Compositions and methods for treating metabolic disorders

Abstract

The present disclosure provides methods for treating metabolic disorders. The methods generally involve administering an effective amount of a compound of Formula I to an individual in need thereof. TIFF2025526296000008.tif33138

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 393,585, filed July 29, 2022, which is incorporated herein by reference in its entirety.

[0002] introduction Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of liver disease worldwide. Clinically, NAFLD describes a continuum of hepatic events ranging from moderate lipid accumulation to more aggressive steatosis accompanied by inflammation, ballooning hepatocytes, fibrosis, cirrhosis, and in some cases, hepatocellular carcinoma (HCC). Excessive lipid accumulation is a major risk factor for disease progression from clinically asymptomatic NAFLD to the inflammatory, fibrotic, and cirrhotic stages of nonalcoholic steatohepatitis (NASH).

[0003] Metabolic disorders such as insulin resistance, hyperglycemia, type 2 diabetes mellitus, obesity, fatty liver disease, glucose intolerance, hyperinsulinemia, metabolic syndrome, and hypertension are major health challenges.

[0004] There is a need in the art for methods for treating metabolic disorders. Summary of the Invention

[0005] overview The present disclosure provides methods for treating metabolic disorders, which generally involve administering an effective amount of a compound of Formula I to an individual in need thereof. [Brief explanation of the drawings]

[0006] [Figure 1] 1A-1C illustrate the dose-dependent effects of TOFA treatment in mice with the progression of CDAHFD-induced NAFLD. [Figure 2A]2A-2I illustrate the effect of TOFA treatment on the progression of 60% kcal fat diet-induced metabolic syndrome and early NAFLD. [Figure 2B] See legend to Figure 2A. [Figure 2C] See legend to Figure 2A. [Figure 2D] See legend to Figure 2A. [Figure 2E] See legend to Figure 2A. [Figure 2F] See legend to Figure 2A. [Figure 2G] See legend to Figure 2A. [Figure 2H] See legend to Figure 2A. [Figure 2I] See legend to Figure 2A. [Figure 3A] 3A-3F show the rescue effect of TOFA treatment on the progression of CDAHFD-induced late-stage NAFLD / NASH in mice. [Figure 3B] See legend to Figure 3A. [Figure 3C] See legend to Figure 3A. [Figure 3D] See legend to Figure 3A. [Figure 3E] See legend to Figure 3A. [Figure 3F] See legend to Figure 3A. [Figure 4A] 4A-4E show the results of RNA sequencing of liver samples from mice treated with TOFA derived from CDAHFD-induced late stage NAFLD / NASH. [Figure 4B] See legend to Figure 4A. [Figure 4C] See legend to Figure 4A. [Figure 4D] See legend to Figure 4A. [Figure 4E] See legend to Figure 4A. [Figure 5A] 5A-5G illustrate the safety and tolerability profile of TOFA treatment in mice fed ad libitum chow. [Figure 5B] See legend to Figure 5A. [Figure 5C] See legend to Figure 5A. [Figure 5D] See legend to Figure 5A. [Figure 5E] See legend to Figure 5A. [Figure 5F] See legend to Figure 5A. [Figure 5G] See legend to Figure 5A. [Figure 6A] 6A-6H illustrate the dose-dependent effects of TOFA treatment in mice with diet-induced obesity using a 60% HFD dietary model. [Figure 6B] See legend to Figure 6A. [Figure 6C] See legend to Figure 6A. [Figure 6D] See legend to Figure 6A. [Figure 6E] See legend to Figure 6A. [Figure 6F] See legend to Figure 6A. [Figure 6G] See legend to Figure 6A. [Figure 6H] See legend to Figure 6A. [Figure 7A] 7A-7D show transcriptional analysis of genes altered in liver by TOFA treatment in a 60% HFD diet-induced obesity mouse model. [Figure 7B] See legend to Figure 7A. [Figure 7C] See legend to Figure 7A. [Figure 7D] See legend to Figure 7A. [Figure 8A] 8A-8I show a detailed analysis of the efficacy of TOFA treatment in a CDAHFD diet-induced mouse model of NAFLD / NASH. [Figure 8B] See legend to Figure 8A. [Figure 8C] See legend to Figure 8A. [Figure 8D] See legend to Figure 8A. [Figure 8E] See legend to Figure 8A. [Figure 8F] See legend to Figure 8A. [Figure 8G] See legend to Figure 8A. [Figure 8H] See legend to Figure 8A. [Figure 8I] See legend to Figure 8A. [Figure 9A] 9A-9I show a comparison of the benchmark efficacy of TOFA compared to vehicle control, filsocostat, fenofibrate, and the combination treatment of filsocostat and fenofibrate. [Figure 9B] See legend to Figure 9A. [Figure 9C] See legend to Figure 9A. [Figure 9D] See legend to Figure 9A. [Figure 9E] See legend to Figure 9A. [Figure 9F] See legend to Figure 9A. [Figure 9G] See legend to Figure 9A. [Figure 9H] See legend to Figure 9A. [Figure 9I] See legend to Figure 9A. [Figure 10A] Figures 10A-10I show treatment efficacy studies of TOFA and semaglutide as monotherapies and in combination. [Figure 10B] See legend to Figure 10A. [Figure 10C] See legend to Figure 10A. [Figure 10D] See legend to Figure 10A. [Figure 10E] See legend to Figure 10A. [Figure 10F] See legend to Figure 10A. [Figure 10G] See legend to Figure 10A. [Figure 10H] See legend to Figure 10A. [Figure 10I]See legend to Figure 10A. [Figure 11A] Figures 11A-11P show the effects of TOFA in a genetic PPARA knockout model on both the CDAHFD diet-induced model of NAFLD / NASH and the 60% kcal fat (HFD) diet-induced model of DIO, respectively. [Figure 11B] See legend to Figure 11A. [Figure 11C] See legend to Figure 11A. [Figure 11D] See legend to Figure 11A. [Figure 11E] See legend to Figure 11A. [Figure 11F] See legend to Figure 11A. [Figure 11G] See legend to Figure 11A. [Figure 11H] See legend to Figure 11A. [Figure 11I] See legend to Figure 11A. [Figure 11J] See legend to Figure 11A. [Figure 11K] See legend to Figure 11A. [Figure 11L] See legend to Figure 11A. [Figure 11M] See legend to Figure 11A. [Figure 11N] See legend to Figure 11A. [Figure 11O] See legend to Figure 11A. [Figure 11P] See legend to Figure 11A.

[0007] definition The terms "diabetes" and "diabetic" refer to a progressive disease of carbohydrate metabolism accompanied by insufficient production or utilization of insulin, which is often characterized by hyperglycemia and glycosuria. The terms "prediabetes" and "prediabetic" refer to a current state in which a subject does not have the characteristics, symptoms, and the like typically observed in diabetes, but has the characteristics, symptoms, and the like that can progress to diabetes if left untreated. The existence of these conditions can be determined, for example, using either fasting plasma glucose (FPG) test or oral glucose tolerance test (OGTT). Both usually require the subject to fast for at least 8 hours before the start of the test. In FPG test, the subject's blood glucose is measured after fasting; generally, the subject fasts overnight, and blood glucose is measured in the morning before the subject eats. Healthy subjects typically have FPG concentrations of about 90 to about 100 mg / dl, subjects with "prediabetes" typically have FPG concentrations of about 100 to about 125 mg / dl, and subjects with "diabetes" typically have FPG levels above about 126 mg / dl. In an OGTT, a subject's blood glucose is measured after fasting and again two hours after consuming a glucose-rich beverage. Two hours after consuming the glucose-rich beverage, healthy subjects typically have blood glucose concentrations below about 140 mg / dl, prediabetic subjects typically have blood glucose concentrations of about 140 to about 199 mg / dl, and diabetic subjects typically have blood glucose concentrations of about 200 mg / dl or greater. The blood glucose levels noted above pertain to human subjects; whereas, in murine subjects, normoglycemia, moderate hyperglycemia, and frank hyperglycemia are measured differently. After a 4-hour fast, healthy murine subjects typically have FPG concentrations of about 100 to about 150 mg / dl, murine subjects with "pre-diabetes" typically have FPG concentrations of about 175 to about 250 mg / dl, and murine subjects with "diabetes" typically have FPG concentrations greater than about 250 mg / dl.

[0008] The term "insulin resistance" as used herein refers to a condition in which normal amounts of insulin fail to produce a normal physiological or molecular response. In some cases, excess physiological amounts of insulin, either endogenously produced or exogenously administered, can overcome insulin resistance in whole or in part and produce a biological response.

[0009] The term "metabolic syndrome" refers to a collection of related traits, including but not limited to hyperinsulinemia, abnormal glucose tolerance, obesity, redistribution of fat to the abdominal or upper body compartment, hypertension, dysfibrinolysis, and dyslipidemia characterized by high triglycerides, low high-density lipoprotein (HDL) cholesterol, and high small low-density lipoprotein (LDL) particles. Subjects with metabolic syndrome are at risk of developing type 2 diabetes and / or other disorders (e.g., atherosclerosis).

[0010] The term "disordered glucose metabolism" encompasses any disorder characterized by a clinical symptom or combination of clinical symptoms associated with elevated levels of glucose and / or elevated levels of insulin in a subject compared to a healthy individual. Elevated levels of glucose and / or insulin can be manifested in the following diseases, disorders, and conditions, among others: hyperglycemia, type 2 diabetes, gestational diabetes, type 1 diabetes, insulin resistance, impaired glucose tolerance, hyperinsulinemia, impaired glucose metabolism, prediabetes, other metabolic disorders (such as metabolic syndrome, also known as syndrome X), and obesity. Polypeptides of the present disclosure and compositions thereof can be used, for example, to achieve and / or maintain glucose homeostasis, e.g., to reduce glucose levels and / or reduce insulin levels in the bloodstream to the range found in a healthy subject.

[0011] As used herein, the term "hyperglycemia" refers to a condition in which an elevated amount of glucose circulates in the plasma of a subject compared to a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including measuring fasting blood glucose levels as described herein.

[0012] As used herein, the term " hyperinsulinemia " refers to the state in which circulating insulin level is elevated, and blood glucose level is either elevated or normal when it is accompanied.Hyperinsulinemia can be caused by the insulin resistance associated with dyslipidemia, such as high triglycerides, high cholesterol, high low-density lipoprotein (LDL) and low high-density lipoprotein (HDL); high uric acid level; polycystic ovarian syndrome; type 2 diabetes and obesity.Hyperinsulinemia can be diagnosed as having a plasma insulin level higher than about 2 μU / mL.

[0013] As used herein, the phrase "weight disorder" refers to a condition associated with excess weight and / or increased appetite.Compared with a reference healthy individual, various parameters are used to determine whether a subject is overweight, including the subject's age, height, sex, and health status.For example, a subject can be considered overweight or obese by assessing the subject's body mass index (BMI), which is calculated by dividing the subject's weight in kilograms by the square of the subject's height in meters.About 18.5 kg / m 2 ~Approx. 24.9kg / m 2 Adults with a BMI in the range of approximately 25 kg / m are considered to have normal weight. 2 ~Approx. 29.9kg / m 2 An adult with a BMI of approximately 30 kg / m2 can be considered overweight (pre-obese). 2Adults with BMI of 100 or higher can be considered obese.Increased appetite is often a contributing factor to excess weight.There are some conditions associated with increased appetite, such as night-time eating syndrome, which is characterized by poor appetite in the morning and overeating at night, and is often accompanied by insomnia, and may be related to damage to the hypothalamus.

