Methods and compositions for inhibition of dihydroorotate dehydrogenase in combination with Anti-CD38 therapeutic agent

Abstract

To provide pharmaceutical combinations of treating a clinical condition, e.g., AML.SOLUTION: A pharmaceutical combination comprising a DHODH inhibitor and an anti-CD38 therapeutic agent such as an anti-CD38 antibody is administered to a subject. The pharmaceutical combination can further comprise one or more additional therapeutic agents.SELECTED DRAWING: Figure 2D

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 953,860, filed December 26, 2019, which is incorporated herein by reference in its entirety. [Background technology]

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

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

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

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

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

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

[0008] In accordance with the purposes of this disclosure, as embodied and broadly described herein, the disclosure relates in one aspect to pharmaceutical combinations and methods of treating a clinical condition, e.g., AML, by administering to a subject a pharmaceutical combination comprising a DHODH inhibitor and an anti-CD38 antibody. The pharmaceutical combination can further comprise one or more additional therapeutic agents. Other clinical conditions that can be treated by the disclosed pharmaceutical compositions, i.e., combination therapies comprising a DHODH inhibitor and an anti-CD38 antibody, and the disclosed methods of combination therapy include, but are not limited to, chronic lymphocytic leukemia, MGUS / multiple myeloma, extranodal natural killer (NK) / T-cell lymphoma, large cell lymphoma, nasal type (ENKTL-N), myelodysplasia, therapy-related myeloid malignancies, acute myeloid leukemia, chronic myelomonocytic leukemia, T-lymphoblastic lymphoma / leukemia, B-lymphoblastic lymphoma / leukemia, Burkitt's leukemia / lymphoma, primary infiltrative lymphoma, Philadelphia-positive acute lymphoblastic leukemia, and immune modulation of solid tumors. Certain non-malignant clinical conditions can also be treated by the disclosed pharmaceutical compositions and methods of treatment, including, but not limited to, aplastic anemia, malignant myeloid-derived suppressor cell depletion, and immunoglobulin light chain amyloidosis (AL).

[0009] Disclosed herein is a pharmaceutical combination comprising an antibody that specifically recognizes CD38 and at least a DHODH inhibitor compound disclosed herein, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the antibody that specifically recognizes CD38 is capable of killing CD38+ cells by antibody-dependent cell-mediated phagocytosis (ADCP), cell fratricide, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and / or complement-dependent cytotoxicity (CDC).

[0010] The disclosed DHODH inhibitors can be any of the DHODH inhibitors disclosed in International Patent Application No. PCT / US19 / 38622, which is incorporated herein by reference. Exemplary DHODH inhibitors disclosed therein are: TIFF2025186252000002.tif381702-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3)

[0011] The disclosed DHODH inhibitors have the structure: TIFF2025186252000003.tif37170, wherein Z 1 , Z 2 , Z 3 , and Z 4 are each independently selected from CH and N; 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2-O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e wherein four of the groups may have a formula, or a pharmaceutically acceptable salt thereof, selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3.

[0012] The disclosed DHODH inhibitors have the structure: TIFF2025186252000004.tif37170, wherein Z 1 is a 5-membered heterocyclic diyl, and R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R31 are each independently selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e wherein four of the groups may have a formula, or a pharmaceutically acceptable salt thereof, selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3.

[0013] The disclosed DHODH inhibitors have the structure: TIFF2025186252000005.tif38170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d can have a formula, or a pharmaceutically acceptable salt thereof, that 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.

[0014] Also disclosed are methods for treating a disease or disorder in a mammal comprising administering to the mammal a therapeutically effective amount of the disclosed pharmaceutical combination.

[0015] Also disclosed are methods for treating a disease or disorder in a mammal comprising administering to the mammal a therapeutically effective amount of the disclosed pharmaceutical combination.

[0016] Also disclosed are methods for the treatment of cancer in a mammal comprising administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical combination.

[0017] Also disclosed is a method for treating a disease or disorder associated with T-cell proliferation in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition.

[0018] Also disclosed are kits comprising a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition; (a) at least one agent known to treat cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation; and (b) instructions for treating cancer, host-versus-graft disease, and / or a disorder associated with T-cell proliferation.

[0019] Also disclosed are methods for producing a medicament comprising combining a therapeutically effective amount of the disclosed pharmaceutical combination with a pharmaceutically acceptable carrier or diluent.

[0020] Although aspects of the present disclosure may be described and claimed in particular statutory classifications, such as systems statutory classifications, this is done for convenience only, and one of ordinary skill in the art will understand that aspects of the present disclosure may be described and claimed in any statutory classification. Unless otherwise expressly stated, it is in no way intended that any method or aspect described herein be construed as requiring its steps to be performed in a particular order. Accordingly, method claims do not specifically recite in the claims or specification that the steps are limited to a particular order, and no order is intended to be inferred in any respect. This also applies to any possible implicit basis for interpretation, including logical considerations regarding the arrangement of steps or operational flow, plain meaning derived from grammatical structure or punctuation, or the number or type of aspects described within the specification. [Brief explanation of the drawings]

[0021] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects and, together with the description, serve to explain the principles of the present disclosure.

[0022] [Figure 1A-1B] Figures 1A and 1B show representative data on the effect of representative DHODH inhibitors on CD38 expression in AML cells. Briefly, MV-411 cells with wild-type (WT) p53 (Figure 1A) or mutant p53 (Figure 1B) were treated with brequinar (BRQ, 1 μM) or Cpd 3 (1 μM) for 72 hours, and then CD38 surface expression was determined by flow cytometry. CD38 mean fluorescence intensity (MFI) was calculated based on the X-median expression. [Figures 2A-2D]Figures 2A-2D show representative data on the effect of a representative DHODH inhibitor in combination with an anti-CD38 antibody in a mouse xenograft model. Figure 2A shows representative data on survival rate versus time after engraftment. Briefly, NSG mice were injected with 0.3 x 10 splenocytes from MV4-11-engrafted leukemia donor mice (N = 7 / group). Starting on day 7 after engraftment, mice were treated with vehicle, 50 mg / kg Cpd3 (oral, indicated as "Cpd 3 (oral)" in the figure) on a Monday / Wednesday / Friday (MWF) dosing schedule, 1 μg / g daratumumab (intraperitoneal, indicated as "Dara (intraperitoneal)" in the figure) on a Tuesday and Friday (TF) dosing schedule, or a combination of Cpd3 and daratumumab (indicated as "Cpd 3 + Dara" in the figure). Cpd3 and daratumumab combination treatment included Cpd3 at 50 mg / kg on a Monday / Wednesday / Friday dosing schedule and daratumumab at 1 μg / kg on a Tuesday and Friday (TF) dosing schedule. Mice were monitored until they reached early / terminal elimination criteria (ERC), and overall survival was calculated using Kapler-Meyer analysis. Arrows indicate the start of treatment. The data show that treatment with either Cpd3 or daratumumab alone showed only a slight improvement in survival compared to the vehicle-treated control group, while combination treatment, i.e., Cpd3 combined with the CD38 antibody daratumumab, dramatically improved survival compared to the other treatment groups, demonstrating the synergistic effect of the combination treatment. Figure 2B shows representative photographic images of spleens isolated from animals from each treatment group when ERC was reached. Treatment type is indicated below each photographic image, as outlined in Figure 2A. The data show that Cpd3 in combination with the CD38 antibody daratumumab reduced tumor burden, i.e., smaller spleen size, compared to other treatment groups. Figure 2C shows representative weight loss data for each treatment group versus time after engraftment. Weight loss is typically associated with leukemia progression and is also associated with DHODH inhibitor treatment. The data show that weight loss corresponded to clearance criteria and was delayed in the Cpd3 + Daratumumab group.Figure 2D shows representative data for the percentage of human CD45+ cells (gated on live cells) for the vehicle and combination treatment groups. Briefly, spleens were isolated from animals from each treatment group upon reaching ERC. The percentage of human CD45+ cells in the spleen was determined by flow cytometry. The data show that combination treatment (Cpd3+Dara) reduced tumor burden in spleens from treated mice compared to the vehicle treatment group. [Figure 3A-3C] Figures 3A-3C show representative data on the effect of representative DHODH inhibitors on CD38 expression in primary AML cells. Briefly, primary AML cells were treated with vehicle (DMSO), brequinar (BRQ, 1 μM), or Cpd3 (1 μM) for 72 hours, and then surface expression of CD11b and CD38 was determined by flow cytometry. Figure 3A shows flow cytometry data for primary AML cells after treatment with vehicle. Figure 3B shows flow cytometry data for primary AML cells after treatment with brequinar. Figure 3C shows flow cytometry data for primary AML cells after treatment with Cpd3. [Figure 4A-4B] Figures 4A and 4B show plots of data obtained from flow cytometry studies of the type shown in Figures 3A-3C. Briefly, primary AML cells were treated with vehicle (DMSO), brequinar (BRQ, 1 μM), BAY2402234 (BAY), or Cpd3 (1 μM) for 72 hours, and then surface expression of CD11b and CD38 was determined by flow cytometry. Mean fluorescence intensity (MFI) plots were normalized to vehicle (DMSO). Figure 4A shows CD11b expression levels after 3 and 7 days of treatment with the indicated agents. Figure 4B shows CD38 expression levels after 3 and 7 days of treatment with the indicated agents. [Figure 5] Figure 5 shows representative data from the treatment of six AML cell lines with different mutational backgrounds. Cell lines were treated for 3 days with the indicated compounds at the indicated concentrations. BRQ = brequinar, BAY = BAY2402234. [Figures 6A-6B]Figures 6A and 6B show representative data for the effect of a representative DHODH inhibitor in combination with an anti-CD38 antibody in a mouse xenograft model using the TIWK (MWF) dosing regimen for the DHODH inhibitor Cpd 4, as described herein below. Figure 6A shows data for the indicated therapeutic agents, including combination treatment with the DHODH inhibitor Cpd 4 with daratumumab (Dara). Figure 6B shows data for the indicated therapeutic agents, including combination treatment with the DHODH inhibitor Cpd 4 with isatuximab (Isa). [Figures 7A-7B] Figures 7A and 7B show representative data for the effect of a representative DHODH inhibitor in combination with an anti-CD38 antibody in a mouse xenograft model using a daily dosing regimen for the DHODH inhibitor Cpd 4, as described herein below. Figure 7A shows data for the indicated therapeutic agents, including combination treatment with the DHODH inhibitor Cpd 4 with daratumumab (Dara). Figure 7B shows data for the indicated therapeutic agents, including combination treatment with the DHODH inhibitor Cpd 4 with isatuximab (Isa). [Figure 8A-8B] Figures 8A and 8B show representative data for the effect of a representative DHODH inhibitor in combination with an anti-CD38 antibody in a mouse xenograft model using a daily dosing regimen for the DHODH inhibitor BAY2402234, as described herein. Figure 8A shows data for the indicated therapeutic agents, including combination treatment with the DHODH inhibitor BAY2402234 with daratumumab (Dara). Figure 8B shows data for the indicated therapeutic agents, including combination treatment with the DHODH inhibitor BAY2402234 with isatuximab (Isa).

[0023] Additional advantages of the present disclosure will be set forth in the detailed description that follows, and in part will be obvious from the detailed description, or may be learned by the practice of the disclosure. The advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure, as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0024] Numerous modifications and other embodiments of the disclosed compositions and methods disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is therefore to be understood that the disclosure is not limited to the particular embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the embodiments described herein. These variations and adaptations are intended to be included within the teachings of the present disclosure and are intended to be encompassed by the scope of the claims herein.

[0025] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0026] As will be apparent to those skilled in the art upon reading this disclosure, the individual embodiments described and illustrated herein have separate components and features that may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0027] Any recited method may be carried out in the order of events recited or in any other order that is logically possible. That is, unless expressly stated otherwise, it is in no way intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Accordingly, method claims are not specifically recited in the claims or the specification to be limited to a particular order of steps, and no order is intended to be inferred in any respect. This also applies to any possible implicit basis for interpretation, including logical considerations regarding the arrangement of steps or operational flow, the plain meaning derived from grammatical structure or punctuation, or the number or type of aspects described within the specification.

[0028] All publications and patents cited herein are cited to disclose and describe the methods and / or materials in connection with which the publications are cited. All such publications and patents are incorporated by reference herein as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and / or materials described in the cited publications and patents, and does not extend to any lexical definitions from the cited publications and patents. Any dictionary definitions within the cited publications and patents that are not expressly repeated in this application should not be treated as such and should not be construed as defining any terms appearing in the appended claims. The citation of any publication is for the disclosure of that publication prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by prior disclosure. Further, the dates of publication provided may be different from the actual publication dates, which may require independent confirmation.

[0029] Although aspects of the present disclosure may be described and claimed in particular statutory classifications, such as systems statutory classifications, this is for convenience only, and those skilled in the art will understand that aspects of the present disclosure may be described and claimed in any statutory classification.

[0030] It should also be understood that the terms used herein are merely for describing specific embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the disclosed compositions and methods belong. Furthermore, it should be understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with the meaning in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0031] Aspects of the present disclosure employ, unless otherwise indicated, techniques of molecular biology, microbiology, organic chemistry, biochemistry, cell biology, vascular biology, and the like, which are within the skill of those of ordinary skill in the art, and which are explained fully in the literature.

[0032] Prior to describing the various aspects of this disclosure, the following definitions are provided and shall be used unless otherwise indicated. Additional terms may be defined elsewhere in this disclosure.

[0033] definition As used herein, "comprising" should be interpreted as specifying the presence of the stated feature, integer, step, or component as referenced, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Furthermore, the terms "by," "comprising," "comprises," "composed of," "including," "includes," "included," "involving," "involves," "involved," and "such as" are each used in an open, non-limiting sense and may be used interchangeably. Furthermore, the term "comprising" is intended to include examples and embodiments encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of."

[0034] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "unimolecular nanoparticle," a "nanocluster," or a "biomimetic vesicle" includes, but is not limited to, two or more such unimolecular nanoparticles, nanoclusters, or biomimetic vesicles, including, but not limited to, combinations of unimolecular nanoparticles, nanoclusters, or biomimetic vesicles.

[0035] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It should be further understood that the endpoints of each range are significant both in relation to the other endpoint, and independently of the other endpoint. It should also be understood that there are multiple values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if a value of "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. Similarly, when values ​​are expressed as approximations, by the use of "about," it should be understood that the particular value forms a further aspect. For example, if a value of "about 10" is disclosed, then "10" is also disclosed.

[0036] When a range is expressed, a further embodiment includes one particular value and / or the other particular value. When a range of values ​​is stated, it is understood that each intervening value (to the nearest tenth of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range), and that stated or intervening value, is included in the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limits in the stated range. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, when a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure; for example, the expression "x to y" includes ranges from "x" to "y," as well as ranges from greater than "x" to less than "y." Ranges can also be expressed as upper limits, e.g., "about x, about y, about z, or less," and should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as the ranges "less than x," "less than y," and "less than z." Similarly, the phrase "about x, y, z, or more" should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as the ranges "greater than x," "greater than y," and "greater than z." Additionally, the phrase "about 'x' to 'y'" (where 'x' and 'y' are numbers) includes "about 'x' to about 'y'."

[0037] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It should be further understood that the endpoints of each range are significant both in relation to the other endpoint, and independently of the other endpoint. It should also be understood that there are multiple values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if a value of "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. Similarly, when values ​​are expressed as approximations, by the use of "about," it should be understood that the particular value forms a further aspect. For example, if a value of "about 10" is disclosed, then "10" is also disclosed.

[0038] It should be understood that such range formats are used for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as range limits, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. By way of example, a numerical range of "about 0.1% to 5%" should be interpreted to include not only the explicitly recited values ​​of about 0.1% to about 5%, but also individual values ​​within the stated range (e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, and about 0.5% to about 4.4%, as well as other possible subranges).

[0039] As used herein, "about," "approximately," "substantially," and the like, when used in connection with a numerical variable, may generally refer to the value of the variable and all values ​​of the variable within experimental error (e.g., within a 95% confidence interval of the mean) or within + / - 10% of the indicated value, whichever is greater. As used herein, the terms "about," "approximately," "at or about," and "substantially" may mean that the amount or value in question may be an exact value or a value that will produce an equivalent result or effect to that recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not, and need not be, exact, but may be approximated and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement error, and the like, as well as other factors known to those skilled in the art, so as to produce an equivalent result or effect. In some circumstances, a value that will produce an equivalent result or effect cannot be reasonably determined. In general, an amount, size, formulation, parameter, or other quantity or characteristic is "about," "approximately," or "around," whether or not expressly stated as such. When "about," "approximately," or "around" is used before a quantitative value, it is understood that the parameter also includes the particular quantitative value itself, unless otherwise specified.

[0040] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0041] As used herein, "dihydroorotate dehydrogenase" and "DHODH" can be used interchangeably and refer to an enzyme encoded by a human gene with a cytogenetic location of 16q22.2 and a molecular location of base pairs 72,008,744 to 72,025,417 on chromosome 16 (Homo sapiens Annotation Release 109, GRCh38.p12). The human gene structure contains nine exons. DHODH is classified as EC 1.3.1.1 and is located intracellularly within mitochondria, where it catalyzes the fourth enzymatic step in de novo pyrimidine biosynthesis. DHODH has also been referred to as DHOdehase, mitochondrial dihydroorotate dehydrogenase, mitochondrial precursor dihydroorotate dehydrogenase, dihydroorotate oxidase, human complement of yeast URA1, POADS, PYRD_HUMAN, and URA1.

[0042] As used herein, unless otherwise specified, the terms "inhibit" or "inhibiting" DHODH or "inhibitor" of DHODH refer to the inhibition of the enzyme DHODH.

[0043] As used herein, "synergy," "synergism," or "synergistic" refers to the greater than expected additive effect of a combination.

[0044] As used herein, the term "in combination with" means that two or more therapeutic agents can be administered to a subject together in a mixture, simultaneously as a single agent, or sequentially as a single agent in any order.

[0045] As used herein, "IC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process, an enzymatic reaction, or a component of a biological or enzymatic process. For example, IC 50refers to the half-maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. For example, IC for DHODH activity 50 DHODH activity can be determined in an in vitro enzyme assay using the methods described herein. Alternatively, activity can be determined in a cell-based assay, including measuring activity or function associated with the inhibition of a target process or enzyme. That is, DHODH activity can be indirectly determined in a cell-based assay of cell proliferation. It is believed that DHODH inhibition can result in growth arrest or inhibition in a suitable cell type. DHODH activity can be determined in suitable cells, such as primary AML cells or AML cell lines, using a cell proliferation assay, such as the MTS assay described herein, or the cell colony formation assay described herein. Suitable cell lines are described later in this specification.

[0046] As used herein, the term "immune" includes cells of the immune system and cells that perform a function or activity in an immune response, such as, but not limited to, T cells, B cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, leukocytes, antigen-presenting cells, and natural killer cells.

[0047] As used herein, the term "DHODH inhibitor" refers to a compound that inhibits the normal enzymatic function of DHODH in converting dihydroorotic acid to orotic acid. Alternatively, a DHODH inhibitor inhibits the transcription or translation of the DHODH gene. In certain embodiments, a DHODH inhibitor is an oligonucleotide that suppresses DHODH gene expression or product activity, for example, by binding to and inhibiting a DHODH nucleic acid (i.e., DNA or mRNA). In certain embodiments, a DHODH inhibitor is an oligonucleotide, for example, an antisense oligonucleotide, shRNA, siRNA, microRNA, or aptamer. In some embodiments, a DHODH inhibitor is a small molecule that binds to and modulates DHODH enzyme function. Examples of DHODH inhibitors include brequinar, leflunomide, redoxal, bidofluzimus, S-2678, 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid (also known as ASLAN003), and teriflunomide.

[0048] As used herein, "brequinar" and "BQR" may be used interchangeably and refer to a compound having a structure represented by the following formula: TIFF2025186252000006.tif33170 Brequinar can also be referred to by its IUPAC chemical name, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid. Common salt forms are brequinar potassium and brequinar sodium (also referred to herein as BQR Na), which are alkali metal salts of the conjugate base of the carboxylic acid. Brequinar is sometimes referred to as DuP-785 or NSC-368390.

[0049] As used herein, "administering" can refer to oral, topical, intravenous, subcutaneous, transdermal, transcutaneous, intramuscular, intraarticular, parenteral, intraarterial, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernosal, intrathecal, intravitreal, intracerebral, intraventricular, intratympanic, intracochlear, rectal, intravaginal, by inhalation, by catheter, by stent, or via an implanted reservoir or other device that actively or passively (e.g., by diffusion) administers the composition to the perivascular space and adventitia. For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or otherwise distribute to surrounding tissues and cells. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Administration can be continuous or intermittent. In various embodiments, the preparations can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparations can be administered prophylactically, i.e., administered for the prevention of a disease or condition.

[0050] As used herein, "therapeutic agent" refers to any substance, compound, molecule, and the like that may be biologically active or otherwise capable of inducing a pharmacological, immunogenic, biological, and / or physiological effect in a subject to which it is administered by local and / or systemic action. A "therapeutic agent" may be a primary active agent, or in other words, a component of a composition that contributes all or part of the composition's effect. A "therapeutic agent" may be a secondary active agent, or in other words, a component of a composition that contributes an additional portion of the composition and / or other effect. As such, the term encompasses compounds or chemicals traditionally considered to be drugs, vaccines, and biopharmaceuticals (including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, and the like). Examples of therapeutic agents are described in well-known references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and include, but are not limited to, pharmaceuticals, vitamins, mineral supplements, substances used in the treatment, prevention, diagnosis, cure, or mitigation of disease or illness, substances that affect the structure or function of the body, or prodrugs, which become biologically active or more active after being placed in a physiological environment.For example, the term "therapeutic agent" includes, but is not limited to, adjuvants, anti-infectives such as antibiotics and antivirals, analgesics and analgesic combinations, appetite suppressants, anti-inflammatory agents, antiepileptics, local and general anesthetics, hypnotics, sedatives, antipsychotics, neuroleptics, antidepressants, anxiolytics, antagonists, neuroleptics, anticholinergics and cholinomimetics, antimuscarinics and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensives, hormones, and nutrients, antiarthritics, antiasthmatics, anticonvulsants, antihistamines, antiemetics, antineoplastics, antipruritics, antipyretics, antispasmodics, cardiovascular preparations (including calcium channel blockers, beta blockers, beta agonists, and antiarrhythmics), antihypertensives, diuretics, vasodilators, Included are compounds or compositions for use in all major therapeutic areas, including central nervous system stimulants, cough and cold preparations, decongestants, diagnostic agents, hormones, bone growth stimulants and bone resorption inhibitors, immunosuppressants, muscle relaxants, psychostimulants, sedatives, tranquilizers, proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized, or recombinantly produced), as well as nucleic acid molecules (either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including polymeric forms of two or more nucleotides, both double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, and the like), small molecules (e.g., doxorubicin), and other biologically active macromolecules such as proteins and enzymes. The drugs may be biologically active agents used in medical applications, including veterinary medicine, and in agriculture, such as with plants, as well as in other fields. The term therapeutic agent also includes, but is not limited to, pharmaceuticals, vitamins, mineral supplements, substances used to treat, prevent, diagnose, cure, or mitigate a disease or illness, or substances that affect the structure or function of the body, or prodrugs that become biologically active or more active after being placed in a defined physiological environment.

[0051] As used herein, a "kit" refers to a collection of at least two components that make up the kit. These components together constitute a functional unit for a given purpose. The individual components may be physically packaged together or separately. For example, a kit that includes instructions for using the kit may or may not physically include the instructions with the other individual components. Alternatively, the instructions may be provided as separate components, either in paper form or in electronic form, which may be provided on a computer-readable memory device, downloaded from an internet website, or provided as a recorded presentation.

[0052] As used herein, "instructions" means documents describing the relevant materials or methodologies associated with the kit. These materials may include any combination of the following: background information, a list of components and their availability (such as purchasing information), brief or detailed protocols for using the kit, troubleshooting, reference materials, technical support, and other related documentation. The instructions can be supplied with the kit or as a separate component, either in paper form or in electronic form, which may be provided on a computer-readable memory device, downloaded from an internet website, or provided as a recorded presentation. The instructions may include one or more documents and are intended to include future revisions.

