# Patent

## Title
1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors

## Abstract

The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I)




wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic receptors—subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. patent application Ser. No. 12/282,663, filed Dec. 9, 2009, which is the National Stage Entry of PCT/EP2007/052442, filed Mar. 15, 2007, which claims priority to (EP) Application No. 06111215.7, filed Mar. 15, 2006, and to (EP) Application No. 07103654.5, filed Mar. 7, 2007, each of which are hereby incorporated herein by reference in its entirety for all purposes.


FIELD OF THE INVENTION
The present invention relates to novel compounds, in particular novel 1,4-disubstituted 3-cyano-pyridone-derivatives that are positive allosteric modulators of metabotropic receptors-subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to the pharmaceutical compositions, the processes to prepare such compounds and compositions and the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.
BACKGROUND OF THE INVENTION
Glutamate is the major amino-acid transmitter in the mammalian central nervous system (CNS). Glutamate plays a major role in numerous physiological functions, such as learning and memory but also sensory perception, development of synaptic plasticity, motor control, respiration, and regulation of cardiovascular function. Furthermore, glutamate is at the centre of several different neurological and psychiatric diseases, where there is an imbalance in glutamatergic neurotransmission.
Glutamate mediates synaptic neurotransmission through the activation of tonotropic glutamate receptors channels (iGluRs), the NMDA, AMPA and kainate receptors which are responsible for fast excitatory transmission (Nakanishi et al., (1998) Brain Res Brain Res Rev., 26:230-235).
In addition, glutamate activates metabotropic glutamate receptors (mGluRs) which have a more modulatory role that contributes to the fine-tuning of synaptic efficacy.
The mGluRs are seven-transmembrane G protein-coupled receptors (GPCRs) belonging to family 3 of GPCRs along with the calcium-sensing, GABAb, and pheromone receptors.
Glutamate activates the mGluRs through binding to the large extracellular amino-terminal domain of the receptor, herein called the orthosteric binding site. This binding induces a conformational change in the receptor which results in the activation of the G-protein and intracellular signalling pathways.
The mGluR family is composed of eight members. They are classified into three groups (group I comprising mGluR1 and mGluR5; group II comprising mGluR2 and mGluR3; group III comprising mGluR4, mGluR6, mGluR7, and mGluR8) according to sequence homology, pharmacological profile, and nature of intracellular signalling cascades activated (Schoepp et al. (1999) Neuropharmacology, 38:1431-76).
Among mGluR members, the mGluR2 subtype is negatively coupled to adenylate cyclase via activation of Gαi-protein, and its activation leads to inhibition of glutamate release in the synapse (Cartmell & Schoepp (2000) J Neurochem 75:889-907). In the CNS, mGluR2 receptors are abundant mainly throughout cortex, thalamic regions, accessory olfactory bulb, hippocampus, amygdala, caudate-putamen and nucleus accumbens (Ohishi et al. (1998) Neurosci Res 30:65-82).
Activating mGluR2 was shown in clinical trials to be efficacious to treat anxiety disorders (Levine et al. (2002) Neuropharmacology 43: 294; Holden (2003) Science 300:1866-68; Grillon et al. (2003) Psychopharmacology 168:446-54; Kellner et al. (2005) Psychopharmacology 179: 310-15). In addition, activating mGluR2 in various animal models was shown to be efficacious, thus representing a potential novel therapeutic approach for the treatment of schizophrenia (reviewed in Schoepp & Marek (2002) Curr Drug Targets. 1:215-25), epilepsy (reviewed in Moldrich et al. (2003) Eur J Pharmacol. 476:3-16), migraine (Johnson et al. (2002) Neuropharmacology 43:291), addiction/drug dependence (Helton et al. (1997) J Pharmacol Exp Ther 284: 651-660), Parkinson's disease (Bradley et al (2000) J Neurosci. 20(9):3085-94), pain (Simmons et al. (2002) Pharmacol Biochem Behav 73:419-27), sleep disorders (Feinberg et al. (2002) Pharmacol Biochem Behav 73:467-74) and Huntington's disease (Schiefer et al. (2004) Brain Res 1019:246-54).
To date, most of the available pharmacological tools targeting mGluRs are orthosteric ligands which activate several members of the family as they are structural analogs of glutamate (Schoepp et al. (1999) Neuropharmacology, 38:1431-76).
A new avenue for developing selective compounds acting at mGluRs is to identify molecules that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site.
Positive allosteric modulators of mGluRs have emerged recently as novel pharmacological entities offering this attractive alternative. This type of molecule has been discovered for several mGluRs (reviewed in Mutel (2002) Expert Opin. Ther. Patents 12:1-8). In particular molecules have been described as mGluR2 positive allosteric modulators (Johnson M P et al. (2003) J Med Chem. 46:3189-92; Pinkerton et al. (2004) J Med Chem. 47:4595-9).
WO2004/092135 (NPS & Astra Zeneca), WO2004/018386, WO2006/014918 and WO2006/015158 (Merck) and WO2001/56990 (Eli Lilly) describe respectively phenyl sulfonamide, acetophenone, indanone and pyridylmethyl sulfonamide derivatives as mGluR2 positive allosteric modulators. However, none of the specifically disclosed compounds are structurally related to the compounds of the invention.
It was demonstrated that such molecules do not activate the receptor by themselves (Johnson M P et al. (2003) J Med Chem. 46:3189-92; Schaffhauser et al. (2003) Mol Pharmacol. 64:798-810). Rather, they enable the receptor to produce a maximal response to a concentration of glutamate which by itself induces a minimal response. Mutational analysis have demonstrated unequivocally that the binding of mGluR2 positive allosteric modulators does not occur at the orthosteric site, but instead at an allosteric site situated within the seven transmembrane region of the receptor (Schaffhauser et al. (2003) Mol Pharmacol. 64:798-810).
Animal data are suggesting that positive allosteric modulators of mGluR2 have the same effects in anxiety and psychosis models as those obtained with orthosteric agonists. Allosteric modulators of mGluR2 were shown to be active in fear-potentiated startle (Johnson et al. (2003) J Med Chem. 46:3189-92; Johnson et al. (2005) Psychopharmacology 179:271-83), and in stress-induced hyperthermia (Johnson et al. (2005) Psychopharmacology 179:271-83) models of anxiety. Furthermore, such compounds were shown to be active in reversal of ketamine- (Govek et al. (2005) Bioorg Med Chem Lett 15(18):4068-72) or amphetamine- (Galici et al. (2005) J Pharm Exp Ther 315(3), 1181-1187) induced hyperlocomotion, and in reversal of amphetamine-induced disruption of prepulse inhibition of the acoustic startle effect (Galici et al. (2005) J Pharm Exp Ther 315(3), 1181-1187) models of schizophrenia.
Positive allosteric modulators enable potentiation of the glutamate response, but they have also been shown to potentiate the response to orthosteric mGluR2 agonists such as LY379268 (Johnson et al. (2004) Biochem Soc Trans 32:881-87) or DCG-IV (Poisik et al. (2005) Neuropharmacology 49:57-69). These data provide evidence for yet another novel therapeutic approach to treat above mentioned neurological diseases involving mGluR2, which would use a combination of a positive allosteric modulator of mGluR2 together with an orthosteric agonist of mGluR2.


DESCRIPTION OF THE INVENTION
The invention relates to compounds having metabotropic glutamate receptor 2 modulator activity. In its most general compound aspect, the present invention provides a compound according to general Formula (I),




a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, 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—; —NR7 cycloC3-7; —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; 1 JH-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-hexahydrobenzo[5,6][1,4]dioxino[2,3-c]pyridinyl; 2,3,4,9-tetrahydro-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 carbonatoms, 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.


The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof.
The invention also relates to the use of a compound according to the invention as a medicament and for the preparation of a medicament for the prevention and/or treatment of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR2 positive allosteric modulators.
In particular, the invention relates to the use of a compound according to the invention for the preparation of a medicament for treating, or preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR2 positive allosteric modulators.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein V1 is selected from the group of a covalent bond, —CH2—; —CH2—CH2—; —CH2—CH2—CH2—; —CH2—CH═CH—; —CH2—CH2—CH2—CH2—; —CH2—CH(CH3)—CH2—; —CH(CH3)—CH2—CH2—CH2—; —CH2—CH(CH3—)CH2—CH2—; and —CH2—CH2—CH(CH3)—CH2—.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein M1 is selected from the group of hydrogen; cycloC3-7alkyl; phenyl; biphenyl; phenyloxy; benzyloxy; furanyl; and pyridinyl; wherein M1 is optionally substituted with one or more radicals selected from the group of halo; C1-3alkyl; polyhaloC1-3alkyl; polyhaloC1-3alkyloxy; cyano; hydroxy; amino; oxo; carboxyl; nitro; thio; formyl; ethanoyl; and C1-3alkyloxy.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein M1 is selected from the group of hydrogen; cycloC3-7alkyl; phenyl; biphenyl; phenyloxy; benzyloxy; furanyl, and pyridinyl; wherein any one of said radicals is optionally substituted with one or more radicals selected from the group of halo; C1-3alkyl; polyhaloC1-3alkyl; polyhaloC1-3alkyloxy; and C1-3alkyloxy.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein V1-M1 is selected from the group of —CH2—CH2—CH2—CH3; —CH2—CH(CH3)—CH3; —CH(CH3)—CH2—CH2—CH3; —CH2—CH(CH3—)CH2—CH3; —CH2—CH2—CH(CH3)—CH3; or V1 is selected from the group of covalent bond; —CH2—; —CH2—CH2—; —CH2—CH2—CH2—; and —CH2—CH═CH—; and M1 is selected from the group of cyclopropyl; cyclopentyl; cyclohexyl; phenyl; biphenyl; phenyloxy; benzyloxy; furanyl; and pyridinyl; wherein each radical M1 is optionally substituted with one or more radicals selected from the group of halo; C1-3alkyl; polyhaloC1-3alkyl; polyhaloC1-3alkyloxy; and C1-3alkyloxy. In a particular embodiment, V1-M1 is —CH2—CH2—CH2—CH3.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein R2 and R3 are each independently hydrogen, chloro, fluoro or methyl. In one particular embodiment, R2 and R3 are each independently hydrogen or methyl. In another particular embodiment, R2 and R3 are each hydrogen. In another particular embodiment, R2 is methyl and R3 is hydrogen.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein L is selected from the group of a covalent bond; —O—; —OCH2—; —OCH2CH2—; —OCH2CH2O—; —OCH2CH2OCH2—; —NR7—; —NR7CH2—; —NR7cycloC3-7; —OCH2CH2N(R7)CH2—; —CH2CH2—; —C≡C—; —C═O—; and —CH═CH—; wherein each of R7, independently of each other, is selected from the group of hydrogen and C1-3alkyl.
In another embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein A is selected from the group of phenyl, piperazinyl, and piperidinyl; wherein each of said radicals is optionally substituted with n radicals R4, wherein n is an integer equal to zero, 1, 2 or 3. In one particular embodiment, n is equal to zero or 1. In another particular embodiment, n is equal to 1.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein R4 is selected from the group of halo; cyano; hydroxy; ethanoyl; alkyl; alkyloxy; alkyloxyalkyl; alkyloxycarbonyl; alkyloxycarbonylalkyl; alkylcarbonyl; alkylcarbonyloxy; alkylcarbonylalkyloxy; polyhaloC1-3alkyl; polyhaloC1-3-alkyloxy; polyhaloC1-3alkylthio; alkylthio; alkylsulfonyl; Het3; Het3-alkyl; Het3-oxy; Het3-oxyalkyl; Het3-alkyloxy; Het3-oxyalkyloxy; Het3-carbonyl; Het3-thioalkyl; aryl; arylalkyl; aryloxy; aryloxyalkyl; arylalkyloxy; arylalkenyl; arylcarbonylalkyl; 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 or O.
In another embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein two radicals R4 may be combined to form a bivalent radical selected from the group of —CH2CH2—O—; —O—CH2—O—; and —O—CH2CH2—O—.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein Het1 is selected from the group of tetrahydropyranyl and pyridinyl; wherein each radical Het1 is optionally substituted with 1, 2 or 3 polyhaloC1-3alkyl substituents.
In one embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein Het3 is selected from the group of pyridinyl; pyrimidinyl; pyridazilyl; pyrazinyl; piperidinyl; pyrrolidinyl; piperazinyl; triazolyl; tetrahydropyranyl; tetrahydro-thiopyran-1,1-dioxide; thiazolyl; oxazolyl; morpholinyl; oxadiazolyl; imidazolyl; benzoxazolyl; benzothienyl; benzofuranyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl; indolinyl; phthalazyl; and benzo[1,3]dioxyl. In one embodiment, 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, oxo, ethanoyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono- and di(alkyl)amino, and C1-3alkyloxy.
In one further embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein

    V1 is selected from the group of a covalent bond, —CH2—; —CH2—CH2—; —CH2—CH2—CH2—; —CH2—CH═CH—; —CH2—CH2—CH2—CH2—; —CH2—CH(CH3)—CH2—; —CH(CH3)—CH2—CH2—CH2—; —CH2—CH(CH3—)CH2—CH2—; and —CH2—CH2—CH(CH3)—CH2—;
    M1 is selected from the group of hydrogen; cycloC3-7alkyl; phenyl; biphenyl; phenyloxy; benzyloxy; furanyl; and pyridinyl; wherein M1 is optionally substituted with one or more radicals selected from the group of halo; C1-3alkyl; polyhaloC1-3alkyl; polyhaloC1-3alkyloxy; and C1-3allyloxy;
    L is selected from the group of covalent bond; —O—; —OCH2—; —OCH2CH2—; —OCH2CH2O—; —OCH2CH2OCH2—; —NR7—; —NR7CH2—; —NR7cycloC3-7; —OCH2CH2N(R7)CH2—; —CH2CH2—; —C≡C—; —C═O—; and —CH═CH—; wherein each of R7, independently of each other, is selected from the group of hydrogen and C1-3alkyl;
    R2 and R3 are each independently of each other hydrogen, halo or alkyl;
    A is selected from the group of phenyl, piperazinyl, and piperidinyl, wherein each radical is optionally substituted with n radicals R4, wherein n is an integer equal to zero or 1;
    R4 is selected from the group of halo; cyano; hydroxy; ethanoyl; alkyl; alkyloxy; alkyloxyalkyl; alkyloxycarbonyl; alkyloxycarbonylalkyl; alkylcarbonyl; alkylcarbonyloxy; alkylcarbonylalkyloxy; polyhaloC1-3alkyl; polyhaloC1-3-alkyloxy; polyhaloC1-3alkylthio; alkylthio; alkylsulfonyl; Het3; Het3-alkyl; Het3-oxy; Het3-oxyalkyl; Het3-alkyloxy; Het3-oxyalkyloxy; Het3-carbonyl; Het3-thioalkyl; aryl; arylalkyl; aryloxy; aryloxyalkyl; arylalkyloxy; arylalkenyl; arylcarbonylalkyl; arylsulfonyl; —NRaRb; alkyl-NRaRb; O-alkyl-NRaRb; —C(═O)—NRaRb; —C(═O)-allyl-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 selected from the group of —CH2CH2—O—; —O—CH2—O—; and —O—CH2CH2—O—;
    Het1 is selected from the group of tetrahydropyranyl and pyridinyl; wherein each radical Het1 is optionally substituted with 1, 2 or 3 polyhaloC1-3alkyl substituents;
    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-hexahydrobenzo[5,6][1,4]dioxino[2,3-c]pyridinyl; 2,3,4,9-tetrahydro-1H-indeno[2,1-c]-pyridinyl; 2,3,4,9-tetrahydro-1H-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; pyrrolidinyl; piperazinyl; triazolyl; tetrahydropyranyl; tetrahydro-thiopyran-1,1-dioxide; thiazolyl; oxazolyl; morpholinyl; oxadiazolyl; imidazolyl; benzoxazolyl; benzothienyl; benzofuranyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl; indolinyl; phthalazyl; and benzo[1,3]dioxyl; 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, oxo, ethanoyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono- and di(alkyl)amino, and C1-3alkyloxy;
    aryl is 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, nitro, ethyloxycarbonyl, and C1-3alkyloxy; and
    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 carbonatoms, 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 cyano, hydroxy, carboxyl, carbamoyl, phenyl, and a bivalent radical —OCH2CH2O—.


In further embodiment, the invention relates to a compound according to general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein the compound is selected from the group of:

    4-(4-(N-acetylmethyl)phenyl)-3-cyano-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-179);
    4-(3,4-dimethoxyphenyl)-3-cyano-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-110);
    3-cyano-4-(3-fluoro-4-methoxyphenyl)-1-(3-methylbutyl)pyridine-2(1)-one (compound 1-114);
    3-cyano-4-(4-hydroxypropylphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-095);
    3-cyano-4-(4-methoxymethylphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-103);
    3-cyano-4-(2-fluoro-4-methoxyphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-113);
    3-cyano-4-(4-(N-morpholyl)phenyl)-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-223);
    3-cyano-1-(3-methylbutyl)-4-(phenylethynyl)pyridine-2(1H)-one (compound 1-267);
    3-cyano-1-butyl-4-[4-(2-methyl-pyridin-4-yloxy)-phenyl]-pyridine-2(1H)-one (compound 1-064); and
    3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (compound 4-047).


In the framework of this application, 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 a saturated hydrocarbon radical from 4 to 12 carbonatoms, 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—. In one embodiment, alkyl is methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In one embodiment, each carbon atom is optionally substituted with one or more radicals selected from the group of cyano, hydroxy, carboxyl, carbamoyl, phenyl, and the bivalent radical —OCH2CH2O—.
The notation C1-6alkyl defines a saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms, such as C6alkyl; C5alkyl; C4alkyl; C3alkyl; C2alkyl; and C1alkyl. Examples of C1-6alkyl are methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, pentyl, and heptyl.
The notation cycloC3-7alkyl defines a saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms, such as cycloC7alkyl; cycloC6alkyl; cycloC6alkyl; cycloC5alkyl; cycloC4alkyl; cycloC3alkyl; and cycloC3alkyl. Examples of cycloC3-7alkyl are cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, and cyclohexyl.
The notation C1-3alkyl defines a saturated, straight or branched hydrocarbon radical having from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl and isopropyl.
In one preferred embodiment, alkyl is C1-6alkyl; in another preferred embodiment alkyl is C3-7cycloalkyl.
In the framework of this application, alkenyl is alkyl, additionally containing one or more double bonds.
In the framework of this application, 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 C1-3alkylox. More preferred, aryl is phenyl or biphenyl. More preferred, aryl 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, nitro, ethyloxycarbonyl, and C1-3alkyloxy. More preferred, aryl is phenyl or biphenyl, 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, nitro, ethyloxycarbonyl, and C1-3alkyloxy.
In the framework of this application, halo is a substituent selected from the group of fluoro, chloro, bromo and iodo. Preferably, halo is bromo, fluoro or chloro.
In the framework of this application, polyhaloC1-3alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 3 carbon atoms, wherein one or more carbon atoms is substituted with one or more halo-atoms. Preferably, polyhaloalkyl is trifluoromethyl.
In the framework of this application, with “compounds according to the invention” is meant a compound according to the general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof.
The pharmaceutically acceptable acid addition salts are defined to comprise the therapeutically active non-toxic acid addition salts forms that the compounds according to Formula (I) are able to form. Said salts can be obtained by treating the base form of the compounds according to Formula (I) with appropriate acids, for example inorganic acids, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.
Conversely said acid addition salt forms can be converted into the free base form by treatment with an appropriate base.
The compounds according to Formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic metal or amine addition salts forms (base addition salts) by treatment with appropriate organic and inorganic bases. Appropriate base salts forms comprise, for example, the ammonium salts, the alkaline and earth alkaline metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hybramine salts, and salts with amino acids, for example arginine and lysine.
Conversely, said salts forms can be converted into the free forms by treatment with an appropriate acid.
Quaternary ammonium salts of compounds according to Formula (I) defines said compounds which are able to form by a reaction between a basic nitrogen of a compound according to Formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, in particular methyliodide and benzyliodide. Other reactants with good leaving groups may also be used, such as, for example, alkyl trifluoromethanesulfonates, alkyl methanesulfonates and alkyl p-toluenesulfonates. A quaternary ammonium salt has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate ions.
The term addition salt as used in the framework of this application also comprises the solvates that the compounds according to Formula (I) as well as the salts thereof, are able to form. Such solvates are, for example, hydrates and alcoholates.
The N-oxide forms of the compounds according to Formula (I) are meant to comprise those compounds of Formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more tertiary nitrogens (e.g. of the piperazinyl or piperidinyl radical) are N-oxidized. Such N-oxides can easily be obtained by a skilled person without any inventive skills and they are obvious alternatives for the compounds according to Formula (I) since these compounds are metabolites, which are formed by oxidation in the human body upon uptake. As is generally known, oxidation is normally the first step involved in drug metabolism (Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages 70-75). As is also generally known, the metabolite form of a compound can also be administered to a human instead of the compound per se, with much the same effects.
The compounds of Formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of Formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible isomeric forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of Formula (I) are obviously intended to be embraced within the scope of this invention.
Following CAS nomenclature conventions, when two stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R*,R*] or [R*S*], where R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [R*,S*] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S—[R*,S*]. If “α” and “β” are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the “α” position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in compounds according to Formula (I)) relative to the position of the highest priority substituent on the reference atom is denominated “α”, if it is on the same side of the mean plane determined by the ring system, or “β”, if it is on the other side of the mean plane determined by the ring system.
The invention also comprises derivative compounds (usually called “pro-drugs”) of the pharmacologically-active compounds according to the invention, which are degraded in vivo to yield the compounds according to the invention. Pro-drugs are usually (but not always) of lower potency at the target receptor than the compounds to which they are degraded. Pro-drugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, the desired compound may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion on pro-drugs may be found in Stella, V. J. et al., “Prodrugs”, Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.
Pro-drugs forms of the pharmacologically-active compounds according to the invention will generally be compounds according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof, having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the formula —COORx, where Rx is a C1-6alkyl, phenyl, benzyl or one of the following groups:




Amidated groups include groups of the formula —CONRYRz, wherein Ry is H, C1-6alkyl, phenyl or benzyl and Rz is —OH, H, C1-6alkyl, phenyl or benzyl. Compounds according to the invention having an amino group may be derivatised with a ketone or an aldehyde such as, for example, formaldehyde to form a Mannich base. This base will hydrolyze with first order kinetics in aqueous solution.
In the framework of this application, with “compounds according to the invention” is meant a compound according to the general Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and a prodrug thereof.
In the framework of this application, an element, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. In particular, when hydrogen is mentioned, it is understood to refer to 1H, 2H, 3H and mixtures thereof; when carbon is mentioned, it is understood to refer to 11C, 12C, 13C, 14C and mixtures thereof; when nitrogen is mentioned, it is understood to refer to 13N, 14N, 15N and mixtures thereof; when oxygen is mentioned, it is understood to refer to 14O, 15O, 16O, 17O, 18O and mixtures thereof; and when fluor is mentioned, it is understood to refer to 18F, 19F and mixtures thereof.
The compounds according to the invention therefore also comprise compounds with one or more isotopes of one or more element, and mixtures thereof, including radioactive compounds, also called radiolabelled compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive isotopes. By the term “radiolabelled compound” is meant any compound according to Formula (I), an N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, which contains at least one radioactive atom. For example, compounds can be labelled with positron or with gamma emitting radioactive isotopes. For radioligand-binding techniques (membrane receptor assay), the 3H-atom or the 125I-atom is the atom of choice to be replaced. For imaging, the most commonly used positron emitting (PET) radioactive isotopes are 11C, 18F, 15O and 13N, all of which are accelerator produced and have half-lives of 20, 100, 2 and 10 minutes respectively. Since the half-lives of these radioactive isotopes are so short, it is only feasible to use them at institutions which have an accelerator on site for their production, thus limiting their use. The most widely used of these are 18F, 99mTc, 201Tl and 123I. The handling of these radioactive isotopes, their production, isolation and incorporation in a molecule are known to the skilled person.
In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Preferably, the radioactive atom is selected from the group of hydrogen, carbon and halogen.
In particular, the radioactive isotope is selected from the group of 3H, 11C, 18F, 122I, 123I, 125I, 131, 75Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected from the group of 3H, 11C and 18F.
A. Preparation of the Final Compounds
Experimental Procedure 1
L is a Covalent Bond
The final compounds according to Formula (I-a), wherein L is a covalent bond, can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (III) according to reaction scheme (1), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, 1,4-dioxane or mixtures of inert solvents such as, for example, 1,4-dioxane/DMF, in the presence of a suitable base, such as, for example, aqueous NaHCO3 or Na2CO3, a Pd-complex catalyst such as, for example, Pd(PPh3)4 under thermal conditions such as, for example, heating the reaction mixture at 150° C. under microwave irradiation, for example for 10 min. In a reaction suitable for Pd mediated coupling with boronic acids or boronic esters, such as, for example, a halo, triflate or pyridinium moiety. Such intermediate compounds may be prepared according to reaction schemes (8), (9) and (10) (see below). R5 and R6 may be hydrogen or alkyl, or may be taken together to form for example the bivalent radical of formula —CH2CH2—, —CH2CH2CH2—, or —C(CH3)2C(CH3)2—.




Experimental Procedure 2
L is Oxygen or Sulfur
The final compounds according to Formula (I-b), wherein L is oxygen or sulfur, can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (IV) according to reaction scheme (2), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, THF, in the presence of a suitable base, such as, for example, NaH, under thermal conditions such as, for example, heating the reaction mixture for example at 80° C. under microwave irradiation for 10 minutes. In reaction scheme (2), all variables are defined as in Formula (I), R1 is V1-M1 and Y is a suitable leaving group, such as, for example, pyridinium.




Experimental Procedure 3
L is Aminoalkyl
The final compounds according to Formula (I-c), wherein L is —NR7—; —NR7CH2—; or —NR7CH2CH2— wherein each of R7, independently of each other, is selected from the group of hydrogen and alkyl, can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (V) according to reaction scheme (3), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, 1,4-dioxane, in the presence of a suitable base, such as, for example, K3PO4, a Pd-complex catalyst such as, for example,




under thermal conditions such as, for example, heating the reaction mixture for example at 80° C. for 12 hours. In reaction scheme (3), all variables are defined as in Formula (I), R1 is V1-M1 and Y is a suitable group for Pd-mediated coupling with amines, such as, for example, halo.

Alternatively, compounds according to Formula (I-c) can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (V) according to reaction scheme (3), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, dimethoxyethane or acetonitrile, in the presence of a suitable base, such as, for example, Cs2CO3 or N,N-diisopropylethylamine, under thermal conditions such as, for example, heating the reaction mixture for example at 160° C. under microwave irradiation for 30 minutes.





Experimental Procedure 4
L is Alkynyl
The final compounds according to Formula (I-d), wherein L is —C≡C—, can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (VI) according to reaction scheme (4), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, THF, in the presence of a suitable base, such as, for example, NEt3, a Pd-complex catalyst such as, for example, PdCl2(PPh3)2 a phosphine such as, for example, PPh3, a copper salt such as, for example, CuI and under thermal conditions such as, for example, heating the reaction mixture for example at 80° C. for 12 hours. In reaction scheme (4), all variables are defined as in Formula (I), R1 is V1-M1 and Y is a group suitable for Pd-mediated coupling with alkynes, such as, for example, halo.




Experimental Procedure 5
L is Alkenyl
The final compounds according to Formula (I-e), wherein L is —C(R8)═C(R9)— can be prepared by reaction of an intermediate of Formula (II) with an intermediate of Formula (VII) in an inert solvent such as, for example, 1,4-dioxane, in the presence of a suitable base, such as, for example, NaHCO3 or Na2CO3, a Pd-complex catalyst such as, for example, Pd(PPh3)4 under thermal conditions such as, for example, heating the reaction mixture at 85° C., for example for 8 hours. In reaction scheme (5), all variables are defined as in Formula (I) and Y is a group suitable for Pd-mediated coupling with boronic acids or boronic esters, such as, for example, a halo, trifluoromethanesulphonyl or pyridinium moiety. Such intermediate compounds may be prepared according to reaction schemes (8), (9) and (10) (see below). R5 and R6 may be hydrogen or alkyl, or may be taken together to form for example the bivalent radical of formula —CH2CH2—, —CH2CH2CH2—, or —C(CH3)2C(CH3)2—. In reaction scheme (5), all variables are defined as in Formula (I) and R1 is V1-M1.




Experimental Procedure 6
The final compounds according to Formula (I-e2), wherein L is —CH═CH— and Formula (I-f2), wherein L is —CH2CH2—, can be prepared by art-known procedures such as, for example, hydrogenation of a final compound of Formula (I-d), prepared according to reaction scheme (6). Additionally, final compounds of Formula (I-f1) and Formula (I-f2) can be prepared from final compounds of Formula (I-c1) and Formula (I-c2) by art-known hydrogenation methods according to reaction scheme (6). Additionally, final compounds of Formula (I-e2) can be prepared by partial reduction of the triple bond of final compounds of Formula (I-d) by art known procedures. In reaction scheme (6), all variables are defined as in Formula (I) and R1 is V1-M1.




Experimental Procedure 7
The compounds according to Formula (I) can be prepared by art known procedures by reacting a compound of Formula (VIII) with an alkylating agent of Formula (IX), such as, for example, isopentylbromide, using a suitable base such as, for example, K2CO3, and an iodine salt such as, for example, KI, in an inert solvent such as, for example, acetonitrile at a moderately high temperature such as, for example, 120° C. In reaction scheme (7), all variables are defined as in Formula (I), R1 is V1-M1 and Z is a suitable leaving group such as, for example, halo.




Additionally, final compounds according to Formula (I) can be prepared by a skilled person using art known procedures by further modifications of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-c) and (I-f) such as, for example:

    
    
        Alkylation of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their structure one or more hydroxy- or amino-substituents with a suitable alkylating agent under thermal conditions using a suitable base.
        Saponification of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their structure one or more alkyloxycarbonyl function by using a suitable saponificating agent such as, for example, NaOH or LiOH.
        Reaction of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their structure one or more carboxylic acid function with ammonia or a primary or secondary amine by using a suitable coupling agent such as, for example O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, to yield the corresponding final compounds of Formula (I), bearing a primary, secondary or tertiary carboxamide function in their structures.
        Reaction of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their structure a primary or secondary amine function with a carboxylic acid by using a suitable coupling agent such as, for example, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate to yield the corresponding final compounds of Formula (I), bearing a primary, secondary or tertiary carboxamide function in their structures.
        Reductive amination of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their structure one or more amino-substituents with a suitable aldehyde under thermal conditions using a suitable reducing agent such as, for example, sodium cyanoborohydride.
        Reaction of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their structure one or more hydroxy-substituents with an alcohol derivative by using a suitable coupling system such as, for example, di-tert-butylazodicarboxylate/triphenylphosphine under thermal conditions.
        1,3-Dipolar cycloaddition of final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their structure a reactive double or triple bond with a suitable dipole to yield the corresponding [3+2] adduct final compounds.
    
    


B. Preparation of the Intermediate Compounds
Experimental Procedure 8
Intermediate compounds of Formula (II-a) can be prepared by reacting an intermediate of Formula (X) with a suitable halogenating agent such as, for example, P(═O)Br3, a reaction that is performed in a suitable reaction-inert solvent such as, for example, DMF, at a moderately elevated temperature such as, for example, 110° C. In reaction scheme (8), all variables are defined as in Formula (I) and R1 is V1-M1.




Experimental Procedure 9
Intermediate compounds of Formula (II-b) can be prepared by reacting an intermediate of Formula (X) with triflic anhydride (also called trifloromethanesulfonic anhydride), a reaction that is performed in a suitable reaction-inert solvent such as, for example, dichloromethane, in the presence of a base such as, for example, pyridine at a low temperature such as, for example, −78° C. In reaction scheme (9), all variables are defined as in Formula (I) and R1 is V1-M1.




Experimental Procedure 10
Intermediate compounds of Formula (II-c) can be prepared by reacting an intermediate compound of Formula (II-b) with pyridine, at a moderately low temperature such as, for example, 40° C. In reaction scheme (10), all variables are defined as in Formula (I) and R1 is V1-M1.




Experimental Procedure 11
Intermediate compounds of Formula (X) can be prepared by art known procedures by reacting an intermediate compound of Formula (XI) with a suitable reagent for methylether-cleavage, such as, for example, NaOH, in a solvent such as, for example, water at a moderately high temperature such as, for example, 100° C. In reaction scheme (11), all variables are defined as in Formula (I) and R1 is V1-M1.




Experimental Procedure 12
Intermediate compounds of Formula (XI) can be prepared by art known procedures by reacting an intermediate of Formula (XII) with an alkylating agent of Formula (IX), such as, for example, isopentylbromide, using a base such as, for example, K2CO3, and, optionally an iodine salt such as, for example, KI, in an inert solvent such as, for example, acetonitrile at a moderately high temperature such as, for example, 120° C. In reaction scheme (12), all variables are defined as in Formula (I), R1 is V1-M1 and Z is a suitable leaving group such as, for example, halo.




Experimental Procedure 13
Intermediate compounds of Formula (III) can be prepared by art known procedures by reacting an intermediate of Formula (XIII) with a suitable boron source such as, for example, bis(pinacolato)diboron in the presence of a Palladium catalyst such as, for example, 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride in a inert solvent such as, for example, dichloromethane, in the presence of a suitable salt such as, for example, potassium acetate at moderately high temperature such as, for example, 110° C. for as for example 16 hours. Additionally, compounds of Formula (III) can be prepared by art known procedures of metal-halogen exchange and subsequent reaction with an appropriate boron source from compounds of Formula (XIII). Thus for example reaction of an intermediate compound of Formula (XIII) with an organolithium compound such as, for example, n-butyllithium at a moderately low temperature such as, for example, −40° C. in an inert solvent such as, for example, THF followed by subsequent reaction with an appropriate boron source such as, for example, trimethoxyborane. In reaction scheme (13), all variables are defined as in Formula (I) and R5 and R6 may be hydrogen or alkyl, or may be taken together to form for example the bivalent radical of formula —CH2CH2—, —CH2CH2CH2—, or —C(CH3)2C(CH3)2—.




The starting materials of Formula (X) and the intermediate compounds according to Formula (III), (IV), (V), (VI), (VII), (IX), (XII) and (XIII) are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.

It is evident that in the foregoing and in the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as, for example, extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as, for example, preparative HPLC.

Pharmacology

The compounds provided in this invention are positive allosteric modulators of metabotropic receptors, in particular they are positive allosteric modulators of mGluR2. The compounds of the present invention do not appear to bind to the glutamate recognition site, the orthosteric ligand site, but instead to an allosteric site within the seven transmembrane region of the receptor. In the presence of glutamate or an agonist of mGluR2, the compounds of this invention increase the mGluR2 response. The compounds provided in this invention are expected to have their effect at mGluR2 by virtue of their ability to increase the response of such receptors to glutamate or mGluR2 agonists, enhancing the response of the receptor. Hence, the present invention relates to a compound for use as a medicine, as well as to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR2 allosteric modulators, in particular positive mGluR2 allosteric modulators.
Also, the present invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating, or preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR2 positive allosteric modulators.
Where the invention is said to relate to the use of a compound or composition according to the invention for the manufacture of a medicament for e.g. the treatment of a mammal, it is understood that such use is to be interpreted in certain jurisdictions as a method of e.g. treatment of a mammal, comprising administering to a mammal in need of such e.g. a treatment, an effective amount of a compound or composition according to the invention.
In particular, the neurological and psychiatric disorders associated with glutamate dysfunction, include one or more of the following conditions or diseases: acute neurological and psychiatric disorders such as, for example, cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including substances such as, for example, opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder.
In particular, the condition or disease is a central nervous system disorder selected from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia.
Preferably, the central nervous system disorder is an anxiety disorder, selected from the group of agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia and other phobias.
Preferably, the central nervous system disorder is a psychotic disorder selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder Preferably, the central nervous system disorder is a personality disorder selected from the group of obsessive-compulsive personality disorder and schizoid, schizotypal disorder.
Preferably, the central nervous system disorder is a substance-related disorder selected from the group of alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal.
Preferably, the central nervous system disorder is an eating disorder selected from the group of anorexia nervosa and bulimia nervosa.
Preferably, the central nervous system disorder is a mood disorder selected from the group of bipolar disorders (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder and substance-induced mood disorder.
Preferably, the central nervous system disorder is migraine.
Preferably, the central nervous system disorder is epilepsy or a convulsive disorder selected from the group of generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, epilepsy partialis continua, and other forms of epilepsy.
Preferably, the central nervous system disorder is attention-deficit/hyperactivity disorder.
Preferably, the central nervous system disorder is a cognitive disorder selected from the group of delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, substance-induced persisting dementia and mild cognitive impairment.
Of the disorders mentioned above, the treatment of anxiety, schizophrenia, migraine, depression, and epilepsy are of particular importance.
At present, the fourth edition of the Diagnostic & Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association provides a diagnostic tool for the identification of the disorders described herein. The person skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders described herein exist, and that these evolve with medical and scientific progresses.
Because such positive allosteric modulators of mGluR2, including compounds of Formula (I), enhance the response of mGluR2 to glutamate, it is an advantage that the present methods utilize endogenous glutamate.
Because positive allosteric modulators of mGluR2, including compounds of Formula (I), enhance the response of mGluR2 to agonists, it is understood that the present invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by administering an effective amount of a positive allosteric modulator of mGluR2, including compounds of Formula (I), in combination with an mGluR2 agonist.
The compounds of the present invention may be utilized in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
Pharmaceutical Compositions
The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof.
The compounds according to the invention, in particular the compounds according to Formula (I), the pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.
To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as, for example, suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as, for example, starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a trans-dermal patch, as a spot-on, as an ointment.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, ininjectable solutions or suspensions and the like, and segregated multiples thereof. Since the compounds according to the invention are potent orally administrable dopamine antagonists, pharmaceutical compositions comprising said compounds for administration orally are especially advantageous.
As already mentioned, the invention also relates to a pharmaceutical composition comprising the compounds according to the invention and one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility as well as to the use of such a composition for the manufacture of a medicament.
The following examples are intended to illustrate but not to limit the scope of the present invention.
Experimental Part
Several methods for preparing the compounds of this invention are illustrated in the following Examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:













AcOEt (ethyl acetate)
M (molar)


AcOH (acetic acid)
MeOH (methanol)


BBr3 (boron tribromide)
mg (milligrams)


BINAP (±)-1,1′-Bi(2-naphthol)
MgSO4 (magnesium sulphate)


Br2 (bromine)
MHz (megahertz)


CDCl3 (deuterated chloroform)
min (minutes)


CCl4 (carbon tetrachloride)
μl (microliters)


DCM (dichloromethane)
ml (milliliters)


MCPBA (3-chloroperbenzoic acid)
mmol (millimol)


DEAD (diethyl azodicarboxylate)
m.p. (melting point)


DIBAL (diisobutyl aluminium hydride)
NaBH(OAc)3 (Sodium triacetoxyboro-



hydride)


DME (dimethoxyethane)
Na2CO3 (sodium carbonate)


DMF (dimethylformamide)
NaH (sodium hydride)


DMSO (dimethyl sulfoxide)
NaHCO3 (sodium bicarbonate)


Dppf (1,1′-bis(diphenylphosphanyl)ferrocene)
NaHMDS (sodium hexamethyldisilazane)


EDCI•HCl (1-3(dimethylaminopropyl)-3-
NaI (sodium iodide)


ethylcarbodiimide, hydrochloride)



Et3N (triethylamine)
NaOtBu (sodium tert-butoxide)


Et2O (diethyl ether)
Na2SO4 (sodium sulphate)


EtOH (ethanol)
NBS (N-bromosuccinimide)


g (grams)
NH4Cl (ammonium chloride)


1H (proton)
NH4OH (ammonium hydroxide)


H2 (hydrogen)
NMR (Nuclear Magnetic Reasonance)


HCl (hydrochloric acid)
Pd2(dba)3 (palladium



(II)dibenzylideneacetone)


HPLC (High Pressure Liquid Chromatography)
PdCl2(dppf)2 (Bis(1,1′-bis(diphenyl-



phosphanyl)ferrocene palladium (II) di-



chloride)


Hz (Hertz)
PdCl2(PPh3)2 (Bis(triphenylphosphine)



palladium (II) dichloride


KBr (potassium bromide)
Pd(OAc)2 (Palladium acetate)


K2CO3 (potassium carbonate)
Pd(PPh3)4



(tetrakis(triphenylphosphine)palladium(0))


KOAc (potassium acetate)
P(═O)Br3 (phosphorousoxybromide)


KI (potassium iodide)
PPh3 (triphenylphosphine)


KOtBu (potassium tert-butoxide)
TFA (trifluoroacetic acid)


KOH (potassium hydroxide)
THF (tetrahydrofuran)


K3PO4 (potassium phosphate)
TLC (thin layer chromatography)


LCMS (Liquid Chromatography Mass Spectrum)
Tf2O (trifloromethanesulfonic anhydride)


