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.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 393,585, filed on July 29, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Nonalcoholic fatty liver disease (NAFLD) has become a major source of liver disease worldwide. Clinically, NAFLD describes a spectrum of liver events from moderate lipid accumulation to more aggressive steatosis with 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 inflammation, fibrosis, and cirrhosis stage of nonalcoholic steatohepatitis (NASH).

[0004] Metabolic disorders such as insulin resistance, hyperglycemia, type 2 diabetes, obesity, fatty liver disease, glucose intolerance, hyperinsulinemia, metabolic syndrome and hypertension are major health problems.

[0005] There is a need in the art for methods of treating metabolic disorders. Summary of the invention

[0006] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figures 1A-1C The dose-dependent effect of TOFA treatment in mice with CDAHFD-induced NAFLD progression was elucidated.

[0008] Figure 2A-2I The effect of TOFA treatment on the progression of 60% kcal fat diet-induced metabolic syndrome and early NAFLD was elucidated.

[0009] Figures 3A-3F The rescue effect of TOFA treatment in CDAHFD-induced advanced NAFLD / NASH progression mice was shown.

[0010] Figures 4A-4E Shown are the results of RNA sequencing of liver samples from CDAHFD-induced advanced NAFLD / NASH mice treated with TOFA.

[0011] Figure 5A-5G The safety and tolerability profile of TOFA treatment in mice fed a free-feed diet was elucidated.

[0012] Figures 6A-6HThe dose-dependent effect of TOFA treatment in mice with diet-induced obesity using a 60% HFD diet model was elucidated.

[0013] Figures 7A-7D Shown is a transcriptional analysis of gene changes from TOFA treatment in the liver of a 60% HFD diet-induced obesity mouse model.

[0014] Figures 8A-8I An in-depth analysis of the therapeutic efficacy of TOFA in the CDAHFD diet-induced NAFLD / NASH mouse model is shown.

[0015] Figures 9A-9I Baseline efficacy comparisons of TOFA compared to vehicle control, Firsocostat, Fenofibrate, and combination treatment of Firsocostat and Fenofibrate are shown.

[0016] Figures 10A-10I Therapeutic efficacy studies of TOFA and Semaglutide as single agent treatments and in combination are shown.

[0017] Figures 11A-11P The effects of TOFA in the genetic PPARA knockout model on models of NAFLD / NASH and DIO induced by both CDAHFD and 60% kcal fat (HFD) diets, respectively, are shown.

[0018] definition

[0019] The terms "diabetes" and "diabetic" refer to a progressive disease of sugar metabolism involving insufficient production or utilization of insulin, which is often characterized by hyperglycemia and glycosuria. The terms "prediabetes" and "prediabetic" refer to a state in which a subject does not have the characteristics, symptoms, etc. typically observed in diabetes, but does have the characteristics, symptoms, etc. that can develop into diabetes if not treated. The presence of these conditions can be determined using, for example, a fasting plasma glucose (FPG) test or an oral glucose tolerance test (OGTT). Both typically require the subject to fast for at least 8 hours before starting the test. In the FPG test, the subject's blood sugar is measured after the fast ends; typically, the subject fasts overnight, and blood sugar is measured in the morning before the subject eats. Healthy subjects will typically have an FPG concentration between about 90 and about 100 mg / dl, subjects with "prediabetes" will typically have an FPG concentration between about 100 and about 125 mg / dl, and subjects with "diabetes" will typically have an FPG level higher than about 126 mg / dl. In OGTT, the blood glucose of the subject is measured after fasting, and is measured again two hours after drinking a beverage rich in glucose. Two hours after drinking a beverage rich in glucose, healthy subjects usually have a blood glucose concentration of about 140 mg / dl or less, prediabetes subjects usually have a blood glucose concentration of about 140 to about 199 mg / dl, and diabetic patients usually have a blood glucose concentration of more than 200 mg / dl. Although the aforementioned blood glucose values ​​are applicable to human subjects, in rodent subjects, normal blood glucose, moderate hyperglycemia and dominant hyperglycemia are calibrated differently. Healthy rodent subjects after fasting for 4 hours will usually have an FPG concentration between about 100 and about 150 mg / dl, rodent subjects with "prediabetes" will usually have an FPG concentration between about 175 and about 250 mg / dl, and mice subjects with "diabetes" will usually have an FPG concentration higher than about 250 mg / dl.

[0020] As used herein, the term "insulin resistance" refers to a condition in which normal amounts of insulin do not produce a normal physiological or molecular response. In some cases, supraphysiological amounts of insulin, whether endogenously produced or exogenously administered, can fully or partially overcome insulin resistance and produce a biological response.

[0021] The term "metabolic syndrome" refers to a cluster of associated features including, but not limited to, hyperinsulinemia, impaired glucose tolerance, obesity, redistribution of fat to abdominal or upper body compartments, hypertension, dysfibrinolysis, and dyslipidemia, characterized by high triglycerides, low high-density lipoprotein (HDL)-cholesterol, and high small, dense low-density lipoprotein (LDL) particles. Subjects with metabolic syndrome are at risk for developing type 2 diabetes and / or other disorders such as atherosclerosis.

[0022] The term "disease of glucose metabolism" includes any disorder characterized by clinical symptoms or a combination of clinical symptoms associated with elevated glucose levels and / or elevated insulin levels in a subject relative to healthy individuals. Elevated glucose and / or insulin levels may be manifested, inter alia, in the following diseases, disorders and conditions: 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, which is also known as syndrome X) and obesity. The polypeptides of the present disclosure and compositions thereof may be used, for example, to achieve and / or maintain glucose homeostasis, e.g., to reduce glucose levels in the bloodstream and / or reduce insulin levels to the range found in healthy subjects.

[0023] As used herein, the term "hyperglycemia" refers to a condition in which the amount of circulating glucose in a subject's plasma is elevated relative to a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including measurement of fasting blood glucose levels as described herein.

[0024] As used herein, the term "hyperinsulinemia" refers to a condition in which the level of circulating insulin is elevated while blood glucose levels are elevated or normal. Hyperinsulinemia can be caused by 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 levels; polycystic ovary syndrome; type 2 diabetes and obesity. Hyperinsulinemia can be diagnosed when the plasma insulin level is above about 2 μU / mL.

[0025] As used herein, the phrase "weight disorder" refers to a condition associated with excess weight and / or increased appetite. Various parameters are used to determine whether a subject is overweight compared to a reference healthy individual, including the subject's age, height, sex, and health status. For example, by assessing the subject's body mass index (BMI), which is calculated by dividing the subject's weight in kilograms by the subject's height in square meters, a subject can be considered overweight or obese. A person having a BMI of about 18.5 kg / m 2 About 24.9kg / m 2Adults with a BMI within the range of 25 kg / m 2 About 29.9kg / m 2 Adults with a BMI between 30 kg / m 2 Adults with a BMI above 1000 Å can be considered obese. Increased appetite often leads to excess weight. There are several conditions associated with increased appetite, including, for example, night eating disorder, which is characterized by anorexia in the morning and polyphagia in the evening, often associated with insomnia, but which may involve hypothalamic damage.

[0026] As used herein, the terms "treatment", "treating" and the like refer to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing a disease and / or an adverse reaction attributable to the disease. As used herein, "treatment" encompasses any treatment of a disease in a mammal, such as a human, and includes: (a) preventing the occurrence of a disease in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease, i.e., preventing its development; and (c) alleviating the disease, i.e., causing regression of the disease.

[0027] The terms "individual", "subject", "host" and "patient" are used interchangeably herein and refer to individual organisms, such as mammals, including but not limited to rodents, apes, humans, non-human primates, ungulates, felines, canines, cattle, sheep, mammalian domestic animals, mammalian sports animals and mammalian pets. In some cases, the "individual" is a human.

[0028] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, and therefore can certainly be varied. It should also be understood that the nomenclature used herein is only for the purpose of describing specific embodiments and is not intended to be limiting, as the scope of the present invention will only be limited by the appended claims.

[0029] Where a range of values ​​is provided, it is understood that unless the context clearly dictates otherwise, each intervening value, to one tenth of the unit of the lower limit, between the upper and lower limits of the range and any other specified or intermediate value in the range is included in the present invention. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also included in the present invention, but are subject to any explicitly excluded limitations in the range. When the range includes one or two limits, ranges excluding either or both of those included limits are also included in the present invention.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials associated with the cited publications.

[0031] It must be noted that the singular forms "a / an" and "the" used herein and in the appended claims include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a compound of Formula I" includes a plurality of such compounds, and reference to "a metabolic disorder" includes reference to one or more metabolic disorders and their equivalents known to those skilled in the art, etc. It is also noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as a prior basis for the use of such exclusive terms such as "solely," "only," etc., or the use of a "negative" limitation in connection with the recitation of claim elements.

[0032] Unless otherwise specified herein or clearly contradictory to the context, the terms "a / an", "the" and similar indicators are to be interpreted as covering both the singular and the plural in the context of describing the present disclosure (particularly in the context of the following claims). Unless otherwise specified, the terms "comprising", "having", "including" and "containing" should be interpreted as open terms (i.e., meaning "including, but not limited to"). Unless otherwise specified herein, the recording of the range of values ​​herein is only intended to serve as a shorthand method for individually quoting each individual value falling within the range, and each individual value is included in this specification as if it is recorded separately herein. For example, if the range 10-15 is disclosed, then 11, 12, 13 and 14 are also disclosed. Unless otherwise specified herein or clearly contradictory to the context, all methods described herein can be performed in any suitable order. Unless otherwise stated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is only intended to better illustrate the embodiments of the present disclosure, rather than to limit the scope of the present disclosure. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the embodiments of the disclosure.

[0033] As used herein, the term "about" used in relation to an amount indicates that the amount may vary by 10% of the amount described. For example, "about 100" means an amount of 90-110. When about is used in the context of a range, "about" is used to refer to a lower amount of a range to mean that the lower amount includes an amount that is 10% lower than the lower amount of the range, and "about" is used to refer to a higher amount of a range to mean that the higher amount includes an amount that is 10% higher than the higher amount of the range. For example, about 100 to about 1000 means that the range extends to 90 to 1100.

[0034] As used herein, the term "and / or" phrases such as "A and / or B" are intended to include both A and B; A or B; A (alone); and B (alone). Similarly, as used herein, the term "and / or" phrases such as "A, B, and / or C" are intended to include 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).

