33. The compound according to aspect 32, wherein R 5c For R 20 .

[0333] Aspect 34. The compound according to aspect 32 or aspect 33, wherein R 20 Selected from -C2-C7 alkylamino and -C2-C7 alkoxy.

[0334] Aspect 35. The compound according to aspect 32 or aspect 33, wherein R 20 It is a halogen.

[0335] Aspect 36. The compound according to any one of Aspects 32 to 35, wherein R 5a R 5b R 5d and R 5e Each of them is selected from halogens and hydrogen.

[0336] Aspect 37. The compound according to aspect 36, wherein R 5a R 5b R 5d and R 5e Each of them is hydrogen.

[0337] Aspect 38. The compound according to any one of Aspects 1 to 37, wherein R 6a R 6b R 6c and R 6d Each of these elements is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen.

[0338] Aspect 39. The compound according to aspect 38, wherein R 6a and R 6b It is independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0339] Aspect 40. The compound according to aspect 39, wherein R 6a and R 6b It is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0340] Aspect 41. The compound according to aspect 40, wherein R 6a and R 6b It is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0341] Aspect 42. The compound according to aspect 38, wherein R 6a and R 6c It is independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0342] Aspect 43. The compound according to aspect 42, wherein R 6a and R 6c It is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0343] Aspect 44. The compound according to aspect 43, wherein R 6a and R 6c It is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0344] Aspect 45. The compound according to aspect 38, wherein R 6a and R 6d It is independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0345] Aspect 46. The compound according to aspect 45, wherein R 6a and R 6d It is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0346] Aspect 47. The compound according to aspect 46, wherein R 6a and R 6d It is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0347] Aspect 48. The compound according to aspect 38, wherein R 6a Selected from -F, -Cl, -SF5, -CN, -N3, -OH and -NH2.

[0348] Aspect 49. The compound according to aspect 38, wherein R 6a Selected from -F, -SF5, -CN, -N3, -OH and -NH2.

[0349] Aspect 50. The compound according to aspect 38, wherein R 6b Selected from -F, -Cl, -SF5, -CN, -N3, -OH and -NH2.

[0350] Aspect 51. The compound according to aspect 38, wherein R 6a Selected from -F, -SF5, -CN, -N3, -OH and -NH2.

[0351] Aspect 52. The compound according to any one of Aspects 1 to 51, wherein R 6c and R 6d Each of them is hydrogen.

[0352] Aspect 53. The compound according to any one of Aspects 1 to 37, wherein R 6a Selected from hydrogen, halogen, ─SF5, ─CN, ─N3, ─OH, ─NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6b R 6c and R 6d Each of them is hydrogen.

[0353] Aspect 54. The compound according to aspect 53, wherein R 6a Selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0354] Aspect 55. The compound according to aspect 54, wherein R 6a Selected from ─F, ─Cl, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0355] Aspect 56. The compound according to aspect 55, wherein R 6a It is -F.

[0356] Aspect 57. The compound according to any one of Aspects 1 to 37, wherein R 6b Selected from hydrogen, halogen, ─SF5, ─CN, ─N3, ─OH, ─NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6a R 6c and R 6d Each of them is hydrogen.

[0357] Aspect 58. The compound according to aspect 57, wherein R 6b Selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0358] Aspect 59. The compound according to aspect 58, wherein R 6b Selected from ─F, ─Cl, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0359] Aspect 60. The compound according to aspect 59, wherein R 6b It is -F.

[0360] Aspect 61. The compound according to any one of Aspects 1 to 37, wherein R 6a and R 6b Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6c and R 6d Each of them is hydrogen.

[0361] Aspect 62. The compound according to aspect 38, wherein R 6a and R 6b Each of them is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0362] Aspect 63. The compound according to aspect 39, wherein R 6a and R 6b Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0363] Aspect 64. The compound according to aspect 40, wherein R 6a and R 6b Each of them is -F.

[0364] Aspect 65. The compound according to any one of Aspects 1 to 37, wherein R 6a and R 6c Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6b and R 6d Each of them is hydrogen.

[0365] Aspect 66. The compound according to aspect 38, wherein R 6a and R 6c Each of them is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0366] Aspect 67. The compound according to aspect 39, wherein R 6a and R 6c Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0367] Aspect 68. The compound according to aspect 40, wherein R 6a and R 6c Each of them is -F.

[0368] Aspect 69. The compound according to any one of Aspects 1 to 37, wherein R 6a and R 6d Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6b and R 6c Each of them is hydrogen.

[0369] Aspect 70. The compound according to aspect 38, wherein R 6a and R 6d Each of them is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0370] Aspect 71. The compound according to aspect 39, wherein R 6a and R6d Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0371] Aspect 72. The compound according to aspect 40, wherein R 6a and R 6d Each of them is -F.

[0372] Aspect 73. The compound according to any one of Aspects 1 to 37, wherein R 6b and R 6c Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6a and R 6d Each of them is hydrogen.

[0373] Aspect 74. The compound according to aspect 38, wherein R 6b and R 6c Each of them is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0374] Aspect 75. The compound according to aspect 39, wherein R 6b and R 6c Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0375] Aspect 76. The compound according to aspect 40, wherein R 6b and R 6c Each of them is -F.

[0376] Aspect 77. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C6-C10 alkyl, -C6-C10 aminoalkyl and -C6-C10 hydroxyalkyl.

[0377] Aspect 78. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C6-C8 alkyl, -C6-C8 aminoalkyl and -C6-C8 hydroxyalkyl.

[0378] Aspect 79. The compound according to any one of Aspects 1 to 76, wherein R 20It is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl and -C5-C10 hydroxyalkyl.

[0379] Aspect 80. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C5-C8 alkyl, -C5-C8 aminoalkyl and -C5-C8 hydroxyalkyl.

[0380] Aspect 81. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C5-C6 alkyl, -C5-C6 aminoalkyl and -C5-C6 hydroxyalkyl.

[0381] Aspect 82. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C4-C10 alkyl, -C4-C10 aminoalkyl and -C4-C10 hydroxyalkyl.

[0382] Aspect 83. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C4-C8 alkyl, -C4-C8 aminoalkyl and -C4-C8 hydroxyalkyl.

[0383] Aspect 84. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C4-C6 alkyl, -C4-C6 aminoalkyl and -C4-C6 hydroxyalkyl.

[0384] Aspect 85. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C4-C5 alkyl, -C4-C5 aminoalkyl and -C4-C5 hydroxyalkyl.

[0385] Aspect 86. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C3-C10 alkyl, -C3-C10 aminoalkyl and -C3-C10 hydroxyalkyl.

[0386] Aspect 87. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C3-C8 alkyl, -C3-C8 aminoalkyl and -C3-C8 hydroxyalkyl.

[0387] Aspect 88. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C3-C6 alkyl, -C3-C6 aminoalkyl and -C3-C6 hydroxyalkyl.

[0388] Aspect 89. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C3-C5 alkyl, -C3-C5 aminoalkyl and -C3-C5 hydroxyalkyl.

[0389] Aspect 90. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C3-C4 alkyl, -C3-C4 aminoalkyl and -C3-C4 hydroxyalkyl.

[0390] Aspect 91. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl and -C2-C10 hydroxyalkyl.

[0391] Aspect 92. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C2-C8 alkyl, -C2-C8 aminoalkyl and -C2-C8 hydroxyalkyl.

[0392] Aspect 93. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C2-C6 alkyl, -C3-C6 aminoalkyl and -C2-C6 hydroxyalkyl.

[0393] Aspect 94. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C2-C5 alkyl, -C2-C5 aminoalkyl and -C2-C5 hydroxyalkyl.

[0394] Aspect 95. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C2-C4 alkyl, -C2-C4 aminoalkyl and -C2-C4 hydroxyalkyl.

[0395] Aspect 96. The compound according to any one of Aspects 1 to 76, wherein R 20 It is selected from hydrogen, -C2-C3 alkyl, -C2-C3 aminoalkyl and -C2-C3 hydroxyalkyl.

[0396] Aspect 97. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C6-C10 alkyldiyl, -C6-C10 aminoalkyldiyl, and -C6-C10 hydroxyalkyldiyl.

[0397] Aspect 98. The compound according to any one of Aspects 1 to 76, wherein R 30 and R31 Each of them is independently selected from hydrogen, -C6-C8 alkyldiyl, -C6-C8 aminoalkyldiyl, and -C6-C8 hydroxyalkyldiyl.

[0398] Aspect 99. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C5-C10 alkyldiyl, -C5-C10 aminoalkyldiyl, and -C5-C10 hydroxyalkyldiyl.

[0399] Aspect 100. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C5-C8 alkyldiyl, -C5-C8 aminoalkyldiyl, and -C5-C8 hydroxyalkyldiyl.