[0053] As used herein, "bonded" can refer to a covalent bond or a non-covalent interaction between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Waals forces, dipole-dipole interactions, dipole-induced dipole interactions, London dispersion forces, hydrogen bonds, halogen bonds, electromagnetic interactions, π-π interactions, cation-π interactions, anion-π interactions, polar π interactions, and hydrophobic effects.

[0054] As used interchangeably herein, the terms "subject," "individual," or "patient" can refer to a vertebrate organism, such as a mammal (e.g., a human). A "subject" can also refer to a cell, a cell population, a tissue, an organ, or an organism, preferably a human, and components thereof. It is understood that a vertebrate can be a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the methods disclosed herein can be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The terms do not denote a particular age or sex. Furthermore, adult and newborn subjects and fetuses, regardless of male or female, are intended to be encompassed. A patient refers to a subject suffering from a clinical condition, disease, or disorder. The term "patient" includes human and veterinary subjects.

[0055] As used herein, the terms "treating" and "treatment" may generally refer to obtaining a desired pharmacological and / or physiological effect. The effect may be, but is not necessarily, prophylactic in terms of preventing or partially preventing a disease, such as cancer, a T-cell proliferation-related disorder or disease, or graft-versus-host disease, or a symptom or condition thereof. The effect may be therapeutic in terms of partially or completely curing a disease, condition, symptom, or adverse effects resulting from the disease, disorder, or condition. As used herein, the term "treatment" may include any treatment of cancer, a T-cell proliferation-related disorder or disease, or graft-versus-host disease in a subject, particularly a human, and may include any one or more of the following: (a) preventing the occurrence of the disease in a subject predisposed to the disease but not yet diagnosed as having it, (b) inhibiting the disease, i.e., arresting its development, and (c) palliating the disease, i.e., reducing or ameliorating the disease and / or its symptoms or condition. As used herein, the term "treatment" may refer to therapeutic treatment only, prophylactic treatment only, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those who already have a disorder and / or those in whom a disorder is to be prevented. As used herein, the term "treating" can include inhibiting a disease, disorder, or condition, e.g., preventing its progression, and alleviating a disease, disorder, or condition, e.g., resulting in the alleviation of a disease, disorder, and / or condition. Treating a disease, disorder, or condition can include improving at least one symptom of a particular disease, disorder, or condition even if the underlying pathophysiology is unaffected, such as, for example, treating a subject's pain by administering an analgesic, even though the analgesic does not treat the cause of the pain.

[0056] As used herein, "dose," "unit dose," or "dosage" may refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or pharmaceutical composition thereof calculated to produce one or more desired responses in association with its administration.

[0057] As used herein, "therapeutic" may mean treating, curing, and / or ameliorating a disease, disorder, condition, or side effect, or slowing the rate of progression of a disease, disorder, condition, or side effect.

[0058] As used herein, "effective amount" can refer to an amount of a compound or pharmaceutical composition disclosed herein that is sufficient to produce a beneficial or desired biological, emotional, medical, or clinical response in a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope an amount effective to enhance or restore substantially normal physiological function.

[0059] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to have an effect on undesired symptoms, but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder, the specific composition used, the patient's age, weight, overall health, sex, and diet, the time of administration, the route of administration, the excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or simultaneously with the specific compound used, and similar factors within the knowledge and skill of health professionals and well known in the medical field. When treating a particular disease or condition, in some cases, the desired response may be to inhibit the progression of the disease or condition. This may simply involve temporarily slowing the progression of the disease. However, in other cases, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to those skilled in the art for any particular disease. The desired response to the treatment of a disease or condition may be to delay or even prevent the onset of the disease or condition.

[0060] For example, it is well within the skill of those skilled in the art to start with a dose of the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Consequently, a single dose of the composition can contain such an amount or a sub-amount to constitute a daily dose. The dosage can be adjusted by an individual physician if any contraindications arise. Generally, it is preferred to use the maximum dose of the pharmacological agent of the present disclosure (alone or in combination with other therapeutic agents), i.e., the maximum safe dose according to sound medical judgment. However, it will be understood by those skilled in the art that a patient may require a lower or tolerable dose for medical reasons, psychological reasons, or almost any other reason.

[0061] Response to a therapeutically effective dose of the disclosed compounds and / or pharmaceutical compositions can be measured, for example, by determining the physiological effect of the treatment or administration, such as a reduction or absence of disease symptoms after administration of the treatment or pharmacological agent. Other assays are known to those skilled in the art and can be used to measure the level of response. The amount of treatment can be varied, for example, by increasing or decreasing the amount of the disclosed compounds and / or pharmaceutical compositions, by changing the disclosed compounds and / or pharmaceutical compositions administered, by changing the route of administration, by changing the timing of administration, etc. Dosages can vary and can be administered in one or more doses per day for one or several days. Guidance on appropriate dosages for a given class of pharmaceutical products can be found in the literature.

[0062] In this disclosure, it should be understood that in some cases, an effective amount or dose of the disclosed compound is the amount of the composition capable of inhibiting DHODH and providing a clinically meaningful reduction in the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system, as a result of DHODH inhibition. For example, an "effective amount" for therapeutic use. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study.

[0063] As used herein, the term "prophylactically effective amount" refers to an amount effective to prevent the development or onset of a disease or condition.

[0064] As used herein, the term "prevent" or "preventing" refers to preventing, avoiding, avoiding, forestalling, deterring, or impeding something from occurring, especially by prior action. Where reduce, inhibit, or hinder is used herein, it should be understood that the use of the other two words is also expressly disclosed unless specifically indicated otherwise.

[0065] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, i.e., does not cause unacceptable levels of undesirable biological effects or interact in a deleterious manner.

[0066] As used herein, the term " pharmaceutically acceptable salt " refers to the salt of an active main drug prepared with an acid or base that is tolerated by biological systems or tolerated by subjects when administered in a therapeutically effective amount, or that is tolerated by biological systems and tolerated by subjects.When a compound of the present disclosure contains a relatively acidic functional group, the neutral form of such a compound can be contacted with a sufficient amount of a desired base, either directly or in a suitable inert solvent, to obtain a base addition salt.Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium salt, potassium salt, calcium salt, ammonium salt, organic amino salt, magnesium salt, lithium salt, strontium salt, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, the neutral form of such a compound can be contacted with a sufficient amount of a desired acid, either directly or in a suitable inert solvent, to obtain an acid addition salt. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginic acid and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like.

[0067] The term "pharmaceutically acceptable ester" refers to an ester of a compound of the present disclosure that hydrolyzes in vivo, including those that readily decompose in the human body to leave the parent compound or its salt. Examples of pharmaceutically acceptable, non-toxic esters of the present disclosure include C1-C6 alkyl esters and C5-C7 cycloalkyl esters, with C1-C4 alkyl esters being preferred. Esters of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be added to a hydroxy group by reacting the compound with acid and an alkyl carboxylic acid, such as acetic acid, or acid and an aryl carboxylic acid, such as benzoic acid. For compounds containing a carboxylic acid group, pharmaceutically acceptable esters can be prepared from the compound by reacting the compound with triethylamine and a base such as an alkyl halide, e.g., methyl iodide, benzyl iodide, cyclopentyl iodide, or an alkyl triflate. They can also be prepared by reacting the compound with an acid, such as hydrochloric acid, and an alcohol, such as ethanol or methanol.

[0068] The term "pharmaceutically acceptable amide" refers to the non-toxic amides of the present disclosure derived from ammonia, primary C1-C6 alkylamines, and secondary C1-C6 dialkylamines. In the case of secondary amines, the amine can also take the form of a 5- or 6-membered heterocyclic ring containing one nitrogen atom. In the case of secondary amines, the amine can also take the form of a 5- or 6-membered heterocyclic ring containing one nitrogen atom. Amides of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reacting the amino group-containing compound with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable amides can be prepared from compounds containing carboxylic acid groups by reacting the compound with a base such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole, and an alkylamine, dialkylamine, e.g., methylamine, diethylamine, and piperidine. They can also be prepared by reacting the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or an arylcarboxylic acid such as benzoic acid, under dehydrating conditions, such as with the addition of molecular sieves. The compositions can contain the compounds of the present disclosure in the form of pharmaceutically acceptable prodrugs.

[0069] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to a prodrug of a compound of the present disclosure that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and is effective for its intended use. The prodrugs of the present disclosure can be rapidly converted in vivo, for example, by hydrolysis in blood, to the parent compound having the structure of the disclosed compound. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0070] As used herein, the term "contacting" refers to bringing the disclosed compounds or pharmaceutical compositions into proximity with a cell, target protein, or other biological entity in such a way that the disclosed compounds or pharmaceutical compositions can affect the activity of the cell, target protein, or other biological entity, either directly, i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly, i.e., by interacting with another molecule, cofactor, or protein on which the activity of the cell, target protein, or other biological entity itself depends.

[0071] Unless otherwise specified, temperatures referred to herein should be understood to be based on atmospheric pressure (ie, 1 atmosphere).

[0072] As used herein, the names of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be used to designate stereochemical priority, E / Z designation, and equivalents. Those skilled in the art can easily verify the structure of a compound when a name is given by either using the naming rules to systematically reduce the compound structure or by using commercially available software such as CHEMDRAW™ (Cambridgesoft Corporation, USA).

[0073] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent and results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, it is also contemplated that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted), unless expressly indicated to the contrary.

[0074] In defining various terms, 1 ","A 2 ","A 3 ", and "A4 " is used herein as a generic symbol to represent various specific substituents. Similarly, "Ar 1 ", "Ar 2 ", "Ar 3 " and "Ar 4 " is used herein as a generic symbol to represent various specific aryl substituents. These symbols can be any substituent, not limited to those disclosed herein, and when in some cases they are defined to be a specific substituent, in other cases they can be defined as some other substituent.

[0075] As used herein, the terms "aliphatic" or "aliphatic group" refer to a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclics) and may be fully saturated or contain one or more unsaturated (but not aromatic) units. Unless otherwise specified, aliphatic groups contain 1 to 20 carbon atoms. Aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, as well as hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0076] As used herein, the term "alkyl" refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. An alkyl group can be cyclic or acyclic. An alkyl group can be branched or unbranched. An alkyl group can also be substituted or unsubstituted. For example, an alkyl group can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A "lower alkyl" group is an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms. Also, the term alkyl group can be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like, up to and including C1-C24 alkyl.

[0077] Throughout this specification, the term "alkyl" is used generally to refer to both unsubstituted and substituted alkyl groups, although substituted alkyl groups are also specifically referred to herein by identifying the particular substituents on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halide, such as fluorine, chlorine, bromine, or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group independently substituted with two or more halides; i.e., each halide substituent need not be the same halide as another halide substituent, nor do multiple instances of halide substituents need not be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxy groups. When "alkyl" is used in one instance and a specific term such as "hydroxyalkyl" is used in another, it is not intended to imply that the term "alkyl" does not also refer to specific terms such as "hydroxyalkyl" and the like.

[0078] As used herein, "aminoalkyl" refers to a straight or branched chain alkyl group in which at least one hydrogen is replaced with an amino group, typically one to three amino groups. Non-limiting examples of aminoalkyl groups include -CH2NH2, -(CH2)2NH2, -CHCH3NH2, -(CH2)2CHCH3NH2, -(CH2)2CHNH2CH2CH3, -CHCH3(CH2)2NH2, and the like.

[0079] As used herein, "alkylamino" refers to an amino group having at least one hydrogen replaced with an alkyl group. Thus, alkylamino refers to the group -NR a R a refers to R a or R b is alkyl; a and R b is independently selected from H and alkyl. Non-limiting examples of alkylamino groups include -NHCH, -NHCHCH, -NH(CH), -N(CH), -N(CH)CHCH, -N(CH)CH, and the like.

[0080] As used herein, "hydroxyalkyl" refers to a straight or branched chain alkyl group in which at least one hydrogen has been replaced with a hydroxy group, typically one to three hydroxy groups. Non-limiting examples of hydroxyalkyl groups include -CHOH, -(CH)OH, -CHCHOH, -(CH)CHCHOH, -(CH)CHOHCHCH, -CHCH(CH)OH, and the like.

[0081] As used herein, the term "alkanediyl" refers to a divalent, straight- and branched-chain saturated hydrocarbon radical having 1 to 6 carbon atoms, unless otherwise specified. For example, "C1-C6 alkanediyl" refers to a divalent, straight- and branched-chain saturated hydrocarbon radical having 1 to 6 carbon atoms, such as methylene, 1,2-ethanediyl (-CH2CH2-), propanediyl or 1,3-propanediyl (-(CH2)3-), butanediyl or 1,4-butanediyl (-(CH2)4-), pentanediyl or 1,5-pentanediyl (-(CH2)5-), hexanediyl or 1,6-hexanediyl (-(CH2)6-), and their branched isomers (e.g., isopropanediyl (-CHCH3CH2-)). Alkanediyl groups can be further substituted, for example, aminoalkanediyl or hydroxyalkanediyl.

[0082] As used herein, "aminoalkanediyl" refers to a straight or branched chain alkanediyl group in which at least one hydrogen is replaced with an amino group, typically one to three amino groups. Non-limiting examples of aminoalkanediyl groups include -CHNH-, -(CH)NH-, -CHCHNH-, -(CH)CHCHNH-, -(CH)CHNH(CH)-, -CHCHNH(CH)-, -CHNH(CH)-, -(CH)NH(CH)-, -CHCH(CH)NH-, and the like.

[0083] As used herein, "hydroxyalkanediyl" refers to a straight or branched chain alkanediyl group in which at least one hydrogen has been replaced with a hydroxy group, typically one to three hydroxy groups. Non-limiting examples of hydroxyalkanediyl groups include -CHOH-, -CHCHOH-, -CCHOH-, -(CH)CCHOH-, -(CH)CHOH(CH)-, -CHCHOH(CH)-, -CHOH(CH)-, -CHCHOH(CH)-, -CHCHCHCHOH-, and the like.

[0084] As used herein, the terms "alkoxy" and "alkoxyl" refer to an alkyl or cycloalkyl group bonded through an ether linkage; i.e., an "alkoxy" group is an A 1 is alkyl or cycloalkyl as defined above; 1 "Alkoxy" also includes polymers of the alkoxy groups described above, i.e., alkoxy is defined as "a" is an integer from 1 to 200, and A 1 , A 2 , and A 3 is an alkyl and / or cycloalkyl group; 1 -OA 2 or -OA 1 -(OA 2 ) a -OA 3The polyether may be a polyether such as

[0085] As used herein, the term "aromatic group" refers to a ring structure having a cyclic cloud of delocalized π electrons above and below the plane of the molecule, the π cloud containing (4n+2) π electrons. Further discussion of aromaticity is found in Chapter 13 (entitled "Aromaticity"), pages 477-497 of Morrison and Boyd, Organic Chemistry (5th Ed., 1987), which is incorporated herein by reference. The term "aromatic group" includes both aryl and heteroaryl groups.

[0086] As used herein, the term "aryl" refers to a group containing any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. Aryl groups can also be substituted or unsubstituted. Aryl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl." Additionally, aryl groups can include multiple ring structures, which can be single ring structures, fused ring structures, or linked via one or more bridging groups, such as carbon-carbon bonds. For example, a biaryl refers to two aryl groups that are linked together through a fused ring structure, as in naphthalene, or through one or more carbon-carbon bonds, as in biphenyl.

[0087] As used herein, the term "cycloalkyl" refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term "heterocycloalkyl" refers to a type of cycloalkyl group defined above, but is included in the meaning of the term "cycloalkyl" in which at least one of the ring carbon atoms is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0088] As used herein, the term "heteroalkyl" refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, where nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroalkyl can be substituted as defined above for alkyl groups.

[0089] As used herein, the term "heteroaryl" refers to an aromatic group having at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, with N-oxides, sulfur oxides, and dioxides being acceptable heteroatom substitutions. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. Heteroaryl groups can be monocyclic or, alternatively, fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0090] As used herein, the term "heterocycle" can be used interchangeably and refers to mono- and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term includes, but is not limited to, "heterocycloalkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle." Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole including 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, thiadiazole including 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole including 1,2,3-triazole, 1,3,4-triazole, tetrazole including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine including 1,2,4-triazine and 1,3,5-triazine, tetrazine including 1,2,4-tetrazine, pyrrolidine, piperidine, piperazine, morpholidine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be C2-heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like, up to and including C2-C18 heterocyclyl. For example, C2 heterocyclyl includes groups having two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, C5 heterocyclyl includes groups having 5 carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.It is understood that a heterocyclyl group may be attached, if chemically possible, through either a heteroatom within the ring or through one of the carbons comprising the heterocyclyl ring.

[0091] As used herein, the term "bicyclic heterocycle" refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl includes ring systems in which an aromatic ring is fused to another aromatic ring, or an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclyl includes ring systems in which a benzene ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, or a pyridine ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0092] As used herein, the term "heterocycloalkyl" refers to an aliphatic, partially unsaturated or fully saturated 3- to 14-membered ring system, including monocyclic and bicyclic and tricyclic ring systems of 3 to 8 atoms. Heterocycloalkyl ring systems contain 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0093] As used herein, the term "amine" or "amino" refers to a group of the formula -NA 1 A 2 and A 1 and A 2 can independently be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A particular example of amino is -NH2.

[0094] The term "carboxylic acid" as used herein is represented by the formula --C(O)OH.

[0095] As used herein, the terms "halo," "halogen," or "halide" can be used interchangeably and refer to F, Cl, Br, or I.

[0096] The terms "hydroxyl" or "hydroxy" as used herein are represented by the formula --OH.

[0097] The term "nitro" as used herein is represented by the formula --NO.sub.2.

[0098] The term "nitrile" or "cyano" as used herein is represented by the formula --CN.

[0099] As used herein, "R" refers to a group of compounds where n is an integer. 1 "," "R 2 "," "R 3 ",..."R n " can independently possess one or more of the groups listed above. For example, R 1When is a straight-chain alkyl group, one of the hydrogen atoms of the alkyl group can be optionally substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending on the group selected, the first group can be incorporated into the second group, or alternatively, the first group can be a pendant group (i.e., attached) to the second group. For example, when using the phrase "an alkyl group comprising an amino group," the amino group can be incorporated into the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is embedded in or attached to the second group.

[0100] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at every position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. It is also contemplated that, in certain embodiments, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted), unless explicitly stated to the contrary.

[0101] As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0102] The term "organic residue" defines a carbon-containing residue, i.e., a residue containing at least one carbon atom, and includes, but is not limited to, the carbon-containing groups, residues, or radicals defined above. Organic residues may contain various heteroatoms or be bonded to another molecule through heteroatoms, including oxygen, nitrogen, sulfur, phosphorus, and the like. Examples of organic residues include, but are not limited to, alkyl or substituted alkyl, alkoxy-substituted alkoxy, mono- or di-substituted amino, amido groups, and the like. Organic residues may preferably contain 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In further embodiments, organic residues may contain 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0103] A close synonym for the term "residue" is the term "radical," which, as used in the specification and final claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure: TIFF2025186252000007.tif18170. In some embodiments, a radical (e.g., alkyl) can be further modified by having one or more "substituent radicals" attached thereto (i.e., substituted alkyl). The number of atoms in a given radical is not critical to the present disclosure unless indicated to the contrary elsewhere herein.

[0104] As defined and used herein, the term "organic radical" contains one or more carbon atoms. An organic radical can have, for example, 1 to 26 carbon atoms, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In further embodiments, an organic radical can have 2 to 26 carbon atoms, 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Organic radicals often have hydrogen bonded to at least some of the carbon atoms of the organic radical. One example of an organic radical that does not contain inorganic atoms is the 5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1 to 10 inorganic heteroatoms bonded to or within it, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, disubstituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfonyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, as these terms are defined elsewhere herein. Some non-limiting examples of organic radicals containing heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals, and the like.

[0105] As defined and used herein, an "inorganic radical" does not contain carbon atoms and therefore includes only atoms other than carbon. Inorganic radicals include bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which may exist individually or be bonded together in chemically stable combinations. Inorganic radicals have up to 10, or preferably 1 to 6 or 1 to 4, inorganic atoms such as those listed above bonded together. Examples of inorganic radicals include, but are not limited to, amino, hydroxy, halogen, nitro, thiol, sulfate, phosphate, and commonly known equivalents. Inorganic radicals do not have metal elements of the periodic table (e.g., alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals) bonded thereto, although such metal ions can sometimes serve as pharmaceutically acceptable cations for anionic inorganic radicals, such as sulfate, phosphate, or similar anionic inorganic radicals. Inorganic radicals do not include metalloid elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or noble gas elements, unless specifically indicated otherwise elsewhere herein.

[0106] As used herein, the term "derivative" means a compound derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to the structures disclosed herein that, based on that similarity, one skilled in the art would expect to exhibit the same or similar activity and utility as the claimed compound, or, as a precursor, to induce the same or similar activity and utility as the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0107] The compounds described herein contain one or more double bonds and can therefore potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the present disclosure includes all such possible isomers, as well as mixtures of such isomers.

[0108] Unless otherwise stated, formulas with chemical bonds shown only with solid lines and not with wedges or dashed lines contemplate each possible isomer, for example, each enantiomer and diastereomer, as well as mixtures of isomers, such as racemic or scalemic mixtures. The compounds described herein contain one or more asymmetric centers and can therefore potentially give rise to diastereomers and optical isomers. Unless otherwise stated, the present disclosure includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0109] Many organic compounds exist in optically active forms, which have the ability to rotate the plane of plane-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 about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. When desired, chiral carbons can be represented by an asterisk ( * ) When a bond to a chiral carbon is shown as a straight line in a disclosed formula, both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are encompassed by the formula. As used in the art, when it is desired to specify the absolute configuration around a chiral carbon, one of the bonds to the chiral carbon can be shown as a wedge (a bond to an atom above the plane) and the other can be shown as a series of short parallel lines or wedges (a bond to an atom below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0110] The compounds described herein comprise atoms of both their natural isotopic abundance and non-natural abundance.The disclosed compounds may be identical to their isotopically labeled or isotopically substituted compounds, but one or more atoms may be replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is typically found in nature.The examples of isotopes that can be incorporated into the compounds of the present disclosure include: 2 H, 3H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 Included within the scope of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as Cl. Compounds further include prodrugs thereof, and pharmaceutically acceptable salts of such compounds or such prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled compounds of the present disclosure, such as 3 H and 14 Those in which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavier isotopes such as H can offer certain therapeutic advantages due to added metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the following procedures by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0111] The compounds described in the present disclosure can exist as solvates.In some cases, the solvent used to prepare solvates is an aqueous solution, and then the solvates are often referred to as hydrates.The compounds can exist as hydrates, which can be obtained, for example, by crystallization from a solvent or aqueous solution.In this regard, one, two, three, or any number of solvents or water molecules can be combined with the compounds according to the present disclosure to form solvates and hydrates.Unless stated to the contrary, the present disclosure includes all such possible solvates.

[0112] The term "cocrystal" refers to a physical association of two or more molecules that achieves stability through non-covalent interactions. One or more components of this molecular complex provide a stable framework within the crystal lattice. In certain cases, the guest molecule is incorporated into the crystal lattice as an anhydrate or solvate. See, for example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. An example of a cocrystal is p-toluenesulfonic acid and benzenesulfonic acid.

[0113] Chemical substances are known to form solids that exist in different ordered states, called polymorphic forms or modifications. Different modifications of polymorphic substances can have significantly different physical properties. Compounds according to the present disclosure can exist in different polymorphic forms, and certain modifications may be metastable. Unless otherwise stated, the present disclosure includes all such possible polymorphic forms.

[0114] Certain materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques well known to those skilled in the art. For example, starting materials and reagents used in preparing the disclosed compounds and compositions are available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or can be synthesized by methods known to those skilled in the art, as described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers, These compounds are either prepared according to procedures described in references such as (Inc., 1989).

[0115] Unless otherwise expressly stated, no method described herein is intended to be construed in any way as requiring its steps to be performed in a particular order. Thus, a method claim does not actually recite an order to be followed by its steps, nor does the claim or description otherwise specifically state that the steps are limited to a particular order, and no order is intended to be inferred in any way. This also applies to any possible implicit basis for interpretation, including logical considerations regarding the arrangement of steps or operational flow, the plain meaning derived from grammatical construction or punctuation, and the number or type of aspects described within the specification.

