1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mglur2-receptors

A compound comprising Formula (I),

• wherein
• V1 is selected from the group of a covalent bond and a bivalent saturated or unsaturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms;
• M1 is selected from the group of hydrogen;
• cycloC3-7alkyl;
• aryl;
• alkylcarbonyl;
• alkyloxy;
• aryloxy;
• arylalkyloxy;
• arylcarbonyl;
• hexahydrothiopyranyl;
• and Het1;
• L is selected from the group of a covalent bond;
• —O—;
• —OCH2—;
• —OCH2CH2—;
• —OCH2CH2O—;
• —OCH2CH2OCH2—;
• —S—;
• —NR7—;
• —NR7CH2—;
• —NR7cycloC3-7;
• —NR7CH2CH2—;
• —OCH2CH2N(R7)CH2—;
• —CH2—;
• —CH2CH2—;
• —CH2CH2CH2;
• —C≡C—;
• —C═O—;
• and —C(R8)═C(R9)—;
• wherein each of R7, independently of each other, is selected from the group of hydrogen and C1-3alkyl;
• and wherein R8 and R9, independently of each other, are selected from the group of hydrogen, halo and C1-3alkyl;
• R2 and R3 are each independently of each other hydrogen, halo or alkyl;
• A is Het2 or phenyl, wherein each radical is optionally substituted with n radicals R4, wherein n is an integer equal to zero, 1, 2 or 3;
• R4 is selected from the group of halo;
• cyano;
• hydroxy;
• oxo;
• formyl;
• ethanoyl;
• carboxyl;
• nitro;
• thio;
• alkyl;
• alkyloxy;
• alkyloxyalkyl;
• alkyloxycarbonyl;
• alkyloxycarbonylalkyl;
• alkylcarbonyl;
• alkylcarbonyloxy;
• alkylcarbonylalkyloxy;
• polyhaloC1-3alkyl;
• polyhaloC1-3alkyloxy;
• polyhaloC1-3alkylthio;
• alkylthio;
• alkylsulfonyl;
• Het3;
• Het3-alkyl;
• Het3-oxy;
• Het3-oxyalkyl;
• Het3-alkyloxy;
• Het3-oxyalkyloxy;
• Het3-carbonyl;
• Het3-carbonylalkyl;
• Het3-thio;
• Het3-thioalkyl;
• Het3-sulfonyl;
• aryl;
• arylalkyl;
• aryloxy;
• aryloxyalkyl;
• arylalkyloxy;
• arylalkenyl;
• arylcarbonylalkyl;
• arylthioalkyl;
• arylsulfonyl;
• —NRaRb;
• alkyl-NRaRb;
• O-alkyl-NRaRb;
• —C(═O)—NRaRb;
• —C(═O)-alkyl-NRaRb;
• and O-alkyl-C(═O)—NRaRb;
• wherein Ra and Rb are selected from the group of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkyloxyalkyl, Het3, Het3alkyl, alkylsulfonyl, alkyl-NRcRd, and C(═O)alkyl-NRcRd, wherein Rc and Rd are selected from the group of hydrogen, alkyl and alkylcarbonyl;
• or two radicals R4 may be combined to form a bivalent radical —X1—C1-6—X2— wherein C1-6 is a saturated or unsaturated, straight or branched hydrocarbon radical having 1 to 6 carbon atoms and X1 and X2 are each independently C, O or NH;
• wherein the bivalent radical is optionally substituted with one or more radicals selected from the group of halo, polyhaloC1-3alkyl, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl and ethanoyl;
• Het1 is selected from the group of tetrahydropyranyl;
• and pyridinyl;
• wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, C1-3alkyl, polyhaloC1-3alkyl, polyhaloC1-3alkyloxy, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, and C1-3alkyloxy;
• Het2 is selected from the group of piperazinyl;
• piperidinyl;
• thienyl;
• furanyl;
• 1H-indazolyl;
• 1H-benzimidazolyl;
• 1,2,3,4-tetrahydro-isoquinolinyl;
• 2,5-diaza-bicyclo[2.2.1]heptyl;
• pyrrolidinyl;
• azetidinyl;
• 2,7-diaza-spiro[3.5]nonyl;
• pyridinyl;
• pyrazolyl;
• indolinyl;
• 1H-indolyl;
• 1H-indazolyl;
• benzomorpholinyl;
• thiazolyl;
• 1,2,3,4-tetrahydroquinolinyl;
• 3,9-diazaspiro[5.5]undecyl;
• 1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolinyl;
• 1,2,3,4,4a,10a-hexahydro-benzo[5,6][1,4]dioxino[2,3-c]pyridinyl;
• 2,3,4,9tetrahydro-1H-indeno[2,1-c]pyridinyl;
• 2,3,4,9-tetrahydro-1H-β-carbolinyl;
• 1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridinyl;
• 1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridinyl;
• [1,4]diazepyl;
• isoxazolyl;
• indanyl;
• and indolyl;
• Het3 is selected from the group of pyridinyl;
• pyrimidinyl;
• pyridazilyl;
• pyrazinyl;
• piperidinyl;
• pyrrolyl;
• pyrrolidinyl;
• piperazinyl;
• triazolyl;
• tetrazolyl;
• indolyl;
• thienyl;
• furanyl;
• tetrahydropyranyl;
• tetrahydro-thiopyran-1,1-dioxide;
• thiazolyl;
• thiadiazolyl;
• isothiazolyl;
• oxazolyl;
• morpholinyl;
• oxadiazolyl;
• isoxazolyl;
• imidazolyl;
• pyrazolyl;
• benzoimidazolyl;
• benzoxazolyl;
• benzothienyl;
• benzothiazolyl;
• benzofuranyl;
• benzomorpholinyl;
• 1,2,3,4-tetrahydro-isoquinolinyl;
• thionaphtyl;
• indolyl;
• indolinyl;
• quinolyl;
• isoquinolyl;
• quinoxalyl;
• phthalazyl;
• benzo[1,3]dioxyl;
• and quinazolyl;
• wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, C1-6alkyl, polyhaloC1-3alkyl, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono- and di(alkyl)amino, and C1-3alkyloxy;
• Aryl is naphthyl, phenyl, or biphenyl;
• wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other selected from the group of halo, C1-3alkyl, polyhaloC1-3alkyl, polyhaloC1-3alkyloxy, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, ethyloxycarbonyl, and C1-3alkyloxy;
• alkyl is a saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms;
• or is a saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms;
• or is saturated hydrocarbon radical from 4 to 12 carbon atoms, comprising at least one saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and at least one saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms;
• wherein each carbon atom may optionally be substituted with one or more radicals selected from the group of halo, polyhaloC1-3alkyl, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, carbamoyl;
• phenyl;
• and a bivalent radical —OCH2CH2O—;
• and
• alkenyl is alkyl, additionally containing one or more double bonds.