WO2011092284A1 - Novel amino acid derivatives and their use as gpr43 receptor modulators - Google Patents

Novel amino acid derivatives and their use as gpr43 receptor modulators Download PDF

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WO2011092284A1
WO2011092284A1 PCT/EP2011/051206 EP2011051206W WO2011092284A1 WO 2011092284 A1 WO2011092284 A1 WO 2011092284A1 EP 2011051206 W EP2011051206 W EP 2011051206W WO 2011092284 A1 WO2011092284 A1 WO 2011092284A1
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acetamido
butanoic acid
phenyl
chlorophenyl
trifluoromethyl
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PCT/EP2011/051206
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French (fr)
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Cyrille Evangelos Brantis
Frédéric OOMS
Jérôme BERNARD
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Euroscreen S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to novel compounds including their pharmaceutically acceptable salts and solvates, 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.
  • GPR43 G-protein coupled receptor 43
  • the compounds of the invention are also useful as tool compounds.
  • 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).
  • GPCRs G-Protein- Coupled Receptors
  • FFAs Free Fatty Acids
  • 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 (MCFA, LCFA) activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 1 1 661 -671, 2007 ).
  • SCFAs short chain fatty acids
  • MCFA, LCFA medium and long chain fatty acids
  • C2 acetate and C3 propionate are the most potent activators of GPR43.
  • 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 ⁇ 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., 1 17, pp 4034-4043, 2007; Ahren Bo, Nature Reviews, 8, pp369-385, 2009). This potential is well supported by recent data.
  • 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. 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 physiolology.
  • GPR43 modulators may be of therapeutic value for the treatment of the above-mentioned disorders.
  • the invention encompasses compounds of general Formula I, their pharmaceutically acceptable salts and solvates as well as methods of use of such compounds or compositions comprising such compounds as modulators of GPR43 activity.
  • the invention provides compounds of general formula I:
  • Ar 1 is a group selected from isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, aryl, tetrahydrofuranyl, tetrahydropyranyl, morpholin-4-yl, piperazin- 1 -yl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, acyl, amino, alkylamin
  • L 1 is Ci-3alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl, hydroxyl or alkoxy;
  • R 1 is H, linear or branched C 1 -C4 alkyl;
  • L is -0-, Ci-3alkylene, ethenylene, ethynylene or C3-4cycloalkylene, each group being optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, or L 2 is N-R 2 where R 2 is H, linear or branched d- C 4 alkyl;
  • Ar is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocycly
  • L 3 is a single bond or a Ci- 2 alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl or hydroxyl;
  • Z is selected from the group consisting of -COOR
  • R is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R 3 is H, methyl or ethyl, and R 3 is hydroxyl -S0 2 CH 3i -S0 2 cyclopropyl or -S0 2 CF 3 ; with the following provisos
  • Ar 2 is not substituted by a pyrimidinylalkyl, dihydropyrimidinyl or 1 ,3,5-triazinyl moiety.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the invention also relates to the use of the above compounds or their pharmaceutically acceptable salts and solvates as modulators of GPR43, preferably as antagonists 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 or solvate of formula (I), to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicament.
  • the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.
  • the invention also relates to the use of the above compounds as tools to investigate the biological consequence of GPR43 receptor modulation or to localize the GPR43 receptor on cell surface.
  • the invention relates to compounds of formula I, as well as their pharmaceutically acceptable salts and solvates.
  • Preferred compounds of formula I and pharmaceutically acceptable salts and solvates thereof are those wherein
  • Ar 1 is a group selected from aryl, preferably phenyl or naphtyl, heteroaryl, preferably pyridinyl, thiophenyl, furanyl or benzothiophenyl, each group being optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl and haloalkyl, preferably Ar 1 is naphtyl or Ar 1 is phenyl optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl or haloalkyl; and/or
  • L 1 is Ci- 2 alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl, hydroxyl or alkoxy, preferably L 1 is -CH 2 - or -CH 2 -CH 2 -; and/or
  • R 1 is H
  • L 2 is -0-, or Ci_ 3 alkylene optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, or L 2 is ethenylene, ethynylene or cyclopropylene, preferably L is -CH 2 - or -CH(CH 3 )-; and/or Ar is a group selected from aryl, preferably phenyl, heteroaryl, preferably thiophenyl or pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo, cyano, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or two substituents form an alkylenedioxy or fused to the aryl or heteroaryl group may be one or more aryl moiety, preferably phenyl, each of said substituents, preferably the latter fused ring system, being optionally substituted by
  • L is Ci-2alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl or hydroxyl, preferably L is -CH 2 -; and/or
  • preferred compounds of Formula I are those of formula la
  • Ar 1 is as defined above in respect to formula I, preferably Ar 1 is a 5 to 6-membered aryl or heteroaryl group, each of which being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, acyl, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydro xycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfinyl, alkylsulfonyl,
  • L 1 is as defined above in respect to formula I, preferably L 1 is a Ci- 2 alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl, hydroxyl or alkoxy, more preferably L 1 is -CH 2 - or -CH 2 -CH 2 -, even more preferably L 1 is -CH 2 -;
  • R 1 is as defined above in respect to formula I, preferably R 1 is H or methyl, more preferably R 1 is H;
  • L is as defined above in respect to formula I, preferably L is -0-, Ci_3alkylene optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, or L 2 is ethenylene, ethynylene or cyclopropylene, more preferably L 2 is -CH 2 - or -CH(CH 3 )-;
  • Ar 2 is as defined above in respect to formula I, preferably Ar 2 is a group selected from aryl, preferably phenyl, heteroaryl, preferably thiophenyl or pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylamino, or two substituents form an alkylenedioxy or fused to the aryl or heteroaryl group may be one or more aryl moiety, preferably phenyl, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alky
  • L is as defined above in respect to formula I, preferably L is a Ci- 2 alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl or hydro xyl, more preferably L 3 is -CH 2 -;
  • Z is as defined above in respect to formula I, preferably Z is -COOR where R is as defined above in respect to formula I, more preferably Z is COOH.
  • Particularly preferred compounds of formula la are those of formula
  • L 3 , and Z are as defined above in respect to formula la.
  • Preferred compounds of formula Ia-1 are those of formula Ia-2
  • Preferred compounds of formula Ia-2 are selected from the group consisting of formulae Ib-2a, Ib-2b, Ib-2c and Ib-2d:
  • R 4 and R 4 are independently selected from H, halo, alkyl, hydroxyl or alkoxy, or R 4 and R 4 together form a cyclopropane ring optionally substituted by one or more halo, alkyl, hydroxyl or alkoxy, preferably R 4 and R 4 are independently selected from H or methyl, or R 4 and R 4 together form a cyclopropane ring optionally substituted by one or more methyl group, more preferably R 4 is H and R 4 is H or methyl, even more preferably R 4 and R 4 are H; and in formula Ib-2b, R , R , R and R are independently selected from H or methyl, preferably R 5 , R 5 , R 5 and R 5 are H.
  • Preferred compounds of formula Ib-2b are those of formula Ib-3:
  • Preferred compounds of formula Ib-2a are those of formula Ib-4:
  • Preferred compounds of formula Ib-4 are selected from the group consisting of formulae Ib-4a and Ib-4b:
  • R , R , R and R are independently selected from H, halo, alkyl, hydroxyl or
  • R , R , R and R are independently selected from H, fluoro or methyl, more preferably R , R and R are H and R is selected from H, fluoro or
  • R , R and R are H and R is selected from H, fluoro or methyl even more preferably R 7 , R 7 ', R 7 " and R 7 '" are H.
  • Preferred compounds of formula Ib-4a are selected from the group consisting of formulae Ib-5a, Ib-5b and Ib-5c:
  • R , R and R 1 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, or R 11 and R 12 , or R 11 and R 12 together with the furanyl or thiophenyl group they are attached to form a benzoiuranyl or benzothiophenyl moiety, preferably R 11 , R n 'and R 12 are H.
  • Preferred compounds of formula Ib-5a are those wherein R , R , R are H, R' " is CF 3 and Y 1 is CH.
  • Preferred compounds of formulae Ib-5b and Ib-5c are those wherein R 11 , R 11 and R 12 are H, and A is S.
  • Preferred compounds of formula Ib-5a are selected from the group consisting of formulae Ib-6a, Ib-6b and Ib-6c:
  • R 4 , R 4 , R 6 , R 6 , R 7 , R 7 , R 8 , R 8 , R 9 , R 10 and Y 1 are as defined above in respect to formula Ib-5a and wherein, in formula Ib-6a, R 13 , R 13 and R 14 are independently selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, preferably R 13 and R 14 are H and R 13 is selected from H, chloro, iodo, methyl or methoxy, or R 13 and R 13 are H and R 14 is selected from H, chloro, iodo, methyl, trifluoromethyl, methoxy, phenoxy;
  • Y 2 is N or C-R 14 , where R 14 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or if Y 3 is CH: R 14 and R 13 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y 2 is N or C-R 14 , where R 14 is selected from H, chloro, methyl, trifluoromethyl, methoxy, phenoxy, more
  • Y' is CH, or C-Cl, even more preferably Y is C-Cl;
  • Y is N under the condition that Y is not N, or Y is C-R , where R is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R 15 and R 14 together form a methylenedioxy group or R 15 and R 14 together with the phenyl group they are attached to form a naphtyl moiety, if Y 2 is C-R 14 , R 15 and R 14 together form a methylenedioxy group or R 15 and R 14 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y 3 is N or C-R 15 , where R 15 is selected from H, chloro, iodo, methyl, trifluoromethyl, methoxy, phenoxy or dimethylamino more preferably Y is CH; and in formulae Ib-6b and Ib-6c, R 16 , R 16 and R 17 are independently selected from
  • Preferred compounds of formula Ib-6a are those wherein R 13 , R 13 , R 14 are H, Y 2 is C-Cl and Y 3 is C-I or CH, preferably CH.
  • Preferred compounds of formulae Ib-6b and Ib-6c are those wherein
  • R 16 , R 16 'and R 17 are H.
  • preferred compounds of formula I are those of formula Ic
  • preferred compounds of formula I are those of formula Id
  • R is as defined above in respect to formula Ia-2;
  • R" and R° are as defined above in respect to formula Ib-4.
  • Preferred compounds of formula Id are those wherein R 6 , R 6 and R are H, and/or
  • Ar 1 is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, acyl, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, or two substitu
  • L 1 is Ci-2alkylene optionally substituted by one or more substituent(s) selected from alkyl group, more preferably L 1 is methylene or ethylene; and/or R 1 is H or methyl, more preferably R 1 is H; and/or
  • L is -0-, Ci_3alkylene, ethenylene, ethynylene or C3_4cycloalkylene, each group being optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, more preferably L 2 is methylene optionally substituted by one or two methyl, ethynylene or cyclopropylene; and/or
  • Ar 2 is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, aralkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, acyl, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, alkylcarbonylamino alkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfin
  • Ar is a group selected from phenyl, thiophenyl or pyridyl group, each group being optionally substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, alkoxy, aryloxy, or two substituents form an methylenedioxy group, or Ar is a naphtyl moiety.
  • substituent(s) selected from halo, alkyl, haloalkyl, alkoxy, aryloxy, or two substituents form an methylenedioxy group, or Ar is a naphtyl moiety.
  • preferred compounds of formula I are selected from the group consisting of formulae Ie-1 , Ie-2, Ie-3 and Ie-4:
  • Preferred compounds of formulae Ie-1 , Ie-2 are those wherein R 4 , R 4 , R and R are H. Further preferred compounds of formulae Ie-1 , Ie-2 are those wherein R , R , R , R and R are H. Other preferred compounds of formula Ie-2 are those wherein R 4 and R 4 together form a cyclopropane ring.
  • preferred compounds of formula I are selected from the group consisting of formulae If-1 and If-2:
  • R , R , R and R are as defined above in respect to formulae Ib-4a and Ib-4b.
  • Preferred compounds of formulae If-1 and If-2 are those wherein R 7 , R 7 , R 7 and R are H.
  • preferred compounds of formula I are selected from the group consisting of formulae Ig-1 , Ig-2 and Ig-3:
  • R , R , R , R ) R , R , R , Y are as defined above in respect to formulae Ib- 5 a, Ib-5b and Ib-5c.
  • Preferred compounds formulae Ig-1 , Ig-2 and Ig-3 are those wherein
  • R 8 , R 8 , R 9 , are H, R 10 is CF 3 and Y 1 is CH.
  • Preferred compounds formulae Ig-2 and Ig-3 are those wherein A is S, and R 11 , R 11 , R 12 are H.
  • preferred compounds of formula I are selected from the group consisting of formulae Ih-1 , Ih-2 and Ih-3:
  • R 13 , R 13 , R 14 , R 16 , R 16 , R 17 , Y 2 and Y 3 are as defined above in respect to formulae Ib-6a, Ib-6b and Ib-6c.
  • Preferred compounds of formulae Ih-1 , Ih-2 and Ih-3 are those wherein R 13 , R 13 , R 14 , are H, Y 2 is C-Cl and Y 3 is CH or C-I, preferably CH.
  • Preferred compounds of formulae Ih-2 and Ih-3 are those wherein R 16 , R 16 and R 17 are H.
  • preferred compounds of formula I are those of formula Ii
  • Particularly preferred compounds of formula Ii are those of formula Ii-
  • Preferred compounds of formula Ii-l are those of formula Ii-2
  • Preferred compounds of formula Ii-2 are selected from the group consisting of formulae Ij-2a, Ij-2b, Ij-2c and Ij-2d:
  • R 4 and R 4 are independently selected from H, halo, alkyl, hydroxyl or alkoxy, or R 4 and R 4 together form a cyclopropane ring optionally substituted by one or more halo, alkyl, hydroxyl or alkoxy, preferably R 4 and R 4 are independently selected from H or methyl, or R 4 and R 4 together form a cyclopropane ring optionally substituted by one or more methyl group, more preferably R 4 is H and R 4 is H or methyl, even more preferably R 4 and R 4 are H; and in formula Ij-2b, R 5 , R 5 ', R 5 " and R 5 '" are independently selected from H or methyl, preferably R 5 , R 5 , R 5 and R 5 are
  • Preferred compounds of formula Ij -2b are those of formula Ij-3 :
  • Preferred compounds of formula Ij-2a are those of formula Ij-4:
  • Preferred compounds of formula Ij-4 are selected from the group consisting of formulae Ij-4a and Ij-4b:
  • R , R , R and R are independently selected from H, halo, alkyl, hydro xyl or
  • R , R , R and R are independently selected from H, fluoro or methyl, more preferably R , R and R are H and R is selected from H, fluoro or methyl, or R , R and R are H and R is selected from H, fluoro or methyl even more preferably R 7 , R 7 , R 7 and R 7 are H.
  • Preferred compounds of formula Ij-4a are selected from the group consisting of formulae Ij-5a, Ij-5b and Ij-5c:
  • Y 1 is N or C-R 9 , where R 9 is selected from H, halo, nitro, cyano, or haloalkyl, or R 9 and R 8 or R 9 and R 10 together form a naphtyl moiety, preferably Y 1 is N or C-R 9 , where R 9 is selected from H, chloro, cyano, CF 3 , more preferably Y 1 is CH;
  • R 8 , R 8 , R 9 and R 10 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, preferably R 9 , R 8 ', R 10 are H and R 8 is selected from H, chloro, cyano or methyl, or R 8°, R 8°' , R 10 are H and R 9 is selected from H, chloro, CF 3 , or cyano, or R 8 , are H and R is selected from H, chloro, cyano, nitro, methyl or CF 3 , or, when Y 1 is CH, R 8 and R 9 or R 9 and R 10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, preferably R 8 and R 9 or R 9 and R 10 together with the phenyl group they are attached to form a naphtyl moiety; and in formulae Ij -5b and Ij-5c, A is
  • R 11 , R n 'and R 12 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, or R 11 and R 12 , or R 11 and R 12 together with the furanyl or thiophenyl group they are attached to form a benzoiuranyl or benzothiophenyl moiety, preferably R 11 , R n 'and R 12 are H.
  • Preferred compounds of formula Ij-5a are those wherei •n R 8 , R 8' , R 9 are H, R 10 i*s CF 3 and Y 1 is CH.
  • Preferred compounds of formulae Ij-5b and Ij -5 c are those wherein R 11 , R 11 and R 12 are H, and A is S.
  • Preferred compounds of formula Ij-5a are selected from the group consisting of formulae Ij-6a, Ij-6b and Ij-6c:
  • R 7 , R 7' , R 8°, R 8°' , R 9', R 1 "0 and Y 1 are as ced above in respect of formula Ij-5a and wherein, in formula Ij-6a, R 13 , R 13 and R 14 are independently selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, preferably R 13 and R 14 are H and R 13 is selected from H, chloro, iodo, methyl or methoxy, or R 13 and R 13 are H and R 14 is selected from H, chloro, iodo, methyl, trinuoromethyl, methoxy, phenoxy;
  • Y 2 is N or C-R 14 , where R 14 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or if Y 3 is CH: R 14 and R 13 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y 2 is N or C-R 14 , where R 14 is selected from H, chloro, methyl, trinuoromethyl, methoxy, phenoxy, more preferably Y 2 is CH, or C-Cl, even more preferably Y 2 is C-Cl;
  • Y 3 is N under the condition that Y 2 is not N, or Y 3 is C-R 15 , where R 15 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R 15 and R 14 together form a methylenedioxy group or R 15 and R 14 together with the phenyl group they are attached to form a naphtyl moiety, if Y 2 is C-R 14 , R 15 and R 14 together form a methylenedioxy group or R 15 and R 14 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y 3 is N or C-R 15 , where R 15 is selected from H, chloro, iodo, methyl, trinuoromethyl, methoxy, phenoxy or dimethylamino more preferably Y 3 is CH; and in formulae Ij -6b and Ij-6c, R 16 , R
  • Preferred compounds of formula Ij-6a are those wherein R 13 , R 13 , R 14 are H, Y 2 is C-Cl and Y 3 is C-I or CH, preferably CH.
  • Preferred compounds of formulae Ij-6b and Ij-6c are those wherein R 16 , R 16 'and R 17 are H.
  • 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, or solvates thereof as antagonists of G-protein coupled receptor 43 (GPR43).
  • GPR43 G-protein coupled receptor 43
  • the invention relates to the use of compounds of formula I and subformulae in particular those of table 1 above, or pharmaceutically acceptable salts and solvates thereof, as GPR43 antagonists.
  • 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.
  • the patient is a warm-blooded animal, more preferably a human.
  • the invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating and/or preventing inflammatory, gastrointestinal and/or metabolic disorders in a patient.
  • the patient is a warm-blooded animal, more preferably a human.
  • a method for modulating GPR43 receptor activity in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said animal an effective amount of compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds of the invention may be administered as part of a combination therapy.
  • a combination therapy comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Such multiple drug regimens often referred to as combination therapy, may be used in the treatment and/or prevention of any of the diseases or conditions mediated by or associated with GPR43 receptor modulation, particularly inflammatory, gastrointestinal and/or metabolic disorders.
  • 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.
  • the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of Formula I or pharmaceutical acceptable salts or solvates 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 or solvates are coadministered in combination with one or more other therapeutic agents such as those described in detail further herein.
  • 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.
  • the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).
  • the invention also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament.
  • the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.
  • a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for modulating GPR43 receptor activity, in a patient, in need of such treatment, which comprises administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the compounds of the invention may be used in monotherapy or in combination therapy.
  • 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.
  • a patient in need thereof preferably a warm-blooded animal, and even more preferably a human
  • additional therapeutic agent and/or active ingredient are those described above.
  • the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • 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.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • 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.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propy
  • 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, des integrants, 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.
  • 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.
  • 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.
  • the invention relates to compounds described herein wherein one or more atom(s) is/are a radioisotope of the same element.
  • the compound is labeled with tritium.
  • radio-labeled compounds are synthesized either by incorporating radio-labeled starting materials or, in the case of tritium, exchange of hydrogen for tritium by known methods.
  • Known methods include (1) electrophilic halogenation, followed by reduction of the halogen in the presence of a tritium source, for example, by hydrogenation with tritium gas in the presence of a palladium catalyst, or (2) exchange of hydrogen for tritium performed in the presence of tritium gas and a suitable organomettalic (e.g. palladium) catalyst.
  • Compounds of the invention labeled with tritium are useful for the discovery of novel medicinal compounds which bind to and modulate the activity, by agonism, partial agonism, or antagonism, of a GPR43 receptor.
  • Such tritium-labeled compounds may be used in assays that measure the displacement of such compounds to assess the binding of ligands that bind to a GPR43 receptor.
  • the invention therefore also relates to the use of a tritium-labeled compound of the invention for assessing the binding of ligands that bind to a GPR43 receptor or, in other words, to a method for assessing the binding of a ligand to a GPR43 receptor comprising contacting the tritium-labeled compound with the GPR43 receptor.
  • the invention relates to compounds described herein additionally comprising one or more atoms of a radioisotope.
  • the compound comprises a radioactive halogen.
  • radio-labeled compounds are synthesized by incorporating radio-labeled starting materials by known methods.
  • Particular embodiments of this aspect of the invention are those in which the radioisotope is selected from 18 F, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br or 82 Br.
  • a most particular embodiment of this aspect of the invention is that in which the radioisotope is 123 I, 125 I, 131 I.
  • Such compounds comprising one or more atoms of a radioisotope are useful as positron emission tomography (PET) ligands and for other uses and techniques to determine the location of a GPR43 receptor. Therefore such compounds can be used as a specific probe for the localization of a GPR43 receptor on cell surfaces.
  • PET positron emission tomography
  • the invention therefore also relates to a method for localizing a GPR43 receptor on cell surfaces comprising contacting a compound of the invention comprising one or more atoms of a radioisotope with a cell surface.
  • 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?”.
  • halo or halogen means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro and iodo.
  • 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.
  • 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.
  • C x - y -alkyl and Cx-Cy-alkyl refer to alkyl groups which comprise from x to y carbon atoms.
  • Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl).
  • Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
  • alkylene 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.
  • alkylene includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1 ,2- dimethylethylene.
  • alkenyl refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3- butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.
  • alkynyl 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.
  • 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.