LiAlH4 (lithium aluminium hydride)
Xantphos (4,5-bis(diphenylphosphino)-



9,9-dimethylxanthene


 















All references to brine refer to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Celsius). All reactions are conducted not under an inert atmosphere at room temperature, unless otherwise noted.
Microwave assisted reactions were performed in a single-mode reactor: EmrysTM Optimizer microwave reactor (Personal Chemistry A.B., currently Biotage). Description of the instrument can be found in www.personalchemistry.com. And in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.). Description of the instrument can be found in www.milestonesci.com.
A. Preparation of the Intermediate Compounds
A1. Intermediate Compound 1




The reaction was carried out under N2 atmosphere. To a solution of commercially available 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (1.00 g, 6.60 mmol, 1 eq) in acetonitrile (45 ml) was added K2CO3 (2.73 g, 19.8 mmol, 3 eq) and isopentylbromide (441 mg, 8.65 mmol, 1.3 eq). The resulting solution was heated at 100° C. for 12 hours. The reaction was then cooled to room temperature and filtered through a pad of celite. The filtrate was then concentrated in vacuo. Subsequently, the crude residue thus obtained was purified by flash chromatography (SiO2, eluting with a gradient elution of between 0-2% MeOH in DCM) to yield intermediate compound 1 as a creamy solid (82%, 5.40 mmol).
A2. Intermediate Compounds 2 and 2′




A solution of intermediate compound 1 (1.5 g, 6.81 mmol) in aqueous NaOH (0.1 N, 75 ml) and THF (20 ml) was heated to 100° C. for 1 hour. The reaction was cooled to 0° C. and acidified by the addition of 1M HCl, adjusting the pH to about 3, at which point a white solid precipitated. The solid was filtered off and dried in vacuo to yield the N-isopentyl substituted intermediate compound 2 as a white solid (1.3 g, 6.30 mmol). In an equal manner was prepared the N-n-butyl substituted intermediate compound 2′.
A3. Intermediate Compounds 3, 3′ and 3′′




The reaction was carried out under N2 atmosphere. To a solution of intermediate compound 2 (2.00 g, 9.66 mmol, 1 eq) in DMF (10 ml) was added cautiously P(═O)Br3 (5.54 g, 19.0 mmol, 2 eq), the resulting solution was then heated at 100° C. into a sealed tube for 2 hours. The reaction was then cooled to room temperature and diluted by H2O (30 ml), the resulting solution was subsequently extracted with AcOEt (3×30 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield an oil. The crude product was purified by flash chromatography (SiO2, eluting with DCM) to yield N-isopentyl substituted intermediate compound 3 as a creamy solid (2.13 g, 82%, 7.92 mmol). In an equal manner was prepared the N-n-butyl substituted intermediate compound 3′ and the N-methylcyclopropyl substituted intermediate compound 3′′.
A4. Intermediate Compound 4




In a round flask containing intermediate compound 2 (100 mg, 0.48 mmol) in DCM (5 ml), were added 3 eq of pyridine (0.118 ml, 1.44 mmol). The mixture was cooled to −78° C. and Tf2O (0.217 ml, 0.528 mmol) was added slowly. The solution was warmed to room temperature and stirred for 1⁄2 hour. The mixture was hydrolized with cold water, extracted with DCM (3×10 ml), washed twice with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to yield intermediate compound 4 (133 mg).
A6. Intermediate Compound 6




The reaction was carried out under nitrogen atmosphere. To a solution of N-(2-bromobenzyl)-acetamide (468 mg, 2.02 mmol) in acetonitrile (45 ml) was added di-tert-butyl dicarbonate (1.34 g, 6.15 mmol) and N,N-dimethaminopyridine (501 mg, 4.1 mmol). The reaction mixture was then stirred at room temperature for 20 min, after which time it was diluted with AcOEt (40 ml) and washed with a saturated solution of NaHCO3 (2×40 ml) and a saturated solution of NH4Cl (3×40 ml). The organic layer was then dried over Na2SO4 and concentrated in vacuo to yield a crude solid. This was purified by short open column chromatography (SiO2, eluting with 2% MeOH in DCM) to yield intermediate compound 6 as a yellow oil (590.00 mg, 89%, 1.79 mmol).
A7. Intermediate Compound 7




To a solution of intermediate compound 6 (200 mg, 0.61 mmol) in DMSO (4 ml) was added bis(pinacolato)diboron (232 mg, 0.913 mmol) and potassium KOAc (180 mg, 1.83 mmol) the solution was then degassed using a stream of nitrogen and then to the reaction mixture was added 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (20.0 mg, 0.0183 mmol). The reaction mixture was then heated at 110° C. under a nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature and diluted with AcOEt (30 ml) and the resulting solution was washed with water (3×15 ml), the organic fraction was then dried over Na2SO4 and concentrated in vacuo to yield the desired compound. The product was purified by short open column chromatography (SiO2, eluting with DCM) to yield intermediate compound 7 as yellow oil (149.0 mg, 89%, 0.054 mmol).
A8. Intermediate Compound 8




The reaction was carried out under N2 atmosphere. 4-Bromobenzeneboronic acid pinacol cyclic ester (300 mg, 1.06 mmol), N-acetylethylenediamine (0.155 ml, 1.59 mmol), Xantphos (123 mg, 0.21 mmol), and Cs2CO3 (518 mg, 1.59 mmol) were added to a mixture of 1,4-dioxane (5.88 ml) and DMF (0.12 ml) at room temperature, and N2 was fluxed through the mixture for 5 min. Pd(OAc)2 (24 mg, 0.1 mmol) was added and the mixture was irradiated under microwave conditions at 170° C. for 10 min into a sealed tube. The reaction was then cooled to room temperature and filtered through a pad of celited. The volatiles were evaporated in vacuum and the residues thus obtained was purified by short open column chromatography (SiO2, eluting with DCM/MeOH(NH3) to yield intermediate compound 8 (80 mg).
A9. Intermediate Compound 9




To a solution of 4-pyridinethiol (149 mg, 1.35 mmol) in dimethylormamide (5 ml) was added K2CO3 (186 mg, 1.35 mmol); the resulting solution was stirred for 12 min and to this subsequently was added a solution of 2-(4-bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (400 mg, 1.35 mmol) and the resulting solution was stirred for 2 hours. The mixture was then diluted by the addition of water (30 ml) and extracted with AcOEt (3×15 ml); the organic layer was subsequently dried over Na2SO4 and concentrated in vacuo to yield the crude product. The crude reaction mixture was subsequently purified by Biotage purification (eluting with DCM) to yield intermediate compound 9. (406.0 mg, 1.24 mmol, 92%).
A10. Intermediate Compound 10




Commercially available 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (4.70 g, 31.29 mmol, 1 eq), 4-(trifluoromethoxy)benzylbromide (5.44 ml, 32.86 mmol, 1.05 eq) and K2CO3 (12.9 g, 93.8 mmol, 3 eq) were mixed in acetonitrile (200 ml). The mixture was heated at 140° C. for 16 hours into a sealed tube. The reaction was then cooled to room temperature and the solvents were evaporated in vacuum. The resulting residue was dissolved in DCM and filtered through a pad of celite. The filtrate was then concentrated in vacuo. Subsequently, the white solid thus obtained was triturated with diethylether to yield intermediate compound 10 as a white solid (9.20 g, 91%).
A11. Intermediate Compound 11




To a solution of intermediate compound 10 (9.20 g, 28.37 mmol) in THF (100 ml) was added aqueous NaOH (0.1 N, 300 ml). The reaction mixture was heated at 100° C. for 4 hours. The reaction was then cooled to room temperature and the THF was evaporated in vacuum. The resulting basic aqueous phase was acidified by the addition of 2 N HCl, adjusting the pH to about 3, at which point a white solid precipitated. The solid was filtered off, washed with diethylether and dried in vacuo to yield the intermediate compound 11 as a white solid (8.05 g, 91%).
A12. Intermediate Compound 12




Intermediate compound 11 (6.57 g, 21.19 mmol, 1 eq) and P(═O)Br3 (12.15 g, 42.39 mmol, 2 eq) were mixed in DMF (125 ml) and the resulting mixture was then heated at 110° C. for 1 hour. The reaction was then cooled to room temperature and diluted with H2O (200 ml), the resulting solution was subsequently extracted with AcOEt (3×75 ml). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, eluting with DCM) to yield intermediate compound 12 as a white solid (6.75 g). In a similar manner was made intermediate compound 12′ wherein the phenyl moiety in the para-position is substituted with a fluor instead of a trifluoromethoxy moiety.
A13. Intermediate Compound 13




To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (500 mg, 2.27 mmol), N-(2-hydroxyethyl)morpholine (330.8 mg, 2.72 mmol) and PPh3 polymer bound (loading 2.15 mmol/g) (2.11 g, 4.54 mmol) in dry DCM (30 ml) at 0° C. was added di-tert-butylazodicarboxylate (784.0 mg, 3.40 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then, the resin was filtered off, washed with DCM and the filtrate concentrated in vacuo. The residue (756.45 mg) was used in the next reaction step without further purification
A14. Intermediate Compound 14




Intermediate compound 3 (200 mg, 0.74 mmol), 1-tert-butoxycarbonylpiperazine (151 mg, 0.81 mmol), K3PO4 (236 mg, 1.1 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane (3 ml) at room temperature. The corresponding mixture was heated at 85° C. in a sealed tube for 16 hours. The mixture was cooled to room temperature, filtered through a pad of celite and washed with DCM. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to yield intermediate compound 14 (200 mg, 72%).
A16. Intermediate Compound 16




A mixture of 5-(4-bromophenyl)-1,3-oxazole (220 mg, 0.98 mmol), bis(pinacolato)-diboron (372 mg, 1.47 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, DCM (24 mg, 0.0294 mmol), KOAc (288 mg, 2.93 mmol) in DMSO (7 ml) was heated at 110° C. for 16 hours. The mixture was cooled to room temperature, diluted with AcOEt (30 ml) and washed with water (3×15 ml). The combined organic layers were dried over Na2SO4, evaporated in vacuum and the residue thus obtained (200 mg) was used in the next reaction step without further purification.
A17. Intermediate Compound 17




A solution of commercially available 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (4.0 g, 0.0266 mol), beta-bromophenetole (5.62 g, 0.0279 mol) and K2CO3 (11.0 g, 0.0799 mol) in CH3CN (150 ml) was heated at reflux for 16 hours. The reaction mixture was then filtered off and the filtrate concentrated in vacuo. The residue was recrystallised from ethylether to yield intermediate compound 17 (7 g, 97%).
A18. Intermediate Compound 18




To a solution of intermediate compound 17 (7.0 g, 0.0259 mol) in MeOH (100 ml) was added aqueous NaOH (0.1 N, 200 ml). The reaction mixture was heated to 100° C. for 3 hours. The reaction was then cooled to room temperature and the MeOH was evaporated in vacuum. The resulting basic aqueous phase was acidified by the addition of 2 N HCl, adjusting the pH to about 3, at which point a white solid precipitated. The solid was collected using a sintered funnel, washed with ethylether and dried in vacuo to yield intermediate compound 18 as white solid (5.78 g, 87%).
A19. Intermediate Compound 19




Intermediate compound 18 (7.10 g, 0.027 mol) and P(═O)Br3 (15.886 g, 0.055 mol) were mixed in DMF (150 ml) and the resulting mixture was then heated at 110° C. for 3 hours. The reaction was then cooled to room temperature and diluted by H2O (100 ml), the resulting solution was subsequently extracted with AcOEt (3×150 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, eluting with DCM) to yield intermediate compound 19 (7.67 g, 89%).
A20. Intermediate Compound 20




In a round flask containing 3-(trifluoromethyl)benzaldehyde ([454-89-7] CAS) (0.872 ml, 0.0065 mol) and 4-piperidinemethanol (0.5 g, 0.0043 mol) in DCE (20-30 ml) and a few drops of AcOH, NaBH(OAc)3 (2.2 g, 0.0107 mol) was added. The mixture was stirred overnight at room temperature, after which time it was washed with a saturated solution of NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography to yield intermediate compound 20 (0.610 g, 56%).
A23. Intermediate Compound 23




In a round flask containing methyl-4-formylbenzoate (5.6 g, 0.034 mol) and morpholine (2 g, 0.023 mol) in DCE (20 ml), few drops of AcOH and molecular sieves (4A) were added. The reaction mixture was stirred at room temperature for 40 min and NaBH(OAc)3 (5 g, 0.023 mol) was added. The mixture was stirred overnight at room temperature, after which time another equivalent of NaBH(OAc)3 (5 g, 0.023 mol) was added. The mixture was stirred at room temperature for 5 hours and was subsequently washed with HCl (1 N) and extracted with DCM. The organic layer was finally washed with a saturated solution of NaHCO3. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (DCM/MeOH(NH3) mixtures) to yield intermediate compound 23 (3 g, 60%)
A24. Intermediate Compound 24




The reaction was carried out under N2 atmosphere. To a solution of intermediate compound 23 (2 g, 0.0085 mol) in THF (12 ml), lithium aluminum hydride (1 M in THF) (17 ml, 0.017 mol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. Then, a saturated solution of NaHCO3 was carefully added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield intermediate compound 24 (1.75 g, 100%) which was used in the next reaction step without further purification.
A28. Intermediate Compound 28




A mixture of intermediate compound 3 (250 mg, 0.93 mmol), tributyl(vinyl)tin (0.325 ml, 1.11 mmol) and Pd(PPh3)4 (22 mg, 0.0186 mmol) in degassed toluene (10 ml) was microwaved at 130° C. for 25 min. The mixture was then cooled to room temperature and solvents were evaporated in vacuum. The residue was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield intermediate compound 28 (100 mg, 50%) as pale yellow solid.
A29. Intermediate Compound 29




To a solution of 4-pyridylcarbinol (15 g, 137.4 mmol) in DCM (200 ml) was added thionyl chloride (43.6 ml) and the resulting reaction mixture was stirred at room temperature for 4 h. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was diluted with DCM and washed with a saturated solution of NaHCO3. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield intermediate compound 29 (17.18 g, 99%).
A30. Intermediate Compound 30




To a mixture of NaH (60% in mineral oil) (0.718 g, 17.96 mmol) in THF (20 ml), a solution of 5-bromoindole (2.34 g, 11.8 mmol) in THF (17 ml) was added dropwise. The resulting mixture was stirred at room temperature for 1 h. Then, intermediate compound 29 (1.81 g, 14.2 mmol) was added and the mixture was heated at 80° C. overnight. The cooled reaction mixture was washed with H2O and extracted with AcOEt. The combined organic layers were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, DCM/MeOH mixtures) to yield intermediate compound 30 (2.73 g, 80%).
A31. Intermediate Compound 31




To a solution of intermediate compound 30 (2.73 g, 9.5 mmol) in DMSO (27 ml) was added bis(pinacolato)diboron (2.414 g, 9.5 mmol) and KOAc (2.8 g, 28.5 mmol). The solution was then degassed using a stream of nitrogen and then to the reaction mixture was added 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (0.23 g, 0.28 mmol). The reaction mixture was then heated at 110° C. overnight under a nitrogen atmosphere. The reaction was then cooled to room temperature and additional amounts of bis(pinacolato)diboron (1.63 g, 6.4 mmol), KOAc (1.89 g, 19.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (0.155 g, 0.19 mmol) were added and the mixture was heated at 130° C. overnight. The cooled reaction mixture was diluted with AcOEt, filtered through a pad of celite and the filtrate was washed with water. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield intermediate compound 31 (4.5 g, quant.) used in the next reaction step without further purification.
A32. Intermediate Compound 32




To a mixture of (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester ([286961-14-6] CAS) (1.5 g, 4.8 mmol) in a mixture of 1,4-dioxane (8 ml) and DMF (2 ml) were added 4-chloro-2-picoline (0.308 g, 2.4 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, DCM (0.293 g, 0.36 mmol) and potassium carbonate (0.993 g, 7.2 mmol). The mixture was then degassed using a stream of nitrogen and then microwaved at 160° C. for 90 min. The cooled reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield intermediate compound 32 (0.5 g, 38%).
A33. Intermediate Compound 33




A solution of intermediate compound 32 (0.5 g, 1.82 mmol) in a 20% solution of TFA in DCM (10 ml) was stirred at room temperature for 4 hours, after which time the solvent was evaporated. The residue (0.5 g) was used in the next reaction step without further purification.
A35. Intermediate Compound 35




To a solution of intermediate compound 2′ (1.5 g, 7.8 mmol) in acetonitrile (13 ml), (4-bromomethylphenyl)boronic acid, pinacol ester (3.0 g, 9.76 mmol) ([138500-85-3] CAS) and cesium carbonate (5.92 g, 15.6 mmol) were added. The reaction mixture was microwaved at 160° C. for 30 min. Then, solvents were evaporated in vacuo and the residue was purified by flash chromatography (SiO2, DCM/MeOH mixtures) to yield intermediate compound 35 (2.93 g, 92%).
A36. Intermediate Compound 36




A mixture of intermediate compound 3 (0.366 g, 1.361 mmol),




(compound described in US 2005187277 A1) (0.436 g, 1.63 mmol, Pd(PPh3)4 (0.157 g, 0.136 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was microwaved at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate evaporated in vacuum. The residue was subsequently purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield intermediate compound 36 (0.55 g, 98%).

A39. Intermediate Compound 39





To a solution of 4-aminomethylphenylboronic acid, pinacol ester (CAS 138500-88-6) (1.2 g, 5.14 mmol) and Et3N (1.42 ml, 10.28 mmol) in DCM (50 ml) stirred at room temperature, di-tert-butyldicarbonate (1.68 g, 7.72 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated in vacuum to yield a residue which was treated with diethylether to yield intermediate compound 39 (1.7 g) as a solid, 99%) used in the next reaction step without further purification.
A40. Intermediate Compound 40




To a solution of intermediate compound 39 (1.7 g, 5.14 mmol) in 1,4-dioxane (3 ml) and a saturated solution of NaCO3 (3 ml) was added intermediate compound 3 (1.15 g, 4.28 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (485.0 mg, 0.42 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate concentrated in vacuo. The crude reaction mixture was then purified by flash chromatography (SiO2, DCM/McOH(NH3) 9:1) to yield intermediate compound 40 (1.3 g, 77%).
A41. Intermediate Compound 41




To a solution of intermediate compound 40 (0.125 g, 0.316 mmol) in DMF (dried, 5 ml) at 0° C., NaH (60% mineral oil; 0.019 mg, 0.474 mmol) was added. The resulting suspension was stirred at 0° C. (under nitrogen atmosphere) for 30 min. Then, 3-fluorobenzylbromide (0.059 ml, 0.474 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Then, water was added and the resulting aqueous mixture was extracted with AcOEt. The organic layer was washed with a saturated solution of NaCl. The combined organic layers were dried over Na2SO4. The crude reaction mixture was then purified by flash chromatography (SiO2, DCM/MeOH(NH3) 9:1) to yield intermediate compound 41 (0.082 g, 51%) as a yellow oil.
A42. Intermediate Compound 42




To a mixture of 4-bromo-2-fluoroaniline (0.6 g, 3.15 mmol), tetrahydro-4H-pyran-4-one (0.68 g, 6.31 mmol) and NaBH(OAc)3 (0.96 g, 4.72 mmol) in DCE (20 ml), molecular sieves (4A) (1 g) were added. The mixture was stirred at room temperature for 16 h. Then, additional amounts of tetrahydro-4H-pyran-4-one (0.34 g, 3.15 mmol) and NaBH(OAc)3 (0.66 g, 3.15 mmol) were added and the mixture was stirred at room temperature for 48 h. Then, the reaction mixture was filtered through a pad of celite and washed with DCM. The filtrate was concentrated in vacuo to yield intermediate compound 42 (0.86 g, quant.) used in the next reaction step without further purification.
A43. Intermediate Compound 43




To a solution of intermediate compound 42 (0.86 g, 3.15 mmol) in DMSO (3 ml) was added bis(pinacolato)diboron (0.80 g, 3.15 mmol) and KOAc (0.93 g, 9.45 mmol) the solution was then degassed using a stream of nitrogen and then to the reaction mixture was added 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (0.07 g, 0.09 mmol). The reaction mixture was then heated at 120° C. under a nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature and diluted with water (50 ml) and the resulting solution was extracted with AcOEt, the organic fraction was then dried over Na2SO4 and concentrated in vacuo to yield intermediate compound 43 (1.01 g, 100%) used in the next reaction step without further purification.
A44. Intermediate Compound 44