[0035] It should be understood that the aspects and embodiments of the present disclosure described herein include "comprising the aspects and embodiments," "consisting of the aspects and embodiments," and "consisting essentially of the aspects and embodiments."

[0036] It will be appreciated that certain features of the invention, which for clarity are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of embodiments relating to the invention are expressly included by the invention and are disclosed herein, just as if each and every combination were individually and expressly disclosed. In addition, all subcombinations of the various embodiments and elements thereof are also expressly included by the invention and are disclosed herein, just as if each and every such subcombination were individually and expressly disclosed herein.

[0037] The publications discussed herein are provided only 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 publications by virtue of prior invention. In addition, the publication dates provided may be different from the actual publication dates, which may require independent confirmation. DETAILED DESCRIPTION

[0038] 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.

[0039] TOFA and TOFA analogs

[0040] In some cases, the present disclosure provides a method of treating a metabolic disorder in an individual, the method 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:

[0041]

[0042] In some cases, the disclosure provides a method of treating a metabolic disorder in an individual, the method comprising administering to the patient a therapeutically effective amount of an analog of TOFA. For example, in some cases, the method of the disclosure comprises administering a compound of formula I:

[0043]

[0044] Where: R 1 For-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 ;

[0045] Each R 2 R 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 is 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 ; or any R 5 and R 6 Together with the nitrogen to which they are both attached, they form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; the compound of formula I is in the form of a single stereoisomer or a mixture thereof or a pharmaceutically acceptable salt thereof.

[0046] Certain chemical groups named herein may be preceded by abbreviated symbols indicating the total number of carbon atoms to be found in the indicated chemical group. 12 Alkyl describes an alkyl group as defined below, having a total of 7 to 12 carbon atoms, and C4-C 12 Cycloalkylalkyl describes 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 be present in substituents of the group being described.

[0047] In addition to the above, unless specified to the contrary, the following terms have the indicated meanings: "amino" refers to a —NH2 residue. "cyano" refers to a —CN residue. "hydroxy" refers to an —OH residue. "imino" refers to an —NH substituent. "nitro" refers to a —NO2 residue. "Oxo" refers to an —O substituent. "thio" refers to an —S substituent. "trifluoromethyl" refers to a —CF3 residue.

[0048] "Alkyl" refers to a straight or branched hydrocarbon chain residue consisting only 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 connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise specifically stated in the specification, an alkyl group may be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, —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; and each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0049] "Alkylene chain" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a residual group, consisting only of carbon and hydrogen, containing no unsaturation and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and to the residual group by a single bond. The points of connection of the alkylene chain to the rest of the molecule and to the residual group can be through one carbon or any two carbons within the chain. Unless otherwise expressly stated in the specification, the alkylene chain can be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -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; and each R 16is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0050] "Aryl" refers to the residue of a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, an aryl residue can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl residues include, but are not limited to, acenaphthene, acenaphthene, acenaphthene, anthracene, azulene, benzene, The term "aryl" or the prefix "ar-" (as in "aralkyl") is intended to include aryl residues optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, heteroaryl, heteroarylalkyl, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -R, -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), where each R14 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0051] "Arylalkyl" refers to a group of the formula -R b —R c The residues, R b is an alkylene chain as defined above and R c is one or more aryl residues as defined above, for example benzyl, diphenylmethyl, etc. The alkylene chain part of the aralkyl residue may be optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl residue may be optionally substituted as described above for the aryl group.

[0052] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon residue consisting only of carbon and hydrogen atoms, which may include a fused or bridged ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and which is saturated or unsaturated and is connected to the rest of the molecule by a single bond. Monocyclic residues include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic residues include, for example, adamantyl, norbornyl, decahydronaphthyl, etc. Unless otherwise expressly stated in the specification, the term "cycloalkyl" is intended to include cycloalkyl residues optionally substituted by one or more substituents independently selected from the group consisting of 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 ,—R15 —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), where each R 14 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0053] "Halo" refers to bromo, chloro, fluoro or iodo.

[0054] "Haloalkyl" refers to an alkyl residue as defined above substituted with one or more halo residues as defined above, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc. The alkyl portion of the haloalkyl residue may be optionally substituted as defined above for an alkyl group.

[0055] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring residue consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified in the specification, the heterocyclyl residue 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 residue can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl residue can be partially or fully saturated. Examples of such heterocyclyl residues include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxo-1,3-dioxol-4-yl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofurfuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise indicated in the specification, the term "heterocyclyl" is intended to include heterocyclyl residues as defined above, optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thio, 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. —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), where each R 14 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0056] "N-heterocyclyl" refers to a heterocyclyl residue as defined above, which contains at least one nitrogen and wherein the point of attachment of the heterocyclyl residue to the rest of the molecule is through the nitrogen atom in the heterocyclyl residue. N-heterocyclyl residues may be optionally substituted as described above for heterocyclyl residues.

[0057] "Heterocyclylalkyl" refers to a group of the formula: b R h The residues, R b is an alkylene chain as defined above and R h is a heterocyclyl residue as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene chain at the nitrogen atom. The alkylene chain of the heterocyclylalkyl residue may be optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl residue may be optionally substituted as defined above for the heterocyclyl group.

[0058] "Heteroaryl" refers to a 5- to 14-membered ring system residue containing hydrogen atoms, 1 to 13 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and at least one aromatic ring. For the purposes of the present invention, heteroaryl residues can be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl residue can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepine, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinetrienyl, oxazolyl, oxirane, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 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 / thienyl. Unless expressly stated otherwise in the specification, the term "heteroaryl" is intended to include heteroaryl residues as defined above, optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thio, 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 142. —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), where each R 14 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0059] "N-heteroaryl" refers to a heteroaryl residue as defined above, which contains at least one nitrogen and wherein the point of attachment of the heteroaryl residue to the rest of the molecule is through a nitrogen atom in the heteroaryl residue. N-heteroaryl residues may be optionally substituted as described above for heteroaryl residues.

[0060] "Heteroarylalkyl" refers to a group of the formula: b R i The residues, R b is an alkylene chain as defined above and R i is a heteroaryl residue as defined above. The heteroaryl part of the heteroarylalkyl residue may be optionally substituted as defined above for a heteroaryl group. The alkylene chain part of the heteroarylalkyl residue may be optionally substituted as defined above for an alkylene chain.

[0061] "Optional" or "optionally" means that the subsequently described event may or may not occur, and is intended to describe situations that include situations where the event or situation occurs as well as situations where it does not occur. For example, "optionally substituted aryl" means that the aryl residue may or may not be substituted, and is intended to describe situations that include substituted aryl residues and unsubstituted aryl residues. When a functional group is described as "optionally substituted", the substituents on the functional group are in turn "optionally substituted", and so on, for purposes of the present invention, such iterations are limited to five times, preferably such iterations are limited to two times.

[0062] "Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0063] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0064] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases which are biologically or otherwise undesirable, as well as salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and salts formed with organic acids such 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, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2- Hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic 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, etc.

[0065] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids that are 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 salts, 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, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, N,N-dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenylethylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Examples of organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0066] "Pharmaceutical composition" refers to a preparation of a compound and a medium generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such a medium may include a pharmaceutically acceptable carrier, diluent, or excipient.

[0067] A "therapeutically effective amount" refers to an amount of a compound that, when administered to a mammal, such as a human, is sufficient to effectively treat the disease or condition of interest in a mammal, such as a human, that suffers from the disease or condition. The amount of a compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease or condition and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art, given his own knowledge and this disclosure.

[0068] The compounds disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomeric forms which may be defined from an absolute stereochemical perspective as (R)- or (S)-, or (D)- or (L)- for amino acids. The compounds disclosed herein are intended 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 may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). Unless otherwise specified, when the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0069] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. 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 each other.

[0070] The use of brackets in a substituent group is used herein to save space. Thus, the use of brackets in a substituent group indicates that the group within the brackets is directly attached to the atom preceding the brackets.

[0071] Among the compounds of formula (I), one embodiment is a compound of formula (I), wherein: R 1 For-O-R 2 ; and R 2 is independently alkyl or heterocyclylalkyl. In this embodiment, one embodiment is a compound of formula (I) selected from the group consisting of 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.

[0072] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 For-O-R 2 ; and R 2is a haloalkyl or substituted aryl. In this embodiment, one embodiment is a compound of formula (I) selected from the group consisting of 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.

[0073] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 For-O-R 3 —OR 2 ; R 2 is optionally substituted heterocyclylalkyl; and R 3 is an optionally substituted alkylene chain. Within this embodiment, one embodiment is a compound of formula (I) which is 3-(tetrahydro-2H-pyran-2-yloxy)propyl 5-(tetradecyloxy)furan-2-carboxylate.

[0074] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 For-O-R 3 —OC(O)—N(R 5 )R 6 ; Each R 2 R is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; 3 is an optionally substituted alkylene chain; and R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or -R 3 —C(O)OR 3 ; and / or any R 5 and R 6Together with the nitrogen to which they are both attached, they form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl. In this embodiment, one embodiment is a compound of formula (I) selected from the following: 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-(3-phenylpyrrolidine-1-carboxylate; 1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl ester; 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.

[0075] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 For-O-R 3 —N(R 5 )R 6 ; R 3 is an optionally substituted alkylene chain; and R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or -R 3 —C(O)OR 4 ; and / or any R 5 and R 6 Together with the nitrogen to which they are both connected, an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl is formed. In this embodiment, an embodiment is a compound of formula (I) selected from: 2-(dimethylamino)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-morpholinylethyl 5-(tetradecyloxy)furan-2-carboxylate; or 3-morpholinylpropyl 5-(tetradecyloxy)furan-2-carboxylate.

[0076] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 For-O-R3 —N(R 4 )C(O)OR 5 ; R 3 is an optionally substituted alkylene chain; and R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.

[0077] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 For-O-R 3 —C(O)OR 5 ; R 3 is an optionally substituted alkylene chain; and R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.