[0400] Aspect 101. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C5-C6 alkyldiyl, -C5-C6 aminoalkyldiyl, and -C5-C6 hydroxyalkyldiyl.

[0401] Aspect 102. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C4-C10 alkyldiyl, -C4-C10 aminoalkyldiyl, and -C4-C10 hydroxyalkyldiyl.

[0402] Aspect 103. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C4-C8 alkyldiyl, -C4-C8 aminoalkyldiyl, and -C4-C8 hydroxyalkyldiyl.

[0403] Aspect 104. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C4-C6 alkyldiyl, -C4-C6 aminoalkyldiyl, and -C4-C6 hydroxyalkyldiyl.

[0404] Aspect 105. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C4-C5 alkyldiyl, -C4-C5 aminoalkyldiyl, and -C4-C5 hydroxyalkyldiyl.

[0405] Aspect 106. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C3-C10 alkyldiyl, -C3-C10 aminoalkyldiyl, and -C3-C10 hydroxyalkyldiyl.

[0406] Aspect 107. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C3-C8 alkyldiyl, -C3-C8 aminoalkyldiyl, and -C3-C8 hydroxyalkyldiyl.

[0407] Aspect 108. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C3-C6 alkyldiyl, -C3-C6 aminoalkyldiyl, and -C3-C6 hydroxyalkyldiyl.

[0408] Aspect 109. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C3-C5 alkyldiyl, -C3-C5 aminoalkyldiyl, and -C3-C5 hydroxyalkyldiyl.

[0409] Aspect 110. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C3-C4 alkyldiyl, -C3-C4 aminoalkyldiyl, and -C3-C4 hydroxyalkyldiyl.

[0410] Aspect 111. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C2-C10 alkyldiyl, -C2-C10 aminoalkyldiyl and -C2-C10 hydroxyalkyldiyl.

[0411] Aspect 112. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C2-C8 alkyldiyl, -C2-C8 aminoalkyldiyl, and -C2-C8 hydroxyalkyldiyl.

[0412] Aspect 113. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31Each of them is independently selected from hydrogen, -C2-C6 alkyldiyl, -C3-C6 aminoalkyldiyl, and -C2-C6 hydroxyalkyldiyl.

[0413] Aspect 114. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C2-C5 alkyldiyl, -C2-C5 aminoalkyldiyl, and -C2-C5 hydroxyalkyldiyl.

[0414] Aspect 115. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C2-C4 alkyldiyl, -C2-C4 aminoalkyldiyl, and -C2-C4 hydroxyalkyldiyl.

[0415] Aspect 116. The compound according to any one of Aspects 1 to 76, wherein R 30 and R 31 Each of them is independently selected from hydrogen, -C2-C3 alkyldiyl, -C2-C3 aminoalkyldiyl and -C2-C3 hydroxyalkyldiyl.

[0416] Aspect 117. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C6-C10 alkyl, -C6-C10 aminoalkyl and -C6-C10 hydroxyalkyl.

[0417] Aspect 118. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C6-C8 alkyl, -C6-C8 aminoalkyl and -C6-C8 hydroxyalkyl.

[0418] Aspect 119. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl and -C5-C10 hydroxyalkyl.

[0419] Aspect 120. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C5-C8 alkyl, -C5-C8 aminoalkyl and -C5-C8 hydroxyalkyl.

[0420] Aspect 121. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C5-C6 alkyl, -C5-C6 aminoalkyl and -C5-C6 hydroxyalkyl.

[0421] Aspect 122. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C4-C10 alkyl, -C4-C10 aminoalkyl and -C4-C10 hydroxyalkyl.

[0422] Aspect 123. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C4-C8 alkyl, -C4-C8 aminoalkyl and -C4-C8 hydroxyalkyl.

[0423] Aspect 124. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C4-C6 alkyl, -C4-C6 aminoalkyl and -C4-C6 hydroxyalkyl.

[0424] Aspect 125. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C4-C5 alkyl, -C4-C5 aminoalkyl and -C4-C5 hydroxyalkyl.

[0425] Aspect 126. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C3-C10 alkyl, -C3-C10 aminoalkyl and -C3-C10 hydroxyalkyl.

[0426] Aspect 127. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C3-C8 alkyl, -C3-C8 aminoalkyl and -C3-C8 hydroxyalkyl.

[0427] Aspect 128. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C3-C6 alkyl, -C3-C6 aminoalkyl and -C3-C6 hydroxyalkyl.

[0428] Aspect 129. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C3-C5 alkyl, -C3-C5 aminoalkyl and -C3-C5 hydroxyalkyl.

[0429] Aspect 130. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C3-C4 alkyl, -C3-C4 aminoalkyl and -C3-C4 hydroxyalkyl.

[0430] Aspect 131. The compound according to any one of aspects 1 to 116, wherein R 40It is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl and -C2-C10 hydroxyalkyl.

[0431] Aspect 132. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C2-C8 alkyl, -C2-C8 aminoalkyl and -C2-C8 hydroxyalkyl.

[0432] Aspect 133. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C2-C6 alkyl, -C3-C6 aminoalkyl and -C2-C6 hydroxyalkyl.

[0433] Aspect 134. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C2-C5 alkyl, -C2-C5 aminoalkyl and -C2-C5 hydroxyalkyl.

[0434] Aspect 135. The compound according to any one of Aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C2-C4 alkyl, -C2-C4 aminoalkyl and -C2-C4 hydroxyalkyl.

[0435] Aspect 136. The compound according to any one of aspects 1 to 116, wherein R 40 It is selected from hydrogen, -C2-C3 alkyl, -C2-C3 aminoalkyl and -C2-C3 hydroxyalkyl.

[0436] Aspect 137. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C6-C10 alkyl, -C6-C10 aminoalkyl and -C6-C10 hydroxyalkyl.

[0437] Aspect 138. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C6-C8 alkyl, -C6-C8 aminoalkyl and -C6-C8 hydroxyalkyl.

[0438] Aspect 139. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl and -C5-C10 hydroxyalkyl.

[0439] Aspect 140. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C5-C8 alkyl, -C5-C8 aminoalkyl and -C5-C8 hydroxyalkyl.

[0440] Aspect 141. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C5-C6 alkyl, -C5-C6 aminoalkyl and -C5-C6 hydroxyalkyl.

[0441] Aspect 142. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C4-C10 alkyl, -C4-C10 aminoalkyl and -C4-C10 hydroxyalkyl.

[0442] Aspect 143. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C4-C8 alkyl, -C4-C8 aminoalkyl and -C4-C8 hydroxyalkyl.

[0443] Aspect 144. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C4-C6 alkyl, -C4-C6 aminoalkyl and -C4-C6 hydroxyalkyl.

[0444] Aspect 145. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C4-C5 alkyl, -C4-C5 aminoalkyl and -C4-C5 hydroxyalkyl.

[0445] Aspect 146. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C3-C10 alkyl, -C3-C10 aminoalkyl and -C3-C10 hydroxyalkyl.

[0446] Aspect 147. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C3-C8 alkyl, -C3-C8 aminoalkyl and -C3-C8 hydroxyalkyl.

[0447] Aspect 148. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C3-C6 alkyl, -C3-C6 aminoalkyl and -C3-C6 hydroxyalkyl.

[0448] Aspect 149. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C3-C5 alkyl, -C3-C5 aminoalkyl and -C3-C5 hydroxyalkyl.

[0449] Aspect 150. The compound according to any one of Aspects 1 to 136, wherein R 50It is selected from hydrogen, -C3-C4 alkyl, -C3-C4 aminoalkyl and -C3-C4 hydroxyalkyl.

[0450] Aspect 151. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl and -C2-C10 hydroxyalkyl.

[0451] Aspect 152. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C2-C8 alkyl, -C2-C8 aminoalkyl and -C2-C8 hydroxyalkyl.

[0452] Aspect 153. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C2-C6 alkyl, -C3-C6 aminoalkyl and -C2-C6 hydroxyalkyl.

[0453] Aspect 154. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C2-C5 alkyl, -C2-C5 aminoalkyl and -C2-C5 hydroxyalkyl.

[0454] Aspect 155. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C2-C4 alkyl, -C2-C4 aminoalkyl and -C2-C4 hydroxyalkyl.

[0455] Aspect 156. The compound according to any one of Aspects 1 to 136, wherein R 50 It is selected from hydrogen, -C2-C3 alkyl, -C2-C3 aminoalkyl and -C2-C3 hydroxyalkyl.

[0456] Aspect 157. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C6-C10 alkyl, -C6-C10 aminoalkyl and -C6-C10 hydroxyalkyl.

[0457] Aspect 158. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C6-C8 alkyl, -C6-C8 aminoalkyl and -C6-C8 hydroxyalkyl.

