WO2025166263A1

WO2025166263A1 - Thiazepine derivatives, pharmaceutical compositions, and uses in managing retinoic acid receptor-related orphan receptor related diseases and conditions

Info

Publication number: WO2025166263A1
Application number: PCT/US2025/014162
Authority: WO
Inventors: Raymond Schinazi; Franck Amblard; Mahesh KASTHURI; Zahira TBER; Eithan Galun; Shanny LAYANI; Osher AMRAN
Original assignee: Hadasit Medical Research Services and Development Co; Emory University
Current assignee: Hadasit Medical Research Services and Development Co; Emory University
Priority date: 2024-01-31
Filing date: 2025-01-31
Publication date: 2025-08-07
Anticipated expiration: 2026-07-31

Abstract

Disclosed herein are heterocyclic compounds that modulate retinoic acid receptor-related orphan receptors and uses in managing related diseases and conditions. In certain embodiments, the heterocyclic compounds are thiazepine derivatives or 11-oxodibenzo[b,f][1,4]thiazepine derivatives. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising compounds disclosed herein for uses reported herein.

Description

THIAZEPINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND USES IN MANAGING RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR

RELATED DISEASES AND CONDITIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/627,704 filed January 31, 2024. The entirety of this application is hereby incorporated by reference for all purposes.

BACKGROUND

Retinoic acid receptor-related orphan receptors (RORs) are type II nuclear receptors that exist in the nucleus. There are three major ROR isoforms RORa (NR1F1), RORp (NR1F2), and RORy (NR1F3). Based on the genes regulated by RORs, these proteins play roles in circadian rhythm, metabolism, immune function, development, brain function, and cancer.

Chai et al. report agonist of RORA attenuates nonalcoholic fatty liver progression in mice via up-regulation of miR122. Gastroenterology, 2020, 159:999-1014.

Simerzin et al. report the complementary strand of microRNA-122 acts as a tumor suppressor by modulating the p53/mouse double minute 2 homolog circuitry. Hepatology, 2016, 64: 1623-1636.

Chai et al report free fatty acids increase hepatic expression and secretion of miR122, which regulates energy storage vs expenditure in liver and peripheral tissues, indicating strategies to reduce triglyceride levels by increasing miR122 for treatment of metabolic syndromes. Gastroenterology, 2017, 153 : 1404-1415.

Kojetin and Burris report that agents targeting RORs have therapeutic potential in the treatment of several diseases, including diabetes, atherosclerosis, autoimmunity, and cancer. Nature Reviews Drug Discovery, 2014, 13: 197-216.

Cook et al report retinoic acid related orphan receptors (RORs) have roles in diseases associated with adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases, and neuropsychiatric disorders. Nucl Receptor Res, 2015, 2: 101185. Qiu et al report retinoic acid receptor-related orphan receptor gamma agonists have potential as small molecule therapeutics for cancer immunotherapy. J Med Chem, 2018, 61, 5794-5804.

Thl7 cells express the RO Ry (Retinoic-acid-receptor-related orphan nuclear receptor gamma), which is a molecular determinant for its polarization through IL-17A expression. Solt et al. report suppression of TH17 differentiation and autoimmunity by a synthetic ROR Ligand. Nature. 2011, 472(7344): 491-494. This indicates that compounds of this class are considered for treatment of Thl7-related diseases and disorders such as host defense against bacterial, fungal, parasitic, and viral infection. Dysregulation of Thl7 cells is related to several immunological disorders such as rheumatic diseases (psoriasis, arthritis, systemic sclerosis, and systemic lupus erythematosus), autoimmune disorders (multiple sclerosis, autoimmune myocarditis, diabetes, and autoimmune thyroiditis), asthma, allergic diseases, and other immune-mediated diseases like inflammatory bowel disease and periodontal disease.

Tinahones et al. report the retinoic acid receptor-related orphan nuclear receptor gamma is a determinant of insulin sensitivity in morbid obesity. Obesity, 2012, 20(3):488-97.

Diseases and conditions associated with receptor-related orphan nuclear receptors are substantial health problems. Thus, there is a need to identify agents that interact with retinoic acid receptor-related orphan nuclear receptors for use in therapeutic applications.

Chen et al. report FGF21 protects the blood-brain barrier by upregulating PPAR via FGFRl/b-klotho after traumatic brain injury. J Neurotrauma, 2018, 35(17):2091-2103.

Hernandez et al report pancreatitis is an FGF21 -deficient state that is corrected by replacement therapy. Sci Transl Med, 2020, 12, eaay5186 (11 pages).

Jiang et al. report FGF21 protects against aggravated blood-brain barrier disruption after ischemic focal stroke. Int J Mol Sci, 2020, 21, 824.

Bolik et al. report inhibition of ADAMI 7 impairs endothelial cell necroptosis and blocks metastasis. J Exp Med, 2022, 219(1): e20201039.

Schinazi et al. report RORs agonist compounds. See WO2022/094435 and WO2019/213584.

Refences cited herein are not an admission of prior art. SUMMARY

Disclosed herein are heterocyclic compounds that modulate retinoic acid receptor-related orphan receptors and uses in managing related diseases and conditions. In certain embodiments, the heterocyclic compounds are thiazepine derivatives or 1 l-oxodibenzo[b,f][l,4]thiazepine derivatives. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising compounds disclosed herein for uses reported herein.

In certain embodiments, this disclosure relates to methods of treating or preventing a retinoic acid receptor-related orphan receptor related disease or condition comprising administering an effective amount of a heterocyclic retinoic acid receptor- related orphan receptor modulator disclosed herein to a subject or human patient in need thereof. In certain embodiments, the disease or condition is cancer or liver cancer.

In certain embodiments, this disclosure relates to methods of treating or preventing cirrhosis, fatty liver disease, or nonalcoholic fatty liver disease (NASH) comprising administering an effective amount of a heterocyclic retinoic acid receptor- related orphan receptor modulator disclosed herein to a subject or human patient in need thereof. In certain embodiments, the subject is diagnosed with cirrhosis of the liver. In certain embodiments, the subject is provided a therapeutic to prevent liver tumor development.

In certain embodiments, this disclosure contemplates methods of providing an antifibrosis effect in the liver comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.

In certain embodiments, this disclosure contemplates methods of reversing chronic liver conditions. In certain embodiment, the conditions are associated with an autoimmune response.

In certain embodiments, this disclosure contemplates methods of treating or preventing pancreatitis comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments the subject is diagnosed with acute pancreatitis.

In certain embodiments, this disclosure relates to the production of a medicament for uses in treating or preventing retinoic acid receptor-related orphan receptor related disease and condition reported herein. In certain embodiments the use is in treating cancer to provide an anti-tumorigenic effect and/or anti-metastasis effect.

In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising compounds disclosed herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical products may be in the form of a tablet, pill, capsule, gel, granule, powder, or aqueous buffer solution.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Figure 1 illustrates a method of making the compound 8-(4-benzylpiperidine-l- carbonyl)dibenzo[b,f][l,4]thiazepin-l l(10H)-one (COMPOUND 8). Abbreviations: DCM Dichloromethane, DIPEA N,N-Diisopropylethylamine, DME Dimethoxy ethane, DMF Dimethylformamide, DMSO Dimethyl sulfoxide, EDCI N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride, EtOAc ethyl acetate, HATU 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate, HOBt Hydroxybenzotriazole, MeOH Methanol, THF tetrahydrofuran, X-phos 2- Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. It is contemplated that preparation of additional derivatives can be prepared by substituting appropriate alternative starting materials.

Figure 2 shows data indicating compound 8 induces miR-122 promoter activity. Hepal- 6 cells were co-transfected with human miR-122 promoter upstream of luciferase, carrying a RORA binding site plasmid and a constitutively expressing Renilla plasmid. One day later, cells were treated with different compound 8 concentrations. DMSO was used as a control. Luciferase activity was measured at different time points post compound 8 treatment. Luciferase was normalized to Renilla Luciferase activity expressed from a co-transfected plasmid. Results are shown in fold change, normalized to compound 8.

Figure 3 shows data indicating compound 8 induces pre-miR-122 expression using RT- qPCR analysis of mRNA extracted from Hepal-6 cells following treatment with 30 pM compound 8 for 24 hours. DMSO was used as a control. Gene expression levels were normalized to I IPRT.

Figure 4 shows data indicating compound 8 induces pre-miR-122 liver expression in vivo. C57BL/6 mice were injected with 15 mg/kg, 30 mg/kg, or with solvent solution. The mice were sacrificed 24 hours, 48 hours, or 72 hours after injection. RT-qPCR analysis of mRNA and microRNA expression was performed from the liver.

Figure 5 shows data indicating compound 8 upregulates miR-122 liver expression in vivo. C57BL/6 mice were injected with 15 mg/kg, 30 mg/kg, 45 mg/kg, or with solvent solution, twice in 24 hours, every 12 hours. The mice were sacrificed 24 hours after the 1st injection and after fasting 4 hours. RT-qPCR analysis of mRNA and microRNA expression was performed from the liver. The data shows effects on the expression of mature miR-122, Pri-miR-122, pre- miR-122 and FGF21.

Figure 6 shows data indicating RORa agonists increase FGF21 expression in human hepatocytes. Dose response RT-qPCR analysis of FGF21 mRNA expression was performed in HUH-7 human hepatocytes after 6 hours treatment of DMSO / lOuM / 20uM / 30uM of two RORa agonists: compound 1 and compound 8. The statistical significance was calculated relative to DMSO and was determined by Student's t test (two-tailed).

Figure 7 shows data on kinetics indicating RORa agonists increase Fgf21 expression in human hepatocytes. RT-qPCR analysis of Fgf21 mRNA expression was performed in HUH-7 human hepatocytes after 6 hours, 12 hours, 24 hours treatment of DMSO / 20 uM of two RORa agonists: compound 1 and compound 8. The statistical significance was calculated relative to DMSO and was determined by Student's t test (two-tailed).

Figure 8 shows data on dose response for compound 8 in in-vivo injections. C57BL/6 mice were injected with 15 mg/kg, 30 mg/kg, 45 mg/kg of compound 8 or with solvent solution, twice in 24h, every 12h. The mice were sacrificed 24h after the 1st injection and after fasting for 4h. Plasma levels of FGF21 protein are shown on the left, and on the right is shown RT-qPCR analysis of Fgf21 mRNA expression from the liver. The statistical significance was calculated relative to DMSO and was determined by Student's t test (two-tailed).

Figure 9 shows data indicating a long-term effect on miR-122 serum levels using compound 8. C57BL/6 mice were injected IP with compound 8 at 30 mg/kg or control twice a week for two weeks. RNA was extracted from serum and RT PCR was performed to determine mature miR-122 levels.

Figure 10A illustrates a timeline of experiments to test whether compound 8 elevates FGF21 and reverses pancreatitis 12h post injection. C57BL/6 mice were injected 7 times with caerulein (CAE) for 7 hours. In addition, the mice were injected with 30 mg/kg of compound 8 or with solvent solution, twice at 2h intervals, and the 1st compound 8 injection was simultaneously with the 1st CAE injection. The mice were sacrificed 12h after the 1st injection.

Figure 10B shows data from RT-qPCR analysis of mRNA Fgf21 and pre-miR122 mRNA. Liver and plasma levels of FGF21 protein expression are shown.

Figure 10C shows edema, inflammation, and myeloperoxidase (MPO) staining scores. Figure 1 1 shows data indicating compound 8 elevates FGF21 , pre-miR122 and pri- miR122 in caerulein-induced pancreatitis 18h post injection. C57BL/6 mice were 7 hourly injected with caerulein (CAE). Thereafter, the mice were injected with 30 mg/kg of compound 8 or with a solvent solution, twice with 2h intervals, the 1st compound 8 injection was simultaneously with the 1st CAE injection. The mice were sacrificed 18h after the 1st injection. RT-qPCR analysis of hepatic mRNA Fgf21 (left), pre-miR122 (middle), and pri-miR122 mRNA (right) expression was performed from the liver.

Figure 12 shows data on the effects of compound 8 on AldoA (Aldolase A) expression (miR-122 target) in the liver. C57BL/6 mice were injected IP with compound 8 at 30 mg/kg. Mice were harvested from the liver at different time points after injection. RNA was extracted from livers and RT PCR was performed.

Figure 13A shows data on the effects of compound 8 on target AldoA (Aldolase A) expression (miR-122 target) in the kidney. C57BL/6 mice were injected IP with compound 8 at 30 mg/kg or control. RNA was extracted from kidneys at different time points after injection. RT PCR was performed on AldoA (Aldolase A).

Figure 13B shows data on the effects of compound 8 on erythropoietin (Epo) expression in the kidney. C57BL/6 mice were injected IP with compound 8 at 30 mg/kg or control. Mice were harvested at different time points after injection. RNA was extracted from kidneys and RT PCR was performed.

Figure 14 shows data indicating compound 8 has a long term effect on liver genes. C57BL/6 mice were injected IP with compound 8 at 30 mg/kg or control twice a week for either one or two weeks. RNA was extracted from livers and RT PCR was performed on liver genes. Precursor miR-122 (prel22) is upregulated significantly after 1 weeks of injections indicating compound 8 can be used to upregulate pre-mir-122 expression in the liver for long periods of time.

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is to be understood that an “embodiment” of this disclosure refers to an example, and the invention is not necessarily limited to the example. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the claims allowed during prosecution.

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 this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. 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. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

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 features 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. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

"Subject" refers to any animal, preferably a human patient, livestock, horse, cow, pig, chicken, turkey, mouse, rodent, monkey, dog, cat, or other domestic pet. As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subj ect and disease condition being treated, e.g., the weight and age of the subj ect, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

As used herein, the term "combination with" when used to describe administration of an agent with an additional treatment means such that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof, such that multiple agents are available at some overlapping time.

The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight, branched, primary, secondary, or tertiary hydrocarbons, including both substituted and unsubstituted alkyl groups. The alkyl group can be optionally substituted with any moiety including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF₃ and CH₂CF₃.

In the text, whenever the term “C” (alkyl range) is used, the term independently includes each member of that class as if specifically and separately set out. The term “alkyl” includes Ci-22 alkyl moieties, and the term “lower alkyl” includes C]_₆ alkyl moieties. It is understood to those of ordinary skill in the art that the relevant alkyl radical is named by replacing the suffix “-ane” with the suffix “-yl”.

The term “alkenyl” refers to an unsaturated, hydrocarbon radical, linear, or branched, in so much as it contains one or more double bonds. The alkenyl group disclosed herein can be optionally substituted with any moiety including but not limited to but not limited to those described for substituents on alkyl moieties. Non-limiting examples of alkenyl groups include ethylene, methylethylene, isopropylidene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, and 1,4-butane-diyl.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds. The alkynyl group can be optionally substituted with any moiety including but not limited to those described above for alkyl moieties. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl, pentyn-l-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-l-yl, hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused. Aryl includes polycyclic ring systems containing aromatic and nonaromatic rings, as long as one of the rings is aromatic. Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl. The aryl group can be optionally substituted with substituents as described above for alkyl moieties. Additional examples of aryl substituents include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, arylamino, arylalkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroaryl sulfonyl, aroyl, heteroaroyl, hydroxyarylalkyl, hydoxyheteroarylalkyl, haloalkoxyalkyl, aryl, arylalkyl, aryloxy, arylalkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryl oxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl.

The term “alkylaryl” refer to an aryl group (radical) with an alkyl substituent. The term “arylalkyl” refer to an alkyl group (radical) with an aryl substituent.

The term “halo,” as used herein, includes chloro, bromo, iodo, and fluoro. The term “acyl” refers to an alkylcarbonyl or arylcarbonyl in which the non-carbonyl moiety of the group is selected from the group consisting of straight, branched, or cyclic alkyl or lower alkyl, arylalkyl, benzyl (benzoyl), aryl (aroyl), wherein the acyl group is optionally substituted with halogen (F, Cl, Br, or I), alkyl (including but not limited to C C₂, C₃, and C₄) or alkoxy (including but not limited to C C₂, C₃, and C₄), such as alkoxyalkyl, methoxymethyl, aryloxy, such as phenoxymethyl, sulfonate esters such as alkyl or arylalkyl sulphonyl including but not limited to methanesulfonyl, mono, di or triphosphate ester, trityl or monomethoxytrityl, benzyl, trialkylsilyl (e.g., dimethyl-t-butylsilyl) or diphenylmethyl silyl.

