Thiadiazolone derivatives and their use as AMPK agonists for treating diabetes and related diseases

Abstract

The present invention relates to compounds of formula I, wherein: R 1 As defined in the specification, or a pharmaceutically acceptable salt or solvate thereof, the compound can be used to treat disorders or conditions that are ameliorated by activation of AMPK, particularly as a prodrug.

Description

Technical Field

[0001] The present invention relates to novel compounds and the use of these compounds in medicine. In particular, the present invention relates to compounds that are useful in treating disorders or conditions that are ameliorated by activation of AMP-activated protein kinase. Background Art

[0002] AMP-activated protein kinase (AMPK) is a protein kinase composed of three protein subunits that is activated by hormones, cytokines, exercise, and stresses that reduce cellular energy status (e.g., glucose deprivation). AMPK activation increases processes that generate adenosine 5'-triphosphate (ATP), such as fatty acid oxidation, and inhibits other processes that consume ATP but are not essential for survival, such as fatty acid synthesis, glycerol lipid synthesis, and protein synthesis. Conversely, when cells are exposed to a sustained excess of glucose, AMPK activity decreases, while fatty acid synthesis, glycerol lipid synthesis, and protein synthesis are enhanced. AMPK is therefore a protein kinase that plays an important role in cellular energy homeostasis. Consequently, AMPK activation combines with glucose-lowering effects to trigger several other biological effects, including inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and reduction of hyperinsulinemia.

[0003] In view of the above, AMPK is a preferred target for treating metabolic syndrome, especially type 2 diabetes. AMPK is also involved in many pathways that are important for many different diseases (for example, AMPK is also involved in many pathways that are important for CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).

[0004] AMPK is also involved in many pathways important for cancer. Several tumor suppressors are part of the AMPK pathway. AMPK acts as a negative regulator of the mammalian TOR (mTOR) and EF2 pathways, both of which are key regulators of cell growth and proliferation. Therefore, deregulation may be associated with diseases such as cancer (and diabetes). Therefore, AMPK activators may be used as anticancer drugs.

[0005] AMPK activator drugs (such as metformin and 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (hereinafter referred to as the compound of Formula II)) have been shown to be effective in treating pain. Das and colleagues reported that post-injury treatment with AMPK activator drugs in mice after lumbar disc puncture reduced mechanical hypersensitivity (Das V et al., Reg Anesth Pain Med 2019;0:1–5.doi:10.1136 / rapm-2019-100839). Similarly, Das and colleagues also reported that early treatment with AMPK activator drugs reduced mechanical hypersensitivity in a mouse postoperative pain model (Das V et al., Reg Anesth Pain Med 2019;0:1-6.doi:10.1136 / rapm-2019-100651). These drugs also normalize the AMPK pathway in the dorsal root ganglion. Therefore, AMPK activators could be used to treat pain, particularly postoperative pain.

[0006] It has also been shown that hepatic steatosis can be regulated by AMPK (Zhao et al., J.Biol.Chem.2020 295:12279-12289). Activation of AMPK inhibits de novo lipogenesis in the liver while promoting fatty acid oxidation (β-oxidation). AMPK activation also reduces the release of free fatty acids in adipose tissue, preventing hepatic steatosis. It has been reported that pharmacological activation of AMPK in the liver promotes beneficial effects on multiple aspects of non-alcoholic fatty liver disease (NAFLD). For example, in murine and ape animal models, it was found that activation of AMPK improved non-alcoholic steatohepatitis (NASH). Therefore, AMPK activators can be used to treat NAFLD and NASH.

[0007] An example of an AMPK activator is 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (ie, the compound of formula II), which was first disclosed in WO 2011 / 004162.

[0008]

[0009] As AMPK agonists (i.e., AMPK activators), compounds of Formula II can be used to treat disorders or conditions that are improved by activation of AMPK. Such compounds can be used to treat cardiovascular diseases (such as heart failure), diabetic nephropathy, type 2 diabetes, insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, pain, opioid addiction, obesity, cancer, inflammation (including chronic inflammatory diseases), autoimmune diseases, osteoporosis, and intestinal disease.

[0010] Although many AMPK activators are known, there is still a need to develop new compounds to treat disorders or conditions that are improved by AMPK activation. The present inventors have now discovered new compounds that are metabolized in vivo to form known AMPK activators, surprisingly enhancing the bioavailability of these AMPK activators. The compounds have also been found to activate AMPK.

[0011] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an admission that the document is part of the state of the art or is common general knowledge. Summary of the Invention

[0012] In a first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

[0013]

[0014] where R 1 Selected from -C(O)-C2H4-CO2H and -PO3H2.

[0015] These compounds, including pharmaceutically acceptable salts and solvates thereof, may be referred to herein as "compounds of the present invention."

[0016] It has been found that the compounds of the present invention are metabolized in vivo to form 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (referred to herein as the compound of Formula II), which is known to be an AMPK activator. In this regard, the compounds of the present invention can be considered to be prodrugs of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0017] Pharmaceutically acceptable salts include basic salts. Such salts can be formed by conventional methods, for example, by reacting the free acid or phosphoric acid form of a compound of the present invention with one or more equivalents of a suitable base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., in a vacuum, by freeze drying, or by filtration). Salts can also be prepared using techniques known to those skilled in the art, for example, by exchanging the counterion of a compound of the present invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0018] Pharmaceutically acceptable salts of potential use include those discussed in J. Pharmaceutical Sciences, 66: 1-19 (1977) by Berge et al. In some embodiments, salts can be prepared in situ during the final separation and / or purification process of the compound of the present invention, or prepared separately by reaction of the free acid functional group with a suitable inorganic or organic base. Suitable counterions of the salt include, but are not limited to, metals such as sodium, potassium and calcium, or amines such as triethylammonium and lysine. Specific pharmaceutically acceptable addition salts that may be mentioned include alkali metal salts, alkaline earth metal salts or quaternary ammonium salts of the compound of formula I.

[0019] "Alkali metals" are metals that exist in Group I of the Periodic Table of the Elements along with hydrogen, most notably lithium, sodium, potassium, rubidium, and cesium. It will therefore be understood that an "alkali metal salt" is a compound consisting of a combination of one or more alkali metal cations and one or more associated anions.

[0020] "Alkaline earth metals" are metals present in Group II of the Periodic Table of the Elements, most notably magnesium, calcium, strontium, and barium. It will therefore be understood that an "alkaline earth metal salt" is a compound consisting of a combination of one or more alkaline earth metal cations and one or more associated anions.

[0021] "Quaternary ammonium" cations are of the structure [NR4] + A positively charged ion, where each R can independently represent H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or aryl. Alternatively, a "quaternary ammonium" cation is a cationic form (particularly a protonated form) of an amino acid, such as an amino acid with a positively charged side chain (e.g., lysine, histidine, or arginine). Thus, it is understood that a "quaternary ammonium salt" is a compound composed of a combination of one or more quaternary ammonium cations and one or more associated anions.

[0022] Unless otherwise specified, alkyl groups as defined herein may be linear or, when there are a sufficient number (i.e., at least two or three, as the case may be), branched and / or cyclic (thus forming a cycloalkyl group). When there are a sufficient number (i.e., at least four) of carbon atoms, these groups may also be partially cyclic (thus forming a partial cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl, and cyclohexyl. Similarly, partially cyclic alkyl groups (which may also be referred to as "partial cycloalkyl groups") that may be mentioned include cyclopropylmethyl.

[0023] Unless otherwise specified, alkenyl groups as defined herein may be straight chain or, when there are a sufficient number (i.e. a minimum of three) of carbon atoms, branched. For the avoidance of doubt, specific alkenyl groups that may be mentioned include straight chain (i.e. unbranched) alkenyl groups.

[0024] Unless otherwise specified, alkynyl groups as defined herein may be straight chain or, when there are a sufficient number (i.e. a minimum of four) of carbon atoms, branched. For the avoidance of doubt, specific alkynyl groups that may be mentioned include straight chain (i.e. unbranched) alkynyl groups.

[0025] For the avoidance of doubt, unless otherwise specified, groups referred to herein as "alkyl," "alkenyl," and / or "alkynyl" will be deemed to refer to the highest degree of unsaturation of the bonds present in these groups. For example, such groups having a carbon-carbon double bond and, in the same group, a carbon-carbon triple bond will be referred to as "alkynyl."