[0014] As used herein, the term "treatment," "treating," and similar terms refer to obtaining a desired pharmacological and / or physiological effect. The effect can be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the harmful effects attributable to the disease. As used herein, "treatment" encompasses any treatment of a disease in a mammal, for example, a human, and includes (a) preventing the onset of a disease in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, i.e., preventing its development; and (c) alleviating the disease, i.e., causing the regression of the disease.

[0015] The terms "individual," "subject," "host," and "patient," used interchangeably herein, refer to individual organisms, e.g., mammals, including but not limited to, murines, simians, humans, non-human primates, ungulates, felines, canines, cattle, sheep, mammalian livestock, mammalian sport animals, and mammalian pets. In some cases, the "individual" is a human.

[0016] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. 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 invention will be limited only by the appended claims.

[0017] When a range of values is provided, it is understood that each intervening value between the upper and lower limit of that range, to one-tenth of the unit of the lower limit unless the context clearly dictates otherwise, and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. When the stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the invention.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.Although any method and material similar or equivalent to those described herein can also be used in the practice or testing of this invention, currently preferred method and material are described.All publications mentioned herein are incorporated by reference in order to disclose and describe the method and / or material related to which publication is cited.

[0019] It should be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound of Formula I" includes a plurality of such compounds, and a reference to "the metabolic disorder" includes a reference to one or more metabolic disorders and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as a basis precedent for the use of exclusive terminology such as "only," "only," and the like, or the use of a "negative" limitation in connection with the recitation of claim elements.

[0020] In the context of describing this disclosure (particularly in the context of the appended claims), use of the terms "a," "an," and "the," and similar referents, are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted. The recitation of ranges of values herein is merely intended to serve as a shorthand method for individually referring to each separate value within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually listed herein. For example, if a range of 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better elucidate aspects of the disclosure and does not impose limitations on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of aspects of the disclosure.

[0021] As used herein, the term "about" in relation to a quantity indicates that the quantity may vary by 10% of the stated amount. For example, "about 100" means an amount of 90 to 110. When "about" is used in the context of a range, "about" used with respect to a lower amount in a range means that the lower amount includes an amount 10% lower than the lower amount in the range, and "about" used with respect to a higher amount in a range means that the higher amount includes an amount 10% higher than the higher amount in the range. For example, about 100 to about 1000 means that the range spans 90 to 1100.

[0022] The term "and / or" when used herein in phrases such as "A and / or B" is intended to include both A and B; A or B; A alone; and B alone. Similarly, the term "and / or" when used herein in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0023] It is understood that aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0024] It will be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the present invention are specifically embraced by the present invention and are disclosed herein as if each and every combination were individually and explicitly disclosed. In addition, all subcombinations of the various embodiments and elements thereof are also specifically embraced by the present invention and are disclosed herein as if each and every such subcombination were individually and explicitly disclosed herein.

[0025] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description The present disclosure provides methods for treating metabolic disorders, which generally involve administering an effective amount of a compound of Formula I to an individual in need thereof.

[0027] TOFA and TOFA analogs In some cases, the present disclosure provides a method of treating a metabolic disorder in an individual, comprising administering to the patient a therapeutically effective amount of 5-(tetradecyloxy)-2-furoic acid (TOFA) or a TOFA analog or derivative. TOFA has the following structure: TIFF2025526296000002.tif25128

[0028] In some cases, the present disclosure provides a method for treating a metabolic disorder in an individual, comprising administering to the patient a therapeutically effective amount of an analog of TOFA. For example, in some cases, the method of ... of Formula I, either as a single stereoisomer or as a mixture thereof. TIFF2025526296000003.tif27128 or a pharmaceutically acceptable salt thereof, comprising: During the ceremony, R 1 is R 1 -OR 2 , -OR 3 -OR 2 , -OR 3 -OC(O)-N(R 5 )R 6 , -OR 3 -N(R 5 )R 6 , -OR 3 -N(R 4 )C(O)OR 5 , -OR 3 -C(O)OR 5 , -OR 3 -C(O)N(R 5 )R 6 , or -N(R 5 )S(O)2-R 4 and; Each R 2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 3 is independently an optionally substituted alkylene chain; R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 5are independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; Each R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 4 is, or Any R 5 and R 6 taken together with the nitrogen to which they are both attached form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl.

[0029] Certain chemical groups named herein may be preceded by an abbreviation indicating the total number of carbon atoms found in the indicated chemical group. For example: C7-C 12 Alkyl refers to an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, C4 to C 12 Cycloalkylalkyl depicts a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the depicted group.

[0030] In addition to the above, unless otherwise specified, the following terms have the meanings indicated: "amino" refers to the -NH2 radical. "cyano" refers to the -CN radical. "hydroxy" refers to the -OH radical. "imino" refers to the =NH substituent. "nitro" refers to the -NO2 radical. "oxo" refers to the =O substituent. "thioxo" refers to the =S substituent. "trifluoromethyl" refers to the -CF3 radical.

[0031] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms or 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specifically stated in the specification, an alkyl group may be one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )S(O) t R 16 (where t is 1 to 2), -S(O) t OR 16 (where t is 1 to 2), -S(O) p R 16 (where p is 0 to 2), and -S(O) t N(R 14 )2 (where t is 1 to 2), where each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0032] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, that connects the rest of the molecule to a radical group, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, an alkylene chain can be selected from the group consisting of one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, -O- ... 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )S(O) t R 16 (where t is 1 to 2), -S(O) t OR 16 (where t is 1 to 2), -S(O) p R 16 (where p is 0 to 2), and -S(O) t N(R 14 )2 (where t is 1 to 2), where each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 16is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0033] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this invention, an aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, the term "aryl," or the prefix "ar-" (as in "aralkyl"), refers to any of the following: alkyl, akenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, heteroaryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (where t is 1 to 2), -R 15 -N=C(OR 14 )R14 , -R 15 -S(O) t OR 16 (where t is 1 to 2), -R 15 -S(O) p R 16 (where p is 0 to 2), and -R 15 -S(O) t N(R 14 )2, where t is 1 to 2, wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 15 are independently a direct bond or a linear or branched alkylene or alkenylene chain; each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0034] "Aralkyl" means a group of the formula -R b -R c where R b is an alkylene chain as defined above, and R c is one or more aryl radicals as defined above, e.g., aralkyl is benzyl, diphenylmethyl, and the like. The alkylene chain portion of the aralkyl radical can be optionally substituted as described above for an alkylene chain. The aryl portion of the aralkyl radical can be optionally substituted as described above for an aryl group.

[0035] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. Unless otherwise specifically stated herein, the term "cycloalkyl" includes alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (where t is 1 to 2), -R 15 -N=C(OR 14 )R 14 , -R 15 -S(O) t OR 16 (where t is 1 to 2), -R 15 -S(O) p R 16 (where p is 0 to 2), and -R 15-S(O) t N(R 14 )2 (where t is 1 to 2), wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 15 are independently a direct bond or a linear or branched alkylene or alkenylene chain; each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0036] "Halo" refers to bromo, chloro, fluoro, or iodo.

[0037] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl portion of the haloalkyl radical can be optionally substituted as defined above for an alkyl group.

[0038] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical, which consists of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxo-1,3-dioxol-4yl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in this specification, the term "heterocyclyl" includes alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)OR 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (where t is 1 to 2), -R 15 -N=C(OR 14 )R 14 , -R 15 -(S(O) t OR 16 (where t is 1 to 2), -R 15 -S(O) p R 16 (where p is 0 to 2), and -R 15 -S(O) t N(R 14 )2 (where t is 1 to 2), wherein each R 14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 15 are independently a direct bond or a linear or branched alkylene or alkenylene chain; each R 16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0039] "N-heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical may be optionally substituted as described above for heterocyclyl radicals.

[0040] "Heterocyclylalkyl" means a group of the formula -R b R h where R b is an alkylene chain as defined above, and R h is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be attached to the alkylene chain at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical can be optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical can be optionally substituted as defined above for a heterocyclyl group.

[0041] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this invention, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl Examples of phenyl include, but are not limited to, phenyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless stated otherwise specifically in this specification, the term "heteroaryl" includes alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (where t is 1 to 2), -R 15 -N=C(OR 14 )R 14 , -R 15 -S(O) t OR 16 (where t is 1 to 2), -R 15 -S(O) p R 16 (where p is 0 to 2), and -R 15 -S(O) t N(R 14 )2 (where t is 1 to 2), wherein each R 14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R15 are independently a direct bond or a linear or branched alkylene or alkenylene chain; each R 16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0042] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical may be optionally substituted as described above for heteroaryl radicals.

[0043] "Heteroarylalkyl" means a group of the formula -R b R i where R b is an alkylene chain as defined above, and R i is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group. The alkylene chain part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkylene chain.

[0044] "Optional" or "optionally" means that the event described below may or may not occur, and the description includes instances in which the event or event occurs and instances in which it does not occur. For example, "optionally substituted aryl" means that the aryl radical may be substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl radicals. When a functional group is described as "optionally substituted," and then a substituent on the functional group is also "optionally substituted," and so on, for purposes of this invention, such repetitions are limited to five, and preferably such repetitions are limited to two.

[0045] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, flow agent, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0046] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0047] "Pharmaceutically acceptable acid addition salts" refer to those which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable, and include those salts of inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid , glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0048] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Examples of inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, including ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like; salts of substituted amines, including naturally occurring substituted amines; salts of cyclic amines; and salts of basic ion exchange resins. Examples of organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0049] A "pharmaceutical composition" refers to a formulation of a compound and a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal, such as a human. Such a vehicle can include a pharmaceutically acceptable carrier, diluent, or excipient.

[0050] A "therapeutically effective amount" refers to the amount of a compound that, when administered to a mammal, e.g., a human, is sufficient to treat the disease or condition of interest in a mammal, e.g., a human, having the disease or condition. The amount of a compound that constitutes a "therapeutically effective amount" varies depending on the compound, the disease or condition and its severity, the mode of administration, and the age of the mammal being treated, but can be determined routinely by one of ordinary skill in the art given their own knowledge and this disclosure.

[0051] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The compounds disclosed herein are meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example, using chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0052] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds, but having different three-dimensional structures that are not interconvertible. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0053] The use of parentheses in substituent groups is used herein to conserve space, and thus indicates that the group enclosed within the parentheses is directly attached to the atom preceding the parentheses.

[0054] Among the compounds of formula (I), one embodiment is a compound of formula (I), wherein R 1 -OR 2 and;R 2 is independently alkyl or heterocyclylalkyl. Within this embodiment, one embodiment is a compound of Formula (I) selected from isopropyl 5-(tetradecyloxy)furan-2-carboxylate; 4-methylpentyl 5-(tetradecyloxy)furan-2-carboxylate; and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 5-(tetradecyloxy)furan-2-carboxylate.

