AU2015202588B2 - Pyrrolidine carboxylic acid derivatives, pharmaceutical composition and methods for use in treating metabolic disorders as agonists of G-Protein Coupled Receptor 43 (GPR43) - Google Patents

Abstract

The present invention is directed to novel compounds of formula (I) and their use in treating and/or preventing metabolic diseases. Figure I 1h0I 35 Compun~d 2 MUM compound 1 OKImoud Smt .. mun 4... U z VV "peQ~." Of Miae1 ~t -"a R3- -R 4' Ar -L1 L3-Z 'L2, L 2-Ar 2 6484816 1 (GHMatters) P90475.AU.1 JENNYP Figure 1 - Vehicle c 0 .. Compound 2 a100 E Compound 1 90- A Compound 111 Lu _T Compound 8 a Compound 10 0 Compound 4 70- -- ---0su Compound 113 Compound 5 Statistics: One-Way ANOVA and Dunneis post-oc *'<001 treated vs vehicle

Description

PYRROLIDINE OR THIAZOLIDINE CARBOXYLIC ACID DERIVATIVES, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN TREATING METABOLIC DISORDERSAS AS AGONISTS OF G- PROTEIN COUPLED RECEPTOR 43 (GPR43)

The present invention relates to novel compounds including their pharmaceutically acceptable salts, solvates and prodrugs, which are agonists or partial agonists of G-protein coupled receptor 43 (GPR43) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of Type 2 diabetes mellitus and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

[BACKGROUND OF THE INVENTION]

Under normal conditions, Free Fatty Acids (FFAs) are implicated in numerous physiological processes by serving as fuel in various metabolic pathways and/or acting as signaling molecules in different tissues such as the heart, liver, skeletal muscle, adipocytes and the pancreas (Newsholme et al., Biochem. J., 80 pp 655-662, 1961; Prentki et al, Endocrine Reviews, PubMed print ahead, 2008). Among FFAs, the short-chain fatty acids (SCFAs, carbon length C2-C6) are generated during anaerobic bacterial fermentation of fiber in the gut (Sellin et al., News. Physiol. Sci., 14, pp 58-64, 1999). Long-chain fatty acids (LCFAs, carbon length C14-C24) are products of dietary intake from adipose tissues and liver (McArthur et al., J. Lipid. Res., 40, pp 1371-1383, 1999).

Obesity is an increasing, worldwide public health problem associated with devastating pathologies such as type 2 diabetes (T2D) and dyslipidemia (Wild et al., Diabetes Care 27, pp 1047-1053, 2004). Dyslipidemia is characterized by high levels of triglycerides and/or LDL (bad cholesterol) or low levels of HDL (good cholesterol). Dyslipidemia is a key independent risk factor for cardiovascular diseases. It has long been suggested that FFAs are implicated in the regulation and/or genesis of these diseases (Fraze et al., J. Clin. Endocrinol.

Metab., 61, pp 807-811, 1985). It is well established that regular intake of dietary fiber has several beneficial metabolic effects such as lowering of plasma cholesterol and triglyceride levels (Anderson et al, J. Am. Coll. Nutr., 23, pp 5 -17, 2004). Specifically, dietary fiber has been shown to increase endogenous levels of SCFAs, leading to the suppression of cholesterol synthesis and improvement in glucose tolerance in rat (Berggren et al., Br. J. Nutr., 76, pp 287-294, 1996), as well as the reduction of hyperglycemia in a diabetic mice model (Sakakibara et al., Biochem. Biophys. Res. Com., 344, pp 597-604, 2006).

Drug therapies are available to address both T2D and dyslipidemia. Specifically, statins, fibrates and nicotinic acid or combinations thereof are often considered as a first line therapy in dyslipidemia whereas metformin, sulphonylureas and thiazolidinediones are three, widely-used classes of oral antidiabetic drugs (Tenenbaum et al., Cardiovascular Diabetology, 5, pp20-23, 2006). Although theses therapies are widespread in their use, the common appearance of adverse effects or lack of efficacy after long-term use causes concern. Moreover, the growing patient population suffering from T2D, dyslipidemia and associated metabolic diseases creates a demand for new entrants into this therapeutic market. GPR43 (also named FFA2R) belongs to a subfamily of G-Protein-Coupled Receptors (GPCRs), including GPR40 and GPR41 that have been identified as receptor for FFAs (Le Poul et al., J. Biol Chem. 278, 25481-489, 2003; Covington et al., Biochemical Society transaction 34, 770-773, 2006). The 3 family members share 30 to 40% sequence identity with specificity toward different fatty acids carbon chain lengths, with SCFAs (short chain fatty acids: six carbons molecules or shorter) activating GPR41 and GPR43; and medium and long chain fatty acids (MCFA, LCFA) activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 11 661-671, 2007 ). C2 acetate and C3 propionate are the most potent activators of GPR43. GPR43 is mainly coupled with Gq-proteins, with some evidence for its possible coupling with Gi/o pathways as well. GPR43 is strongly expressed in adipocytes. Also there is evidence suggesting that GPR43 is overexpressed in pancreatic β-cells in prediabetic states as shown in W02006/036688A2. Recent papers confirmed the GPR43 expression in pancreatic islets (Ahren, Nature Reviews, 8 pp396-385; 2009; Regard et al., J; Clin. Invst., 117 pp4034-4043, 2007). In adipocyte cells, GPR43 is induced during the differentiation process and increased during the high fat feeding in rodents, suggesting that GPR43 may affect adipocyte functions (Hong et al., Endocrinology, 146 pp5092-5099, 2005). Indeed, it has been reported that acetate and propionate may stimulate adipogenesis via GPR43. In addition siRNA results hinted that acetate and propionate may inhibit lipolysis in adipocytes via GPR43 activation (Hong et al., Endocrinology, 146 pp5092-5099, 2005). It is interesting to note that the effect of acetate on reducing plasma free fatty acids level has been documented in humans (Suokas et al., Alcoholism, clinical and experimental research, 12 pp52-58, 1988; Laurent et al., European journal of clinical nutrition, 49 pp484-491, 1995). In addition, it has been shown that (i) adipocytes treated with GPR43 endogenous SCFA ligands exhibit a reduction in lipolytic activity and such inhibition of lypolysis is the result of GPR43 activation and (ii) GPR43 activation by acetate results in the reduction of plasma free fatty acids level in vivo (Ge et al., Endocrinology, 149 pp4519-26, 2008). Recently two GPR43 positive allosteric modulator molecules have been shown able to inhibit the lipolysis in adipocytes similarly to that of GPR43 endogenous SCFA ligands (Lee et al., Mol Pharmacol, 74(6) ppl599-1609, 2008). Such results suggest a potential role of GPR43 in regulating plasma lipid profiles and aspects of metabolic syndrome.

On this basis, new agonists or partial agonists of GPR43 may be of therapeutic value for T2D mellitus and conditions that are associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

[SUMMARY OF THE INVENTION]

The invention encompasses compounds of general Formula I, their pharmaceutically acceptable salts, solvates and prodrugs as well as methods of use of such compounds or compositions comprising such compounds as modulators of GPR43 activity.

In a general aspect, the invention provides compounds of general formula I:

and pharmaceutically acceptable salts,solvates and prodrugs thereof, wherein

Ar1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a linear or branched C3-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocycloalkyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo; L1 is a single bond, C1-C3 alkylene, C3-C6 cycloalkylene, C2-C3 alkenylene, C2-C3 alkynylene, each of which being optionally substituted by one or more group(s) selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl; R1 is H, linear or branched C1-C4 alkyl; E is N, C-R5 where R5 is H, linear or branched C1-C4 alkyl; D is CO or D is where D is linked to E eiher

on the nitrogen or the carbonyl and R6 is H, alkyl, C2-C4 alkenyl, C2- C4 alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl or alkoxyalkyl, and under the condition that E is C-R5; L2 is a single bond, C1-C4 alkylene, C3-C6 cycloalkylene, C2-C3 alkenylene, C2-C3 alkynylene each of which being optionally substituted by one or more group(s) selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl or alkoxyalkyl;

Ar2 is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino, alkylamino, aminoalkyl, arylcarbonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, oxo or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocyclyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocyclyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or methyl group, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a fluoro group, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, amino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, oxo, aralkyl, heteroarylalkyl, alkoxyalkoxy, alkoxyalkyl, and haloalkoxyalkyl. R2 is H; L3 is a single bond, C1-C3 alkylene, C3-C6 cycloalkylene, C2-C3 alkenylene or C2-C3 alkynylene each of which being optionally substituted by one or more group(s) selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl; Z is selected from the group consisting of -COOR,

wherein R is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R7 is H, methyl or ethyl, and R7 is hydroxyl -SCkChh, -SCkcyclopropyl or -SO2CF3; the bond represented by the dotted line is either absent or present; R3 is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, acetyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo; R3 is H or C1-C4 alkyl, or R3 is absent if the dotted line is present; R4 is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, or R4 forms together with R3 a cyclopropane ring optionally substituted by one or more group selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, or haloalkoxy, under the condition that the dotted line is absent; R4 is H, C1-C4 alkyl, or R4 is absent if the dotted line is present; under the condition that the compound of formula (I) is not (2S)-methyl 1 -benzoyl-5-mesitylpyrrolidine-2-carboxylate, (2S)-methyl l-benzoyl-5-(2,4,6-triethylphenyl)pyrrolidine-2-carboxylate, (25.55) -l-benzoyl-5-mesitylpyrrolidine-2-carboxylic acid, (2S)-methyl 1 -benzoyl-5-propylpyrrolidine-2-carboxylate, (25.55) -methyl 1-benzoyl-5-propylpyrrolidine-2-carboxylate, (2S,5R)-methyl 1 -benzoyl-5-propylpyrrolidine-2-carboxylate, (2S,5R)-5-(tert-butyl)-1 -(4-phenylbutanoyl)pyrrolidine-2-carboxylic acid, (2S,5R)-methyl 5-(tert-butyl)-1 -(4-phenylbutanoyl)pyrrolidine-2-carboxylate, (2R,5R)-1 -(4-bromothiophene-2-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid, (2R,5S)-l-(3-bromo-2,6-dimethoxybenzoyl)-5-phenylpyrrolidine-2-carboxylic acid, tert-butyl 2-[(2R,5S)-2-ethoxycarbonyl-5-phenyl-pyrrolidine-l-carbonyl]indoline-1-carboxylate, (2R,5S)-l-(l-ieri-butoxycarbonylindoline-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylic acid, l-[7-(4-?er?-butyl-phcnoxy)-1 -cyclopentylmethyl-isoquinoline-3-carbonyl]-(5R)-phenyl-pyrrolidine-(2S)-carboxylic acid.

Advantageously, the compounds of the invention or pharmaceutically acceptable salts, solvates and prodrugs thereof are those described above in respect to formula (I) with the following provisos:

Ar2 is not phthalazin-6-yl, pyrido[2,3-d]pyridazin-2-yl, pyrido[2,3-d]pyridazin-3-yl, or pyrazino[2,3-d]pyridazin-2-yl; and/or each of R3 and R4 is not a pyrimid-2-ylamino group substituted at position 6 by a bicyclic heteroaryl group, if the bond represented as a dotted line is absent; and/or R3 is not a mono substituted hydroxymethyl; and/or

The D-L2-Ar2 moiety is not

wherein L is H or alkyl and L’ is selected from phenyl, naphtyl, indolyl, quinolyl, phenylamino.

In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention also relates to the use of the above compounds or their pharmaceutically acceptable salts, solvates and prodrugs as modulators of GPR43, preferably as agonists or partial agonists of GPR43.

The invention further provides methods of treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate of formula (I), to a patient in need thereof Preferably the patient is a warm-blooded animal, more preferably a human.

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicament. Preferably, the medicament is used for the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, , metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

In a preferred embodiment the disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae.

The present invention as claimed herein is described in the following item 1:

1. A compound of formula F

F wherein R’ is OH or Cl; A0, A0, A1, A2, A3, A4 and A5 are selected from the combinations 1 to 7, 9,10,13 to 15, 17 to 21, 23 and 24:

[DETAILED DESCRIPTION OF THE INVENTION]

As noted above, the invention relates to compounds of formula I, as well as their pharmaceutically acceptable salts, solvates and prodrugs.

Preferred compounds of formula I and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein all the following descriptions are independently the dotted line is absent and E is N; and/or L1 is a single bond, preferably a single bond drawn as a solid wedge; and/or L3 is a single bond, preferably a single bond drawn as a solid wedge; and/or Z is selected from the group consisting of -COOR wherein R is defined as above in respect to formula I, preferably Z is COOH; and/or R3 is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, 5-membered heterocyclyl, heterocyclylalkyl, aryl, aralkyl, 5-membered heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroaryl carbonyloxy, arylalkyloxy, acetyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, preferably R3 is H, cyano, alkyl, haloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, alkoxyalkyl, haloalkoxy, aminoalkyl, arylalkyloxy, acetyl, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoylalkyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or a bicyclic ring made by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl fused to one cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, or R3 forms together with R4 a cyclopropane ring substituted by one or more group selected from halo, haloalkyl, or haloalkoxy, under the condition that the bond represented by the dotted line is absent, more preferably R3 is H, cyano, alkyl, preferably methyl, aralkyl, preferably benzyl, acetyl linked to the E containing ring by bond drawn as a dotted wedge, alkoxyalkyl preferably methoxymethyl, even more preferably R3 is H; and/or R4 is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, or R4 forms together with R3 a cyclopropane ring substituted by one or more haloalkyl, haloalkoxy, under the condition that the dotted line is absent, preferably R4 is H, methyl or cyano, more preferably R4 is H; and/or R3 and R4’ are independently H or methyl, preferably R3 is H or methyl and R4 is H, more preferably R3 and R4 are both H; and/or D is CO and L2 is a single bond; and/or

Ar1 is a 5- to 6-membered aryl or heteroaryl group, or a 3- to 6-membered cycloalkyl group, or a linear or branched C3-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, C1-C4 alkoxy preferably methoxy, C1-C4 haloalkoxy preferably OCF3 or OCHF2, C1-C4 alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, C1-C4 alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, C1-C4 alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, C1-C4 alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl group they are attached to, or fused to the aryl, heteroaryl or cycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, more preferably Ar1 is a phenyl, pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl, isobutyl or isopentyl group, each of said phenyl, pyridin-2-yl, pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 haloalkyl preferably CF3 or CHF2, cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, C1-C4 alkoxy preferably methoxy, C1-C4 haloalkoxy preferably OCF3 or OCHF2, C1-C4 alkylamino, alkylcarbonylamino, carbamoyl, C1-C4 alkylcarbamoyl, carbamoylamino, C1-C4 alkylcarbamoylamino, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, still more preferably Ar1 is a phenyl, cyclohexyl, isobutyl or isopentyl group, said phenyl or eye lo hexyl, group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 haloalkyl preferably CF3 or CHF2, cycloalkyl, aryl preferably phenyl, heteroaryl preferably hydroxyl, C1-C4 alkoxy preferably methoxy, C1-C4 haloalkoxy preferably OCF3 or OCHF2, C1-C4 alkylamino, alkylcarbonylamino, alkylsulfonyl, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, even more preferably Ar1 is a phenyl or isobutyl group, said phenyl group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano or C1-C4 alkyl preferably methyl, alkoxy preferably methoxy; and/or R1 is H or methyl, preferably R1 is H; and/or R2 is H; and/or

Ar2 is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxy carbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, oxo, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocycloalkyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl preferably CF3, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or methyl group, preferably phenyl, 4-chlorophenyl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl, cycloalkyloxy, cycloalky lalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted with one fluoro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably carbamoylmethyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl preferably (piperidin-l-yl)sulfonyl, (morpholin-4-yl)sulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, oxo, aralkyl, heteroarylalkyl, alkoxyalkoxy, alkoxyalkyl, and haloalkoxyalkyl, more preferably Ar2 is an aryl or heteroaryl preferably pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of said aryl, heteroaryl, cycloalkyl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or two substituents form an alkylenedioxy group or a halo alkylenedioxy group, or fused to the cycloalkyl or hetero cycloalkyl group may be one aryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, cyanomethyl, alkoxy preferably methoxy, ethoxy, isopropoxy, cycloalkyl, cycloalkylalkyloxy, alkoxyalkoxy, aryloxy, aralkyloxy optionally substituted with one fluoro, amino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably Ar2 is an aryl preferably phenyl, heteroaryl preferably pyridyl, heterocyclyl preferably piperidinyl, C2-C6 alkyl group preferably isobutyl, each of said aryl, heteroaryl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl, heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazol-2-yl, alkoxy preferably methoxy, ethoxy and isopropyloxy, alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy and 3,3-diphenylpropan-l-oxy heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, arylcarbonyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, alkyl preferably methyl, cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2- methoxyethoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted with one fluoro, preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino.

In one embodiment, preferred compounds of Formula I are those of formula lb:

Ib and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1 is as defined above in respect to formula I, preferably Ar1 is a 5- to 6-membered aryl or heteroaryl group, or a 3- to 6-membered cycloalkyl group, or a linear or branched C3-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, C1-C4 alkoxy, Cj-C4 haloalkoxy preferably OCF3 or OCHF2, C1-C4 alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, C1-C4 alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, C1-C4 alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, C1-C4 alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl group they are attached to, or fused to the aryl or heteroaryl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, more preferably Ar1 is a 5- to 6-membered aryl preferably phenyl, 5- to 6-membered heteroaryl group preferably pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl, isobutyl or isopentyl each of said phenyl, pyridin-2-yl, pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 alkoxy preferably methoxy, aryl preferably phenyl, still more preferably Ar1 is aryl preferably phenyl, cyclohexyl, isobutyl or isopentyl, said phenyl group being optionally substituted by one or more halo group preferably bromo, chloro or fluoro, cyano, methyl, phenyl or methoxy, further more preferably Ar1 is phenyl, cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, 1,l'-biphenyl-2-yl, 4-cyanophenyl, even more preferably Ar1 is isobutyl, cyclohexyl, phenyl , 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, still even more preferably Ar1 is isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl; L1 is as defined above in respect to formula I, preferably L1 is a single bond or a methylene optionally being substituted by one or more substituents selected from fluoro or methyl, more preferably L1 is a single bond drawn as a solid or dotted wedge, even more preferably a single bond drawn as a solid wedge; R1 is as defined above in respect to formula I, preferably R1 is H or methyl, more preferably R1 is H; E is as defined above in respect to formula I, preferably E is N; D is as defined above in respect of formula I, preferably D is CO; L2 is as defined above in respect to formula I, preferably L2 is a single bond, Ci-C3 alkylene optionally being substituted by one or more substituents selected from fluoro or methyl, more preferably L2 is a single bond;

Ar2 is as defined above in respect to formula I, preferably Ar2 is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, oxo, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or two substituents form a cycloalkyl or heterocycloalkyl moiety together with the cycloalkyl or heterocyclyl group they are attached to, or fused to the aryl, heteroaryl, cycloalkyl or heterocyclyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or methyl group, preferably phenyl, 4-chlorophenyl, 4-tolyl, heteroaryl, cycloalkylalkyl, heteroalkyl, aralkyl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy, haloalkoxy haloalkoxy preferably trifluoromethoxy, 1,1,1-trifluoroethyloxy, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, alkoxyalkyl, haloalkoxyalkyl, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably carbamoylmethyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl preferably (piperidin-l-yl)sulfonyl, (morpholin-4-yl)sulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, oxo, more preferably Ar2 is an aryl or heteroaryl preferably pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or two substituents form an alkylenedioxy group or a halo alkylenedioxy group, or fused to the cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, cyanomethyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably Ar2 is an aryl preferably phenyl, heteroaryl preferably pyridyl, heterocyclyl preferably piperidinyl, C2-C6 alkyl group preferably isobutyl, each of said aryl, heteroaryl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, preferably methyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, nitro, alkyl preferably methyl, cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl- N-methylsulfonyl)amino, further more preferably Ar2 is a biaryl consisting of two 6-membered aryl moieties preferably biphenyl, more preferably a biphenyl linked to L2 at position 4’ and monosubstituted at position 2, or Ar2 is a heterobiaryl consisting of one 6-membered aryl moiety and one 6-membered heteroaryl moiety or two 6-membered heteroaryl moieties, said heterobiaryl being linked to L2 either on the aryl or on the heteroaryl moiety and being preferably phenylpyridyl, pyrimidinylphenyl, pyridazinylphenyl, pyrazinylphenyl, or Ar2 is an aryl or heteroaryl optionally substituted by one group selected from arylalkyloxy, aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl and heteroaryl groups being optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, or Ar2 is a piperidinyl ring linked to L2 at position 4 and N substituted with a phenyl, 4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said phenyl moiety being further substituted by one or more substituents selected from halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, haloalkyl preferably CF3, alkoxy preferably methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl, (morpholin-4-yl)sulfonyl, alksulfamoyl preferably methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar2 is 4’-(2-methoxy-1,1 '-biphenyl), 4’-(2-methyl-1,1 -biphenyl), 4’-(2-fluoro-1,1 -biphenyl), 4’-(4-chloro-1,1 ’-biphenyl), 4’-(2-chloro-1,1 -biphenyl), 4’-(2-chloro-2’-methoxy- 1.1 ’-biphenyl), 4’-(2-(2-methoxyethoxy)-1,1 ’-biphenyl), 4’-(2-(methoxymethyl)-Ι,Γ-biphenyl), 4’-(4-methoxy-l,l'-biphenyl), 4’-(4-cyano-l,l'-biphenyl), 4’-(3-chloro-1,1 ’-biphenyl), 4’-(2-chloro-1,1 ’-biphenyl), 4’-(4-methylsulfonylamino- 1.1 ’-biphenyl), 4 ’-(2-trifluoromethoxy-1,1 ’-biphenyl), 4 ’-(2-isopropoxy-1,1'- biphenyl), 4’-(2-cyclopropylmethyloxy-l, 1 ’-biphenyl), 4’-(2-cyano-1,1 ’-biphenyl), 4’-(2,6-dimethoxy-l,l'-biphenyl), 4’-(2,4-dichloro-l,l'-biphenyl), 4’-(2- trifluoromethyl-1,1 '-biphenyl), 4 ’-(2-methoxy-4-chloro-1,1 '-biphenyl), 4 ’-(2,4-dimethoxy-1,1 '-biphenyl), 4-(2,2'-dimethoxy-1,1 '-biphenyl), 4-(naphtalen-2- yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl, 4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(2-methoxypyridin-3-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl, 4-(2,4-dimethoxypyrimidin-6-yl)phenyl, 4-(2,4- dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl, 4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl, (4-phenoxymethyl)phenyl, optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, more preferably fluoro, alkyl preferably methyl, alkoxy preferably methoxy, or Ar2 is 4’-(2,4-difluoro-l,l'-biphenyl), 4’-(3’-methyl-1,1'-biphenyl), 4’-(3’-fluoro-l,r-biphenyl), 4’-(2-fluoro-4-methoxy-l,l'-biphenyl), 4’-(4-fluoro-2-methoxy-1,1 '-biphenyl), 4’-(2,3-dimethoxy-1,1 ’-biphenyl), 4 ’-(3,4-dimethoxy-1,1 ’-biphenyl), 4’-(2,3,4-trimethoxy-1,1 ’-biphenyl), 4’-(2,3,6- trimethoxy-1,1 -biphenyl), 4’-(3,5-dimethoxy-1,1 ’-biphenyl), 4 ’-(2,5-dimethoxy- 1,1 -biphenyl), 4’-(2-isopropyl-1,1 -biphenyl), 4’-(2,2’-dimethoxy-1,1 ’-biphenyl), 4’-(2’-fluoro,2-dimethoxy-1,1 ’-biphenyl), 4’-(2-ethyl-1,1 -biphenyl), 4’-(4-propyl-1, Γ-biphenyl), 4’-(4-terf-butyl-l, 1 ’-biphenyl), 4’-(2-methoxy-4- methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methoxy-4-acetylamino-1,1 ’-biphenyl), 4’-(3-hydroxycarbamimidoyl-1,1 ’-biphenyl), 4’-(4-amino-2-methoxy-1,1’- biphenyl), 4’-(3-carbamoyl-1,1 ’-biphenyl), 4’-(5-cyano-2,3-dimethoxy-1, Γ- biphenyl), 4’-(2-cyano-4,5-dimethoxy-l, 1 ’-biphenyl), 4’-(3,4,5-trimethoxy-l, 1 ’-biphenyl), 4’-(2-cyanomethyl-4,5-dimethoxy-l,l'-biphenyl), 4’-(2-fluoro-5-cyano-1,1 ’-biphenyl), 4 ’-(2 ’-fluoro-3,4-dimethoxy-1,1 ’-biphenyl), 4 ’-(3- carbamoyl-4-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-methoxy-1,1 ’-biphenyl), 4’-(2’-fluoro-4-methylsulfonylamino-1,1 ’-biphenyl), 4’-(2 ’-fluoro-3- methylsulfonylamino-1,1 ’-biphenyl), 4’-(2-cyano-2’-fluoro-1,1 ’-biphenyl), 4’-(2-chloro-5-cyano-1,1 ’-biphenyl), 4 ’ -(2-cyano-4-trifluoromethyl-1,1 ’-biphenyl), 4 ’ -(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-1,1 ’-biphenyl), 4’-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1 ’-biphenyl), 4’-(4-methylsulfonyl-1,1'- biphenyl), 4’-(3-methylsulfonylamino-1,1 ’-biphenyl), 4’-(4-amino-2-methyl-1,1'-biphenyl), 4’-(5-cyano-2-methyl-1,1 ’-biphenyl), 4’-(5-cyano-2-methoxy-1,1'-biphenyl), 4’-(3-cyano-l,l'-biphenyl), 4’-(2-cyano-3-methoxy-l,r-biphenyl), 4’-(2-methyl-3-methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methyl-3-acetylamino- 1,1 ’-biphenyl), 4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl, 4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl, 4-(2-methoxy-6-methylpyridin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl, 4-(2,6- dimethylpyridin-5-yl)phenyl, 4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl, 4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl, 4-(4,6-dimethoxy-pyridin-3-yl)phenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl, 4-(6-methoxy-pyridin-3-yl)-3- fluorophenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl, 4-(4,6- dimethoxy-pyrimidin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-5-yl)-3- methoxyphenyl, 4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3- yl)phenyl, 4-(2-methoxy-pyrimidin-3-yl)phenyl, 3-methoxy-2-(2- methoxyphenyl)pyridin-5 -yl, 3 -methoxy-2-(5 -cyano-2-methoxyphenyl)pyridin-5 -yl, 3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl, 2-(2,4- dimethoxyphenyl)pyridin-5-yl, 1 -(2-cyano-4-trifluoromethyl)piperidin-4-yl, 1 -(2-nitro-4-trifhioromethyl)piperidin-4-yl, l-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; R2 is H; L3 is as defined above in respect to formula I, preferably L3 is a single bond, Ci-C3 alkylene optionally substituted by one or more group(s) selected from chloro, fluoro, alkyl preferably methyl, alkoxy preferably methoxy, or haloalkyl, preferably L3 is a single bond, more preferably L3 is a single bond drawn as a solid wedge; Z is as defined above in respect to formula I, preferably Z is COOR where R is as defined above in respect of formula I, more preferably Z is COOH; R3 is as defined above in respect to formula I, preferably R3 is H, cyano, alkyl, preferably methyl, aralkyl, preferably benzyl, hydroxyalkyl preferably hydroxymethyl, alkoxyalkyl preferably methoxymethyl, acetyl linked to the E containing ring by a bond drawn as a dotted wedge, arylsulfonyl preferably phenylsulfonyl, more preferably R3 is H; R3’ is as defined above in respect of formula I, preferably R3 is H or methyl, more preferably R3 is H; R4 is as defined above in respect to formula I, preferably R4 is H, cyano or methyl, more preferably R4 is H; R4’ is as defined above in respect to formula I, preferably R4 is H or methyl, more preferably R4’ is H; the bond represented by the dotted line is either absent or present, preferably the dotted line is absent.

Particularly preferred compounds of formula lb are those of formula Ib-la

Ib-la and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar1, Ar2, R1, R2, R3, R3, R4, R4 , L2, L3, D and Z are as defined above in respect of formula lb.

Preferred compounds of formula Ib-la are those of formula Ib-lb

Ib-lb and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar1, Ar2, R1, R2, R3, R3, R4, R4’, L2 and D are as defined above in respect of formula lb and R is as defined above in respect of formula I.

Preferred compounds of formula Ib-lb are those of formula Ib-lc

Ib-lc and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar1, Ar2, R1, R2, L2 and D are as defined above in respect of formula lb and R is as defined above in respect of formula I.