The term “lower acyl” refers to an acyl group in which the non-carbonyl moiety is lower alkyl.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals having alkyl moieties, such as methoxy radical. The “alkoxy” radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.

The term “alkylamino” denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.

The terms arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical. The term “arylalkylamino”, embraces arylalkyl radicals attached to an amino radical. The term arylalkylamino denotes “monoarylalkylamino” and “diarylalkylamino” containing one or two arylalkyl radicals, respectively, attached to an amino radical. The term arylalkylamino further denotes “monoarylalkyl monoalkylamino” containing one arylalkyl radical and one alkyl radical attached to an amino radical.

The term “heteroatom,” as used herein, refers to silicon, oxygen, sulfur, nitrogen, and phosphorus.

The term “heterocyclic,” and “heterocyclyl,” refer to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, or sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, nonaromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like. Further, a second ring may share the same carbon or different carbons to form a spiro ring, condensed ring, or bridged ring.

Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" or “cycloalkyl” groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.

"Heterocarbocycles" or heterocarbocyclyl" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrroli dinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

The terms “heteroaryl” or “heteroaromatic,” as used herein, refer to an aromatic that includes at least one nitrogen, oxygen, phosphorus, silicon, or sulfur in the aromatic ring. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives such as a 1- methylimidazol-5-yl substituent.

Nonlimiting examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4- triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines, thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N⁶- alkylpurines, N⁶ -benzylpurine, N⁶-halopurine, N⁶- vinypurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2- mercaptopyrmidine, uracil, N⁵- alkylpyrimidines, N⁵ -benzylpyrimidines, N⁵-halopyrimidines, N³ -vinyl pyrimidine, N³ -acetylenic pyrimidine, N⁵-acyl pyrimidine, N⁵ -hydroxy alkyl purine, and N⁶-thioalkyl purine, and isoxazolyl. The heteroaromatic group can be optionally substituted as described above for aryl. The heterocyclic or heteroaromatic group can be optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, and dialkylamino. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired.

The term “protected” as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis, and are described, for example, in Greene et al., Protective Groups in Organic Synthesis, supra. Suitable protecting groups are well known to those skilled in the art, and include trimethyl silyl, dimethylhexylsilyl, t-butyl di methyl silyl, and t- butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl. The heterocyclic or heteroaromatic group can be substituted with any moiety including but not limited to but not limited to those described above for aryl.

"Alkylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio is methylthio, (e.g., -S-CH3).

"Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, and t-butoxy.

"Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bride (e.g., -(C=O)alkyl).

"Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (e.g., -S(=O)2alkyl) such as mesyl and the like, "aryl sulfonyl" refers to an aryl attached through a sulfonyl bridge (e.g., -S(=O)2aryl), and “aminosulfonyl” refers to an amino attached through a sulfonyl bridge (e.g., -S(=O)2NH2). " Alkylsulfinyl" refers to an alkyl as defined above attached through a sulfinyl bridge (e.g., -S(=O)alkyl).

"Aminoalkyl" refers to an amino group attached through an alkyl bridge. An example of an aminoalkyl is aminomethyl, (e.g., NH2-CH2-).

"Hydroxy alkyl" refers to a hydroxy group attached through an alkyl bridge. An example of a hydroxyalkyl is hydroxyethyl, (e.g., HO-CH2CH2-).

"Phosphate" refers to a phosphate group, or up to three phosphate groups, attached through an oxygen bridge(s) (e.g., monophosphate -0-P=0(0H)2, diphosphate, -O-P=O(OH)-O- P=0(0H)2, -O-P=O(OH)-O-P=O(OH)-O-P=O(OH)₂).

“Phosphonate” refers to a phosphate group with an alkyl group substitution for an oxygen (e g., -CH₂-P=O(OH)₂).

“Phosphate ester” refers to a phosphate group with one or more alkoxy group substitution(s) for a hydroxyl group(s) (e.g., -O-P=O(O-Et)2)

“Thiophosphate” refers to a phosphate group with a sulfur substitution for an oxygen (e.g., -O-P=S(OH)₂).

The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, C1-10 alkyl, C2- 10 alkenyl or C2-10 alkynyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, -NRaS02Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)₂Ra, -OS(=O)₂Ra and -S(=O)2ORa. Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl. The term "optionally substituted," as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.

As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds. 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 preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

"Cancer" refers any of various cellular diseases with malignant neoplasms characterized by the proliferation of cells. It is not intended that the diseased cells must actually invade surrounding tissue and metastasize to new body sites. Cancer can involve any tissue of the body and have many different forms in each body area. Within the context of certain embodiments, whether "cancer is reduced" may be identified by a variety of diagnostic manners known to one skill in the art including, but not limited to, observation the reduction in size or number of tumor masses or if an increase of apoptosis of cancer cells observed, e.g., if more than a 5 % increase in apoptosis of cancer cells is observed for a sample compound compared to a control without the compound. It may also be identified by a change in relevant biomarker or gene expression profile, such as PSA for prostate cancer, HER2 for breast cancer, or others.

A “chemotherapy agent,” “chemotherapeutic,” “anti-cancer agent” or the like, refer to molecules that are recognized to aid in the treatment of a cancer. Contemplated examples include the following molecules or derivatives such as abemaciclib, abiraterone acetate, methotrexate, paclitaxel, adriamycin, acalabrutinib, brentuximab vedotin, ado-trastuzumab emtansine, aflibercept, afatinib, netupitant, palonosetron, imiquimod, aldesleukin, alectinib, alemtuzumab, pemetrexed disodium, copanlisib, melphalan, brigatinib, chlorambucil, amifostine, aminolevulinic acid, anastrozole, apalutamide, aprepitant, pamidronate disodium, exemestane, nelarabine, arsenic trioxide, ofatumumab, atezolizumab, bevacizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, carmustine, belinostat, bendamustine, inotuzumab ozogamicin, bevacizumab, bexarotene, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, brigatinib, busulfan, irinotecan, capecitabine, fluorouracil, carboplatin, carfilzomib, ceritinib, daunorubicin, cetuximab, cisplatin, cladribine, cyclophosphamide, clofarabine, cobimetinib, cabozantinib-S-malate, dactinomycin, crizotinib, ifosfamide, ramucirumab, cytarabine, dabrafenib, dacarbazine, decitabine, daratumumab, dasatinib, defibrotide, degarelix, denileukin diftitox, denosumab, dexamethasone, dexrazoxane, dinutuximab, docetaxel, doxorubicin, durvalumab, rasburicase, epirubicin, elotuzumab, oxaliplatin, eltrombopag olamine, enasidenib, enzalutamide, eribulin, vismodegib, erlotinib, etoposide, everolimus, raloxifene, toremifene, panobinostat, fulvestrant, letrozole, filgrastim, fludarabine, flutamide, pralatrexate, obinutuzumab, gefitinib, gemcitabine, gemtuzumab ozogamicin, glucarpidase, goserelin, propranolol, trastuzumab, topotecan, palbociclib, ibritumomab tiuxetan, ibrutinib, ponatinib, idarubicin, idelalisib, imatinib, talimogene laherparepvec, ipilimumab, romidepsin, ixabepilone, ixazomib, ruxolitinib, cabazitaxel, palifermin, pembrolizumab, ribociclib, tisagenlecleucel, lanreotide, lapatinib, olaratumab, lenalidomide, lenvatinib, leucovorin, leuprolide, lomustine, trifluridine, olaparib, vincristine, procarbazine, mechlorethamine, megestrol, trametinib, temozolomide, methylnaltrexone bromide, midostaurin, mitomycin C, mitoxantrone, plerixafor, vinorelbine, necitumumab, neratinib, sorafenib, nilutamide, nilotinib, niraparib, nivolumab, tamoxifen, romiplostim, sonidegib, omacetaxine, pegaspargase, ondansetron, osimertinib, panitumumab, pazopanib, interferon alfa-2b, pertuzumab, pomalidomide, mercaptopurine, regorafenib, rituximab, rolapitant, rucaparib, siltuximab, sunitinib, thioguanine, temsirolimus, thalidomide, thiotepa, trabectedin, valrubicin, vandetanib, vinblastine, vemurafenib, vorinostat, zoledronic acid, or combinations thereof such as cyclophosphamide, methotrexate, 5 -fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); mustine, vincristine, procarbazine, prednisolone (MOPP); adriamycin, bleomycin, vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5- fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); methotrexate, vincristine, doxorubicin, cisplatin (MVAC).

An “antibiotic” refers to molecules that are recognized to aid in the treatment of a bacteria. Examples include agents such as sulfanilamide, sulfamethizole, sulfamethoxazole, sulfapyridine, trimethoprim, pyrimethamine, nalidixic acids, norfloxacin, ciprofloxacin, cinoxacin, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, pefloxacin, sparfloxacin, trovafloxacin, penicillins (amoxicillin, ampicillin, azlocillin, carbenicillin, cioxacillin, dicloxacillin, flucloxacillin, hetacillin, oxacillin, mezlocillin, penicillin G, penicillin V, piperacillin), cephalosporins (cefacetrile, cefadroxil, cefalexin, cefalonium, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor, cefonicid, ceforanide, cefprozil, cefuroxime, cefuzonam, cefmetazole, cefoxitin, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefotiam, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefepime), carbapenems (imipenem, ertapenem, meropenem) monobactams (aztreonam) oxytetracycline, chlortetracycline, clomocycline, demeclocycline, tetracycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, chloramphenicol, amikacin, gentamicin, framycetin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, telithromycin, colistin, bacitracin, tyrothricin, furazolidone, metronidazole, tinidazole, isoniazid, pyrazinamide, ethionamide, nystatin, amphotericin-B, hamycin, miconazole, clotrimazole, ketoconazole, fluconazole, lincomycin, clindamycin, spectinomycin, fosfomycin, loracarbef, polymyxin B, polymyxin B Sulfate, ramoplanin, teicoplanin, vancomycin, nitrofurantoin or combinations thereof.

An “antiviral” refers to molecules that are recognized to aid in the treatment of a viruses. Examples include agents such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, baloxavir, boceprevir, cidofovir, combivir, , daclatasvir, darunavir, delavirdine, didanosine, docosanol, dolutegravir, edoxudine, enfuvirtide, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscamet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin , rilpivirine, raltegravir, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate (TAF), tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine or combinations thereof.

An “anti-inflammatory” refers to molecules that are recognized to aid in the reduction in immune responses. Examples include agents such as aceclofenac, acemetacin, acetyl-salicylic acid, 5-aminoacetyl salicylic acid, alclofenac, amfenac, bendazac, benoxaprofen, bermoprofen, 5- bromo salicylic acid acetate, butibufen, caffeic acid, carprofen, cinmetacin, clidanac, clopirac, sodium diclofenac, diflunisal, 3,4-dihydroxybenzoic acid, etodolac, felbinac, fenbufen, fendosal, fenoprofen, fentiazac, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, 1 -hydroxynaphthoic acid, ibuprofen, indomethacin, indoprofen, isoxepac, ketoprofen, ketorolac, loxoprofen, meclofenamic acid, mefenamic acid, 3, 4-methylenedi oxy cinnamic acid, montelukast, mycophenolic acid, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, pirprofen, pranoprofen, sulindac, suprofen, tiaprofenic acid, tinoridine acid, tolfenamic acid, tolmetin, xenbucin, ximoprofen, zaltoprofen, zomepirac, or combinations thereof. Stereoisomerism and Polymorphism

Compounds described herein can have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present disclosure. Compounds of the present disclosure having a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds can exhibit polymorphism. The present disclosure encompasses racemic, optically active, polymorphic, or stereoisomeric forms, or mixtures thereof, of a compound of the disclosure, which possess the useful properties described herein. The optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution. One can either purify the respective compound, then derivatize the compound to form the compounds described herein or purify the compound themselves.

Optically active forms of the compounds can be prepared using any method known in the art, including but not limited to by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, z.c., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis: a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations: a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations: a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions: this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non- racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC). The stationary phase can be made of chiral material, or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography: a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents: a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes: a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.

Chiral chromatography, including but not limited to simulated moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available.

Salt or Prodrug Formulations

Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.

In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate and a-glycerophosphate. Suitable inorganic salts can also be formed from, including but not limited to, sulfate, nitrate, bicarbonate, and carbonate salts. For certain transdermal applications, it can be preferred to use fatty acid salts of the compounds described herein. Examples of suitable salts include salts of the compounds with stearic acid, oleic acid, linoleic acid, palmitic acid, caprylic acid, and capric acid.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. In those cases where a compound includes multiple amine groups, the salts can be formed with any number of the amine groups. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.

A prodrug is a pharmacological substance that is administered in an inactive (or significantly less active) form and subsequently metabolized in vivo to an active metabolite. Getting more drug to the desired target at a lower dose is often the rationale behind the use of a prodrug and is generally attributed to better absorption, distribution, metabolism, and/or excretion (ADME) properties. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor. Additionally, the use of a prodrug strategy can increase the selectivity of the drug for its intended target thus reducing the potential for off target effects.

The term “pharmaceutically acceptable salt or prodrug” is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as an ester) compound which, upon administration to a patient, provides the compound. The compounds can also be prepared in the form of water-soluble prodrugs. Water-soluble prodrugs are well- known to those of skill in the art, and include, for example, those disclosed in Bundgaard et al., "A novel solution-stable, water-soluble prodrug type for drugs containing a hydroxyl or an NH- acidic group," J. Med. Chem. 32(12):2503-2507, 1989, Matsumoto et al., Bioorganic & Medicinal Chemistry Letters, Vol. 11, Issue 4, 26 February 2001, Pages 605-609, and Stella et al., “Prodrug strategies to overcome poor water solubility,” Advanced Drug Delivery Reviews, Volume 59, Issue 7, 30 July 2007, Pages 677-694.

As the name suggests, water-soluble prodrugs are formulated using the aqueous solubility of the drug and for enhancing the oral drug delivery, generally includes the addition of an ionizable group to the parent compound (such as phosphate, carboxylate, or sulfonate group). Water-soluble ester prodrugs can improve the aqueous solubility of poorly soluble drugs that contain a hydroxyl group. Commonly used esters for forming prodrugs are those containing ionizable groups such as alkyl esters of carboxylic acid or dicarboxylic acid hemiesters. Phosphate esters, such as oxymethylphosphate (OMP) and oxy ethyl phosphate (OEP) prodrugs, offer one way to increase the oral bioavailability of many sparingly water-soluble drugs. Pegylated prodrugs, either added to directly, or via a spacer, such as an amino acid spacer (Feng et al., Bioorganic & Medicinal Chemistry Letters, Volume 12, Issue 22, 18 November 2002, Pages 3301-3303), can also increase water-solubility.

Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Contemplated phosphate or phosphonate prodrugs include mono- or bis-esters (oxygen or thiol linked esters) or mono- or bis-amidates or mixed phosphate or phosphonate esters and amidates of an alkyl optionally substituted, aryl optionally substituted, heteroaryl optional substituted, benzyl optionally substituted, para substituted benzyl, e.g. -CH2C6H4X (X = H, OAc, O-alkyl), acyloxyalkyl, e.g., -CH2OC(O)C(CH3)3 (pivaloyloxymethyl, POM) optionally substituted, alkoxycarbonyloxy alkyl, e.g., -CH2OC(O)OCH(CH3)2 (isopropyl oxy carbonyl oxy methyl), or (propargyloxycarbonyl, POC) optionally substituted, -S-acylthioalkyl (SATE), e.g., -CH2CH2SC(O)R wherein R is hydroxy, alkyl, alkoxy, thiol, alkylthiol, amino, alkylamino, dialkylamino, wherein R is optionally substituted, cyclic diesters, e.g., 2-hy droxy- 1,3,2- dioxaphosphinane 2-oxide optionally substituted, unsymmetrical diesters, e.g., cyclosaligenyl (cycloSal) a prodrug that contains a 2-hydroxy-4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide optionally substituted, and (HepDirect™) a prodrug that contains a 2-hy droxy-4-phenyl- 1,3,2- dioxaphosphinane 2-oxide optionally substituted, cyclic mixed ester and amidate, steroidal ester or amidate, e g., cholesteryl optionally substituted, and internal cyclic diester or cyclic mixed ester amidate optionally substituted, glycerol-fatty alcohol esters and amidates, e.g., -CH₂OCH2(CH₂)14CH3, pivaloyloxymethyl or aryloxy pivaloyloxymethyl esters or amidates optionally substituted, and variations based on mono- or bis-amidates optionally substituted.