[0078] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 For-O-R 3 —C(O)N(R 5 )R 6 ; R 3 is an optionally substituted alkylene chain; and R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or -R 3 —C(O)OR 4 ; or any R 5 and R 6Together with the nitrogen to which they are both attached, they form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl. In this embodiment, one embodiment is a compound of formula (I) selected from the following: 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-phenylpiperazine-1-yl)-5-(tetradecyloxy)furan-2-carboxylate. 1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylic acid (S)-benzyl 1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylate.

[0079] In the compound of formula (I), another embodiment is a compound of formula (I), wherein: R 1 N(R 5 )S(O)2—R 4 ; R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and R 5 is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl. Within this embodiment, one embodiment is a compound of formula (I) which is 5-(tetradecyloxy)-N-tosylfuran-2-carboxamide.

[0080] Among the pharmaceutical compositions, one embodiment is wherein the pharmaceutical composition is an oral composition, which comprises an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0081] Pharmaceutical composition

[0082] The compound of formula I, or a pharmaceutically acceptable salt thereof, may be in the form of a composition suitable for administration to a subject. Typically, such a composition is a "pharmaceutical composition" comprising a compound of formula I (or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In some cases, the compound of formula I (or a pharmaceutically acceptable salt thereof) is present in a therapeutically effective amount. The pharmaceutical composition may be used in the methods of the present disclosure; thus, for example, the pharmaceutical composition may be administered to a subject to practice the therapeutic and preventive methods and uses described herein.

[0083] 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 provided herein. In addition, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds described herein (e.g., hypoglycemic agents) to treat or prevent diseases, disorders, and conditions contemplated by the present disclosure.

[0084] The pharmaceutical composition typically comprises a therapeutically effective amount of a compound of formula I (or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable 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, methyl parabens, ethyl or n-propyl paraben), emulsifiers, suspending agents, dispersants, solvents, fillers, expanders, detergents, buffers, solvents, diluents and / or adjuvants. For example, a suitable solvent may be a physiological saline solution or citrate buffered saline, which may be supplemented with other substances commonly used for parenteral administration in a pharmaceutical composition. Neutral buffered saline or saline mixed with serum albumin is another exemplary solvent. Those skilled in the art will readily appreciate the various buffers that can be used in pharmaceutical compositions and dosage forms. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer component can be a water-soluble material such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffers 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).

[0085] After the pharmaceutical composition is formulated, it can be stored in a sterile vial in the form of a solution, suspension, gel, emulsion, solid, dehydrated or lyophilized powder. Such a formulation can be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a disposable container (e.g., a disposable vial, ampoule, syringe, or autoinjector (similar to, for example, an EpiPen). TM )), while in other embodiments multiple use containers (e.g., multiple use vials) are 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 the skilled person. Depot injections, which are usually administered subcutaneously or intramuscularly, can also be used to release the polypeptides disclosed herein within a limited time. Depot injections are usually solid-based or oil-based, and usually include at least one formulation component proposed herein. Those of ordinary skill in the art are familiar with the possible formulations and uses of depot injections.

[0086] The pharmaceutical composition can be present in the form of a sterile injectable aqueous or oleagenous suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned herein. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable diluents, solvents and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, phosphate buffered saline (PBS), ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof. In addition, sterile, non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil that can be used includes synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. By including an agent that delays absorption (e.g., aluminum monostearate or gelatin), extended absorption of a special injectable preparation can be achieved.

[0087] Pharmaceutical compositions containing active ingredients (e.g., compounds of Formula I (or pharmaceutically acceptable salts thereof)) can be in a form suitable for oral use, such as tablets, capsules, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents, such as sweeteners, flavoring agents, coloring agents and preservatives, to provide pharmaceutically refined and palatable formulations. Tablets, capsules, etc. contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch, or alginic acid; adhesives such as starch, gelatin or gum arabic, and lubricants such as magnesium stearate, stearic acid or talc.

[0088] Tablets, capsules, etc. suitable for oral administration can be uncoated or coated by known technology to delay disintegration and absorption in the gastrointestinal tract and thereby provide lasting effect.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be adopted.They can also be coated by technology known in the art to form osmotic therapeutic tablets for controlled release.Other reagents include biodegradable or biocompatible particles or polymeric substances, such as polyester, polyamino acid, hydrogel, polyvinyl pyrrolidone, polyanhydride, polyglycolic acid, ethylene vinyl acetate, methylcellulose, carboxymethyl cellulose, protamine sulfate or lactide / glycolide copolymer, polylactide / glycolide copolymer or ethylene vinyl acetate copolymer, to control the delivery of the composition used.For example, oral medicaments can be embedded in microcapsules prepared by coacervation technology or by interfacial polymerization, respectively by using hydroxymethyl cellulose or gelatin-microcapsules or poly (methyl methacrylate) microcapsules, or in colloidal drug delivery systems. Colloidal dispersion systems include macromolecular 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. Pat. Nos. 4,235,871, 4,501,728, and 4,837,028. The preparation methods of the above-mentioned formulations will be apparent to those skilled in the art.

[0089] Formulations for oral use may also 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.

[0090] Aqueous suspensions contain active substances mixed with excipients suitable for their manufacture. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of olefin oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain fatty alcohols (e.g., heptadecaethyleneoxyhexadecanoate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0091] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions can contain thickeners, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those mentioned above, and flavoring agents can be added to provide a palatable oral formulation.

[0092] 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, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0093] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soy, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0094] The formulation may also include carriers to protect the composition from 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 may be used.

[0095] In some cases, the compound of Formula I (or a pharmaceutically acceptable salt thereof) is not formulated for topical administration.

[0096] method

[0097] The methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0098] "Therapeutically effective amount" refers to administering a medicament to a subject alone or as part of a pharmaceutical composition, in a single dose or as part of a series of doses, in an amount that can have any detectable, positive effect on any symptom, aspect or characteristic of a disease, disorder or condition when administered to a patient. The therapeutically effective amount can be determined by measuring the relevant physiological effects. In some cases, for example, in the case of hyperglycemic conditions, lowering or reducing blood sugar or improving a glucose tolerance test can be used to determine whether the amount of the medicament is effective for treating hyperglycemic conditions. The therapeutically effective amount can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the subject's condition, etc. Unless expressly stated otherwise, "compound of Formula I" is intended to include pharmaceutically acceptable salts of the compound of Formula I.

[0099] In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to reduce or lower any level (e.g., baseline level) of fasting plasma glucose (FPG) when administered in one or more doses, wherein, for example, the amount is sufficient to reduce FPG levels above 200 mg / dl to below 200 mg / dl, wherein the amount is sufficient to reduce FPG levels between 175 mg / dl and 200 mg / dl to below the starting level, wherein the amount is sufficient to reduce FPG levels between 150 mg / dl and 175 mg / dl to below the starting level, wherein the amount is sufficient to reduce FPG levels between 125 mg / dl and 150 mg / dl to below the starting level, and so on (e.g., reducing FPG levels to below 125 mg / dl, to below 120 mg / dl, to below 115 mg / dl, to below 110 mg / dl, etc.).

[0100] 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 lower hemoglobin A1c (HbA1c) levels by more than about 10% to 9%, more than about 9% to 8%, more than about 8% to 7%, more than about 7% to 6%, more than about 6% to 5%, etc. In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to reduce or lower 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.

[0101] In some cases, a therapeutically effective amount of a compound of Formula I is an amount sufficient to result in insulin levels within the normal range when administered in one or more doses.

[0102] In some cases, the therapeutically effective amount of a compound of Formula I is an amount sufficient to cause serum alanine aminotransferase (ALT) levels to be within the normal range when administered at one or more doses. In some cases, the 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% when administered at one or more doses, compared to serum ALT levels before treatment. In some cases, the therapeutically effective amount of a compound of Formula I is an amount sufficient to cause serum aspartate aminotransferase (AST) to be within the normal range when administered at one or more doses. In some cases, the therapeutically effective amount of a compound of Formula I is an amount sufficient 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% when administered at one or more doses, compared to serum AST levels before treatment.

[0103] In some cases, the effective amount of a compound of Formula I is an amount that produces the desired result relative to a healthy subject when administered to a subject at one or more doses. For example, an effective dose can be a dose that achieves a desired reduction relative to the blood glucose and insulin of a healthy subject when administered to a subject with elevated blood glucose and / or plasma insulin, reducing 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%, at least about 60%, at least about 70%, at least about 80% or more than 80%.

[0104] Route of administration

[0105] 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.

[0106] dose

[0107] Formula I compound can be administered to the subject in an amount depending on, for example, the target of administration (e.g., the desired degree of elimination); the age, weight, sex, and health and physical condition of the subject to be treated; the characteristics of the compound and / or the administered preparation; the route of administration; and the characteristics of the disease, disorder, illness, or its symptom (e.g., the severity of glucose / insulin imbalance and the stage of disorder). The dosage regimen can also take into account the presence, characteristics, and degree of any adverse reactions associated with the administered (one or more) medicaments. Effective dose amounts and dosage regimens can be easily determined from, for example, safety and dose escalation tests, in vivo studies (e.g., animal models), and other methods known to the technician.

[0108] Typically, dosing parameters specify a dosage amount that is below the amount that may be irreversibly toxic to the subject (i.e., the maximum tolerated dose, "MTD") and not less than the amount required to produce a measurable effect on the subject. Such an amount is determined by, for example, pharmacokinetic and pharmacodynamic parameters ("ADME") related to absorption, distribution, metabolism, and excretion, taking into account the route of administration and other factors.

[0109] The effective dose (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect in a portion of the subjects taking the drug. The "half effective dose" or ED50 of a drug refers to the dose or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which the drug is administered. Although ED50 is generally used as a measure of reasonable expectations of the effect of a drug, it is not necessarily a dose that a clinician may consider appropriate considering all relevant factors. Therefore, in some cases, the effective amount is greater than the calculated ED50, in other cases, the effective amount is less than the calculated ED50, and in other cases, the effective amount is the same as the calculated ED50.

[0110] An appropriate dosage level will generally be about 0.001 to 100 mg / kg patient body weight per day, which can be administered in single or multiple doses.

[0111] In some cases, the dosage level will be about 0.01 to about 25 mg / kg / day, and in other embodiments about 0.05 to about 10 mg / kg / day per day. Suitable dosage levels may be about 0.01 to 25 mg / kg / day, or about 0.05 to 10 mg / kg / day, or about 0.1 to 5 mg / kg / day. Within this range, the dosage may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0 mg / kg / day.

