EA040041B1 - SULFONAMIDES AS GPR40 AND GPR120 AGONISTS - Google Patents

Description

Said compounds are successfully used in the treatment of diseases or disorders modulated by GPR120 and/or GPR40, such as, for example, diabetes (particularly type 2 diabetes), reduced oral glucose tolerance, insulin resistance, obesity, obesity-related disorders. , metabolic syndrome, dyslipidemia, elevated low-density lipoprotein, elevated triglycerides, obesity-induced inflammation, osteoporosis, and obesity-related cardiovascular disorders.

Brief description of the invention

The claimed invention relates to compounds having activity as G protein-coupled receptor 120 (GPR120) and/or 40 (GPR40) agonists, pharmaceutical compositions containing them and their use in the treatment of diseases or disorders modulated by said GPRs, such as such as diabetes (particularly type 2 diabetes), impaired oral glucose tolerance, insulin resistance, obesity, obesity-related disorders, metabolic syndrome, dyslipidemia, elevated low-density lipoprotein, elevated triglycerides caused by obesity inflammation, osteoporosis and obesity-related disorders of the cardiovascular system.

Background of the invention

The superfamily of G protein-coupled receptors (GPCRs) consists of receptors involved in the recognition of a wide range of chemical compounds, including nutrients, hormones, and neurotransmitters. The proteins GPR40 and GPR120, also known as free fatty acid receptors 1 and 4 (FFA1-4), are activated by medium and long chain saturated and unsaturated fatty acids derived from dietary triglycerides [Hudson B.D. et al., Adv Pharmacol (2011), 62: pp. 175-218]. Studies have shown that in humans and rodents, GPR40 was initially expressed in various parts of the brain and basophilic cells of the pancreas [Briscoe C.P. et al., J Biol Chem (2003), 278(13): p. 11303-11], the activation of GPR40 in which leads to an increased concentration of intracellular calcium and subsequent secretion of insulin. GPR40 is also expressed by intestinal argentaffinocytes [Edfalk, S. et al., Diabetes (2008), 57(9): pp. 2280-7; Liou A.P. et al., Gastroenterology (2011), 140(3): pp. 903-12], in which the receptor is activated by fatty acids causing the release of incretin hormones such as glucagon-like peptide-1 (GLP-1). GPR120 is also highly expressed in the gut (colon enteroendocrine L cells and cell lines such as STC-1), as well as in the lungs, thymus, spleen, and pancreas [Hirasawa A. et al., Nat Med (2005), 11(1): pp. 90-4; Taneera J. et al., Cell Metab (2012), 16(1): pp. 122-34; Tanaka T. et al., Naunyn Schmiedebergs Arch Pharmacol (2008), 377(4-6): pp. 523-7].

With regard to GPR40, activation of GPR120 in enteroendocrine cells increases the concentration of intracellular calcium, which leads to the secretion of GLP-1.

GLP-1 is a peptide produced in the gastrointestinal tract, secreted by intestinal L-cells after a meal. GLP-1 has a strong effect on glycemic regulation by stimulating glucose-dependent insulin secretion, proinsulin gene expression, and basophilic cell proliferative pathways [Drucker D.J., Cell Metab (2006), 3(3): pp. 153-65]. GLP-1 secretion is reduced in patients with type 2 diabetes, which may contribute in part to the hyperglycemia observed in these patients [Mannucci E. et al., Diabet Med (2000), 17(10): pp. 713-9]. The proven efficacy of GLP-1 in lowering glycemia has led to the approval of the GLP-1 receptor agonist exendin-4 (Byetta) and Liraglutide (Victoza), as well as the GLP-1 peptidase inhibitors Dipeptidyl peptidase-4 (DPP-4), in the treatment of patients with type 2 diabetes (T2D). At least initially, patients with type 2 diabetes (T2D) do not require insulin treatment, as beta cells respond by increasing their own insulin production. As the disease progresses, the compensatory response fails to produce insulin and maintain normal glucose levels, leading the patient to the need for pharmaceutical treatment.

Conventional therapies that target either insulin resistance (metformin, thiazolidinediones) or insulin release from beta cells (sulfoulureas, exanatide) have been associated with a risk of developing hypoglycemia. Therefore, treatments based on glucose-dependent mechanisms of action that induce insulin secretion in beta cells are needed.

Selective activation of GPR-40 and/or GPR-120 may represent a potential therapeutic benefit in the treatment of type 2 diabetes and related conditions with minimal risk of hypoglycemia. GPR120 is also expressed in adipocytes, which play an important role in differentiation and maturation. Increased mRNA levels during adipocyte differentiation have been described in in vitro models of adipogenesis as well as in human adipose tissue [Gotoh C. et al., Biochem Biophys Res Commun (2007), 354(2): pp. 591-7]. Studies have shown that GPR120 expression in human adipose tissue was significantly higher in obese patients compared to controls, suggesting that GPR120 expression might be increased by dietary lipid accumulation. The same study showed that mice fed a high-fat, low-GPR120 diet became obese [Ichimura A. et al., Nature (2012), 483(7389): pp. 350-4]. These data indicate that GPR120 acts as a lipid sensor, and inhibition of lipolysis by a GPR120 agonist would decrease blood FFA concentrations, normalizing lipid levels and indeed leading to improved insulin resistance. Based on clinical studies that correlated body fat mass with lower bone density and increased risk of fracture, it was assumed that lipids had a direct effect on bones. The effects of GPR120/40 agonists were therefore tested on the example of therapeutic molecules in the regulation of bone metabolism [Cornish J. et al., Endocrinology (2008),

- 1 040041

149(11): pp. 5688-95].

Finally, it has been shown that GPR120 on macrophages can be activated by omega-3 fatty acids to suppress the release of inflammatory cytokines. The anti-inflammatory action of GPR120 is mediated by the β-arrestin signaling pathway [Oh D.Y. et al., Cell (2010), 142: pp. 687-98]. In vivo experiments in obese mice with an orally administered GPR120 agonist have demonstrated potent anti-inflammatory effects of GPR120 activation and subsequent improved glucose tolerance, reduced hyperinsulinemia, increased insulin sensitivity, and reduced fatty liver disease [Oh D.Y. et al., Nat Med (2014), 20: cmp.942-7].

WO 2014/073904 discloses a novel compound with a GPR40 receptor agonist effect that promotes insulin secretion and inhibits the rise in blood sugar after a glucose tolerance test, and thus has a beneficial effect in the treatment of diabetes and its complications, a method for its preparation and pharmaceutical a composition containing this compound as an active ingredient. WO 2014/209034 discloses new biaryl derivatives as GPR120 agonists, a method for their preparation and a pharmaceutical composition containing these compounds as active ingredients and their use in the prevention or treatment of diabetes, complications of diabetes, obesity, non-alcoholic fatty liver disease, steatohepatitis, osteoporosis or inflammation . US 2011184031 discloses a new phenyl compound, in particular an aralkyl carboxylic acid compound with a GPR120 and/or GPR40 agonistic effect.

WO 2016/057731 concerns the use of new compounds that are GPR40 agonists in the treatment of various diseases, syndromes and disorders, including type 2 diabetes mellitus, obesity, obesity-related disorders, impaired glucose tolerance, insulin resistance, metabolic syndrome, other factors cardiovascular risk factors such as hypertension and cardiovascular risk factors associated with uncontrolled cholesterol and/or lipid levels, osteoporosis, inflammation and eczema.

US20150274672 describes compounds as GPR120 modulators for the treatment and/or prevention of diabetes, obesity, hyperlipidemia, inflammation and related disorders.

Brief summary of the invention

The purpose of the claimed invention is to provide new GPR120 and/or GPR40 agonists.

The authors of the claimed invention discovered a new class of substituted benzenesulfonamides that act as GPR120 and/or GPR40 agonists.

These compounds are useful in the treatment of diseases or disorders modulated by said GPRs.

Terms

Unless otherwise indicated, all notes, technical and other scientific terminology used in this description are intended for the understanding of those skilled in the art to whose attention this description is intended. In some cases, terms with commonly understood meanings are defined here for clarity and/or ease of reference; thus, the inclusion of such definitions here should not be construed as representing significant differences from conventionally accepted terms in the art.

The term physiologically acceptable excipient as used herein refers to a substance devoid of any pharmacological effect of its own and which does not produce adverse reactions when administered to a mammal, preferably a human. Physiologically acceptable excipients (fillers) are known in the art and are disclosed, for example, in the Handbook of Pharmaceutical Excipients, sixth edition 2009, incorporated herein by reference.

The term pharmaceutically acceptable salts as used herein refers to those salts which have the biological efficacy and properties of the salt-forming compound and do not produce adverse reactions when administered to a mammal, preferably a human. Pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include, but are not limited to, carbonate, hydrochloride, hydrobromide, sulfate, bisulfate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulfonate, and p-toluenesulfonate. Additional information on pharmaceutically acceptable salts can be found in the Handbook of pharmaceutical salts, P. Stahl, C Wermuth, WILEY-VCH, 127-133, 2008, incorporated herein by reference.

The term halogen as used herein refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term C1-C6 alkyl as used herein refers to a branched or linear hydrocarbon containing from 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, p-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, ppentyl, p-hexyl.

The term aryl as used herein refers to aromatic mono- and polycarbocyclic ring systems in which the individual carbocyclic rings in the polycarbocyclic ring systems can be fused or attached to each other via a single bond. coming up

- 2 040041 Common aryl groups include, but are not limited to, phenyl, naphthyl and biphenyl.

The term heterocycle as used herein refers to a 4-, 5-, 6-, 7- or 8-membered monocyclic ring, saturated or unsaturated, which is composed of carbon atoms and one or more heteroatoms selected from N, O and S, and in in which, alternatively, the nitrogen and sulfur heteroatoms may be oxidized and the nitrogen heteroatom may be quaternized. The heterocyclic ring may be attached to any heteroatom or carbon atom, provided that the attachment results in a stable structure. The term also includes any bicyclic system in which any of the above heterocyclic rings is fused to an aryl or other heterocycle. If the heterocyclic ring is an aromatic heterocyclic ring, it may be defined as a heteroaromatic ring.

The term five-membered heterocyclic ring as used herein refers to a saturated or unsaturated ring having five ring atoms, with 1, 2, 3, or 4 ring atoms independently selected from N, O, and S. The term also includes any bicyclic system.

Exemplary five-membered heterocycles - thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3oxadiazolyl, 1,2, 4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, benzimidazole, etc. .

The term "unsaturated ring" as used herein refers to a ring that is partially or completely unsaturated. For example, an unsaturated monocyclic C ₆ ring refers to cyclohexene, cyclohexadiene, and benzene.

The term substituted as used herein refers to mono- or poly-substitution with a named (or indefinite) substituent, to the extent that this single or multiple substitution is chemically possible.

For example, a carbocycle or heterocycle substituted with more than one substituent may have multiple substituents on the same ring atom, to the extent that the substitution is chemically possible. The ring sulfur atom in a saturated heterocycle can, for example, as a rule, be substituted with one (-S (=O)-) or two oxo groups (-SO2-).

The terms approximately and approximately in this specification refer to the range of experimental error that can occur in a measurement.

The terms consisting of, having, including, and containing are to be construed as open terms (i.e., meaning including, but not limited to), and should also be considered as auxiliary terms for the terms consists essentially of, consists essentially of, consists of, or consists of .

The terms consists essentially of, consisting essentially of are to be construed as semi-closed terms, meaning that no other components are included that substantially affect the essential and novel features of the invention (additional excipients may thus be included).

The terms consists of, consisting of should be construed as a closed term.