[0458] Aspect 159. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl and -C5-C10 hydroxyalkyl.

[0459] Aspect 160. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C5-C8 alkyl, -C5-C8 aminoalkyl and -C5-C8 hydroxyalkyl.

[0460] Aspect 161. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C5-C6 alkyl, -C5-C6 aminoalkyl and -C5-C6 hydroxyalkyl.

[0461] Aspect 162. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C4-C10 alkyl, -C4-C10 aminoalkyl and -C4-C10 hydroxyalkyl.

[0462] Aspect 163. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C4-C8 alkyl, -C4-C8 aminoalkyl and -C4-C8 hydroxyalkyl.

[0463] Aspect 164. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C4-C6 alkyl, -C4-C6 aminoalkyl and -C4-C6 hydroxyalkyl.

[0464] Aspect 165. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C4-C5 alkyl, -C4-C5 aminoalkyl and -C4-C5 hydroxyalkyl.

[0465] Aspect 166. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C3-C10 alkyl, -C3-C10 aminoalkyl and -C3-C10 hydroxyalkyl.

[0466] Aspect 167. The compound according to any one of Aspects 1 to 136, wherein R 60 It is selected from hydrogen, -C3-C8 alkyl, -C3-C8 aminoalkyl and -C3-C8 hydroxyalkyl.

[0467] Aspect 168. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C3-C6 alkyl, -C3-C6 aminoalkyl and -C3-C6 hydroxyalkyl.

[0468] Aspect 169. The compound according to any one of Aspects 1 to 156, wherein R 60It is selected from hydrogen, -C3-C5 alkyl, -C3-C5 aminoalkyl and -C3-C5 hydroxyalkyl.

[0469] Aspect 170. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C3-C4 alkyl, -C3-C4 aminoalkyl and -C3-C4 hydroxyalkyl.

[0470] Aspect 171. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl and -C2-C10 hydroxyalkyl.

[0471] Aspect 172. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C2-C8 alkyl, -C2-C8 aminoalkyl and -C2-C8 hydroxyalkyl.

[0472] Aspect 173. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C2-C6 alkyl, -C3-C6 aminoalkyl and -C2-C6 hydroxyalkyl.

[0473] Aspect 174. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C2-C5 alkyl, -C2-C5 aminoalkyl and -C2-C5 hydroxyalkyl.

[0474] Aspect 175. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C2-C4 alkyl, -C2-C4 aminoalkyl and -C2-C4 hydroxyalkyl.

[0475] Aspect 176. The compound according to any one of Aspects 1 to 156, wherein R 60 It is selected from hydrogen, -C2-C3 alkyl, -C2-C3 aminoalkyl and -C2-C3 hydroxyalkyl.

[0476] Aspect 177. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C6-C10 alkyl, -C6-C10 aminoalkyl and -C6-C10 hydroxyalkyl.

[0477] Aspect 178. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C6-C8 alkyl, -C6-C8 aminoalkyl and -C6-C8 hydroxyalkyl.

[0478] Aspect 179. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl and -C5-C10 hydroxyalkyl.

[0479] Aspect 180. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C5-C8 alkyl, -C5-C8 aminoalkyl and -C5-C8 hydroxyalkyl.

[0480] Aspect 181. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C5-C6 alkyl, -C5-C6 aminoalkyl and -C5-C6 hydroxyalkyl.

[0481] Aspect 182. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C4-C10 alkyl, -C4-C10 aminoalkyl and -C4-C10 hydroxyalkyl.

[0482] Aspect 183. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C4-C8 alkyl, -C4-C8 aminoalkyl and -C4-C8 hydroxyalkyl.

[0483] Aspect 184. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C4-C6 alkyl, -C4-C6 aminoalkyl and -C4-C6 hydroxyalkyl.

[0484] Aspect 185. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C4-C5 alkyl, -C4-C5 aminoalkyl and -C4-C5 hydroxyalkyl.

[0485] Aspect 186. The compound according to any one of aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C3-C10 alkyl, -C3-C10 aminoalkyl and -C3-C10 hydroxyalkyl.

[0486] Aspect 187. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C3-C8 alkyl, -C3-C8 aminoalkyl and -C3-C8 hydroxyalkyl.

[0487] Aspect 188. The compound according to any one of Aspects 1 to 176, wherein R 70It is selected from hydrogen, -C3-C6 alkyl, -C3-C6 aminoalkyl and -C3-C6 hydroxyalkyl.

[0488] Aspect 189. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C3-C5 alkyl, -C3-C5 aminoalkyl and -C3-C5 hydroxyalkyl.

[0489] Aspect 190. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C3-C4 alkyl, -C3-C4 aminoalkyl and -C3-C4 hydroxyalkyl.

[0490] Aspect 191. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl and -C2-C10 hydroxyalkyl.

[0491] Aspect 192. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C2-C8 alkyl, -C2-C8 aminoalkyl and -C2-C8 hydroxyalkyl.

[0492] Aspect 193. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C2-C6 alkyl, -C3-C6 aminoalkyl and -C2-C6 hydroxyalkyl.

[0493] Aspect 194. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C2-C5 alkyl, -C2-C5 aminoalkyl and -C2-C5 hydroxyalkyl.

[0494] Aspect 195. The compound according to any one of Aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C2-C4 alkyl, -C2-C4 aminoalkyl and -C2-C4 hydroxyalkyl.

[0495] Aspect 196. The compound according to any one of aspects 1 to 176, wherein R 70 It is selected from hydrogen, -C2-C3 alkyl, -C2-C3 aminoalkyl and -C2-C3 hydroxyalkyl.

[0496] Aspect 197. The compound according to any one of Aspects 1 to 196, wherein A 1Selected from ─O─, ─NH─, ─NCH3─, ─NCH2CH3─, ─N(CH2)2CH3─, ─NCH(CH3)2─, ─N(CH2)3CH3─ and ─N(CH2)4CH3─.

[0497] Aspect 198. The compound according to aspect 197, wherein A 1 Selected from ─O─, ─NH─, ─NCH3─ and ─NCH2CH3─.

[0498] Aspect 199. The compound according to aspect 197, wherein A 1 It is ─O─.

[0499] Aspect 200. The compound according to aspect 197, wherein A 1 It is ─NH─.

[0500] Aspect 201. The compound according to aspect 197, wherein A 1 It is ─NCH3─.

[0501] Aspect 202. The compound according to aspect 197, wherein A 1 It is ─NCH2CH3─.

[0502] Aspect 203. The compound according to any one of Aspects 1 to 202, wherein A 2 Selected from ─O─, ─NH─, ─NCH3─, ─NCH2CH3─, ─N(CH2)2CH3─, ─NCH(CH3)2─, ─N(CH2)3CH3─ and ─N(CH2)4CH3─.

[0503] Aspect 204. The compound according to aspect 203, wherein A 2 Selected from ─O─, ─NH─, ─NCH3─ and ─NCH2CH3─.

[0504] Aspect 205. The compound according to aspect 203, wherein A 2 It is ─O─.

[0505] Aspect 206. The compound according to aspect 203, wherein A 2 It is ─NH─.

[0506] Aspect 207. The compound according to aspect 203, wherein A 2 It is ─NCH3─.

[0507] Aspect 208. The compound according to aspect 203, wherein A 2 It is ─NCH2CH3─.

[0508] Aspect 209. The compound according to any one of aspects 1 to 208, wherein A 3 Selected from ─O─, ─NH─, ─NCH3─, ─NCH2CH3─, ─N(CH2)2CH3─, ─NCH(CH3)2─, ─N(CH2)3CH3─ and ─N(CH2)4CH3─.

[0509] Aspect 210. The compound according to aspect 209, wherein A 3 Selected from ─O─, ─NH─, ─NCH3─ and ─NCH2CH3─.

[0510] Aspect 211. The compound according to aspect 209, wherein A 3 It is ─O─.

[0511] Aspect 212. The compound according to aspect 209, wherein A 3 It is ─NH─.

[0512] Aspect 213. The compound according to aspect 209, wherein A 3 It is ─NCH3─.

[0513] Aspect 214. The compound according to aspect 209, wherein A 3 It is ─NCH2CH3─.

[0514] Aspect 215. The compound according to any one of Aspects 1 to 214, wherein Ar 1 It is an unsubstituted phenyl group.

[0515] Aspect 216. The compound according to any one of aspects 1 to 214, wherein Ar 1 It is a phenyl group substituted with a group selected from the following: 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 heterocyclic alkyl.

[0516] Aspect 217. The compound according to aspect 216, wherein Ar 1 It is a phenyl group substituted with a group selected from the following: halogen, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─OCH3, ─NHCH3, ─N(CH3)2, ─CH2OH, ─CH3, ─CH2Cl, ─CHCl2, ─CCl3, ─CHF2, ─CH2F and ─CF3.