[0055] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 -OR 2 and;R 2 is haloalkyl or substituted aryl. Within this embodiment, one embodiment is a compound of Formula (I) selected from 2,2,2-trifluoroethyl 5-(tetradecyloxy)furan-2-carboxylate; 2,2,2-trichloroethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate; and 2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid.

[0056] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 -OR 3 -OR 2 and;R 2 is optionally substituted heterocyclylalkyl; R 3 is an optionally substituted alkylene chain. Within this embodiment, one embodiment is a compound of formula (I) that is 3-(tetrahydro-2H-pyran-2-yloxy)propyl 5-(tetradecyloxy)furan-2-carboxylate.

[0057] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 -OR 3 -OC(O)-N(R 5 )R 6 and each R 2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 3 is an optionally substituted alkylene chain; R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 3 and / or any R 5 and R 6taken together with the nitrogen to which they are both attached form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl. Within this embodiment, one embodiment is 1-(benzyl(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 1-((2-ethoxy-2-oxoethyl)(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 4-(2S)-2-benzyl 1-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)pyrrolidine-1,2-dicarboxylate; 1-(4-phenylcyclohexanecarbonyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl 3-phenylpyrrolidine-1-carboxylate silyl; 1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl 3,4-dihydroisoquinoline-2(1H)-carboxylate; 1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl piperidine-1-carboxylate; 1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl morpholine-4-carboxylate; 1-tert-butyl 4-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)piperazine-1,4-dicarboxylate; and 1-(dicyclohexylcarbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate.

[0058] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 -OR 3 -N(R 5 )R 6 and;R 3 is an optionally substituted alkylene chain; R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; R 6is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 4 and / or any R 5 and R 6 taken together with the nitrogen to which they are both attached form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl. Within this embodiment, one embodiment is a compound of formula (I) selected from 2-(dimethylamino)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-morpholinoethyl 5-(tetradecyloxy)furan-2-carboxylate; or 3-morpholinopropyl 5-(tetradecyloxy)furan-2-carboxylate.

[0059] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 -OR 3 -N(R 4 )C(O)OR 5 and;R 3 is an optionally substituted alkylene chain; R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl.

[0060] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 -OR 3 -C(O)OR 5 and;R 3 is an optionally substituted alkylene chain; R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl.

[0061] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 -OR 3 -C(O)N(R 5 )R 6 and;R 3 is an optionally substituted alkylene chain; R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 4 or R 5 and R 6taken together with the nitrogen to which they are both attached form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl. Within this embodiment, one embodiment is 2-(benzyl(methyl)amino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; tert-butyl 4-(2-(5-tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazine-1-carboxylate; 2-(dicyclohexylamino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-oxo-2-(4-phenylpiperazin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate; 2-((2 2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; and (S)-benzyl 1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylate.

[0062] Another embodiment of the compounds of formula (I) is a compound of formula (I) wherein R 1 is -N(R 5 )S(O)2-R 4 and;R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 5are independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl. Within this embodiment, one embodiment is a compound of formula (I) that is 5-(tetradecyloxy)-N-tosylfuran-2-carboxamide.

[0063] Among the pharmaceutical compositions, one embodiment is one in which the pharmaceutical composition is an oral composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0064] Pharmaceutical Compositions The compound of formula I or its pharmaceutically acceptable salt can be in the form of a composition suitable for administration to a subject. Generally, such a composition is a "pharmaceutical composition" comprising the compound of formula I (or its pharmaceutically acceptable salt) and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients. In some cases, the compound of formula I (or its pharmaceutically acceptable salt) is present in a therapeutically effective amount. The pharmaceutical composition can be used in the methods disclosed in the present invention; thus, for example, the pharmaceutical composition can be administered to a subject to practice the therapeutic and prophylactic methods and uses described herein.

[0065] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein. Moreover, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds (e.g., glucose-lowering agents) as described herein to treat or prevent the diseases, disorders, and conditions contemplated by the present disclosure.

[0066] Pharmaceutical compositions typically contain a therapeutically effective amount of a compound of Formula I (or its pharmaceutically acceptable salt) and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl, p-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be saline solution or citrate-buffered saline, optionally supplemented with other substances commonly used in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize various buffers that can be used in pharmaceutical compositions and dosage forms. Typical buffer solutions include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffer solutions may be water-soluble substances such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0067] After the pharmaceutical composition is formulated, it can be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form requiring reconstitution before use, a liquid form requiring dilution before use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an auto-injector (e.g., similar to EpiPen™)), while in other embodiments, a multi-use container (e.g., a multi-use vial) is provided. Any drug delivery device can be used to deliver the compound of Formula I (or a pharmaceutically acceptable salt thereof), including implants (e.g., implantable pumps) and catheter systems, both of which are well known to those skilled in the art. Depot injections, typically administered subcutaneously or intramuscularly, can also be utilized to release the polypeptides disclosed herein over a period of time. Depot injections are usually either solid-based or oil-based and generally contain at least one of the formulation components described herein. Those skilled in the art are familiar with the possible formulations and uses of depot injections.

[0068] The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension or oleagenous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, may be employed. In addition, fatty acids, such as oleic acid, find use in the preparation of injectables. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0069] Pharmaceutical compositions containing the active ingredient (e.g., a compound of Formula I (or a pharmaceutically acceptable salt thereof)) may be in a form suitable for oral use, such as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or as syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide pharmaceutically elegant and palatable preparations. Tablets, capsules, and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binders, for example, starch, gelatin, or acacia, and lubricants, for example, magnesium stearate, stearic acid, or talc.

[0070] Tablets, capsules, and the like suitable for oral administration may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be employed. These may be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or polymeric materials, such as polyesters, polyamine acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolide copolymers, polylactide / glycolide copolymers, or ethylene vinyl acetate copolymers, to control delivery of the administered composition. For example, oral agents can be encapsulated in microcapsules prepared by coacervation or interfacial polymerization, respectively, by using hydroxymethylcellulose microcapsules, gelatin microcapsules, or poly(methyl methchlorate) microcapsules, or can be encapsulated in colloidal drug delivery systems.Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.Methods for preparing liposomes are described, for example, in U.S. Patent Nos. 4,235,871, 4,501,728, and 4,837,028.Methods for preparing the above-mentioned formulations will be clear to those skilled in the art.

[0071] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0072] Aqueous suspensions contain the active substance in a mixture with excipients suitable for their manufacture.Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing agents or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate).Aqueous suspensions can also contain one or more preservatives.

[0073] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol.In order to provide a palatable oral preparation, sweeteners and flavoring agents, such as those mentioned above, can be added.

[0074] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0075] The pharmaceutical composition of the present disclosure can also be in the form of oil-in-water emulsion.Oil phase can be vegetable oil, such as olive oil or peanut oil, or mineral oil, such as liquid paraffin, or their mixture.Suitable emulsifying agent can be naturally occurring gum, such as gum arabic or gum tragacanth; naturally occurring phospholipid, such as soybean, lecithin, and the ester or partial ester derived from fatty acid; hexitol anhydride, such as sorbitan monooleate; and the condensation product of partial ester and ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0076] The formulation can also include carriers to protect the composition against rapid degradation or elimination from the body, such as controlled release formulations, including implants, liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time delay material such as glyceryl monostearate or glyceryl stearate, alone or in combination with a wax, can be employed.

[0077] In some cases, the compound of formula I (or a pharmaceutically acceptable salt thereof) is not formulated for topical administration.

[0078] method The methods of the present disclosure include administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0079] "Therapeutically effective amount" refers to the administration of an agent to a subject, either alone or as part of a pharmaceutical composition, in an amount capable of producing any detectable positive effect on any symptom, aspect, or characteristic of a disease, disorder, or condition when administered to a patient, either in a single dose or as part of a series of doses. A therapeutically effective amount can be ascertained by measuring the relevant physiological effect. In some cases, for example, in the case of a hyperglycemic condition, a drop or reduction in blood glucose or an improvement in a glucose tolerance test can be used to determine whether the amount of agent is effective to treat the hyperglycemic condition. A therapeutically effective amount can be adjusted in relation to the dosing regimen and diagnostic analysis of the subject's condition, and the like. "Compounds of Formula I" is meant to include pharmaceutically acceptable salts of compounds of Formula I, unless specifically stated otherwise.

[0080] In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient, when administered in one or more doses, to reduce or decrease any level (e.g., baseline level) of fasting plasma glucose (FPG), where, for example, the amount is sufficient to reduce an FPG level above 200 mg / dl to below 200 mg / dl, the amount is sufficient to reduce an FPG level of 175 mg / dl to 200 mg / dl to below the starting level, the amount is sufficient to reduce an FPG level of 150 mg / dl to 175 mg / dl to below the starting level, the amount is sufficient to reduce an FPG level of 125 mg / dl to 150 mg / dl, and so on (e.g., reduce FPG levels to below 125 mg / dl, below 120 mg / dl, below 115 mg / dl, below 110 mg / dl, etc.).

[0081] In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient, when administered in one or more doses, to reduce or decrease hemoglobin A1c (HbA1c) levels from about greater than 10% to 9%, from about greater than 9% to 8%, from about greater than 8% to 7%, from about greater than 7% to 6%, from about greater than 6% to 5%, and so on. In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to reduce or decrease HbA1c levels by about 0.1%, 0.25%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 33%, 35%, 40%, 45%, 50% or more.

[0082] In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to provide insulin levels in the normal range when administered in one or more doses.

[0083] In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to bring serum alanine transaminase (ALT) levels into the normal range when administered in one or more doses. In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to reduce serum ALT levels by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or more than 50% compared to the serum ALT level before treatment when administered in one or more doses. In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to bring serum aspartate transaminase (AST) into the normal range when administered in one or more doses. In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient, when administered in one or more doses, to reduce serum AST levels by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or more than 50% compared to serum AST levels before treatment.

[0084] In some cases, an effective amount of a compound of Formula I is an amount that, when administered in one or more doses to a subject, produces a desired result compared to a healthy subject. For example, an effective dose can be an amount that, when administered to a subject with elevated plasma glucose and / or plasma insulin, achieves a desired reduction of at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more than 80% in plasma glucose and / or plasma insulin compared to a healthy subject.

[0085] Administration route Suitable routes of administration include oral, rectal, nasal, pulmonary, topical, subcutaneous, intramuscular, intraperitoneal, intravenous, intradermal, intrathecal, and epidural. In some cases, the route of administration is oral.

[0086] Dosage The compound of Formula I can be administered to a subject in an amount that depends on, for example, the goal of administration (e.g., the desired degree of recovery); the age, weight, sex, and health and physical condition of the subject being treated; the nature of the compound and / or formulation being administered; the route of administration; and the nature of disease, disorder, condition, or its symptoms (e.g., the severity of glucose / insulin dysregulation and the stage of the disorder).Dosage regimens can also take into account the existence, nature, and degree of any adverse effects associated with the administered agent.The amount and dosage regimen of effective dosage can be easily determined, for example, from safety tests and dose escalation tests, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0087] Generally, dosing parameters dictate that the amount administered is less than the amount that would be irreversibly toxic to the subject (i.e., the maximum tolerated dose, "MTD") and greater than or equal to the amount required to produce a measurable effect in the subject. Such amounts are determined by, for example, pharmacokinetic and pharmacodynamic parameters related to absorption, distribution, metabolism, and excretion ("ADME"), taking into account the route of administration and other factors.