[0116] Disclosed are components used to prepare the disclosed compositions, as well as the compositions themselves used within the methods disclosed herein. These and other materials are disclosed herein, and when combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that specific reference to each of the various individual and collective combinations and permutations of these compounds cannot be explicitly disclosed, but each is specifically contemplated and described herein. For example, when a particular compound is disclosed and discussed, and multiple modifications that can be made to multiple molecules comprising the compound are discussed, what is specifically contemplated is any and all combinations and permutations of the compounds and modifications that are possible, unless stated to the contrary. Thus, when classes of molecules A, B, and C, and classes of molecules D, E, and F are disclosed, and example combined molecules A-D are disclosed, each is individually and collectively contemplated, even if not individually listed, meaning that combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the subgroups A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application, including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, where there are various additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific aspect or combination of aspects of the disclosed methods.

[0117] It is understood that the compositions disclosed herein have certain functions, and that certain structural requirements for performing the disclosed functions are disclosed herein, and that there are a variety of structures that can perform the same function associated with the disclosed structures, and that these structures will typically achieve the same result.

[0118] Combination therapy - treatment with a DHODH inhibitor and an anti-CD38 antibody. The present disclosure relates to a pharmaceutical combination comprising at least one compound capable of inhibiting dihydroorotate dehydrogenase (DHODH), i.e., a DHODH inhibitor, and an anti-CD38 antibody. Also described herein are methods for administering the disclosed pharmaceutical combination to a subject in need thereof. In some embodiments, the subject may have a disease or disorder associated with DHODH activity such as cancer (blood or solid), an autoimmune disease, cancer-associated MDSC depletion, a disease or disorder associated with T-cell proliferation, or graft-versus-host disease, including but not limited to chronic lymphocytic leukemia, MGUS / multiple myeloma, extranodal natural killer (NK) / T-cell lymphoma, large cell lymphoma, nasal type (ENKTL-N), myelodysplasia, therapy-related myeloid malignancies, acute myeloid leukemia, chronic myelocytic leukemia, T-lymphoblastic leukemia / leukemia, B-lymphoblastic lymphoma / leukemia, Burkitt's leukemia / lymphoma, primary infiltrating lymphoma, Philadelphia-positive acute lymphoblastic leukemia, and solid tumor immunization. Certain non-malignant clinical conditions can also be treated by the disclosed pharmaceutical compositions and methods of treatment, including, but not limited to, aplastic anemia, malignant myeloid-derived suppressor cell depletion, and immunoglobulin light chain amyloidosis (AL).

[0119] In particular, as disclosed herein in the Examples below, treatment of AML cells with representative DHODH inhibitors can be associated with upregulation of CD38 expression in these same cells. CD38 has been associated with differentiation in AML and response to differentiation therapy (see Prus et al., Leukemia and Lymphoma 2003, vol. 44: issue 4). It has also been previously observed that targeting CD38 with therapeutic antibodies such as daratumumab can be effective when combined with the differentiation agent all-trans retinoic acid ("ATRA"; Buteyn et al., International Immunology 2018, vol. 30 no. 8). Specifically, these studies demonstrated that ATRA was able to induce CD38 expression in the MV4-11 cell line and induce AML cell fratricide with daratumumab.

[0120] This paper discloses that the combination of DHODH inhibitor and therapeutic antibody that binds to CD38 has a significant effect on the median survival time determined in mouse xenograft model.Without wishing to be bound by a specific theory, the combination of DHODH inhibitor and anti-CD38 antibody can partially induce AML cell fratricide, leading to improved survival rate and reduced tumor burden.

[0121] The present disclosure relates to a pharmaceutical composition comprising a combination of a DHODH inhibitor and an anti-CD38 antibody. It is understood that the "combination" may be a combination such as a co-formulated pharmaceutical composition. Alternatively, the "combination" may be in the form of a co-package, so that both therapeutic agents, i.e., the DHODH inhibitor and the anti-CD38 antibody, are packaged in such a manner that they are dispensed simultaneously, sequentially, or on a fixed schedule relative to each other, or a combination thereof. In some embodiments, the dose can also be sequenced to enhance the expression of CD38 on tumor cells before administering the CD38 antibody.

[0122] As used herein with respect to a "synergistic effect," or clinical condition, the therapeutic effect, e.g., tumor therapeutic effect, of the combination of a DHODH inhibitor and an anti-CD38 antibody includes tumor growth inhibition, including tumor suppression, tumor growth or regrowth delay, and / or substantial elimination of established tumors, and including inhibition of tumor re-establishment after cessation of treatment, which is significantly superior to the tumor therapeutic effect of the DHODH inhibitor or anti-CD38 antibody alone, or to the additive tumor therapeutic effects of the isolated agents, in terms of the amount, degree, extent, and / or rate of inhibition, and / or time to inhibited re-establishment. Thus, a "synergistically effective amount" of a DHODH inhibitor or a "synergistically effective amount" of an anti-CD38 antibody is an amount that results in a "synergistic effect" of the DHODH inhibitor and anti-CD38 antibody, including an amount where both agents act synergistically to substantially inhibit, delay, or suppress tumor growth, substantially eliminate established tumors, and / or substantially inhibit, delay, or suppress tumor re-establishment.

[0123] A pharmaceutical combination comprising an anti-CD38 antibody and a DHODH inhibitor can be used, for example, to inhibit, reduce, decrease, block, or prevent the proliferation of cells expressing CD38 on their surface. A combination therapy comprising an anti-CD38 antibody and a DHODH inhibitor can be used, for example, to induce, promote, or enhance apoptosis of cells expressing CD38 on their surface. The cells expressing CD38 can be lymphocytes, autoimmune lymphocytes, or tumor cells such as leukemia cells, multiple myeloma cells, or lymphoma cells.

[0124] The present disclosure further relates to a method for treating a clinical condition, such as AML, by administering a combination therapy comprising a DHODH inhibitor and an anti-CD38 antibody to a subject. The combination therapy can further comprise one or more additional therapeutic agents. Other clinical conditions that can be treated by the disclosed pharmaceutical compositions, i.e., combination therapy comprising a DHODH inhibitor and an anti-CD38 antibody, and the disclosed method of combination therapy include, but are not limited to, chronic lymphocytic leukemia, MGUS / multiple myeloma, extranodal natural killer (NK) / T-cell lymphoma, large cell lymphoma, nasal type (ENKTL-N), myelodysplasia, therapy-related myeloid malignancies, acute myeloid leukemia, chronic myelomonocytic leukemia, T-lymphoblastic lymphoma / leukemia, B-lymphoblastic lymphoma / leukemia, Burkitt's leukemia / lymphoma, primary infiltrative lymphoma, Philadelphia-positive acute lymphoblastic leukemia, and immune modulation of solid tumors. Certain non-malignant clinical conditions can also be treated by the disclosed pharmaceutical compositions and methods of treatment, including, but not limited to, aplastic anemia, malignant myeloid-derived suppressor cell depletion, and immunoglobulin light chain amyloidosis (AL).

[0125] Since the activity of pharmaceutical combinations depends on the dose used, it is therefore possible to use lower doses and increase activity while reducing toxicity, taking into account the synergistic aspects of the combinations disclosed herein.The improved efficacy of the combinations disclosed herein can be demonstrated by determining therapeutic synergy.A combination exhibits therapeutic synergy if it is therapeutically superior to the best tested drug used alone at the maximum tolerated dose, or at the maximum dose tested if toxicity cannot be reached in the animal species.

[0126] The components of the disclosed pharmaceutical combinations may be administered simultaneously, semi-simultaneously, separately, or spaced over a period of time to obtain maximum effectiveness of the combination, and each administration can vary in duration from bolus administration to continuous infusion.

[0127] Consequently, for purposes of this disclosure, combinations are not limited exclusively to those achieved by physical association of the components, nor are they limited to those permitting separate administration, which may be simultaneous or spaced apart over a period of time.

[0128] The pharmaceutical combinations according to the present disclosure are preferably compositions that can be administered parenterally, however, for localized topical therapy, these compositions can be administered orally, subcutaneously, or intraperitoneally.

[0129] The composition for parenteral administration is generally a pharmaceutically acceptable sterile solution or suspension, which can be optionally prepared when needed.Non-aqueous solutions or suspensions can be prepared using natural vegetable oils such as olive oil, sesame oil, or liquid petroleum, or injectable organic esters such as ethyl oleate.Sterile aqueous solutions can consist of a solution of the product in water.Aqueous solutions are suitable for intravenous administration, provided that the pH is appropriately adjusted and the solution is made isotonic, for example, with a sufficient amount of sodium chloride or glucose.Sterilization can be carried out by heating or any other means that do not adversely affect the composition.The combination can also be in the form of liposomes or in the form of association with a carrier such as cyclodextrin or polyethylene glycol.

[0130] Accordingly, the present disclosure also encompasses the use of the above pharmaceutical combinations for the manufacture of a medicament for the treatment of the disclosed clinical conditions or diseases, including, but not limited to, chronic lymphocytic leukemia, MGUS / multiple myeloma, extranodal natural killer (NK) / T-cell lymphoma, large cell lymphoma, nasal type (ENKTL-N), myelodysplasia, therapy-related myeloid malignancies, acute myeloid leukemia, chronic myelomonocytic leukemia, T-lymphoblastic lymphoma / leukemia, B-lymphoblastic lymphoma / leukemia, Burkitt's leukemia / lymphoma, primary infiltrating lymphoma, Philadelphia-positive acute lymphoblastic leukemia, and immunomodulation of solid tumors.

[0131] Another aspect of the present disclosure is a packaging material comprising: (a) packaging material; (b) a combination of an antibody that specifically recognizes CD38 and at least one DHODH inhibitor, wherein the antibody is capable of killing CD38+ cells by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC); and (c) a combination of the combination that is capable of treating chronic lymphocytic leukemia, MGUS / multiple myeloma, extranodal natural killer (NK) / T-cell lymphoma, large cell lymphoma, and a label or package insert contained within the packaging material indicating that the composition is effective for treating the disclosed clinical conditions or disorders, including, but not limited to, acute myeloid leukemia, chronic myelomonocytic leukemia, T lymphoblastic lymphoma / leukemia, B lymphoblastic lymphoma / leukemia, Burkitt's leukemia / lymphoma, primary infiltrating lymphoma, Philadelphia-positive acute lymphoblastic leukemia, and immunomodulation of solid tumors.

[0132] Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one of ordinary skill in the art upon examination of the following figures, detailed description, and examples, and all such additional compositions, compounds, features, and advantages are intended to be included within this description and be within the scope of the present disclosure.

[0133] Anti-CD38 therapeutic agents. In the disclosed pharmaceutical compositions and methods of treating clinical conditions, DHODH inhibitors are used in conjunction with anti-CD38 therapeutic agents. In various embodiments, the anti-CD38 therapeutic agent includes a therapeutic agent that reduces the number of CD38-expressing cells and / or the level of cell membrane concentration of CD38 protein.

[0134] In various embodiments, a suitable anti-CD38 therapeutic agent can be one of the anti-CD38 antibodies disclosed herein or any other suitable anti-CD38 antibody known to one of skill in the art. As used herein, "anti-CD38 antibody" refers to any antibody that recognizes a CD38 epitope, including, but not limited to, chimeric or humanized antibodies, antibody fragments, antibody-drug conjugates, radioimmunotherapy antibody conjugates (e.g., radionuclides labeled with anti-CD38 antibodies), nanobodies, bispecific antibodies, trispecific antibodies, single variable domain antibodies, or combinations thereof.

[0135] In various embodiments, the anti-CD38 therapeutic agent can comprise a cell therapy, e.g., an antigen-specific adoptive cell therapy, including, but not limited to, a CAR-expressing T cell (i.e., a CAR T-based cell therapy comprising a CAR T cell having at least partial specificity for an antigen, such as CD-38). In further embodiments, the anti-CD38 therapeutic agent comprises a CAR-T therapeutic agent targeting CD38-expressing cells. In some cases, the CAR-T therapeutic agent induces apoptosis of CD38-positive cells.

[0136] As used herein, the terms "T lymphocyte" and "T cell" are used interchangeably and refer to a major type of white blood cell that completes maturation in the thymus and has various roles in the immune system, including identifying specific foreign antigens in the body and activating and deactivating other immune cells. T cells can be any T cell, such as cultured T cells, e.g., primary T cells, or T cells from cultured T cell lines, e.g., Jurkat, SupTl, etc., or T cells obtained from a mammal. T cells can be CD3+ cells. T cells can be any type of T cell and can be at any stage of development, including, but not limited to, CD4+ / CD8+ double-positive T cells, CD4+ helper T cells (e.g., Th1 cells and Th2 cells), CD8+ T cells (e.g., cytotoxic T cells), peripheral blood mononuclear cells (PBMCs), peripheral blood leukocytes (PBLs), tumor-infiltrating lymphocytes (TILs), memory T cells, naive T cells, regulator T cells, gamma delta T cells (gd T cells), and the like. Additional types of helper T cells include cells such as Th3 (Treg), Th17, Th9, or Tfh cells. Additional types of memory T cells include cells such as central memory T cells (Tcm cells) and effector memory T cells (Tern cells and TEMRA cells). T cells can also refer to genetically engineered T cells, such as T cells modified to express a T cell receptor (TCR) or chimeric antigen receptor (CAR). T cells can also be differentiated from stem or progenitor cells.

[0137] "CD4+ T cells" refer to a subset of T cells that express CD4 on their surface and are associated with cell-mediated immune responses. They are characterized by their secretory profile after stimulation, which may include the secretion of cytokines such as IFN-γ, TNF-α, IL2, IL4, and IL10. "CD4" is a 55-kD glycoprotein that was first defined as a differentiation antigen on T lymphocytes but is also found on other cells, including monocytes / macrophages. The CD4 antigen is a member of the immunoglobulin supergene family and participates as an associative recognition element in MHC (major histocompatibility complex) class II-restricted immune responses. On T lymphocytes, they define helper / inducer subsets.

[0138] Suitable anti-CD38 CAR T cells for use as anti-CD38 therapeutics can include those engineered through retroviral vector-mediated transduction of the transmembrane domain of CD8α, the intracellular domains of 4-1BB and CD3ζ, and an anti-CD38 single-chain variable domain (scFv), such as those described by Mihara and co-workers (Leukemia. 2012 Feb;26(2):365-7), Drent et al. (Mol Ther. 2017 Aug 2;25(8):1946-1958), and Drent, et al. (Haematologica. 2016 May;101(5):616-25).

[0139] In various embodiments, the anti-CD38 therapeutic agent can be a CD38 CAR-T, a CD38 DAR-T, and / or a CD38 antibody-drug conjugate as previously described by Sorrento Therapeutics.

[0140] As used herein, "CAR T" refers to chimeric antigen receptor T cells for adoptive cellular immunotherapy.

[0141] As used herein, "DAR T" refers to a dimeric antigen receptor T cell, for example, expressing a dimeric antigen receptor in the T cell receptor (TCR) alpha chain constant region (TRAC). In this way, TRAC is knocked out and the antigen is injected into its locus. Dimeric antigen receptors (DAR) can utilize Fab instead of the scFv used by conventional chimeric antigen receptor (CAR) T cells.

[0142] Additional exemplary, but non-limiting, anti-CD38 therapeutic agents useful in the disclosed pharmaceutical compositions and methods include those listed herein in Tables 1-3 below. TIFF2025186252000008.tif104170TIFF2025186252000009.tif192170TIFF2025186252000010.tif183170TIFF2025186252000011.tif33170 TIFF2025186252000012.tif154170TIFF2025186252000013.tif155170TIFF2025186252000014.tif171170TIFF2025186252000015.tif60170

[0143] Anti-CD38 antibody. In the disclosed pharmaceutical compositions and methods for treating clinical conditions, DHODH inhibitors are used together with anti-CD38 antibodies. A suitable anti-CD38 antibody can be one of the anti-CD38 antibodies disclosed herein or any other suitable anti-CD38 antibody known to those skilled in the art. An antibody that recognizes CD38 can kill CD38+ cells by antibody-dependent cell-mediated phagocytosis (ADCP), cell fratricide, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and / or complement-dependent cytotoxicity (CDC).

[0144] As used herein, "ADCC" or "antibody-dependent cell-mediated cytotoxicity" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibody on target cells and subsequently cause lysis of the target cells. ADCC correlates with binding to FcγRIIIa, and increased binding to FcγRIIIa leads to increased ADCC activity.

[0145] "ADCP" or antibody-dependent cell-mediated phagocytosis, as used herein, refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibody on target cells and subsequently cause phagocytosis of the target cells.

[0146] In various embodiments, the antibody that recognizes CD38 is selected from daratumumab, isatuximab (SAR650984), felzalutamab, ISB-1342, Y-150, ISB-1908, KPMW-101, AMG-424, XmAb-13243, XmAb-13551, MOR202 (MorphoSys AG), TAK-079, TAK-169, KP-1196, BM38, TJ202, and combinations thereof. In further embodiments, the antibody that recognizes CD38 is selected from the antibodies set forth in Tables 1 and 2 above, including combinations of such antibodies.

[0147] Exemplary useful antibodies include monoclonal antibodies 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39, which specifically recognize CD38 and are described in PCT application WO2008 / 047242, the entire contents of which are incorporated herein by reference. These anti-CD38 antibodies can kill CD38+ cells by three different cytotoxic mechanisms: induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). In addition, these antibodies can directly induce apoptosis of CD38+ cells, even without the presence of stromal cells or stromal-derived cytokines. Hybridoma cell lines producing the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39 murine anti-CD38 antibodies were deposited on June 21, 2006, under accession numbers PTA-7667, PTA-7669, PTA-7670, PTA-7666, PTA-7668, and PTA-7671, respectively (as described in WO2008 / 047242) at the American Type Culture Collection (10801 University Bldg., Manassas, Va., 20110-2209, USA). Further exemplary useful antibodies for the disclosed pharmaceutical combinations include those disclosed in U.S. Patent Application No. 2018 / 0066069.

[0148] Antibodies against CD38, such as daratumumab, MOR202, or SAR650984, are being evaluated for their effectiveness in treating hematological malignancies and plasma cell disorders, including multiple myeloma, and are currently being evaluated in clinics. Each antibody has been found to bind to a different part of the extracellular domain of CD38, and each shows a different clinical response (e.g., antitumor effect). Daratumumab, available from Johnson & Johnson (Janssen Biotech) / Genmab as Darzalex®, is described in de Weers et al., “Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors,” J. Immunology, 2010, 186(3):1840-1848; MOR202, available from Celgene Corp. / Morphosys, is described in U.S. Pat. No. 8,877,899; and SAR650984, available from Sanofi / Immunogen as isatuximab, is described in Park et al., “SAR650984: A Potent Anti-CD38 Therapeutic Antibody with Three Mechanisms of Action (Apoptosis, ADCC, CDC) for Hematological Malignancies,” BLOOD, vol. 1. 12, No. 11, November 2008, p. 951, and Deckert et al., "SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38+ Hematologic Malignancies," Clin Cancer Res 2014;20:4574-83, and U.S. Patent No. 8,153,765.Table 1 below lists several antibodies, or fragments thereof, that bind to CD38 and their epitopes (binding sites) on the CD38 molecule, some or all of which may be useful in accordance with various aspects of the present disclosure. In various aspects, the disclosed anti-CD38 antibodies used in the disclosed pharmaceutical combinations are capable of killing CD38+ cells by antibody-dependent cell-mediated phagocytosis (ADCP), cell fratricide, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). The anti-CD38 antibody can be selected from daratumumab, isatuximab (SAR650984), MOR202 (MorphoSys AG), and TAK-079.

[0149] In various further embodiments, suitable anti-CD38 antibodies useful in the disclosed pharmaceutical compositions and methods include those set forth in Tables 1 and 2 above.

[0150] In still further aspects, suitable anti-CD38 antibodies useful in the disclosed pharmaceutical compositions and methods include trispecific antibodies such as those described in Sanofi Phase 1:CD3xCD28xCD38 asset SAR442257 "ClinicalTrials.gov Identifier: NCT04401020."

[0151] Thus, the present disclosure provides isolated anti-CD38 antibodies that specifically bind to human CD38 protein (and, as described below, additionally preferably specifically bind to primate CD38 protein). Accordingly, reference to an anti-CD38 antibody refers to an antibody, as defined above, that is capable of binding to CD38. CD38 is a 45 kD type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. That is, generally, CD38 possesses a short intracytoplasmic tail, a transmembrane domain, and an extracellular domain, and in certain embodiments, antibodies of the present disclosure bind to the extracellular portion of the CD38 protein. The CD38 protein is a bifunctional ectoenzyme that can catalyze the conversion of NAD+ to cyclic ADP-ribose (cADPR) and hydrolyze cADPR to ADP-ribose. CD38 is upregulated and is involved in many hematopoietic malignancies.

[0152] As known in the art, CD38 protein is found in several species. Particularly useful in the present disclosure are antibodies that bind to both human and primate CD38 proteins, particularly primates used in clinical trials, such as cynomolgus monkeys (Macaca fascicularis, sometimes referred to herein as "cyno"). "Human CD38" or "human CD38 antigen" refers to the protein of SEQ ID NO: 1 or a functional fragment thereof, such as an epitope defined herein.

[0153] In some embodiments, the anti-CD38 antibodies of the present disclosure interact with CD38 at several amino acid residues, including K121, F135, Q139, D141, M142, D202, V203, H205, Q236, E239, W241, 5274, C275, K276, F284, C287, V288, K289, N290, P291, E292, D293.

[0154] In some embodiments, the anti-CD38 antibodies of the present disclosure optionally (and in some cases preferably) do not bind to other members of the CD38 family, such as CD157.

[0155] The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies, chimeric antibodies, and antibody fragments of any isotype, such as IgG, IgM, IgA, IgD, and IgE. A typical IgG antibody consists of two identical heavy chains and two identical light chains joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called "complementarity-determining regions" ("CDRs") or "hypervariable regions," which are primarily responsible for binding an epitope of an antigen. These are usually referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus. The more highly conserved portions of the variable region outside the CDRs are called "framework regions." "Antibodies" include monoclonal, polyclonal, bispecific, multispecific, murine, chimeric, fragment, humanized, and human antibodies.

[0156] A "naked antibody" is an antibody or antigen-binding fragment thereof that is not conjugated to a therapeutic or diagnostic agent. The Fc portion of an intact, naked antibody can provide effector functions such as complement fixation and ADCC (see, e.g., Markrides, Pharmacol Rev 50:59-87, 1998). Other mechanisms by which naked antibodies induce cell death may include apoptosis. (Vaswani and Hamilton, Ann Allergy Asthma Immunol 81:105-119, 1998.)

[0157] An "antibody fragment" is a portion of an intact antibody, such as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, dAb, and the like. Regardless of structure, an antibody fragment binds with the same antigen recognized by the full-length antibody. For example, antibody fragments include isolated fragments consisting of the variable regions, such as an "Fv" fragment consisting of the variable regions of the heavy and light chains, or a recombinant single-chain polypeptide molecule in which the light and heavy chain variable regions are connected by a peptide linker ("scFv protein"). A "single-chain antibody," often abbreviated as "scFv," consists of a polypeptide chain containing both VH and VL domains that interact to form an antigen-binding site. The VH and VL domains are usually linked by a peptide of 1 to 25 amino acid residues. Antibody fragments also include diabodies, triabodies, and single-domain antibodies (dAbs).

[0158] A "chimeric antibody" is a recombinant protein that contains variable domains, including the complementarity-determining regions (CDRs), of an antibody derived from one species, preferably a rodent antibody, while the constant domains of the antibody molecule are derived from those of a human antibody. For veterinary applications, the constant domains of a chimeric antibody may be derived from those of another species, such as a cat or dog.

[0159] A "humanized antibody" is a recombinant protein in which the CDRs of an antibody derived from one species, e.g., a rodent antibody, are transferred from the heavy and light chains of the rodent antibody to human heavy and light chain variable domains containing human framework region (FR) sequences. The constant domains of the antibody molecule are derived from the constant domains of a human antibody. To maintain binding activity, a limited number of FR amino acid residues from the parent (e.g., murine) antibody can be substituted for the corresponding human FR residues.