[0026] As may be used herein, the term aryl may refer to an aromatic group. Such a group may be monocyclic or bicyclic and, when bicyclic, may be fully or partially aromatic. 6-10 Aryl, in particular phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, etc. (eg phenyl and naphthyl). For the avoidance of doubt, the point of attachment of a substituent on an aryl group may be via any suitable carbon atom of the ring system.

[0027] Thus, an “alkali metal salt,” “alkaline earth metal salt,” or “quaternary ammonium salt” of a compound of formula I refers to a compound comprising one or more alkali metal, alkaline earth metal, or quaternary ammonium cations (e.g., lithium, magnesium, calcium, ammonium, tetramethylammonium, and in particular sodium and potassium) and one or more anions of a compound of formula I.

[0028] In particular, alkali metal salts, alkaline earth metal salts and quaternary ammonium salts of compounds of formula I may be mentioned, including compounds of formula III,

[0029]

[0030] and a compound of formula IV,

[0031]

[0032] where X + represents an alkali metal, alkaline earth metal or quaternary ammonium (eg lithium, magnesium, calcium, ammonium, tetramethylammonium, in particular sodium and potassium) cation, with appropriate stoichiometric adjustments depending on the charge of the ion.

[0033] Those skilled in the art will recognize that pharmaceutically acceptable salts (eg, alkali metal salts, alkaline earth metal salts, or quaternary ammonium salts) of compounds of Formula I may dissociate into their anionic and cationic components when dissolved in a suitable solvent (eg, water).

[0034] Pharmaceutically acceptable salts of compounds of formula I can be prepared according to techniques well known to those skilled in the art. For example, compounds of formula I can be reacted with a suitable alkali metal hydroxide or an alternative alkali metal base compound. Salt conversion techniques can also be used to convert one salt into another.

[0035] In certain embodiments, the pharmaceutically acceptable salt is a sodium salt or a potassium salt of a compound of Formula I. Preferably, the pharmaceutically acceptable salt is a sodium salt.

[0036] The compounds disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and it is intended that the invention encompass both solvated and unsolvated forms of the compounds of the invention.

[0037] The term "solvate" refers to a complex formed by a solute and a solvent with a variable stoichiometry. For the purposes of the present invention, such a solvent does not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing variable amounts of water.

[0038] The compounds of Formula I contain double bonds and can therefore exist as E (trans (entgegen)) and Z (cis (zusammen)) geometric isomers around each individual double bond. All such isomers and mixtures thereof are included within the scope of the present invention.

[0039] The compounds of formula I may exist as regioisomers and may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the present invention.

[0040] The present invention also includes isotopically labeled compounds of formula I, which are identical to the compounds described herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (or the most abundant atomic mass or mass number found in nature). All isotopes of any particular atom or element specified herein are included within the scope of the present invention. Thus, compounds of formula I also include deuterated compounds, i.e., compounds of formula I in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0041] Throughout the specification, structures may or may not be represented by chemical names. In the event of any problems with nomenclature, the structure will be the standard. Where a compound may exist as a tautomer (e.g., in an alternative resonance form), the described structure represents one of possible tautomeric forms, wherein the actual tautomeric form observed may vary according to environmental factors such as solvent, temperature, or pH. All tautomeric (and resonance) forms and mixtures thereof are included within the scope of the present invention.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0043] For the avoidance of doubt, those skilled in the art will understand that references herein to particular aspects of the invention (such as the first aspect of the invention) will include references to all embodiments and specific features thereof, which may be combined to form further embodiments and features of the invention.

[0044] In certain embodiments, the compound of Formula I is Compound 3:

[0045]

[0046] or a pharmaceutically acceptable salt or solvate thereof. Compound 3 is known as 4-({(5Z)-5-[(4-chlorobenzoyl)imino]-2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-4-yl}methoxy)-4-oxobutanoic acid. In another embodiment, the compound of the present invention is the sodium salt of Compound 3.

[0047] In other embodiments, the compound of Formula I is Compound 5A:

[0048]

[0049] or a pharmaceutically acceptable salt or solvate thereof. Compound 5A is referred to as {(5Z)-5-[(4-chlorobenzoyl)imino]-2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-4-yl}methylphosphonic acid. In another embodiment, the compound of the present invention is the sodium salt of Compound 5A, specifically disodium {(5Z)-5-[(4-chlorobenzoyl)imino]-2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-4-yl}methylphosphonic acid (referred to herein as "Compound 5").

[0050] The compounds of the present invention can be considered as prodrugs of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide because they have been found to decompose in vivo to form the compound. 4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can also be described as a compound of formula II:

[0051]

[0052] The term "prodrug" refers to a compound that, after oral or parenteral administration, is metabolized in vivo to produce an experimentally detectable amount of the pharmaceutically active compound within a predetermined time period, for example, within a dosing interval of 6 to 24 hours (i.e., one to four times a day). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs" pl-92, Elsevier, New York-Oxford (1985).

[0053] It has been found that administration of the compounds of the present invention surprisingly results in a significant increase in the bioavailability and systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to the bioavailability and systemic exposure observed following administration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0054] The bioavailability of a drug is the amount of an administered dose that reaches the systemic circulation in the form of the drug. Adequate bioavailability is important for achieving therapeutically active concentrations at the site of action. Improvements (i.e., increases) in bioavailability can be measured by measuring C in the blood of a subject after administration of a compound (or a pharmaceutical formulation thereof). maxThe compounds and formulations of the present invention can be used for the therapies described herein in subjects in need of such treatment. Examples of subjects include animals such as mammals. Examples of specific mammals include, for example, primates (e.g., humans, male or female), cattle, horses, dogs, and cats. Preferably, the subject is a human.

[0055] The term "C max " and "AUC" will be well understood by those skilled in the art as referring, in the present context, to the peak plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide following administration (e.g., to a human subject) and the integral of the concentration / time curve of the substance following administration of a compound of the invention (or a formulation thereof), respectively.

[0056] It has been found that administration of the compounds of the present invention results in a particularly enhanced in vivo bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide, as demonstrated by the data in the Examples. These data demonstrate that when the compounds are administered to mammalian subjects, the plasma exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is increased compared to the plasma exposure observed following administration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0057] Thus, administration of the compounds of the present invention can increase the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to administration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. In this context, the phrase "increase bioavailability" means that administration of the compounds of the present invention results in a greater systemically available fraction of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in the body compared to administration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. The increase in the systemically available portion of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be at least about 10%, (at least) about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% (i.e., 2-fold), about 150%, about 200% (i.e., 3-fold), about 250%, about 300% (i.e., 4-fold), about 350%, or about 400% (i.e., 5-fold).

[0058] The improvement in bioavailability provided by the compounds of the present invention can be demonstrated using suitable methods known in the art. For example, the improvement in bioavailability can be demonstrated by comparing the pharmacokinetic data (e.g., AUC data) of subjects who have been administered a compound of the present invention with the corresponding data of subjects who have been administered 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0059] As shown in the Examples, the compounds of the present invention have comparable stability to 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in mildly alkaline solutions (e.g., at pH 7.4). Therefore, the compounds of the present invention are suitable for preparation into pharmaceutical formulations for administration to patients. However, both the compounds of the present invention and the compound of Formula II exhibit reduced stability under acidic conditions, and therefore, unless adequate protection is provided for the orally administered formulation, decomposition in the gastric environment is likely to occur.

[0060] It was also found that the compounds of the present invention are surprisingly effective in activating AMPK, as demonstrated by the data in the Examples. As AMPK activators (i.e., AMPK agonists), the compounds of the present invention can be used to treat disorders or conditions that are improved by the activation of AMPK. Therefore, these compounds can be used to treat the specific diseases described herein.

[0061] The compounds of the present invention can be prepared from 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. 4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be prepared according to techniques well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be prepared according to the techniques described in International Patent Application WO 2011 / 004162, the entire contents of which are incorporated herein by reference.

[0062] The compounds of the invention described herein can be prepared according to techniques well known to those skilled in the art, such as those described in the examples provided below.

[0063] Formula I compounds can be obtained from available starting materials according to standard techniques by methods similar to those known in the literature or by conventional synthetic procedures, using suitable reagents and reaction conditions. In this respect, the skilled person can particularly refer to " Comprehensive Organic Synthesis " by BMTrost and I. Fleming, Pergamon Press, 1991.