[0088] Effective dose (ED) is the dose or amount of an active substance that produces a therapeutic response or desired effect in a proportion of subjects who take it. The "median effective dose" or ED50 of an active substance is the dose or amount of an active substance that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although ED50 is generally used as a measure of the reasonable expected value of the effect of an active substance, it is not necessarily the dose that a clinician can determine as appropriate by taking into account all relevant factors. Thus, in some situations, the effective amount exceeds the calculated ED50, in other situations, the effective amount is less than the calculated ED50, and in still other situations, the effective amount is the same as the calculated ED50.

[0089] Suitable dosage levels are generally about 0.001 to 100 mg / kg of patient body weight per day, which can be administered in single or multiple doses.

[0090] In some cases, dosage levels are from about 0.01 to about 25 mg / kg per day, and in other embodiments, from about 0.05 to about 10 mg / kg per day. Suitable dosage levels may be from about 0.01 to 25 mg / kg per day, from about 0.05 to 10 mg / kg per day, or from about 0.1 to 5 mg / kg per day. Within this range, dosages may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0 mg / kg per day.

[0091] In some cases, the therapeutically effective amount of the compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, stereoisomer, or isomer thereof, is about 25 mg per day, about 50 mg per day, about 75 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, or about 400 mg per day. In some embodiments, the therapeutically effective amount of the compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, stereoisomer, or isomer thereof, is about 50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, or about 400 mg per day. In some embodiments, the therapeutically effective amount of the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, stereoisomer, or isomer is up to 25 mg per day, up to 50 mg per day, up to 75 mg per day, up to 100 mg per day, up to 150 mg per day, up to 200 mg per day, up to 400 mg per day, up to 600 mg per day, up to 800 mg per day, or up to 1000 mg per day. In some embodiments, the therapeutically effective amount of the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer is up to 400 mg per day.

[0092] For oral administration, the compositions can be provided in the form of tablets, capsules, and the like containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient. The compounds of Formula I can be administered, for example, on a regimen of 1 to 4 times per day, often once or twice per day.

[0093] The dosage of the compound of Formula I can be repeated at an appropriate frequency, which can range from once per day to once every three months, depending on the pharmacokinetics (e.g., half-life) and pharmacodynamic response (e.g., duration of therapeutic effect of the compound) of the compound. In some cases, the dosage is repeated as frequently as once per week to once every three months. In other examples, the compound of Formula I is administered approximately once per month.

[0094] In certain embodiments, the dosage of the compound of Formula I is contained in a "unit dosage form." The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined amount of a compound of Formula I, either alone or in combination with one or more additional active substances, sufficient to produce the desired effect. It will be understood that the parameters of the unit dosage form depend on the particular active substance and the effect to be achieved.

[0095] Combination therapy The present disclosure contemplates the use of the compound of formula I in combination with one or more additional active substances (e.g., one or more additional active therapeutic agents) or other preventive or therapeutic modalities.In such combination therapy, various active substances often have different mechanisms of action.Such combination therapy can be particularly advantageous by reducing the dose of one or more active substances, thereby reducing or eliminating the adverse effects associated with one or more active substances;In addition, such combination therapy can have a synergistic therapeutic or preventive effect on the underlying disease, disorder or condition.

[0096] As used herein, "combination" is meant to include therapies that can be administered separately, e.g., those formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a "co-formulation").

[0097] In certain cases, the compound of Formula I and at least one additional active substance are administered or applied sequentially, for example, when one active substance is administered before one or more other active substances.In other cases, the compound of Formula I and at least one additional active substance are administered simultaneously, for example, when two or more active substances are administered at the same time or approximately the same time; two or more active substances can be in two or more separate preparations, or can be combined in a single preparation (i.e., co-formulation).No matter whether two or more active substances are administered sequentially or simultaneously, they are considered to be administered in combination for the purpose of the present disclosure.

[0098] The compounds of formula I can be used in combination with other agents useful for treating the disorders or conditions described herein, including those normally administered to subjects suffering from obesity, eating disorders, hyperglycemia, hyperinsulinemia, glucose intolerance, and other disorders of glucose metabolism.

[0099] The present disclosure contemplates combination therapy with numerous agents (and classes thereof), including: (1) agents that involve stimulation of insulin secretion, including insulin, insulin mimetics, and sulfonylureas (e.g., chlorpropamide, tolazamide, acetohexamide, tolbutamide, glyburide, glimepiride, glipizide) and meglitinides (e.g., mitiglinide, repaglinide, and nateglinide); (2) biguanides (e.g., metformin and its pharmaceutically acceptable salts, particularly metformin); (3) alpha-glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol) and other agents that slow the digestion of carbohydrates and thereby their absorption from the intestine, thereby reducing postprandial hyperglycemia; (4) alpha-glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol) and other agents that slow the digestion of carbohydrates and therefore their absorption from the intestine, thereby reducing postprandial hyperglycemia; (4) Thiazolidinediones (e.g., rosiglitazone, troglitazone, pioglitazone, glipizide, balaglitazone, rivoglitazone, netoglitazone, AMG131, MBX2044, mitoglitazone, losiglita ... pioglitazone, glipizide, balaglitazone, rivoglitazone, netoglitazone, AMG131, MBX2044, mitoglitazone, losiglitazone, troglitazone, pioglitazone, glipizide, balaglitazone, rivoglitazone, net beglitazone, IDR-105, troglitazone, englitazone, ciglitazone, adaglitazone, darglitazone; (5) DPP-IV inhibitors (e.g., alogliptin, omarigliptin, linagliptin, vildagliptin, and sitagliptin) and glucagon-like peptide-1 (GLP-1) and GLP-1 agonists and analogs (e.g., exenatide (BYETTA and ITCA650 (subcutaneously inserted osmotic pumps that deliver exenatide analogs over a 12-month period; Intarcia, Boston, Mass.)))) and glucagon-like peptides, including GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof); and (6) and DPP-IV resistant analogs (incretin mimetics), PPAR gamma agonists, fenofibrillators, PPAR alpha agonists such as carboxylic acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), dual-acting PPAR agonists (e.g., ZYH2, ZYH1, GFT505, tiglitazar, muraglitazar, aleglitazar, soderglitazar, and naveglitazar), pan-acting PPAR agonists, PTP1B inhibitors, - (e.g., ISIS-113715 and TTP814), SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogroflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211), insulin secretagogues, angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., losartan, valsartan, candesartan, olmesartan, telmesartan); and similar.

[0100] subject Subjects suitable for treatment with the methods of the present disclosure include individuals with metabolic disorders. Subjects suitable for treatment with the methods of the present disclosure include obese individuals. Subjects suitable for treatment with the methods of the present disclosure include individuals with type 2 diabetes. Subjects suitable for treatment with the methods of the present disclosure include individuals with diabetic retinopathy. Subjects suitable for treatment with the methods of the present disclosure include individuals with non-alcoholic fatty liver disease (NAFLD). Subjects suitable for treatment with the methods of the present disclosure include individuals with non-alcoholic steatohepatitis (NASH).

[0101] In some cases, individuals with and / or diagnosed with non-alcoholic fatty liver disease (NAFLD) are specifically excluded. In some cases, individuals with and / or diagnosed with non-alcoholic steatohepatitis (NAS) are specifically excluded.

[0102] Examples of Non-Limiting Aspects of the Disclosure The above-described aspects of the present subject matter, including embodiments, may be useful alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing, certain non-limiting aspects of the present disclosure are provided below. As will be apparent to those skilled in the art upon reading this disclosure, each of the individually numbered aspects can be used with or combined with any of the preceding or subsequent individually numbered aspects. This is intended to provide support for all such combinations of aspects, and is not limited to the combinations of aspects expressly provided below: Aspect 1. A method of treating a metabolic disorder in an individual, comprising administering to a subject a compound of Formula I, either as a single stereoisomer or as a mixture thereof. TIFF2025526296000004.tif27128 or a pharmaceutically acceptable salt thereof to said individual: During the ceremony, R 1 is R 1 -OR2 , -OR 3 -OR 2 , -OR 3 -OC(O)-N(R 5 )R 6 , -OR 3 -N(R 5 )R 6 , -OR 3 -N(R 4 )C(O)OR 5 , -OR 3 -C(O)OR 5 , -OR 3 -C(O)N(R 5 )R 6 , or -N(R 5 )S(O)2-R 4 and; Each R 2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 3 is independently an optionally substituted alkylene chain; R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 5 are independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; Each R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 4 is, or Any R 5 and R 6taken together with the nitrogen to which they are both attached form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl. Aspect 2. The method of Aspect 1, wherein the compound is 5-(tetradecyloxy)-2-furoic acid. Aspect 3. The method of Aspect 1 or Aspect 2, wherein the metabolic disorder is insulin resistance, hyperglycemia, type 2 diabetes mellitus, obesity, fatty liver disease, glucose intolerance, hyperinsulinemia, metabolic syndrome, or hypertension. Aspect 4. The method of any one of Aspects 1-3, wherein the metabolic disorder comprises insulin resistance. Aspect 5. The method of any one of Aspects 1-3, wherein the metabolic disorder comprises metabolic syndrome. Aspect 6 The method of any one of Aspects 1-3, wherein the metabolic disorder comprises type 2 diabetes mellitus. Aspect 7. The method of any one of Aspects 1-6, wherein the individual has a body mass index of >30.0. Aspect 8. The method of any one of Aspects 1-7, wherein the administering step results in serum insulin levels in the normal range. Aspect 9. The method of any one of Aspects 1-7, wherein the administering step results in blood glucose levels in the normal range. Aspect 10 The method of any one of Aspects 1-9, further comprising administering at least one additional therapeutic agent. Aspect 11. The method of Aspect 10, wherein the at least one additional therapeutic agent is insulin, an insulin analog, a biguanidine, or a thiazolidinedione. Aspect 12. The method of any one of Aspects 1-11, wherein the administering step is via oral administration. Aspect 13 The method of any one of Aspects 1-12, wherein the compound of Formula I is administered daily. Aspect 14 The method of any one of Aspects 1-12, wherein the compound of Formula I is administered once a week. Aspect 15 The method of any one of Aspects 1-12, wherein the compound of Formula I is administered via controlled delivery. Aspect 16 The method of Aspect 15, wherein the compound of Formula I is present in an implantable delivery device. Aspect 17. A method of treating metabolic syndrome in an individual, comprising administering to a subject a compound of formula I, as a single stereoisomer or a mixture thereof. TIFF2025526296000005.tif27128 or a pharmaceutically acceptable salt thereof to said individual: During the ceremony, R 1 is R 1 -OR 2 , -OR 3 -OR 2 , -OR 3 -OC(O)-N(R 5 )R 6 , -OR 3 -N(R 5 )R 6 , -OR 3 -N(R 4 )C(O)OR 5 , -OR 3 -C(O)OR 5 , -OR 3 -C(O)N(R 5 )R 6 , or -N(R 5 )S(O)2-R 4 and; Each R 2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 3 is independently an optionally substituted alkylene chain; R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 5are independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; Each R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 4 is, or Any R 5 and R 6 taken together with the nitrogen to which they are both attached form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl. Aspect 18. The method of Aspect 17, wherein the compound is 5-(tetradecyloxy)-2-furoic acid. Aspect 19. The method of Aspect 17 or Aspect 18, wherein the administering step is via oral administration. Aspect 20. The method of any one of Aspects 17-19, wherein the compound of Formula I is administered daily. Aspect 21 The method of any one of Aspects 17-19, wherein the compound of Formula I is administered once a week. Aspect 22. The method of any one of Aspects 17-19, wherein the compound of Formula I is administered via controlled delivery. Aspect 23. The method of Aspect 22, wherein the compound of Formula I is present in an implantable delivery device. [Example]

[0103] The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be expected. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, such as bp, base pair; kb, kilobase; pl, picoliter; s or sec, second; min, minute; h or hr, hour; aa, amino acid; kb, kilobase; bp, base pair; nt, nucleotide; im, intramuscular (intramuscular); ip, intraperitoneal (intraperitoneal); sc, subcutaneous (subcutaneous); and the like.