Detailed description of the invention

The first object of the claimed invention is a compound with formula (I)

(I) and its pharmaceutically acceptable salts, wherein

A is phenyl, naphthyl, biphenyl, or a saturated or unsaturated five-membered heterocycle having 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S;

R ¹ , R ² , R ³ are individually selected from the group consisting of -H, -halogen, -CF ₃ , -CN, -CH2CN, -OMe, -OCF3, -OH, phenyl, -OPh, -OCH2Ph, - OCH2OMe, -OCH2CN -NO2, -NR'R, linear or branched C1-C6 alkyl, -O(CH ₂ )pS(O) ₂ Me and a heterocycle with a five-membered ring having five ring atoms, in which 1, 2, 3 or 4 ring atoms individually selected from N, O and S;

in which R' and R are individually -H or C1-C4 alkyl;

wherein the phenyl and the five-membered heterocycle are individually unsubstituted or substituted with a group selected from the group consisting of linear or branched C1-C4 alkyl, halogen, -OMe and -OH;

p has a value from 1 to 4;

X represents -CH ₂ or -C(O);

n is 0, 1 or 2;

- 3 040041

R ⁴ is -YC(O)OH, where Y is a C4-C18 straight chain hydrocarbon, saturated or unsaturated;

R ⁴ is in the meta or para position on the aromatic ring;

wherein when A is phenyl, n is O, Y is C ₄ hydrocarbon, at least one of said R ¹ , R ² , R ³ is not hydrogen;

wherein when A is phenyl, n is O, Y is C ₄ hydrocarbon, R ¹ and R ² are hydrogen, R ³ is not Cl at the para position in the aromatic ring, or in which the compound of formula (I) is 7-( 3-(N-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2-yl)sulfamoyl)phenyl)heptanoic acid.

Y is a straight chain C6-C10 hydrocarbon, saturated or unsaturated.

In said compound, the five-membered heterocycle is selected from the group consisting of thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, alternatively, partially saturated.

In said compound, R ¹ , R ² , R ³ is individually selected from the group consisting of -H, -halogen, -CF ₃ , -OMe, -OH, phenyl, -OPh, -OCH ₂ Ph, -OCH ₂ OMe, -OCH2CN -NO ₂ , -NH ₂ , -NMe ₂ , linear or branched C1-C ₆ alkyl and -O(CH ₂ ) _P -S(O) ₂ Me.

According to the claimed invention, n can be equal to 0 or 1.

In said compound, R ⁴ may be in the meta position on the aromatic ring.

Preferred compounds of formula (I) according to the claimed invention are selected from the following list:

7-(3-(M-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (1);

7-(3-(M-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid (2);

7-(3-(M-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (3);

7-(3-(M-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (4);

7-(3-(M-(4-(dimethylamino)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (5);

7-(3-(M-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid (6);

7-(3-(1\1-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (7);

- 4 040041

7-(3-(M-(4-methoxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (8);

7-(3-(N-(6-fluoro-4-methyl-[1,1'-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid (9);

7-(3-(N-(5-fluoro-3-methyl-[1,1'-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid (10);

6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid (11);

7-(3-(M-(3,5-dimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl)heptanoic acid (12);

7-(3-(M-(2,4-Dimethylthiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (13);

7-(3-(M-(4,5-dimethylthiazol-2-yl)sulfamoyl)phenyl)heptanoic acid (14);

7-(3-(M-(4,5-dimethyloxazol-2-yl)sulfamoyl)phenyl)heptanoic acid (15);

7-(3-(M-(5-phenyl-1,2,4-thiadiazol-3-yl)sulfamoyl)phenyl)heptanoic acid (16);

7-(3-(M-(3-methyl-1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (17);

7-(3-(M-(5-methyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)heptanoic acid (18);

7-(3-(M-(3,5-dimethylisoxazol-4-yl)sulfamoyl)phenyl)heptanoic acid (19);

7-(3-(M-(5-methyl-4H-1,2,4-triazol-3-yl)sulfamoyl)phenyl)heptanoic acid (20);

7-(3-(M-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid (21);

7-(3-(M-(3-phenylisothiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (22);

7-{3-[(5-hydroxynaphthalen-1-yl)sulfamoyl]phenyl}heptanoic acid (23);

7-{3-[(4-fluoro-2,6-dimethylbenzoyl)sulfamoyl]phenyl}heptanoic acid (24);

7-{4-[(4-fluoro-2,6-dimethylphenyl)sulfamoyl]phenyl}heptanoic acid (25);

7-(3-(M-(2-ethyl-2H-1,2,3-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid (26);

7-(3-(M-(2-methyl-2H-tetrazol-5-yl)sulfamoyl)phenyl)heptanoic acid (27);

7-(3-(N-(4-methyl-4,5-dihydro-rooxazol-2-yl)sulfamoyl)phenyl)heptanoic acid (28);

7-(3-(M-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2yl)sulfamoyl)phenyl)heptanoic acid (29);

7-(3-(M-(3-phenylisothiazol-4-yl)sulfamoyl)phenyl)heptanoic acid (30);

7-(3-(N-(4-hydroxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (31);

7-(3-(M-(3,5-dimethyl-[1,1'-biphenyl]-4-yl)sulfamoyl)phenyl)heptanoic acid (32);

7-(3-(M-(2,6-dimethyl-4-phenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33);

7-(3-(M-(4-(benzyloxy)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (34);

7-(3-(M-(2,6-dimethyl-4-(3(methylsulfonyl)propoxy)phenyl)sulfamoyl)phenyl)heptanoic acid (35).

More preferred compounds of formula (I) according to the claimed invention are selected from the following list:

- 5 040041

7-(3-(M-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (1);

7-(3-(M-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid (2);

7-(3-(M-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (3);

7-(3-(M-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (4);

7-(3-(M-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid (6);

7-(3-(1\1-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (7)

7-(3-(N-(6-fluoro-4-methyl-[1,1'-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid (9);

7-(3-(N-(5-fluoro-3-methyl-[1,1'-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid (10);

6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid (11);

7-(3-(M-(2,6-dimethyl-4-phenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33).

A separate object of this invention is a pharmaceutical composition containing as an active ingredient at least one of the aforementioned compounds (specified in any of claims 1 to 8 of the formula of this invention) in combination with physiologically acceptable excipients. According to a preferred embodiment of the invention, also in combination with the previous embodiments, the pharmaceutical compositions can be administered via intravenous, intraperitoneal, inhalation, topical or oral administration.

However, the pharmaceutical compositions of this invention may be presented in solid or liquid form.

Another object of this invention is the use of the aforementioned compounds of formula (I) for the prevention and/or treatment of a disease or disorder modulated by GPR120 and/or GPR40.

Wherein, said disease or disorder is: diabetes (particularly type 2 diabetes), decreased oral glucose tolerance, insulin resistance, obesity, obesity-related disorders, metabolic syndrome, dyslipidemia, elevated low-density lipoprotein, elevated triglyceride levels, obesity-induced inflammation, osteoporosis and obesity-related disorders of the cardiovascular system. Another object of the claimed invention is the use of a compound of formula (I) wherein A is phenyl, R ¹ , R ² and R ³ are hydrogen, n is 0 and R ⁴ is -(CH ₂ ) ₄ -C(O )OH, for the prevention and/or treatment of a disease or disorder modulated by GPR120 and/or GPR40.

A further object of the claimed invention is the use of a compound of formula (I) wherein A is phenyl, R ¹ and R ² are hydrogen, R ³ is Cl in the para position on the aromatic ring, n is 0 and R ⁴ is -(CH2 )4-C(O)OH, for the prevention and/or treatment of a disease or disorder modulated by GPR120 and/or GPR40. Preferably, said disease or disorder modulated by GPR120 and/or GPR40 is: diabetes (particularly type 2 diabetes), reduced oral glucose tolerance, insulin resistance, obesity, obesity-related disorders, metabolic syndrome, dyslipidemia , elevated low-density lipoprotein, elevated triglycerides, obesity-induced inflammation, osteoporosis, and obesity-related cardiovascular disorders.

Pharmaceutical compositions of this invention, presented in solid or liquid form, are conveniently packaged using conventional techniques and excipients, such as those described in Remington's Pharmaceutical Sciences Handbook MACK Publishing, New York, 18 ^th ed., 1990. Compounds according to the claimed invention can administered as the sole active principle or in combination with other therapeutically active compounds.

The administration of the compounds according to the claimed invention can be carried out intravenously or intraperitoneally, by jet injection, in dermatological preparations (creams, lotions, sprays and ointments), inhalation, and also orally in the form of capsules, tablets, syrup, controlled release formulations, etc.

The average daily dose depends on several factors such as the severity of the disease, condition, age, sex and weight of the patient. The dose will generally range from 1 to 1500 mg of the compounds of formula (I) per day, optionally divided into several doses.

As will be shown in the experimental section, the aforementioned compounds are evaluated by measuring activity in the GPR120 and GPR40 receptor mediated calcium mobilization assay and GLP-1 secretion in enteroendocrine cells.

Example 36 describes that the present inventors have found that the aforementioned compounds 1-35 are potent GRP120 and/or GPR40 agonists. The GPR agonist activity of all compounds was determined in vitro by measuring intracellular calcium levels in CHO-k1 cells stably expressing human GPR120 or GPR40. All compounds showed concentration-dependent increases in intracellular calcium with an AC50 of 2 to 18 µm for GPR120 and an AC50 of 5 to 13 µm for GPR40, as shown in Table 1. 1. These responses to each compound reflected the activation of GPR120 and GPR40 as no responses were observed in wild-type cells.

In addition, as detailed in Example 37, all of the above compounds were tested in vitro to evaluate GLP-1 secretion in rat STC-1 and human NCI-H716 enteroendocrine cell lines.

Compound treatment provided a significant increase in GLP-1: the best molecules in the series were compound 9 (14.5 and 6.2-fold increases compared to dimethyl sulfoxide in STC-1 and NCI-H716, respectively) and compound 10, which showed 4.7 and 2.5-fold increases in dimethyl sulfoxide in STC-1 and NCI-H716, respectively (Table 1). The following examples illustrate the claimed invention without limiting its essence.

Examples

Synthesis of compounds 1-35.

The compounds listed in the table. 1 were synthesized according to the procedures described in the following schemes and examples.

Scheme 1. Procedure A for the synthesis of compounds o

H ₂ , MeOH

Pyridine - Pyridine, DMAP - DMAP, Acetone - Acetone, min - mi

Scheme 2. Procedure B for the synthesis of pyridine compounds, DMAP yjL

Acetone, 60°C _R ' ^NH 'b o

NaOH, Dioxane

Pyridine - Pyridine, DMAP - DMAP, Acetone - Acetone, Dioxane - Dioxane

Materials and methods.

All reagents were purchased from Sigma-Aldrich, Fluorochem and Alfa Aesar and used without further purification. NMR spectra were recorded in the indicated solvent with tetramethylsilane (TMS) as internal standard on a Bruker Avance3 400 MHz spectrometer. Chemical shifts are reported in ppm relative to the internal standard. Abbreviations used: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=double doublets, bs=broad signal. Interaction constants (J values) are given in Hz. Analytical HPLC-MS spectra were recorded on a Surveyor instrument (THERMO FINNIGAN) in combination with an LCQ DECA XP-PLUS (THERMO FINNIGAN) equipped with a C18 reverse phase column (10 μM, 4.6 mm x 150 mm) Phenomenex Gemini. The elution mixture consisted of ammonium formate/formic acid buffer and acetonitrile 10 mM pH 4.2 and was used with a gradient from 90:10 to 10:90 with a flow rate of 0.200 ml/min. All MS experiments were performed using electrospray ionization in the mode of detecting positively and negatively charged ions.