To a solution of NaH (60% in mineral oil) (0.13 g, 3.25 mmol) in DMF (5 ml) was added commercially available 4-bromophenol (0.50 g, 2.89 mmol) and the reaction was stirred at room temperature for 10 min. Then, 4-chloro-2-picoline (0.30 g, 2.40 mmol) was added and the resulting reaction mixture was then microwaved at 150° C. for 10 min. After cooling, the mixture was diluted with water and extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue thus obtained was purified by flash chromatography (DCM) to yield intermediate compound 44 (0.52 g, 81%).
A45. Intermediate Compound 45




To a solution of intermediate compound 44 (0.50 g, 1.89 mmol) in DMSO (5 ml) was added bis(pinacolato)diboron (0.72 g, 2.84 mmol) and KOAc (0.56 g, 5.68 mmol) the solution was then degassed using a stream of nitrogen and then to the reaction mixture was added 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (0.05 g, 0.06 mmol). The reaction mixture was then heated at 110° C. under a nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature and diluted with water and the resulting solution was extracted with AcOEt, the organic fraction was then dried over Na2SO4 and concentrated in vacuo to yield intermediate compound 45 (0.58 g, 100%) used in the next reaction step without further purification.
B. Preparation of the Final Compounds
B1. Final Compound 1-110




To a solution of 3,4-dimethoxyphenylboronic acid (740.0 mg, 4.08 mmol) in 1,4-dioxane (14 ml) and a saturated solution of NaHCO3 (14 ml) was added intermediate compound 3 (1.00 g, 3.70 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh)4 (641.0 mg, 0.55 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate concentrated in vacuo. The crude reaction mixture was then purified by flash chromatography (eluting with a solvent gradient 0-2% MeOH in DCM) to yield the desired compound. The compound was then recrystallised from diethylether to yield the final compound 1-110 (940.0 mg, 2.88 mmol, 78%).
B2. Final Compound 1-179




Intermediate compound 4 (150 mg, 0.44 mmol), and 4-(acetamidomethyl)phenylboronic acid (129 mg, 0.67 mmol) were mixed in 1,4-dioxane (5 ml) and Et3N (0.12 ml, 0.89 mmol) at room temperature and N2 was flushed through the mixture for 5 min. Pd(PPh3)4 (77 mg, 0.067 mmol) was added and the resulting mixture was heated at 90° C. for 2 hours. The mixture was cooled to room temperature, diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3×20 ml). The combined organics layers were dried over Na2SO4, evaporated in vacuum and the residue thus obtained was purified by column chromatography (SiO2, DCM/AcOEt) to yield 16 mg of final compound 1-179 as a white solid.
B3. Final Compound 1-114




Intermediate compound 4 (150 mg, 0.44 mmol), 3-fluoro-4-methoxyphenylboronic acid (110 mg, 0.67 mmol) were mixed in 1,4-dioxane (5 ml) and Et3N (0.12 ml, 0.89 mmol) at room temperature and N2 was flushed through the mixture for 5 min. Pd(PPh3)4 (77 mg, 0.067 mmol) was added and the resulting mixture was heated at 90° C. for 2 hours. The mixture was cooled to room temperature, diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3×20 ml). The combined organics layers were dried over Na2SO4, evaporated in vacuum and the residue thus obtained was purified by column chromatography (SiO2, DCM/AcOEt) to yield 43 mg of final compound 1-114 as a yellow solid.
B4. Final Compound 1-095




Intermediate compound 4 (150 mg, 0.44 mmol) and 4-(3-hydroxypropyl)-phenylboronic acid (120 mg, 0.67 mmol) were mixed in 1,4-dioxane (5 ml) and Et3N (0.12 ml, 0.89 mmol) at room temperature and N2 was flushed through the mixture for 5 min. Pd(PPh3)4 (77 mg, 0.067 mmol) was added and the resulting mixture was heated at 90° C. for 2 hours. The mixture was cooled to room temperature, diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3×20 ml). The combined organics layers were dried over Na2SO4, evaporated in vacuum and the residue thus obtained was purified by column chromatography (SiO2, DCM/AcOEt) to yield 40 mg of final compound 1-095 as a white solid.
B5. Final Compound 1-103




Intermediate compound 4 (150 mg, 0.44 mmol), 4-(methoxymethyl)phenylboronic acid (110 mg, 0.67 mmol) were mixed in 1,4-dioxane (5 ml) and Et3N (0.12 ml, 0.89 mmol) at room temperature and N2 was flushed through the mixture for 5 min. Pd(PPh3)4 (77 mg, 0.067 mmol) was added and the resulting mixture was heated at 90° C. for 2 hours. The mixture was cooled to room temperature, diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3×20 ml). The combined organics layers were dried over Na2SO4, evaporated in vacuum and the residue thus obtained was purified by column chromatography (SiO2, DCM/AcOEt) to yield 52 mg of final compound 1-103 as a white solid.
B6. Final Compound 1-178




To a solution of intermediate compound 7 (220.0 mg, 0.58 mmol), in 1,4-dioxane (6 ml) and a saturated solution of Na2CO3 (6 ml) was added intermediate compound 3 (173 mg, 0.65 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (101.0 mg, 0.088 mmol). The reaction was then microwaved at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate concentrated in vacuo. The crude reaction mixture was then purified by preparative HPLC to yield the pure final compound 1-178 (51 mg, 0.15 mmol, 26%).
B7. Final Compound 1-097




To a solution of 4-hydroxyphenylboronic acid (336 mg, 2.44 mmol), in 1,4-dioxane (20 ml) and a saturated solution of NEt3 (0.615 ml, 4.43 mmol) was added final compound 5-052 (750 mg, 1.79 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (384 mg, 0.33 mmol). The reaction was heated at 90° C. for 2 hours into a sealed tube. The resulting reaction mixture cooled to room temperature, was diluted with water and brine and extracted with AcOEt. The organic layer was dried over Na2SO4 and vacuum concentrated. The crude reaction mixture was then purified by flash chromatography (SiO2, eluting with mixtures of heptane/AcOEt) to yield the final compound 1-097 (230 mg, 45%).
B8. Final Compound 1-274




To a solution of phenol (0.042 ml, 0.48 mmol) in dry THF (3 ml) at room temperature, NaH (60% in mineral oil, 13.83 mg, 0.96 mmol) was added. The resulting mixture was stirred at room temperature for 5 min. Final compound 5-052 (100 mg, 0.24 mmol) was added. The mixture was microwaved into a scaled tube for 10 min at 80° C. The mixture was cooled to room temperature, solvents were evaporated in vacuo and the residue thus obtained was purified by column chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield 55 mg of final compound 1-274 as a white solid.
B9. Final Compound 1-298




Intermediate compound 3 (100 mg, 0.371 mmol), aniline (0.067 ml, 0.743 mmol) K3PO4 (158 mg, 0.745 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane (15 ml) at room temperature. The corresponding mixture was stirred at 80° C. (oil bath temperature) into a sealed tube for 12 hours. The mixture was cooled to room temperature and AcOEt (30 ml) and NaHCO3 (10 ml, aqueous saturated solution) were added to the reaction mixture. Layers were separated and the organic one was dried over Na2SO4. Solvents were evaporated in vacuum and the residue thus obtained was purified by flash chromatography to yield final compound 1-298 (50 mg).
B10. Final Compound 1-267




Reaction under nitrogen atmosphere. Intermediate compound 3 (150 mg, 0.557 mmol), phenylacetylene (0.064 ml, 0.580 mmol), PdCl2(PPh3)2 (19.6 mg, 0.028 mmol) PPh3 (3.7 mg, 0.014 mmol) and NEt3 (0.078 ml, 2.23 mmol) were mixed in THF (6 ml) at room temperature and N2 was flushed through the mixture for 5 min. CuI (1.3 mg, 0.007 mmol) was added and the resulting mixture was heated at 90° C. (oil bath temperature) into a sealed tube for 10 hours. The reaction mixture was cooled to room temperature and aqueous Na2S2O4 (saturated solution) was added. DCM (30 ml) was added and the layers were separated. The organic layer was washed with aqueous NaHCO3 (saturated solution), dried over Na2SO4 and vacuum concentrated. The residue thus obtained was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield final compound 1-267 (57 mg).
B11. Final Compound 1-260




10% Pd/C (10 mg) was added to a solution of final compound 1-267 (45 mg, 0.155 mmol) and 1,4-cyclohexadiene (0.22 ml, 2.32 mmol) in MeOH (5 ml) at room temperature. The resulting mixture was stirred into a sealed tube for 12 hours. The catalyst was filtered off and solvents were evaporated in vacuo. The residue thus obtained was taken up in MeOH (15 ml) and 10% Pd/C (10 mg) was added. The resulting mixture was hydrogenated with hydrogen (20 psi) for 3 hours. The catalyst was filtered off and the solvent was evaporated. The residue thus obtained was purified by flash chromatography (SiO2, DCM/McOH(NH3) mixtures) and then by reverse phase HPLC chromatography to yield final compound 1-260 as a white solid (1.63 mg).

B12. Final Compound 1-182





To a solution of intermediate compound 8 (80 mg, 0.62 mmol), in 1,4-dioxane (1 ml) and a saturated solution of Na2CO3 (1 ml) was added intermediate compound 3 (64.34 mg, 0.239 mmol). The resulting solution was degassed using a stream of nitrogen and to this solution was added Pd(PPh3)4 (41.4 mg, 0.035 mmol). The reaction was then microwaved at 140° C. for 5 min. The resulting reaction mixture was subsequently filtered through a pad of celite and AcOEt (10 ml) was added. H2O (10 ml) was added and layers were separated. The organic layers were dried (Mg2SO4) and vacuum concentrated. The resulting residue was then purified by column chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield the pure final compound 1-182 (28 mg) as bright yellow solid.
B13. Final Compound 1-258




To a solution of intermediate compound 9 (121 mg, 0.371 mmol), in 1,4-dioxane (3 ml) and a saturated solution of NaHCO3 (3 ml) was added intermediate compound 3 (100 g, 3.71 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (64.0 mg, 0.056 mmol). The reaction was then microwaved at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate concentrated in vacuo. The crude reaction mixture was then purified by HPLC purification to yield final compound 1-258 (13.0 mg, 0.034 mmol, 10%).
B14. Final Compound 1-239




Intermediate compound 4 (150 mg, 0.44 mmol) and 4-(methyl-3-propanoate)phenylboronic acid (140 mg, 0.67 mmol) were mixed in 1,4-dioxane (5 ml) and Et3N (0.12 ml, 0.89 mmol) at room temperature, and N2 was flushed through the mixture for 5 min. Pd(PPh3)4 (77 mg, 0.06 mmol) was added to the mixture and the resulting mixture was heated at 90° C. for 2 hours. The mixture was cooled to room temperature, diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3×20 ml). The combined organics layers were dried over Na2SO4, evaporated in vacuum and the residue thus obtained was purified by column chromatography (SiO2, DCM/AcOEt) to yield 63 mg of final compound 1-239 as a yellow solid.
B15. Final Compound 1-240




To a solution of final compound 1-239 (20 mg, 0.057 mmol) in THF/H2O 1:1 (4 ml) at 0° C. was added lithium hydroxide (24 mg, 0.57 mmol). The reaction mixture was stirred for 30 min and the solution was concentrated. The pH was adjusted to pH=2 with a 1 N solution of HCl and the precipite thus formed was filtered off and dried, to yield 10 mg of the final compound 1-240 as a white solid.
B16. Final Compound 2-043




Intermediate compound 12 (300 mg, 0.804 mmol), 1-(2-phenylethyl)piperazine (0.176 ml, 0.964 mmol) K3PO4 (341 mg, 1.60 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane (6 ml) at room temperature. The corresponding mixture was heated at 110° C. into a sealed tube for 16 hours. The mixture was cooled to room temperature, filtered through a pad of celite and washed with AcOEt. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to yield final compound 2-043 as a pale yellow solid (349 mg, 90%).
B17. Final Compound 1-037




Intermediate compound 12 (350 mg, 0.938 mmol) and intermediate compound 13 (375 mg, 1.12 mmol) were mixed in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (108.3 mg, 0.093 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and washed with AcOEt. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to yield the final compound 1-037 (305.6 mg, 65%).
B18. Final Compound 2-022




A mixture of final compound 2-056 (150 mg, 0.55 mmol), 3-chloro-4-(trifluoromethoxy)benzyl bromide (0.16 ml, 0.55 mmol) and K2CO3 (150 mg, 1.1 mmol) in DMF (2 ml) was stirred overnight at room temperature. The resulting reaction mixture was then filtered through a pad of celite and washed with AcOEt. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to yield the desired compound. The compound was then recrystallised from diethylether to yield the final compound 2-022 (170 mg, 64%).
B19. Final Compound 1-250




Intermediate compound 3 (198 mg, 0.74 mmol) and intermediate compound 16 (200 mg, 0.74 mmol) were mixed in 1,4-dioxane (5 ml) and a saturated solution of Na2CO3 (5 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (128 mg, 0.115 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and washed with AcOEt. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to yield the final compound 1-250 (63.9 mg, 26%, yield based on two subsequent reaction steps).
B20. Final Compound 1-223




Intermediate compound 3 (727 mg, 2.70 mmol) and commercially available 4-(morpholino)phenylboronic acid (560 mg, 2.70 mmol) were mixed in 1,4-dioxane (10 ml) and a saturated solution of Na2CO3 (10 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (468 mg, 0.405 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate was washed with water (10 ml). The combined organic layers were dried over Na2SO4 and evaporated in vacuum. The crude reaction mixture was subsequently purified by flash chromatography to yield the desired compound. The compound was then recrystallised from ethylether to yield the final compound 1-223 (620 mg, 65%).
B21. Final Compound 1-049




Intermediate compound 19 (250 mg, 0.783 mmol) and 3-chloro-4-isopropoxy-phenylboronic acid (159 mg, 0.86 mmol) were mixed in 1,4-dioxane (2.5 ml) and a saturated solution of NaHCO3 (2.5 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (130 mg, 0.11 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate evaporated in vacuum. The crude reaction mixture was subsequently purified by flash chromatography to yield the desired compound. The compound was then recrystallised from diethylether to yield the final compound 1-049 as a white solid (65 mg, 21%).
B22. Final Compound 4-020




Intermediate compound 3 (100 mg, 0.37 mmol), 4-(3-trifluoromethylbenzyloxy)-piperidine (115.11 mg, 0.444 mmol), K3PO4 (150 mg, 0.70 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane (5 ml) at room temperature. The corresponding mixture was heated at 85° C. into a scaled tube for 16 hours. The mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to yield final compound 4-020 as a white gummy solid (90 mg, 55%).
B23. Final Compound 4-044




Intermediate compound 3 (150 mg, 0.406 mmol), 4,4-(phenylpiperidin-4-yl)-morpholine (113.3 mg, 0.46 mmol), K3PO4 (200 mg, 0.94 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane (4 ml) at room temperature. The corresponding mixture was heated at 85° C. into a sealed tube for 36 hours. The mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue thus obtained was purified by prep. HPLC to yield final compound 4-044 as pale yellow solid (123 mg, 51%).
B24. Final Compound 2-028




Intermediate compound 3 (226 mg, 0.84 mmol), 1-(2-pyrimidyl)piperazine dihydrochloride (228 mg, 0.96 mmol), K3PO4 (612 mg, 2.88 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane (5 ml) at room temperature. The corresponding mixture was heated at 85° C. into a sealed tube for 36 hours. The mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to yield final compound 2-028 as a pale creamy solid (258 mg, 87%).
B25. Final Compound 3-009




A mixture of intermediate compound 20 (0.223 g, 0.00081 mol, 1.1 eq.) and NaH (60% dispersion in mineral oil, 0.035 g, 0.00088 mol, 1.2 eq.) in DME (1.5 ml) was stirred at room temperature over 10 min. Then, intermediate compound 3 (0.20 g, 0.00074 mol, 1 eq.) was added slowly. The resulting reaction mixture was microwaved at 130° C. for 20 min. The mixture was cooled to room temperature and solvents were evaporated in vacuum. The residue was suspended in DCM, filtered off and the filtrate concentrated in vacuo. The crude reaction mixture was then purified by flash chromatography to yield final compound 3-009 (146 mg, 47%).
B26. Final Compound 3-008




To a solution of final compound 3-016 (346 mg, 1.19 mmol) and 3-(trifluoromethyl)benzaldehyde ([454-89-7] CAS) (262 mg, 1.5 mmol) in DCE (40 ml), NaBH(OAc)3 (760 mg, 3.6 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 3 hours. Then, the mixture was quenched with an aqueous solution of NH4Cl. The combined organic layers were concentrated in vacuo. The crude product was purified by flash chromatography to yield final compound 3-008 (370 mg) as a pale brown solid.
B27. Final Compound 1-271




To a mixture of intermediate compound 11 (200 mg, 0.64 mmol), intermediate compound 24 (267 mg, 1.28 mmol) and PPh3 (309 mg, 1.15 mmol) in THF (5 ml) was added di-tert-butylazodicarboxylate (279 mg, 1.21 mmol). The reaction mixture was microwaved at 120° C. over 20 min. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (eluting with a solvent gradient 10-20% DCM/MeOH(NH3) to give the final compound 1-271 (219.7 mg, 70%).
B28. Final Compound 3-014




To a solution of final compound 3-018 (191 mg, 0.70 mmol) and 3-(trifluoromethyl)benzaldehyde ([454-89-7] CAS) (174 mg, 1 mmol) in DCE (16 ml), NaBH(OAc)3 (443 mg, 2.1 mmol) was added portionwise. The mixture was stirred at room temperature for 3 hours, after which time it was quenched with a saturated solution of NH4Cl. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography to yield final compound 3-014 as white solid (270 mg, 89%).
B29. Final Compound 2-036




To a mixture of intermediate compound 2 (0.2 g, 0.971 mmol), K2CO3 (0.268 g, 1.942 mmol) and NaI (cat.) in acetonitrile (12 ml), 1-(2-chloroethyl)-4-pyridin-2-yl-piperazine (0.393 g, 1.748 mmol) was added. The reaction mixture was microwaved twice at 150° C. for 10 min. Then, DCM was added and the mixture was filtered off. The filtrate was washed with a saturated solution of NaHCO3. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (DCM/MeOH(NH3) mixtures) to give final compound 2-036 (152.5 mg, 40%) as off white solid.
B30. Final Compound 5-007




To a solution of intermediate compound 28 (35 mg, 0.161 mmol) in DCM (6 ml) a drop of TFA was added. Then, N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (46 mg, 0.193 mmol) was slowly added and the resulting reaction mixture was stirred at room temperature for 2 hours. Then, solvents were evaporated in vacuum and the residue was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield final compound 1-131 (6 mg, 10%).
B31. Final Compound 2-055




A mixture of intermediate compound 12′ (250 mg, 0.81 mmol), 1-(2-pyridyl)-piperazine (0.129 ml, 0.85 mmol) and diisopropylethylamine (0.416 ml, 2.4 mmol) in acetonitrile (5 ml) was microwaved at 160° C. for 30 min. The mixture was cooled to room temperature and the solvents were evaporated in vacuum. The residue thus obtained was purified by flash chromatography (SiO2, DCM/MeOH mixtures) to yield final compound 2-055 (192 mg, 61%) as a white solid.
B32. Final Compound 5-020




Intermediate compound 3 (0.6 g, 2.20 mmol) and intermediate compound 31 (3.69 g, 3.79 mmol) were mixed in 1,4-dioxane (7 ml) and a saturated solution of Na2CO3 (6 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.39 g, 0.33 mmol). The reaction was then microwaved into a sealed tube at 140° C. for 5 min. The resulting reaction mixture was then diluted with AcOEt, filtered through a pad of celite and the filtrate was washed with water (10 ml). The combined organic layers were dried over Na2SO4 and evaporated in vacuum. The crude reaction mixture was subsequently purified by flash chromatography to yield the desired compound. The compound was then recrystallised from diethylether to yield the final compound 5-020 (0.39 g, 44%).
B33. Final Compound 4-047




A mixture of intermediate compound 3′′ (0.3 g, 1.18 mmol), 4-phenylpiperidine (0.286 g, 1.77 mmol) and diisopropylethylamine (0.615 ml, 3.54 mmol) in acetonitrile (5 ml) was microwaved at 150° C. for 20 min. The mixture was cooled to room temperature and the solvents were evaporated in vacuum. The residue thus obtained was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield the desired compound. The compound was then recrystallised from ethylether to yield the final compound 4-047 (0.29 g, 73%)
B34. Final Compound 4-003




A mixture of final compound 5-054 (0.37 g, 1.05 mmol) and palladium (10% on activated carbon) (catalytic amount) in EtOH (10 ml) was stirred under a hydrogen atmosphere at 50 psi for 3 hours. The catalyst was then filtered off and the filtrate was concentrated in vacuo. The residue thus obtained was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield final compound 4-003 (0.21 g, 57%).
B35. Final Compound 1-306