[0160] A "human antibody" is an antibody obtained from a transgenic mouse that has been genetically engineered to produce specific human antibodies in response to antigen challenge. In this technique, elements of human heavy and light chain loci are introduced into a mouse strain derived from an embryonic stem cell line containing targeted disruptions of the endogenous heavy and light chain loci. The transgenic mouse is capable of synthesizing human antibodies specific to human antigens, and the mouse can be used to produce human antibody-secreting hybridomas. Methods for obtaining human antibodies from transgenic mice are described in Green et al., Nature Genet. 7:13 (1994), Lonberg et al., Nature 368:856 (1994), and Taylor et al., Int. Immun. 6:579 (1994). Human antibodies can also be constructed by genetic or chromosomal transfection methods, as well as phage display technology, all of which are known in the art. (See, e.g., McCafferty et al., 1990, Nature 348:552-553 for the production of human antibodies and fragments thereof in vitro from immunoglobulin variable domain gene repertoires from unimmunized donors.) In this technique, antibody variable domain genes are cloned in frame into either a major or minor coat protein gene of a filamentous bacteriophage, and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. In this way, the phage mimics some of the properties of B cells. Phage display can be performed in a variety of formats, for reviews of which see, e.g., Johnson and Chiswell, Current Opinion in Structural Biology 3:5564-571 (1993). Human antibodies can also be generated by in vitro activated B cells. (See U.S. Patent Nos. 5,567,610 and 5,229,275).

[0161] As used herein, the term "antibody fusion protein" refers to a recombinantly produced antigen-binding molecule in which an antibody or antibody fragment is linked to the same or a different antibody or antibody fragment, or to another protein or peptide, such as a DDD or AD peptide. Fusion proteins can contain a single antibody component, a multivalent or multispecific combination of different antibody components, or multiple copies of the same antibody component. Fusion proteins can additionally contain an antibody or antibody fragment and a therapeutic agent. Examples of therapeutic agents suitable for such fusion proteins include immunomodulators and toxins. One preferred toxin is a ribonuclease (RNase), preferably a recombinant RNase. A preferred immunomodulator can be an interferon, such as interferon α, interferon β, or interferon λ.

[0162] A "multispecific antibody" is an antibody that can simultaneously bind to at least two targets of different structures, e.g., two different antigens, two different epitopes on the same antigen, or a hapten and / or antigen or epitope. A "multivalent antibody" is an antibody that can simultaneously bind to at least two targets of the same or different structures. Valency indicates how many binding arms or sites an antibody has for a single antigen or epitope, i.e., monovalent, bivalent, trivalent, or multivalent. The multivalency of an antibody means that it can utilize multiple interactions in binding to an antigen, thus increasing the affinity of binding to the antigen. Specificity indicates the number of antigens or epitopes to which the antibody can bind, i.e., monospecific, bispecific, trispecific, or multispecific. Using these definitions, a natural antibody, e.g., an IgG, is bivalent because it has two binding arms, but monospecific because it binds to one epitope. A multispecific, multivalent antibody is a construct that has two or more binding sites of different specificities.

[0163] A "bispecific antibody" is an antibody that can simultaneously bind to two targets of different structures. Bispecific antibodies (bsAb) and bispecific antibody fragments (bsFab) can have at least one arm that specifically binds to, for example, T cells, NK cells, monocytes, or neutrophils, and at least one other arm that specifically binds to an antigen produced by or associated with a pathological cell, tissue, organ, or pathogen, such as a tumor-associated antigen. A variety of bispecific antibodies can be produced using molecular engineering.

[0164] An antibody preparation or composition described herein is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significant. An agent is physiologically significant if its presence results in a detectable change in the physiology of the recipient subject. In certain embodiments, an antibody preparation is physiologically significant if its presence causes an anti-tumor response or alleviates the signs and symptoms of an infectious disease state. A physiologically significant effect can be the elicitation of a humoral and / or cellular immune response in the recipient subject, leading to growth inhibition or death of target cells.

[0165] In various aspects, the antibodies disclosed herein include single domain antibodies, for example, single domain antibodies derived from the Camelidae family. In the "Camelidae" family, immunoglobulins that lack light polypeptide chains are found. "Camelidae" includes Old World camelids (Camelus bactrianus and Camelus dromaderius) and New World camelids (e.g., Lama paccos, Lama glama, and Lama vicugna).

[0166] It should be noted that the term "nanobody," as used herein in its broadest sense, is not limited to a particular biological source or a particular method of preparation. For example, nanobodies herein generally refer to antibodies that: (1) contain the V of a naturally occurring heavy chain antibody; H By isolating the H domain, (2) naturally occurring V H(3) naturally occurring V H By "humanizing" the H domain or by such a humanized V H (4) by "camelization" of naturally occurring VH domains from any animal species, in particular from mammalian species such as humans, or by expression of nucleic acids encoding such camelized VH domains; (5) by "camelization" of "domain antibodies" or "Dabs" as described in the art, or by expression of nucleic acids encoding such camelized VH domains; (6) by using synthetic or semi-synthetic techniques for preparing proteins, polypeptides, or other amino acid sequences known per se; (7) by preparing nucleic acids encoding Nanobodies using techniques for nucleic acid synthesis known per se, followed by expression of the nucleic acids so obtained; and / or (8) by any combination of one or more of the foregoing. One preferred class of Nanobodies is the VH domain of naturally occurring heavy chain antibodies directed against BACE1. H As further described herein, such VH domains H The H sequence can generally be obtained by suitably immunizing a Camelidae species with BACE1 (i.e., so as to raise an immune response and / or heavy chain antibodies directed against BACE1), by obtaining a suitable biological sample from the Camelidae (such as a blood sample, serum sample, or sample of B cells), and starting from the sample and using any suitable technique known per se, by isolating a V directed against BACE1. H The sequences can be generated or obtained by generating the H sequence. Such techniques will be apparent to those skilled in the art.

[0167] Alternatively, such naturally occurring V against BACE1 H The H domain can be identified as a Camelidae V H domain by screening such a library using BACE1 or at least one portion, fragment, antigenic determinant, or epitope thereof, for example, using one or more known screening techniques per se.H The VH sequences can be obtained from a naive library of VH sequences. Such libraries and techniques are described, for example, in WO9937681, WO0190190, WO03025020, and WO03035694. Alternatively, the VH sequences can be obtained from a naive library of VH sequences. H V obtained from the H library H Natural V such as H library H Improved synthetic or semi-synthetic libraries derived from the H library can be used, for example, by techniques such as random mutagenesis and / or CDR shuffling as described in WO0043507. H Yet another technique for obtaining H sequences is to suitably immunize a transgenic mammal capable of expressing heavy chain antibodies (i.e., to raise an immune response and / or heavy chain antibodies directed against BACE1), obtain a suitable biological sample from the transgenic mammal (such as a blood sample, a serum sample, or a sample of B cells), and then, starting from the sample, extract V sequences directed against BACE1 using any suitable technique known per se. H For example, for this purpose, heavy chain antibody-expressing mice and the additional methods and techniques described in WO02085945 and WO04049794 can be used.

[0168] A particularly preferred class of Nanobodies herein are naturally occurring V H H domain, i.e., a naturally occurring V HThese include Nanobodies with amino acid sequences that have been "humanized" by replacing one or more amino acid residues in the amino acid sequence of the H sequence (in particular in the framework sequences) with one or more of the amino acid residues that occur at the corresponding positions in the VH domain from a conventional four-chain antibody of human origin. This can be done in a manner known per se, which will be clear to the skilled artisan, for example, based on the further explanations herein and the prior art on humanization referred to herein. Again, such humanized Nanobodies of the invention can be obtained in any suitable manner known per se (i.e., as indicated in points (1) to (8) above) and therefore, strictly speaking, can be obtained by replacing one or more amino acid residues in the amino acid sequence of the VH domain with one or more of the amino acid residues that occur at the corresponding positions in the VH domain from a conventional four-chain antibody of human origin. H It should be noted that the present invention is not limited to polypeptides obtained using polypeptides containing an H domain as a starting material.

[0169] Another particularly preferred class of Nanobodies of the invention corresponds to the amino acid sequence of a naturally occurring VH domain, i.e., one or more amino acid residues within the amino acid sequence of a naturally occurring VH domain from a conventional four-chain antibody are replaced with one or more amino acid residues from the VH domain of a heavy chain antibody. HThese include Nanobodies with amino acid sequences that have been "camelized" by replacing one or more of the amino acid residues occurring at the corresponding positions in the H domain with one or more of the amino acid residues occurring at the corresponding positions in the H domain. Such "camelization" substitutions are preferably inserted at amino acid positions that form and / or are present at the VH-VL interface, as defined herein, and / or at so-called camelid hallmark residues (see, for example, WO9404678). Preferably, the VH sequence used as starting material or starting point for generating or designing camelized Nanobodies is preferably a VH sequence of mammalian origin, more preferably a human VH sequence, such as a VH3 sequence. However, it should be noted that such camelized Nanobodies of the present invention can be obtained by any suitable method known per se (i.e., as indicated in points (1) to (8) above), and are therefore not strictly limited to polypeptides obtained using a polypeptide comprising a naturally occurring VH domain as starting material. For example, both "humanization" and "camelization" refer to the conversion of a naturally occurring VH domain, respectively. H This can be done by providing a nucleotide sequence encoding the H or VH domain, and then, in a manner known per se, altering one or more codons in the nucleotide sequence in such a way that the new nucleotide sequence encodes a "humanized" or "camelized" Nanobody of the invention, respectively. This nucleic acid can then be expressed, in a manner known per se, to provide the desired Nanobody of the invention.

[0170] Alternatively, each of the naturally occurring V H Based on the amino acid sequence of the H or VH domain, the amino acid sequence of the desired humanized or camelized Nanobody of the invention can be designed and then synthesized de novo using techniques for peptide synthesis known per se. HBased on the amino acid or nucleotide sequence of the H or VH domain, respectively, a nucleotide sequence encoding the desired humanized or camelized Nanobody of the invention can be designed and then synthesized de novo using techniques for nucleic acid synthesis known per se, and the nucleic acid so obtained can then be expressed in a manner known per se to provide the desired Nanobody of the invention. H Other suitable methods and techniques for obtaining a Nanobody of the invention and / or a nucleic acid encoding same will be apparent to those skilled in the art and can be used, for example, to obtain a Nanobody of the invention or a nucleotide sequence or nucleic acid encoding same by starting from a VH sequence and substituting one or more parts of one or more naturally occurring VH sequences (such as one or more FR sequences and / or CDR sequences), one or more naturally occurring VH sequences, ... H It may involve combining in a suitable manner one or more portions of an H sequence (such as one or more FR or CDR sequences), and / or one or more synthetic or semi-synthetic sequences.

[0171] A molecule such as an antibody is "isolated" if it has been altered and / or removed from its natural environment by human intervention. However, an isolated antibody that specifically binds to an epitope, isoform, or variant of CD38, e.g., human CD38 or cynomolgus monkey CD38, may have cross-reactivity to other related antigens from other species, such as, for example, CD38 species homologs. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0172] Alternatively, antibodies may be in a variety of structures, including, but not limited to, antibody fragments, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to as "antibody conjugates"), and fragments of each.

[0173] In one embodiment, the antibody is an antibody fragment. Specific antibody fragments include (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains, (ii) a Fd fragment consisting of the VH and CH1 domains, (iii) a Fv fragment consisting of the VL and VH domains of a single antibody, (iv) a dAb fragment consisting of a single variable region (Ward et al., 1989, Nature 341:544-546, fully incorporated by reference), (v) an isolated CDR region, (vi) a F(ab')2 fragment, which is a bivalent fragment comprising two linked Fab fragments, and (vii) a single-chain Fv fragment (scFv), in which the VH and VL domains are linked by a peptide linker, allowing the two domains to associate to form an antigen-binding site (Bird et al., 1988, Science 242:423-426, Huston et al., fully incorporated by reference). al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883, entirely incorporated by reference), (viii) bispecific single-chain Fvs (WO 03 / 1161, incorporated herein by reference), and (ix) "diabodies" or "triabodies," which are multivalent or multispecific fragments constructed by gene fusion (Tomlinson et al., 2000, Methods Enzymol. 326:461-479, WO 94 / 13804; Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448, all entirely incorporated by reference).

[0174] As used herein, the terms "target antigen" and "epitope" can be used interchangeably and refer to a molecule specifically bound by the variable region of a given antibody. A target antigen can be a protein, carbohydrate, lipid, or other chemical compound. Numerous suitable target antigens are described below. Thus, an anti-CD38 antibody as disclosed herein has as its target antigen one or more portions of CD38, such as the amino acid and carbohydrate moieties of CD38, including both continuous and non-contiguous portions of the CD38 molecule as defined by the primary sequence of the CD38 molecule. That is, a CD38 target antigen can include secondary or tertiary structures within the CD38 molecule, including one or more amino acid moieties, one or more carbohydrate moieties, and combinations thereof.

[0175] An epitope may include amino acid residues that are directly involved in binding (also called the immunodominant component of the epitope) and other amino acid residues that are not directly involved in binding, such as amino acid residues that are effectively blocked by the specific antigen-binding peptide, in other words, amino acid residues within the area occupied by the specific antigen-binding peptide.

[0176] Epitopes can be either conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are produced by adjacent amino acid residues within the polypeptide chain. Conformational and nonconformational epitopes can be distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[0177] An epitope typically includes at least 3, and more usually at least 5 or 8-10 amino acids in a unique spatial conformation. Antibodies that recognize the same epitope can be verified in a simple immunoassay demonstrating the ability of one antibody to block the binding of another antibody to a target antigen, e.g., "binning."

[0178] "Specific binding" or "specifically binds," or "specific for" a particular antigen or epitope, means binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule, which is generally a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0179] Specific binding to a particular antigen or epitope is, for example, at least about 10 -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -7 M, at least about 10 -8 M, at least about 10 -9 M, alternatively at least about 10 -10 M, at least about 10 -11 M, at least about 10 -12 This can be demonstrated by an antibody having a KD, or dissociation constant, for an antigen or epitope found on CD38 of M or greater, where KD refers to the dissociation rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds to an antigen has a KD that is 20, 50, 100, 500, 1000, 5,000, 10,000, or more times greater than that of a control molecule for that antigen or epitope.

[0180] Specific binding to a particular antigen or epitope found on CD38 can also be demonstrated, for example, by an antibody having a K or K for the antigen or epitope that is at least 20, 50, 100, 500, 1000, 5000, 10000, or more times greater for the epitope relative to a control, where K or K refers to the association rate of a particular antibody-antigen interaction.

[0181] In some embodiments, antibodies can be a mixture derived from different species, e.g., chimeric and / or humanized antibodies. Generally, both "chimeric antibodies" and "humanized antibodies" refer to antibodies that combine regions from two or more species. For example, a "chimeric antibody" traditionally contains variable regions from a mouse (or sometimes a rat) and constant regions from a human. A "humanized antibody" generally refers to a non-human antibody in which the variable domain framework regions have been swapped for sequences found in human antibodies.

[0182] In some cases, the anti-CD38 antibody of the present disclosure is a humanized antibody. As used herein, the term "humanized antibody" refers to a chimeric antibody containing minimal sequence derived from non-human immunoglobulin. The goal of humanization is to reduce the immunogenicity of xenogeneic antibodies, such as murine antibodies, for introduction into humans while maintaining the antibody's full antigen-binding affinity and specificity. Humanized antibodies, or antibodies adapted for non-rejection by other mammals, can be produced using several techniques, such as resurfacing and CDR grafting. As used herein, resurfacing techniques use a combination of molecular modeling, statistical analysis, and mutagenesis to modify the non-CDR surfaces of antibody variable regions to resemble the surfaces of known antibodies of the target host. CDR grafting techniques involve, for example, replacing the complementarity-determining regions of a murine antibody with human framework domains. See, for example, WO92 / 22653. A humanized chimeric antibody preferably has complementarity determining regions (CDRs) derived substantially or exclusively from corresponding human antibody regions, and constant and variable regions other than the CDRs derived substantially or exclusively from a mammal other than a human.

[0183] Humanized antibodies may also contain residues that are not found in either human or non-human antibodies. Humanized antibodies may be, for example, hyperhumanized antibodies as described in U.S. Patent No. 7,732,578. Antibodies may be humanized chimeric antibodies. Humanized antibodies also include antibodies with constant region sequences, e.g., variable region framework sequences, that are artificial consensus sequences based on multiple human antibodies.

[0184] A fully human antibody is an antibody whose entire molecule is human or otherwise of human origin, or whose amino acid sequence is identical or substantially identical to a human antibody sequence. Fully human antibodies include, for example, those obtained from a human V gene library in which human genes encoding the variable regions of the antibody are recombinantly expressed. Fully human antibodies can also be expressed in cells from other organisms (e.g., mice and xenomouse technology) or transformed with genes encoding human antibodies. Fully human antibodies can still contain amino acid residues not encoded by human sequences, for example, mutations introduced by random or site-specific mutagenesis.

[0185] The anti-CD38 antibody can be a full-length antibody of any class, such as IgG1, IgG2, or IgG4. In certain embodiments, the anti-CD38 antibody can be a full-length IgG4 antibody. The constant domains of such antibodies are preferably human. The variable regions of such antibodies can be of non-human origin, or preferably human origin, or humanized. Antibody fragments can also be used instead of full-length antibodies.

[0186] In some embodiments, anti-CD38 antibodies may comprise non-immunoglobulin-derived protein frameworks, e.g., see (Ku & Schutz, Proc. Natl. Acad. Sci. USA 92:6552-6556, 1995), which describes the four-helix bundle protein cytochrome b562 with two loops randomized to create CDRs selected for antigen binding.

[0187] Natural sequence variation may exist between heavy and light chains and the genes encoding them; therefore, one of skill in the art would expect to find a level of variation within the amino acid sequences of the antibodies described and exemplified herein, or the genes encoding them. The term antibody encompasses sequence variants that maintain CD38-binding specificity, and preferably substantially maintain the affinity of the parent antibody. Such an expectation arises in part from the degenerate nature of the genetic code and the known evolutionary success of conservative amino acid sequence variations, which do not significantly alter the properties of the encoded protein. Thus, such variants and homologs are considered substantially identical to one another and are included within the scope of the present disclosure. Thus, antibodies include variants with single or multiple amino acid substitutions, deletions, additions, or replacements that retain the biological properties (e.g., binding specificity and affinity) of the parent antibody. Variants are preferably conservative, but can be non-conservative.

[0188] The amino acid positions assigned to complementarity-determining regions (CDRs) and framework regions (FRs) may be defined according to the Kabat sequence (also referred to herein as the Kabat numbering system) in Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991. In addition, the amino acid positions assigned to CDRs and FRs may be defined according to the Enhanced Chothia numbering scheme (http: / / www.bioinfo.org.uk / mdex.html). The heavy chain constant region of an antibody may be defined according to the EU numbering system (see Edelman, GM et al. (1969)., Proc. Natl. Acad. USA, 63, 78-85).

[0189] According to the Kabat numbering system, VH FRs and CDRs can be positioned as residues 1-30 (FR1), 31-35 (CDR1), 36-49 (FR2), 50-65 (CDR2), 66-94 (FR3), 95-102 (CDR3), and 103-113 (FR4), and VL FRs and CDRs can be positioned as residues 1-23 (FR1), 24-34 (CDR1), 35-49 (FR2), 50-56 (CDR2), 57-88 (FR3), 89-97 (CDR3), and 98-107 (FR4). In some cases, the variable regions can be increased in length, and according to the Kabat numbering system, some amino acids can be designated by a number followed by a letter. The present specification is not limited to the FWRs and CDRs defined by the Kabat numbering system, but includes all numbering systems, including the canonical numbering system, or the system of Chothia et al. (1987) J. Mol. Biol. 196:901-17, Chothia et al. (1989) Nature 342:877-83, and / or Al-Lazikani et al. (1997) J. Mol. Biol. 273:927-48, the numbering system of Honnegher et al. (2001) J. Mol. Biol., 309:657-70, or the IMGT system described in Giudicelli et al. (1997) Nucleic Acids Res. 25:206-11. In some embodiments, CDRs are defined according to the Kabat numbering system.

[0190] In certain embodiments, for any of the heavy chain CDR2 subdomains described herein, the five C-terminal amino acids according to the Kabat numbering system may not be directly involved in antigen binding, and therefore, it will be understood that any one or more of these five C-terminal amino acids may be substituted with another naturally occurring amino acid without substantially adversely affecting antigen binding. In some embodiments, for any of the light chain CDR1 subdomains described herein, the four N-terminal amino acids according to the Kabat numbering system may not be directly involved in antigen binding, and therefore, it will be understood that any one or more of these four amino acids may be substituted with another naturally occurring amino acid without substantially adversely affecting antigen binding. For example, as described in Padlan et al. (1995) FASEB J.9:133-139, the five C-terminal amino acids of the heavy chain CDR2 and / or the four N-terminal amino acids of the light chain CDR1 may not be involved in antigen binding. In some embodiments, both the heavy chain CDR2 and the light chain CDR1 are not directly involved in antigen binding.

[0191] In some embodiments, chemical analogs of amino acids may be used in the antibodies described and / or exemplified herein. The use of chemical analogs of amino acids is useful, for example, to stabilize molecules when they need to be administered to a subject. Amino acid analogs contemplated herein include, but are not limited to, side chain modifications, the incorporation of unnatural amino acids and / or their derivatives during peptide, polypeptide, or protein synthesis, and the use of crosslinkers and other methods that impose conformational constraints on protein molecules or their analogs. Anti-CD38 antibodies may contain post-translational modifications or moieties that may affect antibody activity or stability. These modifications or moieties include, but are not limited to, methylated, acetylated, glycosylated, sulfation, phosphorylated, carboxylated, and amidated moieties, as well as other moieties known in the art. Moieties include any chemical group or combination of groups commonly found on immunoglobulin molecules in nature or otherwise added to antibodies by recombinant expression systems, including prokaryotic and eukaryotic expression systems.

[0192] Covalent modification of antibodies is included within the scope of the present disclosure and is generally, but not necessarily, performed post-translationally. For example, some types of covalent modification of antibodies are introduced into the molecule by reacting specific amino acid residues of antibodies with organic derivatizing agents that can react with selected side chains or N- or C-terminal residues. Examples of side chain modifications contemplated by the present disclosure include modification of amino groups, such as by reductive alkylation, such as by reaction with aldehydes followed by reduction with NaBH4, amidation with methylacetimidate, acylation with acetic anhydride, carbamoylation of amino groups with cyanate, trinitrobenzylation of amino groups with 2,4,6-trinitrobenzenesulfonic acid (TNBS), acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride, and pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH4.

[0193] The guanidine group of arginine residues can be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal, and glyoxal. Carboxyl groups can be modified by carbodiimide activation via O-acylisourea formation followed by subsequent derivatization to the corresponding amide, for example. Sulfhydryl groups can be modified by carboxymethylation with iodoacetic acid or iodoacetamide, performic acid oxidation to cysteic acid, mixed disulfide formation with other thiol compounds, reaction with maleimide, maleic anhydride, or other substituted maleimides, formation of mercury derivatives with 4-chloromercuribenzoate, 4-chloromercuriphenylsulfonate, phenylmercuric chloride, 2-chloromercuri-4-nitrophenol, and other mercury compounds, and carbamoylation with cyanate at alkaline pH. Tryptophan residues can be modified, for example, by oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulfenyl halides. Tyrosine residues can be altered by nitration with tetranitromethane to form 3-nitrotyrosine derivatives. Modification of the imidazole ring of histidine residues can be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate.

[0194] Crosslinkers include, for example, (CH2) with n=1 to n=6. n Homobifunctional crosslinkers such as bifunctional imidoesters with spacer groups, glutaraldehyde, N-hydroxysuccinimide esters, and heterobifunctional reagents that typically contain an amino-reactive moiety such as N-hydroxysuccinimide and another group-specific reactive moiety such as a maleimide or dithio moiety (SH) or carbodiimide (COOH) can be used to stabilize the 3D conformation of anti-CD38 antibodies. In some embodiments, antibodies can be derivatized with known protecting / blocking groups to prevent proteolytic cleavage or to improve activity or stability.

[0195] Anti-CD38 antibodies may be affinity matured or contain amino acid changes that reduce immunogenicity, for example, by removing predicted MHC class II binding motifs. The therapeutic utility of the antibodies described herein may be further enhanced by modulating their functional characteristics, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), serum half-life, biodistribution and binding to Fc receptors, or any combination thereof. This modulation may be achieved by protein engineering, glycoengineering, or chemical methods. Depending on the required therapeutic application, it may be advantageous to increase or decrease any of these activities. An example of glycoengineering is using the Potelligent® method as described in Shinkawa T. et al. (2003) J. Biol. Chem. 278:3466-73.