[0112] In some cases, the therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, stereoisomer, or isomer thereof is about 25 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, or about 400 mg / day. In some embodiments, the therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, stereoisomer, or isomer thereof is about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, or about 400 mg / day. In some embodiments, the therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, stereoisomer, or isomer thereof is up to 25 mg / day, up to 50 mg / day, up to 75 mg / day, up to 100 mg / day, up to 150 mg, up to 200 mg, up to 400 mg / day, up to 600 mg / day, up to 800 mg / day, or up to 1000 mg / day. In some embodiments, the therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is up to 400 mg / day.

[0113] For oral administration, the composition can be provided in the form of tablets, capsules, etc., containing 1.0 to 1000 mg 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 mg of active ingredient. For example, the compound of formula I can be administered 1 to 4 times a day, and often once or twice a day.

[0114] Depending on the pharmacokinetics (e.g., half-life) and pharmacodynamic response (e.g., duration of the therapeutic effect of the compound) of the compound, the dosage of the compound of formula I may be repeated at an appropriate frequency, which may be within the range of once a day to once every three months. In some cases, repeated administration is often between once a week and once every three months. In other cases, the compound of formula I is administered approximately once a month.

[0115] 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 the compound of Formula I, alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be appreciated that the parameters of the unit dosage form will depend on the specific agent and the effect to be achieved.

[0116] Combination therapy

[0117] The present disclosure contemplates the use of a compound of formula I in combination with one or more additional agents (e.g., one or more additional active therapeutic agents) or other preventive or therapeutic modalities. In such a combination therapy, various active agents often have different mechanisms of action. Such a combination therapy can be particularly advantageous by allowing the dosage of one or more agents to be reduced, thereby reducing or eliminating adverse reactions associated with one or more agents; in addition, such a combination therapy can have a synergistic therapeutic or preventive effect on the underlying disease, disorder or condition.

[0118] As used herein, "combination" is intended to include therapies that can be administered separately, e.g., separately formulated for separate administration (e.g., as may be provided in a kit), as well as therapies that can be administered together in a single formulation (ie, a "co-formulation").

[0119] In some cases, the compound of formula I and at least one other agent are administered or applied in sequence, for example, one of the agents is administered prior to one or more other agents. In other cases, the compound of formula I and at least one other agent are administered simultaneously, for example, two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate preparations or combined into a single preparation (i.e., a co-formulation). Regardless of whether two or more agents are administered in sequence or simultaneously, for the purposes of this disclosure, they are considered to be administered in combination.

[0120] The compounds of Formula I may be used in combination with other agents useful in the treatment of the disorders or conditions presented herein, including those agents typically administered to subjects with obesity, eating disorders, hyperglycemia, hyperinsulinemia, glucose intolerance and other glucose metabolism disorders.

[0121] The present disclosure contemplates combination therapies with a variety of agents (and classes thereof), including 1) insulin, insulin mimetics, and agents that stimulate insulin secretion, including sulfonylureas (e.g., chlorpropamide, tolazamide, acetohexamide, tolbutamide, glyburide, glimepiride, glipizide) and meglitinides (e.g., meglitinide, repaglinide, and nateglinide); 2) biguanides (e.g., metformin, and pharmaceutically acceptable salts thereof, particularly metformin hydrochloride and extended release formulations thereof, such as Glumetza TM 、Fortamet TM and GlucophageXR TM) and other agents that work by promoting glucose utilization, reducing hepatic glucose production and / or reducing intestinal glucose output; 3) α-glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol) and other agents that slow carbohydrate digestion, thereby slowing absorption from the intestine and reducing postprandial hyperglycemia; 4) thiazolidinediones (e.g., rosiglitazone, troglitazone, pioglitazone, glipizide, basiglitazone, rivoglitazone, netoglitazone, AMG 131, MBX2044, miglitazone, lobeglitazone, IDR-105, troglitazone, englitazone, ciglitazone, adaglitazone, daglitazone, enhance insulin action (e.g., by insulin sensitization), including insulin, and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro, insulin detemir, insulin selenolide, insulin selenoheptazone ... detemir, insulin glulisine, and inhaled formulations of each), thereby promoting glucose utilization in peripheral tissues; 5) glucagon-like peptides, including DPP-IV inhibitors (e.g., alogliptin, omagliptin, 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 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 anti-DPP-IV analogs (incretin mimetics PPARγ agonists, PPARα agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), dual-acting PPAR agonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, moglitazar, aleglitazar, soglitazar, and naleglitazar), pan-acting PPAR agonists, PTP1B inhibitors (e.g., ISIS-113715 and TTP814), SGLT inhibitors (e.g., AS P1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211), insulin secretagogues, angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, mavipril, perindopril, quinapril, ramipril, spirapril, temopril or trandolapril), angiotensin II receptor antagonists (e.g., losartan, valsartan, candesartan, olmesartan, telmesartan); etc.

[0122] Subjects

[0123] 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 type II 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).

[0124] In some cases, individuals suffering from and / or diagnosed with non-alcoholic fatty liver disease (NAFLD) are specifically excluded. In some cases, individuals suffering from and / or diagnosed with non-alcoholic steatohepatitis (NAS) are specifically excluded.

[0125] Examples of non-limiting aspects of the present disclosure

[0126] The aspects of the inventive subject matter described above, including embodiments, may be beneficial alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure are provided below. As will be apparent to one skilled in the art upon reading this disclosure, each individually numbered aspect may be used or combined with any preceding or succeeding individually numbered aspect. This is intended to provide support for all such combinations of aspects, and is not limited to the combinations of aspects explicitly provided below:

[0127] Aspect 1. A method for treating a metabolic disorder in an individual, the method comprising administering to the individual an effective amount of a compound of formula I:

[0128]

[0129] Where: R 1 For-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 ;

[0130] Each R 2 R 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 4is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; each R 5 is 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 ; or any R 5 and R 6 Together with the nitrogen to which they are both attached, they form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; the compound of formula I is in the form of a single stereoisomer or a mixture thereof or a pharmaceutically acceptable salt thereof.

[0131] Aspect 2. The method of aspect 1, wherein the compound is 5-(tetradecyloxy)-2-furoic acid.

[0132] Aspect 3. The method of Aspect 1 or Aspect 2, wherein the metabolic disorder is insulin resistance, hyperglycemia, type 2 diabetes, obesity, fatty liver disease, glucose intolerance, hyperinsulinemia, metabolic syndrome or hypertension.

[0133] Aspect 4. The method of any one of Aspects 1-3, wherein the metabolic disorder comprises insulin resistance.

[0134] Aspect 5. The method of any one of Aspects 1-3, wherein the metabolic disorder comprises metabolic syndrome.

[0135] Aspect 6. The method of any one of Aspects 1-3, wherein the metabolic disorder comprises type 2 diabetes.

[0136] Aspect 7. The method of any one of Aspects 1-6, wherein the individual has a body mass index >30.0.

[0137] Aspect 8. The method of any one of Aspects 1-7, wherein said administration results in serum insulin levels within the normal range.

[0138] Aspect 9. The method of any one of Aspects 1-7, wherein said administration results in blood glucose levels within the normal range.

[0139] Aspect 10. The method of any one of Aspects 1-9, further comprising administering at least one additional therapeutic agent.

[0140] Aspect 11. The method of Aspect 10, wherein at least one additional therapeutic agent is insulin, an insulin analog, a biguanide, or a thiazolidinedione.

[0141] Aspect 12. The method of any one of methods 1-11, wherein the administration is oral administration.

[0142] Aspect 13. The method according to any one of aspects 1 to 12, wherein the compound of formula I is administered daily.

[0143] Aspect 14. The method according to any one of aspects 1 to 12, wherein the compound of formula I is administered once a week.

[0144] Aspect 15. The method of any one of Aspects 1-12, wherein the compound of formula I is administered by controlled delivery.

[0145] Aspect 16. The method of Aspect 15, wherein the compound of formula I is present in an implantable delivery device.

[0146] Aspect 17. A method for treating metabolic syndrome in an individual, the method comprising administering to the individual an effective amount of a compound of formula I:

[0147]

[0148] Where: R 1 For-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 ;

[0149] Each R 2 R 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 5is 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 ; or any R 5 and R 6 Together with the nitrogen to which they are both attached, they form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; the compound of formula I is in the form of a single stereoisomer or a mixture thereof or a pharmaceutically acceptable salt thereof.

[0150] Aspect 18. The method of aspect 17, wherein the compound is 5-(tetradecyloxy)-2-furoic acid.

[0151] Aspect 19. The method of Aspect 17 or Aspect 18, wherein the administration is oral administration.

[0152] Aspect 20. The method according to any one of Aspects 17 to 19, wherein the compound of formula I is administered daily.

[0153] Aspect 21. The method according to any one of Aspects 17-19, wherein the compound of formula I is administered once a week.

[0154] Aspect 22. The method of any one of Aspects 17-19, wherein the compound of formula I is administered by controlled delivery.

[0155] Aspect 23. The method of Aspect 22, wherein the compound of formula I is present in an implantable delivery device.

[0156] Example

[0157] The following examples are put forward so as to provide one of ordinary skill in the art with a complete disclosure and description of how to make and use the 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 experiments below 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 errors and deviations should be accounted for. 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, e.g., bp, base pair; kb, kilobase; pl, picoliter; or sec, second; min, minute; h or hr, hour; aa, amino acid; kb, kilobase; bp, base pair; nt, nucleotide; im, intramuscular; ip, intraperitoneal; sc, subcutaneous; etc.

[0158] Example 1: Effect of TOFA on nonalcoholic fatty liver disease induced by a choline-deficient high-fat diet (CDAHFD) in mice Dose-dependent effects in the progression of NAFLD

[0159] method

[0160] Six-week-old C57BL / 6 male mice were fed with an L-amino acid diet (Research Diets A06071302i) with 60 kcal% fat, 0.1% methionine and no choline added, and then a vehicle (control) or TOFA was introduced by gavage for another three weeks (Fig. 1a). Twice a day, mice were gavaged with a changing dose of TOFA (0, 25, 50, 125 or 250 mg / kg / day). After the six-week study was terminated, serum and liver samples were collected. Serum liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by commercially available kits (abcam 105134 and abcam 105135, respectively). Liver triglycerides were detected in liver samples by commercially available kits (abcam 65336). Based on hematoxylin and eosin (H&E) staining of liver samples, liver samples were also scored for the degree of hepatic steatosis.

[0161] result

[0162] Mice treated orally with TOFA showed a dose-dependent decrease in serum ALT and AST activity levels ( Figure 1B Similarly, lipid levels in the liver decreased in a dose-dependent manner based on TOFA concentration, as quantified by liver triglyceride content per gram of liver ( Figure 1C , left). This is supported by the observation that the extent of hepatic steatosis decreased with increasing doses of TOFA ( Figure 1C , right). These findings indicate that TOFA was well tolerated and clearly reduced lipid accumulation in the liver.

[0163] Figures 1A-1C The dose-dependent effect of TOFA treatment in mice with CDAHFD-induced NAFLD progression was elucidated. Figure 1A The experimental time course is shown. Mice were fed a CDAHFD for 3 weeks and then treated orally with different concentrations of TOFA for 3 weeks. Figure 1B is a graph illustrating the activity levels of liver injury biomarkers, with alanine aminotransferase (ALT) on the left and aspartate aminotransferase (AST) on the right. Figure 1C is a graph illustrating the lipid status of the liver by quantitative measurement of liver triglycerides (left) and scoring assessment of hepatic steatosis from hematoxylin and eosin (H&E) stained liver sections (right). The Brown-Forsythe and Welch one-way ANOVA statistical test was used to determine statistical significance.

[0164] Example 2.Rescue effect of TOFA on early hepatic steatosis and related metabolic disorders induced by a 60% kcal fat diet in mice.

[0165] method

[0166] Six-week-old C57BL / 6 male mice were fed a 60 kcal% fat diet (Research Diets A12492i) for seven weeks and then introduced vehicle (control) or an initial loading dose of 250 mg / kg TOFA by oral gavage twice daily for one week ( Figure 2A ). Then, mice were treated with vehicle (control) or 125mg / kg TOFA maintenance dose by gavage twice a day for another three weeks. The weight of mice was tracked during the whole time course. After three weeks of treatment, intraperitoneal glucose tolerance test (IP-GTT) and insulin tolerance test (IP-ITT) were performed. Before these tests, mice were fasted for 6 hours, then challenged with 1g / kg D-glucose or 0.75U / kg HumulinR (Eli Lilly), and blood glucose levels were monitored for 2 hours (Bayer Contour Next). Venous fasting blood was collected through the tail vein and used to measure fasting insulin levels by commercially available ELISA kits (CrystalChem90080). Before harvest, mice underwent whole body composition analysis (EchoMRI TM 2012). After the 11-week study was terminated, serum and liver samples were collected. Serum liver injury biomarkers, ALT and AST, were measured by commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured by commercially available kits (abcam65336).

[0167] result

[0168] Mice treated with TOFA showed weight loss compared to vehicle control treated mice, demonstrating the efficacy of TOFA as a weight and fat reducing agent without affecting food intake ( Figure 2B , Figure 2C This was supported by a significant reduction in fat mass and an increase in lean mass relative to total body weight in TOFA-treated mice ( Figure 2D IP-GTT showed that TOFA-treated mice became more glucose tolerant over time through improved glucose clearance ( Figure 2E In addition, TOFA-treated mice had large improvements in fasting blood glucose levels, as well as significantly reduced fasting insulin levels ( Figure 2E , 2FIP-ITT highlighted the improved insulin sensitivity via glucose clearance response due to TOFA treatment in mice ( Figure 2G ). While not being bound by theory, inhibition of ACC activity by TOFA and subsequent reduction in fatty acid synthesis may contribute to improvements in these metabolic parameters in glucose homeostasis through reduction of ectopic lipids in the liver that 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 explain the shortened time course of diet-induced damage from the high-fat diet. Relative to other diet-induced NAFLD timelines and diets, this diet time course most closely mimics the early metabolic disorders that are closely associated with the progression of NAFLD (e.g., obesity complications, diabetes, metabolic syndrome). However, TOFA treatment significantly reduced triglyceride levels in both liver and serum ( Fig.2I ). As speculated, the overall reduction in lipid circulation in the body can contribute to the overall improved metabolic homeostasis. Therefore, these results show that TOFA is an effective agent for reducing early NAFLD-related metabolic disorders by reducing the lipid load in the body.

[0169] Figure 2A-2I The effect of TOFA treatment on the progression of metabolic syndrome and early NAFLD induced by a 60% kcal fat diet was elucidated. Figure 2A The experimental timeline is shown. Mice were fed a 60% kcal fat diet for seven weeks, then treated orally with TOFA (250 mg / kg loading dose for one week, then 125 mg / kg maintenance dose for three weeks, twice daily) for four weeks. Metabolic profiling began in the last week of treatment. Figure 2B is a graph that tracks the change in weight over the time course of the experiment. Figure 2C is a graph tracking the cumulative intake of a 60% kcal fat diet over the time course of the experiment. Figure 2D is a graph illustrating changes in fat and lean mass relative to body weight as measured by EchoMRI.

[0170] Figure 2E is a graph illustrating blood glucose levels over time during an intraperitoneal glucose challenge (IP-GTT) (left). 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) (left). The area under the curve is shown on the right. Figure 2H is a graph illustrating the activity levels of liver injury biomarkers, with alanine aminotransferase (ALT) on the left and aspartate aminotransferase (AST) on the right. Fig.2IIt is a diagram illustrating the body fat status through quantitative measurement of liver triglycerides (left side) and quantitative measurement of serum lipid levels (right side).

[0171] Example 3 .Rescue effect of TOFA in CDAHFD-induced advanced NAFLD / NASH progression in mice.

[0172] method

[0173] Six-week-old C57BL / 6 male mice were fed an L-amino acid diet with 60 kcal% fat, 0.1% methionine and no added choline (ResearchDiets A06071302i) for eight weeks and then introduced daily with vehicle (control) or 250 mg / kg TOFA by controlled gavage twice daily for another four weeks ( Figure 3A ). After the 12-week study was terminated, serum and liver samples were collected. Serum liver injury biomarkers, ALT and AST, were measured by commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured by commercially available kits (abcam65336). Liver samples were fixed in 4% paraformaldehyde and embedded in paraffin blocks for sectioning, then stained with hematoxylin and eosin (H&E) or picrosirius red (Picrosirius Red), with a fast green background. Frozen fresh liver tissue was embedded in OCT, sectioned, and subsequently stained with Oil Red O.

[0174] result

[0175] Mice treated with TOFA showed a significant decrease in serum ALT activity levels and a mean decrease in serum AST levels ( Figure 3B ). In addition, TOFA treatment reduced liver triglyceride content without increasing serum triglyceride levels (Figure 3c). Histopathological evaluation in TOFA-treated mice showed a reduction in the extent of hepatic steatosis, as well as a reduction in other disease pathology markers such as inflammation, ballooning, and fibrosis, as scored using the metrics outlined in Kleiner et al. (2005) ( Figure 2D , Figure 2E ). Histological staining revealed reduced lipid content by Oil Red O, reduced cytoplasmic vacuolization by H&E, and reduced fibrosis by Sirius Red staining with TOFA treatment ( Figure 2F Overall, these results suggest that TOFA is effective in ameliorating advanced NAFLD progression and NASH pathology while minimizing potential adverse metabolic effects previously reported with other ACC inhibitors, such as elevated serum triglyceride levels.

[0176] Figures 3A-3FThe rescue effect of TOFA treatment in CDAHFD-induced advanced NAFLD / NASH progression in mice was shown. Figure 3A Experimental timeline is shown. Mice were fed CDAHFD for eight weeks and then treated orally with TOFA (250 mg / kg daily in two divided doses) for four weeks. Figure 3B It is a graph illustrating the activity levels of liver damage markers, with alanine aminotransferase (ALT) on the left and aspartate aminotransferase (AST) on the right. Figure 3C It is a diagram illustrating the body fat status through quantitative measurement of liver triglycerides (left side) and quantitative measurement of serum lipid levels (right side). Figure 3D is a diagram illustrating the scoring evaluation of hepatic steatosis from hematoxylin and eosin (H&E)-stained liver sections. Figure 3E is a graph illustrating the histopathological scoring evaluation of liver inflammation, hepatocellular ballooning, and fibrosis from hematoxylin and eosin and Sirius red stained liver sections. Figure 3F Panels showing Oil Red O, Hematoxylin and Eosin, and Sirius Red stained liver sections. Scale bar 50 μm. Statistical significance was determined using Student's unpaired t-test.

[0177] Example 4 Whole-genome RNA sequencing of liver samples from CDAHFD-induced advanced NAFLD / NASH mice treated with vehicle or TOFA

[0178] method

[0179] Liver samples were collected from mice in Example 3 (see above). Total RNA was extracted from liver tissue (Qiagen RNeasy kit), cDNA libraries were constructed (Roche KAPA HyperPrep kit), sequenced on the NovaSeq6000 platform (Novogene), and downstream analysis procedures were performed. Differentially expressed genes (DEGs) were defined by at least a log2-fold change (2-fold in the linear scale) with an FDR cutoff of 0.05. For validation, cDNA was prepared from total RNA according to the manufacturer's protocol (BioRAD iScript TMReverse transcription) and quantitative polymerase chain reaction (qPCR) were performed on the QuantStudio6 system (Applied Biosystems) with Fast SYBR Green Mix (ThermoFisher). Protein expression levels were measured by Western blotting using anti-very low density lipoprotein receptor (VLDLR) antibody (AF2258, 1:2000) and anti-β-tubulin antibody (CST2146, 1:1000). The membrane was developed using horseradish peroxidase (HRP) secondary antibody (1:5000) and visualized using enhanced chemiluminescent HRP substrate (Thermo34577).

[0180] result

[0181] Interestingly, RNA sequencing 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, particularly PPAR-α. Several of the most highly upregulated genes observed upon TOFA treatment were canonical PPAR-α target genes ( Figure 4A Specific analysis of the PPAR signaling pathway (from the 2021KEGG 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 genes significantly upregulated in processes such as oxidative phosphorylation, fatty acid metabolism, and peroxisome, all of which are processes closely related to the action of the PPAR signaling pathway ( Figure 4C A negative correlation between TOFA treatment and inflammatory response was also observed, supporting the safety and efficacy of TOFA treatment in reducing inflammatory markers of NAFLD pathology ( Figure 4C , lower right). Among the genes upregulated by TOFA treatment, there was a significant increase in the expression of the very low density lipoprotein receptor (VLDLR) gene, a PPAR-α target gene ( Figure 4D This increase in mRNA expression levels was translated into an increase in protein expression levels of VLDLR in TOFA-treated liver samples ( Figure 4E ). Previous studies have demonstrated the role of upregulating VLDLR by PPAR-α agonists (e.g., fenofibrate) to mediate the triglyceride-lowering effect. This preliminary data connects the potential relationship between the TOFA effect of VLDLR upregulation and the effect of PPAR-α agonists, via the fenofibrate-PPAR-α-VLDLR signaling axis, to induce a triglyceride-lowering effect. Thus, without being bound by theory, TOFA or derivatives for the treatment of fatty liver disease and its associated metabolic disorders could utilize a multifaceted, multipharmacological approach through ACC inhibition and PPAR agonism.

[0182] Figures 4A-4E Shown are the results of RNA sequencing of liver samples from CDAHFD-induced advanced NAFLD / NASH mice treated with TOFA. Figure 4A It is a volcano plot of differentially up-regulated and down-regulated genes. Differential genes are at an FDR cutoff of 0.05 and a change cutoff of 2-fold. Figure 4B This is a heatmap illustrating up- and down-regulated genes in the PPAR signaling pathway, taken from the KEGG_2021_Human database. Columns represent samples and rows represent genes. Colors indicate gene expression levels relative to the average expression of all samples (log2 RPKM). Figure 4C GSEA plots of differentially regulated genes enriched in several landmark gene sets: oxidative phosphorylation (upper left), fatty acid metabolism (upper right), peroxisome (lower left), and inflammatory response (lower right). The normalized enrichment score (NES) and false discovery rate (FDR) for each marker are shown. Figure 4D It is a graph illustrating the expression of VLDLR mRNA relative to r18S mRNA in mouse liver. Figure 4E is a Western blot image of VLDLR and β-tubulin expression levels in mouse liver samples. Statistical significance was determined using Student's unpaired t-test.

[0183] Example 5 .Tolerability and toxicity of TOFA in mice

[0184] method

[0185] Eleven week-old C57BL / 6J male mice were fed with PicoLab rodent diet (Purina 5053) or standard diet, free access to food, and treated by gavage twice a day (BID) with control or 125mg / kg, for 3 weeks. Mouse weight was followed during the whole time course. After the study was terminated, serum and liver samples were collected. Serum biomarkers such as blood urea nitrogen (BUN) and creatinine were assessed by commercially available test kits (respectively abcam83362 and Cayman700460). In addition, liver and serum triglyceride and cholesterol levels were measured by commercially available test kits (respectively abcam65336 and abcam65390).

[0186] result

[0187] No weight changes were observed in mice treated with TOFA over the course of treatment, and no weight differences were observed between TOFA-treated and vehicle-treated mice ( Figure 5A Serum biomarkers such as BUN ( Figure 5B ) and creatinine ( Figure 5C ) analysis showed no drug-induced renal injury. Decreased liver triglyceride levels were observed ( Figure 5D), which is characteristic of this class of metabolic regulators. In addition, there was no significant change in serum triglyceride levels ( Figure 5E ), which is a unique observation among other small molecules targeting the same enzyme (ACC1 / 2). Fig. 5F ) or serum ( Figure 5G ) Cholesterol levels did not change in mice. These findings suggest that TOFA is orally bioavailable, suitable for twice-daily or less frequent dosing, and is well tolerated in mice.

[0188] Figure 5A-5B The safety and tolerability profile of TOFA treatment in mice fed a free-feed diet was elucidated. Figure 5A is a graph tracking the change in weight over the time course of the experiment. Figure 5B is a graph illustrating the blood urea nitrogen (BUN) level in serum. Figure 5C is a graph illustrating the level of creatinine in serum. Figure 5D is a diagram illustrating quantitative measurement of liver triglycerides. Figure 5E is a diagram illustrating quantitative measurement of serum triglycerides. Fig. 5F is a diagram illustrating quantitative measurement of liver cholesterol. Figure 5G is a graph illustrating the quantitative measurement of serum total cholesterol. Statistical significance was determined using Student's unpaired t-test.

[0189] Example 6. Dose-dependent effects of TOFA in a 60% HFD mouse model of diet-induced obesity (DIO)

[0190] method

[0191] Six-week-old C57BL / 6J male mice were fed a 60 kcal% fat diet (Research Diets A12492i) for ten weeks, then introduced vehicle (control) or TOFA at varying doses for an additional two weeks. TOFA was administered orally at 12.5, 25, 62.5, or 125 mg / kg twice daily. Mouse weight and food intake were monitored during the treatment time course. Prior to harvest, mice underwent whole body composition analysis (EchoMRI TM 2012). After the 12-week study was terminated, serum and liver samples were collected. Liver and serum triglyceride and cholesterol levels were measured by commercially available kits (abcam65336 and abcam65390, respectively). Additional liver samples were fixed in 4% paraformaldehyde and embedded in paraffin blocks for sectioning and subsequently stained with hematoxylin and eosin (H&E).

[0192] result

[0193] After treatment with TOFA, mice showed weight loss at the highest dose (125 mg / kg twice daily), confirming that the effective dose ( Fig. 6A Administration at lower concentrations resulted in small or negligible changes in body weight compared to vehicle control-treated mice ( Figure 6B The changes in body weight between treatment groups were not attributable to changes in food intake during treatment, which remained constant over the time course ( Figure 6C Body composition analysis revealed a decrease in fat mass as a percentage of body weight in the highest dose treatment group, whereas overall lean mass did not change between all treatment groups, attributing the weight changes to a decrease in fat mass ( Fig.6D The concept of changes in lipid levels in vivo was further supported by analysis of liver triglycerides, which were significantly reduced in the highest dose regimen ( Fig. 6E Most notably, in serum triglyceride levels ( Fig. 6F ) and serum cholesterol levels, especially both HDL and VLDL / LDL fractions ( Figure 6G ), with a dose-dependent reduction. Histological analysis of liver sections revealed that hepatic steatosis improved in a dose-dependent manner and provided additional support that 125 mg / kg, twice daily was the most effective dosing regimen ( Figure 6H Overall, these results show that TOFA acts in a dose-dependent manner to address multiple features of metabolic syndrome and further support the metabolic benefits of TOFA treatment in a mouse diet-induced model of metabolic syndrome (see Example 2).

[0194] Figures 6A-6H The dose-dependent effect of TOFA treatment in mice with diet-induced obesity in the 60% HFD diet model was elucidated. Fig. 6A is a graph tracking weight changes over the time course of treatment. Figure 6B is a graph illustrating the total percent body weight change from the beginning to the end of the treatment time course. Figure 6C is a graph illustrating food intake of a 60% kcal fat diet over the experimental time course.

[0195] Fig.6D is a graph illustrating changes in fat and lean mass relative to body weight, as measured by EchoMRI. Fig. 6E is a diagram illustrating quantitative measurement of liver triglycerides. Fig. 6F is a diagram illustrating quantitative measurement of serum triglycerides. Figure 6G is a graph illustrating quantitative measurement of HDL cholesterol, VLDL / LDL cholesterol, and serum total cholesterol. Figure 6HAre panels showing representative images of hematoxylin and eosin staining of liver sections at 10x magnification. Statistical significance was determined using Brown-Forsythe and Welch one-way ANOVA statistical test.

[0196] Example 7. Transcriptional profiling of liver samples from the 60% HFD mouse model of diet-induced obesity and associated metabolic disorders

[0197] method

[0198] Six-week-old C57BL / 6J male mice were fed a 60 kcal% fat diet (Research Diets A12492i) for seven weeks and then introduced a control or 125 mg / kg, twice daily, initial loading dose of TOFA, daily by controlled gavage for one week ( Figure 2A ). The mice were then treated with vehicle or 62.5 mg / kg, twice daily, maintenance dose of TOFA, daily by gavage for an additional three weeks. Liver samples were collected after the 11-week study termination. Total RNA was extracted from liver tissue (Qiagen RNeasy kit 74106), cDNA libraries were constructed (Roche KAPA HyperPrep kit), sequenced on the NovaSeq6000 platform (Novogene), and downstream analysis processes were performed. Differentially expressed genes (DEGs) were defined by at least one log2-fold change (2-fold in the linear scale) with an FDR cutoff of 0.05. For validation, cDNA was prepared using total RNA according to the manufacturer's protocol (BioRAD iScript TM Reverse transcription) and qPCR was performed on a QuantStudio6 system (Applied Biosystems) with Fast SYBR Green Mix (ThermoFisher A25742).

[0199] result

[0200] In support of the results of Example 4, RNA sequencing 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 that was consistent in different diet-induced models of severe metabolic disease. Several of the most highly upregulated genes seen with TOFA treatment were standard PPAR-α target genes, as well as significantly downregulated genes that are negatively regulated by PPAR-α activation ( Fig. 7A ). Analysis of transcriptional regulatory relationships of upregulated genes from the TRRUST Transcription Factor 2019 Reference Database revealed that PPARA is one of the main factors in transcriptional regulation after TOFA treatment ( Figure 7BThis observation was further supported by a specific analysis of genes in the PPAR signaling pathway from the BioPlanet2019 database, which highlighted that TOFA treatment upregulates various genes under the transcriptional control of PPAR ( Figure 7C ). Various genes identified as downstream PPAR targets from RNA sequencing analysis were confirmed by reverse transcription-qPCR (RT-qPCR) to be upregulated from TOFA treatment and are involved in various processes of lipid homeostasis, such as fatty acid β-oxidation, acyl-CoA processing, and lipoprotein uptake and metabolism ( Fig.7D These results support a similar transcriptional activity signature of TOFA regardless of the dietary challenge mouse model and stage of metabolic disease severity.

[0201] Figures 7A-7D Shown is a transcriptional analysis of gene changes in liver from a TOFA-treated 60% HFD diet-induced obesity mouse model. Fig. 7A It is a volcano plot of differentially up-regulated and down-regulated genes. Differential genes are at an FDR cutoff of 0.05 and a change cutoff of 2-fold. Figure 7B is a bar table showing the p-values ​​of some of the most significantly upregulated transcription factor signatures in the upregulated gene pool from the TRRUST transcription factor 2019 reference database. Figure 7C This is a heatmap illustrating up- and down-regulated genes in the PPAR signaling pathway, taken from the BioPlanet 2019 database. Columns represent samples and rows represent genes. Colors indicate gene expression levels relative to the mean expression of all samples (log2 RPKM). Fig.7D is a graph illustrating the expression of mouse liver mRNA levels for selected genes with PPAR transcriptional regulation, grouped by functional commonality, relative to the expression of r18s mRNA. Statistical significance was determined using Student's unpaired t-test.

[0202] Example 8 .In-depth study of the rescue effect of TOFA in CDAHFD-induced advanced NAFLD / NASH progression in mice

[0203] method

[0204] Six-week-old C57BL / 6J male mice were fed with an L-amino acid diet (CDAHFD; Research Diets A06071302i) with 60kcal% fat, 0.1% methionine and no choline added for eight weeks. Ten subjects were randomly assigned to vehicle (control) treatment or 125mg / kg, twice daily, TOFA treatment, delivered by gavage, for another four weeks. During the entire treatment time course, the weight of the mice was monitored. After the 12-week study was terminated, serum and liver samples were collected. Serum liver injury biomarkers, ALT and AST, were measured by commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured by commercially available kits (abcam65336). According to the manufacturer's protocol, total RNA was extracted from liver tissue (Qiagen RNeasy kit 74106), and cDNA was prepared (BioRADiScript TM Quantitative PCR (qPCR) was performed using the Fast SYBR Green Mix (ThermoFisher A25742) on a QuantStudio6 system (Applied Biosystems).

[0205] result

[0206] Significant differences in body weight were observed starting approximately 10 days after the start of treatment and became more pronounced until study termination ( Fig. 8A Compared with vehicle control treated mice, TOFA treated mice had a significant decrease in body weight ( Figure 8B Analysis of serum biomarkers of liver injury showed ALT ( Fig.8D ) and AST( Fig.8D ) trended downward. In addition, in TOFA-treated mice, there was a significant decrease in liver triglyceride levels ( Fig.8D ) and the presence of reduced liver hydrogen peroxide levels, indicating a reduction in reactive oxygen species (ROS) ( Figure 8F ). Analysis of liver analytes supports the concept of improved liver health by TOFA treatment in a diet-induced model of NAFLD / NASH. Inflammatory genes, such as Il1b and Tnfa, were evaluated by RT-qPCR as biomarkers of inflammation. The results showed decreased expression of these inflammation-related genes ( Figure 8G In addition, expression of genes involved in collagen biosynthesis was reduced, as assessed by qPCR, indicating reduced fibrosis ( Figure 8H). As seen in Examples 4 and 7, transcriptional activity from the PPAR signaling network can 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 lipogenesis, that were upregulated with TOFA treatment ( Figure 8I ). These results all support and provide additional evidence for previously observed results (Examples 3 and 4) of the role of TOFA in addressing multiple aspects of NAFLD / NASH such as metabolic dysregulation, inflammation and fibrosis.

[0207] Figures 8A-8I An in-depth analysis of the therapeutic efficacy of TOFA in the CDAHFD diet-induced mouse model of NAFLD / NASH is shown. Fig. 8A is a graph that tracks weight changes over the course of treatment. Figure 8B is a graph illustrating the total percent body weight change between the beginning and end of the treatment period. Figure 8C is a graph illustrating serum alanine aminotransferase (ALT) activity levels. Fig.8D is a graph illustrating serum aspartate aminotransferase (AST) activity levels. Fig. 8E is a diagram illustrating quantitative measurement of liver triglycerides. Figure 8F is a graph illustrating the quantitative measurement of hepatic hydrogen peroxide. Figure 8G The graphs illustrate the expression levels of mouse liver mRNAs associated with inflammation relative to the expression of r18s mRNA.

[0208] Example 9 In a benchmark study, TOFA demonstrated comparable potency to a leading clinical candidate for NASH in a CDAHFD-induced advanced NAFLD / NASH mouse model.

[0209] method

[0210] Six-week-old C57BL / 6J male mice were fed with an L-amino acid diet (CDAHFD; Research Diets A06071302i) with 60kcal% fat, 0.1% methionine and no choline added. Mice were randomly assigned to a treatment group of a combined dose of vehicle (control), 250mg / kg TOFA, 5mg / kg Firsocostat (Gilead Sciences), 50mg / kg Firsocostat, or 5mg / kg Firsocostat and 50mg / kg Firsocostat. All treatments were delivered by gavage once a day (QD) for another four weeks. Mouse weight and food intake were monitored during the treatment time course. After the 12-week study was terminated, liver and serum samples were collected. Serum liver injury biomarkers, ALT and AST, were measured by commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured by commercially available kits (abcam65336). Total RNA was extracted from liver tissue (Qiagen RNeasy kit 74106) and cDNA was prepared (BioRAD iScript TM Reverse transcription). Quantitative PCR (qPCR) was performed on a QuantStudio6 system (Applied Biosciences) with a fast SYBR Green Mix (ThermoFisher A25742). Protein expression levels of liver samples were measured by Western blotting using anti-VLDLR antibody (AF2258, 1:2000), anti-CPT1A antibody (CST12252, 1:1000) and anti-histone H3 antibody (CST9715, 1:1000). The membrane was developed using an HRP secondary antibody (1:5000) and visualized using an enhanced chemiluminescent HRP substrate (Thermo34577). Additional liver samples were fixed in 4% paraformaldehyde and embedded in paraffin blocks for sectioning and subsequently stained with hematoxylin and eosin (H&E).

[0211] result

[0212] To evaluate the effect of TOFA compared with other clinical candidates of the same molecular targeting class, diet-induced NAFLD / NASH mice were treated with optimal doses of vehicle control, TOFA, Firsocostat (ACC1 / 2 inhibitor, Gilead Sciences), Fenofibrate (PPAR-α agonist), or a combination of Firsocostat and Fenofibrate. In all treatment regimens, TOFA-treated mice demonstrated significant weight loss compared with vehicle control-treated mice, while all other treatment regimens had comparable body weight changes ( Fig. 9A , Fig. 9B ). Weight changes are not attributable to changes in food intake ( Fig. 9C ). Liver injury biomarkers, such as ALT ( Fig.9D ) and AST( Fig.9E ), revealed that TOFA treatment resulted in similar levels of ALT and AST reductions with Firsocostat alone and in combination. Most notably, TOFA treatment had a strong reduction in liver triglyceride levels relative to Firsocostat treatment and vehicle control treatment ( Fig.9F ). TOFA treatment significantly reduced liver injury relative to vehicle control treatment to an extent comparable or greater than that of firsocostat, fenofibrate, or the combination of both agents. RT-qPCR analysis additionally showed specific, comparable responses with TOFA treatment relative to the other treatment regimens, such as upregulation of genes involved in inflammation (e.g., Il1b and Il6) and collagen synthesis (e.g., Col1a1 and Col3a) ( Figure 9G Furthermore, TOFA treatment induced unique increases in PPARA downstream targets, such as Vldlr and Cpt1a, which were not observed with other treatment regimens ( Figure 9G ). Western blot analysis of protein expression levels supported the RT-qPCR observations, such that TOFA treatment increased the protein expression levels of VLDLR and CPT1A to a greater extent than the other treatment regimens ( Figure 9H ). Histological analysis by H&E staining further supported our observations that the level of steatosis in the TOFA-treated group was reduced relative to controls and that the improvement was comparable to that of the other treatment regimens ( Fig.9I ). Taken together, these results provide evidence for the use of TOFA in an effective, single-regimen dosing regimen with comparable efficacy to leading clinical candidates in the CDAHFD mouse model of diet-induced NAFLD / NASH.

[0213] Example 10. TOFA demonstrates efficacy as a combination agent with other metabolic modulating therapeutics, such as GLP1 receptor agonists

[0214] method

[0215] Six-week-old C57BL / 6J male mice were fed with an L-amino acid diet (CDAHFD; Research Diets A06071302i) with 60 kcal% fat, 0.1% methionine and no choline added for eight weeks. Mice were randomly assigned to treatment groups with a combined dose of vehicle (control), 250 mg / kg TOFA, 5 nmol / kg semaglutide (Novo Nordisk), or 250 mg / kg TOFA plus 5 nmol / kg semaglutide. TOFA was administered by gavage. Semaglutide administration was up-titrated at the beginning of the treatment regimen and delivered by subcutaneous injection at the posterior shoulder / neck flank. All treatments were delivered once daily for another four weeks. Mouse weight and food intake were monitored during the treatment time course. After the 12-week study was terminated, liver and serum samples were collected. Serum liver injury biomarkers, ALT and AST, were measured by commercially available kits (abcam105134 and Cayman701640, respectively). Hepatic 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 (BioRAD iScript TM Reverse transcription). Quantitative PCR (qPCR) was performed on a QuantStudio6 system (Applied Biosciences) with a fast SYBR Green Mix (ThermoFisher A25742). Total RNA was extracted from liver tissue (Qiagen RNeasy kit 74106), and cDNA was prepared according to the manufacturer's protocol (BioRADiScriptTM reverse transcription). Quantitative PCR (qPCR) was performed on a QuantStudio6 system (Applied Biosciences) with a fast SYBR Green Mix (ThermoFisher A25742). Additional liver samples were fixed in 4% paraformaldehyde and embedded in paraffin blocks for sectioning and subsequently stained with hematoxylin and eosin (H&E) or picrosirius red (fast green dye background).