Other preferred compounds of formula Ib-lb are those of formula

Ib-lb’

Ib-lb’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R2 is as defined above in respect of formula lb and R is as defined above in respect of formula I; R1 is H; D is C=0; L2 is single bond;

Ar1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered cycloalkyl group, or a linear or branched C3-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, each of said aryl or heteroaryl substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, preferably Ar1 is a 5- to 6-membered aryl preferably phenyl, 5- to 6-membered heteroaryl group preferably pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl, isobutyl or isopentyl each of said phenyl, pyridin-2-yl, pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 alkoxy preferably methoxy, aryl preferably phenyl, still more preferably Ar1 is aryl preferably phenyl, cyclohexyl, isobutyl or isopentyl, said phenyl group being optionally substituted by one or more halo group preferably bromo, chloro or fluoro, cyano, methyl, phenyl or methoxy, further more preferably Ar1 is phenyl, cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, l,l'-biphenyl-2-yl, 4-cyanophenyl, even more preferably Ar1 is isobutyl, cyclohexyl, phenyl , 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, still even more preferably Ar1 is isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl;

Ar2 is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino, alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl, heteroaryl, cycloalkyl or heterocyclyl group may be one or more aryl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and haloalkoxyalkyl; preferably Ar2 is an aryl or heteroaryl preferably pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert- butyl, haloalkyl preferably CF3, cyanomethyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably Ar2 is an aryl preferably phenyl, heteroaryl preferably pyridyl, heterocyclyl preferably piperidinyl, C2-C6 alkyl group preferably isobutyl, each of said aryl, heteroaryl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, preferably methyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, nitro, alkyl preferably methyl, cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonylalkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, further more preferably Ar2 is a biaryl consisting of two 6-membered aryl moieties preferably biphenyl, more preferably a biphenyl linked to L2 at position 4’ and monosubstituted at position 2, or Ar2 is a heterobiaryl consisting of one 6-membered aryl moiety and one 6-membered heteroaryl moiety or two 6-membered heteroaryl moieties, said heterobiaryl being linked to L2 either on the aryl or on the heteroaryl moiety and being preferably phenylpyridyl, pyrimidinylphenyl, pyridazinylphenyl, pyrazinylphenyl, or Ar2 is an aryl or heteroaryl optionally substituted by one group selected from arylalkyloxy, aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl and heteroaryl groups being optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, or Ar2 is a piperidinyl ring linked to L2 at position 4 and N substituted with a phenyl, 4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said phenyl moiety being further substituted by one or more substituents selected from halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, haloalkyl preferably CF3, alkoxy preferably methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl, (morpholin-4-yl)sulfonyl, alksulfamoyl preferably methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar2 is 4’-(2-methoxy-1,1 '-biphenyl), 4’-(2-methyl-1,1 '-biphenyl), 4’-(2-fluoro-1,1 -biphenyl), 4’-(4-chloro-1,1 '-biphenyl), 4’-(2-chloro-1,1 ’-biphenyl), 4’-(2-chloro-2’-methoxy- 1.1 ’-biphenyl), 4’-(2-(2-methoxyethoxy)-1,1 ’-biphenyl), 4’-(2-(methoxymethyl)-Ι,Γ-biphenyl), 4’-(4-methoxy-l,l'-biphenyl), 4’-(4-cyano-l,l'-biphenyl), 4’-(3-chloro-1,1 ’-biphenyl), 4 ’-(2-chloro-1,1 ’-biphenyl), 4 ’-(4-methylsulfonylamino- 1.1 ’-biphenyl), 4 ’ -(2-trifluoromethoxy-1,1 ’-biphenyl), 4 ’-(2-isopropoxy-1,1'- biphenyl), 4 ’ -(2-cyclopropylmethyloxy-1,1 ’-biphenyl), 4 ’-(2-cyano-1,1 ’-biphenyl), 4’-(2,6-dimethoxy-1,1 ’-biphenyl), 4’-(2,4-dichloro-1,1 ’-biphenyl), 4’-(2- trifluoromethyl-1,1 ’-biphenyl), 4’-(2-methoxy-4-chloro-1,1 ’-biphenyl), 4’-(2,4-dimethoxy-1,1 ’-biphenyl), 4-(2,2'-dimethoxy-1,1 ’-biphenyl), 4-(naphtalen-2- yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl, 4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(2-methoxypyridin-3-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl, 4- (pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl, 4-(2,4-dimethoxypyrimidin-6-yl)phenyl, 4-(2,4- dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl, 4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl, (4-phenoxymethyl)phenyl, optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, more preferably fluoro, alkyl preferably methyl, alkoxy preferably methoxy, or Ar2 is 4’-(2,4-difluoro-l,l'-biphenyl), 4’-(3’-methyl-1,1'-biphenyl), 4’-(3’-fluoro-l,r-biphenyl), 4’-(2-fluoro-4-methoxy-l,l'-biphenyl), 4’-(4-fluoro-2-methoxy-1,1 '-biphenyl), 4’-(2,3-dimethoxy-1,1 ’-biphenyl), 4 ’-(3,4-dimethoxy-1,1 ’-biphenyl), 4 ’-(2,3,4-trimethoxy-1,1 ’-biphenyl), 4 ’-(2,3,6- trimethoxy-1,1 ’-biphenyl), 4’-(3,5-dimethoxy-1,1 ’-biphenyl), 4’-(2,5-dimethoxy- 1.1 '-biphenyl), 4’-(2-isopropyl-1,1 '-biphenyl), 4’-(2,2’-dimethoxy-1,1 ’-biphenyl), 4’-(2’-fhioro,2-dimethoxy-1,1 '-biphenyl), 4’-(2-ethyl-1,1 ’-biphenyl), 4’-(4-propyl-1, Γ-biphenyl), 4’-(4-fert-butyl-l, 1 ’-biphenyl), 4’-(2-methoxy-4- methylsulfonylamino-1,1 '-biphenyl), 4 ’-(2-methoxy-4-acetylamino-1,1 -biphenyl), 4’-(3-hydroxycarbamimidoyl-1,1 ’-biphenyl), 4’-(4-amino-2-methoxy-1,1’- biphenyl), 4’-(3-carbamoyl-1, Γ-biphenyl), 4’-(5-cyano-2,3-dimethoxy-1,1’-biphenyl), 4’-(2-cyano-4,5-dimethoxy-1,1 ’-biphenyl), 4’-(3,4,5-trimethoxy-l, 1 ’-biphenyl), 4’-(2-cyanomethyl-4,5-dimethoxy-l, Γ-biphenyl), 4’-(2-fluoro-5-cyano-1,1 ’-biphenyl), 4 ’-(2 ’-fluoro-3,4-dimethoxy-1,1 ’-biphenyl), 4 ’-(3- carbamoyl-4-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-methoxy-1,1 '-biphenyl), 4’-(2’-fluoro-4-methylsulfonylamino-l, Γ-biphenyl), 4’-(2’-fluoro-3- methylsulfonylamino-1,1 ’-biphenyl), 4’-(2-cyano-2’-fluoro-1,1 ’-biphenyl), 4’-(2-chloro-5-cyano-l,Γ-biphenyl), 4’-(2-cyano-4-trifluoromethyl-1,1 ’-biphenyl), 4’-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-l,l'-biphenyl), 4’-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1 ’-biphenyl), 4’-(4-methylsulfonyl-1,1'-biphenyl), 4’-(3-methylsulfonylamino-1,1 ’-biphenyl), 4’-(4-amino-2-methyl-1,1’-biphenyl), 4’-(5-cyano-2-methyl-1,1 ’-biphenyl), 4’-(5-cyano-2-methoxy-1,1’-biphenyl), 4’-(3-cyano-l,l’-biphenyl), 4’-(2-cyano-3-methoxy-l,l’-biphenyl), 4’-(2-methyl-3-methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methyl-3-acetylamino- 1.1 ’-biphenyl), 4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl, 4-(2-ethoxypyridin- 5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl, 4-(2-methoxy-6-methylpyridin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl, 4-(2,6- dimethylpyridin-5-yl)phenyl, 4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl, 4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl, 4-(4,6-dimethoxy-pyridin-3-yl)phenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl, 4-(6-methoxy-pyridin-3-yl)-3- fluorophenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl, 4-(4,6- dimethoxy-pyrimidin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-5-yl)-3- methoxyphenyl, 4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3- yl)phenyl, 4-(2-methoxy-pyrimidin-3-yl)phenyl, 3-methoxy-2-(2- methoxyphenyl)pyridin-5 -yl, 3 -methoxy-2-(5 -cyano-2-methoxyphenyl)pyridin-5 -yl, 3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl, 2-(2,4- dimethoxyphenyl)pyridin-5-yl, 1 -(2-cyano-4-trifluoromethyl)piperidin-4-yl, 1 -(2-nitro-4-trifluoromethyl)piperidin-4-yl, l-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; R3 is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl, arylsulfonyl; R3 is H or C1-C4 alkyl; R4 is H, cyano, C1-C4 alkyl.

Preferred compounds of formula Ib-lc or lb-lb’ are those of formula Ib-ld

Ib-ld and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar1, Ar2, R1 and R2 are as defined above in respect of formula lb in case of preferred compounds of formula Ib-lc, or lb-lb’ in case of preferred compounds of formula lb-lb’, and R is as defined above in respect of formula I.

Preferred compounds of formula Ib-ld are those of formula Ib-le

Ib-le and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar2, R1 and R2 are as defined above in respect of formula lb or Ib-lb’; R is as defined above in respect of formula I; R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, heterocyclyloxy, alkylamino, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, preferably R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, alkylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, more preferably R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, cyano, C1-C4 alkyl preferably methyl, aryl preferably phenyl, alkoxy preferably methoxy, still more preferably R8, R8, R9, R9 and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, alkyl preferably methyl, still more preferably R is Br, Cl or F, preferably Cl and R , R9, R9 and R10 are independently selected from H or F, or R9 is Cl or F and R8, R8’, R9 and R10 are H, or R9 and R9 are F and R8, R8 and R10 are H, or R10 is Cl or F and R8, R8, R9 and R9’ are H, even more preferably R8 is Br, Cl or F and R8’, R9, R9’ and R10 are H, or R8 and R9 are F and R8’, R9’ and R10 are H, or R8 and R10 are F and R8, R9 and R9’ are H.

Preferred compounds of formula Ib-le are those of formula Ib-lf

Ib-lf and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar2 is as defined above in respect of formula lb or Ib-lb’; R is as defined above in respect of formula I; R8, R8 , R9, R9’ and R10 are as defined above in respect of formula Ib-le.

Preferred compounds of formula Ib-lf are those of formula Ib-lg

Ib-lg and phannaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect of formula Ib-le; R11, R11, R12, R12’ and R16 are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkyloxycarbonyl, aminoalkylalkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, 11 12 12 16 16 haloalkylsulfonylamino, or one or more of R and R , or R and R , or R and -1 Λ 9 R , or R and R form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12 , or R12’ and R11’ form together a cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably trifluoromethoxt, 1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or one or more of R and R , or R and R , or R and R12, or R12 and R11 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11 form together an aryl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy, alkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino and oxo, more preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or one or more of R and R , or R and R , or R16 and R12’, or R12’ and R11’ form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11’ form together an aryl, or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl preferably CF3 or CHF2, cycloalkyl preferably cyclohexyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, haloalkyl preferably trifluoromethyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Ib-lg are those of formula Ib-lgl

Ib-lgl and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8 , R9, R9’ and R10 are as defined above in respect of formula Ib-le; R16 is as defined above in respect to formula Ib-lg, preferably R16 is selected from halo preferably chloro, alkyl preferably methyl or isobutyl, cycloalkyl preferably cyclohexyl, aryl preferably phenyl, heteroaryl preferably pyridyl, thiophen-3-yl, pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl, alkoxy preferably methoxy, isopropyloxy more preferably isopropyloxy, haloalkoxy, preferably OCF3, OCHF2, more preferably OCF3, cycloalkylalkyloxy preferably cyclopropylmethyloxy, arylalkyloxy preferably phenethyloxy or benzyloxy, heteroarylalkyloxy preferably pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, arylcarbonyl preferably phenylcarbonyl, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, cyanomethyl, cycloalkyl, aryl optionally substituted by a chloro or methyl group, hydroxyl, alkoxy preferably methoxy, ethoxy, isopropoxy, haloalkoxy preferably trifluoromethoxy, 1,1,1-trifluoroethyloxy, aryloxy preferably phenoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy optionally substituted by one fluoro preferably benzyloxy, 4-fluorobenzyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, amino, alkylcarbonylamino preferably acetylamino, carbamoyl, carbamoylmethyloxy, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, oxo, more preferably R16 is selected from alkyl preferably isobutyl, or R16 is alkoxy preferably isopropyloxy, or R16 is heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, or R16 is aryl preferably a phenyl, preferably a phenyl monosubstituted at position 2 by one group selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, alkyl preferably methyl, alkoxy preferably methoxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, or R16 is 2,4-difluorophenyl, 2-fluoro-4-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxy-4-methylsulfonylaminophenyl, 4-acetylamino-2-methoxyphenyl, 4-amino-2-methoxyhenyl, 5-cyano-2,3-dimethoxyphenyl, 2-cyano-4,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-cyano-4-methoxyphenyl, 3 -methylsulfonylaminophenyl, 4-methylsulfonylaminophenyl, 2-chloro-5 - cyanophenyl, 2-cyano-4-trifluoromethylphenyl, 2-methyl-3-(N-methyl-N-methylsulfonyl)aminophenyl, 2-methoxy-4-(N-methyl-N- methylsulfonyl)aminophenyl, 4-methylsulfonylphenyl, 3- methylsulfonylaminophenyl, 4-methylsulfonylaminophenyl, 3-amino-2-methyl, 5-cyano-2-methylphenyl, 5-cyano-2-methoxyphenyl, 2-methyl-3- methylsulfonylamino, 3-cyano-2-methoxyphenyl, or R16 is aralkyl preferably benzyl, or R16 is heteroaryl preferably 4,6-dimethoxypyrimidin-2-yl, 2-methoxypyrimidin-3 -yl, 2,4-dimethoxypyrimidin-5 -yl, 2-methoxypyridin-3 -yl, 2,6-dimethoxy-pyridin-3-yl, 2-(2-methoxyethoxy)-pyridin-3-yl, 2- methoxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-6-yl, preferably 2-methoxypyrimidin-3-yl, (2,4-dimethoxy)pyrimidin-5-yl, 2-methoxypyrimidin-5-yl, 2,6-dimethoxy-pyridin-3-yl, more preferably (2,4-dimethoxy)pyrimidin-5-yl, 2,6-dimethoxy-pyridin-3-yl, 2-chloro-6-methoxypyrimidin-5-yl, 2-methoxy-6-methylpyridin-5-yl, 2,6-dimethylpyridin-5-yl, 2,6-dimethoxypyrimidin-5-yl, 4-methoxypyridin-3-yl, 2-methoxypyridin-5-yl, 2,4-dimethoxypyridin-5-yl, 2,6-dimethoxypyridazin-5-yl, 2,6-dimethoxypyridin-5-yl, 5-methoxypyridin-3-yl, 4,6-dimethoxypyrimidin-5-yl, 3-methoxypyridin-4-yl, 4-methoxypyridin-3-yl, or R16 is, arylalkyloxy preferably phenethyloxy, benzyloxy, 2-fluorobenzyloxy, more preferably 2-fluorobenzyloxy, or R16 is aryloxyalkyl preferably phenoxymethyl.

Preferred compounds of formula Ib-lgl are those of formula Ib- lgla

Ib-lgla and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect of formula Ib-le; R17, R17’, R18’ and R19 are independently selected from H, halo preferably chloro and fluoro more preferably fluoro, cyano, alkyl preferably methyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl, cycloalkylalkyloxy, aryloxy, aralkyloxy, haloalkoxyalkyl, alkylamino, alkylsulfonyl preferably methylsulfonyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, preferably R , R , R and R are independently selected from H, halo preferably chloro and fluoro more preferably fluoro, cyano, alkyl preferably methyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl, cycloalkylalkyloxy, aryloxy, aralkyloxy, alkylamino, alkylsulfonyl preferably methylsulfonyl, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, more preferably R , R , R and R are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, alkyl preferably methyl, haloalkyl preferably CF3 or CHF2, alkoxy preferably methoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy preferably (2-methoxy)ethoxy, alkylamino preferably dimethylamino, more preferably R17 , R18 and R19 are H and R17 is methoxy, (2-methoxy)ethoxy or R17, R18’ and R19 are H and R is methoxy, or R , R and R are H and R is chloro, methyl, methoxy, dimethylamino, or R and R are H and: a) both R and R are methyl or methoxy, or b) R17 is methyl and R19 is methoxy, or R17, R17 and R19 are H and R is methoxy even more preferably R , R and R are H and R is methoxy, or R and R are H and: a) both R and R are methyl or methoxy, or b) R17 is methyl and R19 is methoxy, or R17, R17 and R19 are H and R is methoxy.

Other preferred compounds of formula Ib-lg are those of formula

Ib-lg2

Ib-lg2 and phannaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect to formula Ib-le; R12 and R12 are as defined above in respect to formula Ib-lg, preferably R12 and R12’ are independently selected from H, halo preferably chloro, cyano, nitro, alkyl preferably ethyl, isopropyl, haloalkyl preferably CF3 or CHF2, aryl preferably phenyl, hydroxyl, alkoxy preferably methoxy or ethoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, arylalkyloxy preferably phenethyloxy or benzyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, alkoxy, alkyl, cycloalkyl, alkylsulfonyl preferably methylsulfonyl, more preferably R12 is H or alkoxy preferably methoxy or ethoxy, more preferably methoxy and R12 is halo preferably chloro, alkoxy preferably methoxy or ethoxy, more preferably methoxy, arylalkyloxy preferably phenethyloxy, benzyloxy or 3,3- diphenylpropan-l-oxy, optionally substituted by halo preferably chloro or fluoro, 12 alkoxy, alkyl, alkylsulfonyl preferably methylsulfonyl, even more preferably R is methoxy and R12 is methoxy, chloro, benzyloxy, (4-chlorobenzyl)oxy, (4-methylsulfonylbenzyl)oxy.

Other preferred compounds of formula Ib-lg are those of formula

Ib-lh

Ib-lh and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8 , R9, R9 and R10 are as defined above in respect to formula Ib-le; L4 is a single bond, -C(O)-, -0-, -0-Ci-C3-alkylene or -Ci-C3-alkylene-0-optionally substituted by one or more group selected from fluoro or methyl, preferably L4 is a single bond, -0-, -0-Ci-C2-alkylene, -Ci-alkylene-O-optionally substituted by one or more group selected from fluoro or methyl, more preferably L4 is a single bond, -OCH2, -0(CH2)2- or -CH20-; 11 ii’ j2 i2? R11, R11, R and R are as defined above in respect to formula Ib-lg, preferably R11 and R11 are H and R12 and R12 are independently selected from H, halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, isopropyl, haloalkyl preferably CF3 or CHF2, hydroxyl, alkoxy preferably methoxy or ethoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, more preferably R11 and R11’ are H, R12 is H, fluoro, chloro, methyl, -CF3, alkoxy preferably methoxy or ethoxy, more preferably methoxy and R12 is halo preferably chloro, alkoxy preferably methoxy or ethoxy, more preferably methoxy, or R11, R11 and R12 are H and R12 is fluoro, chloro, methyl, CF3, methoxy, even more preferably R11 and R11’ are H, R12 is H or methoxy and R12’ is methoxy,chloro, or R11, R11’ and R12’ are H and R12 is fluoro, chloro, methyl, CF3, methoxy; R13, R13’, R14, R14’ and R15 are independently selected from H, halo preferably chloro and fluoro more preferably fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3 or CHF2, cyanomethyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl, cycloalkylalkyloxy, aralkyloxy optionally substituted by one fluoro, haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, preferably R13, R13’, R14, R14’ and R15 are independently selected from H, halo preferably chloro and fluoro more preferably fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl, cycloalkylalkyloxy, aralkyloxy optionally substituted by one fluoro, haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino, more preferably R13, R13, R14, R14’ and R15 are independently selected from H, halo preferably chloro and fluoro more preferably fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably -CF3 or CHF2, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy preferably 2-methoxyethoxy, cycloalkyloxy, cycloalkylalkyloxy, alkoxyalkyl preferably methoxymethyl, haloalkoxyalkyl, amino, alkylcarbonylamino preferably acetylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, still more preferably R13, R13’, R14, R14’ and R15 are independently selected from H, halo preferably chloro and fluoro, more preferably fluoro, cyano, nitro, alkyl preferably methyl, haloalkyl preferably -CF3 or -CHF2, alkoxyalkyl preferably methoxymethyl, alkoxy preferably methoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy preferably 2-methoxyethoxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, even more preferably R13, R13 , R14 and R14’ are H and R15 is H, chloro, methyl or methoxy, methylsulfonyl, methylsulfonylamino, preferably H, methylsulfonyl, methylsulfonylamino, or R13’, R14, R14’ and R15 are H and R13 is methoxy or chloro, preferably chloro, or R13, R13 , R14 and R15 are H and R14 is methylsulfonylamino, or R13 , R14 and R14 are H and R13 and R15 are a) both F, or b) R13 is F and R15 is methoxy, or c) R13 is methoxy and R15 is F, or d) R13 is methoxy and R15 is acetylamino, or e) R13 is methoxy and R15 is amino, or f) R13 is cyano and R15 is methoxy, or g) R13 is chloro and R15 is cyano, or h) R13 is cyano and R15 is trifluoromethyl, or i) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R13, R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13, R13 and R14 are H and R14 and R15 are both methoxy, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R14 is methoxy and R14 is cyano, or c) R14 is methyl and R14 is cyano, or R13, R13 and R15 are H and R14 and R14 are both methoxy, or R13 and R14 are H and R13, R14 and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14’ are methoxy, or R13 and R14 are methoxy and R13’ and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14 and R15 are methoxy.

Preferred compounds of formula Ib-lh are those of formula Ib-lhl

Ib-lhl and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect to formula Ib-le; R12 is as defined above in respect to formula Ib-lh, preferably R12 is H, fluoro, chloro, methyl, CF3, nitro, cyano, methoxy or cyclopropylmethyloxy; R13, R13 , R14, R14 and R15 are as defined above in respect to formula Ib-lh, preferably R13 , R14, R14 and R15 are H and R13 is chloro, cyano, hydroxyl, methyl, trifluoromethyl, cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF3, cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy, (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy, carbamoylmethyloxy, or R13, R13 , R14 and R15 are H and R14 is chloro, methylsulfonylamino, or R13, R13 , R14 and R14’ are H and R15 is chloro, methylsulfonylamino, R13 , R14 and R14 are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) 13 15 13 15 both F, or c) R is F and R is methoxy, or d) R is methoxy and R is F, or e) 13 15 13 15 R is methoxy and R is acetylamino, or f) R is methoxy and R is amino, or 13 15 13 15 13 g) R is cyano and R is methoxy, or h) R is chloro and R is cyano, or i) R is cyano and R15 is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14 and R15 are H and both R13 and R13 are methoxy, or R13, R13 and R15 are H and both R14 and R14 are fluoro, methoxy, or R13, R13’ and R14’ are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methoxy and R14 is cyano, or c) R13 is methyl and R14 is cyano, or R13 and R14 are H and R13 , R14 and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14 and R15 are methoxy, more preferably R13, R14, R14 and R15 are H and R13 is chloro, cyano, trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy, or R13, R13 , R14 and R15 are H and R14 is chloro, or R13, R13 , R14 and R14 are H and R15 is chloro, methylsulfonylamino, or R13 , R14 and R14 are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) both F, or c) R13 is F and R15 is methoxy, or d) R13 is methoxy and R15 is F, or e) R13 is methoxy and R15 is acetylamino, or f) R is methoxy and R is amino, or g) R is cyano and R is methoxy, or h) R is chloro and R is cyano, or i) R is cyano and R is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14 and R15 are H and both R13 and R13 are methoxy, or R13, R13 and R14 are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methoxy and R14’ is cyano, or c) R13 is methyl and R14 is cyano, or R13 and R14 are H and R13, R14’ and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14’ and R15 are methoxy.

Other preferred compounds of formula Ib-lg are those of formula

Ib-lh’

Ib-lh’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8, R9, R9 and R10 are as defined above in respect to formula Ib-le; R12 is as defined above in respect to formula Ib-lg, preferably R12 is H, fluoro, chloro, methyl, CF3, or methoxy more preferably R12 is H or methoxy; R16 is selected from the group of heteroaryl moieties consisting of:

,wherein the arrow marks the attachment point to the phenyl ring; R17, R17’, R18, R18’ and R19 are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3 or CHF2, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl preferably methoxymethyl, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, haloalkylsulfonylamino, preferably R17, R17, R18 and R19 are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino, carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonylamino, more preferably R , R , R and R are independently selected from H, halo preferably chloro, alkoxy preferably methoxy, even more preferably R17, R17, R18 and R19 are independently selected from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Ib-lh’ are those wherein R16 is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4- dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5 -yl, 2-methoxypyrimidin-5 -yl, 2-methoxypyrimidin-3-yl.

Still other preferred compounds of formula Ib-lg are those of formula Ib-lh”

Ib-lh” and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R8 is F or Cl and R9 is H, or both R8 and R9 are F; R is H, methyl, ethyl or tert-butyl; A°, A0, A1, A2, A3, A4 and A5 are selected from the combinations 1 to 24:

Still other preferred compounds of formula Ib-lg are those of formula Ib-li

Ib-li and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8 , R9, R9 and R10 are as defined above in respect to formula Ib-lf; L4, R11, R11’, R12’ R13, R13, R14, R14’ and R15 is as defined above in respect to formula Ib-lh; R16 is as defined above in respect to formula Ib-lg, preferably R16 is selected from H, halo preferably chloro or fluoro more preferably chloro, alkyl, haloalkyl preferably CF3 or CHF2, aryl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, or R16 forms together with R12’ an alkylenedioxy group or a haloalkylenedioxy group, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, alkoxy, alkyl, alkylsulfonyl, more preferably R16 is selected from H, halo preferably chloro and fluoro more preferably chloro, alkyl, haloalkyl preferably CF3 or CHF2, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, haloalkoxyalkyl, or R16 forms together with R12’ an alkylenedioxy group or a haloalkylenedioxy group, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, alkoxy, alkyl, cycloalkyl, alkylsulfonyl.

Other preferred compounds of formula Ib-lf are those of formula

Ib-lj

Ib-lj and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8 , R9, R9 and R10 are as defined above in respect of formula Ib-lf; L4 is as defined above in respect to formula Ib-lh, preferably L4 is a single bond; R11 and R11 are as defined above in respect to formula Ib-lh, preferably R11 and R11’ are H; R12 is as defined above in respect to formula Ib-lh, preferably R12 is H or methoxy, more preferably R12 is H; R13, R13’, R14, R14’ and R15 are as defined above in respect to formula Ib-lh, preferably R13’, R14, R14’ and R15 are H and R13 is chloro, fluoro, methoxy, or R13, R13 , R14 and R15 are H and R14 is methoxy, or R13 , R14 and R15 are H and a) both R13 and R14’ are chloro or b) R13 is methoxy and R14 is cyano, or R13, R14 and R14 are H and both R13 and R15 are methoxy more preferably R13 , R14, R14 and R15 are H and R13 is chloro, or R13, R14 and R15 are H and both R13 and R14 are chloro.

Other preferred compounds of formula Ib-lf are those of formula

Ib-lk

Ib-lk and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect of formula Ib-le; 129 129 R is H, fluoro, chloro, CF3, methyl or methoxy, preferably R is H or methoxy, more preferably R12’ is methoxy; R17, R17’, R18’ and R19 are independently selected from H, halo preferably chloro and fluoro, more preferably fluoro, cyano, nitro, alkyl preferably methyl, haloalkyl preferably CF3 or CHF2, alkoxyalkyl preferably methoxymethy, alkoxy preferably methoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy preferably 2-methoxyethoxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, preferably R and R are H and both R and R19 are methoxy.

Other preferred compounds of formula Ib-lf are those of formula lb-11

lb-11 and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8, R9, R9 and R10 are as defined above in respect of formula Ib-le; R20 is an aryl or heteroaryl, each of said aryl or heteroaryl being optionally substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, cyano, nitro, phenyl optionally substituted by one chloro, alkoxy, heterocyclylsulfonyl, alkylsulfamoyl or alkylsulfonylamino, preferably R20 is a phenyl optionally substituted by one or more substituent(s) selected from halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably CF3, cyano, nitro, alkoxy preferably methoxy, heterocyclylsulfonyl preferably (piperidin-l-yl)sulfonyl, (morpholin-4-yl)sulfonyl, alksulfamoyl preferably diethylaminosulfonyl, alkylsulfonylamino preferably methylsulfonylamino, or R20 is 4-(4-chlorophenyl)thiazol-2-yl, or R20 is a benzoxazol-2-yl, more preferably R20 is 2-methoxyphenyl, 2-cyano-4-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 2-nitro-4-trifluoromethylphenyl, 2-nitro-4-(piperidin-1 -yl)sulfonyl phenyl, 4-(morpholin-4-yl)sulfonylphenyl, 2-nitro-4-diethylaminosulfonyl phenyl, 2-nitro-4-tolyl, 2-cyano-4-nitrophenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 3-methoxy-4-nitrophenyl, 5-chloro-2- nitrophenyl, 2-cyano-4-methylsulfonylaminophenyl, 2-cyano-4-methoxyphenyl, 2-methylsulfonylamino-4-trifluoromethylphenyl, 2-nitrophenyl, 4-cyanophenyl, 2-methoxy-4-trifluoromethylphenyl, or R20 is 4-(4-chlorophenyl)thiazol-2-yl, or R2" is a benzoxazol-2-yl, even more preferably R20 is 2-cyano-4-trifluoromethylphenyl, 2-nitro-4-trifluoromethylphenyl, 2-methoxy-4-trifluoromethylphenyl.

Other preferred compounds of formula lb are those of formula Ib-2

Ib-2 and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1, Ar2, R1, R2, R3, R3, R4, R4, L2, L3, D, E and Z are as defined above in respect of formula lb; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ib-2 and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Further preferred compounds of formula lb are those of formula Ib-3

Ib-3 and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1, Ar2, R1, R2, R3, R3, R4, R4, L1, L2, D and E are as defined above in respect of formula lb, R is as defined above in respect of formula I; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ib-3 and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein dotted line is absent.

Yet other preferred compounds of formula lb are those of formula

Ib-4

Ib-4 and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1, Ar2, R1, R2, L1, L2, L3, D, E and Z are as defined above in respect of formula lb; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ib-4 and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Further preferred compounds of formula lb are those of formula Ib-5

Ib-5 and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1, Ar2, L1, L3, R1, R2, R3, R3 , R4, R4 and Z are as defined above in respect of formula lb; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ib-5 and pharmaceutically acceptable salts, olvates and prodrugs thereof are those wherein the dotted line is absent.