[0196] Another type of covalent modification is altered glycosylation. In another embodiment, the antibodies disclosed herein can be modified to contain one or more engineered glycoforms. As used herein, "engineered glycoform" refers to a carbohydrate composition covalently attached to an antibody that is chemically different from that of the parent antibody. Engineered glycoforms can be useful for a variety of purposes, including, but not limited to, enhancing or reducing effector function. A preferred form of engineered glycoform is afucosylation, which has been shown to correlate with increased ADCC function, presumably through tighter binding to the FcγRIIIa receptor. In this context, "afucosylation" means that the majority of antibodies produced in host cells are substantially devoid of fucose; for example, 90-95-98% of generated antibodies lack significant fucose as a component of the antibody's carbohydrate moiety (typically attached at N297 in the Fc region). Functionally defined, afucosylated antibodies generally exhibit at least 50% or greater affinity for the FcγRIIIa receptor.

[0197] Engineered glycoforms can be produced by a variety of methods known in the art (see, for example, Umana et al., 1999, Nat Biotechnol 17:176-180; Davies et al., 2001, Biotechnol Bioeng 74:288-294; Shields et al., 2002, J Biol Chem 277:26733-26740; Shinkawa et al., 2003, J Biol Chem 278:3466-3473; U.S. Patent No. 6,602,684; U.S. Patent No. 10 / 277,370; U.S. Patent No. 10 / 113,929; PCT WO 00 / 61739A1; PCT WO 01 / 29246A1; PCT WO 02 / 31140A1; PCT WO 02 / 30954A1 (Potelligent® technology [Biowa, Inc., Princeton, NJ], GlycoMAb® glycosylation engineering technology [Glycart Biotechnology AG, Zurich, Switzerland]). Many of these techniques are based on controlling the level of fucosylated oligosaccharides covalently attached to the Fc region and / or bisecting the oligosaccharides, for example, by expressing IgG in various engineered or otherwise engineered organisms or cell lines (e.g., Lec-13 CHO cells or rat hybridoma YB2 / 0 cells by modulating enzymes involved in the glycosylation pathway (e.g., FUT8 [α1,6-fucosyltransferase] and / or β1-4-N-acetylglucosaminyltransferase III [GnTIII])), or by modifying the carbohydrate after the IgG has been expressed. For example, Seattle Biotechnology Genetics' "glycoengineered antibodies" or "SEA technology" works by adding modified sugars that inhibit fucosylation during production. See, e.g., 20090317869, incorporated herein by reference in its entirety. Engineered glycoforms typically refer to different carbohydrates or oligosaccharides, and thus antibodies can contain engineered glycoforms.

[0198] Alternatively, an engineered glycoform can refer to an IgG variant that contains different carbohydrates or oligosaccharides. As is known in the art, glycosylation patterns can depend on both the sequence of the protein (e.g., the presence or absence of specific glycosylated amino acid residues, discussed below), or the host cell or organism in which the protein is produced. Specific expression systems are discussed below.

[0199] Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used.

[0200] Addition of glycosylation sites to an antibody is conveniently accomplished by modifying the amino acid sequence to contain one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). Modifications can also be made by adding or substituting one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). To facilitate this, the antibody amino acid sequence is preferably modified through changes at the DNA level, particularly by mutating the DNA encoding the target polypeptide at preselected bases to generate codons that translate into the desired amino acids.

[0201] Anti-CD38 antibodies may contain modifications that modify their serum half-life and biodistribution, including modifications that modulate the antibody's interaction with the neonatal Fc receptor (FcRn), a receptor that protects IgG from catabolism and plays an important role in maintaining high serum antibody concentrations. Serum half-life-modulating modifications may occur within the Fc region of IgG1 or IgG4, including the triple substitution M252Y / S254T / T256E (numbered according to the EU numbering system (Edelman, GM et al. (1969) Proc. Natl. Acad. USA 63, 78-85)) (e.g., SEO ID No. 13, SEO ID No. 14, SEO ID No. 15, SEO ID No. 16), as described in U.S. Patent No. 7,083,784. Other substitutions can occur at positions 250 and 428 (see, e.g., U.S. Pat. No. 7,217,797) and positions 307, 380, and 434 (see, e.g., WO 00 / 42072). Examples of constant domain amino acid substitutions that modulate Fc receptor binding and subsequent functions mediated by these receptors, including FcRn binding and serum half-life, are described in U.S. Patent Publications 2009 / 0142340, 2009 / 0068175, and 2009 / 0092599. Naked antibodies can omit or remove the heavy chain C-terminal lysine to reduce heterogeneity. The S228P (EU numbering) substitution in human IgG4 can stabilize antibody Fab arm exchange in vivo (Labrin et al. (2009) Nature Biotechnology 27:8; 767-773).

[0202] It is known that glycans linked to antibody molecules affect the interaction of antibodies with Fc receptors and glycan receptors, thereby affecting antibody activity, including serum half-life. Therefore, certain glycoforms that modulate desired antibody activity can confer therapeutic benefits. Methods for producing engineered glycoforms include, but are not limited to, those described in U.S. Patent Nos. 6,602,684, 7,326,681, and 7,388,081, and PCT Publication No. WO08 / 006554. Alternatively, antibody sequences can be modified to remove relevant glycoform attachment sites.

[0203] The anti-CD38 antibody is preferably at a concentration of about 1 x 10 -4 M. In some embodiments, the Kd is about 1 x 10 -5 In yet other embodiments, the Kd is less than about 1 x 10 -6 In other embodiments, the Kd is less than about 1 x 10 -7 In other embodiments, the Kd is less than about 1 x 10 -8 In other embodiments, the Kd is less than about 1 x 10 -9 In other embodiments, the Kd is less than about 1 x 10 -10 In yet other embodiments, the Kd is less than about 1 x 10 -11 In some embodiments, the Kd is less than about 1 x 10 -12 In other embodiments, the Kd is less than about 1 x 10 -13 In other embodiments, the Kd is less than about 1 x 10 -14 In yet other embodiments, the Kd is less than about 1 x 10 -15 M or less. Affinity values ​​refer to those obtained by standard methodologies, including Biacore™ analysis or surface plasmon resonance, such as analysis using an Octet® Red 96 (Forte Bio) Dip-and-Read system.

[0204] The anti-CD38 antibody is preferably capable of binding to CD38-positive cells. The antibody may bind to CD38-positive cells with an EC50 value of less than about 100 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 75 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 50 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 30 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 25 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 20 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 18 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 15 nM. The antibody may bind to CD38-positive cells with an EC50 value of less than about 13 nM. The antibody can bind to CD38-positive cells with an EC50 value of less than about 10 nM. Such anti-CD38 antibody variants can be engineered and expressed so that the antibody has reduced immunogenicity, increased stability, and increased half-life in circulation without significant loss of the antibody's specificity or affinity for the CD38 antigen. These mutant antibodies can be fused to attenuated interferon.

[0205] Strategies and methods for antibody resurfacing, as well as other methods for reducing the immunogenicity of antibodies in different hosts, are disclosed in U.S. Pat. No. 5,639,641, which is incorporated herein by reference in its entirety. Antibodies can be humanized using a variety of other techniques, including CDR grafting (EP 0239400, WO 91 / 09967, U.S. Pat. Nos. 5,530,101 and 5,585,089), veneering or resurfacing (EP 0592106, EP 0519596, Padlan EA, 1991, Molecular Immunology 28(4 / 5):489-498, Studnicka GM et al., 1994, Protein Engineering, 7(6):805-814, Roguska MA et al., 1994, PNAS, 91:969-973), chain shuffling (U.S. Pat. No. 5,565,332), and identification of flexible residues (PCT / US2008 / 074381). Human antibodies can be produced by a variety of methods known in the art, including phage display methods. See also U.S. Patent Nos. 4,444,887, 4,716,111, 5,545,806, and 5,814,318, and International Patent Application Publication Nos. WO98 / 46645, WO98 / 50433, WO98 / 24893, WO98 / 16654, WO96 / 34096, WO96 / 33735, and WO91 / 10741, which references are incorporated by reference in their entireties.

[0206] DHODH inhibitor compounds. In the disclosed pharmaceutical compositions and methods of treating clinical conditions, a DHODH inhibitor is used together with an anti-CD38 antibody. A suitable DHODH inhibitor may be one of the DHODH inhibitors disclosed herein or any other DHODH inhibitor known to those skilled in the art.

[0207] Exemplary disclosed DHODH inhibitors have the structure: TIFF2025186252000016.tif38170, wherein Z1 , Z 2 , Z 3 , and Z 4 are each independently selected from CH and N; 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e wherein four of the groups may have a formula, or a pharmaceutically acceptable salt thereof, selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3.

[0208] Further exemplary disclosed DHODH inhibitors have the structure: TIFF2025186252000017.tif38170, wherein Z 1 is a 5-membered heterocyclic diyl, and R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are each independently selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e wherein four of the groups may have a formula, or a pharmaceutically acceptable salt thereof, selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3.

[0209] Further exemplary disclosed DHODH inhibitors have the structure: TIFF2025186252000018.tif38170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a, R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d can have a formula, or a pharmaceutically acceptable salt thereof, that 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.

[0210] These and other exemplary disclosed DHODH inhibitors are described in further detail below by reference to DHODH inhibitor compounds—Groups I, II, III, IV, and V.

[0211] DHODH inhibitor compounds - Group I The disclosed DHODH inhibitors can be any DHODH inhibitor as disclosed in International Patent Application No. PCT / US19 / 38622, which is incorporated herein by reference and further described herein. For convenience, compounds of this structural type will be referred to as DHODH inhibitor compounds—Group I.

[0212] Disclosed is a compound having the structure: DHODH inhibitor compounds—Group I compounds having the formula represented by TIFF2025186252000019.tif36170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 is selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; R 40 and R 41 each independently represents -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1is a phenyl group substituted with one, two, or three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C3 alkyl, —C1-C3 alkoxy, —C1-C3 haloalkyl, —C1-C3 aminoalkyl, —C1-C3 alkylamino, —C1-C3 haloalkylamino, —C1-C3 hydroxyalkyl, —C1-C3 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e are independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 , or a pharmaceutically acceptable salt thereof.

[0213] Also disclosed is a compound having the structure: DHODH inhibitor compounds—Group I compounds having the formula represented by TIFF2025186252000020.tif38170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 2-O- and -NR 60 - selected from R 60 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 is selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; R 40 and R 41 each independently represents -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with one, two, or three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C3 alkyl, —C1-C3 alkoxy, —C1-C3 haloalkyl, —C1-C3 aminoalkyl, —C1-C3 alkylamino, —C1-C3 haloalkylamino, —C1-C3 hydroxyalkyl, —C1-C3 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5b , R 5c , R 5d , and R 5e is a compound, or a pharmaceutically acceptable salt thereof, wherein each of is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .

[0214] Also disclosed is a compound having the structure: DHODH inhibitor compounds—Group I compounds having the formula represented by TIFF2025186252000021.tif37170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5b But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 is selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; R 40 and R 41each independently represents -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with one, two, or three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C3 alkyl, —C1-C3 alkoxy, —C1-C3 haloalkyl, —C1-C3 aminoalkyl, —C1-C3 alkylamino, —C1-C3 haloalkylamino, —C1-C3 hydroxyalkyl, —C1-C3 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5b , R 5c , R 5d , and R 5e is a compound, or a pharmaceutically acceptable salt thereof, wherein each of is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .

[0215] Also disclosed is a compound having the structure: DHODH inhibitor compounds—Group I compounds having the formula represented by TIFF2025186252000022.tif38170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5c But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 A is selected from the group having the formula 1-O- and -NR 50 - selected from R 50 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 is selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; R 40 and R 41 each independently represents -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with one, two, or three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C3 alkyl, —C1-C3 alkoxy, —C1-C3 haloalkyl, —C1-C3 aminoalkyl, —C1-C3 alkylamino, —C1-C3 haloalkylamino, —C1-C3 hydroxyalkyl, —C1-C3 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5d , and R 5e is a compound, or a pharmaceutically acceptable salt thereof, wherein each of is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .

[0216] Also disclosed is a compound having the structure: DHODH inhibitor compounds - Group I compounds having the formula represented by TIFF2025186252000023.tif27170, wherein Ar 1 is phenyl substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —O(C-C alkyl), —(C-C alkanediyl)-OH, —O(C-C alkanediyl)-OH, —CHO(C-C alkyl), —(CH)O(C-C alkyl), C-C haloalkyl, —O(C-C haloalkyl), and C-C hydroxyalkyl; R 1 and R 2 are each independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, -CF2CF3, and Ar 2 is selected from Ar 2 is phenyl independently substituted with 1, 2, or 3 groups selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 1 and R 2 At least one of the groups is not hydrogen, but R 3 is selected from hydrogen and C1-C7 alkyl, and R 4 But -S(O) j R 10 , -(C=O)OR 11 , and -(C=O)NR 12a R 12b where j is an integer selected from 0, 1, and 2, and R 10 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; R 11 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; R 12a and R 12bare each independently selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0217] Also disclosed is a compound having the structure: DHODH inhibitor compounds—Group I compounds having the formula represented by TIFF2025186252000024.tif34170, wherein R 1 and R 2 are each independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, -CF2CF3, and Ar 2 is selected from Ar 2 is phenyl independently substituted with 1, 2, or 3 groups selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 1 and R 2 At least one of the groups is not hydrogen, but R 3 is selected from hydrogen and C1-C7 alkyl, and R 4 But -S(O) j R 10 , -(C=O)OR 11 , and -(C=O)NR 12a R 12b where j is an integer selected from 0, 1, and 2, and R 10 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; R 11 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; R 12a and R 12b are each independently selected from hydrogen, C-C alkyl, C-C hydroxyalkyl, and C-C haloalkyl; 5is selected from -OH, -O(C1-C7 alkyl), -(C1-C7 alkanediyl)-OH, -CHO(C1-C7 alkyl), -(CH)O(C1-C7 alkyl), and C1-C7 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0218] Also disclosed is a compound having the structure: DHODH inhibitor compounds—Group I compounds having the formula represented by TIFF2025186252000025.tif38170, wherein R 1 is selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5b and R 5c Each of the following is independently -R 20 , hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3; R 20 is selected from C-C alkylamino and C-C alkoxy; R 5b and R 5c One of them is -R 20 and each R 5a , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 , or a pharmaceutically acceptable salt thereof.

[0219] Also disclosed is a compound having the structure: TIFF2025186252000026.tif371702-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3), a DHODH inhibitor compound - a Group I compound.

[0220] Also disclosed is a compound having the structure: TIFF2025186252000027.tif331702-(3'-butoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd4) is a DHODH inhibitor compound - a Group I compound.

[0221] It is understood that the disclosed DHODH inhibitor compounds include salt forms, for example, DHODH inhibitor compounds - Group I compounds may be in the sodium salt form, such as: TIFF2025186252000028.tif331702-(3'-Butoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylate sodium (Cpd4Na).

[0222] The following list of exemplary embodiments supports and is supported by the disclosure provided herein for the DHODH inhibitor compounds-I group. Aspect 1. A compound having a formula represented by the structure: TIFF2025186252000029.tif26170, Ar 1 is one, two, or three groups independently selected from halogen, —OH, —O(C-C alkyl), —(C-C alkanediyl)-OH, —O(C-C alkanediyl)-OH, —CHO(C-C alkyl), —(CH)O(C-C alkyl), —C-C haloalkyl, —O(C-C haloalkyl), and —C-C hydro-substituted phenyloxyalkyl; R 1 and R 2 are each independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, -CF2CF3, and Ar 2 is selected from Ar 2 is phenyl independently substituted with 1, 2, or 3 groups selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 1 and R 2 At least one of the groups is not hydrogen, but R3 is selected from hydrogen and C1-C7 alkyl, and R 4 But -S(O) j R 10 , -(C=O)OR 11 , and -(C=O)NR 12a R 12b where j is an integer selected from 0, 1, and 2, and R 10 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; R 11 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; R 12a and R 12b each of which is independently selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl, or a pharmaceutically acceptable salt thereof. Aspect 2. Structure: TIFF2025186252000030.tif32170, wherein R 5 is selected from halogen, —OH, —O(C-C alkyl)-OH, —(C-C alkanediyl)-OH, —O(C-C alkanediyl)-OH, —CHO(C-C alkyl), —(CH)O(C-C alkyl), C-C haloalkyl, —O(C-C haloalkyl), and C-C hydroxyalkyl, or a pharmaceutically acceptable salt thereof. Aspect 3.R 5 The compound according to embodiment 2, wherein is halogen, C1-C7 haloalkyl, or -O(C1-C7 haloalkyl). Aspect 4.R 5 A compound according to embodiment 3, wherein is a halogen. Aspect 5.R 5 is F. Aspect 6.R 5 is —OCF 3 , —OCH 2 CF 3 , or —OCF 2 CF 3 . Aspect 7.R 5is —OH, —O(C1-C7 alkyl), —(C1-C7 alkanediyl)-OH, —O(C1-C7 alkanediyl)-OH, —CHO(C1-C7 alkyl), —(CH2)2O(C1-C7 alkyl), or C1-C7 hydroxyalkyl. Aspect 8.R 5 is —O(C1-C7 alkyl), —(C1-C7 alkanediyl)-OH, —O(C1-C7 alkanediyl)-OH, —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 9.R 5 is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —O(CH2)3CH3, —OCH2CH(CH3)2, —OCH(CH2CH3)(CH3), —CH2OH, —(CH2)2OH, —(CH2)3OH, —(CH2)4OH, —CH2OCH3, —CH2OCH2CH3, —CHO(CH2)2CH3, —CHOCH(CH3)2, —CHOCH(CH2CH3)2(CH3), —(CH2)2OCH3, —(CH2)2OCH2CH3, —(CH2)2O(CH2)2CH3, —(CH2)2OCH(CH3)2, or —(CH2)2OCH(CH2CH3)2(CH3). Aspect 10.R 5 is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2OCH3, —CH2OCH2CH3, —CHO(CH2)2CH3, —CHOCH(CH3)2, —CHOCH(CH2CH3)2(CH3), —(CH2)2OCH3, —(CH2)2OCH2CH3, —(CH2)2O(CH2)2CH3, —(CH2)2OCH(CH3)2, or —(CH2)2OCH(CH2CH3)2(CH3). Aspect 11.R 5is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2OCH3, —CH2OCH2CH3, —(CH2)2OCH3, or —(CH2)2OCH2CH3. Aspect 12.R 5 is —OCH 3 , —OCH 2 CH 3 , —CH 2 OH, —(CH 2 ) 2 OH, —CH 2 OCH 3 , or —CH 2 OCH 2 CH 3 . Aspect 13.R 5 is —OCH 3 or —OCH 2 CH 3 . Aspect 14.R 1 Aspect 14. The compound of any one of aspects 1-13, wherein is selected from halogen, -SF5, -CF3, and -CF2CF3. Aspect 15.R 1 A compound according to embodiment 14, wherein is halogen. Aspect 16.R 1 is F or Cl. Aspect 17.R 1 is F. Aspect 18.R 1 is selected from -SF5, -CF3, and -CF2CF3. Aspect 19.R 1 A compound according to embodiment 14, wherein is —SF5. Aspect 20.R 2 Aspect 20. The compound of any one of aspects 1-19, wherein is selected from halogen, -SF5, -CF3, and -CF2CF3. Aspect 21.R 2 21. The compound according to embodiment 20, wherein is halogen. Aspect 22.R 2 22. The compound according to embodiment 21, wherein is F or Cl. Aspect 23.R 2 is F. Aspect 24.R 2 is selected from -SF5, -CF3, and -CF2CF3. Aspect 25.R 2 21. The compound according to embodiment 20, wherein is —SF5. Aspect 26.R 3 Aspect 26. The compound according to any one of aspects 1 to 25, wherein is selected from halogen and C1-C3 alkyl. Aspect 27.R 3 27. The compound according to embodiment 26, wherein is hydrogen or methyl. Aspect 28.R 3 27. The compound according to embodiment 26, wherein is hydrogen. Aspect 29.R 3 27. The compound according to embodiment 26, wherein is methyl. Aspect 30.R 4 But -S(O) j R 10 30. The compound of any one of aspects 1 to 29, wherein: Aspect 31. A compound according to aspect 30, wherein j is 1 or 2. Aspect 32.R 10 is hydrogen or C1-C3 alkyl. Aspect 33.R 10 32. The compound according to any one of embodiments 30 to 31, wherein is hydrogen. Aspect 34.R 10 is C1-C3 alkyl. Aspect 35.R 10 is methyl or ethyl. Aspect 36.R 10 is methyl. Aspect 37.R 4 is —SO 2 H or —SO 2 CH 3 . Aspect 38.R 10 The compound according to any one of embodiments 30 to 31, wherein is C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl. Aspect 39.R 4 -(C=O)OR 11 26. The compound according to any one of aspects 1 to 25, wherein: Aspect 40.R 11is selected from hydrogen, methyl, and ethyl. Aspect 41.R 11 A compound according to embodiment 39, wherein is hydrogen. Aspect 42. The compound is R 4 42. The compound according to aspect 41, which is a pharmaceutically acceptable salt of Aspect 43.R 4 43. The compound according to aspect 42, wherein the pharmaceutically acceptable salt of is the lithium, sodium, or potassium salt thereof. Aspect 44.R 4 43. The compound according to aspect 42, wherein the pharmaceutically acceptable salt of is the sodium salt thereof. Aspect 45.R 11 is selected from C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl. Aspect 46.R 11 is selected from methyl, ethyl, —CHF 2 , —CH 2 F, —CF 3 , —CHCl 2 , —CH 2 Cl, —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —CH 2 OH, and —(CH 2 ) 2 OH. Aspect 47.R 11 is selected from methyl, ethyl, —CHF 2 , —CH 2 F, —CF 3 , —CHCl 2 , —CH 2 Cl, —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , and —CH 2 CCl 3 . Aspect 48.R 11 is selected from methyl, ethyl, —CHF 2 , —CH 2 F, —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , and —CH 2 CF 3 . Aspect 49.R 11 is selected from methyl and ethyl. Aspect 50.R 11 is selected from methyl, —CHF 2 , —CH 2 F, —CF 3 , —CHCl 2 , —CH 2 Cl, —CCl 3 , and —CH 2 OH. Aspect 51.R 4 -(C=O)NR 12a R 12b 26. The compound according to any one of aspects 1 to 25, wherein: Aspect 52.R 12a and R 12b is independently selected from hydrogen and C1-C3 alkyl. Aspect 53.R 12a and R 12b 52. The compound of embodiment 51, wherein each of is hydrogen. Aspect 54.R 12a is hydrogen and R 12b is hydrogen or C1-C3 alkyl. Aspect 55.R 12a is hydrogen and R 12b is C1-C3 alkyl. Aspect 56. Formula: TIFF2025186252000031.tif33170 2. The compound of embodiment 1, having a structure represented by: Aspect 57. The compound according to aspect 56, wherein the compound is a pharmaceutically acceptable salt thereof. Embodiment 58. The compound according to embodiment 57, wherein the pharmaceutically acceptable salt is a sodium, potassium, or lithium salt. Aspect 59. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000032.tif141170, or a combination thereof. Aspect 60. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000033.tif138170, or a combination thereof. Embodiment 61. The compound according to embodiment 59 or 60, wherein the compound is a pharmaceutically acceptable salt thereof. Embodiment 62. The compound according to embodiment 61, wherein the pharmaceutically acceptable salt is a sodium, potassium, or lithium salt. Aspect 63. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000034.tif137170, or a combination thereof. Aspect 64. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000035.tif138170, or a combination thereof. Embodiment 65. The compound according to embodiment 63 or 64, wherein the compound is a pharmaceutically acceptable salt thereof. Embodiment 66. The compound according to embodiment 65, wherein the pharmaceutically acceptable salt is a sodium, potassium, or lithium salt. Aspect 67. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000036.tif135170, or a combination thereof. Aspect 68. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000037.tif127170, or a combination thereof. Embodiment 69. The compound according to embodiment 67 or 68, wherein the compound is a pharmaceutically acceptable salt thereof. Embodiment 70. The compound according to embodiment 69, wherein the pharmaceutically acceptable salt is a sodium, potassium, or lithium salt. Aspect 71. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000038.tif33170. Aspect 72. The compound according to aspect 71, wherein the compound is a pharmaceutically acceptable salt thereof. Embodiment 73. The compound according to embodiment 72, wherein the pharmaceutically acceptable salt is a sodium, potassium, or lithium salt. Aspect 74. Formula: TIFF2025186252000039.tif76170 or a combination thereof, In the formula, M p+ represents a counterion or a moiety that forms a pharmaceutically acceptable salt; and p is an integer having a value of 1, 2, or 3. Aspect 75. Formula: 75. The compound of embodiment 74, having a structure represented by TIFF2025186252000040.tif138170, or a combination thereof. Aspect 76. Formula: 75. The compound of embodiment 74, having a structure represented by TIFF2025186252000041.tif141170, or a combination thereof. Aspect 77. Formula: 75. The compound of embodiment 74, having a structure represented by TIFF2025186252000042.tif140170, or a combination thereof. Aspect 78.M p+ But Li + , K. + , Na + , ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 78. The compound of any one of embodiments 74-77, wherein the compound is selected from: Aspect 79.M + But Na + 79. The compound of embodiment 78, wherein Aspect 80. TIFF2025186252000043.tif178170 or a subgroup thereof. Aspect 81. 22. The compound of embodiment 21, wherein the compound is present as TIFF2025186252000044.tif138170 or a subgroup thereof. Aspect 82. 22. The compound of embodiment 21, wherein the compound is present as TIFF2025186252000045.tif125170 or a subgroup thereof. Aspect 83. 22. The compound of embodiment 21, wherein the compound is present as TIFF2025186252000046.tif126170 or a subgroup thereof. Aspect 84. 22. The compound of embodiment 21, wherein the compound is present as TIFF2025186252000047.tif128170 or a subgroup thereof. 85. The compound comprises a compound having a conjugate base form and a Li + , K. + , Na + , ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 85. The compound of any one of embodiments 81 to 84, which is a pharmaceutically acceptable salt thereof, comprising a counterion selected from: 86. The counter ion is Na + 83. The compound of embodiment 82, wherein Aspect 87. A compound having a formula represented by the following structure: TIFF2025186252000048.tif39170, R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R50 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from -C1-C10 aminoalkyl, -C1-C10 alkylamino, and -C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 is selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; R 40 and R 41 each independently represents -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with one, two, or three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C3 alkyl, —C1-C3 alkoxy, —C1-C3 haloalkyl, —C1-C3 aminoalkyl, —C1-C3 alkylamino, —C1-C3 haloalkylamino, —C1-C3 hydroxyalkyl, —C1-C3 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e or a pharmaceutically acceptable salt thereof, wherein four of are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3. Aspect 88.R5a But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 R is selected from the group having the formula 5b , R 5c , R 5d , and R 5e 88. The compound of embodiment 87, wherein each of is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 89.R 5a But R 20 89. The compound of embodiment 88, wherein Aspect 90.R 20 90. The compound of any one of embodiments 88 or 89, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 91.R 20 90. The compound according to any one of embodiments 88 or 89, wherein is halogen. Aspect 92.R 5b , R 5c , R 5d , and R 5e 92. The compound of any one of embodiments 87-91, wherein each of is selected from halogen and hydrogen. Aspect 93.R 5b , R 5c , R 5d , and R 5e 93. The compound of embodiment 92, wherein each of is hydrogen. Aspect 94.R 1 Aspect 94. The compound of any one of aspects 88-93, wherein is halogen. Aspect 95.R 1 95. The compound according to embodiment 94, wherein is fluoro. Aspect 96.R 5b But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 R is selected from the group having the formula 5a , R 5c , R 5d , and R 5e 88. The compound of embodiment 87, wherein each of is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 97.R 5b But R 20 97. The compound of embodiment 96, wherein Aspect 98.R 20 98. The compound according to any one of embodiments 96 to 97, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 99.R 20 98. The compound according to embodiment 96 or 97, wherein is halogen. Aspect 100.R 5a , R 5c , R 5d , and R 5e 99. The compound of any one of embodiments 96-99, wherein each of is selected from halogen and hydrogen. Aspect 101.R 5a , R 5c , R 5d , and R 5e 101. The compound according to embodiment 100, wherein each of Aspect 102.R 1 A compound according to any one of aspects 96 to 101, wherein is halogen. Aspect 103.R 1A compound according to embodiment 102, wherein is fluoro. Aspect 104.R 5c But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 40 -A 3 -R 41 R is selected from the group having the formula 5a , R 5b , R 5d , and R 5e 88. The compound of embodiment 87, wherein each of is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 105.R 5c But R 20 105. The compound according to embodiment 104, wherein Aspect 106.R 20 A compound according to any one of embodiments 104 to 105, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 107.R 20 106. The compound according to embodiment 104 or 105, wherein is halogen. Aspect 108.R 5a , R 5b , R 5d , and R 5e 108. The compound according to any one of embodiments 104 to 107, wherein each of is selected from halogen and hydrogen. Aspect 109.R 5a , R 5b , R 5d , and R 5e