Intermediate compound 35 (0.25 g, 0.61 mmol) and commercially available 2-bromo-6-methylpyridine (0.158 g, 0.92 mmol) were mixed in 1,4-dioxane (2 ml) and a saturated solution of NaHCO3 (2 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.10 g, 0.09 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate was washed with water (10 ml). The combined organic layers were dried over Na2SO4 and evaporated in vacuum. The crude reaction mixture was subsequently purified by flash chromatography to yield final compound 1-306 (0.078 g, 34%).
B36. Final Compound 5-015




To a solution of final compound 5-014 (0.04 g, 0.130 mmol), prepared by the reaction pathway B1, and diisopropylethylamine (0.068 ml, 0.392 mmol) in DCM (2 ml), acetyl chloride (0.014 ml, 0.196 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. Then, the solvents were evaporated in vacuum and the residue thus obtained was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield final compound 5-015 (0.045 g, 99%).
B37. Final Compound 1-198




To a solution of intermediate compound 41 (0.082 mg. 0.163 mmol) in DCM (10 ml), TFA (5 ml) was added. The resulting solution was stirred at room temperature for 3 hours. Then, solvent was evaporated in vacuo and the residue was dissolved in DCM, washed with a saturated solution of NaHCO3 and NaCl. The combined organic layers were dried over Na2SO4 and concentrated in vacuo The residue was purified by flash chromatography (DCM/MeOH(NH3) mixtures) to give final compound 1-198 (17 mg, 26%) as a white solid.
B38. Final Compound 1-185




To a mixture of final compound 1-308 (0.2 g, 0.533 mmol) in 1,4-dioxane (10 ml), N-methyl-2-methoxyethylamine (0.0711 mg, 0.8 mmol), Paladium diacetate (0.0118 mg, 0.053 mmol) and Xantphos (0.0616 mg, 0.8 mmol) were added. The reaction mixture was stirred in a sealed tube at 120° C. for 16 hours. The resulting reaction mixture was then filtered through a pad of celite, washed with AcOEt. The filtrate was washed with a saturated solution of NaCl. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (DCM/MeOH 9:1) to give final compound 1-185 (24 mg, 12%) as a yellow solid.
B39. Final Compound 1-226




To a solution of final compound 1-224 (0.147 mg, 0.385 mmol) in DCM (20 ml) at 0° C., BBr3 (0.182 ml, 1.92 mmol) was added. The resulting solution was warmed up to room temperature and stirred for 16 hours. Then, an aqueous solution of NH4OH was added. The resulting aqueous solution was extracted with methylenehlorine, washed with a saturated solution of NaCl. The combined organic layers were dried over MgSO4 and concentrated in vacuo The residue was purified by flash chromatography (DCM/MeOH(NH3) 9:1) to give final compound 1-226 (28 mg, 20%) as yellow solid.
B40. Final Compound 5-052




The reaction was carried out under N2 atmosphere. Intermediate compound 4 (26 mg, 0.077 mmol) was dissolved in pyridine (1 ml, 12.26 mmol). The resulting solution was heated for 1 hour at 40° C. The mixture was cooled to room temperature and solvents were evaporated in vacuum. The residue thus obtained was treated with 1,4-dioxane to yield a white solid that was filtered off, dried in vacuum and identified as final compound 5-052 (25 mg; white solid).
B41. Final Compound 2-056




A solution of intermediate compound 14 (200 mg, 0.53 mmol) in a mixture of TFA/DCM (20%) (5 ml) was stirred overnight at room temperature. The mixture was basified by the addition of K2CO3 (saturated solution). The organic layer was then dried over MgSO4 and concentrated in vacuo. The residue was identified as final compound 2-056 (150 mg) and was used in the next reaction step without further purification.
B42. Final Compound 3-015




To a mixture of 1-tert-butoxycarbonyl-4-hydroxypiperidine (447 mg, 2.22 mmol) in DME (8 ml), NaH (60% in mineral oil) was added and the reaction mixture was stirred at room temperature for 5 min. Then, intermediate compound 3 (500 mg, 1.85 mmol) was added and the resulting reaction mixture was microwaved at 130° C. for 30 min. The reaction was then cooled to room temperature and filtered off. The filtrate was concentrated in vacuo to yield final compound 3-015 as brown oil (460 mg).
B43. Final Compound 3-016




To a solution of final compound 3-015 (460 mg, 1.18 mmol) in MeOH (50 ml), amberlyst-15 polymer bound (loading 4.6 mmol/g) (0.77 g, 3.54 mmol) was added. The resulting mixture was shaken at room temperature for 12 hours. Then, the resin was filtered off and the solvent was discarded. The resin was suspended in MeOH/NH3 (50 ml) and shaken at room temperature for 3 hours. The resin was filtered off and the filtrate was concentrated in vacuo to give the final compound 3-016 (350 mg) as a pale brown solid.
B44. Final Compound 5-053




A mixture of intermediate compound 3 (1 g, 3.71 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.26 g, 4.08 mmol) and Pd(PPh3)4 (0.642 g, 0.556 mmol) in 1,4-dioxane (6 ml) and a saturated solution of Na—HCO3 (6 ml) was microwaved at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and the filtrate evaporated in vacuum. The crude reaction mixture was subsequently purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield final compound 5-053 (0.57 g, 41%) as a white solid.
B45. Final Compound 3-017




A mixture of final compound 5-053 (530 mg, 1.42 mmol) and palladium (10% on activated carbon) (catalytic amount) in AcOEt (50 ml) was stirred under a hydrogen atmosphere at 50 psi for 4 hours. The catalyst was then filtered off and the filtrate was concentrated in vacuo to give final compound 3-017 as colorless oil (540 mg, quant.). The compound thus obtained was used in the next reaction steps without further purification.
B46. Final Compound 3-018




To a solution of final compound 3-017 (540 mg, 1.44 mmol) in MeOH (50 ml), amberlyst-15 (loading 4.6 mmol/g) (1 g, 4.6 mmol) was added. The resulting mixture was shaken at room temperature for 12 hours. Then, the resin was filtered off and the solvent was discarded. The resin was suspended in MeOH/NH3 (50 ml) and shaken at room temperature for 3 hours. The resin was filtered off and the filtrate was concentrated in vacuo to yield final compound 3-018 (198 mg) as yellow oil.
B47. Final Compound 5-054




A mixture of intermediate compound 3′ (0.34 g, 1.33 mmol), intermediate compound 33 (0.5 g, 1.73 mmol) and diisopropylethylamine (0.925 ml, 5.32 mmol) in acetonitrile (3 ml) was microwaved at 150° C. for 20 min. The mixture was cooled to room temperature and the solvents were evaporated in vacuum. The residue thus obtained was purified by flash chromatography (SiO2, DCM/MeOH(NH3) mixtures) to yield final compound 5-054 (0.37 g, 79%).
B48. Final Compound 1-307




To a solution of intermediate compound 36 (0.55 mg. 1.76 mmol) in DCM (20 ml), TFA (10 ml) was added. The resulting solution was stirred at room temperature for 2 hours. Then, solvent was evaporated in vacuo and the residue was dissolved in DCM, washed with a saturated solution of NaHCO3 and NaCl. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield final compound 1-307 (0.310 g, 74%) used in the next reaction step without further purification.
B49. Final Compound 1-308




To a suspension of copper (II) bromide (0.2 g, 0.89 mmol) and tert-butylnitrite (0.178 ml, 1.48 mmol) in acetonitrile (29 ml) at 0° C. was added dropwise final compound 1-307 (0.31 g, 0.99 mmol) within 5 min at 0° C. The mixture was stirred at 0° C. for 1 hour, then warmed to room temperature and gradually heated at 65° C. for 1 hour. The resulting reaction mixture was then filtered through a pad of celite, washed with acetonitrile and the filtrate evaporated in vacuum to yield final compound 1-308 (0.464 g) used in the next reaction step without further purification.
B50. Final Compound 1-190




Intermediate compound 43 (0.30 g, 1.11 mmol) and intermediate compound 3 (0.43 g, 1.33 mmol) were mixed in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.12 g, 0.1 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and washed with AcOEt. The filtrate was washed with brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue thus obtained was purified by prep. HPLC to yield final compound 1-190 (0.04 g, 9%).
B51. Final Compound 1-064




Intermediate compound 3 (0.48 g, 1.89 mmol) and intermediate compound 45 (0.59 g, 1.89 mmol) were mixed in 1,4-dioxane (4 ml) and a saturated solution of NaHCO3 (4 ml). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.22 g, 0.19 mmol). The reaction was then microwaved into a sealed tube at 150° C. for 10 min. The resulting reaction mixture was then filtered through a pad of celite and washed with AcOEt. The filtrate was washed with brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue thus obtained was purified by flash chromatography (DCM/MeOH mixtures) to yield final compound 1-064 (0.16 g, 25%).
The final compounds in the following Tables have been synthesised according to the previous examples, as denoted in the column denoted as “Exp. Nr”. The compound denoted with the asterisk has been exemplified in the Examples.







TABLE 1A







Compounds wherein L is a covalent bond.








 











Co.
Exp





nr.
nr.
V1
M1
- - - -L-A





1-001
B2
cb










 


1-002
B2
cb










 


1-003
B1
- - - -CH2- - - -










 


1-004
B3
- - - -CH2- - - -










 


1-005
B3
- - - -CH2- - - -










 


1-006
B3
- - - -CH2- - - -










 


1-007
B1
- - - -CH2- - - -










 


1-008
B2
- - - -CH2- - - -










 


1-009
B2
- - - -CH2- - - -










 


1-010
B1
- - - -CH2- - - -










 


1-011
B1
- - - -CH2- - - -










 


1-012
B1
- - - -CH2- - - -










 


1-013
B1
- - - -CH2- - - -










 


1-014
B1
- - - -CH2- - - -










 


1-015
B2
- - - -CH2- - - -










 


1-016
B1
- - - -CH2- - - -










 


1-017
B1
- - - -CH2- - - -










 


1-018
B2
- - - -CH2- - - -










 


1-019
B2
- - - -CH2- - - -










 


1-020
B2
- - - -CH2- - - -










 


1-021
B1
- - - -CH2- - - -










 


1-022
B1
- - - -CH2- - - -










 


1-023
B2
- - - -CH2- - - -










 


1-024
B1
- - - -CH2- - - -










 


1-025
B1
- - - -CH2- - - -










 


1-026
B1
- - - -CH2- - - -










 


1-027
B1
- - - -CH2- - - -










 


1-028
B2
- - - -CH2- - - -










 


1-029
B2
- - - -CH2- - - -










 


1-030
B1
- - - -CH2- - - -










 


1-031
B1
- - - -CH2- - - -










 


1-032
B1
- - - -CH2- - - -










 


1-033
B1
- - - -CH2- - - -










 


1-034
B1
- - - -CH2- - - -










 


1-035
B1
- - - -CH2- - - -










 


1-036
B1
- - - -CH2- - - -










 


1-037
B17*
- - - -CH2- - - -










 


1-038
B1
- - - -CH2- - - -










 


1-039
B1
- - - -CH2- - - -










 


1-040
B1
- - - -CH2- - - -










 


1-041
B1
- - - -CH2- - - -










 


1-042
B1
- - - -CH2- - - -










 


1-043
B2
- - - -CH2- - - -










 


1-044
B1
- - - -CH2- - - -










 


1-045
B1
- - - -CH2- - - -










 


1-046
B2
- - - -CH2- - - -










 


1-047
B2
- - - -CH2—CH2- - - -










 


1-048
B1
- - - -CH2—CH2- - - -










 


1-049
B21*
- - - -CH2—CH2- - - -










 


1-050
B2
- - - -CH2—CH2—CH2- - - -
- - - -H






 


1-051
B2
- - - -CH2—CH2—CH2- - - -










 


1-052
B2
- - - -CH2—CH2—CH2- - - -










 


1-053
B1
- - - -CH2—CH2—CH2- - - -










 


1-054
B2
- - - -CH2—CH═CH- - - -










 


1-055
B1
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-056
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-057
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-058
B1
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-059
B2
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-060
B1
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-061
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-062
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-063
B1
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-064
B51*
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-065
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-066
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-067
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-068
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-069
B29
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-070
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-071
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-072
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-073
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-074
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-075
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-076
B3
- - - -CH2—CH2—CH2—CH2- - - -
- - - -H






 


1-077
B2
- - - -CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-078
B3
- - - -CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-079
B2
- - - -CH(CH3)—CH2—CH2—CH2- - - -
- - - -H






 


1-080
B2
- - - -CH2—CH(CH3)—CH2—CH2- - - -
- - - -H






 


1-081
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-082
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-083
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-084
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-085
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-086
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-087
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-088
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-089
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-090
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-091
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-092
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-093
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-094
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-095
B4*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-096
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-097
B7*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-098
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-099
B37
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-100
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-101
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-102
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-103
B5*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-104
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-105
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-106
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-107
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-108
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-109
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-110
B1*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-111
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-112
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-113
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-114
B3*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-115
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-116
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-308
B49*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-117
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-118
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-119
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-120
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-121
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-122
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-123
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-124
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-125
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-126
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-127
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-128
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-129
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-130
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-131
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-132
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-133
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-134
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-135
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-136
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-137
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-138
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-139
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-140
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-141
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-142
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-143
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-144
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-145
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-146
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-147
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-148
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-149
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-150
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-151
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-152
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-153
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-154
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-155
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-156
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-157
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-158
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-159
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-160
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-161
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-162
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-163
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-164
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-165
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-166
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-167
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-168
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-169
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-170
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-305
B37
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-171
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-172
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-173
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-174
B37
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-307
B48*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-175
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-176
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-177
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-178
B6*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-179
B2*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-180
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-181
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-182
B12*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-183
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-184
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-185
B38*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-186
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-187
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-188
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-189
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-190
B50*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-191
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-192
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-193
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-194
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-195
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-196
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-197
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-198
B37*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-199
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-200
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-201
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-202
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-203
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-204
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-205
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-206
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-207
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-208
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-209
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-210
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-211
B28
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-212
B29
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-213
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-214
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-215
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-216
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-217
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-218
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-219
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-220
B9
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-221
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-222
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-223
B20*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-224
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-225
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-226
B39*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-227
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-228
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-229
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-230
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-231
B38
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-232
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-233
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-234
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-235
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-236
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-237
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-238
B2
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-239
B14*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-240
B15*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-241
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-242
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-243
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-244
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-245
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-246
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-247
B3
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-248
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-249
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-250
B19*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-251
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-252
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-253
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-254
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-255
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-256
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-257
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-258
B13*
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H






 


1-259
B1
- - - -CH2—CH2—CH(CH3)—CH2- - - -
- - - -H




















TABLE 1B







Compounds wherein L is a saturated or unsaturated alkyl chain.








 











Co.
Exp





nr.
nr.
V1
M1
—L—A





1-260
B11*
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-261
B11
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-262
B11
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-263
B11
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-264
B11
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-265
B11
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-266
B11
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-267
B10*
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-268
B10
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-269
B10
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-270
B10
—CH2—CH2—CH(CH3)—CH2—
—H




















TABLE 1C







Compounds wherein L contains an O-atom.








 











Co.
Exp





nr.
nr.
V1
M1
—L—A





1-271
B27*
—CH2—










 


1-272
B29
—CH2—










 


1-273
B8
—CH2—CH2—CH2—CH2—
—H






 


1-306
B35*
—CH2—CH2—CH2—CH2—
—H






 


1-274
B8*
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-275
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-276
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-277
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-278
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-279
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-280
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-281
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-282
B8
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-283
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-284
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-285
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-286
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-287
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-288
B27
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-289
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-290
B29
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-291
B8
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-292
B27
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-293
B29
—CH2—CH2—CH(CH3)—CH2—
—H




















TABLE 1D







Compounds wherein L contains a N-atom.








 











Co.
Exp





nr.
nr.
V1
M1
—L—A





1-294
B31
—CH2—










 


1-295
B29
—CH2—










 


1-296
B29
—CH2—CH2—CH2—CH2—
—H






 


1-297
B31
—CH2—CH2—CH2—CH2—
—H






 


1-298
B9*
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-299
B9
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-300
B9
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-301
B9
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-302
B9
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-303
B9
—CH2—CH2—CH(CH3)—CH2—
—H






 


1-304
B9
—CH2—CH2—CH(CH3)—CH2—
—H




















TABLE 2







Compounds prepared according to the Examples wherein A is piperazinyl.








 











Co.
Exp





nr.
nr.
—V1—M1
—L—
—R4





2-001
B28
—CH2—CH2—CH2—CH3
cb






 


2-002
B18
—CH2—CH2—CH2—CH3
cb






 


2-003
B28
—CH2—CH2—CH2—CH3
cb






 


2-004
B33
—CH2—CH2—CH2—CH3
cb






 


2-005
B33
—CH2—CH2—CH2—CH3
cb






 


2-006
B33
—CH2—CH2—CH2—CH3
cb






 


2-007
B33
—CH2—CH2—CH2—CH3
cb






 


2-008
B33
—CH2—CH2—CH2—CH3
cb






 


2-009
B33
—CH2—CH2—CH2—CH3
cb






 


2-010
B18
—CH2CH(CH3)2
cb






 


2-056
B41*
—CH2—CH2—CH(CH3)2
cb
—


 


2-011
B23
—CH2—CH2—CH(CH3)2
cb






 


2-012
B23
—CH2—CH2—CH(CH3)2
cb






 


2-013
B33
—CH2—CH2—CH(CH3)2
cb






 


2-014
B33
—CH2—CH2—CH(CH3)2
cb






 


2-015
B23
—CH2—CH2—CH(CH3)2
cb






 


2-016
B33
—CH2—CH2—CH(CH3)2
cb






 


2-017
B33
—CH2—CH2—CH(CH3)2
cb






 


2-018
B33
—CH2—CH2—CH(CH3)2
cb






 


2-019
B33
—CH2—CH2—CH(CH3)2
cb






 


2-020
B33
—CH2—CH2—CH(CH3)2
cb






 


2-021
B33
—CH2—CH2—CH(CH3)2
cb






 


2-022
B33
—CH2—CH2—CH(CH3)2
cb






 


2-023
B23
—CH2—CH2—CH(CH3)2
cb






 


2-024
B23
—CH2—CH2—CH(CH3)2
cb






 


2-025
B23
—CH2—CH2—CH(CH3)2
cb






 


2-026
B23
—CH2—CH2—CH(CH3)2
cb






 


2-027
B23
—CH2—CH2—CH(CH3)2
cb






 


2-028
B24*
—CH2—CH2—CH(CH3)2
cb






 


2-029
B23
—CH2—CH2—CH(CH3)2
cb






 


2-030
B23
—CH2—CH2—CH(CH3)2
cb






 


2-031
B23
—CH2—CH2—CH(CH3)2
cb






 


2-032
B23
—CH2—CH2—CH(CH3)2
cb






 


2-033
B23
—CH2—CH2—CH(CH3)2
cb






 


2-034
B23
—CH2—CH2—CH(CH3)2
cb






 


2-035
B23
—CH2—CH2—CH(CH3)2
cb






 


2-036
B29*
—CH2—CH2—CH(CH3)2
—O(CH2)2—






 


2-037
B33
—CH2—CH2—CH(CH3)2
—(C═O)—






 


2-038
B28




cb






 


2-039
B28




cb






 


2-040
B28




cb






 


2-041
B33




cb






 


2-042
B23




cb






 


2-043
B16*




cb






 


2-044
B23




cb






 


2-045
B33




cb






 


2-046
B18




cb






 


2-047
B23




cb






 


2-048
B23




cb






 


2-049
B18*




cb






 


2-050
B18




cb






 


2-051
B18




cb






 


2-052
B18




cb






 


2-055
B31*




cb






 


2-053
B18




cb






 


2-054
B18




cb




















TABLE 3







Compounds prepared according to the Examples wherein A is 4-piperidinyl.








 











Co.
Exp





nr.
nr.
—V1—M1
—L—
—R4





3-001
B10
—CH2—CH2—CH2—CH3
cb






 


3-002
B18
—CH2—CH2—CH2—CH3
—O—






 


3-018
B46*
—CH2—CH2—CH(CH3)2
cb
—


 


3-017
B45*
—CH2—CH2—CH(CH3)2
cb






 


3-014
B28*
—CH2—CH2—CH(CH3)2
cb






 


3-003
B23
—CH2—CH2—CH(CH3)2
—NH—






 


3-004
B18
—CH2—CH2—CH(CH3)2
—NH—






 


3-005
B23
—CH2—CH2—CH(CH3)2
—N(CH3)—






 


3-006
B23
—CH2—CH2—CH(CH3)2
—N(CH3)—






 


3-016
B43*
—CH2—CH2—CH(CH3)2
—O—
—


 


3-007
B25
—CH2—CH2—CH(CH3)2
—O—






 


3-015
B42*
—CH2—CH2—CH(CH3)2
—O—






 


3-008
B26*
—CH2—CH2—CH(CH3)2
—O—






 


3-009
B25*
—CH2—CH2—CH(CH3)2
—OCH2—






 


3-010
B18




—NH—






 


3-011
B33




—NH—






 


3-012
B18




—O—






 


3-013
B23




—N(CH3)—




















TABLE 4







Compounds prepared according to the Examples wherein A is 1-piperidinyl.