Further preferred compounds of formula lb are those of formula Ib- 6

Ib-6 and pharmaceutically acceptable salts, solvates and prodrugs thereof,wherein

Ar1, Ar2, L1, L2, L3, R3, R3 , R4, R4 , D, E and Z are as defined above in respect of formula lb; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ib-6 and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

In yet another embodiment, preferred compounds of Formula I are those of formula Ic:

Ic and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1, Ar2, L1, L2, L3, R1, R2, R3, R3 , R4, R4 , D, E and Z are as defined above in respect of formula I; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ic and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Other preferred compounds of formula Ic are those of formula Ic-lb’:

Ic-lb’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R2 is as defined above in respect of formula Ic and R is as defined above in respect of formula I; R1 is H; D is C=0; L2 is single bond;

Ar1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered cycloalkyl group, or a linear or branched C3-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, each of said aryl or heteroaryl substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, preferably Ar1 is a 5- to 6-membered aryl preferably phenyl, 5- to 6-membered heteroaryl group preferably pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl, isobutyl or isopentyl each of said phenyl, pyridin-2-yl, pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 alkoxy preferably methoxy, aryl preferably phenyl, still more preferably Ar1 is aryl preferably phenyl, cyclohexyl, isobutyl or isopentyl, said phenyl group being optionally substituted by one or more halo group preferably bromo, chloro or fluoro, cyano, methyl, phenyl or methoxy, further more preferably Ar1 is phenyl, cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, l,l'-biphenyl-2-yl, 4-cyanophenyl, even more preferably Ar1 is isobutyl, cyclohexyl, phenyl , 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, still even more preferably Ar1 is isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl;

Ar2 is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino, alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl, heteroaryl, cycloalkyl or heterocyclyl group may be one or more aryl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and haloalkoxyalkyl; preferably Ar2 is an aryl or heteroaryl preferably pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, cyanomethyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably Ar2 is an aryl preferably phenyl, heteroaryl preferably pyridyl, heterocyclyl preferably piperidinyl, C2-C6 alkyl group preferably isobutyl, each of said aryl, heteroaryl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, preferably methyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, nitro, alkyl preferably methyl, cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonylalkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, further more preferably Ar2 is a biaryl consisting of two 6-membered aryl moieties preferably biphenyl, more preferably a biphenyl linked to L2 at position 4’ and monosubstituted at position 2, or Ar2 is a heterobiaryl consisting of one 6-membered aryl moiety and one 6-membered heteroaryl moiety or two 6-membered heteroaryl moieties, said heterobiaryl being linked to L2 either on the aryl or on the heteroaryl moiety and being preferably phenylpyridyl, pyrimidinylphenyl, pyridazinylphenyl, pyrazinylphenyl, or Ar2 is an aryl or heteroaryl optionally substituted by one group selected from arylalkyloxy, aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl and heteroaryl groups being optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, or Ar2 is a piperidinyl ring linked to L2 at position 4 and N substituted with a phenyl, 4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said phenyl moiety being further substituted by one or more substituents selected from halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, haloalkyl preferably CF3, alkoxy preferably methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl, (morpholin-4-yl)sulfonyl, alksulfamoyl preferably methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar2 is 4’-(2-methoxy-1,1 ’-biphenyl), 4’-(2-methyl-1,1 ’-biphenyl), 4’-(2-fluoro-1,1 ’-biphenyl), 4’-(4-chloro-1,1 ’-biphenyl), 4’-(2-chloro-1,1 ’-biphenyl), 4’-(2-chloro-2'-methoxy-1,Γ-biphenyl), 4’-(2-(2-methoxyethoxy)-l,Γ-biphenyl), 4’-(2-(methoxymethyl)-Ι,Γ-biphenyl), 4’-(4-methoxy-l,l'-biphenyl), 4’-(4-cyano-l,l'-biphenyl), 4’-(3- chloro-1,1 ’-biphenyl), 4 ’-(2-chloro-1,1 ’-biphenyl), 4 ’-(4-methylsulfonylamino- 1.1 ’-biphenyl), 4 ’-(2-trifluoromethoxy-1,1 ’-biphenyl), 4 ’-(2-isopropoxy-1,1'- biphenyl), 4’-(2-cyclopropylmethyloxy-1,1 ’-biphenyl), 4’-(2-cyano-1,1 ’-biphenyl), 4 ’ -(2,6-dimethoxy-1,1 ’-biphenyl), 4 ’-(2,4-dichloro-1,1 ’-biphenyl), 4 ’-(2- trifluoromethyl-1,1 ’-biphenyl), 4’-(2-methoxy-4-chloro-1,1 ’-biphenyl), 4’-(2,4-dimethoxy-1,1 ’-biphenyl), 4-(2,2'-dimethoxy-1,1 ’-biphenyl), 4-(naphtalen-2- yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl, 4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(2-methoxypyridin-3-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl, 4-(2,4-dimethoxypyrimidin-6-yl)phenyl, 4-(2,4- dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl, 4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl, (4-phenoxymethyl)phenyl, optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, more preferably fluoro, alkyl preferably methyl, alkoxy preferably methoxy, or Ar2 is 4’-(2,4-difluoro-l,l'-biphenyl), 4’-(3’-methyl-1,1'-biphenyl), 4’-(3’-fluoro-l,r-biphenyl), 4’-(2-fluoro-4-methoxy-l,l'-biphenyl), 4’-(4-fluoro-2-methoxy-1,1 ’-biphenyl), 4’-(2,3-dimethoxy-1,1 ’-biphenyl), 4 ’-(3,4-dimethoxy-1,1 ’-biphenyl), 4’-(2,3,4-trimethoxy-1,1 ’-biphenyl), 4’-(2,3,6- trimethoxy-1,1 ’-biphenyl), 4’-(3,5-dimethoxy-1,1 ’-biphenyl), 4 ’-(2,5-dimethoxy- 1.1 ’-biphenyl), 4’-(2-isopropyl-1,1 ’-biphenyl), 4’-(2,2’-dimethoxy-1,1 ’-biphenyl), 4’-(2’-fluoro,2-dimethoxy-l, 1 ’-biphenyl), 4’-(2-ethyl-1,1 ’-biphenyl), 4’-(4-propyl- 1.1 ’-biphenyl), 4 ’-(4-terf-butyl-1,1 ’-biphenyl), 4 ’ -(2-methoxy-4- methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methoxy-4-acetylamino-1,1 ’-biphenyl), 4’-(3-hydroxycarbamimidoyl-1,1 ’-biphenyl), 4’-(4-amino-2-methoxy-1,1’- biphenyl), 4’-(3-carbamoyl-1,1 ’-biphenyl), 4’-(5-cyano-2,3-dimethoxy-1,1’- biphenyl), 4’-(2-cyano-4,5-dimethoxy-l, 1 ’-biphenyl), 4’-(3,4,5-trimethoxy-l, 1 '-biphenyl), 4’-(2-cyanomethyl-4,5-dimethoxy-1,1’-biphenyl), 4’-(2-fluoro-5-cyano-1,1 ’-biphenyl), 4 ’-(2 ’-fluoro-3,4-dimethoxy-1,1 ’-biphenyl), 4 ’-(3- carbamoyl-4-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-methoxy-1,1 ’-biphenyl), 4’-(2’-fluoro-4-methylsulfonylamino-1,1 ’-biphenyl), 4’-(2’-fluoro-3- methylsulfonylamino-1,1 ’-biphenyl), 4’-(2-cyano-2’-fluoro-1,1 ’-biphenyl), 4’-(2-chloro-5-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-trifluoromethyl-1,1 ’-biphenyl), 4’-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-l,r-biphenyl), 4’-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1 ’-biphenyl), 4’-(4-methylsulfonyl-1,1'-biphenyl), 4’-(3-methylsulfonylamino-1,1 ’-biphenyl), 4’-(4-amino-2-methyl-1,1'-biphenyl), 4’-(5-cyano-2-methyl-1,1 ’-biphenyl), 4’-(5-cyano-2-methoxy-1,1'-biphenyl), 4’-(3-cyano-l,l'-biphenyl), 4’-(2-cyano-3-methoxy-l,r-biphenyl), 4’-(2-methyl-3-methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methyl-3-acetylamino- 1,1 ’-biphenyl), 4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl, 4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl, 4-(2-methoxy-6-methylpyridin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl, 4-(2,6- dimethylpyridin-5-yl)phenyl, 4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl, 4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl, 4-(4,6-dimethoxy-pyridin-3-yl)phenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl, 4-(6-methoxy-pyridin-3-yl)-3- fluorophenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl, 4-(4,6- dimethoxy-pyrimidin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-5-yl)-3- methoxyphenyl, 4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3- yl)phenyl, 4-(2-methoxy-pyrimidin-3-yl)phenyl, 3-methoxy-2-(2- methoxyphenyl)pyridin-5 -yl, 3 -methoxy-2-(5 -cyano-2-methoxyphenyl)pyridin-5 -yl, 3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl, 2-(2,4- dimethoxyphenyl)pyridin-5-yl, 1 -(2-cyano-4-trifluoromethyl)piperidin-4-yl, 1 -(2-nitro-4-trifluoroniethyl)piperidin-4-yl, l-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; R3 is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl, arylsulfonyl; R3 is H or C1-C4 alkyl; R4 is H, cyano, C1-C4 alkyl.

Preferred compounds of formula Ic-lb’ are those of formula Ic-lg:

Ic-lg and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, heterocyclyloxy, alkylamino, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaiyloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, aiylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, preferably R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, alkylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, more preferably R8, R8’, R9, R9 and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, cyano, C1-C4 alkyl preferably methyl, aryl preferably phenyl, alkoxy preferably methoxy, still more preferably R8, R8, R9, R9 and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, alkyl preferably methyl, still more preferably R8 is Br, Cl or F, preferably Cl and R8 , R9, R9 and R10 are independently selected from H or F, or R9 is Cl or F and R8, R8 , R9 and R10 are H, or R9 and R9 are F and R8, R8 and R10 are H, or R10 is Cl

O OJ Q Q? O or F and R , R , R and R are H, even more preferably R is Br, Cl or F and R8 , R9, R9 and R10 are H, or R8 and R9 are F and R8 , R9 and R10 are H, or R8 and R10 are F and R8 , R9 and R9 are H; R11, R11, R12, R12’ and R16 are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkyloxycarbonyl, aminoalkylalkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R11 and R12, or R12 and R16, or R16 and R12’, or R12 and R11 form an alkylenedioxy group or a halo alky lenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12 , or R12 and R11 form together a cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably trifluoromethoxt, 1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12’ and R11’ form together an aryl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy, alkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino and oxo, more preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or one or more of R and R , or R and R , or R16 and R12, or R12 and R11 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11 form together an aryl, or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl preferably CF3 or CHF2, cycloalkyl preferably cyclohexyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, haloalkyl preferably trifluoromethyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Ic-lg are those of formula Ic-lhl:

Ic-lhl and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8 , R9, R9 and R10 are as defined above in respect to formula Ic-lg; R12 is as defined above in respect to formula Ic-lg, preferably R12 is H, fluoro, chloro, methyl, CF3, nitro, cyano, methoxy or cyclopropylmethyloxy; R13, R13’, R14, R14’ and R15 are as defined above in respect to formula Ic-lg, preferably R13, R14, R14’ and R15 are H and R13 is chloro, cyano, hydroxyl, methyl, trifluoromethyl, cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF3, cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy, (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy, carbamoylmethyloxy, or R13, R13, R14’ and R15 are H and R14 is chloro, methylsulfonylamino, or R13, R13 , R14 and R14’ are H and R15 is chloro, methylsulfonylamino, R13, R14 and R14’ are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) both F, or c) R is F and R is methoxy, or cl) R is methoxy and R is F, or e) _ 1Ί ic -| ·> ic R is methoxy and R is acetylamino, or f) R is methoxy and R is amino, or _ -| ip _ 1Λ ip _ -| 1 g) R is cyano and R is methoxy, or h) R is chloro and R is cyano, or i) R is cyano and R15 is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14’ and R15 are H and both R13 and R13’ are methoxy, or R13, R13 and R15 are H and both R14 and R14 are fluoro, methoxy, or R13, R13’ and R14’ are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methoxy and R14 is cyano, or c) R13 is methyl and R14 is cyano, or R13 and R14 are H and R13 , R14 and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14 and R15 are methoxy, more preferably R13, R14, R14 and R15 are H and R13 is chloro, cyano, trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy, or R13, R13 , R14 and R15 are H and R14 is chloro, or R13, R13 , R14 and R14 are H and R15 is chloro, methylsulfonylamino, or R13 , R14 and R14 are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) both F, or c) R13 is F and R15 is methoxy, or d) R13 is methoxy and R15 is F, or e) R13 is methoxy and R15 is acetylamino, or f) R is methoxy and R is amino, or g) R is cyano and R is methoxy, or h) R is chloro and R is cyano, or i) R is cyano and R is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14 and R15 are H and both R13 and R13 are methoxy, or R13, R13 and R14 are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methoxy and R14 is cyano, or c) R13 is methyl and R14 is cyano, or R13 and R14 are H and R13 , R14 and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14 and R15 are methoxy.

Other preferred compounds of formula Ic-lg are those of formula

Ic-lh’:

Ic-lh’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect to formula Ic-lg; R is as defined above in respect to formula Ic-lg, preferably R is H, fluoro, chloro, methyl, CF3, or methoxy more preferably R12 is H or methoxy; R16 is selected from the group of heteroaryl moieties consisting of:

,wherein the arrow marks the attachment point to the phenyl ring; R17, R17, R18, R18 and R19 are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3 or CHF2, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl preferably methoxymethyl, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, haloalkylsulfonylamino, preferably R , R , R and R are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino, carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonylamino, more preferably R , R , R and R are independently selected from H, halo preferably chloro, alkoxy preferably methoxy, even more _ I 1 «5 4 09 _ I Λ preferably R , R , R and R are independently selected from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Ic-lh’ are those wherein R16 is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxypyrimidin-3-yl.

In yet another embodiment, preferred compounds of Formula I are those of formula Id:

Id and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1, Ar2, L1, L2, L3, R1, R2, R3, R3’, R4, R4’, D, E and Z are as defined above in respect of formula I; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Id and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Other preferred compounds of formula Id are those of formula Id-lb’:

Id-lb’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R2 is as defined above in respect of formula Id and R is as defined above in respect of formula I; R1 is H; D is C=0; L2 is single bond;

Ar1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered cycloalkyl group, or a linear or branched C3-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, each of said aryl or heteroaryl substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, preferably Ar1 is a 5- to 6-membered aryl preferably phenyl, 5- to 6-membered heteroaryl group preferably pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl, isobutyl or isopentyl each of said phenyl, pyridin-2-yl, pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 alkoxy preferably methoxy, aryl preferably phenyl, still more preferably Ar1 is aryl preferably phenyl, cyclohexyl, isobutyl or isopentyl, said phenyl group being optionally substituted by one or more halo group preferably bromo, chloro or fluoro, cyano, methyl, phenyl or methoxy, further more preferably Ar1 is phenyl, cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 2,4- dichlorophenyl, 2-bromophenyl, 2-cyanophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, l,l'-biphenyl-2-yl, 4-cyanophenyl, even more preferably Ar1 is isobutyl, cyclohexyl, phenyl , 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, still even more preferably Ar1 is isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl;

Ar2 is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino, alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl, heteroaryl, cycloalkyl or heterocyclyl group may be one or more aryl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and haloalkoxyalkyl; preferably Ar2 is an aryl or heteroaryl preferably pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, cyanomethyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably Ar2 is an aryl preferably phenyl, heteroaryl preferably pyridyl, heterocyclyl preferably piperidinyl, C2-C6 alkyl group preferably isobutyl, each of said aryl, heteroaryl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, preferably methyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, nitro, alkyl preferably methyl, cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonylalkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, further more preferably Ar2 is a biaryl consisting of two 6-membered aryl moieties preferably biphenyl, more preferably a biphenyl linked to L2 at position 4’ and monosubstituted at position 2, or Ar2 is a heterobiaryl consisting of one 6-membered aryl moiety and one 6-membered heteroaryl moiety or two 6-membered heteroaryl moieties, said heterobiaryl being linked to L2 either on the aryl or on the heteroaryl moiety and being preferably phenylpyridyl, pyrimidinylphenyl, pyridazinylphenyl, pyrazinylphenyl, or Ar2 is an aryl or heteroaryl optionally substituted by one group selected from arylalkyloxy, aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl and heteroaryl groups being optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, or Ar2 is a piperidinyl ring linked to L2 at position 4 and N substituted with a phenyl, 4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said phenyl moiety being further substituted by one or more substituents selected from halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, haloalkyl preferably CF3, alkoxy preferably methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl, (morpholin-4-yl)sulfonyl, alksulfamoyl preferably methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar2 is 4’-(2-methoxy-1,1 ’-biphenyl), 4’-(2-methyl-1,1 ’-biphenyl), 4’-(2-fluoro-1,1 ’-biphenyl), 4’-(4-chloro-1,1 ’-biphenyl), 4’-(2-chloro-1,1 ’-biphenyl), 4’-(2-chloro-2'-methoxy- 1.1 ’-biphenyl), 4’-(2-(2-methoxyethoxy)-1,1 ’-biphenyl), 4’-(2-(methoxymethyl)-Ι,Γ-biphenyl), 4’-(4-methoxy-l,l'-biphenyl), 4’-(4-cyano-l,l'-biphenyl), 4’-(3-chloro-1,1 ’-biphenyl), 4 ’-(2-chloro-1,1 ’-biphenyl), 4 ’-(4-methylsulfonylamino- 1.1 ’-biphenyl), 4 ’-(2-trifluoromethoxy-1,1 ’-biphenyl), 4 ’-(2-isopropoxy-1,1'- biphenyl), 4’-(2-cyclopropylmethyloxy-1,1 ’-biphenyl), 4’-(2-cyano-1,1 ’-biphenyl), 4 ’-(2,6-dimethoxy-1,1 ’-biphenyl), 4 ’-(2,4-dichloro-1,1 ’-biphenyl), 4’-(2-trifluoromethyl-1,1 ’-biphenyl), 4’-(2-methoxy-4-chloro-1,1 ’-biphenyl), 4’-(2,4-dimethoxy-1,1 ’-biphenyl), 4-(2,2’-dimethoxy-1,1 ’-biphenyl), 4-(naphtalen-2- yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl, 4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(2-methoxypyridin-3-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl, 4-(2,4-dimethoxypyrimidin-6-yl)phenyl, 4-(2,4- dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl, 4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl, (4-phenoxymethyl)phenyl, optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, more preferably fluoro, alkyl preferably methyl, alkoxy preferably methoxy, or Ar2 is 4’-(2,4-difluoro-l,l'-biphenyl), 4’-(3’-methyl-1,1'-biphenyl), 4’-(3’-fluoro-l,r-biphenyl), 4’-(2-fluoro-4-methoxy-l,l'-biphenyl), 4’-(4-fluoro-2-methoxy-1,1 ’-biphenyl), 4’-(2,3-dimethoxy-1,1 ’-biphenyl), 4 ’-(3,4-dimethoxy-1,1 ’-biphenyl), 4’-(2,3,4-trimethoxy-l, Γ-biphenyl), 4’-(2,3,6-trimethoxy-1,1 ’-biphenyl), 4’-(3,5-dimethoxy-1,1 ’-biphenyl), 4’-(2,5-dimethoxy- 1.1 ’-biphenyl), 4’-(2-isopropyl-1,1 ’-biphenyl), 4’-(2,2’-dimethoxy-1,1 ’-biphenyl), 4’-(2’-fluoro,2-dimethoxy-1,1 ’-biphenyl), 4’-(2-ethyl-1,1 ’-biphenyl), 4 ’-(4-propyl-1, Γ-biphenyl), 4’-(4-tert-butyl-l, 1 ’-biphenyl), 4’-(2-methoxy-4- methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methoxy-4-acetylamino-1,1 ’-biphenyl), 4’-(3-hydroxycarbamimidoyl-1,1 ’-biphenyl), 4’-(4-amino-2-methoxy-1,1'- biphenyl), 4’-(3-carbamoyl-1,1 ’-biphenyl), 4’-(5-cyano-2,3-dimethoxy-1,1'- biphenyl), 4’-(2-cyano-4,5-dimethoxy-l, 1 '-biphenyl), 4’-(3,4,5-trimethoxy-l, 1 'biphenyl), 4’-(2-cyanomethyl-4,5-dimethoxy-l,r-biphenyl), 4’-(2-fluoro-5-cyano-1,1 '-biphenyl), 4 ’-(2 ’-fluoro-3,4-dimethoxy-1,1 '-biphenyl), 4 ’-(3- carbamoyl-4-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-methoxy-1,1 ’-biphenyl), 4’-(2’-fluoro-4-methylsulfonylamino-l,r-biphenyl), 4’-(2’-fluoro-3- methylsulfonylamino-1,1 ’-biphenyl), 4’-(2-cyano-2’-fluoro-1,1 ’-biphenyl), 4’-(2-chloro-5-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-trifluoromethyl-1,1 ’-biphenyl), 4’-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-l,r-biphenyl), 4’-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1 ’-biphenyl), 4’-(4-methylsulfonyl-1,1’-biphenyl), 4’-(3-methylsulfonylamino-1,1 ’-biphenyl), 4’-(4-amino-2-methyl-1,1’-biphenyl), 4’-(5-cyano-2-methyl-1,1 ’-biphenyl), 4’-(5-cyano-2-methoxy-1, Γ- biphenyl), 4’-(3-cyano-l,l'-biphenyl), 4’-(2-cyano-3-methoxy-l,r-biphenyl), 4’-(2-methyl-3-methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methyl-3-acetylamino- 1,1 ’-biphenyl), 4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl, 4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl, 4-(2-methoxy-6-methylpyridin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl, 4-(2,6- dimethylpyridin-5-yl)phenyl, 4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl, 4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl, 4-(4,6-dimethoxy-pyridin-3-yl)phenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl, 4-(6-methoxy-pyridin-3-yl)-3- fluorophenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl, 4-(4,6- dimethoxy-pyrimidin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-5-yl)-3- methoxyphenyl, 4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3- yl)phenyl, 4-(2-methoxy-pyrimidin-3-yl)phenyl, 3-methoxy-2-(2- methoxyphenyl)pyridin-5 -yl, 3 -methoxy-2-(5 -cyano-2-methoxyphenyl)pyridin-5 -yl, 3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl, 2-(2,4- dimethoxyphenyl)pyridin-5-yl, 1 -(2-cyano-4-trifluoromethyl)piperidin-4-yl, 1 -(2-nitro-4-trifluoroniethyl)piperidin-4-yl, l-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; R3 is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl, arylsulfonyl; R3 is H or C1-C4 alkyl; R4 is H, cyano, C1-C4 alkyl.

Preferred compounds of formula Id-lb’ are those of formula Id-lg:

Id-lg and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, heterocyclyloxy, alkylamino, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, aiylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9, or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, preferably R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, alkylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9, or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, more preferably R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, cyano, C1-C4 alkyl preferably methyl, aryl preferably phenyl, alkoxy preferably methoxy, still more preferably R8, R8 , R9, R9 and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, alkyl preferably methyl, still more preferably R8 is Br, Cl or F, preferably Cl and R8 , R9, R9 and R10 are independently selected from H or F, or R9 is Cl or F and R8, R8 , R9 and R10 are H, or R9 and R9 are F and R8, R8 and R10 are H, or R10 is Cl

O OJ Q Q? O or F and R , R , R and R are H, even more preferably R is Br, Cl or F and R8 , R9, R9 and R10 are H, or R8 and R9 are F and R8 , R9 and R10 are H, or R8 and R10 are F and R8 , R9 and R9 are H; R11, R11, R12, R12’ and R16 are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkyloxycarbonyl, aminoalkylalkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11’ form an alkylenedioxy group or a halo alky lenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and Rir form together a cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably trifluoromethoxt, 1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11’ form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11 form together an aryl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy, alkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino and oxo, more preferably R , R , R , R and R are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or one or more of R and R , or R and R , or R and R , or R and R form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12 and R11 form together an aryl, or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl preferably CF3 or CHF2, cycloalkyl preferably cyclohexyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, haloalkyl preferably trifluoromethyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Id-lg are those of formula Id-lhl:

Id-lhl and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect to formula Id-lg; R12 is as defined above in respect to formula Id-lg, preferably R12 is H, fluoro, chloro, methyl, CF3, nitro, cyano, methoxy or cyclopropylmethyloxy; R13, R13’, R14, R14’ and R15 are as defined above in respect to formula Id-lg, preferably R13, R14, R14’ and R15 are H and R13 is chloro, cyano, hydroxyl, methyl, trifluoromethyl, cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF3, cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy, (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy, carbamoylmethyloxy, or R13, R13, R14’ and R15 are H and R14 is chloro, methylsulfonylamino, or R13, R13 , R14 and R14’ are H and R15 is chloro, methylsulfonylamino, R13, R14 and R14’ are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) both F, or c) R is F and R is methoxy, or cl) R is methoxy and R is F, or e) _ 1Ί ic -| ·> ic R is methoxy and R is acetylamino, or f) R is methoxy and R is amino, or _ -| ip _ 1Λ ip _ -| 1 g) R is cyano and R is methoxy, or h) R is chloro and R is cyano, or i) R is cyano and R15 is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14’ and R15 are H and both R13 and R13’ are methoxy, or R13, R13 and R15 are H and both R14 and R14 are fluoro, methoxy, or R13, R13’ and R14’ are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methoxy and R14 is cyano, or c) R13 is methyl and R14 is cyano, or R13 and R14 are H and R13 , R14 and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14 and R15 are methoxy, more preferably R13, R14, R14 and R15 are H and R13 is chloro, cyano, trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy, or R13, R13 , R14 and R15 are H and R14 is chloro, or R13, R13 , R14 and R14 are H and R15 is chloro, methylsulfonylamino, or R13 , R14 and R14 are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) both F, or c) R13 is F and R15 is methoxy, or d) R13 is methoxy and R15 is F, or e) R13 is methoxy and R15 is acetylamino, or f) R is methoxy and R is amino, or g) R is cyano and R is methoxy, or h) R is chloro and R is cyano, or i) R is cyano and R is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14 and R15 are H and both R13 and R13 are methoxy, or R13, R13 and R14 are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13 , R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methoxy and R14 is cyano, or c) R13 is methyl and R14 is cyano, or R13 and R14 are H and R13 , R14 and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14 and R15 are methoxy.

Other preferred compounds of formula Id-lg are those of formula

Id-lh’:

Id-lli’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8’, R9, R9’ and R10 are as defined above in respect to formula Id-lg; R is as defined above in respect to formula Id-lg, preferably R is H, fluoro, chloro, methyl, CF3, or methoxy more preferably R12 is H or methoxy; R16 is selected from the group of heteroaryl moieties consisting of:

,wherein the arrow marks the attachment point to the phenyl ring; R17, R17, R18, R18 and R19 are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3 or CHF2, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl preferably methoxymethyl, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, haloalkylsulfonylamino, preferably R17, R17, R18 and R19 are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino, carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonylamino, more preferably R , R , R and R are independently selected from H, halo preferably chloro, alkoxy preferably methoxy, even more preferably R17, R17, R18 and R19 are independently selected from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Id-lh’ are those wherein R16 is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5 -yl, 2-methoxypyrimidin-5 -yl, 2-methoxypyrimidin-3-yl.

In yet another embodiment, preferred compounds of Formula I are those of formula Ie:

Ie and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar1, Ar2, L1, L2, L3, R1, R2, R3, R3, R4, R4, D, E and Z are as defined above in respect of formula I; and the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ie and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Other preferred compounds of formula Ie are those of formula Ie-lb’:

Ie-lb’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R2 is as defined above in respect of formula Ie and R is as defined above in respect of formula I; R1 is H; D is C=0; L2 is single bond;

Ar1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered cycloalkyl group, or a linear or branched C3-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, each of said aryl or heteroaryl substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, preferably Ar1 is a 5- to 6-membered aryl preferably phenyl, 5- to 6-membered heteroaryl group preferably pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl, isobutyl or isopentyl each of said phenyl, pyridin-2-yl, pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally substituted by one or more group(s) selected from halo preferably bromo, chloro or fluoro, cyano, C1-C4 alkyl preferably methyl, C1-C4 alkoxy preferably methoxy, aryl preferably phenyl, still more preferably Ar1 is aryl preferably phenyl, cyclohexyl, isobutyl or isopentyl, said phenyl group being optionally substituted by one or more halo group preferably bromo, chloro or fluoro, cyano, methyl, phenyl or methoxy, further more preferably Ar1 is phenyl, cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, l,l'-biphenyl-2-yl, 4-cyanophenyl, even more preferably Ar1 is isobutyl, cyclohexyl, phenyl , 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, still even more preferably Ar1 is isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl;

Ar2 is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino, alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl, heteroaryl, cycloalkyl or heterocyclyl group may be one or more aryl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and haloalkoxyalkyl; preferably Ar2 is an aryl or heteroaryl preferably pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C2-C6 alkyl group, each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, cyanomethyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably Ar2 is an aryl preferably phenyl, heteroaryl preferably pyridyl, heterocyclyl preferably piperidinyl, C2-C6 alkyl group preferably isobutyl, each of said aryl, heteroaryl and heterocyclyl groups being optionally substituted by one or more group(s) selected from halo preferably chloro and fluoro, cyano, nitro, alkyl, preferably methyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, more preferably fluoro, cyano, nitro, alkyl preferably methyl, cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonylalkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, further more preferably Ar2 is a biaryl consisting of two 6-membered aryl moieties preferably biphenyl, more preferably a biphenyl linked to L2 at position 4’ and monosubstituted at position 2, or Ar2 is a heterobiaryl consisting of one 6-membered aryl moiety and one 6-membered heteroaryl moiety or two 6-membered heteroaryl moieties, said heterobiaryl being linked to L2 either on the aryl or on the heteroaryl moiety and being preferably phenylpyridyl, pyrimidinylphenyl, pyridazinylphenyl, pyrazinylphenyl, or Ar is an aryl or heteroaryl optionally substituted by one group selected from arylalkyloxy, aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl and heteroaryl groups being optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro preferably benzyloxy or 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, or Ar is a pipendinyl ring linked to L2 at position 4 and N substituted with a phenyl, 4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said phenyl moiety being further substituted by one or more substituents selected from halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, haloalkyl preferably CF3, alkoxy preferably methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl, (morpholin-4-yl)sulfonyl, alksulfamoyl preferably methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar2 is 4’-(2-methoxy-1,1 ’-biphenyl), 4’-(2-methyl-1,1 ’-biphenyl), 4’-(2-fluoro-1,1 ’-biphenyl), 4’-(4-chloro-1,1 ’-biphenyl), 4’-(2-chloro-1,1 ’-biphenyl), 4 ’-(2-chloro-2'-methoxy- 1.1 ’-biphenyl), 4’-(2-(2-methoxyethoxy)-1,1 ’-biphenyl), 4 ’-(2-(methoxymethyl)-Ι,Γ-biphenyl), 4’-(4-methoxy-l,l'-biphenyl), 4’-(4-cyano-l,l'-biphenyl), 4’-(3-chloro-1,1 ’-biphenyl), 4’-(2-chloro-1,1 ’-biphenyl), 4’-(4-methylsulfonylamino- 1.1 ’-biphenyl), 4’-(2-trifluoromethoxy-l, 1 ’-biphenyl), 4’-(2-isopropoxy-1,1'- biphenyl), 4 ’-(2-cyclopropylmethyloxy-1,1 ’-biphenyl), 4 ’-(2-cyano-1,1 ’-biphenyl), 4’-(2,6-dimethoxy-1, Γ-biphenyl), 4’-(2,4-dichloro-1,1 ’-biphenyl), 4’-(2- trifhioromethyl-1,1 ’-biphenyl), 4’-(2-methoxy-4-chloro-1,1 ’-biphenyl), 4’-(2,4-dimethoxy-1,1 ’-biphenyl), 4-(2,2'-dimethoxy-1,1 ’-biphenyl), 4-(naphtalen-2- yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl, 4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(2-methoxypyridin-3-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl, 4-(2,4-dimethoxypyrimidin-6-yl)phenyl, 4-(2,4- dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl, 4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl, (4-phenoxymethyl)phenyl, optionally substituted by one or more group(s) selected from halo preferably chloro or fluoro, more preferably fluoro, alkyl preferably methyl, alkoxy preferably methoxy, or Ar2 is 4’-(2,4-difluoro-l,l'-biphenyl), 4’-(3’-methyl-1,1'-biphenyl), 4’-(3’-fluoro-l,l'-biphenyl), 4’-(2-fluoro-4-methoxy-l,l’-biphenyl), 4’-(4-fluoro-2-methoxy-1,1 ’-biphenyl), 4’-(2,3-dimethoxy-1,1 ’-biphenyl), 4 ’-(3,4-dimethoxy-1,1 ’-biphenyl), 4 ’-(2,3,4-trimethoxy-1,1 ’-biphenyl), 4 ’-(2,3,6- trimethoxy-1,1 ’-biphenyl), 4’-(3,5-dimethoxy-1,1 ’-biphenyl), 4’-(2,5-dimethoxy-1,Γ-biphenyl), 4’-(2-isopropyl-1,1 ’-biphenyl), 4’-(2,2’-dimethoxy-l, 1 ’-biphenyl), 4’-(2’-fluoro,2-dimethoxy-1,1 ’-biphenyl), 4’-(2-ethyl-1,1 ’-biphenyl), 4 ’-(4-propyl- 1.1 ’-biphenyl), 4 ’-(4-tert-butyl-1,1 ’-biphenyl), 4 ’-(2-methoxy-4- methylsulfonylamino-1,1 ’-biphenyl), 4’-(2-methoxy-4-acetylamino-1,1 ’-biphenyl), 4’-(3-hydroxycarbamimidoyl-1,1 ’-biphenyl), 4’-(4-amino-2-methoxy-1,1'- biphenyl), 4’-(3-carbamoyl-1,1 ’-biphenyl), 4’-(5-cyano-2,3-dimethoxy-1,1'-biphenyl), 4’-(2-cyano-4,5-dimethoxy-l, 1 ’-biphenyl), 4’-(3,4,5-trimethoxy-l, 1 'biphenyl), 4’-(2-cyanomethyl-4,5-dimethoxy-l,l'-biphenyl), 4’-(2-fluoro-5-cyano-1,1 '-biphenyl), 4 ’-(2 ’-fluoro-3,4-dimethoxy-1,1 '-biphenyl), 4 ’-(3- carbamoyl-4-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-methoxy-1,1 ’-biphenyl), 4’-(2’-fluoro-4-methylsulfonylamino-l,r-biphenyl), 4’-(2’-fluoro-3- methylsulfonylamino-1,1 ’-biphenyl), 4’-(2-cyano-2’-fluoro-1,1 ’-biphenyl), 4’-(2-chloro-5-cyano-1,1 ’-biphenyl), 4’-(2-cyano-4-trifluoromethyl-1,1 ’-biphenyl), 4’-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-l,r-biphenyl), 4’-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1 ’-biphenyl), 4’-(4-methylsulfonyl-1,1’-biphenyl), 4’-(3-methylsulfonylamino-1,1 ’-biphenyl), 4’-(4-amino-2-methyl-1,1’-biphenyl), 4’-(5-cyano-2-methyl-1,1 ’-biphenyl), 4’-(5-cyano-2-methoxy-1, Γ-biphenyl), 4’-(3-cyano-l,l'-biphenyl), 4’-(2-cyano-3-methoxy-l,l'-biphenyl), 4’-(2-methyl-3-methylsulfonylamino-1,1 ’-biphenyl), 4 ’-(2-methyl-3-acetylamino- 1,1 ’-biphenyl), 4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl, 4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl, 4-(2-methoxy-6-methylpyridin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl, 4-(2,6- dimethylpyridin-5-yl)phenyl, 4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl, 4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl, 4-(4,6-dimethoxy-pyridin-3-yl)phenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)phenyl, 4-(2,6-dimethoxy-pyridin-3-yl)phenyl, 4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl, 4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl, 4-(6-methoxy-pyridin-3-yl)-3- fluorophenyl, 4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl, 4-(4,6- dimethoxy-pyrimidin-5-yl)phenyl, 4-(2-methoxy-pyrimidin-5-yl)-3- methoxyphenyl, 4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3- yl)phenyl, 4-(2-methoxy-pyrimidin-3-yl)phenyl, 3-methoxy-2-(2- methoxyphenyl)pyridin-5 -yl, 3 -methoxy-2-(5 -cyano-2-methoxyphenyl)pyridin-5 -yl, 3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl, 2-(2,4- dimethoxyphenyl)pyridin-5-yl, 1 -(2-cyano-4-trifluoromethyl)piperidin-4-yl, 1 -(2- nitro-4-trifluoromethyl)piperidin-4-yl, l-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; R3 is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl, arylsulfonyl; R3 is H or C1-C4 alkyl; R4 is H, cyano, C1-C4 alkyl.

