WO2016001224A1

WO2016001224A1 - Novel activators of amp-activated protein kinases

Info

Publication number: WO2016001224A1
Application number: PCT/EP2015/064848
Authority: WO
Inventors: Mathilde Muzerelle; Robert Lysek; Nathalie Bellocq; Marc Lang
Original assignee: Debiopharm International SA
Current assignee: Debiopharm International SA
Priority date: 2014-06-30
Filing date: 2015-06-30
Publication date: 2016-01-07
Anticipated expiration: 2016-12-30

Abstract

The present invention relates to a compound of structural Formula (I) or a salt thereof, which is useful as a direct AMPK activator. A further aspect of the present invention relates to use of said compound for the treatment of AMPK related diseases and to a pharmaceutical composition containing said compound.

Description

Novel Activators of AMP-activated protein kinases

BACKGROUND

Metabolic disorders such as diabetes, insulin resistance, dyslipidemia, hypertension, overweight, obesity, etc. are well recognized as factors increasing the cardiovascular risk.

For example, diabetes, and particularly type 2 diabetes, is a complex metabolic disorder with many risk factors and implications. In patients with type 2 diabetes, hyperglycemia is the major risk factor for microvascular complications, and 70% to 80% of such patients will die of macrovascular disease. Type 2 diabetes patients with atherogenic dyslipidemia, which includes elevated plasma triglycerides, low HDL-C and a preponderance of small dense LDL particles, have a higher risk of atherosclerosis. Therefore, treatment of type 2 diabetes should address both hyperglycemia to prevent microvascular disease (such as retinopathy, neuropathy, nephropathy) and atherogenic dyslipidemia to prevent macrovascular complications (Reasner CA. J Cardiovasc Pharmacol. 2008, 52 (2): 136-44). This currently requires multiple medications, including antidiabetic and lipid-lowering agents (and antihypertensive agents, if necessary), to sufficiently manage all aspects of the pathology of this disease. Unfortunately, only about 7% of patients with diabetes achieve control of their hyperglycemia (A1C < 7.0%), dyslipidemia (total cholesterol < 200 mg/dL [5.18 mmol/L]), and hypertension (biood pressure < 130/80 mm Hg) (Saydah SH et al. JAMA. 2004; 291 :335-342).

There is currently hardly any drug available that is active on more than one cardiovascular risk factor. Thus, in view of minimizing the need for multiple medications to treat a single patient, there remains a need for a drug that acts on more than one cardiovascular risk factor in patients with metabolic disorders.

The AMP-activated protein kinase (AMPK) acts as an intracellular metabolic sensor in a variety of ceils, where it monitors and responds to variations in the AMP:ATP ratio (Hardie et al, Annu. Rev. Biochem. 67:821-855, 1998). AMPK is switched on by any cellular stress that causes a rise in the AMP:ATP ratio, either by interfering with ATP production (e.g. hypoxia, glucose deprivation or ischemia), or increasing ATP consumption (e.g. muscle contraction) (Hardie DG, Ross FA, Hawley SA., Nat Rev Mol Cell Biol. 13(4):251-62, 2012). Upon activation of AMPK, the enzyme phosphorylates a number of protein substrates to decrease further ATP usage by the ceil. Besides its function as a sensor of cellular energy status, AMPK also plays a critical role in the energy balance of the whole organism. For example, activation of AMPK switches on catabo!ic pathways that generate ATP in skeletal muscle and in the heart (glucose uptake and glycolysis, fatty acid uptake and oxidation), while it switches off ATP consuming processes, in particular anabolic (biosynthetic) pathways (fatty acid synthesis in adipose cells, fatty acid and cholesterol synthesis as well as gluconeogenesis in liver) (Hardie DG, Ross FA, Hawfey SA., Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62). Furthermore, AMPK may be involved in blood flow regulation through endothelial nitric oxide synthase stimulation (Buhl et al, Diabetes 2002, 51 , 2199-206). In addition, AMPK is activated, for example, by hormones and cytokines, including leptin and adiponectin, which increase AMPK signalling.

All those properties combine to make activation of AMPK a target of choice in the treatment of metabolic disorders, such as for example diabetes, insulin resistance, dyslipidemia, hypertension, overweight and obesity.

AMPK activity is found in all tissues, including liver, kidney, muscle, lung, and brain (Cheung et al., Biochem. J. 346:659-669, 2000). In terms of structure, AMPK is a heterotrimeric complex consisting of a catalytic subunit (a) and two regulatory subunits (β and γ). The AMPK complex is evolutionarity conserved and can also be found in yeast and plants. Mammalian AMPK is composed of different isoforms of subunits: α1 , a2, β1 , β2, γ1 , y2, and γ3 (Hardie and Hawley, BioEssays 23:11 12-1 1 19, 2001) leading to 12 possible heterotrimeric combinations. The a2 isoform is predominately found in skeletal and cardiac muscle AMPK; both the a1 and a2 isoforms are found in hepatic AMPK; while in pancreatic islet β-celts the a1 isoform AMPK predominates (Quentin T et al., Histol Histopathol. 201 1 , 26(5):589-96). While the β1 isoform is abundant in rodent liver, the β2 isoform is highly expressed in human liver and skeletal muscle (Wu J et al., Journal of Biological Chemistry 2013, 288, 50: 35904-12).

It has been shown that metformin activates AMPK by an indirect mechanism, i.e. inhibition of complex I of the respiratory chain (Owen MR et al. Biochemical Journal, 2000, 348, 607-614), suggesting that it may activate AMPK by increasing cellular AMP:ATP ratio. Thiazolidinediones (TZD) can also activate AMPK by an indirect effect via the adiponectin release (Hardie DG. Annual Review of Pharmacology and Toxicology, 2007, 47: 185-210), which may account for many of the long term effects of TZD, and by an adiponectin-independent effect, probably the inhibition of complex I of the respiratory chain, and thus increase of cellular AMP:ATP ratio, as metformin does.

Recently, several AMPK activators have been disclosed in the patent literature. However, only for a limited number of these compounds data has been provided in support of a direct AMPK activation mechanism. In addition, no direct AMPK activator has yet been tested in clinical trials (Giordanetto F et a!., Expert Opin. Ther. Patents, 2012, 22; 12, 1467-1477).

WO 2009/100130 A1 discloses 2,3-benzopyrrole derivatives acting as AMPK modulators. The AMPK activity of the corresponding compounds was evaluated in vitro by phosphorylation of the amino-termina! fragment of human acetyl CoA carboxylase-type 1 , amino acids 1 -120.

A group of structurally related 3H-imidazolo[4,5-b]pyridines have been disclosed in WO 2012/1 16145 A1. Several compounds disclosed in this document were tested in an in vitro AMPK activation assay using recombinant human AMPK complex 1 (containing α1 β1γ1 ). They activate AMPK α1 β1γ1 at greater or equal 223% of the maximum activation by AMP and have EC50 values as low as 0.3 pmolar. Activation of AMPK β2 was not investigated.

US 2013/0184240 A1 describes a library of 3H-imidazolo[4,5-b]pyridines and 2,3-benzopyrroles. The activity of some compounds of US 2013/0184240 A1 was evaluated using a human AMPK α1 β1γ1 as well as human AMPK α2β2γ1. Further examples of structurally similar compounds are disclosed in WO 2014/069426 A1 , Also this document primarily focusses on activation of AMPK α2β2γ1 as a target protein kinase.

WO 2014/031468 discloses a library of benzimidazole hexahydrofuro[3,2-b]furan derivatives for use as activators of AMP-protein kinases. Activation of human recombinant AMPK complex 1 (containing α1 β1γ1) or AMPK complex 7 (containing α2β1γ1) for some of the disclosed compounds was tested in an in vitro AMPK activation assay.

Accordingly, the present invention aims to provide novel AMPK activators having a high activity towards human AMPK.

SUMMARY OF THE INVENTION

The first aspect of the present invention relates a compound of general Formula (I):

(0 or a salt thereof, wherein

R2 is represented by Formula (II)

(II)

X is represented by -0-, -S-, -S{0)-, -S(0)2- -NH- or -CH2-;

Y and Z are independently represented by =CF5- or =N-;

R3 and R⁵ are independently represented by a hydrogen atom, a halogen atom, a hydroxyl group, or by one of the following: a C-j.g saturated aliphatic group, a Cj.g alkoxy group, a C- .Q alkylamino group, a C3.Q cycloalkoxy group, a 03.5 cycloalky!amino group, a

C4.Q alkylcycloalkoxy group, a C4.Q alkylcycloalkylamino group, a C4.Q cycloafkylalkoxy group, or a C4.5 cycloafkylaikylamino group, each being optionally substituted with at least one halogen atom;

R⁴ is an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one substituent selected from -OR⁶, -NHR⁶ -NR⁶R⁷ and -S(0)R⁶; wherein if R⁴ is an aliphatic or a heteroaliphatic group, the substituent selected from -OR⁶, -NHR⁶, -NR⁶R⁷, and -S(0)R⁶ is directly linked to a primary carbon atom; and

if R⁴ is an aromatic or a heteroaromatic group, the substituent selected from -OR⁶,

-NHR⁶, -NR⁶R⁷, and -S(0)R⁶ is directly linked to a carbon atom or a heteroatom of the aromatic or heteroaromatic moiety;

and

R¹ , R⁶ and R⁷ are independently represented by a C-| .Q saturated aliphatic group or by a hydrogen atom.