  • 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.
  • haloalkyl radicals include chloro methyl, 1 -bromoethyl, fiuoromethyl, difiuoro methyl, trifiuoro methyl, 1 ,1 ,1 -trifluoroethyl and the like.
  • 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.
  • cycloalkylene refers to a saturated homocyclic hydrocarbyl biradical of Formula C n H2 n -2.
  • Suitable cycloalkylene groups are C3-6 cycloalkylene group, preferably a C3-5 cycloalkylene (i.e.
  • heterocycloalkyl 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 'Tieterocyclyl”, “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
  • aryl 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.
  • 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.
  • heteroaryl ring where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
  • heteroaryl 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,
  • 'Tieteroarylene as used herein means divalent carbocyclic aromatic ring systems including pyridinylene and the like.
  • X is selected from: 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
  • pyridazinyl pyrazinyl X is selected from: X is selected from:
  • 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 stereo isomeric 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.
  • 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.
  • bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (— ), a zigzag line ( ), a solid wedge ( ), or a dotted wedge ( ).
  • 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, oxa
  • 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.
  • pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • the compounds of the invention contain a hydro gen -donating heteroatom (e.g. NH)
  • the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • compositions of Formula I may be prepared by one or more of these methods:
  • 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.
  • 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.
  • 'hydrate' is employed when said solvent is water.
  • references to compounds of formula I include references to salts, solvates, multi- component complexes and liquid crystals thereof.
  • the compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of formula I.
  • 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.
  • 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.
  • prodrug 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.
  • predrug 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.
  • any atom of the compounds of the invention may present as any of its isotopes.
  • any hydrogen atom may be tritium, and any F, I or Br radical may be the radioisotope selected from 18 F, 123 I, 125 I,
  • a most parti *cular embodi *ment of thi *s aspect of the invention is that the radioisotope is tritium, 123 I, 125 I, 131 I.
  • 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.
  • human refers to suject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • treat means to include alleviating or abrogating a condition or disease and/or its attendant symptoms.
  • prevent refers 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.
  • terapéuticaally effective amount means the amount of active agent or active ingredient (e. g. GPR43 modulator) which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • administration means providing the active agent or active ingredient (e. g. a GPR43 modulator), 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.
  • active agent e.g. a GPR43 modulator
  • administering means providing the active agent or active ingredient (e. g. a GPR43 modulator), 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.
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
  • antagonist means a compound which competitively or non-competitively binds to a receptor at the same site as an agonist (for example, the endogenous ligand), but does not activate an intracellular response initiated by an active form of the receptor. An antagonist thereby inhibits the intracellular response induced by an agonist.
  • pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
  • pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
  • inflammatory disorders are those pertaining to, characterized by, causing, resulting from or becoming affected by inflammation
  • 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 ⁇ 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
  • metabolic disorders includes but is not limited to 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).
  • dyslipidemia such as mixed or diabetic dyslipidemia
  • hypercholesterolemia low HDL cholesterol, high LDL cholesterol
  • hyperlipidemia hypertriglyceridemia
  • hypoglycemia hyperglycemia
  • glucose intolerance insulin resistance
  • 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 Bowed Syndrome (IBS); intestinal injury disorders such as short-bowel syndrome; diseases involving intestinal barrier dysfunction such as pancreatitis, proctitis and pouchitis.
  • IBS Irritable Bowed Syndrome
  • Tr (trityl), DIEA ( ,N-diisopropylethylamine),
  • HPLC-MS spectra were obtained on Waters instruments using Electropsray ionization (ESI). Samples were injected by a Waters 2767 sample manager. A Waters 2525 binary pump module is linked to a Waters 2996 photodiode array detector and a Waters micromass ZQ-2000. The column used is a Sunfire CI 8 5 ⁇ . Eluent is a mixture of solution A (0.1 % HC0 2 H in H 2 0) and solution B (0.1 % HC0 2 H in MeCN): 5% solution B for lmin, gradient from 5% solution B to 95% solution B over 4 min, 95% solution B for 0.2 min and 5% solution B for 0.8min.
  • ESI Electropsray ionization
  • Trityl-OH D-series lanterns were purchased from Mimotopes International and freeze -dried for 18h before use in a CHRIST ALPHA 1-2 LD.
  • a wash cycle for the SynPhase lanterns means adding wash solvent, shaking at rt for 5min and decanting the wash solvent.
  • Trityl-OH D-series lanterns were converted to Trityl-Cl D-series lanterns with acetyl chloride in DCM prior to the anchoring of N-Fmoc amino-acid with Et 3 N in DMF/DCM.
  • the synthesis was adapted from the Mimotopes International SynPhase Chemistry Note SCN009-2.
  • the amino-ester may be acylated with the desired carboxylic acid using coupling reagents such as HOBt and TBTU, the subsequent saponification with LiOH or NaOH or KOH in a mixture of H 2 0 and organic solvents such as THF or MeOH would yield the N-acyl beta-amino acid compounds as well as done with the solid phase synthesis using Trityl D-series lanterns.
  • coupling reagents such as HOBt and TBTU
  • Fmoc protected beta amino-acids can be synthesized by the Arndt-Eistert reaction from N-Fmoc-alpha-aminodiazoketones using silver benzoate in 1 ,4-dioxane/H 2 0 under microwave irradiation as shown in Scheme 5 and reported by Basanagoud et al. in Lett. Pept. Sci. 2002, 9, 231 . silver benzoate
  • Beta amino-ester building blocks may also be obtained via the enantioselective hydrogenation of enamine intermediates as described by M. Kubryk et al. in Tetrahedron Asymmetry 2006, 17, 205 and shown in Scheme 6.
  • Phenylacetic acid may be converted in two steps to the keto-ester intermediate using CDI and mono-methyl potassium malonate. Treatment of this keto-ester with ammonium acetate may provide the enamine which can be hydro genated enantioselectively using [Rh(COD)Ci] 2 and chiral ferrocenyl ligand L in TFE to give the amino-ester building block in a crystalline form upon salt formation with S-CSA in IP A.
  • This methodology may be adapted to synthesize the other enantiomer when adapting the enantioselective hydrogenation conditions by changing the catalyst and ligand. Such conditions are reported by Hsiao et al. in J. Am. Chem. Soc, 2004, 126, 9918. Enantioselective hydrogenation of enamines are also reported by Hou et al. in J. Am. Chem. Soc. 2006, 128, 11774.
  • Isosterism is a concept defined by I. Langmuir in J. Am. Chem. Soc. 1919, 41, 1549 and developed by H.L. Friedman in Symposium on Chemical-Biological correlations, National Council Publication, Washington, DC (1951).
  • bioisosteres refers to "groups or molecules which have chemical and physical similarities producing similar biological effects” (as defined in Chem. Soc. Rev. 1979, 8, 563). Suitable well known bioisosteric replacements of carboxylic acid groups are reported in The practice of medicinal chemistry, 2 nd edition, by C.G. Wermuth.
  • Tetrazole analogs may be synthesized in one step by conversion of the corresponding amido -nitriles using sodium azide and ammonium chloride as shown in Scheme 7 and reported by Matthews et al. in J. Comb. Chem. 2000, 1, 19.
  • Amido-nitriles may be obtained from commercially available amino -nitriles by acylation with the desired carboxylic acid using standard coupling reagents such as HOBt and TBTU; or with the desired acyl chloride in THF in the presence of Et 3 N or DIEA.
  • Mimotopes Fmoc Rink amide SynPhase D-series PS lanterns can be Fmoc deprotected with a solution of piperidine in DMF.
  • the Fmoc amino-acid may be anchored onto the lantern using DIC and HOBt coupling reagents. These two steps are described in the Mimotopes SynPhase Chemical Note SCN 001 -3.
  • the Fmoc- group can be removed with a solution of piperidine in DMF and the acylation may be done using HOBt and TBTU coupling reagents.
  • the desired carboxamide would then be cleaved from the lantern under acidic conditions as reported in the Mimotopes SynPhase Chemical Note SCN 002-3.
  • the carboxamide may be converted to the desired amido-nitrile using cyanuric chloride in DMF as reported by Maetz and Rodriguez in Tetrahedron Lett. 1997, 38, 4221.
  • Carboxamide intermediates may be obtained in one step from the corresponding carboxylic acid using EDCI and ammonium carbonate in THF as reported by Arienti et al. in J. Med. Chem. 2005, 48, 1873.
  • amino-nitrile starting materials may be obtained from commercially available amino-alcohols using the synthetic route described in Scheme 9.
  • the amino-alcohol may be converted to a iert-butyl carbamate using di-tert- butyldicarbonate and Lewis acid ⁇ ( ⁇ 4) 2 .6 ⁇ 2 0 in an organic solvent such as DCM or iert-butanol as reported by Bartoli et al. in Synlett 2004, 10, 1794.
  • Conversion of alcohol to the mesylate intermediate and treatment with sodium cyanide should provide the nitrile as described by Kokotou et al. in Org. Prep. Proced. Int. 1994, 26, 599.
  • Subsequent Boc deprotection using TFA in DCM may yield the desired amino- nitrile.
  • Sulphonylamide analogs may be obtained in one step from the carboxylic precursor as shown in Scheme 10. 3
  • the carboxylic acid may be converted to the sulphonylamide using (trifluoromethyl)sulphonamide, DMAP and morphoCDI in DCM as reported by Hutchinson et al. in J. Med. Chem. 1993, 36, 2771 (1993).
  • Hydroxamic acid analogs may be obtained in two steps from the carboxylic acids as shown in Scheme 11.
  • the carboxylic acid may be converted to the corresponding O-trityl-hydroxamic acid using O-trityl-hydroxylamine and DCC in AcOEt; the trityl group may then be removed under acidic conditions to give the desired hydroxamic acid analog.
  • Oxo-oxadiazole analogs synthetic route n°6
  • Oxo-oxadiazole analogs may be obtained in two steps from nitriles as shown in Scheme 12.
  • the nitrile may be converted to the amide-oxime using hydroxylamine hydrochloride and triethylamine in DMSO.
  • Treatment of the amide-oxime with 2-ethylhexyl chloro formate, pyridine in DMF and subsequent refluxing in xylene may give the desired oxo-oxadiazole analog.
  • Such procedures are reported by Kohara et al. in J. Med. Chem. 1996, 39, 5228.
  • Oxo-thiadiazole analogs may be obtained in two steps from nitriles as shown in Scheme 13.
  • the nitrile may be converted to the amide-oxime using hydroxylamine hydrochloride and triethylamine in DMSO.
  • Treatment of the amide-oxime with TCDI in THF and then silica gel in CHCls/MeOH may give the desired oxo-thiadiazole analog.
  • Hydroxymethylphosphinyl analogs may be obtained in two steps from bromides as shown in Scheme 14.
  • the bromide may be converted to the phosphinic ester using diethyl methylphosphonite in toluene.
  • Treatment of the phosphinic ester with bromotrimethylsilane in DCM may give the desired hydroxymethylphosphinyl analog.
  • Such procedures were reported by Drysdale et al. in J. Med. Chem. 1992, 35, 2573.
  • the bromide starting materials may be obtained from commercially available amino- alcohols using the synthetic route described in Scheme 15.
  • Scheme 15 a suggested synthesis of bromide intermediates from amino-alcohols
  • the amino-alcohol may be converted to the trityl ether using trityl chloride in pyridine as reported by J.L. Yuan et al. in Org. Prep. Proced. Int. 2004, 36, 164.
  • Subsequent acylation with the standard HOBt and TBTU coupling reagents and trityl deprotection with TFA in DCM may provide the alcohol-amide intermediate.
  • General methods for trityl protection and deprotection of alcohols are listed in Greene's Protective Groups in Organic Synthesis, 4th Edition, by P.G.M. Wutz and T.W. Greene.
  • Phosphonyl analogs may be obtained in two steps from the bromide precursor as shown in Scheme 17.
  • the bromide may be converted to the diethyl phosphonate intermediate using triethylphosphite as reported by Pillarsetty et al. in J. Am. Chem. Soc. 2005, 127, 331 . Subsequent acidolysis of the diethyl phosphonate intermediate with concentrated HCl may give the desired phosphonyl analog based on the methods for the preparation of phosphonic acids claimed in patent US 2007004937.
  • Tetrazole amide analogs may be obtained in one step from carboxylic acids as shown in Schem
  • Triazole analogs may be obtained in one step from carboxylic acids as shown in Scheme 19.
  • the carboxylic acid may be converted to the ethyl ester using thionyl chloride in ethanol which upon treatment with hydrazine in EtOH may provide the hydrazide intermediate.
  • thionyl chloride in ethanol which upon treatment with hydrazine in EtOH may provide the hydrazide intermediate.
  • Such procedures were reported by Elsinghorst et al. in J. Med. Chem. 2006, 25, 7540.
  • Treatment of the hydrazide intermediate with potassium thiocyanate in EtOH should give the triazole analog as reported by Kelarev et al. in Z. Org. Khim. 1993, 29, 388.
  • 2,4-Thiazolidinedione analogs may be obtained in three steps from the amino-esters as shown in Scheme 20.
  • the amino-ester CSA salt which may be obtained using synthetic route n°2, may be acylated using the standard HOBt, TBTU coupling reagents to give the amido-ester which may then be reduced to the amido -aldehyde using DIBAL-H.
  • the amido- aldehyde may be converted to the 2,4-thiazolidinedione analogs using a procedure reported by Momose et al. in J. Med. Chem. 2002, 45, 1518 (2002).
  • Example 3 Intermediate and Compound synthesis
  • the 30 Trityl-Cl were added to a 25mL reaction vessel containing a solution of Fmoc-(S)-3-amino-4-(4-trifluoromethylphenyl)butanoic acid (2eq, 2.1mmol, 0.984g), DIEA (5.2eq, 5.46mmol, 0.9mL) in 15mL of anhydrous DCM/anhydrous DMF (1/1).
  • the RVs were inerted with argon and shaken at rt for 20h. Solvents were decanted and the lanterns transferred to a lOOmL RV.
  • the lanterns were washed twice with 50mL DMF/DCM (1/1) and twice with 50mL of DCM and then air dried for 30min.
  • the loading of amino-acid on the lanterns was measured using the following procedure. 1 lantern with Fmoc-(S)-3-amino-5-(4-trifluoromethylphenyl)pentanoic acid anchored was added to a 25mL RV containing 1 OmL of a solution of 20 % (v/v) piperidine in DMF. The RV was shaken at rt for 30min. ImL of the reaction solution was diluted in lOmL of a solution of 20 % (v/v) piperidine in DMF. The absorbance (A301) of the resulting solution was measured at 301nm.
  • 29 lanterns with Fmo c-(S)-3-amino-5-(4-trifluoromethylphenyl)butanoic acid anchored were added to a lOOmL RV containing 50mL of a solution of 20 % (v/v) piperidine in DMF.
  • the RV was shaken at rt for 30min.
  • Solvents were decanted and the lanterns were washed twice with 50mL of DMF and twice with 50mL of DCM and then air dried for 30min.

Abstract

The present invention is directed to novel compounds of formula (I) and their use in treating and/or preventing inflammatory, gastrointestinal and/or metabolic disorders.

Description

NOVEL AMINO ACID DERIVATIVES AND THEIR USE AS GPR43 RECEPTOR MODULATORS
The present invention relates to novel compounds including their pharmaceutically acceptable salts and solvates, 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. The compounds of the invention are also useful as tool compounds.
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 (MCFA, LCFA) 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., 1 17, pp 4034-4043, 2007; Ahren Bo, Nature Reviews, 8, pp369-385, 2009). This potential is well supported by recent data. Using an 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. 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 physiolology. 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.
There is a continuing need for novel agents for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders, particularly ones that are well tolerated and with limited adverse effects. On this basis, GPR43 modulators may be of therapeutic value for the treatment of the above-mentioned disorders.
SUMMARY OF THE INVENTION
The invention encompasses compounds of general Formula I, their pharmaceutically acceptable salts and solvates 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:
Figure imgf000004_0001
(I), and pharmaceutically acceptable salts and solvates thereof, wherein
Ar1 is a group selected from isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, aryl, tetrahydrofuranyl, tetrahydropyranyl, morpholin-4-yl, piperazin- 1 -yl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, acyl, amino, alkylamino, eye lo alky lamino, arylamino, heteroarylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkyl c arb o nylo xy , hetero cyc lylc arb o nylo xy , arylc arb o nylo xy , heteroarylcarbonyloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydro xycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, cycloalkylsulfamoyl, arylsulfamoyl, heterocyclylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, aminoalkyl, c arb o xy, alko xyc arb o nyl , alkylc arb o nylo xy , alkylc arb o nylamino , haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino;
L1 is Ci-3alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl, hydroxyl or alkoxy; R1 is H, linear or branched C1-C4 alkyl;
L is -0-, Ci-3alkylene, ethenylene, ethynylene or C3-4cycloalkylene, each group being optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, or L2 is N-R2 where R2 is H, linear or branched d- C4 alkyl; Ar is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, acyl, amino, alkylamino, cycloalkylamino, arylamino, heteroarylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, cycloalkylsulfamoyl, arylsulfamoyl, heterocyclylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino;
L3 is a single bond or a Ci-2alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl or hydroxyl;
Z is selected from the group consisting of -COOR,
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000008_0004
wherein R is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R3 is H, methyl or ethyl, and R3 is hydroxyl -S02CH3i -S02cyclopropyl or -S02CF3; with the following provisos
1 - when Z is COOR, L is neither a single bond nor -CH(OH)-;
2- the compound of formula I is none of the compounds listed below:
- (S) -methyl 3-((S)-2 -methoxy-2 -phenylac etamido)-5 -phenylpentano ate ,
- (R)-methyl 3-((S)-2-methoxy-2-phenylacetamido)-5-phenylpentanoate, - (S)-ethyl 4-(4-nitrophenyl)-3-((phenoxycarbonyl)amino)butanoate, - 3-(3-([l,r-biphenyl]-4-yl)ureido)-4-phenylbutanoic acid,
- 3-(3-(4-phenoxyphenyl)ureido)-4-phenylbutanoic acid,
- (R)-3 -(2-(3 -bromophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid,
- (S)-4-phenyl-3-(2-(l ,3,9-trimethyl-2,6-dioxo-2,3,6,9-tetrahydro-lH-purin-8- yl)acetamido)butanoic acid,
- 2,2-difluoro-3-(2-phenylacetamido)octanoic acid; and,
3- Ar2 is not substituted by a pyrimidinylalkyl, dihydropyrimidinyl or 1 ,3,5-triazinyl moiety.
In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.
The invention also relates to the use of the above compounds or their pharmaceutically acceptable salts and solvates as modulators of GPR43, preferably as antagonists 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 or solvate of formula (I), to a patient in need thereof. Preferably the patient is a warm-blooded animal, more preferably a human. The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicament. Preferably, the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.
The invention also relates to the use of the above compounds as tools to investigate the biological consequence of GPR43 receptor modulation or to localize the GPR43 receptor on cell surface.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, the invention relates to compounds of formula I, as well as their pharmaceutically acceptable salts and solvates.
Preferred compounds of formula I and pharmaceutically acceptable salts and solvates thereof are those wherein
Ar1 is a group selected from aryl, preferably phenyl or naphtyl, heteroaryl, preferably pyridinyl, thiophenyl, furanyl or benzothiophenyl, each group being optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl and haloalkyl, preferably Ar1 is naphtyl or Ar1 is phenyl optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl or haloalkyl; and/or
L1 is Ci-2alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl, hydroxyl or alkoxy, preferably L1 is -CH2- or -CH2-CH2-; and/or
R1 is H; and/or
L2 is -0-, or Ci_3alkylene optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, or L2 is ethenylene, ethynylene or cyclopropylene, preferably L is -CH2- or -CH(CH3)-; and/or Ar is a group selected from aryl, preferably phenyl, heteroaryl, preferably thiophenyl or pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo, cyano, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or two substituents form an alkylenedioxy or fused to the aryl or heteroaryl group may be one or more aryl moiety, preferably phenyl, each of said substituents, preferably the latter fused ring system, being optionally substituted by one or more further substituent(s) selected from halo, cyano, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or two substituents form an alkylenedioxy, preferably from halo, cyano, alkyl, haloalkyl or alkoxy, preferably Ar2 is a group selected from phenyl, thiophenyl or pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, alkoxy, aryloxy, or two substituents form an methylenedioxy group, or Ar is a naphtyl moiety; and/or
L is Ci-2alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl or hydroxyl, preferably L is -CH2-; and/or
Z is COOH.
In one embodiment, preferred compounds of Formula I are those of formula la
Figure imgf000011_0001
la and pharmaceutically acceptable salts and solvates thereof, wherein
Ar1 is as defined above in respect to formula I, preferably Ar1 is a 5 to 6-membered aryl or heteroaryl group, each of which being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, acyl, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydro xycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one or more aryl, or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from oxo, nitro, cyano, alkyl, haloalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino , more preferably Ar1 is a group selected from aryl, preferably phenyl or naphtyl, more preferably phenyl, heteroaryl, preferably pyridinyl or thiophenyl, furanyl or benzothiophenyl, more preferably pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo preferably chloro, nitro, cyano, alkyl preferably methyl, and haloalkyl preferably trifluoromethyl;
L1 is as defined above in respect to formula I, preferably L1 is a Ci-2alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl, hydroxyl or alkoxy, more preferably L1 is -CH2- or -CH2-CH2-, even more preferably L1 is -CH2-;
R1 is as defined above in respect to formula I, preferably R1 is H or methyl, more preferably R1 is H;
2 2
L is as defined above in respect to formula I, preferably L is -0-, Ci_3alkylene optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, or L2 is ethenylene, ethynylene or cyclopropylene, more preferably L2 is -CH2- or -CH(CH3)-;
Ar2 is as defined above in respect to formula I, preferably Ar2 is a group selected from aryl, preferably phenyl, heteroaryl, preferably thiophenyl or pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylamino, or two substituents form an alkylenedioxy or fused to the aryl or heteroaryl group may be one or more aryl moiety, preferably phenyl, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, or two substituents together form an alkylenedioxy group, more preferably Ar2 is a group selected from aryl, preferably phenyl, heteroaryl, preferably thiophenyl or pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo, cyano, alkyl, preferably methyl, haloalkyl, preferably trifluoromethyl, aralkyl, preferably benzyl, alkoxy, preferably methoxy, aryloxy, preferably phenoxy, alkylamino, preferably dimethylamino, or two substituents form an alkylenedioxy, preferably methylenedioxy, or fused to the aryl or heteroaryl group may be one or more aryl moiety, thus forming a bicyclic ring system which is preferably a naphtyl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, or two substituents together form an alkylenedioxy group, even more preferably Ar is a group selected from phenyl, thiophenyl or pyridinyl, each group being optionally substituted by one or more substituent(s) selected from halo preferably chloro, iodo, alkyl preferably methyl, haloalkyl preferably trifluoromethyl, alkoxy, aryloxy preferably phenoxy, or two substituents form an methylenedioxy group, or Ar is a naphtyl moiety;
3 · 3
L is as defined above in respect to formula I, preferably L is a Ci-2alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl or hydro xyl, more preferably L3 is -CH2-;
Z is as defined above in respect to formula I, preferably Z is -COOR where R is as defined above in respect to formula I, more preferably Z is COOH.
