The present invention relates to novel compounds including their pharmaceutically acceptable salts, solvates, and prodrugs, which are modulators of G- protein coupled receptor 43 (GPR43) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.

[BACKGROUND OF THE INVENTION]

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 Free Fatty Acids (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% sequences identity with specificity toward different fatty acids carbon chain lengths, with short chain fatty acids (SCFAs: six carbons molecules or shorter) activating GPR41 and GPR43 and medium and long chain fatty acids activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 1 1 661-671 , 2007 ). C2 acetate and C3 propionate are the most potent activators of GPR43.

The expression of GPR43 by immune cells (neutrophils, monocytes, peripheral blood mononuclear cells, B-lymphocytes and polymorphonuclear cells), in part of the gastro-intestinal tract and by white adipocytes cells as well as pancreatic β cells strongly suggested its potential as target in inflammatory, gastrointestinal and/or metabolic disorders (Milligan et al. BJP 158, ppl46-153, 2009; Regard et al, J. Clin. Inv., 117, pp40344043, 2007; Ahren Bo, Nature Reviews, 8, pp369-385, 2009). This potential is well supported by recent data. Using a GPR43 knockout mouse, Ge et al, (Endocrinology, 149, pp4519-

4526, 2008) found that neither acetate nor propionate was able to inhibit lipolysis in primary adipocytes isolated from the GPR43-/- mouse, suggesting that GPR43 is able to inhibit lipolysis and therefore, regulate plasma free fatty acid levels. Several data have shown that GPR43 is implicated in the regulation of plasma free fatty acid and glucose homeostasis, indicating that GPR43 could be an emerging target for the treatment of type 2 diabetes, obesity, dyslipidemia and insulin resistance (Tiwari, Current Opinion in Investigational Drugs, 11(4), pp385-393, 2010).

Recent studies have shown that both acetate and proprionate decreased LPS- stimulated TNF-a release from neutrophils. In addition proprionate dose-dependently suppressed IL-6 mRNA and protein release from colitis mouse colon organ cultures. TNF- α and members of the interleukin family are known to play role in the pathogenesis of IBD (Fuss, Curr Drug Targets Inflamm allergy 2003, 2: 101-112; Tedelind et al, World J. Gastroenterol 2007, 13(20): 2826-2832). Further, GPR43 has been described to regulate the anti-inflammatory responses by short chain fatty acids in various in vivo models such as colitis, rheumatoid arthritis and asthma through a regulation of the neutrophil physio lo logy. SCFA-mediated GPR43 activation decreased TNF-a and ΜΙΡ-Ια levels in mouse DSS colitis model, as well as neutrophil chemotactic responsiveness (Maslowski et al, Nature, 2009, 461(7268): 1282-1286).

Taken together these results suggest that therapeutic strategies based on GPR43, the major receptor for acetate and propionate, could be useful in treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders. On this basis, new agonists or partial agonists of GPR43 may be of therapeutic value for the treatment and/or prevention of the above-mentioned disorders.

[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:

Ar ¹ — L ¹ — R Ar ² — Ar ³

I and pharmaceutically acceptable salts , solvates, and prodrugs thereof, wherein:

Ar ¹ is a C3-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocyclyl, 6-membered aryl or 5 to 6- membered heteroaryl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, phenyl or haloalkoxy; L ¹ is a single bond, -CH ₂ -, -CHCH3 or -C(CH ₃ ) ₂ ;

Ar ² is a 6-membered aryl group or a 5 to 6-membered heteroaryl group, each of which being optionally substituted by one or more halo or alkyl group(s);

Ar ³ is a 5 to 6-membered aryl optionally substituted by one or more halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy or haloalkoxy group(s), by one aryl or heteoaryl group, each of said aryl or heteroaryl group may be further substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkylalkyloxy, aralkyloxy, alkoxyalkoxy optionally substituted by an alkoxy group, haloalkoxy, haloalkoxyalkoxy, amino, alkylamino, N,N-(cycloalkyl)(alkyl)amino, N,N-(aralkyl)(alkyl)amino, heterocyclyl, heterocyclylcarbonyl, heteroaryl, or fused to the aryl or heteroaryl group may be one heterocyclyl or heteroaryl ring, thus forming a fused bicyclic system, each of said substituents may be substituted by one or more alkyl, halo or oxo group(s);

R is a 7 to 9-membered heterocyclyl ring selected from the group consisting of:

ring-l ring-ll ring-Ill ring-IV

ring-VII ring-VIII wherein:

L ¹ is attached to the ring at position a and Ar ² is attached to the nitrogen atom at position b; the bonds represented by the dotted lines are independently a single bond, a double bond or a triple bond; at least one of the bonds represented by the dotted lines depicted as "c" and "d" in ring- VII is a single bond;

D is C=0; when the dotted line in ring-I is a single bond, R ¹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, Ci- C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, and R ¹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ² is selected from H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, hetero arylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, hetero arylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino , heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alky lo xycarbony lamino , hetero cyclylo xyc arbony lamino , arylo xycarbony lamino , hetero aryloxycarbonylamino, alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and R ² is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, or R ² forms together with R ² a =CH ₂ or oxo moiety; when the dotted line in ring-I is a double bond R ¹ is selected from H, fluoro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, and R ¹ is absent; R ² is selected from H, fluoro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, and R ² is absent; when the dotted line in ring-I is a triple bond R ¹ , R ¹ , R ² and R ² are absent; R ³ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ³ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R ³ forms together with R ³ an oxo moiety; when the dotted line in ring-II is a single bond, R ⁴ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁴ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ⁵ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁵ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; or R ⁵ forms together with R ⁵ an oxo moiety; when the dotted line in ring-II is a double bond, R ⁴ is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁴ is absent; R ⁵ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁵ is absent; when the dotted line in ring- II is a triple bond R ⁴ , R ^4' , R ⁵ and R ⁵ are absent;

R ⁶ and R ^6' are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ⁷ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ⁷ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl, C1-C4 haloalkoxyalkyl, or R ⁷ forms together with R ⁷ an oxo moiety;

R ⁸ is H or C1-C4 alkyl; R ⁹ and R ⁹ are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;

R ¹⁰ and R ^10' are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; when the dotted line in ring-V is a single bond, R ¹¹ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹¹ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹² is selected from H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, hetero arylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, hetero arylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino , heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alky lo xycarbony lamino , hetero cyclylo xyc arbony lamino , arylo xycarbony lamino , hetero aryloxycarbonylamino, alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino; R ¹² is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R ¹² forms together with R ¹² a =CH ₂ or oxo moiety; when the dotted line in ring-V is a double bond, R ¹¹ is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹¹ is absent; R ¹² is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; and R ¹² is absent when the dotted line in ring- V is a triple bond, R ¹¹ , R ^11' , R ¹² , and R ^12' are absent; R is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci- C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹³ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, or R ¹³ forms together with R ¹³ an oxo moiety; when the dotted line in ring- VI is a single bond, R ¹⁴ is selected from H, fluoro, chloro, Ci- C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁴ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁵ is H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino, heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alkyloxycarbonylamino , heterocyclyloxycarbonylamin o , a ry loxycarbonylamino, heteroaryloxycarbonylamino, alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino; R ¹⁵ is selected from H, fluoro, chloro, Ci- C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl or R ¹⁵ forms together with R ¹⁵ a =CH ₂ or oxo moiety; when the dotted line in ring- VI is a double bond, R ¹⁴ is selected from H, fluoro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁴ is absent; R ¹⁵ is selected from H, fluoro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; and R ¹⁵ is absent; when the dotted line in ring- VI is a triple bond, R ¹⁴ , R ^14' , R ¹⁵ , and R ¹⁵ are absent;

R ¹⁶ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci- C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁶ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, or R ¹⁶ forms together with R ¹⁶ an oxo moiety;

R ¹⁷ and R ^17' are independently selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; when the dotted lines depicted by "c" and "d" in ring- VII are both single bonds, R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalky; one of R ¹⁹ or R ²⁰ is selected from H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino , heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alky lo xycarbony lamino , hetero cyclylo xyc arbony lamino , arylo xycarbony lamino , heteroaryloxycarbonylamino, alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and the other one is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci- C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; or R ¹⁹ forms together with R ¹⁹ a =CH ₂ or oxo moiety and R ²⁰ is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; or R ²⁰ forms together with R ²⁰ a =CH ₂ or oxo moiety and R ¹⁹ is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl; when the dotted line depicted by a "c" in ring- VII is a single bond and the dotted line depicted by a "d" in ring- VII is a double bond, R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, Ci- C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalky; R ¹⁹ and R ²⁰ are independently selected from H, C ₁ -C ₄ alkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁹ and R ²⁰ are absent; when the dotted line depicted by a "c" in ring- VII is a single bond and the dotted line depicted by a "d" in ring- VII is a triple bond, R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, Ci- C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalky; R ¹⁹ , R ^19' , R ²⁰ and R ^20' are absent; when the dotted line depicted by a "c" in ring- VII is a double bond and the dotted line depicted by a "d" in ring- VII is a single bond, R ¹⁸ and R ¹⁹ are independently selected from H, C ₁ -C ₄ alkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁸ and R ¹⁹ are absent; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or Ci- C ₄ haloalkoxyalkyl; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalky; when the dotted line depicted by a "c" in ring- VII is a triple bond and the dotted line depicted by a "d" in ring- VII is a single bond, R ¹⁸ , R ¹⁸ , R ¹⁹ and R ¹⁹ ' are absent; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalky;

L ³ is a single bond, or L ³ is a C ₁ -C3 alkylene optionally substituted by one or more group(s) selected from fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ²¹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci- C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ²¹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, or R ²¹ forms together with R ²¹ an oxo moiety; R ²² and R ²² ' are independently selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl;

R ²³ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci- C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ²³ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl, or R ²³ forms together with R ²³ an oxo moiety;

R ²⁴ is H or Ci-C ₄ alkyl;

R ²⁵ and R ²⁵ are independently selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl;

L ² is a C ₁ -C ₂ alkylene optionally substituted by one or more methyl group(s);

Z is selected from the group consisting of-COOR°, wherein R° is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R is H, methyl or ethyl, and R" is hydroxyl -S0 ₂ CH _3i -S0 ₂ cyclopropyl or -S0 ₂ CF ₃ .

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

The invention also relates to the use of the above compounds or their pharmaceutically acceptable salts and solvates or prodrugs as modulators of GPR43, preferably as agonists or partial agonists of GPR43. The invention further provides methods of treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt, solvate, or prodrug 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, solvate, or prodrug thereof as a medicament. Preferably, the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.

[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

Ar ¹ is C ₃ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, tetrahydropyran-4-yl, 6-membered aryl or 5 membered heteroaryl group, each of which being optionally substituted by one or more group(s) selected from halo, alkyl, haloalkyl, alkoxy or haloalkoxy, preferably Ar ¹ is C ₃ -C ₆ alkyl preferably isopropyl, isobutyl, C ₃ -C ₆ cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, more preferably cyclopentyl, tetrahydropyran-4-yl, 6-membered aryl preferably phenyl, or 5 membered heteroaryl preferably thiazolyl group; and/or L ¹ is a single bond or -CH ₂ -, preferably L ¹ is a single bond; and/or

Ar ² is a 5 to 6-membered heteroaryl group optionally substituted by one or more halo or alkyl group(s), preferably Ar ² is a thiazolyl, thiadiazolyl or pyridinyl group, more preferably Ar ² is a thiazolyl group; and/or

Ar ³ is a 5 to 6-membered aryl optionally substituted by one or more halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy or haloalkoxy group(s), by one aryl or heteoaryl group, each of said aryl or heteroaryl group may be further substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkylalkyloxy, aralkyloxy, alkoxyalkoxy optionally substituted by an alkoxy group, haloalkoxy, haloalkoxyalkoxy, amino, alkylamino, N,N-(cycloalkyl)(alkyl)amino, N,N-(aralkyl)(alkyl)amino, heterocyclyl, heterocyclylcarbonyl, heteroaryl, or fused to the aryl or heteroaryl group may be one heterocyclyl or heteroaryl ring, thus forming a fused bicyclic system, each of said substituents may be substituted by one or more alkyl, halo or oxo group(s), preferably Ar ³ is a phenyl optionally substituted by one or more chloro, fluoro, -CF ₃ or -CF ₂ H, methoxy, -OCF ₃ or -OCF ₂ H group(s), or by one pyridinyl, pyridazinyl or pyrazinyl group, each of said pyridinyl, pyridazinyl or pyrazinyl group may be further substituted by one or more substituent(s) selected chloro, fluoro, methyl, -CF ₃ or -CF ₂ H, methoxy, alkoxyalkoxy optionally substituted by an alkoxy group, haloalkoxy, haloalkoxyalkoxy, dimethylamino, heterocyclyl, heterocyclylcarbonyl, heteroaryl, or fused to the pyridinyl or pyrazinyl group may be one heterocyclyl or heteroaryl ring, thus forming a fused bicyclic system, each of said substituents may be substituted by one or more alkyl, halo or oxo group(s); and/or

D is C=0; and/or

R is selected from ring-I, ring-V, ring- VI and ring-VII, preferably R is ring-V or ring -VI, more preferably R is ring -V; wherein preferably when the dotted line in ring-I is a single bond, R ¹ is selected from H, fluoro, Ci-C ₃ alkyl, preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxy, preferably methoxy, Ci-C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹ is H; R ¹ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl, more preferably R ¹ is H; R ² is selected from H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxy preferably methoxy, Ci-C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, more preferably R ² is selected from H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino, still more preferably R ² is H; R ² is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, or R ² forms together with R ² a =CH ₂ or oxo moiety, more preferably R ² is H; when the dotted line in ring-I is a double bond, R ¹ is selected from H, fluoro, C ₁ -C ₃ alkyl, preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably metho xymethyl, more preferably R ¹ is H; R ¹ is absent; R ² is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably metho xymethyl, more preferably R ² is H; R ² is absent;

R ³ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ³ is H; and/or

R ³ is selected from H, fluoro, C ₁ -C ₃ alkyl preferably methyl, more preferably R ³ is H; and/or

R ¹⁰ and R ¹⁰ ' are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁰ and R ¹⁰ are H; and/or when the dotted line in ring-V is a single bond, R ¹¹ is selected from H, fluoro, C ₁ -C ₃ alkyl, preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxy, preferably methoxy, Ci-C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl; more preferably R ¹¹ is H; R ¹¹ is selected from H, fluoro, C ₁ -C ₃ alkyl preferably methyl; more preferably R ¹¹ is H; R ¹² is selected from H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, more preferably R ¹² is H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino, still more preferably R ¹² is H, fluoro, hydroxyl, even more preferably R ¹² is H, hydroxyl and the bond linking R ¹² to R is drawn as a solid wedge or a dotted wedge, preferably as a solid wedge when R ¹¹ is H or as a dotted wedge when R ¹¹ is hydroxyl, even more preferably R ¹² is H, hydroxyl and the bond linking R ¹² to R is drawn as a solid wedge; R ¹² is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, or R ¹² forms together with R ¹² a =CH ₂ or oxo moiety, more preferably R ¹² is H; when the dotted line in ring-V is a double bond, R ¹¹ is selected from H, fluoro, Ci- C ₃ alkyl, preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy- Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹¹ is H; R ¹¹ is absent; R ¹² is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹² is H; R ¹² is absent; and/or