Isotopes

Compounds described herein include isotopically labeled compounds, which are identical to those recited in the various formula and structures presented herein, but for the fact that one or more atoms are enriched with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into the present compounds including isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ^3?S, ¹⁸F, ³⁶C1, respectively. Certain isotopically labeled compounds described herein, for example those into which radioactive isotopes such as ²H are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, in some embodiments, substitution with isotopes such as deuterium, i.e., ²H, can affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

Compounds

In certain embodiments, this disclosure relates to thiazepine derivative compounds of Formula (A):

Formula (A) or a pharmaceutically acceptable salt or prodrug thereof, wherein substituents are reported herein. In certain embodiments, the compound is a Retinoic Acid Receptor-like Orphan Receptor (ROR) agonist, e.g., alpha or gamma agonist.

In certain embodiments, this disclosure relates to compounds of Formula (A): or a pharmaceutically acceptable salt or prodrug thereof, wherein: one of X and Z is selected from the bridging group consisting of -NH-, -N(NH₂)-,

-NH(OH)-, -N(Ci-io alkyl)-, -N(C₃-IO cycloalkyl)-, -N(C₂-IO alkenyl)-, -N(C₂-IO alkynyl)-,

-N(aryl)-, -N(heteroaryl)-,

-0-, -CH -, -CH(Ci io alkyl)-, -C(Ci-io alkyl)?-, -CH(C₃-IO cycloalkyl)-, -CH(C2-IO alkenyl)-, -CH(C₂-IO alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF₂-, -CCI2-, -CH(CF₃)-, -CH(OH)-, -CH(0-Ci-io alkyl)-, -CH(NH₂)-, -CH(NH-Ci-io alkyl)-, and -CH(C(O)NH₂)-, and the other one of X and Z is selected from the group consisting of -C(O)-, -SO2-, -NH(C(O))-, -CH2-, -CH(Ci-io alkyl)-, -C(Ci-io alkyl)₂-, -CH(C₃-IO cycloalkyl)-, -CH(C2-IO alkenyl)-, -CH(C2-IO alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF2-, -CCI2-, -CH(CF₃)-, -CH(OH)-, -CH(O-alkyl)-, -CH(NH₂)-, -CH(NHCi-io alkyl)-, and -CH(C(O)NH₂)-;

A and B are, independently, a phenyl ring, a five-membered heteroaromatic ring containing one, two or three nitrogen, oxygen, or sulfur atoms, or a six-membered heteroaromatic ring containing one, two or three nitrogen atoms; u and v are independently 0, 1, 2, 3 or 4 substituents other than hydrogen; wherein optionally that at least one of u and v is 1, 2, 3, or 4;

R¹’ and R²’ are independently hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C₃-io cycloalkyl, C₃-io cycloalkenyl, C₃-io heterocycloalkyl, C₃-io heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴;

R¹’ and R²’ can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴;

C ring is a saturated or unsaturated carbocyclyl heterocyclyl, or a heteroaryl; which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴;

R³’ is hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl; w is 0, 1, 2, 3 or 4 substituents other than hydrogen;

R⁴’ is hydrogen, -COOH, -CH2-COOH;

R³’ is hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl; n is 1, 2, 3, 4 or 5;

D is O, S, NH or CH₂;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH2-COOH; each R¹ and R² are independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³, -C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH2, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)₂, -NR³C(O)N(R³)2, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)2, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO₂NH₂, -SO2NHR³, -SO₂N(R³)₂, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)₂, -C(N)OH, -C(N)OCH₃, -CN, -N3, -NO2, -CF₃, -CF2CF3, -OCF3, -OCF2CF3, halogen (F, Cl, Br, or I), -CH2-phosphonate, -CH2O-phosphate, -CH₂P(O)(OH)₂, -CH₂P(O)(OR³)₂, -CH₂P(O)(OR³)(NR³), -CH₂P(O)(NR³)₂,

-CH₂P(0)(OH)(OCI-IO alkyl-O-C 1-20 alkyl), or -CH₂-cycloSal monophosphate prodrug; and when two R’s and two R²s are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴; each R⁴ are independently C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, arylalkyl, alkylaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, -OH, -NH2, -C(O)NH₂, -C(O)NHOH, -SO2NH2, -COOH, -C(O)H, -C(N)NH₂, -C(N)OH, -CN, -N3, -NO₂, -CF₃, -CF₂CF₃, -OCF₃, -OCF₂CF₃, halogen (F, Cl, Br, or I), -P(O)(OH)₂, -P(0)(OH)(OCI-IO alkyl-O-Ci-20 alkyl), -CH₂P(O)(OH)₂, -CH₂P(O)(OR⁵)₂, -CH₂P(O)(OR⁵)(NR⁵), -CH₂P(O)(NR⁵)₂, -CH₂P(0)(OH)(OCI-IO alkyl-0-Ci-₂o alkyl), and -CH₂- cycloSal monophosphate prodrugs; each R⁵ is independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; and each R⁷ and R⁸ are independently H, CH3, naturally or non-naturally occurring amino acid substituents, chain groups, e.g., hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH )2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(0H)CH3, -CH2-3 -indoyl, -CH2COOH, -CH2CH2COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH₂)4NH₂, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R⁸ and the NH2 bound to the same carbon R⁸ is covalently bonded to come together to form a 2-pyrrolidinyl ring, wherein R⁷ and R⁸ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R⁹;

R⁹ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxy carbonyl, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R⁹ is optionally substituted with one or more, the same or different, R¹⁰; and

R¹⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, this disclosure relates to compounds of Formula (A): or a pharmaceutically acceptable salt or prodrug thereof, wherein: one of X and Z is selected from the group consisting of -NH-, -N(NH2)-, -N(OH)-, -N(Ci-io alkyl)-, -N(C3-IO cycloalkyl)-, -N(C2-IO alkenyl)-, -N(C2-IO alkynyl)-,

-N(aryl)-, -N(heteroaryl)-

-CH(Ci-io alkyl)-, C(Ci-io alkyl)2-, -CH(C3-IO cycloalkyl)-, -CH(C2-IO alkenyl, -CH(C2-io alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF2-, -CCI2-, -CH(CF₃)-, -CH(OH)-, -CH(0-Ci-io alkyl)-, -CH(NH₂)-, -CH(NH-CI-IO alkyl)-, and -CH(C(O)NH₂)- ; and the other one of X and Z is selected from the group consisting of -C(O)-, -SO2-, -NH(C(O)))-, -CH2-, -CH(Ci-io alkyl)-, C(Ci-io alkyl)₂-, -CH(C₃-IO cycloalkyl)-, -CH(C₂-IO alkenyl, -CH(C2-IO alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF2-, -CCI2-, -CH(CF3)-, -CH(OH)-, -CH(O-alkyl)-, -CH(NH₂)-, -CH(NHCi-io alkyl)-, and -CH(C(O)NH₂)-;

A and B are, independently, phenyl, a five-membered heteroaromatic ring containing one, two or three nitrogen, oxygen, or sulfur atoms, or a six-membered heteroaromatic ring containing one, two or three nitrogen atoms; u and v are independently 0, 1, 2, 3 or 4; with the proviso that at least one of u and v is 1, 2, 3, or 4; each R¹ and R² are independently R³, OH, OR³, SR³, S(O)R³, SO2R³, C(O)R³, C(O)OR³, OC(O)R³, OC(O)OR³, NH2, NHR³, NHC(O)R³, NR³C(O)R³, NHS(O)₂R³, NR³S(O)₂R³, NHC(O)OR³, NR³C(O)OR³, NHC(O)NH₂, NHC(O)NHR³, NHC(O)N(R³)₂, NR³C(O)N(R³)₂, C(O)NH₂, C(O)NHR³, C(O)N(R³)2, C(O)NHOH, C(O)NHOR³, C(O)NHSO₂R³, C(O)NR³SO₂R³, SO2NH2, SO2NHR³, SO₂N(R³)2, COOH, C(O)H, C(N)NH₂, C(N)NHR³, C(N)N(R³)2, C(N)OH, C(N)OCH3, CN, N3, NO2, CF₃, CF2CF3, 0CF3, OCF2CF3, halo (F, Cl, Br, or I), -CH2-phosphonate, -CH2O-phosphate, CH2P(O)(OH)2, CH2P(O)(OR³)2, CH₂P(O)(OR³)(NHR³), CH₂P(O)(NHR³)2, CH₂P(0)(OH)(OCI-IO alkyl-O-Ci-20 alkyl), or CH2- cycloSal monophosphate prodrug; wherein the term phosphate includes monophosphate, diphosphate, triphosphate, and stabilized phosphate prodrugs, and the term phosphonate includes the same prodrugs that are present in the phosphate prodrugs; and when two R s or two R²s are on adjacent carbon, they can come together to form a saturated or unsaturated carbocyclyl, aryl, or heterocyclyl; each R³ is, independently hydrogen, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, C1-10 alkyl, C2-10 alkenyl or C₂-io alkynyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴, OH, OR⁴, SR⁴, S(O)R⁴, SO2R⁴, C(O)R⁴, C(O)OR⁴, OC(O)R⁴, OC(O)OR⁴, NH2, NHR⁴, NHC(O)R⁴, NR⁴C(O)R⁴, NHS(O)₂R⁴, NR⁴S(O)₂R⁴, NHC(O)OR⁴, NR⁴C(O)OR⁴, NHC(O)NH₂, NHC(O)NHR⁴, NHC(O)N(R⁴)₂, NR⁴C(O)N(R⁴)₂, C(O)NH₂, C(O)NHR⁴, C(O)N(R⁴)₂, C(O)NHOH, C(O)NHOR⁴, C(O)NHSO₂R⁴, C(O)NR⁴SO₂R⁴, SO₂NH₂, SO₂NHR⁴, SO₂N(R⁴)₂, COOH, C(O)H, C(N)NH₂, C(N)NHR⁴, C(N)N(R⁴)₂, C(N)OH, C(N)OCH⁴, CN, N₃, NO₂, CF3, CF₂CF3, OCF3, OCF₂CF3, halo (F, Cl, Br, or I), P(O)(OH)₂, P(O)(OR⁴)₂, P(O)(OR⁴)(NR⁴), P(O)(NR⁴)₂, P(0)(OH)(OCI-IO alkyl-0-Ci-₂o alkyl), cycloSal monophosphate prodrugs, CH₂P(O)(OH)₂, CH₂P(O)(OR⁴)₂, CH₂P(O)(OR⁴)(NHR⁴), CH₂P(O)(NHR⁴)₂, CH₂P(0)(OH)(OCI-IO alkyl-0-Ci-₂o alkyl), and CH₂-cycloSal monophosphate prodrugs, each R⁴ are independently selected from hydrogen, aryl, heteroaryl, arylalkyl, alkylaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁵, OH, OR⁵, SR³, S(O)R⁵, SO₂R⁵, C(O)R⁵, C(O)OR⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵, C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO2NHR⁵, SO₂N(R⁵)₂, COOH, C(O)H, C(N)NH₂, C(N)NHR⁵, C(N)N(R⁵)₂, C(N)OH, C(N)OCH₃, CN, N3, NO₂, CF3, CF₂CF₃, OCF3, OCF₂CF₃, halo (F, Cl, Br, or I), P(O)(OH)₂, P(O)(OR⁵)₂, P(O)(OR⁵)(NHR⁵), P(O)(NHR⁵)₂, P(O)(OH)(OCi- 10 alkyl-O-Ci -20 alkyl), and cycloSal monophosphate prodrugs, each R⁵ are independently hydrogen, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁶, OH, OR⁶, SR⁶, S(O)R⁶, SO₂R⁶, C(O)R⁶, C(O)OR⁶, OC(O)R⁶, OC(O)OR⁶, NH₂, NHR⁶, NHC(O)R⁶, NR⁶C(O)R⁶, NHS(O)₂R⁶, NR⁶S(O)₂R⁶, NHC(O)OR⁶, NR⁶C(O)OR⁶, NHC(O)NH₂, NHC(O)NHR⁶, NHC(O)N(R⁶)₂, NR⁶C(O)N(R⁶)₂, C(O)NH₂, C(O)NHR⁶, C(O)N(R⁶)₂, C(O)NHOH, C(O)NHOR⁶, C(O)NHSO₂R⁶, C(O)NR⁶SO₂R⁶, SO₂NH₂, SO2NHR⁶, SO₂N(R⁶)₂, COOH, C(O)H, C(N)NH₂, C(N)NHR⁶, C(N)N(R⁶)₂, C(N)OH, C(N)OCH₃, CN, N₃, NO₂, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br, I, P(O)(OH)2, P(O)(OR⁶)₂, P(O)(OR⁶)(NHR⁶), P(O)(NHR⁴)2, P(0)(OH)(OCI IO alkyl-0-Ci-₂o alkyl), and cycloSal monophosphate prodrugs, each R⁶ are independently hydrogen, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, OH, NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, COOH, C(O)H, C(N)NH₂, C(N)OH, C(N)OCH₃, CN, N₃, NO2, CF3, CF2CF3, OCF3, OCF2CF3, halo (F, Cl, Br, or I), P(O)(OH)₂, P(O)(OH)₂, P(O)(OH)(NH-alkyl), P(O)(NH-alkyl)₂, P(0)(OH)(OCi-io alkyl-0-Ci-₂o alkyl), and cycloSal monophosphate prodrugs, each R⁷ and R⁸ are independently H, CH₃, naturally or non-naturally occurring amino acid substituents, side chain groups, e.g., hydrogen, methyl, isopropyl, sec-butyl, -CH₂CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH₃, -CH2-3-indoyl, -CH₂COOH, -CH₂CH₂COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH₂SH, -CH₂CH₂SCH₃, -(CH₂)4NH₂, -(CH₂)3NHC(=NH)NH₂, or -CH₂-3-imidazoyl, or R⁸ and the NH₂ form a 2-pyrrolidinyl ring, wherein R⁷ and R⁸ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R⁹;

R⁹ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)₂amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R⁹ is optionally substituted with one or more, the same or different, R¹⁰; and

R¹⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, one of X and Z is -C(O)-, -SO2-, or -NH(C(O))-, and the other is -NH-, -N(NH₂)-, -N(OH)-, -N(CI-IO alkyl)-, -N(C₃-IO cycloalkyl)-, -N(C₂-IO alkenyl)-, -N(C₂-IO wherein R⁴ is C1-10 alkyl, C3-10 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 halo alkyl, C1-10 alkyl- aryl, or Ci-io haloalkyl-aryl and m is 0, 1, 2, 3 or 4.