[00113] A compound according to embodiment 108, wherein each of is hydrogen. Aspect 110.R 1 110. The compound according to any one of aspects 104 to 109, wherein is halogen. Aspect 111.R 1 111. The compound according to embodiment 110, wherein is fluoro. Aspect 112. TIFF2025186252000049.tif162170TIFF2025186252000050.tif184170TIFF2025186252000051.tif165170TIFF2025186252000052.tif188170TIFF2025186252000053.tif160170TIFF2025186252000054.tif31170, or a subgroup thereof. Aspect 113. 88. The compound of embodiment 87, wherein the compound is present as TIFF2025186252000055.tif165170 or a subgroup thereof. Aspect 114. The compound comprises a compound having a conjugate base form and a Li + , K. + , Na + , ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 and a counterion selected from: 115. The counter ion is Na + 115. The compound of embodiment 114, wherein

[0223] DHODH Inhibitor Compounds - Group II The disclosed DHODH inhibitors can be any DHODH inhibitor as disclosed in International Patent Application No. PCT / US20 / 66682, which is incorporated herein by reference and further described herein. For convenience, compounds of this structural type will be referred to as DHODH inhibitor compounds—Group II.

[0224] Disclosed is a compound having the structure: DHODH inhibitor compounds - Group II compounds having the formula represented by TIFF2025186252000056.tif39170, wherein Z 1 , Z 2 , Z 3 , and Z 4 are each independently selected from CH and N; 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e or a pharmaceutically acceptable salt thereof, wherein four of are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3.

[0225] The following list of exemplary embodiments supports and is supported by the disclosure provided herein for DHODH inhibitor compounds—Family II. Aspect 1. A compound having a formula represented by the structure: TIFF2025186252000057.tif38170, Z 1 , Z 2 , Z 3 , and Z 4are each independently selected from CH and N; 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n AR 1 where n is an integer selected from 1, 2, and 3; and AR 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e or a pharmaceutically acceptable salt thereof, wherein four of are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3. Aspect 2.R 1 The compound according to embodiment 1, wherein is selected from halogen, —SF5, —CF3, and —CF2CF3. Aspect 3.R 1 The compound of embodiment 2, wherein is halogen. Aspect 4.R 1 is F or Cl. Aspect 5.R 1 is F. Aspect 6.R 1 is selected from -SF5, -CF3, and -CF2CF3. Aspect 7.R 1 The compound according to embodiment 2, wherein is —SF5. Aspect 8.R5c The compound of any one of aspects 1-7, wherein is halogen, C1-C7 haloalkyl, or -O(C1-C7 haloalkyl). Aspect 9.R 5c

[0023] A compound according to embodiment 8, wherein is halogen. Aspect 10.R 5c is F. Aspect 11.R 5c is —OCF 3 , —OCH 2 CF 3 , or —OCF 2 CF 3 . Aspect 12.R 5c is —OH, —O(C1-C7 alkyl), —C1-C7 hydroxyalkyl, —O—(C1-C7 hydroxyalkyl), —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Embodiment 13. —O(C1-C7 alkyl), —(C1-C7 alkanediyl)-OH, —O(C1-C7 alkanediyl)-OH, —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 14.R 5c 14. The compound of embodiment 13, wherein is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —O(CH2)3CH3, —OCH2CH(CH3)2, —OCH(CH2CH3)(CH3), —CH2OH, —(CH2)2OH, —(CH2)3OH, —(CH2)4OH, —CH2OCH3, —CH2OCH2CH3, —CHO(CH2)2CH3, —CHOCH(CH3)2, —CHOCH(CH2CH3)2(CH3), —(CH2)2OCH3, —(CH2)2OCH2CH3, —(CH2)2O(CH2)2CH3, —(CH2)2OCH(CH3)2, or —(CH2)2OCH(CH2CH3)2(CH3). Aspect 15.R 5cis —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2OCH3, —CH2OCH2CH3, —CHO(CH2)2CH3, —CHOCH(CH3)2, —CHOCH(CH2CH3)2(CH3), —(CH2)2OCH3, —(CH2)2OCH2CH3, —(CH2)2O(CH2)2CH3, —(CH2)2OCH(CH3)2, or —(CH2)2OCH(CH2CH3)2(CH3). Aspect 16.R 5c is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2OCH3, —CH2OCH2CH3, —(CH2)2OCH3, or —(CH2)2OCH2CH3. Aspect 17.R 5c is —OCH 3 , —OCH 2 CH 3 , —CH 2 OH, —(CH 2 ) 2 OH, —CH 2 OCH 3 , or —CH 2 OCH 2 CH 3 . Aspect 18.R 5c is —OCH 3 or —OCH 2 CH 3 . Aspect 19.R 5a , R 5b , R 5d , and R 5e 19. The compound of any one of aspects 12-18, wherein each of is hydrogen. Aspect 20.R 5a But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 R is selected from the group having the formula5b , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 21.R 5a But R 20 21. The compound of embodiment 20, wherein Aspect 22.R 20 22. The compound of any one of aspects 20 or 21, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 23.R 20 22. The compound according to any one of aspects 20 or 21, wherein is halogen. Aspect 24.R 5b , R 5c , R 5d , and R 5e Aspect 24. The compound of any one of aspects 1-23, wherein each of is selected from halogen and hydrogen. Aspect 25.R 5b , R 5c , R 5d , and R 5e 25. The compound according to embodiment 24, wherein each of is hydrogen. Aspect 26.R 5b But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 R is selected from the group having the formula 5a , R 5c , R 5d , and R 5eis independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 27.R 5b But R 20 27. The compound of embodiment 26, wherein Aspect 28.R 20 28. The compound according to any one of embodiments 26 to 27, wherein is selected from —C2-C7 alkylamino and —C2-C7 alkoxy. Aspect 29.R 20 28. The compound according to embodiment 26 or 27, wherein is halogen. Aspect 30.R 5a , R 5c , R 5d , and R 5e 30. The compound of any one of embodiments 26-29, wherein each of is selected from halogen and hydrogen. Aspect 31.R 5a , R 5c , R 5d , and R 5e 31. The compound according to embodiment 30, wherein each of is hydrogen. Aspect 32.R 5c But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 R is selected from the group having the formula 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 33.R5c But R 20 33. The compound of embodiment 32, wherein Aspect 34.R 20 A compound according to any one of embodiments 32 to 33, wherein is selected from —C2-C7 alkylamino and —C2-C7 alkoxy. Aspect 35.R 20 A compound according to any one of embodiments 32 to 33, wherein is halogen. Aspect 36.R 5a , R 5b , R 5d , and R 5e A compound according to any one of embodiments 32 to 35, wherein each of is selected from halogen and hydrogen. Aspect 37.R 5a , R 5b , R 5d , and R 5e 37. The compound according to embodiment 36, wherein each of is hydrogen. formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000058.tif145170, or a subgroup thereof. Aspect 39. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000059.tif131170, or a subgroup thereof. Aspect 40. TIFF2025186252000060.tif32170TIFF2025186252000061.tif162170TIFF2025186252000062.tif155170TIFF2025186252000063.tif169170TIFF2025186252000064.tif163170TIFF2025186252000065.tif165170TIFF2025186252000066.tif189170TIFF2025186252000067.tif30170, or a subgroup thereof. Aspect 41. TIFF2025186252000068.tif95170 or a subgroup thereof. Aspect 42. The compound comprises a compound having a conjugate base form and a Li + , K. + , Na + , ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 42. The compound of any one of aspects 1-41, which is a pharmaceutically acceptable salt thereof, comprising a counterion selected from: 43. The counter ion is Na + 43. The compound of embodiment 42, wherein

[0226] DHODH inhibitor compounds - Group III. The disclosed DHODH inhibitors can be any DHODH inhibitor as disclosed in International Patent Application No. PCT / US20 / 66684, which is incorporated herein by reference and further described herein. For convenience, compounds of this structural type will be referred to as DHODH inhibitor compounds—Family III.

[0227] Disclosed is a compound having the structure: DHODH inhibitor compounds - Group III compounds having the formula represented by TIFF2025186252000069.tif38170, wherein Z 1 is a 5-membered heterocyclic diyl, and R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are each independently selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e or a pharmaceutically acceptable salt thereof, wherein four of are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3.

[0228] The following list of exemplary embodiments supports and is supported by the disclosure provided herein for DHODH inhibitor compounds—Family III. Aspect 1. A compound having a formula represented by the structure: TIFF2025186252000070.tif37170, Z 1 is a 5-membered heterocyclic diyl, and R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40A is selected from the group having the formula 1 -O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are each independently selected from -C1-C10 alkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -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 AR 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5eor a pharmaceutically acceptable salt thereof, wherein four of are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3. Aspect 2. Z1 has the structure: 2. The compound of embodiment 1, having a formula represented by TIFF2025186252000071.tif99170 or a subgroup thereof. Aspect 3.R 1 The compound according to embodiment 1, wherein is selected from halogen, —SF5, —CF3, and —CF2CF3. Aspect 4.R 1 A compound according to embodiment 3, wherein is a halogen. Aspect 5.R 1 is F or Cl. Aspect 6.R 1 is F. Aspect 7.R 1 is selected from -SF5, -CF3, and -CF2CF3. Aspect 8.R 1 The compound according to embodiment 3, wherein is —SF5. Aspect 9.R 5c The compound of any one of aspects 1-8, wherein is halogen, C1-C7 haloalkyl, or -O(C1-C7 haloalkyl). Aspect 10.R 5c

[0023] A compound according to embodiment 9, wherein is halogen. Aspect 11.R 5c is F. Aspect 12.R 5c is —OCF 3 , —OCH 2 CF 3 , or —OCF 2 CF 3 . Aspect 13.R 5c is —OH, —O(C1-C7 alkyl), —C1-C7 hydroxyalkyl, —O—(C1-C7 hydroxyalkyl), —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 14.R 5cis —O(C1-C7 alkyl), —(C1-C7 alkanediyl)-OH, —O(C1-C7 alkanediyl)-OH, —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 15.R 5c is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —O(CH2)3CH3, —OCH2CH(CH3)2, —OCH(CH2CH3)(CH3), —CH2OH, —(CH2)2OH, —(CH2)3OH, —(CH2)4OH, —CH2OCH3, —CH2OCH2CH3, —CHO(CH2)2CH3, —CHOCH(CH3)2, —CHOCH(CH2CH3)2(CH3), —(CH2)2OCH3, —(CH2)2OCH2CH3, —(CH2)2O(CH2)2CH3, —(CH2)2OCH(CH3)2, or —(CH2)2OCH(CH2CH3)2(CH3). Aspect 16.R 5c is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2OCH3, —CH2OCH2CH3, —CHO(CH2)2CH3, —CHOCH(CH3)2, —CHOCH(CH2CH3)2(CH3), —(CH2)2OCH3, —(CH2)2OCH2CH3, —(CH2)2O(CH2)2CH3, —(CH2)2OCH(CH3)2, or —(CH2)2OCH(CH2CH3)2(CH3). Aspect 17.R 5c is —OCH3, —OCH2CH3, —O(CH2)2CH3, —OCH(CH3)2, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2OCH3, —CH2OCH2CH3, —(CH2)2OCH3, or —(CH2)2OCH2CH3. Aspect 18.R 5c is —OCH 3 , —OCH 2 CH 3 , —CH 2 OH, —(CH 2 ) 2 OH, —CH 2 OCH 3 , or —CH 2 OCH 2 CH 3 . Aspect 19.R 5c is —OCH 3 or —OCH 2 CH 3 . Aspect 20.R 5a , R 5b , R 5d , and R 5e 20. The compound of any one of aspects 13-19, wherein each of is hydrogen. Aspect 21.R 5a But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 R is selected from the group having the formula 5b , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 22.R 5a But R 20 22. The compound of embodiment 21, wherein Aspect 23.R 20 Aspect 23. The compound of any one of aspects 21 or 22, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 24.R 20 23. The compound according to any one of aspects 21 or 22, wherein is halogen. Aspect 25.R 5b , R 5c , R 5d , and R 5e Aspect 25. The compound of any one of aspects 1-24, wherein each of is selected from halogen and hydrogen. Aspect 26.R 5b, R 5c , R 5d , and R 5e 26. The compound according to embodiment 25, wherein each of is hydrogen. Aspect 27.R 5b But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 R is selected from the group having the formula 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 28.R 5b But R 20 28. The compound of embodiment 27, wherein Aspect 29.R 20 A compound according to any one of embodiments 27 to 28, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 30.R 20 29. The compound according to embodiment 27 or 28, wherein is halogen. Aspect 31.R 5a , R 5c , R 5d , and R 5e A compound according to any one of embodiments 27 to 30, wherein each of is selected from halogen and hydrogen. Aspect 32.R 5a , R 5c , R 5d , and R 5e 32. The compound according to embodiment 31, wherein each of is hydrogen. Aspect 33.R 5cBut, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 R is selected from the group having the formula 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 34.R 5c But R 20 34. The compound of embodiment 33, wherein Aspect 35.R 20 A compound according to any one of aspects 33 and 34, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 36.R 20 A compound according to any one of embodiments 33 to 34, wherein is halogen. Aspect 37.R 5a , R 5b , R 5d , and R 5e 37. The compound of any one of embodiments 33-36, wherein each of is selected from halogen and hydrogen. Aspect 38.R 5a , R 5b , R 5d , and R 5e 38. The compound according to embodiment 37, wherein each of Aspect 39. TIFF2025186252000072.tif131170 or a subgroup thereof. Aspect 40. The compound comprises a compound having a conjugate base form and a Li +, K. + , Na + , ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 and a counterion selected from: 41. The counter ion is Na + 115. The compound of embodiment 114, wherein

[0229] DHODH Inhibitor Compounds - Group IV The disclosed DHODH inhibitors can be any DHODH inhibitor as disclosed in International Patent Application No. PCT / US20 / 67065, which is incorporated herein by reference and further described herein. For convenience, compounds of this structural type will be referred to as DHODH inhibitor compounds—Group IV.

[0230] Disclosed is a compound having the structure: DHODH inhibitor compounds—Group IV compounds having the formula represented by TIFF2025186252000073.tif38170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is halogen, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1 is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1 is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0231] Disclosed herein is a compound having the structure: TIFF2025186252000074.tif38170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1-O- and -NR 50 - selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 - selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 - selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5efour of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d are each independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0232] Disclosed herein is a compound having the structure: TIFF2025186252000075.tif39170, wherein R 1 is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of them has the structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5efour of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d are each independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, R 6a , R 6b , R 6c , and R 6d can be independently selected from hydrogen, halogen, C-C alkyl, C-C alkoxy, and C-C haloalkyl. 6a and R 6b is independently selected from hydrogen and halogen. 6a is fluoro or R 6b is fluoro, or a combination thereof. 6c and R 6d can be hydrogen.