[0517] Aspect 218. The compound according to aspect 216, wherein Ar 1 It is a phenyl group substituted with a group selected from the following: halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0518] Aspect 219. The compound according to aspect 216, wherein Ar 1 It is a phenyl group substituted with a group selected from the following: -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0519] Aspect 220. The compound according to any one of aspects 1 to 214, wherein Ar 1 It is a phenyl group substituted with two independent groups selected from the following: 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.

[0520] Aspect 221. The compound according to aspect 220, wherein Ar 1 It is a phenyl group substituted by two independent groups selected from the following: halogen, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─OCH3, ─NHCH3, ─N(CH3)2, ─CH2OH, ─CH3, ─CH2Cl, ─CHCl2, ─CCl3, ─CHF2, ─CH2F and ─CF3.

[0521] Aspect 222. The compound according to aspect 220, wherein Ar 1 It is a phenyl group substituted by two independent groups selected from the following: halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0522] Aspect 223. The compound according to aspect 220, wherein Ar 1 It is a phenyl group substituted by two independent groups selected from the following: -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0523] Aspect 224. The compound according to any one of aspects 1 to 214, wherein Ar 1It is a phenyl group substituted with three independent groups selected from the following: 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.

[0524] Aspect 225. The compound according to aspect 224, wherein Ar 1 It is a phenyl group substituted by three independent groups selected from the following: halogen, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─OCH3, ─NHCH3, ─N(CH3)2, ─CH2OH, ─CH3, ─CH2Cl, ─CHCl2, ─CCl3, ─CHF2, ─CH2F and ─CF3.

[0525] Aspect 226. The compound according to aspect 224, wherein Ar 1 It is a phenyl group substituted by three independent groups selected from the following: halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0526] Aspect 227. The compound according to aspect 224, wherein Ar 1 It is a phenyl group substituted by three independent groups selected from the following: -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0527] Aspect 228. The compound according to aspect 1 has a structure represented by the following formula:

[0528]

[0529]

[0530] Or a combination thereof.

[0531] Aspect 229. The compound according to aspect 1 has a structure represented by the following formula:

[0532]

[0533]

[0534] Or a combination thereof.

[0535] Aspect 230. The compound according to aspect 1 has a structure represented by the following formula:

[0536]

[0537]

[0538] Or a combination thereof.

[0539] Aspect 231. The compound according to aspect 1 has a structure represented by the following formula:

[0540]

[0541] Or a combination thereof.

[0542] Aspect 232. The compound according to aspect 1 has a structure represented by the following formula:

[0543] Or a combination thereof.

[0544] Aspect 233. The compound according to aspect 1 has a structure represented by the following formula:

[0545]

[0546]

[0547] Or a combination thereof.

[0548] Aspect 234. The compound according to aspect 1 has a structure represented by the following formula:

[0549]

[0550]

[0551] Or a combination thereof.

[0552] Aspect 235. The compound according to aspect 1 has a structure represented by the following formula:

[0553]

[0554]

[0555] Or a combination thereof.

[0556] Aspect 236. The compound according to aspect 1 has a structure represented by the following formula:

[0557]

[0558] Or a combination thereof.

[0559] Aspect 237. The compound according to aspect 1 has a structure represented by the following formula:

[0560]

[0561] Or a combination thereof.

[0562] Aspect 238. The compound according to any one of aspects 228 to 237, wherein R 1 Selected from halogens, -SF5, -CF3 and -CF2CF3.

[0563] Aspect 239. The compound according to aspect 238, wherein R 1 It is a halogen or -SF5.

[0564] Aspect 240. The compound according to aspect 238, wherein R 1 It can be either -F or -Cl.

[0565] Aspect 241. The compound according to aspect 238, wherein R 1 It is -F.

[0566] Aspect 242. The compound according to aspect 238, wherein R 1 It is ─Cl.

[0567] Aspect 243. The compound according to aspect 238, wherein R 1 It is SF5.

[0568] Aspect 244. The compound according to aspect 238, wherein R 1 Selected from -CF3 and -CF2CF3.

[0569] Aspect 245. The compound according to any one of aspects 228 to 237, wherein R 6a R 6b R 6c and R 6d Each of these elements is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl, provided that R 6a R 6b R 6c and R 6d At least one of them is not hydrogen.

[0570] Aspect 246. The compound according to aspect 245, wherein R 6a and R 6bIt is independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0571] Aspect 247. The compound according to aspect 246, wherein R 6a and R 6b It is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0572] Aspect 248. The compound according to aspect 247, wherein R 6a and R 6b It is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0573] Aspect 249. The compound according to aspect 245, wherein R 6a and R 6c It is independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0574] Aspect 250. The compound according to aspect 249, wherein R 6a and R 6c It is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0575] Aspect 251. The compound according to aspect 250, wherein R 6a and R 6c It is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0576] Aspect 252. The compound according to aspect 245, wherein R 6a and R 6d It is independently selected from hydrogen, halogens, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0577] Aspect 253. The compound according to aspect 252, wherein R 6a and R 6d It is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0578] Aspect 254. The compound according to aspect 253, wherein R 6a and R6d It is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0579] Aspect 255. The compound according to aspect 245, wherein R 6a Selected from -F, -Cl, -SF5, -CN, -N3, -OH and -NH2.

[0580] Aspect 256. The compound according to aspect 245, wherein R 6a Selected from -F, -SF5, -CN, -N3, -OH and -NH2.

[0581] Aspect 257. The compound according to aspect 245, wherein R 6b Selected from -F, -Cl, -SF5, -CN, -N3, -OH and -NH2.

[0582] Aspect 258. The compound according to aspect 245, wherein R 6a Selected from -F, -SF5, -CN, -N3, -OH and -NH2.

[0583] Aspect 259. The compound according to any one of aspects 245 to 259, wherein R 6c and R 6d Each of them is hydrogen.

[0584] Aspect 260. The compound according to any one of aspects 228 to 237, wherein R 6a Selected from hydrogen, halogen, ─SF5, ─CN, ─N3, ─OH, ─NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6b R 6c and R 6d Each of them is hydrogen.

[0585] Aspect 261. The compound according to aspect 260, wherein R 6a Selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0586] Aspect 262. The compound according to aspect 261, wherein R 6a Selected from ─F, ─Cl, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0587] Aspect 263. The compound according to aspect 262, wherein R 6aIt is -F.

[0588] Aspect 264. The compound according to any one of aspects 228 to 237, wherein R 6b Selected from hydrogen, halogen, ─SF5, ─CN, ─N3, ─OH, ─NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6a R 6c and R 6d Each of them is hydrogen.

[0589] Aspect 265. The compound according to aspect 264, wherein R 6b Selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0590] Aspect 266. The compound according to aspect 265, wherein R 6b Selected from ─F, ─Cl, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0591] Aspect 267. The compound according to aspect 266, wherein R 6b It is -F.

[0592] Aspect 268. The compound according to any one of aspects 228 to 237, wherein R 6a and R 6b Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6c and R 6d Each of them is hydrogen.

[0593] Aspect 269. The compound according to aspect 268, wherein R 6a and R 6b Each of them is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0594] Aspect 270. The compound according to aspect 269, wherein R 6a and R 6b Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0595] Aspect 271. The compound according to aspect 270, wherein R 6a and R 6b Each of them is -F.

[0596] Aspect 272. The compound according to any one of aspects 228 to 237, wherein R 6a and R 6c Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6b and R 6d Each of them is hydrogen.

[0597] Aspect 273. The compound according to aspect 272, wherein R 6a and R 6c Each of them is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0598] Aspect 274. The compound according to aspect 273, wherein R 6a and R 6c Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0599] Aspect 275. The compound according to aspect 274, wherein R 6a and R 6c Each of them is -F.

[0600] Aspect 276. The compound according to any one of Aspects 228 to 237, wherein R 6a and R 6d Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6b and R 6c Each of them is hydrogen.

[0601] Aspect 277. The compound according to aspect 276, wherein R 6a and R 6d Each of b is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F, and ─CF3.

[0602] Aspect 278. The compound according to aspect 277, wherein R 6a and R 6d Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0603] Aspect 279. The compound according to aspect 278, wherein R 6a and R 6d Each of them is -F.

[0604] Aspect 280. The compound according to any one of aspects 228 to 237, wherein R 6b and R 6c Each of them is independently selected from halogens, -SF5, -CN, -N3, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, and C1-C3 hydroxyalkyl; and wherein R 6a and R 6d Each of them is hydrogen.