[0064] For example, there is provided a process for preparing a compound of the invention as defined above, the process comprising:

[0065] (i) reacting a compound of formula V with a suitable acid or anhydride (e.g. succinic anhydride) in the presence of a suitable base (e.g. 4-dimethylaminopyridine) and a suitable solvent (e.g. tetrahydrofuran) according to procedures known to those skilled in the art:

[0066]

[0067] (ii) reacting a compound of formula VI with a suitable acid or a suitable acid salt (e.g. phosphoric acid, optionally in the form of ammonium dihydrogen phosphate) in the presence of a suitable base (e.g. 4-tributylamine) and a suitable solvent (e.g. dichloromethane) according to procedures known to those skilled in the art:

[0068]

[0069] The compound of formula V can be obtained from available starting materials by conventional synthetic procedures using appropriate reagents and reaction conditions according to standard techniques. For example, the compound of formula V can be prepared by reacting a compound of formula II with formaldehyde in the presence of a suitable base (e.g., triethylamine) and a suitable solvent (e.g., N,N-dimethylformamide) according to procedures known to those skilled in the art:

[0070]

[0071] Similarly, compounds of formula VI can also be obtained from available starting materials by conventional synthetic procedures using appropriate reagents and reaction conditions according to standard techniques. For example, compounds of formula VI can be prepared by reacting compounds of formula V with a chlorinating agent (e.g., thionyl chloride) according to procedures known to those skilled in the art.

[0072] Similarly, the compound of formula II (i.e., 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide; referred to as compound 1 in the examples) can be prepared according to techniques well known to those skilled in the art, such as the techniques described in International Patent Application No. WO 2011 / 004162.

[0073] The compounds of the present invention can be isolated from their reaction mixtures and, if desired, purified using conventional techniques known to those skilled in the art. Thus, the methods for preparing the compounds of the present invention as described herein can include isolating and optionally purifying the compounds of the present invention as a final step.

[0074] pharmaceutical preparations

[0075] As shown herein, the compounds of the present invention can be used as therapeutic agents to treat a variety of medical disorders or conditions. Typically, the compounds of the present invention will be administered to a subject in need thereof in the form of a pharmaceutical formulation.

[0076] According to a second aspect of the present invention, a pharmaceutical preparation comprising a compound of formula I (or a pharmaceutically acceptable salt or solvate thereof) is provided. Such preparations are referred to herein as preparations of the present invention. All embodiments and specific features thereof described herein with respect to the first aspect of the present invention are disclosed herein with respect to the second aspect of the present invention.

[0077] The pharmaceutical formulations of the second aspect of the invention may be prepared according to standard and / or accepted pharmaceutical practice.

[0078] In one embodiment of the second aspect of the invention, the compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) is the sole active pharmaceutical ingredient present in the formulation. In another embodiment of the second aspect of the invention, the compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) is present in the formulation together with one or more other active pharmaceutical ingredients, or can be administered as part of a combination therapy with one or more other active pharmaceutical ingredients.

[0079] The preparation of the second aspect of the present invention will generally be provided as a mixture comprising a compound of the present invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. One or more pharmaceutically acceptable excipients can be selected according to standard pharmaceutical practice with full consideration of the intended route of administration. Such pharmaceutically acceptable excipients are preferably chemically inert to the active compound and preferably do not have harmful side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations can be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief review of drug delivery methods can also be found in, for example, Langer, Science 249, 1527 (1990).

[0080] It has been found that pH-altering excipients are particularly advantageous in the formulations of the present invention. pH-altering excipients are those that substantially alter the pH of an aqueous solution of the formulation compared to the pH of an aqueous solution of the same formulation without the additional excipient. A pH-altering excipient can increase (or decrease) the pH of an aqueous solution of the formulation (e.g., to pH 8 or higher) compared to an aqueous solution of the same formulation without the excipient. Such excipients can be used to increase (i.e., improve) the water solubility and / or stability of the compounds of the present invention in the formulation.

[0081] In the formulations of the present invention, it has been found that basic excipients are useful in combination with the compounds of the present invention, particularly with compound 5 and its other salts, and result in improved solubility of the compounds. Thus, in a particular embodiment of the second aspect of the invention, at least one pharmaceutically acceptable excipient is a basic excipient.

[0082] As used herein, the term "alkaline excipient" refers to a pharmaceutically acceptable excipient that increases the microenvironmental pH of a formulation. It has been found that adjusting the microenvironmental pH of a formulation can improve the dissolution of the active ingredient in the formulation, which in turn can enhance the oral absorption of the active ingredient. Specific alkaline excipients that may be mentioned include magnesium oxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate. In a specific embodiment, the alkaline excipient is magnesium oxide.

[0083] Other pharmaceutically acceptable excipients may also be present in the formulations of the present invention (in addition to the alkaline excipient or in the absence of such excipients). For example, the formulations of the present invention may contain lubricants, binders, fillers, surfactants, diluents, anti-adherents, coatings, flavorings, colorants, glidants, preservatives, sweeteners, disintegrants, adsorbents, buffers, antioxidants, chelating agents, dissolution promoters, dissolution retardants and / or wetting agents.

[0084] Specific pharmaceutically acceptable excipients that may be mentioned include microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate, colloidal silicon dioxide, anhydrous lactose, dicalcium phosphate, mannitol, pregelatinized starch, hydroxypropyl cellulose, povidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, sodium stearyl fumarate, talc, hydroxypropyl methylcellulose, polysorbate 80, sodium lauryl sulfate, poloxamer 188, poloxamer 407, propylene glycol, titanium dioxide, hypromellose phthalate, hypromellose acetate succinate, methacrylic acid, methyl methacrylate copolymer,

[0085] In preparing pharmaceutical formulations of the compounds of the present invention for oral administration, the compounds of the present invention may be mixed together or separately with one or more of the pharmaceutical excipients listed above (including basic excipients).

[0086] The mixture of the compound of the present invention and one or more pharmaceutically acceptable excipients can be processed into micropills (pellet) or granules (granule), or compressed into tablets. Therefore, the pharmaceutical preparation of the present invention includes a preparation for oral administration in the form of tablets, mini tablets, blocks (block), micropills, particles (particle), granules or powders. The mixture of the compound of the present invention and one or more pharmaceutically acceptable excipients can also be provided in a form suitable for subcutaneous or intramuscular delivery, such as an injectable solution or a lyophilized powder suitable for reconstructing in a suitable fluid before administration.

[0087] It will be understood by those skilled in the art that the formulations described herein can act systemically and therefore can be administered accordingly using appropriate techniques known to those skilled in the art. The formulations described herein are typically administered orally, subcutaneously, or intramuscularly in a suitable pharmaceutically acceptable dosage form. The pharmaceutical formulations of the second aspect of the present invention are preferably oral pharmaceutical formulations.

[0088] The preparation of the present invention can be prepared for oral administration in the form of capsules. For example, capsules such as soft gelatin capsules can be prepared that contain the compound of the present invention (or its pharmaceutically acceptable salt or solvate) alone or optionally with a suitable solvent (e.g., vegetable oil, fat, etc.). Similarly, hard gelatin capsules can contain the compound of the present invention (or its pharmaceutically acceptable salt or solvate) alone or in combination with solid powder ingredients such as disaccharides (e.g., lactose or sucrose), alcohol sugars (e.g., sorbitol or mannitol), plant starches (e.g., potato starch or corn starch), polysaccharides (e.g., amylopectin or cellulose derivatives), or gelling agents (e.g., gelatin).

[0089] Specific pharmaceutical formulations of the present invention include those provided in the form of capsules or tablets, for example, for oral administration.

[0090] The preparation intended for oral administration may further include an enteric coating to prevent or minimize dissolution or disintegration in the gastric environment. Therefore, the oral preparation (such as capsule or tablet) coated with an enteric coating can provide the targeted release of the compound of the present invention (or its pharmaceutically acceptable salt or solvate) individually in the small intestine. For example, the enteric coating may be present on the surface of the preparation (such as on the surface of a tablet or capsule). Therefore, in a specific embodiment, the preparation further includes an enteric coating.

[0091] It may be desirable to minimize dissolution or disintegration of a capsule or tablet (etc.) in the gastric environment and / or to provide targeted release of the active ingredient in the small intestine. Thus, in certain embodiments, an enteric coating is present on the capsule or tablet. For example, the coating may be provided as an outer layer on the capsule or tablet.