[0234] The following list of exemplary embodiments supports and is supported by the disclosure provided herein for DHODH inhibitor compounds—Group IV. Aspect 1. A compound having a formula represented by the structure: DHODH inhibitor compounds—Group IV compounds having the formula represented by TIFF2025186252000076.tif37170, wherein R 1is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of the structures:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is halogen, -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 hydroxyalkyl, -C1-C10 alkylamino, -C1-C10 alkoxy, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40 is -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, -(CH2) n Cy 1 , and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Cy 1is a C3-C10 cycloalkyl group or a C2-C9 heterocycloalkyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof. Aspect 2. A compound having a formula represented by the structure: TIFF2025186252000077.tif38170, R 1is selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, —CF3, and —CF2CF3; R 5a , R 5b , R 5c , R 5d , and R 5e One of them has the structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 A is selected from the group having the formula 1 -O- and -NR 50 Selected from R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 2 -O- and -NR 60 Selected from R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; A 3 -O- and -NR 70 Selected from R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl; R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy; R 30 and R 31 are independently selected from -C1-C10 alkanediyl, -C1-C10 haloalkanediyl, -C1-C10 aminoalkanediyl, and -C1-C10 hydroxyalkanediyl; 40is selected from -C1-C10 alkyl, -C1-C10 haloalkyl, -C1-C10 aminoalkyl, -C1-C10 hydroxyalkyl, and -(CH2) n Ar 1 wherein n is an integer selected from 1, 2, and 3; and Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl; R 5a , R 5b , R 5c , R 5d , and R 5e four of R are independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, —CF, and —CFCF; 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d are independently selected from hydrogen, halogen, —SF5, —CN, —N3, —OH, —NH2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C1-C10 hydroxyalkyl, or a pharmaceutically acceptable salt thereof. Aspect 3.R 1 A compound according to any one of embodiments 1 to 2, wherein is selected from halogen, —SF5, —CF3, and —CF2CF3. Aspect 4.R 1 The compound of embodiment 3, wherein is halogen or -SF5. Aspect 5.R 1 The compound of embodiment 4, wherein is —F or —Cl. Aspect 6.R1 A compound according to embodiment 4, wherein is —F. Aspect 7.R 1 The compound of embodiment 4, wherein is —Cl. Aspect 8.R 1 The compound of embodiment 4, wherein is —SF5. Aspect 9.R 1 is selected from -SF5, -CF3, and -CF2CF3. Aspect 10.R 1 A compound according to embodiment 9, wherein is —SF5. Aspect 11.R 1 is selected from -CF3 and -CF2CF3. Aspect 12.R 5c The compound of any one of aspects 1-11, wherein is halogen, C1-C7 haloalkyl, or -O(C1-C7 haloalkyl). Aspect 13.R 5c 13. The compound according to embodiment 12, wherein is halogen. Aspect 14.R 5c is F. Aspect 15.R 5c is —OCF 3 , —OCH 2 CF 3 , or —OCF 2 CF 3 . Aspect 16.R 5c is —OH, —O(C1-C7 alkyl), —C1-C7 hydroxyalkyl, —O—(C1-C7 hydroxyalkyl), —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 17.R 5c is —O(C1-C7 alkyl), —(C1-C7 alkanediyl)-OH, —O(C1-C7 alkanediyl)-OH, —CHO(C1-C7 alkyl), or —(CH)O(C1-C7 alkyl). Aspect 18.R 5c is —OCH 3 or —OCH 2 CH 3 . Aspect 19.R 5a , R5b , R 5d , and R 5e 19. The compound of any one of aspects 16-18, wherein each of is hydrogen. Aspect 20.R 5a But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 R is selected from the group having the formula 5b , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 21.R 5a But R 20 21. The compound of embodiment 20, wherein Aspect 22.R 20 22. The compound of any one of aspects 20 or 21, wherein is selected from -C2-C7 alkylamino and -C2-C7 alkoxy. Aspect 23.R 20 22. The compound according to any one of aspects 20 or 21, wherein is halogen. Aspect 24.R 5b , R 5c , R 5d , and R 5e Aspect 24. The compound of any one of aspects 1-23, wherein each of is selected from halogen and hydrogen. Aspect 25.R 5b , R 5c , R 5d , and R 5e 25. The compound according to embodiment 24, wherein each of is hydrogen. Aspect 26.R 5b But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 R is selected from the group having the formula 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CF3, and -CF2CF3. Aspect 27.R 5b But R 20 27. The compound of embodiment 26, wherein Aspect 28.R 20 28. The compound according to any one of embodiments 26 to 27, wherein is selected from —C2-C7 alkylamino and —C2-C7 alkoxy. Aspect 29.R 20 28. The compound according to embodiment 26 or 27, wherein is halogen. Aspect 30.R 5a , R 5c , R 5d , and R 5e 30. The compound of any one of embodiments 26-29, wherein each of is selected from halogen and hydrogen. Aspect 31.R 5a , R 5c , R 5d , and R 5e 31. The compound according to embodiment 30, wherein each of is hydrogen. Aspect 32.R 5c But, structure:-R 20 , -R 30 -A 1 -R 40 , -A 1 -R40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 R is selected from the group having the formula 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 . Aspect 33.R 5c But R 20 33. The compound of embodiment 32, wherein Aspect 34.R 20 A compound according to any one of embodiments 32 to 33, wherein is selected from —C2-C7 alkylamino and —C2-C7 alkoxy. Aspect 35.R 20 A compound according to any one of embodiments 32 to 33, wherein is halogen. Aspect 36.R 5a , R 5b , R 5d , and R 5e A compound according to any one of embodiments 32 to 35, wherein each of is selected from halogen and hydrogen. Aspect 37.R 5a , R 5b , R 5d , and R 5e 37. The compound according to embodiment 36, wherein each of is hydrogen. Aspect 38.R 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6dis independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl. Aspect 39.R 6a and R 6b is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 40.R 6a and R 6b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 41.R 6a and R 6b is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 42.R 6a and R 6c is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 43.R 6a and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 44.R 6a and R 6c is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 45.R 6a and R 6d is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 46.R 6a and R 6d is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 47.R 6a and R 6d is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 48.R 6a is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 49.R 6a is selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 50.R 6b is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 51.R 6a is selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Aspect 52.R 6c and R 6d 52. The compound of any one of embodiments 1-51, wherein each of is hydrogen. Aspect 53.R 6a is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b , R 6c , and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 54.R 6a is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 55.R6a 55. The compound of embodiment 54, wherein is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 56.R 6a 56. The compound according to embodiment 55, wherein is —F. Aspect 57.R 6b is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a , R 6c , and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 58.R 6b is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 59.R 6b is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 60.R 6b 60. The compound of embodiment 59, wherein is —F. Aspect 61.R 6a and R 6b are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6c and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 62.R 6a and R 6b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 63.R 6a and R 6bis independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 64.R 6a and R 6b 41. The compound according to embodiment 40, wherein each of Aspect 65.R 6a and R 6c are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 66.R 6a and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 67.R 6a and R 6c is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 68.R 6a and R 6c 41. The compound according to embodiment 40, wherein each of Aspect 69.R 6a and R 6d are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6c Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 70.R 6a and R 6dis independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 71.R 6a and R 6d is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 72.R 6a and R 6d 41. The compound according to embodiment 40, wherein each of Aspect 73.R 6b and R 6c are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a and R 6d Aspect 38. The compound of any one of aspects 1-37, wherein each of is hydrogen. Aspect 74.R 6b and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 75.R 6b and R 6c is independently selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 76.R 6b and R 6c 41. The compound according to embodiment 40, wherein each of Aspect 77.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 78.R 20Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 79.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 80.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Aspect 81.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 82.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 83.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 84.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 85.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 86.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 87.R 20The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 88.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 89.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 90.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Aspect 91.R 20 Aspect 77. The compound of any one of aspects 1-76, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Aspect 92.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 93.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 94.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 95.R 20 The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 96.R 20The compound of any one of aspects 1-76, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 97.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C6-C10 alkanediyl, —C6-C10 aminoalkanediyl, and —C6-C10 hydroxyalkanediyl. Aspect 98.R 30 and R 31 is independently selected from hydrogen, —C6-C8 alkanediyl, —C6-C8 aminoalkanediyl, and —C6-C8 hydroxyalkanediyl. Aspect 99.R 30 and R 31 The compound of any one of embodiments 1-76, wherein each of is independently selected from hydrogen, —C5-C10 alkanediyl, —C5-C10 aminoalkanediyl, and —C5-C10 hydroxyalkanediyl. Aspect 100.R 30 and R 31 The compound of any one of embodiments 1-76, wherein each of is independently selected from hydrogen, —C5-C8 alkanediyl, —C5-C8 aminoalkanediyl, and —C5-C8 hydroxyalkanediyl. Aspect 101.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C5-C6 alkanediyl, —C5-C6 aminoalkanediyl, and —C5-C6 hydroxyalkanediyl. Aspect 102.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C4-C10 alkanediyl, —C4-C10 aminoalkanediyl, and —C4-C10 hydroxyalkanediyl. Aspect 103.R 30 and R31 is independently selected from hydrogen, —C4-C8 alkanediyl, —C4-C8 aminoalkanediyl, and —C4-C8 hydroxyalkanediyl. Aspect 104.R 30 and R 31 is independently selected from hydrogen, —C4-C6 alkanediyl, —C4-C6 aminoalkanediyl, and —C4-C6 hydroxyalkanediyl. Aspect 105.R 30 and R 31 is independently selected from hydrogen, —C4-C5 alkanediyl, —C4-C5 aminoalkanediyl, and —C4-C5 hydroxyalkanediyl. Aspect 106.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C3-C10 alkanediyl, —C3-C10 aminoalkanediyl, and —C3-C10 hydroxyalkanediyl. Aspect 107.R 30 and R 31 is independently selected from hydrogen, —C3-C8 alkanediyl, —C3-C8 aminoalkanediyl, and —C3-C8 hydroxyalkanediyl. Aspect 108.R 30 and R 31 is independently selected from hydrogen, —C3-C6 alkanediyl, —C3-C6 aminoalkanediyl, and —C3-C6 hydroxyalkanediyl. Aspect 109.R 30 and R 31 The compound of any one of aspects 1-76, wherein each of is independently selected from hydrogen, —C3-C5 alkanediyl, —C3-C5 aminoalkanediyl, and —C3-C5 hydroxyalkanediyl. Aspect 110.R 30 and R 31 is independently selected from hydrogen, —C3-C4 alkanediyl, —C3-C4 aminoalkanediyl, and —C3-C4 hydroxyalkanediyl. Aspect 111.R 30 and R 31 The compound of any one of embodiments 1-76, wherein each of is independently selected from hydrogen, —C2-C10 alkanediyl, —C2-C10 aminoalkanediyl, and —C2-C10 hydroxyalkanediyl. Aspect 112.R 30 and R 31 is independently selected from hydrogen, —C2-C8 alkanediyl, —C2-C8 aminoalkanediyl, and —C2-C8 hydroxyalkanediyl. Aspect 113.R 30 and R 31 is independently selected from hydrogen, —C2-C6 alkanediyl, —C3-C6 aminoalkanediyl, and —C2-C6 hydroxyalkanediyl. Aspect 114.R 30 and R 31 is independently selected from hydrogen, —C2-C5 alkanediyl, —C2-C5 aminoalkanediyl, and —C2-C5 hydroxyalkanediyl. Aspect 115.R 30 and R 31 is independently selected from hydrogen, —C2-C4 alkanediyl, —C2-C4 aminoalkanediyl, and —C2-C4 hydroxyalkanediyl. Aspect 116.R 30 and R 31is independently selected from hydrogen, —C2-C3 alkanediyl, —C2-C3 aminoalkanediyl, and —C2-C3 hydroxyalkanediyl. Aspect 117.R 40 Aspect 117. The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 118.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 119.R 40 The compound according to any one of embodiments 1-116, wherein is selected from hydrogen, —C5-C10 alkyl, —C5-C10 aminoalkyl, and —C5-C10 hydroxyalkyl. Aspect 120.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Manner 121.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 122.R 40 Aspect 117. The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 123.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 124.R 40 The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 125.R 40 The compound according to any one of aspects 1-116, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 126.R 40 The compound according to any one of aspects 1-116, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 127.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 128.R 40 The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Manner 129.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 130.R 40 The compound of any one of aspects 1-116, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Aspect 131.R 40 The compound according to any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C10 alkyl, —C2-C10 aminoalkyl, and —C2-C10 hydroxyalkyl. Aspect 132.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 133.R 40The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 134.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 135.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 136.R 40 The compound of any one of embodiments 1-116, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 137.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 138.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 139.R 50 Aspect 137. The compound according to any one of aspects 1-136, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 140.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Aspect 141.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 142.R50 Aspect 137. The compound according to any one of aspects 1-136, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 143.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 144.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 145.R 50 The compound according to any one of aspects 1-136, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 146.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 147.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 148.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 149.R 50 The compound according to any one of aspects 1-136, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 150.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Aspect 151.R 50 Aspect 137. The compound of any one of aspects 1-136, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Aspect 152.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 153.R 50 The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 154.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 155.R 50 The compound of any one of aspects 1-136, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 156.R 50 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 157.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 158.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Aspect 159.R 60 Aspect 157. The compound according to any one of aspects 1-156, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 160.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C5-C8 alkyl, —C5-C8 aminoalkyl, and —C5-C8 hydroxyalkyl. Aspect 161.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 162.R 60 Aspect 157. The compound according to any one of aspects 1-156, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 163.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 164.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 165.R 60 The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 166.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 167.R 60 The compound of any one of embodiments 1-136, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 168.R 60The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 169.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Aspect 170.R 60 The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Manner 171.R 60 Aspect 157. The compound of any one of aspects 1-156, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Aspect 172.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 173.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 174.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 175.R 60 The compound of any one of aspects 1-156, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 176.R 60 The compound of any one of embodiments 1-156, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 177.R 70Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C6-C10 alkyl, —C6-C10 aminoalkyl, and —C6-C10 hydroxyalkyl. Aspect 178.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C6-C8 alkyl, —C6-C8 aminoalkyl, and —C6-C8 hydroxyalkyl. Manner 179.R 70 Aspect 177. The compound according to any one of aspects 1-176, wherein is selected from hydrogen, -C5-C10 alkyl, -C5-C10 aminoalkyl, and -C5-C10 hydroxyalkyl. Aspect 180.R 70 Aspect 177. A compound according to any one of aspects 1 to 176, wherein is selected from hydrogen, -C5-C8 alkyl, -C5-C8 aminoalkyl, and -C5-C8 hydroxyalkyl. Aspect 181.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C5-C6 alkyl, —C5-C6 aminoalkyl, and —C5-C6 hydroxyalkyl. Aspect 182.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C4-C10 alkyl, —C4-C10 aminoalkyl, and —C4-C10 hydroxyalkyl. Aspect 183.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C4-C8 alkyl, —C4-C8 aminoalkyl, and —C4-C8 hydroxyalkyl. Aspect 184.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C4-C6 alkyl, —C4-C6 aminoalkyl, and —C4-C6 hydroxyalkyl. Aspect 185.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C4-C5 alkyl, —C4-C5 aminoalkyl, and —C4-C5 hydroxyalkyl. Aspect 186.R70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C3-C10 alkyl, —C3-C10 aminoalkyl, and —C3-C10 hydroxyalkyl. Aspect 187.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C3-C8 alkyl, —C3-C8 aminoalkyl, and —C3-C8 hydroxyalkyl. Aspect 188.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, —C3-C6 alkyl, —C3-C6 aminoalkyl, and —C3-C6 hydroxyalkyl. Aspect 189.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C3-C5 alkyl, —C3-C5 aminoalkyl, and —C3-C5 hydroxyalkyl. Manner 190.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C3-C4 alkyl, —C3-C4 aminoalkyl, and —C3-C4 hydroxyalkyl. Manner 191.R 70 Aspect 177. The compound of any one of aspects 1-176, wherein is selected from hydrogen, -C2-C10 alkyl, -C2-C10 aminoalkyl, and -C2-C10 hydroxyalkyl. Manner 192.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C8 alkyl, —C2-C8 aminoalkyl, and —C2-C8 hydroxyalkyl. Aspect 193.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C6 alkyl, —C3-C6 aminoalkyl, and —C2-C6 hydroxyalkyl. Aspect 194.R 70 The compound according to any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C5 alkyl, —C2-C5 aminoalkyl, and —C2-C5 hydroxyalkyl. Aspect 195.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C4 alkyl, —C2-C4 aminoalkyl, and —C2-C4 hydroxyalkyl. Aspect 196.R 70 The compound of any one of embodiments 1-176, wherein is selected from hydrogen, —C2-C3 alkyl, —C2-C3 aminoalkyl, and —C2-C3 hydroxyalkyl. Aspect 197.A 1 is selected from —O—, —NH—, —NCH3—, —NCH2CH3—, —N(CH2)2CH3—, —NCH(CH3)2—, —N(CH2)3CH3—, and —N(CH2)4CH3—. Aspect 198.A 1 198. The compound according to embodiment 197, wherein is selected from —O—, —NH—, —NCH 3 —, and —NCH 2 CH 3 —. Aspect 199.A 1 198. The compound according to embodiment 197, wherein is —O—. Aspect 200.A 1 198. The compound according to embodiment 197, wherein is —NH—. Aspect 201.A 1 198. The compound according to embodiment 197, wherein is —NCH3—. Aspect 202.A 1 198. The compound according to embodiment 197, wherein is —NCH 2 CH 3 —. Aspect 203.A 2 The compound of any one of embodiments 1 to 202, wherein is selected from —O—, —NH—, —NCH3—, —NCH2CH3—, —N(CH2)2CH3—, —NCH(CH3)2—, —N(CH2)3CH3—, and —N(CH2)4CH3—. Aspect 204.A 2 204. The compound according to embodiment 203, wherein is selected from —O—, —NH—, —NCH 3 —, and —NCH 2 CH 3 —. Aspect 205.A 2 204. The compound according to embodiment 203, wherein is —O—. Aspect 206.A 2204. The compound according to embodiment 203, wherein is —NH—. Aspect 207.A 2 204. The compound according to embodiment 203, wherein is —NCH 3 —. Aspect 208.A 2 204. The compound according to embodiment 203, wherein is —NCH 2 CH 3 —. Aspect 209.A 3 The compound of any one of embodiments 1 to 208, wherein is selected from —O—, —NH—, —NCH 3 —, —NCH 2 CH 3 —, —N(CH 2 ) 2 CH 3 —, —NCH(CH 3 ) 2 —, —N(CH 2 ) 3 CH 3 —, and —N(CH 2 ) 4 CH 3 —. Aspect 210.A 3 210. The compound according to embodiment 209, wherein is selected from —O—, —NH—, —NCH 3 —, and —NCH 2 CH 3 —. Aspect 211.A 3 210. The compound according to embodiment 209, wherein is —O—. Aspect 212.A 3 209. The compound according to embodiment 209, wherein is —NH—. Aspect 213.A 3 209. The compound according to embodiment 209, wherein Aspect 214.A 3 209. The compound according to embodiment 209, wherein is —NCH 2 CH 3 —. Aspect 215.Ar 1 The compound according to any one of embodiments 1 to 214, wherein is an unsubstituted phenyl group. Aspect 216.Ar 1 is a phenyl group substituted with one group selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl. Aspect 217.Ar 1is a phenyl group substituted with one group selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —OCH3, —NHCH3, —N(CH3)2, —CH2OH, —CH3, —CH2Cl, —CHCl2, —CCl3, —CHF2, —CH2F, and —CF3. Aspect 218.Ar 1 217. The compound according to embodiment 216, wherein is a phenyl group substituted with one group selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 219.Ar 1 217. The compound according to embodiment 216, wherein is a phenyl group substituted with one group selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 220.Ar 1 is a phenyl group substituted with two groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl. Aspect 221.Ar 1 is a phenyl group substituted with two groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —OCH3, —NHCH3, —N(CH3)2, —CH2OH, —CH3, —CH2Cl, —CHCl2, —CCl3, —CHF2, —CH2F, and —CF3. Aspect 222.Ar 1 is a phenyl group substituted with two groups independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 223.Ar 1is a phenyl group substituted with two groups independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 224.Ar 1 is a phenyl group substituted with three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —C1-C4 alkyl, —C1-C4 alkoxy, —C1-C4 haloalkyl, —C1-C4 aminoalkyl, —C1-C4 alkylamino, —C1-C4 haloalkylamino, —C1-C4 hydroxyalkyl, —C1-C4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl. Aspect 225.Ar 1 is a phenyl group substituted with three groups independently selected from halogen, —SF5, —CN, —N3, —OH, —NH2, —OCH3, —NHCH3, —N(CH3)2, —CH2OH, —CH3, —CH2Cl, —CHCl2, —CCl3, —CHF2, —CH2F, and —CF3. Aspect 226.Ar 1 is a phenyl group substituted with three groups independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 227.Ar 1 is a phenyl group substituted with three groups independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 228. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000078.tif169170, or a combination thereof. Aspect 229. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000079.tif98170, or a combination thereof. Aspect 230. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000080.tif100170, or a combination thereof. Aspect 231. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000081.tif94170, or a combination thereof. Aspect 232. Formula: 2. The compound of embodiment 1, having a structure represented by: TIFF2025186252000082.tif94170TIFF2025186252000083.tif104170, or a combination thereof. Aspect 233. Formula: 2. The compound of embodiment 1, having a structure represented by: TIFF2025186252000084.tif62170TIFF2025186252000085.tif135170, or a combination thereof. Aspect 234. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000086.tif95170, or a combination thereof. Aspect 235. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000087.tif127170, or a combination thereof. Aspect 236. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000088.tif71170, or a combination thereof. Aspect 237. Formula: 2. The compound of embodiment 1, having a structure represented by TIFF2025186252000089.tif105170, or a combination thereof. Manner 238.R 1 The compound according to any one of embodiments 228-237, wherein is selected from halogen, —SF 5 , —CF 3 , and —CF 2 CF 3 . Manner 239.R 1239. The compound according to embodiment 238, wherein is halogen or —SF 5 . Aspect 240.R 1 239. The compound according to embodiment 238, wherein is —F or —Cl. Aspect 241.R 1 239. The compound according to embodiment 238, wherein is —F. Aspect 242.R 1 239. The compound according to embodiment 238, wherein is —Cl. Aspect 243.R 1 239. The compound according to embodiment 238, wherein is —SF5. Aspect 244.R 1 is selected from -CF3 and -CF2CF3. Aspect 245.R 6a , R 6b , R 6c , and R 6d provided that at least one of R 6a , R 6b , R 6c , and R 6d is independently selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl. Aspect 246.R 6a and R 6b is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 247.R 6a and R 6b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Aspect 248.R 6a and R 6bis independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 249.R 6a and R 6c is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 250.R 6a and R 6c is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 251.R 6a and R 6c is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 252.R 6a and R 6d is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 253.R 6a and R 6d is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 254.R 6a and R 6d is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 255.R 6a 246. The compound according to embodiment 245, wherein is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 256.R 6a is selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 257.R 6b 246. The compound according to embodiment 245, wherein is selected from —F, —Cl, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 258.R 6a is selected from —F, —SF 5 , —CN, —N 3 , —OH, and —NH 2 . Manner 259.R 6c and R 6d 259. The compound of any one of embodiments 245 to 259, wherein each of is hydrogen. Manner 260.R 6a is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b , R 6c , and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 261.R 6a 261. The compound according to embodiment 260, wherein is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 262.R 6a 262. The compound according to embodiment 261, wherein is selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 263.R 6a 263. The compound according to embodiment 262, wherein Aspect 264.R 6b is selected from hydrogen, halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a , R 6c , and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Aspect 265.R 6b265. The compound according to embodiment 264, wherein is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 266.R 6b 266. The compound of embodiment 265, wherein is selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 267.R 6b 267. The compound according to embodiment 266, wherein is —F. Manner 268.R 6a and R 6b are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6c and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 269.R 6a and R 6b 269. The compound according to embodiment 268, wherein each of is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 270.R 6a and R 6b 270. The compound of embodiment 269, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 271.R 6a and R 6b 271. The compound according to embodiment 270, wherein each of Manner 272.R 6a and R 6c are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6dThe compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 273.R 6a and R 6c 273. The compound according to embodiment 272, wherein each of is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 274.R 6a and R 6c 274. The compound of embodiment 273, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 275.R 6a and R 6c 275. The compound according to embodiment 274, wherein each of Manner 276.R 6a and R 6d are each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6b and R 6c The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 277.R 6a and R 6d 277. The compound according to embodiment 276, wherein each b is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 278.R 6a and R 6d 278. The compound of embodiment 277, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Manner 279.R 6a and R 6d 279. The compound according to embodiment 278, wherein each of Aspect 280.R 6b and R 6care each independently selected from halogen, —SF, —CN, —N, —OH, —NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C aminoalkyl, and C-C hydroxyalkyl; R 6a and R 6d The compound of any one of embodiments 228-237, wherein each of is hydrogen. Manner 281.R 6b and R 6c 281. The compound according to embodiment 280, wherein each of is independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CHF 2 , —CH 2 F, and —CF 3 . Manner 282.R 6b and R 6c 282. The compound of embodiment 281, wherein each of is independently selected from -F, -Cl, -SF5, -CN, -N3, -OH, -NH2, -CHF2, -CH2F, and -CF3. Aspect 283.R 6b and R 6c 283. The compound according to embodiment 282, wherein each of Aspect 284. Formula: 2. The compound of embodiment 1, having a structure represented by: TIFF2025186252000090.tif33170TIFF2025186252000091.tif171170TIFF2025186252000092.tif165170TIFF2025186252000093.tif98170, or a combination thereof. Aspect 285. TIFF2025186252000094.tif64170TIFF2025186252000095.tif164170TIFF2025186252000096.tif164170TIFF2025186252000097.tif165170TIFF2025186252000098.tif189170TIFF2025186252000099.tif168170, or a subgroup thereof. Aspect 286. TIFF2025186252000100.tif63170, or a combination thereof. Aspect 287. The compound is a compound selected from the group consisting of a conjugate base form of the compound and Li+, K+, Na+, ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 and a counterion selected from: 288. The counter ion is Na + The compound of embodiment 0, wherein

[0235] DHODH inhibitor compounds - Group V The disclosed DHODH inhibitors can be other DHODH inhibitors as disclosed herein below, referred to as DHODH inhibitor compounds—Group V.

[0236] In various embodiments, DHODH inhibitor compounds disclosed herein—exemplary DHODH inhibitors of Group V include brequinar, leflunomide, redoxal, bidofluzimus, S-2678, 2-(3,5-difluoro-3′-methoxybiphenyl-4-ylamino)nicotinic acid (also known as ASLAN003), BAY-2402234 (—N-(2-chloro-6-fluorophenyl)-4-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)-2-methyl-2-propan-2-yl)oxy). benzamide), AG-636 (1-methyl-5-(2'-methyl[1,1'-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid), PTC-299 (4-chlorophenyl (S)-6-chloro-1-(4-methoxyphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate), JNJ-74856665, Meds433, RP7214, ML390, laflunimus, tenovin-1, tenovin-6, hDHODH-IN-4, DHODH-IN-11, and teriflunomide.

[0237] In various embodiments, the DHODH inhibitor compounds disclosed herein—exemplary DHODH inhibitors of Group V are represented by formula (II) (disclosed in WO2008 / 077639, incorporated herein by reference): TIFF2025186252000101.tif73170, teriflunomide, leflunomide, ●Basic G 1 One of the groups is a nitrogen atom or a group CR c and the other group represents CR c represents ●G 2 is a nitrogen atom or a group CR d represents ●R 1 C may be optionally substituted with 1, 2, or 3 substituents selected from halogen, hydroxy, and halogen and hydroxyl. 3-8cycloalkyl, which may be optionally substituted with 1, 2, or 3 substituents selected from the group including hydrogen, halogen, C 1-4 alkyl, ●R 2 C may be optionally substituted with 1, 2, or 3 substituents selected from halogen, hydroxy, and halogen and hydroxyl. 3-8 cycloalkyl, which may be optionally substituted with 1, 2, or 3 substituents selected from the group including hydrogen, halogen, C 1-4 alkyl, ●R a , R b , and R c are independently halogen, hydroxy, and C 1-4 hydrogen, halogen, C optionally substituted by 1, 2, or 3 substituents selected from the group including alkoxy 1-4 represents a radical selected from the group including alkyl, ●R d C may be optionally substituted with 1, 2, or 3 substituents selected from halogen, hydroxy, and halogen and hydroxyl. 3-8 cycloalkyl, which may be optionally substituted with 1, 2, or 3 substituents selected from the group including halogen, hydroxyl, C 1-4 hydrogen, halogen, hydroxyl, C, which may be substituted by 1, 2, or 3 substituents selected from the group including alkoxy; 1-4 alkyl, ●G 3 and G 4 one of which is a nitrogen atom and the other is CH, • M is hydrogen or a pharmaceutically acceptable cation.

[0238] In a further aspect, the compound of formula (II) comprises a group R a and R b At least one of represents a hydrogen atom, and G 2 Based on CR d When R dC, which may be optionally substituted with 1, 2, or 3 substituents selected from halogen, hydroxy, and halogen and hydroxyl; 3-8 cycloalkyl, C 1-4 with the proviso that it represents a group selected from alkoxy.