In certain embodiments, this disclosure relates to compounds of formula (B): or a pharmaceutically acceptable salt or prodrug thereof, wherein:

A and B are, independently, a phenyl ring, a five-membered heteroaromatic ring containing one, two or three nitrogen, oxygen, or sulfur atoms, or a six-membered heteroaromatic ring containing one, two or three nitrogen atoms;

R¹’ and R²’ are independently hydrogen, Ci-io alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴; R¹’ and R²’ can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴;

R³’ is hydrogen, Ci-io alkyl, C2-10 alkenyl or C2-10 alkynyl; w is 0, 1, 2, 3 or 4 substituents other than hydrogen;

R⁴’ is hydrogen, -COOH, -CH2-COOH;

R⁵’ is hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl; n is 1, 2, 3, 4 or 5;

D is O, S, NH or CH₂;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH2-COOH; u and v are independently 0, 1, 2, 3 or 4 substituents other than hydrogen; wherein optionally that at least one of u and v is 1, 2, 3, or 4; each R¹ and R² are independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³, -C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH2, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)₂, -NR³C(O)N(R³)2, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)2, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO2NH2, -SO2NHR³, -SO₂N(R³)2, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)₂, -C(N)OH, -C(N)OCH₃, -CN, -N.3, -NO2, -CF3, -CF2CF3, -OCF3, -OCF₂CF3, halogen (F, Cl, Br, or I), -CH₂-phosphonate, -CH₂O-phosphate, -CH₂P(O)(OH)₂, -CH₂P(O)(OR³)2, -CH₂P(O)(OR³)(NR³), -CH₂P(O)(NR³)₂,

-CH₂P(0)(OH)(OCI-IO alkyl-O-Ci -20 alkyl), or -CH₂-cycloSal monophosphate prodrug; and when two R^xs and two R²s are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴; each R⁴ are independently Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, arylalkyl, alkylaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, -OH, -NH2, -C(O)NH₂, -C(O)NHOH, -SO2NH2, -COOH, -C(O)H, -C(N)NH₂, -C(N)OH, -CN, -N3, -NO2, -CF3, -CF2CF3, -OCF3, -OCF2CF3, halogen (F, Cl, Br, or I), -P(O)(OH)₂, -P(0)(OH)(OCI-IO alkyl-O-Ci-20 alkyl), -CH₂P(O)(OH)₂, -CH₂P(O)(OR⁵)2, -CH₂P(O)(OR⁵)(NR⁵), -CH₂P(O)(NR⁵)₂, -CH₂P(0)(OH)(OCI-IO alkyl-O-Ci-20 alkyl), and -CH₂- cycloSal monophosphate prodrugs; each R⁵ is independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; and each R⁷ and R⁸ are independently H, CH3, naturally or non-naturally occurring amino acid substituents, chain groups, e.g., hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(0H)CH3, -CH2-3 -indoyl, -CH2COOH,

-CH2CH2COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH₂)4NH₂, -(CH₂)3NHC(=NH)NH₂, or -CH2-3-imidazoyl, or R⁸ and the NH2 bound to the same carbon R⁸ is covalently bonded to come together to form a 2-pyrrolidinyl ring, wherein R⁷ and R⁸ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R⁹;

R⁹ is Ci-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl )2ami no, alkanoyl, alkoxycarbonyl, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R⁹ is optionally substituted with one or more, the same or different, R¹⁰; and

R¹⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N, ' idi ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, one of R¹ and R² is C(O)NHR⁴, C(O)(NHR⁴)2, wherein R⁴ is Ci-io alkyl, C3-10 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 halo alkyl, C1-10 alkylaryl, or Ci-10 haloalkyl-aryl and m is 0, 1, 2, 3 or 4.

In certain embodiments, this disclosure relates to a compound having the formula: 8-(4-benzylpiperidine-l-carbonyl)dibenzo[b,f][l,4]thiazepin-l l(10H)-one;

8-(4-benzylcy clohexane-l-carbonyl)dibenzo[b,f][l,4]thi azepin- 1 l(10H)-one;

-((4-benzylpiperidin-l-yl)sulfonyl)dibenzo[b,f][l,4]thiazepin-l l(10H)-one; -(4-(2-phenylpropan-2-yl)piperidine- 1 -carbonyl)dibenzo[b,f] [ 1 ,4]thiazepin- 11(10H)-one; -(4-(difluoro(phenyl)methyl)piperidine- 1 -carbonyl)dibenzo[b,f] [ 1 ,4]thiazepin- 11(1 OH)-one; -(4-phenethylpiperi dine- l-carbonyl)dibenzo[b,f][l,4]thiazepin-l 1(10H)-one;

(8-(4-benzylpiperidine- 1 -carbonyl)- 11 -oxodibenzo [b , f] [ 1 ,4]thiazepin- 10(1 lH)-yl)methyl dihydrogen phosphate; (8-(4-benzylpiperidine- 1 -carbonyl)- 11 -oxodibenzo[b,f] [ 1 ,4]thiazepin- 10(1 lH)-yl)methyl L- alaninate;

(8-(4-benzylpiperidine-l -carbonyl)- 1 l-oxodibenzo[b,f][l,4]thiazepin-10(l lH)-yl)methyl D- alaninate;

(8-(4-benzylpiperidine- 1 -carbonyl)- 1 l-oxodibenzo[b, f][l,4]thiazepin- 10(1 lH)-yl)methyl 2- amino-2-methylpropanoate; (8-(4-benzylpiperidine-l-carbonyl)-l l-oxodibenzo[b,f][l,4]thiazepin-10(l lH)-yl)methyl 2- amino-2-methylbutanoate; or a pharmaceutically acceptable salt or prodrug thereof.

In certain embodiments, this disclosure relates to a compound of Formula (A):

Formula (A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: one of X and Z is selected from the bridging group consisting of -NH-, -N(NH2)-, -NH(OH)-, -N(Ci-io alkyl)-, -N(C3-IO cycloalkyl)-, -N(C2-IO alkenyl)-, -N(C2-IO alkynyl)-,

-N(aryl)-, -N(heteroaryl)-, -CH(Ci-io alkyl)-, -C(Ci-io alkyl)2-, -CH(C₃-IO cycloalkyl)-, -CH(C2-IO alkenyl)-, -CH(C2-IO alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF2-, -CCI2-, -CH(CF₃)-, -CH(OH)-, -CH(0-Ci-io alkyl)-, -CH(NH₂)-, -CH(NH-CI-IO alkyl)-, and -CH(C(O)NH₂)-; and the other one of X and Z is selected from the group consisting of -C(O)-, -SO2-, -NH(C(O))-, -CH2-, -CH(Ci-io alkyl)-, -C(Ci-io alkyl)₂-, -CH(C₃-IO cycloalkyl)-, -CH(C2-IO alkenyl)-, -CH(C2-io alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF2-, -CCI2-, -CH(CF₃)-, -CH(OH)-, -CH(O-alkyl)-, -CH(NH₂)-, -CH(NHCi-io alkyl)-, and -CH(C(O)NH₂)-;

A and B are, independently, a phenyl ring, a five-membered heteroaromatic ring containing one, two or three nitrogen, oxygen, or sulfur atoms, or a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms; u and v are independently 0, 1, 2, 3 or 4 substituents other than hydrogen; wherein optionally that at least one of u and v is 1, 2, 3, or 4; each R¹ and R² are independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³, -C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH2, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)₂, -NR³C(O)N(R³)2, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)2, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO2NH2, -SO2NHR³, -SO₂N(R³)2, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)2, -C(N)OH, -C(N)OCH₃, -CN, -N₃, -NO2, -CF₃, -CF₂CF₃, -OCF₃, -OCF2CF₃, halogen (F, Cl, Br, or I), -CH2-phosphonate, -QHO-phosphate, -CH₂P(O)(OH)2, -CH₂P(O)(OR³)2, -CH₂P(O)(OR³)(NHR³), -CH₂P(O)(NHR³)2,

-CH₂P(0)(OH)(OCI-IO alkyl-O-Ci -20 alkyl), or -CH2-cycloSal monophosphate prodrug; or when two R's and two R²s are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴; each R⁴ are independently C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, arylalkyl, alkylaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, -OH, -NH2, -C(O)NH₂, -C(O)NHOH, -SO2NH2, -COOH, -C(O)H, -C(N)NH₂, -C(N)OH, -CN, -N₃, -NO2, -CF₃, -CF₂CF₃, -OCF₃, -OCF₂CF₃, halogen (F, Cl, Br, or I), -P(0)(0H)2, -P(O)(OH)(OCi-i0 alkyl-O-Ci-20 alkyl), -CH₂P(O)(OH)₂, -CH₂P(O)(OR⁵)₂, -CH₂P(O)(OR⁵)(NHR⁵), -CH₂P(O)(NHR⁵)₂, -CH₂P(0)(OH)(OCI-IO alkyl-O-Ci-20 alkyl), and -CH2-cycloSal monophosphate prodrugs; each R⁵ is independently hydrogen, Ci-io alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; and each R⁷ and R⁸ are independently H, CH3, naturally or non-naturally occurring amino acid substituents, chain groups, e.g., hydrogen, methyl, isopropyl, sec-butyl, -CH₂CH(CH3)₂, benzyl, p-hydroxybenzyl, -CH2OH, -CH(0H)CH3, -CH2-3 -indoyl, -CH2COOH,

-CH2CH2COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH₂SH, -CH₂CH₂SCH3, -(CH₂)₄NH₂, -(CH₂)3NHC(=NH)NH₂, or -CH₂-3-imidazoyl, or R⁸ and the NH₂ form a 2-pyrrolidinyl ring, wherein R⁷ and R⁸ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R⁹;

R⁹ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)₂amino, alkanoyl, alkoxycarbonyl, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R⁹ is optionally substituted with one or more, the same or different, R¹⁰; and

R¹⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl. In certain embodiments, one of X and Z is -C(O)-, -SO₂-, or -NH(C(O))-, and the other is -NH-, -N(NH₂)-, -NH(OH)-, -N(CI-IO alkyl)-, -N(C₃-IO cycloalkyl)-, -N(C₂-IO alkenyl)-, -N(C₂- alkynyl)-, -N(aryl)-, or -N(heteroaryl)-, In certain embodiments, one of R¹ and R² is C(O)NHR₃, C(O)N(R³)₂, or C(O)R³.

In certain embodiments, one of R¹ and R² is C(O)NHR₃, C(O)N(R³)₂, or C(O)R³ and R³ is C3-10 cycloalkyl, substituted with one or more, the same or different, R⁴.

In certain embodiments, one of R¹ and R² is selected from: wherein R⁴ is Ci-io alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 halo alkyl, C1-10 alkyl-aryl, or C1-10 haloalkyl-aryl and m is 0, 1, 2, 3 or 4.

In certain embodiments, this disclosure relates to compounds of Formula (C):

Formula (C) or a pharmaceutically acceptable salt or prodrug thereof wherein,

Q is N or CH;

V is -CH₂CH₂-, -CH₂-, or a bond from Q to the methylene (CH₂) bridge;

W is -CH₂CH₂-, -CH₂-, or a bond from Q to the carbon bonded to R¹¹; R¹⁸ is selected from hydrogen, -NH2, -OH, -C1-10 alkyl, -C3-10 cycloalkyl, -C2-10 alkenyl, -C2-10 alkynyl), -aryl, -heteroaryl, benzoyl, benzyl, alkoxy, thioalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, phosphate, wherein R¹⁸ is optionally substituted with one or more, the same or different, R¹⁹; wherein each R¹ is independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³, -C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH2, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)2, -NR³C(O)N(R³)2, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)2, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO2NH2, -SO2NHR³, -SO₂N(R³)2, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)2, -C(N)OH, -C(N)0CH3, -CN, -N3, -NO2, -CF3, -CF2CF3,

-OCF3, -OCF2CF3, halogen (F, Cl, Br, or I), -CH2-phosphonate, -CH2O-phosphate, -CH₂P(O)(OH)2, -CH₂P(O)(OR³)2, -CH₂P(O)(OR³)(NR³), -CH₂P(O)(NR³)2,

-CH₂P(0)(OH)(OCI-IO alkyl-O-Ci -20 alkyl), or -CH2-cycloSal monophosphate prodrug; and when two R's are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, or C3-10 heterocycloalkenyl; R¹’ and R²’ can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴;

R⁴’ is hydrogen, -COOH, -CH2-COOH;

D is O, S, NH or CH₂;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH2-COOH;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are individually selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are optionally substituted with one or more, the same or different, R¹⁹; and

R¹⁹ is Ci-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl )2ami no, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R¹⁹ is optionally substituted with one or more, the same or different, R²⁰; and

R²⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N, ' idi ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, this disclosure relates to compounds of Formula (C):

Formula (C) or prodrugs or salts thereof wherein,

Q is N or CH;

V is -CH2CH2-, -CH2-, or a bond from Q to the methylene (CH2) bridge;

W is -CH2CH2-, -CH2-, or a bond from Q to the carbon bonded to R¹¹;

R¹¹, R¹², R¹³, R¹⁴, R^1?, R¹⁶, R¹⁷ and R¹⁸ are individually selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R¹ R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are optionally substituted with one or more, the same or different, R¹⁹; and

R¹⁹ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R¹⁹ is optionally substituted with one or more, the same or different, R²⁰; and

R²⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, di methyl ami no, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiment, this disclosure relates to compounds of Formula (D):

Formula (D) or a pharmaceutically acceptable salt or prodrug thereof wherein,

Q is N or CH;

V is -CH2CH2-, -CH2-, or a bond from Q to the methylene (CH2) bridge;

W is -CH2CH2-, -CH2-, or a bond from Q to the carbon bonded to R¹⁰;

Y is O, S, or NH;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷, are individually selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷, are optionally substituted with one or more, the same or different, R¹⁹; and

wherein each R¹ is independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³, -C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH₂, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)₂, -NR³C(O)N(R³)₂, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)₂, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO₂NH₂, -SO₂NHR³, -SO₂N(R³)₂, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)₂, -C(N)OH, -C(N)OCH3, -CN, -N3, -NO2, -CF3, -CF2CF3, -OCF3, -OCF₂CF3, halogen (F, Cl, Br, or I), -CH₂-phosphonate, -CH₂O-phosphate, -CH₂P(O)(OH)₂, -CH₂P(O)(OR³)₂, -CH₂P(O)(OR³)(NR³), -CH₂P(O)(NR³)₂,

-CH₂P(0)(OH)(OCI-IO alkyl-0-Ci-₂o alkyl), or -CH₂-cycloSal monophosphate prodrug; and when two R's are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, or C3-10 heterocycloal keny 1 ;

C ring is a saturated or unsaturated carbocyclyl heterocyclyl, or a heteroaryl;

R⁴’ is hydrogen, -COOH, -CH₂-COOH;

D is O, S, NH or CH₂;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH₂-COOH; R¹⁹ is Ci-io alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl )2ami no, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R¹⁹ is optionally substituted with one or more, the same or different, R²⁰; and

R²⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiment, this disclosure relates to compounds of Formula (D):

Formula (D) or prodrugs or salts thereof wherein,

Q is N or CH;

V is -CH2CH2-, -CH2-, or a bond from Q to the methylene (CH2) bridge;

W is -CH2CH2-, -CH2-, or a bond from Q to the carbon bonded to R¹¹;

Y is O, S, or NH;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are individually selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R¹¹, R¹², R¹³, R¹⁴, R^1?, R¹⁶, and R¹⁷ are optionally substituted with one or more, the same or different, R¹⁹; and

R¹⁹ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphate, phosphonate, thiophosphate, thiophosphonate, phosphate ester, phosphonate ester, thiophosphate ester, thiophosphonate ester, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R¹⁹ is optionally substituted with one or more, the same or different, R²⁰; or

R²⁰ is Ci-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one or more, the same or different, R²¹; and

R²¹ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiment, this disclosure relates to compounds of Formula (E):

Formula (E) or prodrugs or salts thereof wherein,

Q is N or CH;

V is -CH2CH2-, -CH2-, or a bond from Q to the methylene (CH2) bridge;

W is -CH2CH2-, -CH2-, or a bond from Q to the carbon bonded to R¹¹;

Y is O, S, or NH;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are individually selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are optionally substituted with one or more, the same or different, R¹⁹;

R¹⁹ is C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphate, phosphonate, thiophosphate, thiophosphonate, phosphate ester, phosphonate ester, thiophosphate ester, thiophosphonate ester, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R¹⁹ is optionally substituted with one or more, the same or different, R²⁰; or

R²⁰ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one or more, the same or different, R²¹;

R²¹ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl;

R²² and R²³ are independently H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CHS)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(0H)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH₂SH, -CH2CH2SCH3, -(CH₂)4NH₂, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R²³ and the NH2 form a 2-pyrrolidinyl ring, wherein R²² or R²³ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R²⁴;

R²⁴ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R²⁴ is optionally substituted with one or more, the same or different, R²⁵; and

R²⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, this disclosure relates to a compound disclosed herein optionally substituted with one or more substituents.

In certain embodiments, compounds disclosed herein are isolated, enantiomerically pure, and substantially free of impurities. In certain embodiments, compounds disclosed herein are in a composition wherein a specific isomer is in excess of 60%, 70%, 80%, 90%, 93%, 95%, or 97% enantiomeric excess and/or diastereomeric excess.

Methods of Use

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) of a disease affected by Retinoic Acid Receptor-like Orphan Receptor (ROR) modulators comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof. In certain embodiments, the disease or condition is cancer or liver cancer.