[0605] Aspect 281. The compound according to aspect 280, wherein R 6b and R 6c Each of them is independently selected from halogens, ─SF5, ─CN, ─N3, ─OH, ─NH2, ─CHF2, ─CH2F and ─CF3.

[0606] Aspect 282. The compound according to aspect 281, wherein R 6b and R 6c Each of them is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F and -CF3.

[0607] Aspect 283. The compound according to aspect 282, wherein R 6b and R 6c Each of them is -F.

[0608] Aspect 284. The compound according to aspect 1 has a structure represented by the following formula:

[0609]

[0610]

[0611] Or a combination thereof.

[0612] Aspect 285. The compound according to aspect 1 is represented as:

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619] Or their subgroups.

[0620] Aspect 286. The compound according to aspect 1 is represented as:

[0621] Or a combination thereof.

[0622] Aspect 287. The compound according to any one of Aspects 1 to 286, wherein the compound is a pharmaceutically acceptable salt comprising the conjugate base form of the compound and a counterion selected from Li+, K+, Na+, ammonium, tetramethylammonium, tetraethylammonium, Fe... +2 Cu +2 Zn +2 Mg +2 Ca +2 Al +3 Fe +3 And their combinations.

[0623] Aspect 288. The compound according to aspect 0, wherein the counterion is Na + .

[0624] Aspect 289. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 288, and a pharmaceutically acceptable carrier.

[0625] Aspect 290. The pharmaceutical composition according to aspect 289 further comprises at least one known agent for treating cancer.

[0626] Aspect 291. The pharmaceutical composition according to aspect 290, wherein the at least one pharmaceutical agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof.

[0627] Aspect 292. The pharmaceutical composition according to aspect 291, wherein the DNA methyltransferase inhibitor is 5-aza-2'-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination thereof.

[0628] Aspect 293. The pharmaceutical composition according to aspect 291, wherein the HDAC inhibitor is vorinostat, entenostat, pabistat, trogostatin A, moxistat, belistat, dacistat, gemivestat, tubastatin A, pracinostat, zolcistat, quinsinostat, romidesin, valproic acid, AR-42 (OSU-HDAC42), tycodinalin, rosinol, aspirin, or a combination thereof.

[0629] Aspect 294. The pharmaceutical composition according to aspect 291, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof.

[0630] Aspect 295. The pharmaceutical composition according to aspect 291, wherein the mTor inhibitor is BEZ235, everolimus, tesiromolimus, rapamycin, AZD8055, or a combination thereof.

[0631] Aspect 296. The pharmaceutical composition according to aspect 291, wherein the cytotoxic agent is an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, an mTor inhibitor, or other chemotherapeutic agent.

[0632] Aspect 297. The pharmaceutical composition according to aspect 296, wherein the antitumor antibiotic is selected from one or more of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dermatomycin, epirubicin, idarubicin, procainamide, mitomycin, pentostatin, and pentorubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0633] Aspect 298. The pharmaceutical composition according to aspect 296, wherein the antimetabolite is selected from one or more of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, fluorouridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0634] Aspect 299. The pharmaceutical composition according to aspect 296, wherein the alkylating agent is selected from one or more of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, nitrogen mustard, temozolomide, thiotepa, bendamustine, and streptozotocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0635] Aspect 300. The pharmaceutical composition according to aspect 296, wherein the mitotic inhibitor is selected from one or more of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixaprone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0636] Aspect 301. The pharmaceutical composition according to aspect 296, wherein the mTor inhibitor is everolimus, sirolimus, tesimolimus, or a combination thereof.

[0637] Aspect 302. The pharmaceutical composition according to aspect 296, wherein another chemotherapeutic agent is an anthracycline, cytarabine, a purine analogue, sorafenib, gemtuzumab ozomicin, rituximab, or a combination thereof.

[0638] Aspect 303. The pharmaceutical composition according to aspect 302, wherein the anthracycline is daunorubicin, idarubicin, or a combination thereof.

[0639] Aspect 304. The pharmaceutical composition according to aspect 302, wherein the purine analog is cladribine, fludarabine, clofarabine, or a combination thereof.

[0640] Aspect 305. The pharmaceutical composition according to aspect 289 further comprises at least one known agent for treating GVHD.

[0641] Aspect 306. The pharmaceutical composition according to aspect 305, wherein the at least one known agent for treating GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other known agents for treating GVHD.

[0642] Aspect 307. The pharmaceutical composition according to aspect 306, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof.

[0643] Aspect 308. The pharmaceutical composition according to aspect 306, wherein the tyrosine kinase inhibitor is imatinib, ruxotinib, or a combination thereof.

[0644] Aspect 309. The pharmaceutical composition according to aspect 306, wherein the mTor inhibitor is everolimus, sirolimus, tesimolimus, or a combination thereof.

[0645] Aspect 310. The pharmaceutical composition according to aspect 306, wherein another known agent for treating GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, styraxone, hydroxychloroquine, or combinations thereof.

[0646] Aspect 311. The pharmaceutical composition according to aspect 289 further includes the step of administering a therapeutically effective amount of at least one known agent for treating autoimmune disorders or diseases.

[0647] Aspect 312. The pharmaceutical composition according to aspect 311, wherein the at least one known agent for treating autoimmune disorders or diseases is selected from: (a) disease-relieving antirheumatic drugs; (b) nonsteroidal anti-inflammatory drugs; (c) selective COX-2 inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs, including p70S6 kinase inhibitors; and inosine monophosphate dehydrogenase inhibitors; (f) steroids; (g) biological response modifiers; and (h) other agents that can be used to treat autoimmune disorders.

[0648] Aspect 313. The pharmaceutical composition according to aspect 312, wherein the disease-relieving antirheumatic drug is selected from methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auronorgestrel, sulfasalazine, and combinations thereof.

[0649] Aspect 314. The pharmaceutical composition according to aspect 312, wherein the nonsteroidal anti-inflammatory drug is selected from indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogs, acetaminophen, and combinations thereof.

[0650] Aspect 315. The pharmaceutical composition according to aspect 312, wherein the COX-2 selective inhibitor is selected from celecoxib, rofecoxib, etoricoxib, vardicoxib, romecoxib, and combinations thereof.

[0651] Aspect 316. The pharmaceutical composition according to aspect 312, wherein the immunosuppressive drug is selected from calcineurin inhibitors, such as cyclosporine and FK506; p70S6 kinase inhibitors, such as sirolimus and rapamycin; inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil; leflunomide, cyclophosphamide, azathioprine, and combinations thereof.

[0652] Aspect 317. The pharmaceutical composition according to aspect 312, wherein the steroid is selected from prednisone, betamethasone, budesonide, and dexamethasone, and combinations thereof.

[0653] Aspect 318. The pharmaceutical composition according to aspect 312, wherein the biological response modifier is selected from TNFα antagonists, such as infliximab, adalimumab, and etanercept; IL-1 receptor antagonists, such as anakinin; humanized or chimeric antibodies or fusion proteins, such as afacilipep, efalizumab, and dalizumab; anti-chemokine antibodies; anti-interleukin antibodies; and combinations thereof.

[0654] Aspect 319. The pharmaceutical composition according to aspect 312, wherein other agents that can be used to treat autoimmune disorders are selected from chemokine receptor antagonists or modulators, cannabinoid receptor antagonists or modulators, matrix metalloproteinase inhibitors, TNFα convertase, nitric oxide synthase or phosphodiesterase IV such as roflumilast or sillolast; inhibitors of p38MAP kinase, NF-κβ pathway or IL-1 receptor-associated kinase, or inhibitors involving the interaction of adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, α4β7, MAdCAM-1 and αvβ3; and combinations thereof.

[0655] Aspect 320. A method for treating a disease or disorder in a mammal, the method comprising the steps of: administering to the mammal a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 288, or a pharmaceutical composition according to any one of Aspects 289 to 319.

[0656] Aspect 321. The method according to aspect 320, wherein the mammal is a human.

[0657] Aspect 322. The method according to aspect 320, wherein prior to the application step, the mammal has been diagnosed as needing treatment for the disorder.

[0658] Aspect 323. The method according to aspect 322, wherein the disorder or disease is associated with abnormal, increased or distorted dihydroorotate dehydrogenase (DHODH) activity.

[0659] Aspect 324. The method according to aspect 323, wherein the disorder or disease can be treated by inhibiting the activity of dihydroorotate dehydrogenase (DHODH).

[0660] Aspect 325. The method according to any one of aspects 320 to 324 further includes the step of identifying a mammal in need of treatment for the disorder or disease.

[0661] Aspect 326. The method according to aspect 325, wherein the disorder or disease is associated with abnormal, increased or distorted dihydroorotate dehydrogenase (DHODH) activity.