[0092] The term "enteric coating" refers to a substance (e.g., a polymer) that is incorporated into an orally administered drug (e.g., applied to the surface of a tablet or capsule) and inhibits the drug's dissolution or disintegration in the gastric environment. Enteric coatings are generally stable at the highly acidic pH found in the stomach, but break down rapidly at the higher pH of the small intestine. Thus, enteric coatings prevent the release of the active ingredient in the drug until it reaches the small intestine.

[0093] The present invention can use any enteric coating known to those skilled in the art.The specific enteric coating materials that can be mentioned include those comprising the enteric coating of following material: beeswax, shellac, alkyl cellulose polymer resin (for example ethyl cellulose polymer, carboxymethyl ethyl cellulose or hydroxypropyl methylcellulose phthalate) or acrylic polymer resin (for example acrylic acid and methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, methacrylate copolymer, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer), cellulose acetate phthalate and polyvinyl acetate phthalate.The specific polyacrylic resin that can be mentioned is polyacrylic resin HB-50.

[0094] Pharmaceutical formulations that may be mentioned include those in which the compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) is present in a total amount of at least 1% (or at least 10%, at least 30% or at least 50%) of the formulation weight and up to 99% of the formulation weight. The weight ratio of the compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) to all components of the pharmaceutical formulation (i.e., the compound of the invention and all pharmaceutical excipients, such as adjuvants, diluents and carriers) is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) and up to 99:1.

[0095] As used herein, "therapeutically effective amount", "effective amount" and "dose" refer to the amount of the compound of the present invention (or its pharmaceutically acceptable salt or solvate) sufficient to produce the desired clinical effect, which can be a therapeutic effect and / or a beneficial effect. The effective amount or dosage will vary with the age or general condition of the subject (e.g., human), the severity of the condition being treated, the specific agent being administered, the duration of treatment, the nature of any simultaneous treatment, the pharmaceutically acceptable excipient used, and similar factors within the knowledge and expertise of those skilled in the art. Where appropriate, those skilled in the art can determine the "therapeutically effective amount", "effective amount" or "dose" in any individual case by reference to relevant texts and literature and / or by using routine experiments. Those skilled in the art will appreciate that the therapeutic effect does not need to be complete or curative, as long as some benefit is provided to the subject.

[0096] It will be appreciated by those skilled in the art that the compounds of the present invention and their preparations can be administered (for example, by one or more preparations as described herein) with different dosages, and suitable dosage is easily determined by those skilled in the art. The total dose of the compound of the present invention (or its pharmaceutically acceptable salt or solvate) administered to a subject in need thereof can be in the range of about 0.01 milligrams / day (mg / days) to about 3000mg / days, about 0.1mg / days to about 2000mg / days or about 1mg / days to about 1000mg / days (for example, about 10mg / days to about 500mg / days). Such dosage can be the oral dose of the preparation of the second aspect of the present invention. When the compound of the present invention (or its pharmaceutically acceptable salt or solvate) is administered intramuscularly or subcutaneously, it will be appreciated by those skilled in the art that dosage should be adjusted accordingly.

[0097] When administered orally, treatment with such a formulation can include administering a unit dose formulation containing from about 0.01 mg to about 3000 mg of the compound of the invention, for example, from about 0.1 mg to about 2000 mg or from about 1 mg to about 1000 mg (e.g., from about 10 mg to about 500 mg). Advantageously, treatment can include administering the compound of the invention using a single daily dose (e.g., in the form of one or more capsules containing the formulation). Alternatively, the total daily dose of the compound of the invention can be administered twice, three times, or four times a day (e.g., with reference to a dosage as described herein, twice a day, for example, a dosage of 100 mg, 250 mg, 500 mg, or 1000 mg, twice a day) in divided doses. A skilled physician will appreciate that dosage will vary from subject to subject.

[0098] In a specific embodiment, the daily dose of a compound of the invention administered to a subject is in the range of about 1 to about 3000 mg, preferably about 1 to about 1000 mg.

[0099] As used herein, the term "about" when referring to a measurable value, such as an amount of a compound, a dosage, a time, a temperature, etc., refers to a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is contemplated that in each case, these terms can be replaced by a notation such as "±10%" (or by indicating the variance of a specific amount calculated based on the relevant value). It is also contemplated that in each case, these terms can be deleted.

[0100] For the avoidance of doubt, in the context of the present invention, the dose administered to a subject, particularly a human subject, should be sufficient to produce a therapeutic response in the subject within a reasonable timeframe. Those skilled in the art will recognize that the selection of the exact dose and composition, as well as the most appropriate delivery regimen, will also be influenced, inter alia, by the pharmacological properties of the formulation; the nature and severity of the condition being treated; the physical condition and mental acuity of the recipient and the potency of the specific compound; the age, condition, weight, sex and response of the subject being treated; and the stage / severity of the disease.

[0101] In any case, a practicing physician or other technician will be able to routinely determine the actual dosage that is most suitable for an individual subject. The above dosages are examples of average cases; of course, there may be individual cases where higher or lower dosage ranges are applicable, and these are within the scope of the present invention.

[0102] Combinations and component kits

[0103] Those skilled in the art will appreciate that treatment with the compounds of the present invention may further include (ie, be combined with) other treatments for the same condition.

[0104] In particular, the compounds of the present invention may also be combined with one or more other (i.e., different) therapeutic agents (i.e., therapeutic agents that are not compounds of the present invention) that are useful for treating disorders or conditions that are improved by activation of AMPK. Such combination products providing for the combined administration of a compound of the present invention with one or more other therapeutic agents may be presented as separate formulations, wherein at least one of these formulations contains a compound of the present invention and at least one contains the other therapeutic agent, or may be presented (i.e., formulated) as a combined formulation (i.e., presented as a single formulation comprising a compound of the present invention and one or more other therapeutic agents).

[0105] Therefore, according to a third aspect of the present invention, there is provided a combination product comprising:

[0106] (I) a compound of the invention as defined above (ie, in the first aspect of the invention, including all embodiments and special features thereof); and

[0107] (II) one or more other therapeutic agents that are useful in treating disorders or conditions that are ameliorated by activation of AMPK (e.g., cardiovascular diseases (such as heart failure) described herein, diabetic nephropathy, etc.),

[0108] Each of components (I) and (II) is optionally mixed with one or more pharmaceutically acceptable excipients.

[0109] In a fourth aspect of the present invention, there is provided a kit-of-parts comprising:

[0110] (a) a pharmaceutical formulation as defined above (ie in the second aspect of the invention); and

[0111] (b) one or more other therapeutic agents useful for treating disorders or conditions ameliorated by activation of AMPK (e.g., cardiovascular diseases (e.g., heart failure), diabetic nephropathy, etc., as described herein), optionally in admixture with one or more pharmaceutically acceptable excipients,

[0112] The components (a) and (b) are each provided in a form suitable for co-administration (ie, simultaneous or sequential) with the other component.

[0113] With respect to the kits of parts described herein, "administration in conjunction with" (and similarly "administered in conjunction with") includes the sequential, separate or simultaneous administration of the corresponding formulations as part of a medical intervention for the treatment of related conditions.

[0114] Thus, for purposes of the present invention, the term "administration in conjunction with" (and similarly "administered in conjunction with") includes the administration of two active ingredients (i.e., a compound of the present invention and another agent for treating a disorder or condition ameliorated by activation of AMPK, or a composition comprising the same) together or sufficiently close in time (optionally repeated) to produce a greater beneficial effect on the patient during the treatment of the relevant condition than if either agent were administered alone (optionally repeated) in the absence of the other component during the same treatment. Determining whether a combination provides a greater beneficial effect in the treatment of a particular condition and during its treatment will depend on the condition to be treated, but can be routinely accomplished by one skilled in the art.

[0115] In addition, in the context of the present invention, the term "in conjunction with" includes that one or the other of the two formulations can be administered before, after, and / or at the same time as the other component (optionally repeatedly). When used in this context, the terms "administered simultaneously" and "administered at the same time as" include separate doses of a compound of the present invention and another compound for treating a disorder or condition improved by activating AMPK, or a pharmaceutically acceptable salt thereof, administered within 48 hours of each other (e.g., within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes).

[0116] Other therapeutic agents that can be used to treat disorders or conditions that are improved by activation of AMPK (e.g., heart failure, diabetic nephropathy, etc. as described herein) are well known to those skilled in the art. Preferably, the other therapeutic agent will be selected from the group consisting of biguanide antihyperglycemic agents and sodium-glucose transporter 2 (SGLT2) inhibitors (and pharmaceutically acceptable salts and solvates thereof).

[0117] Biguanide antihyperglycemic agents that may be mentioned include phenformin, buformin, and in particular metformin (and pharmaceutically acceptable salts thereof). Thus, in one embodiment, the compounds of the present invention may be provided in combination with metformin (or a pharmaceutically acceptable salt thereof) to treat any of the diseases disclosed herein.

[0118] Those skilled in the art will appreciate that a sodium-glucose transporter 2 inhibitor is a substance or agent that causes a reduction in one or more functions of sodium-glucose transporter 2, and by "reduction in the function of sodium-glucose transporter 2" we include a cessation of one or more functions of sodium-glucose transporter 2 or a reduction in the rate of a particular function. The particular function that may be fully or partially inhibited is the ability of sodium-glucose transporter 2 to act as a glucose transporter.

[0119] In certain embodiments, the sodium-glucose transporter 2 inhibitor is gliflozin. Gliflozins are a class of known small molecule sodium-glucose transporter 2 inhibitors. Hawley et al. (Diabetes, 2016, 65, 2784–2794) and Villani et al. (Molecular Metabolism, 2016, 5, 1048–1056) recently discussed the possible mechanism of action of certain gliflozins. Particular gliflozins that may be mentioned include canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin, sergliflozin (e.g. sergliflozine tabonate), remogliflozin (e.g. remogliflozine tabonate), ertugliflozin and sotagliflozin, and pharmaceutically acceptable salts and solvates thereof.

[0120] Medical uses

[0121] As shown herein, the compounds of the present invention are useful as pharmaceuticals.The compounds of the present invention are useful because they are pharmacologically active and / or are metabolized in vivo following oral or parenteral administration to form pharmacologically active compounds.

[0122] Therefore, according to a fifth aspect of the present invention, there is provided a compound of the invention as defined above (i.e., a compound as defined in the first aspect of the invention), or a pharmaceutical formulation, combination product or kit of parts as defined in relation to the second, third and fourth aspects of the invention, for use in medicine. For the avoidance of doubt, reference to a compound as defined in the first aspect of the invention includes reference to a compound of formula I (including all embodiments thereof) and pharmaceutically acceptable salts and solvates thereof.

[0123] The compounds of the present invention (i.e., compounds as defined in the first aspect of the present invention) and formulations, combination products, and kits containing the compounds are particularly useful for treating disorders or conditions that are improved by activation of AMP-activated protein kinase (AMPK). Thus, in a sixth aspect of the present invention, there is provided a compound of the present invention or a formulation comprising the compound for use in treating disorders or conditions that are improved by activation of AMPK.

[0124] Similarly, there is provided a use of a compound of the present invention or a formulation comprising the compound in the preparation of a medicament for treating a disorder or condition improved by activation of AMPK. In another alternative sixth aspect of the present invention, there is provided a method for treating a disorder or condition improved by activation of AMPK, comprising administering a compound of the present invention (or a formulation comprising the compound) to a subject (e.g., a human) in need thereof.

[0125] "Activation of AMPK" means that the steady-state phosphorylation level of the Thr-172 portion of the AMPK-α subunit is increased compared to the steady-state phosphorylation level in the absence of the compound of Formula I or its active metabolite (e.g., 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide). Alternatively or additionally, it means that any other protein downstream of AMPK, such as acetyl-CoA carboxylase (ACC), has a higher steady-state phosphorylation level.

[0126] The term "disorder or condition improved by activation of AMPK" will be understood by those skilled in the art to include cardiovascular disease (such as heart failure), diabetic nephropathy, diabetes (such as type 2 diabetes), insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, pain, opioid addiction, obesity, cancer, inflammation (including chronic inflammatory diseases), autoimmune diseases, osteoporosis and bowel disease. Other diseases or conditions that can be improved by activation of AMPK include hyperinsulinemia and related conditions, conditions / disorders in which fibrosis plays a role, sexual dysfunction and neurodegenerative diseases.

[0127] The term "cancer" will be understood by those skilled in the art to include one or more diseases in the following class of disorders characterized by the uncontrolled division of cells and the ability of these cells to invade other tissues by invasion, proliferation, direct growth into adjacent tissues, or implantation into distant locations by metastasis. "Proliferation" includes an increase in the number and / or size of cancer cells. "Metastasis" refers to the movement or migration (e.g., invasiveness) of cancer cells from the site of a primary tumor in a subject's body to one or more other areas in the subject's body where the cells can then form secondary tumors.

[0128] Therefore, the compounds of the present invention may be suitable for treating any cancer type, including all tumors (non-solid and solid tumors, preferably solid tumors, such as epithelial cancer (carcinoma), adenoma, adenocarcinoma, blood cancer, regardless of organ). For example, the cancer cell may be selected from the group consisting of breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and airway, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph nodes and gastrointestinal tract cancer cells. Preferably, the cancer is selected from colon cancer (including colorectal adenoma), breast cancer (such as postmenopausal breast cancer), endometrial cancer, hematopoietic system cancer (such as leukemia, lymphoma, etc.), thyroid cancer, kidney cancer, esophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer. More preferably, the cancer is selected from the group consisting of colon, prostate and breast cancer, in particular breast cancer. Where the cancer is a non-solid tumor, it is preferably a hematopoietic tumor, such as a leukemia (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL). Preferably, the cancer cell is a breast cancer cell.

[0129] Those skilled in the art will understand that the term "diabetes" (i.e., diabetes mellitus) refers to type 1 (insulin-dependent) diabetes and type 2 (non-insulin-dependent) diabetes, both of which involve dysfunction of glucose homeostasis. The compounds of the present invention and their formulations may be particularly suitable for treating type 1 diabetes and / or type 2 diabetes. The compounds of the present invention are particularly suitable for treating type 2 diabetes.

[0130] In addition to being useful for treating diabetes, the compounds of the present invention are also suitable for treating diabetic kidney disease (i.e., diabetic nephropathy). "Diabetic nephropathy" refers to kidney damage caused by diabetes and is a serious complication of both type 1 and type 2 diabetes. Diabetic nephropathy affects the kidneys' ability to remove waste products from the blood and excrete them in urine, and can lead to kidney failure.

[0131] In addition, the compounds of the present invention are also suitable for treating chronic kidney disease, including chronic kidney disease in the absence of type 2 diabetes. "Chronic kidney disease" is a condition characterized by a gradual loss of kidney function over time. Chronic kidney disease is typically caused by one or more other diseases or conditions that affect the kidneys, such as high blood pressure, diabetes, high cholesterol, kidney infection, glomerulonephritis, polycystic kidney disease, urinary tract obstruction, urine flow obstruction, and long-term medication use.

[0132] The term "hyperinsulinemia or an associated condition" will be understood by those skilled in the art to include hyperinsulinemia, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinemia in childhood, hypercholesterolemia, hypertension, obesity, fatty liver condition, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions (such as stroke), systemic lupus erythematosus, neurodegenerative diseases (such as Alzheimer's disease) and polycystic ovary syndrome. Other disease states include progressive renal disease, such as chronic renal failure.

[0133] In particular, the compounds of the present invention and their preparations are suitable for treating obesity associated with hyperinsulinemia and / or cardiovascular diseases associated with hyperinsulinemia.

[0134] The compounds of the present invention and their formulations may also be suitable for treating cardiovascular diseases, such as heart failure, where the cardiovascular diseases are not associated with hyperinsulinemia. Similarly, the compounds of the present invention and their formulations may also be suitable for treating obesity that is not associated with hyperinsulinemia. For the avoidance of doubt, treatments for obesity and / or cardiovascular diseases (such as heart failure) where AMPK activation may be beneficial are included within the scope of the present invention.

[0135] Conditions / disorders in which fibrosis plays a role include, but are not limited to, scar healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis and cardiovascular fibrosis (including endomyocardial fibrosis), systemic sclerosis, cirrhosis of the liver, macular degeneration, retinal and vitreoretinopathy, Crohn's disease / inflammatory bowel disease, postoperative scar tissue formation, radiation- and chemotherapeutic drug-induced fibrosis, and cardiovascular fibrosis.

[0136] The compounds of the present invention may also be useful in treating sexual dysfunction (eg, treating erectile dysfunction). The compounds of the present invention may also be useful in treating inflammation.

[0137] Neurodegenerative diseases that may be mentioned include Alzheimer's disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine disorders such as spinal bulbar muscular atrophy (SBMA), dentatorubral pallidohypothalamic atrophy (DRPLA) and some spinocerebellar ataxias (SCA).

[0138] The compounds of the present invention are useful in treating non-alcoholic fatty liver disease (NAFLD).

[0139] Non-alcoholic fatty liver disease (NAFLD) is defined as excess fat accumulation (steatosis) in the form of triglycerides in the liver (defined histologically as accumulation in greater than 5% of hepatocytes). It is the most common liver disorder in developed countries (e.g., affecting approximately 30% of adults in the United States), and most patients are asymptomatic. If left untreated, the condition may gradually worsen and may eventually lead to cirrhosis of the liver. NAFLD is particularly prevalent in obese patients, with approximately 80% of patients believed to have the disease.

[0140] If the patient's alcohol consumption is not considered a major contributing factor, NAFLD can be diagnosed. A typical threshold for diagnosing fatty liver disease as "not related to alcohol" is a daily intake of less than 20g for female subjects and less than 30g for male subjects.

[0141] Specific diseases or conditions associated with NAFLD include metabolic conditions such as diabetes, hypertension, obesity, dyslipidemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, acute fatty liver of pregnancy, and lipodystrophy. Other non-alcohol-related factors associated with fatty liver disease include malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, polycystic ovary syndrome, and diverticular disease.

[0142] Non-alcoholic steatohepatitis (NASH) is the most aggressive form of NAFLD and is a condition in which excess fat accumulates (fatty degeneration) accompanied by liver inflammation. In advanced stages, NASH can lead to the development of liver scar tissue (fibrosis), ultimately leading to cirrhosis. As described above, it has been found that the compounds of the present invention can be used to treat NAFLD and inflammation. It can be seen from this that the compounds of the present invention can also be used to treat NASH. Therefore, in a further embodiment, the treatment is non-alcoholic steatohepatitis (NASH).

[0143] It has been shown that AMPK activator compounds (such as 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (i.e., compound of formula II)) can treat pain (Das V et al., Reg Anesth Pain Med 2019; 0:1–5.doi:10.1136 / rapm-2019-100839 and Das V et al., Reg Anesth Pain Med 2019; 0:1–6.doi:10.1136 / rapm-2019-100651) and these compounds can be considered analgesics. It can therefore be concluded that since the compounds of the present invention are able to activate AMPK, or are metabolized in the body to form known AMPK activator compounds, the compounds of the present invention can be used to treat pain. In particular, the compounds of the present invention can be used to treat patients suffering from severe pain, chronic pain, or for managing pain after surgery.

[0144] Opioid-based therapies, such as opioid analgesics, are used to treat severe chronic cancer pain, acute pain (e.g., during surgical recovery and breakthrough pain), and their use in the management of chronic non-malignant pain is increasing. However, the increasing use of opioid-based therapies to treat pain has led to an increase in opioid dependence (e.g., opioid addiction). As known to those skilled in the art, the compounds of the present invention can be used as AMPK activators to replace opioid-based therapies to treat pain. Therefore, the compounds of the present invention can be used to treat opioid addiction.

[0145] Specific autoimmune diseases known to those skilled in the art include Crohn's disease / inflammatory bowel disease, systemic lupus erythematosus, and type 1 diabetes.

[0146] Specific bowel diseases that should be mentioned include Crohn's disease / inflammatory bowel disease and gastrointestinal cancers.

[0147] Those skilled in the art will understand that references to "treatment" of a particular condition (or similarly, "treating" the condition) are to be taken in accordance with their standard meaning in the medical arts. In particular, these terms may refer to achieving a reduction in the severity and / or frequency of one or more clinical symptoms associated with the disease, as determined by a physician treating a subject suffering from, or susceptible to, such symptoms.

[0148] It will be understood by those skilled in the art that such treatment or prevention will be performed in a subject in need thereof. Those skilled in the art can use conventional techniques to assess the subject's demand for such treatment or prevention. In the context of the present invention, a "subject" in need of a compound of the present invention includes a subject suffering from a disorder or condition that is improved by activation of AMPK. As used herein, the terms "disease" and "disorder" (and similarly, the terms condition, illness, medical problem, etc.) can be used interchangeably.

[0149] Without wishing to be bound by theory, it is believed that administration of the compounds of the present invention enhances the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in the systemic circulation. It has been shown that, in certain instances, administration of a formulation containing a compound of the present invention provides approximately a two-fold increase in plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to administration of a formulation containing 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0150] The compounds of the present invention (and their formulations) may have the following advantages: compared to other therapies known in the prior art (whether for the above-mentioned indications or other indications), they may be more effective, less toxic, longer-lasting, more potent, produce fewer side effects, be more readily absorbed and / or have better pharmacokinetic characteristics (e.g., higher oral bioavailability and / or lower clearance), and / or have other useful pharmacological, physical or chemical properties. In particular, the compounds of the present invention may have the following advantages: they are more effective and / or exhibit favorable properties in vivo.

[0151] Attached photos

[0152] The following drawings are provided to illustrate various aspects of the inventive concept and are not intended to limit the scope of the invention unless otherwise specified herein.

[0153] Figure 1 Shown are immunoblot images demonstrating that compounds 3 and 5 increased the phosphorylation of AMPK in a dose-dependent manner.

[0154] Figure 2 Comparative results of oral pharmacokinetic studies using Compound 1 and Compound 3 are shown. Example

[0155] The present invention is illustrated in more detail in the following non-limiting examples.

[0156] The reaction schemes described below are intended to provide a general description of methods for preparing the compounds of the present invention.The examples provided herein are intended to illustrate but not limit the compounds of the present invention, and the preparation of these compounds and intermediates.

[0157] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are either commercially available or can be conventionally prepared by procedures described in the literature, for example, Houben-Weyl "Science of Synthesis" Vol. 1-48, Georg Thieme Verlag and subsequent editions.

[0158] The reaction can be carried out in a manner known to those skilled in the art of organic synthesis in the presence of a suitable solvent or diluent or a mixture thereof. If desired, the reaction can also be carried out in the presence of an acid or base, by cooling or heating, for example, in a temperature range of about -30°C to about 150°C. In some embodiments, the reaction is carried out in a temperature range of about 0°C to about 100°C, more particularly, in a temperature range of room temperature to about 80°C, in an open or closed reaction vessel and / or in an atmosphere of an inert gas (e.g., nitrogen).

[0159] Abbreviations

[0160] The abbreviations used herein are known to those skilled in the art. In particular, the following abbreviations may be used herein.

[0161] AUC: Area under the concentration-time curve

[0162] aq: aqueous solution

[0163] bw: weight

[0164] C max : Peak plasma concentration

[0165] d: doublet

[0166] DCM: dichloromethane

[0167] DMF: dimethylformamide

[0168] DMAP: 4-dimethylaminopyridine

[0169] DMSO: dimethyl sulfoxide

[0170] ESI: electrospray ionization

[0171] Et3N: triethylamine

[0172] EtOH: ethanol

[0173] g: grams

[0174] h: hour

[0175] HPLC: High Performance Liquid Chromatography

[0176] LC: Liquid chromatography

[0177] LCMS: Liquid chromatography-mass spectrometry

[0178] LC-MS / MS: Liquid chromatography-(tandem) mass spectrometry

[0179] LLOQ: Lower limit of quantification

[0180] m: multiple peaks

[0181] MeOD: methanol-d4

[0182] Min: minutes

[0183] mL: milliliters

[0184] MRT: Mean residence time

[0185] nBu3N: tributylamine

[0186] ND: Not Detected

[0187] NMR: Nuclear Magnetic Resonance

[0188] RT: room temperature

[0189] s: singlet peak

[0190] T 1 / 2 :half life

[0191] T max : Time to peak plasma concentration

[0192] THF: Tetrahydrofuran

[0193] TLC: Thin layer chromatography

[0194] Instrument conditions

[0195] LC parameters

[0196]

[0197] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.

[0198] Example 1: 4-({(5Z)-5-[(4-chlorobenzoyl)imino]-2-[(4-chlorophenyl)methyl]-3-oxo- Preparation of 1,2,4-thiadiazolidin-4-yl}methoxy)-4-oxobutanoic acid

[0199]

[0200] Compound 1: 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

[0201] Compound 1 was prepared according to the procedure described in WO 2011 / 004162.

[0202] Compound 2: 4-chloro-N-{2-[(4-chlorophenyl)methyl]-4-(hydroxymethyl)-3-oxo-1,2,4-thiadiazolidine-5-ylidene}benzamide

[0203] To a stirred solution of compound 1 (10 g, 0.026 mol) in DMF (200 mL) was added Et3N (15 mL, 0.105 mol) and 37% formaldehyde (8.5 mL, 0.105 mol). The reaction mixture was stirred at room temperature for 12 to 14 hours.

[0204] The reaction mixture was then concentrated to remove DMF. The crude material obtained was slurried in water (100 mL) for 30 minutes. The slurry was filtered and dried at ambient temperature to give compound 2 (9.6 g, 90.5% yield) as a white solid.

[0205] Compound 3: 4-({(5Z)-5-[(4-chlorobenzoyl)imino]-2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-4-yl}methoxy)-4-oxobutanoic acid

[0206] To a stirred solution of compound 2 (10 g, 0.024 mol) in THF (200 mL) was added DMAP (0.44 g, 0.004 mol) and succinic anhydride (7.29 g, 0.072 mol). The reaction mixture was stirred at room temperature for 12 hours.

[0207] After completion (as observed by TLC), the reaction mixture was concentrated to remove THF. The crude material obtained was diluted with THF (100 mL), stirred at room temperature for 1 hour and filtered to afford compound 3 (7.3 g, 59% yield) as a white solid.

[0208] 1 H NMR (300MHz, MeOD) δ (ppm): 2.61 (m, 4H), 4.72 (s, 2H), 6.10 (s, 2H), 7.29 (dd, 4H), 7.41 (d, 2H), 8.12 (d, 2H).

[0209] LCMS: 510.4 [M+H].

[0210] HPLC: purity greater than 98% at 13.6 minutes.

[0211] Example 2: {(5Z)-5-[(4-chlorobenzoyl)imino]-2-[(4-chlorophenyl)methyl]-3-oxo-1,2, Preparation of 4-thiadiazolidin-4-ylmethyl phosphate disodium

[0212]

[0213] Compound 2: 4-chloro-N-{2-[(4-chlorophenyl)methyl]-4-(hydroxymethyl)-3-oxo-1,2,4-thiadiazolidine-5-ylidene}benzamide

[0214] Compound 2 was prepared according to the procedure described in Example 1.

[0215] Compound 4: 4-chloro-N-{4-(chloromethyl)-2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidine-5-ylidene}benzamide

[0216] A mixture of compound 2 (10 g, 0.0243 mol) and thionyl chloride (60 mL) was heated to 75° C. over a period of 3 hours.

[0217] After completion (as observed by TLC), the reaction mixture was concentrated and the crude product was washed with diethyl ether (3 x 100 mL) to afford compound 4 (9.5 g, 90% yield) as a white solid.

[0218] Compound 5: Disodium {(5Z)-5-[(4-chlorobenzoyl)imino]-2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-4-yl}methylphosphate

[0219] To a stirred solution of phosphoric acid (85%, 15.1 g, 0.154 mol) in ethanol (60 mL) was added tributylamine (83 mL, 0.35 mol) at ambient temperature. The solvent was removed by evaporation and the residue was dissolved in DCM (60 mL). The DCM solution was dried over sodium sulfate, filtered and evaporated to give di-tributyl-ammonium dihydrogen phosphate.

[0220] A mixture of compound 4 (3.0 g, 0.007 mol) and the above-prepared tributylammonium dihydrogen phosphate was dissolved in DCM (60 mL) and stirred for 10 minutes. The reaction mixture was distilled off at 40°C, and the resulting residue was heated on a water bath at 60°C for 10 to 15 minutes. The residue was redissolved in DCM (6 mL), the DCM was distilled off, and the resulting residue was heated on a water bath at 60°C for 10 to 15 minutes. The above procedure was repeated four times.

[0221] After completing (as observed by TLC), residue is dissolved in DCM (4mL), and washed with water (3x4 mL).Organic phase is separated, dried over anhydrous sodium sulfate, filtered and concentrated.The crude product obtained by evaporation is dissolved in water, and alkalized (pH 9 to 9.5) with 0.2M sodium hydroxide.After alkalization, filter the mixture and freeze-dried filtrate, obtain compound 5 (0.6g, 17.5% yield) as white solid.

[0222] 1 H NMR (300MHz, DMSO-D6) δ (ppm): 4.78 (s, 2H), 5.55 (s, 2H), 7.40 (dd, 4H), 7.55 (d, 2H), 8.19 (d, 2H).

[0223] LCMS: 490.1 [M+H].

[0224] HPLC: purity greater than 98% at 8.2 minutes.

[0225] Example 3 - Solubility of compounds at different pH

[0226] method

[0227] About 5 mg of each test compound (Compounds 1 and 5) was weighed in duplicate and each weighed sample was transferred to a separate centrifuge tube containing 5 mL of the corresponding buffer. All tubes were tightly stoppered and stirred at a constant rate using an orbital shaker at 30 ± 1 °C.

[0228] After 24 hours, remove one test tube of each buffer solution from the shaker. Transfer 50 μL of buffer solution from each removed test tube to a 10 mL test tube and fill to the mark with diluent. Then transfer 2.5 mL of supernatant from each test tube to a 50 mL test tube and fill to 25 mL.

[0229] The nominal concentration of the solution in each 50 mL test tube was 5 μg / mL.

[0230] Linear solutions from 40 ng / mL to 10,000 ng / mL were drawn.

[0231] result

[0232] The results of the solubility experiments are listed in Tables 1 and 2 below.

[0233] The results showed that compound 5 had higher solubility in alkaline solutions (i.e., pH>7) and under weakly acidic conditions compared to compound 1. In particular, compound 5 had a higher solubility in alkaline solutions than compound 1, up to 30 times higher.

[0234] Table 1. Two-hour solubility study results for compounds 1 and 5

[0235]

[0236] Note: ND means not detected, the concentration is below LLOQ;

[0237] *HPLC analysis of compound 5

[0238] Table 2. 20-hour solubility study results for compounds 1 and 5

[0239]

[0240] Note: ND means not detected, the concentration is below LLOQ;

[0241] *HPLC analysis of compound 5

[0242] Example 4 - Stability of Compounds

[0243] 5 μM solutions of compounds 1, 3, and 5 in USP buffer (pH 7.40) were prepared from 5 mM DMSO stock solutions. The solutions were incubated at 37° C. for 120 minutes with shaking at 400 rpm using a thermomixer.

[0244] After time intervals of 0, 15, 30, 60 and 120 minutes, aliquots of sufficient volume of compound solution were removed, diluted to the final concentration and analyzed.

[0245] result

[0246] The results of the stability experiments are listed in Table 3 below.

[0247] The results showed that compounds 3 and 5 had comparable stability to compound 1 in mild alkaline solution (i.e., pH = 7.4).

[0248] Table 3. Comparative stability data in phosphate buffer (pH: 7.40)

[0249]

[0250] Example 5 - Activation of AMPK

[0251] INS-1E insulinoma cell culture and compound treatment

[0252] INS-1E cells were cultured as described in Steneberg et al., JCI Insight. 2018; 3(12):e99114. https: / / doi.org / 10.1172 / jci.insight.99114, using 5% instead of 10% fetal bovine serum for plating.

[0253] Compound 3 was dissolved in DMSO at 10 mM and frozen at -20°C.

[0254] Compound 5 was dissolved at 10 mM in a 50:50 water / DMSO mixture, incubated in an ultrasonic bath (VWR ultrasonic cleaner) at room temperature for 15 minutes, and stored at room temperature.

[0255] INS-1E cells were treated with increasing doses of compounds 3 and 5 for 4 and 16 hours, respectively, in serum-free medium according to the method described in Steneberg et al., JCI Insight. 2018; 3(12):e99114. https: / / doi.org / 10.1172 / jci.insight.99114.