In certain embodiments, this disclosure relates to methods of treating or preventing cirrhosis, fatty liver disease, or nonalcoholic fatty liver disease comprising administering an effective amount of a heterocyclic retinoic acid receptor- related orphan receptor modulator disclosed herein to a subject or human patient in need thereof. In certain embodiments, the subject is diagnosed with cirrhosis of the liver. In certain embodiments, the subject is provided a therapeutic to prevent liver tumor development.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) pancreatitis comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) of a disease affected by Retinoic Acid Receptor-like Orphan Receptor (ROR) modulators comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof, wherein the disease is selected from the group consisting of increased lipid and cholesterol levels, particularly high LDL-cholesterol, high triglycerides, low HDL-cholesterol, dyslipidemia, diseases of cholesterol absorption, atherosclerotic disease, coronary artery disease, cerebrovascular arterial disease, peripheral vascular disease, aortic aneurysms, carotid atherosclerotic conditions, cholestatic disorders, peripheral occlusive disease, ischemic stroke, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, diabetic nephropathy, obesity, cholesterol gallstone disease, cholestasis/fibrosis of the liver, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), hepatic ischemia reperfusion injury, or non-alcoholic fatty liver disease (NAFLD); autoimmune disorders such as, but not limited to, rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, Pernicious anemia, chronic graft-versus- host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis, chronic obstructive pulmonary disease (COPD) and amyotrophic lateral sclerosis.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) glioblastoma comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) sarcopenia comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) stroke comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) cancer, liver cancer, colon cancer, prostate cancer, breast cancer, hematological cancer, lymphoid cancer, brain cancer, glioblastoma, myeloid cancer, multiple myeloma, leukemia, lymphoma, metastasis, or to suppress tumor growth comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

The cancer to be treated or prevented in the context of the present disclosure may be any type of FGF21-associated cancer or tumor. These tumors or cancer include, and are not limited to, tumors of the hematopoietic and lymphoid tissues or hematopoietic and lymphoid malignancies, tumors that affect the blood, bone marrow, lymph, and lymphatic system. Hematological malignancies may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages and mast cells; the lymphoid cell line produces B, T, NK and plasma cells. Lymphomas, lymphocytic leukemias, and myeloma are from the lymphoid line, while acute and chronic myelogenous leukemia, myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin.

Also contemplated are malignancies located in the colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, hypophysis, testicles, ovaries, thymus, thyroid), eye, head and neck, nervous system (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thorax and genito-urinary apparatus and, more particularly, childhood acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, adult (primary) hepatocellular cancer, adult (primary) liver cancer, adult acute lymphocytic leukemia, adult acute myeloid leukemia, adult Hodgkin's disease, adult Hodgkin's lymphoma, adult lymphocytic leukemia, adult non-Hodgkin's lymphoma, adult primary liver cancer, adult soft tissue sarcoma, AIDS-related lymphoma, AIDS-related malignant tumors, anal cancer, astrocytoma, cancer of the biliary tract, cancer of the bladder, bone cancer, brain stem glioma, brain tumors, breast cancer, cancer of the renal pelvis and ureter, primary central nervous system lymphoma, central nervous system lymphoma, cerebellar astrocytoma, brain astrocytoma, cancer of the cervix, childhood (primary) hepatocellular cancer, childhood (primary) liver cancer, childhood acute lymphoblastic leukemia, childhood acute myeloid leukemia, childhood brain stem glioma, childhood cerebellar astrocytoma, childhood brain astrocytoma, childhood extracranial germ cell tumors, childhood Hodgkin's disease, childhood Hodgkin's lymphoma, childhood visual pathway and hypothalamic glioma, childhood lymphoblastic leukemia, childhood medulloblastoma, childhood non-Hodgkin's lymphoma, childhood supratentorial primitive neuroectodermal and pineal tumors, childhood primary liver cancer, childhood rhabdomyosarcoma, childhood soft tissue sarcoma, childhood visual pathway and hypothalamic glioma, chronic lymphocytic leukemia, chronic myeloid leukemia, cancer of the colon, cutaneous T-cell lymphoma, endocrine pancreatic islet cells carcinoma, endometrial cancer, ependymoma, epithelial cancer, cancer of the esophagus, Ewing's sarcoma and related tumors, cancer of the exocrine pancreas, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic biliary tract cancer, cancer of the eye, breast cancer in women, Gaucher's disease, cancer of the gallbladder, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal tumors, germ cell tumors, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Hodgkin's disease, Hodgkin's lymphoma, hypergammaglobulinemia, hypopharyngeal cancer, intestinal cancers, intraocular melanoma, islet cell carcinoma, islet cell pancreatic cancer, Kaposi's sarcoma, cancer of kidney, cancer of the larynx, cancer of the lip and mouth, cancer of the liver, cancer of the lung, lymphoproliferative disorders, macroglobulinemia, breast cancer in men, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, mesothelioma, occult primary metastatic squamous neck cancer, primary metastatic squamous neck cancer, metastatic squamous neck cancer, multiple myeloma, multiple myeloma/plasmatic cell neoplasia, myelodysplastic syndrome, myelogenous leukemia, myeloid leukemia, myeloproliferative disorders, paranasal sinus and nasal cavity cancer, nasopharyngeal cancer, neuroblastoma, nonHodgkin's lymphoma during pregnancy, non-melanoma skin cancer, non-small cell lung cancer, metastatic squamous neck cancer with occult primary, buccopharyngeal cancer, malignant fibrous histiocytoma, malignant fibrous osteosarcoma/histiocytoma of the bone, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, paraproteinemias, purpura, parathyroid cancer, cancer of the penis, phaeochromocytoma, hypophysis tumor, neoplasia of plasmatic cells/multiple myeloma, primary central nervous system lymphoma, primary liver cancer, prostate cancer, rectal cancer, renal cell cancer, cancer of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, cancer of the salivary glands, sarcoidosis, sarcomas, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous neck cancer, stomach cancer, pineal and supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, transitional renal pelvis and ureter cancer, trophoblastic tumors, cell cancer of the renal pelvis and ureter, cancer of the urethra, cancer of the uterus, uterine sarcoma, vaginal cancer, optic pathway and hypothalamic glioma, cancer of the vulva, Waldenstrom's macroglobulinemia, Wilms' tumor and any other hyperproliferative disease, as well as neoplasia, located in the system of a previously mentioned organ.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a disease or condition associated with metabolism, e.g., type I or type II diabetes, obesity, Gaucher's disease, hemochromatosis, tiredness, weight loss or gain, nausea and vomiting, comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a diseases or condition associated with immune function or development, e g., prevent undesirable auto immune reactions, e.g., rheumatoid arthritis, comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a diseases or condition associated with brain function, e.g., to improve memory, to prevent loss of cognition due to a concussion or other head injury, comprising administering an effective treatment amount of a compound disclosed herein to a subject, e g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a diseases or condition associated with circadian rhythm, e.g., insomnia, hypersomnia, comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) alcoholic or nonalcoholic fatty liver disease, alcoholic or non-alcoholic steatohepatitis or cirrhosis comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) atherosclerosis comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof. In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) macular degeneration or retinal deterioration comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a bacterial, fungal, parasitic, or viral infection comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) an inflammatory disease, e.g., arthritis, bronchiectasis, cystic fibrosis, comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a neuropsychiatric disorder, e.g., headaches, depression, hallucinations, schizophrenia, comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) an immunological disorder such as rheumatic diseases, e.g., psoriasis, arthritis, systemic sclerosis, and systemic lupus erythematosus, comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) an autoimmune disorder, e.g., multiple sclerosis, autoimmune myocarditis, diabetes, and autoimmune thyroiditis comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) asthma or an allergic disease comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) immune-mediated diseases, e.g., inflammatory bowel disease and periodontal disease comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) insulin resistance or impaired insulin sensitivity comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a central nervous system (CNS) disease associated with ROR comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) sleep disorder or anxiety a comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) a neurodegenerative disease such as Parkinson's or Alzheimer's disease comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing (prophylaxis) rheumatic diseases (psoriasis, arthritis, systemic sclerosis, and systemic lupus erythematosus), autoimmune disorders (multiple sclerosis, autoimmune myocarditis, diabetes, and autoimmune thyroiditis), asthma, allergic diseases, and other immune-mediated diseases like inflammatory bowel disease and periodontal disease comprising administering an effective treatment amount of a compound disclosed herein to a subject, e.g., human patient, in need thereof.

The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once or can be divided into a number of smaller doses to be administered at varying intervals of time.

With regard to any of the methods disclosed herein, compound(s) of this disclosure are administered in combination with a second active therapeutic agent.

In certain embodiments, the second therapeutic agent is selected from the group consisting of agents used to treat metabolic disorders, liver diseases, immune disorders, CNS disorders or diseases, and cancer, i.e., anti-cancer agent.

In certain embodiments, the active agent is an anti-diabetic or anti-insulin resistance agent. In certain embodiments, the anti-diabetic or anti-insulin resistance agent is selected from the group consisting of a glitazone, rosiglitazone, pioglitazone, a sulfonylurea, metformin, insulin, an insulin mimetic, a DPP4 inhibitor, a GLP1 receptor agonist, a glucagon receptor antagonist, and an anti-obesity agent.

In certain embodiments, the active agent is anti-TNF agent or an immune-suppressive glucocorticoid.

In certain embodiments, the active agent is a platinum compound, a Vinca alkaloid or analog thereof, a taxane, or a nitrogen mustard.

In certain embodiments, the active agent is selected from the group consisting of cholesterol biosynthesis inhibitors, squalene epoxidase inhibitors; plasma HDL-raising agents; human peroxisome proliferator activated receptor (PPAR) gamma agonists; PPAR alpha agonists; PPAR dual alpha/gamma agonists; farnesoid X receptor (FXR) modulators; bile acid sequestrants; bile acid transport inhibitors; nicotinic acid, niacinamide; cholesterol absorption inhibitors; acyl-coenzyme A: cholesterol O-acyl transferase (ACAT) inhibitors; selective estrogen receptor modulators; LXR alpha or beta agonists, antagonists or partial agonists; microsomal triglyceride transfer protein (MTP) inhibitors, anti-diabetes agents; SGLT-2 inhibitors, sergliflozin, AVE 2268; Glucokinase activators; anti-obesity agents, growth hormone agonists, adrenergic uptake inhibitors, serotonin reuptake/transporter inhibitors, 5-HT/NA (serotonin/noradrenaline) reuptake inhibitors, dopamine reuptake inhibitors, 5-HT, NA and DA reuptake blockers, steroidal plant extracts, NPY1 or 5 (neuropeptide Y1 or Y5) antagonists, NPY2 (neuropeptide Y2) agonists, MC4 (melanocortin 4) agonists, CCK-A (cholecystokinin-A) agonists, GHSRla (growth hormone secretagogue receptor) antagonist/inverse agonists, ghrelin antibody, MCH1R (melanin concentrating hormone 1R) antagonists, MCH2R (melanin concentrating hormone 2R) agonist/antagonists, H3 (histamine receptor 3) inverse agonists or antagonists, Hl (histamine 1 receptor) agonists, FAS (Fatty acid synthase) inhibitors, ACC-1 (acetyl-CoA carboxylase-1) inhibitors, P3 (beta adrenergic receptor 3) agonists, DGAT-2 (diacylglycerol acyltransferase 2) inhibitors, DGAT-1 (diacylglycerol acyltransferase 1) inhibitors, CRF (corticotropin releasing factor) agonists, Galanin antagonists, UCP-1, 2 or 3 (uncoupling protein- 1, 2 or 3) activators, leptin, leptin derivatives, opioid antagonists, orexin antagonists, BRS3 agonists, GLP-1 (glucagons-like peptide-1) agonists, IL-6 agonists, a-MSH agonists, AgRP antagonists, BRS3 (bombesin receptor subtype 3) agonists, 5-HT1B agonists, POMC antagonists, ciliary neurotrophic factor, NN2211, Topiramate, glucocorticoid antagonist, Exendin-4 agonists, serotonin receptor 2C agonists, phosphodiesterase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, cannabinoid-1 receptor inverse agonists or antagonists, lipase inhibitors; cyclooxygenase-2 inhibitors; thrombin inhibitors; platelet aggregation inhibitors vitamin B6 and pharmaceutically acceptable salts thereof; vitamin Bl 2; folic acid or a pharmaceutically acceptable salt or ester thereof; antioxidant vitamins; beta blockers ; angiotensin converting enzyme inhibitors; calcium channel blockers; aspirin; fatty-acid/bile-acid conjugates; caspase inhibitors thyroid hormone receptor modulators; agents other than LXR ligands that enhance ATP-Binding Cassette Transporter- Al gene expression; and bisphosphonate compounds.

In certain embodiments, the additional active agent is an agent that modifies host metabolism. In certain embodiments, the agent that modifies host metabolism is selected from the group consisting of clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, ritonavir, saquinavir, suboxone, telithromycin, aprepitant, erythromycin, fluconazole, verapamil, diltiazem, cimetidine, amiodarone, boceprevir, chloramphenicol, ciprofloxacin, delavirdine, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, telaprevir, and voriconazole. Pharmaceutical compositions

In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a heterocyclic compound disclosed herein that modulates a retinoic acid receptor-related orphan receptors disclosed herein and a pharmaceutically acceptable carrier or excipient. While it is possible that, for use in therapy, a therapeutically effective amount of a compound disclosed herein may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation. Accordingly, the disclosure further provides a pharmaceutical composition comprising a compound disclosed herein. Pharmaceutical compositions typically comprise an effective amount of a compound(s) and a suitable pharmaceutical acceptable carrier. The preparations can be prepared in a manner known per se, which usually involves mixing the compounds according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.

In certain embodiments, the disclosure relates to pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pill, tablet, or capsule or the composition is an aqueous buffer, e.g., a pH between 6 and 8. In certain embodiments, the pharmaceutically acceptable excipient is selected from a filler, glidant, binder, disintegrant, lubricant, and saccharide.

The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and/or excipients. The carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the disclosure there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound disclosed herein with one or more pharmaceutically acceptable carriers, diluents and/or excipients. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, particles, powder, lotion, or gel. In certain embodiments, the pharmaceutical composition is in the form of a neutral pH buffered solution optionally comprising isotonic saline or a pharmaceutically acceptable mono or polysaccharide. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising thiazepine derivatives disclosed herein and a pharmaceutically acceptable excipient for uses reported herein. In certain embodiments, the excipient is a sterilized aqueous solution.

In certain embodiments, the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, com starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.

In certain embodiments, the tablets, pills, capsules, troches and the like can contain any of the ingredients disclosed herein, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. In certain embodiments, when the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.

In certain embodiments, it is contemplated that compound disclosed herein can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup can contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

In certain embodiments, compounds disclosed herein, or a pharmaceutically acceptable prodrug or salts thereof, can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflammatory agents, or other antiviral compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

In certain embodiments, the pharmaceutical composition is in the form of a transdermal composition or a nanoparticulate composition.

In some embodiments, the compositions are present in the form of transdermal formulations, such as that used in the FDA-approved agonist rotigotine transdermal (Neupro™ patch). Another suitable formulation is that described in U.S. Publication No. 2008/0050424, entitled “Transdermal Therapeutic System for Treating Parkinsonism.” This formulation includes a silicone or acrylate-based adhesive and can include an additive having increased solubility for the active substance, in an amount effective to increase dissolving capacity of the matrix for the active substance.

The transdermal formulations can be single-phase matrices that include a backing layer, an active substance-containing self-adhesive matrix, and a protective film to be removed prior to use. More complicated embodiments contain multiple-layer matrices that may also contain nonadhesive layers and control membranes. If a polyacrylate adhesive is used, it can be crosslinked with multivalent metal ions such as zinc, calcium, aluminum, or titanium ions, such as aluminum acetylacetonate and titanium acetyl acetonate.

When silicone adhesives are used, they are typically polydimethylsiloxanes. However, other organic residues such as, for example, ethyl groups or phenyl groups may in principle be present instead of the methyl groups. Because the active compounds are amines, it may be advantageous to use amine-resistant adhesives. Representative acrylate-based polymer adhesives include acrylic acid, acrylamide, hexylacrylate, 2-ethylhexylacrylate, hydroxyethylacrylate, octylacrylate, butylacrylate, methylacrylate, glycidylacrylate, methacrylic acid, methacrylamide, hexyl methacryl ate, 2-ethylhexylmethacrylate, octylmethacrylate, methylmethacrylate, glycidylmethacrylate, vinylacetate, vinylpyrrolidone, and combinations thereof. It is contemplated that the adhesive has a suitable dissolving capacity for the active substance, and the active substance is able to move within the matrix and cross through the contact surface to the skin.