[0662] Aspect 327. The method according to aspect 326, wherein the disorder or disease can be treated by inhibiting the activity of dihydroorotate dehydrogenase (DHODH).

[0663] Aspect 328. The method according to any one of aspects 320 to 327, wherein the obstacle is cancer.

[0664] Aspect 329. The method according to aspect 328, wherein the cancer is selected from breast cancer, kidney cancer, stomach 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.

[0665] Aspect 330. The method according to aspect 328, wherein the cancer is a hematologic cancer.

[0666] Aspect 331. The method according to aspect 330, wherein the hematologic cancer is leukemia, lymphoma, myeloma, myelodysplastic syndrome or myeloproliferative neoplasm.

[0667] Aspect 332. The method according to aspect 331, wherein the hematologic cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkert lymphoma, Hodgkin lymphoma and non-Hodgkin lymphoma.

[0668] Aspect 333. The method according to aspect 332, wherein the hematologic cancer is chronic myeloid leukemia (CML) or acute myeloid leukemia (AML).

[0669] Aspect 334. The method according to any one of aspects 320 to 333 further includes the step of administering a therapeutically effective amount of at least one known cancer-treating agent.

[0670] Aspect 335. The method according to aspect 334, wherein the at least one agent is selected from uramustine, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, piperobromidine, tratamiflu, triethylthiophosphatidylcholine, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vincristine, vinorelbine, vindesin, bleomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemetrexed, idarubicin, paclitaxel, docetaxel, ixaspirin, safran, topotecan, and irizoline. Linotecan, Deoxymyotrophic Acid, Mitomycin C, L-Asparaginase, Interferon, Etoposide, Teniposide, 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoromethyltestosterone, Drotahistamine Propionate, Testrolide, Medroxyprogesterone acetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorestradiol, Hydroxyprogesterone, Ammoniaglutide, Estrogen, Acetic Acid Medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, and angiostatin.

[0671] Aspect 336. The method according to aspect 334, 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.

[0672] Aspect 337. The method according to aspect 336, wherein the DNA methyltransferase inhibitor is 5-aza-2'-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination thereof.

[0673] Aspect 338. The method according to aspect 336, wherein the HDAC inhibitor is vorinostat, entenostat, pabistat, trichostatin A, moxistat, belistat, dacistat, givitasterin, tubastatin A, pracinostat, zolcistat, quinsinostat, romidesin, valproic acid, AR-42 (OSU-HDAC42), tycodinalin, rosinol, aspirin, or a combination thereof.

[0674] Aspect 339. The method according to aspect 336, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof.

[0675] Aspect 340. The method according to aspect 336, wherein the mTor inhibitor is BEZ235, everolimus, tesiromolimus, rapamycin, AZD8055, or a combination thereof.

[0676] Aspect 341. The method according to aspect 336, wherein the cytotoxic agent is an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, an mTor inhibitor, or other chemotherapeutic agent.

[0677] Aspect 342. The method according to aspect 341, wherein the antitumor antibiotic is selected from one or more of doxorubicin, mitoxantrone, bleomycin, daunorubicin, cytosine, epirubicin, idarubicin, procainamide, mitomycin, pentostatin, and pentorubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0678] Aspect 343. The method according to aspect 341, wherein the antimetabolite is selected from one or more of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, fluorouridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0679] Aspect 344. The method according to aspect 341, wherein the alkylating agent is selected from one or more of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, nitrogen mustard, temozolomide, thiotepa, bendamustine, and streptozotocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0680] Aspect 345. The method according to aspect 341, wherein the mitotic inhibitor is selected from one or more of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixaprone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0681] Aspect 346. The method according to aspect 341, wherein the mTor inhibitor is everolimus, sirolimus, tesimolimus, or a combination thereof.

[0682] Aspect 347. The method according to aspect 341, wherein another chemotherapeutic agent is an anthracycline, cytarabine, a purine analogue, sorafenib, gemtuzumab ozomicin, rituximab, or a combination thereof.

[0683] Aspect 348. The method according to aspect 347, wherein the anthracycline is daunorubicin, idarubicin, or a combination thereof.

[0684] Aspect 349. The method according to aspect 347, wherein the purine analogue is cladribine, fludarabine, chlorofarabine, or a combination thereof.

[0685] Aspect 350. The method according to any one of aspects 334 to 349, wherein the at least one compound and the at least one pharmaceutical agent are applied sequentially.

[0686] Aspect 351. The method according to any one of aspects 334 to 349, wherein the at least one compound and the at least one pharmaceutical agent are administered simultaneously.

[0687] Aspect 352. The method according to any one of aspects 334 to 349, wherein the at least one compound and the at least one pharmaceutical agent are formulated together.

[0688] Aspect 353. The method according to any one of aspects 334 to 349, wherein the at least one compound and the at least one pharmaceutical agent are co-packaged.

[0689] Aspect 354. The method according to any one of aspects 320 to 325, wherein the barrier is mediated by T cell proliferation.

[0690] Aspect 355. The method according to aspect 354, wherein the obstacle is psoriasis.

[0691] Aspect 356. The method according to aspect 354, wherein the barrier is graft-versus-host disease (GVHD).

[0692] Aspect 357. The method according to aspect 356, wherein the GVHD is related to organ transplantation, allogeneic transplantation, xenotransplantation or hematopoietic stem cell transplantation.

[0693] Aspect 358. The method according to aspect 356 or aspect 357, wherein the GVHD is acute GVHD.

[0694] Aspect 359. The method according to aspect 356 or aspect 357, wherein the GVHD is chronic GVHD.

[0695] Aspect 360. The method according to any one of aspects 356 to 359 further includes the step of administering a therapeutically effective amount of at least one known agent for treating GVHD.

[0696] Aspect 361. The method according to aspect 360, wherein the at least one known agent for treating GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other known agents for treating GVHD.

[0697] Aspect 362. The method according to aspect 361, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof.

[0698] Aspect 363. The method according to aspect 361, wherein the tyrosine kinase inhibitor is imatinib, ruxotinib, or a combination thereof.

[0699] Aspect 364. The method according to aspect 361, wherein the mTor inhibitor is everolimus, sirolimus, tesimolimus, or a combination thereof.

[0700] Aspect 365. According to the method of aspect 361, another known agent for treating GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, styraxone, hydroxychloroquine, or a combination thereof.

[0701] Aspect 366. The method according to any one of aspects 320 to 325, wherein the barrier is associated with T cell proliferation.

[0702] Aspect 367. The method according to any one of aspects 320 to 325, wherein the obstacle is an autoimmune disorder or disease.

[0703] Aspect 368. The method according to aspect 367, wherein the autoimmune disorder or disease is selected from lupus, rheumatoid arthritis, ankylosing spondylitis, glomerulonephritis, minimal change disease, ulcerative colitis, Crohn's disease, Addison's disease, adult-onset Still's disease, alopecia areata, autoimmune hepatitis, autoimmune angioedema, Bechtel's disease, pemphigoid and its variants, celiac disease, chronic inflammatory demyelinating polyneuropathy, Chug-Strauss syndrome, CREST syndrome, dermatomyositis, neuromyelitis optica, discoid lupus, fibromyalgia, giant cell arteritis, giant cell myocarditis, Goodyear's disease, etc. Bastian disease, Evan syndrome, autoimmune hemolytic anemia, immune thrombocytopenic purpura, allergic purpura, IgA nephropathy, IgG4-related sclerotic diseases, juvenile arthritis, juvenile diabetes, Kawasaki disease, leukocyte rupture vasculitis, mixed connective tissue disease, multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, autoimmune neutropenia, optic neuritis, peripheral neuropathy, POEMS syndrome, polymyositis, primary biliary cirrhosis, non-alcoholic liver disease and related cirrhosis, psoriasis, scleroderma, sarcoidosis, temporal arteritis, vasculitis, and uveitis.

[0704] Aspect 369. The method according to aspect 367 or aspect 368 further includes the step of administering a therapeutically effective amount of at least one known agent for treating autoimmune disorders or diseases.

[0705] Aspect 370. The method according to aspect 369, wherein the at least one known agent for treating autoimmune disorders or diseases is selected from: (a) disease-relieving antirheumatic drugs; (b) nonsteroidal anti-inflammatory drugs; (c) selective COX-2 inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs, including p70S6 kinase inhibitors; and inosine monophosphate dehydrogenase inhibitors; (f) steroids; (g) biological response modifiers; and (h) other agents capable of treating autoimmune disorders.

[0706] Aspect 371. The method according to aspect 370, wherein the disease-relieving antirheumatic drug is selected from methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auronorgestrel, sulfasalazine, and combinations thereof.

[0707] Aspect 372. The method according to aspect 370, wherein the nonsteroidal anti-inflammatory drug is selected from indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogues, acetaminophen, and combinations thereof.