[0216] result

[0217] Because TOFA exhibits a unique mechanism of action compared to other metabolic modulators, such as GLP-1 receptor agonists, TOFA was used as a combination agent with semaglutide (Novo Nordisk) to test efficacy in the CDAHFD mouse model of diet-induced NAFLD / NASH. Immediately after treatment initiation, both the single treatment groups and the combination treatment groups with semaglutide experienced weight loss, consistent with previous observations of semaglutide as a weight loss modulator ( Fig. 10A At the end of the treatment time course, it was revealed that TOFA-treated mice experienced a lesser degree of weight loss compared to semaglutide-treated mice, but that the combination-treated (TOFA and semaglutide) mice experienced a greater weight loss relative to the single-agent treatment groups and the vehicle control treatment group ( Fig. 10B The weight changes were not due to changes in food intake during the treatment time course ( Fig. 10C RT-qPCR analysis of liver samples revealed a specific response of TOFA in response to inflammation that was not observed in mice treated with semaglutide alone ( Fig. 10D ). Analysis of genes involved in collagen biosynthesis by RT-qPCR showed a strong inhibitory effect of both TOFA and semaglutide in reducing mRNA levels, while the combination treatment showed a trend towards further reduction in mRNA expression levels ( Fig. 10D ). Hepatic triglyceride analysis revealed that mice treated with semaglutide had a trending decrease in hepatic triglyceride levels relative to vehicle control treatment, while mice treated with TOFA had a strong, significant decrease in hepatic triglyceride levels ( Fig. 10E The combination treatment had the greatest reduction in overall hepatic triglyceride levels ( Fig. 10E Serum ALT analysis showed a similar trend toward moderate reductions in ALT levels from both the single-agent regimen and the combination therapy ( Fig.10F Single-agent TOFA treatment was the only group with a confirmed decrease in serum AST levels, which may be attributed to non-liver-specific expression of AST that may contribute to serum AST levels, such as in the kidney, heart, and skeletal muscle ( Figure 10G Serum biomarker analysis further supports the use of TOFA as an effective therapeutic agent to reduce liver injury as read out from liver injury biomarkers. Relative to control, semaglutide treatment alone presented a moderate reduction in steatosis compared to a greater reduction in steatosis in liver sections treated with TOFA alone, with histological analysis by H&E showing a similar trend to that observed therein, and the greatest reduction in steatosis ( Fig. 10H Similarly, the aforementioned histological trends were noted in picrosirius red staining for fibrosis content ( Fig.10I). In summary, TOFA represents a potential candidate as a combination agent with a clinical lead drug with an orthogonal target and mechanism. Based on preliminary observations, the semaglutide-TOFA combination results highlight the tolerability of TOFA for combination, the lack of observed drug-drug antagonist effects, and the improvement of the combination in addressing the shortcomings of semaglutide alone in terms of therapeutic efficacy, such as metabolism and inflammation.

[0218] Example 11. TOFA has unexpected effects compared to other small molecules of the same type, such as complementarity and broad functionality, including activation of PPARA

[0219] method

[0220] Six-week-old genetic PPARA knockout (PPARA KO) male mice were fed an L-amino acid diet with 60 kcal% fat, 0.1% methionine, and no added choline (CDAHFD; Research Diets A06071302i) for three weeks or a 60 kcal% fat diet (DIO; Research Diets A12492i) for eight weeks, followed by the introduction of vehicle (control) or 125 mg / kg TOFA twice daily by oral gavage for an additional two weeks (respectively). Fig.11A and Fig.11J ). C57BL / 6J (WT) mice were fed with CDAHFD and subjected to similar experimental symptoms and time course. Mouse weight and adverse events were monitored during the treatment time course. After the study was terminated, serum and liver samples were collected. Serum liver injury biomarkers, ALT and AST, were measured by commercially available kits (abcam105134 and abcam105135, respectively). Liver and serum triglyceride levels were measured by commercially available kits (abcam65336). Total RNA was extracted from liver tissue according to the manufacturer's protocol (Qiagen RNeasy kit 74106), and cDNA was prepared (BioRAD iScript TMReverse transcription). Quantitative PCR (qPCR) was performed on a QuantStudio6 system (Applied Biosciences) with a fast SYBR Green Mix (ThermoFisher A25742). Total RNA was extracted from liver tissue (Qiagen RNeasy kit 74106), and cDNA was prepared according to the manufacturer's protocol (BioRAD iScriptTM reverse transcription). Quantitative PCR (qPCR) was performed on a QuantStudio6 system (Applied Biosciences) with a fast SYBR Green Mix (ThermoFisher A25742). Protein expression levels of liver samples were measured by Western blot using anti-ACC1 / 2 antibody (CST3662, 1:1000), anti-VLDLR antibody (AF2258, 1:2000), anti-CPT1A antibody (CST12252, 1:1000), anti-PPARA antibody (abcam126285, 1:1000) and anti-β-tubulin antibody (CST2146, 1:1000). The membrane was developed using HRP secondary antibody (1:5000) and visualized using enhanced chemiluminescent HRP substrate (Thermo34577). Additional liver samples were fixed in 4% paraformaldehyde and embedded in paraffin blocks for sectioning, and subsequently stained with hematoxylin and eosin (H&E). Frozen fresh liver tissue was embedded in OCT, sectioned, and then stained with Oil Red O.

[0221] result

[0222] In the CDAHFD diet-induced NAFLD / NASH mouse model with PPARA KO, the overall TOFA treatment regimen induced a trend toward weight loss ( Fig. 11B Analysis of serum biomarkers of liver injury, such as ALT and AST, revealed marginal decreases in ALT and AST levels ( Fig.11E and Fig.11D In addition, liver triglyceride analysis showed no significant decrease in liver lipid levels ( Fig.11E ), in contrast to previous studies in wild-type mice ( Figure 3C and Fig. 8E RT-qPCR analysis of Cpt1a, a gene involved in fatty acid β-oxidation, revealed that the induction of Cpt1a mRNA was specific to TOFA treatment in wild-type mice, and this upregulatory response by TOFA treatment was attenuated in PPARA KO mice ( Fig.11FThis observation was 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-α. Protein expression levels of the aforementioned proteins were increased in TOFA-treated wild-type mice relative to each vehicle control-treated counterpart, but this response was not observed in TOFA-treated PPARA KO mice ( Fig.11G Histological analysis by H&E revealed minimal reduction in hepatic steatosis ( Fig.11H ) and minimal changes in lipid content were revealed by Oil Red O ( Fig.11I These two histological observations are clearly different from previous observations in wild-type mice treated with TOFA ( Figure 3F Together, these results provide evidence for a distinct mechanistic dependency of TOFA on the PPARA signaling network to mediate its beneficial effects in diet-induced NAFLD / NASH models. In a diet-induced obesity (DIO) model with a 60% HFD, TOFA treatment in PPARA KO mice resulted in a decrease in body weight ( Figure 11K ) and resulted in significant differences in total body weight change over the course of treatment ( Fig.11L ). Adverse events were observed in PPARA KO mice treated with TOFA during the two-week treatment period ( Fig.11M ). Serum triglyceride analysis of control and TOFA-treated PPARA KO mice revealed elevated serum lipid levels in TOFA-treated mice ( Fig.11N ). These observations suggest that, given the known role of PPARA for lowering serum triglyceride levels, TOFA's mechanism of action on PPARA counteracts such adverse events. RT-qPCR analysis of Vldlr, a gene involved in lipoprotein uptake and under the transcriptional control of PPARA, has shown a blunted response in TOFA-treated PPARA KO mice ( Fig.11O ), which was unexpected given that Vldlr was consistently upregulated in TOFA-treated HFD-fed wild-type mice (Fig. 7i). Histological comparison between H&E-stained liver sections of control-treated and TOFA-treated PPARA KO mice revealed minimal changes in hepatic steatosis, further supporting the concept that the effects of TOFA treatment are diminished in the absence of PPARA ( Figure 11P To our knowledge, our results show the first empirical evidence for an unexpected mechanistic dependency of TOFA on PPARA signaling in response to severe metabolic disease in a mouse diet-induced disease model.

[0223] Although the present invention has been described with reference to its specific embodiments, it will be appreciated 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 present invention. In addition, many modifications may be made to adapt specific circumstances, materials, compositions of matter, processes, process steps or steps to the goals, spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.

Claims

1. A method for treating a metabolic disorder in an individual, the method comprising administering to the individual an effective amount of a compound of formula I: in: 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 R 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 is 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 ; or any R 5 and R 6 Together with the nitrogen to which they are both attached, they form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; the compound of formula I is in the form of a single stereoisomer or a mixture thereof or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the compound is 5-(tetradecyloxy)-2-furoic acid.

3. The method of claim 1 or claim 2, wherein the metabolic disorder is insulin resistance, hyperglycemia, type 2 diabetes, obesity, fatty liver disease, glucose intolerance, hyperinsulinemia, metabolic syndrome, or hypertension.

4. The method of any one of claims 1-3, wherein the metabolic disorder comprises insulin resistance.

5. The method of any one of claims 1-3, wherein the metabolic disorder comprises metabolic syndrome.

6. The method of any one of claims 1-3, wherein the metabolic disorder comprises type 2 diabetes.

7. The method of any one of claims 1-6, wherein the individual has a body mass index >30.

0.

8. The method of any one of claims 1-7, wherein the administration results in serum insulin levels within the normal range.

9. The method of any one of claims 1-7, wherein the administration results in blood glucose levels within the normal range.

10. The method of any one of claims 1-9, further comprising administering at least one additional therapeutic agent.

11. The method of claim 10, wherein the at least one additional therapeutic agent is insulin, an insulin analog, a biguanide, or a thiazolidinedione.

12. The method according to any one of claims 1-11, wherein the administration is oral administration.

13. The method according to any one of claims 1 to 12, wherein the compound of formula I is administered daily.

14. The method according to any one of claims 1 to 12, wherein the compound of formula I is administered once a week.

15. The method of any one of claims 1-12, wherein the compound of formula I is administered by controlled delivery.

16. The method of claim 15, wherein the compound of formula I is present in an implantable delivery device.

17. A method for treating metabolic syndrome in an individual, the method comprising administering to the individual an effective amount of a compound of formula I: in: 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 R 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 is 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 ; or any R 5 and R 6 Together with the nitrogen to which they are both attached, they form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; the compound of formula I is in the form of a single stereoisomer or a mixture thereof or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the compound is 5-(tetradecyloxy)-2-furoic acid.

19. The method of claim 17 or claim 18, wherein the administration is oral administration.

20. The method according to any one of claims 17 to 19, wherein the compound of formula I is administered daily.

21. The method according to any one of claims 17-19, wherein the compound of formula I is administered once a week.

22. The method of any one of claims 17-19, wherein the compound of formula I is administered by controlled delivery.

23. The method of claim 22, wherein the compound of formula I is present in an implantable delivery device.

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