R ¹³ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹³ is H; and/or

R ¹³ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl, more preferably R ¹³ is H; and/or when the dotted line in ring- VI is a single bond, R ¹⁴ is selected from H, fluoro, chloro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁴ is H; R ¹⁴ is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl; more preferably R ¹⁴ is selected from H, fluoro, methyl, -CHF ₂ , hydroxymethyl, methoxymethyl, still more preferably R ¹⁴ is H; R ¹⁵ is selected from H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, more preferably R ¹⁵ is H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino, still more preferably R ¹⁵ is H, fluoro, hydroxyl, even more preferably R ¹⁵ is H, hydroxyl and the bond linking R ¹⁵ to R is drawn as a solid wedge or a dotted wedge, preferably as a solid wedge when R ¹⁴ is H or as a dotted wedge when R ¹⁴ is hydroxyl, even more preferably R ¹⁵ is H, hydroxyl and the bond linking R ¹⁵ to R is drawn as a solid wedge; R ¹⁵ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁵ is H; when the dotted line in ring- VI is a double bond R ¹⁴ is selected from H, fluoro, Ci- C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci- C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxyalkyl preferably methoxymethyl; more preferably R ¹⁴ is selected from H, fluoro, methyl, -CHF ₂ , hydroxymethyl, methoxymethyl; still more preferably R ¹⁴ is H; R ¹⁴ is absent; R ¹⁵ is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or - CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, more preferably R ¹⁵ is H; R ¹⁵ is absent; and/or

R ¹⁶ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁶ is H; and/or

R ¹⁶ is selected from H, fluoro, C ₁ -C ₃ alkyl preferably methyl, more preferably R ¹⁶ is H; and/or

R ¹⁷ and R ¹⁷ ' are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁷ and R ¹⁷ are H; and/or when the dotted lines depicted by "c" and "d" in ring- VII are both single bonds, R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁸ is selected from H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl; still preferably R ¹⁸ is H; R ¹⁸ is selected from H, fluoro, C ₁ -C ₃ alkyl preferably methyl preferably R ¹⁸ is H; one of R ¹⁹ or R ²⁰ is selected from H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or - CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, and the other one is selected from H, fluoro, chloro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably - CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl; more preferably one of R ¹⁹ or R ²⁰ IS selected from H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino, and the other one is selected from H, fluoro, chloro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl; still more preferably R ¹⁹ and R ²⁰ are independently selected from H, fluoro and hydroxyl; even more preferably R ¹⁹ and R ²⁰ are independently selected from H and hydroxyl and the bonds linking R ¹⁹ and R ²⁰ to R are independently drawn as a solid wedge or a dotted wedge, preferably as a solid wedge when only one of R ¹⁹ and R ²⁰ is hydroxyl, preferably as a dotted wedge when both R ¹⁹ and R ²⁰ are hydroxyl; R ¹⁹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl more preferably R ¹⁹ is H; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably - CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ²⁰ is H; when the dotted line depicted by a "c" in ring- VII is a single bond and the dotted line depicted by a "d" in ring- VII is a double bond, R ¹⁸ is selected from H, fluoro, chloro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁸ is selected from H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl; still more preferably R ¹⁸ is H; R ¹⁸ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl, more preferably R ¹⁸ is H; R ¹⁹ and R ²⁰ are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl; more preferably R ¹⁹ and R ²⁰ are H; R ¹⁹ and R ²⁰ are absent; when the dotted line depicted by a "c" in ring- VII is a double bond and the dotted line depicted by a "d" in ring- VII is a single bond, R ¹⁸ is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy- Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably

18 18' 19 20 methoxymethyl, more preferably R is H; R is absent; R and R are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C3 alkoxyalkyl preferably methoxymethyl; more preferably R and R ²⁰ are independently selected from H, fluoro, methyl, -CHF ₂ , hydroxymethyl, methoxymethyl; still more preferably R ¹⁹ and R ²⁰ are H; R ¹⁹ is absent; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C4 alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, or R ²⁰ forms together with R ²⁰ a =CH ₂ or oxo moiety, preferably R ²⁰ is H; and/or

R ²¹ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -

OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ²¹ is selected from H, fluoro, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethy, still more preferably R ²¹ is H; and/or

R ²¹ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl, more preferably R ²¹ is H; and/or

L ³ is a single bond; and/or when R is selected from ring-II, ring III, ring IV and ring VIII

R ⁴ , R ^4' , R ⁵ and R ⁵ are H; and/or

R ⁶ , R ^6' , R ⁷ and R ^7' are H; and/or R ⁸ , R ⁹ and R ^9' are H; and/or

R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ²⁵ and R ²⁵ are H; and/or

L ² is a methylene optionally substituted by one or more methyl group(s), preferably L ² is CH ₂ ; and/or

Z is selected from the group consisting of -COOR ⁰ , wherein R° is H or linear or branched alkyl, preferably Z is -COOH. In one embodiment preferred compounds of Formula I are those of formula

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

R is as defined above in respect to formula I, preferably R is selected from ring-I, ring-II, ring-V, ring- VI, ring- VII and ring- VIII, more preferably R is selected from ring-I, ring-V, ring VI and ring- VII, still more preferably R is ring-V or ring VI, even more preferably R is ring-V; Ar ¹ is as defined above in respect to formula I, preferably Ar ¹ is isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-difluorocyclohexan-l-yl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, furanyl, thiophenyl or thiazolyl, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy or haloalkoxy, more preferably Ar ¹ is isopropyl, isobutyl, cyclopropyl, cyclopentyl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, phenyl , 2- fluorophenyl, 4-chlorophenyl, 4-tolyl, 4-methoxyphenyl, furan-2-yl, thiophen-2-yl, thiazol- 2-yl or thiazol-4-yl, still more preferably Ar ¹ is isopropyl, isobutyl, cyclopropyl, cyclopentyl, tetrahydropyran-4-yl, or phenyl, even more preferably Ar ¹ is cyclopropyl, cyclopentyl; Ar ³ is as defined above in respect to formula I, preferably Ar ³ is a phenyl optionally substituted by one or more halo preferably chloro or fluoro, cyano, alkyl preferably methyl or isopropyl, haloalkyl preferably -CHF ₂ or -CF ₃ , hydroxyl, alkoxy preferably methoxy, haloalkoxy preferably -OCHF ₂ or -OCF ₃ group(s), by one phenyl, pyridinyl, pyridazinyl or pyrazinyl group, each of said phenyl, pyridinyl, pyridazinyl or pyrazinyl group may be further substituted by one or more substituent(s) selected from halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably -CHF ₂ or -CF ₃ , hydroxyl, alkoxy preferably methoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, alkoxyalkoxy optionally substituted by an alkoxy group preferably (2-methoxyethyl)oxy, (2-ethoxyethyl)oxy, 2-(isopropyloxyethyl)oxy, (3-methoxybutan-2- yl)oxy, (l-methoxy-2-methylpropan-2-yl)oxy, ((3S)-3-methoxybutan-2-yl)oxy, ((3R)-3- methoxybutan-2-yl)oxy, haloalkoxyalkoxy preferably (2-(2,2,2-trifluoroethoxy)ethyl)oxy, (2-(2-ethoxyethoxy)ethyl)oxy, alkylamino preferably dimethylamino, N,N- (cycloalkyl)(alkyl)amino preferably N,N-(cyclohexyl)(methyl)amino, N,N- (aralkyl)(alkyl)amino preferably N,N-(benzyl)(methyl)amino, heterocyclyl preferably azetidinyl, pyrrolidinyl, morpholinyl, heterocyclylcarbonyl preferably (pyrrolidin- lyl)carbonyl, heteroaryl preferably furan-2-yl, thiophen-2-yl, 3,5-dimethyl-lH-pyrazol-l- yl, pyrazol-l-yl, 2-methyltetrazol-5-yl, 1,3,4-triazol-l-yl, or fused to the pyridinyl or pyrazinyl group may be one heterocyclyl preferably pyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinyl or heteroaryl preferably pyrrolyl, pyrazolyl, triazolyl ring, thus forming a fused bicyclic system, each of said substituents may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s), more preferably Ar ³ is a phenyl optionally substituted by one or more halo preferably chloro, fluoro, by one pyridinyl, pyridazinyl or pyrazinyl group, each of said pyridinyl, pyridazinyl or pyrazinyl group may be further substituted by one or more substituent(s) selected from halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably -CHF ₂ or -CF ₃ , alkoxy preferably methoxy, alkoxyalkoxy optionally substituted by an alkoxy group preferably (2-methoxyethyl)oxy, 2-(isopropyloxyethyl)oxy, ((3S)-3-methoxybutan-2-yl)oxy, ((3R)-3-methoxybutan-2-yl)oxy, alkylamino preferably dimethylamino, heterocyclyl preferably pyrrolidinyl, morpholinyl, heterocyclylcarbonyl preferably (pyrrolidin-lyl)carbonyl, heteroaryl preferably 3,5-dimethyl-lH-pyrazol-l-yl, pyrazol-l-yl, or fused to the pyridinyl or pyrazinyl group may be one heterocyclyl preferably pyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, or heteroaryl preferably pyrrolyl, pyrazolyl, triazolyl ring, thus forming a fused bicyclic system, each of said substituents may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s), even more preferably Ar ³ is phenyl, 2- chlorophenyl, 2-fluorophenyl, 2,5-dichlorophenyl, 2-(6-methoxypyridin-3-yl)phenyl, 2-(6- (2-oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl, 2-(6-(3 -methyl-2-oxopyrrolidin- 1 -yl)pyridin-3 - yl)phenyl, 2-(6-methoxypyrazin-3-yl)phenyl, 2-(6-(2-oxopyrrolidin- 1 -yl)pyrazin-3- yl)phenyl, 2-(6-methoxypyridazin-3-yl)phenyl, even more preferably Ar ³ is phenyl, 2- chlorophenyl, 2-fluorophenyl, 2,5-dichlorophenyl, 2-(6-methoxypyridin-3-yl)phenyl, 2-(6- (2-oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl, 2-(6-methoxypyrazin-3 -yl)phenyl. X is S or O, preferably X is S;

Y is CH or N, preferably Y is CH;

the heterocyclic group is substituted with Ar either in position 4 or 5 , preferably in position 4; and

H, halo, cyano, hydro xyl, linear or branched C ₁ -C ₃ alkyl, C ₁ -C ₃ hydro xyalkyl, Ci-

26

C3 haloalkyl, preferably R is H, methyl, F, CI, or CF ₃ , more preferably R. ^o is H or F, still more R is preferably H; if Y is N, R ^2b is absent.

Preferred compounds of formula la are those of formula Ia-1

Ia-1 harmaceutically acceptable salts, solvates, and prodrugs thereof, wherein

R, Ar ¹ , Ar ³ and R ²⁶ are as defined above in respect to formula la, preferably R ²⁶ is H or F, more preferably R ²⁶ is H.

Preferred compounds of formula Ia-1 are those of formula Ia-2

Ia-2 and pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R, Ar ¹ and R ²⁶ are as defined above in respect to formula Ia-1;

R ²⁷ is H, halo preferably chloro or fluoro, cyano, alkyl preferably methyl or isopropyl, haloalkyl preferably -CHF ₂ or -CF ₃ , hydroxyl, alkoxy preferably methoxy, haloalkoxy preferably -OCHF ₂ or -OCF ₃ , phenyl, pyridinyl, pyridazinyl or pyrazinyl, each of said phenyl, pyridinyl, pyridazinyl or pyrazinyl group may be further substituted by one or more substituent(s) selected from halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably -CHF ₂ or -CF ₃ , hydroxyl, alkoxy preferably methoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, alkoxyalkoxy optionally substituted by an alkoxy group preferably (2-methoxyethyl)oxy, (2-ethoxyethyl)oxy, 2-(isopropyloxyethyl)oxy, (3-methoxybutan-2-yl)oxy, (l-methoxy-2- methylpropan-2-yl) o xy , ((3 S)-3 -methoxybutan-2-yl)oxy, ((3R)-3 -methoxybutan-2-yl)oxy, h a l o a l k o x y a l k o x y p r e fe r a b l y (2-(2,2,2-trifluoroethoxy)ethyl)oxy, (2-(2- ethoxyethoxy)ethyl)oxy, alkylamino preferably dimethylamino, N,N- (cycloalkyl)(alkyl)amino preferably N,N-(cyclohexyl)(methyl)amino, N,N- (aralkyl)(alkyl)amino preferably N,N-(benzyl)(methyl)amino, heterocyclyl preferably azetidinyl, pyrrolidinyl, morpholinyl, heterocyclylcarbonyl preferably (pyrrolidin- lyl)carbonyl, heteroaryl preferably furan-2-yl, thiophen-2-yl, 3,5-dimethyl-lH-pyrazol-l- yl, pyrazol-l-yl, 2-methyltetrazol-5-yl, 1,3,4-triazol-l-yl, or fused to the pyridinyl or pyrazinyl group may be one heterocyclyl preferably pyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinyl or heteroaryl preferably pyrrolyl, pyrazolyl, triazolyl ring, thus forming a fused bicyclic system, each of said substituents may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s), preferably R ²⁷ is H, halo preferably chloro or fluoro, pyridinyl, pyridazinyl or pyrazinyl, each of said pyridinyl or pyrazinyl group may be further substituted by one or more substituent(s) selected from halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably -CHF ₂ or -CF ₃ , alkoxy preferably methoxy, alkoxyalkoxy optionally substituted by an alkoxy group preferably (2-methoxyethyl)oxy, 2-(isopropyloxyethyl)oxy, ((3S)-3-methoxybutan-2-yl)oxy, ((3R)-3-methoxybutan-2-yl)oxy, alkylamino preferably dimethylamino, heterocyclyl preferably pyrrolidinyl, morpholinyl, heterocyclylcarbonyl preferably (pyrrolidin-lyl)carbonyl, heteroaryl preferably 3,5-dimethyl-lH-pyrazol-l-yl, pyrazol-l-yl, or fused to the pyridinyl or pyrazinyl group may be one heterocyclyl preferably pyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, or heteroaryl preferably pyrrolyl, pyrazolyl, triazolyl ring, thus forming a fused bicyclic system, each of said substituents may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s), more preferably R ²⁷ is H, chloro, fluoro, 6- methoxypyridin-3 -yl, 6-(2-oxopyrrolidin- 1 -yl)pyridin-3 -yl, 6-(3 -methyl-2-oxopyrrolidin- 1 - yl)pyridin-3-yl, 6-(3-fluoro-2-oxopyrrolidin-l-yl)pyridin-3-yl, 6-methoxypyrazin-3-yl, 6- (2-oxopyrrolidin-l-yl)pyrazin-3-yl, 6-methoxypyridazin-3-yl, even more preferably R ²⁷ is chloro, fluoro, 6-methoxypyridin-3-yl, 6-(2-oxopyrrolidin-l-yl)pyridin-3-yl, 6- methoxypyrazin-3 -yl;

R ^27' is H;

R ²⁸ is H, halo, cyano, alkyl preferably methyl, haloalkyl, hydroxyl, alkoxy preferably methoxy, haloalkoxy, preferably R ²⁸ is H, fluoro, chloro, cyano, -CHF ₂ , -CF ₃ or -OCF ₃ more preferably R ²⁸ is H;

R ^28' is H, halo, cyano, alkyl preferably methyl, haloalkyl, hydroxyl, alkoxy preferably methoxy, haloalkoxy, preferably R ²⁸ is H, fluoro, chloro, -CF ₃ , -OCHF ₂ or -OCF ₃ more preferably R ²⁸ is H;

R ²⁹ is H, halo, cyano, alkyl, alkoxy, preferably R ²⁹ is H, chloro, fluoro, methyl or methoxy more preferably R ²⁹ is H.