 











Co.
Exp





nr.
nr.
—V1—M1
—L—
—R4





4-001
B10
—CH2 CH2 CH2CH3
cb






 


4-002
B10
—CH2 CH2 CH2CH3
cb






 


4-003
B34*
—CH2 CH2 CH2CH3
cb






 


4-004
B27
—CH2 CH2 CH2CH3
cb






 


4-005
B25
—CH2 CH2 CH2CH3
cb






 


4-006
B33
—CH2 CH2 CH2CH3
cb






 


4-007
B27
—CH2 CH2 CH2CH3
cb






 


4-008
B27
—CH2 CH2 CH2CH3
cb






 


4-009
B33
—CH2 CH2 CH2CH3
cb






 


4-010
B23
—CH2—CH2—CH(CH3)2
cb
c —CF3


 


4-012
B33
—CH2—CH2—CH(CH3)2
cb






 


4-013
B33
—CH2—CH2—CH(CH3)2
cb






 


4-014
B33
—CH2—CH2—CH(CH3)2
cb






 


4-015
B33
—CH2—CH2—CH(CH3)2
cb






 


4-016
B33
—CH2—CH2—CH(CH3)2
cb






 


4-017
B33
—CH2—CH2—CH(CH3)2
cb






 


4-018
B33
—CH2—CH2—CH(CH3)2
cb






 


4-019
B33
—CH2—CH2—CH(CH3)2
cb






 


4-020
B22*
—CH2—CH2—CH(CH3)2
cb






 


4-021
B33
—CH2—CH2—CH(CH3)2
cb






 


4-022
B33
—CH2—CH2—CH(CH3)2
cb






 


4-023
B23
—CH2—CH2—CH(CH3)2
cb






 


4-024
B23
—CH2—CH2—CH(CH3)2
cb






 


4-025
B23
—CH2—CH2—CH(CH3)2
cb






 


4-026
B23
—CH2—CH2—CH(CH3)2
cb






 


4-027
B23
—CH2—CH2—CH(CH3)2
cb






 


4-028
B23
—CH2—CH2—CH(CH3)2
cb






 


4-029
B23
—CH2—CH2—CH(CH3)2
cb






 


4-030
B23
—CH2—CH2—CH(CH3)2
cb






 


4-031
B23
—CH2—CH2—CH(CH3)2
cb






 


4-032
B23
—CH2—CH2—CH(CH3)2
cb






 


4-033
B23
—CH2—CH2—CH(CH3)2
cb






 


4-034
B23
—CH2—CH2—CH(CH3)2
cb






 


4-035
B23
—CH2—CH2—CH(CH3)2
cb






 


4-036
B23
—CH2—CH2—CH(CH3)2
cb






 


4-037
B23
—CH2—CH2—CH(CH3)2
cb






 


4-038
B23
—CH2—CH2—CH(CH3)2
cb






 


4-039
B23
—CH2—CH2—CH(CH3)2
cb






 


4-040
B23
—CH2—CH2—CH(CH3)2
cb






 


4-041
B23
—CH2—CH2—CH(CH3)2
cb






 


4-042
B23
—CH2—CH2—CH(CH3)2
cb






 


4-043
B23
—CH2—CH2—CH(CH3)2
cb






 


4-044
B23*
—CH2—CH2—CH(CH3)2
cb






 












 


4-045
B33
—CH2—CH2—CH(CH3)2
cb






 


4-046
B33
—CH2—CH2—CH(CH3)2
cb






 


4-047
B33*




cb






 


4-048
B33




cb






 


4-049
B23




cb






 


4-050
B23




cb






 


4-051
B23




cb






 


4-052
B25




cb






 


4-053
B33




cb






 


4-054
B33




cb






 


4-055
B37




cb






 


4-056
B23




cb






 


4-057
B26




cb






 


4-058
B23




cb






 


4-059
B26




cb






 


4-060
B26




cb






 


4-061
B23




cb






 


4-062
B33




cb






 


4-063
B33




cb






 


4-064
B23




cb






 


4-065
B23




cb






 


4-066
B33




cb




















TABLE 5







Other compounds prepared according to the Examples wherein A is a N-containing heterocycle








 












Co.
Exp






nr.
nr.
—V1—M1
—L—
a-A-b
—R4





5-054
B47*
—CH2 CH2 CH2CH3
cb










 


5-023
B1
—CH2 CH2 CH2CH3
cb










 


5-001
B11
—CH2 CH2 CH2CH3
cb










 


5-002
B1
—CH2 CH2 CH2CH3
cb










 


5-003
B23
—CH2—CH2—CH(CH3)2
cb




—


 


5-004
B33
—CH2—CH2—CH(CH3)2
cb










 


5-005
B33
—CH2—CH2—CH(CH3)2
cb










 


5-006
B33
—CH2—CH2—CH(CH3)2
cb










 


5-007*
B30
—CH2—CH2—CH(CH3)2
cb










 


5-008
B23
—CH2—CH2—CH(CH3)2
cb










 


5-009
B33
—CH2—CH2—CH(CH3)2
cb










 


5-053
B44*
—CH2—CH2—CH(CH3)2
cb










 


5-052
B40*
—CH2—CH2—CH(CH3)2
cb




— trifluoromethylsulfonic acid (salt form)


 


5-010
B1
—CH2—CH2—CH(CH3)2
cb




—O—CH3


 


5-011
B1
—CH2—CH2—CH(CH3)2
cb




—(CH2)3OH


 


5-012
B1
—CH2—CH2—CH(CH3)2
cb




—


 


5-013
B1
—CH2—CH2—CH(CH3)2
cb










 


5-014
B1
—CH2—CH2—CH(CH3)2
cb




—


 


5-015
B36*
—CH2—CH2—CH(CH3)2
cb










 


5-016
B1
—CH2—CH2—CH(CH3)2
cb




—


 


5-017
B1
—CH2—CH2—CH(CH3)2
cb




—


 


5-018
B1
—CH2—CH2—CH(CH3)2
cb




—CH3


 


5-019
B1
—CH2—CH2—CH(CH3)2
cb










 


5-020
B32
—CH2—CH2—CH(CH3)2
cb










 


5-021
B1
—CH2—CH2—CH(CH3)2
cb




—


 


5-022
B1
—CH2—CH2—CH(CH3)2
cb




—


 


5-024
B1
—CH2—CH2—CH(CH3)2
cb










 


5-025
B1
—CH2—CH2—CH(CH3)2
cb










 


5-026
B1
—CH2—CH2—CH(CH3)2
cb




—CH3


 


5-027
B1
—CH2—CH2—CH(CH3)2
cb










 


5-028
B1
—CH2—CH2—CH(CH3)2
cb










 


5-029
B23
—CH2—CH2—CH(CH3)2
cb




—


 


5-030
B23
—CH2—CH2—CH(CH3)2
cb




—


 


5-031
B23
—CH2—CH2—CH(CH3)2
cb




—


 


5-032
B23
—CH2—CH2—CH(CH3)2
cb










 


5-033
B23
—CH2—CH2—CH(CH3)2
cb




—


 


5-034
B33
—CH2—CH2—CH(CH3)2
cb










 


5-035
B33
—CH2—CH2—CH(CH3)2
cb




—OCH3


 


5-036
B33
—CH2—CH2—CH(CH3)2
cb




—


 


5-037
B33
—CH2—CH2—CH(CH3)2
cb




—


 


5-038
B33
—CH2—CH2—CH(CH3)2
cb




—F


 


5-039
B33
—CH2—CH2—CH(CH3)2
cb




—


 


5-040
B33
—CH2—CH2—CH(CH3)2
cb










 


5-041
B33
—CH2—CH2—CH(CH3)2
cb




—


 


5-042
B33
—CH2—CH2—CH(CH3)2
cb




—Cl


 


5-043
B33
—CH2—CH2—CH(CH3)2
cb










 


5-044
B33
—CH2—CH2—CH(CH3)2
cb










 


5-045
B1
—CH2—CH2—CH(CH3)2
—OCH2—










 


5-046
B29
—CH2—CH2—CH(CH3)2
—O(CH2)2—




—F


 


5-047
B1
—CH2—CH2—CH(CH3)2
—NH—










 


5-048
B33
—CH2—CH2—CH(CH3)2
—N(CH3)—










 


5-049
B10












—


 


5-050
B33




cb




—N(CH3)2


 


5-051
B1




cb




—





a-A-b: a is the side with the R4 moiety; b is the side with the L moiety













TABLE 6







Compounds prepared according to the Examples wherein R2 is not hydrogen.








 












Co.
Exp.






nr.
nr.
V1
M1
R2
—L—A





6-001
B1
—CH2—CH2—CH(CH3)—CH2—
—H
—CH3













C. Physico-Chemical Data

LCMS-Methods:

LCMS—General Procedure A

The HPLC gradient was supplied by a Alliance 2795XE comprising a quaternary pump with degasser, an autosampler, a column oven, a photo diode-array detector (PDA 2996) and a column as specified in the respective methods below. Flow from the column was split to a MS detector. MS detectors were configured with electrospray ionization source. Nitrogen was used as the nebulizer gas. Mass spectra were acquired from 50 to 600 in 0.5 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140° C. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
LCMS—General Procedure B
The HPLC gradient was supplied by a HP 1100 from Agilent Technologies comprising a pump (quaternary or binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS detector. The MS detector was configured with an electrospray ionization source. Nitrogen was used as the nebulizer gas. The source temperature was maintained at 140° C. Data acquisition was performed with MassLynx-Openlynx software.
LCMS—General Procedure C
The LC gradient was supplied by an Acquity UPLC (Waters) system comprising a binary pump, a sample organizer, a column heater (set at 55° C.) and diode-array detector (DAD). Flow from the column was split to a MS detector. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
Method 1
In addition to general procedure A: Reversed phase HPLC was carried out on an Zorbax-C18 cartridge (3.5 μm, 4.6×50 mm) from Agilent Technologies, with a flow rate of 1 ml/min. The column oven was set at 25° C. Two mobile phases (mobile phase A: water+0.5% of formic acid; mobile phase B: acetonitrile+0.5% of formic acid) were used. First, 95% A and 5% B was hold for 0.1 minutes. Then a gradient was applied to 100% B at 5 minutes, kept till 6.0 minutes and equilibrated to initial conditions at 6.5 minutes until 7.0 minutes. Typical injection volumes of 5-20 μL were used. ES MS detector was used, acquiring both in positive and negative ionization modes. Cone voltage was 30 V for positive and 63 V for negative ionization mode.
Method 2
In addition to general procedure A: Reversed phase HPLC was carried out on an Zorbax-C18 cartridge (1.8 μm, 4.6×30 mm) from Agilent Technologies, with a flow rate of 1.5 ml/min. The column oven was set at 30° C. Two mobile phases (mobile phase A: water+0.05% of formic acid; mobile phase B: acetonitrile+0.05% of formic acid) were used. The gradient conditions used are: 90% A and 10% B to 100% B at 3.5 minutes, kept till 3.7 minutes and equilibrated to initial conditions at 3.8 minutes until 4.5 minutes. Typical injection volumes of 5-20 μL were used. ES MS detector was used, acquiring both in positive and negative ionization modes. Cone voltage was 30 V for positive and 63 V for negative ionization mode.
Method 3
In addition to general procedure B: Reversed phase HPLC was carried out on an ACE-C18 column (3.0 μm, 4.6×30 mm) from Advanced Chromatography Technologies, with a flow rate of 1.5 ml/min, at 40° C. The gradient conditions used are: 80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes and equilibrated to initial conditions at 7.5 minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass spectra (Time of Flight, TOF) were acquired only in positive ionization mode by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillary needle voltage was 2.5 kV for positive ionization mode and the cone voltage was 20 V. Leucine-Enkephaline was the standard substance used for the lock mass calibration.
Method 4
In addition to general procedure B: Same as Method 3, but using 10 μL of injection volume.
Method 5
In addition to general procedure B: Reversed phase HPLC was carried out on an ACE-C18 column (3.0 μm, 4.6×30 mm) from Advanced Chromatography Technologies, with a flow rate of 1.5 ml/min, at 40° C. The gradient conditions used are: 80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes and equilibrated to initial conditions at 7.5 minutes until 9.0 minutes. Injection volume 5 μl. Low-resolution mass spectra (ZQ detector; quadrupole) were acquired by scanning from 100 to 1000 in 1.0 second using a dwell time of 0.3 seconds. The capillary needle voltage was 3 kV. The cone voltage was 20 V and 50 V for positive ionization mode and 20 V for negative ionization mode.
Method 6
In addition to general procedure C: Reversed phase UPLC was carried out on a bridged ethylsiloxane/silica (BEH) C18 column (1.7 μm, 2.1×50 mm) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1% formic acid in H2O/methanol 95/5; mobile phase B: methanol) were used to run a gradient condition from 95% A to 5% A, 95% B in 1.3 minutes and hold for 0.2 minutes. An injection volume of 0.5 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
Method 7
In addition to general procedure B: Reversed phase HPLC was carried out on an XDB-C18 cartridge (1.8 μm, 2.1×30 mm) from Agilent, at 60° C. with a flow rate of 1 ml/min, at 60° C. The gradient conditions used are: 90% A (0.5 g/l ammonium acetate solution), 5% B (acetonitrile), 5% C (methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes and equilibrated to initial conditions at 7.5 minutes until 9.0 minutes. Injection volume 2 μl. High-resolution mass spectra (Time of Flight, TOF) were acquired only in positive ionization mode by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillary needle voltage was 2.5 kV and the cone voltage was 20 V. Leucine-Enkephaline was the standard substance used for the lock mass calibration.
Method 8
In addition to general procedure B: Reversed phase HPLC was carried out on a XDB-C18 cartridge (1.8 μm, 4.6×30 mm) from Agilent, with a flow rate of 1.5 ml/min, at 60° C. The gradient conditions used are: 80% A (0.5 g/l ammonium acetate solution), 20% B (mixture of Acetonitrile/Methanol, 1/1) to 100% B in 6.5 minutes, kept till 7 minutes and equilibrated to initial conditions at 7.5 minutes until 9.0 minutes. Injection volume 5 μl. Low-resolution mass spectra (ZQ detector; quadrupole) were acquired by scanning from 100 to 1000 in 1.0 second using a dwell time of 0.3 second. The capillary needle voltage was 3 kV. The cone voltage was 20 V and 50 V for positive ionization mode and 20 V for negative ionization mode.
Method 9
In addition to general procedure B: Reversed phase HPLC was carried out on an ACE-C18 column (3.0 μm, 4.6×30 mm) from Advanced Chromatography Technologies, with a flow rate of 1.5 ml/min, at 40° C. The gradient conditions used are: 80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes and equilibrated to initial conditions at 7.5 minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass spectra (Time of Flight, TOF) were acquired by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.3 seconds. The capillary needle voltage was 2.5 kV for positive ionization mode and 2.9 kV for negative ionization mode. The cone voltage was 20 V for both positive and negative ionization modes. Leucine-Enkephaline was the standard substance used for the lock mass calibration.
Melting point determination was performed in open capillary tubes either on a Buchi B-540 or Mettler FP62.







TABLE 7







Physico-chemical data for the compounds. For salt


forms, the [MH+] of the free base was reported.