A further aspect of the present invention relates to the use of the compound of general Formula (I) or a salt or solvate thereof for the treatment of a human or animal body, in particular, the present invention relates to the use of the compound of the general Formula (I) or a salt or a solvate thereof for use in the treatment or prophylaxis of a disorder responsive to AMPK activation. In a particular embodiment, the disorder responsive to AMPK activation is a metabolic disorder such as e.g. diabetes, dyslipidemia, hyperglycemia or hypertension.

Yet a further aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of general Formula (I), or a salt or solvate thereof as active ingredient. In a particular embodiment, said pharmaceutical composition may be an oral dosage form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of the general Formula (I):

(I)

or to a salt thereof.

The substituent R² in the general Formula (I) is represented by the Formula (II):

(il)

As will be appreciated by one skilled in the art, the substituent R² possesses four stereogenic centres and, therefore, the Formula (II) describes 16 distinct stereoisomers. Accordingly, the compound of the present invention may be present in the form of a substantially pure stereoisomer or as a mixture of two or more diastereomers and/or enantiomers.

In some embodiments of the present invention, the substituent R² can be represented by the Formula (Ila):

(Ila) The Formula (lla) describes 2 distinct stereoisomers. Thus, the compound of the present invention may be present in the form of a substantially pure stereoisomer or as a mixture of two diastereomers.

In yet a more preferred embodiment of the present invention, the substituent R² is represented by the 1 ,4-3,6-dianhydromannitol residue i.e. by the Formula (lib):

(lib)

The substituent X in the general Formula (I) can be represented by -0-, -S-, -S(O)- -S(0)2- -NH- or -CH2- Preferably, X in the general Formula (I) is represented by -0-, -S-, -NH- or -CH2-. In a particularly preferred embodiment, X in the general Formula (I) is represented by -0-.

The substituents Y and Z in the general Formula (I) may be independently represented by

=CR⁵- or =N- Thus, the corresponding aromatic or heteroaromatic moiety comprising the substituents Y and Z may be a phenylene, a pyridinylene or a pyridazilene group.

The substituents R³ and R⁵ in the general Formula (I) are independently represented by a hydrogen atom, a halogen atom, a hydroxyl group, or by one of the following: a C-j .g saturated aliphatic group, a C-j.g alkoxy group, a C-j.g alkylamino group, a C^-Q cycloalkoxy group, a

C3-6 cycloalkylamino group, a C^Q alkylcycloalkoxy group, a C4.Q alkylcycloalkylamino group, a C .Q cycloalkylalkoxy group, or a C4.Q cycloalkyialkylamino group, each being optionally substituted with at !east one halogen atom

In the present application, the term "halogen atom" may refer to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a fluorine atom or a chlorine atom being particularly preferred.

The term "saturated aliphatic group" refers to a straight chain or a branched alkyi group, a cycloa!kyl group, an alkylcycloalkyl group or a cycloaikylalkyl group. Accordingly, the term "Cf-6 saturated aliphatic group" includes C-^.g aikyl C3-6 cyc!oalkyl groups, C4..5 alkylcycloalkyl groups and C4._Q cycloalkyiaikyl groups.

Examples of C - β aikyl groups include but are not limited to methyl, ethyl, /i-propyl, /-propyl, n-butyl, sec. -butyl, ferf.-butyl, n-pentyl and n-hexyl groups. In one preferred embodiment of the present invention, the C-j.g aikyl group is a straight chain or branched aikyl group having 1 to 4 carbon atoms. In a particularly preferred embodiment, the term "Cf.g aikyl group" refers to methyl, ethyl or n-propyl.

The term "C^Q cycloalkyl group" may refer to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "C4.Q alkylcycloalkyl group" may, for instance, refer to a cyciopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl or to cyclopentylmethyi group.

A "C4.5 cycloalkylalkyi group" in the general Formula (I) may be represented inter alia by methylcyclopropy!, methylcyclobutyl or methylcyclopentyl groups, which may be (E) or (Z) isomers.

Accordingly, the terms "alkoxy", "cycloalkoxf, "alkylcycloalkoxy" and "cycloalkylalkoxf refer to substituents comprising aikyl, cycloalkyl, alkylcycloalkyl and cycloalkylalkyi groups, respectively, singularly bonded to an oxygen atom. Similarly, the terms "alkylamino", "cycloalkylamino", "alkylcycloalkylamino" and "cycloalkylalkylamino" refer to substituents comprising aikyl, cycloalkyl, alkylcycloalkyl and cycloalkylalkyi groups, respectively, singularly bonded to -NH-.

The C†.Q saturated aliphatic group may be optionally substituted with at least one halogen atom.

Thus, in some embodiments, the corresponding substituent may be a perfluorated C .Q alky! group such as, for instance, trifluoromethyi, pentafluoroethyl or n-heptafluoropropyl. In a particularly preferred embodiment of the present invention, the term "C^.g saturated aliphatic group optionally substituted with at least one halogen atom" refers to a trifluoromethyi group.

According to the present invention, the saturated aliphatic group may contain one or several heteroatoms such as O, S, N etc. Thus, the term "saturated aliphatic group" includes substituents such as -CH2OCH3, -CH2 (CH3)2 etc.

R1 , R6 and R? in the general Formula (I) are independently represented by a C _Q saturated aliphatic group or by a hydrogen atom. In a preferred embodiment of the present invention, R R⁶ and R⁷ are hydrogen atoms or C^.g a!kyl groups, hydrogen atoms being particularly preferred.

In the general Formula (I) R⁴ may be an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one substituent selected from -OR⁶, a hydroxyl group, -NHR⁶ -NR⁶R⁷ and -S(0)R⁶.

As used herein, the "aliphatic group" is non-aromatic moiety that may be saturated (e.g. only comprise single bond) or contain one or more units of unsaturation, (e.g. double and/or triple bonds). An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen and may be substituted or unsubstituted. Thus, the term "aliphatic group" as used herein includes alicyclic groups. An aliphatic group preferably contains between about 1 and about 24 carbon atoms, more preferably between about 4 to about 24 carbon atoms, more preferably between about 4-12 carbon atoms, more typically between about 4 and about 8 carbon atoms. In yet a more preferred embodiment, the aliphatic group is a C-| _6 saturated aliphatic group as defined above.

The term "heteroaliphatic group" refers to a non-aromatic moiety containing at least one atom different from hydrogen and carbon. The heteroaliphatic group may be saturated (e.g. only comprise single bond) or contain one or more units of unsaturation, (e.g. double and/or triple bonds). The heteroaliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen and may be substituted or unsubstituted. Thus, the term "heteroaliphatic group" as used herein includes heteroalicyclic groups. A heteroaliphatic group preferably contains between about 1 and about 24 carbon atoms, more preferably between about 4 to about 24 carbon atoms, more preferably between about 4-12 carbon atoms, more typically between about 4 and about 8 carbon atoms. Examples of heteroaliphatic groups include saturated 3 to 6- membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazotidiny!, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g. thiazolidinyl, efc). Particularly preferred examples of heteroaliphatic groups according to the present invention include inter alia optionally substituted pyrroiidino groups and an optionally substituted morpholino groups.

According to the present invention, the aliphatic group or the heteroaliphatic group comprises at least one primary carbon atom which is substituted with at least one substituent selected from - OR⁶, -NHR⁶, -NR⁶R⁷, and -S(0)R⁶. Thus, the substituent selected from -OR⁶, -NHR⁶, - NR6>R7 _anc| _s(0)R6 is directly bound to a methylene group. Thus, in a preferred embodiment, may bear a primary alcoholic group or a primary amino group.

The term "aromatic group", means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The aromatic group may contain carbon and hydrogen atoms and may be substituted or unsubstituted. The term "aromatic group" embraces aromatic substituents such as phenyl, naphthyl, and biphenyl. In a preferred embodiment, the term "aromatic group" refers to an optionally substituted phenyl group.

Accordingly, the term "heteroaromatic group", embrace partially unsaturated and unsaturated heteroatom-containing cyclic substituents, where the heteroatoms may be selected from nitrogen, sulphur and oxygen. Examples of partially unsaturated heteroaromatic groups include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heteroaromatic groups may include a pentavalent nitrogen, such as in tetrazoiium and pyridinium radicals. The term "heteroaromatic group" also embraces substituents where heteroaromatic moieties are fused with aryl or cycloalkyl moieties. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.