Certain pharmaceutically acceptable salts tend to be more preferred for use in transdermal formulations because they can help the active substance pass the barrier of the stratum corneum. Examples include fatty acid salts, such as stearic acid and oleic acid salts. Oleate and stearate salts are relatively lipophilic and can even act as a permeation enhancer in the skin.

Permeation enhancers can also be used. Representative permeation enhancers include fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerol, or its fatty acid esters, N- methylpyrrolidone, terpenes such as limonene, alpha-pinene, alpha- terpineol, carvone, carveol, limonene oxide, pinene oxide, and 1,8-eucalyptol.

The patches can generally be prepared by dissolving or suspending the active agent in ethanol or in another suitable organic solvent, then adding the adhesive solution with stirring. Additional auxiliary substances can be added either to the adhesive solution, the active substance solution or to the active substance-containing adhesive solution. The solution can then be coated onto a suitable sheet, the solvents removed, a backing layer laminated onto the matrix layer, and patches punched out of the total laminate.

In certain embodiments, compounds described herein can also be administered in the form of nanoparticulate compositions. In one embodiment, controlled release nanoparticulate formulations comprise a nanoparticulate active agent to be administered and a rate-controlling polymer which prolongs the release of the agent following administration. In this embodiment, the compositions can release the active agent, following administration, for a time period ranging from about 2 to about 24 hours or up to 30 days or longer.

Nanoparticulate compositions can comprise particles of the active agents described herein, having a non-crosslinked surface stabilizer adsorbed onto, or associated with, their surface. The average particle size of the nanoparticles is typically less than about 800 nm, more typically less than about 600 nm, still more typically less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm. In one aspect of this embodiment, at least 50% of the particles of active agent have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques. A variety of surface stabilizers are typically used with nanoparticulate compositions to prevent the particles from clumping or aggregating. Representative surface stabilizers are selected from the group consisting of gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl-cellulose phthalate, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, dialkyl esters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, decanoyl-N-methylglucamide, n-decyl -D- glucopyranoside, n-decyl-D-maltopyranoside, n-dodecyl-D-glucopyranoside, n-dodecyl-D- maltoside, heptanoyl-N-methylglucamide, n-heptyl-D-glucopyranoside, n-heptyl-D-thio- glucoside, n-hexyl-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-D- glucopyranoside, octanoyl-N-methylglucamide, n-octyl-D-glucopyranoside, and octyl-D-thio- glucopyranoside. Lysozymes can also be used as surface stabilizers for nanoparticulate compositions. Certain nanoparticles such as poly(lactic-co-glycolic acid) (PLGA)-nanoparticles are used to target the liver when given by intravenous (IV) or subcutaneously (SQ).

Representative rate controlling polymers into which the nanoparticles can be formulated include chitosan, polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetaldiethylamino acetate, poly(alkylmethacrylate), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound disclosed herein (as a freebase, solvate (including hydrate) or salt, in any form), depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, a sub-dose or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate, delayed, and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual), rectal, nasal, inhalation, topical (including transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s), excipient(s) or diluent. Generally, the carrier, excipient or diluent employed in the pharmaceutical formulation is "non-toxic," meaning that it/they is/are deemed safe for consumption in the amount delivered in the pharmaceutical composition, and "inert" meaning that it/they does/do not appreciably react with or result in an undesired effect on the therapeutic activity of the active ingredient.

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as liquid-filled or solid capsules; immediate, delayed, or controlled release tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions, water-in-oil liquid emulsions or oral strips, such as impregnated gel strips.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral pharmaceutically acceptable carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present. Solid capsules are made by preparing a powder mixture, as described above, and fdling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com 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. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating, or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture can be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia, mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds disclosed herein can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Solutions and syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a pharmaceutically acceptable alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a pharmaceutically acceptable vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, unit dosage formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.

The compounds of the disclosure can also be administered in the form of 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.

Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouth washes.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, metered dose inhalers, dry powder inhalers, nebulizers, or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation of pharmaceutically acceptable tonicity with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multidose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

In certain embodiments, the pharmaceutical composition comprising a heterocyclic compound that modulates a retinoic acid receptor-related orphan receptor as reported herein comprises a second active agent, e.g., relevant for managing a disease or condition reported herein.

In certain embodiments, the second active agent is anticancer agent, antiviral agent, antibacterial agent, diuretic, beta blocker. In certain embodiments, the second active agent is lactulose, trimethoprim, sulfamethoxazole, rifaximin, spironolactone, furosemide, calcium, vitamin D, thiamine, propranolol, carvedilol, or combinations thereof.

In certain embodiments, the active agent is an anti-diabetic or anti-insulin resistance agent.

In certain embodiments, the anti-diabetic or anti-insulin resistance agent is selected from the group consisting of a glitazone, a sulfonylurea, metformin, insulin, an insulin mimetic, a DPP4 inhibitor, a GLP1 receptor agonist, a glucagon receptor antagonist, and an anti-obesity agent.

In certain embodiments, the additional active agent is an anti-TNF agent or an immune- suppressive glucocorticoid.

In certain embodiments, the additional active agent is a platinum compound, a Vinca alkaloid or analog thereof, a taxane, or a nitrogen mustard.

In certain embodiments, the additional active agent is selected from the group consisting of cholesterol biosynthesis inhibitors (HMG CoA reductase inhibitors, e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, and rivastatin); squalene epoxidase inhibitors (e g. terbinafine); plasma HDL-raising agents (e.g. CETP inhibitors e g. anacetrapib, R1658); human peroxisome proliferator activated receptor (PPAR) gamma agonists (e.g., thiazolidinediones e.g. rosiglitazone, troglitazone, and pioglitazone); PPAR alpha agonists (e.g. clofibrate, fenofibrate, and gemfibrozil); PPAR dual alpha/gamma agonists (e.g. muraglitazar, aleglitazar, peliglitazar, elafibranor); farnesoid X receptor (FXR) modulators (e.g., obeticholic acid, LMB763, LJN45, etc.); bile acid sequestrants (e.g., anion exchange resins, or quaternary amines (e g. cholestyramine or colestipol)); bile acid transport inhibitors (BATi); nicotinic acid, niacinamide; cholesterol absorption inhibitors (e.g. ezetimibe); acyl-coenzyme A:cholesterol O-acyl transferase (ACAT) inhibitors (e.g., avasimibe); selective estrogen receptor modulators (e.g. raloxifene or tamoxifen); LXR alpha or beta agonists, antagonists or partial agonists (e.g., 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, T0901317 or GW3965); microsomal triglyceride transfer protein (MTP) inhibitors, anti-diabetes agents such as, e.g. insulin and insulin analogs (e g. insulin lyspro, inhaled formulations comprising insulin; sulfonylureas and analogues (e.g. tolazamide, chlorpropamide, glipizide, glimepiride, glyburide, glibenclamide, tolbutamide, acetohexamide, glipizide), biguanides (e.g., metformin or metformin hydrochloride, phenformin, buformin) alpha2-antagonists and imidazolines (e.g. midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan), thiazolidinediones (e g., pioglitazone hydrochloride, rosiglitazone maleate, ciglitazone, troglitazone or balaglitazone), alpha-glucosidase inhibitors (e.g. miglitol, acarbose, epalrestat, or voglibose), meglitinides (e.g. repaglinide or nateglinide), DPP-4 inhibitors (e.g., sitagliptin phosphate, saxagliptin, vildagliptin, alogliptin or denagliptin), incretins (e.g. glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. exenatide (Byetta™), NN2211 (liraglutide), GLP-l(7-36) amide and its analogs, GLP-l(7-37) and its analogs, AVE-0010 (ZP-10), R1583 (taspoglutide), GSK-716155 (albiglutide), BRX-0585 and CJC-1134-PC (Exendin-4 :PC-D AC™ and glucose-dependent in suli notropic peptide (GIP)); amylin agonists (e.g. pramlintide, AC-137); insulin secretagogues (e.g. linogliride, nateglinide, repaglinide, mitiglinide calcium hydrate or meglitinide); SGLT-2 inhibitors (e.g. dapagliflozin, sergliflozin, AVE 2268; Glucokinase activators such as the compounds disclosed in e.g. WO 00/58293 Al; anti-obesity agents such as nerve growth factor agonist (e.g. axokine), growth hormone agonists (e.g. AOD-9604), adrenergic uptake inhibitors (e.g. GW-320659), 5-HT (serotonin) reuptake/transporter inhibitors (e.g. Prozac™), 5-HT/NA (serotonin/noradrenaline) reuptake inhibitors (e.g. sibutramine), DA (dopamine) reuptake inhibitors (e.g. bupropion), 5-HT, NA and DA reuptake blockers, steroidal plant extracts (e g. P57), NPY1 or 5 (neuropeptide Y Y1 or Y5) antagonists, NPY2 (neuropeptide Y Y2) agonists, MC4 (melanocortin 4) agonists, CCK-A (cholecystokinin-A) agonists, GHSRla (growth hormone secretagogue receptor) antagonist/inverse agonists, ghrelin antibody, MCH1R (melanin concentrating hormone 1R) antagonists (e g. SNAP 7941), MCH2R (melanin concentrating hormone 2R) agoni st/antagoni sts, H3 (histamine receptor 3) inverse agonists or antagonists, Hl (histamine 1 receptor) agonists, FAS (Fatty acid synthase) inhibitors, ACC-1 (acetyl-CoA carboxylase-1) inhibitors, P3 (beta adrenergic receptor 3) agonists, DGAT-2 (diacylglycerol acyltransferase 2) inhibitors, DGAT-1 (diacylglycerol acyltransferase 1) inhibitors, CRF (corticotropin releasing factor) agonists, Galanin antagonists, UCP-1 (uncoupling protein- 1), 2 or 3 activators, leptin or a leptin derivatives, opioid antagonists, orexin antagonists, BRS3 agonists, GLP-1 (glucagon-like peptide-1) agonists, IL-6 agonists, a-MSH agonists, AgRP antagonists, BRS3 (bombesin receptor subtype 3) agonists, 5-HT1B agonists, POMC antagonists, CNTF (ciliary neurotrophic factor or CNTF derivative), NN2211, topiramate, glucocorticoid antagonist, exendin-4 agonists, 5-HT2C (serotonin receptor 2C) agonists (e.g. lorcaserin), PDE (phosphodiesterase) inhibitors, fatty acid transporter inhibitors, di carboxyl ate transporter inhibitors, glucose transporter inhibitors, CB-1 (cannabinoid- 1 receptor) inverse agonists or antagonists (e.g. SR141716), lipase inhibitors (e.g., orlistat); cyclooxygenase-2 (COX-2) inhibitors (e.g. rofecoxib and celecoxib); thrombin inhibitors (e.g., heparin, argatroban, melagatran, dabigatran); platelet aggregation inhibitors (e.g. glycoprotein Ilb/IIIa fibrinogen receptor antagonists or aspirin); vitamin B6 and pharmaceutically acceptable salts thereof; vitamin B 12; vitamin E; folic acid or a pharmaceutically acceptable salt or ester thereof; antioxidant vitamins such as C and E and beta carotene; beta blockers (e.g. angiotensin II receptor antagonists such as losartan, irbesartan or valsartan; angiotensin converting enzyme inhibitors such as enalapril and captopril; calcium channel blockers such as nifedipine and diltiazem; endothelial antagonists; aspirin; fatty-acid/bile-acid conjugates (aramchol); caspase inhibitors (emricasan); immunomodulators (cenicriviroc, etc.); thyroid hormone receptor modulators (MB07811, MGL-3196, etc.); agents other than LXR ligands that enhance ATP- Binding Cassette Transporter-Al gene expression; and bisphosphonate compounds (e.g., alendronate sodium).

In certain embodiments, the additional active agent is an agent that modifies host metabolism. In certain embodiments, the agent that modifies host metabolism is selected from the group consisting of clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, ritonavir, saquinavir, suboxone, telithromycin, aprepitant, erythromycin, fluconazole, verapamil, diltiazem, cimetidine, amiodarone, boceprevir, chloramphenicol, ciprofloxacin, delavirdine, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, telaprevir, and voriconazole.

In certain embodiments, this disclosure contemplates a kit comprising a pharmaceutical composition or a compound disclosed herein and a container optionally with a suitable diluent. Further components of the kit may be instructions for use, administration means, such as syringes, catheters, brushes, etc. (if the compositions are not already provided in the administration means) or other components necessary for use in medical (surgical) practice, such as substitute needles or catheters, extra vials or further wound cover means. In certain embodiments, the kit comprises a syringe housing the dry and stable hemostatic composition and a syringe containing a diluent (or provided to take up the diluent from another diluent container).

EXAMPLES

Treating or preventing cancer and liver damage

MicroRNA 122 (miR122) is a known tumor suppressive microRNA. Numerous targets of miR122 are involved in tumorigenesis, such as ADAM17 and MDM2 (the regulator of p53). Increasing miR122 levels in the liver will have a negative effect on liver tumor development. In miR122 KO mice liver tumors develop. Interestingly in these KO mice it was observed that the development of fibrosis starts by the age of 2-3 weeks. In addition, numerous liver clinical conditions such as autoimmune liver diseases are associated with a decrease in miR122. These conditions are a risk for the development of primary liver cancers.

Thus, this disclosure contemplates the use of compounds disclosed herein in the context of anti-tumor and anti -metastasis, uses in clinical conditions as cirrhosis to prevent tumor development, use as an anti-fibrosis effect, and uses to reverse chronic liver autoimmune conditions.

Treating or preventing fatty liver disease

An increase in miR122 reverses nonalcoholic fatty liver disease (NASH). It is contemplated that compounds disclosed herein reverse NASH due to increases miR122. Thus, this disclosure contemplates the use of compounds disclosed herein in reversing fatty liver, NASH, and related conditions. Treating or preventing pancreatitis

FGF21 reverses pancreatitis in mice. However, this entails the administration of the FGF21 protein or derivatives. Compounds disclosed herein increase FGF21. FGF21 is predominantly produced by the liver. Thus, this disclosure contemplates the use of compounds disclosed herein in the treatment of acute pancreatitis and for the prevention of the development of acute pancreatitis. In certain embodiments, the patient is exposed to endoscopic retrograde cholangiopancreatography (ERCP) and is administered compounds disclosed herein such as compound 8 to prevent pancreatitis, before or after the ERCP procedure.

Compound (1) chemical name 8-(4-benzylpiperidine-l-carbonyl)-5,10-dihydro-llH-di benzo[b,e][l,4]diazepin-l 1-one

Compound 1 is reported in WO2019/213584.