Co.
Melting point

RT
LCMS



Nr
(° C.)
[MH+]
(min)
Method
Physical form















1-003

339
4.38
Method 3
White solid


1-004

378
4.00
Method 3
White solid


1-005

413
4.54
Method 3
Pale yellow solid


1-006

427
4.43
Method 8
Pale yellow solid


1-007
159
363
2.92
Method 2
Light yellow solid


1-008
148
299
4.59
Method 1
White solid


1-009
149
293
4.43
Method 3
Yellow solid


1-010
decomposes
336
5.00
Method 5
Yellow solid


1-011
 60
323
4.43
Method 3
Yellow solid


1-012
decomposes
323
4.55
Method 3
Yellow solid


1-013
128
337
2.95
Method 2
White solid


1-014
143
391
3.22
Method 2
Yellow solid


1-015

307

Method 1
Solid


1-016

331
2.56
Method 2
Light yellow solid


1-017

331
2.60
Method 2
Light brown solid


1-018
155
291
4.19
Method 1
Yellow solid


1-019
118
307
4.45
Method 1
White solid


1-021

331
2.59
Method 2
Light yellow solid


1-022

335
3.92
Method 3
Light brown solid


1-023

295
1.15
Method 6
Beige solid


1-024
181
385
2.70
Method 2
Light yellow solid


1-025

397
4.92
Method 3
Light brown solid


1-026

351
2.62
Method 2
White solid


1-027

351
2.63
Method 2
Light yellow solid


1-028
180
327
4.54
Method 1
Pink solid


1-030
153
371
2.76
Method 2
White solid


1-031
167
468
4.62
Method 3
White solid


1-032
190
456
2.70
Method 2
Yellow solid


1-033
 97
470
4.47
Method 3
White solid


1-034

498
4.53
Method 8
White solid


1-035
136
498
4.52
Method 8
White solid


1-036

498
5.19
Method 3
White solid


1-037
184
500
4.47
Method 3
White solid


1-038
140
514
4.64
Method 3
White solid


1-039
169
401
2.78
Method 2
White solid


1-040
180
429
2.47
Method 2
White solid


1-041
155
463
3.17
Method 2
Beige solid


1-042
185
363
2.90
Method 2
White solid


1-043
185
288
2.71
Method 1
Beige solid


1-044
141
288
3.34
Method 1
White solid


1-045
160
288
2.81
Method 1
Solid


1-046
185
362
3.96
Method 1
White solid


1-047

317
4.09
Method 3
Pale yellow solid


1-048
188
347
4.20
Method 4
White solid


1-049
decomposes
409
5.13
Method 3
White solid


1-050
135
245
3.85
Method 1
Yellow solid


1-051

305
4.29
Method 1
Yellow solid


1-052
118
321
4.40
Method 1
Yellow solid


1-053
decomposes
315
4.25
Method 3
White solid


1-055
123
337
2.73
Method 2
White solid


1-056
195
352
3.64
Method 7
Bright yellow solid


1-057
136
371
4.04
Method 3
White solid


1-058
122
336
4.72
Method 7
Yellow solid


1-059
103
259
4.18
Method 1
Yellow solid


1-060

347
3.00
Method 3
Pale brown solid


1-061

346
3.93
Method 3
Pale yellow solid


1-062

346
3.61
Method 7
White solid


1-063
102
374
4.16
Method 3
White solid


1-064
121
360
3.97
Method 7
White solid


1-065

360
4.22
Method 7
White solid


1-066

364
3.79
Method 3
White solid


1-067

414
4.68
Method 7
White solid


1-068
decomposes
414
4.67
Method 7
Off white solid


1-069

414
4.40
Method 7
Off white solid


1-070

380
4.10
Method 7
Off white solid


1-071

371
3.86
Method 7
White solid


1-072

371
3.90
Method 7
White solid


1-073

431
4.32
Method 3
Off white solid


1-074

347
3.32
Method 7
White solid


1-075

347
3.36
Method 7
White solid


1-076

347
3.55
Method 7
White solid


1-077
108
259
3.92
Method 1
Beige solid


1-078
170
346
3.06
Method 8
White solid


1-079
103
273
4.22
Method 1
White solid


1-080
149
267
4.45
Method 1
White solid


1-081

257
4.13
Method 1
Yellow solid


1-082
123
273
4.29
Method 1
Yellow solid


1-083

307
4.66
Method 4
Yellow solid


1-084
142
267
4.25
Method 1
White solid


1-085
102
281
2.72
Method 2
White solid


1-086
168
323
3.16
Method 2
Orange solid


1-087
125
285
3.97
Method 3
Pale yellow solid


1-088
161
285
4.09
Method 4
White solid


1-089
decomposes
285
4.07
Method 3
White solid


1-090
123
301
2.74
Method 2
White solid


1-091
137
301
2.76
Method 2
Yellow solid


1-092

423
5.01
Method 3
White solid


1-093
172
343
3.05
Method 2
Off white solid


1-094
131
343
3.03
Method 2
Light yellow solid


1-095
 85
325
3.76
Method 1
White solid


1-096
201
283
3.72
Method 1
Light brown solid


1-097
210
283
3.66
Method 1
White solid


1-098
145
297
2.04
Method 2
White solid


1-099

327
3.35
Method 3
Beige solid


1-100

297
4.11
Method 5
Yellow oil


1-101
 96
297
4.31
Method 1
White solid


1-102
 99
270
4.07
Method 1
Light yellow solid


1-103
 91
311
4.22
Method 1
White solid


1-104

311
4.52
Method 3
Cream solid


1-105
107
325
2.96
Method 2
Light orange solid


1-106

339
4.54
Method 3
Pale yellow solid


1-107
 67
311
2.51
Method 2
Light yellow solid


1-108

313
3.51
Method 3
Cream solid


1-109

357
3.35
Method 3
White solid


1-110
 52
327
4.03
Method 3
Yellow solid


1-111
129
325
2.89
Method 2
Light yellow solid


1-112
149
331
4.33
Method 7
White solid


1-113
 65
315
4.35
Method 1
White solid


1-114
133
315
4.30
Method 1
Yellow solid


1-115
154
357
3.06
Method 2
White solid


1-116

333
2.69
Method 2
White oil


1-117
166
359
5.21
Method 5
White solid


1-118
decomposes
339
3.68
Method 3
White solid


1-119
decomposes
333
4.39
Method 5
Cream solid


1-120
122
351
4.74
Method 3
Yellow solid


1-121

363
4.67
Method 3
White solid


1-122
131
381
4.61
Method 3
White solid


1-123
189
399
4.92
Method 3
White solid


1-124

385
5.88
Method 3
Pale yellow solid


1-125

355
4.00
Method 3
White solid


1-126
decomposes
353
4.08
Method 5
Cream solid


1-127
156
354
3.52
Method 1
White solid


1-128
107
368
2.05
Method 1
White solid


1-129

384
3.23
Method 3
Cream solid


1-130
159
340
3.06
Method 3
White Solid


1-131
132
322
2.42
Method 2
Pink solid


1-132

336
3.98
Method 3
White solid


1-133

337
4.72
Method 7
White solid


1-134
294
371
5.40
Method 3
Cream solid


1-135

351
5.33
Method 4
White solid


1-136

397
4.64
Method 5
Cream solid


1-137

411
4.78
Method 3
White solid


1-138

441
4.70
Method 3
Cream solid


1-139

396
3.95
Method 3
Pale brown solid


1-140

359
5.13
Method 3
White solid


1-141

373
5.38
Method 3
White solid


1-142

403
5.01
Method 3
White solid


1-143
118
389
3.07
Method 2
White solid


1-144
100
403
3.03
Method 2
White solid


1-145
212
403
3.02
Method 2
White solid


1-146
139
391
3.07
Method 2
White solid


1-147
146
391
3.07
Method 2
White solid


1-148
173
391
3.06
Method 2
Yellow solid


1-149
120
407
3.23
Method 2
White solid


1-150
177
407
3.18
Method 2
White solid


1-151
154
398
2.89
Method 2
White solid


1-152
193
384
2.86
Method 2
White solid


1-153
171
398
2.89
Method 2
Yellow solid


1-154

360
4.23
Method 3
White solid


1-155
132
360
4.07
Method 7
Off white solid


1-156
139
360
4.09
Method 3
Off white solid


1-157
162
374
4.36
Method 5
White solid


1-158
142
374
4.23
Method 5
Cream solid


1-159
171
374
4.25
Method 5
White solid


1-160

374
4.18
Method 3
Cream solid


1-161

378
4.17
Method 3
White solid


1-162
156
392
4.21
Method 3
Pale brown solid


1-163
202
442
2.94
Method 2
White solid


1-164
165
408
2.82
Method 2
White solid


1-165

408
2.15
Method 2
White solid


1-166

404
4.05
Method 3
Cream solid


1-167

404
4.05
Method 3
White solid


1-168
decomposes
364
3.27
Method 5
Freeze-dried


1-169
144
3.94
2.62
Method 2
Beige solid


1-170

282
3.10
Method 3
Yellow solid


1-171
189
296
3.97
Method 3
Bright yellow solid


1-172
137
310
4.51
Method 1
Green solid


1-173
130
324
1.81
Method 2
Grey solid


1-174

340
4.02
Method 9
Yellow solid


1-175
 75
324
3.54
Method 1
Brown solid


1-176
198
324
3.55
Method 1
White solid


1-177
112
352
2.13
Method 2
White solid


1-178
157
338
3.39
Method 1
Beige solid


1-179
144
338
3.39
Method 1
White solid


1-180




Yellow solid


1-181
decomposes
353
2.79
Method 3
Pale yellow solid


1-182

367
3.31
Method 3
Bright yellow solid


1-183

354
5.04
Method 3
Pale yellow solid


1-184

368
3.30
Method 3
White solid


1-185

384
4.45
Method 4
Yellow solid


1-186
269
321
3.47
Method 3
Pale brown solid


1-187

322
4.52
Method 3
Yellow


1-188

364
5.66
Method 3
Bright yellow solid


1-189

384
4.22
Method 3
Yellow solid


1-190

384
4.21
Method 7
Yellow solid


1-191
decomposes
400
4.48
Method 7
Pale yellow solid


1-192
119



Bright yellow solid


1-193

358
5.21
Method 3
Brown solid


1-194

372
5.17
Method 3
Yellow solid


1-195

372
5.35
Method 3
Bright yellow oil


1-196

386
5.33
Method 3
Yellow solid


1-197

418
5.47
Method 3
White solid


1-198

404
4.71
Method 3
White solid


1-199
136
390
2.93
Method 2
Yellow solid


1-200
162
390
2.94
Method 2
Yellow solid


1-201

342
3.35
Method 3
Cream solid


1-202
146
406
3.07
Method 2
Yellow solid


1-203
173
402
2.90
Method 2
Yellow solid


1-204
157
397
2.75
Method 2
Yellow solid


1-205

456
5.69
Method 3
Yellow solid


1-206
209
397
2.74
Method 2
Yellow solid


1-207

379
2.68
Method 3
Yellow solid


1-208

359
3.35
Method 7
Pale yellow solid


1-209

373
4.08
Method 3
Yellow solid


1-210
 73
373
4.01
Method 3
Yellow solid


1-211
142
401
4.53
Method 3
Pale yellow solid


1-212
294
401
4.44
Method 3
Pale yellow solid


1-213
 96
401
1.61
Method 2
White solid


1-214

326
4.26
Method 3
Brown solid


1-215
 70
360
3.70
Method 1
White solid


1-216
191
360
3.67
Method 1
White solid


1-217

414
3.49
Method 7
Bright yellow solid


1-218

336
5.10
Method 3
Yellow solid


1-219

350
5.32
Method 5
Bright yellow solid


1-220
213
366
3.79
Method 3
Yellow solid


1-221

380
4.60
Method 4
Yellow solid


1-222

352
4.17
Method 5
Yellow solid


1-223
171
352
4.09
Method 3
Yellow solid


1-224
decomposes
368
3.67
Method 4
Yellow solid


1-225
151
382
4.08
Method 3
Yellow solid


1-226
118
430
4.80
Method 3
Yellow solid


1-227
162
380
4.79
Method 3
Yellow solid


1-228
148
400
5.19
Method 3
Bright yellow solid


1-229
148
366
3.94
Method 3
White solid


1-230
143
393
3.98
Method 3
Yellow solid


1-231
decomposes
393
3.68
Method 3
Yellow solid


1-232

391
4.77
Method 3
Yellow solid


1-233

427
5.45
Method 4
Orange solid


1-234

428
3.94
Method 3
Orange solid


1-235
151
333
3.57
Method 5
White solid


1-236
decomposes
334
3.50
Method 5
Pale yellow solid


1-237




Yellow solid


1-238
130
309
4.02
Method 1
Beige Solid


1-239
120
353
4.34
Method 1
Yellow solid


1-240
169
339
3.73
Method 1
White solid


1-241
172
338
1.94
Method 2
White solid


1-242
(oil)
325
2.54
Method 2
Black oil


1-243
166
338
2.05
Method 2
Off white solid


1-244
122
352
2.10
Method 2
White solid


1-245
135-140
414
2.62
Method 2
White solid


1-246

350
3.50
Method 3
Cream solid


1-247
217
587
5.02
Method 8
White solid


1-248

347
3.44
Method 3
White solid


1-249

350
3.68
Method 7
Yellow solid


1-250

334
3.89
Method 3
White solid


1-251
117
309
4.09
Method 3
Off white solid


1-252
120-121
311
4.24
Method 1
Beige solid


1-253

325
4.14
Method 3
White solid


1-254
122
306
2.37
Method 2
White solid


1-255
233
494
2.78
Method 2
Yellow solid


1-256
128
313
4.55
Method 1
Yellow solid


1-257
181
345
3.69
Method 1
White solid


1-258

390
4.35
Method 4
Colourless oil


1-259

323
4.62
Method 3
Pale grey solid


1-260

295
4.46
Method 4
White solid


1-261

293
4.70
Method 3
Yellow solid


1-262

338
4.75
Method 3
White solid


1-263
decomposes
338
4.83
Method 5
Creamy green solid


1-264

325
4.46
Method 3
White solid


1-265
 88
325
4.52
Method 5
White solid


1-266

323
4.51
Method 3
Yellow solid


1-267

291
4.78
Method 3
Brown solid


1-268

321
4.85
Method 3
Cream solid


1-269

334
5.24
Method 3
White solid


1-270
166
334
5.24
Method 5
Orange solid


1-271

500
4.41
Method 3
White solid


1-272

401
4.78
Method 3
White solid


1-273

347
4.15
Method 7
White solid


1-274
decomposes
283
4.05
Method 3
White solid


1-275
174
297
4.10
Method 5
White solid


1-276

311
4.33
Method 5
White


1-277

365
4.65
Method 3
White solid


1-278

375
4.54
Method 3
White solid


1-279
116
381
4.69
Method 3
White solid


1-280

327
4.18
Method 5
White solid


1-281
 83
341
4.21
Method 5
White solid


1-282
153
313
4.12
Method 3
White solid


1-283

345
4.08
Method 3
Pale pink solid


1-284
190
363
4.32
Method 5
White solid


1-285
200
381
4.83
Method 5
White solid


1-286

322
3.73
Method 3
Pale yellow solid


1-287

397
4.99
Method 3
Pale yellow solid


1-288
169
323
4.30
Method 3
White solid


1-289

403
5.02
Method 3
Pale yellow


1-290
148
445
5.24
Method 3
White solid


1-291

352
5.16
Method 3
Pale yellow solid


1-292
154
396
3.82
Method 3
White solid


1-293
209
372
4.43
Method 3
White solid


1-294

306
3.97
Method 3
White solid


1-295

359
3.31
Method 3
Yellow solid


1-296
151
361
3.57
Method 7
Off white solid


1-297

350
4.78
Method 7
Pale yellow solid


1-298
decomposes
282
3.97
Method 3
Cream solid


1-299

296
4.00
Method 3
Pale brown oil


1-300
decomposes
367
3.91
Method 3
White solid


1-301
decomposes
374
5.13
Method 3
Yellow solid


1-302

375
4.01
Method 3
Yellow solid


1-303

310
4.14
Method 3
White solid


1-304

322
4.51
Method 7
White solid


1-306

374
4.22
Method 7


2-001
183
437
4.95
Method 3
Pale yellow solid


2-002
127
469
5.26
Method 3
White solid


2-003
134
455
5.13
Method 3
Pale yellow solid


2-004

338
3.36
Method 3
Pale yellow solid


2-005

367
4.07
Method 3
White solid


2-006

379
4.08
Method 3
Pale yellow solid


2-007

369
3.76
Method 3
Off white solid


2-008

382
3.45
Method 3
Pale yellow solid


2-009

424
3.34
Method 3
Pale yellow solid


2-010
112
469
5.21
Method 3
White solid


2-011

351
4.40
Method 3
Yellow solid


2-012

365
4.44
Method 3
White solid


2-013

381
4.32
Method 3
Pale yellow solid


2-014

433
5.04
Method 3
White solid


2-015
decomposes
401
4.66
Method 3
Beige solid


2-016

409
4.33
Method 3
White solid


2-017

379
4.55
Method 3
Pale brown solid


2-018

391
4.75
Method 3
Pale yellow oil


2-019

413
4.49
Method 3
Yellow gum


2-020

463
5.05
Method 3
Pale yellow solid


2-021

379
4.99
Method 3
Pale yellow solid


2-022
256
483
5.49
Method 3
White solid


2-023

366
3.32
Method 3
Yellow gum


2-024

352
3.83
Method 3
Yellow solid


2-025

366
4.17
Method 3
Yellow solid


2-026
135
420
4.69
Method 3
White solid


2-027

377
3.72
Method 3
Off white solid


2-028

353
3.56
Method 3
Pale creamy solid


2-029
155
421
4.71
Method 3
Pale brown solid


2-030

353
2.80
Method 3
Yellow solid


2-031
245
387
3.38
Method 3
Yellow solid


2-032

383
3.40
Method 3
Yellow solid


2-033

429
4.23
Method 3
Yellow gum


2-034
decomposes
417
3.89
Method 3
Pale yellow solid


2-035
288
392
4.15
Method 3
White solid


2-036
159
396
3.67
Method 3
Off white solid


2-037
223



White solid


2-038
140
435
4.73
Method 3
White solid


2-039
125
467
5.05
Method 3
White solid


2-040
157



Pale yellow solid


2-041
decomposes
365
3.38
Method 3
Pale brown solid


2-042
decomposes
469
4.91
Method 3
White solid


2-043
110
483
4.97
Method 3
Pale yellow solid


2-044
156
487
4.93
Method 4
White solid


2-045
decomposes
519
5.47
Method 3
Pale yellow solid


2-046
 92
497
3.96
Method 8
Yellow solid


2-047

470
3.94
Method 3
Yellow solid


2-048
258
524
5.04
Method 3
White solid


2-049

403
4.27
Method 4
Light brown solid


2-050

421
4.39
Method 3
White solid


2-051
239
439
4.49
Method 3
White solid


2-052

439
4.59
Method 3
White solid


2-053

415
4.48
Method 3
White solid


2-054

429
4.42
Method 3
Yellow oil


2-055

390
3.59
Method 3
White solid


3-001
124
338
3.57
Method 7
Pale yellow solid


3-002




White solid


3-003
125
379
4.41
Method 3
White solid


3-004
188
434
4.90
Method 3
Off white solid


3-005

393
4.47
Method 3
White solid


3-006
131
461
5.22
Method 3
White solid


3-007
208
380
4.35
Method 3
White solid


3-008

448
5.10
Method 3
Pale brown solid


3-009
117
462
5.20
Method 3
Off white solid


3-010
187



White solid


3-011
decomposes
351
2.55
Method 3
White solid


3-012

432
4.60
Method 3
Cream solid


3-013
211
497
4.95
Method 3
White solid


3-014

432
5.35
Method 3
White solid


4-001

337
3.28
Method 3
White solid


4-002

337
3.22
Method 7
White solid


4-003
132
351
3.33
Method 7


4-004
188
353
3.20
Method 3
Cream solid


4-005

353
3.87
Method 3
Cream solid


4-006

367
3.94
Method 7
White solid


4-007

367
3.51
Method 7
Pale yellow solid


4-008

381
3.79
Method 7
White solid


4-009

377
3.91
Method 7
White solid


4-010

342
4.19
Method 3
White solid


4-012
296
378
4.48
Method 3
White solid


4-013

350
5.06
Method 3
White solid


4-014
decomposes
350
4.76
Method 3
White solid


4-015

364
5.33
Method 3
Yellow oil


4-016
112
418
5.09
Method 7
White solid


4-017

380
5.18
Method 3
White solid


4-018

384
4.94
Method 3
White solid


4-019
100
412
5.18
Method 3
White solid


4-020

448
5.43
Method 3
White gummy solid


4-021
decomposes
410
4.82
Method 3
White solid


4-022

464
5.30
Method 3
White solid


4-023

365
4.43
Method 3
Beige solid


4-025
283
447
4.63
Method 3
White solid


4-026

393
4.41
Method 3
Brown solid


4-027
113
411
4.57
Method 3
White solid


4-028

461
5.25
Method 3
White solid


4-029
 91
461
5.28
Method 3
White solid


4-030

425
5.09
Method 3
White foam


4-031
141
447
5.31
Method 3
White solid


4-032

475
5.02
Method 3


4-033

475
5.03
Method 3
Yellow solid


4-034
253
405
4.4
Method 3
Pale brown solid


4-035

389
4.93
Method 3
Pale yellow solid


4-036

405
5.29
Method 3
Browm gummy oil


4-037
 78
407
4.86
Method 3
Yellow solid


4-038
214
391
4.35
Method 3
Beige solid


4-039
123
408
5.09
Method 3
White solid


4-040
113
412
4.91
Method 3
Pale cream solid


4-041

418
4.82
Method 3
Pale brown solid


4-042
decomposes
433
4.13
Method 7
Yellow solid


4-043
138
379
4.64
Method 3
White solid


4-044

435
4.53
Method 3
Pale yellow solid


4-045

380
4.93
Method 3
White solid


4-046
282
414
3.73
Method 3
White solid


4-047
128
334
4.05
Method 7
White solid


4-048

378
4.38
Method 7
Off white solid


4-049
138
497
4.89
Method 3
White solid


4-050
decomposes
491
4.20
Method 3
White solid


4-051
decomposes
509
4.88
Method 3
Pale brown solid


4-052

499
4.39
Method 7
Pale brown solid


4-053

485
3.85
Method 7
Yellow solid


4-054




Cream solid


4-055
155
435
3.85
Method 3
Cream solid


4-056

431
4.16
Method 3
Cream solid


4-057
242
449
4.54
Method 3
Cream solid


4-058

499
5.05
Method 3
White solid


4-059
157
475
5.27
Method 3
White solid


4-060
 96



Off white solid


4-061
175
447
4.20
Method 3
Cream solid


4-062
139
454
5.06
Method 3
White solid


4-063

471
3.56
Method 7
Off white solid


4-064
159
443
4.43
Method 3
White solid


4-065

511
5.24
Method 3
White solid


4-066

400
4.83
Method 3
White solid


5-001
decomposes
384
3.31
Method 3
Off white solid


5-002
  164.7
398
3.24
Method 3
White solid


5-003
decomposes
322
4.33
Method 3
White solid


5-004

377
4.2
Method 3
Pale cream gum


5-005
 96
447
5.16
Method 3
White solid


5-006
100
397
4.71
Method 3
White solid


5-007

350
4.75
Method 3
Colourless oil


5-008
102
436
5.11
Method 3
White solid


5-009

473
4.97
Method 3
White solid


5-010
118
298
2.37
Method 2
White solid


5-011

326
2.96
Method 3
Pale brown solid


5-012

257
2.72
Method 3
White solid


5-013

347
4.26
Method 3
White solid


5-014

308
3.92
Method 5
Orange solid


5-015

350
3.75
Method 5
Pale yellow solid


5-016
decomposes
306
3.93
Method 3
Pale brown solid


5-017
decomposes
306
3.84
Method 3
Pale green solid


5-018
281
320
4.37
Method 3
Pale yellow solid


5-019

382
5.31
Method 3
Pale yellow solid


5-020
232
397
4.21
Method 3
Cream solid


5-021
decomposes
307
3.31
Method 3
Syrup


5-022

307
2.93
Method 3
Beige solid


5-023
decomposes
384
3.51
Method 3
Cream solid


5-024
284
398
3.53
Method 3
Cream solid


5-025

398
3.72
Method 3
Cream solid


5-026
decomposes
338
4.43
Method 5
Bright yellow solid


5-027
decomposes
347
4.08
Method 7
White solid


5-028

364
4.87
Method 3
White solid


5-029
234
307
3.89
Method 3
Pale yellow solid


5-030

324
4.4
Method 3
Cream solid


5-031
134
322
4.72
Method 3
Yellow solid


5-032

382
4.04
Method 3
White solid


5-033

376
5.35
Method 3
White solid


5-034

421
4.44
Method 3
Pale cream solid


5-035
169
406
5.04
Method 3
White solid


5-036

394
4.96
Method 3
White solid


5-037
217
380
4.57
Method 3
Cream solid


5-038
141



Cream solid


5-039
276
361
4.52
Method 3
White solid


5-040
111
393
4.87
Method 3
Cream solid


5-041
130
362
4.85
Method 3
White solid


5-042

412
5.73
Method 3
Pale yellow


5-043
decomposes
365
4.57
Method 3
Pale yellow solid


5-044

395
4.51
Method 3
Brown gummy solid


5-045

378
4.06
Method 3
White solid


5-046

370
4.08
Method 4
White solid


5-047

349
4.37
Method 3
White solid


5-048

441
5.22
Method 3
Colourless oil


5-049

318
4.39
Method 3
Pale grey solid


5-050

407
3.66
Method 3
White solid


5-051
166
410
2.63
Method 2
Grey solid


6-001
175
341
5.54
Method 2
Beige solid





decomposes = product decomposes in the course of the determination.