Preferred compounds of formula Ia-2 are those of formula Ia-3

Ia-3 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein R, Ar ¹ and R ²⁶ are as defined above in respect to formula Ia-2; R ^27' is H;

R ²⁸ is as defined above in respect to formula Ia-2, preferably R ²⁸ is H or fluoro, more preferably R ²⁸ is H;

28' 28'

R is as defined above in respect to formula Ia-2, preferably R is H, chloro or fluoro, more preferably R ²⁸ is H;

R ²⁹ is as defined above in respect to formula Ia-2, preferably R ²⁹ is H, chloro or fluoro, more preferably R ²⁹ is H;

R ³⁰ is H, halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably - CHF ₂ or -CF ₃ , hydro xyl, alkoxy preferably methoxy, preferably R ³⁰ is H, chloro;

R ³¹ is alkoxy preferably methoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, alkoxyalkoxy optionally substituted by an alkoxy group preferably (2-methoxyethyl)oxy, (2-ethoxyethyl)oxy, 2-(isopropyloxyethyl)oxy, (3- methoxybutan-2-yl) o xy , (1 -methoxy-2-methylpropan-2-yl)oxy, ((3 S)-3 -methoxybutan-2- yl)o xy , ( (3 R)-3-methoxybutan-2-yl)oxy, haloalkoxyalkoxy preferably (2-(2,2,2- trifluoroethoxy)ethyl) o x y , (2-(2-ethoxyethoxy)ethyl)oxy, alkylamino preferably dimethylamino, N,N-(cycloalkyl)(alkyl)amino preferably N,N-(cyclohexyl)(methyl)amino, N,N-(aralkyl)(alkyl)amino preferably N,N-(benzyl)(methyl)amino, heterocyclyl preferably azetidinyl, pyrrolidinyl, morpholinyl, heterocyclylcarbonyl preferably (pyrrolidin- lyl)carbonyl, heteroaryl preferably furan-2-yl, thiophen-2-yl, 3,5-dimethyl-lH-pyrazol-l- yl, pyrazol-l-yl, 2-methyltetrazol-5-yl, 1,3,4-triazol-l-yl, each of said substituents may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s), preferably R ³¹ is alkoxy preferably methoxy, alkoxyalkoxy optionally substituted by an alkoxy group preferably (2-methoxyethyl)oxy, 2-(isopropyloxyethyl)oxy, ((3S)-3- methoxybutan-2-yl) o x y , ( ( 3 R)-3-methoxybutan-2-yl)oxy, alkylamino preferably dimethylamino, heterocyclyl preferably pyrrolidinyl, morpholinyl, heterocyclylcarbonyl preferably (pyrrolidin-lyl)carbonyl, heteroaryl preferably 3,5-dimethyl-lH-pyrazol-l-yl, pyrazol-l-yl, each of said substituents may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s), more preferably R ³¹ is methoxy, 2-oxopyrrolidin-l-yl, 3-methyl-2-oxopyrrolidin-l-yl, 3-fluoro-2-oxopyrrolidin-l-yl even more preferably R ³¹ is methoxy, 2-oxopyrrolidin-l-yl; or

R ³⁰ and R ³¹ together form a heterocyclyl preferably pyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, or heteroaryl preferably pyrrolyl, pyrazolyl or triazolyl ring, thus forming a fused bicyclic system which may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s);

X ¹ is N or C-R ³² wherein R ³² is H;

2 32' 32' 32'

X is N or C-R wherein R is H or alkoxy preferably R is H or methoxy, more preferably R ³² is H, preferably X ² is N or CH, more preferably X ² is CH.

Preferred compounds of formula Ia-3 are those wherein the moiety is selected from: H, X ² is CH and R ³¹ is methoxy or 2-oxopyrrolidin-l-yl.

Other preferred compounds of formula Ia-2 are those of formula Ia-4

Ia-4 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein R and Ar ¹ are as defined above in respect to formula Ia-2;

27 28' 27 28'

R" and R ⁱ⁰ are as defined above in respect to formula Ia-2, preferably R and R are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, -CF ₃ , -CHF ₂ , -OCF ₃ or -OCHF ₂ , more preferably R ²⁷ is H, chloro or fluoro and R ²⁸ is selected from H, halo, -CF ₃ , -CHF ₂ , -OCF ₃ or -OCHF ₂ , preferably chloro and fluoro, even more preferably R ²⁷ is chloro or fluoro and R ²⁸ is H, or R ²⁷ is H and R ^28' is -OCF ₃ or -OCHF ₂ , even more preferably R ²⁷ is chloro or fluoro and R ²⁸ is H.

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

lb and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein R, Ar ¹ and Ar ³ are as defined above in respect to formula la; X ³ is CH or N;

R ³³ and R ^33' are independently selected from H, halo, cyano, hydro xyl, linear or branched C1-C ₃ alkyl, C1-C ₃ haloalkyl, preferably R ³³ and R ³³ are independently selected from H, F, CI, or CF ₃ , more preferably R ³³ and R ^33' are H;

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

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

1 3 33 33'

R, Ar ¹ , Ar R~ and R ^{^} are as defined above in respect to formula lb.

In another embodiment, preferred compounds of Formula I are those of formulae Id-1, Id-2, Id-3, Id-4, Id-5, Id-6, Id-7 and Id-8:

ld-7 ld-8 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein

Ar ¹ , Ar ² , Ar ³ , L ¹ , L ² , D, and Z are as defined above in respect to formula I; the bonds represented by the dotted lines are independently either absent or present thus making the bonds represented by = independently a single bond or a double bond respectively, preferably the dotted lines are absent; at least one of the bonds represented by the dotted lines depicted as "c" and "d" in formula Id-7 is a single bond; when the dotted line in formula Id-1 is absent, R ¹ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ¹ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ² is selected from H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, hetero arylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, hetero arylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino , heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alky lo xycarbony lamino , hetero cyclylo xyc arbony lamino , arylo xycarbony lamino , hetero aryloxycarbonylamino, alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and R ² is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R ² forms together with R ² a =CH ₂ or oxo moiety; when the dotted line in formula Id-1 is present, R ¹ is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ¹ is absent; R ² is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ² is absent;

R ³ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ³ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R ³ forms together with R ³ an oxo moiety; when the dotted line in formula Id-2 is absent, R ⁴ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁴ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ⁵ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁵ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; or R ⁵ forms together with R ⁵ an oxo moiety; when the dotted line in formula Id-2 is present, R ⁴ is selected from H, fiuoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁴ is absent; R ⁵ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, and R ⁵ is absent;

R ⁶ and R ^6' are independently selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;

R ⁷ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ⁷ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl, C1-C4 haloalkoxyalkyl, or R ⁷ forms together with R ⁷ an oxo moiety;

R ⁸ is H or C1-C4 alkyl;

R ⁹ and R ⁹ are independently selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;

R ¹⁰ and R ^10' are independently selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; when the dotted line in formula Id-5 is absent, R ¹¹ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹¹ is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R is H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino, heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alkyloxycarbonylamino , hetero cycly lo xycarbony lamino , arylo xycarbony lamino , hetero arylo xycarbonylamino , alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino; R ¹² is selected from H, fluoro, chloro, Ci- C ₄ alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R ¹² forms together with R ¹² a =CH ₂ or oxo moiety; when the dotted line in formula Id-5 is present, R ¹¹ is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹¹ is absent; R ¹² is H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; and R ¹² is absent

R ¹³ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹³ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R ¹³ forms together with R ¹³ an oxo moiety; when the dotted line in formula Id-6 is absent, R ¹⁴ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹⁴ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹⁵ is selected from H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, hetero arylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, hetero arylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino , heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alky lo xycarbony lamino , hetero cyclylo xyc arbony lamino , arylo xycarbony lamino , hetero aryloxycarbonylamino, alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino; R ¹⁵ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl or R ¹⁵ forms together with R ¹⁵ a =CH ₂ or oxo moiety; when the dotted line in formula Id-6 is present, R ¹⁴ is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹⁴ is absent; R ¹⁵ is selected from H, fluoro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; and R ¹⁵ is absent;

R ¹⁶ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R ¹⁶ is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R ¹⁶ forms together with R ¹⁶ an oxo moiety;

R ¹⁷ and R ^17' are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; when the dotted lines depicted by "c" and "d" in formula Id-7 are both absent, R is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalky; one of R ¹⁹ or R ²⁰ is selected from H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, amino, alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbamoylamino, cycloalkylcarbamoylamino, heterocyclylcarbamoylamino, arylcarbamoylamino , heteroarylcarbamoylamino , alkoxycarbonylamino , cyclo alky lo xycarbony lamino , hetero cyclylo xyc arbony lamino , arylo xycarbony lamino , heteroaryloxycarbonylamino, alkylsulfamoylamino, cycloalkylsulfamoylamino, heterocyclylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and the other one is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, hydroxy-Ci- C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; R ¹⁹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; or R ¹⁹ forms together with R ¹⁹ a =CH ₂ or oxo moiety and R ²⁰ is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-Ci-C ₄ alkyl, C ₁ -C ₄ alkoxyalkyl or C ₁ -C ₄ haloalkoxyalkyl; or R ²⁰ forms together with R ²⁰ a =CH ₂ or oxo moiety and R ¹⁹ is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl; when the dotted line depicted by a "c" in formula Id-7 is absent and the dotted line depicted by a "d" in formula Id-7 is present, R is selected from H, fluoro, chloro, C ₁ -C4 alkyl, Ci- C ₄ haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl; R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalky; R ¹⁹ and R ²⁰ are independently selected from H, C ₁ -C4 alkyl, hydroxy-Ci-C4 alkyl, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl; R ¹⁹ and R ²⁰ are absent; when the dotted line depicted by a "c" in formula Id-7 is present and the dotted line depicted by a "d" in formula Id-7 is absent, R ¹⁸ and R ¹⁹ are independently selected from H, C ₁ -C4 alkyl, hydroxy-Ci-C4 alkyl, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl; R ¹⁸ and R ¹⁹ are absent; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C ₁ -C4 alkoxy, C ₁ -C4 haloalkoxy, C ₁ -C4 alkoxyalkyl or Ci- C4 haloalkoxyalkyl; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalky;

R ²¹ is selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C ₁ -C4 alkoxy, C ₁ -C4 haloalkoxy, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl; R ²¹ is selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl, or R ²¹ forms together with R ²¹ an oxo moiety;

R ²² and R ^22' are independently selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl;

R ²³ is selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C ₁ -C4 alkoxy, C ₁ -C4 haloalkoxy, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl; R ²³ is selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C ₁ -C4 alkoxyalkyl or C ₁ -C4 haloalkoxyalkyl, or R ²³ forms together with R ²³ an oxo moiety;

R ²⁴ is H or Ci-C ₄ alkyl; and

R ²⁵ and R ²⁵ are independently selected from H, fluoro, chloro, C ₁ -C4 alkyl, C ₁ -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl.

In one embodiment, compounds of formula Id-6 are those wherein the bond linking carbon to which L ² -Z is attached and D is drawn as a solid wedge:

Among the compounds of formulae Id-1 , Id-2, Id-3, Id-4, Id-5, Id-6, Id-7 and Id-8 those of formulae Id-1, Id-2, Id-5, Id-6, Id-7 and Id-8 are preferred.

Among the compounds of formulae Id-1 , Id-2, Id-5, Id-6, Id-7 and Id-8 those of formulae Id-1, Id-5, Id-6 and Id-7 are preferred.

Among the compounds of formulae Id-1 , Id-5, Id-6 and Id-7 those of formula Id-5 and Id-6 are preferred.

Among the compounds of formulae Id-5 and Id-6, those of formula Id-5 are preferred.

Preferred compounds of formulae Id-1 , Id-2, Id-3, Id-4, Id-5, Id-6, Id-7 and Id-8 are those of formulae Ie-1, Ie-2, Ie-3, Ie-4, Ie-5, Ie-6, Ie-7 and Ie-8 respectively:

le-7 le-8 harmaceutically acceptable salts, and solvates, or prodrugs thereof, wherein

Ar ¹ and Ar ³ are as defined above in respect to formula la;

Ar ² is as defined above in respect to formula I, preferably Ar ² is a 5 to 6-membered heteroaryl group, preferably thiazolyl, thiadiazolyl or pyridinyl, each of which being optionally substituted by one or more halo, preferably fluoro, or alkyl, preferably methyl, group(s) preferably Ar ² is a thiazolyl connected to the ring nitrogen at position 2 and to Ar ³ at position 4 and optionally substituted by a fluoro at position 5, preferably unsubstituted at position 5, or Ar ² is a thiadiazolyl connected to the ring nitrogen at position 2 and to Ar ³ at position 5, more preferably Ar ² is a thiazolyl connected to the ring nitrogen at position 2 and to Ar ³ at position 4;

R IV ¹ . R IV ¹ ' , R IV ² . R IV ² ' . R IV ³ . R IV ³ ' . R IV ⁴ . R IV ⁴ ' . R IV ⁵ . R IV ⁵ ' . R IV ⁶ . R IV ⁶ ' . R IV ⁷ . R IV ⁷ ' . R IV ⁸ . R IV ⁹ . R IV ⁹ ' . RIV ¹⁰ . R IV ¹⁰ ' . RIV ¹¹ . RIV ¹¹ ' ,

_R 12 _R 12' _R 13 _R 13' _R 14 _R 14' _R 15 _R 15' _R 16 _R 16' _R 17 _R 17' _R 18 _R 18' _R 19 _R 19' _R 20 _R 20' IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV ,

R ²¹ , R ^21' , R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ²⁵ , R ²⁵ , and the dotted lines are as defined above in respect to formulae Id-1, Id-2, Id-3, Id-4, Id-5, Id-6, Id-7 and Id-8, preferably: when the dotted line in formula Ie-1 is absent, R ¹ is selected from H, fluoro, C ₁ -C ₃ alkyl, preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxy, preferably methoxy, Ci-C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹ is H; R ¹ is selected from H, fluoro, C ₁ -C ₃ alkyl preferably methyl, more preferably R ¹ is H; R ² is H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy- C ₁ -C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, more preferably R ² is H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino still more preferably R ² is H; R ² is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, Ci- C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, or R ² forms together with R ² a =CH ₂ or oxo moiety, more preferably R ² is H; when the dotted line in formula Ie-1 is present, R ¹ is selected from H, fluoro, C ₁ -C ₃ alkyl, preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹ is H; R ¹ is absent; R ² is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ² is H; R ² is absent; R ³ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ³ is H;

R ³ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl, more preferably R ³ is H;

R ⁴ , R ^4' , R ⁵ and R ⁵ are H; R ⁶ , R ^6' , R ⁷ and R ^7' are H; R ⁸ , R ⁹ and R ^9' are H;

R ¹⁰ and R ^10' are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁰ and R ¹⁰ are H; when the dotted line in formula Ie-5 is absent, R ¹¹ is selected from H, fluoro, Ci-C ₃ alkyl, preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxy, preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl; more preferably R ¹¹ is H; R ¹¹ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl; more preferably R ¹¹ is H; R ¹² is H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, more preferably R ¹² is H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino, still more preferably R is H, fluoro, hydroxyl, even more preferably R is H, hydroxyl and the bond linking R ¹² to R is drawn as a solid wedge or a dotted wedge, preferably as a solid wedge when R ¹¹ is H or as a dotted wedge when R ¹¹ is hydroxyl, even more preferably R ¹² is H, hydroxyl and the bond linking R ¹² to R is drawn as a solid wedge; R ¹² is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydro xymethyl, C ₁ -C ₃ alkoxyalkyl preferably metho xymethyl, or R ¹² forms together with R ¹² a =CH ₂ or oxo moiety, preferably R ¹² is H; when the dotted line in formula Ie-5 is present, R ¹¹ is selected from H, fluoro, C ₁ -C ₃ alkyl, preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydro xymethyl, C ₁ -C ₃ alkoxyalkyl preferably metho xymethyl, more preferably R ¹¹ is H; R ¹¹ is absent; R ¹² is H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydro xymethyl, C ₁ -C ₃ alkoxyalkyl preferably metho xymethyl, more preferably R ¹² is H; R ¹² is absent;