[0104] Example 1: Dose-dependent effects of TOFA on the progression of choline-deficient high-fat diet (CDAHFD)-induced nonalcoholic fatty liver disease (NAFLD) in mice method Six-week-old C57BL / 6 male mice were fed an L-amino acid diet (Research Diets A06071302i) containing 60 kcal% fat, 0.1% methionine, and no choline for 3 weeks, followed by an oral gavage of either vehicle (control) or TOFA for an additional 3 weeks (Figure 1a). Mice were orally gavaged twice daily with various doses of TOFA (0, 25, 50, 125, or 250 mg / kg per day). Serum and liver samples were collected at the end of the study at week 6. Serum liver injury biomarkers, alanine transaminase (ALT) and aspartate transaminase (AST), were measured using commercially available kits (abcam105134 and abcam105135, respectively). Liver triglycerides were detected in liver samples using a commercially available kit (abcam65336). Liver samples were also scored for the degree of hepatic steatosis based on their hematoxylin and eosin (H&E) staining.

[0105] result Orally treated mice with TOFA showed a dose-dependent decrease in serum ALT and AST activity levels (Figure 1B). Similarly, liver lipid levels were decreased in a dose-dependent manner based on TOFA concentration, as quantitatively indicated by hepatic triglyceride content per gram of liver (Figure 1C, left). This is supported by the observation that the degree of hepatic steatosis decreased in correlation with increasing TOFA doses (Figure 1C, right). These findings indicate that TOFA is well tolerated and specifically reduces lipid accumulation in the liver.

[0106] Figures 1A–1C illustrate the dose-dependent effects of TOFA treatment in mice with the progression of CDAHFD-induced NAFLD. Figure 1A shows the time course of the experiment. Mice were fed a CDAHFD for 3 weeks and then orally treated with different concentrations of TOFA for 3 weeks. Figure 1B is a graph illustrating the activity levels of liver injury biomarkers: alanine aminotransferase (ALT) on the left and aspartate aminotransferase (AST) on the right. Figure 1C is a graph illustrating the hepatic lipid profile through quantitative measurement of hepatic triglycerides on the left and scoring assessment of hepatic steatosis on hematoxylin and eosin (H&E)-stained liver sections on the right. Statistical significance was determined using Brown-Forsythe's one-way ANOVA and Welch's one-way ANOVA statistical tests.

[0107] Example 2. Rescue effect of TOFA on early fatty liver and associated metabolic disorders induced by a 60% kcal fat diet in mice method Six-week-old C57BL / 6 male mice were fed a 60 kcal% fat diet (Research Diets A12492i) for 7 weeks, followed by administration of either vehicle (control) or an initial loading dose of 250 mg / kg TOFA via oral gavage twice daily for 1 week (Figure 2A). Mice were then treated with either vehicle (control) or a maintenance dose of 125 mg / kg TOFA via gavage twice daily for an additional 3 weeks. Mouse weights were tracked throughout the entire time course. After 3 weeks of treatment, intraperitoneal glucose tolerance tests (IP-GTT) and insulin tolerance tests (IP-ITT) were performed. Prior to these tests, mice were fasted for 6 hours and then challenged with either 1 g / kg D-glucose or 0.75 U / kg Humulin® (Eli Lilly), and blood glucose levels were monitored for 2 hours (Bayer Contour Next). Fasting venous blood was collected via the tail vein and used to measure fasting insulin levels using a commercially available ELISA kit (CrystalChem90080). Before harvesting, mice underwent whole-body composition analysis (EchoMRI™ 2012). At the end of the study at 11 weeks, serum and liver samples were collected. Serum liver injury biomarkers ALT and AST were measured using commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured using commercially available kits (abcam65336).

[0108] result Mice treated with TOFA exhibited weight loss compared with vehicle-treated mice, demonstrating the efficacy of TOFA as a weight-loss and fat-reducing agent without affecting food intake (Figure 2B, 2C). This is supported by a significant reduction in fat mass relative to total body weight and an increase in lean mass in TOFA-treated mice (Figure 2D). IP-GTT demonstrated that TOFA-treated mice had better glucose tolerance via improved glucose clearance over time (Figure 2E). Furthermore, TOFA-treated mice exhibited greatly improved fasting blood glucose levels as well as significantly reduced fasting insulin levels (Figures 2E, 2F). IP-ITT highlighted the improved insulin sensitivity via the glucose clearance response as a result of TOFA treatment in mice (Figure 2G). Without being bound by theory, inhibition of ACC activity by TOFA and the subsequent reduction in fatty acid synthesis may contribute to the improvement of these metabolic parameters in glucose homeostasis by reducing ectopic lipids in the liver, which contribute to NAFLD pathology and progression (e.g., insulin resistance). Serum analysis revealed no significant changes in serum ALT and AST biomarkers (Figure 2H). This may be explained by the shortened time course of diet-induced damage caused by the high-fat diet. Compared with other diet-induced NAFLD timelines and diets, this dietary time course most closely mimics early metabolic dysregulation strongly associated with NAFLD progression (e.g., obesity complications, diabetes mellitus, metabolic syndrome). However, TOFA treatment significantly reduced both hepatic and serum triglyceride levels (Figure 2I). As expected, a general reduction in circulating lipids throughout the body may contribute to improved overall metabolic homeostasis. Thus, these results indicate that TOFA is an effective agent in reducing the metabolic dysregulation associated with early stage NAFLD by reducing the lipid load in the body.

[0109] Figures 2A-2I illustrate the effects of TOFA treatment on the progression of a 60% kcal fat diet-induced metabolic syndrome and early NAFLD. Figure 2A shows the experimental timeline. Mice were fed a 60% kcal fat diet for 7 weeks and then orally treated with TOFA for 4 weeks (a loading dose of 250 mg / kg delivered daily for 1 week, followed by a maintenance dose of 125 mg / kg delivered in two doses daily for 3 weeks). Metabolic profiling began during the final week of treatment. Figure 2B is a graph tracking weight change over the time course of the experiment. Figure 2C is a graph tracking cumulative intake of the 60% fat diet over the time course of the experiment. Figure 2D is a graph illustrating changes in fat mass and lean mass relative to body weight, as measured by EchoMRI. Figure 2E is a graph illustrating blood glucose levels over time during an intraperitoneal glucose challenge (IP-GTT) on the left. A representation of the area under the curve is shown on the right. Figure 2F is a graph illustrating fasting serum insulin levels. Figure 2G is a graph illustrating blood glucose levels over time during an intraperitoneal insulin challenge (IP-ITT) on the left. A representation of the area under the curve is shown on the right. Figure 2H is a graph illustrating the activity levels of liver injury biomarkers: alanine aminotransferase (ALT) on the left and aspartate aminotransferase (AST) on the right. Figure 2I is a graph illustrating body lipid status through quantitative measurement of liver triglycerides on the left and serum lipid levels on the right.

[0110] Example 3 Rescue effect of TOFA on the progression of CDAHFD-induced late-stage NAFLD / NASH in mice method Six-week-old C57BL / 6 male mice were fed an L-amino acid diet (Research Diets A06071302i) containing 60 kcal% fat, 0.1% methionine, and no choline for 8 weeks, followed by twice-daily controlled oral gavage of either vehicle (control) or 250 mg / kg TOFA for an additional 4 weeks (Figure 3A). At the end of the study at week 12, serum and liver samples were collected. Serum liver injury biomarkers, ALT and AST, were measured using commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured using commercially available kits (abcam65336). Liver samples were fixed in 4% paraformaldehyde, embedded in paraffin blocks for sectioning, and then stained with hematoxylin and eosin (H&E) or picrosirius red with a fast green dye background. Freshly frozen liver tissue was embedded in OCT, sectioned, and subsequently stained with Oil Red O.

[0111] result Mice treated with TOFA showed a significant decrease in serum ALT activity levels and a mean reduction in serum AST levels (Figure 3B). Furthermore, TOFA treatment reduced hepatic triglyceride content without an increase in serum triglyceride levels (Figure 3C). Histopathological evaluation revealed a decrease in the degree of hepatic steatosis in TOFA-treated mice, as well as other pathological markers of disease, such as inflammation, ballooning, and fibrosis, as scored by the metrics outlined in Kleiner et al. (2005) (Figure 2D, Figure 2E). Histological staining revealed that TOFA treatment reduced lipid content by Oil Red O, cytoplasmic vacuolization by H&E, and fibrosis by picrosirius red staining (Figure 2F). Overall, these results demonstrate that TOFA is effective in mitigating the progression of late-stage NAFLD and NASH pathology while minimizing potential adverse metabolic effects previously reported with other ACC inhibitors, such as elevated serum triglycerides.

[0112] Figures 3A–3F show the rescue effect of TOFA treatment on the progression of CDAHFD-induced late-stage NAFLD / NASH in mice. Figure 3A shows the experimental timeline. Mice were fed a CDAHFD for 8 weeks and then orally treated with TOFA (250 mg / kg twice daily) for 4 weeks. Figure 3B is a graph illustrating the activity levels of liver injury biomarkers: alanine aminotransferase (ALT) on the left and aspartate aminotransferase (AST) on the right. Figure 3C is a graph illustrating the body lipid profile through quantitative measurement of hepatic triglycerides on the left and serum lipid levels on the right. Figure 3D is a graph illustrating the scoring assessment of hepatic steatosis using hematoxylin-eosin-stained liver sections. Figure 3E is a graph illustrating the scored histopathological assessment of liver inflammation, hepatocellular ballooning, and fibrosis in liver sections stained with hematoxylin and eosin and Sirius Red. Figure 3F is a panel showing representative images of liver sections stained with Oil Red O, hematoxylin and eosin, and Sirius Red. Scale bars are 50 μm. Statistical significance was determined using an unpaired Student's t-test.