[0239] In a further aspect, an exemplary DHODH inhibitor of DHODH inhibitor compounds—Group V is 2-(3,5-difluoro-3′-methoxybiphenyl-4-ylamino)nicotinic acid (referred to herein as ASLAN003) or a pharmaceutically acceptable salt thereof, particularly: It could be TIFF2025186252000102.tif58170.

[0240] In a further aspect, exemplary DHODH inhibitors of Group V—DHODH inhibitor compounds that may be employed in the methods or pharmaceutical combinations of the present disclosure include: Teriflunomide, which has the following structure: TIFF2025186252000103.tif47170 Compounds disclosed in WO97 / 34600, which is incorporated herein by reference; Leflunomide, which has the following structure: TIFF2025186252000104.tif43170 ● DHODH inhibitors of formula (1) as disclosed in WO99 / 45926, which is incorporated herein by reference; - compounds of formula (1) as disclosed in WO2003 / 006425, which is incorporated herein by reference; - DHODH inhibitors of formula (1) as disclosed in WO2004 / 056746, which is incorporated herein by reference; - compounds of formula (1) as disclosed in WO2006 / 022442, which is incorporated herein by reference; and - Includes the DHODH inhibitors disclosed in WO2009 / 021696, which is incorporated herein by reference. Suitable salts of DHODH inhibitors include those disclosed in WO2010 / 102826, WO2010 / 10225, and WO2010 / 102824, each of which is incorporated herein by reference.

[0241] In a further aspect, DHODH inhibitor compounds—Exemplary DHODH inhibitors of Group V have the structure: TIFF2025186252000105.tif39170, wherein A is an aromatic or non-aromatic 5- or 6-membered hydrocarbon ring, and optionally one or more of the carbon atoms is replaced with a group X, where X is independently S, O, N, NR 4 , SO2, and SO; L is a single bond or NH; D is selected from the group consisting of 0, S, SO2, NR 4 , or CH2, and Z 1 is 0, S, or NR 5 and Z 2 is 0, S, or NR 5 and R 1independently represent H, halogen, haloalkanyl, haloalkenyl, haloalkynyl, haloalkanyloxy, haloalkenyloxy, haloalkynyloxy, -CO2R"; -SO3H, -OH, -CONR*R"; -CR"O, -SO2-NR*R"; -NO2, -SO2-R"; -SO-R*; -CN, alkanyloxy, alkenyloxy, alkynyloxy, alkanylthio, alkenylthio, alkynylthio, aryl, -NR"-CO2-R'; -NR"-CO-R*; -NR"-SO2-R'; -O-CO-R*; -O-CO2-R* , -O-CO-NR*R", cycloalkyl, heterocycloalkyl, alkanylamino, alkenylamino, alkynylamino, hydroxyalkanylamino, hydroxyalkenylamino, hydroxyalkynylamino, -SH, heteroaryl, alkanyl, alkenyl, or alkynyl, and R* independently represents H, alkanyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aminoalkanyl, aminoalkenyl, aminoalkynyl, alkanyloxy, alkenyloxy, alkynyloxy, -OH, -SH, alkani represents thio, alkenylthio, alkynylthio, hydroxyalkanyl, hydroxyalkenyl, hydroxyalkynyl, haloalkanyl, haloalkenyl, haloalkynyl, haloalkanyloxy, haloalkenyloxy, haloalkynyloxy, aryl, or heteroaryl, and R' is independently H, -CO2R", -CONR"R'", -CR"O, -SO2NR", -NR"-CO-haloalkanyl, haloalkenyl, haloalkynyl, -NO2, -NR"-SO2-haloalkanyl, haloalkenyl, haloalkynyl, -NR"-SO2-a alkanyl, -NR"-SO2-alkenyl, -NR"-SO2-alkynyl, -SO2-alkanyl, -SO2-alkenyl, -SO2-alkynyl, -NR"-CO-alkanyl, -NR"-CO-alkenyl, -NR"-CO-alkynyl, -CN, alkanyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aminoalkanyl, aminoalkenyl, aminoalkynyl, alkanylamino, alkenylamino, alkynylamino, alkanyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, -OH, -SH,R" independently represents hydrogen, haloalkanyl, haloalkenyl, haloalkynyl, hydroxyalkanyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyalkanylamino, hydroxyalkenylamino, hydroxyalkynylamino, halogen, haloalkanyl, haloalkenyl, haloalkynyl, haloalkanyloxy, haloalkenyloxy, haloalkynyloxy, aryl, aralkyl, or heteroaryl; R" independently represents hydrogen, haloalkanyl, haloalkenyl, haloalkynyl, hydroxyalkanyl, hydroxyalkenyl, hydroxyalkynyl, alkanyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminoalkanyl, aminoalkenyl, or aminoalkynyl; R'" independently represents H or alkanyl; R, 2 is H or OR 6 , NHR 7 , N.R. 7 OR 7 or R 2 forms a 5- to 7-membered, preferably 5- or 6-membered heterocyclic ring together with the nitrogen atom bonded to R8, and R 2 is -[CH2] s and R 8 does not exist, R 3 is H, alkanyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, alkanyloxy, alkenyloxy, alkynyloxy, -O-aryl, -O-cycloalkyl, -O-heterocycloalkyl, halogen, aminoalkanyl, aminoalkenyl, aminoalkynyl, alkanylamino, alkenylamino, alkynylamino, hydroxylamino, hydroxylalkanyl, hydroxylalkenyl, hydroxylalkynyl, haloalkanyloxy, haloalkenyloxy, haloalkynyloxy, heteroaryl, alkanylthio, alkenylthio, alkynylthio, -S-aryl, -S-cycloalkyl, -S-heterocycloalkyl, aralkyl, haloalkanyl, haloalkenyl, or haloalkynyl; R 4is H, alkanyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 5 is H, OH, alkanyloxy, alkenyloxy, alkynyloxy, O-aryl, alkanyl, alkenyl, alkynyl or aryl, and R 6 is H, alkanyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, alkanyloxyalkanyl, alkanyloxyalkenyl, alkanyloxyalkynyl, alkenyloxyalkanyl, alkenyloxyalkenyl, alkenyloxyalkynyl, alkynyloxyalkanyl, alkynyloxyalkenyl, alkynyloxyalkynyl, acylalkanyl, (acyloxy)alkanyl, (acyloxy)alkenyl, (acyloxy)alkynylacyl, asymmetric (acyloxy)alkanyl diester, asymmetric (acyloxy)alkenyl diester, asymmetric (acyloxy)alkynyl diester, or dialkanyl phosphate, dialkenyl phosphate, or dialkynyl phosphate; R 7 is H, OH, alkanyl, alkenyl, alkynyl, aryl, alkanyloxy, alkenyloxy, alkynyloxy, -O-aryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, or -O-heterocycloalkyl; R 8is H, alkanyl, alkenyl, or alkynyl; E is an alkanyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl group, or a fused bicyclic or tricyclic ring system in which one phenyl ring is fused to one or two monocyclic cycloalkyl or heterocycloalkyl rings, or one bicyclic cycloalkyl or heterocycloalkyl ring, or two phenyl rings are fused to monocyclic cycloalkyl or heterocycloalkyl rings, wherein the monocyclic and bicyclic cycloalkyl and heterocycloalkyl rings are as defined herein, and all of the foregoing groups are optionally substituted with one or more substituents R′. and Y is H, halogen, haloalkanyl, haloalkenyl, haloalkynyl, haloalkanyloxy, haloalkenyloxy, haloalkynyloxy, alkanyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl group, or a fused bicyclic or tricyclic ring system in which one phenyl ring is fused to one or two monocyclic cycloalkyl or heterocycloalkyl rings, or one bicyclic cycloalkyl or heterocycloalkyl ring, or two phenyl rings are fused to monocyclic cycloalkyl or heterocycloalkyl rings, all of the foregoing groups may optionally be substituted with one or more substituents R′, or Y is TIFF2025186252000106.tif39170, As disclosed in U.S. Patent Publication No. 2019 / 0025313, the entirety of which is incorporated herein by reference, m is 0 or 1, n is 0 or 1, p is 0 or 1, q is 0 or 1, r is 0 or 1, s is 0 to 2, and t is 0 to 3.

[0242] For use in the present disclosure, DHODH inhibitors include known inhibitors as well as compounds identified herein as inhibitors.Known DHODH inhibitors include the immunomodulatory drugs teriflunomide and leflunomide.Other inhibitors include, but are not limited to, those disclosed in, for example, Baumgartner et al.(2006)J.Med.Chem.49(4):1239-1247, Lolli et al.(2012)Eur.J.Med.Chem.49:102-109, Lucas-Hourani et al.(2015)J.Med.Chem.58(14):5579-5598.

[0243] Known compounds not previously known to be inhibitors of DHODH include those disclosed in International Patent Publication No. WO 2006 / 118607, specifically incorporated herein by reference. Such compositions include GSK983, a tetrahydrocarbazole (see Harvey et al. (2009) Antiviral Res. 82(1):1-11), which inhibits the in vitro replication of a variety of unrelated viruses with EC50 values ​​of 5-20 nM, and analogs thereof. Such compounds have the structure: TIFF2025186252000107.tif36170, wherein n is 0, 1, or 2, t is 0 or 1, and X is -NH-, -O-, -R 10 -, -OR 10 -, -R 15 O-, -R 10 OR 10 -, -NR 10 -, -R 10 N-, -R 10 NR 10 -, -R 10 S(O) m -, or -R 10 S(O) m R 10 - and Y is -C(O)- or -S(O) m -, and each R is the same or different and independently represents halogen, haloalkyl, akyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10 Cycloalkyl, Ay, -NHR 10 Ay, Het, -NHHet, -NHR 10 Het, -OR 2 , -OAy, -OHet, -R 10 OR 2 , -NR 2 R 3 , -NR 2 Ay, -R 10 NR 2 R 3 , -R 10 NR 2 Ay, -R 10 C(O)R 2 , -C(O)R 2 , -CO2R 2 , -R 10 CO2R 2 , -C(O)NR 2 R 3 , -C(O)Ay, -C(O)NR 2 Ay, -C(O)Het, -C(O)NHR 10 Het, -R 10 C(O)NR 2 R 3 , -C(S)NR 2 R 3 , -R 10 C(S)NR 2 R 3 , -R 10 NHC(NH)NR 2 R 3 , -C(NH)NR 2 R 3 , -R 10 C(NH)NR 2 R 3 , -S(O)NR 2 R 3 , -S(O)NR 2 Ay, -R 10 SO2NHCOR 2 , -R 10 SO2NR 2 R 3 , -R 10 SO2R 2 , -S(O) m R 2 , -S(O) m Ay, cyano, nitro, or azido, and each R 1are the same or different and are halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloakyl, cycloalkenyl, -R 10 Cycloakyl, Ay, -NHR 10 Ay, Met, -NHHet, -NHR 10 Het, -OR 2 , -OAy, -OHet, -R 10 OR 2 , -NR 2 R 3 , -NR 2 Ay, -R 10 NR 2 R 3 , -R 10 NR 2 Ay, -R 10 C(O)R 2 , -C(O)R 2 , -CO2R 2 , -C(O)NR 2 R 3 , -C(O)Ay, -C(O)NR 2 Ay, -C(O)Het, -C(O)NHR 10 Het, -R 10 C(O)NR 2 R 3 , -C(S)NR 2 R 3 , -R 10 C(S)NR 2 R 3 , -R 10 NHC(NH)NR 3 R 3 , -C(NH)NR 2 R 3 , -R 10 C(NH)NR 2 R 3 , -S(O)NR 2 R 3 , -S(O)NR 2 Ay, -R 10 SO2NHCOR 2 , -R 10 NR 2 T 3 , -R 10 SO2R 2 , -S(O) m R 2 , -S(O) mAy, cyano, nitro, or azido; each m is independently 0, 1, or 2; and each R 10 are the same or different and are independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene, and alkynylene; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; R 2 and R 3 are the same or different and independently represent H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, -R 10 Cycloakyl, -R 10 OH, -R 10 (OR 10 ) w , and -R 10 NR 4 R 5 wherein w is 1 to 10; and R 4 and R 6 are the same or different and are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; Ay represents an aryl group; Het represents a 5- or 6-membered heterocyclyl or heteroaryl group; ring A is aryl or heteroaryl, provided that when ring A is aryl, t is 0, and Y is SO2, then p is not 0; and salts, solvates, and physiologically functional derivatives thereof.

[0244] In some embodiments, the inhibitor of DHODH is GSK983 or an analog thereof, including but not limited to 6Br-pF, 6Br-oTol, and GSK984, which compounds have the following structure: TIFF2025186252000108.tif194170

[0245] The disclosed DHODH inhibitor may be a compound known to inhibit DHODH, which has already been approved by drug regulatory authorities or is in preclinical or clinical development.Exemplary other DHODH inhibitors include ASLAN-003, brequinar, BAY-2402234, AG-636, PTC-299, teriflunomide, leflunomide, DSM-265, olorofim (F-901318), bidofludimus (IMU-838), PP-001, IMU-935, laflunimus (AP-325), RP-7214, 4SC-302, DSM-421, LAS-187247, ABR-224050, FK-778, or combinations thereof.

[0246] In various aspects, the disclosed compounds are also intended to include their biological equivalents. The term "bioequivalent" refers to a compound or group that possesses approximately the same molecular shape and volume, approximately the same electron distribution, and exhibits similar physical and biological properties. Examples of such equivalents include (i) fluorine to hydrogen, (ii) oxo to thia, (iii) hydroxyl to amide, (iv) carbonyl to oxime, and (v) carboxylate to tetrazole. Examples of such bioisosteric substitutions can be found in the literature, including (i) Burger A, Relation of chemical structure and biological activity (Medicinal Chemistry Third ed., Burger A, ed.; Wiley-Interscience; New York, 1970, 64-80); (ii) Burger, A.; "Isosterism and bioisosterism in drug design"; Prog. Drug Res. 1991, 37, 287-371; (iii) Burger A, "Isosterism and bioanalogy in drug design", Med. Chem. Res. 1994, 4, 89-92; (iv) Clark RD, Ferguson AM, Cramer RD, "Bioisosterism and molecular diversity", Perspect. Drug Discovery Des. 1998, 9 / 10 / 11, 213-224; (v) Koyanagi T, Haga T, "Bioisosterism in agrochemicals”, ACS Symp. Ser. 1995, 584, 15-24, (vi) Kubinyi H, “Molecular similarities. Part 1.Chemical structure and biological activity”, Pharm. Unserer Zeit 1998, 27, 92-106, (vii) Lipinski C A.; “Bioisosterism in drug design”; Annu. Rep. Med. Chem.1986, 21, 283-91, (viii) Patani GA, LaVoie EJ, “Bioisosterism: A rational approach in drug design”, Chem.Rev. (Washington, DC) 1996, 96, 3147-3176, (ix) Soskic V, Joksimovic J, “Bioisosteric approach in the design of new dopaminergic / serotonergic (x) Thornber CW, “Isosterism and molecular modification in drug design”, Chem. Soc. Rev. 1979, 8, 563-80. .

[0247] In a further embodiment, a bioisostere is an atom, ion, or molecule whose electron periphery can be considered substantially identical. The term bioisostere is usually used to refer to a portion of an entire molecule, as opposed to the entire molecule itself. Bioisosteric substitution involves using one bioisostere to replace another, with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. Thus, the bioisostere in this case is an atom or group of atoms with similar size, shape, and electron density. Preferred bioisosteres of esters, amides, or carboxylic acids are compounds containing two sites for hydrogen-bonding tolerance. In one embodiment, the bioisostere of an ester, amide, or carboxylic acid is a five-membered monocyclic heteroaryl ring, such as optionally substituted 1H-imidazolyl, optionally substituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or optionally substituted [1,2,4]oxadiazolyl.

[0248] In various embodiments, the disclosed compounds are also intended to include isotopically labeled or isotopically substituted variants thereof, i.e., compounds identical to the described compounds, but in which one or more atoms have been replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 Included within the scope of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl. Compounds further include prodrugs thereof, and pharmaceutically acceptable salts of such compounds or such prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled compounds of the present disclosure, such as 3 H and 14 Those in which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavier isotopes such as H can offer certain therapeutic advantages due to added metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the following procedures by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0249] In various embodiments, the disclosed compounds may possess at least one asymmetric center and may exist in the form of their racemates, in the form of pure enantiomers and / or diastereomers, or in the form of mixtures of these enantiomers and / or diastereomers. Stereoisomers may exist in any proportion of mixtures. In some embodiments, where this is possible, the disclosed compounds may exist in the form of tautomers.

[0250] Thus, for example, the disclosed compounds that possess one or more chiral centers and occur as racemates can be separated into optical isomers, i.e., enantiomers or diastereomers, using methods known per se. This separation can be brought about by column separation on a chiral phase, or by recrystallization from an optically active solvent, or by derivatization with an optically active acid or base, or with an optically active reagent such as an optically active alcohol, followed by cleavage of the residue.

[0251] In various embodiments, the disclosed compounds may be in the form of cocrystals. The term "cocrystal" refers to a physical association of two or more molecules that achieves stability through non-covalent interactions. One or more components of the molecular complex provide a stable framework within the crystal lattice. In certain cases, the guest molecule is incorporated into the crystal lattice as an anhydride or solvate. See, for example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Preferred cocrystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0252] The term "pharmaceutically acceptable co-crystal" means one that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0253] In a further aspect, the disclosed compounds can be isolated as solvates, particularly hydrates of the disclosed compounds, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In this regard, one, two, three, or any number of solvate or water molecules can combine with a compound according to the present disclosure to form solvates and hydrates.

[0254] The disclosed compounds can be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, and salts formed with suitable organic ligands, for example, quaternary ammonium salts, which can be prepared by reacting drug compounds with suitable pharmaceutically acceptable bases. Salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or after final isolation, by reacting free base functions, such as secondary or tertiary amines, of the disclosed compounds with suitable inorganic or organic acids, or by reacting free acid functions, such as carboxylic acids, of the disclosed compounds with suitable inorganic or organic bases.

[0255] Acid addition salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or by reacting a moiety containing one or more nitrogen groups with a suitable acid. In various embodiments, acids that can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. In a further embodiment, salts further include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate), nicotinic acid The basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfides such as dimethyl, diethyl, dibutyl, and diamyl; long chain halides such as decyl chlorides, bromides, and iodides; lauryl, myristyl, and stearyl; aralkyl halides such as benzyl bromide and phenethyl bromide; and others.

[0256] Base addition salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or separately, by reacting the carboxylic acid moiety with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia, or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. In a further aspect, bases that can be used in the preparation of pharmaceutically acceptable salts include ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

[0257] The disclosed compounds can be advantageously utilized as building blocks of degradation molecules. Thus, in various embodiments, the disclosed compounds can be used as ligands, linkers, or adjacent chemical structures within proteolysis targeting complexes or targeted proteolysis complexes. For example...

Claims

1. (i) at least one DHODH inhibitor compound or a pharmaceutically acceptable salt thereof; (ii) at least one anti-CD38 therapeutic agent; and A combination drug for treating cancer or GVHD, comprising:

10. The DHODH inhibitor compound of claim 1, wherein the DHODH inhibitor compound has the structure: A compound having a formula represented by wherein R 1 is selected from halogen and —CF 3 ; R 5b or R 5c is —R 20 , where R 20 is selected from —C1-C10 alkylamino and —C1-C10 alkoxy; When R 5b is —R 20 , each R 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ; When R 5c is —R 20 , each R 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ; A pharmaceutical combination wherein the at least one anti-CD38 therapeutic agent comprises an antibody that recognizes CD38.

2. The pharmaceutical combination of claim 1, wherein R 1 is halogen and R 20 is selected from -C2-C7 alkylamino and -C2-C7 alkoxy.

3. The combination pharmaceutical of claim 1, wherein the antibody that recognizes CD38 is capable of killing CD38+ cells by antibody-dependent cell-mediated phagocytosis (ADCP), cell fratricide, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and / or complement-dependent cytotoxicity (CDC).

4. The combination pharmaceutical of claim 3, wherein the antibody that recognizes CD38 comprises a chimeric or humanized antibody, an antibody fragment, an antibody-drug conjugate, a nanobody, a bispecific antibody, a trispecific antibody, a single variable domain antibody, or a combination thereof.

5. The combination pharmaceutical according to claim 4, wherein the antibody that recognizes CD38 is selected from daratumumab, isatuximab (SAR650984), felzalutamab, ISB-1342, Y-150, ISB-1908, KPMW-101, AMG-424, XmAb-13243, XmAb-13551, MOR202 (MorphoSys AG), TAK-079, TAK-169, KP-1196, BM38, TJ202, and combinations thereof.

6. The combination pharmaceutical of claim 1, wherein R 5b is -R 20 and each of R 5a , R 5c , R 5d and R 5e is independently selected from hydrogen and halogen, or R 5c is -R 20 and each of R 5a , R 5b , R 5d and R 5e is independently selected from hydrogen and halogen.

7. The combination drug according to claim 1, wherein R 1 is fluorine.

8. The DHODH inhibitor compound of claim 7, 2. The pharmaceutical combination of claim 1, wherein the compound is a hydroxybenzoate or a subgroup thereof.

9. The pharmaceutical combination of claim 1, wherein the pharmaceutically acceptable salt of the DHODH inhibitor compound comprises a conjugate base form of the DHODH inhibitor 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 combinations thereof.

10. A combination pharmaceutical as described in claim 1 for treating cancer, further comprising at least one drug known to treat cancer.

11. The pharmaceutical combination of claim 10 for treating cancer, 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.

12. The combination pharmaceutical of claim 1 for treating GVHD, further comprising at least one agent known to treat GVHD.

13. The combination pharmaceutical of claim 12 for treating GVHD, wherein at least one of the drugs known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or another drug known to treat GVHD. (i) at least one DHODH inhibitor compound or a pharmaceutically acceptable salt thereof; (ii) at least one anti-CD38 therapeutic agent; and (iii) instructions for treating cancer or GVHD; A kit for treating cancer or GVHD, comprising:

10. The DHODH inhibitor compound of claim 1, wherein the DHODH inhibitor compound has the structure: A compound having a formula represented by wherein R 1 is selected from halogen and —CF 3 ; R 5b or R 5c is —R 20 , where R 20 is selected from —C1-C10 alkylamino and —C1-C10 alkoxy; When R 5b is —R 20 , each R 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ; When R 5c is —R 20 , each R 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ; The kit, wherein the at least one anti-CD38 therapeutic agent comprises an antibody that recognizes CD38.

15. The kit of claim 14, wherein R 1 is halogen and R 20 is selected from -C2-C7 alkylamino and -C2-C7 alkoxy.

16. The kit of claim 15, wherein the antibody that recognizes CD38 is capable of killing CD38+ cells by antibody-dependent cell-mediated phagocytosis (ADCP), cell fratricide, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and / or complement-dependent cytotoxicity (CDC).

17. The kit of claim 16, wherein the antibody that recognizes CD38 comprises a chimeric or humanized antibody, an antibody fragment, an antibody-drug conjugate, a nanobody, a bispecific antibody, a trispecific antibody, a single variable domain antibody, or a combination thereof.

18. The kit according to claim 17, wherein the antibody recognizing CD38 is selected from daratumumab, isatuximab (SAR650984), felzalutamab, ISB-1342, Y-150, ISB-1908, KPMW-101, AMG-424, XmAb-13243, XmAb-13551, MOR202 (MorphoSys AG), TAK-079, TAK-169, KP-1196, BM38, TJ202, and combinations thereof.

19. The kit described in claim 14, wherein R 5b is -R 20 and each of R 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen and halogen, or R 5c is -R 20 and each of R 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen and halogen.

20. The kit of claim 14, wherein R 1 is fluorine.

21. The DHODH inhibitor compound of claim 1, 15. The kit of claim 14, wherein the kit is present as a subgroup thereof.

22. The kit of claim 14, wherein the pharmaceutically acceptable salt of the DHODH inhibitor compound comprises a conjugate base form of the DHODH inhibitor 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 combinations thereof.

23. The kit of claim 14 for treating cancer, further comprising at least one drug known to treat cancer.

24. The kit of claim 23 for treating cancer, wherein the at least one drug is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof.

25. A kit for treating GVHD as described in claim 14, further comprising at least one agent known to treat GVHD.

26. The kit described in claim 25 for treating GVHD, wherein at least one drug known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other drug known to treat GVHD.

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