Synthesis of Methyl 4-fluoro-3-nitrobenzoate (2)

To a solution of 4-fluoro-3-nitrobenzoic acid (10 g, 54 mmol) in methanol (200 mL) was added cone. H2SO4 (0.5 mL) at room temperature. The reaction mixture was heated at 80 °C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, the crude residue was diluted with H2O (200 ml), the white solid was filtered and washed with water and dried in vacuum to afford the desired compound 2 (9.78 mg, 91 %); 'H NMR (400 MHz, DMSO-d6): 8 8.54 (dd, 7.3, 2.3 Hz, 1H), 8.31 (ddd, .7 = 8.8, 4.3, 2.3 Hz, 1H), 7.73 (dd,

J = 11.1, 8.7 Hz, 1H), 3.90 (s, 3H); ¹³C NMR (101 MHz, DMSO-d6): 158.7 , 156.0 , 136.9, 136.8 (d, J= 10.8 Hz), 127.1 (d, J= 1.6 Hz), 126.7 (d, J= 3.9 Hz), 119.4 (d, J= 21.7 Hz), 52.9; ¹⁹F NMR (377 MHz, DMSO-d6) 8 -111.97, MS (IS): 200.1 m/z: [M + 1] Methyl 4-(2-(methoxycarbonyl)phenylthio)-3-nitrobenzoate (4)

To a solution of methyl 4-fluoro-3-nitrobenzoate 2 (5 g, 25 mmol) and methyl 2- mercaptobenzoate (3.74 mL, 27.25 mmol) in DMF (30 mL) was added CS2CO3 (8.14 g, 25 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 4 h and then cooled to room temperature. Ice water was added to induce the precipitation. The precipitate was filtered, washed with water, and dried. Recrystallization from DCM/ hexane gave 7.8 g (90 %) of the title compound as yellow crystals. ^!H NMR (400 MHz, DMSO-de) 8 8.63 (d, J= 2.0 Hz, 1 H), 8.04 (dd, J = 8.4, 1.8 Hz, 1 H), 7.99- 7.88 (m, 1 H), 7.77 - 7.69 (m, 3 H), 7.05 (d, J = 8.6 Hz, 1 H), 3.88 (s, 3 H), 3.71 (s, 3 H). MS (IS): 348.1 m/z: [M + 1]

4-(2-Carboxyphenylthio)-3-nitrobenzoic acid (5)

To a solution of methyl 4-(2-(methoxycarbonyl)phenylthio)-3-nitrobenzoate 4 (6.80 g, 19.5 mmol) in THF (48 mL) and water (48 mL) was added, at room temperature, LiOH (4.67 g, 195 mmol). The reaction mixture was stirred at 60 °C for 2 h. The organic solvent was removed under vacuum and the aqueous solution was washed with EtOAc and acidified with 2 N HCI until pH about 2. The yellow precipitate was filtered, washed with water, and dried to give 5 (5.6 g, 90%) as a yellow solid which was used directly in the next reaction without further purification. 'H NMR (400 MHz, DMSO-de) 8 13.53 (s, 1 H), 13.27 (s, 1 H), 8.58 (d, J = 2.0 Hz, 1 H), 8.01 (dd, J= 8.6, 2.0 Hz, 1 H), 7.85 - 7.95 (m, 1 H), 7.48 - 7.68 (m, 3 H), 7.07 (d, J = 8.6 Hz, 1 H); MS (IS): 320.0 m/z: [M + 1]

3-Ainino-4-(2-carboxy-phenylsulfanyl)-benzoic acid (6)

To a solution of 4-(2-carboxyphenylthio)-3-nitrobenzoic acid 5 (5.26 g, 16.47 mmol) in MeOH (180 mL) was added, at room temperature, platinum (IV) oxide (180 mg) and Pd/C (10%, 362 mg). A balloon containing H2 was connected to the flask and the reaction flask was repeatedly evacuated and refilled with H2. The reaction was stirred under H2 for 16 h before addition of more Pd/C (10%, 362 mg) and additional stirring under H2 for 32 h. The reaction mixture was filtered through a pad of celite and concentrated under vacuum to give 6 (3.80 g, 80%) as a grey-yellow solid which was used directly in the next reaction without further purification. 'H NMR (400 MHz, DMSO-d₆) 8 13.00 (s, 2H), 7.93 (dd, J= 7.7, 1.0 Hz, 1H), 7.42 (s, IH), 7.40-7.31 (m, 2H), 7.18 (t, J = 7.4 Hz, IH), 7.13 (dd, J = 8.0, 1 .6 Hz, IH), 6.61 (d, J = 7.8 Hz, IH), 5.55 (s , 2H); MS (IS): 290.2 m/z: [M + 1] ll-Oxo-10,ll-dihydrodibenzo[b,fI|l,4|thiazepine-8-carboxylic acid (7)

To a solution of 3-amino-4-(2-carboxyphenylthio)benzoic acid 6 (3.42 g, 11.83 mmol) in THF (70 mL) was added, at 0 °C, l,l'-carbonyldiimidazole (CDI) (7.67 g, 47.32 mmol) portionwise. The reaction mixture was warmed and stirred at room temperature overnight. The reaction mixture was poured into 200 mL of ice water before addition of concentrated HCI to reach pH = 2. The precipitate was filtered, washed with water, and dried under vacuum. Precipitation from EtOAc/ DCM/hexane (1/1/5) gave 7 (2.56 g, 80%). 'H NMR (400 MHz, DMSO-d₆) 813.22 (s, IH), 10.81 (s, IH), 7.78 (s, IH), 7.72-7.64 (m, 3H), 7.57-7.44 (m, 3H). MS (IS): 272.1 m/z: [M + 1],

8-(4-benzylpiperidine-l-carbonyl)dibenzo[b,f][l,4]thiazepin-ll(10H)-one (8)

To a stirred solution of compound 7 (1,5 g, 5.53 mmol) in DMF (50 ml) under inert atmosphere, were added EDCI, HCI (1,69 mg, 8.84 mmol), HOBt (1.19 mg, 8.84 mmol), 4- benzylpiperidine (1.29 ml, 7.19 mmol) and DIPEA (2.88 ml, 16.59 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 20 h. After completion of the reaction, water was added and the solid was filtered and washed with water. The crude product was purified by column chromatography eluting with DCM/Methanol (99: 1) to give 8 as a white solid (1.66 mg, 70%); ¹ H NMR (400 MHz, DMSO-de) 8 10.79 (s, IH), 7.70 (dd, J = 7.4, 1.7 Hz, IH), 7.61 (d, J= 7.9 Hz, IH), 7.54 (td, J= 6.8, 6.0, 1.7 Hz, IH), 7.51 - 7.44 (m, 2H), 7.27 (dd, J= 8.4, 6.4 Hz, 2H), 7.21 - 7.11 (m, 5H), 4.49 - 4.35 (m, IH), 3.49 (q, J= 14.8, 14.3 Hz, IH), 2.94 (q, J = 15.3, 10.1 Hz, IH), 2.68 (p, J = 14.9, 13.2 Hz, IH), 2.54 (d, 2H), 1.84 - 1.68 (m, IH), 1.72 - 1.58 (m, IH), 1.49-1.46 (m, IH), 1.21 - 0.99 (m, 2H). MS (IS): 429.1 m/z: [M + 1]; HRMS (ESI) [M + H]+ calcd for C26H25N2O2S 429. 1558, found:429.1628.

Cellular Toxicity Assays

The toxicity of the compound was assessed in human PBM, CEM (human lymphoblastoid), and Huh-7 cells. Cycloheximide was included as positive cytotoxic control, and untreated cells exposed to solvent were included as negative controls. The cytotoxicity IC50 is obtained from the concentration-response curve using the median effective method. The results are shown in Table 1 below:

Table 1 RORa Activity by Luciferase Reporter

Hepal-6 cells were transfected with a luciferase reporter plasmid containing the miR- 122 promoter (extends to -900 from the transcription start site) with intact wild-type (WT) RORa response element (RORE) or mutated RORE (mut). The cells were treated with a compound (compound 8) one day (24 hours) post-transfection at the indicated concentrations. The results are presented in Figure 2. Luciferase expression was measured after 6, 18, 24 and 48 hours of treatment and normalized to Renilla Luciferase activity expressed from a co-transfected pRL plasmid. The pRL Vector, which provides constitutive expression of Renilla luciferase, is used in combination with a firefly luciferase vector to co-transfect cells. Expression of Renilla luciferase provides an internal control value to which expression of the experimental firefly luciferase reporter gene may be normalized. A dose-dependent increase of luciferase expression for a compound indicates use on WT RORE. Mutating the RORE negates activity of a compound. Data indicates RORa activity of a compound as an agonist. Similar results were obtained in HUH-7 cells. This assay can be used to evaluate other compounds described herein. Where compounds increase luciferase expression, they are RORa agonists, and where they decrease luciferase expression, they are RORa antagonists (or partial agonists or allosteric inhibitors).

Expression of RORa-regulated microRNA

Hepal-6 cells were treated with 30 pM of a compound (compound 8) or vehicle (DMSO) for 24 hours. The results are presented in Figure 3. Secreted microRNA levels (pre-miR-122) in the medium of Hepal-6 cells were analyzed by qRT-PCR and were normalized to HPRT.

Long-term Effect of Compound 8 on the Expression of RORa-regulated microRNA

For evaluation of the long-term effect of compound 8, mice were injected with 30 mg/kg twice a week for two weeks. Plasma miR-122 levels were determined by qRT-PCR and normalized to spiked in C. elegans miR-39. Data indicated that the long-term administration of the compound, upregulated miR-122 secretion. (Fig. 9).

Modulation of Thl7 Populations

Human peripheral blood mononuclear cells (PBMCs) are isolated from four healthy donors. Four experiments are conducted and analyzed by flow cytometry over a 3-day assay. The control group had no drug treatment, a second were treated with 10 pM of compound, a third group is stimulated with PHA/IL-2 without treatment, and the fourth group is stimulated with PHA/IL-2 and incubated with 10 pM the compound. Data indicates compounds have no effect on total viability of CD4+ T cells even under PHA/IL-2 stimulation. Further, the compound has no effect on Thl7 populations in the absence of PHA/IL-2 stimulation. The compound decreases Th 17 total population in PBM cells relative to vehicle-control in the presence of PHA/IL-2 stimulation.

Modulation of RORa-Regulated Genes in C57BL/6 Mice

Healthy C57BL/6 mice were injected i.p. once with compound 8, at different concentrations, or solvent control, and the modulation of various RORa-regulated genes was detected, specifically pre-miR-122 in liver (Fig. 4), miR-122 in liver (Fig. 5), AldoA in liver (Fig.12), AldoA in kidney (Fig. 13A), Epo in kidney (Fig. 13B). For evaluation of mature miR-122, Pri-miR-122, pre-miR-122 and FGF21 liver expression, mice were injected with 15, 30 or 45 mg/kg of compound or solvent control. Mice were sacrificed at 24, 48 and 72 hours post-injection (Fig. 4). Mature miR-122, Pri-miR-122, pre-miR-122 and FGF21 levels were determined by qRT-PCR for each time point. MicroRNA levels were normalized to RNU6, mRNA levels were normalized to HPRT. Data indicates that after administration of the compound, mature miR-122 levels, pri-miR-122 and FGF21 levels were increased after injection of 45 mg/kg. In addition, pre-miR-122 and FGF21 levels were also increased further to injection of 15 and 30 mg/kg, respectively.

FGF21 has been shown to have beneficial pharmacological effects on Type 2 Diabetes, obesity, and NAFLD. A single injection of FGF21 in obese (ob/ob) mice and DIO mice, can cause a rapid reduction in blood glucose and plasma insulin levels. Therefore, by inducing the increase on FGF21 levels, compound 8 may be used in the treatment of diabetes, obesity and NAFLD (e g. NASH).

Plasma miR-122 was normalized to spiked in C. elegans miR-39; and mRNA levels are normalized to HPRT. Data indicates that after administration of the compound, miR-122 levels are increased in plasma and liver post-injection. Data not shown. Further, the RORa-regulated gene Gpase6 is significantly up-regulated up to 7 days post-injection.

For evaluation of AldoA expression in liver (Fig. 12) or kidney (Fig. 13A), mice were injected with 30 mg/kg of compound or solvent control. Mice were sacrificed at 24-, 48- and 72-hours post-injection. AldoA mRNA levels were determined by qRT-PCR for each time point and normalized to HPRT. Data indicates that after administration of the compound, AldoA mRNA levels were increased after 24 hours in liver (Fig.12) or after 48 and 72 hours in kidney (Fig. 13 A).

For evaluation of Epo expression in kidney (Fig. 13B), mice were injected with 30 mg/kg of compound or saline control. Mice were sacrificed at 24-, 48- and 72-hours post-injection. Epo mRNA levels were determined by qRT-PCR for each time point and normalized to HPRT. Data indicates that after administration of the compound, Epo mRNA levels were decreased after 72 hours (Fig. 13B). Effect of RORa Modulation in a Pancreatitis Mice Model

Pancreatitis was induced in C57BL/6 mice by caerulein administration (50 pg/kg, 7 ip injections), as shown in Fig. 10A. In addition, the mice were injected with 30 mg/kg of compound 8 or with solvent solution, twice at 2h intervals, at time 0 and after 2 hours. The results show that hepatic pre-miR-122 mRNA and plasma FGF21 were elevated (Fig. 10B), while myeloperoxidase (MPO) levels were decreased after compound 8 injection (Fig. 10C). These results are consistent with compound 8 reversing pancreatitis 12h post injection.

Furthermore, Figure 11 shows data indicating compound 8 elevates FGF21, pre-miR122 and pri-miR122 in the liver of caerulein-induced pancreatitis mice,18h post injection.

Weight loss in High-Fat-Diet C57BL/6 Mice is Due to RORa Modulation

C57BL/6 mice are fed a 50% high fat diet (HFD) for four weeks. The control cohort receives three hydrodynamic tail vein injections of a 5 pg anti-miR-control and six i.p injections of saline over three weeks. A second cohort is hydrodynamic tail vein injected with 5 pg ant- miR-122 (the reverse complement that inhibits activity of miR-122) three times and i.p injections of saline six times over three weeks. A third cohort is injected i.p. with a compound (7.5 mg/kg) twice a week plus anti-miR-control once a week over the course of 3 weeks. The final cohort is injected i.p. with the compound (7.5 mg/kg) twice a week plus ant-miR-122 injections once a week over the course of 3 weeks.

When injected only with ant-miR-control, mice go from approximately 28 g to 30 g over the course of the treatment. Treatment with anti-miR-122 results in a larger weight gain to a final body weight of 32 g. The group treated with the compound and anti-miR-control have statistically lower body weight at the end of the experiment compared to the control group (lacking the compound). Co-administration of the and anti-mir-122 does not decrease body weight. Secretion of miR-122 is enhanced when treated with the compound, which could be reduced to baseline levels with co-administration of anti-mir-122. These results suggest that body weight loss is specifically due to the compound modulated secretion of miR-122.

Modulation of Liver Triglycerides and Lipid Accumulation in Sgpl30FC Mice

Sgpl30FC mice specifically blocks IL-6 trans-signaling without affecting classic IL-6 signaling. These mice are useful models for non-alcoholic steatohepatitis (NASH) since they exhibit symptoms of the disease including hepatomegaly, steatosis, and liver inflammation. Nine-month-old Sgpl30FC mice are injected i.p. with a compound (7.5 mg/kg) or vehicle control twice a week for four weeks (total of 8 injections). The mice are sacrificed after 4 weeks, triglyceride levels are measured from liver and skeletal muscle and hepatic lipid accumulation is visualized using H&E staining.

Treatment with a compound significantly reduces liver triglyceride levels by approximately 3-fold. Without treatment (injection of saline control), lipid droplets accumulate in the liver visualized as white blobs in H&E staining. Treatment with a compound markedly reduces lipid accumulation and droplet formation in mice.

Test compounds and Anti-miR injections to mice.

C57BL/6 male mice, 7-8 weeks old, or Sgpl30FC, 9-month-old male mice, are injected i.p. with 7.5 mg/kg compound dissolved in saline and 3% DMSO. Saline is injected as control. Mice are hydrodynamic tail vain injected with antagomiR-122 or anti-miR-control (negative control) (5pg/mouse in E5ml saline). Mice are sacrificed.