Particularly preferred compounds of formula la are those of formula
Ia-1
Figure imgf000013_0001
Ia-1
1 2 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar ,
L3, and Z are as defined above in respect to formula la.
Preferred compounds of formula Ia-1 are those of formula Ia-2
Figure imgf000014_0001
Ia-2
1 2 1 2 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , L , and L3 are as defined above in respect of formula la and R is as defined above in respect to formula I, preferably R is H or linear or branched alkyl, acyloxyalkyl, dioxolene, more preferably R is H.
Preferred compounds of formula Ia-2 are selected from the group consisting of formulae Ib-2a, Ib-2b, Ib-2c and Ib-2d:
Figure imgf000015_0001
lb-2a lb-2b
Figure imgf000015_0002
lb-2c lb-2d and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, and L3 are as defined above in respect to formula Ia-2, and wherein in formula Ib-2a, R4 and R4 are independently selected from H, halo, alkyl, hydroxyl or alkoxy, or R4 and R4 together form a cyclopropane ring optionally substituted by one or more halo, alkyl, hydroxyl or alkoxy, preferably R4 and R4 are independently selected from H or methyl, or R4 and R4 together form a cyclopropane ring optionally substituted by one or more methyl group, more preferably R4 is H and R4 is H or methyl, even more preferably R4 and R4 are H; and in formula Ib-2b, R , R , R and R are independently selected from H or methyl, preferably R5, R5 , R5 and R5 are H.
Preferred compounds of formula Ib-2b are those of formula Ib-3:
Figure imgf000016_0001
Ib-3,
1 2 1 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , and L3 are as defined above in respect to formula la.
Preferred compounds of formula Ib-2a are those of formula Ib-4:
Figure imgf000016_0002
Ib-4, and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, R4 and R4' are as defined above in respect to formula Ib-2a and wherein R6 and R6' are independently selected from H, halo or alkyl, preferably R6 and R6 are independently selected from H or methyl, more preferably R6 is H and R6 is H or methyl, even more preferably R6 and R6 are H.
Preferred compounds of formula Ib-4 are selected from the group consisting of formulae Ib-4a and Ib-4b:
Figure imgf000017_0001
lb-4a lb-4b and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, R4, R4 , R6 and R6 are as defined above in respect to formula Ib-4 and wherein
7 7' 7" '"
R , R , R and R are independently selected from H, halo, alkyl, hydroxyl or
7 7' 7"
alkoxy, preferably R , R , R and R are independently selected from H, fluoro or methyl, more preferably R , R and R are H and R is selected from H, fluoro or
7 7' 7" 7'"
methyl, or R , R and R are H and R is selected from H, fluoro or methyl even more preferably R7, R7', R7" and R7'" are H.
Preferred compounds of formula Ib-4a are selected from the group consisting of formulae Ib-5a, Ib-5b and Ib-5c:
Figure imgf000017_0002
lb-5a lb-5b lb-5c and pharmaceutically acceptable salts, and solvates thereof, wherein Ar2, R4, R4 , R6, R6 , R7 and R7' are as defined above in respect to formula Ib-4a and wherein, in formula Ib-5a, Y1 is N or C-R9 , where R9 is selected from H, halo, nitro, cyano, or haloalkyl, or R9 and R8 or R9 and R10 together form a naphtyl moiety, preferably Y1 is N or C-R9 , where R9 is selected from H, chloro, cyano, CF3, more preferably Y1 is CH; R°, R° , R* and R are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, preferably R9, R8 , R10 are H and R8 is selected from H, chloro, cyano or methyl, or R 8°, R 8°' , R 10 are H and R 9 is selected from H, chloro, CF3, or cyano, or R 8 , R8 , R9 are H and R10 is selected from H, chloro, cyano, nitro, methyl or CF3, or, when Y1 is CH, R8 and R9 or R9 and R10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, preferably R8 and R9 or R9 and R10 together with the phenyl group they are attached to form a naphtyl moiety; and in formulae Ib-5b and Ib-5c, A is O or S, preferably S;
R , R and R1 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, or R11 and R12, or R11 and R12 together with the furanyl or thiophenyl group they are attached to form a benzoiuranyl or benzothiophenyl moiety, preferably R11, Rn'and R12 are H.
Preferred compounds of formula Ib-5a are those wherein R , R , R are H, R' " is CF3 and Y1 is CH. Preferred compounds of formulae Ib-5b and Ib-5c are those wherein R11, R11 and R12 are H, and A is S.
Preferred compounds of formula Ib-5a are selected from the group consisting of formulae Ib-6a, Ib-6b and Ib-6c:
Figure imgf000019_0001
lb-6a |b-6b lb-6c and pharmaceutically acceptable salts and solvates thereof, wherein R4, R4 , R6, R6 , R7, R7 , R8, R8 , R9, R10 and Y1 are as defined above in respect to formula Ib-5a and wherein, in formula Ib-6a, R13, R13 and R14 are independently selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, preferably R13 and R14 are H and R13 is selected from H, chloro, iodo, methyl or methoxy, or R13 and R13 are H and R14 is selected from H, chloro, iodo, methyl, trifluoromethyl, methoxy, phenoxy;
Y2 is N or C-R14 , where R14 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or if Y3 is CH: R14 and R13 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y2 is N or C-R14 , where R14 is selected from H, chloro, methyl, trifluoromethyl, methoxy, phenoxy, more
2 2
preferably Y' is CH, or C-Cl, even more preferably Y is C-Cl;
3 2 3 15 15
Y is N under the condition that Y is not N, or Y is C-R , where R is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety, if Y2 is C-R14 , R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y3 is N or C-R15, where R15 is selected from H, chloro, iodo, methyl, trifluoromethyl, methoxy, phenoxy or dimethylamino more preferably Y is CH; and in formulae Ib-6b and Ib-6c, R16, R16 and R17 are independently selected from H, chloro, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R16 and R17, or R16 and R17 together with the thiophenyl group they are attached to form a benzothiophenyl moiety, preferably R16, R16 and R17 are H.
Preferred compounds of formula Ib-6a are those wherein R13, R13 , R14 are H, Y2 is C-Cl and Y3 is C-I or CH, preferably CH. Preferred compounds of formulae Ib-6b and Ib-6c are those wherein
R16, R16'and R17 are H.
In another embodiment, preferred compounds of formula I are those of formula Ic
Figure imgf000020_0001
Ic, and pharmaceutically acceptable salts, and solvates thereof, wherein Ar1, Ar2, L1, L2, L3, and Z are as defined above in respect to formula la.
In another embodiment, preferred compounds of formula I are those of formula Id
Figure imgf000020_0002
Id,
1 2 1 2 and pharmaceutically acceptable salts, and solvates thereof, wherein Ar , Ar , L , L , and R1 are as defined above in respect to formula la;
R is as defined above in respect to formula Ia-2;
R" and R° are as defined above in respect to formula Ib-4.
Preferred compounds of formula Id are those wherein R6, R6 and R are H, and/or
Ar1 is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, acyl, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one phenyl group, the latter fused ring system being optionally substituted by one or more further substituent(s) selected from halo, nitro, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, acylamino, carbamoyl, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, haloalkylsulfonylamino, more preferably Ar1 is aryl optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl, or haloalkyl; and/or
L1 is Ci-2alkylene optionally substituted by one or more substituent(s) selected from alkyl group, more preferably L1 is methylene or ethylene; and/or R1 is H or methyl, more preferably R1 is H; and/or
L is -0-, Ci_3alkylene, ethenylene, ethynylene or C3_4cycloalkylene, each group being optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, more preferably L2 is methylene optionally substituted by one or two methyl, ethynylene or cyclopropylene; and/or
Ar2 is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, aralkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, acyl, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylalkyloxy, alkylcarbonylamino, alkylcarbonylamino alkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one aryl or heteroaryl moiety, the latter fused ring system being optionally substituted by one or more further substituent(s) selected from halo, nitro, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, acylamino, carbamoyl, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, haloalkylsulfonylamino, more preferably Ar is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, nitro, cyano, alkyl, haloalkyl, alkynyl, aralkyl, hydroxyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, acyl, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, acylamino, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one phenyl moiety, the latter fused ring system being optionally substituted by one or more further substituent(s) selected from halo, nitro, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, acylamino, carbamoyl, alkylsulfonyl, haloalkylsulfonyl, alkylsulfonylamino, 2
haloalkylsulfonylamino, even more preferably Ar is a group selected from phenyl, thiophenyl or pyridyl group, each group being optionally substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, alkoxy, aryloxy, or two substituents form an methylenedioxy group, or Ar is a naphtyl moiety.In another embodiment, preferred compounds of formula I are selected from the group consisting of formulae Ie-1 , Ie-2, Ie-3 and Ie-4:
Figure imgf000023_0001
Figure imgf000023_0002
le-3 le-4 and pharmaceutically acceptable salts, and solvates thereof, wherein Ar1, Ar2, L1, L3, R1 and Z are as defined above in respect to formula la; R , R , R , R , R and R are as defined above in respect to formulae Ib-2a, Ib-2b.
Preferred compounds of formulae Ie-1 , Ie-2 are those wherein R4, R4 , R and R are H. Further preferred compounds of formulae Ie-1 , Ie-2 are those wherein R , R , R , R , R and R are H. Other preferred compounds of formula Ie-2 are those wherein R4 and R4 together form a cyclopropane ring.
In another embodiment, preferred compounds of formula I are selected from the group consisting of formulae If-1 and If-2:
Figure imgf000024_0001
lf-1 |f-2 and pharmaceutically acceptable salts, and solvates thereof, wherein Ar1, Ar2, L2, L3, R1 and Z are as defined above in respect to formula la;
R , R , R and R are as defined above in respect to formulae Ib-4a and Ib-4b. Preferred compounds of formulae If-1 and If-2 are those wherein R7, R7 , R7 and R are H.
In another embodiment, preferred compounds of formula I are selected from the group consisting of formulae Ig-1 , Ig-2 and Ig-3:
Figure imgf000024_0002
2 1 2 3 and pharmaceutically acceptable salts, and solvates thereof, wherein Ar , L , L , L , R1 and Z are as defined above in respect to formula la;
A, R , R , R , R ) R , R , R , Y are as defined above in respect to formulae Ib- 5 a, Ib-5b and Ib-5c. Preferred compounds formulae Ig-1 , Ig-2 and Ig-3 are those wherein
R8, R8 , R9, are H, R10 is CF3 and Y1 is CH. Preferred compounds formulae Ig-2 and Ig-3 are those wherein A is S, and R11, R11 , R12 are H.
In another embodiment, preferred compounds of formula I are selected from the group consisting of formulae Ih-1 , Ih-2 and Ih-3:
Figure imgf000025_0001
Ih-1 lh"2 Ih-3
1 1 2 and pharmaceutically acceptable salts, and solvates thereof, wherein Ar , L , L , L3and Z are as defined above in respect to formula la;
R13, R13 , R14, R16, R16 , R17, Y2 and Y3 are as defined above in respect to formulae Ib-6a, Ib-6b and Ib-6c. Preferred compounds of formulae Ih-1 , Ih-2 and Ih-3 are those wherein R13, R13 , R14, are H, Y2 is C-Cl and Y3 is CH or C-I, preferably CH. Preferred compounds of formulae Ih-2 and Ih-3 are those wherein R16, R16 and R17are H.
In another embodiment, preferred compounds of formula I are those of formula Ii
Figure imgf000026_0001
Ii, and pharmaceutically acceptable salts, and solvates thereof, wherein Ar1, Ar2, L1, L2, iA R1 and Z are as defined above in respect to formula la. Preferred compounds of formula Ii are those wherein L2 and L3 are
CH2, R1 is H and Z is COOH.
Particularly preferred compounds of formula Ii are those of formula Ii-
1
Figure imgf000026_0002
Ii-l and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, L2, L3, and Z are as defined above in respect to formula Ii.
Preferred compounds of formula Ii-l are those of formula Ii-2
Figure imgf000027_0001
Ii-2 and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, L2, and L3 are as defined above in respect of formula Ii and R is as defined above in respect to formula I, preferably R is H or linear or branched alkyl, acyloxyalkyl, dioxolene, more preferably R is H.
Preferred compounds of formula Ii-2 are selected from the group consisting of formulae Ij-2a, Ij-2b, Ij-2c and Ij-2d:
Figure imgf000028_0001
Figure imgf000028_0002
lj-2c lj-2d and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, and L3 are as defined above in respect to formula Ii-2, and wherein in formula Ij-2a, R4 and R4 are independently selected from H, halo, alkyl, hydroxyl or alkoxy, or R4 and R4 together form a cyclopropane ring optionally substituted by one or more halo, alkyl, hydroxyl or alkoxy, preferably R4 and R4 are independently selected from H or methyl, or R4 and R4 together form a cyclopropane ring optionally substituted by one or more methyl group, more preferably R4 is H and R4 is H or methyl, even more preferably R4 and R4 are H; and in formula Ij-2b, R5, R5', R5" and R5'" are independently selected from H or methyl, preferably R5, R5 , R5 and R5 are H.
Preferred compounds of formula Ij -2b are those of formula Ij-3 :
Figure imgf000029_0001
Ij-3,
1 2 1 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , and L3 are as defined above in respect to formula Ii.
Preferred compounds of formula Ij-2a are those of formula Ij-4:
Figure imgf000029_0002
Ij-4, and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, R4 and R4' are as defined above in respect to formula Ij-2a and wherein R6 and R6' are independently selected from H, halo or alkyl, preferably R6 and R6 are independently selected from H or methyl, more preferably R6 is H and R6 is H or methyl, even more preferably R6 and R6 are H.
Preferred compounds of formula Ij-4 are selected from the group consisting of formulae Ij-4a and Ij-4b:
Figure imgf000030_0001
and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, R4, R4 , R" and R° are as defined above in respect to formula Ij-4 and wherein
R , R , R and R are independently selected from H, halo, alkyl, hydro xyl or
7 7' 7" 7'"
alkoxy, preferably R , R , R and R are independently selected from H, fluoro or methyl, more preferably R , R and R are H and R is selected from H, fluoro or methyl, or R , R and R are H and R is selected from H, fluoro or methyl even more preferably R7, R7 , R7 and R7 are H.
Preferred compounds of formula Ij-4a are selected from the group consisting of formulae Ij-5a, Ij-5b and Ij-5c:
Figure imgf000030_0002
i-5a i-5b i-5c and pharmaceutically acceptable salts, and solvates thereof, wherein Ar2, R4, R4 , R6, R ', R and R' are as defined above in respect to formula Ij-4a and wherein, in formula Ij-5a, Y1 is N or C-R9 , where R9 is selected from H, halo, nitro, cyano, or haloalkyl, or R9 and R8 or R9 and R10 together form a naphtyl moiety, preferably Y1 is N or C-R9 , where R9 is selected from H, chloro, cyano, CF3, more preferably Y1 is CH;
R8, R8 , R9 and R10 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, preferably R9, R8', R10 are H and R8 is selected from H, chloro, cyano or methyl, or R 8°, R 8°' , R 10 are H and R 9 is selected from H, chloro, CF3, or cyano, or R 8 , are H and R is selected from H, chloro, cyano, nitro, methyl or CF3, or, when Y1 is CH, R8 and R9 or R9 and R10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, preferably R8 and R9 or R9 and R10 together with the phenyl group they are attached to form a naphtyl moiety; and in formulae Ij -5b and Ij-5c, A is O or S, preferably S;
R11, Rn'and R12 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, or R11 and R12, or R11 and R12 together with the furanyl or thiophenyl group they are attached to form a benzoiuranyl or benzothiophenyl moiety, preferably R11, Rn'and R12 are H.
Preferred compounds of formula Ij-5a are those wherei •n R 8 , R 8' , R 9 are H, R 10 i*s CF3 and Y1 is CH.
Preferred compounds of formulae Ij-5b and Ij -5 c are those wherein R11, R11 and R12 are H, and A is S. Preferred compounds of formula Ij-5a are selected from the group consisting of formulae Ij-6a, Ij-6b and Ij-6c:
Figure imgf000032_0001
lj-6a |j-6b lj-6c and pharmaceutically acceptable salts and solvates thereof, wherein R4, R4 , R6, R6 ,
R 7 , R 7' , R 8°, R 8°' , R 9', R 1 "0 and Y 1 are as denned above in respect of formula Ij-5a and wherein, in formula Ij-6a, R13, R13 and R14 are independently selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, preferably R13 and R14 are H and R13 is selected from H, chloro, iodo, methyl or methoxy, or R13 and R13 are H and R14 is selected from H, chloro, iodo, methyl, trinuoromethyl, methoxy, phenoxy;
Y2 is N or C-R14 , where R14 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or if Y3 is CH: R14 and R13 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y2 is N or C-R14 , where R14 is selected from H, chloro, methyl, trinuoromethyl, methoxy, phenoxy, more preferably Y2 is CH, or C-Cl, even more preferably Y2 is C-Cl;
Y 3 is N under the condition that Y 2 is not N, or Y 3 is C-R 15 , where R 15 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety, if Y2 is C-R14 , R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety, preferably Y3 is N or C-R15, where R15 is selected from H, chloro, iodo, methyl, trinuoromethyl, methoxy, phenoxy or dimethylamino more preferably Y3 is CH; and in formulae Ij -6b and Ij-6c, R16, R16 and R17 are independently selected from H, chloro, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R16 and R17, or R16 and R17 together with the thiophenyl group they are attached to form a benzothiophenyl moiety, preferably R16, R16 and R17 are H.
Preferred compounds of formula Ij-6a are those wherein R13, R13 , R14 are H, Y2 is C-Cl and Y3 is C-I or CH, preferably CH.
Preferred compounds of formulae Ij-6b and Ij-6c are those wherein R16, R16'and R17 are H.