[0113] Example 4. Whole-genome RNA sequencing of liver samples from CDAHFD-induced late-stage NAFLD / NASH mice treated with vehicle or TOFA method Liver samples were collected from the mice in Example 3 (see above). Total RNA was extracted from the liver tissue (Qiagen RNeasy kit), a cDNA library was constructed (Roche KAPA HyperPrep kit), and sequenced on the NovaSeq6000 platform (Novogene), followed by downstream analysis. Differentially expressed genes (DEGs) were defined by a fold change of at least 1 log2 (2-fold on a linear scale) with an FDR cutoff of 0.05. For validation, cDNA was prepared using total RNA (BioRAD iScript™ Reverse Transcription) according to the manufacturer's protocol, and quantitative polymerase chain reaction (qPCR) was performed using fast SYBR Green Mix (ThermoFisher) on a QuantStudio6 System (Applied Biosystems). Protein expression levels were measured by Western blot using antibodies against the very low-density lipoprotein receptor (VLDLR) (AF2258, 1:2000) and b-tubulin (CST2146, 1:1000). Membranes were developed using a horseradish peroxidase (HRP) secondary antibody (1:5000) and visualized using an enhanced chemiluminescence HRP substrate (Thermo34577).

[0114] result Interestingly, RNA-seq analysis of liver samples revealed a potential role for TOFA in influencing the transcriptional activity of the peroxisome proliferator-activated receptor (PPAR) nuclear hormone receptor superfamily, specifically PPAR-alpha. Some of the most upregulated genes observed with TOFA treatment are canonical PPAR-alpha target genes (Figure 4A). Specific analysis of the PPAR signaling pathway (from the 2021 KEGG Human Database) showed that TOFA treatment upregulated various genes under the transcriptional control of PPAR (Figure 4B). This observation was further confirmed by various GSEA heatmaps of significantly upregulated genes in processes such as oxidative phosphorylation, fatty acid metabolism, and peroxisome function, all of which are closely related to the action of the PPAR signaling pathway (Figure 4C). A negative correlation with inflammatory responses by TOFA treatment was also observed, supporting the safety and efficacy of TOFA treatment for reducing inflammatory markers of NAFLD pathology (Figure 4C, bottom right). Among the genes upregulated by TOFA treatment, the expression of the very low-density lipoprotein receptor (VLDLR) gene, a PPAR-alpha target gene, was significantly increased (Figure 4D). This increase in mRNA expression level translated into increased protein expression levels of VLDLR in TOFA-treated liver samples (Figure 4E). Previous studies have demonstrated the role of VLDLR upregulation in mediating triglyceride-lowering effects through PPAR-alpha agonism (e.g., fenofibrate). This preliminary data connects the potential relationship between the action of TOFA on VLDLR upregulation and the action of PPAR-alpha agonists through the fenofibrate-PPAR-alpha-VLDLR signaling axis to induce triglyceride-lowering effects. Therefore, without being bound by theory, the use of TOFA or its derivatives in the treatment of fatty liver disease and its associated metabolic dysregulation may utilize a multifaceted polypharmacological approach through ACC inhibition and PPAR agonism.

[0115] Figures 4A-4E show the results of RNA sequencing of liver samples from mice treated with TOFA derived from CDAHFD-induced late-stage NAFLD / NASH. Figure 4A is a volcano plot of differentially up- and down-regulated genes. Differential genes at an FDR cutoff of 0.05 and a fold-change cutoff of 2. Figure 4B is a heatmap illustrating up- and down-regulated genes in the PPAR signaling pathway, retrieved from the KEGG_2021_human database. Columns represent samples, and rows represent genes. Color indicates gene expression levels (log2 RPKM) relative to the average expression across all samples. Figure 4C is a GSEA plot of differentially regulated genes enriched in several hallmark gene sets: oxidative phosphorylation (top left), fatty acid metabolism (top right), peroxisomes (bottom left), and inflammatory response (bottom right). The normalized enrichment score (NES) and false discovery rate (FDR) are shown for each hallmark. Figure 4D is a graph illustrating the expression of mouse liver VLDLR mRNA relative to the expression of r18S mRNA. Figure 4E is a Western blot image of VLDLR and beta-tubulin protein expression levels in mouse liver samples. Statistical significance was determined using an unpaired Student's t-test.

[0116] Example 5. Tolerability and toxicity of TOFA in mice method Eleven-week-old C57BL / 6J male mice were fed PicoLab Rodent Diet (Purina 5053) or chow ad libitum while being treated with either control or 125 mg / kg BID by oral gavage for 3 weeks. Mouse weights were monitored throughout the entire time course. Serum and liver samples were collected at the end of the study. Serum biomarkers, such as blood urea nitrogen (BUN) and creatinine, were assessed using commercially available kits (abcam83362 and Cayman700460, respectively). Additionally, liver and serum triglyceride and cholesterol levels were measured using commercially available kits (abcam65336 and abcam65390, respectively).

[0117] result No weight changes were observed in TOFA-treated mice over the course of treatment, and there was no difference in weight between TOFA-treated and vehicle-treated mice (Figure 5A). Analysis of serum biomarkers, such as BUN (Figure 5B) and creatinine (Figure 5C), indicated the absence of drug-induced renal injury. A decrease in hepatic triglyceride levels was observed (Figure 5D), which is characteristic of this class of metabolic modulators. Furthermore, there was no significant change in serum triglyceride levels (Figure 5E), a unique observation among other small molecules targeting the same enzyme (ACC1 / 2). No changes were observed in liver cholesterol levels (Figure 5F) or serum cholesterol levels (Figure 5G). These findings indicate that TOFA is orally bioavailable, suitable for a BID or less frequent dosing regimen, and well-tolerated in mice.

[0118] Figures 5A-5B illustrate the safety and tolerability profile of TOFA treatment in mice fed chow ad libitum. Figure 5A is a graph tracking weight change over the time course of the experiment. Figure 5B is a graph illustrating serum blood urea nitrogen (BUN) levels. Figure 5C is a graph illustrating serum creatinine levels. Figure 5D is a graph illustrating quantitative measurement of liver triglycerides. Figure 5E is a graph illustrating quantitative measurement of serum triglycerides. Figure 5F is a graph illustrating quantitative measurement of liver cholesterol. Figure 5G is a graph illustrating quantitative measurement of total serum cholesterol. Statistical significance was determined using an unpaired Student's t-test.

[0119] Example 6 Dose-dependent effects of TOFA in a 60% HFD mouse model of diet-induced obesity (DIO) method Six-week-old C57BL / 6J male mice were fed a 60 kcal% fat diet (Research Diets A12492i) for 10 weeks, followed by an additional two weeks of either vehicle (control) or various doses of TOFA. TOFA was administered orally twice daily at doses of 12.5, 25, 62.5, or 125 mg / kg. Mouse weight and food intake were monitored throughout the treatment time course. Before harvest, mice underwent whole-body composition analysis (EchoMRI™ 2012). Serum and liver samples were collected at the end of the study at week 12. Liver and serum triglyceride and cholesterol levels were measured using commercially available kits (abcam65336 and abcam65390, respectively). Additional liver samples were fixed in 4% paraformaldehyde and embedded in paraffin blocks for sectioning, followed by staining with hematoxylin and eosin (H&E).

[0120] result When treated with TOFA, mice exhibited weight loss at the highest dose (125 mg / kg BID), demonstrating an efficacious dose (Figure 6A). Dosing at lower concentrations resulted in smaller or negligible changes in body weight, comparable to vehicle-control-treated mice (Figure 6B). Changes in body weight between treatment groups were not attributable to changes in food intake during treatment and remained constant over time (Figure 6C). Body composition analysis revealed a decrease in fat mass as a percentage of body weight in the highest-dose treatment group, with no change in overall lean mass across all treatment groups, attributing weight changes to a decrease in fat mass (Figure 6D). Analysis of liver triglycerides further supports the notion of altered body lipid levels, with a significant decrease in liver triglyceride levels in the highest-dose treatment regimen (Figure 6E). Most notably, serum triglyceride levels (Figure 6F) and serum cholesterol levels, specifically both HDL and VLDL / LDL fractions (Figure 6G), were dose-dependently reduced. Histological analysis of liver sections revealed a dose-dependent improvement in hepatic steatosis, providing further support for 125 mg / kg BID as the most effective dosing regimen (Figure 6H). Overall, these results demonstrate that TOFA acts in a dose-dependent manner to address multiple features of metabolic syndrome, further supporting the metabolic benefits conferred by TOFA treatment in a diet-induced mouse model of metabolic syndrome (see Example 2).

[0121] Figures 6A-6H illustrate the dose-dependent effects of TOFA treatment in mice with diet-induced obesity using a 60% HFD dietary model. Figure 6A is a graph tracking weight change over the treatment time course. Figure 6B is a graph illustrating the total percentage weight change from the beginning to the end of the treatment time course. Figure 6C is a graph illustrating food intake on a 60 kcal% fat diet over the experimental time course. Figure 6D is a graph illustrating changes in fat mass and lean mass relative to body weight, as measured by EchoMRI. Figure 6E is a graph illustrating quantitative measurements of liver triglycerides. Figure 6F is a graph illustrating quantitative measurements of serum triglycerides. Figure 6G is a graph illustrating quantitative measurements of HDL cholesterol, VLDL / LDL cholesterol, and total serum cholesterol. Figure 6H is a panel showing a representative image of hematoxylin-eosin stained liver sections at 10x magnification. Brown-Forsythe one-way ANOVA and Welch's one-way ANOVA statistical tests were used to determine statistical significance.

[0122] Example 7 Transcriptional analysis of liver samples from a 60% HFD mouse model of diet-induced obesity and associated metabolic disorders method Six-week-old C57BL / 6J male mice were fed a 60 kcal / % fat diet (Research Diets A12492i) for 7 weeks, followed by daily administration of either a control or an initial loading dose of TOFA at 125 mg / kg BID via controlled oral gavage for 1 week (Figure 2A). Mice were then treated with either vehicle (control) or a maintenance dose of TOFA at 62.5 mg / kg BID via daily oral gavage for an additional 3 weeks. Liver samples were collected at the end of the study at week 11. Total RNA was extracted from liver tissue (Qiagen RNeasy kit 74106), cDNA libraries were constructed (Roche KAPA HyperPrep kit), and sequenced on a NovaSeq6000 platform (Novogene). A downstream analysis pipeline was performed. Differentially expressed genes (DEGs) were defined by a fold change of at least 1 log2 (2-fold on a linear scale) with an FDR cutoff of 0.05. For validation, total RNA was used to prepare cDNA (BioRAD iScript™ Reverse Transcription) according to the manufacturer's protocol, and qPCR was performed using fast SYBR Green Mix (ThermoFisher A25742) on a QuantStudio6 System (Applied Biosystems).

[0123] result Supporting the results of Example 4, RNA-seq analysis of liver samples revealed a potential role for TOFA in influencing the transcriptional activity of the peroxisome proliferator-activated receptor (PPAR) signaling network, an observation conserved in different diet-induced models of severe metabolic disease. Some of the most up-regulated genes observed with TOFA treatment were canonical PPAR-alpha target genes, as well as notable down-regulated genes negatively regulated by PPAR-alpha activation (Figure 7A). Transcriptional regulatory relationship analysis of up-regulated genes from the TRRUST Transcription Factors 2019 reference database revealed that PPARα is one of the major factors in transcriptional regulation after TOFA treatment (Figure 7B). This observation was further supported by specific analysis of genes in the PPAR signaling pathway from the BioPlanet 2019 database, highlighting that TOFA treatment up-regulated various genes under the transcriptional control of PPARα (Figure 7C). Reverse transcription-qPCR (RT-qPCR) confirmed that various genes identified by RNA-seq analysis as downstream targets of PPARs were upregulated by TOFA treatment and involved in various processes in lipid homeostasis, such as fatty acid beta-oxidation, acyl-CoA processing, and lipoprotein uptake and metabolism (Figure 7D). These results confirm that the transcriptional activity signature of TOFA is similar regardless of the diet-challenged mouse model and the stage of metabolic disease severity.

[0124] Figures 7A-7D show transcriptional analysis of genes altered in liver by TOFA treatment in a 60% HFD diet-induced obesity mouse model. Figure 7A is a volcano plot of differentially up-regulated and down-regulated genes. Differential genes at an FDR cutoff of 0.05 and a fold-change cutoff of 2. Figure 7B is a bar-formatted table showing p-values of some of the most up-regulated transcription factor signatures from a pool of up-regulated genes from the TRRUST Transcription Factor 2019 reference database. Figure 7C is a heatmap illustrating up-regulated and down-regulated genes in the PPAR signaling pathway obtained from the BioPlanet 2019 database. Columns represent samples, and rows represent genes. Color indicates gene expression levels (log2 RPKM) relative to the average expression across all samples. Figure 7D is a graph illustrating the expression of mouse liver mRNA levels of selected genes with PPAR transcriptional regulation, grouped by functional commonality, relative to the expression of r18s mRNA. Statistical significance was determined using an unpaired Student's t-test.

[0125] Example 8 A detailed investigation of the rescue effect of TOFA on the progression of CDAHFD-induced late-stage NAFLD / NASH in mice method Six-week-old C57BL / 6J male mice were fed an L-amino acid diet (CDAHFD; Research Diets A06071302i) containing 60 kcal% fat, 0.1% methionine, and no added choline for 8 weeks. Ten subjects were randomly assigned to receive either vehicle (control) treatment or 125 mg / kg TOFA twice daily, delivered by oral gavage, for an additional 4 weeks. Mice were monitored for weight throughout the treatment course. Serum and liver samples were collected at the end of the study at week 12. Serum liver injury biomarkers, ALT and AST, were measured using commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured using commercially available kits (abcam65336). Total RNA was extracted from liver tissue (Qiagen RNeasy Kit 74106), and cDNA was prepared according to the manufacturer's protocol (BioRAD iScript™ Reverse Transcription). Quantitative PCR (qPCR) was performed using fast SYBR Green Mix (ThermoFisher A25742) on a QuantStudio6 System (Applied Biosciences).

[0126] result Significant differences in body weight were observed approximately 10 days after the start of treatment, and the differences continued to increase significantly until the end of the study (Figure 8A). TOFA-treated mice showed a significant decrease in body weight compared to vehicle-treated mice (Figure 8B). Analysis of serum biomarkers of liver injury showed a trend toward decreased ALT (Figure 8D) and AST (Figure 8D). Furthermore, TOFA-treated mice showed a significant decrease in hepatic triglyceride levels (Figure 8D), as well as decreased hepatic hydrogen peroxide levels, indicating a decrease in reactive oxygen species (ROS) (Figure 8F). Analysis of liver samples supports the notion that TOFA treatment improves liver health in a diet-induced model of NAFLD / NASH. Inflammatory genes, such as Il1b and Tnfa, were evaluated by RT-qPCR as biomarkers of inflammation. Results indicate a decrease in the expression of these inflammation-related genes (Figure 8G). Furthermore, the expression of genes involved in collagen biosynthesis was decreased as assessed by qPCR, indicating reduced fibrosis (Figure 8H). As seen in Examples 4 and 7, there is transcriptional activity from the PPAR signaling network that may contribute to the therapeutic effects of TOFA. RT-qPCR analysis of selected genes with PPAR regulatory elements revealed several genes involved in various processes, such as beta-oxidation and lipid biosynthesis, that were upregulated by TOFA treatment (Figure 8I). All these results support and provide further evidence for previous observations (Examples 3 and 4) of the role of TOFA in addressing various aspects of NAFLD / NASH, such as metabolic dysregulation, inflammation, and fibrosis.

[0127] Figures 8A-8I show a detailed analysis of the efficacy of TOFA treatment in a CDAHFD diet-induced mouse model of NAFLD / NASH. Figure 8A is a graph tracking weight change over the time course of treatment. Figure 8B is a graph illustrating the total percentage weight change between the beginning and end of the treatment period. Figure 8C is a graph illustrating serum alanine aminotransferase (ALT) activity levels. Figure 8D is a graph illustrating serum aspartate aminotransferase (AST) activity levels. Figure 8E is a graph illustrating quantitative measurement of hepatic triglycerides. Figure 8F is a graph illustrating quantitative measurement of hepatic hydrogen peroxide. Figure 8G is a graph illustrating the expression levels of inflammation-related mouse liver mRNAs relative to r18s mRNA expression.

[0128] Example 9. TOFA demonstrated comparable efficacy in a benchmark study compared to a leading clinical candidate for NASH using a mouse model of CDAHFD-induced late-stage NAFLD / NASH method Six-week-old C57BL / 6J male mice were fed an L-amino acid diet (CDAHFD; Research Diets A06071302i) containing 60 kcal% fat, 0.1% methionine, and no added choline for 8 weeks. Mice were randomly assigned to treatment groups containing vehicle (control), 250 mg / kg TOFA, 5 mg / kg filsocostat (Gilead Sciences), 50 mg / kg fenofibrate, or a combination dose of 5 mg / kg filsocostat and 50 mg / kg fenofibrate. All treatments were delivered QD by oral gavage for an additional 4 weeks. Mouse weight and food intake were monitored throughout the treatment time course. Liver and serum samples were collected at the end of the study at 12 weeks. Serum liver injury biomarkers, ALT and AST, were measured using commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured using commercially available kits (abcam65336). Total RNA was extracted from liver tissue (Qiagen RNeasy Kit 74106), and cDNA was prepared according to the manufacturer's protocol (BioRAD iScript™ Reverse Transcription). Quantitative PCR (qPCR) was performed using fast SYBR Green Mix (ThermoFisher A25742) on a QuantStudio6 System (Applied Biosciences). Protein expression levels in liver samples were measured by Western blot using antibodies against VLDLR (AF2258, 1:2000), CPT1A (CST12252, 1:1000), and histone H3 (CST9715, 1:1000). Membranes were developed using an HRP secondary antibody (1:5000) and visualized using enhanced chemiluminescence HRP substrate (Thermo34577). Additional liver samples were fixed in 4% paraformaldehyde, embedded in paraffin blocks for sectioning, and then stained with hematoxylin and eosin (H&E).

[0129] result To evaluate the efficacy of TOFA compared with other clinical candidates in the same molecular target class, mice with diet-induced NAFLD / NASH were treated with optimal dosages of either vehicle control, TOFA, filsocostat (an ACC1 / 2 inhibitor, Gilead Sciences), fenofibrate (a PPAR-alpha agonist), or a combination of filsocostat and fenofibrate. Among all treatment regimens, TOFA-treated mice demonstrated significant weight loss, whereas all other treatment regimens had comparable weight changes compared with vehicle control-treated mice (Figures 9A and 9B). The changes in weight were not due to changes in food intake (Figure 9C). Serum analysis of liver injury biomarkers, such as ALT (Figure 9D) and AST (Figure 9E), revealed that TOFA treatment resulted in similar levels of ALT and AST reductions as filsocostat treatment alone and in combination. Most notably, TOFA treatment strongly reduced hepatic triglyceride levels compared with filsocostat and vehicle control treatments (Figure 9F). TOFA treatment significantly reduced liver injury compared with vehicle control treatment, to a similar or greater extent than filsocostat, fenofibrate, or the combination of the two agents. RT-qPCR analysis further demonstrated specific and comparable responses of TOFA treatment compared with other treatment regimens, including genes involved in inflammation (e.g., Il1b and Il6) and collagen synthesis (e.g., Col1a1 and Col3a) (Figure 9G). Furthermore, TOFA treatment induced a unique increase in downstream targets of PPARA, such as Vldlr and Cpt1a, which was not observed with other treatment regimens (Figure 9G). Western blot analysis of protein expression levels confirmed the RT-qPCR observations, as TOFA treatment increased the protein expression levels of VLDLR and CPT1A to a greater extent than other treatment regimens (Figure 9H). Histological analysis by H&E staining further confirmed our observations of reduced levels of steatosis in the TOFA-treated group compared to controls, and comparable levels of improvement compared to other treatment regimens (Figure 9I).Taken together, these results provide evidence for the use of TOFA as an effective single-regimen dosing with comparable efficacy to leading clinical candidates in the CDAHFD mouse model of diet-induced NAFLD / NASH.

[0130] Example 10. TOFA demonstrates efficacy as a combination agent with other metabolic modulating therapeutics, such as GLP1 receptor agonists method Six-week-old C57BL / 6J male mice were fed an L-amino acid diet (CDAHFD; Research Diets A06071302i) containing 60 kcal% fat, 0.1% methionine, and no added choline for 8 weeks. Mice were randomly assigned to treatment groups receiving vehicle (control), 250 mg / kg TOFA, 5 nmol / kg semaglutide (Novo Nordisk), or a combination dose of 250 mg / kg TOFA and 5 nmol / kg semaglutide. TOFA was administered by oral gavage. Semaglutide dosage was titrated at the beginning of the treatment regimen and delivered via subcutaneous injection in the dorsal / lateral shoulder / neck region. All treatments were delivered QD for an additional 4 weeks. Mouse weight and food intake were monitored throughout the treatment time course. Liver and serum samples were collected at the end of the study at week 12. Serum liver injury biomarkers, ALT and AST, were measured using commercially available kits (abcam105134 and Cayman701640, respectively). Liver and serum triglyceride levels were measured using commercially available kits (abcam65336). Total RNA was extracted from liver tissue (Qiagen RNeasy Kit 74106), and cDNA was prepared according to the manufacturer's protocol (BioRAD iScript™ Reverse Transcription). Quantitative PCR (qPCR) was performed using fast SYBR Green Mix (ThermoFisher A25742) on a QuantStudio6 System (Applied Biosciences). Additional liver samples were fixed in 4% paraformaldehyde, embedded in paraffin blocks for sectioning, and then stained with hematoxylin and eosin (H&E) or Sirius Red with a fast green dye background.