R ¹³ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹³ is H;

R ¹³ is selected from H, fluoro, C ₁ -C ₃ alkyl preferably methyl, more preferably R ¹³ is H; when the dotted line in formula Ie-6 is absent, R ¹⁴ is selected from H, fluoro, chloro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁴ is H; R ¹⁴ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₃ alkoxyalkyl preferably methoxymethyl; more preferably R ¹⁴ is selected from H, fluoro, methyl, -CHF ₂ , hydro xymethyl, methoxymethyl, still more preferably R ¹⁴ is H; R ¹⁵ is H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydro xyl, hydroxy-Ci-C ₃ alkyl preferably hydro xymethyl, Ci-C ₃ alkoxy preferably methoxy, Ci-C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, more preferably R ¹⁵ is H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino, still more preferably R ¹⁵ is H, fluoro, hydroxyl, even more preferably R ¹⁵ is H, hydroxyl and the bond linking R ¹⁵ to R is drawn as a solid wedge or a dotted wedge, preferably as a solid wedge when R ¹⁴ is H or as a dotted wedge when R ¹⁴ is hydroxyl, even more preferably R ¹⁵ is H, hydroxyl and the bond linking R ¹⁵ to R is drawn as a solid wedge; R ¹⁵ is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁵ is H; when the dotted line in formula Ie-6 is present, R ¹⁴ is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₂ alkoxyalkyl preferably methoxymethyl; more preferably R ¹⁴ is selected from H, fluoro, methyl, -CHF ₂ , hydroxymethyl, methoxymethyl; still more preferably R ¹⁴ is H; R ¹⁴ is absent; R ¹⁵ is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or - CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, more preferably R ¹⁵ is H; R ¹⁵ is absent;

R ¹⁶ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁶ is H; R ¹⁶ is selected from H, fluoro, C ₁ -C3 alkyl preferably methyl, more preferably R ¹⁶ is H;

R ¹⁷ and R ¹⁷ ' are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁷ and R ¹⁷ are H; when the dotted lines depicted by "c" and "d" in formula Ie-7 are both absent, R ¹⁸ is selected from H, fluoro, chloro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁸ is selected from H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl; more preferably R ¹⁸ is H; R ¹⁸ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl more preferably R ¹⁸ is H; one of R ¹⁹ or R ²⁰ is selected from H, fluoro, chloro, Ci-C ₆ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, aralkyloxy preferably benzyloxy, aralkylamino preferably benzylamino, alkylcarbonylamino preferably acetylamino, alkylsulfonylamino preferably methylsulfonylamino, and the other one is selected from H, fluoro, chloro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably - CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl; more preferably one of R ¹⁹ or R ²⁰ IS selected from H, fluoro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl, benzylamino, and the other one is selected from H, fluoro, chloro, methyl, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethyl; still more preferably R ¹⁹ and R ²⁰ are independently selected from H, fluoro and hydroxyl; even more preferably R ¹⁹ and R ²⁰ are independently selected from H and hydroxyl and the bonds linking R ¹⁹ and R ²⁰ to R are independently drawn as a solid wedge or a dotted wedge, preferably as a solid wedge when only one of R and R is hydroxyl, preferably as a dotted wedge when both R ¹⁹ and R ²⁰ are hydroxyl; R ¹⁹ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁹ is H; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C ₄ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably - CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ²⁰ is H; when the dotted line depicted by a "c" in ring-VII absent and the dotted line depicted by a "d" in formula Ie-7 is present, R ¹⁸ is selected from H, fluoro, chloro, Ci-C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, C ₁ -C ₂ alkoxy preferably methoxy, C ₁ -C ₂ haloalkoxy preferably -OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁸ is H; R ¹⁸ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl more preferably R ^18' is H; R ¹⁹ and R ²⁰ are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl; more preferably R ¹⁹ and R ²⁰ are H; R ¹⁹ and R ²⁰ are absent; when the dotted line depicted by a "c" in formula Ie-7 is present and the dotted line depicted by a "d" in formula Ie-7 is absent R ¹⁸ is selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ¹⁸ is selected from H, fluoro, methyl, -CHF ₂ , hydroxymethyl, methoxymethyl; still more preferably R 18 is H; R 18' is absent; R 19 and R 20 are independently selected from H, fluoro, C ₁ -C ₂ alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl; more preferably R ¹⁹ and R ²⁰ are independently selected from H, fluoro, methyl, -CHF ₂ , hydroxymethyl, methoxymethyl; still more preferably R ¹⁹ and R ²⁰ are H; R ¹⁹ is absent; R ²⁰ is selected from H, fluoro, chloro, C ₁ -C4 alkyl preferably methyl, C ₁ -C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₃ alkoxyalkyl preferably methoxymethyl, or R ²⁰ forms together with R ²⁰ a =CH ₂ or oxo moiety, more preferably R ²⁰ is H;

R ²¹ is selected from H, fluoro, Ci-C ₂ alkyl preferably methyl, Ci-C ₂ haloalkyl preferably -CF ₃ or -CHF ₂ , hydroxyl, hydroxy-Ci-C ₃ alkyl preferably hydroxymethyl, Ci-C ₂ alkoxy preferably methoxy, Ci-C ₂ haloalkoxy preferably - OCF ₃ or -OCHF ₂ , Ci-C ₃ alkoxyalkyl preferably methoxymethyl, more preferably R ²¹ is selected from H, fluoro, -CHF ₂ , hydroxyl, hydroxymethyl, methoxy, methoxymethy, still more preferably R ²¹ is H; R ²¹ is selected from H, fluoro, Ci-C ₃ alkyl preferably methyl, more preferably R ²¹ is H;

_R 22 _R 22 _R 23 _R 23 _R 24 _R 25 ^ _R 25 ^ _R

In one embodiment, compounds of formula Ie-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid wedge:

Among the compounds of formulae Ie-1 , Ie-2, Ie-3, Ie-4, Ie-5, Ie-6, Ie-7 and Ie-8 those of formulae Ie-1, Ie-2, Ie-5, Ie-6, Ie-7 and Ie-8 are preferred.

Among the compounds of formulae Ie-1, Ie-2, Ie-5, Ie-6, Ie-7 and Ie-8 those of formulae Ie- 1, Ie-5, Ie-6 and Ie-7 are preferred.

Among the compounds of formulae Ie-1 , Ie-5, Ie-6 and Ie-7 those of formula Ie-5 and Ie-6 are preferred. Among the compounds of formulae Ie-5 and Ie-6, those of formula Ie-5 are preferred.

Preferred compounds of formulae Ie-1, Ie-2, Ie-3, Ie-4, Ie-5, Ie-6, Ie-7 and Ie-8 are those formulae If-1, If-2, If-3, If-4, If-5, If-6, If-7 and If-8 respectively:

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

Ar ¹ , Ar ³ , R ²⁶ , X and Y are as defined above in respect to formula la;

R IV ¹ . R IV ¹ ' , R IV ² . R IV ² ' . R IV ³ . R IV ³ ' . R IV ⁴ . R IV ⁴ ' . R IV ⁵ . R IV ⁵ ' . R IV ⁶ . R IV ⁶ ' . R IV ⁷ . R IV ⁷ ' . R IV ⁸ . R IV ⁹ . R IV ⁹ ' . RIV ¹⁰ . R IV ¹⁰ ' . RIV ¹¹ . RIV ¹¹ ' , cr _R 12 _r 12' _r 13 _r 13' _r 14 _r 14' _r 15 _r 15' _r 16 _r 16' _r 17 _r 17' _r 18 _r 18' _r 19 _r 19' _r 20 _r 20' D IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV ,

R ²¹ , R ^21' , R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ²⁵ and R ²⁵ and the dotted lines are as defined above in respect to formulae Ie-1, Ie-2, Ie-3, Ie-4, Ie-5, Ie-6, Ie-7 and Ie-8.

In one embodiment, compounds of formula If-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid0 wedge:

Among the compounds of formulae If-l , If-2, If-3, If-4, If-5, If-6, If-7 and If-8 those of formulae If-l , If-2, If-5, If-6, If-7 and If-8 are preferred.

Among the compounds of formulae If-l , If-2, If-5, If-6, If-7 and If-8 those of formulae If-l , If-5, If-6 and If-7 are preferred.

Among the compounds of formulae If-l , If-5 , If-6 and If-7 those of formula If-5 and If-6 are preferred.

Among the compounds of formulae If-5 and If-6, those of formula If-5 are preferred.

Preferred compounds of formulae If-l , If-2, If-3, If-4, If-5, If-6, If-7 and If-8 are those of formulae Ig-1 , Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8 respectively:

harmaceutically acceptable salts, solvates, and prodrugs thereof, wherein Ar ¹ , Ar ³ and R ²⁶ are as defined above in respect to formula Ia-1;

R IV ¹ . R IV ¹ ' , R IV ² . R IV ² ' . R IV ³ . R IV ³ ' . R IV ⁴ . R IV ⁴ ' . R IV ⁵ . R IV ⁵ ' . R IV ⁶ . R IV ⁶ ' . R IV ⁷ . R IV ⁷ ' . R IV ⁸ . R IV ⁹ . R IV ⁹ ' . RIV ¹⁰ . R IV ¹⁰ ' . RIV ¹¹ . RIV ¹¹ ' ,

_R 12 _R 12' _R 13 _R 13' _R 14 _R 14' _R 15 _R 15' _R 16 _R 16' _R 17 _R 17' _R 18 _R 18' _R 19 _R 19' _R 20 _R 20' IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV ,

R ²¹ , R ^21' , R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ²⁵ and R ²⁵ and the dotted lines are as defined above in respect to formulae If-1, If-2, If-3, If-4, If-5, If-6, If-7 and If-8.

In one embodiment, compounds of formula Ig-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid wedge:

Among the compounds of formulae Ig-1 , Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8 those of formulae Ig-1, Ig-2, Ig-5, Ig-6, Ig-7 and Ig-8 are preferred.

Among the compounds of formulae Ig-1 , Ig-2, Ig-5, Ig-6, Ig-7 and Ig-8 those of formulae Ig-1, Ig-5, Ig-6 and Ig-7 are preferred.

Among the compounds of formulae Ig-1 , Ig-5, Ig-6 and Ig-7 those of formula Ig-5 and Ig-6 are preferred.

Among the compounds of formulae Ig-5 and Ig-6, those of formula Ig-5 are preferred.

Preferred compounds of formulae Ig-1 , Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8 are those of formulae Ih-1, Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8 respectively: 52

and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein Ar ¹ , R ²⁶ , R ²⁷ , R ²⁷ , R ²⁸ , R ²⁸ and R ²⁹ are as defined above in respect to formula Ia-2;

R IV ¹ . R IV ¹ ' , R IV ² . R IV ² ' . R IV ³ . R IV ³ ' . R IV ⁴ . R IV ⁴ ' . R IV ⁵ . R IV ⁵ ' . R IV ⁶ . R IV ⁶ ' . R IV ⁷ . R IV ⁷ ' . R IV ⁸ . R IV ⁹ . R IV ⁹ ' . RIV ¹⁰ . R IV ¹⁰ ' . RIV ¹¹ . RIV ¹¹ ' ,

_R 12 _R 12' _R 13 _R 13' _R 14 _R 14' _R 15 _R 15' _R 16 _R 16' _R 17 _R 17' _R 18 _R 18' _R 19 _R 19' _R 20 _R 20' IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV , R ²¹ , R ^21' , R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ²⁵ and R ²⁵ and the dotted lines are as defined above in respect to formulae Ig-1, Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8.

In one embodiment, compounds of formula Ih-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid wedge:

Among the compounds of formulae Ih-1 , Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8 those of formulae Ih-1, Ih-2, Ih-5, Ih-6, Ih-7 and Ih-8 are preferred.

Among the compounds of formulae Ih-1 , Ih-2, Ih-5, Ih-6, Ih-7 and Ih-8 those of formulae Ih-1, Ih-5, Ih-6 and Ih-7 are preferred. Among the compounds of formulae Ih-1 , Ih-5, Ih-6 and Ih-7 those of formula Ih-5 and Ih-6 are preferred.

Among the compounds of formulae Ih-5 and Ih-6, those of formula Ih-5 are preferred.

Preferred compounds of formulae Ih-1 , Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8 are those of formulae Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8 respectively: 54

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

Ar ¹ , R ²⁶ , R ^27' , R ²⁸ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , X ¹ and X ² are as defined above in respect to formula Ia-3;

R IV ¹ . R IV ¹ ' , R IV ² . R IV ² ' . R IV ³ . R IV ³ ' . R IV ⁴ . R IV ⁴ ' . R IV ⁵ . R IV ⁵ ' . R IV ⁶ . R IV ⁶ ' . R IV ⁷ . R IV ⁷ ' . R IV ⁸ . R IV ⁹ . R IV ⁹ ' . RIV ¹⁰ . R IV ¹⁰ ' . RIV ¹¹ . RIV ¹¹ ' , cr _R 12 _r 12' _r 13 _r 13' _r 14 _r 14' _r 15 _r 15' _r 16 _r 16' _r 17 _r 17' _r 18 _r 18' _r 19 _r 19' _r 20 _r 20' D IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV ,

R ²¹ , R ^21' , R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ²⁵ and R ²⁵ and the dotted lines are as defined above in respect to formulae Ih-1, Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8.

In one embodiment, compounds of formula Ii-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid 0 wedge:

Preferred c mpounds of formulae Ii-l, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8 are those

wherein the moiety is selected from:

more preferably

Further preferred compounds of formulae Ii-l , Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8 are those wherein R ^27' , R ²⁸ , R ²⁸ , R ²⁹ , R ³⁰ are H, X ² is CH and R ³¹ is methoxy or 2- oxopyrrolidin- 1 -yl.

Among the compounds of formulae Ii-l , Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8 those of formulae Ii-l , Ii-2, Ii-5, Ii-6, Ii-7 and Ii-8 are preferred.

Among the compounds of formulae Ii-l , Ii-2, Ii-5, Ii-6, Ii-7 and Ii-8 those of formulae Ii-l , Ii-5, Ii-6 and Ii-7 are preferred.

Among the compounds of formulae Ii-l , Ii-5, Ii-6 and Ii-7 those of formula Ii-5 and Ii-6 are preferred.

Among the compounds of formulae Ii-5 and Ii-6, those of formula Ii-5 are preferred.

Other preferred compounds of formulae Ih-1 , Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8 are those of formulae Ij-1 , Ij-2, Ij-3, Ij-4, Ij-5, Ij-6, Ij-7 and Ij-8 respectively:

lj-4

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

Ar 1 , R 26 , R 27 and R 28' are as defined above in respect to formula Ia-4;

R IV ¹ . R IV ¹ ' , R IV ² . R IV ² ' . R IV ³ . R IV ³ ' . R IV ⁴ . R IV ⁴ ' . R IV ⁵ . R IV ⁵ ' . R IV ⁶ . R IV ⁶ ' . R IV ⁷ . R IV ⁷ ' . R IV ⁸ . R IV ⁹ . R IV ⁹ ' . RIV ¹⁰ . R IV ¹⁰ ' . RIV ¹¹ . RIV ¹¹ ' , cr _R 12 _r 12' _r 13 _r 13' _r 14 _r 14' _r 15 _r 15' _r 16 _r 16' _r 17 _r 17' _r 18 _r 18' _r 19 _r 19' _r 20 _r 20' D IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV ,

R ²¹ , R ^21' , R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ²⁵ and R ²⁵ and the dotted lines are as defined above in respect to formulae Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8.

Among the compounds of formulae Ij-l, Ij-2, Ij-3, Ij-4, Ij-5, Ij-6, Ij-7 and Ij-8 those of formulae Ij-l, Ij-2, Ij-5, Ij-6, Ij-7 and Ij-8 are preferred. 0 Among the compounds of formulae Ij-l, Ij-2, Ij-5, Ij-6, Ij-7 and Ij-8 those of formulae Ij-l, Ij-5, Ij-6 and Ij-7 are preferred.

Among the compounds of formulae Ij-l, Ij-5, and Ij-7 those of formula Ij-5 and Ij-6 are preferred. Among the compounds of formulae Ij-5 and Ij-6, those of formula Ij-5 are preferred.

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

Table 1 :

Compd Structure

n° Compound name (M+H)+

2-((3S,4S)-l-(4-(2- chlorophenyl)thiazol-2-yl)-2-oxo-

1 4-phenyl-2,3 ,4,7-tetrahydro- 1 H- 439.9 azepin-3-yl)acetic acid

2-((3S,4R)-l-(4-(2- chlorophenyl)thiazol-2-yl)-2-oxo-

2 4-phenyl-2, 3 ,4,7-tetrahydro- 1 H- 439.9 azepin-3-yl)acetic acid

2-((3R,4S)-l-(4-(2- chlorophenyl)thiazol-2-yl)-2-oxo-

3 4-phenyl-2, 3 ,4,7-tetrahydro- 1 H- 439.9 azepin-3-yl)acetic acid

2-((3R,4R)-l-(4-(2- chlorophenyl)thiazol-2-yl)-2-oxo-

4 4-phenyl-2, 3 ,4,7-tetrahydro- 1 H- 439.9 azepin-3-yl)acetic acid

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of table 1 were named using ChemDraw Ultra 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 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 inflammatory, gastrointestinal and/or metabolic disorders.

The invention also provides for a method for delaying in patient the onset of inflammatory, gastrointestinal and/or metabolic disorders 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, solvates or prodrug thereof for treating and/or preventing inflammatory, gastrointestinal and/or metabolic disorders.

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, solvate or prodrug thereof.

According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts or 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, solvate or prodrug 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 inflammatory, gastrointestinal and/or metabolic disorders. The use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of disorders 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, or prodrugs are coadministered in combination with one or more other therapeutic agents. 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, solvate or prodrug 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, solvate or prodrug thereof as active ingredient, additional therapeutic agents and/or active ingredients.

Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as active ingredient.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament. Preferably, the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.

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, solvate or prodrug 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, solvate or prodrug thereof.

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

Preferably, the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders As set forth above, the compounds of the invention, their pharmaceutically acceptable salts, solvates, or 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 warm-blooded 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 invention 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 compound(s). 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, micro crystalline 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 the 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, 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 C _n H2 _n +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.

Suitable alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /- butyl, 5-butyl and /-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, /so-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl and /-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-dimethylethylene. 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-pentanedienyl 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- trifluoro ethyl and the like.

The term "cycloalkyl" 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, cyclobutyl, 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.

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 quaternized. 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 multi-ring 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 -y 1 , tetr ahy droiso quino lin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-y 1 , t h i o m o rp h o l i n-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1 ,4-oxathianyl, lH-pyrrolizinyl, tetr ahy dro- 1,1- dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.

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

pyrrolidinyl tetrahydrofuranyl imidazolinyl oxazolidinyl thiazolidinyl

piperidinyl tetrahydropyranyl piperazinyl morpholinyl 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. Non-limiting 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.

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 quaternized. 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- ajpyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzo furanyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2- benzisoxazolyl, 2,1-benzisoxazolyl, 1, 3 -benzo thiazolyl, 1,2-benzoisothiazolyl, 2,1- benzo isothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3- benzo thiadiazolyl, 2, 1,3 -benzo thiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2- ajpyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-y 1 , 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:

X is selected from: X is selected from: X is selected from: Y is selected from:

N. O or S N, O or S N. O or S C, N

Examples: Examples: Examples: Examples:

pyrrolyl imidazolyl pyrazolyl pyridyl

furanyl oxazolyl isooxazolyl pyrimidinyl

thiophenyl thiazolyl isothiazolyl

7 1 7 1

X is selected from: X is selected from:

N. O or S N, O or S

Examples: Examples:

indolyl benzimidazolyl

benzofuranyl benzoxazolyl

benzothiophenyl benzothiazolyl

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.

(2-pyridinyl)phenyl (3-pyridinyl)phenyl (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 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 ( ^■ww ), a solid wedge ( ), or a dotted wedge ( ). 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.

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, trifluoro acetate 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, OH), 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 iso topically- 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 diastereo isomeric 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.

As used herein the term "inflammatory disorders" are those pertaining to, characterized by, causing, resulting from or becoming affected by inflammation. Such inflammatory diseases include but are not limited to rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis, osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; non-alcoholic steatohepatitis (NASH); asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.

As used herein the term "metabolic disorders" includes but is not limited to type I and 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).

As used herein the term "gastrointestinal disorders" means diseases selected from the group consisting of gastrointestinal hypermotility disorders, including but not limited to any type of diarrhea, such as, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease and other types of diarrhea; Irritable Bowel Syndrome (IBS); intestinal injury disorders such as short-bowel syndrome; diseases involving intestinal barrier dysfunction such as pancreatitis, proctitis and pouchitis.

The present invention will be better understood with reference to the following examples. These examples are intended to represent specific embodiments of the invention, and are not intended to limit 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 F ₂₅₄ . 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 KMn0 ₄ revelator (KMn0 ₄ , Na ₂ C0 ₃ , NaOH, H ₂ 0) 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 CI 8. Eluent was a mixture of solution A (0.1% TFA in H ₂ 0) and solution B (0.1% TFA in MeCN). 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 Ethano 1 (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 CI 8 Eluent was a mixture of solution A (0.1% TFA in H ₂ 0) and solution B (0.1% TFA in MeCN). The gradient was adapted depending on impurities present in samples, to allow sufficient separation between impurities and target compound.

1H and ¹³ C 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:

Ac: Acetyl,

Bn: Benzyl,

BuLi: Butyllithium,

Cp: cyclopentadienyl,

DAST : Diethylaminosulfurtrifluoride,

DCM: Dichloro methane,

DCE: 1,2-Dichloroethane,

DIEA: N,N-diisopropylethylamine,

ee: Enantiomeric excess,

eq: Equivalent,

EtOAc: Ethyl acetate,

EtOH: Ethanol,

g: Grams,

Grubbs cat. : Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium,

h: Hours, HATU: 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tretramethyluronium hexafluorophosphate , HMDS: Hexamethyldisilazane,

IPA: Isopropanol,

L: Liters,

MeCN: Acetonitrile,

MeOH: Methanol,

Me: Methyl,

μί: Microliters,

mg: Milligrams,

min: Minutes,

mL: Milliliters,

mmol: Millimoles,

mol: Moles,

MW: Molecular weight,

NMM: N-methylmorpholine,

NMO: N-methylmorpholine-N-oxide,

P: UV purity at 254nm determined by HPLC-MS,

PE: Petroleum ether,

rf: retention fraction

rm or RM: reaction mixture.

rt: Retention time,

RT: Room temperature,

SIBX: Stabilized 2-iodoxybenzoic acid,

tBu: tert-Butyl

TCT: 2,4,6-trichloro[l ,3,5]triazine,

TFA: Trifluoro acetic acid,

THF: Tetrahydrofuran,

TLC: Thin layer chromatography,

Y: Yield,

For clarity reasons the synthetic schemes below are exemplified with specific substituents and stereochemistry but they can indeed be adapted easily by those skilled in the art to access compounds of the invention and are meant to be general methods.

General Synthetic Schemes

A general method for the synthesis of compounds of the invention containing ring I, ring V or ring VII is outlined in scheme 1.

1.7 1.8 1.9

Scheme 1: General synthetic route for the compounds containing ring I, ring V or ring VII

The general method depicted in scheme 1 enabled the synthesis of intermediates of formula A

A wherein,

R ^a is chloro and R ^b is isopropyl, isobutyl, cyclopropyl, cyclopentyl, tetrahydropyran-4-yl, phenyl, or biphen-4-yl; or

R ^a is 2-methoxypyridin-5-yl and R ^b is isopropyl, cyclopentyl or phenyl; or

R ^a is 2-methoxypyrazin-5-yl and R ^b is isopropyl; or

R ^a is 2-(2-oxopyrrolidin-l-yl)pyridin-5-yl and R ^b is isopropyl, cyclopentyl or phenyl.

Selected methods to achieve ring substitutions for the compounds containg ring I, ring V or ring VII are shown below in Scheme 2.

2.1

(precursor to compound n°6) TFA/DCM TFA/DCM

ί ί

compound n°26 compound n°25

Scheme 2: Selected methods to achieve ring substitutions for the compounds containg ring I, ring V or ring VII.

Suggested methods and known literature references to achieve other ring substitutions for the compounds containg ring I, ring V or ring VII are shown below in Scheme 3.

C. Fava et al., Tetrahedron: Asymmetry 1 (2003) 3697-3703

compound n°55

Scheme 3: Suggested methods to achieve ring substitutions for the compounds containg ring I, ring V or ring VII

A suggested method for the synthesis of compounds of the invention containing ring is outlined in scheme 4.

4.3 4.4

Scheme 4: Suggested synthetic route for the compounds containing ring II. A suggested method for the synthesis of compounds of the invention containing ring III is outlined in scheme 5.

-78°C-0°C

5.1 5.2 5.3

5.6 compound n°68

Scheme 5: Suggested synthetic route for the compounds containing ring III.

A suggested general method for the synthesis of compounds of the invention containing ring IV is outlined in scheme 6.

6.4 6.5 compound n°69

Scheme 6: Suggested method for the preparation of the compounds of the invention containg ring IV.

A general method for the synthesis of compounds of the invention containing rings outlined in scheme 7.

7.1 7.2 7.3

R= Aryl, coupling, ref.: Tetrahedron Letters 46 (2005) 2997-3001

R=Alkyl, Reductive amination, ref.: Tetrahedron Letters 41 (2000) 8225-8230

7.6

7.5 R=Ph, compound n°19

R=cyclopentyl, compound n°32

Scheme 7: General method for the synthesis of compounds of the invention containing ring

VI.

The general method depicted in scheme 7 enabled the synthesis of intermediates of formula B

wherein,

R ^c is chloro and R ^d is cyclopentyl or phenyl; or R ^c is 2-methoxypyridin-5-yl and R ^d is isopropyl or cyclopentyl.

A suggested general method for the synthesis of compounds of the invention containing ring VIII is outlined in scheme 8.

8.1 8.2 compound n°70

J. Org. Chem. 2002, 67, 6272-6274

Scheme 8: Suggested method for the preparation of the compounds of the invention containg ring VIII.

A suggested synthesis of compound n°28 is outlined in scheme 9.

9.4 9.5 compound n°28

Scheme 9: Suggested method for the preparation of compounds n°28.

General methods for the synthesis heterobiaryl amine intermediates

Biaryl- or heterobiaryl-thiazole amine intermediates were synthesized using Suzuki approach as shown in schemes 10 and 1 1. General scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates 10.3 using Suzuki approach (Scheme 10):

Scheme 10: General scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates 10.3 using Suzuki approach. Alternative general scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates 10.3 using Suzuki approach (Scheme 11):

10.1 11.1 10.3

Scheme 11: Alternative general scheme for the preparation of biaryl- or heterobiaryl- thiazole amine intermediates 10.3 using Suzuki approach.

Intermediates 10.1 and 12.4 can be made using Hantzsch-type synthetic methodology as shown in Scheme 12. Thus, halogenation of substituted acetophenones 12.1 (Larock, R. C. Comprehensive Org Transf 2 ^nd Ed., Wiley, 1999, pp 709-719; White et al. J. Med. Chem. 1996, 39, 4382-95) and subsequent condensation with thiourea 12.3 (Swain et al. J. Med. Chem. 1991, 34, 140-151; Bartoli et al. J. Med. Chem. 1998, 41, 1855-68) will furnish 4-aryl-2-amino-thiazole intermediates.

use of microwave

1 0.1 (X=Br) Scheme 12: General scheme for the preparation of 4-aryl-2-amino-thiazole intermediates using Hantzsch-type synthetic approach.

Alternatively, synthesis of intermediates 12.4 can be achieved through the method described by Rudolph (Rudolph, J. Tetrahedron 2000, 56, 3161)

Scheme 13: General scheme for the preparation of 4-aryl-2-amino-thiazole intermediates using Rudolph's synthetic approach.

Acetophenone intermediates 12.1 can be prepared as described in Scheme 14.

General synthetic scheme for the preparation of substituted acetophenone intermediates 12.1 through Weinreb amide approach (Scheme 14):

14.1 14.2 12.1

Scheme 14: General synthetic scheme for the preparation of substituted acetophenone intermediates 12.1 through Weinreb amide approach.

Thiourea intermediates 12.3 can be prepared as described in Scheme 15.

General synthetic scheme for the preparation of substituted thiourea intermediates 12.3

(Scheme 15):

15.1 15.2 12.3

Scheme 15: General synthetic scheme for the preparation of substituted thiourea

intermediates 12.3.

General Method A: synthesis of succininic acid intermediates 1.5.

This general method is depicted with the synthesis of (2S,3S)-2-(2-(tert-butoxy)- 2-oxoethyl)-3-phenylhex-5-enoic acid, intermediate la.

Step 1 : synthesis of (S)-4-benzyl-3-cinnamoyloxazolidin-2-one.

(4S)-4-Benzyl-l,3-oxazolidinon-2-one (39 mmol, 6.9 g) was dissolved in distilled THF (100 mL) under Argon. A 2.5 M solution of nBuli in hexanes (39 mmol, 15.6 mL) was added dropwise at -78°C. After 20 min, a solution of cinnamoyl chloride (35.5 mmol, 5.9g) in THF was added dropwise at the same temperature. The reaction mixture was stirred for 30 min at -78 °C and then 1 h at 0°C. The mixture was quenched with a saturated aqueous solution of NH ₄ C1, THF was removed under vacuum. Residue was taken up with EtOAc, washed twice with NaOH IN and once with brine. The organic layer was then dried over MgSC^, filtered and concentrated under reduced pressure. The resulting white solid was triturated in petrolum ether, filtered and dried. Y: 9.85 g (82%), P: >90%, rt=4.47 min (gradient A), (M+H) ⁺ =308 Step 2: synthesis of (S)-4-benzyl-3-((S)-3-phenylhex-5-enoyl)oxazolidin-2-one.

To a dry-oven schlenck protected from light with an aluminum foil and flushed with argon, was added copper (I) bromide DMS complex (9.27 mmol, 1.906 mL) in anhydrous THF (40 mL). To this slurry solution, was added dropwise a 1M solution of allylmagnesium bromide in Et ₂ 0 (16.07 mmol, 16.07 mL) over 30 min at -78°C under argon and the resulting solution was stirred at the same temperature for 1.5 h. A solution of (S)-4-benzyl- 3-cinnamoyloxazolidin-2-one (6.18 mmol, 1.9 g) in THF (60 mL) was added to the above solution at -78°C and stirring was continued 2.5 h. The reaction was then quenched at - 78°C by addition of a saturated aqueous solution of NH ₄ C1 and the RM was allowed to reach RT, the mixture was extracted twice with EtOAc. Combinated organic layers were dried over MgS0 ₄ , filtered and dried under vacuum. Crude was purified by flash chromatography (PE/EtOAc = 9/1) to yield title product as a colorless solid. Y: 1.6 g (76%), P>99%, rt=4.8 min (gradient A), (M+H) ⁺ = 350. Step 3 : synthesis of (3S,4S)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3- carbonyl)-4-phenylhept-6-enoate.

In a round bottom flask was added (S)-4-benzyl-3-((S)-3-phenylhex-5-enoyl)oxazolidin- 2-one (4.58 mmol, 1.6 g) in THF (69 mL) under argon. The mixture was cooled down to -78°C and a 1M solution of NaHMDS in THF (5.95 mmol, 5.95 mL) was added over 5 min. The solution was stirred for 30 min, and tert-butyl bromoacetate (6.87 mmol, 1.015 mL) was added. The reaction was stirred at -78°C for 50 min. The reaction was quenched at -78°C by addition of a saturated aqueous solution of NH ₄ C1 and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered and concentrated to afford 2.39g of a yellow oil. The crude oil was purified on a silica gel column (PE/EtOAc = 9/1) to afford 1.8g of a colorless oil. Y: 1.8 g (83%), P>98%, rt=5.2 min (gradient A), (M+H-tBu) ⁺ = 408.

Step 4: synthesis of (2S,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-phenylhex-5-enoic acid, intermediate la.

Hydrogen peroxide (30%> in water, 15.5mmol, 1.6 mL) was added dropwise over 15 min to a stirred solution of (4S)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-4- phenylhept-6-enoate (3.88 mmol, 1.8 g) in THF/water (4/1, 25 mL) at 0°C under a nitrogen atmosphere. Stirring was continued for 10 min then a solution of LiOH

(6.21mmol, 150mg) in water (20 mL) was added dropwise over 5 min. The mixture was allowed to warm to RT slowly. The mixture was cooled on ice and a solution of sodium sulfite (10.4 mmol, 1.31 g) in water (8 mL) was added dropwise, causing a small exo therm. The bulk of THF was evaporated in vacuo to leave the aqueous layer (pH=12-13). The aqueous layer was washed with Et ₂ 0 (3x100 mL) and then cooled on ice and acidified to pH 1-2 with a 6M aqueous HC1 solution, extracted with EtOAc (5x100 mL), dried (MgSC^) and evaporated in vacuo to yield intermediate la as a colorless oil. lg. Y: 1 g (85%), P>95%, rt=4.2 min (gradient A), (M+H-56) ⁺ = 248.

General method A was used for the synthesis of the following intermediates:

intermediate lb: (2S,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-phenylpent-4-enoic acid,

intermediate lc: (2S,3R)-2-(2-(tert-butoxy)-2-oxoethyl)-3-phenylpent-4-enoic acid,

intermediate Id: (2R,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-phenylpent-4-enoic acid,

intermediate le: (2R,3R)-2-(2-(tert-butoxy)-2-oxoethyl)-3-phenylpent-4-enoic acid,

intermediate If: (2S,3R)-2-(2-(tert-butoxy)-2-oxoethyl)-3-cyclopentylhex-5- enoic acid, was synthesized from (E)-3-cyclopentylacryloyl chloride which was obtained from cyclopentanecarbaldehyde: Step 1 : synthesis of (E)-methyl 3-cyclopentylacrylate.

To a solution of n-BuLi (2.5M in hexanes, 1.57mL) in anhydrous THF (4 mL), at 0°C under nitrogen, was added dropwise a solution of methylphosphonoacetate (715 mg) in anhydrous THF (2 mL). Reaction mixture was stirred for 10 min at 0°C and a solution of cyclopentanecarbaldehyde (351 mg) in anhydrous THF (2 mL) was added dropwise. The mixture was allowed to reach RT over 1 h. Reaction mixture was washed 4 x with an aqueous solution of NaHS0 ₃ (10%) and the organic layer was separated, dried over MgS0 ₄ and concentrated in vacuo. Crude was purified on silica gel (PE/EtOAc=99/l) (TLC: PE/EtOAc 96/4, rf=0.6) to yield title product in mixture with its Z isomer as a colorless oil. Y: 405 mg, P>90%.

Step 2: synthesis of (E)-3-cyclopentylacrylic acid.

To a solution of (E)-methyl 3-cyclopentylacrylate (400 mg, 2.6 mmol) in THF (5 mL), was added NBu ₄ OH (1.5M in THF, 3.45 mL) and the mixture was stirred at RT for 2h. 4 more equivalents of NBu ₄ OH were added and reaction was complete after a further 2h at RT. The reaction mixture was washed twice with aqueous HCl (6N) and the organic layer was separated with EtOAc, dried over MgS0 ₄ and concentrated in vacuo to yield title product.

Another and preferred variant for the synthesis of (E)-3-cyclopentylacrylic acid is:

To a solution of (E)-methyl 3-cyclopentylacrylate (26g, 169 mmol) in THF/H ₂ 0 (400 mL, 1/1), was added LiOH (16.2g, 675mmol) and the mixture was stirred at RT for 12h.. The reaction mixture was quenched with aqueous HCl (6N) and the organic layer was separated with EtOAc (2x), dried over MgS0 ₄ and concentrated in vacuo to yield title product Y=23g (97%)

Step 3 : synthesis of (E)-3-cyclopentylacryloyl chloride.

To a solution of (E)-3-cyclopentylacrylic acid (1.4 mmol, 20 mg,) in anhydrous THF (5 mL) under nitrogen at 0°C, was added Et ₃ N (1.7 mmol, 228 μί) and the solution was cooled at -70°C. Pivaloyl chloride (1.6 mmol, 193 μί) was added and a thick suspension formed. After 15 min, the reaction mixture was warmed to and kept at 0°C for 40 min. The mixture was used as such for the next reaction with (S)-4- benzyloxazolidin-2-one. intermediate lg: (2S,3R)-2-(2-(tert-butoxy)-2-oxoethyl)-3-(tetrahydro-2H- pyran-4-yl)hex-5-enoic acid was synthesized from tetrahydro-2H-pyran-4-carbaldehyde as described above for intermediate If,

intermediate lh: (2S,3S)-3-(biphenyl-4-yl)-2-(2-tert-butoxy-2-oxoethyl)hex-5- enoic acid,

intermediate li: (2S,3R)-2-(2-(tert-butoxy)-2-oxoethyl)-3-isopropylhex-5-enoi c acid,

intermediate lj : (2S,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-isobutylhex-5-enoic acid,

intermediate lk: (2S,3R)-2-(2-(tert-butoxy)-2-oxoethyl)-3-cyclopropylhex-5- enoic acid was synthesized from cyclopropanecarbaldehyde as described above for intermediate If

General Method B: synthesis of 2-amino-4-arylthiazole intermediates 1.6. This general method is depicted with the synthesis of N-allyl-4-(2-chlorophenyl)thiazol- 2-amine, intermediate 2a.

A solution of 2-bromo-l-(2-chlorophenyl)ethanone (100 mmol, 23.35 g) was stirred in ethanol (300 mL) and allylthiourea (100 mmol, 11.62 g) was added. The mixture was heated to refiux for 2h then cooled to RT and most of the ethanol was removed by evaporation. This mixture was suspended in DCM and washed with saturated aqueous sodium hydrogen carbonate solution (2 x 900 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was added to a silica gel column and was eluted with PE/EtOAc = 98/2. (TLC: PE/EtOAc = 98/2: rf 0.15) to afford title product as a yellow solid. Y: 17.9 g (70%), P>99%, rt=3.2 min (gradient A), (M+H) ⁺ = 251.

General method B was used for the synthesis of the following intermediates:

intermediate 2b: N-homoallyl-4-(2-chlorophenyl)thiazol-2-amine,

intermediate 2c: 4-(2-bromophenyl)-N-allylthiazol-2-amine,

intermediate 2e: N-allyl-4-(2,5-dichlorophenyl)thiazol-2-amine,

intermediate 2f: 4-(2-chlorophenyl)thiazol-2-amine,

intermediate 2h: N-allyl-4-phenylthiazol-2-amine,

intermediate 2i: 4-(2-fluorophenyl)thiazol-2-amine.

intermediate 2j : 4-(2-bromophenyl)thiazol-2-amine.

intermediate 2k: N-allyl-4-(2-(5 -methoxypyrazin-2-yl)phenyl)thiazo 1-2-amine

General Method C: synthesis of 2-amino-4-biarylaminothiazole and 2-amino-4- heterobiarylaminothiazole intermediates 1.6.

This general method is depicted with the synthesis of l-(5-(2-(2-(allylamino)thiazol-4- yl)phenyl)pyridin-2-yl)pyrrolidin-2-one, intermediate 2d. Step 1 : synthesis of 2-(2-(allylamino)thiazol-4-yl)phenylboronic acid.

To a stirred solution of N-allyl-4-(2-bromophenyl)thiazol-2-amine (intermediate 2c) (1.2 g, 4 mmol) in THF (20 mL) at -78°C was added dropwise a 2.5M solution of nBuLi in hexanes (8.72 mmol, 3.49 mL). After 15 min, triisopropyl borate (12 mmol, 2.76 mL) was rapidly added. After a further hour at -78°C, the rm was warmed to RT and stirred for lh. The reaction mixture was evaporated to dryness and residue analyzed by LCMS showing title product to be 50% pure (rt = 2.8 min). The residue was dissolved in toluene (10 mL) thus obtaining a 0.2M solution of title product to be used as such in the next step.

Step 2: synthesis of l-(5-(2-(2-(allylamino)thiazol-4-yl)phenyl)pyridin-2- yl)pyrrolidin-2-one, intermediate 2d.

A solution of 2-(2-(allylamino)thiazol-4-yl)phenylboronic acid (0.5 g, 1.9 mmol), 2M solution of potassium carbonate in water (2.88 mmol, 1.4 mL) and l-(5- bromopyridin-2-yl)pyrrolidin-2-one (0.232 g, 0.961 mmol) in toluene (12 mL) was degassed (3 vacuum/N ₂ cycles and then Ar bubbling). Tetrakis(triphenyl- phosphine)palladium (0) (0.096 mmol, 0.11 g) was then added and the rm was heated at reflux overnight. The reaction mixture was cooled down to RT, diluted with EtOAc, washed with brine and concentrated in vacuo. Crude was purified by flash chromatography (PE/EtOAc = 95/5 -> 7/3), TLC: PE/EtOAc = 7/3, rf=0.2) to yield title product as brown powder. Y: 0.17 g (64%), P>99%, rt=3.2 min (gradient A), (M+H) ⁺ = 377.

General Method C was also used for the synthesis of:

intermediate 2g: N-allyl-4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2-amine, intermediate 21: 4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2-amine from intermediate 2j.

General Method D: synthesis of compounds 1.9. (scheme 1)

This general method is depicted with the synthesis of Example 1: compound n°6: 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid.

Step 1 : synthesis of (3S,4S)-tert-butyl 3-(allyl(4-(2-chlorophenyl)thiazol-2- yl)carbamoyl)-4-phenylhept-6-enoate.

To a solution of (2S,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-phenylhex-5-enoic acid (intermediate la) (1.04 mmol, 318 mg) in anhydrous MeCN (5 mL) was added HATU (1.04 mmol, 395 mg). After 5 min was added N-allyl-4-(2-chlorophenyl)thiazol-2-amine (intermediate 2a) (262 mg, 1.04 mmol) and DIE A (1.14 mmol, 199 μί). Reaction mixture was stirred overnight at 60°C. and then concentrated under vacuum. The residue was purified by flash chromatography (PE/EtOAc= 98/2, rf=0.27) to yield title compound. Y: 505 mg (90 %), P>95%, rt=5 min (gradient A), (M+H) ⁺ =537.

Step 2: synthesis of tert-butyl 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2- oxo-4-phenyl-l,2, 3,4,5, 8-hexahydroazocin-3-yl)acetate.

To an oven dried-oven schlenck, under Argon pressure, was added 1 ^st generation Grubbs' catalyst (Grubbs' cat.) (0.193 mmol, 159 mg) and anhydrous DCM (2 mL). To this purple mixture, was added a solution of (3S,4S)-tert-butyl 3-(allyl(4-(2- chlorophenyl)thiazol-2-yl)carbamoyl)-4-phenylhept-6-enoate (2.07 g, 3.85 mmol) in anhydrous DCM (220 mL). The mixture evolved from purple to brown during the addition. The mixture was heated at reflux until completion and cooled to RT, ethyl vinyl ether was added and the solution was stirred 30 minutes. The mixture was concentrated under vacuum and the residue was purified on silica gel column, eluted with PE/EtOAc = 98/2 (rf 0.2), to yield title product. Y: 1.83 g (93 %), P>99%, rt=5.9 min (gradient A), (M+H) ⁺ =509.

Step 3: synthesis of 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-1,2, 3,4,5, 8-hexahydroazocin-3-yl)acetic acid, compound n°6.

To a solution of (3S,4S)-tert-butyl 3-(allyl(4-(2-chlorophenyl)thiazol-2- yl)carbamoyl)-4-phenylhept-6-enoate (0.064 mmol, 100 mg) in DCM (1 mL) was added

TFA (0.3 mL). Reaction mixture was stirred at RT until completion of the reaction. Reaction mixture was then diluted with EtOAc and the organic layer was washed (5x10 mL) with an aqueous NaHS0 ₃ solution (10%), brine (2xl0mL) and water (2xl0mL), dried aver anhydrous magnesium sulfate and concentrated in vacuo to yield compound n°6. Y: 90 mg (88 %), P>99%, rt=4.98 min (gradient B), (M+H) ⁺ =454. ^! HNMR (CDC1 ₃ ): 5=7.97 (d, 1H), 7.58 (s, 1H), [7.36 (d,), 7.3-7.1 (m), 7.09 (d), (10H)], 6.09- 5.83 (m, 3H), 4.68 (d, 1H), 3.99 (m, 1H), 3.15 (m, 1H), 2.73-2.6 (m, 2H), 2.33 (dd, 1H), 2.1 (m, 1H).

General Method E: synthesis of intermediates 7.4. (scheme 7) This general method is depicted with the synthesis of (R)-4-tert-butyl 1 -methyl 2-(N- cyclopentyl-4-oxobutanamido)succinate, intermediate 3a.

Step 1 : synthesis of (R)-4-(tert-butoxy)-2-(cyclopentylamino)-4-oxobutanoic acid

A mixture of (R)-2-amino-4-tert-butoxy-4-oxobutanoic acid (1.586 mmol, 300 mg) and cyclopentanone (3.17 mmol, 0.280 mL) was stirred under an atmosphere of hydrogen at room temperature in absolute ethanol (3 mL) in the presence of Pd(OH) ₂ on carbon (0.032 mmol, 44.5 mg). The RM was stirred overnight, then filtered over a pad of celite and washed with EtOAc. The filtrate was concentrated in vacuo to afford title product as a white solid which was used without further purification.

Step 2: synthesis of (R)-4-tert-butyl 1 -methyl 2-(cyclopentylamino)succinate. Preparation of the diazomethane solution: (Organic Syntheses, Coll. Vol. 2, p.165 (1943); Vol. 15, p.3 (1935))

In an appropriate beaker, were added diethyl ether (100 mL) and a freshly prepared solution of KOH (40% in water) (291 mmol, 29.1 mL). To this solution cooled to 0-5 °C was added portion-wise 1 -methyl- 1 -nitrosourea (97 mmol, 1 1.76 g). The ether phase became deep yellow. After complete addition, the organic layer was carefully transferred to another beaker containing KOH (pellets) in order to dry the diazomethane solution.

Esterification:

In a glass tube, containing a solution of (R)-4-tert-butoxy-2-(cyclopentylamino)-4- oxobutanoic acid (1.516 mmol, 390 mg) in 10 mL of Et ₂ 0, cooled to 0°C with an iced bath, was added dropwise under a N ₂ flow, the diazomethane solution (12.35 mmol, 19 mL) until complete conversion: a persistant yellow color was obtained. Reaction was stopped by addition of acetic acid (1 mL). The RM was diluted with EtOAc and washed with a saturated aqueous solution of NaHC0 ₃ , dried over MgS0 ₄ , filtered and concentrated in vacuo. The crude product was purified on silica gel column, eluted with (PE/EtOAc 98/2 -> 5/5), (TLC: PE/EtOAc = 9/1, rf= 0.3) to afford title product as a colorless oil. Y: 1.26 g, rt=4.5 min (gradient A). Step 3: synthesis of (R)-4-tert-butyl 1 -methyl 2-(N-cyclopentylpent-4- enamido)succinate.

To a solution of (R)-4-tert-butyl 1-methyl 2-(cyclopentylamino)succinate (1.776 mmol, 482 mg) in DCM (1.8 mL) at RT was added N-methylmorpholine (2.66 mmol, 293 μί). After stirring for 5 minutes, a solution of pent-4-enoyl chloride (8.88 mmol, 980 μί) in DCM (1 mL) was added dropwise at 0°C. The mixture was stirred for 30min and quenched with a saturated aqueous solution of NH ₄ C1 and the organic layer was separated, dried over MgS0 ₄ and concentrated to give a yellow oil. Crude was purified on silica gel, (PE/EtOAc=9/l -> 85/15), (TLC: PE/EtOAc = 9/1, rf=0.24, KMn0 ₄ rev.) to afford title compound as a colorless oil. Y: 59%, rt=4.5 min (gradient A).

Step 4: synthesis of (R)-4-tert-butyl 1-methyl 2-(N-cyclopentyl-4- oxobutanamido)succinate, intermediate 3a.

To a solution of (R)-4-tert-butyl 1-methyl 2-(N-cyclopentylpent-4-enamido)succinate (0.965mmol, 341 mg) in THF/H ₂ 0 (3/1, 8mL) was added a solution of 4 % of Os0 ₄ in water (0.096 mmol, 590μί) followed by NaI0 ₄ (2.89 mmol, 619 mg). The reaction mixture was stirred at RT for 2 h and then quenched with aqueous Na ₂ S ₂ 0 ₃ IN. The aqueous layer was extracted twice with EtOAc. Combined organic layers were washed with brine, dried over MgS0 ₄ , filtered and concentrated under vaccum to afford 344 mg of crude product. The crude was purified on silica gel column (gradient: PE/EtOAc=9/l -> PE/EtOAc/DCM=5/4/l), (TLC: PE/EtOAc = 75/25, rf=0.15, KMn0 ₄ rev.), to afford title product as a colorless oil. Y: 83%, rt=3.8 min (gradient A), (M+H) =356. General method E was also used for the synthesis of the following intermediates: intermediate 3b: 4-tert-butyl 1 -methyl 2-(4-oxo-N-phenylbutanamido)succinate which was obtained from (R)-4-tert-butoxy-4-oxo-2-(phenylamino)butanoic acid which was synthesized as follows from (R)-2-amino-4-tert-butoxy-4-oxobutanoic acid:

Bromobenzene (0.881 mmol, 0.093 mL), copper (I) iodide (0.176 mmol, 33.6 mg), (R)- 2-amino-4-tert-butoxy-4-oxobutanoic acid (1.321 mmol, 250 mg), tribasic potassium posphate (5.29 mmol, 1.12 g), N,N-dimethylethanolamine (2.64 mmol, 0.265 mL) and water (2.6 mL) were mixed in a carrousel tube with a magnetic stirbar. The flask was air purged and filled with nitrogen. The reaction mixture was vigorously stirred at 90°C for 46 h until almost all the bromobenzene was consumed, as determined by LC-MS. The flask was cooled to RT and rm was poured on ice. HC1 6N was added dropwise with stirring until precipitation was observed and the color changed from blue to green. The final pH of the solution was adjusted to pH = 4-5. The acidified solution was extracted with EtOAc (3x). The combined organics were washed with brine and water and the solvent was evaporated to yield title compound as a yellow oil. Y: 55 mg (24%), P=100%, rt=3.9 min (gradient A), (M+H) ⁺ =266. intermediate 3c: 3-(N-isopropyl-4-oxobutanamido)-4-methoxy-4-oxobutanoic acid which was obtained from (R)-2-amino-4-tert-butoxy-4-oxobutanoic acid and propan-2- one following general method E:

General Method F: synthesis of compounds 7.6. (scheme 7)

This general method is depicted with the synthesis of

Example 2: compound n°32 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-l-cyclopentyl-3,8- dioxo- 1 ,4-diazocan-2-yl)acetic acid.

Step 1 : synthesis of 4-tert-butyl 1 -methyl 2-(4-((4-(2-chlorophenyl)thiazol-2- yl)amino)-N-cyclopentylbutanamido)succinate.

To a solution of 4-tert-butyl 1 -methyl 2-(N-cyclopentyl-4-oxobutanamido)succinate, intermediate 3a, (0.802 mmol, 0.285 g) in DCE (10 mL) and AcOH (3.41 mmol, 0.195 mL) was added 5-(2-chlorophenyl)thiazol-2-amine (intermediate 2f) (0.802 mmol, 0.169 g) followed by 4 A crushed molecular sieves and the resulting mixture was stirred at RT under nitrogen atmosphere for 7 h. NaBH(OAc) ₃ (2.406 mmol, 0.510 g,) was then added to the solution and the resulting suspension was stirred at RT overnight. The mixture was then quenched with a saturated aqueous solution of sodium bicarbonate (2 mL) and extracted with DCM (2 x 5 mL). The organics were combined, dried over sodium sulfate, filtered and then evaporated under vacuum. Crude was purified on silica gel, eluent (PE/EtOAc=9/l -> 1/1), (TLC: PE/EtOAc = 75/25, rf=0.14), to yield title product. Y: 168 mg (38%), P=100%, rt=4.2 min (gradient A), (M+H) ⁺ =550.

Step 2: synthesis of 4-(tert-butoxy)-2-(4-((4-(2-chlorophenyl)thiazol-2- yl)amino)-N-cyclopentylbutanamido)-4-oxobutanoic acid.

To a solution of 4-tert-butyl 1 -methyl 2-(4-((4-(2-chlorophenyl)thiazol-2-yl)amino)-N- cyclopentylbutanamido)succinate (0.044 mmol, 24 mg) in THF/wate r= 1/1 mixture, was added LiOH (0.175 mmol, 4.18 mg) in one portion. The reaction mixture was stirred at RT for 3h and then was acidified to pH = 1 with HC1 IN and the aqueous layer was extracted twice with EtOAc. Combined organics were dried over MgSC^, filtered and concentrated under vacuum to afford title product as a colorless solid. Y: 25 mg, P=95%, rt=4.04 min (gradient A), (M+H) ⁺ =536.

Step 3 : synthesis of tert-buty l 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-l- cyclopentyl-3,8-dioxo-l,4-diazocan-2-yl)acetate.

To a solution of 4-tert-butoxy-2-(4-(4-(2-chlorophenyl)thiazol-2-ylamino)-N- cyclopentylbutanamido)-4-oxobutanoic acid (0.179 mmol, 96 mg) in CH ₃ CN (2.5 mL),

HATU (0.269 mmol, 102 mg) was added. The mixture was stirred for 10 min, and then DIEA (0.215 mmol, 37.5 μί) was added. The mixture was heated at 45 °C for 4h. The RM was concentrated in vacuo, and the crude was purified on silica gel (PE/EtOAc=8/2), (TLC PE/EtOAc = 6/4, rf 0.5), to afford title product as a colorless oil. Y: 50 mg, P=95%, rt=5.23 min (gradient A), (M+H-tBu) ⁺ =462.

Step 4: synthesis of 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-l-cyclopentyl-3,8- dioxo-l,4-diazocan-2-yl)acetic acid, compound n°32.

To a solution of tert-butyl 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-l-cyclopentyl-3,8- dioxo-l,4-diazocan-2-yl)acetate (0.131 mmol, 67.8 mg) in DCM (1.8mL) was added TFA (5.2 mmol, 403 μί). The rm was stirred at RT until reaction completion. The RM was diluted with EtOAc, and washed with aqueous NaHS0 ₃ 10 % w/w (5 x 25 mL), brine (5 mL) and water (5 mL). The organic layer was dried over MgSC^ and concentrated under reduced pressure to yield title product which was lyophilised overnight. P=95%, rt=4.4 min (gradient B), (M+H) ⁺ =463. ^! HNMR (CDC1 ₃ ): 5=7.9 (d, 1H), 7.54 (s, 1H), 7.46 (d,), 7.33-7.25 (m, 3H), 5.48-5.3 (m, 2H), 4.16-3.97 (m, 1H), 3.65-3.47 (m, 2H), 3.05-2.75 (m, 2H), 2.25 (m, 1H), 2.1 (m, 2H), 1.9-1.6 (m, 4H), 1.6- 1.3 (m, 3H).

The following examples were synthesized from intermediates and using general methods described above.

Example 3: compound n°l : 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4-phenyl - 2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates lb and 2a using general method D.

Example 4: compound n°2: 2-((3S,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4-phenyl - 2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates lc and 2a using general method D.

Example 5: compound n°3: 2-((3R,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4-phenyl - 2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates Id and 2a using general method D.

Example 6: compound n°4: 2-((3R,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates le and 2a using general method D. Example 7: compound n°5: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenylazepan-3-yl)acetic acid:

Compound n°l (0.034mmol, 15 mg) was dissolved in MeOH (0.5 mL) and 50% wt Pd/C (1.5mg, 10%owt) was added. The flask was filled with hydrogen and stirred at RT for 3 days. Only 45%> conversion occurred, another 1.5 mg of Pd/C was added and the flask refilled with hydrogen and the rm stirred at RT for another 2 days until complete conversion. The rm was diluted with MeOH and filtered through a pad of celite, then concentrated in vacuo. Crude was purified using a Biotage PEAX SPE cartridge to yield title product. Y: 12mg (80%), rt=4.7min (gradient B), (M+H) ⁺ = 442.

Example 8: compound n°7: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-hydroxy-2- oxo-4-phenylazocan-3-yl)acetic acid:

Step 1 : synthesis of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-2-oxo-4-phenylazocan-3-yl)acetate.

To a solution of compound n° 6 (44 mg) in Et ₂ 0 (4 mL) at 0°C was added a 1M solution of borane.THF complex (346 μί). The mixture was allowed to warm to RT and stirred for 4h at RT. The reaction mixture was cooled again to 0°C and a solution of 50% H ₂ 0 ₂ in water (2.64 mL) and 2M NaOH (1.32 mL) was added. After 30 min the rm was poured onto a saturated aqueous solution of NaHCOs and extracted with Et ₂ 0. Combined organics were dried over MgS0 ₄ and concentrated in vacuo. Crude was purified by column chromatography (PE/EtOAc=9/l then DCM/EtOAc=99/l) to yield title product. Y: 24.2 mg (53%), P=98%, rt=5.2 min (gradient A), (M+H) ⁺ =527. tert-butyl 2-((3S,4S)-l-(4-(2- chlorophenyl)thiazol-2-yl)-6-hydroxy-2-oxo-4-phenylazocan-3- yl)acetate was also recovered during the chromatography.

Step 2: synthesis of compound n°7.

Intermediate obtained in step 1 was treated with TFA and DCM, as described in step 3 of general method D and provided title compound upon flash chromatography purification (DCM/MeOH=99/l). Y: 6 mg (28%), P=90%, rt=4.3 min (gradient B), (M+H) ⁺ =472. Example 9: c o m p o u n d n ° 9 : 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopentyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates If and 2a using general method D.

Example 10: compound n°l l : 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-2,3,4,5,8,9-hexahydro-lH-azonin-3-yl)acetic acid was synthesized from intermediates la and 2b using general method D.

Example 11: compound n°12: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenylazocan-3-yl)acetic acid was synthesized from compound n°6 using the hydrogenation procedure detailed for the synthesis of compound n°5.

Example 12: compound n°13: 2-((3S,4S,Z)-l-(4-(2,5-dichlorophenyl)thiazol-2-yl)-2-oxo- 4-phenyl-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates la and 2e using general method D.

Example 13: compound n°14: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6-hydroxy-2- oxo-4-phenylazepan-3-yl)acetic acid was synthesized from compound n°l using the hydroboration and TFA deprotection steps as described for the synthesis of compound n°7. 7¾rt-butyl 2-((3S,4S,5R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-5-hydroxy-2 -oxo-4- phenylazepan-3-yl)acetate was also recovered during the chromatography.

Example 14: compound n°16: 2-((3S,4S)-l-(4-(2,5-dichlorophenyl)thiazol-2-yl)-2-oxo-4- phenylazocan-3-yl)acetic acid was synthesized from compound n°13 using the hydrogenation procedure detailed for the synthesis of compound n°5.

Example 15: compound n°17: 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- (tetrahydro-2H-pyran-4-yl)-l,2, 3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates lg and 2a using general method D.

Example 16: compound n°18: 2-((3S,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- (tetrahydro-2H-pyran-4-yl)azocan-3-yl)acetic acid was synthesized from compound n°17 using the hydrogenation procedure detailed for the synthesis of compound n°5.

Example 17: compound n°19: 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-3,8-dioxo-l-phenyl- l,4-diazocan-2-yl)acetic acid was synthesized from intermediates 3b and 2f using general method F.

Example 18: compound n°20: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6-hydroxy-2- oxo-4-phenylazocan-3-yl)acetic acid:

tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6-hydroxy-2-ox o-4-phenylazocan- 3-yl)acetate which was obtained during step 1 of compound n°7's synthesis was reacted with TFA in DCM as described in step 2 of compound n°7's synthesis; which yielded title compound after flash chromatography purification (DCM/MeOH=99/l). Y: 18 mg (47%), P=96%, rt=3.4 min (gradient B), (M+H) ⁺ =472.

Example 19: c omp ound n°21 : 2-((3S,4S,5R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-5- hydroxy-2-oxo-4-phenylazepan-3-yl)acetic acid:

tert-b u t y 1 2-((3S,4S,5R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-5-hydroxy-2 -oxo-4- phenylazepan-3-yl)acetate which was obtained during step 1 of compound n°14's synthesis was reacted with TFA in DCM as described in step 2 of compound n°7's synthesis; this yielded title compound after flash chromatography purification (DCM/MeOH=95/5).

Example 20: compound n°22: 2-((3S,4S)-l-(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol- 2-yl)-2-oxo-4-phenyl-2,3,4,7-tetrahydro-lH-azepin-3-yl)aceti c acid was synthesized from intermediates lb and 2g using general method D. Example 21: compound n°23: 2-((3S,4S)-l-(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol- 2-yl)-2-oxo-4-phenylazepan-3-yl)acetic acid was synthesized from compound n°22 using the hydrogenation procedure detailed for the synthesis of compound n°5.

Example 22: compound n°24: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-fluoro-2- oxo-4-phenylazocan-3-yl)acetic acid:

step 1 : synthesis of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-fluoro-2-oxo - 4-phenylazocan-3-yl)acetate

A solution of compound n° 7 (1 eq) in chloroform at -50°C was treated with DAST (2.2 eq). The RM was warmed to RT and stirred for 2 days. The rm was quenched with a saturated aqueous solution of NaHC0 ₃ and extracted (3 x) with DCM, combined organics were drid and concentrated in vacuo. Crude was purified by flash chromatography (PE/EtOAc) to yield title compound with the dehydrated side product; the mixture was used as such for the next step.

Step 2: synthesis of compound n°24

Intermediate obtained in step 1 was treated with TFA and DCM, as described in step 3 of general method D which provided crude title product. Crude was purified by preparative HPLC to yield title compound. Y: 2 mg, P>90%, rt=7.79 min (gradient B), (M+H) ⁺ =474.

Example 23: compound n°25: 2-((3S,4S,6S,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6,7- dihydroxy-2-oxo-4-phenylazocan-3-yl)acetic acid and compound n°26: 2-((3S,4S,6S,7R)- l-(4-(2-chlorophenyl)thiazol-2-yl)-6,7-dihydroxy-2-oxo-4-phe nylazocan-3-yl)acetic acid: A solution of 4-methylmorpholine (1.336 mmol, 135 mg) and a catalytic amount of a 4wt% solution osmium tetroxide in distilled water (0.039 mmol, 0.240 mL) in distilled water (0.3 M, 230 μί) at RT was added slowly to a solution of tert-butyl 2-((3S,4S,Z)- 1 -(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4-phenyl- 1 ,2,3,4,5,8-hexahydroazocin-3- yl)acetate (compound n°6's precursor)(0.393 mmol, 200mg) in THF/acetone = 1/1 (4.4 mL, 0.1 M). After the addition, a brown color appeared and 2 min later a white suspension formed. After 2 hours at RT, the rm was quenched with Na ₂ S ₂ 0 ₃ sat. solution and extracted with EtOAc, washed with brine. The organic layer was separated, dried over MgS0 ₄ , filtered and concentrated in vacuo. Crude product was then purified by chromatography on silica gel (eluent PE/EtOAc=8/2 -> 5/5) to yield:

1) tert-butyl 2-((3S,4S,6S,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6,7-dihy droxy-2-oxo- 4-phenylazocan-3-yl)acetate as a colorless solid. Y: 90 mg, rt=5.04min, (M+H) ⁺ =544. Treatment with HCl 4N in dioxane and sodium bisulfite work up yielded compound n°25. Y: 18 mg (84%).

2) tert-butyl 2-((3S,4S,6R,7S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6,7-dihy droxy-2-oxo- 4-phenylazocan-3-yl)acetate as a colorless solid. Y: 70 mg, rt=4.76min, (M+H) ⁺ =544. Treatment with HCl 4N in dioxane, sodium bisulfite work up and Biotage PEAX SPE purification yielded compound n°26. Y: 19 mg (96%).

Example 24: c o m p o u n d n ° 2 7 : 2-((3S,4S,Z)-4-([l,l'-biphenyl]-4-yl)-l-(4-(2- chlorophenyl)thiazol-2-yl)-2-oxo- 1,2,3,4,5 , 8-hexahydroazocin-3 -y l) acetic acid was synthesized from intermediates lh and 2a using general method D. Example 25: compound n°29: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2,7-dioxo- 4-phenylazocan-3-yl)acetic acid:

To a solution of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-hydroxy-2- oxo-4-phenylazocan-3-yl)acetate (compound n°7's precursor) (0.095 mmol, 50 mg) in DCM (5 mL) was added pyridinium chlorochromate (0.237 mmol, 51.1 mg) in one portion. The rm was stirred at RT for 4 days. The rm was filtered over a celite pad.The filtrate was concentrated under vaccum. The residue was suspended in DCM, and then filtered on a celite pad and concentrated once again. Residue was disolved in EtOAc and washed with aqueous HCl IN, brine and a saturated aqueous solution of NaHC0 ₃ . The organic layer was dried over MgSC^, and concentrated in vacuo to afford tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2,7-dioxo-4-ph enylazocan-3-yl)acetate as a pale yellow oil . Y: 42 mg (84%), P=100%, rt=5.4 min, (M+H) ⁺ =525. The product was treated with TFA in DCM and provided upon a soldium bisulfite work up compound n°29 as a colorless powder. Y: 6 mg (67%), P>80%.

Example 26: compound n°30: 2-((3S,4S,Z)-2-oxo-l-(4-(2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)-4-phenyl-l,2,3,4,5,8-he xahydroazocin-3-yl)acetic acid was synthesized from intermediates la and 2d using general method D.

Example 27: c omp o und n°31 : 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- (isopropylamino)-2-oxo-4-phenylazocan-3-yl)acetic acid:

step 1 : synthesis of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- (isopropylamino)-2-oxo-4-phenylazocan-3-yl)acetate

To a suspension of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2,7-dioxo- 4-phenylazocan-3-yl)acetate (compound n°29's precursor) (0.029 mmol, 15 mg), isopropylamine (0.031 mmol, 2.7 uL) and sodium triacetoxyborohydride (0.04 mmol, 8.5 mg) in DCE (1 mL) was added acetic acid (0.02 mmol, 1.2 μΐ,) and the resulting mixture was stirred at RT overnight. The reaction mixture was treated with aqueous saturated NaHC0 ₃ , extracted with DCM, dried over MgSC^, filtered and concentrated in vacuo to give title product as a colorless oil. Y: 8 mg (49%), rt=4.5 and 5 min (gradient A), (M+H) ⁺ =568. step 2: synthesis of compound n°31

Intermediate obtained in step 1 was treated with TFA and DCM, as described in step 3 of general method D which provided title product. Y: 10 mg, P=100%, rt=4.1 min (gradient A), (M+H) ⁺ =513.

Example 28: compound n° 33 : 2-((3S,4S,7S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-2-oxo-4-phenylazocan-3-yl)acetic acid

Purification of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-hydroxy-2- oxo-4-phenylazocan-3-yl)acetate (compound n°7's precursor) on silica gel with PE/EtOAc = 8/2, (TLC: PE/ EtOAc 7/3, rf=0.2), provided tert-butyl 2-((3S,4S,7S)-l-(4- (2-chlorophenyl)thiazol-2-yl)-7-hydroxy-2-oxo-4-phenylazocan -3-yl)acetate. P= 100%, rt=5.17 min (gradient B). This product was treated with TFA and DCM, as described in step 3 of general method D and provided compound n°33. Y: 30 mg (36%), P=100%>, rt=4.4 min (gradient B), (M+H) ⁺ =472.

Example 29: compound n°34 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- isopropyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates li and 2a using general method D.

Example 30: compound n°36: 2-((3S,4S,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-2-oxo-4-phenylazocan-3-yl)acetic acid was obtained using the same procedure as for compound n°33.

Example 31: compound n°37: 2-((3S,4R,7S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopentyl-7-hydroxy-2-oxoazocan-3-yl)acetic acid and compound n° 38 : 2- ((3S,4R,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4-cyclopentyl -7-hydroxy-2-oxoazocan- 3-yl)acetic acid were synthesized from compound n°9 using the methodology described for the synthesis of compound n°7.

Example 32: compound n°39 : 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- isobutyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates lj and 2a using general method D.

Example 33: compound n°40 : 2-((3S,4R,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-4-isopropyl-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°34 using the methodology described for the synthesis of compound n°7.

Example 34: compound n°41 : 2-((3S,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopentyl-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°9 using the hydrogenation procedure detailed for the synthesis of compound n°5. Example 35: compound n°42 : 2-((3S,4R,Z)-4-cyclopentyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)-l,2,3,4 ,5,8-hexahydroazocin-3- yl)acetic acid was synthesized from intermediates If and 2d using general method D. Example 36: compound n°43: 2-((3S,4R)-4-cyclopentyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)azocan-3-yl)acetic acid was

synthesized from compound n°42 using the hydrogenation procedure detailed for the synthesis of compound n°5.

Example 37: compound n°44: 2-((3S,4R,Z)-4-cyclopentyl-2-oxo-l-(4-phenylthiazol-2- yl)-l,2, 3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates If and 2h using general method D. Example 38: c omp ound n ° 45 : 2-((3S,4R,Z)-4-cyclopentyl-l-(4-(2- fluorophenyl)thiazol-2-yl)-2-oxo-l,2,3,4,5,8-hexahydroazocin -3-yl)acetic acid was synthesized from intermediates If and 2i using general method D.

Example 39: compound n°46: 2-((3S,4R,Z)-4-cyclopentyl-l-(4-(2-(6-methoxypyridin- 3-yl)phenyl)thiazol-2-yl)-2-oxo-l,2,3,4,5,8-hexahydroazocin- 3-yl)acetic acid was synthesized from intermediates If and 2g using general method D.

Example 40: compound n°47: 2-((3S,4S)-7-(benzylamino)-l-(4-(2-chlorophenyl)thiazol-2- yl)-2-oxo-4-phenylazocan-3-yl)acetic acid was synthesized using the methodology used for the synthesis of compound n°31 , replacing isopropylamine with benzylamine.

Example 41: compound n°48: 2-((3S,4R,Z)-4-isopropyl-l-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-2-oxo-l, 2,3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates li and 2g using general method D.

Example 42: compound n°49 : 2-((3S,4R,Z)-4-isopropyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)-l,2,3,4 ,5,8-hexahydroazocin-3- yl)acetic acid was synthesized from intermediates li and 2d using general method D. Example 43: compound n°50 : 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopropyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates lk and 2a using general method D. Example 44: compound n° 62 : 2-((3S,4S,Z)-l-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-2-oxo-4-phenyl- 1 ,2,3 ,4,5 ,8-hexahydroazocin-3-y l)acetic acid was synthesized from intermediates la and 2g using general method D.

Example 45: compound n° 63 : 2-((3S,4R)-4-isopropyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)azocan-3 -yl)acetic acid was synthesized from compound n°49 using the hydrogenation procedure detailed for the synthesis of compound n°5.

Example 46: compound n°64: 2-((3S,4R)-4-isopropyl-l-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°62 using the hydrogenation procedure detailed for the synthesis of compound n°5.

Example 47: c o m p o u n d n °116: 2-(l-isopropyl-4-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-3,8-dioxo-l,4-diazocan-2-yl)acetic acid was synthesized from intermediates 3c and 2g using general method F.

Example 48: compound n°117: 2-((3S,4R,Z)-4-isopropyl-l-(4-(2-(5-methoxypyrazin-2- yl)phenyl)thiazol-2-yl)-2-oxo-l, 2,3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates li and 2k using general method D.

Example 49: compound n°118: 2-((3S,4R,Z)-4-isopropyl-l-(4-(2-(5-methoxypyrazin-2- yl)phenyl)thiazol-2-yl)-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°l 17 using the hydrogenation procedure detailed for the synthesis of compound n°5. Example 50: c o m p o u n d n °119: 2-(l-cyclopentyl-4-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-3,8-dioxo-l,4-diazocan-2-yl)acetic acid was synthesized from intermediates 3a and 2g using general method F. BIOLOGY EXAMPLES

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents the effect of compound 9 on GLP-1 release from rat lower intestinal GLP-1 secreting cells.

Figure 2 represents the inhibition of in-vitro TNFa release from LPS-stimulated PBMC following the activation by the compounds of the invention.

Figure 3 represents the inhibition of in-vivo lipolysis following the injection of compound 42 in mice.

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- hydro lysable GTP analog, [ ³⁵ S]GTPyS, was used to demonstrate enhance binding of [ ³⁵ S]GTPyS to membranes expressing receptors. The assay uses the ability of GPCR to stimulate [ ³⁵ S]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 MgCl ₂ , 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 MgCl ₂ , 0.3 mM EDTA, lmM 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 performed in the presence of SCFA, and was used to determine the activity of the compounds of the invention.

The [ ³⁵ S]GTPyS assay was incubated in 20 mM HEPES pH 7.4, 100 mM NaCl, 10 μg/ml saponin, 30 mM of MgCl ₂ , 10 μΜ of GDP, 5 μg membrane-expressing hGPR43, 250μg 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 μί 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% (EC ₅₀ ) 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 with an EC ₅₀ ranging from 21 nM to 2930 nM.

Table 3 : EC50 values in GTPy S assay

49 180

50 124

62 151

63 1465

64 223

116 758

117 49

118 274

119 169

GLP-1 release assay.

Rat lower intestinal GLP-1 secreting cells were prepared from eight- week-old male Sprague-Dawley rat. Each well contained 5x 10 ⁴ cells stimulated in assay buffer (DMEM- based medium) containing 5.6 mM glucose with increasing concentration of the compounds of the invention for 1 hour at 37°C in cell incubator. The supernatants were harvested and assessed for GLP-1 using an ELISA (Wako).

When tested in the GLP-1 release assay described above and by way of illustration the compound n° 9 induced a significant and dose-dependent release of GLP-1 from rat lower intestinal cells (Figure 1).

Oral Glucose Tolerance Test (OGTT).

Lean male C57BL/6J mice (7 weeks of age) were kept in a 12/12h light-dark cycle (light from 0600-1800 h) with controlled temperature conditions (22-24°C). At day -1 food was removed from all mice. The acute experiment was performed 17 hours later (day 1). Mice (n=6) were dosed per oral with vehicle (cyclodextin/NaclO.9%) or compounds of the invention (50 mg/kg). At time points -15 and 0 min, baseline blood glucose was measured through a tail bleeding (using a glucometer). Then glucose was administered by oral gavage (2g/kg glucose) and blood glucose was then measured at time points 15, 30, 60 and 120 minutes. The blood glucose area under the curve (AUC) between time t-15 min and time tl20 min was calculated (GraphPad Prism software). The percentages of AUC inhibition induced by the compounds of the invention were calculated following the formula below: % of AUC inhibition = [1- (AUC compound / AUC vehicle)] * 100.

When tested in the above-described assay, preferred compounds of the invention showed a % of AUC inhibition > 13%, indicating that the compounds of invention are able to significantly reduce the level of blood glucose.

Cytokines release from Peripheral Blood Mononuclear Cell assay.

Peripheral blood mononuclear cells (PBMC) are purified from heparinised fresh blood sample on a Lymphoprep gradient. PBMC are plated in 96-well assay plate (2x106 cells/well) and stimulated with or without LPS (100 ng/ml) and increasing concentration of compounds of the invention for 3 hours at 37°C. Cell supernatants are recovered after centrifugation and human soluble TNFa .is quantified using ELISA assay (R&D system) according manufacturer's recommendation.

When tested in the cytokines release from PBMC assay described above and by way of illustration the compounds n° 9; 39 and 43 significantly inhibit the TNFa secretion from PBMC (Figure 2).

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 compounds of the invention 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). Compounds of the invention 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 (200μί blood, Li-heparin, Sarstedt) for determination triglycerides and glycerol and in tri-potassium EDTA added sodium fluoride (200 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).

According to the method described above and by way of illustration the compound n° 42 administered orally, inhibit, 60 minutes following the dosing, in vivo FFA baseline at the concentration of 50mg/kg from normal diet fed mice in comparison to the vehicle (Figure 3).

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 ant it is understood that various changes may be made without departing from the spirit and scope of the invention.