[0256] Immunoblot analysis

[0257] Immunoblot analysis of INS-1E cells was performed as described in Steneberg et al., JCI Insight. 2018;3(12):e99114. https: / / doi.org / 10.1172 / jci.insight.99114. Cell lysates were passed through a 30-gauge needle approximately eight times and centrifuged at 14,000 rpm for 10 minutes at +4°C. Quantification of AMPKα and phosphorylated T172 AMPKα was normalized to that of β-actin.

[0258] result

[0259] The results of the immunoblot analysis are listed in Table 3 below and in Figure 1 Displayed in chart form.

[0260] The results showed that compounds 3 and 5 increased phosphorylated T172 AMPK in cultured INS-1E cells in a dose-dependent manner. Therefore, compounds 3 and 5 are agonists of AMPK.

[0261] Table 4. Ratio between p-T172 AMPK and non-phosphorylated AMPK

[0262] Compound time comparison 2.5 μM 5μM 10 μM 3 (0.1% DMSO) 4 hours 1.00 1.62 1.88 2.95 5 (0.05% DMSO) 16 hours 1.00 1.29 1.62 3.21

[0263] Example 6 - Single-dose oral pharmacokinetic study of compounds 1 and 3 in Sprague Dawley rats

[0264] Preparation of Compound 1

[0265] 10.0 mL of 2% w / v methylcellulose in phosphate buffer (pH 7.5) was added to a 100 mL Erlenmeyer flask along with 1 g of 2 mm glass beads. The solution was stirred vigorously on a magnetic stirrer. 100 mg of compound 1 was slowly added to the solution, and the solution was stirred vigorously for approximately 1 hour. The pH of the preparation was measured to be 7.49. Each preparation was freshly prepared before being administered to the animals. The final concentration of compound 1 in the preparation was 10 mg / mL. The preparation was administered at 5 mL / kg body weight.

[0266] Preparation of Compound 3

[0267] 10.0 mL of 2% w / v methylcellulose in phosphate buffer (pH 7.5) was added to a 100 mL conical flask along with 1 g of 2 mm glass beads. The solution was stirred vigorously on a magnetic stirrer. 134 mg of compound 3 was slowly added to the solution, and the solution was stirred vigorously for about 1 hour. The pH of the preparation was measured to be 7.44. Each preparation was freshly prepared before being administered to the animals. The final concentration of compound 3 in the preparation was 13.4 mg / mL, which is equivalent to 10 mg / mL of compound 1. The preparation was administered at 5 mL / kg body weight.

[0268] Dose selection and rationale for selection

[0269] The doses of 50 mg / kg and 67 mg / kg bw of Compound 1 and Compound 3, respectively, were selected for equimolar dose comparison.

[0270] Dosage administration

[0271] Adult healthy male Sprague Dawley rats, 9 to 11 weeks old, were used for the experiments after a minimum of three days of acclimation. The fed animals were orally administered with formulations of Compound 1 or Compound 3 at a dose of 50 mg / kg or 67 mg / kg body weight, respectively, by oral gavage.

[0272] Blood sampling

[0273] Under light isoflurane anesthesia, blood samples were collected by retroorbital puncture using capillary tubes into pre-labeled tubes containing anticoagulant (K2EDTA: 2 mg / mL blood) over the next 72 hours after dosing, as detailed in Table 6. For blood sampling at multiple time points, alternating right and left eyes were used. The collected blood samples were centrifuged at 6000 rpm and 4°C for 10 minutes, and plasma samples were separated and stored at -80°C until analysis.

[0274] result

[0275] The results of the single-dose oral pharmacokinetic study in rats are shown in Tables 4 and 5 below and in Figure 2 In Table 4, C max 、T max , AUC last , AUC inf , AUC extrap 、T 1 / 2 and MRT last The values ​​are those of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (Compound 1) detected after the administration of Compounds 1 and 3.

[0276] The results showed that the systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide was surprisingly increased two-fold when Compound 3 was administered compared to Compound 1. Thus, the systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide was increased by administering the compounds of the present invention.

[0277] Table 5. Mean plasma pharmacokinetic parameters after administration of compounds 1 and 3

[0278]

[0279] Table 6. Plasma concentrations of compounds 1 and 3

[0280]

[0281] Example 7 - Single-dose oral pharmacokinetic study of compound 5 in Sprague Dawley rats

[0282] Preparation of Compound 5

[0283] 6.0 mL of a 2% w / v methylcellulose solution in phosphate buffer (pH 7.5) was added to a 100 mL Erlenmeyer flask along with 1 g of 2 mm glass beads. The solution was stirred vigorously on a magnetic stirrer. 77 mg of compound 5 was slowly added to the solution, and the solution was stirred vigorously for approximately 1 hour. The pH of the formulation was measured to be 7.43. The formulation was freshly prepared before administration to the animals.

[0284] Dosage administration

[0285] Adult healthy male Sprague Dawley rats, 9 to 11 weeks old, were used for the experiments after a minimum of three days of acclimation. The fed animals were orally administered a formulation of Compound 5 at a dose of 64 mg / kg body weight by oral gavage (5 mL / kg dose volume).

[0286] Blood sampling

[0287] Under light isoflurane anesthesia, blood samples were collected by retroorbital puncture using capillary tubes into prelabeled tubes containing anticoagulant (K2EDTA: 2 mg / mL blood) over the next 72 hours after dosing. For blood sampling at multiple time points, alternating right and left eyes were used. Blood samples were centrifuged at 6000 rpm at 4°C for 10 minutes, and plasma samples were separated and stored at -80°C until analysis.

[0288] result

[0289] The results of the single-dose oral pharmacokinetic study in rats are shown in Tables 7 and 8 below. In Table 7, C max 、T max , AUC last , AUC inf , AUC extrap 、T 1 / 2 and MRT last The value is the value of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (Compound 1) detected after administration of Compound 5. Therefore, Compound 5 acts as a prodrug of Compound 1.

[0290] Table 7. Mean plasma pharmacokinetic parameters after administration of compound 5

[0291] Compound number 5 Dosage (mg / kg bw) 64 <![CDATA[C max (μg / mL)]]> 30.77±9.68 <![CDATA[T max (h)]]> 6.00±0.0 <![CDATA[AUC last (h*μg / mL)]]> 612.21±376.22 <![CDATA[AUC inf (h*μg / mL)]]> 688.74±315.05 <![CDATA[AUC extrap (%)]]> 15.22±14.63 <![CDATA[T 1 / 2 (h)]]> 9.09±2.87 <![CDATA[MRT last (h)]]> 11.72±3.69

[0292] Table 8. Plasma concentration of compound 1 after administration of compound 5

[0293]

Claims

1. Compound of formula I: where R 1 Selected from -C(O)-C2H4-CO2H and -PO3H2, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is an alkali metal salt, an alkaline earth metal salt or a quaternary ammonium salt of the compound of formula I.

5. The compound according to claim 4, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt of the compound of formula I.

6. A compound selected from: or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical preparation comprising a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. The pharmaceutical formulation according to claim 7, wherein the pharmaceutically acceptable excipient is a basic excipient.

9. The pharmaceutical formulation according to claim 7, wherein the pharmaceutically acceptable excipient is selected from magnesium oxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate.

10. The pharmaceutical formulation according to any one of claims 7 to 9, wherein the formulation further comprises an enteric coating.

11. Use of a compound of formula I as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical preparation as defined in any one of claims 7 to 10, in the preparation of a medicament.

12. Use of a compound of formula I as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a formulation as defined in any one of claims 7 to 10, in the preparation of a medicament for treating a disorder or condition ameliorated by activation of AMPK.

13. The use according to claim 12, wherein the disorder or condition improved by activation of AMPK is selected from cardiovascular disease, diabetic nephropathy, type 2 diabetes, insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, pain, opioid addiction, obesity, cancer, inflammation, autoimmune disease, osteoporosis and bowel disease.

14. The use according to claim 12, wherein the disorder or condition improved by activation of AMPK is a condition associated with hyperinsulinemia, selected from obesity and cardiovascular disease.

15. The use according to claim 13, wherein the cardiovascular disease is heart failure.

16. The use according to claim 13, wherein the inflammation comprises a chronic inflammatory disease.

17. Use according to any one of claims 12 to 16, wherein the compound is administered orally, subcutaneously or intramuscularly.

18. A process for preparing a compound as defined in any one of claims 1 to 5, comprising: (i) reacting a compound of formula V with a suitable acid or anhydride: (ii) reacting a compound of formula VI with a suitable acid or a suitable acid salt:

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