All reactions were verified by thin layer chromatography (TLC) performed on Grace Resolv Davisil silica gel plates, 250 µm thick, 60 F254, visualized with UV (254

- 7040041 nm) or stains such as KMnO ₄ , p-anisaldehyde, and cerium ammonium molybdate (CAM). Chromatographic purifications were performed on Grace Resolv Davisil silica 60 silica gel columns. All organic solutions were dried on anhydrous Na ₂ SO ₄ or MgSO ₄ and concentrated on a rotary evaporator. All compounds used for biological testing are at least 98% pure based on analytical HPLC results at 220 and 254 nm unless otherwise noted.

Semi-preparative purifications were performed using HPLC-UV, with a Gilson 321 pump, Gilson 152 UV sensor, Gilson 202 fraction collector, Gilson 506C system interface. Column: Phenomenex Gemini-NX AXIA 150x21.2 mm, 5 µm, 110 A.

General methodology.

Method A.

Synthesis of methyl 7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoate (intermediate a).

4-Fluoro-2,6-dimethylaniline (74.2 mg, 0.533 mmol) was dissolved in anhydrous acetone (1.5 ml). Pyridine (0.65 ml, 8.0 mmol), DMAP (130 mg, 1.07 mmol) and methyl 7-(3-(chlorosulfonyl)phenyl)heptanoate (170 mg, 0.533 mmol) were added and the mixture was refluxed overnight. The mixture was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC (gradient elution with water/acetonitrile containing trifluoroacetic acid) to give the product as a colorless oil (66 mg, yield = 29%). MS (ESI ⁺ ) m/z: 422.2 [M+H] ⁺ .

Example 1 Synthesis of 7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (1).

Methyl 7-(3-(M-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoate (intermediate a, 66 mg, 0.16 mmol) was dissolved in dioxane (3 ml). Aqueous NaOH 2M (1.2 ml, 2.4 mmol) was added and the mixture was stirred at room temperature. After complete saccharification (2 h; HPLC-UV-MS monitoring), the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and washed with aqueous HCl 0.3M (3x5 ml) and brine (3x5 ml), the organic layer was dried (Na2SO4) and concentrated to give 1 as a white solid (56 mg, yield = 88%). 1H-NMR (chloroform-d): δ 1.22 -1.43 (m, 4H) 1.51 -1.67 (m, 4H) 1.99 (s, 6H) 2.35 (t, J=7.02 Hz, 2H) 2.62 (t, J=7.11 Hz, 2H) 6.24 (br s, 1H) 6.71 (d, J=9.2 Hz, 2H) 7.34-7.40 (m, 2H) 7.46-7.54 (m, 2H). MS (ESI ⁺ ) m/z: 408.2 [M+H] ⁺

Method V.

Synthesis of 3-bromo-M-(2,4,6-trimethylbenzyl)benzenesulfonamide (intermediate b).

3-Bromo-N-(2,4,6-trimethylbenzyl)benzenesulfonamide was prepared according to procedure A (221 mg, yield=56%) by reacting mesitylmethanamine (160 mg, 1.07 mmol) with 3-bromobenzenesulfonyl chloride (271 mg, 1.07 mmol). MS (ESI+) m/z: 390.1 [M+Na] ⁺ .

Synthesis of 7-(3-(N-(2,4,6-trimethylbenzene)sulfamoyl)phenyl)heptanoic acid (intermediate c).

3-Bromo-N-(2,4,6-trimethylbenzyl)benzenesulfonamide (intermediate b, 302 mg, 0.820 mmol), potassium carbonate (397 mg, 2.87 mmol), tetrakis(triphenylphosphoranyl)palladium (95 mg, 0.082 mmol), and copper(1) iodide (15.63 mg, 0.082 mmol) was suspended in DME/H2O (1/1 v/v) (2 ml). The resulting mixture was stirred under nitrogen for 5 minutes and hepta-6-novaya acid (0.212 mL, 1.64 mmol) was added. The mixture was subjected to microwave irradiation for 1 hour at 80°C. After removal of DME under reduced pressure, the residue was taken up in ethyl acetate (15 ml) and washed with aqueous HCl 2M (2x10 ml) and brine (2x10 ml). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV to give the product as a colorless oil (206 mg, yield = 61%). MS (ESI ⁺ ) m/z: 279.1 [M+H] ⁺ .

Example 2 Synthesis of 7-(3-(N-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid (2).

Palladium 10 wt%, on carbon (273 mg, 0.256 mmol) was suspended in methanol (10 ml) and 7-(3-(N-(2,4,6-trimethylbenzene)sulfamoyl)phenyl)hepta-6- new acid (intermediate c, 530 mg, 1.28 mmol). Hydrogen bubbles were bubbled through the mixture for 15 minutes, after which the mixture was left to stir at room temperature for 1 hour under a hydrogen atmosphere. In this case, the conversion was complete (HPLC-UV-MS). The mixture was filtered through a Celite® sheet and washed with methanol (30 ml). The mixture was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV to give the product as a colorless oil (390 mg, yield = 73%). ¹ H NMR (300 MHz, chloroform-d) δ ppm 1.20 (d, J=7.03 Hz, 6H) 1.27-1.40 (m, 4H) 1.48-1.70 (m, 4H) 1.99 (s, 6H) 2.35 (t, J=7.58 Hz, 2H) 2.60 (t, J=7.58 Hz, 2H) 2.79 (spt, J=7.03 Hz, 1H) 6.21 (br s, 1H) 6.85 (s, 2H) 7.31-7.43 (m, 2H) 7.48 (s, 1H) 7.53-7.64 (m, 1H). MS (ESI ⁺ ) m/z: 440.2 [M+Na] ⁺ .

Synthesis of compounds 3-35.

Example 3 Synthesis of 7-(3-(N-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (3).

Starting with 4-isopropyl-2,6-dimethylaniline hydrochloride salt (31 mg, 0.16 mmol), methyl 7-(3-(M-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoate (25 mg , yield = 36%), according to method A. MS (ESI ⁺ ) m/z: 446.3 [M+H] ⁺ .

Compound 3 was then obtained by hydrolysis of the ester derivative (25 mg, 0.056

- 8 040041 mmol), as described for compound 1, in the form of a waxy yellow solid (22 mg, yield = 91%). 1Н NMR (300 MHz, chloroform-d) δ ppm 1.20 (d, J=7.03 Hz, 6Н) 1.27 -1.40 (m, 4Н)

1.48 -1.70 (m, 4H) 1.99 (s, 6H) 2.35 (t, J=7.58 Hz, 2H) 2.60 (t, J=7.58 Hz, 2H) 2.79 (spt, J=7.03 Hz, 1H) 6.21 (br s, 1H) 6.85 (s, 2H) 7.31 - 7.43 (m, 2H) 7.48 (s, 1H) 7.53-7.64 (m, 1H) MS (ESI ⁺ ) m/z: 432.2 [M+H] ⁺ .

Example 4 Synthesis of 7-(3-(N-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (4).

Starting from 4-chloro-2,6-dimethylaniline (1.50 g, 9.64 mmol), 3-bromo-N-(4-chloro-2,6-dimethylphenyl)benzenesulfonamide was synthesized as described in procedure B to give a mixture mono- and di-sulfonamide, which, by hydrolysis with aqueous NaOH/dioxane, completely converted to mono-sulfonamide (3.00 g, yield = 83%). MS (ESI ⁺ ) m/z: 395.9 [M+Na] ⁺ .

This sulfonamide (2.90 g, 7.74 mmol) was then combined with hepta-6-noic acid (2.00 ml, 15.5 mmol) as described in procedure B to give 7-(3-(N-(4 -chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (980 mg, yield = 32%). MS (ESI ⁺ ) m/z. 420.1 [M+H] ⁺ .

Compound 4 was then obtained by reduction of an alkyne derivative (980 mg, 2.33 mmol) as described for compound 2 as a white solid (158 mg, yield = 16%). 1Н NMR (300 MHz, chloroform-d) δ ppm 1.27 -1.43 (m, 4Н) 1.51 - 1.69 (m, 4Н) 1.99 (s, 6Н) 2.37 (t, J=7.31 Hz, 2Н) 2.62 (t, J =7.59 Hz, 2H) 6.56 (s, 1H) 7.01 (s, 2H) 7.37 - 7.41 (m, 2H) 7.48 - 7.57 (m, 2H). MS (ESI ⁺ ) m/z. 446.1 [M+Na] ⁺ .

Example 5 Synthesis of 7-(3-(N-(4-(dimethylamino)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (5).

Starting with N1,N1,3,5-tetramethylbenzene-1,4-diamine (19.7 mg, 0.120 mmol), ethyl 7-(3-(N-(4(dimethylamino)-2,6-dimethylphenyl)sulfamoyl) phenyl)heptanoate was prepared (21 mg, yield = 38%) as described in Method A. MS (ESI ⁺ ) m/z. 461.3 [M+H] ⁺ .

Compound 5 was then obtained by hydrolysis of the ester derivative (21 mg, 0.046 mmol) as described for compound 1 as a beige solid (19 mg, yield = 97%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.26-1.40 (m, 4 H) 1.48-1.69 (m, 4 H) 1.95 (s, 6 H) 2.34 (t, J=7.30 Hz, 2H) 2.61 (t, J=7.58 Hz, 2H) 2.90 (s, 6H) 6.01 (s, 1H) 6.37 (s, 2H) 7.30 - 7.41 (m, 2H) 7.47 - 7.61 (m, 2H) MS (ESI+ ) m/z: 433.2 [M+H] ⁺ .

Example 6 Synthesis of 7-(3-(N-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid (6).

Starting with 2,6-dimethyl-4-(trifluoromethyl)aniline hydrochloride salt (34 mg, 0.15 mmol) gave ethyl 7-(3-(N-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl) phenyl) heptanoate (11.4 mg, yield=16%) as described in Method A. MS (ESI ⁺ ) m/z: 486.2 [M+H] ⁺ .

Compound 6 was then obtained by hydrolysis of the ester derivative (5.7 mg, 0.012 mmol) as described for compound 1 as a beige solid (2.0 mg, yield = 37%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.29 - 1.43 (m, 4H) 1.53 - 1.70 (m, 4H) 2.17 (s, 6H) 2.41 (t, J=7.36 Hz, 2H) 2.64 (t , J=7.44 Hz, 2H) 6.47 (s, 1H) 7.13 - 7.42 (m, 4 H) 7.46 - 7.70 (m, 2H) MS (ESI ⁺ ) m/z: 480.2 [M+Na] ⁺ .

Example 7 Synthesis of 7-(3-(N-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (7).

Starting with 4-bromo-2,6-dimethylaniline (24 mg, 0.12 mmol), ethyl 7-(3-(N-(4-6pom-2,6dimethylphenyl)sulfamoyl)phenyl)heptanoate (9.5 mg, yield = 16 %) as described in Method A. MS (ESI ⁺ ) m/z: 496.1 [M+H] ⁺ .

Compound 7 was then obtained by hydrolysis of the ester derivative (8.5 mg, 0.017 mmol) as described for compound 1 as a white solid (8.0 mg, yield = 99%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.20-1.44 (m, 4 H) 1.48-1.69 (m, 4 H) 1.98 (s, 6 H) 2.36 (t, J=7.30 Hz, 2H) 2.62 (t, J=7.58 Hz, 2H) 6.29 (br s, 1H) 7.16 (s, 2H) 7.33-7.42 (m, 2H) 7.46-7.55 (m, 2H) MS (ESI ⁺ ) m/z: 468.2 [M+H] ⁺ .

Example 8 Synthesis of 7-(3-(M-(4-methoxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (8).

4-Amino-3,5-xylenol (50 mg, 0.36 mmol) and sodium 2-methylpropan-2-olate (52 mg, 0.55 mmol) were dissolved in dry DMF (1 ml) under an argon atmosphere. Iodomethane (0.021 ml, 0.33 mmol) was added and the mixture was stirred overnight. DCM (20 ml) was added and the solution was washed with aqueous NaOH 1M (2x15 ml) and brine (2x15 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (hexane/ethyl acetate 2/1) to give 4-methoxy-2,6-dimethylaniline (24 mg, yield=43%). MS (ESI+) m/z: 152.1 [M+H] ⁺ . Starting with 4-methoxy-2,6-dimethylaniline (24 mg, 0.16 mmol), methyl 7-(3-(N-(4-methoxy2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoate was obtained (12 mg, yield = 17 %) as described in Method A. MS (ESI ⁺ ) m/z: 456.2 [M+Na] ⁺ . The ester derivative (12 mg, 0.028 mmol) was hydrolyzed as described in procedure A to give compound 8 as an orange oil (11 mg, yield = 95%). 1Н NMR (300 MHz, chloroform-d) δ ppm 1.22 -1.36 (m, 4Н) 1.49 -1.66 (m, 4Н) 1.97 (s, 6Н) 2.30 (t, J=6.76 Hz, 2Н) 2.61 (t, J =7.58 Hz, 2H) 3.75 (s, 3 H) 6.53 (s, 1H) 7.31 - 7.39 (m, 3 H) 7.46 - 7.57 (m, 3 H). MS (ESI ⁺ ) m/z: 442.2 [M+Na] ⁺ .

Example 9 Synthesis of 7-(3-(N-(6-fluoro-4-methyl-[1,1'-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid (9).

(1,1'-bis(Diphenylphosphino)ferrocene)dichloropalladium(II) (234 mg, 0.286 mmol), phenylboronic acid (907 mg, 7.44 mmol) and 5-bromo-4-fluoro-2-methylaniline (1.17 g, 5.72 mmol) was dissolved in DME (10 ml). Aqueous sodium carbonate 2M (5.7 ml, 11 mmol) was added and the mixture was subjected to microwave irradiation for 2 h at 120°C. After removal of DME under reduced pressure, the residue was taken up in ethyl acetate (15 ml) and washed with brine (2x10 ml). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV to give 6-fluoro-4-methyl-[1,1'-biphenyl]-3-amine (812 mg, yield = 70%) in in the form of dark oil. MS (ESI+) m/z: 202.1 [M+H] ⁺ .

Starting with 6-fluoro-4-methyl-[1,1'-biphenyl]-3-amine (751 mg, 3.73 mmol), 3-bromo-M-(6-fluoro-4-methyl[1,1'- biphenyl]-3-yl)benzenesulfonamide was synthesized as described in procedure B to give a mixture of mono- and di-sulfonamide which, by hydrolysis with aqueous NaOH/dioxane, completely converted to the monosulfonamide (1.41 g, yield = 89%). MS (ESI ⁺ ) m/z: 442.0 [M+Na] ⁺ . This sulfonamide (1.03 g, 2.46 mmol) was then combined with hepta-6-noic acid (0.63 ml, 4.92 mmol) as described in procedure B to give 7-(3-(N-(6-fluoro-4-methyl- [1,1'-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid (290 mg, yield = 25%). MS (ESI ⁺ ) m/z: 466.2 [M+H] ⁺ .

Compound 9 was then obtained by reduction of an alkyne derivative (290 mg, 0.623 mmol) as described for compound 2 as a white solid (235 mg, yield = 80%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.20-1.33 (m, 4H) 1.47-1.59 (m, 4H) 2.01 (s, 3H) 2.31 (t, J=7.34 Hz, 2H) 2.58 ( t, J=7.56 Hz, 2H) 6.88 (d, J=10.96 Hz, 1H) 7.00 (s, 1H) 7.27 (d, J=7.45 Hz, 1H) 7.32 - 7.43 (m, 7H) 7.51-7.60 (m, 2H) MS (ESI+) m/z: 470.2 [M+H] ⁺ .

Example 10 Synthesis of 7-(3-(N-(5-fluoro-3-methyl-[1,1'-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid (10).

Starting from 2-bromo-4-fluoro-6-methylaniline (360 mg, 1.76 mmol), 5-fluoro-3-methyl-[1,1'biphenyl]-2-amine (336 mg, yield = 94%) was synthesized by Suzuki reaction as described for compound 9. MS (ESI ⁺ ) m/z: 202.1 [M+H] ⁺ .

Starting with 5-fluoro-3-methyl-[1,1'-biphenyl]-2-amine (266 mg, 1.32 mmol), 3-bromo-M-(5-fluoro-3-methyl[1,1'- biphenyl]-2-yl)benzenesulfonamide was synthesized as described in procedure B to give a mixture of mono- and di-sulfonamide which was completely converted by hydrolysis with aqueous NaOH/dioxane to mono-sulfonamide (540 mg, yield = 97%). MS (ESI ⁺ ) m/z: 442.1 [M+Na] ⁺ .

This sulfonamide (540 mg, 1.28 mmol) was then combined with hepta-6-noic acid (0.33 mL, 2.57 mmol) as described in procedure B to give 7-(3-(N-(5-fluoro-3-methyl- [1,1'-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid (290 mg, yield = 41%). MS (ESI ⁺ ) m/z: 466.2 [M+H] ⁺ .

Compound 10 was then obtained by reduction of an alkyne derivative (250 mg, 0.537 mmol) as described for compound 2 as a white solid (75 mg, yield = 30%). 1Н NMR (300 MHz, (chloroform-d): δ ppm 1.24-1.42 (m, 4Н) 1.51 (tt, J=7.34, 7.34 Hz, 2Н) 1.64 (tt, J=7.23, 7.23 Hz, 2Н) 2.36 ( t, J=7.34 Hz, 2H) 2.48 (t, J=7.67 Hz, 2H) 2.52 (s, 3 H) 6.65 (s, 1H) 6.70 (dd, J=8.66, 2.96 Hz, 1H) 6.78 (d, J=6.58 Hz, 2H) 6.95-7.28 (m, 8 H) MS (ESI ⁺ ) m/z: 470.2 [M+H] ⁺ .

Example 11 Synthesis of 6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid (11).

Starting with 2,4,6-trimethylaniline (15 mg, 0.16 mmol), methyl 6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoate (20 mg, yield = 34%) was obtained as described in method A. MS (ESI ⁺ ) m/z: 404.4 [M+H] ⁺ .

Compound 11 was then obtained by hydrolysis of the ester derivative (20 mg, 0.053 mmol) as described for compound 1 as a beige solid (12 mg, yield = 61%). 1H NMR (300 MHz, DMSO-d) δ ppm 1.21-1.32 (m, 2H) 1.42-1.65 (m, 4H) 1.81-2.05 (s, 6H) 2.11-2.23 (m, 5H) 2.65-2.71 (m, 2Н) 6.84 (s, 2Н) 7.41 (s, 1Н) 7.52–7.61 (m, 3Н) 9.1 (br s, 1Н) 11.9 (br s, 1H). MS (ESI ⁺ ) m/z: 390.3 [M+H] ⁺ .

Example 12 Synthesis of 7-(3-(N-(3,5-dimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl)heptanoic acid (12).

Starting with 3,5-dimethyl-1H-pyrazol-4-amine (300 mg, 2.70 mmol) we got methyl 7-(3-(N-(3,5dimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl) heptanoate (380 mg, yield = 35%) as described in Method A. MS (ESI+) m/z: 394.2 [M+H] ⁺ . Compound 12 was then obtained by hydrolysis of the ester derivative (380 mg, 0.966 mmol) as described for compound 1 as a white solid (257 mg, yield = 70%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.30-1.45 (m, 4H) 1.52-1.71 (m, 4H) 2.14 (s, 6H) 2.31 (t, J=7.23 Hz, 2H) 2.66 (t , J=7.41 Hz, 2H) 7.02 (s, 1H) 7.37-7.44 (m, 2H) 7.50-7.66 (m, 2H) MS (ESI ⁺ ) m/z: 380.3 [M+H] ⁺ .

Example 13 Synthesis of 7-(3-(N-(2,4-dimethylthiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (13).

Starting with 2,4-dimethylthiazol-5-amine (250 mg, 1.95 mmol), methyl 7-(3-(N-(2,4-dimethylthiazol-5-yl)sulfamoyl)phenyl)heptanoate (372 mg, yield = 46%) as described in Method A. MS (ESI+) m/z: 411.2 [M+H] ⁺ .

Compound 13 was then obtained by hydrolysis of the ester derivative (372 mg, 0.907

- 10,040,041 mmol) as described for compound 1, as a white solid (257 mg, yield = 71%). 1H

NMR (300 MHz, (chloroform-d): δ ppm 1.28 -1.41 (m, 4H) 1.50 -1.72 (m, 4H) 2.06 (s, 3H) 2.27 (s, 3H) 2.34 (t, J=7.26 Hz, 2H) 2.71 (t, J=7.37 Hz, 2H) 6.94 (s, 1H) 7.12 - 7.31 (m, 2H) 7.48 - 7.56 (m, 2H) MS (ESI ⁺ ) m/z:

397.2 [M+H] ⁺ .

Example 14 Synthesis of 7-(3-(N-(4,5-dimethylthiazol-2-yl)sulfamoyl)phenyl)heptanoic acid (14).

Starting from 4,5-dimethylthiazol-2-amine (15 mg, 0.12 mmol), ethyl 7-(3-(N-(4,5-dimethylthiazol-2yl)sulfamoyl)phenyl)heptanoate (17 mg, Y = 35 %) as described in Method A. MS (ESI ⁺ ) m/z: 425.2 [M+H] ⁺ .

Compound 14 was then obtained by hydrolysis of the ester derivative (17 mg, 0.040 mmol) as described for compound 1 as a white solid (4.3 mg, yield = 27%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.05-1.43 (m, 4H) 1.53-1.72 (m, 4H) 2.13 (s, 6H) 2.30 (t, J=6.49 Hz, 2H) 2.68 (t , J=7.03 Hz, 2H) 7.06 (s, 1H) 7.30-7.37 (m, 2H) 7.68-7.73 (m, 2H) MS (ESI ⁺ ) m/z: 397.1 [M+H] ⁺ .

Example 15 Synthesis of 7-(3-(N-(4,5-dimethyloxazol-2-yl)sulfamoyl)phenyl)heptanoic acid (15).

Starting from 4,5-dimethyloxazol-2-amine (13.5 mg, 0.120 mmol), ethyl 7-(3-(N-(4,5-dimethyloxazol-2yl)sulfamoyl)phenyl)heptanoate (18 mg, yield = 37 %) as described in Method A. MS (ESI ⁺ ) m/z: 409.2 [M+H] ⁺ .

Compound 15 was then obtained by hydrolysis of the ester derivative (3 mg, 7 μmol) as described for compound 1 as an orange waxy solid (2 mg, yield = 71%). ¹ H NMR (300 MHz, chloroform-d) δ ppm 1.07-1.44 (m, 4H) 1.56-1.72 (m, 7H) 1.99 (s, 3H) 2.28 (t, J=6.76 Hz, 2H) 2.61 (t , J=6.94 Hz, 2Н) 6.97 (s, 1H) 7.28-7.34 (m, 2Н) 7.56-7.71 (m, 2Н). MS (ESI+) m/z: 381.2 [M+H] ⁺ .

Example 16 Synthesis of 7-(3-(N-(5-phenyl-1,2,4-thiadiazol-3-yl)sulfamoyl)phenyl)heptanoic acid (16).

Starting with 5-phenyl-1,2,4-thiadiazol-3-amine (17 mg, 0.094 mmol), methyl 7-(3-(H-(5-phenyl-1,2,4-thiadiazol-3-yl)sulfamoyl )phenyl)heptanoate was prepared (7.5 mg, yield = 17%) as described in Method A. MS (ESI ⁺ ) m/z: 460.2 [M+H] ⁺ .

Compound 16 was then obtained by hydrolysis of the ester derivative (2.5 mg, 5.4 µmol) as described for compound 1, as a white solid (2.3 mg, yield = 94%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.12 - 1.45 (m, 4H) 1.55-1.68 (m, 4H) 2.21 (t, J=7.01 Hz, 2H) 2.48 (t, J=6.90 Hz, 2 H) 7.03 (s, 1H) 7.39-7.70 (m, 5 H) 7.84-7.98 (m, 4 H) MS (ESI ⁺ ) m/z: 446.2 [M+H] ⁺ .

Example 17 Synthesis of 7-(3-(N-(3-methyl-1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (17).

Starting with 3-methyl-1,2,4-thiadiazol-5-amine (14 mg, 0.12 mmol), methyl 7-(3-(N-(3-methyl-1,2,4-thiadiazol-5-yl)sulfamoyl )phenyl)heptanoate was prepared (8.1 mg, yield = 16%) as described in Method A. MS (ESI ⁺ ) m/z: 398.2 [M+H] ⁺ . Compound 17 was then obtained by hydrolysis of the ester derivative (2.7 mg, 6.8 µmol) as described for Compound 1 as a yellow waxy solid (0.6 mg, yield = 23%). 1Н NMR (300 MHz, chloroform-d) δ ppm 1.10-1.46 (m, 4Н) 1.55-1.73 (m, 4Н) 2.11 (s, 3Н) 2.31 (t, J=6.91 Hz, 2Н) 2.60 (t, J =7.06 Hz, 2H) 6.88 (br s, 1H) 7.30 - 7.35 (m, 2H) 7.54 7.70 (m, 2H). MS (ESI ⁺ ) m/z: 384.2 [M+H] ⁺ .

Example 18 Synthesis of 7-(3-(N-(5-methyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)heptanoic acid (18).

Starting with 5-methyl-1,3,4-thiadiazol-2-amine (14 mg, 0.12 mmol), methyl 7-(3-(N-(5-methyl-1,3,4-thiadiazol-2-yl)sulfamoyl )phenyl)heptanoate was prepared (12 mg, yield = 25%) as described in Method A. MS (ESI ⁺ ) m/z: 398.2 [M+H] ⁺ . Compound 18 was then obtained by hydrolysis of the ester derivative (1.5 mg, 3.8 µmol) as described for compound 1 as a white solid (1.3 mg, yield = 90%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.11-1.49 (m, 4H) 1.56-1.74 (m, 4H) 2.28 (t, J=6.86 Hz, 2H) 2.53 (s, 3H) 2.62 ( t, J=7.00 Hz, 2H) 7.02 (s, 1H) 7.36-7.47 (m, 2H) 7.64-7.74 (m, 2H) MS (ESI ⁺ ) m/z: 384.1 [M+H] ⁺ .

Example 19 Synthesis of 7-(3-(N-(3,5-dimethylisoxazol-4-yl)sulfamoyl)phenyl)heptanoic acid (19).

Starting with 3,5-dimethylisoxazol-4-amine (14 mg, 0.12 mmol), methyl 7-(3-(N-(3,5-dimethylisoxazol4-yl)sulfamoyl)phenyl)heptanoate was obtained (11 mg, yield = 22 %) according to method A. MS (ESI ⁺ ) m/z: 395.2 [M+H] ⁺ .

Compound 19 was then obtained by hydrolysis of the ester derivative (11 mg, 0.027 mmol) as described for compound 1 as a yellow waxy solid (4.0 mg, yield = 39%). 1Н NMR (300 MHz, chloroform-d) δ ppm 1.24-1.46 (m, 4Н) 1.55-1.71 (m, 4Н) 1.82 (s, 3H) 2.06 (s, 3Н) 2.36 (t, J=7.03 Hz, 3H) 2.67 (t, J=7.58 Hz, 3H) 7.37 - 7.45 (m, 2H) 7.48-7.53 (m, 1H) 7.58 (s, 1H). MS (ESI ⁺ ) m/z: 381.2 [M+H] ⁺ .

Example 20 Synthesis of 7-(3-(H-(5-methyl-4H-1,2,4-triazol-3-yl)sulfamoyl)phenyl)heptanoic acid (20).

Starting with 5-methyl-4H-1,2,4-triazol-3-amine (50 mg, 0.509 mmol), methyl 7-(3-(H-(5-methyl-4H-1,2,4-11 040041 Triazol-3-yl)sulfamoyl)phenyl)heptanoate was prepared (77mg, yield = 40%) as described in Method A.

MS (ESI+) m/z: 381.2 [M+H] ⁺ .

Compound 20 was then obtained by hydrolysis of the ester derivative (50 mg, 0.131 mmol) as described for compound 1 as a white solid (17 mg, yield = 35%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.16 - 1.42 (m, 4H) 1.54 - 1.72 (m, 4H) 2.25 (s, 3H) 2.30 (t, J=6.88 Hz, 2H) 2.58 (t , J=7.02 Hz, 2H) 7.36 - 7.48 (m, 3H) 7.66 (s, 1H) MS (ESI+) m/z: 367.1 [M+H] ⁺ .

Example 21 Synthesis of 7-(3-(M-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid (21).

Starting with 3,5-dimethyl-4H-1,2,4-triazol-4-amine (40 mg, 0.357 mmol), methyl 7-(3-(N-(3,5-dimethyl4H-1,2,4 -triazol-4-yl)sulfamoyl)phenyl)heptanoate was prepared (60 mg, yield = 43%) as described in Method A. MS (ESI ⁺ ) m/z. 395.2 [M+H] ⁺ .

Compound 21 was then obtained by hydrolysis of the ester derivative (60 mg, 0.152 mmol) as described for compound 1 as a white solid (23 mg, yield = 40%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.20-1.45 (m, 4H) 1.56 - 1.72 (m, 4H) 2.44 (s, 6H) 2.32 (t, J=6.90 Hz, 2H) 2.59 (t , J=7.06 Hz, 2H) 7.35-7.43 (m, 2H) 7.73-7.81 (m, 2H) MS (ESI ⁺ ) m/z 381.1 [M+H] ⁺ .

Example 22 Synthesis of 7-(3-(N-(3-phenylisothiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (22).

Starting with 3-phenylisothiazol-5-amine (22 mg, 0.12 mmol), methyl 7-(3-(N-(3-phenylisothiazol-5yl)sulfamoyl)phenyl)heptanoate was obtained (11 mg, yield = 20%) as described in method A. MS (ESI ⁺ ) m/z. 459.2 [M+H] ⁺ .

Compound 22 was then obtained by hydrolysis of the ester derivative (11 mg, 0.025 mmol) as described for compound 1 as a beige solid (6.0 mg, yield = 53%). ¹ H NMR (300 MHz, (chloroform-d): δ ppm 1.15-1.43 (m, 4H) 1.49-1.73 (m, 4H) 2.34 (t, J=7.03 Hz, 2H) 2.65 (t, J=7.03 Hz , 2H) 7.08 (s, 1H) 7.35 - 7.42 (m, 5 H) 7.68-7.88 (m, 4 H) MS (ESI ⁺ ) m/z 445.2 [M+H] ⁺ .

Example 23 Synthesis of 7-{3-[(5-hydroxynaphthalen-1-yl)sulfamoyl]phenyl}heptanoic acid (23).

Starting with 5-aminonaphthalen-1-ol (24 mg, 0.15 mmol), methyl 7-{3-[(5-hydroxynaphthalen-1-yl)sulfamoyl]phenyl}heptanoatemethyl was prepared (34 mg, yield = 51%) as described in method A. MS (ESI ⁺ ) m/z: 442.3 [M+H] ⁺ . Compound 23 was then obtained by hydrolysis of the ester derivative (3.2 mg, 8.4 µmol) as described for compound 1 as a yellow waxy solid (2.2 mg, yield = 71%). 1Н NMR (300 MHz, methanol-d) δ ppm 1.11-1.20(m, 2Н) 1.22-1.40 (m, 5Н) 1.55-1.78 (m, 2Н) 2.21-2.41 (m, 2Н) 2.43-2.56 (m, 2H) 6.73-6.74 (m, 1H) 7.04-7.09 (m, 1H) 7.19-7.22 (m, 1H) 7.28-7.34 (m, 5H) 7.53-7.54 (m, 1H) 8.09-8.11 (m, 1H) . MS (ESI ⁺ ) m/z: 428.4 [M+H] ⁺ .

Example 24 Synthesis of 7-{3-[(4-fluoro-2,6-dimethylbenzoyl)sulfamoyl]phenyl}heptanoic acid (24).

Starting with 4-fluoro-2,6-dimethylbenzamide (18 mg, 0.11 mmol), methyl 7-{3-[(4-fluoro-2,6-dimethylbenzoyl)sulfamoyl]phenyl}heptanoate was obtained (13 mg, yield = 26 %) as described in Method A, the pyridine being replaced with sodium hydride and the reaction carried out in dry DMF. MS (ESI+) m/z: 450.4 [M+H] ⁺ . Compound 24 was then obtained by hydrolysis of the ester derivative (3.9 mg, 8.6 µmol) as described for compound 1 as a yellow waxy solid (3.3 mg, yield = 88%). 1H-NMR (chloroform-d): δ 1.20-1.43 (m, 4H) 1.53-1.57 (m, 4H) 1.90 (s, 6H) 2.34 (t, J=7.03 Hz, 2H) 2.54 (t, J=7.08 Hz, 2H) 6.21 (br s, 1H) 6.67 (d, J=9.2 Hz, 2H) 7.33 -7.41 (m, 2H) 7.47 - 7.54 (m, 2H). MS (ESI ⁺ ) m/z: 436.5 [M+Na] ⁺ .

Example 25 Synthesis of 7-{4-[(4-fluoro-2,6-dimethylphenyl)sulfamoyl]phenyl}heptanoic acid (25).

Starting from 4-fluoro-2,6-dimethylaniline (74.2 mg, 0.533 mmol), methyl 7-{4-[(4-fluoro-2,6-dimethylphenyl)sulfamoyl]phenyl}heptanoate was obtained (81 mg, yield = 36 %) as described in Method A, but starting with methyl 7-[4-(chlorosulfonyl)phenyl]heptanoate. MS (ESI ⁺ ) m/z: 422.4 [M+H] ⁺ .

Compound 25 was then obtained by hydrolysis of the ester derivative as described for Compound 1 as a brown waxy solid (71 mg, yield = 91%). 1HNMR (chloroform-d): δ 1.21-1.45 (m, 4H) 1.50-1.59 (m, 4H) 1.98 (s, 6H) 2.37 (t, J=7.02 Hz, 2H) 2.63 (t, J=7.11 Hz, 2H) 6.25 (br s, 1H) 6.69 (d, J=9.2 Hz, 2H) 7.32-7.38 (m, 2H) 7.45-7.54 (m, 2H). MS (ESI ⁺ ) m/z: 408.3 [M+H] ⁺ .

Example 26 Synthesis of 7-(3-(M-(2-ethyl-2H-1,2,3-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid (26).

Starting with 2-ethyl-2H-1,2,3-triazole-4-amine (17 mg, 0.15 mmol), methyl 7-(3-(N-(2-ethyl-2H-1,2,3triazole-4 -yl)sulfamoyl)phenyl)heptanoate was obtained (16 mg, yield = 26%) as described in method A. MS (ESI ⁺ ) m/z: 395.2 [M+H] ⁺ .

Compound 26 was then obtained by hydrolysis of the ester derivative (16 mg, 0.041 mmol) as described for compound 1 as a beige solid (12 mg, yield = 77%). 1H NMR (400 MHz, acetone-d ₆ ) δ ppm 1.29 - 1.42 (m, 7H) 1.49-1.65 (m, 4H) 2.28 (t, J=7.31 Hz, 2H) 2.69 (t, J=7.63 Hz, 2H ) 4.25 (q, J=7.31 Hz, 2H) 7.40 - 7.51 (m, 3H) 7.58-7.69 (m, 2H). MS (ESI ⁺ ) m/z: 381.2 [M+H] ⁺ .

Example 27 Synthesis of 7-(3-(N-(2-methyl-2H-tetrazol-5-yl)sulfamoyl)phenyl)heptanoic acid (27).

Starting with 2-methyl-2H-tetrazol-5-amine (15 mg, 0.15 mmol), methyl 7-(3-(M-(2-methyl-2H-tetrazol-5yl)sulfamoyl)phenyl)heptanoate (10 mg , yield = 17%) as described in Method A. MS (ESI ⁺ )

- 12040041 m/z: 382.2 [M+H]+.

Compound 27 was then obtained by hydrolysis of the ester derivative (3.6 mg, 9.4 µmol) as described for compound 1 as a white solid (2.0 mg, yield = 58%). 1H

NMR (400 MHz, acetone-d ₆ ) δ pmm 1.33 - 1.44 (m, 4H) 1.49 -1.69 (m, 4H) 2.28 (t, J=6.68 Hz, 2H) 2.81 (t,

J=7.14 Hz, 2H) 3.58 (s, 3H) 7.03 (s, 1H) 7.48 - 7.53 (m, 2H) 7.77 - 7.96 (m, 1H). MS (ESI+) m/z: 368.2 [M+H] ⁺ .

Example 28 Synthesis of 7-(3-(N-(4-methyl-4,5-dihydrooxazol-2-yl)sulfamoyl)phenyl)heptanoic acid (28).

Starting with 4-methyl-4,5-dihydrooxazol-2-amine (15 mg, 0.15 mmol), methyl 7-(3-(N-(4-methyl-4,5dihydrooxazol-2-yl)sulfamoyl)phenyl)heptanoate received (9.5 mg, yield = 16%) as described in method A. MS (ESI+) m/z: 383.2 [M+n] ⁺ .

Compound 28 was then obtained by hydrolysis of the ester derivative (3.6 mg, 9.4 µmol) as described for compound 1 as a white solid (3.0 mg, yield = 87%). 1Н NMR (400 MHz, acetone-d ₆ ) δ pmm 1.23 - 1.43 (m, 5Н) 1.53 -1.69 (m, 4Н) 2.28 (t, J=7.30 Hz, 2Н) 2.70 (t, J=9.50 Hz, 2Н ) 3.98 - 4.12 (m, 1H) 4.24 - 4.37 (m, 1H) 4.57 - 4.66 (m, 1H) 7.43 (m, 1H) 7.56 - 7.77 (m, 2H) 8.18 (br s, 1H). MS (ESI+) m/z: 369.2 [M+H] ⁺ .

Example 29 Synthesis of 7-(3-(N-(3a,4,5,6,7,7α-hexahydro-1H-benzo[d]imudαzol-2-yl)sulfαmoyl)phenyl)heptanoic acid (29).

Starting with 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2-amine (18 mg, 0.13 mmol), 2-ethylhexyl 7-(3-(N-(3a,4 ,5,6,7,7α-Hexαhydro-1H-benzo[d]umidαzol-2-yl)sulfαmoyl)phenyl)heptanoate was prepared (31 mg, yield = 45%) as described in Method A. MS (ESI+) m /z: 520.4 [M+H] ⁺ .

Compound 29 was then obtained by hydrolysis of the ester derivative (4.0 mg, 7.7 µmol) as described for compound 1 as a white solid (3.0 mg, yield = 96%). 1Н NMR (400 MHz, solvent) δ ppm 1.56 - 1.71 (m, 4Н) 1.74 - 1.84 (m, 6Н) 2.01 - 2.16 (m, 6Н) 2.26 (t, J=7.02 Hz, 2Н) 2.70 (t, J =6.82 Hz, 2H) 3.16 (br d, J=8.27 Hz, 1H) 3.57 - 3.64 (m, 1H) 7.02 - 7.06 (m, 1H) 7.12 (br s, 1H) 7.38 7.41 (m, 1H) 7.63 - 7.72 (m, 2H). MS (ESI+) m/z: 408.2 [M+H] ⁺ .

Example 30 Synthesis of 7-(3-(N-(3-phenylisothiazol-4-yl)sulfamoyl)phenyl)heptanoic acid (30).

Starting from 3-phenylisothiazol-4-amine (23 mg, 0.13 mmol), 2-ethylhexyl 7-(3-(N(3-phenylisothiazol4-yl)sulfamoyl)phenyl)heptanoate was obtained (23 mg, yield = 31%) as described in Method A. MS (ESI+) m/z: 557.3 [M+H] ⁺ . Compound 30 was then obtained by hydrolysis of the ester derivative (3.0 mg, 5.4 µmol) as described for compound 1 as a yellow solid (2.0 mg, yield = 84%). ¹ H NMR (300 MHz, (chloroform-d): δ ppm 1.16-1.43 (m, 4H) 1.55-1.71 (m, 4H) 2.22 (t, J=7.00 Hz, 2H) 2.46 (t, J=6.69 Hz , 2H) 7.00 (s, 1H) 7.39 - 7.70 (m, 6H) 7.84-7.98 (m, 4H) MS (ESI+) m/z: 445.2 [M+H] ⁺ .

Example 31 Synthesis of 7-(3-(N-(4-hydroxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (31).

Compound 8 (11 mg, 0.026 mmol) was dissolved in dry DCM (0.5 ml). The mixture was cooled to 0° C. and boron tribromide 1M in DCM (0.072 ml, 0.072 mmol) was added.

The mixture was allowed to warm to room temperature and stirred for 5 hours. Water (1 ml) was added and the mixture was stirred for 10 minutes.

The organic layer was concentrated under reduced pressure, and the residue was purified on silica gel (DCM/MeOH 95/5) to obtain compound 31 as a yellow liquid (2.6 mg, yield = 24%). 1Н NMR (300 MHz, chloroform-d) δ ppm 1.16-1.70 (m, 8Н) 1.85 (s, 6Н) 2.38 (t, J=7.03 Hz, 2Н) 2.57 (t, J=7.46 Hz, 2Н) 6.03 (br s, 1H) 6.48 (s, 2H) 7.30-7.46 (m, 3H) 7.52-7.76 (m, 1H). MS (ESI+) m/z: 406.2 [M+H] ⁺ .

Example 32 Synthesis of 7-(3-(N-(3,5-dimethyl-[1,1'-biphenyl]-4-yl)sulfamoyl)phenyl)heptanoic acid (32).

Starting from 4-bromo-2,6-dimethylaniline (1.0 g, 5.0 mmol), 3,5-dimethyl-[1,1'-biphenyl]-4-amine (354 mg, yield = 36%) was synthesized by the Suzuki reaction , as described for compound 9. MS (ESI+) m/z: 198.2 [M+H] ⁺ .

Starting with 3,5-dimethyl-[1,1'-biphenyl]-4-amine (30.9 mg, 0.157 mmol), methyl 7-(3-(Na(3,5-dimethyl[1,1'-biphenyl] -4-yl)sulfamoyl)phenyl)heptanoate was prepared (13 mg, yield = 17%) as described in Method A. MS (ESI+) m/z: 480.2 [M+H] ⁺ .

Compound 32 was then obtained by hydrolysis of the ester derivative (13 mg, 0.027 mmol) as described for compound 1 as a brown oil (11 mg, yield = 87%). 1Н NMR (300 MHz, chloroform-d) δ ppm 1.22-1.36 (m, 4Н) 1.49-1.69 (m, 4Н) 2.08 (s, 6Н) 2.29 (t, J=7.30 Hz, 2Н) 2.60 (t, J =7.30 Hz, 2H) 6.32 (br s, 1H) 7.22-7.27 (m, 2H) 7.31-7.46 (m, 5H) 7.48 - 7.62 (m, 4H). MS (ESI+) m/z: 488.3 [M+Na]+.

Example 33 Synthesis of 7-(3-(N-(2,6-dimethyl-4-phenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33).

4-Bromo-2,6-dimethylaniline (500 mg, 2.50 mmol), phenol (282 mg, 3.00 mmol), copper (I) iodide (47.6 mg, 0.250 mmol), 1-butyl-1H-imidazole (0.164 ml, 1.25 mmol) and potassium carbonate (691 mg, 5.00 mmol) were suspended in dry toluene (2.5 ml). The mixture was irradiated with microwaves for 2 h at

- 13 040041

150°C. After removing the solvent under reduced pressure, the residue was taken up in ethyl acetate (15 ml) and washed with brine (2x10 ml). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV to give

2,6-dimethyl-4-phenoxyaniline as a brown solid (280 mg, yield =

52%). MS (ESI+) m/z: 214.1 [M+H] ⁺ .

Starting from 2,6-dimethyl-4-phenoxyaniline (33.4 mg, 0.157 mmol), methyl 7-(3-(M-(2,6-dimethyl-4phenoxyphenyl)sulfamoyl)phenyl)heptanoate (17 mg, yield = 22 %) as described in Method A. MS (ESI ⁺ ) m/z: 518.2 [M+Na] ⁺ . Compound 33 was then obtained by hydrolysis of the ester derivative (17 mg, 0.034 mmol) as described for compound 1 as a brown oil (16 mg, yield = 97%). 1H NMR (300 MHz, chloroform-d) δ ppm 1.23-1.37 (m, 4H) 1.52-1.68 (m, 4H) 1.97 (s, 6H) 2.33 (t, J=7.30 Hz, 2H) 2.63 (t, J =7.30 Hz, 2H) 6.21 (br s, 1H) 6.63 (s, 2H) 6.99 (d, J=8.12 Hz, 2H) 7.05-7.19 (m, 1H) 7.29 -7.43 (m, 4H) 7.45 - 7.60 ( m, 2H). MS (ESI ⁺ ) m/z: 504.2 [M+Na] ⁺ .

Example 34 Synthesis of 7-(3-(M-(4-(benzyloxy)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (34).

4-Amino-3,5-dimethylphenol (400 mg, 2.92 mmol) and di-tert-butyl bicarbonate were dissolved in acetone (3 ml) and the mixture was stirred for 22 hours. After removing the solvent under reduced pressure, hexane ( 10 ml). The mixture was stirred for 70 h, then filtered. The solid residue was purified on silica gel (hexane/ethyl acetate 9/1) to give tert-butyl (4-hydroxy-2,6dimethylphenyl)carbamate as a white solid (433 mg, yield = 63%). MS (ESI ⁺ ) m/z: 260.1 [M+Na] ⁺ . Tert-butyl (4-hydroxy-2,6-dimethylphenyl)carbamate (380 mg, 1.60 mmol) was dissolved in dry N,N-dimethylformamide (10 ml). (Bromomethyl)benzene (0.381 ml, 3.20 mmol), potassium carbonate (885 mg, 6.41 mmol) and potassium iodide (798 mg, 4.80 mmol) were added and the mixture was irradiated with microwaves for 2 h at 100°C. Ethyl acetate (20 ml) was added and the mixture was washed with brine (2x10 ml). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV to give tert-butyl (4-(benzyloxy)-2,6dimethylphenyl)carbamate (353 mg, yield = 67%). MS (ESI ⁺ ) m/z: 350.2 [M+Na] ⁺ . tert-Butyl (4(benzyloxy)-2,6-dimethylphenyl)carbamate (353 mg, 1.08 mmol) was dissolved in dry dichloromethane (2 ml). Hydrogen chloride 4M in dioxane (0.54 ml, 2.16 mmol) was added and the mixture was stirred for 12 h.

The solvent was removed under reduced pressure to give 4-(benzyloxy)-2,6dimethylaniline, hydrochloride salt (285 mg, yield=quant) as a beige solid. MS (ESI ⁺ ) m/z: 228.2 [M+H] ⁺ . Starting with 4-(benzyloxy)-2,6-dimethylaniline, hydrochloride salt (41.4 mg, 0.157 mmol), methyl 7-(3-(N-(4-(benzyloxy)-2,6-dimethylphenyl)sulfamoyl)phenyl) heptanoate was prepared (27 mg, yield = 34%) as described in Method A. MS (ESI ⁺ ) m/z: 532.3 [M+Na] ⁺ .

Compound 34 was then obtained by hydrolysis of the ester derivative (27 mg, 0.053 mmol) as described for compound 1 as a beige solid (23 mg, yield = 87%). 1H NMR (300 MHz, (chloroform-d): δ ppm 1.24 - 1.38 (m, 4H) 1.50 - 1.70 (m, 4H) 1.97 (s, 6H) 2.33 (t, J=7.30 Hz, 2H) 2.61 (t , J=7.58 Hz, 2Н) 5.00 (s, 2Н) 6.19 (br s, 1H) 6.62 (s, 2Н) 7.31 - 7.45 (m, 7H) 7.50 -7.58 (m, 2Н) MS (ESI ⁺ ) m /z: 496.2 [M+H] ⁺ .

Example 35 Synthesis of 7-(3-(N-(2,6-dimethyl-4-(3(methylsulfonyl)propoxy)phenyl)sulfamoyl)phenyl)heptanoic acid (35).

4-Methylbenzene-1-sulfonyl chloride (759 mg, 3.98 mmol), 3-(methylsulfonyl)propan-1-ol (500 mg, 3.62 mmol) and triethylamine (0.555 ml, 3.98 mmol) were dissolved in dry dichloromethane ( 5 ml) under nitrogen atmosphere and the mixture was stirred for 12 hours. The solvent was removed under reduced pressure and the residue was purified by semi-preparative HPLC-UV to give 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (881 mg, yield = 83%) in form of a white solid. MS (ESI ⁺ ) m/z: 293.1 [M+H] ⁺ .

tert-Butyl (4-hydroxy-2,6-dimethiphenyl)carbamate (which was synthesized during the preparation of compound 34) (269 mg, 1.13 mmol), 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (398 mg, 1.36 mmol) and carbonate potassium (188 mg, 1.36 mmol) was dissolved in dry N,N-dimethylformamide (2.5 ml) and the mixture was stirred at 80°C under nitrogen atmosphere for 12 h. Ethyl acetate (20 ml) was added and the mixture was washed with brine (2x10 ml). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV to give tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375 mg, yield = 93%) as a white solid. MS (ESI ⁺ ) m/z: 380.2 [M+Na] ⁺ .

Starting with tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375mg, 1.05mmol), 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline , hydrochloride salt (309 mg, yield = quant.) was obtained as described in the synthesis of Compound 34. MS (ESI ⁺ ) m/z: 258.1 [M+H] ⁺ .

Starting with 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline, hydrochloride salt (46.1 mg, 0.157 mmol), methyl 7-(3-(N-(2,6-dimethyl-4-(3 -(methylsulfonyl)propoxy)phenyl)sulfamoyl)phenyl)heptanoate was prepared (33 mg, yield = 39%) as described in Method A. MS (ESI ⁺ ) m/z: 562.3 [M+Na] ⁺ . Compound 35 was then obtained by hydrolysis of the ester derivative (20 mg, 0.046 mmol) as

- 14 040041 described for compound 1, as a white solid (23 mg, yield = 83%). 1H NMR (300

MHz, (chloroform-d): δ ppm 1.24-1.43 (m, 4H) 1.51-1.67 (m, 4H) 1.96 (s, 6H) 2.26-2.41 (m, 4H) 2.61 (t,

J=7.58 Hz, 2H) 2.97 (s, 3H) 3.22-3.31 (m, 2H) 4.04 (t, J=5.68 Hz, 2H) 6.32 (br s, 1H) 6.52 (s, 2H) 7.33-7.41 (m ,

2Н) 7.48-7.58 (m, 2Н) 9.36 (br s, 2Н). MS (ESI ⁺ ) m/z: 526.2 [M+H] ⁺ .

Example 36 GPR120/40 activation: in vitro Ca ²⁺ mobilization.

GPR120/40 activation by all compounds was determined by measuring changes in intracellular calcium levels using a Ca ²⁺ sensitive fluorescent dye.

Experiments were performed using CHO-k1 k-cells stably expressing human GPR120 or GPR40. Cells were plated at 10,000 cells/plate in 384-plates in complete medium and grown overnight at 37° C., 5% CO ₂ . 24 hours after seeding, the cell culture media were removed and the cells were loaded with the Ca ²⁺ fluorescent indicator (Fluo-8 NW dye in Tyrode's buffer). The cell plates loaded with dye were incubated for 1 h at room temperature under a yellow sodium lamp.

Cells were treated with test compounds and controls at 10, 30 and 60 µm. The kinetic response was recorded over a 7 min time interval (using the FLIPRTETRA system). Then, a second introduction of 3x concentrated reference agonist into the cells at ~EC ₅₀ was carried out and the emitted fluorescence signal was measured in an additional time interval of 3 min. Agonist action is expressed as percent activation, with 100% activation as the result at which the response magnitude of the test wells reaches a level identical to the stimulus control (APK of the reference agonist EC ₁₀₀ ). 0% activation is the result at which the reaction magnitude of the test wells reaches a level identical to the neutral control (assay buffer) in the AGO_KRV response magnitude (agonist kinetic response magnitude). The results obtained for each of the compounds are shown in table. 1. Example 37 GPR120/40 activation: in vitro secretion of GLP-1 2x105 STC-1 cells were plated in a 12-plate and treated with the selected compounds 24 hours later. 1x10 ⁶ NCI-H716 cells were differentiated on a matrigel-coated 12-plate and processed 48 hours later. On the day of the experiment, the wells were washed once with 1 ml PBS and the cells were stimulated with 0.5 ml serum, IM phenol red) containing 30 µm of selected compounds in STC1 and 100 µm in differentiated NCIH716 for 30 minutes. DMSO was used as a negative control, α-linolenic acid (ALA) (an endogenous agonist) as a positive control. After stimulation, the supernatants were collected, centrifuged at 4000 rpm for 4' at 4°C, and used for GLP-1 detection by ELISA.

Arylsulfonamide compounds were tested on STC1 cells and the results are summarized in table. 1.

The most active compounds, 1, 2, 3, 4, 6, 7, 9, 10, 11 and 33 showed a high agonistic effect on GPR120 and GPR40 (expressed as AC ₅₀ value in the calcium mobilization test) in the low micromolar range. Also, the same compounds were shown to be effective in GLP1 secretion in both STC1 (mouse) and NCI-H716 (human) enteroendocrine cells, which confirms the potential of using these compounds for further characterization.

- 15 040041

Table 1

ex θΡ Structure Chemical name Ca ²⁺ hGPR120 Ca ²⁺ hGPR40 GLP-1 release DRIVING STC-1 * GSP-1 RELEASE OF WAITING NCI' 1 ABOUT AND_ 7-(3-(N-(4-φτορ-2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 5.24 µm AC50= 140 µm 1.87±0.5 1.08±0.10 2 Q. ^Z ' ^T Ho O U O 7-(3-(14-(2,4,6trimethylbenzyl)sulfa moyl)phenyl)heptanoic acid AC50= 7.09 µm AC50= 11.2 µm 3.2±0.47 2.1±0.52 3 a O X/A °' ^Z ' ^T W ^- 7-(3-(M-(4-isopropyl-2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 1.98 µm AC50= 12.9 µm 2.7±0.31 2.5±0.11 4 U 7-(3-(N-(4-χπορ-2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 4.36 µm AC50= 41.3 µm 4.1±0.54 1.92±0.57 5 'VA— _£ 7-(3-(N-(4- (dimethylamino)-2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 7.9 µm AC50= 10.4 µm 4.0±0.27 1 92±0.14 6 X ^t ,o' ° 7-(3-(N-(2,6-dimethyl l-4(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid AC50= 6 µm AC50= 11.7 µm 4.2±0.45 2.54±0.52 7 XX gr ί 7-(3-(N-(4-bromo-2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 5.72 µm AC50= 19.8 µm 1.8±0.24 19±0.15 8 XXZAA'— T A An 7-(3-(M-(4-methoxy-2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 11.7 µm AC50= 4.7 µm 1.7±0.12 2.1±0.08 9 Ύ°-- _£ 7-(3-(M-(6-fluoro-4-methyl[1,1'-biphenyl]-3yl)sulfamoyl)phenyl)geptanoic acid AC50= 11.2 µm AC50= 8.9 µm 14.5±1.2 4 6.23±1.12 10 θ—X X ° A 7-(3-(M-(5-fluoro-3-methyl[1,1'-biphenyl]-2yl)sulfamoyl)phenyl)geptanoic acid AC50= 16.5 µm AC50= 12.8 µm 4.74±1.5 2.46±0.48 eleven ¹ H 6-{3-[(2,4,6trimethylphenyl)sulfa moyl]phenyl}hexanoic acid AC50= 6.2 µm Inactive 1 71±0.2 1 1.87±0.27 12 — ^t % o ^t o 7-(3-(M-(3,5-dimethyl-1Hpyrazol-4yl)sulfamoyl)phenyl)g eptanoic acid AC50= 13.1 µm AC50= 10.7 µm 1.04±0.3 2 1.41±0.36 13 L o ¹ o 7-(3-(N-(2,4dimethylthiazol-5yl)sulfamoyl)phenyl)geptanoic acid AC50= 15.2 µm AC50= 23.9 µm 1 13±0.1 5 1.03±0.17 14 A. \£A.^ L< x 7-(3-(N-(4,5- dimethylthiazol-2yl)sulfamoyl)phenyl)geptanoic acid AC50= 17.4 µm AC50= 20.8 µm 1.37±0.1 1 1.81±0.67 15 7-(3-(N-(4,5dimethyloxazol-2yl)sulfamoyl)phenyl)geptanoic acid AC50= 24.1 µm AC50= 27.5 µm 1.19±0.8 9 1 80±0.91 15 0¾¾--% 7-(3-(M-(5-phenyl-1,2,4thiadiazol-3yl)sulfamoyl)phenyl)geptanoic acid AC50= 25.9 µm AC50= 17.2 µm 1.31±0.3 2 1 69±0.14 17 0°° /L A L-T 7-(3-(M-(3-methyl-1,2,4thiadiazol-5yl)sulfamoyl)phenyl)geptanoic acid AC50= 22.3 µm AC50= 13.9 µm 1.90±0.5 1 2.19±1.22 18 S O O A nA II ut 7-(3-(M-(5-methyl-1,3,4thiadiazol-2yl)sulfamoyl)phenyl)geptanoic acid AC50= 27.8 µm AC50= 22.4 µm 1.98±0.3 7 1.25±0.80 19 7-(3-(N-(3,5- dimethylisoxazol-4yl)sulfamoyl)phenyl)geptanoic acid AC50= 17.6 µm AC50= 12.1 µm 2.57±0.5 6 2.24±0.39 20 n "Ji Ϊ 7-(3-(M-(5-methyl-4H- 1,2,4-triazole-Zyl)sulfamoyl)phenyl)geptanoic acid AC50= 6.5 µm AC50= 8.2 µm 3.36±0.3 7 3.31±0.28 21 A- /” ^T 7% O / ° from t 7-(3-(N-(3,5-dimethy l-4H1,2,4-triazol-4yl)sulfamoyl)phenyl)geptanoic acid AC50= 17.0 µm AC50= 7.9 µm 2.23±0.9 8 2.57±0.91 22 n S A/ ? ^NpT 7-(3-(N-(3phenylisothiazol-5yl)sulfamoyl)phenyl)geptanoic acid AC50= 10.2 µm AC50= 11.7 µm 3.13±1.2 6 3.71±0.67 23 o M _o o 0^5 7-{3-[(5hydroxynaphthalen-1 yl)sulfamoyl]phenyl}g eptanoic acid AC50= 7.1 µm AC50= 8.2 µm 4.34±0.5 1 4.69±0.41 24 7-{3-[(4-fluoro-2,6dimethylbenzoyl)sulfa moyl]phenyl}heptanoic acid AC50= 5.9 µm AC50= 13.3 µm 4.19±0.7 2 5.01±0.99 25 O YY ° ΛΥ kA A o 7-{4-[(4-fluoro-2,6dimethylphenyl)sulfam oil]phenyl}heptanoic acid AC50= 4.3 µm AC50= 6.1 µm 4.1±0.78 3.2±0.31

- 16 040041

26 7-(3-(M-(2-ethyl-2H-1,2,3triazol-4yl)sulfamoyl)phenyl)geptanoic acid AC50= 18.9 µm AC50= 20.1 µm 1.82+0.4 1 2.81+0.72 27 I 7-(3-(M-(2-methyl-2Htetrazol-5yl)sulfamoyl)phenyl)geptanoic acid AC50= 10.1 µm AC50= 10.7 µm 1.99+0.5 1 2.89+0.55 28 ¹ ο 7-(3-(M-(4-methyl-4,5dihydrooxazol-2yl)sulfamoyl)phenyl)geptanoic acid AC50= 16.1 µm AC50= 7.1 µm 3.64+0.4 3 3.88+1.96 29 Ο Η ΛΑ 7-(3-(N-(3a,4,5,6,7,7ahexahydro-1Hbenzo[d]imidazol2yl)sulfamoyl)phenyl)heptanoic acid AC50= 12.4 µm AC50= 8.4 µm 1.12+0.40 2.89+0.81 thirty ^τ -Αο ΛΑ 0 τ 7-(3-(N-(3phenylisothiazol-4yl)sulfamoyl)phenyl)geptanoic acid AC50= 37.1 µm AC50= 31.2 µm 2.94+1.1 2 2.13+1.83 31 7-(3-(M-(4-hydroxy-2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 9.3 µm AC50= 3.2 µm 3.55+0.8 7 3.70+0.56 32 η τΎ* Αη 7-(3-(M-(3,5-dimethyl[1,1'-biphenyl]-4yl)sulfamoyl)phenyl)geptanoic acid AC50= 11.1 µm AC50= 23.7 µm 3.67+0.90 4.51+0.59 33 % η Τ ή * ^ό 7-(3-(M-(2,6-dimethyl-4phenoxyphenyl)sulfam oil)phenyl)heptanoic acid AC50= 18 µm Inactive 3.0+1.82 1.58+1.27 34 7-(3-(M-(4-(benzyloxy)- 2,6dimethylphenyl)sulfam oil)phenyl)heptanoic acid AC50= 7.0 µm AC50= 12.4 µm 5.5+0.73 4.58+0.26 35 ΪΡ Τη 7-(3-(M-(2,6-dimethyl-4(3(methylsulfonyl)propoxy)phenyl)sulfamoyl)phenyl)heptanoic acid AC50= 6.1 µm AC50= 2.3 µm 4.3+0.61 4.2±0.25

* Multiplicity of test compound growth at 30 µm for 30 min over DMSO (ALA = 6.61±2.45).

** Multiplicity of test compound growth at 100 µm for 30 min over DMSO (ALA = 1.52±0.19).

Claims (17)

CLAIM 1. Compound with formula (I) and its pharmaceutically acceptable salts, in which A is phenyl, naphthyl, biphenyl, or a saturated or unsaturated five-membered heterocycle having 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S; R ¹ , R ² , R ³ are individually selected from the group consisting of -H, -halogen, -CF ₃ , -CN, -CH2CN, -OMe, -OCF3, -OH, phenyl, -OPh, -OCH2Ph, - OCH2OMe, -OCH2CN-NO2, -NR'R, linear or branched C1-C6 alkyl, -O(CH ₂ )pS(O) ₂ Me and a heterocycle with a five-membered ring having five ring atoms, in which 1, 2, 3 or 4 ring atoms individually selected from N, O and S; in which R' and R are individually -H or C1-C ₄ alkyl; wherein the phenyl and the five-membered heterocycle are individually unsubstituted or substituted with a group selected from the group consisting of linear or branched C1- _C4 alkyl, halogen, -OMe and -OH; p has a value from 1 to 4; X represents -CH ₂ or -C(O); n is 0, 1 or 2; R ⁴ is -YC(O)OH, wherein Y is a C ₄ -C ₁₈ straight chain hydrocarbon, saturated or unsaturated; R ⁴ is in the meta or para position on the aromatic ring; wherein when A is phenyl, n is 0, Y is C ₄ hydrocarbon, at least one of said R ¹ , R ² , R ³ is not hydrogen; wherein when A is phenyl, n is 0, Y is a C ₄ hydrocarbon, R ¹ and R ² are hydrogen, R ³ is not Cl at the para position in the aromatic ring, or wherein the compound of formula (I) is 7-( 3-(N-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imi- 17 040041 dazol-2-yl)sulfamoyl)phenyl)heptanoic acid. 2. A compound according to claim 1, wherein Y is a straight chain C6-C1o hydrocarbon, saturated or unsaturated. 3. A compound according to claim 1 or 2, wherein the five-membered ring heterocycle is selected from the group consisting of thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1 ,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4 -thiadiazolyl, 1,3,4-oxadiazolyl optionally partially saturated. 4. The compound according to any one of claims 1 to 3, wherein R ¹ , R ² , R ³ is individually selected from the group consisting of -H, -halogen, -CF ₃ , -OMe, -OH, phenyl, -OPh, - OCH ₂ Ph, -OCH ₂ OMe, -OCH2CN -NO2, -NH2, -NMe ₂ , linear or branched C ₁ -C ₆ alkyl and -O (CH ₂ ) _p -S (O) ₂ Me. 5. A compound according to any one of claims 1 to 4, wherein n is 0 or 1. 6. A compound according to any one of claims 1 to 5, wherein R ⁴ is in the meta position on the aromatic ring. 7. The compound according to any one of claims 1 to 6, which is selected from the list below: 7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (1); 7-(3-(N-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid (2); 7-(3-(N-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (3); 7-(3-(N-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (4); 7-(3-(N-(4-(dimethylamino)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (5); 7-(3-(N-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid (6); 7-(3-(N-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (7); 7-(3-(N-(4-methoxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (8); 7-(3-(N-(6-fluoro-4-methyl-[1,1'-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid (9); 7-(3-(N-(5-fluoro-3-methyl-[1,1'-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid (10); 6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid (11); 7-(3-(N-(3,5-dimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl)heptanoic acid (12); 7-(3-(N-(2,4-dimethylthiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (13); 7-(3-(N-(4,5-dimethylthiazol-2-yl)sulfamoyl)phenyl)heptanoic acid (14); 7-(3-(N-(4,5-dimethyloxazol-2-yl)sulfamoyl)phenyl)heptanoic acid (15); 7-(3-(N-(5-phenyl-1,2,4-thiadiazol-3-yl)sulfamoyl)phenyl)heptanoic acid (16); 7-(3-(N-(3-methyl-1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (17); 7-(3-(N-(5-methyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)hentanoic acid (18); 7-(3-(N-(3,5-dimethylisoxazol-4-yl)sulfamoyl)phenyl)heptanoic acid (19); 7-(3-(N-(5-methyl-4H-1,2,4-triazol-3-yl)sulfamoyl)phenyl)heptanoic acid (20); 7-(3-(N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid (21); 7-(3-(N-(3-phenylisothiazol-5-yl)sulfamoyl)phenyl)heptanoic acid (22); 7-{3-[(5-hydroxynaphthalen-1-yl)sulfamoyl]phenyl}heptanoic acid (23); 7-{3-[(4-fluoro-2,6-dimethylbenzoyl)sulfamoyl]phenyl}heptanoic acid (24); 7-{4-[(4-fluoro-2,6-dimethylphenyl)sulfamoyl]phenyl}heptanoic acid (25); 7-(3-(N-(2-ethyl-2H-1,2,3-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid (26); 7-(3-(N-(2-methyl-2H-tetrazol-5-yl)sulfamoyl)phenyl)heptanoic acid (27); 7-(3-(N-(4-methyl-4,5-dihydrooxazol-2-yl)sulfamoyl)phenyl)heptanoic acid (28); 7-(3-(N-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2-yl)sulfamoyl)phenyl)heptanoic acid (29); 7-(3-(N-(3-phenylisothiazol-4-yl)sulfamoyl)phenyl)heptanoic acid (30); 7-(3-(N-(4-hydroxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (31); 7-(3-(N-(3,5-dimethyl-[1,1'-buphenyl]-4-yl)sulfamoyl)phenyl)hentanoic acid (32); 7-(3-(N-(2,6-dimethyl-4-phenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33); 7-(3-(N-(4-(benzyloxy)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (34); 7-(3-(N-(2,6-dimethyl-4-(3(methylsulfonyl)propoxy)phenyl)sulfamoyl)phenyl)heptanoic acid (35). 8. The compound according to claim 7, which is selected from the following list: 7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (1); 7-(3-(N-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid (2); 7-(3-(N-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (3); 7-(3-(N-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (4); 7-(3-(N-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid (6); 7-(3-(N-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (7); 7-(3-(N-(6-fluoro-4-methyl-[1,1'-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid (9); 7-(3-(N-(5-fluoro-3-methyl-[1,1'-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid (10); 6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid (11); - 18 040041 7-(3-(N-(2,6-dimethyl-4-phenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33). 9. Pharmaceutical composition containing as an active ingredient at least one compound according to any one of claims 1 to 8 in combination with physiologically acceptable excipients. 10. Pharmaceutical composition according to claim 9, formulated for intravenous, intraperitoneal, inhalation, topical or oral administration. I. Pharmaceutical composition according to item 9 or 10, which is presented in solid or liquid form. 12. The use of a compound according to any one of claims 1 to 8 for the prevention and/or treatment of a disease or disorder modulated by GPR120 and/or GPR40. 13. Application according to and. 12, wherein said disease or disorder is: diabetes, oral glucose intolerance, insulin resistance, obesity, obesity-related disorders, metabolic syndrome, dyslipidemia, elevated low-density lipoprotein, elevated triglycerides, obesity-induced inflammatory process, osteoporosis and obesity-related disorders of the cardiac vascular system. 14. Application according to and. 13, wherein said disease or disorder is type 2 diabetes. 15. Use of a compound of formula (I) (I) wherein A is phenyl, R ¹ , R ² and R ³ are hydrogen, η is 0 and R ⁴ is -(CH ₂ )4-C(O)OH, for the prevention and/or treatment of a disease or a disorder modulated by GPR120 and/or GPR40. 16. Use of a compound of formula (I) in which A is phenyl, R ¹ and R ² are hydrogen, R ³ is C1 in the position of the pair in the aromatic ring, n is 0, and R ⁴ is -(CH ₂ )4-C(O)OH, for the prevention and/or treatment of a disease or disorder modulated by GPR120 and/or GPR40. 17. Application according to and. 15 or 16, in which said disease or disorder is: diabetes, decreased oral glucose tolerance, insulin resistance, obesity, obesity-related disorders, metabolic syndrome, dyslipidemia, elevated low-density lipoprotein, elevated triglycerides caused by obesity inflammation, osteoporosis and obesity-related disorders of the cardiovascular system. 18. Application according to and. 17, wherein said disease or disorder is type 2 diabetes.