Particularly preferred compounds of the invention are those listed in Table 1 hereafter:
Table 1 :
Compound
Chemical name (M+H)+ n°
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
4 400.8 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(thiophen-3-yl)acetamido)-4-(4-
5 372.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-phenylacetamido)-4-(4-
6 366.3 (trifiuoromethyl)phenyl)butanoic acid
7 (S)-4-(4-nitrophenyl)-3-(2-(m-tolyl)acetamido)butanoic acid 357.4
8 (S)-4-(4-nitrophenyl)-3-(2-phenylacetamido)butanoic acid 343.3
(S)-4-(4-(trifiuoromethyl)phenyl)-3-(2-(4-
9 434.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
10 377.8 nitrophenyl)butanoic acid
(S)-3-(2-(2-methoxyphenyl)acetamido)-4-(4-
11 396.4 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(m-tolyl)acetamido)butanoic
12 346.8 acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(naphthalen-2-
13 382.9 yl)butanoic acid (R)-5-phenyl-3-(2-(thiophen-3-yl)acetamido)pentanoic acid 318.4
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(p-tolyl)butanoic
346.8 acid
(S)-4-(p-tolyl)-3-(2-(m-tolyl)acetamido)butanoic acid 326.4
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(4-
394.4 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3-
400.8 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-phenylacetamido)butanoic acid 332.8
(S)-4-(4-chlorophenyl)-3-(2-(3-
367.2 chlorophenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(thiophen-3-
338.8 yl)acetamido)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(m-
381.3 tolyl)acetamido)butanoic acid
(S)-3-(2-(thiophen-2-yl)acetamido)-4-(4-
372.4 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(3-
411.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(4-
416.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3 -(2 -(benzo [d] [1,3] dioxol-5 -yl)acetamido)-4-(4-
410.4 (trifluoromethyl)phenyl)butanoic acid
(R)-3 -(2 -(3 -chlorophenyl)acetamido)-5 -phenylpentano ic
346.8 acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(4-
400.8 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(3-
434.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(thiophen-3-
354.4 yl)acetamido)butanoic acid
(S)-3-(2-(naphthalen-l-yl)acetamido)-4-(4-
416.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(p-tolyl)acetamido)-4-(4-
380.4 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(4-
367.2 chlorophenyl)acetamido)butanoic acid (S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(4-
435.2 (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(m-tolyl)acetamido)-4-(4-
380.4 (trifluoromethyl)phenyl)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(4-
416.4 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4-
394.4 (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
400.8 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3,5-
360.8 dimethylphenyl)acetamido )butano ic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-phenylacetamido)butanoic
367.2 acid
(S)-3 -(2 -(3 -chlorophenyl)acetamido)-4-(3 -
400.8 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(thiophen-3-
349.4 yl)acetamido)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(4-
377.8 nitrophenyl)butanoic acid
(R)-3-(2-(4-chlorophenyl)acetamido)-4-(naphthalen-2-
382.9 yl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2,3-
401.7 dichlorophenyl)acetamido)butanoic acid
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(4-
371.4 nitrophenyl)butanoic acid
(3S)-3-(2-phenylpropanamido)-4-(4-
380.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(4-
394.4 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3-
362.8 methoxyphenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3,4-
401.7 dichlorophenyl)acetamido)butanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4-
435.2 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(3-methoxyphenyl)acetamido)-4-(4-
396.4 (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(naphthalen-2-
417.3 yl)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(naphthalen-l-
382.9 yl)acetamido)butanoic acid
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4-
435.2 (trifluoromethyl)phenyl)butanoic acid
(S)-3 -(2 -(3 -chlorophenyl)acetamido)-4-(3 ,4-
401.7 dichlorophenyl)butanoic acid
(S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(4-
412.2 nitrophenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2-
367.2 chlorophenyl)acetamido)butanoic acid
(R)-4- (naphthalen-2 -yl)-3 - (2 -phenylacetamido)butano ic ac id 348.4
(R)-3-(2-phenylacetamido)-4-(4-
366.3 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,6-dichlorophenyl)acetamido)-4-(4-
435.2 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(naphthalen-l-yl)acetamido)-4-(4-
393.4 nitrophenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(thiophen-2-
338.8 yl)acetamido)butanoic acid
(S)-3-(2-(3-methoxyphenyl)acetamido)-4-(4-
373.4 nitrophenyl)butanoic acid
(S)-4-(naphthalen-2-yl)-3-(2-(m-tolyl)acetamido)butanoic
362.4 acid
(S)-3-(2 -(naphthalen-2 -yl)acetamido)-4-(4-
393.4 nitrophenyl)butanoic acid
(R)-3-(2-(4-chlorophenyl)acetamido)-5-phenylpentanoic
346.8 acid
(R)-5-phenyl-3-(2-(4-
380.4
(trifluoromethyl)phenyl)acetamido)pentanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4-
412.2 nitrophenyl)butanoic acid
(S)-3-(2-(o-tolyl)acetamido)-4-(4-
380.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(m-tolyl)acetamido)-4-(4-
380.4 (trifluoromethyl)phenyl)butanoic acid
(3 S)-3 -(( 1 S)-2-phenylcyclopropanecarboxamido)-4-(4-
392.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,4-dichlorophenyl)acetamido)-4-(4-
435.2 (trifluoromethyl)phenyl)butanoic acid (S)-4-(4-nitrophenyl)-3-(2-(thiophen-2-
349.4 yl)acetamido)butanoic acid
(S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(2-
434.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(4-
400.8 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-cyanophenyl)-3-(2-(m-tolyl)acetamido)butanoic
337.4 acid
(S)-3-(2-(3-chloro-4-iodophenyl)acetamido)-4-(4-
526.7 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(l -phenylcyclopropanecarboxamido)-4-(4-
392.4 (trifluoromethyl)phenyl)butanoic acid
(R)-3 -(2 -(thiophen-3 -yl)acetamido)-4-(4-
372.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(4-
377.8 nitrophenyl)butanoic acid
(S)-3-(2-(2-methoxyphenyl)acetamido)-4-(4-
373.4 nitrophenyl)butanoic acid
(S)-3-(2-phenylacetamido)-4-(p-tolyl)butanoic acid 312.4
(S)-4-(3-(trifluoromethyl)phenyl)-3-(2-(3-
434.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2,4-
401.7 dichlorophenyl)acetamido)butanoic acid
(R)-3-(2-(2-chlorophenyl)acetamido)-4-(naphthalen-2-
382.9 yl)butanoic acid
(R)-3-(2-(4-chlorophenyl)acetamido)-4-(4-
400.8 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
357.8 cyanophenyl)butanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(naphthalen-2-
382.9 yl)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(thiophen-3-
373.3 yl)acetamido)butanoic acid
(R)-5-phenyl-3-(2-(thiophen-2-yl)acetamido)pentanoic acid 318.4
(S)-4-(4-chlorophenyl)-3-(2-(p-tolyl)acetamido)butanoic
346.8 acid
(R)-4-(naphthalen-2-yl)-3-(2-(thiophen-2-
354.4 yl)acetamido)butanoic acid (R)-4-(4-(trifluoromethyl)phenyl)-3-(2-(3-
434.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-(3-
367.2 chlorophenyl)acetamido)butanoic acid
(S)-3-(2-(pyridin-3-yl)acetamido)-4-(4-
367.3 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(naphthalen-2-
382.9 yl)acetamido)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(naphthalen- 1 -
382.9 yl)butanoic acid
(R)-3 -(2 -(2 ,3 -dichlorophenyl)acetamido)-5 -phenylpentano ic
381.3 acid
(S)-3-(2-(benzo[d][l ,3]dioxol-5-yl)acetamido)-4-(4-
376.8 chlorophenyl)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(3-
416.4 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(4-methoxyphenyl)acetamido)-4-(4-
396.4 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(o-tolyl)acetamido)butanoic
346.8 acid
(S)-4-(4-chlorophenyl)-3-(2-(3,4-
360.8 dimethylphenyl)acetamido )butano ic acid
(R)-4-(naphthalen-2-yl)-3-(2-(p-tolyl)acetamido)butanoic
362.4 acid
(S)-4-(4-nitrophenyl)-3-(2-(p-tolyl)acetamido)butanoic acid 357.4
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(naphthalen-l-
417.3 yl)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(3,4-
401.7 dichlorophenyl)butanoic acid
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(3-
394.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3 -(2 -phenylacetamido)-4-(3 -
366.3 (trifluoromethyl)phenyl)butanoic acid
(R)-4-(naphthalen- 1 -yl)-3-(2-(thiophen-3-
354.4 yl)acetamido)butanoic acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(p-tolyl)butanoic
340.4 acid
(3S)-4-(4-chlorophenyl)-3-(2-phenylpropanamido)butanoic
346.8 acid (S)-4-(4-chlorophenyl)-3-(2-(2-
362.8 methoxyphenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(4-
362.8 methoxyphenyl)acetamido)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-(4-
367.2 chlorophenyl)acetamido)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-(thiophen-3-
338.8 yl)acetamido)butanoic acid
(R)-5-phenyl-3-(2-(p-tolyl)acetamido)pentanoic acid 326.4
(S)-4-(naphthalen-2-yl)-3-(2-phenylacetamido)butanoic acid 348.4
(S)-4-(3,4-dichlorophenyl)-3-(2-(3,5-
395.3 dimethylphenyl)acetamido )butano ic acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(3-
400.8 (trifluoromethyl)phenyl)butanoic acid
(R)-4- (naphthalen-2 -yl)-3 - (2 -(m-to lyl)acetamido)butano ic
362.4 acid
(S)-3-(2-(thiophen-3-yl)acetamido)-4-(3-
372.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(3-
435.2 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(p-tolyl)butanoic
381.3 acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-5-phenylpentanoic
340.4 acid
(S)-3-(2 -(naphthalen-2 -yl)acetamido)-4-(p-tolyl)butanoic
362.4 acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(thiophen-2-
373.3 yl)acetamido)butanoic acid
(S)-4-(4-cyanophenyl)-3-(2-(3,5-
351.4 dimethylphenyl)acetamido )butano ic acid
(R)-3-(2-(2-chlorophenyl)acetamido)-4-(4-
400.8 (trifluoromethyl)phenyl)butanoic acid
(R)-5-phenyl-3-(2-phenylacetamido)pentanoic acid 312.4
(R)-4-(4-chlorophenyl)-3-(2-(3,4-
401.7 dichlorophenyl)acetamido)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(2,3-
436.1 dichlorophenyl)acetamido)butanoic acid
(S)-3-(2-(2,4-dichlorophenyl)acetamido)-4-(4-
412.2 nitrophenyl)butanoic acid (R)-4-(3-chlorophenyl)-3-(2-(thiophen-3-
338.8 yl)acetamido)butanoic acid
(R)-3 -(2 -(3 ,4-dichlorophenyl)acetamido)-5 -phenylpentano ic
381.3 acid
(R)-4-(3 -chlorophenyl)-3 -(2-(3-
367.2 chlorophenyl)acetamido)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(naphthalen-2-
382.9 yl)butanoic acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(3,4-
401.7 dichlorophenyl)butanoic acid
(R)-4-(4-cyanophenyl)-3-(2-(2,4-
351.4 dimethylphenyl)acetamido )butano ic acid
(S)-4-(p-tolyl)-3-(2-(3-
380.4
(trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(2-
411.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-4-(naphthalen-2-yl)-3-(2-(3-
416.4 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(4-
411.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-phenylacetamido)butanoic acid 332.8
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(p-tolyl)butanoic
381.3 acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
357.8 cyanophenyl)butanoic acid
(S)-3-(2-(thiophen-3-yl)acetamido)-4-(p-tolyl)butanoic acid 318.4
(S)-3-(2-(2-methoxyphenyl)acetamido)-5-phenylpentanoic
342.4 acid
(S)-3-(2-(thiophen-2-yl)acetamido)-4-(p-tolyl)butanoic acid 318.4
(R)-4-(4-(trifluoromethyl)phenyl)-3-(2-(4-
434.3 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(p-tolyl)butanoic
340.4 acid
(S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(4-
371.4 nitrophenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2-
400.8 (trifluoromethyl)phenyl)acetamido)butanoic acid (3S)-4-(4-nitrophenyl)-3-(2-phenylpropanamido)butanoic
357.4 acid
(S)-4-(3-chlorophenyl)-3-(2-(m-tolyl)acetamido)butanoic
346.8 acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(p-tolyl)butanoic
346.8 acid
(S)-5-phenyl-3-(l-
338.4 phenylcyclopropanecarboxamido)pentanoic acid
(R)-4-(4-cyanophenyl)-3-(2-(3,4-
351.4 dimethylphenyl)acetamido )butano ic acid
(S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(3-
435.2 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(3-
435.2 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(3-phenoxyphenyl)acetamido)-4-(4-
458.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(3-phenylpropiolamido)-4-(4-
376.3 (trifluoromethyl)phenyl)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-(m-tolyl)acetamido)butanoic
346.8 acid
(R)-3-(2-(p-tolyl)acetamido)-4-(4-
380.4 (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
377.8 nitrophenyl)butanoic acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4-
371.4 nitrophenyl)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(3,4-
436.1 dichlorophenyl)acetamido)butanoic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(3-
416.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(3-methoxyphenyl)acetamido)-4-(3-
396.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(o-tolyl)butanoic
346.8 acid
(S)-5-phenyl-3-(2-(4-
380.4
(trifluoromethyl)phenyl)acetamido)pentanoic acid
(S)-4-(3 -chlorophenyl)-3 -(2-(3 -
367.2 chlorophenyl)acetamido)butanoic acid
(R)-3-(2-(2-chlorophenyl)acetamido)-5-phenylpentanoic
346.8 acid (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(naphthalen-2-
417.3 yl)butanoic acid
(S)-3-(2-(naphthalen-l-yl)acetamido)-4-(3-
416.4 (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4-
394.4 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(pyridin-3-
349.4 yl)butanoic acid
(S)-3-(2-(2-methoxyphenyl)acetamido)-4-(o-tolyl)butanoic
342.4 acid
(S)-4-(4-nitrophenyl)-3-(2-(o-tolyl)acetamido)butanoic acid 357.4
(R)-3-(2-(2,4-dimethylphenyl)acetamido)-5-phenylpentanoic
340.4 acid
(S)-4-(2-chlorophenyl)-3-(2-(2-
362.8 methoxyphenyl)acetamido)butanoic acid
(R)-4- (2 -cyanopheny l)-3 -(2 - (o -to lyl)acetamido )butano ic
337.4 acid
(S)-4-(3 -chlorophenyl)-3 -(2-(3,4-
401.7 dichlorophenyl)acetamido)butanoic acid
(R)-3-(2-(benzo[d][l,3]dioxol-5-yl)acetamido)-5-
356.4 phenylpentanoic acid
(S)-4-(4-cyanophenyl)-3-(2-(3,4-
392.2 dichlorophenyl)acetamido)butanoic acid
(R)-4-(4-cyanophenyl)-3-(2-(2,3-
383.4 dimethoxyphenyl)acetamido)butanoic acid
(S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(4-
403.4 nitrophenyl)butanoic acid
(S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(p-
372.4 tolyl)butanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(4-
424.9 phenoxyphenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2,4-
360.8 dimethylphenyl)acetamido )butano ic acid
(R)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(naphthalen-2-
408.5 yl)butanoic acid
(R)-4-(2-cyanophenyl)-3-(2-(2-
391.4 (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(naphthalen-2-
376.5 yl)butanoic acid (S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(2-
426.4 (trifluoromethyl)phenyl)butanoic acid
(R)-4-(2-cyanophenyl)-3-(2-(2,3-
383.4 dimethoxyphenyl)acetamido)butanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(o-tolyl)butanoic
381.3 acid
(R)-5-phenyl-3-(l-
338.4 phenylcyclopropanecarboxamido)pentanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(o-tolyl)acetamido)butanoic
346.8 acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(3,4-
395.3 dimethylphenyl)acetamido )butano ic acid
(R)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(m-
372.4 tolyl)butanoic acid
(R)-5-phenyl-3-(2-(pyridin-4-yl)acetamido)pentanoic acid 313.4
(R)-4-(naphthalen-2-yl)-3-(2-(4-
440.5 phenoxyphenyl)acetamido)butanoic acid
(3R)-5-phenyl-3-(2-phenylpropanamido)pentanoic acid 326.4
(R)-4-(3-cyanophenyl)-3-(2-(2,3-
383.4 dimethoxyphenyl)acetamido)butanoic acid
(S)-4-(3-cyanophenyl)-3-(2-(3,4-
392.2 dichlorophenyl)acetamido)butanoic acid
(R)-4-(2-chlorophenyl)-3-(2-(3-
367.2 chlorophenyl)acetamido)butanoic acid
(R)-4-(4-nitrophenyl)-3-(2-(4-
435.4 phenoxyphenyl)acetamido)butanoic acid
(R)-4-(2-cyanophenyl)-3-(2-(3,4-
351.4 dimethylphenyl)acetamido )butano ic acid
(R)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(m-
340.4 tolyl)butanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-5-phenylpentanoic
381.3 acid
(R)-3 -(2 -(benzo [d] [ 1 ,3 ] dioxol-5 -yl)acetamido)-4-(2-
376.8 chlorophenyl)butanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(2,4-
401.7 dichlorophenyl)acetamido)butanoic acid
(S)-N-(l-(lH-tetrazol-5-yl)-2-(4-
410.8
(trifluoromethyl)phenyl)ethyl)-2 -(3 -chlorophenyl)acetamide (S)-N-(l -(lH-tetrazol-5-yl)-3-(4-
215 (trifluoromethyl)phenyl)propan-2-yl)-2-(3- 424.8 chlorophenyl)acetamide
(S)-2-(2-(3-chlorophenyl)acetamido)-3-(4-
216 (trifluoromethyl)phenyl)-N- 517.8
((tri fiuo ro methyl)sulfonyl)propanamide
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
217 (trifluoromethyl)phenyl)-N- 531.9
((tri fiuo ro methyl)sulfonyl)butan amide
(S)-2-(2-(3-chlorophenyl)acetamido)-N-hydroxy-3-(4-
218 401.8
(trifluoromethyl)phenyl)propanamide
(S)-3-(2-(3-chlorophenyl)acetamido)-N-hydroxy-4-(4-
219 415.8
(trifluoromethyl)phenyl)butanamide
(S)-2-(3-chlorophenyl)-N-(l -(5-oxo-4,5-dihydro-l ,2,4-
220 oxadiazol-3-yl)-2-(4- 426.8
(trifluoromethyl)phenyl)ethyl)acetamide
(S)-2-(3-chlorophenyl)-N-(l -(5-oxo-4,5-dihydro-l ,2,4-
221 thiadiazol-3-yl)-2-(4- 442.9
(trifluoromethyl)phenyl)ethyl)acetamide
((S)-2-(2-(3-chlorophenyl)acetamido)-3-(4-
222 434.8
(trifluoromethyl)phenyl)propyl)(methyl)phosphinic acid
(S)-(2-(2-(3-chlorophenyl)acetamido)-3-(4-
223 436.8
(trifluoromethyl)phenyl)propyl)phosphonic acid
(S)-N-(l -(4H-l ,2,4-triazol-3-yl)-3-(4-
224 (trifluoromethyl)phenyl)propan-2-yl)-2-(3- 423.8 chlorophenyl)acetamide
2-(3-chlorophenyl)-N-((2S)-l -(2,4-dioxothiazolidin-5-yl)-3-
225 471.9
(4-(trifluoromethyl)phenyl)propan-2-yl)acetamide
(S)-2-(2-(3-chlorophenyl)acetamido)-N-(lH-tetrazol-5-yl)-
226 453.8
3-(4-(trifluoromethyl)phenyl)propanamide
Tritiated (S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
227 401.8
(trifluoromethyl)phenyl)butanoic acid harmaceutically acceptable salts and solvates thereof.
The compounds of table 1 were named using ChemDraw Ultra 12 purchased from CambridgeSoft (Cambridge, MA, USA).
The compounds of formula I can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches. The invention further provides the use of the compounds of the invention or pharmaceutically acceptable salts, or solvates thereof as antagonists 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 and solvates thereof, as GPR43 antagonists.
APPLICATION
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 or solvate thereof for the manufacture of a medicament for treating and/or preventing inflammatory, gastrointestinal and/or metabolic disorders in a patient.
Preferably, the patient is a warm-blooded animal, more preferably a human.
According to a further feature of the present invention there is provided a method for modulating GPR43 receptor activity, in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said animal an effective amount of compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts or solvates may be administered as part of a combination therapy. Thus, are included within the scope of the present invention embodiments comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients. Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment and/or prevention of any of the diseases or conditions mediated by or associated with GPR43 receptor modulation, particularly 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 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 modulator compounds of Formula I or pharmaceutical acceptable salts or solvates 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 modulator 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 pharmaceutical acceptable salts or solvates 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 or solvates are coadministered in combination with one or more other therapeutic agents such as those described in detail further herein. In the above-described embodiment combinations of the present invention, the compound of Formula I, a pharmaceutically acceptable salt or solvate thereof and other therapeutic active agents may be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration, either serially or simultaneously. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).
The invention also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.
The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament. Preferably, the medicament is used for the treatment and/or prevention of 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 or solvate thereof for the manufacture of a medicament for modulating GPR43 receptor activity, in a patient, in need of such treatment, which comprises administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
Preferably, the patient is a warm-blooded animal, more preferably a human.
As set forth above, the compounds of the invention, their pharmaceutically acceptable salts or solvates 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 inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, des integrants, 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.
In a further aspect the invention relates to compounds described herein wherein one or more atom(s) is/are a radioisotope of the same element. In a particular form of this aspect of the invention the compound is labeled with tritium. Such radio-labeled compounds are synthesized either by incorporating radio-labeled starting materials or, in the case of tritium, exchange of hydrogen for tritium by known methods. Known methods include (1) electrophilic halogenation, followed by reduction of the halogen in the presence of a tritium source, for example, by hydrogenation with tritium gas in the presence of a palladium catalyst, or (2) exchange of hydrogen for tritium performed in the presence of tritium gas and a suitable organomettalic (e.g. palladium) catalyst.
Compounds of the invention labeled with tritium are useful for the discovery of novel medicinal compounds which bind to and modulate the activity, by agonism, partial agonism, or antagonism, of a GPR43 receptor. Such tritium-labeled compounds may be used in assays that measure the displacement of such compounds to assess the binding of ligands that bind to a GPR43 receptor. The invention therefore also relates to the use of a tritium-labeled compound of the invention for assessing the binding of ligands that bind to a GPR43 receptor or, in other words, to a method for assessing the binding of a ligand to a GPR43 receptor comprising contacting the tritium-labeled compound with the GPR43 receptor. In a further aspect the invention relates to compounds described herein additionally comprising one or more atoms of a radioisotope. In a particular form of this aspect of the invention the compound comprises a radioactive halogen. Such radio-labeled compounds are synthesized by incorporating radio-labeled starting materials by known methods. Particular embodiments of this aspect of the invention are those in which the radioisotope is selected from 18F, 123I, 125I, 131I, 75Br, 76Br, 77Br or 82Br. A most particular embodiment of this aspect of the invention is that in which the radioisotope is 123 I, 125 I, 131 I. Such compounds comprising one or more atoms of a radioisotope are useful as positron emission tomography (PET) ligands and for other uses and techniques to determine the location of a GPR43 receptor. Therefore such compounds can be used as a specific probe for the localization of a GPR43 receptor on cell surfaces. The invention therefore also relates to a method for localizing a GPR43 receptor on cell surfaces comprising contacting a compound of the invention comprising one or more atoms of a radioisotope with a cell surface. 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, chloro and iodo.
The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula CnH2n+i wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Cx-y -alkyl and Cx-Cy-alkyl refer to alkyl groups which comprise from x to y carbon atoms.
Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-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-pentadienyl and the like.
The term "alkynyl" as used herein refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Non limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers-and the like. The terms "alkenylene" and "alkynylene" respectively mean an alkenyl group or an alkinyl group as defined above having two single bonds as points of attachment to other groups.
The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloro methyl, 1 -bromoethyl, fiuoromethyl, difiuoro methyl, trifiuoro methyl, 1 ,1 ,1 -trifluoroethyl 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. Therefore, "cycloalkylene" herein refers to a saturated homocyclic hydrocarbyl biradical of Formula CnH2n-2. Suitable cycloalkylene groups are C3-6 cycloalkylene group, preferably a C3-5 cycloalkylene (i.e. 1 ,1-cyclopropylene, 1 ,2- cyclopropylene, 1 , 1-cyclobutylene, 1 ,2-cyclobutylene, 1 ,3-cyclobutylene, 1 ,3- cyclopentylene,or 1 ,1-cyclopentylene), more preferably a C3-4 cycloalkylene (i.e. 1 ,3- cyclopropylene, 1 ,1-cyclopropylene, 1 ,1-cyclobutylene, 1 ,2-cyclobutylene).
Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocycloalkyl" or "heterocyclyl". The terms 'Tieterocyclyl", "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-l -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1 , 3-dioxolanyl, 1 ,4- oxathianyl, lH-pyrrolizinyl, tetrahydro-l,l -dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl. The 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- a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2, 1 -benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l ,2-a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo- pyridazin-l(6H)-y 1 , 2-oxopyridin-l(2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.
The term 'Tieteroarylene" 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:
Figure imgf000056_0001
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
Figure imgf000056_0002
1 1
pyridazinyl pyrazinyl 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 "alkylamino" as used herein means an amino group substituted with one or two alkyl groups. This includes monoalkylamino and dialkylamino groups.
The term "carbamoyl" as used herein means a group of formula
Figure imgf000057_0001
wherein the arrow defines the attachment point.
The compounds of Formula I and subformulae thereof contain at least one asymmetric center and thus may exist as different stereo isomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.
The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (— ), a zigzag line ( ), a solid wedge ( ), or a dotted wedge ( ). 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, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2- hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydro gen -donating heteroatom (e.g. NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods:
(i) by reacting the compound of Formula I with the desired acid; (ii) by reacting the compound of Formula I with the desired base;
(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or
(iv) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or by means of a suitable ion exchange column.
All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
All references to compounds of formula I include references to salts, solvates, multi- component complexes and liquid crystals thereof.
The compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of formula I. In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form 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:
Figure imgf000060_0001
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. Within the meaning of the invention any atom of the compounds of the invention may present as any of its isotopes. In particular, any hydrogen atom may be tritium, and any F, I or Br radical may be the radioisotope selected from 18 F, 123 I, 125 I,
131 I, 75 Br, 76 Br, 77 Br or 82 Br. A most parti *cular embodi *ment of thi *s aspect of the invention is that the radioisotope is tritium, 123 I, 125 I, 131 I. 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 modulator) 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 modulator), 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 "antagonist" as used herein means a compound which competitively or non-competitively binds to a receptor at the same site as an agonist (for example, the endogenous ligand), but does not activate an intracellular response initiated by an active form of the receptor. An antagonist thereby inhibits the intracellular response induced by an agonist.
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; type I and type II diabetes; 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 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 Bowed 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 representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.
CHEMISTRY EXAMPLES The following intermediates and general procedures were used to prepare the compounds described herein.
The symbols, abbreviations, schemes and examples are consistent with those used in scientific publications such as the Journal of Medicinal Chemistry or the Bioorganic and Medicinal Chemistry. Specifically but not meant as limiting, the following abbreviations may be used in the examples and throughout the specification:
MW (molecular weight),
μwave (microwave),
eq (equivalent),
g (grams),
mg (milligrams),
L (liters),
mL (milliliters),
iL (microliters),
mol (moles),
mmol (millimoles),
μηιοΐ (micromoles),
nm (nanometer),
rt (room temperature),
h (hours), min (minutes),
TLC (thin layer chromatography),
TR (retention time),
EtOH (ethanol),
MeOH (methanol),
IPA (z'so-propanol),
DCM (dichloro methane),
DMF ( ,N-dimethylfoiTnamide),
THF (tetrahydrofuran),
MeCN (acetonitrile),
Ac (acetyl),
AcOEt (ethyl acetate),
Tr (trityl), DIEA ( ,N-diisopropylethylamine),
Fmoc (Fluorenylmethoxycarbonyl),
HOBt (1 -hydro xybenzotriazole),
TBTU (0-( 1 H-Benzotriazol- 1 -yl)-N,N, ' , '-tetramethyluronium tetrafluoroborate), Boc20 (di-ieri-butyl dicarbonate),
morphoCDI ( l -cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-/ toluenesulfonate),
DMAP (4-(dimethylamino)pyridine),
DIC (di-z'so-propylcarbodiimide), DCC (di-cyclohexyl-carbodiimide),
CDI (1 -1 '-carbonyldiimidazole),
TCDI (1 -1 '-thiocarbonyldiimidazole), PFP (pentafluorophenol),
TFE (1 ,1 ,1 -trifluoroethanol),
S-CSA ((l S)-(+)-10 camphorsulfonic acid),
RV (reaction vessel),
[Rh(COD)Cl]2 (chloro-(l ,5-cyclooctadiene)-rhodium(I)-d i m e r ) , D I B A L-H (diisobutylaluminium hydride).
All temperatures are expressed in °C and all reactions were carried out at room temperature unless otherwise stated.
Analytical thin layer chromatography was used to monitor reactions, establish flash chromatography conditions and verify purity of intermediates or final products. TLC plates used were Merck TLC aluminum sheet silica gel 60 F254 purchased from VWR International. TLC plates were revealed using ultraviolet irradiation (wavelength=254nm or 215nm) at room temperature or bromocresol green spray reagent or KMn04 revelator upon heating at 160°C. Absorbance values were obtained on a Molecular Devices SPECTRA max PLUS 384 spectrophotometer using a 1cm width cuvette.
HPLC-MS spectra were obtained on Waters instruments using Electropsray ionization (ESI). Samples were injected by a Waters 2767 sample manager. A Waters 2525 binary pump module is linked to a Waters 2996 photodiode array detector and a Waters micromass ZQ-2000. The column used is a Sunfire CI 8 5μ. Eluent is a mixture of solution A (0.1 % HC02H in H20) and solution B (0.1 % HC02H in MeCN): 5% solution B for lmin, gradient from 5% solution B to 95% solution B over 4 min, 95% solution B for 0.2 min and 5% solution B for 0.8min.
Enantiomeric excess was determined by HPLC using a chiral column. !H and 13C NMR spectra were recorded on a Bruker instrument at
400MHz. 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 (quartet), 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 International, Anaspec, Bachem, Peptech Corporation.
35μηιο1 Trityl-OH D-series lanterns were purchased from Mimotopes International and freeze -dried for 18h before use in a CHRIST ALPHA 1-2 LD. A wash cycle for the SynPhase lanterns means adding wash solvent, shaking at rt for 5min and decanting the wash solvent.
Undefined (racemic) asymmetric centers that may be present in the compounds of Formula I are interchangeably indicated by drawing a wavy (zigzag) bonds or a straight bond in order to visualize the undefined stereochemical character of the bond (e.g.= mixture of cis and trans).
Example 1: General synthetic route:
Synthetic route n°l
Unless specified, compounds of the present invention were synthesized in 5 steps using the synthetic route detailed in Schemes 1, 2, 3 and 4, starting from commercially available chemicals and Mimotopes International 35μηιο1 Trityl-OH SynPhase D series lanterns (Mimotopes Pty Ltd, Australia). Specifications and use of SynPhase lanterns are reported in Mimotopes International SynPhase Technical Note STN 001 -3. All Mimotopes International chemical, application and technical notes are available from http://www.mimotopes.com. Trityl SynPhaseLanterns are well known solid supports for organic synthesis of organic molecules containing a free carboxylic acid group. Martinez et al. have reported in J. Comb. Chem. 2003, 5, 356 the anchoring of N-Fmoc amino-acids, Fmoc-deprotection, acylation and cleavage chemical steps on Trityl SynPhaseLanterns for the synthesis of a spiroimidazolidinone library.
Figure imgf000067_0001
Mimotopes 35μιηοΙ Tr-OH D-series lantern
Figure imgf000067_0002
Scheme 1: anchoring of N-Fmoc protected amino-acids on trityl D-series lanterns
Trityl-OH D-series lanterns were converted to Trityl-Cl D-series lanterns with acetyl chloride in DCM prior to the anchoring of N-Fmoc amino-acid with Et3N in DMF/DCM. The synthesis was adapted from the Mimotopes International SynPhase Chemistry Note SCN009-2.
Figure imgf000068_0001
n>=1
Scheme 2: deprotection N-Fmoc amino-acids anchored on Trityl D-series lanterns
Deprotection of N-Fmoc amino-acids anchored on Trityl D-series lanterns was carried out using a solution of piperidine in DMF. The deprotection methodology used was adapted from the standard procedure reported by Mimotopes International in their SynPhase Chemistry Note SCN003-3. The loading of the lanterns was determined using the standard procedure reported by Mimotopes International in their SynPhase Chemistry Note SCN003-2.
Figure imgf000068_0002
Scheme 3: N-acylation of amino-acids anchored on Trityl D-series lanterns
Acylation of amino-acids on Trityl D-series lanterns was carried out using standard peptide coupling reagents such as HOBt (Chem. Ber. 1970, 103, 788; Pept. Sci. 2001, 37, 39; Tet. Lett. 1984, 25, 111) and TBTU {Jet. Lett. 1989, 30, 1927; J. Org. Chem. 1996, 61, 2322). The method used was similar method to that reported by Mimotopes in their SynPhase Technical Note STN 002-2.
Figure imgf000068_0003
Scheme 4: cleavage of N-acylamino-acids anchored on Trityl D-series lanterns
Cleavage of N-acylamino-acids anchored on trityl D-series lanterns was carried out under acidic conditions such as TFA in DCM. The method used was reported by Mimo topes International in their SynPhase Technical Note STN 002-2.
An alternative synthetic route is possible when starting from beta amino-ester building blocks for which synthesis is detailed in Scheme 6 below. The amino-ester may be acylated with the desired carboxylic acid using coupling reagents such as HOBt and TBTU, the subsequent saponification with LiOH or NaOH or KOH in a mixture of H20 and organic solvents such as THF or MeOH would yield the N-acyl beta-amino acid compounds as well as done with the solid phase synthesis using Trityl D-series lanterns.
Synthetic route n°2: suggested synthesis of beta amino-acids and beta amino-esters starting materials
E. Juaristi et al. wrote a comprehensive review of different enantioselective synthetic methodologies of beta amino-acids in Curr. Med. Chem. 1999, 6, 983. These methodologies are applicable to the synthesis of the intermediates N-Fmoc beta amino-acids and they should proceed with retention of configuration of the asymmetric carbon.
Fmoc protected beta amino-acids can be synthesized by the Arndt-Eistert reaction from N-Fmoc-alpha-aminodiazoketones using silver benzoate in 1 ,4-dioxane/H20 under microwave irradiation as shown in Scheme 5 and reported by Basanagoud et al. in Lett. Pept. Sci. 2002, 9, 231 . silver benzoate
1 ,4-dioxane/H20
Figure imgf000069_0001
μννβνβ
Scheme 5: a suggested synthesis of Fmoc protected beta amino-acids from N- Fmoc alpha-aminodiazoketone intermediates
Basanagoud et al. detailed such procedures and the synthesis of N-Fmoc alpha- aminodiazoketones intermediates from N-Fmoc alpha amino-acids using TBTU, diazomethane, DIEA in THF in Synth. Comm. 2003, 33, 3089. Other microwave assisted conditions for the rearrangement of Fmoc-alpha-aminodiazoketone to N- Fmoc beta amino-acids using silver trifluoroacetate and silica gel in AcOEt reported by Koch et al. in Synth. Comm. 2005, 35, 2789 may also be used.
Beta amino-ester building blocks may also be obtained via the enantioselective hydrogenation of enamine intermediates as described by M. Kubryk et al. in Tetrahedron Asymmetry 2006, 17, 205 and shown in Scheme 6.
Figure imgf000070_0001
Figure imgf000070_0002
Scheme 6: a suggested synthesis of beta amino-ester building blocks from enamine intermediates
Phenylacetic acid may be converted in two steps to the keto-ester intermediate using CDI and mono-methyl potassium malonate. Treatment of this keto-ester with ammonium acetate may provide the enamine which can be hydro genated enantioselectively using [Rh(COD)Ci]2 and chiral ferrocenyl ligand L in TFE to give the amino-ester building block in a crystalline form upon salt formation with S-CSA in IP A. This methodology may be adapted to synthesize the other enantiomer when adapting the enantioselective hydrogenation conditions by changing the catalyst and ligand. Such conditions are reported by Hsiao et al. in J. Am. Chem. Soc, 2004, 126, 9918. Enantioselective hydrogenation of enamines are also reported by Hou et al. in J. Am. Chem. Soc. 2006, 128, 11774.
Example 2: suggested carboxylic acid bioisosteres synthetic approaches
Synthetic approaches for the preparation of the bioisosteres of the carboxylic acids are suggested hereunder.
Isosterism is a concept defined by I. Langmuir in J. Am. Chem. Soc. 1919, 41, 1549 and developed by H.L. Friedman in Symposium on Chemical-Biological correlations, National Council Publication, Washington, DC (1951). As used herein the term "bioisosteres" refers to "groups or molecules which have chemical and physical similarities producing similar biological effects" (as defined in Chem. Soc. Rev. 1979, 8, 563). Suitable well known bioisosteric replacements of carboxylic acid groups are reported in The practice of medicinal chemistry, 2nd edition, by C.G. Wermuth.
Tetrazole analogs: suggested synthetic route n°3
Tetrazole analogs may be synthesized in one step by conversion of the corresponding amido -nitriles using sodium azide and ammonium chloride as shown in Scheme 7 and reported by Matthews et al. in J. Comb. Chem. 2000, 1, 19.
Figure imgf000071_0001
Scheme 7: a suggested synthesis of tetrazole analogs from amido-nitrile
intermediates
J-J Shie and J-M. Fang also described the conversion of nitriles to tetrazoles using sodium azide and zinc bromide under microwave irradiation in J. Org. Chem. 2007, 72, 3141. Another synthesis of tetrazoles from nitriles using tri-«-butyltin azide in 1 , 2 -diethoxy ethane as described by Harper et al. in J. Med. Chem. 1992, 35, 1191 may be suitable for the synthesis of the tetrazole analogs. Amido-nitriles may be obtained from commercially available amino -nitriles by acylation with the desired carboxylic acid using standard coupling reagents such as HOBt and TBTU; or with the desired acyl chloride in THF in the presence of Et3N or DIEA.
They may also be obtained from the carboxamide precursor using the chemical synthesis shown in Scheme 8.
Figure imgf000072_0001
Mimotopes 35μιηοΙ Rink Amide D-series lantern
Figure imgf000072_0002
Scheme 8: a suggested synthesis of amido-nitriles from carboxamide intermediates
Mimotopes Fmoc Rink amide SynPhase D-series PS lanterns can be Fmoc deprotected with a solution of piperidine in DMF. The Fmoc amino-acid may be anchored onto the lantern using DIC and HOBt coupling reagents. These two steps are described in the Mimotopes SynPhase Chemical Note SCN 001 -3. The Fmoc- group can be removed with a solution of piperidine in DMF and the acylation may be done using HOBt and TBTU coupling reagents. The desired carboxamide would then be cleaved from the lantern under acidic conditions as reported in the Mimotopes SynPhase Chemical Note SCN 002-3. The carboxamide may be converted to the desired amido-nitrile using cyanuric chloride in DMF as reported by Maetz and Rodriguez in Tetrahedron Lett. 1997, 38, 4221.
Carboxamide intermediates may be obtained in one step from the corresponding carboxylic acid using EDCI and ammonium carbonate in THF as reported by Arienti et al. in J. Med. Chem. 2005, 48, 1873.
The amino-nitrile starting materials may be obtained from commercially available amino-alcohols using the synthetic route described in Scheme 9.
Figure imgf000073_0001
solvent
Figure imgf000073_0002
3) TFA, DCM
Scheme 9: a suggested synthesis of amino -nitriles from amino-alcohols
The amino-alcohol may be converted to a iert-butyl carbamate using di-tert- butyldicarbonate and Lewis acid Ζη(Οθ4)2.6Η20 in an organic solvent such as DCM or iert-butanol as reported by Bartoli et al. in Synlett 2004, 10, 1794. Conversion of alcohol to the mesylate intermediate and treatment with sodium cyanide should provide the nitrile as described by Kokotou et al. in Org. Prep. Proced. Int. 1994, 26, 599. Subsequent Boc deprotection using TFA in DCM may yield the desired amino- nitrile. The various methods of Boc deprotections are summarized in the following books: Greene's Protective Groups in Organic Synthesis, 4th Edition, by P.G.M. Wutz and T.W. Greene, Wiley and Protecting groups: foundations of organic chemistry, 3rd edition, by P.J. Kocienski, Thieme.
Sulphonylamides analogs: suggested synthetic route n°4
Sulphonylamide analogs may be obtained in one step from the carboxylic precursor as shown in Scheme 10. 3
Figure imgf000074_0001
Scheme 10: a suggested synthesis of sulphonylamides analogs from carboxylic acids
The carboxylic acid may be converted to the sulphonylamide using (trifluoromethyl)sulphonamide, DMAP and morphoCDI in DCM as reported by Hutchinson et al. in J. Med. Chem. 1993, 36, 2771 (1993).
Hydroxamic acid analogs: suggested synthetic route n°5
Hydroxamic acid analogs may be obtained in two steps from the carboxylic acids as shown in Scheme 11.
Figure imgf000074_0002
Scheme 11: a suggested synthesis of hydroxamic acid analogs from carboxylic acids
The carboxylic acid may be converted to the corresponding O-trityl-hydroxamic acid using O-trityl-hydroxylamine and DCC in AcOEt; the trityl group may then be removed under acidic conditions to give the desired hydroxamic acid analog. These procedures are reported by S.R. Woulfe and M.J. Miller in J. Org. Chem. 1986, 51, 3133.
Oxo-oxadiazole analogs: synthetic route n°6
Oxo-oxadiazole analogs may be obtained in two steps from nitriles as shown in Scheme 12.
Figure imgf000075_0001
Scheme 12: suggested synthesis of oxo-oxadiazole analogs from nitrile intermediates
The nitrile may be converted to the amide-oxime using hydroxylamine hydrochloride and triethylamine in DMSO. Treatment of the amide-oxime with 2-ethylhexyl chloro formate, pyridine in DMF and subsequent refluxing in xylene may give the desired oxo-oxadiazole analog. Such procedures are reported by Kohara et al. in J. Med. Chem. 1996, 39, 5228.
Oxo-thiadiazole analogs: suggested synthetic route n°7
Oxo-thiadiazole analogs may be obtained in two steps from nitriles as shown in Scheme 13.
Figure imgf000075_0002
Scheme 13: a suggested synthesis of oxo-thiadiazole analogs from nitrile
intermediates
The nitrile may be converted to the amide-oxime using hydroxylamine hydrochloride and triethylamine in DMSO. Treatment of the amide-oxime with TCDI in THF and then silica gel in CHCls/MeOH may give the desired oxo-thiadiazole analog. Such procedures were reported by Kohara et al. in J. Med. Chem. 1996, 39, 5228.
Hydrox methylphosphinyl analogs: synthetic route n°8
Hydroxymethylphosphinyl analogs may be obtained in two steps from bromides as shown in Scheme 14.
Figure imgf000076_0001
Scheme 14: a suggested synthesis of hydroxymethylphosphinyl analogs from bromide intermediates
The bromide may be converted to the phosphinic ester using diethyl methylphosphonite in toluene. Treatment of the phosphinic ester with bromotrimethylsilane in DCM may give the desired hydroxymethylphosphinyl analog. Such procedures were reported by Drysdale et al. in J. Med. Chem. 1992, 35, 2573.
The bromide starting materials may be obtained from commercially available amino- alcohols using the synthetic route described in Scheme 15.
Figure imgf000076_0002
Scheme 15 a suggested synthesis of bromide intermediates from amino-alcohols The amino-alcohol may be converted to the trityl ether using trityl chloride in pyridine as reported by J.L. Yuan et al. in Org. Prep. Proced. Int. 2004, 36, 164. Subsequent acylation with the standard HOBt and TBTU coupling reagents and trityl deprotection with TFA in DCM may provide the alcohol-amide intermediate. General methods for trityl protection and deprotection of alcohols are listed in Greene's Protective Groups in Organic Synthesis, 4th Edition, by P.G.M. Wutz and T.W. Greene. Treatment of this alcohol-amide with carbon-tetrabromide and triphenylphosphine in DCM may give the desired bromide as reported by Ackermann et al. in Helv. Chem. Acta. 1990 , 73, 122. Phosphonyl analogs: suggested synthetic route n°9
Phosphonyl analogs may be obtained in two steps from the bromide precursor as shown in Scheme 17.
Figure imgf000077_0001
Scheme 17: a suggested synthesis of phosphonyl analogs from bromide intermediates
The bromide may be converted to the diethyl phosphonate intermediate using triethylphosphite as reported by Pillarsetty et al. in J. Am. Chem. Soc. 2005, 127, 331 . Subsequent acidolysis of the diethyl phosphonate intermediate with concentrated HCl may give the desired phosphonyl analog based on the methods for the preparation of phosphonic acids claimed in patent US 2007004937.
Tetrazole amide analogs: suggested synthetic route n°10
Tetrazole amide analogs may be obtained in one step from carboxylic acids as shown in Schem
Figure imgf000077_0002
Scheme 18: suggested synthesis of tetrazole amide analogs from carboxylic acids The carboxylic acid may be converted to the tetrazole amide analog using 5- aminotetrazole monohydrate with PFP and DCC in DMF. Such a procedure was reported by Drysdale et al. in J. Med. Chem. 1992, 35, 2573. Triazole analogues: suggested synthetic route n°ll
Triazole analogs may be obtained in one step from carboxylic acids as shown in Scheme 19.
Figure imgf000078_0001
Scheme 19: a synthesis of triazole analogs from carboxylic acids
The carboxylic acid may be converted to the ethyl ester using thionyl chloride in ethanol which upon treatment with hydrazine in EtOH may provide the hydrazide intermediate. Such procedures were reported by Elsinghorst et al. in J. Med. Chem. 2006, 25, 7540. Treatment of the hydrazide intermediate with potassium thiocyanate in EtOH should give the triazole analog as reported by Kelarev et al. in Z. Org. Khim. 1993, 29, 388.
2,4-Thiazolidinedione analogs: suggested synthetic route n°12
2,4-Thiazolidinedione analogs may be obtained in three steps from the amino-esters as shown in Scheme 20.
Figure imgf000078_0002
Figure imgf000078_0003
Scheme 20: a suggested synthesis of 2,4-thiazolidinedione analogs from amino-ester intermediates
The amino-ester CSA salt, which may be obtained using synthetic route n°2, may be acylated using the standard HOBt, TBTU coupling reagents to give the amido-ester which may then be reduced to the amido -aldehyde using DIBAL-H. The amido- aldehyde may be converted to the 2,4-thiazolidinedione analogs using a procedure reported by Momose et al. in J. Med. Chem. 2002, 45, 1518 (2002). Example 3: Intermediate and Compound synthesis
Compounds 1 -3 (i.e. intermediates 1-3) were synthesized using the synthetic route n°l . Compound 4 was synthesized using the synthetic route n°l .
Compound 1:
Fmoc-(3S)-3-amino-4-(4-trifiuoromethylphenyl)butanoic acid anchored on Trityl D- series lanterns
Figure imgf000079_0001
30 trityl-O H D-series lanterns were added to a l OOmL reaction vessel (RV) containing 50mL of a solution of 10 % (v/v) acetyl chloride in anhydrous DCM. The RV was inerted with argon and shaken at rt for 3h. Solvents were decanted and the lanterns were washed twice with 50mL of anhydrous DCM. The 50 Trityl-Cl lanterns obtained were used directly for the next step.
The 30 Trityl-Cl were added to a 25mL reaction vessel containing a solution of Fmoc-(S)-3-amino-4-(4-trifluoromethylphenyl)butanoic acid (2eq, 2.1mmol, 0.984g), DIEA (5.2eq, 5.46mmol, 0.9mL) in 15mL of anhydrous DCM/anhydrous DMF (1/1). The RVs were inerted with argon and shaken at rt for 20h. Solvents were decanted and the lanterns transferred to a lOOmL RV. The lanterns were washed twice with 50mL DMF/DCM (1/1) and twice with 50mL of DCM and then air dried for 30min. The loading of amino-acid on the lanterns was measured using the following procedure. 1 lantern with Fmoc-(S)-3-amino-5-(4-trifluoromethylphenyl)pentanoic acid anchored was added to a 25mL RV containing 1 OmL of a solution of 20 % (v/v) piperidine in DMF. The RV was shaken at rt for 30min. ImL of the reaction solution was diluted in lOmL of a solution of 20 % (v/v) piperidine in DMF. The absorbance (A301) of the resulting solution was measured at 301nm. The loading of the lantern can be calculated using the formula established by Mimotopes International: loading L^mol/lantern)=[(A3oi/s)x21xl04] where 8=7800M"1cm"1. A301 was measured as equal to 1.445 giving a loading of L=20^mol/lantern.
Compound 2:
(3S)-3-amino-4-(4-trifiuoromethylphenyl)butanoic acid anchored on Trityl D-series lanterns
Figure imgf000080_0001
29 lanterns with Fmo c-(S)-3-amino-5-(4-trifluoromethylphenyl)butanoic acid anchored were added to a lOOmL RV containing 50mL of a solution of 20 % (v/v) piperidine in DMF. The RV was shaken at rt for 30min. Solvents were decanted and the lanterns were washed twice with 50mL of DMF and twice with 50mL of DCM and then air dried for 30min.
Compound 3:
(3S)-3- {[(3-chlorophenyl)acetyl]amino} -4-[4-(trifluoromethyl) phenyl]butanoic acid anchored on Trityl D-series lanterns
Figure imgf000080_0002
I
30 lanterns with (S)-3-amino-5-(4-trifluoromethylphenyl)butanoic acid anchored were added to a lOOmL RV. To the RV were successively added 6mL of anhydrous DMF, 3-chlorophenylacetic acid (3.4eq, 2.1mmol, 358mg) dissolved in 6mL of anhydrous DMF, HOBt (3.8eq, 2.31mmol, 312mg) and TBTU (3.8eq, 2.31mmol, 742mg) both dissolved in 6mL of anhydrous DMF, DIEA ( 12eq, 7.35mmol, 1 .2 I mL). The RV was shaken at rt for 45min. Solvents were decanted and the lanterns were washed twice with 50mL of DMF and twice with 50mL of DCM and then air dried for 30min. This acylation procedure was repeated once.
Compound 4:
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid
Figure imgf000081_0001
To a lOOmL RV containing 30 lanterns with (3S)-3-{[(3- chlorophenyl)acetyl]amino}-4-[4-(trifiuoromethyl) phenyl]butanoic acid anchored was added 30mL of a solution of 2% (v/v) TFA in DCM. The RV was shaken at rt for 3h. The solution was recovered and the lanterns washed with 20mL of DCM. The cleavage and washing solutions were combined and solvents were removed by reduced pressure evaporation. The colorless solid recovered was purified by flash chromatography (DCM/MeOH/glacial AcOH=99/l/0.1) to give the title compound as a colorless solid (116mg, 48% over 2 steps). !H NMR (400MHz, DMSO-d6) 5=12.2ppm (s, 1H), 8.11 (d, J=8Hz, 1H), 7.55 (d, J=8Hz, 2H), 7.31 (d, 8Hz, 2H), 7.26 (dd, J=1.2Hz, J=4Hz, 2H), 7.2 (s, 1H), 7.05 (m, 1H), 4.25 (m, 1H), 3.33 (s, 2H), 2.99- 2.74 (m, 2H), 2.50-2.40 (m, 2H). HPLC-MS TR=3.46min, m/z=399.96 (MH+).
Compounds 5 to 213
Compounds 5 to 213 were prepared using synthetic route 1 , by analogy to compound n° 4 and starting from the corresponding ad hoc N-Fmoc amino-acid and carboxylic acid starting materials. In Table 3 which is set forth below, exemplary compounds of the invention are set out in tabulated form. In this table, the name of the compound, an arbitrarily assigned compound number and structural information are set out.
Table 3:
Compound
Chemical name (M+H)+ n°
(S)-3-(2-(thiophen-3-yl)acetamido)-4-(4-
5 372.4
(tri fluo romethyl)phenyl)butano ic acid (S)-3-(2-phenylacetamido)-4-(4-
6 366.3 (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(m-
7 357.4 tolyl)acetamido)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-
8 343.3 phenylacetamido)butanoic acid
(S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(4-
9 434.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
10 377.8 nitrophenyl)butanoic acid
(S)-3-(2-(2-methoxyphenyl)acetamido)-4-(4-
1 1 396.4 (tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(m-
12 346.8 tolyl)acetamido)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-
13 382.9 (naphthalen-2-yl)butanoic acid
(R)-5 -phenyl-3 -(2 -(thiophen-3 -
14 318.4 yl)acetamido)pentanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(p-
15 346.8 tolyl)butanoic acid
(S)-4-(p-tolyl)-3-(2-(m-tolyl)acetamido)butanoic
16 326.4 acid
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(4-
17 394.4 (tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(3-
18 400.8
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-
19 332.8 phenylacetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3-
20 367.2 chlorophenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3 -(2 -(thiophen-3 -
21 338.8 yl)acetamido)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(m-
22 381.3 tolyl)acetamido)butanoic acid
(S)-3-(2-(thiophen-2-yl)acetamido)-4-(4-
23 372.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-nitrophenyl)-3-(2-(3-
24 41 1.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(4-
25 416.4
(tri fluo romethyl)phenyl)butano ic acid (S)-3-(2-(benzo[d][l ,3]dioxol-5-yl)acetamido)-4-
26 410.4
(4-(trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-5-
27 346.8 phenylpentanoic acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(4-
28 400.8
(tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(3-
29 434.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(R)-4-(naphthalen-2-yl)-3-(2-(thiophen-3-
30 354.4 yl)acetamido)butanoic acid
(S)-3-(2-(naphthalen-l-yl)acetamido)-4-(4-
31 416.4 (tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(p-tolyl)acetamido)-4-(4-
32 380.4 (tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(4-
33 367.2 chlorophenyl)acetamido)butanoic acid
(S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(4-
34 435.2 (tri fluo romethyl)phenyl)butano ic acid
(R)-3-(2-(m-tolyl)acetamido)-4-(4-
35 380.4 (tri fluo romethyl)phenyl)butano ic acid
(R)-4-(naphthalen-2-yl)-3-(2-(4-
36 416.4
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4-
37 394.4 (tri fluo romethyl)phenyl)butano ic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
38 400.8 (tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(3,5-
39 360.8 dimethylphenyl)acetamido)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-
40 367.2 phenylacetamido)butanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(3-
41 400.8
(tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-nitrophenyl)-3-(2-(thiophen-3-
42 349.4 yl)acetamido)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(4-
43 377.8 nitrophenyl)butanoic acid
(R)-3-(2-(4-chlorophenyl)acetamido)-4-
44 382.9
(naphthalen-2-yl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2,3-
45 401.7 dichlorophenyl)acetamido)butanoic acid (S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(4-
46 371.4 nitrophenyl)butanoic acid
(3S)-3-(2-phenylpropanamido)-4-(4-
47 380.4
(trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(4-
48 394.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(3-
49 362.8 methoxyphenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3,4-
50 401.7 dichlorophenyl)acetamido)butanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4-
51 435.2 (tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(3-methoxyphenyl)acetamido)-4-(4-
52 396.4 (tri fluo romethyl)phenyl)butano ic acid
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-
53 417.3 (naphthalen-2-yl)butanoic acid
(S)-4-(4-chlorophenyl)-3 -(2 -(naphthalen- 1 -
54 382.9 yl)acetamido)butanoic acid
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4-
55 435.2 (tri fluo romethyl)phenyl)butano ic acid
(S)-3 -(2-(3 -chlorophenyl)acetamido)-4-(3 ,4-
56 401.7 dichlorophenyl)butanoic acid
(S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(4-
57 412.2 nitrophenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2-
58 367.2 chlorophenyl)acetamido)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-
59 348.4 phenylacetamido)butanoic acid
(R)-3-(2-phenylacetamido)-4-(4-
60 366.3 (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,6-dichlorophenyl)acetamido)-4-(4-
61 435.2 (tri fluo ro methyl)phenyl)butano ic acid
(S)-3-(2-(naphthalen-l-yl)acetamido)-4-(4-
62 393.4 nitrophenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(thiophen-2-
63 338.8 yl)acetamido)butanoic acid
(S)-3-(2-(3-methoxyphenyl)acetamido)-4-(4-
64 373.4 nitrophenyl)butanoic acid
(S)-4-(naphthalen-2-yl)-3-(2-(m-
65 362.4 tolyl)acetamido)butanoic acid (S)-3-(2-(naphthalen-2-yl)acetamido)-4-(4-
66 393.4 nitrophenyl)butanoic acid
(R)-3-(2-(4-chlorophenyl)acetamido)-5-
67 346.8 phenylpentanoic acid
(R)-5-phenyl-3-(2-(4-
68 380.4
(tri fluo romethyl)phenyl)acetamido )pentano ic ac id
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4-
69 412.2 nitrophenyl)butanoic acid
(S)-3-(2-(o-tolyl)acetamido)-4-(4-
70 380.4 (tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(m-tolyl)acetamido)-4-(4-
71 380.4 (tri fluo romethyl)phenyl)butano ic acid
(3S)-3-((lS)-2-phenylcyclopropanecarboxamido)-
72 392.4 4-(4-(trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,4-dichlorophenyl)acetamido)-4-(4-
73 435.2 (tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-nitrophenyl)-3-(2-(thiophen-2-
74 349.4 yl)acetamido)butanoic acid
(S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(2-
75 434.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(4-
76 400.8 (tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-cyanophenyl)-3-(2-(m-
77 337.4 tolyl)acetamido)butanoic acid
(S)-3-(2-(3-chloro-4-iodophenyl)acetamido)-4-(4-
78 526.7 (tri fluo romethyl)phenyl)butano ic acid
(S)-3-(l-phenylcyclopropanecarboxamido)-4-(4-
79 392.4 (tri fluo romethyl)phenyl)butano ic acid
(R)-3-(2-(thiophen-3-yl)acetamido)-4-(4-
80 372.4 (tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(4-
81 377.8 nitrophenyl)butanoic acid
(S)-3-(2-(2-methoxyphenyl)acetamido)-4-(4-
82 373.4 nitrophenyl)butanoic acid
83 (S)-3-(2-phenylacetamido)-4-(p-tolyl)butanoic acid 312.4
(S)-4-(3-(trifluoromethyl)phenyl)-3-(2-(3-
84 434.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(2,4-
85 401.7 dichlorophenyl)acetamido)butanoic acid (R)-3-(2-(2-chlorophenyl)acetamido)-4-
86 382.9 (naphthalen-2-yl)butanoic acid
(R)-3-(2-(4-chlorophenyl)acetamido)-4-(4-
87 400.8 (tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
88 357.8 cyanophenyl)butanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-
89 382.9 (naphthalen-2-yl)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(thiophen-3-
90 373.3 yl)acetamido)butanoic acid
(R)-5 -phenyl-3 -(2 -(thiophen-2-
91 318.4 yl)acetamido)pentanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(p-
92 346.8 tolyl)acetamido)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(thiophen-2-
93 354.4 yl)acetamido)butanoic acid
(R)-4-(4-(trifluoromethyl)phenyl)-3-(2-(3-
94 434.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(R)-4-(4-chlorophenyl)-3-(2-(3-
95 367.2 chlorophenyl)acetamido)butanoic acid
(S)-3-(2-(pyridin-3-yl)acetamido)-4-(4-
96 367.3 (tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(naphthalen-2-
97 382.9 yl)acetamido)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-
98 382.9 (naphthalen-l-yl)butanoic acid
(R)-3-(2-(2,3-dichlorophenyl)acetamido)-5-
99 381.3 phenylpentanoic acid
(S)-3-(2-(benzo[d][l ,3]dioxol-5-yl)acetamido)-4-
100 376.8
(4-chlorophenyl)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(3-
101 416.4
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(4-methoxyphenyl)acetamido)-4-(4-
102 396.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-4-(4-chlorophenyl)-3-(2-(o-
103 346.8 tolyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3,4-
104 360.8 dimethylphenyl)acetamido)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(p-
105 362.4 tolyl)acetamido)butanoic acid (S)-4-(4-nitrophenyl)-3-(2-(p-
106 357.4 tolyl)acetamido)butanoic acid
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-
107 417.3
(naphthalen-l-yl)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(3,4-
108 401.7 dichlorophenyl)butanoic acid
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(3-
109 394.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-phenylacetamido)-4-(3-
110 366.3
(trifluoromethyl)phenyl)butanoic acid
(R)-4-(naphthalen-l -yl)-3-(2-(thiophen-3-
111 354.4 yl)acetamido)butanoic acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(p-
112 340.4 tolyl)butanoic acid
(3S)-4-(4-chlorophenyl)-3-(2-
113 346.8 phenylpropanamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2-
114 362.8 methoxyphenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(4-
115 362.8 methoxyphenyl)acetamido)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-(4-
116 367.2 chlorophenyl)acetamido)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-(thiophen-3-
117 338.8 yl)acetamido)butanoic acid
(R)-5-phenyl-3-(2-(p-tolyl)acetamido)pentanoic
118 326.4 acid
(S)-4-(naphthalen-2-yl)-3-(2-
119 348.4 phenylacetamido)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(3,5-
120 395.3 dimethylphenyl)acetamido)butanoic acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(3-
121 400.8
(tri fluo romethyl)phenyl)butano ic acid
(R)-4-(naphthalen-2-yl)-3-(2-(m-
122 362.4 tolyl)acetamido)butanoic acid
(S)-3-(2-(thiophen-3-yl)acetamido)-4-(3-
123 372.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(3-
124 435.2
(tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(p-
125 381.3 tolyl)butanoic acid (S)-3-(2-(3,4-dimethylphenyl)acetamido)-5-
126 340.4 phenylpentanoic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(p-
127 362.4 tolyl)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(thiophen-2-
128 373.3 yl)acetamido)butanoic acid
(S)-4-(4-cyanophenyl)-3-(2-(3,5-
129 351.4 dimethylphenyl)acetamido)butanoic acid
(R)-3-(2-(2-chlorophenyl)acetamido)-4-(4-
130 400.8
(tri fluo romethyl)phenyl)butano ic acid
131 (R)-5-phenyl-3-(2-phenylacetamido)pentanoic acid 312.4
(R)-4-(4-chlorophenyl)-3-(2-(3,4-
132 401.7 dichlorophenyl)acetamido)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(2,3-
133 436.1 dichlorophenyl)acetamido)butanoic acid
(S)-3-(2-(2,4-dichlorophenyl)acetamido)-4-(4-
134 412.2 nitrophenyl)butanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(thiophen-3-
135 338.8 yl)acetamido)butanoic acid
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-5-
136 381.3 phenylpentanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(3-
137 367.2 chlorophenyl)acetamido)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-
138 382.9
(naphthalen-2-yl)butanoic acid
(S)-3-(2-(2-chlorophenyl)acetamido)-4-(3,4-
139 401.7 dichlorophenyl)butanoic acid
(R)-4-(4-cyanophenyl)-3-(2-(2,4-
140 351.4 dimethylphenyl)acetamido)butanoic acid
(S)-4-(p-tolyl)-3-(2-(3-
141 380.4
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-4-(4-nitrophenyl)-3-(2-(2-
142 41 1.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-4-(naphthalen-2-yl)-3-(2-(3-
143 416.4
(trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(4-
144 41 1.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(R)-4-(4-chlorophenyl)-3-(2-
145 332.8 phenylacetamido)butanoic acid (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(p-
146 381.3 tolyl)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
147 357.8 cyanophenyl)butanoic acid
(S)-3-(2-(thiophen-3-yl)acetamido)-4-(p-
148 318.4 tolyl)butanoic acid
(S)-3-(2-(2-methoxyphenyl)acetamido)-5-
149 342.4 phenylpentanoic acid
(S)-3-(2-(thiophen-2-yl)acetamido)-4-(p-
150 318.4 tolyl)butanoic acid
(R)-4-(4-(trifluoromethyl)phenyl)-3-(2-(4-
151 434.3
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(p-
152 340.4 tolyl)butanoic acid
(S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(4-
153 371.4 nitrophenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2-
154 400.8
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(3S)-4-(4-nitrophenyl)-3-(2-
155 357.4 phenylpropanamido)butanoic acid
(S)-4-(3-chlorophenyl)-3-(2-(m-
156 346.8 tolyl)acetamido)butanoic acid
(S)-3-(2-(4-chlorophenyl)acetamido)-4-(p-
157 346.8 tolyl)butanoic acid
(S)-5-phenyl-3-(l-
158 338.4 phenylcyclopropanecarboxamido)pentanoic acid
(R)-4-(4-cyanophenyl)-3-(2-(3,4-
159 351.4 dimethylphenyl)acetamido)butanoic acid
(S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(3-
160 435.2
(tri fluo romethyl)phenyl)butano ic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(3-
161 435.2
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(3-phenoxyphenyl)acetamido)-4-(4-
162 458.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-3-(3-phenylpropiolamido)-4-(4-
163 376.3
(trifluoromethyl)phenyl)butanoic acid
(R)-4-(4-chlorophenyl)-3-(2-(m-
164 346.8 tolyl)acetamido)butanoic acid
(R)-3-(2-(p-tolyl)acetamido)-4-(4-
165 380.4
(tri fluo romethyl)phenyl)butano ic acid (R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-
166 377.8 nitrophenyl)butanoic acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4-
167 371.4 nitrophenyl)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(3,4-
168 436.1 dichlorophenyl)acetamido)butanoic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(3-
169 416.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-3 -(2-(3 -methoxyphenyl)acetamido)-4-(3 -
170 396.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(o-
171 346.8 tolyl)butanoic acid
(S)-5-phenyl-3-(2-(4-
172 380.4
(trifluoromethyl)phenyl)acetamido)pentanoic acid
(S)-4-(3-chlorophenyl)-3-(2-(3-
173 367.2 chlorophenyl)acetamido)butanoic acid
(R)-3-(2-(2-chlorophenyl)acetamido)-5-
174 346.8 phenylpentanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-
175 417.3
(naphthalen-2-yl)butanoic acid
(S)-3 -(2-(naphthalen- 1 -yl)acetamido)-4-(3 -
176 416.4
(tri fluo romethyl)phenyl)butano ic acid
(R)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4-
177 394.4
(tri fluo romethyl)phenyl)butano ic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(pyridin-3-
178 349.4 yl)butanoic acid
(S)-3-(2-(2-methoxyphenyl)acetamido)-4-(o-
179 342.4 tolyl)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(o-
180 357.4 tolyl)acetamido)butanoic acid
(R)-3-(2-(2,4-dimethylphenyl)acetamido)-5-
181 340.4 phenylpentanoic acid
(S)-4-(2-chlorophenyl)-3-(2-(2-
182 362.8 methoxyphenyl)acetamido)butanoic acid
(R)-4-(2-cyanophenyl)-3-(2-(o-
183 337.4 tolyl)acetamido)butanoic acid
(S)-4-(3-chlorophenyl)-3-(2-(3,4-
184 401.7 dichlorophenyl)acetamido)butanoic acid
(R)-3-(2-(benzo[d][l,3]dioxol-5-yl)acetamido)-5-
185 356.4 phenylpentanoic acid (S)-4-(4-cyanophenyl)-3-(2-(3,4-
186 392.2 dichlorophenyl)acetamido)butanoic acid
(R)-4-(4-cyanophenyl)-3-(2-(2,3-
187 383.4 dimethoxyphenyl)acetamido)butanoic acid
(S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(4-
188 403.4 nitrophenyl)butanoic acid
(S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(p-
189 372.4 tolyl)butanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(4-
190 424.9 phenoxyphenyl)acetamido)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(2,4-
191 360.8 dimethylphenyl)acetamido)butanoic acid
(R)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-
192 408.5
(naphthalen-2-yl)butanoic acid
(R)-4-(2-cyanophenyl)-3-(2-(2-
193 391.4
(tri fluo romethyl)phenyl)acetamido )butano ic acid
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-
194 376.5
(naphthalen-2-yl)butanoic acid
(S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(2-
195 426.4
(tri fluo romethyl)phenyl)butano ic acid
(R)-4-(2-cyanophenyl)-3-(2-(2,3-
196 383.4 dimethoxyphenyl)acetamido)butanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(o-
197 381.3 tolyl)butanoic acid
(R)-5-phenyl-3-(l -
198 338.4 phenylcyclopropanecarboxamido)pentanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(o-
199 346.8 tolyl)acetamido)butanoic acid
(S)-4-(3,4-dichlorophenyl)-3-(2-(3,4-
200 395.3 dimethylphenyl)acetamido)butanoic acid
(R)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(m-
201 372.4 tolyl)butanoic acid
(R)-5-phenyl-3-(2-(pyridin-4-
202 313.4 yl)acetamido)pentanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(4-
203 440.5 phenoxyphenyl)acetamido)butanoic acid
(3R)-5-phenyl-3-(2-phenylpropanamido)pentanoic
204 326.4 acid
(R)-4-(3-cyanophenyl)-3-(2-(2,3-
205 383.4 dimethoxyphenyl)acetamido)butanoic acid (S)-4-(3-cyanophenyl)-3-(2-(3,4-
206 392.2
dichlorophenyl)acetamido)butanoic acid
(R)-4-(2-chlorophenyl)-3-(2-(3-
207 367.2
chlorophenyl)acetamido)butanoic acid
(R)-4-(4-nitrophenyl)-3-(2-(4-
208 435.4
phenoxyphenyl)acetamido)butanoic acid
(R)-4-(2-cyanophenyl)-3-(2-(3,4-
209 351.4
dimethylphenyl)acetamido)butanoic acid
(R)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(m-
210 340.4
tolyl)butanoic acid
(S)-3-(2-(3,4-dichlorophenyl)acetamido)-5-
211 381.3
phenylpentanoic acid
(R)-3-(2-(benzo[d][l,3]dioxol-5-yl)acetamido)-4-
212 376.8
(2-chlorophenyl)butanoic acid
(R)-4-(3-chlorophenyl)-3-(2-(2,4-
213 401.7
dichlorophenyl)acetamido)butanoic acid
Intermediate 3-chloro-4-iodophenylacetic acid intermediate was made for the synthesis of compound 78, the procedure is described below: Boron trifluoride dihydrate (5mL, leq) was added carefully to a mixture of 3- chlorophenylacetic acid (lOmmol, leq) and N-iodosuccinimide (lOmmol, leq) at room temperature. The reaction mixture was stirred at room temperature overnight and partitioned between DCM and water. The biphasic mixture was stirred and acidified with 1M aqueous HC1. The DCM layer was washed with 1M aqueous solution of sodium metabisulfite, dried and concentrated in vacuo. Crude was purified by flash chromatography (DCM or DCM/MeOH=95/5) to give a colorless solid which was further purified by preparative HPLC. Desired product was obtained as a colorless solid in 34% yield.
Compound 227: Tr i t i a t e d ( S )-3-(2-(3-chlorophenyl)acetamido)-4-(4- (tri fluo ro methyl)phenyl)butano ic acid
Figure imgf000093_0001
Compound 78 (4mg) and 10% palladium on charcoal (lOmg) were transferred to a tritiation vessel with ethanol (2ml) and diisopropylethylamine (50μ1). The mixture was stirred under an atmosphere of tritium gas (5Ci) for 2 hours. The catalyst was removed by filtration through a Millipore HV (0.45μπι) filter and labile activity was removed by repeated evaporations from ethanol (3x5mL). The residue was dissolved in ethanol (25mL). Crude was purified by high performance liquid chromatography on an Ultrasphere ODS column eluting with a water:methanol:trifluoroacetic acid gradient system. The product was collected, rotary evaporated to dryness and residues dissolved in ethanol. The radiochemical purity of title product, determined by high performance liquid chromatography, was 99.2 %.
BIOLOGICAL EXAMPLES BRIEF DESCRIPTION OF DRAWINGS
Figure 1 represents a graph plotting the dose dependent antagonist effect of
35
compound 4 and compound 38 on [ S]-GTPyS binding to the membrane of CHO cells expressing GPR43 in response to propionate stimulation. Compound 4 and compound 38 display an IC50 value of 20 nM and 93 nM, respectively. Data represent the mean ± SD for duplicates data points. Figure 2 represents a graph plotting the dose -dependent antagonist effect of compound 4 on intracellular calcium increase of CHO cells expressing GPR43 in response to propionate stimulation. Compound 4 displays an IC50 value of 10 nM. Data represent the mean ± SD for duplicates data points.
Figure 3 represents a competition radioligand (compound 227) binding assay of the compound 4 and propionate in human GPR43 recombinant cell line.
Figure 4 represents a competition radioligand (compound 227) binding assay of the compound 4 in human neutrophil.
Biological data
The following assays can be used for determination of GPCR activation
Example 4: Membrane binding assay: GTPyS binding assay.
When a GPCR is in its active state, either as a result of ligand binding or constitutive activation, the receptor couples to a G protein and stimulates the release of GDP and subsequent binding of GTP to the G protein. The alpha subunit of the G protein- receptor complex acts as a GTPase and slowly hydrolyses the GTP to GDP, at which point the receptor normally is deactivated. Activated receptors continue to exchange GDP for GTP. The non-hydrolysable GTP analog, [35S]GTPyS , was used to
35
demonstrate enhance binding of [ SJGTPyS to membranes expressing receptors. The
35
assay uses the ability of GPCR to stimulate [ SJGTPyS binding to membranes expressing the relevant receptors. The assay can, therefore, be used in the direct identification method to screen candidate compounds to endogenous GPCR and non- endogenous, constitutively activated GPCRs.
Preparation of membrane extracts:
Membrane extracts were prepared for each clone as follows: the medium was aspirated and the cells were scraped from the plates in Ca++ and Mg++-free Phosphate- buffered saline (PBS). The cells were then centrifuged for 3 min at 1500 g and the pellets were resuspended in buffer A (15 mM Tris-HCl pH 7.5, 2 mM MgCl2, 0.3 mM EDTA, 1 mM EGTA) and homogenized in a glass homogenizer. The crude membrane fraction was collected by two consecutive centrifugation steps at 40.000 x g for 25 min separated by a washing step in buffer A. The final pellet was resuspended in 500 μΐ of buffer B (75 mM Tris-HCl pH 7.5, 12.5 mM MgCl2, 0.3 mM EDTA, ImM EGTA, 250 mM sucrose) and flash frozen in liquid nitrogen. Protein content was assayed by the Folin method.
GTPYS assay (SPA method):
The assay was performed in the presence of SCFA, and was used to determine the activity of the present antagonist.
The GTPy [35S] assay was incubated in 20 mM HEPES pH7.4, 100 mM NaCl, 10 μg/ml saponin, 30 mM of MgCl2, 10 μΜ of GDP, 5 μg membrane-expressing hGPR43, 250μg of wheatgerm agglutinin beads (Amersham, ref RPNQ001), a range concentration of Compounds 4 and 38 (from 30 μΜ to 1 nM) and 600 μΜ of propionate in a final volume of 100 μΐ for 30 min at room temperature. 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 are illustrated in Figure 1. Figure 1 shows the dose- dependent antagonist effect of compounds 4 and 38 on [35S]-GTPyS binding to the membrane of CHO cells expressing GPR43 in response to propionate stimulation. Compounds 4 and 38 displayed an IC50 value of 20 nM and 93nM respectively.
Example 5: Cell based assay: Calcium flux. The Aequorin-based assay.
The aequorin assay uses the responsiveness of mitochondrial apoaequorin to intracellular calcium release induced by the activation of GPCRs (Stables et al., 1997, Anal. Biochem. 252: 1 15-126; Detheux et al., 2000, J. Exp. Med., 192 1501-1508). Briefly, GPCR-expressing clones are transfected to coexpress mitochondrial apoaequorin and Gal 6. Cells are incubated with 5 μΜ Coelenterazine H (Molecular Probes) for 4 hours at room temperature, washed in DMEM-F12 culture medium and resuspended at a concentration of 0.5 x 106 cells/ml (the amount can be changed for optimization). Cells are then mixed with test agonist molecules and light emission by the aequorin is recorded with a luminometer for 30 sec. Results are expressed as Relative Light Units (RLU). Controls include assays using cells not expressing GPCR (mock transfected), in order to exclude possible non-specific effects of the candidate compound.
Aequorin activity or intracellular calcium levels are "changed" if light intensity increases or decreases by 10% or more in a sample of cells, expressing a GPCR and treated with a compound of the invention, relative to a sample of cells expressing the GPCR but not treated with the compound of the invention or relative to a sample of cells not expressing the GPCR (mock-transfected cells) but treated with the compound of the invention.
The assay was performed in the presence of SCFA, to determine the antagonistic activity of compound of the invention.
Figure 2 shows the dose-dependent antagonist effect of compound 4 on intracellular calcium increase in response to propionate stimulation using the aequorin-based assay. Compound 4 displayed an IC50 value of 10 nM.
In Table 4 biological results obtained using the aequorin based assay with compounds of the invention are set out in tabulated form. In this table the calculated % of inhibition at 0.3μΜ is given. The % of inhibition value obtained (in accordance with the protocol set forth above) is represented as follows: "+++" means % Inhibition > 60%; "++" means 40% < % Inhibition < 60%.
TABLE 4
Compound % Inhibition
4 +++
5 +++
6 +++
7 +++
8 +++
9 +++
10 +++
11 +++
12 +++
13 +++
14 +++
15 +++
16 +++
17 +++
18 +++
19 +++
20 +++
21 +++
22 +++ 23 +++
24 +++
25 +++
26 +++
27 +++
28 +++
29 +++
30 +++
31 +++
32 +++
33 +++
34 +++
35 +++
36 +++
37 +++
38 +++
39 +++
40 +++
41 +++
42 +++
43 +++
44 +++
45 +++
46 +++
47 +++
48 +++
49 +++
50 +++
51 +++
52 +++
53 +++
54 +++
55 +++
56 +++
57 +++
58 +++
59 ++
60 ++
61 ++
62 ++
63 ++
64 ++
65 ++
66 ++
67 ++ 68 ++
69 ++
70 ++
71 ++
72 ++
73 ++
74 ++
75 ++
76 ++
77 ++
78 +++
The target selectivity of the compounds of the invention was evaluated at a concentration up to 10 μΜ of compound by using the aequorin assay described above. In such assay, the selectivity was tested on receptors responding to FFAs and having a sequence highly related to GPR43, namely GPR40, GPR41 and GPR120 receptors. By way of example, compound n°4 at a concentration of 10 μΜ does not display cross reactivity on GPR40, GPR41 and GPR120. Such a result indicates the high selectivity of the compounds of the invention on the GPR43 receptor. Example 6: Radioligand Binding assays
Human GPR43 recombinant cell line
Human GPR43 radioligand binding assay is performed by adding successively in the wells of a 96 well plate (Master Block, Greiner, 786201), 50 μΐ of compound of the invention or 50 μΐ of propionate (natural ligand of GPR43) at increasing concentrations (diluted in assay buffer: 50 mM Tris pH 7.4), 25 μΐ radiolabeled antagonist diluted in assay buffer and 25 μΐ of cell membrane extracts (10 μg protein/well). The final concentration of radiolabeled antagonist in the assay is 10 nM. The plate is incubated 60 min at 25°C in a water bath and then filtered over GF/B filters (Perkin Elmer, 6005177, presoaked in 0.05% Brij for 2h at room temperature) with a Filtration unit (Perkin Elmer). The filters are washed 3 times with 0.5 ml of ice-cold wash buffer (50 mM Tris pH 7.4). 50 μΐ of Microscint 20 (Packard), is added and the plate is incubated 15 min on an orbital shaker and then counted with a TopCount™ for 1 min/well.
When tested in the radioligand binding assay described above and by way of illustration the compound n°4 and the propionate decrease the compound 227 radioligand binding in a human GPR43 recombinant cell line (Figure 3). Human neutrophil
Human GPR43 radioligand binding assay is performed by adding successively in the wells of a 96 well plate (Master Block, Greiner, 786201), 50 μΐ of compound of the invention at increasing concentrations (diluted in assay buffer: 50 mM Tris pH 7.4), 25 μΐ radiolabeled antagonist diluted in assay buffer and 25 μΐ of human neutrophil (2.5xl05 cell /well). The final concentration of radiolabeled antagonist in the assay is 10 nM. The plate is incubated 60 min at 25°C in a water bath and then filtered over GF/B filters (Perkin Elmer, 6005177, presoaked in 0.05% Brij for 2h at room temperature) with a Filtration unit (Perkin Elmer). The filters are washed 3 times with 0.5 ml of ice- cold wash buffer (50 mM Tris pH 7.4). 50 μΐ of Microscint 20 (Packard), is added and the plate is incubated 15 min on an orbital shaker and then counted with a TopCount™ for 1 min/well.
When tested in the radioligand binding assay described above and by way of illustration the compound 4 decreases the compound 227 radioligand binding in a human neutrophil (Figure 4).

Claims

1. A compound of formula I:
Figure imgf000100_0001
(I), and pharmaceutically acceptable salts and solvates thereof, wherein
Ar1 is a group selected from isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, aryl, tetrahydrofuranyl, tetrahydropyranyl, morpholin-4-yl, piperazin- 1 -yl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, acyl, amino, alkylamino, cycloalkylamino, arylamino, heteroarylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydro xycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, cycloalkylsulfamoyl, arylsulfamoyl, heterocyclylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino; L1 is Ci-3alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl, hydroxyl or alkoxy;
R1 is H, linear or branched C1-C4 alkyl;
L is -0-, Ci-3alkylene, ethenylene, ethynylene or C3-4cycloalkylene, each group being optionally substituted by one or more substituent(s) selected from selected from halo, alkyl, hydroxyl or alkoxy, or L2 is N-R2 where R2 is H, linear or branched d- C4 alkyl;
Ar2 is a group selected from aryl or heteroaryl, each group being optionally substituted by one or more substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, acyl, amino, alkylamino, cycloalkylamino, arylamino, heteroarylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, alkylcarbonylamino , cycloalkylcarbonylamino , heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, cycloalkylsulfamoyl, arylsulfamoyl, heterocyclylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino or two substituents form an alkylenedioxy group or a haloalkylenedioxy group, or fused to the aryl or heteroaryl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, oxo, nitro, cyano, alkyl, hydroxyalkyl, haloalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino;
L3 is a single bond or a Ci-2alkylene optionally substituted by one or more substituent(s) selected from halo, alkyl or hydroxyl;
Z is selected from the group consisting of -COOR,
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000103_0003
Figure imgf000103_0004
wherein R is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R3 is H, methyl or ethyl, and R3 is hydroxyl -S02CH3i -S02cyclopropyl or -S02CF3; with the following provisos
1 - when Z is COOR, L is neither a single bond nor -CH(OH)-;
2- the compound of formula I is none of the compounds listed below:
- (S) -methyl 3-((S)-2 -methoxy-2 -phenylac etamido)-5 -phenylpentano ate ,
- (R)-methyl 3-((S)-2-methoxy-2-phenylacetamido)-5-phenylpentanoate, - (S)-ethyl 4-(4-nitrophenyl)-3-((phenoxycarbonyl)amino)butanoate, - 3-(3-([l , -biphenyl]-4-yl)ureido)-4-phenylbutanoic acid,
- 3-(3-(4-phenoxyphenyl)ureido)-4-phenylbutanoic acid,
- (R)-3 -(2-(3 -bromophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid,
- (S)-4-phenyl-3-(2-(l ,3,9-trimethyl-2,6-dioxo-2,3,6,9-tetrahydro-lH-purin-8- yl)acetamido)butanoic acid,
- 2,2-difluoro-3-(2-phenylacetamido)octanoic acid; and,
3- Ar2 is not substituted by a pyrimidinylalkyl, dihydropyrimidinyl or 1 ,3,5-triazinyl moiety. 2. The compound of claim 1 having formula la
Figure imgf000104_0001
1 2 1 2 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , L , L3, R1 and Z are as defined in claim 1. 3. The compound of claim 2 having formula la- 1
Figure imgf000104_0002
Ia-1 1 2 1 2 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , L , L3, and Z are as defined in claim 2.
4. The compound of claim 3 having the formula Ia-2
Figure imgf000105_0001
Ia-2
1 2 1 2 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , L , and L3 are as defined in claim 3 and R is as defined in claim 1.
5. The compound of claim 4 having the formula Ib-2a
Figure imgf000105_0002
Ib-2a and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, and L3 are as defined in claim 4, and wherein
R and R are independently selected from H, halo, alkyl, hydro xyl or alkoxy, or R and R together form a cyclopropane ring optionally substituted by one or more halo, alkyl, hydroxyl or alkoxy.
6. The compound of claim 5 having the formula Ib-4
Figure imgf000106_0001
Ib-4, and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, R4 and R4' are as defined above in claim 5 and wherein
R" and R° are independently selected from H, halo or alkyl.
7. The compound of claim 6 having the formula Ib-4a
Figure imgf000106_0002
Ib-4a and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, R4, R4 , R6, R6 are as defined in claim 6; and
R' and R are independently selected from H, halo, alkyl, hydro xyl or alkoxy.
8. The compound of claim 6 having the formula Ib-4b
Figure imgf000107_0001
Ib-4b, and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, R4, R4 R6 and R6 are as defined above in claim 6, and
7 7' 7" '"
R , R , R and R are independently selected from H, halo, alkyl, hydro xyl or alkoxy.
9. The compound of claim 7 having the formula Ib-5a
Figure imgf000107_0002
Ib-5a, and pharmaceutically acceptable salts, and solvates thereof, wherein Ar2, R4, R4 , R6,
7'
and R are as defined in claim 7; and
Y1 is N or C-R9 , where R9 is selected from H, halo, nitro, cyano, or haloalkyl, or R9 and Re or Ry and R together form a naphtyl moiety;
R8, R8 , R9 and R10 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, or when Y1 is CH, R8 and R9 or R9 and R10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to.
10. The compound of claim 9 having the formula Ib-6a
Figure imgf000108_0001
Ib-6a, and pharmaceutically acceptable salts and solvates thereof, wherein R4, R4 , R6, R6 , R7, R7 , R8, R8 , R9, R10 and Y1 are as defined in claim 9, and
R , R1J and R are independently selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino;
Y2 is N or C-R14 , where R14 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or if Y3 is CH: R14 and R13 together with the phenyl group they are attached to form a naphtyl moiety; 3 2 3 15 15
Y is N under the condition that Y is not N, or Y is C-R , where R is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety, if Y2 is C-R14 , R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety.
1 1. The compound of claim 9 having the formula Ib-6b
Figure imgf000109_0001
Ib-6b and pharmaceutically acceptable salts and solvates thereof, wherein R4, R4 , R6, R6 , R7, R7', R8, R8 , R9, R10 and Y1 are as defined in claim 9, and
R16, R16'and R17 are independently selected from H, chloro, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R16 and R17, or R16 and R17 together with the thiophenyl group they are attached to form a benzo thiophenyl moiety.
12. The compound of claim 9 having the formula Ib-6c
Figure imgf000110_0001
Ib-6c and pharmaceutically acceptable salts and solvates thereof, wherein R4, R4 , R6, R6 , R7, R7', R8, R8 , R9, R10 and Y1 are as defined in claim 9, and R , R and R are independently selected from H, chloro, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R16 and R17, or R16 and R17 together with the thiophenyl group they are attached to form a benzo thiophenyl moiety.
13. The compound of claim 1 having the formula Id
Figure imgf000110_0002
Id, and pharmaceutically acceptable salts, and solvates thereof, wherein Ar1, Ar2, L1, L2, R1 and R are as defined above in claim 1 : R" and R° are as defined in claim 6.
14. The compound of claim 1 having the formula Ii-2
Figure imgf000111_0001
Ii-2
1 2 1 2 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , L , L3 and R are as defined in claim 1.
15. The compound of claim 14 having the formula Ij-2a
Figure imgf000111_0002
Ij-2a,
1 2 1 and pharmaceutically acceptable salts and solvates thereof, wherein Ar , Ar , L , and L3 are as defined in claim 14, and
R4 and R4' are independently selected from H, halo, alkyl, hydro xyl or alkoxy, or R4 and R together form a cyclopropane ring optionally substituted by one or more halo, alkyl, hydroxyl or alkoxy.
16. The compound of claim 15 having the formula Ij-4
Figure imgf000112_0001
Ij-4, and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, L1, R4 and R4' are as defined above in claim 15 and
R6 and R6 are independently selected from H, halo or alkyl.
17. The compound of claim 16 having the formula Ij-4a
Figure imgf000112_0002
Ij-4a, and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, R4, R4 R6 and R6 are as defined in claim 16, and
R' and R are independently selected from H, halo, alkyl, hydro xyl or alkoxy.
18. The compound of claim 16 having the formula Ij-4b
Figure imgf000113_0001
1Mb, and pharmaceutically acceptable salts and solvates thereof, wherein Ar1, Ar2, R4, R4 R6 and R6 are as defined in claim 16, and
7 7' 7" '"
R , R , R and R are independently selected from H, halo, alkyl, hydro xyl or alkoxy.
19. The compound of claim 17 having the formula Ij-6a
3'
Figure imgf000113_0002
Ij-6a, and pharmaceutically acceptable salts and solvates thereof, wherein R4, R4 , R6, R6 , R' and R are as defined in claim 17, and
Y1 is N or C-R9 , where R9 is selected from H, halo, nitro, cyano, or haloalkyl, or R9 and R8 or R9 and R10 together form a naphtyl moiety;
R8, R8 , R9 and R10 are independently selected from H, halo, cyano, nitro, alkyl, haloalkyl, or when Y1 is CH, R8 and R9 or R9 and R10 together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to;
R13, R13'and R14 are independently selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino;
Y2 is N or C-R14 , where R14 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or if Y3 is CH: R14 and R13 together with the phenyl group they are attached to form a naphtyl moiety
Y 3 is N under the condition that Y 2 is not N, or Y 3 is C-R 15 , where R 15 is selected from H, chloro, iodo, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety, if Y2 is C-R14 , R15 and R14 together form a methylenedioxy group or R15 and R14 together with the phenyl group they are attached to form a naphtyl moiety.
20. The compound of claim 17 having the formula Ij-6c
Figure imgf000115_0001
Ij-6c, and pharmaceutically acceptable salts and solvates thereof, wherein R4, R4 , R6, R6 , R7, R7', R8, R8 , R9, R10 and Y1 are as defined in claim 19, and R , R and R are independently selected from H, chloro, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, or R16 and R17, or R16 and R17 together with the thiophenyl group they are attached to form a benzo thiophenyl moiety.
21. The compound of claim 1 selected from the group consisting of:
4 (S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-(trifiuoromethyl)phenyl)
butanoic acid
5 (S)-3-(2-(thiophen-3-yl)acetamido)-4-(4-(trifiuoromethyl)phenyl)
butanoic acid
6 (S)-3-(2-phenylacetamido)-4-(4-(trifiuoromethyl)phenyl)butanoic acid
7 (S)-4-(4-nitrophenyl)-3-(2-(m-tolyl)acetamido)butanoic acid
8 (S)-4-(4-nitrophenyl)-3-(2-phenylacetamido)butanoic acid
9 (S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(4-(trifluoromethyl)phenyl)
acetamido)butanoic acid
10 (S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
11 (S)-3-(2-(2-methoxyphenyl)acetamido)-4-(4-(trifiuoromethyl)phenyl)
butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(m-tolyl)acetamido)butanoic acid (R)-3-(2-(3-chlorophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid (R)-5-phenyl-3-(2-(thiophen-3-yl)acetamido)pentanoic acid (S)-3-(2-(3-chlorophenyl)acetamido)-4-(p-tolyl)butanoic acid (S)-4-(p-tolyl)-3-(2-(m-tolyl)acetamido)butanoic acid
(S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3-(trifluoromethyl)phenyl)acetamido) butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-phenylacetamido)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(3-chlorophenyl)acetamido)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(thiophen-3-yl)acetamido)butanoic acid (S)-4-(3,4-dichlorophenyl)-3-(2-(m-tolyl)acetamido)butanoic acid (S)-3-(2-(thiophen-2-yl)acetamido)-4-(4-(trifluoromethyl)phenyl) butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(3-(trifluoromethyl)phenyl)acetamido) butanoic acid
(S)-3-(2-(naphthalen-2-yl)acetamido)-4-(4-(trifluoromethyl)phenyl) butanoic acid
(S)-3-(2-(benzo[d][l ,3]dioxol-5-yl)acetamido)-4-(4-(trifluoromethyl) phenyl)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-5-phenylpentanoic acid (S)-3-(2-(2-chlorophenyl)acetamido)-4-(4-(trifluoromethyl)phenyl) butanoic acid
(S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(3- (trifluoromethyl)phenyl)acetamido)butanoic acid
(R)-4-(naphthalen-2-yl)-3-(2-(thiophen-3-yl)acetamido)butanoic acid (S)-3-(2-(naphthalen-l -yl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid (S)-3-(2-(p-tolyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(4-chlorophenyl)acetamido)butanoic acid (S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(m-tolyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid (R)-4-(naphthalen-2-yl)-3-(2-(4- (trifluoromethyl)phenyl)acetamido)butanoic acid
(S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(3-chlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3,5-dimethylphenyl)acetamido)butanoic acid (S)-4-(3,4-dichlorophenyl)-3-(2-phenylacetamido)butanoic acid (S)-3 -(2 -(3 -chlorophenyl)acetamido)-4-(3 - (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-nitrophenyl)-3-(2-(thiophen-3-yl)acetamido)butanoic acid (S)-3-(2-(4-chlorophenyl)acetamido)-4-(4-nitrophenyl)butanoic acid (R)-3-(2-(4-chlorophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(2,3-dichlorophenyl)acetamido)butanoic acid (S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(4-nitrophenyl)butanoic acid (3S)-3-(2-phenylpropanamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(3-methoxyphenyl)acetamido)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(3,4-dichlorophenyl)acetamido)butanoic acid (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid (S)-3-(2-(3-methoxyphenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid
(S)-4-(4-chlorophenyl)-3-(2-(naphthalen-l -yl)acetamido)butanoic acid (R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(3-chlorophenyl)acetamido)-4-(3,4-dichlorophenyl)butanoic acid (S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(4-nitrophenyl)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(2-chlorophenyl)acetamido)butanoic acid (R)-4-(naphthalen-2-yl)-3-(2-phenylacetamido)butanoic acid (R)-3-(2-phenylacetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid (S)-3-(2-(2,6-dichlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
(S)-3-(2-(naphthalen-l -yl)acetamido)-4-(4-nitrophenyl)butanoic acid (S)-4-(4-chlorophenyl)-3-(2-(thiophen-2-yl)acetamido)butanoic acid (S)-3-(2-(3-methoxyphenyl)acetamido)-4-(4-nitrophenyl)butanoic acid (S)-4-(naphthalen-2-yl)-3-(2-(m-tolyl)acetamido)butanoic acid (S)-3-(2-(naphthalen-2-yl)acetamido)-4-(4-nitrophenyl)butanoic acid (R)-3-(2-(4-chlorophenyl)acetamido)-5-phenylpentanoic acid (R)-5-phenyl-3-(2-(4-(trifluoromethyl)phenyl)acetamido)pentanoic acid (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(4-nitrophenyl)butanoic acid (S)-3-(2-(o-tolyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid (S)-3-(2-(m-tolyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid 72 (3S)-3-((l S)-2-phenylcyclopropanecarboxamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
73 (S)-3-(2-(2,4-dichlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
74 (S)-4-(4-nitrophenyl)-3-(2-(thiophen-2-yl)acetamido)butanoic acid
75 (S)-4-(4-(trifluoromethyl)phenyl)-3-(2-(2- (trifluoromethyl)phenyl)acetamido)butanoic acid
76 (S)-3-(2-(4-chlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
77 (S)-4-(4-cyanophenyl)-3-(2-(m-tolyl)acetamido)butanoic acid
78 (S)-3-(2-(3-chloro-4-iodophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
79 (S)-3-(l -phenylcyclopropanecarboxamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
80 (R)-3-(2-(thiophen-3-yl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid
81 (S)-3-(2-(2-chlorophenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
82 (S)-3-(2-(2-methoxyphenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
83 (S)-3-(2-phenylacetamido)-4-(p-tolyl)butanoic acid
84 (S)-4-(3-(trifluoromethyl)phenyl)-3-(2-(3- (trifluoromethyl)phenyl)acetamido)butanoic acid
85 (S)-4-(4-chlorophenyl)-3-(2-(2,4-dichlorophenyl)acetamido)butanoic acid
86 (R)-3-(2-(2-chlorophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid
87 (R)-3-(2-(4-chlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
88 (S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-cyanophenyl)butanoic acid
89 (S)-3-(2-(3-chlorophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid
90 (S)-4-(3,4-dichlorophenyl)-3-(2-(thiophen-3-yl)acetamido)butanoic acid
91 (R)-5-phenyl-3-(2-(thiophen-2-yl)acetamido)pentanoic acid i n
92 (S)-4-(4-chlorophenyl)-3-(2-(p-tolyl)acetamido)butanoic acid
93 (R)-4-(naphthalen-2-yl)-3-(2-(thiophen-2-yl)acetamido)butanoic acid
94 (R)-4-(4-(trifluoromethyl)phenyl)-3-(2-(3- (trifluoromethyl)phenyl)acetamido)butanoic acid
95 (R)-4-(4-chlorophenyl)-3-(2-(3-chlorophenyl)acetamido)butanoic acid
96 (S)-3-(2-(pyridin-3-yl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid
97 (S)-4-(4-chlorophenyl)-3-(2-(naphthalen-2-yl)acetamido)butanoic acid
98 (R)-3-(2-(3-chlorophenyl)acetamido)-4-(naphthalen- 1 -yl)butanoic acid
99 (R)-3-(2-(2,3-dichlorophenyl)acetamido)-5-phenylpentanoic acid
100 (S)-3-(2-(benzo[d][l ,3]dioxol-5-yl)acetamido)-4-(4- chlorophenyl)butanoic acid
101 (R)-4-(naphthalen-2-yl)-3-(2-(3- (trifluoromethyl)phenyl)acetamido)butanoic acid
102 (S)-3-(2-(4-methoxyphenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
103 (S)-4-(4-chlorophenyl)-3-(2-(o-tolyl)acetamido)butanoic acid
104 (S)-4-(4-chlorophenyl)-3-(2-(3,4-dimethylphenyl)acetamido)butanoic acid
105 (R)-4-(naphthalen-2-yl)-3-(2-(p-tolyl)acetamido)butanoic acid
106 (S)-4-(4-nitrophenyl)-3-(2-(p-tolyl)acetamido)butanoic acid
107 (R)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(naphthalen-l-yl)butanoic acid
108 (S)-3-(2-(4-chlorophenyl)acetamido)-4-(3,4-dichlorophenyl)butanoic acid
109 (S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(3- (trifluoromethyl)phenyl)butanoic acid
110 (S)-3-(2-phenylacetamido)-4-(3-(trifluoromethyl)phenyl)butanoic acid
11 1 (R)-4-(naphthalen- 1 -yl)-3-(2-(thiophen-3-yl)acetamido)butanoic acid 112 (S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(p-tolyl)butanoic acid
113 (3S)-4-(4-chlorophenyl)-3-(2-phenylpropanamido)butanoic acid
114 (S)-4-(4-chlorophenyl)-3-(2-(2-methoxyphenyl)acetamido)butanoic acid
115 (S)-4-(4-chlorophenyl)-3-(2-(4-methoxyphenyl)acetamido)butanoic acid
116 (R)-4-(4-chlorophenyl)-3-(2-(4-chlorophenyl)acetamido)butanoic acid
117 (R)-4-(4-chlorophenyl)-3-(2-(thiophen-3-yl)acetamido)butanoic acid
118 (R)-5-phenyl-3-(2-(p-tolyl)acetamido)pentanoic acid
119 (S)-4-(naphthalen-2-yl)-3-(2-phenylacetamido)butanoic acid
120 (S)-4-(3,4-dichlorophenyl)-3-(2-(3,5-dimethylphenyl)acetamido)butanoic acid
121 (S)-3-(2 -(2-chlorophenyl)acetamido)-4-(3 - (trifluoromethyl)phenyl)butanoic acid
122 (R)-4-(naphthalen-2-yl)-3-(2-(m-tolyl)acetamido)butanoic acid
123 (S)-3-(2-(thiophen-3-yl)acetamido)-4-(3-(trifluoromethyl)phenyl)butanoic acid
124 (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(3- (trifluoromethyl)phenyl)butanoic acid
125 (S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(p-tolyl)butanoic acid
126 (S)-3-(2-(3,4-dimethylphenyl)acetamido)-5-phenylpentanoic acid
127 (S)-3-(2-(naphthalen-2-yl)acetamido)-4-(p-tolyl)butanoic acid
128 (S)-4-(3,4-dichlorophenyl)-3-(2-(thiophen-2-yl)acetamido)butanoic acid
129 (S)-4-(4-cyanophenyl)-3-(2-(3,5-dimethylphenyl)acetamido)butanoic acid
130 (R)-3-(2-(2-chlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
131 (R)-5-phenyl-3-(2-phenylacetamido)pentanoic acid
132 (R)-4-(4-chlorophenyl)-3-(2-(3,4-dichlorophenyl)acetamido)butanoic acid 133 (S)-4-(3,4-dichlorophenyl)-3-(2-(2,3-dichlorophenyl)acetamido)butanoic acid
134 (S)-3-(2-(2,4-dichlorophenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
135 (R)-4-(3-chlorophenyl)-3-(2-(thiophen-3-yl)acetamido)butanoic acid
136 (R)-3-(2-(3,4-dichlorophenyl)acetamido)-5-phenylpentanoic acid
137 (R)-4-(3 -chlorophenyl)-3 -(2-(3 -chlorophenyl)acetamido)butano ic acid
138 (S)-3-(2-(4-chlorophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid
139 (S)-3-(2-(2-chlorophenyl)acetamido)-4-(3,4-dichlorophenyl)butanoic acid
140 (R)-4-(4-cyanophenyl)-3-(2-(2,4-dimethylphenyl)acetamido)butanoic acid
141 (S)-4-(p-tolyl)-3-(2-(3-(trifluoromethyl)phenyl)acetamido)butanoic acid
142 (S)-4-(4-nitrophenyl)-3-(2-(2-(trifluoromethyl)phenyl)acetamido)butanoic acid
143 (S)-4-(naphthalen-2-yl)-3-(2-(3- (trifluoromethyl)phenyl)acetamido)butanoic acid
144 (S)-4-(4-nitrophenyl)-3-(2-(4-(trifluoromethyl)phenyl)acetamido)butanoic acid
145 (R)-4-(4-chlorophenyl)-3-(2-phenylacetamido)butanoic acid
146 (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(p-tolyl)butanoic acid
147 (R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-cyanophenyl)butanoic acid
148 (S)-3-(2-(thiophen-3-yl)acetamido)-4-(p-tolyl)butanoic acid
149 (S)-3-(2-(2-methoxyphenyl)acetamido)-5-phenylpentanoic acid
150 (S)-3-(2-(thiophen-2-yl)acetamido)-4-(p-tolyl)butanoic acid
151 (R)-4-(4-(trifluoromethyl)phenyl)-3-(2-(4- (trifluoromethyl)phenyl)acetamido)butanoic acid
152 (S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(p-tolyl)butanoic acid 153 (S)-3-(2-(2,4-dimethylphenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
154 (S)-4-(4-chlorophenyl)-3-(2-(2- (trifluoromethyl)phenyl)acetamido)butanoic acid
155 (3S)-4-(4-nitrophenyl)-3-(2-phenylpropanamido)butanoic acid
156 (S)-4-(3-chlorophenyl)-3-(2-(m-tolyl)acetamido)butanoic acid
157 (S)-3-(2-(4-chlorophenyl)acetamido)-4-(p-tolyl)butanoic acid
158 (S)-5-phenyl-3-(l-phenylcyclopropanecarboxamido)pentanoic acid
159 (R)-4-(4-cyanophenyl)-3-(2-(3,4-dimethylphenyl)acetamido)butanoic acid
160 (S)-3-(2-(2,3-dichlorophenyl)acetamido)-4-(3- (trifluoromethyl)phenyl)butanoic acid
161 (S)-4-(3,4-dichlorophenyl)-3-(2-(3- (trifluoromethyl)phenyl)acetamido)butanoic acid
162 (S)-3-(2-(3-phenoxyphenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
163 (S)-3-(3-phenylpropiolamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid
164 (R)-4-(4-chlorophenyl)-3-(2-(m-tolyl)acetamido)butanoic acid
165 (R)-3-(2-(p-tolyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid
166 (R)-3-(2-(3-chlorophenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
167 (S)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
168 (S)-4-(3,4-dichlorophenyl)-3-(2-(3,4-dichlorophenyl)acetamido)butanoic acid
169 (S)-3-(2-(naphthalen-2-yl)acetamido)-4-(3- (trifluoromethyl)phenyl)butanoic acid
170 (S)-3-(2-(3-methoxyphenyl)acetamido)-4-(3- (trifluoromethyl)phenyl)butanoic acid
171 (S)-3-(2-(3-chlorophenyl)acetamido)-4-(o-tolyl)butanoic acid
172 (S)-5-phenyl-3-(2-(4-(trifluoromethyl)phenyl)acetamido)pentanoic acid 173 (S)-4-(3-chlorophenyl)-3-(2-(3-chlorophenyl)acetamido)butanoic acid
174 (R)-3-(2-(2-chlorophenyl)acetamido)-5-phenylpentanoic acid
175 (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid
176 (S)-3-(2-(naphthalen-l -yl)acetamido)-4-(3- (trifluoromethyl)phenyl)butanoic acid
177 (R)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid
178 (S)-3-(2-(naphthalen-2-yl)acetamido)-4-(pyridin-3-yl)butanoic acid
179 (S)-3-(2-(2-methoxyphenyl)acetamido)-4-(o-tolyl)butanoic acid
180 (S)-4-(4-nitrophenyl)-3-(2-(o-tolyl)acetamido)butanoic acid
181 (R)-3-(2-(2,4-dimethylphenyl)acetamido)-5-phenylpentanoic acid
182 (S)-4-(2-chlorophenyl)-3-(2-(2-methoxyphenyl)acetamido)butanoic acid
183 (R)-4-(2-cyanophenyl)-3-(2-(o-tolyl)acetamido)butanoic acid
184 (S)-4-(3-chlorophenyl)-3-(2-(3,4-dichlorophenyl)acetamido)butanoic acid
185 (R)-3-(2-(benzo[d] [1 ,3]dioxol-5-yl)acetamido)-5-phenylpentanoic acid
186 (S)-4-(4-cyanophenyl)-3-(2-(3,4-dichlorophenyl)acetamido)butanoic acid
187 (R)-4-(4-cyanophenyl)-3-(2-(2,3-dimethoxyphenyl)acetamido)butanoic acid
188 (S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(4-nitrophenyl)butanoic acid
189 (S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(p-tolyl)butanoic acid
190 (R)-4-(3-chlorophenyl)-3-(2-(4-phenoxyphenyl)acetamido)butanoic acid
191 (S)-4-(4-chlorophenyl)-3-(2-(2,4-dimethylphenyl)acetamido)butanoic acid
192 (R)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid 193 (R)-4-(2-cyanophenyl)-3-(2-(2- (trifluoromethyl)phenyl)acetamido)butanoic acid
194 (S)-3-(2-(3,5-dimethylphenyl)acetamido)-4-(naphthalen-2-yl)butanoic acid
195 (S)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(2- (trifluoromethyl)phenyl)butanoic acid
196 (R)-4-(2-cyanophenyl)-3-(2-(2,3-dimethoxyphenyl)acetamido)butanoic acid
197 (S)-3-(2-(3,4-dichlorophenyl)acetamido)-4-(o-tolyl)butanoic acid
198 (R)-5-phenyl-3-(l-phenylcyclopropanecarboxamido)pentanoic acid
199 (R)-4-(3-chlorophenyl)-3-(2-(o-tolyl)acetamido)butanoic acid
200 (S)-4-(3,4-dichlorophenyl)-3-(2-(3,4-dimethylphenyl)acetamido)butanoic acid
201 (R)-3-(2-(2,3-dimethoxyphenyl)acetamido)-4-(m-tolyl)butanoic acid
202 (R)-5-phenyl-3-(2-(pyridin-4-yl)acetamido)pentanoic acid
203 (R)-4-(naphthalen-2-yl)-3-(2-(4-phenoxyphenyl)acetamido)butanoic acid
204 (3R)-5-phenyl-3-(2-phenylpropanamido)pentanoic acid
205 (R)-4-(3-cyanophenyl)-3-(2-(2,3-dimethoxyphenyl)acetamido)butanoic acid
206 (S)-4-(3-cyanophenyl)-3-(2-(3,4-dichlorophenyl)acetamido)butanoic acid
207 (R)-4-(2-chlorophenyl)-3-(2-(3-chlorophenyl)acetamido)butanoic acid
208 (R)-4-(4-nitrophenyl)-3-(2-(4-phenoxyphenyl)acetamido)butanoic acid
209 (R)-4-(2-cyanophenyl)-3-(2-(3,4-dimethylphenyl)acetamido)butanoic acid
210 (R)-3-(2-(3,4-dimethylphenyl)acetamido)-4-(m-tolyl)butanoic acid
21 1 (S)-3-(2-(3,4-dichlorophenyl)acetamido)-5-phenylpentanoic acid
212 (R)-3-(2-(benzo[d][l,3]dioxol-5-yl)acetamido)-4-(2- chlorophenyl)butanoic acid 213 (R)-4-(3-chlorophenyl)-3-(2-(2,4-dichlorophenyl)acetamido)butanoic acid
214 (S)-N-(l-(lH-tetrazol-5-yl)-2-(4-(trifiuoromethyl)phenyl)ethyl)-2-(3- chlorophenyl)acetamide
215 (S)-N-(l-(lH-tetrazol-5-yl)-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-2- (3 -chlorophenyl)acetamide
216 (S)-2-(2-(3-chlorophenyl)acetamido)-3-(4-(trifluoromethyl)phenyl)-N- ((trifiuoromethyl)sulfonyl)propanamide
217 (S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-(trifluoromethyl)phenyl)-N- ((trifiuoromethyl)sulfonyl)butanamide
218 (S)-2-(2-(3-chlorophenyl)acetamido)-N-hydroxy-3-(4- (trifluoromethyl)phenyl)propanamide
219 (S)-3-(2-(3-chlorophenyl)acetamido)-N-hydroxy-4-(4- (trifluoromethyl)phenyl)butanamide
220 (S)-2-(3-chlorophenyl)-N-(l -(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-2- (4 -(tri fluo romethyl)phenyl)ethyl)acetamide
221 (S)-2-(3-chlorophenyl)-N-(l -(5-oxo-4,5-dihydro-l,2,4-thiadiazol-3-yl)-2- (4 -(tri fluo romethyl)phenyl)ethyl)acetamide
222 ((S)-2-(2-(3-chlorophenyl)acetamido)-3-(4- (trifluoromethyl)phenyl)propyl)(methyl)phosphinic acid
223 (S)-(2-(2-(3-chlorophenyl)acetamido)-3-(4- (trifluoromethyl)phenyl)propyl)phosphonic acid
224 (S)-N-(l -(4H-1 ,2,4-triazol-3-yl)-3-(4-(trifiuoromethyl)phenyl)propan-2- yl)-2-(3-chlorophenyl)acetamide
225 2-(3-chlorophenyl)-N-((2S)-l-(2,4-dioxothiazolidin-5-yl)-3-(4- (trifiuoromethyl)phenyl)propan-2-yl)acetamide
226 (S)-2-(2-(3-chlorophenyl)acetamido)-N-(lH-tetrazol-5-yl)-3-(4- (trifluoromethyl)phenyl)propanamide
227 Tritiated (S)-3-(2-(3-chlorophenyl)acetamido)-4-(4- (trifluoromethyl)phenyl)butanoic acid and pharmaceutically acceptable salts and solvates thereof.
22. A pharmaceutical composition comprising a compound according to any of claims 1 to 21 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
23. Medicament comprising a compound according to any of claims 1 to 21 or a pharmaceutically acceptable salt or solvate thereof.
24. A compound according to any of claims 1 to 21 or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing inflammatory, gastrointestinal and/or metabolic disorders in a patient.
25. The compound according to any one of claims 1 to 21 wherein one or more atom(s) is/are a radioisotope of the same element.
26. Use of a compound according to claim 25 for assessing the binding of ligands that bind to a GPR43 receptor, wherein the compound is tritium labeled.
27. Use of a compound according to claim 25 as a probe for the localization of a GPR43 receptor on cell surfaces.
28. Use of a compound according to claim 25 as positron emission tomography (PET) ligand.
29. Use of a compound according to any of claims 1 to 21 or a pharmaceutically acceptable salt or solvate thereof as a modulator of GPR43 receptor activity.
30. Use according to claim 29, wherein the compound is an antagonist of GPR43 receptor activity.
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