[0131] result Because TOFA exhibits a unique mechanism of action compared with other metabolic modulators such as GLP-1 receptor agonists, we used TOFA in combination with semaglutide (Novo Nordisk) to test its efficacy in a CDAHFD mouse model of diet-induced NAFLD / NASH. Upon initiation of treatment, both the mono- and mono-treated groups and the mono-treated group with semaglutide experienced immediate weight loss, consistent with previous observations of semaglutide as a weight-loss modulator (Figure 10A). At the end of the treatment time course, it was revealed that TOFA-treated mice experienced a smaller degree of weight loss compared with semaglutide-treated mice, whereas the mono- and mono-treated (TOFA and semaglutide) mice experienced a greater weight loss compared with the mono- and mono-treated groups (Figure 10B). The weight change was not due to changes in food intake during the treatment time course (Figure 10C). RT-qPCR analysis of liver samples revealed a specific response of TOFA in addressing inflammation, which was not observed in mice treated with semaglutide alone (Figure 10D). RT-qPCR analysis of genes involved in collagen biosynthesis showed a strong inhibitory effect of both TOFA and semaglutide in reducing mRNA levels, while combination treatment showed a trend toward a further decrease in mRNA expression levels (Figure 10D). Liver triglyceride analysis revealed that, compared with vehicle control treatment, semaglutide-treated mice had a trend toward decreased liver triglyceride levels, while TOFA-treated mice had a stronger, significant reduction in liver triglycerides (Figure 10E). Combination treatment had the greatest reduction in overall liver triglyceride levels (Figure 10E). Analysis of serum ALT showed a similar trend of modest reductions in ALT levels with both single-agent treatment regimens and combination treatment (Figure 10F). Single-agent TOFA treatment was the only group that demonstrated a reduction in serum AST levels, which may be due to non-liver-specific expression of AST, such as in the kidney and cardiac and skeletal muscles, which may contribute to serum AST levels (Figure 10G).Serum biomarker analysis further supports the use of TOFA as an effective therapeutic agent in reducing liver injury, as measured by liver injury biomarkers. Histological analysis by H&E showed a similar trend to that observed, with a moderate reduction in steatosis observed with semaglutide monotherapy, compared with controls, compared with a greater and greatest reduction in steatosis in liver sections treated with TOFA monotherapy (Figure 10H). Similarly, the aforementioned histological trend was observed with Sirius Red staining for fibrotic content (Figure 10I). Overall, TOFA represents a potential candidate for combination with potential clinical leads, with orthogonal targets and mechanisms. The semaglutide-TOFA combination results highlight the tolerability of TOFA in combination, due to the lack of observed drug-drug antagonism and the combination's improvements in addressing shortcomings in the efficacy of semaglutide monotherapy, such as metabolic and inflammatory aspects, based on preliminary observations.

[0132] Example 11 TOFA has unexpected effects compared to other small molecules in its class, including complementary and broad functionality, including PPARA activation. method Six-week-old genetic PPARA knockout (PPARA KO) male mice were fed either a 60 kcal% fat, 0.1% methionine, choline-free L-amino acid diet (CDAHFD; Research Diets A06071302i) for 3 weeks or a 60 kcal% fat diet (DIO; Research Diets A12492i) for 8 weeks, followed by an oral gavage of either vehicle (control) or 125 mg / kg TOFA BID for an additional 2 weeks (Figures 11A and 11J, respectively). C57BL / 6J (WT) mice were fed a CDAHFD and subjected to similar experimental conditions and time course. Mice were monitored for weight and adverse events throughout the treatment time course. Serum and liver samples were collected at the end of the study. Serum liver injury biomarkers, ALT and AST, were measured using commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured using commercially available kits (abcam65336). Total RNA was extracted from liver tissue (Qiagen RNeasy Kit 74106), and cDNA was prepared according to the manufacturer's protocol (BioRAD iScript™ Reverse Transcription). Quantitative PCR (qPCR) was performed using fast SYBR Green Mix (ThermoFisher A25742) on a QuantStudio6 System (Applied Biosciences). Protein expression levels in liver samples were measured by Western blot using antibodies against ACC1 / 2 (CST3662, 1:1000), VLDLR (AF2258, 1:2000), CPT1A (CST12252, 1:1000), PPARA (abcam126285, 1:1000), and beta-tubulin (CST2146, 1:1000). Membranes were developed using an HRP secondary antibody (1:5000) and visualized using enhanced chemiluminescence HRP substrate (Thermo34577).Additional liver samples were fixed in 4% paraformaldehyde and embedded in paraffin blocks for sectioning, followed by staining with hematoxylin and eosin (H&E). Freshly frozen liver tissue was embedded in OCT, sectioned, and subsequently stained with Oil Red O.

[0133] result In a murine CDAHFD diet-induced model of NAFLD / NASH with PPARA KO, the TOFA treatment regimen resulted in an overall trend toward weight loss (Figure 11B). Analysis of serum biomarkers of liver injury, such as ALT and AST, revealed a slight decrease in ALT and AST levels (Figure 11E and Figure 11D, respectively). Furthermore, liver triglyceride analysis did not demonstrate a significant decrease in liver lipid levels (Figure 11E), in contrast to observations in previous studies in wild-type mice (Figure 3C and Figure 8E). RT-qPCR analysis of Cpt1a, a gene involved in fatty acid beta-oxidation, revealed that induction of Cpt1a mRNA was specific to TOFA treatment in wild-type mice, and this upregulation response by TOFA treatment was blunted in PPARA KO mice (Figure 11F). This observation is further supported by Western blot analysis of protein expression levels of selected proteins, such as CPT1A, VLDLR, and ACC1, all of which are direct transcriptional targets of PPAR-alpha. Protein expression levels of the aforementioned proteins were increased in TOFA-treated wild-type mice compared with their respective vehicle-treated counterparts; however, this response was not observed in TOFA-treated PPARA KO mice (Figure 11G). Histological analysis by H&E revealed minimal reduction in hepatic steatosis (Figure 11H) and minimal changes in lipid content by Oil Red O (Figure 11I). Both of these histological observations are strikingly different from previous observations with TOFA treatment in wild-type mice (Figure 3F). Together, these results provide evidence for a unique mechanistic reliance of TOFA on the PPARA signaling network to mediate its beneficial effects in a diet-induced NAFLD / NASH model. In a diet-induced obesity (DIO) model utilizing a 60% HFD, TOFA treatment in PPARA KO mice caused weight loss at the onset of treatment (Figure 11K) and resulted in significant differences in total body weight change throughout the course of treatment (Figure 11L). Adverse events were observed in PPAR KO mice treated with TOFA over the 2-week treatment period (Figure 6M).Serum triglyceride analysis of control and TOFA-treated PPARA KO mice revealed elevated serum lipid levels in TOFA-treated mice (Figure 6N). These observations, given the known role of PPARA in lowering serum triglyceride levels, suggest a mechanistic reliance of TOFA on PPARA to counteract such adverse effects. RT-qPCR analysis of Vldlr, a gene involved in lipoprotein uptake and under the transcriptional control of PPARA, showed a blunted response in TOFA-treated PPARA KO mice (Figure 6O), which is unexpected given the consistent upregulation of Vldlr in HFD-fed wild-type mice treated with TOFA (Figure 7i). Histological comparison of H&E-stained liver sections from control-treated and TOFA-treated PPARA KO mice showed minimal changes in hepatic steatosis, further supporting the notion that the effects of TOFA treatment are blunted in the absence of PPARA (Figure 11P). To our knowledge, our results provide the first empirical evidence for the unexpected mechanistic reliance of TOFA on PPARA signaling in addressing severe metabolic disease in a mouse diet-induced disease model.

[0134] While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step(s), to the objective, spirit, and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

1. A pharmaceutical composition for treating metabolic disorders in an individual, comprising formula I as a single stereoisomer or a mixture thereof. The pharmaceutical composition comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof: During the ceremony, R 1 is -O-R 2 、-O-R 3 -OR 2 、-O-R 3 -OC(O)-N(R 5 )R 6 、-O-R 3 -N(R 5 )R 6 、-O-R 3 -N(R 4 )C(O)OR 5 、-O-R 3 -C(O)OR 5 、-O-R 3 -C(O)N(R 5 )R 6 、or -N(R 5 )S(O) 2 -R 4 ; Each R 2 These are independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 3 These are independently substituted alkylene chains; R 4 is an optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 5 These are independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; Each R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 4 is, or Any R 5 and R 6 These, together with the nitrogen to which they are bound, form an optionally substituted N-heterocycline or optionally substituted N-heteroaryl.

2. The pharmaceutical composition according to claim 1, wherein the compound is 5-(tetradecyloxy)-2-furoic acid.

3. The pharmaceutical composition according to claim 1, wherein the metabolic disorder is insulin resistance, hyperglycemia, type 2 diabetes mellitus, obesity, fatty liver disease, glucose intolerance, hyperinsulinemia, metabolic syndrome, or hypertension.

4. The pharmaceutical composition according to claim 1, wherein the metabolic disorder includes insulin resistance.

5. The pharmaceutical composition according to claim 1, wherein the metabolic disorder includes metabolic syndrome.

6. The pharmaceutical composition according to claim 1, wherein the metabolic disorder includes type 2 diabetes mellitus.

7. The pharmaceutical composition according to claim 1, wherein the individual has a body mass index of >30.

0.

8. The pharmaceutical composition according to claim 1, which results in serum insulin levels within the normal range.

9. The pharmaceutical composition according to claim 1, which results in blood glucose levels within the normal range.

10. The pharmaceutical composition according to claim 1, administered in combination with at least one additional therapeutic agent.

11. The pharmaceutical composition according to claim 10, wherein the at least one additional therapeutic agent is insulin, an insulin analog, a biguanidine, or a thiazolidinedione.

12. A pharmaceutical composition according to claim 1, which is administered orally.

13. The pharmaceutical composition according to claim 1, which is administered daily.

14. The pharmaceutical composition according to claim 1, administered once a week.

15. The pharmaceutical composition according to claim 1, administered via controlled delivery.

16. The pharmaceutical composition according to claim 15, which is present in an implantable delivery device.

17. A pharmaceutical composition for treating metabolic syndrome in an individual, comprising formula I as a single stereoisomer or a mixture thereof. The pharmaceutical composition comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof: During the ceremony, R 1 is -OR 2 , -OR 3 -OR 2 , -OR 3 -OC(O)-N(R 5 )R 6 , -OR 3 -N(R 5 )R 6 , -OR 3 -N(R 4 )C(O)OR 5 , -OR 3 -C(O)OR 5 , -OR 3 -C(O)N(R 5 )R 6 , or -N(R 5 )S(O) 2 -R 4 And; Each R 2 These are independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 3 These are independently substituted alkylene chains; R 4 is an optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Each R 5 These are independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl; Each R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, or -R 3 -C(O)OR 4 is, or Any R 5 and R 6 These, together with the nitrogen to which they are bound, form an optionally substituted N-heterocycline or optionally substituted N-heteroaryl.

18. The pharmaceutical composition according to claim 17, wherein the compound is 5-(tetradecyloxy)-2-furoic acid.

19. The pharmaceutical composition according to claim 17, which is administered orally.

20. The pharmaceutical composition according to claim 17, which is administered daily.

21. The pharmaceutical composition according to claim 17, administered once a week.

22. The pharmaceutical composition according to claim 17, administered via controlled delivery.

23. The pharmaceutical composition according to claim 22, which is present in an implantable delivery device.

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