[0708] Aspect 373. The method according to aspect 370, wherein the COX-2 selective inhibitor is selected from celecoxib, rofecoxib, etoricoxib, vardicoxib, romecoxib, and combinations thereof.

[0709] Aspect 374. The method according to aspect 370, wherein the immunosuppressive drug is selected from calcineurin inhibitors, such as cyclosporine and FK506; p70S6 kinase inhibitors, such as sirolimus and rapamycin; inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil; leflunomide, cyclophosphamide, azathioprine, and combinations thereof.

[0710] Aspect 375. The method according to aspect 370, wherein the steroid is selected from prednisone, betamethasone, budesonide, and dexamethasone, and combinations thereof.

[0711] Aspect 376. The method according to aspect 370, wherein the biological response modulator is selected from TNFα antagonists, such as infliximab, adalimumab, and etanercept; IL-1 receptor antagonists, such as anakinin; humanized or chimeric antibodies or fusion proteins, such as afacilipep, efalizumab, and dalizumab; anti-chemokine antibodies; anti-interleukin antibodies; and combinations thereof.

[0712] Aspect 377. The method according to aspect 370, wherein other agents that can be used to treat autoimmune disorders are selected from chemokine receptor antagonists or modulators, cannabinoid receptor antagonists or modulators, matrix metalloproteinase inhibitors, TNFα convertase, nitric oxide synthase or phosphodiesterase IV such as roflumilast or sillolast; inhibitors of p38 MAP kinase, NF-κβ pathway or IL-1 receptor-associated kinase, or inhibitors involving the interaction of adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, α4β7, MAdCAM-1 and αvβ3; and combinations thereof.

[0713] Aspect 378. A method for inhibiting dihydroorotate dehydrogenase activity in at least one cell, the method comprising the step of contacting the at least one cell with a therapeutically effective amount of at least one compound according to any one of aspects 1 to 288 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of aspects 289 to 319.

[0714] Aspect 379. The method according to aspect 378, wherein the cell is mammalian.

[0715] Aspect 380. The method according to aspect 379, wherein the cell is human.

[0716] Aspect 381. The method according to any one of aspects 378 to 380, wherein the cell has been isolated from a mammal prior to the contact step.

[0717] Aspect 382. The method according to any one of aspects 378 to 380, wherein the contact is achieved by application to a mammal.

[0718] Aspect 383. The method according to aspect 382, ​​wherein prior to the administration step, the mammal has been diagnosed as requiring inhibition of dihydroorotate dehydrogenase activity.

[0719] Aspect 384. The method according to aspect 383, wherein prior to the administration step, the mammal has been diagnosed as requiring treatment for a disorder related to dihydroorotate dehydrogenase activity.

[0720] Aspect 385. The method according to any one of aspects 378 to 384, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase using a cell-free enzymatic assay, with an IC50 of less than about 1,000 nM.

[0721] Aspect 386. The method according to aspect 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 500 nM.

[0722] Aspect 387. The method according to aspect 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 250 nM.

[0723] Aspect 388. The method according to aspect 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 100 nM.

[0724] Aspect 389. The method according to aspect 385, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than about 50 nM.

[0725] A kit comprising a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 288, or a pharmaceutical composition according to any one of aspects 289 to 319; and:

[0726] (a) at least one known agent for treating cancer, host resistance to graft disease, and / or disorders associated with T cell proliferation; and

[0727] (b) Instructions for use in the treatment of cancer, host resistance to graft disease and / or disorders related to T cell proliferation.

[0728] Aspect 391. The kit according to aspect 390, wherein the at least one compound or pharmaceutical composition and the at least one pharmaceutical agent are co-formulated.

[0729] Aspect 392. The kit according to aspect 390, wherein the at least one compound or pharmaceutical composition and the at least one pharmaceutical agent are co-packaged.

[0730] Aspect 393. The kit according to aspect 390 also includes instructions for providing the compound related to the surgery.

[0731] Aspect 394. The kit according to aspect 393, wherein the instructions specify that surgery should be performed prior to the administration of at least one compound.

[0732] Aspect 395. The kit according to aspect 393, wherein the instructions specify that surgery should be performed after the administration of at least one compound.

[0733] Aspect 396. The kit according to aspect 393, wherein the specification specifies that the administration of at least one compound is for the purpose of achieving preoperative tumor reduction.

[0734] Aspect 397. The kit according to aspect 393, wherein the instructions specify that the surgery is performed almost simultaneously with the administration of at least one compound.

[0735] Aspect 398. The kit according to aspect 390 further includes instructions for providing at least one compound or pharmaceutical composition in relation to radiotherapy.

[0736] Aspect 399. The kit according to aspect 398, wherein the instructions specify that radiation therapy should be performed prior to the administration of at least one compound.

[0737] Aspect 400. The kit according to aspect 398, wherein the specification specifies that radiotherapy is performed after the step of administering at least one compound.

[0738] Aspect 401. The kit according to aspect 398, wherein the specification specifies that radiotherapy is performed almost simultaneously with the step of administering at least one compound.

[0739] Aspect 402. The kit according to aspect 390 further includes multiple dosage forms, the multiple dosage forms including one or more doses; wherein each dose contains a therapeutically effective amount of the at least one compound or the pharmaceutical composition and the at least one agent.

[0740] Aspect 403. The kit according to aspect 402, wherein each dose of the at least one compound or pharmaceutical composition and the at least one agent are co-formulated.

[0741] Aspect 404. The kit according to aspect 402, wherein each dose of the at least one compound or pharmaceutical composition and the at least one pharmaceutical agent are co-packaged.

[0742] Aspect 405. The kit according to aspect 402, wherein the dosage form is formulated for oral and / or intravenous administration.

[0743] Aspect 406. The kit according to aspect 402, wherein the dosage form is formulated for oral administration.

[0744] Aspect 407. The kit according to aspect 402, wherein the dosage form is formulated for intravenous administration.

[0745] Aspect 408. The kit according to aspect 402, wherein the dosage form of the at least one compound or the pharmaceutical composition is formulated for oral administration, and the dosage form of the at least one pharmaceutical agent is formulated for intravenous administration.

[0746] Aspect 409. The kit according to aspect 402, wherein the dosage form of the at least one compound or the pharmaceutical composition is formulated for intravenous administration, and the dosage form of the at least one pharmaceutical agent is formulated for oral administration.

[0747] As can be seen from the preceding text, all aspects of this paper are well-suited to achieving all the purposes and objects described above, as well as other obvious and structurally inherent advantages.

[0748] Although the specific elements and steps are discussed in connection with each other, it should be understood that any element and / or step provided herein is contemplated as being able to be combined with any other element and / or step, whether or not such other element and / or step is explicitly provided, while still remaining within the scope provided herein.

[0749] It should be understood that certain features and sub-combinations are practical and can be used without reference to other features and sub-combinations. The scope of the claims contemplates this situation, and this situation is within the scope of the claims.

[0750] Since many possible aspects can be made without departing from its scope, it should be understood that all content shown or illustrated in the accompanying drawings and description should be interpreted as illustrative rather than restrictive.

[0751] It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting. Those skilled in the art will recognize many variations and adaptations of the various aspects described herein. These variations and modifications are intended to be included within the teachings of this disclosure and to be covered by the claims herein. Having now described aspects of this disclosure, the following embodiments generally illustrate some additional aspects of this disclosure. While various aspects of this disclosure are described in conjunction with the following embodiments and corresponding text and drawings, they are not intended to limit the aspects of this disclosure to that description. Rather, all alternatives, modifications, and equivalents are intended to cover those included within the spirit and scope of this disclosure.

[0752] Example

[0753] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to prepare and evaluate the compounds, compositions, articles, apparatus, and / or methods claimed herein, and the examples are intended purely as examples of this disclosure and are not intended to limit the scope of what the inventors consider to be the disclosure. Efforts have been made to ensure the accuracy of figures (e.g., quantities, temperatures, etc.), but some errors and deviations should be accounted for. Unless otherwise specified, parts are parts by weight, temperatures are in °C or at ambient temperature, and pressures are at or near atmospheric pressure.

[0754] 1. Example 1: Synthesis of representative disclosed compounds

[0755] Synthesis of 2-(4′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd1) The target compound 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.

[0756]

[0757] Step 1 - Suzuki CouplingTo a solution of 1-(4-bromo-3-fluorophenyl)ethyl-1-one 1 (300 mg, 1.38 mmol) and 4-ethoxyphenylboronic acid 2 (252 mg, 1.52 mmol) in 1-propanol (3.2 mL, 0.43 M), palladium acetate (1.5 mg, 0.007 mmol), XPhos (9 mg, 0.019 mmol), and sodium carbonate aqueous solution (2 M, 1.50 mL) were added, followed by water (0.10 mL). The reaction mixture was stirred at 100 °C for 1 hour (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 Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude substance. The crude substance was purified by rapid column chromatography using dichloromethane / hexane to give 1-(4′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one (3), as a white solid (305 mg, 85% yield).