The term "heteroaromatic group" further embraces unsaturated heteroatom-containing cyclic substituents. Examples thereof include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrtdazinyl, triazolyl (e.g. 4/--1 ,2,4-triazolyl, f H-1 ,2,3-triazolyl, 2H-1 ,2,3- triazoiyi, etc.) tetrazolyt (e.g. 7H-tetrazolyl, 2H-tetrazolyl, etc.), unsaturated condensed group containing 1 to 5 nitrogen atoms, for example, indoiyl, isoindolyi, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g. tetrazolo[1 ,5- b]pyridazinyl, efc.); unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulphur atom, for example, thienyl, efc; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, e.g. oxazo!yl, isoxazolyl, oxadiazolyl (e.g. 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, efc); unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms {e.g. benzoxazolyl, benzoxadiazolyl, efc); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazoly! (e.g. 1 ,2,4-thiadiazo!yl, 1 ,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyI, efc); unsaturated condensed heterocyclyl group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms (e.g. benzothiazolyl, benzothiadiazolyl, etc.) and the like. Particularly preferred examples of heteroaromatic groups as used herein include inter alia 1 -pyrazolyl and 5-amino-1 -pyrazolyl. According to the present invention, the aromatic or the heteroaromatic group is directly substituted by at least one substituent selected from -OR⁶, -NHR⁶, -NR⁶R⁷, and -S(0)R⁶. In other words, at least one substituent selected from -OR⁶, -NHR⁶, -NR⁶R⁷, and -S(0)R⁶ is directly bound to a carbon atom or to a heteroatom of the aromatic or heteroaromatic moiety of

R4. Preferably, R⁴ bears at least one phenolic group, at least one aromatic amino group or at least one aromatic ether group.

The substituent R⁴ in the general Formula (I) is substituted with at least one, preferably with at least two substituents selected from -OR⁶, a hydroxyl group, -NHR⁶, -NR⁶R⁷ and -S(0)R⁶.

For instance, R⁴ in the general Formula (!) may be substituted with at least one, preferably with at least two hydroxyl groups. In yet a more preferred embodiment, R⁴ is an aromatic group substituted with at least one, preferably with at least two phenolic hydroxyl groups or a heteroaromatic group substituted with at least one, preferably with at least two hydroxy! groups.

As will be appreciated by a skilled person, the compounds of the present invention may also exist as several tautomeric forms. For instance, when the substituent R⁴ is a pyridyi group substituted with one or several hydroxyl groups, R⁴ and the corresponding compound of the Formula (I) may exist in a corresponding pyridone form.

As will be appreciated by a skilled person, the subject matter of the present invention is not restricted to the embodiments explicitly described in the application but also encompasses combination of these embodiments. Thus, is to be understood that the preferred features as described in the present application can be combined with each other.

It has been recently demonstrated that skeletal muscles are responsible for taking up a high proportion of the glucose that is cleared from blood and therefore represent an important organ for the regulation of glycemia. The most abundant AMPK isoform expressed in human skeletal muscles is α2β2γ1, followed by α2β2γ3 and α1β2γ1 , the later being expressed in significantly lower amounts. Therefore, AMPK β2 activators and, in particular, activators of the α2β2γ1 AMPK isoform can be expected to have beneficial effects on glycemia and muscle insulin resistance. Accordingly, it is preferred that the compounds of the present invention act as potent AMPK β2 activators and, in particular, as potent activators of the α2β2γ1 AMPK isoform.

The authors of the present invention surprisingly found that the compounds represented by the general Formula (I) generally act as more potent activators of human AMPK, in particular as more potent activators of the isoform α1β2γ1 when compared to the corresponding compounds lacking a group selected from a hydroxyl group, -OR⁶, -NHR⁶, -NR⁶R⁷ and -S(0)R⁶on R⁴. In particular, the presence of at least one, preferably of least two hydroxyl groups on R⁴ shows an advantageous impact on the activity of the compounds of the present invention. If R⁴ is an aromatic or a heteroaromatic group, it may advantageously have at least one, preferably at least two phenolic hydroxyl groups. If R⁴ is an aliphatic or a heteroaliphatic group, it can advantageously have at least one, preferably at least two primary alcoholic hydroxy! groups.

This unexpected technical effect becomes evident upon comparison of the experimental pharmacological data for a compound lacking a group selected from a hydroxyl group, -OR⁶,

-NHR⁶, -NR⁶R⁷ and -S(0)R⁶ (cf e.g. data for the compound 32) and the corresponding data for the structurally related compounds of the present invention (cf. e.g. data for the compounds 1 and 2).

Accordingly, in one embodiment of the present invention, the compound of the present invention is represented by the general Formula (I), wherein

R1 is a hydrogen atom or a C<\ .Q alkyl group;

R2 is represented by Formula (II)

(II)

R3 is a hydrogen atom, a halogen atom, a C-|_g alkyl group being optionally substituted with at least one halogen atom, or a C „Q a!koxy group being optionally substituted with at least one halogen atom;

X is represented by -0-, -S-, -NH- or -CH2-;

Y and Z are independently represented by =CH- or =N-; and

R⁴ is an aliphatic, a heteroaliphatic, an aiicyciic, a heteroalicyclic, an aromatic or a heteroaromatic group, each being substituted with at least one hydroxyl group.

In a further preferred embodiment, the compound of the present invention is represented by the general Formula (I), wherein

R1 is a hydrogen atom;

R2 is represented by Formula (lla)

(Ha)

R3 is a hydrogen atom, or a halogen atom;

R4 is an aromatic group substituted with at least one hydroxyl group or a heteroaromatic group substituted with at least one hydroxy! group; and

Y and Z are both represented by =CH-

!n a further preferred embodiment, the compound of the present invention is represented by the general Formula (I), wherein

X is represented by -0-;

R2 is represented by Formula (li

(Hb)

R3 is a fluorine atom, a chlorine atom, or a hydrogen atom; and

R^ is a substituted phenyl group being represented by Formula (III)

(III)

wherein R^ to R^{1 2} are independently represented by substituents selected from the group consisting of a hydrogen atom, a hydroxyl group, a A/,A/-dimethylaminomethyl group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group. The aromatic and heteroaromatic groups R^ to R^"12 may be substituted by at least one hydroxyl group or a di-C-i _Q-alkylamino group. this embodiment, R^ may be represented by e.g. one of the following Formulae (Ilia)

in yet a further preferred embodiment, the compound of the present invention may be represented by the general Formula (I), wherein

X is -0-;

R2 is represented by Formula (lib)

(lib)

R3 is a fluorine atom, a chlorine atom or a hydrogen atom; and

R⁴ is represented by one of Formulae (Va) to (Vf):

(Vb) (Vc) (Vd)

(Ve) (Vf)

a further preferred embodiment, Y and Z are both represented by

Examples of the corresponding compounds include inter alia those represented by the following structures (17) to (29):

(17) (18)

(29)

Alternatively, the compound of the present invention may be represented by the general Formula (I), wherein

X is represented by -0-;

R2 is represented by Formula (lib)

R3 is a fluorine atom, a chlorine atom or a hydrogen atom;

Y is represented by =N- and Z is represented by =CH-; and

R⁴ is represented by one of Formulae (Vc), (Vd) or (Ve):

(Vd) (Vc) (Ve)

An example of the corresponding embodiment is represented by the following structure (30):

(30) Preferred embodiments of the present invention include the following {1 } to {7}: {1 } A compound of general Formula (I)

(II)

X is represented by -0-, -S-, -S{0)-, -S(0)₂- -NH- or -CH2-;

Y and Z are independently represented by =CR^- or =N-;

R³ and are independently represented by a hydrogen atom, a halogen atom, a hydroxy! group, or by one of the following: a C-i_6 saturated aliphatic group, a C-1.5 alkoxy group, a C-j.g alkylamtno group, a C3.Q cycloalkoxy group, a C3.Q cycioalkylamino group, a C4.5 alkyicycloalkoxy group, a C4.5 alkylcycioalkylamino group, a C4.5 cycloaikylaikoxy group, or a C4.5 cycloaikylaikylamino group, each being optionally substituted with at least one halogen atom;

R⁴ is an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one substituent selected from -OR⁶, -NHR⁶, -NR⁶R⁷, -S(0)R⁶, and -S(0)₂R⁶; and

Ri , R⁶ and R⁷ are independently represented by a C .Q saturated aliphatic group or by a hydrogen atom.

{2} The compound of general Formula (I) according to {1 } or a salt thereof, wherein

Ri is a hydrogen atom or a C ^Q alkyl group;

R2 is represented by Formula (II)

R3 is a hydrogen atom, a halogen atom, a C .Q a!kyl group being optionally substituted with at least one halogen atom, or a C^.g alkoxy group being optionally substituted with at least one halogen atom;

X is represented by -O- -S-, -NH- or -CH2-;

Y and Z are independently represented by =CH- or =N-; and

R⁴ is an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one hydroxyl group.

{3} The compound of general Formula (I) according to {1} or {2} or a salt thereof, wherein R1 is a hydrogen atom;

R² is represented by Formula (lla)

(Ha)

R3 is a hydrogen atom, or a halogen atom;

R⁴ is an aromatic group substituted with at least one hydroxyl group or a heteroaromatic group substituted with at least one hydroxyl group; and

Y and Z are both represented by =CH-

{4} The compound of general Formula (I) according to any of {1} to {3} or a salt thereof, wherein

X is represented by ~0~;

R² is represented by Formula (lib)

(Mb)

R³ is a fluorine atom, a chlorine atom, or a hydrogen atom; and

R4 is a substituted phenyl group ing represented by Formula (III)

(III)

wherein R^ to R^2 are independently represented by substituents selected from the group consisting of a hydrogen atom, a hydroxy! group, a W,/V-dimethylaminomethyl group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group.

{5} The compound of general Formula (I) according to {4}, wherein R⁴ is represented by one of Form lae (Ilia) to (lilc):

The compound of general Formula (I) according to any of {1} to {3} or a salt thereof, wherein

X is represented by -0-;

R2 is represented by Formula (Mb)

R³ is a fluorine atom, a chlorine atom or a hydrogen atom; and represented by one of Formulae (Va) to (Vd):

(Vb) (Vc) (Vd)

The compound of general Formula (I) according to {1 } or {2} or a salt thereof, wherein X is represented by -0-;

R2 is represented by Formula (lib)

R3 is a fluorine atom, a chlorine atom or a hydrogen atom;

R3 is a hydrogen atom, a halogen atom;

Y is represented by =H- and Z is represented by =CH-; and

R4 is represented by one of Formulae (Vc), (Vd) or (Ve):

(Vc) (Vd) (Ve)

A further aspect of the present invention relates to use of the compound of general Formula (I) or a salt or solvate thereof for the treatment of a human or animal body. In particular, the present invention relates to the use of the compound of general Formula (I) or a salt or a solvate thereof for use in the treatment or prophylaxis of a disorder responsive to AMPK activation. The present invention further relates to a method for treatment or prophylaxis of a disorder responsive to AMPK activation comprising administering a compound of general Formula (!) to a patient in need thereof.

As used herein, the term "AMPK activator" refers to a compound that either increases the phosphorylation of downstream substrates of (phosphorylated or not) AMPK, and/or that increases the phosphorylation of AMPK, in particular of the human β2 isoform. As used herein, a "direct AMPK activator" refers to a compound that activates AMPK via direct interaction with at least one of its subunits.

Preferably, the compounds of the present invention are capable of activating 2-containing rA PK heterotrimers at EC 0≤ 150 μΜ and/or activating β1 -containing rAMPK heterotrimers at

EC50≤ 100 μΜ, wherein an in vitro recombinant human AMPK (rAMPK) activation assay as described in the present application is employed. In yet a more preferred embodiment, the compounds of the present invention are capable of activating β2-οοηί3ίη^ rAMPK heterotrimers at EC50≤ 3000 nM and/or activating β1 -containing rAMPK heterotrimers at EC50

< 2500 nM. In a particularly preferred embodiment, the compounds of the present invention are capable of activating 2-containing rAMPK heterotrimers at EC50≤ 150 nM and/or activating β1 -containing rAMPK heterotrimers at EC 0≤ 500 nM. The corresponding in vitro recombinant human AMPK (rAMPK) activation assay is described in Example 2 below.

As used herein, a "disorder responsive to AMPK activation" refers to a disorder, the symptoms of which would be alleviated, or the course of which would be beneficially modified, through activation of AMPK, including without limitation, metabolic disorder, diabetes, dyslipidemia and hypertension. Additionally, a "disorder responsive to AMPK activation" as used herein may be obesity, fatty liver disease, cardiovascular disease, inflammation and cancer.

As used herein, the term "diabetes" includes insulin-dependent diabetes mellitus {i.e. !DDM, also known as type 1 diabetes), non-insulin-dependent diabetes mellitus {i.e. NIDDM, also known as type 2 diabetes), and pre-diabetes. Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type 2 diabetes often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the type 2 diabetic patients are also overweighed or obese. One of the criteria for diagnosing diabetes is the fasting plasma glucose level. A diabetic subject has a fasting plasma glucose level of greater than or equal to 126 mg/dl. A pre-diabetic subject is someone suffering from pre-diabetes. Pre-diabetes is characterized by an impaired fasting plasma glucose level of greater than or equal to 100 mg/dl and less than 126 mg/di; or impaired glucose tolerance; or insulin resistance. A pre-diabetic subject is a subject with impaired fasting glucose (a fasting plasma glucose level of greater than or equal to 100 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (a 2-hour plasma glucose level of > 140 mg/dl and < 200 mg/dl); or insulin resistance, resulting in an increased risk of developing diabetes. Prevention of type 2 diabetes includes treatment of pre-diabetes. As used herein, the term "dyslipidemia" encompasses abnormal levels of any lipid fractions as weil as specific lipoprotein abnormalities. For example, it refers to elevation of plasma cholesterol and/or elevation of triglycerides and/or elevation of free fatty acids and/or low high- density lipoprotein (HDL) level and/or high low-density lipoprotein (LDL) level and/or high very low-density lipoprotein (VLDL) level. Dyslipidemia may for example contribute to the development of atherosclerosis and ultimately symptomatic vascular disease including coronary heart disease. Dyslipidemia may or may not be associated with diabetes.

As used herein, the term "metabolic disorder" encompasses any abnormal chemical reaction disrupting normal metabolism, leading to excessive levels or deficiency of certain substances. Non-limiting examples of metabolic disorders include diabetes, dyslipidemia, hypertension, overweight, obesity, and any combination thereof. A "patient" refers to a mammal, preferably a human.

A further aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of general Formula (I), or a salt or solvate thereof as active ingredient. In a particular embodiment, said pharmaceutical composition may be an oral dosage form. As used herein, the expression "oral dosage form" refers to any form of a pharmaceutical composition that is suitable for oral administration such as tablets, capsules and the like.

Preferably, the salts of the compound of the general Formula (I) are salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, W,W-dibenzylethylenediamine, diethylamine, 2-diethyl- aminoethanol, 2-dimethylaminoethano, ethanolamine, ethylenediamine, W-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The term "pharmaceutically acceptable salf further includes all acceptable salts derived from acids such as quaternary salt, acetate, carbonate, carbamate, sulfonate, strong inorganic acids and the like. In general, pharmaceutically acceptable salts may be used for modifying the solubility or hydrolysis characteristics of a compound, or in sustained release formulations. It will be understood that, as used herein, references to the compound of Formula (I) are meant to also include the pharmaceutically acceptable salts.

As used herein, the term "prophylaxis" (or "prevent' or "prevention") means prohibiting, restraining, or inhibiting the incidence, occurrence or recurrence of a symptom, disorder, condition, or disease. For example, prevention of diabetes, such as diabetes associated with obesity, refers to the administration of a compound of the present invention to prevent the onset of diabetes in a subject in need thereof. A subject in need of preventing diabetes is, for example, a pre-diabetic subject that is overweight or obese.

As used herein, the expression "therapeutically effective amount' means the amount of the compound of Formula (I) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Such response includes, in comparison with a non-treated tissue, system, animal or human; alleviation of the symptoms of the disorder being treated; improved treatment; prevention, elimination or reduction of progress of a disease, condition or disorder. The expression "therapeutically effective amount' also encompasses the amounts which are effective for increasing normal physiological function, upon single or multiple administration of the compound. The therapeutically effective amount can, for example, comprise an amount of about 0.1 to 30 mg/kg per single administration.

As used herein, the term "treating" (or "treat' or "treatment') means slowing, stopping, reducing, alleviating or reversing the progression or severity of a symptom, disorder, condition or disease.

In summary, the compounds of Formula (I) present advantageous properties in decreasing fasting blood glucose, decreasing all fractions of liver lipids and improving circulating lipid profile. These properties can be beneficially used for treating or preventing a variety of disorders related to glucose and/or lipid metabolism in patients in need thereof. Compounds of Formula (I) are thus particularly advantageous as none of the currently available drugs directly affects all of these parameters. In addition, the combined effects of the compounds of structural Formula (I) could not be predicted from previously known structures.

Accordingly, the present invention further relates to uses of the compounds of Formula (I) in the treatment or prevention of disorders responsive to AMPK activation, such as metabolic disorders. In a particular embodiment thereof, the present invention relates to the use or method of use of the compounds of Formula (I) in the treatment or prevention of diabetes. In another particular embodiment, the present invention relates to the use or method of use of the compounds of the present invention in the treatment or prevention of dyslipidemia. It is to be understood that prevention or treatment of several of these disorders may be combined while using the compounds of Formula (I).

Pharmaceutical compositions

In a further aspect, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as active ingredient, and a pharmaceutically acceptable carrier. For example, it relates to pharmaceutical compositions comprising a therapeutically effective amount of an ammonium salt, a calcium salt, a magnesium salt, a potassium salt or a sodium salt of compound of Formula (I) and a pharmaceutically acceptable carrier.

As will be readily understood by a skilled person, the pharmaceutical compositions of the present invention may comprise the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof in form of one or several polymorphs.

The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient, and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the pharmaceutically acceptable carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the compound of Formula (I) and pharmaceutically acceptable excipients.

Any suitable route of administration may be employed for providing a patient, with an effective dosage of a compound of the present invention, including without limitation oral and parenteral (such as intravenous bolus or infusion, injection, intraperitoneal, subcutaneous or intramuscular administration).

Pharmaceutical compositions of the present invention that are suitable for oral administration (oral dosage forms) may be presented in solid or liquid form. Suitable solid oral dosage forms include discrete units such as capsules, pills, cachets, powders (such as effervescent), granules or tablets, and the like, each containing a predetermined amount of the compound of Formula (I) as active ingredient. Suitable liquid oral dosage forms include solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions. Pharmaceutical compositions of the present invention may also be in the form of sustained release formulations. Any inert ingredient that is commonly used as a carrier or diluent may be used in the formulations of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof. A preferred diluent is microcrystaliine cellulose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.

The pharmaceutical compositions of the present invention may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-ftowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent Desirably, each tablet, cachet or capsule contains from about 0.1 to 1 ,000 mg, particularly 0.1 , 0.2, 0.5, 1.0, 5, 10, 25, 50, 75, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 175, 180, 200, 225, 250, 300, 350, 400, 450, 500, 750 and 1 ,000 milligrams of the active ingredient, for the symptomatic adjustment of the dosage to the patient to be treated.

Method of preparation of compound of Formula (I)

The following general methods described hereinafter in the schemes and in examples may be used to prepare compounds of Formula (I) using appropriate materials. If such starting materials are not commercially available, they may be prepared by standard synthetic techniques. Methods for extraction, isolation, purification, treatment known by one skilled in the art may be applied. Moreover, by utilizing the procedure described below, one of ordinary skilled in the art can readily prepare additional compounds of the present invention claimed herein.

It will be appreciated that, where typical or preferred experimental conditions are given (i.e. solvent, temperature, reaction time, stoichiometry of reagents, etc.), other experimental conditions may also be used unless otherwise stated. Compounds of the general Formula (I) might be synthesised by several processes using both solid and/or solution phase chemistry protocols. Depending on the nature of R¹ , R2, R3 R4 χ γ _or z and availability of intermediates, different synthetic strategies may be selected for the synthesis of compounds of Formula (I). For all protection and deprotection methods, see Philip J. Kocienski in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter G. M. Wuts in "Protective groups in organic synthesis", Wiley Interscience, 3^rd Edition 1999.

Examples of synthetic pathways for the preparation of compounds of general Formula (I) are described here below. Optimum reaction conditions may vary with particular reactants or solvent, but such conditions can be determined by the person skilled in the art using routine optimization procedures.

The following reaction schemes illustrate methods that may be used for the synthesis of compounds of general Formula (I) described in this invention. Below, all substituents such as

R¹ , R², R³, R⁴, X, Y or Z have the meaning indicated under the Formula (i) unless expressly stated otherwise.

As a representative example, the compounds of Formula (I) may be prepared following the synthetic pathway described in the General Scheme 1 where each symbol has the same meaning as described earlier, Hal represents a halogen atom such as bromine or chlorine, PG represents a protecting group such as a SEM, PMP, Boc, Fmoc group and the B(W)2 group represents either a boronic acid or a boronic ester. General Scheme 1 illustrates preparation of the compounds of Formula (I) in which ^ is a hydrogen atom. However, as will be appreciated by a skilled person, treatment of such compounds with a suitable alkylating agent or, depending on the nature of R¹ , with a cross-coupling reagent readily yields compounds of Formula (I) in which R¹ is a saturated aliphatic group.

General Scheme 1

Those skilied in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compound is generally isolated in the form of a pharmaceutically acceptable salt, such as those previously described herein, or of a solid.

EXAMPLES

Unless otherwise noted, commercially available starting materials were purchased from commercial suppliers and used without further purification. The starting materials and intermediates which were not commercially available, were prepared as described in the prior art. The MS data provided in the examples described be!ow were obtained as follows: Mass spectrum: LC/MS

Method:

Mobile Phase A: 0.1 % Formic Acid in H₂0 B: ACN, T/%B : 0/5, 1.5/90 ,5/90,5.1/5

Flow rate: 1.0 mL/min

Column: inetex C-18,4.6 x 30 mm, 2.6 pm, 100 A

Abbreviations used in the description of the preparation of the compounds of the present invention are as follows:

°C degrees Celsius;

BBr3 boron tribromide;

DBU ,8-Diazabicyclo[5.4.0]undec-7-ene;

DCM dich!oromethane;

DMA dimethylacetamide;

DMF dimethylformamide;

eq. equivalent;

Et20 Diethylether;

EtOAc ethyl acetate;

g gram;

h hour;

H2O water;

HCI hydrochloric acid;

K2CO3 potassium carbonate;

KOAc potassium acetate;

L liter;

LC/MS liquid chromatography-mass spectrometry;

LiOH lithium hydroxide;

MeOH methanol;

mg milligram;

MgS04 magnesium sulphate;

min minute;

mL milliliter;

mmol millimoles;

mol moles;

N normal; nitrogen;

sodium sulphate;

sodium borohydride;

sodium hydrogen carbonate;

ammonium hydroxide;

2 [1 ,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium;

protecting group;

room temperature;

Retention time

triethy!amine;

trifluoroacetic acid;

tetrahydrofuran.

All temperatures are given in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electron-spray ion-mass spectroscopy.

1. PREPARATION OF THE COMPOUNDS

1.1 Intermediates A were obtained following the synthetic procedure described in WO 2011/106273 A1 :

Intermediate Chemical Name LC/MS

(Rt, mm)

A1 5-Bromo-2-{methylsulfonyl)-1-((2-(trimethylsiiyl)ethoxy)methyl)- 2.72 iH-benzo[d]imidazole

A2 5-Bromo-6-chloro-2-(methylsulfonyl)-1-((2- 2.83

(trimethylsilyl}ethoxy)methyl)-1H-benzo[o]imidazole

A3 5-Bromo-6-fluoro-2-(methylsulfony!)-1-((2- 2.80

(trimethylsilyl)ethoxy)methyl)-1/-/-benzo[c/]imidazole

A4 5-Bromo-6-methyl-2-(methylsulfony!)-1-((2- 2.42

(trimethylsi!yl)ethoxy)methyl)-1H-benzo[cf]imidazole

A5 5-Bromo-6-trifiuoromethyl-2-(methylsulfonyl)-1 -((2- 2.47 (irimethylsilyl)ethoxy)methyl)-1 /-/-benzo[af]irnidazole

A6 5-Bromo-6-methoxy-2-(methylsulfonyl)-1-((2- 2.25

(trimethylsilyl)ethoxy)methyl)-1 /-/-benzo[cf]imidazole

1.2 Intermediates C were obtained following the general synthetic procedure i (Scheme 1):

Scheme 1

To a solution of intermediate A (1 eq.), DBU (3 eq.) in DMA, was added intermediate B (1.5 eq.). The reaction mixture was stirred at RT for 12 h after which time the reaction mixture was diluted with water and the product extracted with EtOAc. Organic layer was washed with brine, dried over gS04 and evaporated under vacuum. Crude material was purified by column chromatography to give the desired material.

Intermediate Chemical Name Exact

Mass (M+H)

C1 (3R, 3aR, 6R, 6aR)-6-((5-Bromo-1 -((2- 471.1

{trimethylsilyl)ethoxy)methyl)-1 H-benzo[d]imidazo!-2- yl)oxy)hexahydrofuro[3,2-b3furan-3-ol

C2 (3R, 3aR, 6R, 6aR)-6-((5-Bromo-6-ch!oro-1 -({2- 505.1

(trimethylsityl)ethoxy)methyl)-1 H-benzo[cf]imidazol-2- yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

C3 {3R, 3aR, 6R, 6aR)-6-((5-Bromo-6-f luoro-1 -((2- 489.0

(tnmethylsily!)ethoxy)methyl)-1H-benzo[cf]imidazol-2- yl)oxy) hexahyd rof u ro[3 , 2-b]f ura n-3-ol

C4 (3aR, 6S, 6aR)-6-((5-Bromo-1 -((2-{trimethylsilyl)ethoxy)methyl)- 471.1

7H-benzo[d]imidazoi-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

C5 (3R, 3aR, 6R, 6af?)-6-((5-Bromo-6-methyl-1 -((2- 485.1

(trtmethylsilyl)ethoxy)methyl)-1 H-benzo[d]imidazol-2- y I ) o xy ) h exa h yd rof u ro [3 , 2- b]f u ra n-3-o I

C6 (3R, 3aR, 6R, 6aR)-6-((5-Bromo-6-(trifluoromethyl)-1 -((2- 539.1

(trimethylsilyl)ethoxy)methyl)-1 /-/-benzo[d]imidazo!-2- yl)oxy)hexahydrofuro[3,2-b]furan-3-o!

C7 (3R, 3aR, 6R, 6aR)-6-((5-Bromo-6-methoxy-1 -((2- 501.1

(trimethy!silyl)ethoxy)methyl)-1 H-benzo[c]innidazol-2- yl)oxy)hexahydrofuro[3,2-b]furan-3-o!

1.3 Intermediates D1 and H1 were obtained following the general synthetic procedure ii (Scheme 2):

ii-bis(pirtacolato)diboron,

Pd(dppf)₂C1₂ DCM, KOAc,

Scheme 2

To a degased ( 2) suspension of intermediate C or E (1 eq.), bis(pinacolato)diboron (1.5 eq.) and KOAc (3 eq.) in dioxane was added Pd{dppf)2Cl2^■ DCM (0.05 eq.) and the reaction was then heated at 100 °C for 12 h. After this time, the reaction mixture was diluted with EtOAc and filtered through a celite pad. The organic filtrate was dried over anhydrous Na2SC>4, concentrated under vacuum and purified by column chromatography to give the desired compound.

Intermediate Chemical Name Exact

Mass (M+H)

D1 {3R,3aR, 6R,6aR)-6-{{5-(4,4,5,5-Te\rame\hy\^ ,3_>2~ 519.2

dioxaborolan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methy!)- 1H- benzo[cf]imidazol-2-yl)oxy)hexahydrofuro[3,2-i ]furan-3-ol

H1 (S)-(1-(4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2- 304.0

yl)phenyl)pyrrolidin-2-yl)methanoi Intermediate E1 was obtained foltowing the procedure described below (Scheme 3):

Scheme 3

Step 1 : 4'-Formyl-2',6'-dimethoxy-[1, 1'-biphenyl]-4-yl trifluoromethanesulfonate

To a cold Solution of 4'-hydroxyl-2_l6-dimethoxy-[1 ,1 '-biphenyl]-4-carbaldehyde (2.0 g, 7.75 mmol, 1.0 eq.), TEA (4.3 mL, 31.0 mmol, 4.0 eq.) in DCM was added triflic anhydride (1.56 mL, 9.3 mmol, 1.2 eq.) In a drop-wise manner over a period of 10 min at -10 °C. The resulting reaction mixture was stirred for another 30 min at -10 °C after which the reaction mixture diluted with DCM (100 mL) and washed with 1 N HCI solution and brine. The organic layer was dried over anhydrous Na2SC>4 and concentrated under vacuum. The obtained crude product was purified by column chromatography to afford the title compound as a !ight yellow solid (1.2 g, 40%).

Step 2: 4'-((Dimethylamino)methyl)-2',6'~dimethoxy-[1, 1 '-biphenyt]-4-yl trifluoromethanesulfonate

To a mixture of 4'-formyl-2\6'-dimethoxy-[1 ,1'-biphenyl]-4-yl trifluoromethanesulfonate (1.2 g, 3.08 mmol, 1.0 eq.), dimethyl amine hydrochloride (0.63 g, 7.69 mmol, 2.5 eq.) in MeOH (25 mL) was added TEA (1.1 mL, 7.69 mmol, 2.5 eq.), followed by titanium isopropoxide (1.82 mL, 6.16 mmol, 2.0 eq.) at room temperature. The reaction mixture was stirred for 6 h and cooled to 10 °C in an ice bath after which NaBH4 (352 mg, 9.24 mmol, 3.0 eq.) was added portion wise over a period of 30 min and the reaction mixture was stirred at RT for about 1 h. After this time, the reaction mixture was cooled to 0 °C and quenched with NH4OH solution

(2.0 mL). The suspension was then filtered through a pad of celite and washed with EtOAc (300 mL). The filtrate was washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum. The obtained product was washed with Et^O and dried under reduced pressure to afford the title compound as an off white solid (820 mg, 82%). LC/MS: 420.1 ( +H)⁺

Step 3: 4'-((Dimethylamino)methyl)-2',6'-dihydroxyl-[1, 1 '-biphenyl]-4-yl trifluoromethanesulfonate To a solution of 4'-((dimethylamino)methyl)-2',6'-dimethoxy-[1 , 1 '-biphenyl]-4-yl trifluoromethanesulfonate (100 mg, 0.24 mmol, 1.0 eq.) in DCM (10 mL) was added BBr3 (1.0 mL, 1.43 mmol, 6.0 eq.) (1 M in DCM) at 0 °C under nitrogen. The reaction mixture was let to return to RT and stirred for 12 h. After this time, the reaction mixture was poured into crushed ice, basified with a saturated aqueous solution of NaHC03 and extracted with DCM (3 x 50 mL).

The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under vacuum. The crude product was washed with n-pentane and drier under reduced pressure to afford the title compound as light brown solid (48 mg, 51 %).

Intermediates F were obtained following general procedure iii (Scheme 4):

Scheme 4

A seal tube was charged with intermediate D (1 eq.), intermediate E (1.1 eq.), aqueous 2CO3

(3 eq.) and D F and was degassed with nitrogen for 5 mtn. Pd(PPh3)4 (0.05 eq.) was added and the reaction mixture was stirred at 110 °C for 1 h. After this time, the reaction mixture was allowed to return to room temperature, filtered through a pad of celite, washed with EtOAc. The filtrate was partitioned between EtOAc and water and the organic layer was washed with water, brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by flash chromatography to afford the desired product. Intermediate Chemical Name Exact

Mass (M+H)

F1 ^((DtmethylaminoJmeth -^-ia-itia Sa ^^aa^-e- 634.3

hydroxylhexahydrofuro[3,2-b]furan-3-yl)oxy)-1 -((2- (trimethylsily l)ethoxy)methyl)-1 H-benzo[cf]imidazol-5-yl)-[1 , 1 '- biphenyl]-2,6-diol

F2 (3R, 3aR, 6R, 6aR)-6-((5-(4-( 1 - 539.3

(Hydroxymethyl)cyclopropyl)pheny!)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-benzo[d]imidazol-2- yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

F3 (3R, 3aR, 6R, 6af?)-6-((6-Chloro-5-(4-(2-hydroxylethyl)phenyi)-1 - 547.3

((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[ci]imidazoi-2- yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

F4 (3R,3aR,6R₎6aR)-6-((5-(5-(2-Hydroxyethoxy)pyridin-2-yl)-1-((2- 531.0

(tnmethy!siiyi)ethoxy)rriethyl)-1 H-benzo[cf]imidazol-2- yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

F5 4-(2-(((3R, 3aR, 6R, 6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan- 592.6

3-yl)oxy)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 -/- benzo[d]imidazof-5-yl)-N-{1 -methyl-1 H-pyrazol-3-yl)benzamide

Intermediates G were obtained following general procedure v (Scheme 5):

Scheme 5

To a solution of intermediate C (1 eq.) in DCM was added TFA at room temperature. Reaction mixture stirred for 12 h. After this time, the reaction mixture was diluted with water and the product extracted with EtOAc. Organic layer was washed with brine and evaporated and the crude material purified by column chromatography to give the desired compound. Intermediate Chemical Name Exact

Mass (M+H)

G1 (3R, 3aR, 6R, 6aR)-6-((5-Bromo-1 H-benzo[c jimidazol-2- 341.0

yl)oxy)hexahydrofuro[3,2-6]furan-3-ol

G2 (3R, 3aR, 6R, 6a )-6-((5-Bromo-6-chioro-1 H-benzo[c/]imidazol- 375.0

2-yl)oxy)hexahydrofuro[3, 2-b]furan-3~ol

G3 (3R, 3aR, 6R, 6aR)-6-((5-Bromo-6-fluoro-1 H-benzo[ci]imidazol-2- 359.0

yl)oxy)hexahydrofuro[3,2-0]furan-3-ol

G4 (3aR, 6S, 6aR)-6-((5-Bromo-1 H-benzo[c/]imidazol-2- 341.0

yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

G5 (3R_;3aR,6 ,6aR)-6-((5-Bromo-6-rnethyl-1 H-benzo[ci]imidazol- 355.1

2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

G6 (3R, 3aR,6R, 6aR)-6-((5-Bromo-6-(trifluoromethyl)-1 H- 409.0

benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3_J2-/)]furan-3-ol

G7 (3R, 3aR, 6R, 6aR)-6-((5-Bromo-6-methoxy- 1H- 371.1

benzo[d]imidazo!-2-yl)oxy)hexahydrofuro[3,2-ib3furan-3-ol intermediate H2 was obtained following the procedure described below {Scheme 6):

Scheme 6

Step 1 : 4'-Bromo-[1, 1 '-biphenyl]-2,6-diol

To a cold solution of 4'-bromo-2,6-dimethoxy-1 ,1'-biphenyl (5.3 g, 18.07 mmol, 1.0 eq.) in DCM (5 mL), BBr3 in DCM (1.0 M) (72 mL, 72.3 mmo!, 4.0 eq.) was added in a drop-wise manner after which the reaction mixture was stirred for 12 h at RT. After this time, the reaction mixture was cooled to 0 °C and quenched with ice cold water. Product extracted with DCM (3 x 100 mL), combined organic layers were washed with saturated NaHC03 solution, dried over Na2S0 and concentrated under vacuum to afford the desired product. LC-MS: 265 (M+). Step 2: 4'-(4,4,5,5~tetramethyl-1,3,2-dioxaborolan-2-yl)-[1, 1 '-biphenyl]-2,^

Title compound was obtained starting from 4'-bromo-[1 ,1 '-biphenyl]-2,6-diol and following the general procedure ii

1.9 Compounds 3, 17, 18, 30 and 37 described below were obtained following general procedure iv (Scheme 7):

Scheme 7

To a solution of the intermediate F (1 eq.) in DCM was added TFA at room temperature. Reaction mixture stirred for 12 h. After this time, the reaction mixture was diluted with DCM and washed with an aqueous saturated solution of aHC03, then brine. The organic layers were dried over gSC>4 and evaporated under vacuum. The solid residue was redissolved in THF to which was added an aqueous solution of LiOH ^■ H2O (4 eq.) and stirred at room temperature for

2 h. After this time the reaction mixture was diluted with water, extracted with EtOAc and the organic layer was washed with water followed by brine, dried over anhydrous a2S0 , filtered and evaporated under vacuum. The residue was then purified by column chromatography to give the desired compound.

1.10 Compounds 1 , 2, 4, 5, 6, 7, 10, 1 1 , 12, 13, 14, 15, 16, 19, 23, 24, 25, 26, 27, 28 and 29 described below were obtained following general procedure tii starting from intermediates G and H (Scheme 8):

Scheme 8

iflustrative compounds according to the present invention are as follows:

*

2. PHARMACOLOGICAL RESULTS OBTAINED WITH THE COMPOUNDS

The compounds 1 - 6 and 17 - 18 of the present invention were assayed in vitro to determine their EC50 against five different rAMPK heterotrimers (two containing the β1 subunit and three containing the β2 subunit). As reference examples, the corresponding EC50 values were also determined for the compounds 31 - 37, which do not fall under the definition of the general Formula (I). The structures of the compounds 31 - 37 are shown below:

(37)

2.1 METHODS

In vitro recombinant human AMPK (rAMPK) activation assay

AMPK activity was measured by the phosphorylation at Ser79 of the amtno-terminal fragment of human acetyl CoA carboxylase-type 1 , amino acids 1 -120 (ACC1/1-120). The fragment was expressed as a biotinylated fusion protein in E. colt. Human rAMPK genes were expressed in the monkey COS7 ceil expression system. The compounds were tested in triplicate at one or both of the following concentration ranges (pM): (A) 45, 15, 5, 1.67, 0.56, 0.185, 0.06, 0.02 and 0.00685, or (B) 1.67, 0.56, 0.185, 0.06, 0.02, 0.00685, 0.002286, 0.0007621 and 0.000254. A positive control comprising AMP (100 μΜ), and a negative control without enzyme, were used. The enzyme assay was conducted in a 5 pL reaction mixture containing compounds of Formula (I) at the indicated concentrations in 80 mM HEPES, pH 7.0, 160 mM NaCI, 2.5 mM MgCl2,

1 mM DTT, 0.05% Tween-20, 100 μΜ ATP with AMPK at 0.08 ng/pL and ACC1/1-120 at 0.004 ng/pL The reaction was carried out at room temperature for 60 minutes and stopped by addition of 5 pL of stop solution consisting of 20 mM EDTA, 100 mM Tris pH 8.0, 0.01 % Tween-20, 0.1 % BSA, 1 :2,000 dilution of anti-pS79 (Acetyl CoA carboxylase-1) purified rabbit monoclonal antibody, 40 pg/mL of AlphaScreen (Perkin Elmer) acceptor beads and 40 pg/mL of AlphaScreen (Perkin Elmer) donor beads. The reaction mixture was further incubated overnight at room temperature and analyzed on a Perkin Elmer Fusion-Alpha microplate analyzer. The AlphaScreen readout for this assay is based on an excitation with laser-stimulated visible light at 680 nm and emission at 520-620 nm. EC50 is calculated with the GraphPadPrism software and is defined as the compound concentration at which the half maximum rAMPK activation is reached. The fold activation equals the ratio of the maximum rAMPK activation that is reached at any compound concentration divided by the rAMPK activation obtained in the absence of compound.

Cellular AMPK activation assay

HepG2 cells culture

One milliliter of HepG2 cells (ATCC, HB-8065) at 1 x 10⁶ cells/mL were thawed in a 175 cm² flask and grown in Minimum Essential Medium with GlutaMAX™ (MEM; Gibco, 32561-029) supplemented with 10% (v/v) heat inactivated fetal bovine serum (FBS; Gibco, 10270-106), 50 units/ml of penicillin and 50 pg/mL of streptomycin (Gibco, 15070-063) in a humidified atmosphere of 95% air and 5% CO2 at 37 °C for 14 days, by changing complete medium and splitting cells three times a week. HepG2 cells were then seeded in 96 well tissue culture plates (Jet Biofil, TCP01 1096) at 40,000 cells/well or, in other cases, 60,000 cells/well in complete medium, incubated 1 hour at room temperature and grown overnight at 37 °C and 5% CO2. The day after, complete medium was removed and cells were rinsed once with PBS 1x (Gibco, 7001 -036) supplemented with 10% FBS for 15 minutes prior to treatment.

C2C12 myoblasts culture

One milliliter of C2C12 myoblasts (ATCC, CRL- 772) at 0.7 x 10⁶ cells/mL were thawed in a

175 cm^ flask and grown in Dulbecco's Modified Eagle Medium with high glucose and pyruvate (DMEM; Gibco, 41966-052) supplemented with 10% (v/v) heat inactivated fetal bovine serum (FBS; Gibco, 10270-106), 50 units/mL of penicillin and 50 pg/mL of streptomycin (Gibco, 15070- 063) in a humidified atmosphere of 95% air and 5% CO2 at 37 °C for 7 days, by changing complete medium and splitting cells three times a week. C2C12 myoblasts were then seeded in 96 well tissue culture plates (Jet Biofil, TCP011096) at 30,000 cells/well or, in other cases, 45,000 cells/well in complete medium, incubated 1 hour at room temperature and grown overnight at 37 °C and 5% CO2. The day after, after cells reached confluence, the complete medium was changed by replacing 10% FBS with 2% heat inactivated horse serum (Gibco, 16050-122) to induce differentiation. The differentiation medium was replaced 3 days after and then every day. After 6 days differentiation, medium was removed and cells were rinsed once with Hank's balanced salt solution (HBSS; Gibco, 14025-050) for 15 minutes prior to treatment.

HepG2 and C2C12 treatment

Cells were treated in triplicate with increasing concentrations of compound (tested ranges of concentrations were 0.01 , 0.03, 0.1 , 0.3, 1 , 3, 10, 30, 100, 300, 1000 μΜ, and vehicle (2% DMSO) for control cells, in PBS 1x supplemented with 10% FBS (for HepG2) or HBSS (for C2C12). In an improved version of the assay, the following concentrations were employed: 0.001 , 0.003, 0.01 , 0.03, 0.1 , 0.3, 1 , 3, 10, 30, 100 μΜ.

After incubation at 37 °C and 5% CO2 for 60 minutes, the buffer was completely removed from the cells and 50 μί. of ice-cold cell lysis buffer 1x (20 mM Tris-HCi (pH 7.5), 150 mM NaCI, 1 mM Na2EDTA, 1 mM EGTA, 1 % Triton, 2.5 mM sodium pyrophosphate, 1 mM beta- glycerophosphate, 1 mM Na3V04, 1 μg/ml leupeptin; Cell Signaling Technology, 9803) freshly supplemented with protease inhibitors 1x (Thermo Scientific, 78437) was added. Cells were lysed by incubation on ice for 10 minutes.

AMPK activity measurement

Celt lysates obtained were used for AMPK activity analysis by direct measurement of the level of phosphorylation of the AMPK substrate acetyl-CoA carboxylase (ACC) on Ser79 by using the bead-based assay technology Alphascreen® (Amplified Luminescent Proximity Homogeneous Assay).

Following gentle pipetting three times up and down, 35 μΐ of cell lysate was transferred to a white 96 well ½ areaplate (Perkin Elmer, 6005569) pre-fifled with 5 μΙ reaction mixture consisting of 1 : 1 ,000 dilution of phospho-ACC (Ser79) (D7D1 1 ) rabbit mAb (Cell Signaling Technology, 1 1818), 10 μg mi of each protein A coated acceptor beads and streptavidin coated donor beads (Perkin Elmer, 6760617) in PBS 1x supplemented with 0.1% (w/v) BSA (Cell Signaling Technology, 9998) and 0.1 % (v/v) Tween 20 (BioRad, 170-6531). This assay approach takes advantage of the biotin group which is found naturally conjugated to ACC. The reaction mixture was incubated overnight (approx. 16 hours) at room temperature in the dark. After overnight incubation, quantification of ACC phosphorylation was achieved by reading plates with an Alpha-enabled, p!ate multimode reader (Perkin Elmer, EnSpire, 2300-001 M), with an excitation at 680 nm and reading emission at 520-620 nm. Nonlinear regression analysis was used to calculate relative EC50 for each compound by using GraphPad Prism software

(version 6). For zero values (vehicle), a concentration four log below the lowest concentration of compound tested was included.

2.2 RESULTS

The results of the rAMPK activation assays are summarized in Table 1 and the results of AMPK activation potency in HepG2 and C2C12 ceils are summarized in Table 2. Compounds having EC50 > 20 μΜ in the rAMPK assay were marked as "Inactive".

Ail tested compounds according to the present invention were active in the employed assays. Compounds 1 - 4 of the present invention are particularly efficient activators of at least five human rAMPK heterotrimers. They have been shown to have an EC50 equal or less than 135 nM on at least three 2-containing heterotrimers and an EC50 equal or less than 479 nM on at least two β1 -containing heterotrimers. Furthermore, compounds 1 - 4 of the present invention activate AMPK expressed by celts, with an EC50 equai or less than 14.1 μΜ in HepG2 cells and an EC50 equal or less than 10.1 μΜ in C2C12 celts. These results illustrate that the compounds of Formula (I) with R⁴ being an aromatic group substituted with at least one, preferably with at least two hydroxyl groups or a heteroaromatic group substituted with at least one, preferably with at least two hydroxyl groups have particularly low EC50 values in the assays.

Contrary thereto, the compounds 31 - 37 (comparative examples) i.e. compounds lacking R⁴ with at least one substituent selected from a hydroxyl group, -NHR6 -NR6R7 and -S(0)R6, showed significantly higher values of EC50 for the corresponding isoforms. Thus, the activity of these compounds was considerably lower.

In particular, the collected data indicate that e.g. a replacement of the morpholine moiety in the compound 32 (Comparative Example) by a substituent R⁴ having at least one, preferably at least two hydroxyl groups (cf. e.g. Compound 2) allows a significant improvement of the activity.

The results further indicate that the compounds of general Formula (I) with R³ being a halogen, preferably a chlorine or fluorine, seem to show better activity than compounds with R³ being a hydrogen.

Table 1 : rAMPK activation potency

1 : Values are means of 2-9 individual values

2 : Comparative Example

ND : not determined

Table 2 : AMPK activation potency in HepG2 and C2C12 ceils

1 : Values are means of 2-4 individual values

2 : Comparative Example

NA : not available

2. Investigation of eADMET properties

ADMET properties of selected compounds of the present invention were investigated using a prediction model. Thus, in the following, so called eADMET values are given.

The results of the eADMET tests are summarized in Table 3.

Thus, the compounds of the present invention display advantageous ADMET properties.

Claims

A compound of general Formula (I)

(I)

or a salt thereof, wherein

R2 is represented by Formula (il)

X is represented by -0-, -S-, -S(O)-, -S(0)2- - H- or -CH2-;

Y and Z are independently represented by =CR^- or =N-;

R3 and R^ are independently represented by a hydrogen atom, a halogen atom, a hydroxyl group, or by one of the foliowing: a C-1.5 saturated aliphatic group, a C^e aikoxy group, a C-j.g aikylamino group, a C3.Q cycloalkoxy group, a C3.Q cycloalky!amtno group, a

C4.5 alkylcycioalkoxy group, a C4.5 alkylcycloalkyiamino group, a C4.5 cycloalkylalkoxy group, or a C4.5 cycloalkylalkylamino group, each being optionally substituted with at least one halogen atom;

R⁴ is an aliphatic or a heteroaltphatic group having at least one primary carbon atom substituted with at least one substituent selected from -OR⁶, -NHR -NR⁶R⁷, and -S(0)R⁶; or

R⁴ is an aromatic or a heteroaromatic group which is directly substituted by at least one substituent selected from -OR⁶, -NHR⁶, -NR⁶R⁷ and -S(0)R⁶; and

R¹ , R⁶ and R⁷ are independently represented by a C-1.5 saturated aliphatic group or by a hydrogen atom.

2. The compound of general Formula (I) according to Claim 1 or a salt thereof, wherein

is a hydrogen atom or a C-j.g alkyl group;

R2 is represented by Formula {II)

(II)

R3 is a hydrogen atom, a halogen atom, a C^ .Q alkyl group being optionally substituted with at least one halogen atom, or a C-_j.g alkoxy group being optionally substituted with at least one halogen atom;

X is represented by -0-, -S-, -NH- or -CH2-;

Y and Z are independently represented by =CH- or =N-; and

3. The compound of general Formula (I) according to Claim 1 or 2 or a salt thereof, wherein R1 is a hydrogen atom;

R² is represented by Formula (lia)

(lla)

R³ is a hydrogen atom, or a halogen atom;

R⁴ is an aromatic group substituted with at least one hydroxyl group or a heteroaromatic substituted with at least one hydroxyl group; and

Y and Z are both represented by =CH-

The compound of general Formula (I) according to any of Claims 1 to 3 or a salt thereof, wherein

X is represented by -0-;

R² is represented by Formula (lib)

(lib)

R3 is a fluorine atom, a chlorine atom, or a hydrogen atom; and

R⁴ is a substituted phenyl group being represented by Formula (III)

(III)

wherein R⁸ to R¹² are independently represented by substituents selected from the group consisting of a hydrogen atom, a hydroxyl group, a Λ/,Ν-dimethylaminomethyl group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group.

5. The compound of general Formula (I) according to Claim 4, wherein R⁴ is represented by one of Formulae (Ilia) to (I lie):

6. The compound of general Formula (I) according to any of Claims 1 to 3 or a salt thereof, wherein

X is represented by -0-;

R2 is represented by Formula (lib)

R3 is a fluorine atom, a chlorine atom or a hydrogen atom; and

(Vb) (Vc) <Vd)

(Ve) (Vf)

The compound of general Formula (I) according to Claim 6, wherein Y and Z are both represented by =CH-.

The compound of general Formula (I) according to Claim 1 or 2 or a salt thereof, where X is represented by ~0-;

R2 is represented by Formula (Mb)

(lib)

R3 is a fluorine atom, a chlorine atom or a hydrogen atom;

R3 is a hydrogen atom, a halogen atom;

Y is represented by =N- and Z is represented by =CH-; and

R⁴ is represented by one of Formulae (Vc), (Vd) or (Ve):

(Vc) (Vd) (Ve)

9. A compound of general Formula (I) according to any of Claims 1 to 8 or a salt thereof for use in the treatment or prophylaxis of a human or animal body.

10. A compound of general Formula (I) according to any of Claims 1 to 8 or a salt thereof for use in the treatment or prophylaxis of a disorder responsive to AMPK activation.

1 1. The compound of general Formula (I) according to any of Claims 1 to 8 or a salt thereof for use according to Claim 10, wherein the disorder responsive to AMPK activation is a metabolic disorder selected from the group consisting of diabetes, dyslipidemia, hyperglycemia and hypertension.

12. The compound of general Formula (I) according to any of Claims 1 to 8 or a salt thereof for use according to Claim 10 or 11 , wherein the disorder responsive to AMPK activation is type 2 diabetes.

13. A method of treatment or prophylaxis of a disorder responsive to AMPK activation, comprising administering to a patient in need thereof a compound of general Formula (I) according to any of Claims 1 to 8 or a salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of general Formula (I) according to any of Claims 1 to 8 or of a salt thereof as active ingredient.

15. The pharmaceutical composition according to Claim 13, wherein said pharmaceutical composition is an oral dosage form.