Nonalcoholic fatty liver disease (NAFLD)

NAFLD is a major healthcare burden and is associated with the metabolic syndrome, the most prevalent and significant western world clinical epidemic. NAFLD that develops to nonalcoholic steatohepatitis (NASH) has no therapy currently, in spite of major efforts. Reduction of hepatic miR-122 causes liver NASH. The mechanism of miR-122 regulation in the liver was investigated. RORa is an activator of miR-122. The RORa activator compound was selected based on its effect on increasing miR-122 levels in the liver, plasma and “remote” tissues for beneficial effects. In NASH models, it is contemplated that compounds reverse histological manifestations of NASH including steatosis, inflammation, and fibrosis. These effects were also associated with beneficial metabolic effects and a reduction in body weight. RORa agonists are therefore proposed as drugs to treat, prevent, and/or reverse NASH.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (A):

Formula (A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: one of X and Z is selected from the bridging group consisting of -NH-, -N(NH₂)-, -NH(OH)-, -N(Ci-io alkyl)-, -N(C₃-IO cycloalkyl)-, -N(C₂-IO alkenyl)-, -N(C₂-IO alkynyl)-,

-O-, -CH2-, -CH(Ci-io alkyl)-, -C(Ci-io alkyl)₂-, -CH(C₃-IO cycloalkyl)-, -CH(C₂-IO alkenyl)-, -CH(C₂-IO alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF2-, -CCI2-, -CH(CF₃)-, -CH(OH)-, -CH(O- C1-10 alkyl)-, -CH(NH₂)-, -CH(NH-CI-IO alkyl)-, and -CH(C(O)NH₂)-, and the other one of X and Z is selected from the group consisting of -C(O)-, -SO₂-, -NH(C(O))-, -CH₂-, -CH(CI-IO alkyl)-, -C(Ci-io alkyl)₂-, -CH(C₃-IO cycloalkyl)-, -CH(C₂-IO alkenyl)-, -CH(C₂-IO alkynyl)-, -CH(aryl)-, -CH(heteroaryl)-, -CF₂-, -CC1₂-, -CH(CF₃)-, -CH(OH)-, -CH(O-alkyl)-, -CH(NH₂)-, -CH(NHCi-io alkyl)-, and -CH(C(O)NH₂)-; A and B are, independently, a phenyl ring, a five-membered heteroaromatic ring containing one, two or three nitrogen, oxygen, or sulfur atoms, or a six-membered heteroaromatic ring containing one, two or three nitrogen atoms; u and v are independently 0, 1, 2, 3 or 4 substituents other than hydrogen; wherein optionally that at least one of u and v is 1, 2, 3, or 4;

R¹’ and R²’ are independently hydrogen, Ci-io alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴;

R⁴’ is hydrogen, -COOH, -CH2-COOH;

R²” is hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl; n is 1, 2, 3, 4 or 5;

D is O, S, NH or CH2;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH2-COOH; each R¹ and R² are independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³, -C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH2, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)₂, -NR³C(O)N(R³)2, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)2, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO2NH2, -SO2NHR³, -SO₂N(R³)2, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)₂, -C(N)OH, -C(N)OCH3, -CN, -N3, -NO2, -CF3, -CF2CF3, -OCF3, -OCF2CF3, halogen (F, Cl, Br, or I), -CH2-phosphonate, -CH2O-phosphate, -CH₂P(O)(OH)₂, -CH₂P(O)(OR³)2, -CH₂P(O)(OR³)(NR³), -CH₂P(O)(NR³)2,

-CH₂P(0)(OH)(OCI-IO alkyl-O-Ci -20 alkyl), or -CH2-cycloSal monophosphate prodrug; and when two R^s and two R²s are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, Ci-io alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴; each R⁴ are independently C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, arylalkyl, alkylaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, -OH, -NH2, -C(O)NH₂, -C(O)NHOH, -SO2NH2, -COOH, -C(O)H, -C(N)NH₂, -C(N)OH, -CN, -N3, -NO2, -CF3, -CF2CF3, -OCF3, -OCF₂CF₃, halogen (F, Cl, Br, or I), -P(O)(OH)₂, -P(0)(OH)(OCI-IO alkyl-O-Ci-20 alkyl), -CH₂P(O)(OH)₂, -CH₂P(O)(OR⁵)₂, -CH₂P(O)(OR⁵)(NR⁵), -CH₂P(O)(NR⁵)₂, -CH₂P(0)(OH)(OCI-IO alkyl-O-Ci-20 alkyl), and -CH₂- cycloSal monophosphate prodrugs; each R⁵ is independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)₂amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; and each R⁷ and R⁸ are independently H, CH3, naturally or non-naturally occurring amino acid substituents, chain groups, e.g., hydrogen, methyl, isopropyl, sec-butyl, -CH₂CH(CH3)₂, benzyl, p -hydroxy benzyl, -CH2OH, -CH(OH)CH3, -CH₂-3 -indoyl, -CH₂COOH, -CH2CH2COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH2SH, -CH₂CH₂SCH3, -(CH₂)₄NH₂, -(CH₂)3NHC(=NH)NH₂, or -CH₂-3-imidazoyl, or R⁸ and the NH₂ bound to the same carbon R⁸ is covalently bonded to come together to form a 2-pyrrolidinyl ring, wherein R⁷ and R⁸ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R⁹;

R⁹ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)₂amino, alkanoyl, alkoxy carbonyl, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R⁹ is optionally substituted with one or more, the same or different, R¹⁰; and R¹⁰ is halogen, nitro, cyano, hydroxy, tri fluorometh oxy, tri fluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N, bidi ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

2. The compound of claim 1, wherein one of X and Z is -C(O)-, -SO2-, or -NH(C(O))-, and the other is -NH-, -N(NH2)-, -NH(OH)-, -N(Ci-io alkyl)-, -N(C3-IO cycloalkyl)-, .

3. A compound of Formula (B):

Formula (B) or a pharmaceutically acceptable salt or prodrug thereof, wherein: A and B are, independently, a phenyl ring, a five-membered heteroaromatic ring containing one, two or three nitrogen, oxygen, or sulfur atoms, or a six-membered heteroaromatic ring containing one, two or three nitrogen atoms;

R⁴’ is hydrogen, -COOH, -CH2-COOH;

D is O, S, NH or CH2;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH2-COOH; u and v are independently 0, 1, 2, 3 or 4 substituents other than hydrogen; wherein optionally that at least one of u and v is 1, 2, 3, or 4; each R¹ and R² are independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³, -C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH2, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)₂, -NR³C(O)N(R³)2, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)2, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO2NH2, -SO2NHR³, -SO₂N(R³)2, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)2, -C(N)OH, -C(N)OCH₃, -CN, -N3, -NO2, -CF3, -CF2CF3, -OCF3, -OCF2CF3, halogen (F, Cl, Br, or I), -CH2-phosphonate, -CH2O-phosphate, -CH₂P(O)(OH)2, -CH₂P(O)(OR³)2, -CH₂P(O)(OR³)(NR³), -CH₂P(O)(NR³)2,

-CH₂P(0)(OH)(OCI-IO alkyl-O-Ci -20 alkyl), or -CH2-cycloSal monophosphate prodrug; and when two R³s and two R²s are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, each of which is unsubstituted or independently substituted with one or more substituents selected from the group consisting of R⁴; each R⁴ are independently Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, arylalkyl, alkylaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkenyl, -OH, -NH2, -C(O)NH₂, -C(O)NHOH, -SO2NH2, -COOH, -C(O)H, -C(N)NH₂, -C(N)OH, -CN, -N3, -NO2, -CF3, -CF2CF3, -OCF3, -OCF2CF3, halogen, -P(O)(OH)₂, -P(0)(OH)(OCi-io alkyl-O-Ci-20 alkyl), -CH₂P(O)(OH)₂, -CH₂P(O)(OR⁵)₂,

-CH₂P(O)(OR⁵)(NR⁵), -CH₂P(O)(NR⁵)₂, -CH₂P(O)(OH)(OCI-10 alkyl-O-Ci-20 alkyl), and -CH₂- cycloSal monophosphate prodrugs; each R⁵ is independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)₂amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; and each R⁷ and R⁸ are independently H, CH3, naturally or non-naturally occurring amino acid substituents, chain groups, e.g., hydrogen, methyl, isopropyl, sec-butyl, -CH₂CH(CH3)₂, benzyl, p-hydroxybenzyl, -CH₂OH, -CH(0H)CH3, -CH₂-3 -indoyl, -CH₂COOH,

-CH₂CH₂COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH₂SH, -CH₂CH₂SCH₃, -(CH₂)₄NH₂, -(CH₂)3NHC(=NH)NH₂, or -CH₂-3-imidazoyl, or R⁸ and the NH₂ bound to the same carbon R⁸ is covalently bonded to come together to form a 2-pyrrolidinyl ring, wherein R⁷ and R⁸ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R⁹;

R¹⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- di ethyl carbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

4. The compound of claims 1-3, wherein one of R¹ and R² is C(0)NHR3, C(O)N(R³)2, or C(O)R³.

5. The compound of claims 1-3, wherein one of R¹ and R² is C(0)NHR3, C(O)N(R³)2, or C(O)R³ and R³ is C3-10 cycloalkyl, substituted with one or more, the same or different, R⁴.

6. The compound of claims 1-3, wherein one of R¹ and R² is selected from: wherein R⁴ is C1-10 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 halo alkyl, C1-10 alkyl-aryl, or C1-10 haloalkyl-aryl and m is 0, 1, 2, 3 or 4.

7. The compound of claim 1 having Formula (C):

Formula (C) or a pharmaceutically acceptable salt or prodrug thereof wherein, Q is N or CH;

V is -CH2CH2-, -CH2-, or a bond from Q to the methylene (CH2) bridge;

W is -CH2CH2-, -CH2-, or a bond from Q to the carbon bonded to R¹¹;

R¹⁸ is selected from hydrogen, -NH2, -OH, -C1-10 alkyl, -C3-10 cycloalkyl, -C2-10 alkenyl, -C2-10 alkynyl, -aryl, -heteroaryl, benzoyl, benzyl, alkoxy, thioalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, phosphate, wherein R¹⁸ is optionally substituted with one or more, the same or different, R¹⁹; wherein each R¹ is independently -OH, -OR³, -SR³, -S(O)R³, -SO2R³, -C(O)R³,

-C(O)OR³, -OC(O)R³, -OC(O)OR³, -NH2, -NHR³, -NHC(O)R³, -NR³C(O)R³, -NHS(O)₂R³, -NR³S(O)₂R³, -NHC(O)OR³, -NR³C(O)OR³, -NHC(O)NH₂, -NHC(O)NHR³, -NHC(O)N(R³)₂, -NR³C(O)N(R³)₂, -C(O)NH₂, -C(O)NHR³, -C(O)N(R³)₂, -C(O)NHOH, -C(O)NHOR³, -C(O)NHSO₂R³, -C(O)NR³SO₂R³, -SO₂NH₂, -SO₂NHR³, -SO₂N(R³)₂, -COOH, -C(O)H, -C(N)NH₂, -C(N)NHR³, -C(N)N(R³)2, -C(N)OH, -C(N)OCH₃, -CN, -N3, -NO2, -CF3, -CF2CF3,

-OCF3, -OCF2CF3, halogen (F, Cl, Br, or I), -CH2-phosphonate, -CH2O-phosphate, -CH₂P(O)(OH)₂, -CH₂P(O)(OR³)₂, -CH₂P(O)(OR³)(NR³), -CH₂P(O)(NR³)2,

-CH₂P(0)(OH)(OCI-IO alkyl-O-Ci -20 alkyl), or -CH2-cycloSal monophosphate prodrug; and when two R's are on adjacent carbons, they can come together to form a saturated or unsaturated carbocyclyl, heterocyclyl, aryl or a heteroaryl; each R³ is, independently hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 heterocycloalkyl, or C3-10 heterocycloalkenyl;

R⁴’ is hydrogen, -COOH, -CH2-COOH;

D is O, S, NH or CH₂;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH2-COOH;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are individually selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2- 10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are optionally substituted with one or more, the same or different, R¹⁹; and

R¹⁹ is Ci-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl )2ami no, alkanoyl, alkoxycarbonyl, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R¹⁹ is optionally substituted with one or more, the same or different, R²⁰; and

R²⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

8. The compound of claim 1 having Formula (D):

Formula (D) or a pharmaceutically acceptable salt or prodrug thereof wherein,

Q is N or CH;

V is -CH2CH2-, -CH2-, or a bond from Q to the methylene (CH2) bridge;

W is -CH2CH2-, -CH2-, or a bond from Q to the carbon bonded to R¹⁰;

Y is O, S, or NH;

C ring is a saturated or unsaturated carbocyclyl heterocyclyl, or a heteroaryl;

R⁴’ is hydrogen, -COOH, -CH₂-COOH;

D is O, S, NH or CH₂;

R⁶’ and R⁷’ are independently hydrogen, -COOH or -CH₂-COOH; R¹⁹ is Ci-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl )2ami no, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R¹⁹ is optionally substituted with one or more, the same or different, R²⁰; and

9. The compound of claim 1 having Formula (E):

Formula (E) or a pharmaceutically acceptable salt or prodrug thereof wherein,

Q is N or CH;

V is -CH2CH2-, -CH2-, or a bond from Q to the methylene (CH2) bridge;

W is -CH2CH2-, -CH2-, or a bond from Q to the carbon bonded to R¹¹; Y is O, S, or NH;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are individually selected from hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are optionally substituted with one or more, the same or different, R¹⁹;

R²⁰ is Ci -10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one or more, the same or different, R²¹;

R²¹ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl;

R²² and R²³ are independently H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CHs)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH₂)₄NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R²³ and the NH2 form a 2-pyrrolidinyl ring, wherein R²² or R²³ and the 2-pyrrolidinyl ring are optionally substituted with one or more, the same or different R²⁴;

R²⁴ is Ci -10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl )2ami no, alkanoyl, alkoxycarbonyl, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R²⁴ is optionally substituted with one or more, the same or different, R²⁵; and

R²⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, tri fluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tertbutoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethyl sulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethylsulfamoyl, N,N- di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl.

10. A compound of claim 1 selected from:

8-(4-benzylpiperi dine- l-carbonyl)dibenzo[b,f][l,4]thi azepin- 1 l(10H)-one;

8-(4-benzylcy clohexane-l-carbonyl)dibenzo[b,f][l,4]thi azepin- 11(10H)-one; 8-((4-benzylpiperidin-l-yl)sulfonyl)dibenzo[b,f][l,4]thiazepin-l l(10H)-one;

8-(4-(2-phenylpropan-2-yl)piperidine- l-carbonyl)dibenzo[b,f][l,4]thi azepin- 11 (10H)- one;

8-(4-(difluoro(phenyl)methyl)piperidine- 1 -carbonyl)dibenzo[b,f] [ 1 ,4]thiazepin- l l(10H)-one;

8-(4-phenethylpiperidine-l-carbonyl)dibenzo[b,f][l,4]thiazepin-l l(10H)-one;

(8-(4-benzylpiperidine-l-carbonyl)-l l-oxodibenzo[b,f][l,4]thiazepin-10(l 1H)- yl)methyl dihydrogen phosphate (8-(4-benzylpiperidine-l -carbonyl)-! l -oxodibenzo[b,f][l ,4]thiazepin-l 0(11H)- yl)methyl L-alaninate;

(8-(4-benzylpiperidine- 1 -carbonyl )- 11 -oxodibenzo[b,f] [ 1 ,4]thiazepin- 10(11 H)- yl)methyl D-alaninate;

(8-(4-benzylpiperidine-l-carbonyl)-l l-oxodibenzo[b,f][l,4]thiazepin-10(l 1H)- yl)methyl 2-amino-2-methylpropanoate;

(8-(4-benzylpiperidine-l-carbonyl)-l l-oxodibenzo[b,f][l,4]thiazepin-10(l 1H)- yl)methyl 2-amino-2-methylbutanoate, or a pharmaceutically acceptable salt or prodrug thereof.

11. A pharmaceutical composition comprising a compound of any of claims 1-10 and a pharmaceutically acceptable carrier or excipient.

12. The pharmaceutical composition of claim 11 in the form of a pill, capsule, tablet, particles, powder, lotion, or gel.

13. The pharmaceutical composition of claim 11 in the form of a neutral pH buffered solution optionally comprising isotonic saline or a pharmaceutically acceptable mono or polysaccharide.

14. The pharmaceutical composition of claim 11, wherein the composition is a transdermal composition or a nanoparticulate composition.

15. The pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.

16. The pharmaceutical composition of claim 11 further comprising a second active agent.

17. The production of a medicament comprising compound as provided in any of claims 1- 10 useful in the treatment, prevention, of management of a disease of condition associated with Retinoic Acid Receptor-like Orphan Receptor (ROR), liver disease, diabetes, obesity, cancer, pancreatitis, metabolic disorder, immune disorders, CNS disorders or diseases, tumor development, and cancer.

18. A method of treating or preventing liver disease comprising administering an effective amount of a compound as provided in claims 1-10 or a pharmaceutical composition as provided in claims 11-16 to a subject in need thereof.

19. The method of claim 18, wherein the subject is exhibiting symptoms of, at risk of, or diagnose with liver disease, liver cancer, cirrhosis of the liver, hepatic encephalopathy, ascites, peripheral oedema, portal hypertension, variceal bleeding, inflammation in the liver, or vitamin deficiency.

20. A method of treating or preventing cancer or retarding tumor growth comprising administering an effective amount of a compound as provided in claims 1-10 to a subject in need thereof.

21. The method of claim 20, wherein the cancer is a FGF21 -associated cancer.

22. The method of claim 20, wherein the cancer is liver cancer.

23. A method of treating or preventing pancreatitis comprising administering an effective amount of a compound as provided in claims 1-10 or a pharmaceutical composition as provided in claims 11-16 to a subject in need thereof.

24. The method of claim 23, wherein the patient is exposed to endoscopic retrograde cholangiopancreatography (ERCP).

25. The method of any of claims 18-24, wherein administering an effective amount of a compound as provided in claims 1-10 or a pharmaceutical composition as provided in claims 11- 16 is in combination with a second active agent.