[0758] Step 2 - Pfeltzinger reaction A mixture of 5-fluoroindigo 4 (174 mg, 1.06 mmol) and an aqueous solution of potassium hydroxide (33%, 4.8 mL, 0.22 M) was stirred and gently heated until a clear yellow solution was formed. A slurry of 1-(4'-ethoxy-2-fluoro-[1,1'-biphenyl]-4-yl)ethyl-1-one 3 (300 mg, 1.16 mmol) in ethanol (7.1 mL, 0.15 M) was added to this solution. The reaction mixture was heated to reflux at 80 °C for 16 hours with stirring (process monitored by TLC), then cooled to room temperature, the ethanol was evaporated, and the solution was acidified to pH 2 with an aqueous solution of HCl (2 M).

[0759] Post-processing and purification procedure I: A yellow solid was formed. 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 Na2SO4 and concentrated to obtain a crude substance, which was purified by rapid column chromatography (using methanol / dichloromethane as eluent) to obtain a yellow solid. The yellow solid was ground with methanol, dichloromethane and / or ethyl acetate to obtain 2-(4′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd1), a grayish-white solid.

[0760] Post-treatment and purification procedure II: Another post-treatment procedure for the Pfizer-Zinger reaction is as follows. The acidified mixture was stirred with the precipitated product 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 entrapped water and dried under vacuum. The resulting powder was ground 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 (Cpd1) as a grayish-white solid (204 mg, 48% yield).

[0761] Synthesis of 2-(3′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd2) Following a synthetic procedure similar to that used to prepare Cpd1, the target compound 2-(3′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd2) was prepared as follows.

[0762]

[0763] Step 1 was performed with 300 mg of 1-(4-bromo-3-fluorophenyl)ethyl-1-one and 275 mg of (3-ethoxyphenyl)boric acid to give 1-(3′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a light pink solid (327 mg, 90% yield). Step 2 (post-treatment / purification procedure I) was performed with 125 mg of 5-fluoroindigo and 200 mg of 1-(3′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one to give 2-(3′-ethoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd2) as a grayish-white solid (60 mg, 20% yield).

[0764] 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 used to prepare Cpd1, the target compound 2-(3′-butoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3) was prepared as follows.

[0765]

[0766] Step 1 was performed with 300 mg of 1-(4-bromo-3-fluorophenyl)ethyl-1-one and 322 mg of (3-butoxyphenyl)boric acid to give 1-(3′-butoxy-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a colorless oil (369 mg, 93% yield). Step 2 (post-treatment / purification procedure I) was performed with 105 mg of 5-fluoroindigo and 200 mg of 1-(3′-butoxy-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one, and after collecting only the pure fraction by column chromatography from ethyl acetate and hexane and grinding with hexane, 2-(3′-butoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3) was given as a grayish-white solid (55 mg, 20% yield).

[0767] 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 used to prepare Cpd1, the target compound 2-(3′-butoxy-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd4) was prepared as follows.

[0768]

[0769] Step 1 was performed with 300 mg of 1-(4-bromo-3-fluorophenyl)ethyl-1-one and 185 mg of phenylboronic acid to give 1-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a white solid (265 mg, 89% yield). Step 2 was performed with 147 mg of 5-fluoroindigo and 200 mg of 1-(2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-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). 110 mg of the 233 mg was recrystallized from DMSO / water to give a white solid (54 mg, 19% yield).

[0770] Synthesis of 2-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd5) Following a synthetic procedure similar to that used to prepare Cpd1, the target compound 2-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd5) was prepared as follows.

[0771]

[0772] Step 1 was performed with 300 mg of 1-(4-bromo-3-fluorophenyl)ethyl-1-one and 185 mg of (2-fluorophenyl)boric acid to give 1-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a white solid (164 mg, 46% yield). Step 2 (post-treatment / purification procedure II) was performed with 108 mg of 5-fluoroindigo and 160 mg of 1-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)ethyl-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, it was ground once with a mixture of ethyl acetate and 10% methanol / dichloromethane to give 2-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd5) as a grayish-white solid (52 mg, 21% yield).

[0773] Synthesis of 2-(4′-(ethylamino)-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd6) become Following a synthetic procedure similar 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.

[0774]

[0775] Step 1. To a solution of 1-(4-bromo-3-fluorophenyl)ethyl-1-one 1 (50 mg, 2.30 mmol) in 1,4-dioxane (5 mL), add bis(pinacol)diborane (614 mg, 2.42 mmol) and potassium acetate (677 mg, 6.90 mmol). Bubble the reaction mixture with argon for 5 minutes and add PdCl2 (dppf) (84 mg, 0.12 mmol), then stir the reaction mixture at 90 °C for 16 hours. Dilute the reaction mixture with ethyl acetate (50 mL) and water (50 mL). Separate the organic layer, wash with brine (40 mL), dry with anhydrous sodium sulfate, and concentrate to obtain the crude substance. The crude substance obtained was purified by rapid column chromatography (using ethyl acetate / hexane) to give 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)ethyl-1-one (460 mg, 76% yield) as a grayish-white solid. Step 2 (post-treatment / purification procedure II) was performed on 450 mg of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)ethyl-1-one and 375 mg of 4-bromo-N-ethylaniline to give 1-(4′-(ethylamino)-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a white solid (310 mg, 71% yield). Posttreatment / purification of 88 mg of 5-fluoroindigo and 150 mg of 1-(4′-(ethylamino)-2-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one yielded 2-(4′-(ethylamino)-2-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd6) as a white solid (93 mg, 43% yield).

[0776] Synthesis of 2-(4′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd7) become Following a synthetic procedure similar 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.

[0777]

[0778] Step 1 was performed with 300 mg of 1-(4-chloro-2,5-difluorophenyl)ethyl-1-one and 274 mg of (4-ethoxyphenyl)boric acid to give 1-(4′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a grayish-white solid (340 mg, 78% yield). Step 2 (post-treatment / purification procedure II) was performed with 120 mg of 5-fluoroindigo and 200 mg of 1-(4′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one to give 2-(4′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd7) as a grayish-white solid (240 mg, 78% yield).

[0779] Synthesis of 2-(3′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd8) become Following a synthetic procedure similar to that used to prepare 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.

[0780]

[0781] Step 1 was performed with 300 mg of 1-(4-chloro-2,5-difluorophenyl)ethyl-1-one and 274 mg of (3-ethoxyphenyl)boronic acid to give 1-(3′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a grayish-white solid (338 mg, 78% yield). Step 2 (post-treatment / purification procedure II) was performed with 120 mg of 5-fluoroindigo and 200 mg of 1-(3′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one to give 260 mg (84%) of 2-(3′-ethoxy-2,5-difluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd8) as a grayish-white solid (260 mg, 84% yield).

[0782] Synthesis of 2-(4′-ethoxy-3-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd9) Following a synthetic procedure similar 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.

[0783]

[0784] Step 1 was performed with 300 mg of 1-(4-bromo-2-fluorophenyl)ethyl-1-one and 241 mg of (4-ethoxyphenyl)boronic acid to give 1-(4′-ethoxy-3-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one as a grayish-white solid (300 mg, 84% yield). Step 2 (post-treatment / purification procedure II) was performed with 127 mg of 5-fluoroindigo and 200 mg of 1-(4′-ethoxy-3-fluoro-[1,1′-biphenyl]-4-yl)ethyl-1-one to give 2-(4′-ethoxy-3-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd9) as a grayish-white solid (150 mg, 48% yield).

[0785] Synthesis of 2-(3′-ethoxy-3-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd10) The target compound 2-(3′-ethoxy-3-fluoro-[1,1′-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd10) was prepared following a synthetic procedure similar to that described for the preparation of Cpd1.

[0786]

[0787] Step 1 was performed with 300 mg of 1-(4-bromo-2-fluorophenyl)ethyl-1-one and 241 mg of (3-ethoxyphenyl)boronic acid to give 313 mg (88%) of 1-(3′-ethoxy-3-...

Claims

1. A compound selected from the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , Or, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 Or, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is selected from the group consisting of: 、 、 、 、 Or, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, wherein the compound is a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt comprising the conjugate base form of the compound and an anti-ion selected from Li + K + Na + Ammonium, tetramethylammonium, tetraethylammonium, Fe +2 Cu +2 Zn +2 Mg +2 Ca +2 Al +3 Fe +3 , and their combinations.

5. The compound according to claim 4, wherein the counterion is Na. + .

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