Preferred compounds of formula Ie-lb’ are those of formula Ie-lg:

Ie-lg and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect of formula I; R8, R8, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, heterocyclyloxy, alkylamino, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, preferably R8, R8’, R9, R9’ and R10 are independently selected from H, halo preferably fluoro, chloro, bromo, cyano, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy preferably OCF3 or OCHF2, alkylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one or more of R8 and R9, or R9 and R10, or R10 and R9 , or R9 and R8 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, more preferably R8, R8 , R9, R9 and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, cyano, C1-C4 alkyl preferably methyl, aryl preferably phenyl, alkoxy preferably methoxy, still more preferably R8, R8 , R9, R9 and R10 are independently selected from H, halo preferably bromo, fluoro or chloro, alkyl preferably methyl, still more preferably R8 is Br, Cl or F, preferably Cl and R8 , R9, R9 and R10 are independently selected from H or F, or R9 is Cl or F and R8, R8 , R9 and R10 are H, or R9 and R9 are F and R8, R8 and R10 are H, or R10 is Cl

O OJ Q Q? O or F and R , R , R and R are H, even more preferably R is Br, Cl or F and R8 , R9, R9 and R10 are H, or R8 and R9 are F and R8 , R9 and R10 are H, or R8 and R10 are F and R8 , R9 and R9 are H; R11, R11, R12, R12’ and R16 are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkyloxycarbonyl, aminoalkylalkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R11 and R12, or R12 and R16, or R16 and R12’, or R12 and R11 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12’ and R11’ form together a cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably trifluoromethoxt, 1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably R , R , R , R and R are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably -OCF3 or -OCHF2, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or one or more of R and R , or R and R , or R and R12, or R12 and R11 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12’ and R11’ form together an aryl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy, alkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino and oxo, more preferably R11, R11, R12, R12 and R16 are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF3 or CHF2, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF3 or OCHF2, alkoxyalkoxy, aryloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or one or more of R and R , or R and R , or R16 and R12, or R12’ and R11 form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R11 and R12, or R12 and R16, or R16 and R12, or R12’ and R11 form together an aryl, or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably R , R , R , R and R16 are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl preferably CF3 or CHF2, cycloalkyl preferably cyclohexyl, heterocyclyl preferably pyrrolidin-l-yl, 4-methylpiperidin-l-yl, aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-l-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, haloalkyl preferably trifluoromethyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Ie-lg are those of formula Ie-lhl:

Ie-lhl and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8 , R9, R9 and R10 are as defined above in respect to formula Ie-lg; R12 is as defined above in respect to formula Ie-lg, preferably R12 is H, fluoro, chloro, methyl, CF3, nitro, cyano, methoxy or cyclopropylmethyloxy; R13, R13’, R14, R14’ and R15 are as defined above in respect to formula Ie-lg, preferably R13 , R14, R14 and R15 are H and R13 is chloro, cyano, hydroxyl, methyl, trifluoromethyl, cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF3, cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy, (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy, carbamoylmethyloxy, or R13, R13 , R14 and R15 are H and R14 is chloro, methylsulfonylamino, or R13, R13 , R14 and R14 are H and R15 is chloro, methylsulfonylamino, R13 , R14 and R14 are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) both F, or c) R is F and R is methoxy, or d) R is methoxy and R is F, or e) R is methoxy and R is acetylamino, or f) R is methoxy and R is amino, or g) R13 is cyano and R15 is methoxy, or h) R13 is chloro and R15 is cyano, or i) R13 is cyano and R15 is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14 and R15 are H and both R13 and R13’ are methoxy, or R13, R13 and R15 are H and both R14 and R14’ are fluoro, methoxy, or R13, R13’ and R14 are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13, R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13 , R14 and R15 are H and R13 and R14’ are a) both methoxy, or b) R13 is methoxy and R14 is cyano, or c) R13 is methyl and R14 is cyano, or R13 and R14 are H and R13, R14 and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and R15 are methoxy and R13 and R14’ are H and R13 is cyano, or R13 and R13 are H and R14, R14’ and R15 are methoxy, more preferably R13, R14, R14 and R15 are H and R13 is chloro, cyano, trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy, or R13, R13 , R14’ and R15 are H and R14 is chloro, or R13, R13 , R14 and R14’ are H and R15 is chloro, methylsulfonylamino, or R13 , R14 and R14 are H and R13 and R15 are a) independently selected from chloro or methoxy, or b) both F, or c) R13 is F and _ -J m _ -J λ _ 1 c _ _ 1 -y _ | m R is methoxy, or d) R is methoxy and R is F, or e) R is methoxy and R is acetylamino, or f) R is methoxy and R is amino, or g) R is cyano and R is methoxy, or h) R is chloro and R is cyano, or i) R is cyano and R is trifluoromethyl, or j) R13 is methoxy and R15 is (N-methyl-N-methylsulfonyl)amino, or R14, R14 and R15 are H and both R13 and R13 are methoxy, or R13, R13 and R14 are H and a) R14 forms together with R15 a phenyl moiety fused to the phenyl ring they are attached to, or b) both R14 and R15 are methoxy, or R13, R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methyl and R14 is methylsulfonylamino, or c) R13 is methoxy and R14 is cyano, or d) R13 is methyl and R14 is amino, or R13, R14 and R15 are H and R13 and R14 are a) both methoxy, or b) R13 is methoxy and R14 is cyano, or c) R13 is methyl and R14’ is cyano, or R13 and R14 are H and R13, R14’ and R15 are methoxy, or R14 and R15 are H and R13, R13 and R14 are methoxy, or R13 and R14 are methoxy and R13 and R15 are H and R14 is cyano, or R14 and Rls are methoxy and R13 and R14 are H and R13 is cyano, or R13 and R13 are H and R14, R14 and R15 are methoxy.

Other preferred compounds of formula Ie-lg are those of formula

Ie-lh’:

Ie-lh’ and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R is as defined above in respect to formula I; R8, R8’, R9, R9 and R10 are as defined above in respect to formula Ie-lg; R12 is as defined above in respect to formula Ie-lg, preferably R12 is H, fluoro, chloro, methyl, CF3, or methoxy more preferably R12 is H or methoxy; R16 is selected from the group of heteroaryl moieties consisting of:

,wherein the arrow marks the attachment point to the phenyl ring; R17, R17’, R18, R18’ and R19 are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3 or CHF2, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl preferably methoxymethyl, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, haloalkylsulfonylamino, preferably R , R , R and R are independently selected from H, halo preferably chloro and fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably CF3, alkoxy preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF3, OCHF2, or 1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino, carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonylamino, more preferably R , R , R and R are independently selected from H, halo preferably chloro, alkoxy preferably methoxy, even more 17 17’ 1 ft’ 10 preferably R , R , R and R are independently selected from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Ie-lh’ are those wherein R16 is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4- dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxypyrimidin-3-yl.

Particularly preferred compounds of the invention are those listed in Table 1 hereafter:

Table 1:

The compounds of table 1 were named using ChemDraw Ultra 12 purchased from CambridgeSoft (Cambridge, MA, USA).

The compounds of formula I can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches.

The invention further provides processes for the preparation of compounds of the invention or a pharmaceutically acceptable salts or solvates thereof.

In one embodiment, the invention further provides a process for the preparation of a compound of formula lb-lb’

Ib-lb’, wherein Ar2 is as defined defined above in respect to formula Ib-lb’;

Ar1 is 2-chlorophenyl, 2-fluorophenyl, 2,3-difluorophenyl; R1, R2, R3, R3 , R4 and R are H; D is C=0; L2 is a single bond; which consists of:

a) the coupling of a compound of formula A

A wherein R8 is Cl or F and R9 is H, or R8 and R9 are both F; R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl, tert-butyldiphenylsilyl, preferably R is methyl, ethyl, or tert-butyl;

with a compound of formula B

B wherein:

Ar2 is as defined defined above in respect to formula lb-lb’; R” is Cl or OL wherein L is a carboxylic acid activating group, followed by b) a alkaline or acidic treatment, hydrogenolysis or treatment with fluoride of the ester intermediate obtained in step a); step b) being optionally followed by conversion of a compound of formula lb-lb’ to a pharmaceutically acceptable salt or solvate thereof.

In another embodiment the invention further provides a process for the preparation of a compound of formula lb-lb’

Ib-lb’, wherein Ar1 R3, R3 , R4 are as defined above in respect to formula Ib-lb’; R1, R2, and R are H; D is C=0; L2 is a single bond;

Ar2 is selected from 4’-(2-methoxy-4-methylsulfonyl-l,r-biphenyl), 4’-(2-methyl-3-methylsulfonylamino-1,1 ’-biphenyl), 4-(2-methoxypyridin-3-yl)phenyl, 4-(2,6-dimethoxypyrimidin-5-yl)phenyl, 3-methoxy-4-(2-methoxypyrimidin-5-yl)phenyl, 4-(3,6-dimethoxypyridazin-5-yl)phenyl, 4’-(5-cyano-2-methoxy-l,l’-biphenyl), 4’-(5-cyano-2-methyl-l,l’-biphenyl), 3-fluoro-4-(3,6- dimethoxypyridazin-5 -yl)phenyl, (4-(4-methoxypyridin-3 -yl)phenyl), (4'- (methylsulfonamido)-[ 1,1 '-biphenyl]-4-yl), (3'-(methylsulfonamido)-[ 1,1 '- biphenyl]-4-yl), (4-(2,4-dimethoxypyrimidin-5-yl)phenyl), (5-methoxy-6- phenylpyridin-3-yl), (4-(4-methoxypyrimidin-5-yl)phenyl), (2,2'-dimethoxy-[ 1,1 '-biphenyl]-4-yl), (3-methoxy-4-(4-methoxypyridin-3-yl)phenyl), (4-(2,4-dimethoxypyrimidin-5-yl)-3-methoxyphenyl), (4’-acetamido-2’-methoxy-[ 1,1 ’- biphenyl]-4-yl), (2’-cyano-4',5’-dimethoxy-[ 1,1 ’-biphenyl]-4-yl), (2'-methoxy-4'-(N-methylmethylsulfonamido)-[ 1,1 '-biphenyl]-4-yl), (6-(2,4-dimethoxyphenyl)pyridin-3-yl), (4-(4,6-dimethoxypyrimidin-5-yl)phenyl), (4-(3-methoxypyridin-4-yl)phenyl); which consists of:

a) the coupling of a compound of formula C

wherein:

Ar\ R3, R3 and R4 are as defined above in respect to formula lb-lb’; R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl, tert-butyldiphenylsilyl, preferably R is methyl, ethyl, or tert-butyl,

with a compound of formula D

wherein R” is Cl or OL, wherein L is a carboxylic acid activating group; A0, A0 , A1, A2, A3, A4 and A5 are selected from the combinations 1 to 24:

followed by b) an alkaline or acidic treatment, a hydrogenolysis or a treatment with fluoride of the ester intermediate obtained in step a); step b) being optionally followed by conversion of a compound of formula lb-lb’ to a pharmaceutically acceptable salt or solvate thereof.

In yet another embodiment, the invention further provides a process for the preparation of a compound of the formula Ib-lh”

Ib-lh” wherein R8 is F or Cl and R9 is H, or both R8 and R9 are F;

Ris H; A°, A° , A1, A2, A3, A4 and A5 are selected from the combinations 1 to 24:

which consists of: a) the coupling of a compound of formula A as defined above with a compound of formula B as defined above, followed by b) an alkaline or acidic treatment, a hydrogenolysis or a treatment with fluoride of the ester intermediate obtained in step a); step b) being optionally followed by conversion of a compound of formula Ib-lh” to a pharmaceutically acceptable salt or solvate thereof.

In one variant of the process for the preparation of a compound of formula Ib-lh” as described above, the compound of formula Ib-lh” is selected from:

Suitable carboxylic acid activating groups L for use in the above processes are benzotriazol-l-yl, 7-azabenzotriazol-l-yl, imidazol-l-yl, preferably 7-azabenzotriazo 1-1 -yl.

In a typical procedure applicable to all of the aforementioned processes, the coupling reactions of a compound of formula B or D wherein R” is OL, are done in the presence of a base such as triethylamine, diisopropylethylamine, preferably diisopropylethylamine, in a suitable solvent such as MeCN, DMF, DCM, preferably MeCN, at a suitable temperature ranging from room temperature to the boiling point of the solvent used, preferably at room temperature. Intermediates of formulae B and D are generated in situ from their corresponding carboxylic acid precursor which is reacted with HOBt, HOBt hydrate, HATU, CDI, pentafluorophenol, preferably with HATU. Preferably, the coupling with an activated carboxylic acid is made using HATU and DIEA in MeCN at room temperature.

In a typical procedure applicable to all of the above-mentioned processes, the coupling reactions of a compound of formula B or D wherein R is

Cl, are done in the presence of a base such as triethylamine, diisopropylethylamine, preferably triethylamine, in a suitable solvent such as MeCN, DMF, DCM preferably DCM, at a suitable temperature ranging from room temperature to the boiling point of the solvent used, preferably at room temperature. Preferably, the coupling with an acyl chloride is made using triethylamine in DCM at room temperature.

In a typical procedure applicable to all of the aforementioned processes, the alkaline treatment of the intermediates obtained after coupling step a) and wherein R is methyl or ethyl, are done in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, trimethyltin hydroxide, preferably lithium hydroxide, in a suitable solvent such as a 1/1 (v/v) mixture of water and THF, DCE, at a suitable temperature ranging from room temperature to the boiling point of the solvent used, preferably at room temperature.

In a typical procedure applicable to all of the above-mentioned processes, the acidic treatment of the intermediates obtained after coupling step a) and wherein R is tert-butyl, are done in the presence of a suitable acid such as HC1 or TFA, in a suitable solvent such as DCM, dioxane, or in a miscible mixture of said solvents, at room temperature.

Those skilled in the art will appreciate that typical procedures applicable to all of the above-mentioned processes for step b) and wherein R is benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl are well known and are indeed reported in Koscienski P.J., Protecting Groups 3rd edition, Thieme, 2005, 394-450.

In a particular embodiment, useful intermediates for the preparation of compounds of the invention are those of formula E:

wherein R8 is Cl or F and R9 is H, or R8 and R9 are both F; R is methyl, ethyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl, tert-butyldiphenylsilyl or R is tert-butyl when R8 is F.

Preferred compounds of formula E are those wherein R is methyl, ethyl, or R is tert-butyl when R8 is F.

In a particular embodiment, useful intermediates for the preparation of compounds of the invention are those of formula F:

wherein R’ is OH or Cl; A0, A0 , A1, A2, A3, A4 and A5 are selected from the combinations 1 to 7, 9,10,13 to 15,17 to 21, 23 and 24 :

The invention further provides the use of the compounds of the invention or pharmaceutically acceptable salts, solvates or prodrugs thereof as agonists or partial agonists of G-protein coupled receptor 43 (GPR43).

Accordingly, in a particularly preferred embodiment, the invention relates to the use of compounds of formula I and subformulae in particular those of table 1 above, or pharmaceutically acceptable salts, solvates and prodrugs thereof, as GPR43 agonists or partial agonists.

[APPLICATIONS]

The compounds of the invention are therefore useful in the prevention and/or treatment of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

In a particular preferred embodiment the diseases are type II diabetes and a lipid disorder such as dyslipidemia.

The invention also provides for a method for delaying in patient the onset of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof to a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably a human.

The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvates thereof for the manufacture of a medicament for use in treating a patient and/or preventing a patient from developing a disease selected from the group consisting of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

Preferably, the patient is a warm-blooded animal, more preferably a human.

According to a further feature of the present invention there is provided a method for modulating GPR43 receptor activity, in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said animal an effective amount of compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts, solvates or prodrugs may be administered as part of a combination therapy. Thus, are included within the scope of the present invention embodiments comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients. Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment and/or prevention of any of the diseases or conditions mediated by or associated with GPR43 receptor modulation, particularly type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH). The use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of diseases within a patient in need of treatment or one at risk of becoming such a patient.

In addition to the requirement of therapeutic efficacy, which may necessitate the use of active agents in addition to the GPR43 agonist or partial agonist compounds of Formula I or their pharmaceutical acceptable salts, solvates or prodrugs thereof, there may be additional rationales which compel or highly recommend the use of combinations of drugs involving active ingredients which represent adjunct therapy, i.e., which complement and supplement the function performed by the GPR43 receptor agonist or partial agonist compounds of the present invention. Suitable supplementary therapeutic agents used for the purpose of auxiliary treatment include drugs which, instead of directly treating or preventing a disease or condition mediated by or associated with GPR43 receptor modulation, treat diseases or conditions which directly result from or indirectly accompany the basic or underlying GPR43 receptor modulated disease or condition.

Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of Formula I or their pharmaceutical acceptable salts, solvates or prodrugs thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates and prodrugs are coadministered in combination with one or more other therapeutic agents such as those described in detail further herein.

Examples of other active ingredients that may be administered in combination with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and either administered separately or in the same pharmaceutical composition, include but are not limited to: (a) PPARy agonists and partial agonists, including both glitazones and non-glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512 and LY-818; (b) Biguanides such as metformin and phenformin; (c) Protein tyrosine phosphatase-IB (PTP-1B) inhibitors, (d) Dipeptidyl peptidase IV (DP-IV) inhibitor, such as MK-0431 and LAF-237; (e) Insulin or insulin mimetics; (f) Sulfonylureas such as tolbutamide and glipizide or related materials; (g) α-glucosidase inhibitors (such as acarbose); (h) agents which improve a patient’s lipid profile such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) cholesterol absorption inhibitors such as for example ezetimibe, (vi) acyl Co A: cholesterol acyltransferase (ACAT)inhibitors such as avasimibe, (vii) CETP inhibitors such as torcetrapib and (viii) phenolic anti-oxidants such as probucol; (i) PPARa/γ dual agonists such as muraglitazar, tesaglitazar, farglitazar and JT-501; (j) PPAR6 agonists such those disclosed in W097/28149; (k) Antiobesity compounds such as fenfluramine, dextenfluramine, phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, MC4R agonists, cannabinoid receptor 1 antagonists/inverse agonists and β3 adrenergic receptor agonists; (l) Ileal bile acid transporter inhibitors; (m) Agents intended for use in inflammatory conditions such as aspirin, non-steroidal, anti-inflammatory drugs, glucocorticoids, azulfidine and cyclo-oxygenase 2 selective inhibitors; (n) Glucagon receptor antagonists; (o) GLP-1; (P) GIP-1; (q) GLP-1 analogs, such as exendins, for example exenitide, and (r) Hydroxysterol dehydrogenase-1 (HSD-1) inhibitors.

The above combinations include combinations of a compound of the present invention or a pharmaceutically acceptable salt or solvate not only with one other active compound but also with two or more active compounds. Non limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors and anti-obesity compounds.

In the above-described embodiment combinations of the present invention, the compound of Formula I, a pharmaceutically acceptable salt or solvate thereof and other therapeutic active agents may be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration, either serially or simultaneously. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).

The invention also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.

The invention also provides a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament. Preferably, the medicament is used for the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

In a particular preferred embodiment the disease are type II diabetes and a lipid disorder such as dyslipidemia.

According to a further feature of the present invention there is provided the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for modulating GPR43 receptor activity, in a patient, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

Preferably, the patient is a warm-blooded animal, more preferably a human.

As set forth above, the compounds of the invention, their pharmaceutically acceptable salts, solvates and prodrugs may be used in monotherapy or in combination therapy. Thus, according to one embodiment, the invention provides the use of a compound of the invention for the manufacture of a medicament for at least one of the purposes described above, wherein said medicament is administered to a patient in need thereof, preferably a warmblooded animal, and even more preferably a human, in combination with at least one additional therapeutic agent and/or active ingredient. The benefits and advantages of such a multiple drug regimen, possible administration regimens as well as suitable additional therapeutic agents and/or active ingredients are those described above.

Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 0,05 and 1000 mg, and usually between 1 and 500 mg, of at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.

Usually, depending on the condition to be prevented or treated and the route of administration, the active compound of the invention will usually be administered between 0.01 to 100 mg per kilogram, more often between 0.1 and 50 mg, such as between 1 and 25 mg, for example about 0.5, 1,5, 10, 15, 20 or 25 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.

[DEFINITIONS]

The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

Where groups may be substituted, such groups may be substituted with one or more substituents, and preferably with one, two or three substituents. Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, cyano, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.

As used herein the terms such as “alkyl, aryl, or cycloalkyl, each being optionally substituted with...” or “alkyl, aryl, or cycloalkyl, optionally substituted with...” encompasses “alkyl optionally substituted with...”, “aryl optionally substituted with...” and “cycloalkyl optionally substituted with..

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.

The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula CnH2n+i wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Cx-y -alkyl and Cx-Cy-alkyl refer to alkyl groups which comprise from x to y carbon atoms.

Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and tert-butyl, pentyl and its isomers (e.g. n-pentyl, isopentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and tert-butyl.

When the suffix "ene" (“alkylene”) is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. The term “alkylene” includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethy lethy lene.

The term “alkenyl” as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.

The term “alkynyl” as used herein refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Non limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers-and the like. The terms “alkenylene” and “alkynylene” respectively mean an alkenyl group or an alkinyl group as defined above having two single bonds as points of attachment to other groups.

The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.

The term “cyclo alkyl” as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclo butyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

When the suffix "ene" is used in conjunction with a cyclic group, this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups.

Therefore, "cycloalkylene" herein refers to a saturated homocyclic hydrocarbyl biradical of Formula CnH2n-2· Suitable cycloalkylene groups are C3-6 cycloalkylene group, preferably a C3-5 cycloalkylene (i.e. l,2cyclopropylene, 1,1-cyclopropylene, 1,1-cyclo butylene, 1,2-cyclo butylene, 1,3-cyclobutylene, 1,3-cyclopentylene,or 1,1-cyclopentylene), more preferably a cycloalkylene (i.e. 1,3-cyclopropylene, 1,1-cyclopropylene, 1,1-cyclobutylene, 1,2-cyclobutylene).

Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as “heterocycloalkyl” or “heterocyclyl”.

The terms "heterocyclyl", “heterocycloalkyl” or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multiring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, lH-pyrrolizinyl, tetrahydro-l,l-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

The ring atoms of heterocyclyl and heterocyclylene moieties are numbered based on scheme below

The term “aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Nonlimiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

The term "arylene" as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, indenylene, pentalenylene, azulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.

The term “arylalkyl” or “aralkyl” refers to a linear or branched alkyl group where one carbon is attached to an aryl ring. Non limiting examples of aralkyl comprise benzyl, phenethyl, (naphtalen-l-yl) or (naphtalen-2-yl)methyl. When an aralkyl group is substituted, the substituent(s) is/are attached either on the alkyl group or on the aryl ring. A “x-membered aralkyl” refers to a linear or branched alkyl group where one carbon is attached to a x-membered aryl ring. Where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzo furanyl, isobenzo furanyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzo iso thiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2- oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

The term "heteroarylene" as used herein means divalent carbocyclic aromatic ring systems including pyridinylene and the like.

The ring atoms of heteroaryl or heteroarylene moieties are numbered on scheme below:

The term “biaryl” as used herein designates two aryl moieties as defined herein linked via a single bond. Non-limiting examples of such biaryl moieties include biphenyl.

The term “heterobiaryl” as used herein designates two heteroaryl moieties as defined herein or a heteroaryl moiety and an aryl moity as defined herein linked via a single bond. Non-limiting examples of such heterobiaryl moieties include pyridinylphenyl which is meant to include (2-pyridinyl)phenyl, (3-pyridinyl)phenyl and (4-pyridinyl)phenyl, bipyridinyl.

The term “alkylamino” as used herein means an amino group substituted with one or two alkyl groups. This includes monoalkylamino and dialkylamino groups.

The term “carbamoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The term “carbamimidoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The term “carbamimidoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The compounds of Formula I and subformulae thereof contain at least one asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.

The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line ( — ), a zigzag line ( ), a solid wedge ( ), or a dotted wedge (......), a solid bar (^^) or a dotted bar (...........).. The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.

The compounds of the invention may also contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. In those compounds, the use of solid or dotted bars is meant to indicate relative stereochemistry. As an example,

The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.

When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods: (i) by reacting the compound of Formula I with the desired acid; (ii) by reacting the compound of Formula I with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or (iv) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

All references to compounds of formula I include references to salts, solvates, multi- component complexes and liquid crystals thereof.

The compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of formula I.

In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.

The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.

The term “prodrug” as used herein means the pharmacologically acceptable derivatives of compounds of formula I such as esters whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters as well as compounds of formula I in which Z is a substituent selected from the table 2 below.

Table 2

The term “predrug”, as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.

The term "patient" refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.

The term “human” refers to suject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).

The terms “treat”, “treating” and “treatment, as used herein, are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention”, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient’s risk of acquiring a condition or disease.

The term "therapeutically effective amount" (or more simply an "effective amount") as used herein means the amount of active agent or active ingredient (e. g. GPR43 agonist or partial agonist) which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.

The term "administration", or a variant thereof (e.g./'administering"), means providing the active agent or active ingredient (e. g. a GPR43 agonist or partial agonist), alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.

By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.

The term “agonist” as used herein means a ligand that activates an intracellular response when it binds to a receptor. An agonist according to the invention may promote internalization of a cell surface receptor such that the cell surface concentration of a receptor is decreased or remove.

The term “partial agonist” as used herein means an agonist which is unable to induce maximal activation of a receptor, regardless of the amount of compound applied on the receptor.

The term “pharmaceutical vehicle” as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

The term “lipid disorder” as used herein means any plasma lipid disorder including but not limited to dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia and hypertriglyceridemia.

The present invention will be better understood with reference to the following examples. These examples are intended to representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.

CHEMISTRY EXAMPLES

All temperatures are expressed in °C and all reactions were carried out at room temperature (RT) unless otherwise stated.

Analytical thin layer chromatography (TLC) was used to monitor reactions, establish flash chromatography conditions and verify purity of intermediates or final products. TLC plates used were Merck TLC aluminium sheet silica gel 60 F254. TLC plates were revealed using ultraviolet irradiation (wavelength=254 nm) at RT or bromocresol green spray reagent at 0.1% in propan-2-ol or KMnCL revelator (KMnCL, Na2C03, NaOH, H20) upon heating at 160°C. HPLC-MS spectra were obtained on Agilent LCMS using Electropsray ionization (ESI). The Agilent instrument includes an Autosampler 1200, a binary pump 1100, a 5 wave length detector 1100 and a 6100 Single Quad. The column used was an XBridge Cl8.

Eluent was a mixture of solution A (0.1% TFA in H2O) and solution B (0.1% TFA in ACN). Gradients used are as follows: gradient A (intermediates characterization): held the initial conditions of 5% solution B for 1 min, increased linearly to 95% solution B in 4 min, held at 95% during 1 min, returned to initial conditions in 0.5 min and maintained for 1 min; gradient B (examples characterization): held the initial conditions of 5% solution B for 1 min, increased linearly to 60% in 10 min, increased linearly to 95% in 0.5 min, held at 95% during 3 min, returned to initial conditions in 0.5 min and maintained for 1 min.

Determination of enantiomeric excess was performed on an Agilent 1100 (binary pump and 5 wavelengths detector) with manual or automatic (Autosampler 1100) injection. Columns used were CHIRALPAK IA CHIRALPAK IB or CHIRALPAK IC in isocratic mode. Mixtures of eluents were selected depending on the separation obtained of enantiomers or diastereosiomers. Usual mixtures were:

Hexane and Ethanol (0.1% TFA)

Hexane and Propanol (0.1% TFA)

Hexane and Ethyl acetate (0.1% TFA)

Hexane and Dichloromethane (0.1 % TFA)

Hexane and tert-butyl methyl ether (0.1% TFA)

Preparative HPLC purifications were carried out on Fractionlynx instrument, from Waters. This instrument consists of a Fraction Collector, a 2767 Sample Manager, a pump control a module II, a 515 HPLC Pump, a 2525 Binary Gradient Module, a Switching Valve, a 2996 Photodiode Array Detector and a Micromass ZQ. The column used was a Waters Sunfire C18 Eluent was a mixture of solution A (0.1% TFA in H20) and solution B (0.1% TFA in ACN). The gradient was adapted depending on impurities present in samples, to allow sufficient separation between impurities and target compound.

Chiral preparative HPLC purification were performed on an Agilent 1100 instrument (binary pump and 5 wavelengths detector) with manual injection using a CHIRALPAK IA or a CHIRALPAK IB column in isocratic mode. Mixtures of eluents were selected depending on the separation of enantiomers or diastereosiomers obtained with the analytical method. Usual mixtures were the same as those used for the determination of ee. 'Η and 13C NMR spectra were recorded on a Bruker ARX 300MHz. Chemical shifts are expressed in parts per million, (ppm, δ units). Coupling constants are expressed in Hertz units (Hz). Splitting patterns describe apparent multiplicities and are described as s (singlet), d (doublet), t (triplet), q (quintet), m (multiplet), or br (broad).

Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, VWR Int., Sopachem or Polymer labs and the following abbreviations are used: ACN or MeCN: Acetonitrile, DCM: Dichloromethane, DCE: 1,2-Dichloroethane,

EtOAc or AcOEt: Ethyl acetate,

EtOH: Ethanol,

MeOH: Methanol, IPA: isopropanol, PE: Petroleum ether, NMP: N-methylpyrrolidinone, RT: Room temperature, DIEA: N,N-diisopropylethylamine, HATU: 0-(7-azabenzotriazo 1-1 -yl)-N,N,N ’ ,N ’ -tretramethyluronium hexafluorophosphate , HOBt: 1-hydroxybenzotriazole or 1-hydroxybenzotriazole hydrate, DMAP: N, N-Dimethylaminopyridine Y: Yield, g: Grams, mg: Milligrams, L: Liters, mL: Milliliters, pL: Micro liters, mol: Moles, mmol: Millimoles, h: Hours, min or mn: Minutes, TLC: Thin layer chromatography, MW: Molecular weight, eq: Equivalent, THF: Tetrahydrofuran, TFA: Trifluoroacetic acid,

Ac: Acetyl, ee: Enantiomeric excess, /Bu: tert- Butyl P: UV purity at 254nm determined by HPLC-MS, rt: Retention time,

BuLi: butyllithium, CDI: carbonyldiimidazole, TBDPS: /er/-butyl-diphcnylsilyl, B0C2O: di-/er/-butyldicarbonatc, TBAF: tetrabutylammonium fluoride, S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl, RM: reaction mixture,

Nu: Nucleophile, DMF: N,N-dimethylformamide, TMS: trimethylsilyl.

General synthetic schemes A general method for the synthesis of most compounds of the invention is outlined in scheme 1.

Scheme 1: A general method for the synthesis of most compounds of the invention

Pyrrolidine methyl acetate intermediate 1.1 was acylated with acyl chlorides or carboxylic acids intermediates 1.2 using standard amide coupling procedures to give epimeric mixture compound 1.3.