D. Pharmacological Examples

The compounds provided in the present invention are positive allosteric modulators of mGluR2. These compounds appear to potentiate glutamate responses by binding to an allosteric site other than the glutamate binding site. The response of mGluR2 to a concentration of glutamate is increased when compounds of Formula (I) are present. Compounds of Formula (I) are expected to have their effect substantially at mGluR2 by virtue of their ability to enhance the function of the receptor. The behaviour of positive allosteric modulators tested at mGluR2 using the [35S]GTPγS binding assay method described below and which is suitable for the identification of such compounds, and more particularly the compounds according to Formula (I), are shown in Table 4.
[35S]GTPγS Binding Assay
The [35S]GTPγS binding is a functional membrane-based assay used to study G-protein coupled receptor (GPCR) function whereby incorporation of a non-hydrolysable form of GTP, [35S]GTPγS (guanosine 5′-triphosphate, labelled with gamma-emitting 35S), is measured. The G-protein o subunit catalyzes the exchange of guanosine 5′-diphosphate (GDP) by guanosine triphosphate (GTP) and on activation of the GPCR by an agonist, [35S]GTPγS, becomes incorporated and cannot be cleaved to continue the exchange cycle (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount of radioactive [35S]GTPγS incorporation is a direct measure of the activity of the G-protein and hence the activity of the agonist can be determined. mGluR2 receptors are shown to be preferentially coupled to Gαi-protein, a preferential coupling for this method, and hence it is widely used to study receptor activation of mGluR2 receptors both in recombinant cell lines and in tissues (Schaffhauser et al 2003, Pinkerton et al, 2004, Mutel et al (1998) Journal of Neurochemistry. 71:2558-64; Schaffhauser et al (1998) Molecular Pharmacology 53:228-33). Here we describe the use of the [35S]GTPγS binding assay using membranes from cells transfected with the human mGluR2 receptor and adapted from Schaffhauser et al ((2003) Molecular Pharmacology 4:798-810) for the detection of the positive allosteric modulation (PAM) properties of the compounds of this invention.
Membrane Preparation
CHO-cells were cultured to pre-confluence and stimulated with 5 mM butyrate for 24 hours, prior to washing in PBS, and then collection by scraping in homogenisation buffer (50 mM Tris-HCl buffer, pH 7.4, 4° C.). Cell lysates were homogenized briefly (15 s) using an ultra-turrax homogenizer. The homogenate was centrifuged at 23 500×g for 10 minutes and the supernatant discarded. The pellet was resuspended in 5 mM Tris-HCl, pH 7.4 and centrifuged again (30 000×g, 20 min, 4° C.). The final pellet was resuspended in 50 mM HEPES, pH 7.4 and stored at −80° C. in appropriate aliquots before use. Protein concentration was determined by the Bradford method (Bio-Rad, USA) with bovine serum albumin as standard.
[35S]GTPγS Binding Assay
Measurement of mGluR2 positive allosteric modulators in membranes containing human mGluR2 was performed using frozen membranes that were thawed and briefly homogenised prior to pre-incubation in 96-well microplates (15 μg/assay well, 30 minutes, 30° C.) in assay buffer (50 mM HEPES pH 7.4, 100 mM NaCl, 3 mM MgCl2, 50 μM GDP, 10 μg/ml saponin,) with increasing concentrations of positive allosteric modulator (from 0.3 nM to 50 μM) and either a minimal pre-determined concentration of glutamate (PAM assay), or no added glutamate. For the PAM assay, membranes were pre-incubated with glutamate at EC25 concentration, i.e. a concentration that gives 25% of the maximal response glutamate, and is in accordance to published data (Pin et al. (1999) Eur. J. Pharmacol. 375:277-294). After addition of [35S]GTPγS (0.1 nM, f.c.) to achieve a total reaction volume of 200 μl, microplates were shaken briefly and further incubated to allow [35S]GTPγS incorporation on activation (30 minutes, 30° C.). The reaction was stopped by rapid vacuum filtration over glass-fibre filter plates (Unifilter 96-well GF/B filter plates, Perkin-Elmer, Downers Grove, USA) microplate using a 96-well plate cell harvester (Filtermate, Perkin-Elmer, USA), and then by washing three times with 300 μl of ice-cold wash buffer (Na2PO4.2H2O 10 mM, NaH2PO4.H2O 10 mM, pH=7.4). Filters were then air-dried, and 40 μl of liquid scintillation cocktail (Microscint-O) was added to each well, and membrane-bound [35S]GTPγS was measured in a 96-well scintillation plate reader (Top-Count, Perkin-Elmer, USA). Non-specific [35S]GTPγS binding is determined in the presence of cold 10 μM GTP. Each curve was performed at least once using duplicate sample per data point and at 11 concentrations.
Data Analysis
The concentration-response curves of representative compounds of the present invention in the presence of added EC25 of mGluR2 agonist glutamate to determine positive allosteric modulation (PAM), were generated using the Prism GraphPad software (Graph Pad Inc, San Diego, USA). The curves were fitted to a four-parameter logistic equation (Y=Bottom+(Top-Bottom)/(1+10^((Log EC50−X)*Hill Slope) allowing determination of EC50 values.







TABLE 8







Pharmacological data for compounds according to


the invention.


All compounds were tested in presence of mGluR2


agonist, glutamate at a predetermined EC25


concentration, to determine positive allosteric


modulation (GTPγS-PAM). Values shown are averages


of duplicate values of 11-concentration response curves,


from at least one experiment. All compounds showed a


pEC50 value of more than 5.0, from 5.1 (weak


activity) to 7.6 (very high activity). The error of


determination of a pEC50 value for a single


experiment is estimated to be about 0.3 log-units.











GTPgS -




hR2




PAM



Co. Nr.
pEC50







1-093
7.6



5-020
7.6



1-204
7.6



1-202
7.5



4-065
7.5



4-066
7.5



1-140
7.4



1-196
7.4



5-033
7.4



4-062
7.4



4-039
7.4



1-151
7.4



1-145
7.4



1-268
7.3



4-016
7.3



1-188
7.3



1-124
7.3



5-041
7.3



1-153
7.3



1-149
7.3



5-019
7.3



4-022
7.3



1-148
7.3



1-206
7.3



4-060
7.3



1-194
7.2



1-141
7.2



1-117
7.2



4-014
7.2



1-287
7.2



1-086
7.2



1-092
7.2



1-144
7.2



1-146
7.2



1-199
7.2



4-031
7.2



1-267
7.1



1-289
7.1



5-039
7.1



1-134
7.1



2-048
7.1



4-019
7.1



1-147
7.1



1-228
7.1



1-143
7.1



1-200
7.1



1-165
7.1



1-163
7.1



1-150
7.1



1-010
7.0



1-270
7.0



1-014
7.0



1-115
7.0



4-015
7.0



4-035
7.0



4-028
7.0



1-152
7.0



1-025
7.0



1-172
6.9



1-285
6.9



1-187
6.9



1-024
6.9



1-013
6.9



1-195
6.9



1-272
6.9



4-020
6.9



4-045
6.9



4-017
6.9



4-037
6.9



5-018
6.9



4-041
6.9



1-226
6.9



1-049
6.9



4-064
6.9



4-029
6.9



1-256
6.8



1-290
6.8



1-269
6.8



1-042
6.8



1-039
6.8



1-123
6.8



1-164
6.8



3-009
6.8



2-022
6.8



1-271
6.8



2-003
6.8



1-004
6.8



2-006
6.8



1-067
6.8



1-083
6.7



1-218
6.7



5-026
6.7



1-219
6.7



1-133
6.7



3-014
6.7



2-026
6.7



1-301
6.7



1-259
6.7



1-040
6.7



5-042
6.7



1-261
6.7



5-038
6.7



4-021
6.7



4-049
6.7



5-048
6.7



2-017
6.7



1-297
6.7



1-008
6.6



5-016
6.6



5-003
6.6



1-277
6.6



5-051
6.6



1-041
6.6



1-205
6.6



5-036
6.6



5-008
6.6



4-036
6.6



2-029
6.6



1-183
6.6



2-043
6.6



4-058
6.6



1-197
6.6



4-059
6.6



3-004
6.6



1-068
6.6



1-258
6.5



1-112
6.5



1-180
6.5



1-266
6.5



5-028
6.5



1-142
6.5



1-030
6.5



1-278
6.5



5-027
6.5



1-111
6.5



5-040
6.5



1-203
6.5



1-022
6.5



3-008
6.5



2-002
6.5



4-047
6.5



1-006
6.5



1-058
6.5



1-191
6.5



4-032
6.4



1-012
6.4



1-157
6.4



1-007
6.4



1-279
6.4



1-105
6.4



4-012
6.4



4-038
6.4



5-037
6.4



1-237
6.4



4-040
6.4



1-221
6.4



1-162
6.4



4-033
6.4



5-025
6.4



5-034
6.4



1-190
6.4



1-247
6.4



1-005
6.4



1-073
6.4



1-064
6.4



1-120
6.3



2-011
6.3



1-026
6.3



1-027
6.3



1-158
6.3



1-159
6.3



1-192
6.3



1-253
6.3



1-167
6.3



5-013
6.3



1-171
6.3



1-291
6.3



1-094
6.3



1-230
6.3



4-018
6.3



1-121
6.3



1-156
6.3



1-154
6.3



4-043
6.3



5-047
6.3



1-227
6.3



4-051
6.3



1-169
6.3



2-040
6.3



1-066
6.3



2-045
6.3



4-005
6.3



4-006
6.3



4-009
6.3



1-155
6.3



1-095
6.2



1-113
6.2



1-021
6.2



1-136
6.2



1-284
6.2



1-126
6.2



1-119
6.2



1-106
6.2



1-160
6.2



1-233
6.2



2-042
6.2



1-116
6.2



2-053
6.2



1-211
6.2



2-016
6.2



1-161
6.2



1-003
6.2



1-036
6.2



2-005
6.2



1-057
6.2



1-273
6.2



1-071
6.2



4-052
6.2



1-070
6.2



1-019
6.1



1-239
6.1



1-214
6.1



1-085
6.1



1-170
6.1



5-017
6.1



1-282
6.1



1-283
6.1



2-028
6.1



2-013
6.1



1-138
6.1



2-025
6.1



1-255
6.1



1-032
6.1



1-245
6.1



1-090
6.1



1-186
6.1



1-038
6.1



2-020
6.1



2-014
6.1



1-035
6.1



2-039
6.1



5-023
6.1



1-114
6.0



1-210
6.0



1-017
6.0



1-263
6.0



1-135
6.0



1-137
6.0



1-099
6.0



2-035
6.0



5-043
6.0



1-122
6.0



1-288
6.0



5-044
6.0



4-042
6.0



1-185
6.0



1-212
6.0



4-057
6.0



1-048
6.0



2-037
6.0



2-010
6.0



1-060
6.0



2-007
6.0



1-063
6.0



5-001
6.0



1-065
6.0



1-046
5.9



1-260
5.9



1-251
5.9



1-275
5.9



1-265
5.9



5-032
5.9



1-208
5.9



1-209
5.9



1-055
5.9



1-234
5.9



1-220
5.9



1-224
5.9



2-015
5.9



2-021
5.9



1-198
5.9



5-007
5.9



4-027
5.9



4-030
5.9



1-292
5.9



1-302
5.9



3-002
5.9



3-012
5.9



1-034
5.9



1-102
5.8



1-097
5.8



1-096
5.8



1-009
5.8



1-274
5.8



1-174
5.8



1-280
5.8



5-015
5.8



1-250
5.8



1-166
5.8



1-264
5.8



1-262
5.8



5-049
5.8



1-091
5.8



5-035
5.8



4-026
5.8



5-021
5.8



2-049
5.8



2-044
5.8



4-061
5.8



1-189
5.8



3-010
5.8



1-231
5.8



2-008
5.8



4-007
5.8



1-072
5.8



4-008
5.8



1-296
5.8



1-082
5.7



1-052
5.7



1-103
5.7



1-223
5.7



1-011
5.7



1-118
5.7



1-104
5.7



5-014
5.7



1-016
5.7



1-236
5.7



2-024
5.7



4-010
5.7



2-033
5.7



1-300
5.7



1-304
5.7



4-013
5.7



1-132
5.7



1-225
5.7



1-037
5.7



5-005
5.7



5-009
5.7



2-004
5.7



4-001
5.7



4-048
5.7



1-018
5.6



1-110
5.6



1-047
5.6



1-088
5.6



1-276
5.6



1-254
5.6



2-018
5.6



1-031
5.6



1-033
5.6



1-131
5.6



4-044
5.6



3-006
5.6



2-050
5.6



5-024
5.6



1-293
5.6



1-056
5.6



1-069
5.6



1-217
5.6



1-179
5.5



1-101
5.5



1-215
5.5



1-238
5.5



1-128
5.5



1-182
5.5



1-089
5.5



1-303
5.5



1-248
5.5



1-107
5.5



4-034
5.5



2-051
5.5



2-001
5.5



2-046
5.5



1-294
5.5



2-041
5.5



4-004
5.5



4-053
5.5



1-077
5.4



1-015
5.4



1-087
5.4



1-298
5.4



1-201
5.4



1-246
5.4



1-184
5.4



1-286
5.4



2-034
5.4



1-249
5.4



1-139
5.4



1-177
5.4



1-242
5.4



2-055
5.4



1-306
5.4



5-045
5.4



5-006
5.4



3-013
5.4



2-052
5.4



1-295
5.4



1-078
5.4



4-002
5.4



1-076
5.4



4-003
5.4



1-079
5.3



1-059
5.3



1-176
5.3



1-053
5.3



5-004
5.3



1-125
5.3



1-109
5.3



1-193
5.3



4-023
5.3



2-047
5.3



2-054
5.3



4-056
5.3



2-038
5.3



1-074
5.3



1-075
5.3



4-063
5.3



1-081
5.2



1-252
5.2



1-168
5.2



1-108
5.2



5-011
5.2



2-019
5.2



1-173
5.2



5-030
5.2



5-031
5.2



1-244
5.2



4-024
5.2



3-007
5.2



2-027
5.2



1-061
5.2



2-009
5.2



5-002
5.2



1-062
5.2



1-084
5.1



1-050
5.1



5-010
5.1



1-127
5.1



1-098
5.1



1-181
5.1



1-281
5.1



1-222
5.1



1-235
5.1



5-029
5.1



1-129
5.1



1-229
5.1



1-213
5.1



3-011
5.1










E. Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates to a final compound of formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof, a quaternary ammonium salt thereof and prodrugs thereof.
Typical examples of recipes for the formulation of the invention are as follows:
1. Tablets

















Active ingredient
5 to 50
mg



Di-calcium phosphate
20
mg



Lactose
30
mg



Talcum
10
mg



Magnesium stearate
5
mg



Potato starch
ad 200
mg










In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
2. Suspension
An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.
3. Injectable
A parenteral composition is prepared by stirring 1.5% by weight of active ingredient of the invention in 10% by volume propylene glycol and water.
4. Ointment

















Active ingredient
5 to 1000
mg



Stearyl alcohol
3
g



Lanoline
5
g



White petroleum
15
g



Water
ad 100
g










In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the thus described invention may be varied in many ways by those skilled in the art.

## Claims

1. A method for treating, a central nervous system disorder in a human, wherein the central nervous system disorder is an anxiety disorder, a psychotic disorder selected from the group consisting of schizophrenia, schizoaffective disorder and schizophreniform disorder, or epilepsy or a convulsive disorder, the method comprising administering to the mammal in need thereof a compound of formula (I):



or a pharmaceutically acceptable salt or stereochemically isomeric form thereof, wherein
V1 is an unsubstituted bivalent saturated straight or branched hydrocarbon radical having from 1 to 6 carbon atoms;
M1 is hydrogen; cycloC3-7alkyl; phenyl optionally substituted with OCF3 or F, phenyloxy; or tetrahydropyranyl;
L is a covalent bond; —O—; —OCH2—; or —NR7—; wherein R7 is hydrogen or an unsubstituted C1-3alkyl;
R2 and R3 are hydrogen;
A is piperidinyl, of a form:




wherein n is 0, 1 or 2;
R4 is, when present at any of b or c positions, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl; polyhaloC1-3alkyl; Het3; Het3-C1-6alkyl; Het3-oxy; Het3-oxy-C1-6alkyl; Het3-C1-6alkyloxy; —NRaRb; or C1-6 alkyl-NRaRb; wherein Ra and Rb are hydrogen, C1-6alkyl or C3-7cycloalkyl;
Het3 is pyridinyl; pyrimidinyl; pyridazinyl; pyrrolyl; indolyl; morpholinyl; oxadiazolyl; benzoxazolyl; benzofuranyl; indolinyl; 1,2,3,4-tetrahydro-isoquinolinyl; phthalazinyl; or benzo[1,3]dioxolyl; wherein each radical is optionally substituted with 1 or 2 substituents, each independently halo, C1-6 alkyl, C3-7 cycloalkyl, polyhaloC1-3 alkyl, cyano, mono(C1-6alkyl)amino, oxo, phenyl, morpholinyl, or C1-3alkyloxy.

2. The method according to claim 1, wherein V1 is —CH2—; —CH2—CH2—; —CH2—CH2—CH2—; —CH2—CH2—CH2—CH2—; —CH2—CH(CH3)—CH2—; —CH(CH3)—CH2—CH2—CH2—; —CH2—CH(CH3)—CH2—CH2—; or —CH2—CH2—CH(CH3)—CH2—.

3. The method according to claim 1, wherein V1-M1 is —CH2—CH2—CH2—CH3; —CH2—CH(CH3)—CH3; —CH(CH3)—CH2—CH2—CH3; —CH2—CH(CH3-)CH2—CH3; or —CH2—CH2—CH(CH3)—CH3; or V1 is —CH2—; —CH2—CH2—; or —CH2—CH2—CH2—; and M1 is cyclopropyl; cyclopentyl; cyclohexyl; phenyl; or phenyloxy.

4. The method according to claim 1, wherein:
V1 is —CH2; —CH2—CH2—; —CH2—CH2—CH2—; —CH2—CH2—CH2—CH2—; —CH2—CH(CH3)—CH2—; —CH(CH3)—CH2—CH2—CH2—; —CH2—CH(CH3-)CH2—CH2—;
or —CH2—CH2—CH(CH3)—CH2—;

M1 is hydrogen; cycloC3-7alkyl; phenyl; or phenyloxy; and
Het3 is pyridinyl; pyrimidinyl; pyridazinyl; morpholinyl; oxadiazolyl; benzoxazolyl;
benzofuranyl; 1,2,3,4-tetrahydro-isoquinolinyl; indolyl; indolinyl; phthalazinyl; or benzo[1,3]dioxolyl; wherein each radical is optionally substituted with 1 or 2 substituents, each independently halo, oxo, C1-6 alkyl, C3-7cycloalkyl, polyhaloC1-3alkyl, cyano, phenyl, morpholinyl, C1-3alkyloxy; or mono(alkyl)amino.

5. The method according to claim 1, wherein Het3 is pyridinyl; pyrimidinyl; morpholinyl, oxadiazolyl; benzofuranyl; indolinyl; or 1,2,3,4 tetrahydro isoquinolinyl; wherein each radical is optionally substituted with 1 or 2 substituents, each independently halo, C1-6alkyl, polyhaloC1-3 alkyl, oxo and phenyl.

6. The method according to claim 1, wherein the compound exists as optical isomers, wherein said compound is either the racemic mixture or the individual optical isomer.

7. The method of claim 1, wherein the central nervous system disorder is an anxiety disorder.

8. The method of claim 1, wherein the central nervous system disorder is an anxiety disorder that is agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, or a posttraumatic stress disorder (PTSD).

9. The method of claim 1, wherein the central nervous system disorder is a psychotic disorder that is schizophrenia, schizoaffective disorder, or schizophreniform disorder.

10. The method of claim 1, wherein the central nervous system disorder is epilepsy or a convulsive disorder that is generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, epilepsy partialis continua, or other form of epilepsy.

11. The method of claim 7, wherein the central nervous system disorder is anxiety, schizophrenia, or epilepsy.

12. The method of claim 1, wherein an orthosteric agonist of mGluR2 is used in combination with a compound of formula (I).

13. The method of claim 1, wherein the compound has a mGluR2 positive allosteric modulation EC50 of about 1 μM or less.

14. The method of claim 1, wherein the compound of formula (I) is: