Methods and compositions for inhibition of dihydroorotate dehydrogenase

Abstract

Disclosed herein are 4,6-substituted-2-(3'-[1,1'-biphenyl]-4-yl)quinoline analogs and pharmaceutically acceptable salts thereof that are inhibitors of dihydroorotate dehydrogenase (DHODH) with properties, including stability and bioavailability as disclosed herein. Also disclosed herein are methods of making the analogs and salts thereof. The disclosed analogs and salts thereof can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation.

Description

Docket No.: 069596.00080(T2024-176PCT) METHODS AND COMPOSITIONS FOR INHIBITION OF DIHYDROOROTATE DEHYDROGENASE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No.63 / 639,455 filed April 26, 2024, which is hereby incorporated by reference in its entirety. FIELD

[0002] This disclosure is generally related to methods, compounds, salts, polymorphs, and compositions for the inhibition of dihydroorotate dehydrogenase. BACKGROUND

[0003] Proliferating cells require a supply of nucleotides for replication of deoxyribonucleic acid (DNA) and transcription of genes to ribonucleic acid (RNA), as well as for a variety of other metabolic processes. Cells can supply such nucleotides by de novo nucleotide synthesis pathways. An important step in the de novo synthesis pathway of pyrimidine nucleotides is the oxidation of dihydroorotate to form orotate. That reaction is catalyzed by dihydroorotate dehydrogenase (DHODH) and that step is one of the rate-limiting steps in the pyrimidine nucleotide synthesis pathway. DHODH has a sub-cellular location in the mitochondrial membrane and uses cytochrome C in the electron transport chain as an electron acceptor for the oxidation of dihydroorotate to orotate.

[0004] Under normal circumstances, the intracellular pool of pyrimidine nucleotides can be replenished by a salvage pathway in which pyrimidine nucleotides are recycled. Although this DHODH-independent mechanism is sufficient for resting lymphocytes, ‘activated’ and proliferating lymphocytes need to substantially increase the available pyrimidine and so become dependent on de novo pyrimidine synthesis. Since orotate is a necessary intermediate in pyrimidine nucleotide synthesis, and since pyrimidine nucleotides are required for DNA replication, gene expression, and carbohydrate metabolism, inhibition of the DHODH enzyme can inhibit cell growth.

[0005] Moreover, rapidly proliferating cells require pyrimidines not only for cellular growth, but also for protein glycosylation, membrane lipid biosynthesis and strand break repair (e.g.,Docket No.: 069596.00080(T2024-176PCT) see Fairbanks et al., J. Biol. Chem.270:29682-29689 (1995)). Under such conditions, in order to meet the increased demand, substantial quantities of pyrimidine nucleotides must be produced in rapidly proliferating cells. Accordingly, DHODH inhibitors are attractive candidates for treating proliferative disorders (e.g., see Liu, S. et al., Structure 8(1):25-33 (2000)), and various studies have shown that DHODH inhibitors can stop the proliferation of tumor cells in some circumstances (e.g., see Loffler, Eur. J. Biochem.107:207-215 (1980)).

[0006] Other circumstances in which DHODH inhibitors have been identified as candidates for the clinical control of rapid cell division include activated immune cells, diseased skin cells, cancers, and infectious agents. Examples of DHODH inhibitors used or being developed for proliferative disorders include brequinar, leflunomide, and teriflunomide. Inhibitors of DHODH have further been disclosed for the treatment or prevention of autoimmune diseases, immune and inflammatory diseases, angioplastic-related disorders, viral, bacterial, and protozoic diseases.

[0007] Although DHODH is an attractive target for therapeutic intervention for a varieity of clinical conditions, including cancer, there remain significant issues with currently described compounds. For example, many of these compounds, including brequinar, suffer from being associated with poor bioavailability, due in part to the poor aqueous solubility and gastrointestinal (GI) uptake. Accordingly, currently described DHODH inhibitors can have limited pharmaceutical efficacy due to such bioavailability issues.

[0008] Despite advances in research directed towards effective and therapeutically useful DHODH inhibitors, there remain a scarcity of compounds that are both efficacious and have the appropriate bioavailability properties. These needs and other needs are addressed by the present disclosure. SUMMARY

[0009] In accordance with the purpose(s) of the disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to compounds that are inhibitors of dihydroorotate dehydrogenase (DHODH), wherein the disclosed compounds, salts, polymorphs and compositions, in some embodiments, have improved pharmacokinetic properties making them extremely useful for therapeutic intervention in a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, e.g., cancer. In various aspects, the disclosed compounds are 4,6-substituted-2-(3’-[1,1'-biphenyl]-4-yl)quinoline analogs and pharmaceutically acceptable salts thereof. In further aspects, the disclosed compounds, in someDocket No.: 069596.00080(T2024-176PCT) instances, can be used in methods of treating (a) a cancer, such as a hematological cancer, including acute myeloid leukemia (AML), and multiple myeloma, (b) graft-versus-host- diseases, and (c) disorders associated with T-cell proliferation. In some aspects, the disclosed compounds, in some cases, can demonstrate flip-flop kinetics when administered orally, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. Moreover, the disclosed compounds, in some embodiments, can demonstrate a sustained pharmacokinetic profile instead of an immediate release profile.

[0010] Disclosed herein are compositions comprising: a salt comprising a conjugate base and a counterion; wherein the conjugate base has a structure of Formula I:wherein R1is halogen or a halide (e.g. F, Cl, Br, or I); and R5is –O(C1-C7 alkyl); and wherein the counterion comprises a cation of one or more of L-arginine, L-lysine, or N-methyl-D-glucamine. In some embodiments, R1is F or Cl. In some embodiments R1is F. In some embodiments, R5is –O(C1-C4 alkyl). In some embodiments, R5is -OCH2CH2CH2CH3; in other embodiments, R5is -OCH2CH3.

[0011] In some embodiments the conjugate base has a structure of Formula II:Docket No.: 069596.00080(T2024-176PCT)

[0012] In some embodiments the conjugate base has a structure of Formula III:Formula III.

[0013] In some variations, the counterion is a cation of L-arginine; in others the counterion is a cation of L-lysine; in still others, the counterion is a cation of N-methyl-D-glucamine.

[0014] In some variation of any aspect or embodiment, the salt in the composition is a crystalline salt. The crystalline salt has a variety of different polymorphs. In some embodiments, the crystalline salt is polymorph Pattern A, polymorph Pattern B, polymorph Pattern C, or polymorph Pattern D. In some variations, the crystalline salt is polymorph Pattern A. In some variations, the crystalline salt is polymorph Pattern B. In other variations, the crystalline salt is polymorph Pattern C. In still other variations, the crystalline salt is polymorph Pattern D.

[0015] In some embodiments the conjugate base has a structure of Formula III; the counterion is a cation of L-lysine; the salt is a crystalline salt; and the crystalline salt is polymorph Pattern A. The anion of Formula III, or Compound III, can be referred to as 2-(3'-butoxy-[1,1'- biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylate.

[0016] Disclosed herein are compositions comprising a first component and a second component, wherein the first component comprises a compound having a structure of Formula IV:Docket No.: 069596.00080(T2024-176PCT) wherein R1is a halogen or halide; and R5is –O(C1-C7 alkyl); and wherein the second component comprises one or more of L-arginine, L-lysine, or N-methyl-D-glucamine. In some embodiments, R1is F or Cl. In some embodiments R1is F. In some embodiments, R5is –O(C1-C4 alkyl). In some embodiments, R5is -OCH2CH2CH2CH3; in other embodiments, R5is -OCH2CH3.

[0017] In some embodiments of a composition described herein, the first component has a structure of Formula V:wherein R5is as described above.

[0018] In some embodiments wherein the first component has the structure of Formula VI:Formula VI.

[0019] The compound of Formula VI, or Compound VI, can also be referred to as 2-(3'-butoxy- [1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid.

[0020] Additionally, in some instances, the second component of a composition described herein comprises L-arginine, L-lysine, N-methyl-D-glucamine, or a combination of two or more of the foregoing. In some cases, the second component is L-arginine. In other variations, the second component is L-lysine. In still other variations, the second component is N-methyl- D-glucamine. Moreover, as described further herein, a composition comprising first and second components such as described above can be a non-ionic composition or mixture, in which the first and second components are not counterions of one another (e.g., a conjugate base pairedDocket No.: 069596.00080(T2024-176PCT) with a counter ion to form an ionic solid). Using L-lysine and Compound VI as a representative example, such a composition can be represented as Composition 1:Composition 1

[0021] Disclosed herein are compositions comprising a first component and a second component, wherein the composition is a crystalline solid. In some embodiments, the crystalline solid is polymorph Pattern A, Pattern B, Pattern C, or Pattern D. In some cases, the crystalline solid is polymorph Pattern A. In other cases, the crystalline solid is polymorph Pattern B. In still other cases, the crystalline solid is polymorph Pattern C. In still other cases, the crystalline solid is polymorph Pattern D.

[0022] Also disclosed herein are compositions comprising a first component and second component wherein the first component is Compound VI, the second component is L-lysine, the composition is a crystalline solid and the crystalline solid is polymorph Pattern A.

[0023] Also disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound or composition and a pharmaceutically acceptable carrier.

[0024] Also disclosed are methods for the treatment of a disease or disorder in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, composition, or pharmaceutical composition.

[0025] Also disclosed are methods for the treatment of a cancer in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, composition, or pharmaceutical composition.

[0026] Also disclosed are methods for the treatment of a graft-versus-host disease in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, composition, or pharmaceutical composition.Docket No.: 069596.00080(T2024-176PCT)

[0027] Also disclosed are methods for the treatment of a disease or disorder associated with T-cell proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, composition, or pharmaceutical composition.

[0028] Additionally disclosed herein are methods for the treatment of a disease or disorder in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a disclosed compound, composition, or pharmaceutical composition. In some embodiments, the mammal is a human.

[0029] In some embodiments, the mammal has been diagnosed with a need for treatment of the disease or disorder prior to administering a disclosed compound, composition, or pharmaceutical composition.

[0030] In some embodiments. the disorder or disease is associated with abnormal, increased, or aberrant dihydroorotate dehydrogenase (DHODH) activity. In other embodiments, the disorder or disease can be treated by inhibition of dihydroorotate dehydrogenase (DHODH) activity. In still other embodiments, the method of treatment comprises the step of identifying a mammal in need of treatment of the disorder or disease.

[0031] Also disclosed herein is a method for inhibiting dihydroorotate dehydrogenase activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, composition or pharmaceutical composition. In some embodiments, the cell is mammalian, such as for example, human. In some embodiments, the cell has been isolated from a mammal prior to the contacting step. In some embodiments, the contacting is done via administration to a mammal. In some embodiments, the mammal has been diagnosed with a need for inhibiting dihydroorotate dehydrogenase activity prior to the administering step. In other embodiments, the mammal has been diagnosed with a need for treatment of a disorder related to dihydroorotate dehydrogenase activity prior to the administering step.

[0032] In some embodiments of any method disclosed herein, the disclosed compound, composition or pharmaceutical composition exhibits inhibition of dihydroorotate dehydrogenase with an IC50of less than 1,000 nM using a cell-free enzymatic assay. In other embodiments, the IC50is less than 500 nM. In still other embodiments, the IC50of less than 250 nM. In still other embodiments, the IC50 is less than 100 nM. In still further embodiments, the IC50is less than 50 nM.Docket No.: 069596.00080(T2024-176PCT)

[0033] In some embodiments of any of the methods disclosed herein, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, the method comprises administering a disclosed compound, composition, or pharmaceutical composition and the at least one additional agent sequentially; in some embodiments, they are administered simultaneously. In some embodiments, a disclosed compound, composition, or pharmaceutical composition and the at least one additional agent are co-formulated; in other instances, they are co-packaged.

[0034] In some embodiments of any of the methods disclosed herein, the disease or disorder is a cancer. In some embodiments, the cancer is breast cancer, renal cancer, gastric cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung cancer, or malignant melanoma. In some embodiments, the cancer is a hematological cancer, such as leukemia, lymphoma, myeloma, myelodysplastic syndrome, or myeloproliferative neoplasm. In other embodiments, the hematological cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocyte leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, or Burkitt's lymphoma. In some embodiments, the hematological cancer is chronic myeloid leukemia or acute myeloid leukemia.

[0035] In some embodiments of any of the methods disclosed herein, the disease or disorder is mediated by T-cell proliferation. In some embodiments, the disorder is psoriasis. In other embodiments, the disorder is graft-versus-host disease (GVHD). In some instances, the GVHD is associated with an organ transplant, an allograft, a xenograft, or a hematopoietic stem cell transplantation. In some instances, the GVHD is acute GVHD. In other instances, the GVHD is chronic GVHD. In some embodiments, the method further comprises the step of administering a therapeutically effective amount of at least one additional agent known to treat GVHD. In some embodiments, the least one additional agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other agent known to treat GVHD.

[0036] In some aspects of any of the methods disclosed herein, the disease or disorder is an autoimmune disorder or disease.In some embodiments, the autoimmune disorder or disease is selected from lupus, rheumatoid arthritis, ankylosing spondylitis, glomerulonephritis, minimalDocket No.: 069596.00080(T2024-176PCT) change disease, ulcerative colitis, Crohns disease, Addison’s disease, adult Still’s disease, alopecia areata, autoimmune hepatitis, autoimmune angioedema, Behçet's disease, pemphigoid and variants thereof, celiac disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, CREST syndrome, dermatomyositis, neuromyelitis optica, discoid lupus, fibromyalgia, giant cell arteritis, giant cell myocarditis, Goodpasteur’s disease, Evans syndrome, autoimmune hemolytic anemia, immune thrombocytopenia, Henoch-Schonlein purpura, IgA nephropathy, IgG4 related sclerosing disease, juvenile arthritis, juvenile diabetes, Kawasaki disease, Leukocytoclastic vasculitis, mixed connective disease, multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, autoimmune neutropenia, optic neuritis, peripheral neuropathy, POEMS syndrome, polymyositis, primary biliary cirrhosis, non- alcoholic hepatosteotosis and associated cirrhosis, psoriasis, scleroderma, sarcoidosis, temporal arteritis, vasculitis, and uveitis. In some embodiments, the method further comprises administering a therapeutically effective amount of at least one additional agent known to treat an autoimmune disorder or disease.

[0037] Also disclosed are kits comprising a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed composition such as a disclosed pharmaceutical composition; and: (a) at least one additional agent known to treat a cancer, a host-versus-graft-disease, and / or a disorder associated with T-cell proliferation; and (b) instructions for treating a cancer, a host-versus-graft-disease, and / or a disorder associated with T-cell proliferation. In some embodiments, the disclosed compound, composition, or pharmaceutical composition and the at least one additional agent are co- formulated; in other instances, they are co-packaged. In some instances, the kit comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of the at least one compound, composition, or pharmaceutical composition and the at least one additional agent. In some embodiments, the dosage forms are formulated for oral administration and / or intravenous administration. Ins ome embodiments, the dosage forms are formulated for oral administration; in other embodiments, the dosage forms are formulated for intravenous administration. In still other embodiments, the dosage form for the at least one compound, composition, or pharmaceutical composition is formulated for oral administration and the dosage form for the at least one additional agent is formulated for intravenous administration. In other embodiments, the at least one compound, composition, or pharmaceutical composition is formulated for intravenous administration and the dosage form for the at least one additional agent is formulated for oral administration.Docket No.: 069596.00080(T2024-176PCT)

[0038] In some embodiments, the kit further comprises instructions to provide the compound in connection with surgery. In some instances, the instructions provide that surgery is performed prior to administering at least one compound, composition or pharmaceutical composition. In other instances, the instructions provide that surgery is performed after the administration. In still other instances, the instructions provide that the administering of at least one compound is to effect presurgical debulking of a tumor. In some embodiments, the instructions provide that surgery is performed at about the same time as the administering of at least one compound. In some embodiments, the instructions include providing the at least least one compound, composition or pharmaceutical composition in connection with radiotherapy. In some instances, the radiotherapy is performed prior to administering of the at least one compound, composition or pharmaceutical composition. In some instances, the radiotherapy is performed after the step of the administering the at least least one compound, composition or pharmaceutical composition. In other instances, the radiotherapy is performed at about the same time as the step of administering the least one compound, composition or pharmaceutical composition.

[0039] Also disclosed are methods for manufacturing a medicament comprising combining at least one compound or composition of the present application with a pharmaceutically acceptable carrier or diluent.

[0040] Also disclosed are uses of a composition of the present application in the manufacture of a medicament for the treatment of a disease or disorder in a mammal such as a cancer, a disorder associated with T-cell proliferation, or a graft-versus-host-disease.

[0041] In some embodiments of any composition, kit or method of treatment comprising at least one additional agent, the at least one additional agent known to treat a cancer is a DNA methyltransferase inhibitor, an HDAC-inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination of two or more of the foregoing. In some variations, the DNA methyltransferase inhibitor is 5-aza-2′-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination of two or more of the foregoing. In some variations, the HDAC-inhibitor is vorinostat, entinostat, panbinostat, trichostatin A, mocetinostat, belinostat, dacinostat, givinostat, tubastatin A, pracinostat, droxinostat, quisinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tacedinaline, rocilinostat, apicidin, or a combination of two or more of the foregoing. In some variations, the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination of two or more of theDocket No.: 069596.00080(T2024-176PCT) foregoing. In some variations, the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination of two or more of the foregoing. In some variations, the cytotoxic agent is an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent or another chemotherapeutic agent. In other variations, the antineoplastic antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other variations, the antimetabolite agent is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In still other variations, the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some variations, the mitotic inhibitor agent is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other variations, the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing. In some variations, the other chemotherapeutic agent is an anthracycline, cytarabine, a purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or a combination of two or more of the foregoing. In other variations, the anthracycline is daunorubicin, idarubicin, or a combination of two or more of the foregoing. In still other variations, the purine analog is cladribine, fludarabine, clofarabine, or a combination of two or more of the foregoing.

[0042] In some embodiments of any composition, kit or method of treatment comprising at least one additional agent, the at least one additional agent known to treat cancer is selected from uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5- fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin,Docket No.: 069596.00080(T2024-176PCT) dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, and vasostatin.

[0043] In some embodiments of any composition, kit or method of treatment comprising at least one additional agent, the at least one additional agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other agent known to treat GVHD. In some variations, the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination of two or more of the foregoing. In some variations, the tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination of two or more of the foregoing. In other variations, the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing. In still other variations, the other agent known to treat GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, halofuginone, hydroxychloroquine, or a combination of two or more of the foregoing

[0044] In some embodiments of any composition, kit or method of treatment comprising at least one additional agent, the at least one additional agent known to treat an autoimmune disorder or disease is selected from the group consisting of: (a) disease modifying antirheumatic drugs; (b) nonsteroidal anitinflammatory drugs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs; (f) steroids; (g) biological response modifiers; and (h) other agents useful for the treatment of autoimmune disorders. In some variations, the disease modifying antirheumatic drug is selected from methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auranofin, sulfasalazine, and combinations thereof. In other variations, the nonsteroidal anitinflammatory drug is selected from indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogs, acetaminophen, and combinationsDocket No.: 069596.00080(T2024-176PCT) thereof. In still other variations, the COX-2 selective inhibitor is selected from celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib, and combinations thereof. In other variations, the immunosuppressive drug is selected from a calcineurin inhibitor such as cyclosporin or FK506; a p70S6 kinase inhibitor such as sirolimus and rapamycin; an inosine monophosphate dehydrogenase inhibitor such as mycophenolate; leflunomide, cyclophosphamide, azathioprine, and combinations thereof. In some variations, the steroid is selected from prednisone, betamethasone, budesonide and dexamethasone, and combinations thereof. In some variations, the biological response modifier is selected from TNFα antagonists such as infliximab, adalimmab and etanercept; IL-1 receptor antagonists such as anakinra; humanized or chimeric antibodies or fusion proteins such as alefacept, efalizumab, daclizumab; anti- chemokine antibodies; anti-interleukin antibodies; and combinations thereof. In other variations, the other agent useful for the treatment of autoimmune disorder is selected from hemokine receptor antagonists or modulators, cannabinoid receptor antagonists or modulators, inhibitors of matrix metalloproteinases, TNFα-converting enzymes, nitric oxide synthetases or phosphodiesterase IV, such as roflumilast or cilomilast; inhibitors of p38 MAP-kinase, the NF- kappaβ, pathway or IL-1 receptor associated kinase or inhibitors of interactions involving adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, α4β7, MAdCAM-1, and αvβ3; and combinations thereof.

[0045] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system or composition statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. BRIEF DESCRIPTION OF THE FIGURES

[0046] The accompanying figures, which are incorporated in and constitute a part of thisDocket No.: 069596.00080(T2024-176PCT) specification, illustrate several aspects and together with the description serve to explain the principles of the disclosure.

[0047] FIG.1 shows an X-ray powder diffraction (XRPD) pattern of C201030009-B free form Pattern #1, batch PJ00844-77-B-DRY1.

[0048] FIG.2 shows a differential scanning calorimetry (DSC) thermogram of C201030009- B free form Pattern #1, batch PJ00844-77-B-DRY1.

[0049] FIG. 3 shows a thermal gravimetric analysis (TGA) thermogram of C201030009-B free form Pattern #1, batch PJ00844-77-B-DRY1.

[0050] FIG. 4 shows an1H-NMR spectrum of C201030009-B free form Pattern #1, batch PJ00844-77-B-DRY1.

[0051] FIG.5 shows a polarized light microscope (PLM) photograph of C201030009-B free form Pattern #1, batch PJ00844-77-B-DRY1.

[0052] FIG. 6 shows an overlay of XRPD patterns for L-lysine salt Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02 and FR02115-4-free form XRPD-02.

[0053] FIG. 7 shows a DSC thermogram of L-lysine salt Pattern A, sample ID FR02115-4- SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02.

[0054] FIG. 8 shows a TGA thermogram of L-lysine salt Pattern A, sample ID FR02115-4- SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02.

[0055] FIG.9 shows an1H-NMR spectrum of L-lysine salt Pattern A, sample ID FR02115-4- SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02

[0056] FIG. 10 shows an overlay of XRPD patterns for sample IDs FR02115-7-SU-RAS3- ACN-Water-ACN-200mg and FR02115-7-RAS3-ACN-Water-ACN.

[0057] FIG.11 shows a DSC thermogram of sample ID FR02115-7-SU-RAS3-ACN-Water- ACN-200mg, Compound VII Pattern B.

[0058] FIG.12 shows a TGA thermogram of sample ID FR02115-7-SU-RAS3-ACN-Water- ACN-200mg, Compound VII Pattern B.

[0059] FIG. 13 shows an1H-NMR spectrum of sample ID FR02115-7-SU-RAS3-ACN- Water-ACN-200mg, Compound VII Pattern B.

[0060] FIG. 14 shows an overlay of XRPD patterns for sample IDs FR02115-7-SU-RAS3-Docket No.: 069596.00080(T2024-176PCT) ACN-Water-ACN-200mg-evaporated-2h and FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g- vacuum-02.

[0061] FIG. 15 shows a DSC thermogram of sample obtained from ACN / Water (4 / 1) by reverse addition of anti-solvent, sample ID FR02115-7-SU-RAS3-ACN-Water-ACN-200mg- evaporated-2h.

[0062] FIG. 16 shows a TGA thermogram of sample obtained from ACN / Water (4 / 1) by reverse addition of anti-solvent, sample ID FR02115-7-SU-RAS3-ACN-Water-ACN-200mg- evaporated-2h.

[0063] FIG. 17 shows an1H-NMR spectrum of sample obtained from ACN / Water (4 / 1) by reverse addition of anti-solvent, sample ID FR02115-7-SU-RAS3-ACN-Water-ACN-200mg- evaporated-2h.

[0064] FIG. 18 shows an overlay of XRPD patterns of sample IDs FR02115-7-SU-FC3- Ethanol-Water-200mg-evaporated-1h and FR02115-7-SU-FC3-Ethanol-Water-200mg.

[0065] FIG. 19 shows an overlay of XRPD patterns of samples obtained by fast cooling-4, sample IDs FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h-190C and FR02115- 7-SU-FC3-Ethanol-Water-200mg-evaporated-1hr-120C and FR02115-7-SU-FC3-Ethanol- Water-200mg.

[0066] FIG. 20 shows a DSC thermogram of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h.

[0067] FIG. 21 shows a DSC thermogram of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h-120C.

[0068] FIG. 22 shows a DSC thermogram of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h-190C.

[0069] FIG. 23 shows a TGA thermogram of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h.

[0070] FIG.24 shows an1H-NMR spectrum of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h.

[0071] FIG.25 shows an1H-NMR spectrum of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h-120C.

[0072] FIG.26 shows an1H-NMR spectrum of sample obtained from Ethanol / Water (4 / 1) byDocket No.: 069596.00080(T2024-176PCT) fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h-190C.

[0073] FIG. 27 shows an overlay of XRPD patterns of samples obtained by fast cooling-5, sample IDs FR02115-7-SU-FC3-Ethanol-Water-300mg-vacuum-3h, FR02115-7-SU-FC3- Ethanol-Water-200mg, FR02115-7-SU-RAS3-ACN-Water-200mg, and FR02115-4-SU-L- lysine salt-2-MeTHF-6.5g-vacuum-02.

[0074] FIG. 28 shows a DSC thermogram of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-300mg-vacuum-3h.

[0075] FIG. 29 shows a TGA thermogram of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-300mg-vacuum-3h.

[0076] FIG.30 shows an1H-NMR spectrum of sample obtained from Ethanol / Water (4 / 1) by fast cooling, sample ID FR02115-7-SU-FC3-Ethanol-Water-300mg-vacuum-3h.

[0077] FIG. 31 shows an overlay of XRPD patterns of samples obtained by stressing C201030009-B L-lysine salt Pattern A, sample IDs FR02115-4-SU-L-lysine salt-2-MeTHF- 6.5g-vacuum-02, FR02115-9-BS1-L-lysine salt Pattern A-25C-92%RH-XRPD, FR02115--9- BS2-L-lysine salt Pattern A-40C-75%RH-XRPD, and FR02115-9-BS3-L-lysine salt Pattern A-60C-light-XRPD.

[0078] FIG. 32A shows a dynamic vapor sorption (DVS) plot of Change in Mass (Ref).of C201030009-B L-lysine salt Pattern A at 25°C, sample ID FR02115-4-SU-L-lysine salt-2- MeTHF-6.5g-vacuum-02.

[0079] FIG. 32B shows a DVS isotherm plot of C201030009-B L-lysine salt Pattern A at 25°C, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02.

[0080] FIG. 32C is a tabulated DVS Isotherm Analysis for sample ID FR02115-9- L-lysine salt Pattern A.

[0081] FIG.33 shows an overlay of XRPD patterns of C201030009-B L-lysine salt Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02 before and after DVS test.

[0082] FIG. 34 shows an overlay of XRPD patterns of samples obtained by compressing C201030009-B L-lysine salt Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF- 6.5g-vacuum-02.

[0083] FIG. 35 shows overlay of XRPD patterns of samples obtained by grinding C201030009-B L-lysine salt Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-Docket No.: 069596.00080(T2024-176PCT) 6.5g-vacuum-02.

[0084] FIG. 36 shows overlay of XRPD patterns of samples obtained by granulating C201030009-B L-lysine salt Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF- 6.5g-vacuum-02.

[0085] FIG. 37A and FIG. 37B each show ion pair chromatography (IPC) results for the original procedure of preparing compound A (Stage 1 of Process 1), discussed in further detail in the Examples.

[0086] FIG.38A and FIG.38B each show IPC results for the updated procedure of preparing compound B (Stage 1 of Process 2), discussed in further detail in the Examples.

[0087] FIG.39A and FIG.39B each show IPC results for the original procedure of preparing compound B (Stage 2 of Process 1), discussed in further detail in the Examples.

[0088] FIG.40A and FIG.40B each show IPC results for the updated procedure of preparing compound B (Stage 2 of Process 2), discussed in further detail in the Examples.

[0089] Additional advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the disclosure. 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 disclosure. DETAILED DESCRIPTION

[0090] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0091] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0092] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and featuresDocket No.: 069596.00080(T2024-176PCT) which 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.

[0093] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0094] All publications and patents cited in this specification 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 herein incorporated by references as if each individual publication or patent were 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 lexicographical definitions from the cited publications and patents. Any lexicographical definition in the publications and patents cited that is not also expressly repeated in the instant application should not be treated as such and should not be read as defining any terms appearing in the accompanying claims. The citation of any publication is for its disclosure 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 virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

[0095] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0096] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. ItDocket No.: 069596.00080(T2024-176PCT) will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0097] Aspects of the present disclosure will employ, unless otherwise indicated, techniques of molecular biology, microbiology, organic chemistry, biochemistry, physiology, cell biology, blood vessel biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

[0098] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions

[0099] As used herein, terms "substantially," "approximately," and "about," as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0100] The term "consists essentially of" (and grammatical variants) shall be given its ordinary meaning and shall also mean that the composition or method referred to can contain additional components as long as the additional components do not materially alter the composition or method. The term "consists of" (and grammatical variants) shall be given its ordinary meaning and shall also mean that the composition or method referred to is closed to additional components. The term "comprising" (and grammatical variants) shall be given its ordinary meaning and shall also mean that the composition or method referred to is open to contain additional components.

[0101] It is also to be understood that the article "a" or "an" refers to "at least one," unless the context of a particular use requires otherwise.

[0102] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. All ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of "1.0 to 10.0" should be considered to include any and all subranges beginning with a minimum value of 1.0 or more and ending with a maximum value of 10.0 or less, e.g., 1.0 to 5.3, or 4.7 to 10.0, or 3.6 to 7.9.Docket No.: 069596.00080(T2024-176PCT)

[0103] When a range of integers is given, the range includes any number falling within the range and the numbers defining ends of the range. For example, when the terms "integer from 1 to 20" is used, the integers included in the range are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., up to and including 20. All ranges disclosed herein are also to be considered to include the end points of the range, unless expressly stated otherwise. For example, a range of "between 5 and 10" should generally be considered to include the end points 5 and 10.

[0104] Further, when the phrase "up to" is used in connection with an amount or quantity, it is to be understood that the amount is at least a detectable amount or quantity. For example, a material present in an amount "up to" a specified amount can be present from a detectable amount and up to and including the specified amount.

[0105] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. 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 use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0106] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub- ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0107] As used herein, "about," "approximately," “substantially,” and the like, when used in connection with a numerical variable, can generally refers to the value of the variable and to all values of the variable that are within the experimental error (e.g., within the 95% confidenceDocket No.: 069596.00080(T2024-176PCT) interval for the mean) or within + / - 10% of the indicated value, whichever is greater. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” can mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0108] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0109] As used herein, “dihydroorotate dehydrogenase” and “DHODH” can be used interchangeably, and refer to an enzyme encoded by a gene in humans 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 gene structure in humans comprises 9 exons. DHODH has an EC classification of 1.3.1.1; an intracellular location within the mitochondria; and catalyzes the fourth enzymatic step in de novo pyrimidine biosynthesis. DHODH has also been referred to as DHOdehase; dihydroorotate dehydrogenase, mitochondrial; dihydroorotate dehydrogenase, mitochondrial precursor; dihydroorotate oxidase; human complement of yeast URA1; POADS; PYRD_HUMAN; and URA1.

[0110] The terms “inhibits”, “inhibiting”, or “inhibitor” of DHODH, as used herein, refer to inhibition of the enzyme DHODH, unless otherwise specified.

[0111] As used herein, “brequinar” and “BQR,” which can be used interchangeably, refer toDocket No.: 069596.00080(T2024-176PCT) the compound having a structure represented by the following formula:. Brequinar can also be referred to by the IUPAC chemical name, or 6-fluoro-2-(2'-fluoro-1,1'- biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid. Common saltf forms are brequinar potassium and brequinar sodium (also referred to herein as BQR Na), which are the alkali metal salts of the conjugate base of the carboxylic acid. Brequinar is sometimes referred as DuP-785 or NSC-368390.

[0112] As used herein, the term “quinoline” or “quinoline analogue” refers to a compound or derivative of a compound, respectively, having a structure represented by the following formula:.

[0113] As used herein, “graft-versus-host-disease,” “graft versus host disease,” and “GVHD” can be used interchangeably, and refer to clinical complications following an allogeneic tissue transplant. It is commonly associated with stem cell or bone marrow transplant but the term also applies to other forms of tissue graft. Immune cells (white blood cells) in the tissue (the graft) recognize the recipient (the host) as “foreign”. The transplanted immune cells then attack the host's body cells. GVHD can also occur after a blood transfusion if the blood products used have not been irradiated or treated with an approved pathogen reduction system.

[0114] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition orDocket No.: 069596.00080(T2024-176PCT) formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0115] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as 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 literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics,Docket No.: 069596.00080(T2024-176PCT) cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- 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, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0116] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components, which in some aspects comprises a therapeutic agent, such as disclosed herein, in the form of a composition, a salt, or polymorph. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0117] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internetDocket No.: 069596.00080(T2024-176PCT) website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0118] As used herein, “attached” can refer to covalent or 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 bonding, halogen bonding, electromagnetic interactions, π-π interactions, cation-π interactions, anion-π interactions, polar π-interactions, and hydrophobic effects.

[0119] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g. human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof. It is understood that a vertebrate can be mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Human subjects include neonates, infants, juveniles, adults and geriatric subjects. The subject "in need of" the methods disclosed herein can be a subject that is experiencing a disease state and / or is anticipated to experience a disease state, and the methods and compositions of the invention are used for therapeutic and / or prophylactic treatment. A patient refers to a subject afflicted with a clinical condition, disease or disorder. The term “patient” includes human and veterinary subjects.

[0120] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a cancer, a disorder or disease associated with T-cell proliferation, or a graft-versus-host-disease. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a cancer, a disorder or disease associated with T-cell proliferation, or a graft-versus-host-disease in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone,Docket No.: 069596.00080(T2024-176PCT) prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0121] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0122] As used herein, “therapy” or “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0123] As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of 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 amounts effective to enhance or restore to substantially normal physiological function. For example, an effective amount can refer to the amount of a composition, compound, or agent that improves a condition in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%.

[0124] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of theDocket No.: 069596.00080(T2024-176PCT) specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

[0125] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0126] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0127] In the present disclosure, it is understood that in some cases, an effective amount orDocket No.: 069596.00080(T2024-176PCT) dose of a disclosed compound is the amount of the composition that is capable of inhibiting DHODH to provide a clinically meaningful decrease in the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system, as a result of inhibiting DHODH. This includes, for example, an “effective amount” for therapeutic uses. In some aspects, an “effective” amount in any individual case is determined using techniques, such as a dose escalation study.

[0128] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0129] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0130] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0131] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic,Docket No.: 069596.00080(T2024-176PCT) benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Amino acids comprise a protonatable group or moiety, such as the amino group, which can be used to prepare a pharmaceutically acceptable salt. In such a cation, the positive charge can be, for example at a quarternary nitrogen, yielding a quaternary ammonium compound. Pharmaceutically acceptable salts as used herein include cations of L-arginine and L-lysine, as well as N-methyl-D-glucamine, and combinations thereof.

[0132] The term “pharmaceutically acceptable ester” refers to esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non-toxic esters of the present disclosure include C 1-to-C 6 alkyl esters and C 5-to-C 7 cycloalkyl esters, although C 1-to-C 4 alkyl esters are preferred in some embodiments. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0133] The term “pharmaceutically acceptable amide” refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1-to-C 6 alkyl amines and secondary C 1-to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6- membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1-to- C 3 alkyl primary amides and C 1-to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkylDocket No.: 069596.00080(T2024-176PCT) amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.

[0134] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, 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 effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0135] The term “contacting” as used herein refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a 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, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.

[0136] It is understood, that unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

[0137] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E / Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAWTM(Cambridgesoft Corporation,Docket No.: 069596.00080(T2024-176PCT) U.S.A.).

[0138] For the general chemical formulas provided herein, if no substituent is indicated, a person of ordinary skill in the art will appreciate that the substituent is hydrogen. A bond that is not connected to an atom but is shown indicates that the position of such substituent is variable. A jagged line, wavy line, or two wavy lines drawn through a bond or at the end of a bond indicates that some additional structure is bonded to that position. Moreover, if no stereochemistry is indicated for compounds having one or more chiral centers, all enantiomers and diasteromers are included. Similarly, for a recitation of aliphatic or alkyl groups, all structural isomers thereof also are included.

[0139] As used herein, the term “substituted” is contemplated 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, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0140] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. Similarly, “Ar1,” “Ar2,” “Ar3,” and “Ar4” are used herein as generic symbols to represent various specific aryl substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0141] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moietyDocket No.: 069596.00080(T2024-176PCT) that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0142] The term “alkyl” as used herein is a branched or unbranched fully saturated aliphatic hydrocarbon group. An alkyl group may have 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. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or straight chain, i.e. unbranched. Examples of branched alklyl groups include, but are not limited to iso- propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group can also be substituted or unsubstituted. For example, the 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. Whenever it appears herein, a numerical range such as “1 to 24” refers broadly to each integer in the given range; e.g., “1 to 24 carbon atoms” means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. A “Cn-Cm alkyl moiety” (e.g., a “C1-C7 alkyl”) is a branched or unbranched fully saturated aliphatic hydrocarbon group having from “n” to “m” carbon atoms (e.g., 1 to 7 carbon atoms, and no more than 7 carbon atoms). By way of example only, “C1-C5 alkyl” indicates that there are one to five carbon atoms in the alkyl chain, e.g., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight- chained), etc. The “alkyl” group may also be a medium size alkyl having 1 to 12 carbon atoms. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a 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 a C1-C24 alkyl.

[0143] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are alsoDocket No.: 069596.00080(T2024-176PCT) specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is 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 meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0144] 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, generally 1-3 amino groups. Non- limiting examples of aminoalkyl groups include ─CH2NH2, ─(CH2)2NH2, ─CHCH3NH2, ─(CH2)2CHCH3NH2, ─(CH2)2CHNH2CH2CH3, ─CHCH3(CH2)2NH2, and the like.

[0145] As used herein “alkylamino” refers to an amino group have at least one hydrogen replaced with an alkyl group. Thus, alkylamino refers to the group —NRaRa, wherein Raand Rbare independently selected form H and alkyl, provided at least one of Raor Rbis an alkyl. Non-limiting examples of alkylamino groups include ─NHCH3, ─NHCH2CH3, ─NH(CH2)2CH3, ─N(CH3)2, ─N(CH3)CH2CH3, ─N(CH3)(CH2)2CH3, and the like.

[0146] As used herein “hydroxyalkyl” refers to a straight or branched chain alkyl group in which at least one hydrogen is replaced with an hydroxy group, generally 1-3 hydroxy groups. Non-limiting examples of hydroxyalkyl groups include ─CH2OH, ─(CH2)2OH, ─CHCH3OH, ─(CH2)2CHCH3OH, ─(CH2)2CHOHCH2CH3, ─CHCH3(CH2)2OH, and the like.

[0147] The term “alkanediyl”, as used herein, unless otherwise indicated, means bivalent straight and branched chain saturated hydrocarbon radicals having carbon atoms. For example, “C1-C6 alkanediyl” would refer to bivalent straight and branched chained saturated hydrocarbon radicals having 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl (—CH2CH2—), propanediyl or 1,3-propanediyl (—(CH2)3—), butanediyl orDocket No.: 069596.00080(T2024-176PCT) 1,4-butanediyl (—(CH2)4—), pentanediyl or 1,5-pentanediyl (—(CH2)5—), hexanediyl or 1,6-hexanediyl (—(CH2)6—) and the branched isomers thereof (e.g., isopropanediyl (─CHCH3CH2—)). Alkanediyl groups can be further substituted, e.g., aminoalkanediyl or hydroxyalkanediyl.

[0148] 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, generally 1-3 amino groups. Non-limiting examples of aminoalkanediyl groups include ─CH2NH─, ─(CH2)2NH─, ─CHCH3NH─, ─(CH2)2CHCH3NH─, ─(CH2)2CHNH2(CH2)2─, ─CH2CHNH2(CH2)2─, ─CH2NH(CH2)2─, ─(CH2)2NH(CH2)2─, ─CHCH3(CH2)2NH─, and the like.

[0149] As used herein, “hydroxyalkanediyl” refers to a straight or branched chain alkanediyl group in which at least one hydrogen is replaced with a hydroxy group, generally 1-3 hydroxy groups. Non-limiting examples of hydroxyalkanediyl groups include ─CHOH─, ─CH2CHOH─, ─CCH3OH─, ─(CH2)2CCH3OH─, ─(CH2)2CHOH(CH2)2─, ─CH2CHOH(CH2)2─, ─CHOH(CH2)2─, ─CH2CHOH(CH2)2─, ─CHCH3CH2CHOH─, and the like.

[0150] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or —OA1—(OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups. By way of example only, an alkoxy group can be, in some embodiments, -O(C1-C7 alkyl); in other embodiments it can be -O(C1-C4 alkyl).

[0151] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0152] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl,Docket No.: 069596.00080(T2024-176PCT) 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.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0153] The terms “amine” or “amino” as used herein are represented by the formula —NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0154] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0155] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0156] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula —OH.

[0157] The term “nitro” as used herein is represented by the formula —NO2.

[0158] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0159] “R1,” “R2,” “R3,” . . . “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within 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(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0160] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitableDocket No.: 069596.00080(T2024-176PCT) substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0161] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0162] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0163] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present disclosure unless it is indicated to the contrary elsewhere herein.Docket No.: 069596.00080(T2024-176PCT)

[0164] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfonyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non- limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0165] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0166] As used herein, the term “derivative” refers to a compound having a structure derivedDocket No.: 069596.00080(T2024-176PCT) from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0167] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the disclosure includes all such possible isomers, as well as mixtures of such isomers.

[0168] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, 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 the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0169] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbonDocket No.: 069596.00080(T2024-176PCT) are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0170] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F, and36Cl, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically- labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0171] The compounds described in the disclosure can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the disclosure to form solvates and hydrates. Unless stated to theDocket No.: 069596.00080(T2024-176PCT) contrary, the disclosure includes all such possible solvates.

[0172] Co-crystals of two or more molecules are typically characterized by a crystal structure that is generally held together by free, reversible, non-covalent interactions. As disclosed herein, co-crystals typically consists of a compound having the structure of any one of Formula IV, V, and VI and at least one other component, such as L-arginine, L-lysine, N-methyl-D- glucamine, in a defined stoichiometric ratio. In some embodiments, the co-crystal may comprise hydrates, solvates, and clathrates. Cocrystals can generally be distinguished from salts by the absence of proton transfer between the components in the cocrystal. See e.g. U.S. Department of Health and Human Services, Food and Drug Administration, “Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry” (February 2018) and “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. 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.

[0173] In an example of an ionic salt, such as Compond VII disclosed herein, the cationic proton on L-lysine may be more equally shared with or transferred to the anionic compound of Formula III, such that the salt can be, in some instances, alternately be described as or transformed into two neutral compounds, as shown in Composition 1:Moreover in some embodiments disclosed herein, a salt and its non-salt form, e.g, Compound VII and Composition 1, can be in equilibrium with each other.

[0174] It is known that chemical substances form solids which are present in different states ofDocket No.: 069596.00080(T2024-176PCT) order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. In general, polymorphism is affected by the ability of a molecule (or its salt, cocrystal, or hydrate) to change its conformation or to form different intermolecular or intra-molecular interactions, (e.g., different hydrogen bond configurations), which is reflected in different atomic arrangements in the crystal lattices of different polymorphs. In contrast, the overall external form of a substance is known as “morphology,” which refers to the external shape of the crystal and the planes present, without reference to the internal structure. A particular crystalline polymorph can display different morphology based on different conditions, such as, for example, growth rate, stirring, and the presence of impurities. The different polymorphs of a substance may possess different energies of the crystal lattice and, thus, in solid state they can show different physical properties such as form, density, melting point, color, stability, solubility, dissolution rate, etc., which can, in turn, effect the stability, dissolution rate and / or bioavailability of a given polymorph and its suitability for use as a pharmaceutical and in pharmaceutical compositions.The compounds according to the disclosure can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the disclosure includes all such possible polymorphic forms.

[0175] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, 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 Inc., 1989).

[0176] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to aDocket No.: 069596.00080(T2024-176PCT) specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0177] Disclosed are the components to be used to prepare the compositions of the disclosure as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B- F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of 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 compositions of the disclosure. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the disclosure.

[0178] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

[0179] Described herein are compounds that can inhibit dihydroorotate dehydrogenase (DHODH) and have therapeutic or clinical utility for a disease or disorder that can be treated by inhibition of DHODH. Also described herein are methods of synthesizing the disclosedDocket No.: 069596.00080(T2024-176PCT) compounds. Also described herein are methods of administering the disclosed compounds to a subject in need thereof. In some aspects, the subject can have a disease or disorder associated with DHODH activity, such as a cancer, a disorder or disease associated with T-cell proliferation, or a graft-versus-host-disease. Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure. Compounds.

[0180] In various aspects, the disclosed compounds, compositions and pharmaceutical compositions comprise 4,6-substituted-2-(3’-[1,1'-biphenyl]-4-yl)quinoline analogs useful as inhibitors of dihydroxyorotate dehydrogenase. Such inhibitors have use as therapeutic agents in a variety of clinical conditions including but not limited to cancer, graft-versus-host disease, and disorders associated with T-cell proliferation. In another aspect, the disclosed compounds comprise pharmaceutically acceptable salts of a conjugate base, such as 4,6-substituted-2-(3’- [1,1'-biphenyl]-4-yl)quinoline analogs and a counterion having a positive charge.

[0181] Disclosed herein are compositions comprising: a salt comprising a conjugate base and a counterion; wherein the conjugate base has a structure of Formula I:wherein R1is halogen or a halide (e.g. F, Cl, Br, or I); and R5is –O(C1-C7 alkyl); and wherein the counterion comprises a cation of one or more of L-arginine, L-lysine, or N-methyl-D-glucamine. In some embodiments, R1is F or Cl. In some embodiments R1is F. In some embodiments, R5is –O(C1-C4 alkyl). In some embodiments, R5is -OCH2CH2CH2CH3; in other embodiments, R5is -OCH2CH3.Docket No.: 069596.00080(T2024-176PCT)

[0182] In some embodiments the conjugate base has a structure of Formula II:Formula II, wherein R5is as defined above.

[0183] In some embodiments the conjugate base has a structure of Formula III:Formula III.

[0184] In some variations, the counterion is a cation of L-arginine; in others the counterion is a cation of L-lysine; in still others, the counterion is a cation of N-methyl-D-glucamine.

[0185] In some variation of any aspect or embodiment, the salt in the composition is a crystalline salt. The crystalline salt has a variety of different polymorphs. In some embodiments, the crystalline salt is polymorph Pattern A, polymorph Pattern B, polymorph Pattern C, or polymorph Pattern D. In some variations, the crystalline salt is polymorph Pattern A. In some variations, the crystalline salt is polymorph Pattern B. In other variations, the crystalline salt is polymorph Pattern C. In still other variations, the crystalline salt is polymorph Pattern D.

[0186] In some embodiments the conjugate base has a structure of Formula III; the counterion is a cation of L-lysine; the salt is a crystalline salt; and the crystalline salt is polymorph Pattern A. The anion of Formula III, or Compound III, can be referred to as 2-(3'-butoxy-[1,1'- biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylate.

[0187] Disclosed herein are compositions comprising a first component and a secondDocket No.: 069596.00080(T2024-176PCT) component, wherein the first component comprises a compound having a structure of Formula IV:wherein R1is a halogen or halide; and R5is –O(C1-C7 alkyl); and wherein the second component comprises one or more of L-arginine, L-lysine, or N-methyl-D-glucamine. In some embodiments, R1is F or Cl. In some embodiments R1is F. In some embodiments, R5is –O(C1-C4 alkyl). In some embodiments, R5is -OCH2CH2CH2CH3; in other embodiments, R5is -OCH2CH3.

[0188] In some embodiments of a composition described herein, the first component has a structure of Formula V:wherein R5is as described above.

[0189] In some embodiments wherein the first component has the structure of Formula VI:Formula VI.Docket No.: 069596.00080(T2024-176PCT)

[0190] The compound of Formula VI, or Compound VI, can also be referred to as 2-(3'-butoxy- [1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid.

[0191] Additionally, in some instances, the second component of a composition described herein comprises L-arginine, L-lysine, N-methyl-D-glucamine, or a combination of two or more of the foregoing. In some cases, the second component is L-arginine. In other variations, the second component is L-lysine. In still other variations, the second component is N-methyl- D-glucamine. Moreover, as described further herein, a composition comprising first and second components such as described above can be a non-ionic composition or mixture, in which the first and second components are not counterions of one another (e.g., a conjugate base paired with a counter ion to form an ionic solid). Using L-lysine and Compound VI as a representative example, such a composition can be represented as Composition 1:Composition 1

[0192] Disclosed herein are compositions comprising a first component and a second component, wherein the composition is a crystalline solid. In some embodiments, the crystalline solid is polymorph Pattern A, Pattern B, Pattern C, or Pattern D. In some cases, the crystalline solid is polymorph Pattern A. In other cases, the crystalline solid is polymorph Pattern B. In still other cases, the crystalline solid is polymorph Pattern C. In still other cases, the crystalline solid is polymorph Pattern D.

[0193] Also disclosed herein are compounds comprising cocrystals comprising a first compound and a second compound, wherein the first compound is a compound having aDocket No.: 069596.00080(T2024-176PCT) formula represented by a structure:, wherein R1is selected from halogen; wherein R5is –O(C1-C7 alkyl); wherein the second compound comprises L-arginine, L-lysine, N-methyl-D-glucamine, and combinations thereof.

[0194] In various aspects, it is contemplated herein that the disclosed compounds further comprise their isotopically-labelled or isotopically-substituted variants, i.e., compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labelled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.

[0195] In a further aspect, the disclosed compounds can be isolated as solvates and, in particular, as hydrates of a disclosed compound, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the disclosure to form solvates and hydrates.Docket No.: 069596.00080(T2024-176PCT)

[0196] 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, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug compound with a suitable pharmaceutically acceptable base. The salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure; or following final isolation by reacting a free base function, such as a secondary or tertiary amine, of a disclosed compound with a suitable inorganic or organic acid; or reacting a free acid function, such as a carboxylic acid, of a disclosed compound with a suitable inorganic or organic base.

[0197] In one aspect, the disclosed compounds, salts or compositions are crystalline polymorphs. In a further aspect, the disclosed compounds, salts or compositions are crystalline polymorph of Pattern A, Pattern B, Pattern C or Pattern D, each as disclosed in the Examples.

[0198] In one aspect, disclosed compounds, salts or compositions polymorphs are of Pattern A. Polymorphs of Pattern A exhibit an X-ray powder diffraction pattern that is substantially similar to, or the same as, the X-ray powder diffraction pattern shown in Figure 6 for L-lysine salt Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02. In some instances, the XRPD pattern comprises peaks at 3.3°± 0.2°, 6.3°± 0.2°, and 20.3° ± 0.2° 2θ. In some instances, the XRPD pattern comprises peaks at 3.5°± 0.5°, 6.5°± 0.5°, and 20.5° ± 0.5° 2θ. In some instances, the XRPD pattern comprises peaks at 3.3°± 0.2°, 6.3°± 0.2°, 12.5°± 0.2°, 20.3°± 0.2°, and 25.3° ± 0.2° 2θ. In other instances, the XRPD pattern comprises peaks at 3.5°± 0.5°, 6.5°± 0.5°, 12.5°± 0.5°, 20.5°± 0.5°, and 25.5° ± 0.5° 2θ.

[0199] In one aspect, the compounds, salts, or crystalline polymorphs of Pattern A have a melting point in a range of about 224.0 °C to about 228.0 °C or about 225.0 °C to about 227.0 °C. In one aspect, the melting point is about 226.0 °C. In one variation, the compounds or crystalline polymorphs have a melting point in a range of 224 °C - 228 °C or 225 °C - 227 °C. In one aspect, the melting point is 226 °C. In one aspect, for the compounds or crystalline polymorph of Pattern A, the thermogravimetry (TGA) results show 1.5% loss at 200ºC; in some embodiments, the polymorph of Pattern A TGA results show between a 1% and 2% loss at 200ºC

[0200] In one aspect, the disclosed compounds, salts or compositions are crystallineDocket No.: 069596.00080(T2024-176PCT) polymorphs of Pattern B. Polymorphs of Pattern B exhibit an X-ray powder diffraction pattern that is substantially similar to, or the same as, the X-ray powder diffraction pattern shown in Figure 10 for sample ID FR02115-7-SU-RAS3-ACN-Water-ACN-200mg. In some instances, the XRPD pattern comprises peaks at 6.0°± 0.5°, 12.0°± 0.5°, 21.5°± 0.5°, and 24.0° ± 0.5° 2θ.

[0201] In one aspect, the compounds or crystalline polymorphs of Pattern B have a melting point in a range of 226.0 °C to 230.0 °C or 227.5 °C to 229.0 °C. In one aspect, the melting point is 228.8 °C. In one aspect, for the compounds or crystalline polymorph of Pattern B, the thermogravimetry (TGA) results show 3.2% loss at 210ºC; in some embodiments, the polymorph of Pattern B TGA results show between a 3% and 4% loss at 210ºC.

[0202] In one aspect, the disclosed compounds, salts or compositions are crystalline polymorphs of Pattern C. Polymorphs of Pattern C exhibit an X-ray powder diffraction pattern that is substantially similar to, or the same as, the X-ray powder diffraction pattern shown in Figure 18 for sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg-evaporated-1h. In some instances, the XRPD pattern comprises peaks at 6.0°± 0.5°, 9.5°± 0.5°, 11.0°± 0.5°, 11.5° ± 0.5° AND 14.0± 0.5° 2θ.

[0203] In one aspect, the compounds or crystalline polymorphs of Pattern C have a melting point in a range of 222.0 °C to 226.0 °C or 223.0 °C to 225.0 °C. In one aspect, the melting point is 223.9 °C. In one aspect, for the compounds or crystalline polymorph of Pattern C, the thermogravimetry (TGA) results show 5.1% loss at 210ºC; in some embodiments, the polymorph of Pattern C TGA results show between a 4.5% and 6% loss at 210ºC

[0204] In one aspect, the disclosed compounds, salts or compositions are crystalline polymorphs of Pattern D. Polymorphs of Pattern D exhibit an X-ray powder diffraction pattern that is substantially similar to, or the same as, the X-ray powder diffraction pattern shown in Figure 27 for sample ID FR02115-7-SU-FC3-Ethanol-Water-300mg-vacuum-3h. In some instances, the XRPD pattern comprises peaks at 5.5°± 0.5°, 17.5°± 0.5°, and 21.0°± 0.5° 2θ.

[0205] In one aspect, the compounds or crystalline polymorphs of Pattern D have a melting point in a range of 230.0 °C to 234.0 °C or 231.0 °C to 266.0 °C. In one aspect, the melting point is 232.3 °C. In one aspect, for the compounds or crystalline polymorph of Pattern D, the thermogravimetry (TGA) results show 0.7% loss at 210ºC; in some embodiments, the polymorph of Pattern D TGA results show between a 0.5% and 1.5% loss at 210ºC.

[0206] Solutions of the compounds or compositions disclosed herein, comprising L-lysine or its salt generally show a peak in a1H NMR spectrum at 2.80 ppm (triplet). In one aspect,Docket No.: 069596.00080(T2024-176PCT) solutions of the compounds or compositions disclosed herein have an1H-NMR spectrum comprising peaks at about 0.97 ppm, 4.09 ppm, 7.88 ppm, and 8.31 ppm; typically the pattern for each peak is: 0.97 ppm (triplet), 4.09 ppm (triplet), 7.88 ppm (doublet), and 8.31 ppm (multiplet). Methods of Making the Compounds.

[0207] In one aspect, the present disclosure relates to methods of making compounds useful as inhibitors of dihydroorotate dehydrogenase (DHODH), which can be useful in the treatment of clinical conditions, diseases, and disorders associated with DHODH dysfunction and other diseases in which DHODH is involved. In one aspect, the disclosure relates to the disclosed synthetic manipulations. In a further aspect, the disclosed compounds comprise the products of the synthetic methods described herein. In a further aspect, the disclosed compounds comprise a compound produced by a synthetic method described herein. In a still further aspect, the disclosure comprises a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier. In a still further aspect, the disclosure comprises a method for manufacturing a medicament comprising combining at least one compound of any of disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.

[0208] The compounds of this disclosure can be prepared by employing reactions as shown in the disclosed schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. The following examples are provided so that the disclosure might be more fully understood, are illustrative only, and should not be construed as limiting. For clarity, examples having a fewer substituent can be shown where multiple substituents are allowed under the definitions disclosed herein.

[0209] It is contemplated that each disclosed method can further comprise additional steps, manipulations, and / or components. It is also contemplated that any one or more step, manipulation, and / or component can be optionally omitted from the disclosure. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed compositions, kits, and uses.

[0210] Briefly, the overall synthesis procedure comprises a two-step reaction procedure, with step 1 comprising a Suzuki-Miyaura Reaction and step 2 comprising Pfitzinger Reaction, usingDocket No.: 069596.00080(T2024-176PCT) Compound VI as a specific example.Step 1 (Suzuki-Miyaura Reaction).Step 2 (Pfitzinger Reaction).

[0211] Two variant processes on the foregoing are provided below in both generic form and a specific example, i.e., Process 1 and Process 2. Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein, providing synthetic pathways for compounds of the present application where R1is halogen and R5is–O(C1-C7 alkyl). Process 1: Generic FormStep 2 (Pfitzinger Reaction).Docket No.: 069596.00080(T2024-176PCT)

[0212] In one aspect, compounds of the present disclosure, e.g. compounds of Formula 5 can be prepared in a two-step reaction as shown above. Briefly, the synthesis of compound of Formula 5 begins in Step 1 with reaction of compounds of Starting Material 1 and 2 to yield compounds of Intermediate 3. Compounds of Starting Material 1, i.e., 4-halosubstituted phenone analogs, e.g., 4-bromoacetophenone, and Starting Material 2, i.e., appropriately substituted phenylboronic acids, e.g., 4-ethoxyphenylboronic acid, can be obtained from commercial sources or can be readily prepared by skilled in the art according to methods described in the literature. For example, both 4-bromophenone and 4-ethoxyphenylboronic acid are available commercially. The reaction of compounds of Starting Material 1 and 2 is typically carried at a molar ratio of Starting Material 1 compound to Starting Material 2 compound of about 5-25:1 out in a suitable solvent, e.g., 1-propanol, in the presence of palladium acetate and triphenylphosphine, at a suitable temperature, e.g. about 75 ºC to about 200 ºC, for a suitable period of time, e.g. about 10 minutes to about 2 hours, in order to ensure that the reaction is complete. The reaction is then cooled to a suitable temperature, e.g., room temperature, and then can be further cooled, e.g., to about 0 °C to obtain suitable crystals, which can be collected by filtration. Other suitable methods of isolating the product will be apparent to one skilled in the art.

[0213] In Step 2, The composition of Intermediate 3, isolated from Step 1, is reacted with compounds of Starting Material 4 to yield the desired disclosed compound of Formula 5 as shown above. Briefly, a mixture of the appropriate isatin, i.e., a compound of Starting Material 4, e.g., 5-fluoroisatin (5-fluoroindoline-2,3-dione), and a suitable base, e.g., aqueous potassium hydroxide solution (33%), are stirred and heated gently. Added to this solution is a slurry of a compound of Intermediate 3, e.g., 1-(4’-ethoxy-[1,1’-biphenyl]-4-yl)ethan-1-one, in an amount of about equimolar to the composition of Starting Material 4, and a suitable solvent, e.g., ethanol. The reaction mixture is then heated to a suitable temperature, e.g., reflux or about 70 °C to about 200 °C, for a suitable period of time, e.g., about 10 minutes to about 3 hours, in order to ensure that the reaction is complete. The reaction is then cooled to a suitable temperature, e.g., room temperature, and then can be further cooled, e.g., to about 0 °C to obtain suitable crystals, which can be collected by filtration. Other suitable methods of isolating the product will be apparent to one skilled in the art. The product may also be further purified if residual solvent is present, e.g., as described herein below for Cpd3.

[0214] In another aspect, a specific example of Process 1 is provided below.Docket No.: 069596.00080(T2024-176PCT) Process 1: Specific ExampleStep 1 (Suzuki-Miyaura Reaction).3a 4a 5aStep 2 (Pfitzinger Reaction).

[0215] In another aspect, substituted 3,4,6,8-substituted-2-([1,1'-biphenyl]-4-yl)quinoline analogs of the present disclosure can be prepared by Process 2 which is generically as shown below, providing synthetic pathways for compounds of the present application where R1is halogen and R5is–O(C1-C7 alkyl). Process 2: Generic FormStep 1 (Suzuki-Miyaura Reaction).Docket No.: 069596.00080(T2024-176PCT)Step 2 (Pfitzinger Reaction).

[0216] In one aspect, compounds of the present disclosure, e.g. compounds of Formula 5 can be prepared in a two-step reaction as shown above. Briefly, the synthesis of compound of Formula 5 begins in Step 1 with reaction of compounds of Starting Material 1 and 2 to yield compounds of Intermediate 3. Compounds of Starting Material 1, i.e., 4-halosubstituted phenone analogs, e.g., 4-bromoacetophenone, and Starting Material 2, i.e., appropriately substituted phenylboronic acids, e.g., 4-n-butoxyphenylboronic acid, can be obtained from commercial sources or can be readily prepared by skilled in the art according to methods described in the literature. For example, both 4-bromophenone and 4-ethoxyphenylboronic acid are available commercially. The reaction of compounds of Starting Material 1 and 2 is typically carried at a molar ratio of Starting Material 1 compound to Starting Material 2 compound of about 1-25:1 out in a suitable solvent, e.g., dimethylacetamide, in the presence of palladium on carbon (Pd / C), at a suitable temperature, e.g. about 30 ºC to about 200 ºC, for a suitable period of time, e.g. about 1 hour to about 24 hours, in order to ensure that the reaction is complete. The reaction is then cooled to a suitable temperature, e.g., room temperature, and then can be further cooled, e.g., to about 0 °C to obtain suitable crystals, which can be collected by filtration. Other suitable methods of isolating the product will be apparent to one skilled in the art.

[0217] In Step 2, The composition of Intermediate 3, isolated from Step 1, is reacted with compounds of Starting Material 4 to yield the desired disclosed compound of Formula 5 as shown above. Briefly, a mixture of potassium hydroxide in a molar ratio of 1-10:1 (KOH to Starting Material 7) and a suitable solvent, e.g., ethanol, is prepared. Added to this solution is a slurry of a compound of Intermediate 3, e.g., 1-(3’-n-butoxy-[1,1’-biphenyl]-4-yl)ethan- 1-one; a compound of Starting Material 4, e.g., 5-fluoroisatin (5-fluoroindoline-2,3-dione),Docket No.: 069596.00080(T2024-176PCT) in a molar ratio of about 1-2:1 (Starting Material 4 to Intermediate 3); and a suitable solvent, e.g., ethanol. The reaction mixture is then heated to a suitable temperature, e.g., reflux or about 70 °C to about 200 °C, for a suitable period of time, e.g., about 10 minutes to about 3 hours, in order to ensure that the reaction is complete. The reaction is then cooled to a suitable temperature, e.g., room temperature, and then can be further cooled, e.g., to about 0 °C to obtain suitable crystals, which can be collected by filtration. Other suitable methods of isolating the product will be apparent to one skilled in the art. The product may also be further purified if residual solvent is present, e.g., as described herein below.

[0218] In another aspect, a specific example of Process 2 is provided below. Process 2: Specific ExampleStep 1 (Suzuki-Miyaura Reaction).3a 4a 5a (Formula VI)Step 2 (Pfitzinger Reaction). Pharmaceutical Compositions.

[0219] In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants. TheDocket No.: 069596.00080(T2024-176PCT) disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences.

[0220] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. In a further aspect, the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially and intratumorally.

[0221] As used herein, “parenteral administration” includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[0222] In various aspects, the present disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof. In a further aspect, a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.

[0223] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable non-toxic bases or acids. For therapeutic use, salts of the disclosed compounds are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparationDocket No.: 069596.00080(T2024-176PCT) or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are contemplated by the present disclosure. Pharmaceutically acceptable acid and base addition salts are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the disclosed compounds are able to form.

[0224] In various aspects, a disclosed compound comprising an acidic group or moiety, e.g., a carboxylic acid group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic base. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.

[0225] Bases which can be used to prepare the pharmaceutically acceptable base-addition salts of the base compounds are those which can form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations such as, alkali metal cations (e.g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine- (meglumine), lower alkanolammonium and other such bases of organic amines. In a further aspect, derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. In various aspects, such pharmaceutically acceptable organic non-toxic bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any of the four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, N,N'-dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine,Docket No.: 069596.00080(T2024-176PCT) quinoline and isoquinoline; benzathine, N-methyl-D-glucamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, hydrabamine salts, and salts with amino acids such as, for example, histidine, arginine, lysine and the like. The foregoing salt forms can be converted by treatment with acid back into the free acid form.

[0226] In various aspects, a disclosed compound comprising a protonatable group or moiety, e.g., an amino group, such as found in L-lysine, L-arginine and L-methly-D-glucamine, can be used to prepare a pharmaceutically acceptable salt. In such a cation, the positive charge can be, for example at a quarternary nitrogen, yielding a quaternary ammonium compound. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic acid. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with a basic reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. These acid addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding basic compounds with an aqueous solution containing the desired pharmacologically acceptable anions and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0227] Acids which can be used to prepare the pharmaceutically acceptable acid-addition salts are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids. Exemplary, but non-limiting, inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like. Exemplary, but non-limiting, organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like. In a further aspect, the acid-addition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0228] In practice, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimateDocket No.: 069596.00080(T2024-176PCT) admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present disclosure, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0229] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. In general, compounds described herein will be administered as pharmaceutical compositions by any one of the following routes: oral, transdermal, intranasal, by suppository, parenteral (e.g., intramuscular, intravenous or subcutaneous), or intrathecal administration. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vialsDocket No.: 069596.00080(T2024-176PCT) for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

[0230] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various aspects, the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof. In a further aspect, a disclosed compound, or pharmaceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0231] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).

[0232] The compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intendedDocket No.: 069596.00080(T2024-176PCT) form of administration and as consistent with conventional pharmaceutical practices. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration. Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used. The compounds may be administered as a dosage that has a known quantity of the compound.

[0233] Because of the ease in administration, oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. However, other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like. Accordingly, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0234] The disclosed pharmaceutical compositions in an oral dosage form can comprise one or more pharmaceutical excipient and / or additive. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also optionally hydrated); glycerol esters andDocket No.: 069596.00080(T2024-176PCT) polyglycerol esters of saturated fatty acids C12H24O2 to C18H36O2 and their mixtures, it being possible for the glycerol hydroxy groups to be totally or also only partly esterified (for example mono-, di- and triglycerides); pharmaceutically acceptable mono- or multivalent alcohols and polyglycols such as polyethylene glycol and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10-18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentacrythritol, sorbitol, mannitol and the like, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glyceroformals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1- C12-alcohols, dimethylacetamide, lactamides, lactates, ethylcarbonates, silicones (in particular medium-viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

[0235] Other auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Conventional coating substances may also be used to produce the oral dosage form. Those that may for example be considered are: polymerizates as well as copolymerizates of acrylic acid and / or methacrylic acid and / or their esters; copolymerizates of acrylic and methacrylic acid esters with a lower ammonium group content (for example Eudragit® RS), copolymerizates of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (for example Eudragit® RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate, carboxy methyl cellulose; methyl cellulose phthalate, methyl cellulose succinate, -phthalate succinate as well as methyl cellulose phthalic acid half ester; zein; ethyl cellulose as well as ethyl cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymerizate; 2-ethyl-hexyl- acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine; and the like.

[0236] Plasticizing agents that may be considered as coating substances in the disclosed oral dosage forms are: citric and tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylatedDocket No.: 069596.00080(T2024-176PCT) monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxyethyl)- adipate; benzophenone; diethyl- and dibutylsebacate, dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, dibutyrate, dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbate 50); sorbitan monooleate; and the like.

[0237] Moreover, suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0238] In various aspects, a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. In a further aspect, a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0239] In various aspects, an oral dosage form, such as a solid dosage form, can comprise a disclosed compound that is attached to polymers as targetable drug carriers or as a prodrug. Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0240] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calciumDocket No.: 069596.00080(T2024-176PCT) phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0241] A tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0242] In various aspects, a solid oral dosage form, such as a tablet, can be coated with an enteric coating to prevent ready decomposition in the stomach. In various aspects, enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate. Akihiko Hasegawa “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form” Chem. Pharm. Bull.33:1615- 1619 (1985). Various enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol. 22:42p (1970)). In a further aspect, the enteric coating may comprise hydroxypropyl-methylcellulose phthalate, methacrylic acid- methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.

[0243] In various aspects, an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier. Examples of water soluble or water insoluble carrier include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, or hydroxypropyl-methylcellulose, ethyl cellulose, or stearic acid.

[0244] In various aspects, an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle. For example, aDocket No.: 069596.00080(T2024-176PCT) liquid dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.

[0245] For the preparation of solutions or suspensions it is, for example, possible to use water, particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulphoxide, triglycerides and the like.

[0246] In the case of a liquid dosage form such as a drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, for example amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary C1-C4-amines or C1-C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such as ethylene diamine, hydroxyethyl theophylline, tromethamine (for example as 0.1 to 20% aqueous solution), aliphatic amino acids.

[0247] In preparing the disclosed liquid dosage form can comprise solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context, polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20. Polyoxyethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containingDocket No.: 069596.00080(T2024-176PCT) compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 mole ethylene oxide per 1 mole glyceride). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. See also Dr. H. P. Fiedler “Lexikon der Hillsstoffe für Pharmazie, Kostnetik und angrenzende Gebiete” 1971, pages 191-195.

[0248] In various aspects, a liquid dosage form can further comprise preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants, antioxidants and complex formers and the like. Complex formers which may be for example be considered are: chelate formers such as ethylenediaminetetracetic acid, nitrilotriacetic acid, diethylenetriamine- pentacetic acid and their salts.

[0249] It may optionally be necessary to stabilize a liquid dosage form with physiologically acceptable bases or buffers to a pH range of approximately 6 to 9. Preference may be given to as neutral or weakly basic a pH value as possible (up to pH 8).

[0250] In order to enhance the solubility and / or the stability of a disclosed compound in a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form, it can be advantageous to employ α-, β- or γ-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β- cyclodextrin. Also co-solvents such as alcohols may improve the solubility and / or the stability of the compounds according to the present disclosure in pharmaceutical compositions.

[0251] In various aspects, a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form can further comprise liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0252] Pharmaceutical compositions of the present disclosure suitable injection, such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0253] Pharmaceutical compositions of the present disclosure suitable for parenteralDocket No.: 069596.00080(T2024-176PCT) administration can include sterile aqueous or oleaginous solutions, suspensions, or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe. The pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0254] Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In some aspects, a disclosed parenteral formulation can comprise about 0.01- 0.1 M, e.g. about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can comprise about 0.9% saline.

[0255] In various aspects, a disclosed parenteral pharmaceutical composition can comprise pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include but not limited to water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like. In a further aspect, a disclosed parenteral pharmaceutical composition can comprise may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. Also contemplated for injectable pharmaceutical compositions are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient.

[0256] In addition to the pharmaceutical compositions described herein above, the disclosedDocket No.: 069596.00080(T2024-176PCT) compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0257] Pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration. As used herein, the phrase “topical application” means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane. By selecting the appropriate carrier and optionally other ingredients that can be included in the composition, as is detailed herein below, the compositions of the present disclosure may be formulated into any form typically employed for topical application. A topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0258] In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

[0259] Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives. The specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience). As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, forDocket No.: 069596.00080(T2024-176PCT) example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.

[0260] Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.

[0261] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the “internal” phase, is generally comprised of petrolatum and / or a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.

[0262] Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information.

[0263] Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid,Docket No.: 069596.00080(T2024-176PCT) which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred organic macromolecules, i.e., gelling agents, are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark Carbopol™. Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene- polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

[0264] Sprays generally provide the active agent in an aqueous and / or alcoholic solution which can be misted onto the skin for delivery. Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated active agent at the site of administration.

[0265] Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application. Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique. Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system. Foams can be water-based or aqueous alkanolic, but are typically formulated with high alcohol content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.

[0266] Skin patches typically comprise a backing, to which a reservoir containing the active agent is attached. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir. Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protectiveDocket No.: 069596.00080(T2024-176PCT) permeable layer can be used to protect the adhesive side of the patch prior to its use. Skin patches may further comprise a removable cover, which serves for protecting it upon storage.

[0267] Examples of patch configuration which can be utilized with the present disclosure include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive. In such a transdermal patch design, the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. In the multi-layer drug-in-adhesive patch a membrane is disposed between two distinct drug- in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.

[0268] Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition. Representative examples of suitable carriers according to the present disclosure therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions. Other suitable carriers according to the present disclosure include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

[0269] Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, comprise a tube. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may include labeling approved by the U.S. Food andDocket No.: 069596.00080(T2024-176PCT) Drug Administration for prescription drugs or of an approved product insert. Compositions comprising the topical composition of the disclosure formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0270] Another patch system configuration which can be used by the present disclosure is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Yet another patch system configuration which can be utilized by the present disclosure is a matrix system design which is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

[0271] Pharmaceutical compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0272] Pharmaceutical compositions containing a compound of the present disclosure, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0273] The pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.

[0274] The disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the activeDocket No.: 069596.00080(T2024-176PCT) ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Pharmaceutical compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0275] The exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present disclosure.

[0276] Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 % by weight; in some embodiments from 0.1 to 70 % by weight, in other embodiments from 0.1 to 50 % by weight of the active ingredient and correspondingly, from 1 to 99.95 % by weight, or from 30 to 99.9 % by weight, or from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition. As shown herein, an oral pharmaceutical composition can comprise between 0.5% and 10% of the active pharmaceutical ingredient (“API”) and the corresponding amount of a salt or composition to be added to such a pharmaceutical formulation can be calculated accordingly. In some instances, the API comprises between 0.5% and 20% of the pharmaceutical formulation. In other instances, the API comprises between 0.75% and 15% or between 1.5% and 7.5% of the pharmaceutical formulation. Other compositions can be used, based the needs of the patient and the mode of administration.Docket No.: 069596.00080(T2024-176PCT)

[0277] In the treatment conditions which require of inhibition dihydroorotate dehydrogenase activity an appropriate dosage level will generally be about 0.01 to 1000 mg per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level will be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active pharmaceutical ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response. As an example, therapeutically effective amounts may range from approximately 0.03 to 50 mg per kilogram body weight of the recipient per day; for example, about 0.1-25 mg / kg / day, or from about 0.5 to 10 mg / kg / day. Thus, for administration to a 70 kg person, the dosage range can be about 1-3,500 mg per day.

[0278] In some of the embodiments of the technology described herein, the pharmaceutical compositions are packaged in unit dosage form. The unit dosage form is effective in treating a disease and / or disorder. Generally, a unit dosage including a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies, and the like. An exemplary unit dosage based on these considerations can also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound, salt or composition disclosed herein can comprise the equivalent of 1 mg of an active pharmaceutical ingredient up to the equivalent of 25 mg of an active pharmaceutical ingredient. In some instances, the unit dosage comprises the equivalent of 2.5 mg of an active pharmaceutical ingredient. In other instances the unit dosage comprises the equivalent of 5 mg or 10 mg of an active pharmaceutical ingredient.

[0279] Alternately, the unit dosage can vary from 3 x 10-5 g / kg to 1 g / kg, such as, l x 10-3g / kg to 1.0 g / kg. Dosage of a compound of the present technology can also vary from 0.01 mg / kg to 100 mg / kg or from 0.1 mg / kg to 10 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 0.5 g / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg toDocket No.: 069596.00080(T2024-176PCT) 100 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 50 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 10 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 5 mg / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 0.5 g / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 100 mg / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 50 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 10 mg / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 5 mg / kg.

[0280] Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day. In various aspects, such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. In a further aspect, dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.

[0281] A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.

[0282] It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with individual patient response.

[0283] The present disclosure is further directed to a method for the manufacture of a medicament for modulating dihydroorotate dehydrogenase activity (e.g., treatment of one or more disorders, such as a cancer or a graft-versus-host-disease, that can be treated via inhibition of dihydroorotate dehydrogenase dysfunction activity) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with aDocket No.: 069596.00080(T2024-176PCT) pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the present disclosure further relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0284] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions.

[0285] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

[0286] As already mentioned, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier. Additionally, the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure.

[0287] As already mentioned, the present disclosure also relates to a pharmaceutical composition comprising a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for a disclosed compound or the other drugs may have utility as well as to the use of such a composition for the manufacture of a medicament. The present disclosure also relates to a combination of disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a therapeutic agent that can be used to treat autoimmune diseases, immune and inflammatory diseases, destructive bone disorders, malignant neoplastic diseases, angiogenic- related disorders, viral diseases, and infectious diseases. The present disclosure also relates to such a combination for use as a medicine. The present disclosure also relates to a product comprising (a) disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and (b) an additional therapeutic agent, as a combined preparation for simultaneous, separate orDocket No.: 069596.00080(T2024-176PCT) sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the modulatory effect of the disclosed compound and the additional therapeutic agent. The different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents. Methods of Using the Compounds.

[0288] In a further aspect, the present disclosure provides methods of treatment comprising administration of a therapeutically effective amount of a disclosed compound or pharmaceutical composition as disclosed herein above to a subject in need thereof. In particular, the disclosed compounds and disclosed pharmaceutical compositions can be used in methods of treating a disease or disorder that are associated with increased, aberrant, or dysfunctional levels of dihydroorotate dehydrogenase (DHODH) activity in a cell, tissue, or organism. That is, the disclosed compounds and disclosed pharmaceutical compositions can be used to inhibit DHODH activity in a cell, tissue or organism to provide a clinical or therapeutic benefit to a subject which has been determined to or been diagnosed to have with increased, aberrant, or dysfunctional levels of dihydroorotate dehydrogenase (DHODH) activity.

[0289] In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a disorder treatable by inhibition of DHODH and / or a need for inhibition of DHODH prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a cancer, a disorder associated with T-cell proliferation, or a may be at risk for graft-versus-host disease or organ rejection following transplantation prior to the administering step. In some aspects of the disclosed methods, the subject has been identified with a need for treatment prior to the administering step.

[0290] The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which compounds disclosed herein or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, aDocket No.: 069596.00080(T2024-176PCT) pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound will be more efficacious than either as a single agent.

[0291] DHODH is an enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidine. It converts dihydroorotate (DHO) to orotate (ORO). Human DHODH is a ubiquitous flavine mononucleotide (FMN) moiety flavoprotein. In a mammalian cell, DHODH is anchored at the inner mitochondrial leaflet and catalyzes the conversion of DHO to ORO, which represents the rate limiting step in the de novo pyrimidine biosynthesis. Kinetic studies indicate a sequential ping-pong mechanism for the conversion of DHO to ORO (e.g., see Knecht et al., Chem. Biol. Interact. 2000, 124, 61-76). The first half-reaction comprises the reduction of DHO to ORO. Electrons are transferred to the FMN which becomes oxidized to dihydroflavin mononucleotide (FMNH2). After dissociation of ORO from the enzyme, FMNH2 is regenerated by a ubiquinone molecule, which is recruited from the inner mitochondrial membrane. Kinetic and structural studies revealed two distinct binding sites for DHO / ORO and ubiquinone, respectively.

[0292] Human DHODH is composed of two domains, a large C-terminal domain (Met78- Arg396) and a smaller N-terminal domain (Met30-Leu68), connected by an extended loop. The large C-terminal domain can be best described as an α / β-barrel fold with a central barrel of eight parallel β strands surrounded by eight α helices. The redox site, formed by the substrate binding pocket and the site that binds the cofactor FMN, is located on this large C-terminal domain. The small N-terminal domain, on the other hand, consists of two α helices (labeled α1 and α2), both connected by a short loop. This small N-terminal domain harbors the binding site for the cofactor ubiquinone. The helices α1 and α2 span a slot of about 10×20 Å2 in the so- called hydrophobic patch, with the short α1-α2 loop at the narrow end of that slot. The slot forms the entrance to a tunnel that ends at the FMN cavity nearby the α1-α2 loop. This tunnel narrows toward the proximal redox site and ends with several charged or polar side chains (Gln47, Tyr356, Thr360, and Arg136). Structural clues, as discussed above, along with kinetic studies suggest that ubiquinone, which can easily diffuse into the mitochondrial inner membrane, uses this tunnel to approach the FMN cofactor for the redox reaction (e.g., see Baumgartner et al., J. Med. Chem.2006, 49, 1239-1247).

[0293] In an organism, DHODH catalyzes the synthesis of pyrimidines, which are necessary for cell growth. An inhibition of DHODH inhibits the growth of (pathologically) fastDocket No.: 069596.00080(T2024-176PCT) proliferating cells, whereas cells which grow at normal speed may obtain their required pyrimidine bases from the normal metabolic cycle. The most important types of cells for the immune response, the lymphocytes, use exclusively the synthesis of pyrimidines for their growth and react particularly sensitively to DHODH inhibition.

[0294] DHODH inhibition results in decreased cellular levels of ribonucleotide uridine monophosphate (rUMP), thus arresting proliferating cells in the Gl phase of the cell cycle. The inhibition of de novo pyrimidine nucleotide synthesis is of great interest in view of the observations that lymphocytes seem not to be able to undergo clonal expansion when this pathway is blocked. Substances that inhibit the growth of lymphocytes are important medicaments for the treatment of auto-immune diseases.

[0295] During homeostatic proliferation, the salvage pathway which is independent of DHODH seems sufficient for the cellular supply with pyrimidine bases. Only, cells with a high turnover and particularly T and B lymphocytes need the de novo pathway to proliferate. In these cells, DHODH inhibition stops the cell cycle progression suppressing DNA synthesis and consequently cell proliferation.

[0296] Therefore, inhibitors of DHODH show beneficial immunosuppressant and antiproliferative effects in human diseases characterized by abnormal and uncontrollable cell proliferation causing chronic inflammation and tissue destruction. The human enzyme dihydroorotate dehydrogenase (DHODH) represents a well-characterized target for small molecular weight Disease Modifying Antirheumatic Drugs (DMARDs).

[0297] Accordingly, in various aspects, the present disclosure pertains to methods of treating a variety of diseases or disorders, including, but not limited to, autoimmune diseases, immune and inflammatory diseases, destructive bone disorders, cancers and malignant neoplastic diseases, angiogenic-related disorders, viral diseases, and infectious diseases.

[0298] In a further aspect, the present disclosure pertains to methods for treating an immunological disorder, inflammatory disorder, cancer or other proliferative disease via inhibition of DHODH by administering to a subject in need of such treatment an effective amount of at least one disclosed compound or at least one disclosed pharmaceutical composition.

[0299] In a further aspect, the present disclosure pertains to methods for treating an immunological disorder, inflammatory disorder, cancer or other proliferative disease via inhibition of DHODH by administering to a patient in need of such treatment an effectiveDocket No.: 069596.00080(T2024-176PCT) amount of at least one disclosed compound or at least one disclosed pharmaceutical composition in combination (simultaneously or sequentially) with at least one other anti- inflammatory, immunomodulator or anti-cancer agent.

[0300] In various aspects, an autoimmune disorder or disease that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, one selected from lupus, rheumatoid arthritis, ankylosing spondylitis, glomerulonephritis, minimal change disease, ulcerative colitis, Crohns disease, Addison’s disease, adult Still’s disease, alopecia areata, autoimmune hepatitis, autoimmune angioedema, Behçet's disease, pemphigoid and variants, celiac disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, CREST syndrome, dermatomyositis, neuromyelitis optica, discoid lupus, fibromyalgia, giant cell arteritis, giant cell myocarditis, Goodpasteur’s disease, Evans syndrome, autoimmune hemolytic anemia, immune thrombocytopenia, Henoch-Schonlein purpura, IgA nephropathy, IgG4 related sclerosing disease, juvenile arthritis, juvenile diabetes, Kawasaki disease, Leukocytoclastic vasculitis, mixed connective disease, multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, autoimmune neutropenia, optic neuritis, peripheral neuropathy, POEMS syndrome, polymyositis, primary biliary cirrhosis, non- alcoholic hepatosteotosis and associated cirrhosis, psoriasis, scleroderma, sarcoidosis, temporal arteritis, vasculitis, and uveitis.

[0301] In a further aspect, autoimmune diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondilytis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, inflammatory bowel disease such as ulcerative colitis and Crohn's disease, Reiter's Syndrome, fibromyalgia and type-1 diabetes.

[0302] Immune and inflammatory diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to asthma, COPD, respiratory distress syndrome, acute or chronic pancreatitis, graft versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis allergic rhinitis, allergic conjunctivitis, Behçet's syndrome, inflammatory eye conditions such as conjunctivitis and uveitis.

[0303] In various aspects, the present disclosure pertains to methods for treating organ rejection diseases or ameliorating and / or preventing organ rejection diseases in patients pre-Docket No.: 069596.00080(T2024-176PCT) disposed to organ rejection by administering to a patient in need of such treatment an effective amount of at least one disclosed compound or disclosed pharmaceutical composition. In a further aspect, the patient has received an organ transplant or is diagnosed as requiring an organ transplant. In a still further aspect, the organ transplant can include, but is not limited to, a transplanted organ of the kidney, liver, skin, heart, pancreas, lung, or combinations thereof.

[0304] In various aspects, the present disclosure pertains to methods for treating Epstein-Barr Virus (EBV) viral lymphoproliferation in the setting of tumor immunosuppression. In a further aspect, the method of treating EBV viral lymphoproliferation can be to provide both continued organ transplantation preservation and also treatment of the underlying EBV lymphoproliferation.

[0305] Destructive bone disorders that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.

[0306] Cancers and malignant neoplastic that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to prostate, ovarian and brain cancer. Carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

[0307] Angiogenesis-related disorders that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to hemangiomas, ocular neovascularization, macular degeneration or diabetic retinopathy.

[0308] Viral diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to HIV infection, hepatitis andDocket No.: 069596.00080(T2024-176PCT) cytomegalovirus infection.

[0309] Infectious diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to sepsis, septic shock, endotoxic shock, Gram negative sepsis, toxic shock syndrome, Shigellosis and other protozoal infestations such as malaria.

[0310] In further aspects, the disclosed compounds or disclosed pharmaceutical compositions can act as modulators of apoptosis, and accordingly, can be useful in the treatment of cancer (including but not limited to those types mentioned herein above), viral infections (including but not limited to herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS- related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

[0311] In further aspects, the disclosed compounds or disclosed pharmaceutical compositions can act to modulate the level of cellular RNA and DNA synthesis. Accordingly, the disclosed compounds and disclosed pharmaceutical compositions can be used in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

[0312] In further aspects, the disclosed compounds or disclosed pharmaceutical compositions can be used in the chemoprevention of cancer. Chemoprevention is understood to be a clinical intervention to inhibit the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse. Accordingly, the disclosed compounds and disclosed pharmaceutical compositions can be used in inhibiting tumor angiogenesis andDocket No.: 069596.00080(T2024-176PCT) metastasis.

[0313] In further aspects, the disclosed compounds and disclosed pharmaceutical compositions can also be combined with other active compounds in the treatment of diseases wherein the inhibition of DHODH is known to show beneficial effect.

[0314] In various aspects, the diseases, conditions or disorders that can benefit from inhibition of DHODH include, but are not limited to, an immune system-related disease (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, dry eye disease, multiple sclerosis, uveitis and disorders of the immune system), cancer or other proliferative disease, hepatic diseases or disorders, renal diseases or disorders.

[0315] In a further aspect, the disclosed compounds and disclosed pharmaceutical compositions can be used as immunosuppressants to prevent transplant graft rejections, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), and graft-versus-host disease. In other embodiments, transplant graft rejections result from tissue or organ transplants. In further embodiments, graft-versus-host disease results from bone marrow or stem cell transplantation.

[0316] In a further aspect, the disclosed compounds and disclosed pharmaceutical compositions can be used in the treatment of a variety of inflammatory diseases including, but not limited to, inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, corneal transplant rejection, dry eye disease, lupus erythematosus, systemic lupus erythematosus, proliferative lupus nephritis, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma and Sjogren's syndrome.

[0317] In a further aspect, the disclosed compounds and disclosed pharmaceutical compositions can be used in the treatment of a variety of diseases including Felty's syndrome, Wegener's granulomatosis, Crohn's disease, sarcoidosis, Still's disease, pemphigoid, TakayasuDocket No.: 069596.00080(T2024-176PCT) arteritis, systemic sclerosis, relapsing polychondritis, refractory IgA nephropathy, SAPHO syndrome (SAS), cytomegalovirus infection including rhinitis or cyst, psoriasis, IgG4 related disease, and multiple myeloma.

[0318] In a further aspect, the disclosed compounds and disclosed pharmaceutical compositions can be used in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic or anticancer agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti- metabolites, such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; BTK inhibitors, SYK inhibitors, ITK inhibitors, PI3-kinase inhibitors, FLT3 inhibitors, EGF inhibitors; PAK inhibitors, VEGF inhibitors; CDK inhibitors; SRC inhibitors; c-Kit inhibitors; Her1 / 2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2) and other protein kinase modulators as well. These agents can be used in combination with differentiation agents such as ATRA, EZH2 inhibitors, DNMT inhibitors, corticosteroids, IDH1 inhibitors, IDH2 inhibitors, and Vitamin C. These agents can be used in combination with small molecules that enhance DNA damage killing in cancer cells including PARP inhibitors, MDM2 inhibitors, NAMPT inhibitors, and HSP90 inhibitors. These agents can be used in combination with antibodies that target cell surface molecules on immune or cancer cells including but not limited to CD33, CD47, CD19, CD20, CD3, CD123, CD70, BAFFR, CD4, CD8, CD56, and CD38. These agents can be used in combination with antibodies or peptides which neutralize cytokines including, but not limited to IL1Beta, IL6, IL10, IL21, TNFA, TNFB, and IFN. These agents can be used in combination with cellular CAR-T cells to diminish cellular proliferation in the setting of significant cytokine release syndrome and neurotoxicity. These agents can be used to diminish T-cell proliferation, cytokine production, and neurotoxicity in combination with bi-specific antibodies or peptide molecules that target in a dual manner T-cells and immune / tumor cell antigens such as, but not limited to CD19, CD20 CD33, CD123, CD38, and CD47. These agents can be used to diminish T-cell proliferation and tissue damage caused by immune check point inhibitor antibodies to targets such as, but not limited to PD1, PDL1, CTLA4, and LAG3.Docket No.: 069596.00080(T2024-176PCT)

[0319] A pharmaceutical combination comprising an anti-CD38 antibody with a DHODH inhibitor may be used, for example, to inhibit, reduce, decrease, block, or prevent prolifera- tion of a cell that expresses CD38 on its surface. A combination therapy comprising an anti- CD38 antibody with a DHODH inhibitor may be used, for example, to induce, facilitate, or enhance apoptosis of a cell that expresses CD38 on its surface. The cell that expresses CD38 may be a lymphocyte, an autoimmune lymphocyte, or a tumor cell such as a leukemia cell, a multiple myeloma cell, or a lymphoma cell. In various aspects, the anti-CD38 therapeutic agent comprises a therapeutic agent that decreases the number of CD38 expressing cells and / or level of cell membrane concentration of CD38 protein.

[0320] In particular, treatment of AML cells with a representative DHODH inhibitor can be associated with an upregulation in CD38 expression in these same cells. CD38 has been associated with differentiation and response to differentiation therapy in AML (see Prus et al, Leukemia and Lymphoma 2003, vol 44: issue 4). It has also been previously observed that targeting CD38 with a therapeutic antibody, such as daratumumab, can be an effective when done in combination with a differentiating agent, all-trans retinoic acid ("ATRA"; Buteyn et al, International Immunology 2018, vol. 30 no. 8). Specifically, these studies showed that ATRA induced CD38 expression in MV4-ll cell line was able to cause AML cellular fratricide with dratumumab.

[0321] In various aspects, a suitable anti-CD38 therapeutic agent can be one of the anti-CD38 antibodies as disclosed in Intl. Pat. Appl. No. PCT / US2020 / 067074, filed December 26, 2020, incorporated herein by reference, or any other suitable anti-CD38 antibody as know to the skilled artisan. As used herein, an "anti-CD38 antibody" refers to any antibody recognizing a CD38 epitope, including, but not limited to, chimeric or humanized antibody, an antibody fragment, an antibody-drug conjugate, a radioim- mune therapy antibody conjugate (e.g., a radionuclide labelled anti-CD38 antibody), a nanobody, a bispecific antibody, a trispecific antibody, a single variable-domain anti-body, or combinations thereof.

[0322] A pharmaceutical combination comprising an anti-CD47-SIRPα therapeutic agent, e.g., an anti-CD47 antibody, and a DHODH inhibitor may be used, for example, to inhibit, reduce, decrease, block, or prevent proliferation of a cell that expresses CD47 on its surface. A combination therapy comprising an anti-CD47 antibody with a DHODH inhibitor may be used, for example, to induce, facilitate, or enhance apoptosis of a cell that expresses CD47 on its surface. The cell that expresses CD47 may be a lymphocyte, an autoimmune lymphocyte, or a tumor cell such as a leukemia cell, a multiple myeloma cell, or a lymphoma cell. In variousDocket No.: 069596.00080(T2024-176PCT) aspects, the anti-CD47-SIRPα therapeutic agent comprises a therapeutic agent that decreases the number of CD47 expressing cells, level of cell membrane concentration of CD47 protein, targets or binds CD47 protein, decreases the number of SIRPa expressing cells, level of cell membrane concentration of SIRPα protein, targets or binds SIRPα protein, and / or interferes with the interaction of CD47 and SIRPα.

[0323] It has been previously observed that CD47-SIRPα interaction can inhibit antibody dependent cell phagocytosis (ADCP). Accordingly, several therapies have been described to interfere with this interaction using anti-CD47 antibodies to prevent its binding to SIRPα or by using SIRPα Fe fusion proteins. CD47 is upregulated in many tumor models allowing the escape from innate immunity surveillance. However, CD47 is also expressed on normal RBCs thus a main adverse event reported with anti-CD47 antibody therapies includes anemia. To alleviate the observed side effects with anti-CD47 antibody therapy, increasing the abundance of surface CD47 on tumor cells could enhance their selectivity. Importantly, combination with agents that enhance innate immunity can further enhance the anti-leukemic activity of CD47- SIRPα directed therapies.

[0324] In various aspects, a suitable anti-CD47-SIRPα therapeutic agent can be one of the anti- CD47 antibodies as disclosed in Intl. Pat. Appl. No. PCT / US2022 / 035834, filed June 30, 2022, incorporated herein by reference, or any other suitable anti-CD47 antibody as known to the skilled artisan. As used herein, an "anti-CD47 antibody" refers to any antibody recognizing a CD47 epitope, including, but not limited to, chimeric or humanized antibody, an antibody fragment, an antibody-drug conjugate, a radioimmune therapy antibody conjugate (e.g., a radionuclide labelled anti-CD47 antibody), a nanobody, a bispecific antibody, a trispecific antibody, a tetraspecific antibody, a single variable-domain antibody, and the like, or combinations of any of the foregoing.

[0325] In various aspects, a suitable anti-CD47-SIRPα therapeutic agent can be one of the anti- SIRPα antibodies as disclosed herein, or any other suitable anti- SIRPα antibody as known to the skilled artisan. As used herein, an "anti-SIRPα antibody" refers to any antibody recognizing a SIRPα epitope, including, but not limited to, chimeric or humanized antibody, an antibody fragment, an antibody-drug conjugate, a radioimmune therapy antibody conjugate (e.g., a radionuclide labelled anti-SIRPα antibody), a nanobody, a bispecific antibody, a trispecific antibody, a tetraspecific antibody, a single variable-domain antibody, and the like, or combinations of any of the foregoing.Docket No.: 069596.00080(T2024-176PCT)

[0326] As used herein, "SIRPα" and "SIRPa" can be used interchangeably and refer to an immuglobulin protein encoded by a gene in humans with with a cytogenetic location of 20p13 and a molecular location of base pairs 1,894,167 to 1,940,592 on chromosome 20 (GRCh37 / hg19 by Entrez Gene). The SIRPa gene and protein are associated with the following database identifiers: HGNC: 9662; NCBI Entrez Gene: 140885; Ensembl: ENSG00000198053; OMIM®: 602461; and UniProtKB / Swiss-Prot: P78324. The protein has 504 amino acids and a molecular mass of 54,967 Da; is N-glycosylated at one or more of Asn110, Asn245, Asn270, Asn292, and Asn319; can act as docking protein and induces translocation of PTPN6, PTPN11 and other binding partners from the cytosol to the plasma membrane; and can support adhesion of cerebellar neurons, neurite outgrowth and glial cell attachment.

[0327] In a further aspect, diseases, disorders or conditions that can be treated or prevented using the disclosed compounds and disclosed pharmaceutical compositions are capable of inhibiting DHODH, and accordingly, useful in the treatment of diseases, conditions or disorders involving inflammation and / or that are related to the immune system. These diseases include, but are not limited, to asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, dry eye disease, neuroinflammatory diseases such as multiple sclerosis, and disorders of the immune system.

[0328] In a further aspect, the disclosed compounds and disclosed pharmaceutical compositions can be used for treating immune and immune-related disorders, including, for example, chronic immune diseases / disorders, acute immune diseases / disorders, autoimmune and immunodeficiency diseases / disorders, diseases / disorders involving inflammation, organ transplant graft rejections and graft-versus-host disease and altered (e.g., hyperactive) immune responses. In a still further aspect, other exemplary immune disorders that can be treated using the disclosed compounds and disclosed pharmaceutical compositions include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, dry eye disease, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.Docket No.: 069596.00080(T2024-176PCT)

[0329] Chronic graft-versus-host disease (cGVHD) is a primary cause of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT) (Baird K, Pavletic SZ. Curr Opin Hematol.2006; 13(6):426–435; Lee SJ, Vogelsang G, Flowers ME. Biol Blood Marrow Transplant.2003; 9(4):215–233; Pidala J, et al. Blood.2011; 117(17):4651–4657; and Arai S, et al. Blood. 2011; 118(15):4242–4249). Drug therapy for cGVHD has been predominantly limited to steroids and calcineurin inhibitors, which are incompletely effective and associated with infections as well as long-term risks of toxicity (Holler, E. Best Pract Res Clin Haematol. 2007; 20(2):281–294). The disclosed compounds can be used for the treatment of cGVHD.

[0330] In some embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents for treating a subject in need thereof. In some embodiments, the one or more additional therapeutic agents are selected from anti-cancer compounds. When a combination therapy is used, the one or more additional therapeutic agents may be administered sequentially or simultaneously with a compound described herein. In some embodiments, the one or more additional therapeutic agents is administered prior to the administration of a compound described herein. In some embodiments, the one or more additional therapeutic agents is administered after the administration of a compound described herein. In some embodiments, the one or more additional therapeutic agents is administered concurrently with the administration of a compound described herein.

[0331] In some embodiments, the one or more additional therapeutic agents is an anti- angiogenesis agent (e.g., an agent that stops tumors from developing new blood vessels). Non- limiting examples of anti-angiogenesis agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKC-beta inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v / beta-3), MMP-2 (matrix metalloproteinase-2) inhibitors, and MMP-9 (matrix metalloproteinase-9) inhibitors. Some preferred anti-angiogenesis agents include sunitinib (Sutent®), bevacizumab (Avastin®), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer).

[0332] Additional anti-angiogenesis agents include vatalanib (CGP 79787), Sorafenib (Nexavar®), pegaptanib octasodium (Macugen®), vandetanib (Zactima®), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis®), Neovastat® (AE 941), tetrathio-molybdata (Coprexa®), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer).Docket No.: 069596.00080(T2024-176PCT)

[0333] Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex®) and UCN 01 (Kyowa Hakka).

[0334] Other examples of anti-angiogenesis agents which can be used in conjunction with a compound disclosed herein include celecoxib (Celebrex®), parecoxib (Dynastat®), deracoxib (SC 59046), lumiracoxib (Preige®), valdecoxib (Bextra®), rofecoxib (Vioxx®), iguratimod (Careram®), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia®).

[0335] Other anti-angiogenesis agents include exisulind (Aptosyn®), salsalate (Amigesic®), diflunisal (Dolobid®), ibuprofen (Motrin®), ketoprofen (Orudis®), nabumetone, (Relafen®), piroxicam (Feldene®), naproxen (Aleve®, Naprosyn®) diclofenac (Voltaren®), indomethacin (Indo-cin®), sulindac (Clinoril®), tolmetin (Tolectin®), etodolac (Lodine®), ketorolac (Toradol®), and oxaprozin (Daypro®).

[0336] Other anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat®), and PCK 3145 (Procyon).

[0337] Other anti-angiogenesis agents include acitretin (Neotigason®), plitidepsin (Aplidine®), cilengtide (EMD 45121974), combretastatin A4 (CA4P), fenretinide (4 HPR), alofuginone (Tempostatin®), Panzem® (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab®), lenalidomide (Revlimid®) squalamine (EVIZON®), thalidomide (Thalomid®), Ukrain® (NSC 631570), Vitaxin® (MEDI 522), and zoledronic acid (Zometa®).

[0338] In some embodiments, the anti-cancer agent is a so called "signal transduction inhibitor" (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicate within the cell). In some cases, signal transduction inhibitors include small molecules, antibodies, and antisense molecules. In some embodiments, signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, in some implementations, signal transduction inhibitors include, for example, ALK inhibitors, ROSI inhibitors, TrkA inhibitors, TrkB inhibitors, TrkC inhibitors, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan- erb, IGF IR inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and so called multi-targeted kinase inhibitors.Docket No.: 069596.00080(T2024-176PCT)

[0339] Some preferred signal transduction inhibitors include gefitinib (Iressa®), cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®), sunitinib (Sutent®), imatinib (Gleevec®), PD325901 (Pfizer), (Tafinlar®), vemurafenib (Zelboraf®), trametinib (Mekinist®), binimetinib (Mektovi®), selumetinib (Koselugo®), and cobimetinib (Cotellic®).

[0340] Additional examples of signal transduction inhibitors include BMS 214662 (Bristol- Myers Squibb), lonafamib (Sarasar®), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3®), panitumumab (Vectibix®), Vandetanib (Zactima®), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene® (TP 38).

[0341] Other examples of signal transduction inhibitor include PF-2341066 (Pfizer), PF- 299804 (Pfizer), canertinib (CI 1033), pertuzumab (Omnitarg®), Lapatinib (Tycerb®), pelitinib (EKB 569), miltefosine (Miltefosin®), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge®), NeuVax® (E75 cancer vaccine), Osidem® (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix®), lapatinib (Tycerb®), PF-299804 (Pfizer), and pertuzumab (Onmitarg®).

[0342] Other examples of signal transduction inhibitors include ARRY 142886 (Array Biopharm), everolimus (Certican®), zotarolimus (Endeavor®), temsirolimus (Torisel®), AP 23573 (ARIAD), and VX 680 (Vertex).

[0343] Additionally, other signal transduction inhibitors include XL 647 (Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), and GI-4000 (GlobeImmune).

[0344] Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), PD 0332991 (Pfizer), AG 024322 (Pfizer), 35 LOXO-101 (Loxo Oncology), crizotinib, and ceritinib.

[0345] In some embodiments, a compound disclosed herein is used together with classical antineoplastic agents. Classical antineoplastic agents include but are not limited to hormonal modulators such as hormonal agents, anti-hormonal agents, androgen agonist agents, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, gene silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-I (PARP-1) inhibitor, microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, geneDocket No.: 069596.00080(T2024-176PCT) therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.

[0346] Examples of classical antineoplastic agents used in combination therapy with a compound disclosed herein, optionally with one or more other agents include, but are not limited to, glucocorticoids, such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi)), Selective Estrogen-Receptor Downregulators (SERDs; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), gonadotropin-releasing hormone (GnRH; also commonly referred to as luteinizing hormone- releasing hormone (LHRH)) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), bicalutamide (Casodex), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide, tamoxifen, exemestane, anastrozole, fadrozole, formestane, letrozole, and combinations thereof.

[0347] Other examples of classical antineoplastic agents used in combination with a compound disclosed herein include, but are not limited to, suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101, Onconase (ranpimase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), topotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosf amide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-Docket No.: 069596.00080(T2024-176PCT) coordinated alkylating compounds, such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof.

[0348] In some embodiments, a compound disclosed herein is used together with dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), pyrimidine antagonists), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda®), cytosine arabinoside, Gemzar® (gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal and including TS-1, a combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained release, and liposomal forms), enocitabine, 5- azacitidine (Vidaza), decitabine, ethynylcytidine, and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N- (3,4-di-hydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc.) and combinations thereof.

[0349] Other examples of classical antineoplastic cytotoxic agents used in combination therapy with a compound disclosed herein, optionally with one or more other agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere ), Ortataxel, paclitaxel (including Taxoprexin, a DHA / paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta®), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar®), Efaproxiral (Efaproxyn®-radiation therapy), bexarotene (Targretin®), Tesmilifene (DPPE, which enhances the efficacy of cytotoxics), Theratope® (Biomira), Tretinoin (Vesanoid®), tirapazamine (Trizaone®), motexafin gadolinium (Xcytrin®) Cotara® (mAb), and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax®) and combinations thereof.

[0350] Further examples of classical antineoplastic agents used in combination therapy with a compound disclosed herein, optionally with one or more other agents, include, but are not limited to, as Advexin (ING 201), TNFerade (GeneVec, one or more compounds which expressDocket No.: 069596.00080(T2024-176PCT) TNFalpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT- 1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, Astra-Zeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and a combination thereof.

[0351] In some embodiments, a compound disclosed herein is used together with immune checkpoint inhibitors. Immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, such as pembrolizumab, nivolumab, and cemiplimab; PD-L1 inhibitors, such as atezolizumab, avelumab, and durvalumab; CTLA-4 inhibitors, such as ipilimumab and tremelimumab; and LAG-3 inhibitors, such as relatlimab; and a combination thereof.

[0352] In some cases, a compound disclosed herein is used together with CDK4 / 6 inhibitors. In some embodiments, CDK4 / 6 inhibitors include but are not limited to palbociclib (Ibrance®), ribociclib (Kisqali®), abemaciclib (Verzenio®), and combinations thereof.

[0353] In some instances, the one or more additional therapeutic agents are stimulator of interferon genes (STING) agonists. STING agonists include but are not limited to CDK-002 (Codiak Biosciences, Inc.), SB-11285 (F-star Therapeutics, Inc.), ulevostinag (Merck & Co. Inc.), BI-1387446 (Boehringer Ingelheim International GmbH), BMS-986301 (Bristol-Myers Squibb), DN-015089 (Shanghai De Novo Pharmatech Co. Ltd.), E-7766 (Eisai Co. Ltd.), GSK3745417 (GSK plc), HG-381 (HitGen Inc.), MK-2118 (Merck & Co., Inc.), ONO-7914 (Ono Pharmaceutical Co. Ltd.), SNX-281 (Stingthera Inc.), SYNB-1891 (Synlogic Inc.), TAK- 500 (Takeda Pharmaceutical Co. Ltd.), TAK-676 (Takeda Pharmaceutical Co. Ltd.), HH- 18202 (Shanghai Haihe Biopharma Co. Ltd.), A-296 (KLUS Pharma Inc.), ALG-031048 (Aligos Therapeutics Inc.), BI-09 (Wistar Institute), c-Di-GMP (Hokkaido University), CRD- 5500 (Takeda Pharmaceutical Co. Ltd.), NZ-IO-STING (Lidds AB; Stipe Therapeutics ApS; CS-Bay Therapeutics Inc.), GSK-532 (GSK plc), IMGS-203 (Immunogenesis Inc.), IMSA-201 (ImmuneSensor Therapeutics Inc.), JNJ-4412 (Johnson & Johnson), JNJ-6196 (Johnson & Johnson; F-star Therapeutics Inc.), ONM-501 (OncoNano Medicine, Inc.), QHL- 816 (Shanghai Affinity Biomedical Technology Co. Ltd.), RVU-24024 (Ryvu Therapeutics SA; University of Pennsylvania; Tsinghua University; Inimmune Corp), and combinations thereof.Docket No.: 069596.00080(T2024-176PCT)

[0354] Further examples of STING agonists used in combination therapy with a compound disclosed herein, optionally with one or more other agents, include, but are not limited to, STI- 001(Stimunity SAS), STIM1 (Stimunity SAS), STING STANDALONE (BioNTech SE) VB- 85247 (Venenum Biodesign LLC), XMT-2068 (Mersana Therapeutics Inc.), XMT-2175 (Mersana Therapeutics Inc.), BJY-806 (Eight Plus One Pharmaceutical Co. Ltd.), IMGS-501 (Immunogenesis Inc.), Immunosynthen (Merck KGaA), JABBX-400 (Jacobio Pharmaceuticals Group Co. Ltd., Mersana Therapeutics Inc.), SA-001 (StingInn LLC; Eternity Bioscience Inc.; Lupin Ltd.; F-star Therapeutics Inc.), STI-002 (Stimunity SAS), ACU-0943 (Aculeus Therapeutics Pty Ltd.; Exelixis Inc.), AVA-VP (Avammune Therapeutics Inc., Repertoire Immune Medicines Inc.), AVA-NP (Avammune Therapeutics Inc., Repertoire Immune Medicines Inc.), OS-101 (OncoSTING LLC), PG-10 (Genochem SAS), SB-11325 (F- star Therapeutics Inc.), SB-11345 (F-star Therapeutics Inc.), SB-11396 (F-star Therapeutics Inc.), SITX-799 (Silicon Therapeutics LLC; Arcus Biosciences Inc.; HitGen Inc.; Nimbus Therapeutics LLC; Bicycle Therapeutics), TTI-10001 (Trillium Therapeutics Inc.), XMT-2056 (Mersana Therapeutics Inc.), and ADUS-100 (Chinook Therapeutics Inc.).

[0355] In some embodiments, a compound herein is used with therapies for colorectal cancer. In some cases, a compound herein is used with fluoropyrimidine-based therapeutics. In some instances, for example, fluoropyrimidine-based therapeutics include but are not limited to capecitabine, fluorouracil (5-FU), FOLFOX (a combination of folinic acid, 5-FU, and oxaliplatin), FOLFIRI (a combination of folinic acid, 5-FU, and irinotecan), CAPOX (a combination of capecitabine and oxaliplatin), floxuridine, irinotecan, and combinations thereof. In other implementations, a compound described herein is used with other known treatments for colorectal cancer, including but not limited to bevacizumab, cetuximab, panitumumab, pembrolizumab, nivolumab, a combination of trastuzumab with pertuzumab and lapatinib, regorafenib, trifluridine, tipiracil, ipilimumab, trastuzumab, ziv-aflibercept, ramucirumab, encorafenib, or a combination thereof. Kits.

[0356] In various aspects, the present disclosure pertains to kits comprising a therapeutically effective amount of at least one disclosed compound, a disclosed product of the methods of making a disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition; and: at least one agent known to treat a cancer, a host-versus- graft-disease, and / or a disorder associated with T-cell proliferation; and instructions for treating a cancer, a host-versus-graft-disease, and / or a disorder associated with T-cell proliferation.Docket No.: 069596.00080(T2024-176PCT)

[0357] The disclosed compounds and / or pharmaceutical compositions comprising the disclosed compounds can conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient. In further aspects, a kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, a kit can contain instructions for preparation and administration of the compositions. The kit can be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0358] In a further aspect, the disclosed kits can be packaged in a daily dosing regimen (e.g., packaged on cards, packaged with dosing cards, packaged on blisters or blow-molded plastics, etc.). Such packaging promotes products and increases patient compliance with drug regimens. Such packaging can also reduce patient confusion. The present disclosure also features such kits further containing instructions for use.

[0359] In a further aspect, the present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the disclosure. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0360] In various aspects, the disclosed kits can also comprise compounds and / or products co- packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.Docket No.: 069596.00080(T2024-176PCT)

[0361] It is contemplated that the disclosed kits can be used in connection with the disclosed methods of making, the disclosed methods of using or treating, and / or the disclosed compositions. Research Tools.

[0362] The disclosed compounds and pharmaceutical compositions have activity as inhibitors of DHODH activity or inhibitors of cell proliferation. As such, the disclosed compounds are also useful as research tools. Accordingly, one aspect of the present disclosure relates to a method of using a compound of the disclosure as a research tool, the method comprising conducting a biological assay using a compound of the disclosure. Compounds of the disclosure can also be used to evaluate new chemical compounds. Thus another aspect of the disclosure relates to a method of evaluating a test compound in a biological assay, comprising: (a) conducting a biological assay with a test compound to provide a first assay value; (b) conducting the biological assay with a compound of the disclosure to provide a second assay value; wherein step (a) is conducted either before, after or concurrently with step (b); and (c) comparing the first assay value from step (a) with the second assay value from step (b). Exemplary biological assays include an in vitro DHODH enzymatic assay or in a cell culture- based assay measuring cell proliferation. Methods suitable for carrying out such assays are described herein. Still another aspect of the disclosure relates to a method of studying a biological system, e.g., a model animal for a clinical condition, or biological sample comprising a DHODH protein, the method comprising: (a) contacting the biological system or sample with a compound of the disclosure; and (b) determining the effects caused by the compound on the biological system or sample.

[0363] Before proceeding to the Examples, it is to be understood that this disclosure is not limited to particular aspects described, and as such may, of course, vary. Other systems, methods, features, and advantages of foam compositions and components thereof will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.Docket No.: 069596.00080(T2024-176PCT)

[0364] From the foregoing, it will be seen that aspects herein are well adapted to attain all the ends and objects hereinabove set forth together with other advantages which are obvious and which are inherent to the structure.

[0365] While specific elements and steps are discussed in connection to one another, it is understood that any element and / or steps provided herein is contemplated as being combinable with any other elements and / or steps regardless of explicit provision of the same while still being within the scope provided herein.

[0366] It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations. This is contemplated by and is within the scope of the claims.

[0367] Since many possible aspects may be made without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawings and detailed description is to be interpreted as illustrative and not in a limiting sense.

[0368] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0369] The following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. EXAMPLES

[0370] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature,Docket No.: 069596.00080(T2024-176PCT) and pressure is at or near atmospheric.

[0371] Instumental Methods. The following instruments and settings were used in the measurements described herein: X-ray Powder Diffractometer (XRPD)Variable Temperature X-ray Powder Diffractometer (VT-XRPD)Differential Scanning Calorimetric (DSC)Docket No.: 069596.00080(T2024-176PCT)Thermal Gravimetric Analysis (TGA)Dynamic Vapor Sorption (DVS)Karl Fischer (KF)Polarized Light Microscope (PLM)Nuclear Magnetic Resonance (NMR)Docket No.: 069596.00080(T2024-176PCT) High Performance Liquid Chromatograph (HPLC)Ion Chromatography (IC) Instrument Metrohm 940 professional IC Sample center 889 IC Detector Conductivity detector Eluent (anion) 3.2 mmol / L Na2CO3 + 1.0 mmol / L NaHCO3 Eluent (cation) 2.5 mmol / L MSA Suppressor solutions 0.5% H2SO4 Column: Anion A SUPP 5-150 or Cation Column C4-150 Column temperature: 30°C Flow rate: 0.7mL / min (anion) or 0.9mL / min (cation) Diluent: ACN / Water=1 / 1, v / v Injection volume: 20μL 1. EXAMPLE 1: SYNTHESIS OF REPRESENTATIVE DISCLOSED COMPOUNDS

[0372] The compounds, salts, polymorphs and compositions of the present disclosure can be prepared by the methods disclosed and described herein, e.g., Processes 1 and 2 as provided herein below and disclosed more generally above. A specific example is disclosed, i.e., examples of Processes 1 and 2 for the preparation of Compound VI, and its conversion to theDocket No.: 069596.00080(T2024-176PCT) Na salt (also known as HOSU-53).2-(3'-butoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Compound VI).Sodium 2-(3'-butoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylate (HOSU-53).

[0373] Example 1.1 - Process 1: Synthesis of Compound VI and Preparation of the Na Salt (HOSU-53).

[0374] General procedure for preparation of compound A. The procedure described herein below was used to prepare compound A, which was used in the preparation of 2-(3'-butoxy- [1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Compound VI).

[0375] The mixture of compound SM1 (40.0 g, 201 mmol, 1.00 eq) in IPA (200 mL) and H2O (100 mL), compound SM2 (42.9 g, 221 mmol, 1.10 eq), Na2CO3 (53.3 g, 502 mmol, 2.50 eq), Pd(OAc)2(451 mg, 2.01 mmol, 0.01 eq) and XPhos (958 mg, 2.01 mmol, 0.01 eq) was added to the mixture. The mixture was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 1 hr under N2 atmosphere. TLC (petroleum ether / ethyl acetate = 20 / 1, compound SM1: Rf= 0.61, compound A: Rf= 0.43) indicated the compound SM1 was consumed completely, and one major new spot with larger polarity was detected. The reactionDocket No.: 069596.00080(T2024-176PCT) mixture was diluted with H2O (800 mL) and extracted with ethyl acetate (400 mL, 300 mL, 200 mL). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered and concentrated. The crude product was triturated with petroleum ether at 25°C for 4 hrs. The mixture was filtered and the filter cake was wash with petroleum ether (30.0 mL) and dry under reduced pressure. Compound A (30.0 g, 109 mmol, 54.5% yield, 98% purity) was obtained as a off-white solid.

[0376] General procedure for preparation of Compound VI. The procedures described herein below were used to prepare 2-(3'-butoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4- carboxylic acid (Compound VI) from compound A.

[0377] The mixture of compound A (30.0 g, 112 mmol, 1.00 eq) in KOH (60.0 mL, 33% purity) was stirred and heated to 35 °C until clear yellow solution formed. Compound SM3 (16.6 g, 101 mmol, 0.90 eq) and EtOH (120 mL) was added to this solution. The reaction mixture was stirring at 80 °C for 12 hrs. TLC (petroleum ether / ethyl acetate = 1 / 1, compound A: Rf = 0.57, compound Compound VI: Rf = 0.35) indicated compound A was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was cooled to 25 °C. The pH was adjusted to 4 with aq. HCl (6 M). The mixture filtered under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 3 / 1 (150 mL) at 20oC for 12 hrs. The mixture was filtered and the filter cake was wash with petroleum ether (30.0 mL) and dry under reduced pressure. Compound VI (20.0 g, 48.1 mmol, 43.1% yield, 97% purity) was obtained as a yellow solid.

[0378] General procedure for preparation of compound HOSU-53. The procedures described herein below were used to prepare sodium 2-(3'-butoxy-[1,1'-biphenyl]-4-yl)-6- fluoroquinoline-4-carboxylate (HOSU-53) from compound Compound VI.Docket No.: 069596.00080(T2024-176PCT)

[0379] To a solution of compound Compound VI (18.0 g, 43.3 mmol, 1.00 eq) in EtOH (120 mL) was added aqueous NaOH (2 M, 21.7 mL, 1.00 eq). The mixture was degassed and purged with N2for 3 times, and then the mixture was stirred at 60 °C for 1 hr under N2atmosphere. The reaction mixture was concentrated under vacuum to removed EtOH. H2O (250 mL) was added to the residue and the mixture was freeze-dried to give the product. HOSU-53 (16.8 g, 38.4 mmol, 88.6% yield) was obtained as a yellow solid. MS (M+1)+: calcd. m / z = 415.17, found m / z = 416.1.

[0380] A further example of Process 1 is as shown in the synthesis scheme immediately below. Process 1:

[0381] In this example, Process 1 provided HOSU-53 in a 24% yield over 2 steps.

[0382] Example 1.2 - Process 2: Synthesis of Compound VI and Preparation of Na SaltDocket No.: 069596.00080(T2024-176PCT) (HOSU-53) Process 2:

[0383] The foregoing process results in a 59% yield of Compound B over 2 steps. Further details of Process 2 follow, along with a comparison of Processes 1 and 2.

[0384] Process 2 / Stage 1: Preparation of a Compound of Formula A: In Process 1, Pd(OAc)2 and X-Phos were used as the catalysts, which can lead to high Pd residual in the product, and multiple extraction operations were involved in the workup process. In Process 2, Pd residual in the product was more easily controlled. Without wishing to be bound by a particular theory, it is believed that use of Pd / C as the catalyst, after reaction complete, allows the desired product to be precipitated from the reaction system directly.

[0385] In one study (Table 1), a reaction on 10 g scale of SM1 was carried out to familiarize the original procedure (Process 1). Ion pair chromatography (IPC) results (Figures 37A and 37B) show SM1 / SM2 / A=0 / 6.0 / 87.3. After workup, 10.5 g A was obtained as a gray solid with 98.8% purity and 75.1% assay yield. This reaction proceeded smoothly and SM1 was consumed completely, however, a concern of this step was Pd residual in the product and multiple extraction operations in the work up process.Docket No.: 069596.00080(T2024-176PCT) Table 1. Preparation of A (Process 1)

[0386] In another study (Table 2), a reaction on a 5 g scale of SM1 was carried out to verify Process 2. IPC (Figures 38A and 38B) show SM1 / SM2 / A was 0.3 / 0.4 / 96.9. After workup, 6.1 g A was obtained as an off-white solid with 99.2% purity in 82.9% assay yield. The reaction proceeded normally and the results met expectation. Table 2. Verify Process 2

[0387] Briefly, for Process 2, to a solution of SM1 (1.0 eq) and SM2 (1.03 eq) in DMAc (5 V) added KF (2.5 eq) and 10% Pd / C (65% H2O content, 0.15 X), swapped with N2 for three times, heat to 45~55oC and stirred for 20~24 h under N2 protection. After the reaction was complete, adjusted to 20~30oC, filter and washed cake with DMAc (1 V), Charged IPA (6 V) into the filtrate in one portion, Charged H2O (15 V) into the solution dropwise. Stirred the result mixture for 0.5 h at 20~30oC, filter and washed cake with H2O / IPA=3:1 (5 V), dried the wet cake at 40~50oC for 20 hr, obtained purified A. High purity A was obtained with 26 ppm Pd residual in the product, and DMAc residual was 4.56%.

[0388] A comparison of Processes 1 and 2 at this step is given below in Table 3. Table 3: Stage 1 (preparation of compound of formula A) Process 1 vs. Process 2Docket No.: 069596.00080(T2024-176PCT)

[0389] Various stress tests of the Process 2 / Stage 1 reaction were conducted. Results given in Tables 4-8 demonstrate that the reaction was easily repeatable. Table 4. Stability of SM1 & SM2 in the reaction systemDocket No.: 069596.00080(T2024-176PCT) Table 5. Oxygen tolerance of the reactionTable 6. Stress test of reaction temperature and reaction timeDocket No.: 069596.00080(T2024-176PCT)Table 7. Stability of wet cake ATable 8. Stability of drying of A

[0390] Process 2 / Stage 2: Preparation of a Compound of Formula B: In Process 2, the amount of SM3 reacted was increased and the reaction time was shortened. Without wishing to be bound by a particular theory, it is believed that increasing the use of SM3 allows for A to be consumed completely, improving the yield, and that shortening the reaction time improves the IPC purity compared to Process 1.

[0391] In one study (Table 9), a reaction on a 2 g scale of A was carried out to familiarize the original procedure (Process 1). IPC (Figures 39A and 39B) showed A / SM3 / B=6.3 / 0 / 88.7. After workup, 2.86 g crude B was obtained as an orange solid with 92.6% purity. After triturating in EA / heptane, 2.4 g B was obtained as a yellow solid with 97.0% purity in 77.5% yield.Docket No.: 069596.00080(T2024-176PCT) Table 9. Preparation of B (Process 2)

[0392] In another study (Table 10), a reaction on a 27 g scale of SM1 was carried out to verify Process 2. IPC (Figures 40A and 40B) showed A / B=1.4 / 85.2. After workup, 25 g of purified A was obtained as yellow solid with 99.1% purity in 66.7% assay yield, no impurity >1%. Table 10. Verify Process 2

[0393] Briefly, for Process 2, a reaction of 15 g of A (prepared as above) was used to prepare B. In this, IPC showed 3.7% A remained (A / B was 3.7 / 84.2), after quenching with 6 N HCl and filtration, a wet cake was obtained with 85.5% purity. After dissolving the crude product in 2-MeTHF and washing with 0.5% NaHCO3 aq., the organic layer was concentrated and then crystallized in THF / MeOH to obtain 13.4 g purified product with no impurity >1%.Docket No.: 069596.00080(T2024-176PCT) Table 11: Stage 2 (preparation of compound of formula B) Process 1 vs. Process 2

[0394] Various stress tests of the Process 2 / Stage 2 reaction were conducted. Results given in Tables 12-20 demonstrate that the reaction was easily repeatable. Stability tests of SM3 and A (Table 12 and Table 13, respectively) demonstrate that both SM3 and A are unstable in the reaction system. The reaction was stable with a prolonged reaction time (Table 14). Longer heating time negatively affected the reaction (Table 15). The addition of 10% DMAc had no significant effect on the reaction (Table 16). Adding the KOH solution at room temperature was preferred (Table 17). B was stable in the quenching solution and under drying conditions (Table 18 and Table 20, respectively). Wet cake B was stable (Table 19).Docket No.: 069596.00080(T2024-176PCT) Table 12. Stability of SM3 in the reaction systemTable 13. Stability of A in the reaction systemTable 14. Stress test of prolonging the reaction timeTable 15. Stress test of prolonging the heating timeDocket No.: 069596.00080(T2024-176PCT) Table 16. Effect of DMAc on the reactionTable 17. Add KOH at higher temp.Table 18. Stability of B in quenching solutionDocket No.: 069596.00080(T2024-176PCT) Table 19. Stability of wet cake BTable 20. Stability of drying of B2. EXAMPLE 2: SALT SCREENING

[0395] Compound VI (WuXi code: C210918001-FP) has an acidic pKa of 3.57 and a basic pKa of 0.37 according to calculation by Marvin Sketch Version 5.6.0.2. It has a molecular weight of 415.46. Compound VI Pattern A, batch PJ00844-15-B-CAK2 was used as starting material in the salt screening study. The Pattern A is an anhydrate.

[0396] Fifteen counterions (Table 21) for the conjugate base of Formula III were selected for screening via slurry, slow evaporation, and anti-solvent. Results are reported in Table 22. Table 21: Counterions Selected for ScreeningDocket No.: 069596.00080(T2024-176PCT)

[0397] Among these salts, the L-arginine salt, the L-lysine salt, the N-methyl-d-glucamine salt and the HCl salt showed good physicochemical characteristics including high crystallinity, good thermal properties, reasonable stoichiometry and good counter ion safety (Table 22). Because the HCl salt had a relative low decomposition temperature, no further evaluation was conducted for this salt. The L-arginine salt Pattern A, the Llysine salt Pattern A and the N- methyl-d-glucamine salt Pattern A were selected as salt candidates for full evaluation in comparison with the current developed physical form, almost amorphous sodium salt, in terms of stability, solubility, hygroscopicity and morphology Table 22: Salt ScreeningDocket No.: 069596.00080(T2024-176PCT)*Low risk; **Medium risk; ***High risk; “N / A” : Not Applicable; “ / / ” : Not carried out Crystallinity and thermal properties of salts

[0398] The sodium salt is an almost amorphous form. DSC showed two endothermic peaks at Tonset of 18.2°C with an enthalpy of about 13J / g and at Tonset of 90.0°C with an enthalpy of about 13J / g. TGA shows about 2.7% weight loss at about 150°C.1HNMR shows no detectable residual solvent. KF shows 4.3% water by weight.

[0399] The L-arginine salt Pattern A is an anhydrate and showed high crystallinity. DSC showed a melting peak at Tonsetof 210.1°C, which is combined with decomposition. TGA shows about 0.7% weight loss at about 180°C.1HNMR showed a stoichiometric equivalent of 1.1 L-arginine and no detectable residual solvent.

[0400] The L-lysine salt Pattern A is an anhydrate and showed high crystallinity. DSC showed a melting peak at Tonsetof 220.9°C, which is combined with decomposition. TGA shows about 1.5% weight loss at about 200°C.1HNMR showed a stoichiometric equivalent of 1.0 L-lysine and no detectable residual solvent.

[0401] The N-methyl-d-glucamine salt Pattern A is an anhydrate and showed high crystallinity. DSC showed an endothermic peak at Tonset of 108.3°C with an enthalpy of about 10J / g, which should correspond to the solid-solid transition, followed by a melting peak at Tonset of 144.5°C with an enthalpy of about 80J / g. TGA shows about 0.2% weight loss at about 140°C.1H-NMR showed stoichiometric equivalent of 1.1N-methyl-d-glucamine and noDocket No.: 069596.00080(T2024-176PCT) detectable residual solvent.

[0402] The HCl salt Pattern A is a hydrate of high crystallinity. DSC shows an endothermic peak at Tonsetof 137.1°C with an enthalpy of about 77J / g and a melting at Tonsetof 188.5°C with an enthalpy of about 88J / g. TGA shows about 0.9% weight loss at about 110°C and about 6.9% weight loss from about 110°C to 150°C.1H-NMR showed a stoichiometric equivalent of 1.1 HCl and no detectable residual solvent. Bulk stability

[0403] Bulk stability of the salt candidates was investigated at 25°C / 92%RH in an open container, at 40°C / 75%RH in an open container and at 60°C in a tight container for 1 week.

[0404] The almost amorphous sodium salt is chemically stable under in the three conditions, but converted to sodium salt Pattern C at 25°C / 92%RH and converted to a form which is similar with sodium salt Pattern B at 40°C / 75%RH and 60°C. The sodium salt Pattern C is not stable after exposure to ambient condition or upon drying.

[0405] The L-arginine salt Pattern A is physically stable, but showed about 1% impurity increase after exposure to 25°C / 92%RH for 1 week. The L-lysine salt Pattern A showed good chemical and physical stability in the three conditions.

[0406] The N-methyl-d-glucamine salt Pattern A showed good chemical and physical stability in the three conditions. Solubility

[0407] Solubility of the salts was measured in 7 aqueous pH buffers and bio-relevant fluids including pH 1.2 HCl buffer, pH 4.5 acetate buffer (50mM), pH 6.8 phosphate buffer (50mM), pH 2.0 SGF, pH 6.5 FaSSIF-v1 and pH 5.0 FeSSIF-v1 at 37°C for 2h and 24h. Residual solids after the solubility test were analyzed by XRPD.

[0408] The almost amorphous sodium salt, the L-arginine salt Pattern A, the L-lysine salt Pattern A and the N-methyl-d-glucamine salt Pattern A showed very low and comparable solubility in these media except in water. All salts showed an obviously higher solubility in water. However, the increased solubility should be due to pH shifting to high end. And they all dissociated to free form Pattern A after solubility measurement.

[0409] At pH 7.4, the kinetic solubility of the lysine salt was 0.528 µM. Table 23 reports the thermodynamic solubility of the lysine salt compared to the sodium salt in various dissolution media: simulated gastric fluid (SGF), simulated intestinal fluid (SIF), fasted state simulatedDocket No.: 069596.00080(T2024-176PCT) intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF). Table 23: Thermodyanmic SolubilityHygroscopicity

[0410] Hygroscopicity of the salts was evaluated by dynamic vapor sorption (DVS) test at 25°C.

[0411] The almost amorphous sodium salt was high hygroscopic. It absorbed about 4.1% water from 0%RH to 70%RH and absorbed about 27.7% water from 70%RH to 95%RH. After the DVS test, the almost amorphous sodium salt converted to a form which is similar with sodium salt Pattern B.

[0412] The L-arginine salt Pattern A was high hygroscopic. It absorbed about 5.7% water from 0%RH to 80%RH and absorbed about 17.3% water from 80%RH to 95%RH. After the DVS test, the sample was still L-arginine salt Pattern A.

[0413] The L-lysine salt Pattern A is high hygroscopic. It absorbed about 6.7% water from 0%RH to 80%RH and absorbed about 18.5% water from 80%RH to 95%RH. After the DVS test, the sample was still L-lysine salt Pattern A.

[0414] The N-methyl-d-glucamine salt Pattern A was high hygroscopic. It absorbed about 4.0% water from 0%RH to 80%RH and absorbed about 15.6% water from 80%RH to 95%RH. After the DVS test, the sample was still N-methyl-d-glucamine salt Pattern A.

[0415] The Lysine salt, Compound VII, had an increased bioavailability in rats (Table 24) compared to the sodium salt. Data from the PK study in dogs are shown in Table 25. Table 24: Rat PK DataDocket No.: 069596.00080(T2024-176PCT)Table 25: Dog PK DataDocket No.: 069596.00080(T2024-176PCT)Sodium vs Lysine Salt Form Bioavailability Analysis

[0416] Monolix (Monolix Suite 2024R1, Antony, France), an established nonlinear mixed- effects modeling platform1, was utilized to characterize the pharmacokinetics of HOSU-53 administered in two distinct salt forms: sodium and lysine. The dataset comprised both intravenous (IV) and oral (PO) administration for the sodium salt, whereas only oral data were available for the lysine salt. A two-compartment model with first-order absorption was developed to describe the concentration-time profiles in rats and dogs. Interindividual variability was included on key parameters, including oral bioavailability (F), clearance (CL), and volume of distribution of the central compartment (V1), and the model was subsequently extended to evaluate the effect of salt form as a covariate on oral bioavailability (F).

[0417] The inclusion of salt form as a covariate on F resulted in a statistically significant improvement in model fit, as evidenced by a greater than 3.84 reduction (p<0.05) in the objective function value (OFV). The model-based estimates indicated that the lysine salt form is associated with a significantly higher F compared to the sodium salt. This observation was further supported by a covariate-stratified analysis of individual parameter estimates, in which the distribution of log-normal transformed F values (logit(F)) demonstrated a clear upward shift for the lysine group compared with the sodium group.

[0418] These findings are in good agreement with the noncompartmental analysis result, where the F for lysine salt reaches nearly 100% while sodium salt only has 55-75%. The use of population pharmacokinetic modeling enabled a robust comparison of the two salt formsDocket No.: 069596.00080(T2024-176PCT) despite the unbalanced study design, where only the sodium salt had corresponding IV data. By assuming a shared systemic disposition model, the relative bioavailability of the lysine salt was reliably estimated. 3. EXAMPLE 3: POLYMORPH SCREENING AND CHARACTERIZATION

[0419] Disclosed herein is a salt comprising the anion of Formula III and a cation of L-lysine. This salt is referred to herein as the “L-lysine salt” or as Compound VII:

[0420] Molecular formula: C26H22FNO3· C6H14N2O2

[0421] Molecular weight: 561.65

[0422] Starting Material Used for Polymorph Screening. As disclosed herein, a variety of cations were evaluated in combination with the anion of Formula III. The starting material used for these analyses was Compound VI, also referred to as 2-(3'-butoxy-[1,1'-biphenyl]-4-yl)-6- fluoroquinoline-4-carboxylic acid. Table 26 summarizes the codes used for the compound, as well as specifying that Compound VI is a polymorph having Pattern #1, designated as the first polymorph identified in the analysis. Table 26: Starting material, Compound VIDocket No.: 069596.00080(T2024-176PCT) Received sample size 8.0 g Table 27: Properties of Compound VI as received.

[0423] Evaluation of Compound VII (L-lysine salt) Polymorph Pattern A Table 28: Physicochemical characteristicsDocket No.: 069596.00080(T2024-176PCT)

[0424] Bulk stability: C201030009-B Compound VII Pattern A, sample ID FR02115-4-SU-L- lysine salt-2-MeTHF-6.5g-vacuum-02 was placed at 25°C / 92% RH in an open container, at 40°C / 75% RH in an open container and at 60°C in a closed container for 1 week. Samples after the stress were characterized by XRPD and HPLC and inspected for color change. Table 29: Bulk stability

[0425] Water Sorption and Desorption Experiments: Water sorption and desorption behavior of C201030009-B L-lysine salt Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF- 6.5g-vacuum-02 was investigated by dynamic vapor sorption( DVS) at 25°C with a cycle of 40-0-95-0-40%RH, dm / dt 0.002, min. equilibration time 60 min and max. equilibration time 360 min. XRPD was measured after the DVS test to determine form change. Table 30: Water sorption and desorption experimentsDocket No.: 069596.00080(T2024-176PCT)“N / A”: Not applicable.

[0426] Compression Simulation Experiments: About 50 mg of Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02 was compressed for 5 minutes under 2 MPa, 5 MPa and 10 MPa with a hydraulic press. Potential form change and degree of crystallinity were evaluated by XRPD.

[0427] Dry Grinding Simulation Experiments: About 10 mg of Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02 was ground manually with a mortar and a pestle for 1 min, 3 min and 5 min. Potential form change and degree of crystallinity were evaluated by XRPD. Table 32: Dry grinding simulation experimentsDocket No.: 069596.00080(T2024-176PCT)

[0428] Wet Granulation Simulation Experiments: Water or ethanol were added drop wise to about 10 mg of Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF- 6.5g-vacuum-02 until the sample was wetted sufficiently. Wet sample was ground gently with a mortar and a pestle. Post granulation sample was dried under ambient condition for 10 min. Potential form change and degree of crystallinity were evaluated by XRPD. Table 33: Wet granulation simulation experiments

[0429] Preparation of Polymorphs

[0430] Preparation of Compound VII Pattern B:

[0431] Compound VII Pattern B, sample ID FR02115-7-SU-RAS3-ACN-Water-ACN-200mg was prepared using the procedure below. • About 200 mg of Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2- MeTHF-6.5g-vacuum-02 was weighed. • 200 mg of Compound VII Pattern A was dissolved in the 25 mL of ACN / water (4 / 1, v / v) at ambient temperature (about 20-25°C). (clear solution) • Obtained solutions were filtered through a 0.45 µm nylon membrane filter by centrifugation at 14,000 rpm. (clear solution) • Obtained clear solution was added into 100 mL of ACN quickly. (suspension)Docket No.: 069596.00080(T2024-176PCT) • After stirred at 25°C with speed of 400 rpm for about 2 hours, precipitates of FR02115- 7-SU-RAS3-ACN-Water-ACN-200mg were collected by centrifugation filtration through a 0.45 µm nylon membrane filter at 14,000 rpm.

[0432] The characterization results of Compound VII Pattern B, sample ID FR02115-7-SU- RAS3-ACN-Water-ACN-200mg are reported in Table 34. Table 34: Characterization Results

[0433] As shown in Figure 11, the1H NMR spectrum of Compound VII shows peaks at least the following chemical shifts, with the noted splits: 0.97 ppm (t); 1.48 ppm (m); 1.77 ppm (m); 1.73 ppm (m); 2.80 ppm (br t); 4.09 ppm (t); 6.99 ppm (br d); 7.29 ppm (m); 7.41 ppm (m); 7.63 ppm (td); 7.88 ppm (m); 8.10 ppm (m); 8.31 ppm (m); and 8.68 ppm (dd).

[0434] Compound VII (L-lysine salt) Pattern B, sample ID FR02115-7-SU-RAS3-ACN- Water-ACN-200mgwas converted to Pattern A under the following circumstances. • Sample of FR02115-7-SU-RAS3-ACN-Water-ACN-200mg was exposed at ambient condition for about 2 hours in the 8mL lid-less vial (about 20-25°C)

[0435] The characterization results of Compound VII Pattern A, sample ID FR02115-7-SU- RAS3-ACN-Water-ACN-200mg-evaporated-2h are reported in Table 35. Table 35: Characterization Results Sample ID FR02115-7-SU-RAS3-ACN-Water-ACN-200mg-evaporated-2hDocket No.: 069596.00080(T2024-176PCT)

[0436] Preparation of Compound VII Pattern C:

[0437] Compound VII Pattern C, sample ID FR02115-7-SU-FC3-Ethanol-Water-200mg- evaporated-1h was prepared using the procedure below. • About 200 mg of Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2- MeTHF-6.5g-vacuum-02 was weighed. • 200 mg of L Compound VII Pattern A was dissolved in the 15 mL of ethanol / water (4 / 1, v / v) at 50°C. (clear solution) • Obtained solution was filtered through a 0.45 µm nylon membrane filter by centrifugation at 14,000 rpm. (clear solution) • Obtained solutions were put into a 0°C ice bath and agitated. And then the solution was transferred and stirring at -20°C. (clear solution) • After stirred at -20°C with speed of 400rpm for about 3 days, the sample was still clear solution. About 1mg Compound VII Pattern C seeds, sample ID FR02115-7-FC3- Ethanol-Water were added. And the mixture was stirring at -20°C. • After stirred at -20°C with speed of 400rpm for additional 1 day, the suspension was filtered through a 0.45 µm nylon membrane filter by centrifugation at 0°C. Then solids were collected after exposed at ambient condition for about 1 hour.

[0438] The characterization results of Compound VII Pattern C, sample ID FR02115-7-SU- FC3-Ethanol-Water-200mg-evaporated-1h were reported in Table 36.Docket No.: 069596.00080(T2024-176PCT) Table 36: Characterization ResultsDocket No.: 069596.00080(T2024-176PCT)

[0439] Preparation of Compound VII Pattern D:

[0440] Compound VII Pattern D, sample ID FR02115-7-SU-FC3-Ethanol-Water-300mg- vacuum-3h was prepared using the procedure below. • About 300 mg of Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2- MeTHF-6.5g-vacuum-02 was dissolved in 4 mL of ethanol / water=4 / 1 (v / v) and 15 mL of mother liquor from sample FR02115-7-SU-FC3-Ethanol-Water-200mg at 50°C. (clear solution) • Obtained solution was filtered through a 0.45 µm nylon membrane filter by centrifugation at 14,000 rpm. (clear solution) • Obtained solution was put into a 0°C ice bath and agitated, and added about 2 mg of l Compound VII Pattern C seeds, samples ID FR02115-7-FC3-Ethanol-Water-200mg. (clear solution) • After stirred in the 0°C ice bath for about 2 hours, the suspension was filtered through a 0.45 µm nylon membrane filter by centrifugation at 0°C. • After dried at 50°C under vacuum for 3 hours, the solids were collected.

[0441] The characterization results of Compound VII Pattern D, sample ID FR02115-7-SU- FC3-Ethanol-Water-300mg-vacuum-3h were reported in Table 37. Table 37: Characterization ResultsDocket No.: 069596.00080(T2024-176PCT) No detectable residual solvent Figure 30

[0442] Comparison of Compound VII Polymorphs Pattern A, B, C and D: Compound VII Pattern A is an anhydrate. It was obtained from most of solvent systems by equilibration, slow cooling, fast cooling, anti-solvent addition, reverse anti-solvent addition and vapor diffusion experiments. Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF- 6.5g-vacuum-02 is of high crystallinity. DSC shows a melting peak at Tonset of 226.0°C. Decomposition occurs upon melting. TGA shows about 1.5% weight loss at about 200°C.1H- NMR shows a 1.0 stoichiometric equivalent of L-lysine and no detectable residual solvent. Competitive equilibration experiments showed that Compound VII Pattern A was stable across a wide temperature range from 5°C to 50°C.

[0443] Compound VII Pattern B is a hydrate. With acetone / water, methanol and acetonitrile / water as solvents, it was obtained by equilibration, slow evaporation, fast evaporation, anti-solvent addition and reverse anti-solvent addition experiments. Compound VII Pattern B, sample ID FR02115-7-RAS3-ACN-Water-ACN is of high crystallinity. It contains about 0.6 equivalent (1.9% by weight) of water according to KF result. DSC shows a dehydration peak at Tonset of 31.0°C with an enthalpy of about 28J / g. Then it melts at Tonset of 229.1°C. Decomposition occurs upon melting. TGA shows about 2.1% weight loss at about 210°C.1H-NMR shows a 1.0 stoichiometric equivalent of L-lysine and no detectable residual solvent. Compound VII Patten B is unstable. It converted to Compound VII Pattern A after exposure to ambient condition for about 2 hours.

[0444] Compound VII Pattern C is an ethanol solvate. It was obtained from ethanol / water by fast cooling experiment. Compound VII Pattern C, sample ID FR02115-7-FC3-Ethanol-Water is of low crystallinity. DSC shows a desolvation peak at Tonset of 75.5°C with an enthalpy of about 27J / g, an endothermic peak at Tonsetof 179.5°C with an enthalpy of about 7J / g and an exothermic peak at Tonset of 208.5°C with an enthalpy of about 25J / g. Then it melts at Tonset of 230.5°C. Decomposition occurs upon melting. TGA shows about 7.0% weight loss at about 210°C.1H-NMR shows stoichiometry equivalent of L-lysine is 1.0 and 0.5 equivalent (3.9% by weight) ethanol. After desolvation, it converted to Pattern D.

[0445] Compound VII Pattern D is an anhydrate. It was obtained by heating Compound VII Pattern C to about 120°C. Compound VII Pattern D, sample ID FR02115-7-SU-FC3-Ethanol-Docket No.: 069596.00080(T2024-176PCT) Water-300mg-vacuum-3h is of low crystallinity. DSC shows an endothermic peak at Tonset of 182.8°C with an enthalpy of about 7J / g and an exothermic peak at Tonset of 214.9°C with an enthalpy of about 23J / g. Then it melts at Tonsetof 232.3°C. Decomposition occurs upon melting. TGA shows about 0.7% weight loss at about 210°C.1H-NMR shows a 1.0 stoichiometric equivalent of L-lysine and no detectable residual solvent.

[0446] Relative stability of the anhydrates Compound VII Pattern A and Compound VII Pattern D was investigated with competitive equilibration experiments at 5°C, 25°C and 50°C. Results showed that the Pattern A was the more stable form.

[0447] Interconversion relationship between forms of Compound VII, the solvate Pattern C, the anhydrate Pattern D, and the anhydrate Pattern E, was investigated by variable temperature XRPD and heat-cool DSC. Pattern C was the initial form. Upon heating to about 120°C, Pattern C (ethanol solvate) converted to Pattern D (anhydrate) after desolvation. And after heating to about 200°C, Pattern D converted to Pattern E. The form transition from Pattern D to E is through an endothermic solid-solid transition. As a result, after exposure to ambient condition, Pattern E converted back to Pattern D.

[0448] Bulk stability of Compound VII Pattern A was evaluated at 25°C / 92%RH in an open container, at 40°C / 75%RH in an open container and at 60°C in a tight container for 1 week. Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02 was physically and chemically stable under these conditions.

[0449] Hygroscopicity of Compound VII Pattern A was evaluated by dynamic vapor sorption (DVS) test at 25°C. Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2- MeTHF-6.5g-vacuum-02 is hygroscopic. It absorbed about 3.3% water from 0%RH to 80%RH and absorbs about 4.9% water from 80%RH to 95%RH at 25°C. After the DVS test, obtained sample was still Compound VII Pattern A.

[0450] Mechanic properties of Compound VII Pattern A were evaluated by compression, grinding and granulation simulation experiments. Compound VII Pattern A, sample ID FR02115-4-SU-L-lysine salt-2-MeTHF-6.5g-vacuum-02 showed good tolerance to compression with no form change and no obvious / slight crystallinity decrease. No form change but significant crystallinity decrease was observed after dry grinding and wet granulation.Docket No.: 069596.00080(T2024-176PCT) 4. EXAMPLE 4: CAPSULES COMPRISING COMPOUND VII, PATTERN A

[0451] Pharmaceutical compositions of the present disclosure can be formulated in unit dosage form for ease of administration and uniformity of dosage. One example of a unit dosage form is a capsule, which can be suitable for oral administration. Examples of such oral formulations are provided herein below, including different capsule formulations comprising amounts of the Active Pharmaceutical Ingredient (“API”), Compound VI. While Compound VI is identified as the API for dosing purposes, it is Compound VII (the “L-lysine salt) Pattern A which is measured and added to the capsule formulation. For purposes of tabulation, the amount of API (Compound VI) to be delivered in each capsule is noted, such as in Tables 39-41, but calculation of the amount of Compound VII which provides the identified amount of API is to be made in each instance, consistent with pharmaceutical formulations.

[0452] Table 38 introduces two different capsule formulations as examples. Proposed components and compositions of the capsules are provided in Tables 39, 40 and 41. Table 38: Description of CapsulesTable 39: Unit composition, pharmaceutical function, quality standards of drug productDocket No.: 069596.00080(T2024-176PCT)*In this example, the equivalent of 2.5 mg or 10 mg of the API, Compound VI, is delivered by combining the appropriate amount of Compound VII, Polymorph A with the identified excipients. Table 40: Batch Formula for 2.5 mg capsulesDocket No.: 069596.00080(T2024-176PCT)*In this example, the equivalent of 2.5 mg of the API, Compound VI, is delivered by combining the appropriate amount of Compound VII, Polymorph A with the identified excipients. Table 41: Batch Formula for 10 mg capsules Capsule BlendDocket No.: 069596.00080(T2024-176PCT)*In this example, the equivalent of 10 mg of the API, Compound VI, is delivered by combining the appropriate amount of Compound VII, Polymorph A with the identified excipients.

[0453] The capsule formulations presented in this Example can include other carriers in addition to or in place of those listed in Tables 39-41, such as starches, sugars, other diluents, granulating agents, other lubricants, binders, other disintegrating agents, and the like. Such carriers and excipients, including those disclosed herein and those familiar to one of skill in the art can also be used.

[0454] For example, other disintegrants, such as those disclosed herein, can be used in addition to or in place of croscarmellose sodium, including but not limited to: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch or microcrystalline cellulose. A disintegrant can also include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0455] As another example, other lubricants such as those disclosed herein can be used in addition to or in place of magnesium stearate, including but not limited to: sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0456] As another example, other diluents, such as those disclosed herein, can be used in addition to or in place of silicified microcrystalline cellulose, including but not limited to: calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.

[0457] Some additional non-limiting example Embodiments are as follows.

[0458] Embodiment 1. A composition comprising: a salt comprising a conjugate base and a counterion; wherein the conjugate base has a structure of Formula I:Docket No.: 069596.00080(T2024-176PCT)Formula I, wherein R1is a halogen; and R5is –O(C1-C7 alkyl); and wherein the counterion comprises a cation of one or more of L-arginine, L-lysine, or N-methyl-D-glucamine.

[0459] Embodiment 2. The composition of Embodiment 1, wherein R1is F or Cl.

[0460] Embodiment 3. The composition of Embodiment 1 or 2, wherein R1is F.

[0461] Embodiment 4. The composition of Embodiment 1, 2 or 3, wherein R5is –O(C1-C4 alkyl).

[0462] Embodiment 5. The composition of Embodiment 1, 2, 3, or 4, wherein R5is -OCH2CH2CH2CH3.

[0463] Embodiment 6. The composition of any of Embodiments 1-5, wherein R5is -OCH2CH3.

[0464] Embodiment 7. The composition of Embodiment 1, wherein the conjugate base has a structure of Formula III:Formula III.

[0465] Embodiment 8. The composition of any of Embodiments 1-7, wherein the counterion is a cation of L-arginine.

[0466] Embodiment 9. The composition of any of Embodiments 1-8, wherein the counterion is a cation of L-lysine.

[0467] Embodiment 10. The composition of any of Embodiments 1-8, wherein the counterionDocket No.: 069596.00080(T2024-176PCT) is a cation of N-methyl-D-glucamine.

[0468] Embodiment 11. The composition of any of Embodiments 1-10, wherein the salt is a crystalline salt.

[0469] Embodiment 12. The composition of Embodiment 11, wherein the crystalline salt is polymorph Pattern A, polymorph Pattern B, polymorph Pattern C, or polymorph Pattern D.

[0470] Embodiment 13. The composition of Embodiment 12, wherein the crystalline salt is polymorph Pattern A.

[0471] Embodiment 14. The composition of Embodiment 12, wherein the crystalline salt is polymorph Pattern B.

[0472] Embodiment 15. The composition of Embodiment 12, wherein the crystalline salt is polymorph Pattern C.

[0473] Embodiment 16. The composition of Embodiment 12, wherein the crystalline salt is polymorph Pattern D.

[0474] Embodiment 17. The composition of Embodiment 7, wherein: the counterion is a cation of L-lysine; the salt is a crystalline salt; and the crystalline salt is polymorph Pattern A.

[0475] Embodiment 18. A composition comprising a first component and a second component: wherein the first component comprises a compound having a structure of Formula IV:wherein R1is a halogen; and R5is –O(C1-C7 alkyl); and wherein the second component comprises one or more of L-arginine, L-lysine, or N-methyl-D-glucamine.

[0476] Embodiment 19. The composition of Embodiment 18, wherein R1is F or Cl.

[0477] Embodiment 20. The composition of any of Embodiments 18-19, wherein R1is F.

[0478] Embodiment 21. The composition of any of Embodiments 18-20, wherein R5is –O(C1- C4 alkyl).Docket No.: 069596.00080(T2024-176PCT)

[0479] Embodiment 22. The composition of any of Embodiments 18-21, wherein R5is -OCH2CH2CH2CH3.

[0480] Embodiment 23. The composition of Embodiment 21, wherein R5is -OCH2CH3.

[0481] Embodiment 24. The composition of Embodiment 18, wherein the first component has the structure of Formula VI:Formula VI.

[0482] Embodiment 25. The composition of any of Embodiments 18-24, wherein the second component is L-arginine.

[0483] Embodiment 26. The composition of any of Embodiments 18-24, wherein the second component is L-lysine.

[0484] Embodiment 27. The composition of any of Embodiments 18-24, wherein the second component is N-methyl-D-glucamine.

[0485] Embodiment 28. The composition of any one of Embodiments 1-27, wherein the composition is a crystalline solid.

[0486] Embodiment 29. The composition of Embodiment 28, wherein the crystalline solid is polymorph Pattern A, Pattern B, Pattern C, or Pattern D.

[0487] Embodiment 30. The composition of Embodiment 29, wherein the crystalline solid is polymorph Pattern A.

[0488] Embodiment 31. The composition of Embodiment 29, wherein the crystalline solid is polymorph Pattern B.

[0489] Embodiment 32. The composition of Embodiment 29, wherein the crystalline solid is polymorph Pattern C.

[0490] Embodiment 33. The composition of Embodiment 29, wherein the crystalline solid is polymorph Pattern D.Docket No.: 069596.00080(T2024-176PCT)

[0491] Embodiment 34. The composition of any of Embodiments 18-24 and 28-31, wherein: the second component is L-lysine; the composition is a crystalline solid; and the crystalline solid is polymorph Pattern A.

[0492] Embodiment 35. A pharmaceutical composition comprising a therapeutically effective amount of a composition of any of Embodiments 1-34 and a pharmaceutically acceptable carrier.

[0493] Embodiment 36. The pharmaceutical composition of Embodiment 35, further comprising at least one additional agent known to treat a cancer.

[0494] Embodiment 37. The pharmaceutical composition of Embodiment 36, wherein the at least one agent is a DNA methyltransferase inhibitor, an HDAC-inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or combinations thereof.

[0495] Embodiment 38. The pharmaceutical composition of Embodiment 37, wherein the DNA methyltransferase inhibitor is 5-aza-2′-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination of two or more of the foregoing.

[0496] Embodiment 39. The pharmaceutical composition of Embodiment 37, wherein the HDAC-inhibitor is vorinostat, entinostat, panbinostat, trichostatin A, mocetinostat, belinostat, dacinostat, givinostat, tubastatin A, pracinostat, droxinostat, quisinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tacedinaline, rocilinostat, apicidin, or a combination of two or more of the foregoing.

[0497] Embodiment 40. The pharmaceutical composition of Embodiment 37, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination of two or more of the foregoing.

[0498] Embodiment 41. The pharmaceutical composition of Embodiment 37, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination of two or more of the foregoing.

[0499] Embodiment 42. The pharmaceutical composition of Embodiment 37, wherein the cytotoxic agent is an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent, or another chemotherapeutic agent.

[0500] Embodiment 43. The pharmaceutical composition of Embodiment 42, wherein the antineoplastic antibiotic agent is doxorubicin, mitoxantrone, bleomycin, daunorubicin,Docket No.: 069596.00080(T2024-176PCT) dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, valrubicin, or a combination of two or more of the foregoing or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0501] Embodiment 44. The pharmaceutical composition of Embodiment 42, wherein the antimetabolite agent is gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, or thioguanine, or a combination of two or more of the foregoing, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0502] Embodiment 45. The pharmaceutical composition of Embodiment 42, wherein the alkylating agent is carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, or streptozocin, or a combination of two or more of the foregoing or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0503] Embodiment 46. The pharmaceutical composition of Embodiment 42, wherein the mitotic inhibitor agent is irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, or teniposide, or a combination of two or more of the foregoing or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0504] Embodiment 47. The pharmaceutical composition of Embodiment 42, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing.

[0505] Embodiment 48. The pharmaceutical composition of Embodiment 42, wherein the other chemotherapeutic agent is an anthracycline, cytarabine, a purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or a combination of two or more of the foregoing.

[0506] Embodiment 49. The pharmaceutical composition of Embodiment 48, wherein the anthracycline is daunorubicin, idarubicin, or a combination thereof.

[0507] Embodiment 50. The pharmaceutical composition of Embodiment 48, wherein the purine analog is cladribine, fludarabine, clofarabine, or a combination of two or more of the foregoing.

[0508] Embodiment 51. The pharmaceutical composition of any one of Embodiments 35-50,Docket No.: 069596.00080(T2024-176PCT) further comprising at least one additional agent known to treat GVHD.

[0509] Embodiment 52. The pharmaceutical composition of Embodiment 51, wherein the least one additional agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other agent known to treat GVHD.

[0510] Embodiment 53. The pharmaceutical composition of Embodiment 51, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination of two or more of the foregoing.

[0511] Embodiment 54. The pharmaceutical composition of Embodiment 51, wherein tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination thereof.

[0512] Embodiment 55. The pharmaceutical composition of Embodiment 51, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing.

[0513] Embodiment 56. The pharmaceutical composition of Embodiment 51, wherein the other agent known to treat GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, halofuginone, hydroxychloroquine, or a combination of two or more of the foregoing.

[0514] Embodiment 57. The pharmaceutical composition of Embodiment 35, further comprising a therapeutically effective amount of at least one additional agent known to treat an autoimmune disorder or disease.

[0515] Embodiment 58. The pharmaceutical composition of Embodiment 57, wherein the at least one additional agent known to treat an autoimmune disorder or disease is selected from the group consisting of: (a) disease modifying antirheumatic drugs; (b) nonsteroidal anitinflammatory drugs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs; (f) steroids; (g) biological response modifiers; and (h) other agents useful for the treatment of autoimmune disorders.

[0516] Embodiment 59. The pharmaceutical composition of Embodiment 58 wherein the immunosuppressive drug is a a calcineurin inhibitor,...

Claims

Docket No.: 069596.00080(T2024-176PCT) CLAIMS 1. A composition comprising: a salt comprising a conjugate base and a counterion; wherein the conjugate base has a structure of Formula I:wherein R1is a halogen; and R5is –O(C1-C7 alkyl); and wherein the counterion comprises a cation of one or more of L-arginine, L-lysine, or N- methyl-D-glucamine.

2. The composition of claim 1, wherein R1is F or Cl.

3. The composition of claim 2, wherein R1is F.

4. The composition of claim 1, wherein R5is –O(C1-C4 alkyl).

5. The composition of claim 4, wherein R5is -OCH2CH2CH2CH3.

6. The composition of claim 4, wherein R5is -OCH2CH3.Docket No.: 069596.00080(T2024-176PCT) 7. The composition of claim 1, wherein the conjugate base has a structure of Formula III:Formula III.

8. The composition of claim 1, wherein the counterion is a cation of L-arginine.

9. The composition of claim 1, wherein the counterion is a cation of L-lysine.

10. The composition of claim 1, wherein the counterion is a cation of N-methyl-D- glucamine.

11. The composition of any one of claims 1-10, wherein the salt is a crystalline salt.

12. The composition of claim 11, wherein the crystalline salt is polymorph Pattern A, polymorph Pattern B, polymorph Pattern C, or polymorph Pattern D.

13. The composition of claim 12, wherein the crystalline salt is polymorph Pattern A.

14. The composition of claim 12, wherein the crystalline salt is polymorph Pattern B.

15. The composition of claim 12, wherein the crystalline salt is polymorph Pattern C.

16. The composition of claim 12, wherein the crystalline salt is polymorph Pattern D.Docket No.: 069596.00080(T2024-176PCT) 17. The composition of claim 7, wherein: the counterion is a cation of L-lysine; the salt is a crystalline salt; and the crystalline salt is polymorph Pattern A.

18. A composition comprising a first component and a second component: wherein the first component comprises a compound having a structure of Formula IV:wherein R1is a halogen; and R5is –O(C1-C7 alkyl); and wherein the second component comprises one or more of L-arginine, L-lysine, or N-methyl-D-glucamine.

19. The composition of claim 18, wherein R1is F or Cl.

20. The composition of claim 19, wherein R1is F.

21. The composition of claim 18, wherein R5is –O(C1-C4 alkyl).

22. The composition of claim 21, wherein R5is -OCH2CH2CH2CH3.

23. The composition of claim 21, wherein R5is -OCH2CH3.Docket No.: 069596.00080(T2024-176PCT) 24. The composition of claim 18, wherein the first component has the structure of Formula VI:Formula VI.

25. The composition of claim 18, wherein the second component is L-arginine.

26. The composition of claim 18, wherein the second component is L-lysine.

27. The composition of claim 18, wherein the second component is N-methyl-D-glucamine.

28. The composition of any one of claims 18-27, wherein the composition is a crystalline solid.

29. The composition of claim 28, wherein the crystalline solid is polymorph Pattern A, Pattern B, Pattern C, or Pattern D.

30. The composition of claim 29, wherein the crystalline solid is polymorph Pattern A.

31. The composition of claim 29, wherein the crystalline solid is polymorph Pattern B.

32. The composition of claim 29, wherein the crystalline solid is polymorph Pattern C.Docket No.: 069596.00080(T2024-176PCT) 33. The composition of claim 29, wherein the crystalline solid is polymorph Pattern D.

34. The composition of claim 24, wherein: the second component is L-lysine; the composition is a crystalline solid; and the crystalline solid is polymorph Pattern A.

35. A pharmaceutical composition comprising a therapeutically effective amount of a composition of any of claims 1-34 and a pharmaceutically acceptable carrier.

36. The pharmaceutical composition of claim 35, further comprising at least one additional agent known to treat a cancer.

37. The pharmaceutical composition of claim 36, wherein the at least one agent is a DNA methyltransferase inhibitor, an HDAC-inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or combinations thereof.

38. The pharmaceutical composition of claim 37, wherein the DNA methyltransferase inhibitor is 5-aza-2′-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination of two or more of the foregoing.

39. The pharmaceutical composition of claim 37, wherein the HDAC-inhibitor is vorinostat, entinostat, panbinostat, trichostatin A, mocetinostat, belinostat, dacinostat, givinostat, tubastatin A, pracinostat, droxinostat, quisinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tacedinaline, rocilinostat, apicidin, or a combination of two or more of the foregoing.Docket No.: 069596.00080(T2024-176PCT) 40. The pharmaceutical composition of claim 37, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination of two or more of the foregoing.

41. The pharmaceutical composition of claim 37, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination of two or more of the foregoing.

42. The pharmaceutical composition of claim 37, wherein the cytotoxic agent is an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent, or another chemotherapeutic agent.

43. The pharmaceutical composition of claim 42, wherein the antineoplastic antibiotic agent is doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, valrubicin, or a combination of two or more of the foregoing or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

44. The pharmaceutical composition of claim 42, wherein the antimetabolite agent is gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, or thioguanine, or a combination of two or more of the foregoing, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

45. The pharmaceutical composition of claim 42, wherein the alkylating agent is carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, or streptozocin, or a combination of two or more of the foregoing or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.Docket No.: 069596.00080(T2024-176PCT) 46. The pharmaceutical composition of claim 42, wherein the mitotic inhibitor agent is irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, or teniposide, or a combination of two or more of the foregoing or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

47. The pharmaceutical composition of claim 42, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing.

48. The pharmaceutical composition of claim 42, wherein the other chemotherapeutic agent is an anthracycline, cytarabine, a purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or a combination of two or more of the foregoing.

49. The pharmaceutical composition of claim 48, wherein the anthracycline is daunorubicin, idarubicin, or a combination thereof.

50. The pharmaceutical composition of claim 48, wherein the purine analog is cladribine, fludarabine, clofarabine, or a combination of two or more of the foregoing.

51. The pharmaceutical composition of any one of claims 35-50, further comprising at least one additional agent known to treat GVHD.

52. The pharmaceutical composition of claim 51, wherein the least one additional agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other agent known to treat GVHD.

53. The pharmaceutical composition of claim 51, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone,Docket No.: 069596.00080(T2024-176PCT) beclomethasone, or a combination of two or more of the foregoing.

54. The pharmaceutical composition of claim 51, wherein tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination thereof.

55. The pharmaceutical composition of claim 51, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing.

56. The pharmaceutical composition of claim 51, wherein the other agent known to treat GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, halofuginone, hydroxychloroquine, or a combination of two or more of the foregoing.

57. The pharmaceutical composition of claim 35, further comprising a therapeutically effective amount of at least one additional agent known to treat an autoimmune disorder or disease.

58. The pharmaceutical composition of claim 57, wherein the at least one additional agent known to treat an autoimmune disorder or disease is selected from the group consisting of: (a) disease modifying antirheumatic drugs; (b) nonsteroidal anitinflammatory drugs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs; (f) steroids; (g) biological response modifiers; and (h) other agents useful for the treatment of autoimmune disorders.

59. The pharmaceutical composition of claim 58 wherein the immunosuppressive drug is a a calcineurin inhibitor, a p70S6 kinase inhibitor, an inosine monophosphate dehydrogenase inhibitor, or a combination of two or more of the foregoing.Docket No.: 069596.00080(T2024-176PCT) 60. The pharmaceutical composition of claim 58, wherein the disease modifying antirheumatic drug is methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auranofin, sulfasalazine, or a combination of two or more of the foregoing.

61. The pharmaceutical composition of claim 58, wherein the nonsteroidal anitinflammatory drug is indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogs, acetaminophen, or a combination of two or more of the foregoing.

62. The pharmaceutical composition of claim 58, wherein the COX-2 selective inhibitor is celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib, or a combination of two or more of the foregoing.

63. The pharmaceutical composition of claim 59, wherein: (a) the calcineurin inhibitor is cyclosporin or FK506; or (b) the p70S6 kinase inhibitor is sirolimus or rapamycin; or (c) the inosine monophosphate dehydrogenase inhibitor is mycophenolate; leflunomide, cyclophosphamide, or azathioprine.

64. The pharmaceutical composition of claim 58, wherein the steroid is prednisone, betamethasone, budesonide and dexamethasone, or a combination of two or more of the foregoing.

65. The pharmaceutical composition of claim 58, wherein the biological response modifier is a TNFα antagonist, an IL-1 receptor antagonist; an anti-chemokine antibody; or an anti-interleukin antibody; or a combination of two or more of the foregoing.

66. The pharmaceutical composition of claim 65, wherein (a) the TNFα antagonist is infliximab, adalimmab or etanercept; or (b) the IL-1 receptor antagonist is anakinra; alefacept, efalizumab, daclizumab orDocket No.: 069596.00080(T2024-176PCT) humanized, chimeric antibodies or fusion proteins.

67. The pharmaceutical composition of claim 57, wherein the other agent useful for the treatment of autoimmune disorder is selected from hemokine receptor antagonists or modulators, cannabinoid receptor antagonists or modulators, inhibitors of matrix metalloproteinases, TNFα-converting enzymes, nitric oxide synthetases or phosphodiesterase IV, such as roflumilast or cilomilast; inhibitors of p38 MAP-kinase, the NF-kappaβ, pathway or IL-1 receptor associated kinase or inhibitors of interactions involving adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, α4β7, MAdCAM-1, and αvβ3; and combinations thereof.

68. A method for the treatment of a disease or disorder in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one composition of any one of claims 1-Error! Reference source not found. or the pharmaceutical composition of any of claims 35-67.

69. The method of claim 68, wherein the mammal is a human.

70. The method of claim 69, wherein the mammal has been diagnosed with a need for treatment of the disease or disorder prior to the administering step.

71. The method of claim 68, wherein the disorder or disease is associated with abnormal, increased, or aberrant dihydroorotate dehydrogenase (DHODH) activity.

72. The method of claim 68, wherein the disorder or disease can be treated by inhibition of dihydroorotate dehydrogenase (DHODH) activity.

73. The method of claim 68, further comprising the step of identifying a mammal in need of treatment of the disorder or disease.Docket No.: 069596.00080(T2024-176PCT) 74. The method of claim 68, wherein the disease or disorder is a cancer.

75. The method of claim 74, wherein the cancer is breast cancer, renal cancer, gastric cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung cancer, or malignant melanoma.

76. The method of claim 74, wherein the cancer is a hematological cancer.

77. The method of claim 76, wherein the hematological cancer is leukemia, lymphoma, myeloma, myelodysplastic syndrome, or myeloproliferative neoplasm.

78. The method of claim 76, wherein the hematological cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocyte leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, or Burkitt's lymphoma.

79. The method of claim 76, wherein the hematological cancer is chronic myeloid leukemia (CML) or acute myeloid leukemia (AML).

80. The method of claim 74, further comprising the step of administering a therapeutically effective amount of at least one additional agent known to treat a cancer.

81. The method of claim 80, wherein the at least one additional agent is uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman,Docket No.: 069596.00080(T2024-176PCT) triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5- fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin or a combination of two or more of the foregoing.

82. The method of claim 80, wherein the at least one additional agent is a DNA methyltransferase inhibitor, an HDAC-inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination of two or more of the foregoing.

83. The method of claim 82, wherein the DNA methyltransferase inhibitor is 5-aza-2′- deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination of two or more of the foregoing.

84. The method of claim 82, wherein the HDAC-inhibitor is vorinostat, entinostat, panbinostat, trichostatin A, mocetinostat, belinostat, dacinostat, givinostat, tubastatin A, pracinostat, droxinostat, quisinostat, romidepsin, valproic acid, AR-42 (OSU- HDAC42), tacedinaline, rocilinostat, apicidin, or a combination of two or more of the foregoing.Docket No.: 069596.00080(T2024-176PCT) 85. The method of claim 82, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination of two or more of the foregoing.

86. The method of claim 82, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination of two or more of the foregoing.

87. The method of claim 82, wherein the cytotoxic agent is an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent or other chemotherapeutic agent.

88. The method of claim 87, wherein the alkylating agent is carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, streptozocin, or a combination of two or more of the foregoing, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

89. The method of claim 87, wherein the antineoplastic antibiotic agent is doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, valrubicin, or a combination of two or more of the foregoing, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

90. The method of claim 87, wherein the antimetabolite agent is gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, thioguanine, or a combination of two or more of the foregoing, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

91. The method of claim 87, wherein the mitotic inhibitor agent is irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone,Docket No.: 069596.00080(T2024-176PCT) vinorelbine, vinblastine, teniposide, or a combination of two or more of the foregoing, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

92. The method of claim 87, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing.

93. The method of claim 87, wherein the other chemotherapeutic agent is an anthracycline, cytarabine, a purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or a combination of two or more of the foregoing.

94. The method of claim 93, wherein the anthracycline is daunorubicin and / or idarubicin.

95. The method of claim 93, wherein the purine analog is cladribine, fludarabine, clofarabine, or a combination of two or more of the foregoing.

96. The method of any one of claims 80-95, wherein the at least one composition and the at least one additional agent are administered sequentially.

97. The method of any one of claims 80-95, wherein the at least one composition and the at least one additional agent are administered simultaneously.

98. The method of any one of claims 80-95, wherein the at least one composition and the at least one additional agent are co-formulated.

99. The method of any one of claims 80-95, wherein the at least one composition and the at least one additional agent are co-packaged.

100. The method of claim 73, wherein the disorder is mediated by T-cell proliferation.Docket No.: 069596.00080(T2024-176PCT) 101. The method of claim 73, wherein the disorder is psoriasis.

102. The method of claim 73, wherein the disorder is graft-versus-host disease (GVHD).

103. The method of claim 102, wherein the GVHD is associated with an organ transplant, an allograft, a xenograft, or a hematopoietic stem cell transplantation.

104. The method of claim 102, wherein the GVHD is acute GVHD.

105. The method of claim 102, wherein the GVHD is chronic GVHD.

106. The method of claim 105, further comprising the step of administering a therapeutically effective amount of at least one additional agent known to treat GVHD.

107. The method of claim 106, wherein the least one additional agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other agent known to treat GVHD.

108. The method of claim 107, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination of two or more of the foregoing.

109. The method of claim 107, wherein tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination of two or more of the foregoing.

110. The method of claim 107, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination of two or more of the foregoing.Docket No.: 069596.00080(T2024-176PCT) 111. The method of claim 107, wherein the other agent known to treat GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, halofuginone, hydroxychloroquine, or a combination of two or more of the foregoing.

112. The method of claim 73, wherein the disorder is an autoimmune disorder or disease.

113. The method of claim 112, wherein the autoimmune disorder or disease is selected from lupus, rheumatoid arthritis, ankylosing spondylitis, glomerulonephritis, minimal change disease, ulcerative colitis, Crohns disease, Addison’s disease, adult Still’s disease, alopecia areata, autoimmune hepatitis, autoimmune angioedema, Behçet's disease, pemphigoid and variants, celiac disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, CREST syndrome, dermatomyositis, neuromyelitis optica, discoid lupus, fibromyalgia, giant cell arteritis, giant cell myocarditis, Goodpasteur’s disease, Evans syndrome, autoimmune hemolytic anemia, immune thrombocytopenia, Henoch-Schonlein purpura, IgA nephropathy, IgG4 related sclerosing disease, juvenile arthritis, juvenile diabetes, Kawasaki disease, Leukocytoclastic vasculitis, mixed connective disease, multiple sclerosis, multifocal motor neuropathy, myasthenia gravis, autoimmune neutropenia, optic neuritis, peripheral neuropathy, POEMS syndrome, polymyositis, primary biliary cirrhosis, non- alcoholic hepatosteotosis and associated cirrhosis, psoriasis, scleroderma, sarcoidosis, temporal arteritis, vasculitis, and uveitis.

114. The method of claim 112, further comprising the step of administering a therapeutically effective amount of at least one additional agent known to treat an autoimmune disorder or disease.

115. The method of claim 114, wherein the at least one additional agent known to treat an autoimmune disorder or disease is selected from the group consisting of: (a) disease modifying antirheumatic drugs; (b) nonsteroidal anitinflammatory drugs; (c) COX-2Docket No.: 069596.00080(T2024-176PCT) selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs, including p70S6 kinase inhibitors; and inosine monophosphate dehydrogenase inhibitors; (f) steroids; (g) biological response modifiers; and (h) other agents useful for the treatment of autoimmune disorders.

116. The method of claim 115, wherein the disease modifying antirheumatic drug is methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auranofin, sulfasalazine, or a combination of two or more of the foregoing.

117. The method of claim 115, wherein the nonsteroidal anitinflammatory drug is indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogs, acetaminophen, or a combination of two or more of the foregoing.

118. The method of claim 115, wherein the COX-2 selective inhibitor is celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib, or a combination of two or more of the foregoing.

119. The method of claim 115, wherein the immunosuppressive drug is a calcineurin inhibitor such as cyclosporin and FK506; a p70S6 kinase inhibitor such as sirolimus and rapamycin; an inosine monophosphate dehydrogenase inhibitor such as mycophenolate; leflunomide, cyclophosphamide, azathioprine, or a combination of two or more of the foregoing.

120. The method of claim 115, wherein the steroid is prednisone, betamethasone, budesonide and dexamethasone, or a combination of two or more of the foregoing.

121. The method of claim 115, wherein the biological response modifier is a TNFα antagonist, such as infliximab, adalimmab and etanercept; an IL-1 receptor antagonist such as anakinra; humanized or chimeric antibodies or fusion proteins such as alefacept, efalizumab, daclizumab; an anti-chemokine antibody; an anti-interleukin antibody; or aDocket No.: 069596.00080(T2024-176PCT) combination of two or more of the foregoing.

122. The method of claim 115, wherein the other additional agent useful for the treatment of autoimmune disorder is selected from hemokine receptor antagonists or modulators, cannabinoid receptor antagonists or modulators, inhibitors of matrix metalloproteinases, TNFα-converting enzymes, nitric oxide synthetases or phosphodiesterase IV, such as roflumilast or cilomilast; inhibitors of p38 MAP-kinase, the NF-kappaβ, pathway or IL- 1 receptor associated kinase or inhibitors of interactions involving adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, α4β7, MAdCAM-1, and αvβ3; and combinations thereof.

123. A method for inhibiting dihydroorotate dehydrogenase activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one composition of any one of claims 1-Error! Reference source not found. or the pharmaceutical composition of any of claims 35-67.

124. The method of claim 123, wherein the cell is mammalian.

125. The method of claim 124, wherein the cell is human.

126. The method of claim 123, wherein the cell has been isolated from a mammal prior to the contacting step.

127. The method of claim 123, wherein contacting is via administration to a mammal.

128. The method of claim 127, wherein the mammal has been diagnosed with a need for inhibiting dihydroorotate dehydrogenase activity prior to the administering step.

129. The method of claim 127, wherein the mammal has been diagnosed with a need forDocket No.: 069596.00080(T2024-176PCT) treatment of a disorder related to dihydroorotate dehydrogenase activity prior to the administering step.

130. The method of claim 123, wherein the compound exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than 1,000 nM using a cell-free enzymatic assay.

131. The method of claim 130, exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than 500 nM.

132. The method of claim 130, exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than 250 nM.

133. The method of claim 130, exhibits inhibition of dihydroorotate dehydrogenase with an IC50 of less than 100 nM.

134. The method of claim 130, exhibits inhibition of dihydroorotate dehydrogenase with an IC50of less than 50 nM.

135. A kit comprising a therapeutically effective amount of at least one composition of any one of claims 1-Error! Reference source not found. or the pharmaceutical composition of any of claims 35-67, and: (a) at least one additional agent known to treat a cancer, a host-versus-graft-disease, and / or a disorder associated with T-cell proliferation; and (b) instructions for treating a cancer, a host-versus-graft-disease, and / or a disorder associated with T-cell proliferation.

136. The kit of claim 135, wherein the at least one composition or the pharmaceutical composition and the at least one agent are co-formulated.

137. The kit of claim 135, wherein the at least one composition or the pharmaceuticalDocket No.: 069596.00080(T2024-176PCT) composition and the at least one agent are co-packaged.

138. The kit of claim 135, further comprising instructions to provide the compound in connection with surgery.

139. The kit of claim 138, wherein the instructions provide that surgery is performed prior to the administering of the at least one composition.

140. The kit of claim 138, wherein the instructions provide that surgery is performed after the administering of the at least one composition.

141. The kit of claim 138, wherein the instructions provide that the administering of the at least one composition is to effect presurgical debulking of a tumor.

142. The kit of claim 138, wherein the instructions provide that surgery is performed at about the same time as the administering of the at least one composition.

143. The kit of claim 135, further comprising instructions to provide the at least one composition or the pharmaceutical composition in connection with radiotherapy.

144. The kit of claim 143, wherein the instructions provide that radiotherapy is performed prior to the administering of the at least one composition.

145. The kit of claim 143, wherein the instructions provide that radiotherapy is performed after the step of the administering of the at least one composition.

146. The kit of claim 143, wherein the instructions provide that radiotherapy is performed at about the same time as the step of the administering of the at least one composition.Docket No.: 069596.00080(T2024-176PCT) 147. The kit of claim 135, further comprising a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of the at least one composition or the pharmaceutical composition and the at least one additional agent.

148. The kit of claim 147, wherein each dose of the at least one composition or the pharmaceutical composition and the at least one additional agent are co-formulated.

149. The kit of claim 147, wherein each dose of the at least one composition or the pharmaceutical composition and the at least one additional agent are co-packaged.

150. The kit of claim 147, wherein the dosage forms are formulated for oral administration and / or intravenous administration.

151. The kit of claim 147, wherein the dosage forms are formulated for oral administration.

152. The kit of claim 147, wherein the dosage forms are formulated for intravenous administration.

153. The kit of claim 147, wherein the dosage form for the at least one composition or the pharmaceutical composition is formulated for oral administration and the dosage form for the at least one additional agent is formulated for intravenous administration.

154. The kit of claim 147, wherein the dosage form for the at least one composition or the pharmaceutical composition is formulated for intravenous administration and the dosage form for the at least one additional agent is formulated for oral administration.

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