In some cases epimers 1.3a and 1.3b were separated by chromatography (flash chromatography or preparative HPLC); subsequent saponification of intermediates 1.3a and 1.3b with lithium hydroxide afforded the desired carboxylic acid products 1.4 and 1.5 respectively.

Otherwise intermediate 1.3 was saponified with lithium hydroxide to give epimeric mixture 1.6 which was purified by chromatography (flash chromatography or preparative HPLC) to give desired carboxylic acid products 1.4 and 1.5.

Pyrrolidine ester intermediates 1.1 were synthesized from aryl or alkyl Grignard or aryl-lithium reagents as shown in scheme 2.

Scheme 2: Synthetic scheme for the preparation of pyrrolidine ester intermediates 1.1

Addition of aryl or alkyl Grignard or aryl-lithium 2.1 to N-Boc-L-pyroglutamic acid methyl ester 2.2 provided intermediate 2.3, as described by Colandrea et al. in Bioorg. &amp; Med. Chem. Lett. 2006, 16, 2905-2908 and Ying-zi Xu et al. in J. Org. Chem. 1999, 64, 4069-4078. One pot Boc deprotection and cyclic imine formation under acidic conditions afforded cyclic imine intermediate 2.4 which could be reduced either by hydrogenation or by borohydride reagent to give the pyrrolidine ester intermediate 1.1. In some cases epimers 1.1a and 1.1b were separated by flash chromatography.

Aryl or alkyl Grignard and aryl-lithium reagents 2.1 were prepared using the methodologies shown in scheme

Scheme 3: Synthetic scheme for the preparation of aryl or alkyl magnesium and aryl-lithium reagents

Aryl or alkyl Grignard reagents 2.1a were prepared from aryl halides either by method 1 (isopropyl megnasium chloride/lithium chloride) or by method 2 (magnesium) and aryl-lithium reagents 2.1b were synthesized by method 3 (n-butyllithium). N-Boc-L-pyroglutamic acid methyl ester 2.2 was synthesized using the methodology shown in scheme 4

Scheme 4: Synthetic scheme for the preparation of N-Boc-L-pyroglutamic acid methyl ester 2.2 L-pyroglutamic acid 4.1 was converted to the methyl ester 4.2 which upon Boc protection with di-fert-butyl dicarbonate afforded intermediate 2.2.

Biaryl and heterobiaryl carboxylic acid intermediates 1.2a were synthesized using one of the three routes (a, b or c) shown in scheme 5.

Scheme 5: Synthetic scheme for the preparation of biaryl carboxylic acid intermediates 1.2a

Suzuki coupling between 5.1 and 5.2 provided biaryl ester intermediate 5.3, subsequent saponification with lithium hydroxide afforded biaryl carboxylic acid intermediate 1.2a.

Aralkyloxyaryl carboxylic acid intermediates 1.2 were synthesized using the methodology shown in scheme 6 for benzyloxybenzoic acid intermediates 1.2b.

Scheme 6: Synthetic scheme for the preparation of benzyloxybenzoic acid intermediates 1.2b

Methyl 3,5-dihydroxybenzoate 6.1 was methylated with dimehylsulfate to give intermediate 6.2. Benzylation with benzyl halide reagent 6.3 provided ester intermediate 6.4 which upon subsequent saponification with lithium hydroxide afforded benzyloxybenzoic acid intermediates 1.2b

Additional synthetic schemes

Synthesis of compound n°24 is depicted in scheme 7.

Scheme 7: Synthesis of compound n°24

Synthesis of methyl substituted pyrrolidinone intermediates 2.2 is depicted in scheme 8.

Scheme 8: Synthesis of methyl substituted pyrrolidinone intermediates

Dipolar cycloaddition methodology is exemplified with the synthesis of compound n° 217 and is depicted in scheme 9.

Scheme 9: Dipolar cycloaddition methodology. Synthesis of compound n° 268 is depicted in scheme 10.

Scheme 10: Synthesis of compound n° 268.

Synthesis of intermediate 3-methoxy-4-(4-methylpiperidin-l-yl)benzoic acid used in the preparation of compound n°261 is depicted in scheme 11.

Scheme 11: Synthesis of intermediate 3-methoxy-4-(4-methylpiperidin-l- yl)benzoic acid

The synthesis of compound n° 393 is depicted in scheme 12.

Scheme 12: synthesis of compound n°393. The synthesis of compound n°369 is depicted in scheme 13.

Scheme 13: synthesis of compound n°369. Synthesis of compound n° 279 is depicted in scheme 14.

Scheme 14: synthesis of compound n°279

General methods

General method A: synthesis of pyrrolidine ester intermediates 1.1

General method A is examplified with the synthesis of intermediate la (2S,5R)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate, intermediate lb (2S,5S)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate and intermediate If (2S,5R)-methyl 5-(pyridin-2-yl)pyrrolidine-2-carboxylate from 2-bromopyridine (route 3, conditions E).

Sten 1: synthesis of (2-chlorophenyl)magnesium chloride: route 1.

To a 2M solution of isopropylmagnesium chloride in anhydrous THF (5.76 mmol) was added lithium chloride (5.76 mmol) in distilled THF in a Schlenk tube under Ar atmosphere at RT. The reaction mixture was cooled to -15°C and 1-bromo-2-chlorobenzene (5.35 mmol) was added and the RM was stirred at -15°C for another 3h. This crude solution of (2-chlorophenyl)magnesium chloride was cooled to -40°C and used as such in step 2.

Step 2: synthesis of (S)-methyl 2-((/er/-butoxycarbonyl)amino)-5-(2-chlorophenyl)-5-oxopentanoate.

To the_crude solution of (2-chlorophenyl)magnesium chloride obtained in step 1 was added at -40°C under Ar a solution of (S)-l-tert-butyl 2-methyl 5-oxopyrrolidine-l,2-dicarboxylate (4.11 mmol) in distilled THF (4mL). The reaction mixture was stirred at - 40°C for 2h and then quenched with lOmL of a saturated aqueous solution of ammonium chloride. The mixture was extracted three times with AcOEt, combined organics were dried over anhydrous MgSC>4 and concentrated in vacuo. Crude was purified by flash chromatography (eluent: cyclohexane/AcOEt) to yield title compound. Y: 425 mg (29%), P: >95%, rt=4.24 min, (M+H)+= 256.

Step 3: synthesis of (S)-methyl 5-(2-chlorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate. TFA (2 mL) was added to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-5-(2-chlorophenyl)-5-oxopentanoate (1.08 mmol) in DCM (2mL) and the reaction mixture was stirred at RT for 2h. The RM was evaporated to dryness to yield title compound. Y: 574 mg (56%), P: >95%, rt=2.85 min, (M+H)+= 238.

Step 4:

Reaction conditions C: synthesis of intermediate la (2S,5R)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate and intermediate lb (2S,5S)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate.

Sodium triacetoxyborohydride (0.091 mol) was added portionwise to a stirred solution of (S)-methyl 5-(2-chlorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (0.076 mol) in 1,2-dichloroethane (200 mL) at RT under a nitrogen atmosphere. TFA (0.76 mol) was added and the reaction mixture was stirred at RT for 1.5 h. LCMS showed starting material still remaining so further TFA (-lOrnL) was added (to give pH 3-4) and stirring continued for a further 1.5 h. All starting material was consumed, water (30 mL) was added followed by saturated aqueous NaHCCL (-400 mL) until neutral pH. The separated aqueous layer was extracted with DCM (2 x 300ml) and the combined organics dried over anhydrous MgSCL and evaporated in vacuo to give a yellow oil (17.5 g). Crude was purified by column chromatography (eluent: PE/EtOAc) to give, as colourless oils, intermediate la: Y: 12 g (66%), P: >95%, rt=2.73 min, (M+H)+= 240 and intermediate lb Y: 3 g (16%), P: >95%, (M+H)+= 240.

Reaction conditions D: synthesis of intermediate (2S)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate.

Sodium cyanobrorohydride (2.9 mmol) was added to a solution of (S)-methyl 5-(2-chlorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (2.42 mmol) in anhydrous MeOH (20 mL) and the reaction mixture was stirred at RT for lh. The RM was quenched with water and extracted with DCM. Combined organics were dried over anhydrous MgSCL and concentrated in vacuo to yield title compound. Y: 338 mg (59%), P: >95%, rt=2.73 min, (M+H)+= 240.

Reaction conditions E: synthesis of intermediate If: (2S,5R)-methyl 5-(pyridin-2-yl)pyrrolidine-2-carboxylate from 2-bromopyridine (route 3).

In a lOmL round bottomed flask was dissolved (S)-methyl 5-(pyridin-2-yl)-3,4-dihydro-2H-pyrroIe-2-carboxylate (0.208 mmol) in IPA (550 pL) to give a brown solution. Palladium on carbon (3.95 pmol) (10%w/w) was added, and reaction was stirred under H2 atmosphere.

Reaction mixture was stirred overnight at RT. The mixture was filtered through celite and concentrated under reduced pressure to give intermediate If in a quantitative yield. Y: 12 g (66%), P: >95%, rt=2.34 min, (M+H)+= 207.

The following intermediates were synthesized from ad-hoc reagents using general method A: intermediate lc: (2S,5R)-methyl 5-(3-chloropyridin-2-yl)pyrrolidine-2- carboxylate from 2-bromo-3-chloropyridine (route 3, conditions C); intermediate le: (2S)-methyl 5-([l,T-biphenyl]-3-yl)pyrrolidine-2- carboxylate from biphenyl-3-ylmagnesium bromide (conditions C); intermediate lg: (2S)-methyl 5-(2-fluorophenyl)pyrrolidine-2- carboxylate from l-bromo-2-fluorobenzene (route 1, conditions C), rt=2.5 min (gradient A); intermediate li: (2S)-methyl 5-(2-methoxyphenyl)pyrrolidine-2- carboxylate l-bromo-2-methoxybenzene (route 1, conditions D); intermediate lj: (2R)-methyl 5-(2-chlorophenyl)pyrrolidine-2- carboxylate from l-bromo-2-chlorobenzene (route 1, conditions D); intermediate lk: (2S)-methyl 5-(4-chlorophenyl)pyrrolidine-2- carboxylate from 4-chlorophenylmagnesium bromide (conditions C); intermediate 11: (2S)-methyl 5-([l,r-biphenyl]-4-yl)pyrrolidine-2- carboxylate from [l,r-biphenyl]-4-ylmagnesium bromide (conditions C); intermediate lm: (2S)-methyl 5-(2-chlorobenzyl)pyrrolidine-2- carboxylate from 2-chlorobenzylmagnesium chloride (conditions C); intermediate In: (2S)-methyl 5-cyclohexylpyrrolidine-2-carboxylate from cyclohexylmagnesium chloride (conditions C); intermediate lo: (2S)-methyl 5-([l,r-biphenyl]-2-yl)pyrrolidine-2-carboxylate from [l,l'-biphenyl]-2-ybnagnesium bromide (conditions C); mtermediate lp: (2S,5R)-methyl 5-(2-chlorophenyl)-4,4- dimethylpyrrolidine-2-carboxylate (conditions C), starting from (S)-l-tert-butyl 2-methyl 4,4-dimethyl-5-oxopyrrolidine-l,2-dicarboxylate obtained using the synthetic route described in scheme 8; intermediate lq: (2S,5R)-methyl 5-(2-chlorophenyl)-4- methylpyrrolidine-2-carboxylate (conditions C), starting from (S)-l-/er/-butyl 2-methyl-4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate; intermediate lr: (2S,5R)-methyl 5-(pyridin-3-yl)pyrrolidine-2- carboxylate; intermediate Is: (2S,5R)-methyl 5-(o-tolyl)pyrrolidine-2-carboxylate; intermediate It: (2S,5R)-methyl 5-phenylpyrrolidine-2-carboxylate (condition E); intermediate lu: (2S,5R)-methyl 5-(3-chlorophenyl)pynOlidine-2- carboxylate (route 1, conditions C); intermediate lv: (2S,5R)-methyl 5-(4-chlorophenyl)pyrrolidine-2- carboxylate (route 1, conditions C); intermediate lw: (2S,5R)-5-(3-fhiorophenyl)pyrrolidine-2-carboxylic acid (route 1, conditions E); intermediate lx: (2S,5R)-methyl 5-(4-fhiorophenyl)pyrrolidine-2- carboxylate (route 1, conditions E); intermediate ly: (2S,5R)-methyl 5-cyclohexylpyrrolidine-2-carboxylate was synthesized by hydrogenation of intermediate It using PtC>2 in MeOH, intermediate lz: (2R,5R)-methyl 5-(2-fhiorophenyl)pyrrolidine-2- carboxylate (route 1, conditions C); intermediate lal: (2S,5S)-methyl 5-(2-fluorophenyl)pyrrolidine-2- carboxylate(route 1, conditions C); intermediate lbl: (2R,5S)-methyl 5-(2-fluorophenyl)pyrrolidine-2-carboxylate(route 1, conditions C); intermediate lcl: (2S,5R)-methyl 5-(2,6-difluorophenyl)pyrrolidine-2-carboxylate(route 1, conditions E); intermediate ldl: (2S,5R)-methyl 5-(2,4-difluorophenyl)pyrrolidine-2-carboxylate(route 1, conditions E); intermediate lei: (2S,5R)-methyl 5-(2,4-dichlorophenyl)pyrrolidine-2-carboxylate(route 1, conditions C); intermediate lfl: (2S,5R)-methyl 5-isobutylpyrrolidine-2- carboxylate(route 2, conditions E); intermediate lgl: (2S,5R)-methyl 5-isopropylpyrrolidine-2- carboxylate(route 1, conditions E); intermediate lhl: (2S,5R)-methyl 5-cyclopentylpyrrolidine-2-carboxylate (conditions E); intermediate 111: (2S,5R)-methyl 5-(2-bromophenyl)pyrrolidine-2- carboxylate (route 1, conditions C); intermediate ljl: (2S,5S)-methyl 5-isopentylpyrrolidine-2-carboxylate (route 2, conditions E); intermediate lkl: (2S,5R)-methyl 5-(2,4-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions E); intermediate 111: (2S,5R)-methyl 5-(3,5-difluorophenyl)pyrrolidine-2- icarboxylate (route 1, conditions C); intermediate 1ml: (2S,5R)-methyl 5-(3,4-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C); intermediate lnl: (2S,5R)-methyl 5-(2,3-difluorophenyl)pyrrolidine-2carboxylate (route 1, conditions C), rt=2.6min (gradient A); intermediate lol: (2S,5R)-methyl 5-(2,5-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C); intermediate lpl: (2S,5R)-methyl 5-(4-cyanophenyl)pyrrolidine-2- carboxylate. (route 1, conditions C).

General method B: synthesis of aryloxyaryl carboxylic acid intermediates 1.2b

General method B is examplified with the synthesis of intermediate 2a 3-(benzyloxy)-5-methoxybenzoic acid.

Step 1: synthesis of methyl 3-hydroxy-5-methoxybenzoate.

To a solution of methyl 3,5-dihydroxybenzoate (29.76 mmol) in anhydrous acetone (40 mL) was added dimethylsulfate (29.69 mmol), tetrabutylammonium iodide (2.97 mmol) and potassium carbonate (59.42 mmol). The reaction mixture was stirred at RT overnight. The RM was diluted with water and extracted with AcOEt. Combined organics were dried over anhydrous MgSCL and concentrated in vacuo. Crude was purified by flash chromatography (eluent: PE/AcOEt ) to yield title compound. Y: 1.7 g (31%), P: >95%, rt=3.75 min, (M+H)+= 183.

Step 2: synthesis of methyl 3-(benzyloxy)-5-methoxybenzoate.

To a solution of methyl 3-hydroxy-5-methoxybenzoate (0.55 mmol) in anhydrous acetone (2 mL) was added benzyl bromide (0.55 mmol), potassium carbonate (0.66 mmol) and sodium iodide (0.055 mmol). The reaction mixture was stirred at 55°C for 5h. The RM was diluted with AcOEt and a 1M aqueous solution of sodium hydroxide. The organic layer was separated, dried over anhydrous MgS04 and concentrated in vacuo. Crude was purified by flash chromatography (eluent: PE/AcOEt) to yield title compound. Y: 104 mg (69%), P: >95%, rt=4.53 min, (M+H)+= 273.

Step 3: synthesis of intermediate 2a 3-(benzyloxy)-5-methoxybenzoic acid.

To a solution of methyl 3-(benzyloxy)-5-methoxybenzoate (0.38 mmol) in THF (1 mL) was added a solution of lithium hydroxide (1.53 mmol) in water (1 mL). The reaction mixture was stirred at RT overnight. The RM was quenched with a 1M HC1 aqueous solution and extracted three times with DCM. Combined organics were dried over anhydrous MgSC>4 and concentrated in vacuo to yield title compound. Y: 92 mg (94%), P: >95%, rt=3.95 mn, (M+H)+= 259.

The following intermediates were synthesized from ad-hoc reagents using general method B: intermediate 2b: 3-((4-chlorobenzyl)oxy)-5-methoxybenzoic acid, intermediate 2c: 3-methoxy-5-phenethoxybenzoic acid, intermediate 2d: 3-(3,3-diphenylpropoxy)-5-methoxybenzoic acid, intermediate 2e: 3-methoxy-5-((4-(methylsulfonyl)benzyl)oxy)benzoic acid, intermediate 2f: 3-methoxy-5-(2-methoxyethoxy)benzoic acid, intermediate 2g: 3-((3,5-dimethylisoxazol-4-yl)methoxy)-5-methoxybenzoic acid,

General method C: synthesis of most compounds of the invention

General method C is examplified with the synthesis of Example 1: compound n°l: (2S,5R)-5-(2-chlorophenyl)-1 -(2'-methoxy-[ 1,1 -biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Step 1: synthesis of (2S,5R)-methyl 5-(2-chlorophenyl)-l-(2'-methoxy-[1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate

Conditions A:

In a lOOmL round bottom flask, under argon, was dissolved 2'-methoxybiphenyl-4-carboxylic acid (15.714 g, 68.8 mmol) in DCM (138 mL). A white suspension was obtained to which were successively added thionyl chloride (7.49 mL, 103 mmol) and DMF (0.107 mL, 1.377 mmol). Reaction mixture was heated at reflux (40°C) 3 hours. The solution was allowed to reach spontaneously RT (yellow-orange solution). RM was concentrated under reduced pressure. Removal of the excess of thionyl chloride was done by two co-evaporation cycles with DCM. The resulting brown residue was dried under vacuum to afford 17g of a brown solid. Crude product was used without further purification in the next step.

In a 500 mL round bottom flask were introduced under argon methyl (2S,5R)-5-(2-chlorophenyl)pyrrolidine-2-carboxylate (15 g, 62.6 mmol), DCM (62.4 mL) and ΕΐβΝ (9.59 mL, 68.8 mmol). To this solution cooled to 0°C, was added dropwise (via an addition funnel) a solution of 2'-methoxybiphenyl-4-carbonyl chloride (16.98 g, 68.8 mmol) in DCM (83 mL) (dark brown solution). The RM was stirred from 0°C to RT overnight. The RM was transferred to a separation funnel and washed with 25 mL of HC1 6M diluted with 75mL water. The organic layer was dried under stirring with MgSCL in the presence of 0.3g of Norit AS, filtered and concentrated to afford 34 g of a light brown foaming oily residue. Purification by column chromatography (eluent: EtOAc/PE: 1/2 ) yielded desired product as a beige solid. Y: 25.4 g (90 %), P > 95%.

Conditions B: To a solution of 2'-methoxybiphenyl-4-carboxylic acid 2b (1.1 mmol) in anhydrous ACN (2 mL) was added HATU (1.1 mmol). After 5 min was added (2S,5R)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate la (1 mmol) and DIEA (1.2 mmol). Reaction mixture was stirred at RT for 4 days. Reaction mixture was diluted with AcOEt and washed with saturated aqueous solution of NaHCCE and with water. The organic phase was dried over MgSCL and evaporated. Crude was purified by flash chromatography (eluent: cyclohexane/AcOEt) to yield title compound. Y: 300 mg (67%), P>95%, rt= 4.85 min (M+H)+ =451.

Step 2: synthesis of Example 1: compound n°l: (2S,5R)-5-(2-chlorophenyl)-1 -(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

To a solution of (2S,5R)-methyl 5-(2-chlorophenyl)-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)pyrrohdine-2-carboxylate (0.67 mmol) in THF (5 mL) was added a solution of lithium hydroxide (2.67 mmol) in water (5 mL). The reaction mixture was stirred at RT overnight. The RM was quenched with a 1M HC1 aqueous solution and extracted twice with AcOEt. Combined organics were dried over anhydrous MgS04 and concentrated in vacuo to yield title compound as a colorless solid. Y: 250 mg (86%), P: >95%, rt=6.05 min, (M+H)+= 436.

General method D: synthesis of biaryl carboxylic acid intermediates 1.2a

Three routes (a, b and c) were used in the preparation of biaryl or heterobiaryl intermediates.

Route a is examplified with the synthesis of intermediate 2h 2'-methoxy-[l,l'-biphenyl]-4-carboxylic acid.

Step 1: synthesis of methyl 2'-methoxy-[l,l'-biphenyl]-4-carboxylate A mixture of methyl-4-iodobenzoate (86.2g, 0.33 mol) and 2-methoxyphenyl boronic acid (50.0 g, 0.33 mol) in toluene (975 mL) and EtOH (525 mL) was degassed with nitrogen bubbling for 30 minutes. Pd(PPh3)4 (19.0 g, 16.5 mmol) and 4M aqueous Na2C03 (271.5 mL, 1.09 mol) were added and the mixture stirred at 100°C under a nitrogen atmosphere overnight. After cooling to room temperature, EtOAc (1.5 L) and water (1.5 L) were added, and the separated organic layer was dried (Na2S04) and evaporated in vacuo to leave a brown oily solid (107 g). The residue was purified by column chromatography using an increasing gradient from 5-50% EtOAc/petrol to give title product as a yellow solid. Y: 51 g (64%), P>80%.

Step 2: synthesis of intermediate 2h 2'-methoxy-[l,l'-biphenyl]-4-carboxylic acid L1OH.H2O (89 g, 2.1 mol) was added to a stirred suspension of methyl 2'-methoxy-[l,l'-biphenyl]-4-carboxylate(51 g, 0.21 mol) in a mixture of THF (500 mL) and H2O (1 L). Further amounts of THF (~500 mL) and H20 (~1 L) were added to dissolve the majority of the solids. After stirring overnight at room temperature, more solids had precipitated and starting material still remained. The mixture was heated to 50°C for 4 hours, after which time all solids had dissolved and no starting material remained. After cooling to room temperature, saturated aqueous citric acid was added until pH = 6-7, which produced a white precipitate. THF was removed by evaporation in vacuo and the resulting suspension filtered. The solid was washed with water several times and dried at 50°C overnight to give intermediate 2h as an off-white solid. Y: 43 g (90%), P>90%.

Route b is exemplified with the synthesis of intermediate 2s2 4-(2-methoxypyrimidin-4-yl)benzo ic acid.

Step 1: synthesis of methyl 4-(2-methoxypyrimidin-4-yl)benzoate

In an oven dried glass tube, were introduced under argon 4-methoxycarbonylphenylboronic acid (381 mg, 2.116 mmol) and 4-bromo-2-methoxypyrimidine (200mg, 1.058 mmol).Three vacuum/Argon cycles were performed and toluene (5 mL) was added, followed by a 2M aqueous solution of K2CO3 (0.106 mmol). The resulting mixture was degassed (argon bubbling into the solution for 5-10 minutes).

Tetrakis(triphenylphosphine)palladium(0) (0.1 mmol) was then added and the mixture was heated to 95°C overnight. The mixture was cooled down to room temperature and then diluted with EtOAc and washed with brine. The aqueous layer was further extracted with EtOAc and the combined organic layers were dried and concentrated. The residue was purified on silica gel (cyclohexane / EtOAc), furnishing 243 mg of desired product as a pale yellow solid (94% yield).

Step 2: synthesis of intermediate 2s2 4-(2-methoxypyrimidin-4-yl)benzoic acid The same conditions as in step 2 of route a were used.

The following intermediates were synthesized from ad-hoc reagents using general method D route b: intermediate 2i: 2',5'-dichloro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2j: 4-(pyrimidin-5-yl)benzoic acid; intermediate 2k: 4-(furan-3-yl)benzoic acid; intermediate 21: 4-(6-methoxypyridin-3-yl)benzoic acid, intermediate 2m: 4-(3-fluoropyridin-4-yl)benzoic acid; intermediate 2n: 4-(pyridin-3-yl)benzoic acid; intermediate 2o: 4-(6-(dimethylamino)pyridin-3-yl)benzoic acid; intermediate 2p: 4-(pyridin-4-yl)benzoic acid; intermediate 2q: 4-(6-methylpyridin-3-yl)benzoic acid; intermediate 2r: 4-(2-methoxypyridin-3-yl)benzoic acid, rt=3.4 min (gradient A); intermediate 2s: 4'-methoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2t: 4'-cyano-[l,r-biphenyl]-4-carboxylic acid; intermediate 2u: 4-(4-methoxypyridin-3-yl)benzoic acid; intermediate 2v: 4'-chloro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2w: 3'-chloro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2x: 2'-chloro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2y: 4'-(methylsulfonamido)-[l,r-biphenyl]-4-carboxylic acid; intermediate 2z: 3'-(methylsulfonamido)-[l,r-biphenyl]-4-carboxylic acid; intermediate 2al: 2'-(methylsulfonamido)-[ 1,1 ’-biphenyl]-4-carboxylic acid; intermediate 2b 1: 4-(naphthalen-2-yl)benzoic acid; intermediate 2cl: 3’,5'-difluoro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2dl: 2'-hydroxy-[l,l'-biphenyl]-4-carboxylic acid; intermediate 2el: 2'-(trifluoromethoxy)-[l,r-biphenyl]-4-carboxylic acid; intermediate 2fl: 4-(3-fluoropyridin-4-yl)benzoic acid; intermediate 2gl: 4-(6-chloropyridin-3-yl)benzoic acid; intermediate 2hl: 4-(6-fluoropyridin-3-yl)benzoic acid; intermediate 2il: 5-methoxy-6-phenylnicotinic acid; intermediate 2j 1: 4-(3-methoxypyridin-4-yl)benzoic acid; intermediate 2kl: 2-methoxy-[l,l'-biphenyl]-4-carboxylic acid; intermediate 211: 4-(6-chloropyridin-3-yl)benzoic acid; intermediate 2ml: 4-(6-fluoropyridin-3-yl)benzoic acid; intermediate 2nl: 4-(thiophen-3-yl)benzoic acid; intermediate 2ol: 4-cyclohexylbenzoic acid; intermediate 2pl: 2'-(methylsulfonyl)-[l,r-biphenyl]-4-carboxylic acid; intermediate 2ql: 4-(pyrimidin-2-yl)benzoic acid; intermediate 2rl: 4-(4,6-dimethoxypyrimidin-2-yl)benzoic acid; intermediate 2sl: 4-(2,4-dimethoxypyrimidin-5-yl)benzoic acid, rt=3.4 min (gradient A); intermediate 2tl: 4-(2-methoxypyrimidin-5-yl)benzoic acid; intermediate 2ul: 4-(pyridin-2-yl)benzoic acid; intermediate 2vl: 2'-cyano-[l,r-biphenyl]-4-carboxylic acid; intermediate 2wl: 2',6'-dimethoxy-[l,r-biphenyl]-4-carboxybc acid, intermediate 2x1: 2',4'-dichloro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2yl: 2'-(trifluoromethyl)-[l,r-biphenyl]-4-carboxylic acid; intermediate 2zl: 2,2'-dimethoxy-[l,r-biphenyl]-4-carboxybc acid; intermediate 2a2: 4'-chloro-2'-methoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2b2: 4-(4-methoxypyrimidin-5-yl)benzoic acid; intermediate 2c2: 4-(3-fluoropyridin-4-yl)benzoic acid; intermediate 2d2: 2-chlorobiphenyl-4-carboxylic acid; intermediate 2e2: 2'-chloro-2-methoxybiphenyl-4-carboxylic acid, intermediate 2f2: 3-methoxy-4-(pyrimidin-5-yl)benzoic acid; intermediate 2g2: 2'-(methoxymethyl)biphenyl-4-carboxylic acid; intermediate 2h2: 4-(2,6-dimethoxypyridin-3-yl)benzoic acid; intermediate 2i2: 3-methoxy-4-(2-methoxypyrimidin-5-yl)benzoic acid, rt=3.2 min (gradient A); intermediate 2j2: 4-(5-methoxypyrazin-2-yl)benzoic acid; intermediate 2k2: 4-(3-methoxypyrazin-2-yl)benzoic acid; intermediate 212: 4-(2-chloro-4-(dimethylamino)pyrimidin-5 -yl)benzo ic acid; intermediate 2m2: 4-(2,6-dimethoxypyrimidin-4-yl)benzoic acid; intermediate 2n2: 4-(2-methylthiophen-3-yl)benzoic acid; intermediate 2o2: methyl 2',6'-dichlorobiphenyl-4-carboxylate; intermediate 2p2: 2’ -chloro-4'-methoxy-[ 1,1 ’-biphenyl]-4-carboxylic acid; intermediate 2q2: 2'-(dimethylamino)-[l,r-biphenyl]-4-carboxylic acid; intermediate 2r2: 3-methoxy-[l,l'-biphenyl]-4-carboxylic acid; intermediate 2t2: 4-(2-chloro-4-methoxypyrimidin-5-yl)benzoic acid; intermediate 2u2: 4-(3-methoxypyridin-2-yl)benzoic acid; intermediate 2v2: 2-(trifluoromethyl)-[l,r-biphenyl]-4-carboxylic acid; intermediate 2w2: 2',4'-difluoro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2x2: 2-methyl-[Ι,Γ-biphenyl]-4-carboxylic acid; intermediate 2y2: 3-chloro-4-(pyrimidin-4-yl)benzoic acid; intermediate 2z2: 2-fluoro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2a3: 2'-fluoro-4'-methoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2b3: 4'-fluoro-2'-methoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2c3: 4-(6-ethoxypyridin-3-yl)benzoic acid; intermediate 2d3: 4-(6-isopropoxypyridin-3-yl)benzoic acid; intermediate 2e3: 4-(6-methoxy-2-methylpyridin-3-yl)benzoic acid; intermediate 2f3: 3-chloro-4-(2-methoxypyrimidin-4-yl)benzoic acid; intermediate 2g3: 3-chloro-4-(pyrimidin-5-yl)benzoic acid;intermediate 2h3: 2',3’-dimethoxy-[l,r-biphenyl]-4-carboxybc acid; intermediate 213: 3',4’-dimethoxy-[l,r-biphenyl]-4-carboxybc acid; intermediate 2j3: 2',3',4'-trimethoxy-[l,r-biphenyl]-4-carboxybc acid; intermediate 2k3: 2',3',6'-trimethoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 213: 3',5'-dimethoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2m3: 2',5'-dimethoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2n3: 2'-isopropyl-[l,r-biphenyl]-4-carboxylic acid; intermediate 2o3 ;2'-ethyl-[l,r-biphenyl]-4-carboxylic acid; intermediate 2p3 :4-(2,6-dimethylpyridin-3-yl)benzoic acid; intermediate 2q3 :4-(2,4-bis(benzyloxy)pyrimidin-5-yl)benzoic acid; intermediate 2r3 :3-chloro-4-(6-methoxypyridin-3-yl)benzoic acid; intermediate 2s3 :5-methoxy-6-(2-methoxyphenyl)nicotinic acid; intermediate 2t3 :5-methoxy-6-(2-methoxyphenyl)nicotinic acid; intermediate 2u3 :3'-cyano-2'-methoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2v3 :3'-cyano-2',4'-bis(2,2,2-trifluoroethoxy)-[ 1,1 -biphenyl]-4-carboxylic acid; intermediate 2w3 :3'-amino-2'-methyl-[l,r-biphenyl]-4-carboxylic acid; intermediate 2x3: 2'-methyl-3'-(methylsulfonamido)-[ 1,1 -biphenyl]-4- carboxylic acid was obtained by sulfonylation of methyl 3'-amino-2'-methyl-[l,r-biphenyl]-4-carboxylate (which was synthesized using general method D, route b) and subsequent saponification. Sulfonylation procedure (as in J. Org. Chem. 2003, 68, 5300-5309): methyl 3'-amino-2'-methylbiphenyl-4-carboxylate (0.83 mmol) was dissolved in dry Et20 (5 mL) and cooled to 0 °C. Then pyridine (5.00 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (5.00 mmol). The reaction was stirred at RT for 2h. The precipitate was filtered and washed with Εί2<3. The organic layer was washed with HC1 1M aqueous solution, brine, dried and concentrated, furnishing 265 mg of desired prioduct as a brown oil in a quantitative yield; intermediate 2y3: 3'-acetamido-2'-methyl-[ 1,1 -biphenyl]-4-carboxylic acid was obtained by acetylation of methyl 3'-amino-2'-methyl-[l,r-biphenyl]-4-carboxylate (which was synthesized using general method D, route b) and subsequent saponification ._Acetylation procedure: to a solution of methyl 3'-amino-2'-methylbiphenyl-4-carboxylate (0.83 mmol) in dry DCM (5 mL) under N2 was added acetyl chloride (0.95 mmol), followed by Et3N (0.91 mmol). The RM was stirred at RT ovemight.The RM was then concentrated and the crude purified on silica gel (cyclohexane / EtOAc), furnishing 205 mg of desired product as a yellow oil (87% yield); intermediate 2z3: 5'-cyano-2'-methoxy-[l,r-biphenyl]-4-carboxylic acid, rt=3.7 min (gradient A); intermediate 2a4: 5'-cyano-2'-methyl-[l,r-biphenyl]-4-carboxylic acid, rt=3.9 min (gradient A); intermediate 2b4: 4-(4,6-dimethoxypyridin-3-yl)benzoic acid; intermediate 2c4: 4'-acetamido-2'-methoxy-[ 1,1 '-biphenyl]-4-carboxylic acid was obtained by the nitro group reduction of methyl 2'-methoxy-4'-nitro-[l,l'-biphenyl]-4-carboxylate (which was synthesized using general method D, route b) followed by acetylation with acetyl chloride (procedure described in the synthesis of intermediate 2y3) and saponification; intermediate 2d4: 3-methoxy-4-(5-methoxypyridin-3-yl)benzoic acid; intermediate 2e4: 2',3,6'-trimethoxy-[2,3'-bipyridine]-5-carboxylic acid; intermediate 2f4: 5'-cyano-2',3'-dimethoxy-[l, 1 '-biphenyl]-4-carboxylic acid; intermediate 2g4: 2’ -cyano-4',5'-dimethoxy-[ 1, r-biphenyl]-4-carboxylic acid; intermediate 2h4: 3',4',5'-trimethoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2i4: 2'-(cyanomethyl)-4',5’-dimethoxy-[ 1,1 -biphenyl]-4- carboxylic acid; intermediate 2j4: 3',4'-dicyano-[l,r-biphenyl]-4-carboxylic acid; intermediate 2k4: 5'-cyano-2'-fluoro-[l,r-biphenyl]-4-carboxylic acid; intermediate 214: 2-fluoro-3',4'-dimethoxy-[ 1,1 -biphenyl]-4-carboxy lie acid; intermediate 2m4: 4-(2,6-dimethoxypyridin-3-yl)-3-fluorobenzoic acid; intermediate 2n4: 3-fluoro-4-(6-methoxypyridin-3-yl)benzoic acid; intermediate 2r4: 4-(3,6-dimethoxypyridazin-4-yl)benzoic acid, rt=3.2 min (gradient A); intermediate 2s4: 2'-cyano-4'-methoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2u4: 3'-cyano-4'-fluoro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2v4: 2'-chloro-5'-cyano-[l,r-biphenyl]-4-carboxylic acid; intermediate 2w4: 2'-cyano-4'-(trifluoromethyl)-[ 1,1 ’-biphenyl]-4- carboxylic acid; intermediate 2x4: 2'-methyl-3’-(N-methylmethylsulfonamido)-[ 1,1 '- biphenyl]-4-carboxylic acid was obtained by sulfonylation of methyl 3'-amino-2’-methyl-[l,r-biphenyl]-4-carboxylate, followed by sulfonamide N-methylation with iodomethane, and subsequent saponification. Methyl 3'-amino-2'-methyl-[l,l'-biphenyl]-4-carboxylate was synthesized using general method D (route b); sulfonamide N-methylation procedure: in a glass tube was introduced methyl 2'-methyl-3’-(methylsulfonamido)biphenyl-4-carboxylate (0.438 mmol) and sodium hydride (0.570 mmol) in dry DMF (2 mL) at room temperature under argon atmosphere. After 30 minutes at room temperature, iodomethane (1.315 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Brine was then added and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSCL and concentrated under reduced pressure, furnishing crude desired product as a pale yellow oil in a quantitative yield; rt=3.4 min (gradient A) intermediate 2y4: 6-(5-cyano-2-methoxyphenyl)-5-methoxynicotinic acid; intermediate 2z4: 6-(2,4-dimethoxyphenyl)-5-methoxynicotinic acid; intermediate 2a5: 6-(2,4-dimethoxyphenyl)nicotinic acid; intermediate 2f5: 4-(4,6-dimethoxypyrimidin-5-yl)benzoic acid.

Route c is exemplified for the synthesis of intermediate 2g5 3-chloro-4-(2,4-dimethoxypyrimidin-5 -yl)benzo ic acid

Step 1: synthesis of methyl 3-chloro-4-(2,4-dimethoxypyrimidin-5-yl)benzoate

In a oven dried glass tube were introduced under argon 2-chloro-4-(methoxycarbonyl)phenylboronic acid (2.0 mmol) and 5-iodo-2,4-dimethoxypyrimidine (1.0 mmol). The tube was subjected to three vacuum/argon cycles and toluene (5 mL) was added, followed by a 2M aqueous solution of K2CO3 (3.0 mmol). The resulting mixture was degassed (argon bubbling into the solution for 5-10 minutes). Tris(dibenzylideneacetone)dipalladium(0) (5%) and S-Phos (10%) were then added and mixture was heated to 95°C overnight. The mixture was cooled down to room temperature and then diluted with EtOAc and washed with brine. The aqueous layer was further extracted with EtOAc and the combined organic layers were dried and concentrated. The residue was purified on silica gel (cyclohex / EtOAc), furnishing 143 mg of desired product as a pale yellow solid (93% yield).

Step 2: saponification using same procedure of 2h synthesis.

The following intermediates were synthesized from ad-hoc reagents using general method D route c: intermediate 2h5: 2-fluoro-2'-methoxy-[l,r-biphenyl]-4-carboxylic acid; intermediate 2j5: 5-(2-methoxyphenyl)pyrazine-2-carboxylic acid; intermediate 2k5: 3-methoxy-4-(4-methoxypyridin-3-yl)benzoic acid; intermediate 215: 3-methoxy-4-(6-methoxypyridin-3-yl)benzoic acid; intermediate 2m5: 3-chloro-4-(2-methoxypyrimidin-5-yl)benzoic acid (exemplified above); intermediate 2n5: 4-(2,4-dimethoxypyrimidin-5-yl)-3-methoxybenzoic acid;

intermediate 2r4: 4-(3,6-dimethoxypyridazin-4-yl)benzoic acid; intermediate 2p5: 2’-methoxy-4'-(methylsulfonamido)-[ 1,1 -biphenyl]-4-carboxylic acid was obtained by the nitro group reduction of methyl 2'-methoxy-4'-nitro-[l,r-biphenyl]-4-carboxylate (which was synthesized using general method D, route c) followed by sulfonylation with methanesulfonyl chloride (procedure described in the synthesis of intermediate 2x3) and saponification. Nitro reduction procedure: to a solution of methyl 2'-methoxy-4'-nitrobiphenyl-4-carboxylate (1.184 mmol) in anhydrous EtOH (35 ml) was added a slurry of Raney Ni in water (0.4 mL). The mixture was stirred at 50°C overnight. The RM was filtered on celite, and the solid was washed with MeOH. The filtrate was evaporated to yield desired product which was used without further purification; intermediate 2q5: 4-(2,6-dimethoxypyridin-3-yl)benzoic acid; intermediate 2s5: 2-fluoro-4'-(methylsulfonamido)-[ 1,1 -biphenyl]-4- carboxylic acid was obtained by sulfonylation of methyl 4'-amino-2-fluoro-[l,r-biphenyl]-4-carboxylate and subsequent saponification, methyl 4'-amino-2-fluoro-[l,l'-biphenyl]-4-carboxylate was synthetized using general method D, route c; intermediate 2t5: 2-fluoro-3'-(methylsulfonamido)-[ 1,1 -biphenyl]-4- carboxylic acid was obtained by sulfonylation of methyl 3'-amino-2-fluoro-[l,r-biphenyl]-4-carboxylate and subsequent saponification, methyl 3'-amino-2-fluoro-[l,l'-biphenyl]-4-carboxylate was synthetized using general method D, route c; intermediate 2u5: 2'-cyano-2-fluoro-[l,r-biphenyl]-4-carboxylic acid; intermediate 2v5: 2'-methoxy-4'-(N-methylmethylsulfonamido)-[ 1,1 '- biphenyl]-4-carboxylic acid was obtained by the nitro group reduction of 2'-methoxy-4'-nitro-[l,r-biphenyl]-4-carboxylate, followed by sulfonylation with methanesulfonyl chloride, followed by sulfonamide N-methylation with iodomethane, and subsequent saponification; rt=3.7 min (gradient A). Methyl 2’-methoxy-4’-nitro-[l,r-biphenyl]-4-carboxylate was synthesized using general method D (route c).

Intermediate 2w5 4-(3,6-dimethoxypyridazin-4-yl)-3-fluorobenzoic acid which was obtained from methyl 4-bromo-3-fluorobenzoate and (3,6-dimethoxypyridazin-4-yl)boronic acid using a Suzuki coupling procedure described in the literature (/. Org. Chem., 2008, 73, 2176-2181); rt=3.5 min (gradient A).

Unless otherwise stated compounds in examples 2 to 44 were synthesized from intermediate la and commercially available carboxylic acids or acyl chlorides using general method C.

Example 2: compound n°2: (2S,5R)-5-(2-chlorophenyl)-l-(2'-methyl-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 3: compound n°3: (2S,5R)-l-(3-((4-chlorobenzyl)oxy)-5- methoxybenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 4: compound n°4: (2S,5R)-5-(2-chlorophenyl)-l-(2'-fluoro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2b using general method C.

Example 5: compound n°5: (2S,5R)-5-(2-chlorophenyl)-l-(4'-methyl-[l,l'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid .

Example 6: compound n°6: (2S,5R)-5-(2-chlorophenyl)-l-(3-methoxy-5-phenethoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2c using general method C.

Example 8: compound n°8: (2S,5R)-l-([l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrohdine-2-carboxylic acid.

Example 9: compound n°9: (2S,5R)-5-(2-chlorophenyl)-1-(3-(3,3-diphenylpropoxy)-5-methoxybenzoyl)pyrrohdine-2-carboxylic acid was synthesized from intermediates la and 2d using general method C.

Example 10: compound n°10: (2S,5R)-5-(2-chlorophenyl)-l-(3'-fluoro-[1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 11: compound n°ll: (2S,5R)-5-(2-chlorophenyl)-l-(3'-methyl-[1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 12: compound n°12: (2S,5R)-5-(2-chlorophenyl)-l-(3-methoxy-5-((4-(methylsulfonyl)benzyl)oxy)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2e using general method C.

Example 13: compound n°13: (2S,5R)-5-(2-chlorophenyl)-l-(3'-methoxy-[1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 14: compound n°14: (2S,5R)-5-(2-chlorophenyl)-1-(3,5- dimethoxybenzoyl)pyrro lidine-2-carboxylic acid.

Example 15: compound n°15: (2S,5R)-5-(2-chlorophenyl)-1-(4-(phenoxymethyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 16: compound n°16: (2S,5R)-5-(2-chlorophenyl)-1-(4-((2-fluorobenzyl)oxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 17: compound n°17: (2S,5R)-l-(3-chloro-5-methoxybenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 18: compound n°18: (2S,5R)-5-(2-chlorophenyl)-l-(4'- fluoro-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 19: compound n°19: (2S,5R)-5-(2-chlorophenyl)-1-(4-phenethoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 20: compound n°20: (2S,5R)-5-(2-chlorophenyl)-l-(chroman-3-carbonyl)pyrrolidine-2-carboxylic acid.

Example 21: compound n°21: (2S,5R)-5-(2-chlorophenyl)-l-(3,5- diethoxybenzoyl)pyrro lidine-2-carboxylic acid.

Example 23: compound n°23: (2S,5R)-5-(2-chlorophenyl)-1-(3- phenethoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 24: compound n°24: (2S)-l-([l,l'-biphenyl]-4-carbonyl)-4-benzyl-5-phenylpyrrolidine-2-carboxylic acid was synthesized as described in scheme 24.

Example 25: compound n°25: (2S,5R)-5-(2-chlorophenyl)-1-(1,2,3,4-tetrahydronaphthalene-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 26: compound n°26: (2S,5R)-5-(2-chlorophenyl)-1-(4- isobutylbenzoyl)pyrrolidine-2-carboxylic acid.

Example 27: compound n°27: (2S,5R)-5-(2-chlorophenyl)-1-(2,2- difluorobenzo[d][ 1,3]dioxole-6-carbonyl)pyrrolidine-2-carboxylic acid.

Example 28: compound n°28: (2S,5R)-l-([l,l'-biphenyl]-4-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid.

Example 29: compound n°29: (2S,5R)-5-(2-chlorophenyl)-l-(3-fluoro-5-methoxybenzoyl)pyrro lidine-2-carboxylic acid.

Example 30: compound n°30: (2S,5R)-5-(2-chlorophenyl)-1-(6-phenylnicotinoyl)pynOlidine-2-carboxylic acid.

Example 31: compound n°31: (2S,5R)-5-(2-chlorophenyl)-l-(3-methoxy-5-(2-methoxyethoxy)benzoyl)pynOlidine-2-carboxylic acid was synthesized from intermediates la and 2f using general method C.

Example 32: compound n°32: (2S,5R)-5-(2-chlorophenyl)-l-(3'-methoxy-[1,1 '-biphenyl]-3-carbonyl)pyrrolidine-2-carboxylic acid.

Example 33: compound n°33: (2S,5R)-5-(2-chlorophenyl)-l-(3-methoxy-5-(trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 34: compound n°34: (2S,5R)-5-(2-chlorophenyl)-l-(l-(4- methoxyphenyl)-5-phenyl-lH-pyrazole-3-carbonyl)pyrrolidine-2-carboxylic acid.

Example 35: compound n°35: (2S,5R)-5-(2-chlorophenyl)-1-(4-isopropoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 36: compound n°36: (2S,5R)-5-(2-chlorophenyl)-l-(3-((3,5-dimethylisoxazol-4-yl)methoxy)-5-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2g using general method C.

Example 37: compound n°37: (2S,5R)-5-(2-chlorophenyl)-1-(2,3-dihydro-lH-indene-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 38: compound n°38: (2S,5R)-5-(2-chlorophenyl)-l-(3-methyl-5-(trifluoromethoxy)benzoyl)pyrro lidine-2-carboxylic acid.

Example 39: compound n°39: (2S,5R)-l-(3-(benzyloxy)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 40: compound n°40: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 41: compound n°41: (2S,5R)-5-(2-chlorophenyl)-1-(2- phenylpyrimidine-5-carbonyl)pyrrolidine-2-carboxylic acid.

Example 42: compound n°42: (2S,5R)-5-(2-chlorophenyl)-1-(4- (trifluoromethoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 43: compound n°43: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 44: compound n°44: 4-((2S,5R)-2-carboxy-5-(2- chlorophenyl)pyrrolidine-1 -carbonyl)-2,6-dimethoxypyrimidin-1 -ium formate.

Example 45: compound n°45: (2S,5R)-5-(2-chlorophenyl)-1-(4- phenylbutanoyl)pyrro lidine-2-carboxylic acid.

Example 46: compound n°46: (2S,5R)-5-(2-chlorophenyl)-l-(3-methyl-5-(trifluoromethyl)benzoyl)pyrro lidine-2-carboxylie acid.

Example 47: compound n°47: (2S,5R)-l-([l,l'-biphenyl]-4-carbonyl)-5-(3-chloropyridin-2-yl)pyrrolidine-2-carboxylic acid intermediate lc using general method C.

Example 48: compound n°48: (2S,5R)-5-(2-chlorophenyl)-l-(3-hydroxy-5-(trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 49: compound n°49: (2S,5S)-5-(2-chlorophenyl)-l-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lb using general method C.

Example 50: compound n°50: (2S,5R)-l-(3,5-dimethoxybenzoyl)-5-phenylpyrrolidine-2-carboxylic acid was synthesized from intermediate Id ((2S,5R)-methyl 5-phenylpyrrolidine-2-carboxylate). Id was synthesized from commercially available (2S,5R)-1 -(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid using the synthetic steps described in scheme 4.

Example 51: compound n°51: (S)-5-([l,l ’-biphenyl]-3-yl)-1-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate le using general method C.

Example 52: compound n°52: (2S,5R)-5-(2-chlorophenyl)-1-(3- phenylpropanoyl)pyrrolidine-2-carboxylic acid.

Example 53: compound n°53: (2S,5S)-5-(2-chlorophenyl)-l-(2'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lb using general method C.

Example 54: compound n°54: (2S,5R)-l-([l,l'-biphenyl]-4-carbonyl)-5-(pyridin-2-yl)pyrrolidine-2-carboxylic acid was synthesized from intermediate If using general method C.

Example 55: compound n°55: (2S,5R)-5-(2-chlorophenyl)-1-(5- phenylpicolinoyl)pyrrolidine-2-carboxylic acid.

Example 57: compound n°57: (2S,5R)-5-(2-fluorophenyl)-1-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lg using general method C.

Example 58: compound n°58: (2S,5R)-l-(2-([l,l'-biphenyl]-4-yl)acetyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 59: compound n°59: (2R,5S)-l-([l,l'-biphenyl]-4-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid was synthesized from intermediate lh using general method C. lh was synthesized from commercially available (2R,5S)-1-(feri-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid using the synthetic steps described in scheme 4.

Example 60: compound n°60: (2S,5R)-5-phenyl-1-(2- phenylacetyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate Id using general method C.

Example 61: compound n°61: (2R,5S)-5-phenyl-1-(2- phenylacetyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lh using general method C.

Example 62: compound n°62: (2S,5R)-l-(3-methoxybenzoyl)-5-(2-methoxyphenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate li using general method C.

Example 63: compound n°63: (2R,5S)-5-(2-chlorophenyl)-l-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lj using general method C.

Example 64: compound n°64: (2R,5R)-5-(2-chlorophenyl)-1-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lj using general method C.

Example 65: compound n°65: (2S)-5-(4-chlorophenyl)-1-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lk using general method C.

Example 66: compound n°66: (2S)-5-([l,l'-biphenyl]-4-yl)-l-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 11 using general method C.

Example 67: compound n°67: (2S,5R)-methyl 5-(2-chlorophenyl)-l-(3-methoxybenzoyl)pyrrolidine-2-carboxylate was synthesized using general method C without the last saponification step.

Example 68: compound n°68: (2S)-5-(2-chlorobenzyl)-l-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lm using general method C.

Example 69: compound n°69: (2S)-5-cyclo hexyl-1-(3- methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate In using general method C.

Example 70: compound n°70: (2S,5R)-5-(2-chlorophenyl)-1-(2-(3- methoxyphenyl)acetyl)pyrrolidine-2-carboxylic acid.

Example 71: compound n°71: (2S,5S)-5-(2-chlorophenyl)-l-(3,5- dimethoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lb using general method C.

Example 72: compound n°72: (2S,5R)-5-([l,l'-biphenyl]-2-yl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lo using general method C.

Example 74: compound n°74: 2-((2S,5R)-5-(2-chlorophenyl)-1-(3- methoxybenzoyl)pyrrolidin-2-yl)acetic acid. Compound n°40 was reacted with ethyl chloro formate (1.03 eq) in THF in the presence of triethylamine (1.03 eq) and then was added a solution of diazomethane in diethyl ether (2 eq), the mixture was stirred at RT for 2.5 days. Reaction mixture was quenched with a 10% aqueous solution of citric acid and diluted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, then concentrated in vacuo. The residue was dissolved in MeOH and silver benzoate (1 eq) and triethylamine (2 eq) were added. The RM was stirred at RT for 45 min and diluted with AcOEt, washed with a saturated aqueous solution of sodium bicarbonate and brine 1M aqueous HC1, dried over anhydrous MgSC>4 and evaporated to dryness to yield title compound.

Example 75: compound n°75: (2S,5R)-5-(2-chlorophenyl)-1-(6- phenylpyrimidine-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 76: compound n°77: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2- chlorophenyl)nicotinoyl)pyrro lidine-2-carboxylic acid.

Example 77: compound n°78: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2- methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 78: compound n°79: (2S,5R)-5-(2-chlorophenyl)-1-(6-(3- fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 79: compound n°80: (2S,5R)-5-(2-chlorophenyl)-1-(6-(3- methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 80: compound n°81: (2S,5R)-5-(2-chlorophenyl)-1-(6-(4- methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 81: compound n°82: (2S,5R)-5-(2-chlorophenyl)-1-(6-(4- fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 82: compound n°83: (2S,5R)-5-(2-chlorophenyl)-1-(2-(2- chlorophenyl)pyrimidine-5-carbonyl)pyrrolidine-2-carboxylic acid.

Example 83: compound n°84: (2S,5R)-5-(2-chlorophenyl)-l-(2-methyl-6-phenylnicotinoyl)pyrrolidine-2-carboxylic acid.

Example 84: compound n°88: (2S,5R)-5-(2-chlorophenyl)-l-(4-(pyridin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was was synthesized from intermediates la and 2ul using general method C.

Example 85: compound n°89: (2S,5R)-l-(4-((4- chlorophenoxy)methyl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 86: compound n°91: (2S,5R)-5-(2-chlorophenyl)-l-(4-((4- methoxyphenoxy)methyl)benzoyl)pyrrolidine-2-carboxylic acid

Example 87: compound n°92: (2S,5R)-l-(4-((2- chlorophenoxy)methyl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate lb using general method C.

Example 88: compound n°95: (2S,5R)-1-(4-((3- chlorophenoxy)methyl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 89: compound n°96: (2S,5R)-5-(2-chlorophenyl)-l-(4-((p- tolyloxy)methyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 90: compound n°99: (2S,5R)-5-(2-chlorophenyl)-1-(4-((3,5- dimethylisoxazol-4-yl)methoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 91: compound n°102: (2S,5R)-5-(2-chlorophenyl)-l-(4-(pyridin-4-ylmethoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 92: compound n°104: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5- methyl-1 H-pyrazol-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 93: compound n°105: (2S,5R)-5-(2-chlorophenyl)-1-(4- (isoxazol-5-yl)benzoyl)pynOlidine-2-carboxylic acid.

Example 94: compound n°106: (2S,5R)-l-(4-(4H-l,2,4-triazol-4- yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 95: compound n°107: (2S,5R)-5-(2-chlorophenyl)-l-(4-(5-(p-tolyl)- 1H-1,2,3-triazol-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 96: compound n° 108: (2S,5R)-5-(2-chlorophenyl)-l-(4-(5-oxo-3-phenyl-4,5-dihydro-ΙΗ-pyrazol-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 97: compound n°109: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5- methyl-3 -(trifluoromethyl)-1 H-pyrazo 1-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 98: compound n° 110: (2S,5R)-l-(4-(lH-pyrazol-l-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 99: compound n°lll: (2S,5R)-5-(2-chlorophenyl)-l-(4-(oxazol-5-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 100: compound n°112: (2S,5R)-5-(2-chlorophenyl)-l-(4-(3,5- dimethyl-1 H-pyrazol-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 101: compound n°113: (2S,5R)-5-(2-chlorophenyl)-l-(2',5- dichloro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2i using general method C.

Example 102: compound n°114: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2j using general method C.

Example 103: compound n°115: (2S,5R)-5-(2-chlorophenyl)-l-(4-(furan-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2k using general method C.

Example 104: compound n°116: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 21 using general method C.

Example 105: compound n°117: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3- fluoropyridin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2m using general method C.

Example 106: compound n°118: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2n using general method C.

Example 107: compound n°119: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- (dimethylamino)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2o using general method C.

Example 108: compound n°120: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2p using general method C.

Example 109: compound n°121: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- methylpyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2q using general method C.

Example 110: compound n°122: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2r using general method C.

Example 111: compound n°123: (2S,5R)-5-(2-chlorophenyl)-1-(4-methoxy- [1,1 ’-biphenyl] -4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2s using general method C.

Example 112: compound n°124: (2S,5R)-5-(2-chlorophenyl)-l-(4'-cyano-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2t using general method C.

Example 113: compound n°125: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2u using general method C.

Example 114: compound n°126: (2S,5R)-l-(4'-chloro-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2v using general method C.

Example 115: compound n°127: (2S,5R)-l-(3'-chloro-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2w using general method C.

Example 116: compound n°128: (2S,5R)-l-(2'-chloro-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2x using general method C.

Example 117: compound n°129: (2S,5R)-5-(2-chlorophenyl)-1-(4- (methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2y using general method C.

Example 118: compound n°130: (2S,5R)-5-(2-chlorophenyl)-1-(3- (methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2z using general method C.

Example 119: compound n°131: (2S,5R)-5-(2-chlorophenyl)-1-(2- (methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2al using general method C.

Example 120: compound n°132: (2S,5R)-5-(2-chlorophenyl)-1-(4- (naphthalen-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2bl using general method C.

Example 121: compound n°133: (2S,5R)-5-(2-chlorophenyl)-l-(3',5'-difluoro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2cl using general method C.

Example 122: compound n°134: (2S,5R)-5-(2-chlorophenyl)-1-(2- hydroxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2dl using general method C.

Example 123: compound n°135: (2S,5R)-5-(2-chlorophenyl)-l-(2'- (trifluoromethoxy)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2el using general method C.

Example 124: compound n°136: (2S,5R)-l-(2'-(benzyloxy)-[l,l'- biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 125: compound n°137: (2S,5R)-5-(2-chlorophenyl)-l-(2’- phenoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 126: compound n°138: (2S,5R)-5-(2-chlorophenyl)-1-(2- isopropoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 127: compound n°139: (2S,5R)-5-(2-chlorophenyl)-1-(2- isobutoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 128: compound n°140: (2S,5R)-5-(2-chlorophenyl)-1-(2- (cyclopropylmethoxy)-[l, 1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 129: compound n°141: (2S,5R)-5-(2-chlorophenyl)-1-(2-((4-fluorobenzyl)oxy)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 130: compound n°142: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-chloropyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 211 using general method C.

Example 131: compound n°143: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-fluoropyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2ml using general method C.

Example 132: compound n°149: (2S,5R)-5-(2-chlorophenyl)-1-(4- (thiophen-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2nl using general method C.

Example 133: compound n°150: (2S,5R)-5-(2-chlorophenyl)-1-(4-cyclohexylbenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2ol using general method C.

Example 134: compound n° 152: (2S,5R)-5-(2-chlorophenyl)-l-(9-oxo-9H-fluorene-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 135: compound n°153: (2S,5R)-5-(2-chlorophenyl)-l-(2- (methylsulfonyl)-[ 1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxy lie acid was synthesized from intermediates la and 2pl using general method C.

Example 136: compound n°155: (2S,5R)-5-(2-chlorophenyl)-l-(9-methyl-9H-carbazo le-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 137: compound n°156: (2S,5R)-5-(2-chlorophenyl)-1-(4- phenoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 138: compound n°157: (2S,5R)-l-(4-benzylbenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 139: compound n°158: (2S,5R)-l-(4-benzoylbenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 140: compound n°159: (2S,5R)-5-(2-chlorophenyl)-1-(4- (pyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2ql using general method C.

Example 141: compound n°160: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6-dimethoxypyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2rl using general method C.

Example 142: compound n°161: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2sl using general method C.

Example 143: compound n°162: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2tl using general method C.

Example 144: compound n°168: (2S,5R)-5-(2-chlorophenyl)-l-(cyclohexanecarbonyl)pyrrolidine-2-carboxylic acid.

Example 145: compound n°169: (2S,5R)-5-(2-chlorophenyl)-1-(4-methylpentanoyl)pyrro lidine-2-carboxylic acid.

Example 146: compound n°172: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-methylpiperidin-1 -yl)-3-nitrobenzoyl)pyrrolidine-2-carboxylic acid.

Example 147: compound n°173: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- oxopiperidin-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 148: compound n°174: (2S,5R)-5-(2-chlorophenyl)-l-(3-methyl-4-morpholinobenzoyl)pyrrolidine-2-carboxylic acid.

Example 149: compound n°175: (2S,5R)-5-(2-chlorophenyl)-1-(4- (piperidin-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 150: compound n°176: (2S,5R)-5-(2-chlorophenyl)-1-(4- morpholinobenzoyl)pyrrolidine-2-carboxylic acid.

Example 151: compound n°177: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2- cyanophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 152: compound n°178: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4- chlorophenyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylic acid.

Example 153: compound n°179: (2S,5R)-5-(2-chlorophenyl)-1-(4- phenylcyclohexanecarbonyl)pyrro lidine-2-carboxylic acid.

Example 154: compound n°183: ((2R,5S)-2-(2-chlorophenyl)-5-(lH- tetrazol-5-yl)pyrrolidin-1 -yl)(2'-methoxy-[ 1,1 '-biphenyl]-4-yl)methanone:

Step 1: synthesis of (2S,5R)-5-(2-chlorophenyl)-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxamide

In a glass tube containing compound n°l (0.2 g, 0.459 mmol) in THF (5 mL) were added CDI (0.167 g, 0.11 mmol). The RM was stirred at RT for 30mn, then NH3 bubbling in the RM for 1 mn. The RM was diluted with HC1 1M and extracted with EtOAc. The organic layer was dried overnight over MgS04. The concentrated in vacuo and the residue (164 mg) diluted in MeCN and passed through a new PE-AX (2 g) cartridge. The filtrate was concentrated to yield title intermediate. Y: 0.14 g (70%), P > 80%, rt=4.08 mn (gradient A).

Step 2: synthesis of (2S,5R)-5-(2-chlorophenyl)-l-(2'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carbonitrile

In a 50 mL round bottom flask containing (2S,5R)-5-(2-chlorophenyl)-1-(2-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxamide (0.14 g, 0.322 mmol) were added DMF (3.22 mL). The RM was degassed and placed under Ar. Cyanuric chloride (0.059 g, 0.322 mmol) was added and the RM stirred at RT for 90 mn.The RM was diluted with NaHCCE (aqueous saturated solution) and extracted with AcOEt. The organic phase was washed with brine (2x), dried over MgSCU filtered and concentrated to afford 126mg of title product. Y: 0.126 g (94%), P > 80%, rt = 4.53 mn (gradient A), (M+H)+=417/419.

Step 3: synthesis of compound n° 183

In a oven-dried glass tube were added under Ar sodium azide (0.086 g, 1.330 mmol) and THF (5 mL). Were added successively aluminium chloride (0.101 g, 0.756 mmol) and (2S,5R)-5-(2-chlorophenyl)-l-(2'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carbonitrile (0.126 g, 0.302 mmol) diluted in lmL THF. The RM was heated at 60°C overnight. Sodium azide (0.086 g, 1.33 mmol) and aluminium chloride (0.101 g, 0.756 mmol) were added and the RM stirred at 60°C for another 7h. The RM was allowed to reach RT and quenched with HC1 6N and extracted with AcOEt (2x). The organic layer was dried over MgS04, filtered and concentrated to afford 160mg of crude product as a yellow oil. Crude was purified by flash chromatography (DCM/MeOH : 95/5) and SPE using a PEAX cartridge and elution with ACN, then ACN + HC1. Crude in MeCN solution from the PEAX fractions were concentrated in vacuo. Residue lyophilized in ACN/Water (2 mL / 1 mL). Y: 13mg (9%), P=100 %, rt =5.19 mn (gradient B), (M+H)+=460.

Example 155: compound n°184: (2R,5S)-5-(2-chlorophenyl)-l-(2'- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lj and 2h using general method C.

Example 160: compound n°189: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2- fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 162: compound n°191: (2S,5R)-5-(2-chlorophenyl)-1-(5- methoxy-6-phenylnicotinoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2il using general method C.

Example 163: compound n°192: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- methoxyphenoxy)benzoyl)pyrro lidine-2-carboxylic acid.

Example 164: compound n°193: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3- methoxypyridin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2jl using general method C.

Example 165: compound n°194: (2S)-5-(2-chlorophenyl)-l-(2'-methoxy-[1,1 '-biphenyl]-4-carbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid was synthesized from intermediates lp and 2h using general method C.

Example 166: compound n°195: (2S)-5-(2-chlorophenyl)-l-(2'-methoxy-[1,1 ’-biphenyl]-4-carbonyl)-4-methylpyrrolidine-2-carboxylic acid was synthesized from intermediates lq and 2h using general method C.

Example 167: compound n°196: (2S,5R)-5-(2-chlorophenyl)-1-(2-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2kl using general method C.

Example 168: compound n°197: (2S,5R)-5-(2-chlorophenyl)-l-(2’-cyano-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2vl using general method C.

Example 169: compound n°198: (2S,5R)-5-(2-chlorophenyl)-l-(2’,6’-dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2wl using general method C.

Example 170: compound n°199: (2S,5R)-5-(2-chlorophenyl)-l-(2',4'-dichloro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2x1 using general method C.

Example 171: compound n°200: (2S,5R)-5-(2-chlorophenyl)-1-(2-(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2yl using general method C.

Example 172: compound n°201: (2S,5R)-5-(2-chlorophenyl)-1-(2,2- dimethoxy-[l ,l'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2zl using general method C.

Example 173: compound n°202: (2S,5R)-l-(4'-chloro-2'-methoxy-[l,l'-biphenyl] -4-carbonyl)-5 -(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2a2 using general method C.

Example 174: compound n°203: (2S,5R)-5-(2-chlorophenyl)-l-(4-(4- methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2b2 using general method C.

Example 175: compound n°204: (2S,5R)-5-(2-chlorophenyl)-l-(2',4'- dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2c2 using general method C.

Example 176: compound n°205: (2S,5R)-l-([l,l'-biphenyl]-4-carbonyl)-5-(pyridin-3-yl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lr using general method C.

Example 177: compound n°206: (2R,5R)-5-(2-chlorophenyl)-1-(2-methoxy-[ 1,1 -biphenyl]-4-carbonyl)pyrrolidine-2-carboxy lie acid was synthesized from intermediate lj using general method C.

Example 178: compound n°207: (2S,5R)-5-(2-chlorophenyl)-l-(l-phenyl-lH-benzo[d]imidazole-5-carbonyl)pyrrolidine-2-carboxylic acid.

Example 179: compound n°208: (2S,5R)-methyl 5-(2-chlorophenyl)-l-(2'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate was obtained in step 1 of general method C.

Example 180: compound n°217: (2S,4S,5S)-5-(2-chlorophenyl)-l-(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)-4-(phenylsulfonyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology described in scheme 9.

Example 181: compound n°220: (2S,5R)-5-(2-chlorophenyl)-4-cyano-l-(2’-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology described in scheme 9.

Example 182: compound n°224: (2S,5R)-l-(2-chloro-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2d2 using general method C.

Example 183: compound n°225: (2S,5R)-l-(2'-chloro-2-methoxy-[l,l'-biphenyl] -4-carbonyl)-5 -(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2e2 using general method C.

Example 184: compound n°226: (2S,5R)-5-(2-chlorophenyl)-1-(2-(2-methoxyethoxy)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and 2’-(2-methoxyethoxy)biphenyl-4-carboxylic acid which was obtained by saponification of methyl 2-(2-methoxyethoxy)biphenyl-4-carboxylate. The latter intermediate was prepared using Mitsunobu chemistry:

To a solution of methyl 2’-hydroxybiphenyl-4-carboxylate (300 mg, 1.31 mmol), triphenylphosphine (517 mg, 1.97 mmol) and 2-methoxyethanol (130 pL, 1.64 mmol) in THF (12.5 mL) was added slowly diisopropylazodicarboxylate (388 pL, 1.97 mmol) at 0°C. The mixture was stirred at RT overnight and the reaction was quenched with methanol. The reaction mixture was diluted with water and extracted with DCM (25 mL). The organic layer was washed with water, dried and concentrated in vacuo. Crude was purified by column chromatography (cyclohexane/ EtOAc = 1/1) to yield 2'-(2-methoxyethoxy)biphenyl-4-carboxylate as a yellow oil. Y: 450 mg (78 %), P: 65%, rt= 2.5 mn (gradient A), Rf (cyclohexane/EtOAc = 95/5)=0.75.

Example 185: compound n°230: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2f2 using general method C.

Example 186: compound n°231: (2S,5R)-l-(2'-carbamimidoyl-[l,r-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Step 1:

To a solution of compound n° 197 precursor (2S,5R)-methyl 5-(2-chlorophenyl)-l-(2'-cyano-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate (100 mg, 0.225 mmol) and hydoxylamine hydrochloride (32 mg, 0.45 mmol) in EtOH (1 mL) was triethylamine(64 pL, 0.45 mmol) dropwise at room temperature. The mixture was stirred at reflux for 2 days. The mixture was cooled to RT and concentrated. Crude was purified by column chromatography (DCM/ MeOH = 98/2) to yield (2S,5R)-methyl5-(2-chlorophenyl)-l-(2'-((E)-N'- hydroxycarbamimidoyl)biphenylcarbonyl)pyrrohdine-2-carboxylate as a colorless solid. Y: 113 mg (63 %), P: >80%, rt= 3.6 mn (gradient A), Rf (DCM/ MeOH = 9/1)=0.3.

Step 2: A solution of (2S,5R)-methyl5-(2-chlorophenyl)-l-(2'-((E)-N'-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrohdine-2-carboxylate in (EtOH/THF/AcOH=l/l/0.025) (2 mL) was hydrogenated at RT for 45 min. under atmospheric pressure of H2 using a slurry solution of Raney nickel catalyst in water (2 vacuum/N2 cycles and then 2 vacuum/H2 cycles). The catalyst was filtered off over Celite and the filtrate was concentrated in vacuo to yield (2S,5R)-methyl l-(2'-carbamimidoylbiphenylcarbonyl)-5-(2-chlorophenyl)pyrrohdine-2-carboxylate as a greenish solid. Y: 64 mg (99 %), P: 70%, rt= 3.5 mn (gradient A).

Step 3: (2S,5R)-methyl 1 -(2'-carbamimidoylbiphenylcarbonyl)-5-(2- chlorophenyl)pyrrolidine-2-carboxylate was saponified as exemplified in general method C to provide compound n° 231.

Example 187: compound n°232: (2S,5R)-5-(2-fluorophenyl)-1-(2-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg using general method C.

Example 188: compound n°233: (2S,5R)-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)-5-(o-tolyl)pyrrohdine-2-carboxylic acid was synthesized from intermediates Is using general method C.

Example 189: compound n°234: (2S,5R)-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)-5-(2-methoxyphenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates li using general method C.

Example 190: compound n°235: (2S,5R)-5-(2-chlorophenyl)-1-(2-(methoxymethyl)- [ 1,1 ’-biphenyl] -4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2g2 using general method C.

Example 191: compound n°236: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6-dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2h2 using general method C.

Example 192: compound n°237: (2S,5R)-5-(2-chlorophenyl)-l-(3- methoxy-4-(2-methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2i2 using general method C.

Example 193: compound n°238: (2S,5R)-5-(2-chlorophenyl)-l-(4-(5-methoxypyrazin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2j2 using general method C.

Example 194: compound n°239: (2S,5R)-5-(2-chlorophenyl)-l-(4-(2-(2-methoxyethoxy)pyridin-3 -yl)benzoyl)pyrro lidine-2-carboxylic acid was synthesized from intermediate la and 4-(2-(2-methoxyethoxy)pyridin-3-yl)benzoic acid which was obtained by saponification of methyl 4-(2-(2-methoxyethoxy)pyridin-3-yl)benzoate. The latter intermediate was prepared using Mitsunobu chemistry as described for the synthesis of compound n° 226.

Example 195: compound n°240: (2S,5R)-5-(2-chlorophenyl)-l-(4-(3-methoxypyrazin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2k2 using general method C.

Example 196: compound n°241: (2S,5R)-l-(4-(2-chloro-4- (dimethy lamino)pyrimidin-5 -yl)benzoyl)-5 -(2-chlorophenyl)pyrro lidine-2-carboxylic acid was synthesized from intermediates la and 212 using general method C.

Example 197: compound n°242: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6-dimethoxypyrimidin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2m2 using general method C.

Example 198: compound n°227: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- methylthiophen-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2n2 using general method C and further purified by preparative HPLC.

Example 199: compound n°228: (2S,5R)-5-(2-chlorophenyl)-l-(2',6'- dichloro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2o2 using general method C.

Example 200: compound n°229: (2S,5R)-l-(2'-chloro-4'-methoxy-[l,T-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2p2 using general method C.

Example 201: compound n°243: (2S,5R)-5-(2-chlorophenyl)-l-(2'- (dimethylamino)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2q2 using general method C.

Example 202: compound n°246: (2S,5R)-5-(2-fluorophenyl)-1-(4-(2- methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2r using general method C.

Example 203: compound n°247: (2S,5R)-1-(4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2sl using general method C.

Example 204: compound n°249: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2r2 using general method C.

Example 205: compound n°269: (2S,5R)-1-(4-(2,6-dimethoxypyridin-3-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2h2 using general method C.

Example 206: compound n°261: (2S,5R)-5-(2-chlorophenyl)-1-(3- methoxy-4-(4-methylpiperidin-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 3-methoxy-4-(4-methylpiperidin-l-yl)benzoic acid using general method C (condition B). The synthesis of 3-methoxy-4-(4-methylpiperidin-l-yl)benzoic acid is depicted in scheme 11.

Example 207: compound n°272: (2S,5R)-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid was synthesized from intermediates It and 2h using general method C (condition A).

Example 208: compound n°273: (2S,5R)-5-(3-chlorophenyl)-l-(2’- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lu and 2h using general method C (condition A).

Example 209: compound n°274: (2S,5R)-5-(4-chlorophenyl)-l-(2’- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lv and 2h using general method C (condition A).

Example 210: compound n°275: (2S,5R)-5-(3-fluorophenyl)-l-(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lw and 2h using general method C (condition A).

Example 211: compound n°276: (2S,5R)-5-(4-fluorophenyl)-l-(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lx and 2h using general method C (condition A).

Example 212: compound n°278: (2S,5R)-4-acetyl-5-(2-chlorophenyl)-l-(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from (2S,4S,5R)-methyl 4-acetyl-5-(2-chlorophenyl)pyrrolidine-2-carboxylate using the same dipolar cycloaddition methodology as shown in scheme 9, except for the last step (Mc^SnOH (lOeq), DCE, 90°C) instead of (TFA, DCM).

Example 213: compound n°279: (2S,4S,5R)-5-(2-chlorophenyl)-1-(2-methoxy-[ 1,1 ’-biphenyl]-4-carbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxy lie acid was synthesized from (2S,4S,5R)-4-tert-butyl 2-methyl 5-(2-chlorophenyl)-1 -(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2,4-dicarboxylate which was obtained using the dipolar cycloaddition methodology shown in scheme 9. Last steps to perform the synthesis of compound n°279 are depicted in scheme 14.

Example 214: compound n°280: (2S,5R)-5-(2-chlorophenyl)-l-(4-(2-methoxypyrimidin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2s2 using general method C (condition B).

Example 215: compound n°281: (2S,5R)-5-cyclohexyl-l-(2'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates ly and 2h using general method C (condition B).

Example 216: compound n°283: (2S,5R)-l-(4-(2-chloro-4- methoxypyrirnidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2t2 using general method C (condition B).

Example 217: compound n°284: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3-methoxypyridin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2u2 using general method C (condition B).

Example 218: compound n°285: (2R,5R)-5-(2-fluorophenyl)-1-(2- methoxy-[l, 1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lz and 2h using general method C (condition A).

Example 219: compound n°286: (2S,5S)-5-(2-fluorophenyl)-l-(2- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lal and 2h using general method C (condition A).

Example 220: compound n°287: (2R,5S)-5-(2-fluorophenyl)-l-(2'- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lbl and 2h using general method C (condition A).

Example 221: compound n°288: (2S,5R)-5-(2-chlorophenyl)-1-(2- (trifluoromethyl)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2v2 using general method C (condition B).

Example 222: compound n°289: (2S,5R)-5-(2-chlorophenyl)-l-(2',4'-difluoro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2w2 using general method C (condition B).

Example 223: compound n°290: (2S,5R)-5-(2-chlorophenyl)-l-(2-methyl-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2x2 using general method C (condition B).

Example 224: compound n°291: (2S,5R)-5-(2,6-difluorophenyl)-1-(2- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lcl and 2h using general method C (condition A).

Example 225: compound n°292: (2S,5R)-5-(2,4-difluorophenyl)-1-(2- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates ldl and 2h using general method C (condition A).

Example 226: compound n°293: (2S,5R)-5-(2,4-dichlorophenyl)-1-(2- methoxy-[ 1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acidwas synthesized from intermediates lei and 2h using general method C (condition A).

Example 227: compound n°294: (2S,5R)-5-isobutyl-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lfl and 2h using general method C (condition A).

Example 228: compound n°295: (2S,5R)-5-isopropyl-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates Igl and 2h using general method C (condition A).

Example 229: compound n°296: (2S,5R)-l-(3-chloro-4-(pyrimidin-4- yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2y2 using general method C (condition B).

Example 230: compound n°297: (2S,5R)-5-(2-chlorophenyl)-l-(2-fluoro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2z2 using general method C (conditions B).

Example 231: compound n°298: (2S,5R)-5-(2-chlorophenyl)-l-(2'-fluoro-4'-methoxy-[ 1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2a3 using general method C (conditions B).

Example 232: compound n°299: (2S,5R)-5-(2-chlorophenyl)-l-(4’-fluoro-2’-methoxy-[ 1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2b3 using general method C (conditions B).

Example 233: compound n°300: (2S,5R)-5-(2-chlorophenyl)-1 -(4-(6- ethoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2c3 using general method C (conditions B).

Example 234: compound n°301: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- isopropoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2d3 using general method C (condition B).

Example 234: compound n°302: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- methoxy-2-methylpyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2e3 using general method C (condition B).

Example 235: compound n°303: (2S,5R)-l-(3-chloro-4-(2- methoxypyrimidin-4-yl)benzoyl)-5-(2-chlorophenyl)pynOlidine-2-carboxylic acid was synthesized from intermediates la and 2D using general method C (condition B).

Example 236: compound n°304: (2S,5R)-l-(3-chloro-4-(pyrimidin-5- yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2g3 using general method C (condition B).

Example 237: compound n°305: (2S,5R)-5-(2-chlorophenyl)-4-cyano-l-(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)-3-methylpyrrolidine-2-carboxylic acid was synthesized using the 1,3-dipolar cycloaddition shown in scheme 9.

Example 238: compound n°306: (2S,4S,5R)-5-(2-chlorophenyl)-4-cyano-1 -(2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)-4-methylpyrrolidine-2-carboxylic acid was synthesized using the 1,3-dipolar cycloaddition shown in scheme 9.

Example 239: compound n°307: (2S,5R)-5-(2-chlorophenyl)-l-(2',3'- dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2h3 using general method C (condition B).

Example 240: compound n°308: (2S,5R)-5-(2-chlorophenyl)-l-(3',4'- dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 213 using general method C (condition B).

Example 241: compound n°309: (2S,5R)-5-(2-chlorophenyl)-l-(2',3',4'-trimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2j3 using general method C (condition B).

Example 242: compound n°310: (2S,5R)-5-(2-chlorophenyl)-l-(2',3',6'-trimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2k3 using general method C (condition B).

Example 243: compound n°311: (2S,5R)-5-(2-chlorophenyl)-l-(3',5'- dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 213 using general method C (condition B).

Example 244: compound n°312: (2S,5R)-5-(2-chlorophenyl)-l-(2',5'- dimethoxy- [1,1 -biphenyl] -4-carbony l)pyrro lidine-2-carboxylic acid was synthesized from intermediates la and 2m3 using general method C (condition B).

Example 245: compound n°313: (2S,5R)-5-(2-chlorophenyl)-1-(2-isopropyl-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2n3 using general method C (condition B).

Example 246: compound n°314: (2S,5R)-1-(2,2'-dimethoxy-[ 1,1'-biphenyl] -4-carbonyl)-5 -(2-fluorophenyl)pyrrolidine-2-carboxy lie acid was synthesized from intermediates lg and 2zl using general method C (condition B).

Example 247: compound n°315: (2S,5R)-l-(2-fluoro-2'-methoxy-[l,l'-biphenyl] -4-carbonyl)-5 -(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2h5 using general method C (condition B).

Example 248: compound n°316: (2S,5R)-5-(2-chlorophenyl)-l-(2-fluoro-2'-methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2h5 using general method C (condition B).

Example 249: compound n°318: (2S,5R)-5-cyclopentyl-l-(2'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lhl and 2h using general method C (condition A).

Example 250: compound n°319: (2S,5R)-5-(2-chlorophenyl)-l-(2'-ethyl-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2o3 using general method C (condition B).

Example 251: compound n°320: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6-dimethylpyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2p3 using general method C (condition B).

Example 252: compound n°321: (2S,5R)-1-(4-(2,4- bis(benzyloxy)pyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pynOlidine-2-carboxylic acid was synthesized from intermediates la and 2q3 using general method C (conditions B).

Example 253: compound n°322: (2S,5R)-l-([l,l':4',r'-terphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l,r:4',l"-terphenyl]-4-carboxylic acid using general method C (conditions B).

Example 254: compound n°323: (2S,5R)-5-(2-chlorophenyl)-l-(4'-propyl-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial 4'-propyl-[l,l'-biphenyl]-4-carboxylic acid using general method C (conditions B).

Example 255: compound n°324: (2S,5R)-l-(4'-(tert-butyl)-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial 4'-(tert-butyl)-[l,l'-biphenyl]-4-carboxylic acid using general method C (conditions B).

Example 256: compound n°325: (2S,5R)-l-(3-chloro-4-(2,4- dimethoxypyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2g5 using general method C (conditions B).

Example 257: compound n°326: (2S,5R)-5-(2-chlorophenyl)-1-(5-(2-methoxyphenyl)pyrazine-2-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2j5 using general method C (conditions B).

Example 258: compound n°327: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(4-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2k5 using general method C (conditions B).

Example 259: compound n°328: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(6-methoxypyridin-3 -y l)benzoyl)pyrro lidine-2-carboxylic acid was synthesized from intermediates la and 215 using general method C (conditions B).

Example 260: compound n°329: (2S,5R)-l-(3-chloro-4-(2- methoxypyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2m5 using general method C (conditions B).

Example 261: compound n°330: (2S,5R)-l-(3-chloro-4-(6- methoxypyridin-3-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2r3 using general method C (conditions B).

Example 262: compound n°331: (2S,5R)-5-(2-chlorophenyl)-l-(l-(4-(4- chlorophenyl)thiazol-2-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial 1-(4-(4-chlorophenyl)thiazol-2-yl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 263: compound n°332: (2S,5R)-5-(2-fluorophenyl)-1-(5- methoxy-6-(2-methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2s3 using general method C (conditions B).

Example 264: compound n°333: (2S,5R)-l-(l-(benzo[d]oxazol-2- yl)piperidine-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(benzo[d]oxazol-2-yl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 265: compound n°334: (2S,5R)-5-(2-chlorophenyl)-1-(3- methoxy-4-(pyrrolidin-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as shown in scheme 11, replacing 4-methylpiperidine with pyrrolidine.

Example 266: compound n°335: (2S,5R)-5-(2-chlorophenyl)-1-(5- methoxy-6-(2-methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2t3 using general method C (conditions B).

Example 267: compound n°336: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2- methoxyphenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as shown in scheme 13 replacing 2-cyano-4-trifluoromethyl-bromobenzene with 2-methoxy-bromobenzene.

Example 268: compound n°337: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5-yl)-3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2n5 using general method C (conditions B).

Example 269: compound n°338: (2S,5R)-5-(2-bromophenyl)-l-(2'- methoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lil and 2h using general method C (conditions A).

Example 270: compound n°339: (2S,5R)-5-(2-chlorophenyl)-l-(3'-cyano-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial 3'-cyano-[l,l'-biphenyl]-4-carboxylic acid using general method C (conditions B).

Example 271: compound n°340: (2S,5R)-5-(2-chlorophenyl)-l-(3'-cyano-2'-methoxy- [1,1 -biphenyl] -4-carbonyl)pyrro lidine-2-carboxylic acid was synthesized from intermediates la and 2u3 using general method C (conditions A) .

Example 272: compound n°341: (2S,5R)-5-(2-chlorophenyl)-l-(3'-cyano-2',4'-bis(2,2,2-trifluoroethoxy)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2v3 using general method C (conditions B).

Example 273: compound n°342: (2S,5R)-l-(3'-amino-2'-methyl-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2w3 using general method C (conditions B) .

Example 274: compound n°343: (2S,5R)-5-(2-chlorophenyl)-l-(2'-methyl-3’-(methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2x3 using general method C (conditions B).

Example 275: compound n°344: (2S,5R)-l-(3’-acetamido-2'-methyl-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2y3 using general method C (conditions B).

Example 276: compound n°345: (2S,5R)-5-(2-chlorophenyl)-l-(5'-cyano-2’-methoxy-[ 1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2z3 using general method C (conditions B).

Example 277: compound n°346: (2S,5R)-5-(2-chlorophenyl)-l-(5'-cyano-2'-methyl-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2a4 using general method C (conditions B).

Example 278: compound n°347: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6-dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2b4 using general method C (conditions B).

Example 279: compound n°348: (2S,5R)-5-(2-chlorophenyl)-l-(4-(3,6-dimethoxypyridazin-4-yl)benzoyl)pyrrohdine-2-carboxylic acid was synthesized from intermediates la and 2r4 using general method C (conditions B).

Example 280: compound n°349: (2S,5S)-5-isopentyl-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)pyrrohdine-2-carboxylic acid was synthesized from intermediates Ijl and 2h using general method C (conditions A).

Example 281: compound n°350: (2S,5R)-5-(2-chlorophenyl)-1-(2-methoxy-4'-(methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2p5 using general method C (conditions B).

Example 282: compound n°351: (2S,5R)-l-(4'-acetamido-2'-methoxy-[1,1 '-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2c4 using general method C (conditions B).

Example 283: compound n°352: (2S,5R)-1-(3'-carbamimidoyl-[ 1,1'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from (2S,5R)-methyl 5-(2-chlorophenyl)-l-(3'- cyanobiphenylcarbonyl)pyrrolidine-2-carboxylate which was obtained from intermediate la and commercial 3’-cyanobiphenyl-4-carboxylic acid using general method C (conditions B).

Step 1: To a solution of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3-cyanobiphenylcarbonyl)pyrrolidine-2-carboxylate (1.0 mmol) and hydoxylamine hydrochloride (2.0 mmol) in dry EtOH (5 mL) under N2 was added NEt3 (2.0 mmol) dropwise at RT. The mixture was stirred under reflux overnight. The mixture was cooled down to RT, concentrated and purified on silica gel (cyclohex / EtOAc), furnishing 300 mg of (2S,5R)-methyl 5-(2-chlorophenyl)-l-(3'-((E)-N'-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrolidine-2-carboxylate as a white solid (60% yield).

Step 2: A solution of (2S,5R)-methyl 5-(2-chlorophenyl)-l-(3'-((E)-N'-hydroxycarbamimidoyl)biphenylcarbonyl)pyrro lidine-2-carboxylate (0.42 mmo 1) in EtOH/THF/AcOH (3mL/3mL/0.1mL) was hydrogenated at RT under atmospheric pressure using a slurry solution of Raney nickel catalyst in water (0.5 mL) for 5h. The catalyst was filtered off over Celite and the filtrate was concentrated, furnishing 160 mg of white solid (83% yield).

Step 3: Saponification using standard methodology described in general method C.

Example 284: compound n°353: (2S,5R)-5-(2-chlorophenyl)-l-(3'-((E)-N-hydroxycarbamimidoyl)- [ 1,1 ’-biphenyl] -4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from (2S,5R)-methyl 5-(2-chlorophenyl)-l-(3'-((E)-N'-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrolidine-2-carboxylate (step 1 of synthesis of compound n°352) using the saponification standard methodology described in general method C: (2S,5R)-l-(3'-carbamoyl-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was obtained by hydrolysis and saponification using LiOH of (2S,5R)-methyl 5-(2-chlorophenyl)-l-(3’-cyanobiphenylcarbonyl)pyrrolidine-2-carboxylate which was obtained from intermediate la and commercial 3’-cyanobiphenyl-4-carboxylic acid using general method C (conditions B).

Example 285: compound n°360: (2S,5R)-5-(2-chlorophenyl)-l-(5'-cyano-2',3'-dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2f4 using general method C (conditions B).

Example 286: compound n°361: (2S,5R)-5-(2-chlorophenyl)-l-(2'-cyano-4',5'-dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2g4 using general method C (conditions B).

Example 287: compound n°362: (2S,5R)-5-(2-chlorophenyl)-l-(3',4',5'-trimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2h4 using general method C (conditions B).

Example 288: compound n°363: (2S,5R)-5-(2-chlorophenyl)-l-(2'- (cyanomethyl)-4',5'-dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2i4 using general method C (conditions B).

Example 289: compound n°364: (2S,5R)-5-(2-chlorophenyl)-l-(3',4'-dicyano-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2j4 using general method C (conditions B).

Example 290: compound n°365: (2S,5R)-5-(2-chlorophenyl)-l-(5'-cyano-2'-fluoro-[ 1,1 -biphenyl]-4-carbonyl)pyrrolidine-2-carboxy lie acid was synthesized from intermediates la and 2k4 using general method C (conditions B).

Example 291: compound n°366: (2S,5R)-5-(2-chlorophenyl)-l-(2-fluoro-3',4'-dimethoxy-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 214 using general method C (conditions B).

Example 292: compound n°367: (2S,5R)-5-(2-chlorophenyl)-l-(4-(2,6-dimethoxypyridin-3-yl)-3-fluorobenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2m4 using general method C (conditions B).

Example 293: compound n°368: (2S,5R)-5-(2-chlorophenyl)-l-(3-fluoro-4-(6-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates la and 2n4 using general method C (conditions B).

Example 294: compound n°369: (2S,5R)-5-(2-chlorophenyl)-1-( 1-(2-cyano-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology shown in scheme 13.

Example 295: compound n°370: (2S,5R)-l-(l-(2-chloro-4- (trifluoromethyl)phenyl)piperidine-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology shown in scheme 13 replacing 2-cyano-4-trifluoromethyl-bromobenzene with 2-chloro-4-trifluoromethy 1-bro mobenzene.

Example 296: compound n°371: (2S,5R)-l-(5'-cyano-2'-methoxy-[l,l'-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2z3 using general method C (conditions B).

Exemple 297: compound n°372: (2S,5R)-1-(4-(2,6-dimethoxypyridin-3-yl)-3-fluorobenzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2m4 using general method C (conditions B).

Example 298: compound n°373: (2S,5R)-l-(3-fluoro-4-(6- methoxypyridin-3-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates lg and 2n4 using general method C (conditions B).

Example 299: compound n°374: (2S,5R)-1-(4-(3,6-dimethoxypyridazin-4-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2r4 using general method C (conditions B).

Example 300: compound n°375: (2S,5R)-l-(3'-carbamoyl-4'-cyano-[l,r-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was obtained by the hydrolysis of the nitrile moiety of (2S,5R)-methyl 5-(2-chlorophenyl)-1 -(3',4'-dicyano-[ 1,1 -biphenyl]-4-carbonyl)pyrro hdine-2-carboxylate and subsequent saponification using LiOH. (2S,5R)-methyl 5-(2-chlorophenyl)-1 -(3',4'-dicyano-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates la and intermediate 2j4 using general method C (conditions B).

Example 302: compound n°376: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 303: compound n°377: (2S,5R)-5-(2-chlorophenyl)-1-( 1-(4-(morpholinosulfonyl)-2-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(2-nitro-4-(piperidin-l-ylsulfonyl)phenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 304: compound n°378: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2-nitro-4-(piperidin-l-ylsulfonyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(4-(N,N-diethylsulfamoyl)-2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 305: compound n°379: (2S,5R)-5-(2-chlorophenyl)-l-(l-(4-(N,N-diethylsulfamoyl)-2-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial 1-(4-methyl-2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 306: compound n°380: (2S,5R)-5-(2-chlorophenyl)-1-( 1-(4-methyl-2-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as depicted in scheme 12, replacing 2-nitro-4-trifluoromethyl-fluorobenzene by 2-nitro-4-methyl-fluorobenzene.

Example 307: compound n°381: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2- cyano-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as depicted in scheme 12, replacing 2-nitro-4-trifluoromethyl-fluorobenzene by 2-cyano-4-methyl-fluorobenzene.

Example 308: compound n°382: (2S,5R)-5-(2-chlorophenyl)-1-( 1-(4- nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(4-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 309: compound n°383: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2- fluoro-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as depicted in scheme 13, replacing 2-cyano-4-trifluoromethyl-bromobenzene by 2-fluoro-4-nitro-bromobenzene.

Example 310: compound n°384: (2S,5R)-5-(2-chlorophenyl)-l-(l-(3- methoxy-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(3-methoxy-4-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 311: compound n°385: (2S,5R)-l-(l-(5-chloro-2- nitrophenyl)piperidine-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(5-chloro-2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 312: compound n°386: (2S,5R)-5-(2-cyanophenyl)-l-(2'- methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by cyanation of (2S,5R)-methyl 5-(2-bromophenyl)-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate and subsequent saponification. (2S,5R)-methyl 5-(2-bromophenyl)-1 -(2'-methoxy-[ 1,1 '-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates lil and 2h using general method C, (conditions A). Cyanation method of cyanation: In a carrousel tube were introduced NMP (0.2 mL), /-PrOH (9.7 pL), sodium carbonate (0.021 g, 0.202 mmol), palladium(II) acetate (0.908 mg, 4.05 pmol) and (2S,5R)-methyl 5-(2-bromophenyl)-1 -(2’-methoxy-[ 1,1 -biphenyl]-4- carbonyl)pyrrolidine-2-carboxylate (0.1 g, 0.202 mmol). The RM was heated at 140°C and potassium ferrocyanide.3H20 (0.026 g, 0.061 mmol) was added. Heating was stopped and the RM was stirred overnight. The RM was diluted with water and extracted with three times with EtOAc. The aqueous layer was acidified (a color change from brown to blue was observed) and extracted twice with diethyl ether. The combined organic layers were dried over MgSC>4, filtered and concentrated to afford a brown residue. Crude was purified by flash chromatography (EtOAc/PE : 1/2) to yield compound n°386. Y=10%, P>90%.

Example 313: compound n°387: (2S,5R)-5-(2-chlorophenyl)-l-(2’-cyano-4'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2s4 using general method C (conditions B).

Example 314: compound n°388: (2S,5R)-5-(2-chlorophenyl)-l-(2-fluoro-4'-(methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2s5 using general method C (conditions B).

Example 315: compound n°389: (2S,5R)-5-(2-chlorophenyl)-l-(2-fluoro-3'-(methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2t5 using general method C (conditions B).

Example 316: compound n°390: (2S,5R)-5-(2-chlorophenyl)-l-(2'-cyano-2-fluoro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2u5 using general method C (conditions B).

Example 317: compound n°391: (2S,5R)-5-(2-chlorophenyl)-1-( 1-(2- cyano-4-(methylsulfonamido)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by reduction of nitro, sulfonylation and saponification of (2S,5R)-methyl 5-(2-chlorophenyl)-l-(l-(2-cyano-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate which was obtained from intermediate la and commercial l-(2-cyano-4-nitrophenyl)piperidine-4-carboxylic acid using general method C, condition B.

Example 318: compound n°392: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2- cyano-4-methoxyphenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained using the same methodology as shown in scheme 13 replacing 2-cyano-4-trifluoromethyl-bromobenzene with 2-cyano-4-methoxy-bromobenzene.

Example 319: compound n°393: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2- (methylsulfonamido)-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by reduction of the nitro group of (2S,5R)-methyl 5-(2-chlorophenyl)-l-(l-(2-nitro-4- (trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate, followed by sulfonylation with methane sulfonyl chloride, and subsequent saponification. (2S,5R)-methyl-5-(2-chlorophenyl)-1 -(1 -(2-nitro-4- (trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates la and commercial l-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 320: compound n°394: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2- nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 321: compound n°395: (2S,5R)-5-(2-chlorophenyl)-l-(l-(4- cyanophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial l-(4-cyanophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 322: compound n°396: (2S,5R)-5-(3,5-difluorophenyl)-l-(2- methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 111 and intermediate 2h using general method C (conditions A).

Example 323: compound n°397: (2S,5R)-5-(3,4-difluorophenyl)-l-(2'- methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1ml and intermediate 2h using general method C (conditions A).

Example 324: compound n°398: (2S,5R)-5-(2,3-difluorophenyl)-l-(2'- methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates lnl and intermediate 2h using general method C (conditions A).

Example 325: compound n°399: (2S,5R)-5-(2,5-difluorophenyl)-1-(2-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates lol and intermediate 2h using general method C (conditions A).Example 326: compound n°400: (2S,5R)-5-([l,r-biphenyl]-2-yl)-l-(2'- methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by Suzuki coupling (2S,5R)-methyl 5-(2-bromophenyl)-l-(2'-methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate with phenylboronic acid and subsequent saponification. (2S,5R)-methyl 5-(2-bromophenyl)-l-(2'-methoxy-[l,l'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates lil and 2h using general method C (conditions A).

Example 327: compound n°401: (2S,5R)-l-(2'-cyano-4'-methoxy-[l,r-biphenyl] -4-carbonyl)-5 -(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates lg and 2s4 using general method C (conditions B).

Example 328: compound n°402: (2S,5R)-5-(4-cyanophenyl)-l-(2'- methoxy-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates lpl and 2h using general method C (conditions A).

Example 329: compound n°403: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methyl-4-(phenylsulfonyl)- 1H-1,2,3-triazol-1 -yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate la and commercial 4-(5-methyl-4-(phenylsulfonyl)-lH-l,2,3-tnazol-l-yl)benzoic acid using general method C (conditions B).

Example 330: compound n°404: (2S,5R)-5-(2-chlorophenyl)-l-(3'-cyano-4'-fluoro-[l,r-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2u4 using general method C (conditions B).

Example 331: compound n°405: (2S,5R)-l-(2'-chloro-5'-cyano-[l,l'-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2v4 using general method C (conditions B).

Example 332: compound n°406: (2S,5R)-5-(2-chlorophenyl)-l-(2'-cyano-4’-(trifluoromethyl)-[ 1,1 ’-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2w4 using general method C (conditions B).

Example 333: compound n°407: (2S,5R)-5-(2-chlorophenyl)-l-(l-(2-rnethoxy-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained using the same methodology as depicted in scheme 12, replacing 2-nitro-4-trifluoromethyl-fluorobenzene by 2-methoxy-4-trifluoromethyl-fluorobenzene.

Example 334: compound n°408: (2S,5R)-5-(2-chlorophenyl)-l-(2'-methyl-3'-(N-methylmethylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2x4 using general method C (conditions B).

Example 335: compound n°409: (2S,5R)-5-(2-chlorophenyl)-1-(2-methoxy-4'-(N-methylmethylsulfonamido)-[ 1,1 -biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2v5 using general method C (conditions B).

Example 336: compound n°410: (2S,5R)-5-(2-chlorophenyl)-1-(6-(5-cyano-2-methoxyphenyl)-5-methoxynicotinoyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2y4 using general method C (conditions B).

Example 337: compound n°411: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2,4-dimethoxyphenyl)-5-methoxynicotinoyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2z4 using general method C (conditions B).

Example 338: compound n°412: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2,4-dimethoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid was obtained from intermediates la and intermediate 2a5 using general method C (conditions B).

Example 339: compound n°413: (2S,5R)-l-(2'-cyano-4'-(trifluoromethyl)-[1,1 '-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates lg and intermediate 2w4 using general method C (conditions B).

Example 340: compound n°414: (2S,5R)-l-(3'-cyano-4'-fluoro-[l,r-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates lg and intermediate 2u4 using general method C (conditions B).

Example 341: compound n°415: (2S,5R)-l-(2'-chloro-5'-cyano-[l,l'-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates lg and intermediate 2v4 using general method C (conditions B).

Example 342: compound n°416: (2S,5R)-5-(2-chlorophenyl)-l-(4-(3,6-dimethoxypyridazin-4-yl)-3-fluorobenzoyl)pyrrolidine-2-carboxylic acid was synthetized from la and 2w5 using general method C (conditions B).

Example 343: compound n°417: (2S,5R)-5-(2-fluorophenyl)-l-(2'-methyl-3’-(N-methylmethylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates lg and 2x4 using general method C (conditions B).

Example 344: compound n°418: (2S,5R)-5-(2-fluorophenyl)-l-(2'- methoxy-4'-(N-methylmethylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthetized from lg and 2v5 using general method C (conditions B).

Example 345: compound n°419: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6-dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthetized from la and 2f5 using general method C (conditions B).

Example 346: compound n°420: (2S,5R)-5-(2,3-difluorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates lnl and 2sl using general method C (conditions B).

Example 347: compound n°421: (2S,5R)-l-(5'-cyano-2'-methyl-[l,l'-biphenyl]-4-carbonyl)-5-(2,3-difluorophenyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates lnl and 2a4 using general method C (conditions B).

Example 348: compound n°354: (2S,5R)-5-(2-fluorophenyl)-1-(2-methoxy-4'-(methylsulfonamido)-[ 1,1 '-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates lg and 2p5 using general method C (conditions B).

Example 349: compound n°355: (2S,5R)-5-(2,4-difluorophenyl)-1-(4-(2,6-dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates lkl and 2q5 using general method C (conditions B).

Example 350: compound n°356: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(5 -methoxypyridin-3 -y l)benzoyl)pyrro lidine-2-carboxylic acid was synthetized from intermediates la and 2d4 using general method C (conditions B).

Example 351: compound n°357: (2S,5R)-l-(4'-amino-2'-methoxy-[l,r-biphenyl] -4-carbonyl)-5 -(2-chlorophenyl)pyrro lidine-2-carboxylic acid was synthetized from intermediate la and methyl 2'-methoxy-4'-amino-[l,r-biphenyl]-4-carboxylate obtained in the synthesis of intermediate 2p5.

Example 352: compound n°358: (2S,5R)-5-(2-chlorophenyl)-l-(2',3,6'-trimethoxy- [2,3 '-bipyr idine] -5 -carbonyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates la and 2e4 using general method C (conditions B).

BIOLOGY EXAMPLES

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents the effect of compounds 1; 2; 4; 5; 8; 10; 11 and 13 on isoprenaline-induced lipolysis in adipocytes isolated from normal rat. Compounds are tested at 30μΜ final concentration.

Figures 2A and 2B represent the inhibition of blood glucose concentration in OGTT assay following bi-daily injection (at 50 mg/kg) of compound 1 during 28 days.

Membrane binding assay: GTPyS binding assay.

The following assay can be used for determination of GPR43 activation. When a GPCR is in its active state, either as a result of ligand binding or constitutive activation, the receptor couples to a G protein and stimulates the release of GDP and subsequent binding of GTP to the G protein. The alpha subunit of the G protein-receptor complex acts as a GTPase and slowly hydrolyses the GTP to GDP, at which point the receptor normally is deactivated. Activated receptors continue to exchange GDP for GTP. The non-hydrolysable GTP analog, [35S]GTPyS, was used to demonstrate enhance binding of [35S]GTPyS to membranes expressing receptors. The assay uses the ability of GPCR to stimulate [35S]GTPyS binding to membranes expressing the relevant receptors. The assay can, therefore, be used in the direct identification method to screen candidate compounds to endogenous or not endogenous GPCR.

Preparation of membrane extracts:

Membrane extracts were prepared from cells expressing the human GPR43 receptor (hGPR43) as follows: the medium was aspirated and the cells were scraped from the plates in Ca++ and Mg++-free Phosphate-buffered saline (PBS). The cells were then centrifuged for 3 min at 1500 g and the pellets were resuspended in buffer A (15 mM Tris-HCl pH 7.5, 2 mM MgCl2, 0.3 mM EDTA, 1 mM EGTA) and homogenized in a glass homogenizer. The crude membrane fraction was collected by two consecutive centrifugation steps at 40.000 x g for 25 min separated by a washing step in buffer A. The final pellet was resuspended in 500 μΐ of buffer B (75 mM Tris-HCl pH 7.5, 12.5 mM MgCl2, 0.3 mM EDTA, ImM EGTA, 250 mM sucrose) and flash frozen in liquid nitrogen. Protein content was assayed by the Folin method. GTPyS assay (SPA method):

The assay was used to determine the activity of the compounds of the invention. The [35S]GTPyS assay was incubated in 20 mM HEPES pH7.4, 100 mM NaCl, 10 pg/ml saponin, 30 mM of MgCF, 10 μΜ of GDP, 5 μg membrane-expressing hGPR43, 250pg of wheatgerm agglutinin beads (Amersham, ref: RPNQ001), a range concentration of compounds of the invention (from 30 μΜ to 1 nM) in a final volume of 100 μΐ for 30 min at room temperature. The SCFA propionate was used at 1 mM final concentration as positive control. The plates were then centrifuged for 10 minutes at 2000 rpm, incubated for 2 hours at room temperature and counted for 1 min in a scintillation counter (TopCount,

PerkinElmer). The results of the tested compounds are reported as the concentration of the compound required to reach 50% (EC50) of the maximum level of the activation induced by these compounds.

When tested in the assay described above and by way of illustration the compounds in Table 3 activate GPR43 receptor. The EC50 value obtained is represented as follows: “+++” means EC50 < 200 nM; “++” means 200nM < EC50 <1 μΜ; “+” means EC50 >1 μΜ .

Table 3: Compounds EC50 values in GTPy35S assay.

Radioligand Binding (RLB) assay with cell membrane extracts from human GPR43 recombinant cell line

Human GPR43 radioligand binding assay is performed by adding successively in the wells of a 96 well plate (Master Block, Greiner, 786201), 50 μΐ of compound of the invention at increasing concentrations (diluted in assay buffer: 50 mM Tris pH 7.4), 25 μΐ radiolabeled antagonist (ie. compound n°277 described in EP10305100.9) diluted in assay buffer and 25 μΐ cell membrane extracts (10 pg protein/well). The final concentration of radiolabeled antagonist in the assay is 10 nM. The plate is incubated 60 min at 25°C in a water bath and then filtered over GF/B filters (Perkin Elmer, 6005177, presoaked in 0.05% Brij for 2h at room temperature) with a Filtration unit (Perkin Elmer). The filters are washed 3 times with 0.5 ml of ice-cold wash buffer (50 mM Tris pH 7.4). 50 μΐ of Microscint 20 (Packard), is added and the plate is incubated 15 min on an orbital shaker and then counted with a TopCount™ for 1 min/well.

In Table 4 biological results obtained using the RLB assay as described above with compounds of the invention are set out in tabulated form. In this table, the constant of inhibition of radioligand binding carried out by the compound of the invention (Ki) is given. The Ki values (nM) obtained is represented as follows: “+++” means Ki < ΙμΜ; “++” means ΙμΜ < Ki < 2μΜ; “+” means 2μΜ < Ki.

Table 4: Compounds Ki values in RLB assay.

Cell based assay: Calcium flux. The Aequorin-based assay.

The following assay can be used for determination of GPR43 activation. The aequorin assay uses the responsiveness of mitochondrial apoaequorin to intracellular calcium release induced by the activation of GPCRs (Stables et al., 1997, Anal. Biochem. 252:115-126; Detheux et al., 2000, J. Exp. Med., 192 1501-1508). Briefly, GPCR-expressing clones are transfected to coexpress mitochondrial apoaequorin and Gal6. Cells expressing GPR43 receptor are incubated with 5 μΜ Coelenterazine H (Molecular Probes) for 4 hours at room temperature, washed in DMEM-F12 culture medium and resuspended at a concentration of 0.5 x 106 cells/ml (the amount can be changed for optimization). Cells are then mixed with test compounds and light emission by the aequorin is recorded with a luminometer for 30 sec. Results are expressed as Relative Light

Units (RLU). Controls include assays using cells not expressing GPR43 (mock transfected), in order to exclude possible non-specific effects of the candidate compound.

Aequorin activity or intracellular calcium levels are “changed” if light intensity increases or decreases by 10% or more in a sample of cells, expressing a GPR43 and treated with a compound of the invention, relative to a sample of cells expressing the GPR43 but not treated with the compound of the invention or relative to a sample of cells not expressing the GPR43 (mock-transfected cells) but treated with the compound of the invention.

Cell based assay: Intracellular Inositol-Phosphate accumulation assay. (Gq-associated receptor)

The following assay can be used for determination of GPR43 activation. On day 1, GPR43-expressing cells in mid-log phase are detached with PBS-EDTA, centrifuged at 2000 x g for 2 min and resuspended in medium without antibiotics. After counting, cells are resuspended at 4 x 105 cells/ml (the amount can be changed for optimization) in medium without antibiotics, distributed in a 96 well plate (ΙΟΟμΙ/well) and the plate is incubated overnight at 37°C with 5% CO2. On day 2, the medium is removed and the compounds of the invention, at increasing concentrations, are added (24pl/well) and the plate is incubated for 30 min. at 37°C in a humidified atmosphere of 95% air with 5% CO2. The IP1 concentrations are then estimated using the IP1-HTRF assay kit (Cisbio international, France) following the manufacturer recommendations.

Cell based assay: cAMP accumulation assay (Gi/0 associated receptor)

The following assay can be used for determination of GPR43 activation. Cells expressing GPR43 in mid-log phase and grown in media without antibiotics are detached with PBS-EDTA, centrifuged and resuspended in media without antibiotics. Cells are counted and resuspended in assay buffer at 4.2 x 105 cells/ml. 96 well plates are filled with 12 μΐ of cells (5 x 103 cells/well), 6 μΐ of compound of the invention at increasing concentrations and 6 μΐ of Forskolin (final concentration of 10 μΜ). The plate is then incubated for 30 min, at room temperature. After addition of the lysis buffer, cAMP concentrations are estimated, according to the manufacturer specification, with the HTRF kit from Cis-Bio International.

In vitro assays to assess compound activity in 3T3-L1 cell line. 3T3-L1 adipocytes cell line has been described as cellular model to assess compounds mimicking insulin-mediated effect such as inhibition of lipolysis and activation of glucose uptake.

Linolvsis. 3T3-L1 cells (ATCC) are cultured in Dulbecco’s modified eagle’s medium (DMEM) containing 10% (v/v) bovine serum (fresh regular medium) in 24 well plate. On day 0 (2 days after 3T3-L1 preadipocytes reached confluence), cells are induced to differentiate by insulin (10pg/ml), IBMX (0.5 mM) and dexamethasone (1 μΜ). On day 3 and every other 3rd day thereafter, fresh regular medium is substituted until day 14.

On day 14, the medium is removed and cells are washed twice with 1 ml of a wash buffer (Hank’s balanced salt solution). The wash solution is removed and the SCFA or the tested compounds, or a combination of both, are added at the desired concentration in Hank’s buffer supplemented with 2% BSA-FAF and incubated for 10 minutes a 37°C. Then, isoproterenol (100 nM) is added to induce lipolysis and incubate for 30 minutes at 37°C. The supernatants are collected in a glycerol-free container. 25μ1 (the amount can be changed for optimization) of cell-free supernatants are dispensed in 96-well microtiter plate, 25 μΐ of free glycerol assay reagent (Chemicon, the amount can be changed for optimization) is added in each well and the assay plate is incubated for 15 minutes at room temperature. The absorbance is recorded with a spectrophotometer at 540 or 560 nm. Using the supernatants, the free fatty acids amount can be assessed using the NEFA assay kit (Wako) according the manufacturer’s recommendations.

Glucose Uptake. 3T3-L1 cells are differentiated as described previously with or without of 30 μΜ of tested compounds (the concentration can be changed for optimization) during the 14 days of differentiation. The day of the experiment, the cells are washed twice with a KREBS-Ringer bicarbonate (pH 7.3) supplemented with 2 mM sodium pyruvate and starved for 30 minutes in the same buffer at 37°C in an atmosphere containing 5% C02 and 95% 02. Various amount of SCFA, tested compounds or combination of both are then added with or without 10 nM of insulin (the amount can be changed for optimization) for 30 minutes at 37°C in an atmosphere containing 5% C02 and 95% 02. Then, D-(3H)-2 deoxyglucose (0.2 pCi/wcll) and D-2-deoxyglucose (O.lmM) is added for 30 minutes. To stop the reaction, the cells are immersed in ice-cold saline buffer, washed for 30 min, and then dissolved in NaOH 1M at 55°C for 60 minutes. NaOH is neutralized with HC11M. The 3H labeled radioactivity of an aliquot of the extract is counted in the presence of a scintillation buffer.

In vitro assays to assess compound activity in NCI-H716 cell line.

Human intestinal cell line NCI-H716 has been described as cellular model to assess compounds mimicking nutrient-mediated effect such as glucagon-like peptide-1 (GLP-1) secretion. GLP-1 release. NCI-H716 cells (ATCC, Manassas) are cultured in Dulbecco’s modified eagle’s medium (DMEM) containing 10% (v/v) bovine serum, 2 mM L-glutamine, 100 IU/ml penicillin and 100 pg/ml streptomycin in 75 ml flask. Cell adhesion and endocrine differentiation is initiated by growing cells in 96-well plate coated with matrigel in High Glucose DMEM containing 10% (v/v) bovine serum, 2 mM L-glutamine, 100 IU/ml penicillin and 100 pg/ml streptomycin for 2 days.

On day 2, the medium is removed and cells are washed once with a pre-warmed wash buffer (Phosphate Buffered salt solution). The wash solution is removed and the SCFA or the tested compounds, or a combination of both, are added at the desired concentration in High Glucose DMEM containing 0.1% (v/v) bovine serum and incubated for 2 hours at 37°C. The supernatants are collected in a container. Using the cell-free supernatants, the GLP-1 amount is assessed using a GLP-1 specific ELISA assay kit according the manufacturer’s recommendations (ALPCON).

Ex vivo assays to assess compound activity in adipocytes from normal rat or mice and High-fat diet fed mice.

Mice C56Black6 male are housed in Makrolon type IV group housing cages (56 x 35 x 20 cm3) throughout the experimental phase. Animals’ cages litters are changed once a week. They are housed in groups of 10 animals at 12 light dark (at 8h30 pm lights off), 22 +/- 2 °C and 50 +/- 5 % relative humidity. Animals are acclimated one week. During the whole phase, standard diet or diet high in energy from fat (Research Diets, New Brunswick, NJ) and tap water are provided ad libitum. The animals are 16 weeks old at the time of the study.

For keeping only mice that have responded to the high fat diet, fasted glycemia are measured in these mice just before performing the ex-vivo study.

Glucose uptake assay in isolated adipocytes.

Animals are killed by cervical dislocation and epididymal fat pads are removed and digested in collagenase buffer at 37°C/120rpm for approximately 50 minutes. The digest is filtered through gauze to recover the adipocytes, which are washed and resuspended in Krebs-Ringer Hepes (KRH) buffer containing 1% BSA, 200nM adenosine and 2mM glucose.

Isolated adipocytes are washed in glucose-free KRH-buffer and resuspended to 30%. Adipocytes are then incubated at 37°C/80 rpm with either the tested compound (30μΜ, 10μΜ and ΙμΜ) in the presence or absence of insulin (lOnM) for 30 min. 2-deoxyglucose and 2-deoxy-D-[l-3H]-glucose (3H-2-DOG) are added and incubation continued for 10 min. The reactions are then stopped by addition of cytochalasin b followed by centrifugation through dinonylphthalate to recover the adipocytes. The uptake of 3H-2-DOG- was measured by scintillation. Each data point is investigated in triplicates in two independent experiments.

Lipolysis assay in isolated adipocytes.

Isolated adipocytes are diluted to 5% in KRH-bufifer and are pre-treated with the tested compound (30μΜ, ΙΟμΜ and ΙμΜ) for 30 min at 37°C/120rpm. After the pre-treatment, Isoprenaline (ΙμΜ) is added to the adipocytes followed by 30 min incubation at 37 °C/150 rpm. The reactions are put on ice and the buffer is assayed spectrophotometrically for the production of NADH+ from glycerol breakdown in reactions catalyzed by glycerol kinase and glycerol-3-phosphate dehydrogenase and/or Non Esterified Fatty Acid (NEFA). Each data point is investigated in triplicates in two independent experiments.

According to the method described above and by way of illustration the compounds n° 1; 2; 4; 5; 8; 10; 11 and 13 inhibit isoprenaline-induced lipolysis in adipocytes from normal rat, at the concentration of 30μΜ (Figure 1).

In vivo assay to assess compound activity in rodent diabetes model.

Genetic rodent models:

Rodent models of T2D associated with obesity and insulin resistance have been developed. Genetic models such as db/db and ob/ob in mice and fa/fa in Zucker rats have been developed for understanding the pathophysiology of disease and testing candidate therapeutic compounds. The homozygous animals, C57 Black/6-db/db mice developed by Jackson Laboratory are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J Clin Invest, 1990, 85:962-967), whereas heterozygotes are lean and normoglycemic. In the db/db model, mice progressively develop insulinopenia with age, a feature commonly observed in late stages of human T2D when sugar levels are insufficiently controlled. Since this model resembles that of human T2D, the compounds are tested for activities including, but not limited to, lowering of plasma glucose and triglycerides. Zucker (fa/fa) rats are severely obese, hyperinsulinemic, and insulin resistant, and the fa/fa mutation may be the rat equivalent of the murine db mutation.

Genetically altered obese diabetic mice (db/db) (male, 7-9 weeks old) are housed under standard laboratory conditions at 22°C and 50% relative humidity, and maintained on a diet of Purina rodent chow and water ad libitum. Prior to treatment, blood is collected from the tail vein of each animal and blood glucose concentrations are determined using one touch basic glucose monitor system (Lifescan). Mice that have plasma glucose levels between 250 to 500 mg/dl are used. Each treatment group consists of several mice that are distributed so that the mean of glucose levels are equivalent in each group at the start of the study. Db/db mice are dosed by micro-osmotic pumps, inserted using isoflurane anesthesia, to provide compounds of the invention, saline, or an irrelevant compound to the mice intravenously (i.v). Blood is sampled from the tail vein at intervals thereafter and analyzed for blood glucose concentrations. Significant differences between groups (comparing compounds of the invention to saline-treated) are evaluated using Student t-test.

Ob/ob or obese mice are leptin-deficient mice that eat excessively and become profoundly obese, hyperinsulinemic and hyperglycemic. It is an animal model of type II diabetes. Such model can be used for oral glucose tolerance tests (OGTTs). A total of sixteen (16) male ob/ob mice (6 weeks of age) were obtained from Harlan. Upon arrival to the animal unit, mice were housed 4 per cage in rodent cages mounted with feeders containing regular chow. The mice were put in a 12/12h light-dark cycle (light from 0600-1800 h) with controlled temperature conditions (22-24°C). Fed blood glucose and body-weight was measured on day -2 in the morning between 08:00 AM and 09:00 AM. Animals were randomized into 2 groups according to fed glucose levels (on day -2). The 16 mice with blood glucose and body-weight closest to the mean were distributed into the following groups: Group 1: Vehicle p.o. bi-daily, (n=8) and Group 2: Compound of the invention, p.o., bi-daily, (n=8).

Day 1 is the first day of dosing. Animals were dosed with compounds of the invention at 07:00 AM and 04:00 PM for 28 days. On the evening of day 27, food was removed and mice were transferred to clean cages. Mice were fasted for the subsequent 17 hours until the OGTT was performed. At -15 min, blood glucose was measured (using a glucose analyzer) and animals were dosed with compounds of the invention or vehicle. At time point 0, blood glucose was measured again and glucose was administered by oral gavage (lg/kg glucose). The blood glucose was then measured at time points 15, 30, 45, 60 and 120 minutes. The blood glucose area under the curve (AUC) from time -15 to 120 min was then calculated (GraphPad software). The percentages of AUC inhibition induced by compounds of the invention were calculated as follows: % of AUC inhibition: [1-(AUC compound/AUC vehicule)]*100.

When tested in the above-described assay, the compound 1 showed a % of AUC inhibition of 40%, indicating that compound 1 is able to significantly reduce the level of blood glucose in diabetic animal model (Figures 2A and 2B).

The high-fat diet fed mouse:

This model was originally introduced by Surwit et al. in 1988. The model has shown to be accompanied by insulin resistance, as determined by intravenous glucose tolerance tests, and of insufficient islet compensation to the insulin resistance. The model has, accordingly, been used in studies on pathophysiology of impaired glucose tolerance (IGT) and type 2 diabetes and for development of new treatments. C57BL/6J mice are maintained in a temperature-controlled room (22°C) on a 12-h light-dark cycle. One week after arrival, mice are divided into two groups and are fed either a high-fat diet or received continuous feeding of a normal diet for up to 12 months. On caloric basis, the high-fat diet consist of 58% fat from lard, 25.6% carbohydrate, and 16.4% protein (total 23.4 kJ/g), whereas the normal diet contains 11.4% fat, 62.8% carbohydrate, and 25.8% protein (total 12.6 kJ/g). Food intake and body weight are measured once a week, and blood samples are taken at indicated time points from the intraorbital retrobulbar plexus from nonfasted anesthetized mice.

For intravenous glucose tolerance tests (IVGTTs), 4-h fasted mice are anesthetized with 7.2 mg/kg fluanison/fenlanyl and 15.3 mg/kg midazolam. Thereafter a blood sample is taken from the retrobulbar, intraorbital, capillary plexus, after which D-glucose (1 g/kg) is injected intravenously in a tail vein (volume load 10 1/ g). Additional blood samples are taken at 1, 5, 10, 20, 50, and 75 min after injection. Following immediate centrifugation at 4C, plasma is separated and stored at -20C until analysis. For oral glucose tolerance tests (OGTTs), 16-h fasted anesthetized mice are given 150 mg glucose by gavage through a gastric tube (outer diameter 1.2 mm), which is inserted in the stomach. Blood samples are taken at 0, 15, 30, 60, 90, and 120 min after glucose administration and handled as above.

Administration of the compounds: Five-week-old mice are fed a high-fat or a normal diet for 8 weeks. After 4 weeks, the mice are additionally given the compound of the invention in their drinking water (0.3 mg/ml, the amount can be changed for optimization. Control groups are given tap water without compound. After another 4 weeks, the mice are subjected to an OGTT as described above. Insulin and glucose measurements: Insulin is determined enzymatically using an ELISA assay kit (Linco Research, St. Charles, MO). Plasma glucose is determined by the glucose oxidase method.

In vivo assay to assess compound anti-obesity activity in rodent model.

Mouse acute food intake and weight change:

Male C57BL/6N wild-type mice are weighed and vehicle or the tested compounds are administered by oral gavage to male mice approximately 30 min prior to the onset of the dark phase of the light cycle. Mice are fed ad libitum in the dark phase following dosing. A preweighed aliquot of a highly palatable medium high fat diet is provided in the food hopper of the cage 5 min prior to the onset of the dark phase of the light cycle and weighed 2 and 18h after the onset of the dark phase of the light cycle.

Acute studies in Diet-induced obesity (DIO) rats:

For acute experiments, male Sprague-Dawley DIO rats from Charles River Laboratories are raised from 4 weeks of age on a diet moderately high fat (32% kcal) and high in sucrose (25% kcal). Animals are used at 12 weeks of age and are maintained on a 12/12h light dark cycle. The rats are randomized into groups (n=6/group) for the tested compounds and vehicle dosing. Rats are weighed 17h after dosing to determine effects on overnight body weight gain. The tested compounds are administered orally or s.c. at amount desired lh before the start of the dark cycle. Powdered food is provided in food cups which are weighed continuously at 5 min intervals over 18h and the data are recorded using a computerized system.

Chronic studies in Diet-induced obesity rats:

For the 14-day chronic experiment, male Sprague-Dawley DIO rats are obtained as described above. Animals are used at 15 weeks of age and are maintained on a 12/12 hour light-dark cycle. Rats are conditioned to dosing for 4 days prior to baseline measurements, using an oral gavage or a s.c. route of vehicle. Thereafter, animals are dosed daily with vehicle or compound by oral gavage or s.c.. The tested compound or vehicle is administered lh before the dark cycle for 14 days. Body composition is measured by dual energy X-ray densitometry (DEXAscan) 5 days prior to the study and at the end of the 14-day study. Daily endpoints included body weight and food intake.

In vivo assay to assess compound anti-lipolytic activity in rodent model.

Male C57BL/6N wild-type are housed one per cage in a room maintained on a 12h light/dark cycle under constant temperature (22-25°C) with ad libitum access to food and water. The anti-lipolytic effects of the tested compounds are studied in awake mice. Animals are fasted overnight before experimental use. On the day of the experiment, animals are put in metabolic cages and left undisturbed to acclimate to the environment for l-2h. blood samples are taken at indicated time points from the intraorbital retrobulbar plexus. A 1% sodium citrate saline solution is used to flush the lines. A pre-treatment blood sample is obtained from each animal to determine baseline values for free fatty acids (FFA) and triglycerides (TG). The tested compounds are given via oral gavage, sc injection, iv injection or ip injection for each different series of experiments. Blood samples are collected into pre-cooled tubes pre-coated with heparin (200μ1 blood, Li-heparin, Sarstedt) for determination triglycerides and glycerol and in tri-potassium EDTA added sodium fluoride (200 μΐ blood, K3-EDTA, 1.6 mg/mL + 1% NaF, Sarstedt) for determination of plasma free fatty acids. The tubes are placed on wet ice pending processing. Blood samples will be centrifuged at 4000 x g, at 4°C, 15 min the resulting plasma will be transferred into non-coated tubes and stored at -80°C until analyses. The plasma is thawed at 4°C for determinations of FFA and TG using commercial kits (Wako Chemicals).

While embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation and it is understood that various changes may be made without departing from the spirit and scope of the invention.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. 79$8663_1 (GHMatlers) P90475.AU.1

Claims (2)

1. A compound of formula F

F wherein R’ is OH or Cl; A0, A0 , A1, A2, A3, A4 and A5 are selected from the combinations 1 to 7, 9,10,13 to 15, 17 to 21, 23 and 24\