HK1125381B - 1,4 -di substituted 3-cyano-pyridone derivatives and their use as positive mglur2-receptor modulators - Google Patents

Description

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

Technical Field

The present invention relates to novel compounds, in particular novel 1, 4-disubstituted 3-cyano-pyridone derivatives as positive allosteric modulators of the metabotropic receptor-2 subtype ("mGluR 2"), 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 pharmaceutical compositions and processes to prepare such compounds and compositions, as well as the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

Background

Glutamate is the major amino acid transmitter in the mammalian Central Nervous System (CNS). Glutamate plays a major role in a variety of physiological functions, such as learning and memory, as well as sensory perception, synaptic developmental plasticity, motor control, respiratory and cardiovascular function regulation. Furthermore, glutamate is a central problem in several different neurological and psychiatric diseases where an imbalance in glutamatergic neurotransmission exists.

Glutamate mediates synaptic neurotransmission by activating ionotropic glutamate receptor (iGluR) channels, NMDA receptors, AMPA receptors and kainate receptors responsible for rapid excitatory transmission (Nakanishi et al, (1998) Brain Res Rev., 26: 230-) -235).

In addition, glutamate activates metabotropic glutamate receptors (mglurs) which have more modulatory effects that contribute to fine-tuning synaptic efficacy.

mglurs are seven transmembrane G-protein coupled receptors (GPCRs) that together with calcium-sensitive receptors, GABAb receptors and pheromone receptors belong to GPCR family 3.

Glutamate activates the receptor by binding to the large extracellular amino-terminal region of mGluR (referred to herein as the orthosteric binding site). This binding induces a conformational change in the receptor, leading to activation of G-proteins and intracellular signaling pathways.

The mGluR family consists of 8 members. They are divided into three groups (group I including mGluR1 and mGluR 5; group II including mGluR2 and mGluR 3; group III including mGluR4, mGluR6, mGluR7 and mGluR8) based on their sequence homology, pharmacological properties and the nature of the intracellular signaling cascade that is activated (Schoepp et al (1999) Neuropharmacology, 38: 1431-76).

Among the mGluR members, the mGluR2 subtype is negatively coupled to adenylate cyclase by activation of the G.alpha.i-protein, and its activation leads to inhibition of glutamate release in the synapse (Cartmlll & Schoepp (2000) J Neurochem 75: 889-. In the CNS, mGluR2 receptors are abundant, distributed mainly in the cortex, thalamic regions, accessory olfactory bulb, hippocampus, amygdala (amygdala), caudate putamen and nucleus accumbens (Ohishi et al (1998) Neurosci Res 30: 65-82).

Activation of mGluR2 was found to be effective in treating anxiety in clinical trials (Levine et al (2002) Neuropharmacology 43: 294; Holden (2003) Science 300: 1866-68; Grilon et al (2003) Psychopharmacology 168: 446-54; Kellner et al (2005) Psychopharmacology 179: 310-15). Furthermore, activating mGluR2 was found to be effective in different animal models and therefore represents a possible new treatment for 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) JPharmacol Exp Ther 284: 651-660), Parkinson's disease (Bradley et al (2000) JNeurospora. 20 (9): 3085-94), pain (Simmons et al (2002) Pharmacol 73: 419-27), sleep disorders (Feinberg et al (2002) Biomcbehavv 73: huntington-74) and Braille Res [ 101246-54 ] Schoeph et al (2002) Biochem Biohav. 246: 246-2004).

To date, the majority of available pharmacological tools for targeting mGluR are vicinal ligands that activate several members of the family, since they are structural analogues of glutamate (Schoepp et al (1999) Neuropharmacology, 38: 1431-76).

One new approach to developing selective compounds that act at mglurs is to identify molecules that act through allosteric mechanisms that modulate the receptor by binding to a site other than the highly conserved orthosteric binding site.

mGluR positive allosteric modulators have recently emerged as novel pharmacological entities offering this attractive alternative. Such molecules have been found to be useful for several mGluRs (reviewed in Mutel (2002) Expert Opin. Ther. Patents12: 1-8). In particular, these molecules are described as positive allosteric modulators of mGluR2 (Johnson MP 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 benzenesulfonamide, acetophenone, 2, 3-dihydro-1-indanone (indanone) and picolyl sulfonamide derivatives, respectively, as positive allosteric modulators of mGluR 2. However, none of these specifically disclosed compounds are structurally related to the compounds of the present invention.

These molecules have not been shown to activate the receptor themselves (Johnson MP et al (2003) J MedChem.46: 3189-92; Schaffhauser et al (2003) Mol Pharmacol.64: 798-. However, it enables the receptor to produce a maximal response to glutamate concentrations which themselves induce a minimal response. Mutational analysis has clearly demonstrated that binding of the positive allosteric modulators of mGluR2 occurs not in the ortho position, but at an allosteric site located within the seven transmembrane regions of the receptor (Schaffhauser et al (2003) Mol Pharmacol.64: 798-810).

Animal data indicate that positive allosteric modulators of mGluR2 have the same effect on anxiety and psychiatric models as compared to orthosteric agonists. mGluR2 allosteric modulators have been shown to be active in fear-enhanced startle (Johnson et al (2003) J Med chem.46: 3189-92; Johnson et al (2005) Psychopharmacology 179: 271-83) and stress-induced hyperthermia (Johnson et al (2005) Psychopharmacology 179: 271-83). Furthermore, studies have shown that these compounds are active in retroketamine (Govek et al (2005) Bioorg Med ChemLett15 (18): 4068-72) or amphetamine (Galici et al (2005) J PharmExp Ther315(3), 1181-.

Positive allosteric modulators are capable of enhancing glutamate responses, but they have also been shown to enhance responses to ortho-mGluR 2 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 another novel therapeutic approach to treat the above mentioned neurological disorders involving mGluR2, namely the use of a combination of a mGluR2 positive allosteric modulator with an mGluR2 orthosteric agonist.

Disclosure of Invention

The present invention relates to compounds having metabotropic glutamate receptor 2 modulator activity. In its most general 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

V¹Selected from covalent bonds and divalent saturated or unsaturated, straight chain or branched chain alkyl groups with 1-6 carbon atoms;

M¹selected from hydrogen, ring C_3-7Alkyl, aryl, alkylcarbonyl, alkoxy, aryloxy, arylalkoxy,Arylcarbonyl, hexahydrothiopyranyl and Het¹；

L is selected from the group consisting of a covalent bond, -O-, -OCH₂-、-OCH₂CH₂-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-、-S-、-NR⁷-、-NR⁷CH₂-、-NR⁷Ring C_3-7、-NR⁷CH₂CH₂-、-OCH₂CH₂N(R⁷)CH₂-、-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-C.ident.C-, -C ═ O-, and-C (R)⁸)＝C(R⁹) -, wherein each R⁷Independently of one another, from hydrogen and C_1-3Alkyl radical, wherein R⁸And R⁹Independently of one another, from hydrogen, halogen and C_1-3An alkyl group;

R²and R³Each independently of the others, hydrogen, halogen or alkyl;

a is Het²Or phenyl, wherein each radical is optionally substituted by n radicals R⁴Wherein n is an integer equal to 0, 1, 2 or 3;

R⁴selected from the group consisting of halogen, cyano, hydroxy, oxo, formyl, acetyl, carboxy, nitro, thio, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylalkoxy, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, polyhalo C_1-3Alkylthio, alkylsulfonyl, Het³、Het³-alkyl, Het³-oxy, Het³-oxyalkyl, Het³-alkoxy, Het³-oxoxy radical, Het³-carbonyl, Het³-carbonylalkyl, Het³Thio, Het³-thioalkyl, Het³-sulfonyl, aryl, aralkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkenyl, arylcarbonylalkyl, arylsulfanyl, arylsulfonyl, -NR^aR^balkyl-NR^aR^bO-alkyl-NR^aR^b、-C(＝O)-NR^aR^b-C (═ O) -alkyl-NR^aR^bAnd O-alkyl-C (═ O) -NR^aR^bWherein R is^aAnd R^bSelected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkoxyalkyl, Het³、Het³-alkyl, alkylsulfonyl, alkyl-NR^cR^dAnd C (═ O) alkyl-NR^cR^dWherein R is^cAnd R^dSelected from hydrogen, alkyl and alkylcarbonyl;

or two radicals R⁴Can combine to form a divalent group-X¹-C_1-6-X²-, in which C_1-6Is a saturated or unsaturated, straight-chain or branched-chain hydrocarbon group of 1 to 6 carbon atoms, and X¹And X²Each independently C, O or NH; wherein the divalent group is optionally substituted with one or more groups selected from: halogen, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl and acetyl;

Het¹selected from tetrahydropyranyl and pyridinyl, wherein each group is optionally substituted with 1, 2 or 3 substituents independently of each other selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl and C_1-3An alkoxy group;

Het²selected from piperazinyl, piperidinyl, thienyl, furyl, 1H-indazolyl, 1H-benzimidazolyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 2, 5-diaza-bicyclo [ 2.2.1%]Heptyl, pyrrolidinyl, azetidinyl, 2, 7-diaza-spiro [3.5 ]]-nonyl, pyridyl, 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, 10 b-octahydro-benzo [ f]Quinolyl, 1, 2, 3, 4, 4a, 10 a-hexahydro-benzo [5, 6 ]][1，4]Dioxin and dioxinAnd (dioxino) [2, 3-c ]]Pyridyl, 2, 3, 4, 9-tetrahydro-1H-indeno [2, 1-c ]]-pyridyl, 2, 3, 4, 9-tetrahydro-1H- β -carbolinyl, 1, 2, 3, 4-tetrahydro-benzo [4, 5 ]]-furo (furo) [2, 3-c ]]Pyridyl, 1, 2, 3, 4-tetrahydrobenzo [4, 5 ]]Thieno [2, 3-c]Pyridyl group, [1, 4 ] or a salt thereof]Diazepanyl (diazepanyl), isoxazolyl, indanyl, and indolyl;

Het³selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolyl, pyrrolidinyl, piperazinyl, triazolyl, tetrazolyl, indolyl, thienyl, furyl, tetrahydropyranyl, tetrahydrothiopyran-1, 1-dioxide, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, morpholinyl, oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzomorpholinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, thionaphthyl, indolyl, indolinyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl (phthalazyl), benzo [1, 3, 4-tetrahydroisoquinolyl)]Dioxaalkyl (benzol [1, 1 ]]dioxyl) and quinazolinyl; wherein each group is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C_1-6Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono (alkyl) amino and di (alkyl) amino, and C_1-3An alkoxy group;

aryl is naphthyl, phenyl or biphenyl, wherein each group is optionally substituted with 1, 2 or 3 substituents independently from each other selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl, ethoxycarbonyl and C_1-3An alkoxy group; the alkyl group is a saturated straight-chain or branched-chain hydrocarbon group having 1 to 6 carbon atoms, or a saturated cyclic hydrocarbon group having 3 to 7 carbon atoms, or 4 to 12 carbon atomsThe saturated hydrocarbon group of (1) which comprises at least one saturated straight-chain or branched-chain hydrocarbon group having 1 to 6 carbon atoms and at least one saturated cyclic hydrocarbon group having 3 to 7 carbon atoms; wherein each carbon atom is optionally substituted by one or more groups selected from: halogen, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl, carbamoyl, phenyl and a divalent radical-OCH₂CH₂O-; and

alkenyl is alkyl which additionally contains 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 is also directed to the use of a compound of the invention as a medicament and in the manufacture of a medicament for the prevention and/or treatment of conditions in mammals, including humans, wherein the treatment or prevention is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR 2.

In particular, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention, amelioration, control or reduction of risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal (including a human), wherein said treatment or prevention is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR 2.

Detailed Description

In one embodiment, the present invention relates to a compound of 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 V¹Selected from covalent bonds, -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 present invention relates to a compound of 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 M¹Selected from hydrogen, ring C_3-7Alkyl, phenyl, biphenyl, phenoxy, benzyloxy, furyl, and pyridyl; wherein M is¹Optionally substituted with one or more groups selected from: halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl and C_1-3An alkoxy group.

In one embodiment, the present invention relates to a compound of 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 M¹Selected from hydrogen, ring C_3-7Alkyl, phenyl, biphenyl, phenoxy, benzyloxy, furyl, and pyridyl; wherein any of said groups is optionally substituted with one or more groups selected from: halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy and C_1-3An alkoxy group.

In one embodiment, the present invention relates to a compound of 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-M¹Is selected from-CH₂-CH₂-CH₂-CH₃、-CH₂-CH(CH₃)-CH₃、-CH(CH₃)-CH₂-CH₂-CH₃、-CH₂-CH(CH₃)-CH₂-CH₃、-CH₂-CH₂-CH(CH₃)-CH₃(ii) a Or V¹Selected from covalent bonds, -CH₂-、-CH₂-CH₂-、-CH₂-CH₂-CH₂-and-CH₂-CH ═ CH —; and M¹Selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, phenoxy, benzyloxy, furyl, and pyridyl; wherein each group M¹Optionally substituted with one or more groups selected from: halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy and C_1-3An alkoxy group. In a specific embodiment, V¹-M¹is-CH₂-CH₂-CH₂-CH₃。

In one embodiment, the present invention relates to a compound of 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 R²And R³Each independently hydrogen, chlorine, fluorine or methyl. In one embodiment, R²And R³Each independently hydrogen or methyl. In another specific embodiment, R²And R³Each is hydrogen. In another specific embodiment, R²Is methyl, R³Is hydrogen.

In one embodiment, the present invention relates to a compound of 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 consisting of a covalent bond, -O-, -OCH₂-、-OCH₂CH₂-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-、-NR⁷-、-NR⁷CH₂-、-NR⁷Ring C_3-7、-OCH₂CH₂N(R⁷)CH₂-、-CH₂CH₂-, -C.ident.C-, -C ═ O-and-CH ═ CH-, in which each R is identical to the other⁷Independently of one another, from hydrogenAnd C_1-3An alkyl group.

In another embodiment, the present invention relates to a compound of 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 phenyl, piperazinyl and piperidinyl, wherein each of said groups is optionally substituted with N groups R⁴Wherein n is an integer equal to 0, 1, 2 or 3. In a particular embodiment, n is equal to 0 or 1. In another specific embodiment, n is equal to 1.

In one embodiment, the present invention relates to a compound of 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 R⁴Selected from the group consisting of halogen, cyano, hydroxy, acetyl, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylalkoxy, polyhaloC_1-3Alkyl, polyhalo C_1-3Alkoxy, polyhalo C_1-3Alkylthio, alkylsulfonyl, Het³、Het³-alkyl, Het³-oxy, Het³-oxyalkyl, Het³-alkoxy, Het³-oxoxy radical, Het³-carbonyl, Het³-sulfanyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkenyl, arylcarbonylalkyl, arylsulfonyl, -NR^aR^balkyl-NR^aR^bO-alkyl-NR^aR^b、-C(＝O)-NR^aR^b-C (═ O) -alkyl-NR^aR^bAnd O-alkyl-C (═ O) -NR^aR^bWherein R is^aAnd R^bSelected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkoxyalkyl, Het³、Het³Alkyl, alkylsulfonyl, alkyl-NR^cR^dAnd C (═ O) alkyl-NR^cR^dWherein R is^cAnd R^dSelected from hydrogen, alkyl and alkylcarbonyl; or two radicals R⁴Can combine to form a divalent group-X¹-C_1-6-X²-, in which C_1-6Is a saturated or unsaturated, straight-chain or branched-chain hydrocarbon group of 1 to 6 carbon atoms, and X¹And X²Each independently is C or O.

In another embodiment, the invention relates to compounds of 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 R⁴Can combine to form a compound selected from-CH₂CH₂-O-、-O-CH₂-O-and-O-CH₂CH₂A divalent group of-O-.

In one embodiment, the invention relates to a compound of 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 Het¹Selected from tetrahydropyranyl and pyridinyl, wherein each group Het¹Optionally substituted by 1, 2 or 3 polyhalogens C_1-3Alkyl substituents.

In one embodiment, the invention relates to a compound of 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 Het³Selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolyl, tetrahydropyranyl, tetrahydrothiopyran-1, 1-dioxide, thiazolyl, oxazolyl, morpholinyl, oxadiazolyl, imidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, indolyl, indolinyl, phthalazinyl, and benzo [1, 3]A dioxanyl group. In one embodiment, each group is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C_1-6Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, oxo, acetyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono (alkyl) amino and di (alkyl) amino, and C_1-3An alkoxy group.

In another embodiment, the present invention relates to a compound of 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

V¹Selected from covalent bonds, -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-；

M¹Selected from hydrogen, ring C_3-7Alkyl, phenyl, biphenyl, phenoxy, benzyloxy, furyl, and pyridyl; wherein M is¹Optionally substituted with one or more groups selected from: halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy and C_1-3An alkoxy group;

l is selected from the group consisting of a covalent bond, -O-, -OCH₂-、-OCH₂CH₂-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-、-NR⁷-、-NR⁷CH₂-、-NR⁷Ring C_3-7、-OCH₂CH₂N(R⁷)CH₂-、-CH₂CH₂-, -C.ident.C-, -C ═ O-and-CH ═ CH-, in which each R is identical to the other⁷Independently of one another, from hydrogen and C_1-3An alkyl group;

R²and R³Independently of one another, hydrogen, halogen or alkyl;

a is selected from phenyl, piperazinyl and piperidinyl, wherein each of said groups is optionally substituted with n groups R⁴Wherein n is an integer equal to 0 or 1;

R⁴selected from halogen, cyano, hydroxy, acetyl, alkyl,Alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylalkoxy, polyhaloC_1-3Alkyl, polyhalo C_1-3Alkoxy, polyhalo C_1-3Alkylthio, alkylsulfonyl, Het³、Het³-alkyl, Het³-oxy, Het³-oxyalkyl, Het³-alkoxy, Het³-oxoxy radical, Het³-carbonyl, Het³-sulfanyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkenyl, arylcarbonylalkyl, arylsulfonyl, -NR^aR^balkyl-NR^aR^bO-alkyl-NR^aR^b、-C(＝O)-NR^aR^b-C (═ O) -alkyl-NR^aR^bAnd O-alkyl-C (═ O) -NR^aR^bWherein R is^aAnd R^bSelected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkoxyalkyl, Het³、Het³-alkyl, alkylsulfonyl, alkyl-NR^cR^dAnd C (═ O) alkyl-NR^cR^dWherein R is^cAnd R^dSelected from hydrogen, alkyl and alkylcarbonyl; or two radicals R⁴Can combine to form a compound selected from-CH₂CH₂-O-、-O-CH₂-O-and-O-CH₂CH₂-a divalent radical of O-;

Het¹selected from tetrahydropyranyl and pyridinyl, wherein each group Het¹Optionally substituted by 1, 2 or 3 polyhalogens C_1-3Alkyl substituents;

Het²selected from piperazinyl, piperidinyl, thienyl, furyl, 1H-indazolyl, 1H-benzimidazolyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 2, 5-diaza-bicyclo [ 2.2.1%]Heptyl, pyrrolidinyl, azetidinyl, 2, 7-diaza-spiro [3.5 ]]-nonyl, pyridyl, 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, 10 b-octahydro-benzeneAnd [ f]Quinolyl, 1, 2, 3, 4, 4a, 10 a-hexahydro-benzo [5, 6 ]][1，4]Dioxino [2, 3-c ]]Pyridyl, 2, 3, 4, 9-tetrahydro-1H-indeno [2, 1-c ]]-pyridyl, 2, 3, 4, 9-tetrahydro-1H-beta-carbolinyl, 1, 2, 3, 4-tetrahydro-benzo [4, 5 ]]-furo [2, 3-c ]]Pyridyl, 1, 2, 3, 4-tetrahydrobenzo [4, 5 ]]Thieno [2, 3-c]Pyridyl group, [1, 4 ] or a salt thereof]Diazepanyl, isoxazolyl, indanyl and indolyl;

Het³selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolyl, tetrahydropyranyl, tetrahydrothiopyran-1, 1-dioxide, thiazolyl, oxazolyl, morpholinyl, oxadiazolyl, imidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, indolyl, indolinyl, phthalazinyl, and benzo [1, 3]A dioxanyl group; wherein each group is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C_1-6Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, oxo, acetyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono (alkyl) amino and di (alkyl) amino, and C_1-3An alkoxy group; aryl is phenyl or biphenyl, wherein each group is optionally substituted with 1, 2 or 3 substituents independently from each other selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, nitro, ethoxycarbonyl and C_1-3An alkoxy group; and the alkyl is a saturated straight chain or branched chain hydrocarbon group with 1 to 6 carbon atoms, or a saturated cyclic hydrocarbon group with 3 to 7 carbon atoms, or a saturated hydrocarbon group with 4 to 12 carbon atoms, and comprises at least one saturated straight chain or branched chain hydrocarbon group with 1 to 6 carbon atoms and at least one saturated cyclic hydrocarbon group with 3 to 7 carbon atoms; wherein each carbon atom may be optionally substituted by one or more groups selected from: cyano, hydroxy, carboxy, carbamoyl, phenyl and a divalent radical-OCH₂CH₂O-。

In another embodiment, the present invention relates to a compound of 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 said compound is selected from the group consisting of:

-4- (4- (N-acetylmethyl) phenyl) -3-cyano-1- (3-methylbutyl) pyridin-2 (1H) -one (compound 1-179);

-4- (3, 4-dimethoxyphenyl) -3-cyano-1- (3-methylbutyl) pyridin-2 (1H) -one (compound 1-110);

-3-cyano-4- (3-fluoro-4-methoxyphenyl) -1- (3-methylbutyl) pyridin-2 (1H) -one (compound 1-114);

-3-cyano-4- (4-hydroxypropylphenyl) -1- (3-methylbutyl) pyridin-2 (1H) -one (compound 1-095);

-3-cyano-4- (4-methoxymethylphenyl) -1- (3-methylbutyl) pyridin-2 (1H) -one (compound 1-103);

-3-cyano-4- (2-fluoro-4-methoxyphenyl) -1- (3-methylbutyl) pyridin-2 (1H) -one (compound 1-113);

-3-cyano-4- (4- (N-morpholinyl (morpholino) phenyl) -1- (3-methylbutyl) pyridin-2 (1H) -one (compound 1-223);

-3-cyano-1- (3-methylbutyl) -4- (phenylethynyl) pyridin-2 (1H) -one (compound 1-267);

-3-cyano-1-butyl-4- [4- (2-methyl-pyridin-4-yloxy) -phenyl ] -pyridin-2 (1H) -one (compound 1-064); and

-3-cyano-1-cyclopropylmethyl-4- (4-phenyl-piperidin-1-yl) -pyridin-2 (1H) -one (compound 4-047).

In the context of the present application, alkyl is a saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms, or a saturated cyclic hydrocarbon radical having from 3 to 7 carbon atoms, or a saturated hydrocarbon radical having from 4 to 12 carbon atoms, comprising at least one saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms and at least one saturated linear or branched-chain hydrocarbon radical having from 3 to 7 carbon atomsA cyclic hydrocarbon group; wherein each carbon atom is optionally substituted by one or more groups selected from: halogen, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl, carbamoyl, phenyl and a divalent radical-OCH₂CH₂O-is formed. 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 a group selected from cyano, hydroxy, carboxy, carbamoyl, phenyl and a divalent group-OCH₂CH₂O-is substituted by one or more groups.

Symbol C_1-6Alkyl defines a saturated straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms, such as C₆Alkyl radical, C₅Alkyl radical, C₄Alkyl radical, C₃Alkyl radical, C₂Alkyl and C₁An alkyl group. C_1-6Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl and heptyl.

Symbol ring C_3-7Alkyl defines a saturated cyclic hydrocarbon radical having 3 to 7 carbon atoms, e.g. ring C₇Alkyl, ring C₆Alkyl, ring C₆Alkyl, ring C₅Alkyl, ring C₄Alkyl, ring C₃Alkyl and Ring C₃An alkyl group. Ring C_3-7Examples of alkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl and cyclohexyl.

Symbol C_1-3Alkyl defines a saturated straight or branched chain hydrocarbon group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl and isopropyl.

In a preferred embodiment, alkyl is C_1-6An alkyl group; in another preferred embodiment, alkyl is C_3-7A cycloalkyl group.

Within the scope of this application, alkenyl is alkyl which additionally contains one or more double bonds.

In the context of the present application, aryl is naphthyl, phenyl or biphenyl; wherein each group is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl, ethoxycarbonyl and C_1-3An alkoxy group. More preferably, aryl is phenyl or biphenyl. More preferably, aryl is optionally substituted with 1, 2 or 3 substituents independently from each other selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, nitro, ethoxycarbonyl and C_1-3An alkoxy group. More preferably, aryl is phenyl or biphenyl, optionally substituted with 1, 2 or 3 substituents independently from each other selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, nitro, ethoxycarbonyl and C_1-3An alkoxy group.

In the context of the present application, halogen is a substituent selected from the group consisting of fluorine, chlorine, bromine and iodine. Preferably, halogen is bromine, fluorine or chlorine.

Within the scope of the present application, polyhalogenated C_1-3The alkyl group is a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms, wherein one or more carbon atoms are substituted with one or more halogen atoms. Preferably, the polyhaloalkyl is trifluoromethyl.

Within the scope of the present application, "compound of the invention" means a compound of 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.

Pharmaceutically acceptable acid addition salts are defined to include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The salts may be obtained by treating the base form of the compound of formula (I) with a suitable acid, for example, an inorganic acid, such as hydrohalic acids (particularly hydrochloric, hydrobromic), sulfuric, nitric and phosphoric acids; organic acids such as acetic acid, glycolic acid, propionic 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 a suitable base.

The compounds of formula (I) containing an acidic proton may also be converted into their therapeutically active non-toxic metal addition salt or amine addition salt forms (base addition salts) by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, the ammonium salts, the alkali metal and alkaline earth metal salts, especially the lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, for example the benzathine, N-methyl-D-glucamine, hydroxylamine (hybramine) salts, salts with amino acids, for example arginine and lysine.

Conversely, the salt form may be converted to the free form by treatment with a suitable acid.

Quaternary ammonium salts of compounds of formula (I) define compounds which can be formed by reacting the basic nitrogen of a compound of formula (I) with a suitable quaternising agent, for example an optionally substituted alkyl, aryl or arylalkyl halide, especially methyl and benzyl iodide. Other reactants having good leaving groups may also be used, such as alkyl triflates, alkyl mesylates and alkyl p-toluenesulfonates. The quaternary ammonium salt has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloride, bromide, iodide, trifluoroacetate and acetate.

The term addition salt as used within the scope of the present application also includes the solvates which the compounds of formula (I) and their salts are able to form. Such solvates are, for example, hydrates and alcoholates.

The N-oxide forms of the compounds of formula (I) are intended to include those compounds of formula (I) in which one or several nitrogen atoms are oxidized to the so-called N-oxide, in particular those N-oxides in which one or more of the tertiary nitrogens (e.g. piperazine or piperidinyl) are N-oxidized. These N-oxides are readily available to the person skilled in the art without any inventive technique and are obvious alternatives to the compounds of formula (I) since these compounds are metabolites formed by oxidation when absorbed in the human body. It is well known that oxidation is often the first step involved in drug metabolism (Textbook of Organic medical and Pharmaceutical Chemistry, 1977, pages 70-75). It is also well known that metabolite forms of the compounds can also be administered to humans in place of the compounds themselves, and have about the same effect.

The compounds of formula (I) may be converted to the corresponding N-oxide form according to procedures well known in the art for converting a trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids such as benzoic acid peroxide or halogen substituted benzoic acid peroxides, for example 3-chloroperoxybenzoic acid, peroxy alkanoic acids such as peracetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as methylene chloride, and mixtures of these solvents.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More specifically, the stereocenter (stereogenic center) may have either the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis or trans configuration. The compound comprising a double bond may have the E or Z stereochemistry of the double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of the present invention.

According to CAS nomenclature rules, when two stereocenters of known absolute configuration are present in a molecule, the R or S descriptor is assigned (based on Cahn-Ingold-Prelog order rule) to the lowest numbered chiral center, the reference center. The configuration of the second stereocenter uses the relative descriptor [ R ]^＊，R^＊]Or [ R ]^＊，S^＊]Is shown in (A) wherein R is^＊Always designated as reference center, [ R ]^＊，R^＊]Denotes a center having the same chirality, [ R ]^＊，S^＊]Representing centers of different chirality. For example, if the least numbered chiral center in the molecule has the S configuration and the second center is R, the stereodescriptor will be designated S- [ R ]^＊，S^＊]. If "α" and "β" are used: the position of the highest priority substituent on an asymmetric carbon atom in the ring system having the lowest ring number is always arbitrarily at the "α" position of the average plane defined by the ring system. The position of the highest priority substituent on another asymmetric carbon atom of the ring system (hydrogen atom in the compound of formula (I)) relative to the position of the highest priority substituent on the reference atom is designated "α" if it is on the same side of the mean plane defined by the ring system and "β" if it is on the other side of the mean plane defined by the ring system.

The present invention also includes derivative compounds (often referred to as "prodrugs") of the pharmacologically active compounds according to the present invention which degrade in vivo to yield the compounds of the present invention. The prodrug is generally (but not always) less potent at the target receptor than the compound that results from its degradation. Prodrugs 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 have very poor solubility, it may be difficult to cross mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion of Prodrugs can be found in Stella, V.J., et al, "prodrug", Drug Delivery Systems, 1985, pp.112-176 and Drugs, 1985, 29, pp.455-473.

The prodrug forms of the pharmacologically active compounds according to the invention will generally be the compounds of the general formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof, said prodrug forms having an esterified or amidated acid group. These esterified acid groups include the formula-COOR^XWherein R is^xIs C_1-6Alkyl, phenyl, benzyl or one of the following groups:

amidated groups include the formula-CONR^yR^zWherein R is^yIs H, C_1-6Alkyl, phenyl or benzyl, R^zis-OH, H, C_1-6Alkyl, phenyl or benzyl. The compounds of the present invention having an amino group can be derivatized to form a Mannich base using a ketone or aldehyde (e.g., formaldehyde). The base will hydrolyze in aqueous solution according to first order kinetics.

Within the scope of the present application, "compound of the invention" means a compound of general formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof and a prodrug thereof.

Within the scope of this application, especially when reference is made to compounds of formula (I), the term element includes all isotopes and isotopic mixtures of that element, whether naturally occurring or synthetically produced, having natural abundance or isotopically enriched form. In particular, when hydrogen is mentioned, it is to be understood as meaning¹H、²H、³H and mixtures thereof; when referring to carbon, it is to be understood as meaning¹¹C、¹²C、¹³C、¹⁴C and mixtures thereof; when referring to nitrogen, it is to be understood as meaning¹³N、¹⁴N、¹⁵N and mixtures thereof; when referring to oxygen, it is to be understood as meaning¹⁴O、¹⁵O、¹⁶O、¹⁷O、¹⁸O and mixtures thereof; when fluorine is mentioned, it is to be understood as meaning¹⁸F、¹⁹F and mixtures thereof.

Thus, the compounds of the present invention also include compounds having one or more isotopes of one or more elements, and mixtures thereof, including radioactive compounds (also known as radiolabeled compounds) in which one or more non-radioactive atoms have been replaced by one of its radioactive isotopes. The term "radiolabeled compound" means any compound of general formula (I), an N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, which comprises at least one radioactive atom. For example, compounds may be labeled by positrons or radioisotopes that emit gamma rays. For radioligand binding techniques (membrane receptor methods),³h atom or¹²⁵The I atom is the selected atom that is replaced. For imaging, the most commonly used Positron Emitting (PET) radioisotopes are¹¹C、¹⁸F、¹⁵O and¹³n, all of which are accelerator produced and have half-lives of 20, 100, 2 and 10 minutes, respectively. Since the half-life of these radioisotopes is so short, they are only suitable for use in research institutions having accelerators at their production, thus limiting their use. The most widely used of these radioisotopes is¹⁸F、^99mTc、²⁰¹Tl and¹²³I. the handling of these radioisotopes, their production, isolation and incorporation into molecules are well known to those skilled in the art.

In particular, the radioactive atoms are selected from hydrogen, carbon, nitrogen, sulfur, oxygen and halogens. Preferably, the radioactive atom is selected from hydrogen, carbon and halogen.

In particular, the radioisotope is selected from³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷Br and⁸²br is added. Preferably, the radioisotope is selected from³H、¹¹C and¹⁸F。

A.preparation of the Final Compounds

Experimental method 1(L is a covalent bond)

The final compound of formula (I-a), wherein L is a covalent bond, may be prepared according to reaction scheme (1) by reacting an intermediate compound of formula (II) with a compound of formula (III) in a suitable solvent inert to the reaction (e.g. 1, 4-dioxane) or a mixture of inert solvents (e.g. 1, 4-dioxane/DMF) in a suitable base (e.g. NaHCO)₃Or Na₂CO₃Aqueous solution), Pd-complex catalyst (e.g., Pd (PPh)₃)₄) In the presence of (a) heating the reaction mixture, for example for 10 minutes, under thermal conditions, for example under microwave irradiation at 150 ℃. In reactions suitable for Pd mediated coupling with boronic acids or boronic esters, for example halogen, triflate or pyridinium moieties. These intermediate compounds can be prepared according to reaction schemes (8), (9) and (10) (see below). R⁵And R⁶May be hydrogen or alkyl, or may together form, for example, the formula-CH₂CH₂-、-CH₂CH₂CH₂-or-C (CH)₃)₂C(CH₃)₂A divalent group of (a).

Reaction scheme 1

Experimental method 2(L is oxygen or sulfur)

The final compounds of formula (I-b), wherein L is oxygen or sulfur, can be prepared according to reaction scheme (2) by reacting the intermediate compounds of formula (II) with the compounds of formula (IV) in a suitable reaction-inert solvent, such as THFThe reaction mixture is heated in the presence of a suitable base (e.g. NaH) for 10 minutes under thermal conditions, e.g. under microwave irradiation, e.g. at 80 ℃. In reaction scheme (2), all variables are as defined in formula (I), R¹Is V¹-M¹And Y is a suitable leaving group, such as pyridinium.

Reaction scheme 2

Experimental method 3(L is aminoalkyl)

The final compound of formula (I-c) (wherein L is-NR)⁷-、-NR⁷CH₂-or-NR⁷CH₂CH₂-, wherein each R⁷Independently of one another from hydrogen and alkyl) can be prepared according to reaction scheme (3) by reacting an intermediate compound of formula (II) with a compound of formula (V) in a suitable solvent inert to the reaction (e.g. 1, 4-dioxane) in a suitable base (e.g. K)₃PO₄) Pd-complex catalysts (e.g. Pd-complex catalysts)) In the presence of (a) under thermal conditions, for example at 80 ℃, for example by heating the reaction mixture for 12 hours. In reaction scheme (3), all variables are as defined in formula (I), R¹Is V¹-M¹And Y is a suitable group for Pd-mediated coupling to amines, such as a halogen.

Alternatively, the compounds of formula (I-c) may be prepared according to reaction scheme (3) by reacting an intermediate compound of formula (II) with a compound of formula (V) in a suitable solvent inert to the reaction (e.g. dimethoxyethane or acetonitrile), in a suitable base (e.g. Cs)₂CO₃Or N, N-diisopropylethylamine) under thermal conditions, for example under microwave irradiation, at 160 ℃, for example by heating the reaction mixture for 30 minutes.

Reaction scheme 3

Experimental method 4(L is alkynyl)

The final compound of formula (I-d) (wherein L is^-C≡C-) Can be prepared according to reaction scheme (4) by reacting an intermediate compound of formula (II) with a compound of formula (VI) in a suitable solvent inert to the reaction, such as THF, in a suitable base, such as NEt₃) Pd-complex catalysts (e.g. PdCl)₂(PPh₃)₂) Phosphines (e.g. PPh)₃) Copper salts (e.g. CuI) under thermal conditions, e.g. at 80 ℃, e.g. heating the reaction mixture for 12 hours. In reaction scheme (4), all variables are as defined in formula (I), R¹Is V¹-M¹Y is a suitable group for Pd-mediated coupling to an alkyne, for example a halogen.

Reaction scheme 4

Experimental method 5(L is alkenyl)

The final compound of formula (I-e) (wherein L is-C (R)⁸)＝C(R⁹) -) can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (VII) in an inert solvent (e.g. 1, 4-dioxane) in a suitable base (e.g. NaHCO)₃Or Na₂CO₃) Pd-complex catalysts (e.g. Pd (PPh)₃)₄) In the presence of (a), heating the reaction mixture under thermal conditions, for example at 85 ℃, for example for 8 hours. In reaction scheme (5), all variables are as defined in formula (I), Y is suitable for Pd-mediated reaction with boronic acidOr a boronic ester coupling group, such as a halogen, trifluoromethanesulfonyl or pyridinium moiety. Such intermediate compounds may be prepared according to reaction schemes (8), (9) and (10) (see below). R⁵And R⁶May be hydrogen or alkyl, or may together form, for example, the formula-CH₂CH₂-、-CH₂CH₂CH₂-or-C (CH)₃)₂C(CH₃)₂A divalent group of (a). In reaction scheme (5), all variables are as defined in formula (I), R¹Is V¹-M¹。

Reaction scheme 5

Experimental method 6

Formula (I-e2) (wherein L is-CH ═ CH-) and formula (I-f2) (wherein L is-CH)₂CH₂-) can be prepared according to reaction scheme (6) by methods well known in the art, such as hydrogenation of the final compound of formula (I-d). In addition, the final compounds of formula (I-f1) and formula (I-f2) can be prepared from the final compounds of formula (I-e1) and formula (I-e2) according to reaction scheme (6) by hydrogenation methods well known in the art. Alternatively, the final compound of formula (I-e2) can be prepared by partial reduction of the triple bond of the final compound of formula (I-d) using methods known in the art. In reaction scheme (6), all variables are as defined in formula (I), R¹Is V¹-M¹。

Reaction scheme 6

Experimental method 7

The compounds of formula (I) can be prepared byMethods known in the art, using suitable bases (e.g. K)₂CO₃) And an iodide salt (e.g., KI), by reacting a compound of formula (VIII) with an alkylating agent of formula (IX) (e.g., isoamyl bromide) in an inert solvent (e.g., acetonitrile) at an appropriately elevated temperature (e.g., 120 ℃). In reaction scheme (7), all variables are as defined in formula (I), R¹Is V¹-M¹And Z is a suitable leaving group, such as halogen.

Reaction scheme 7

In addition, the final compounds of formula (I) can be prepared by further modification of the final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) by known methods by those skilled in the art, for example:

alkylation of the final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) containing one or more hydroxy or amino substituents in their structure with a suitable alkylating agent under thermal conditions using a suitable base.

-saponification of the final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) containing in their structure one or more alkoxycarbonyl functions by using a suitable saponifying agent, such as NaOH or LiOH.

-the final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) containing one or more carboxylic acid functions in their structure are obtained by reaction with ammonia or a primary or secondary amine using a suitable coupling agent, such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, to give the corresponding final compounds of formula (I) containing a primary, secondary or tertiary carboxamide function in their structure.

The final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) containing primary or secondary amine functions in their structure are obtained by reaction of carboxylic acids with suitable coupling agents, such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, to give the corresponding final compounds of formula (I) containing primary, secondary or tertiary carboxamide functions in their structure.

The final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) containing one or more amino substituents in their structure are subjected to reductive amination under thermal conditions using a suitable reducing agent, such as sodium cyanoborohydride, with the appropriate aldehyde.

The final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) containing one or more hydroxy substituents in their structure are reacted with alcohol derivatives under thermal conditions by using suitable coupling systems, for example di-tert-butyl azodicarboxylate/triphenylphosphine.

-reaction of the final compounds of formulae (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) containing in their structure an activated double or triple bond with a1, 3-dipolar cycloaddition of a suitable dipole (dipole) to give the corresponding final compounds of the [3+2] adducts.

B. Preparation of intermediate compounds

Experimental method 8

The intermediate compounds of formula (II-a) may be prepared by reacting an intermediate of formula (X) with a suitable halogenating agent (e.g. P (═ O) Br₃) By reaction in a suitable reaction-inert solvent, such as DMF, at an appropriately elevated temperature, such as 110 ℃. In reaction scheme (8), all variables are as defined in formula (I), R¹Is V¹-M¹。

Reaction scheme 8

Experimental method 9

The intermediate compounds of formula (II-b) can be prepared by methods known in the art by reacting an intermediate of formula (X) with triflic anhydride (also known as triflic anhydride) in a suitable solvent inert to the reaction, such as dichloromethane, in the presence of a base, such as pyridine, at low temperature, such as-78 ℃. In reaction scheme (9), all variables are as defined in formula (I), R¹Is V¹-M¹。

Reaction scheme 9

Experimental method 10

The intermediate compound of formula (II-c) can be prepared by reacting the intermediate compound of formula (II-b) with pyridine at a suitably low temperature (e.g., 40 ℃) by methods known in the art. In reaction scheme (10), all variables are as defined in formula (I), R¹Is V¹-M¹。

Reaction scheme 10

Experimental method 11

The intermediate compound of formula (X) may be prepared by methods known in the art by reacting the intermediate compound of formula (XI) with a suitable reagent for the cleavage of dimethyl ether (e.g. NaOH) in a solvent (e.g. water) at a suitably high temperature (e.g. 100 ℃). In reaction scheme (11), all variables are as defined in formula (I), R¹Is V¹-M¹。

Reaction scheme 11

Experimental method 12

The intermediate compounds of formula (XI) can be prepared by methods known in the art by reacting an intermediate of formula (XII) with an alkylating agent of formula (IX) (e.g., isopentyl bromide), using a base (e.g., K)₂CO₃) And optionally an iodide salt (e.g., KI), in an inert solvent (e.g., acetonitrile) at a suitably elevated temperature (e.g., 120 ℃). In reaction scheme (12), all variables are as defined in formula (I), R¹Is V¹-M¹And Z is a suitable leaving group, such as halogen.

Reaction scheme 12

Experimental method 13

The intermediate compound of formula (III) may be prepared by reaction of an intermediate of formula (XIII) with a suitable boron source, such as bis (pinacolato) diboron, in the presence of a palladium catalyst, such as1, 1' -bis (diphenylphosphino) ferrocenepalladium (II) dichloride, in an inert solvent, such as dichloromethane, in the presence of a suitable salt, such as potassium acetate, at a suitably high temperature, such as 110 c, for example, for 16 hours, using methods known in the art. In addition, the compounds of formula (III) can be prepared using methods known in the art of metal-halogen exchange and subsequent reaction with a suitable boron source from compounds of formula (XIII). Thus, for example, an intermediate compound of formula (XIII) is reacted with an organolithium compound (e.g. n-butyllithium) at a suitably low temperature (e.g. -40 ℃) in an inert solvent (e.g. THF), followed by reaction with a suitable boron source (e.g. tri-n-butyllithium)Methoxyborane). In reaction scheme (13), all variables are as defined in formula (I), R⁵And R⁶May be hydrogen or alkyl or may together form, for example, the formula-CH₂CH₂-、-CH₂CH₂CH₂-or-C (CH)₃)₂C(CH₃)₂A divalent group of (a).

Reaction scheme 13

The starting materials of formula (X) and the intermediate compounds of formulae (III), (IV), (V), (VI), (VII), (IX), (XII) and (XIII) are commercially available compounds or can be prepared according to conventional reaction methods well known in the art.

Obviously, in the above and below reactions, the reaction product may be isolated from the reaction medium and, if desired, further purified according to methods generally known in the art (e.g., extraction, crystallization, and chromatography). It is also clear that the reaction products present in more than one enantiomer may be separated from their mixtures by known techniques, in particular preparative chromatography (e.g. preparative HPLC).

Pharmacology of

The compounds provided by the present invention are positive allosteric modulators of metabotropic receptors, in particular they are positive allosteric modulators of mGluR 2. The compounds of the present invention do not appear to bind to the glutamate recognition site-ortho ligand site, but rather to an allosteric site within the seven transmembrane region of the receptor. The compounds of the invention increase the response of mGluR2 in the presence of glutamate or an mGluR2 agonist. The compounds provided by the present invention are expected to act at mGluR2 by their ability to increase the response of these receptors to glutamate or mGluR2 agonists, thereby enhancing the response of the receptors. Accordingly, the present invention relates to compounds for use as medicaments, as well as to the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment or prevention of a condition in a mammal (including a human), wherein the treatment or prevention is affected or facilitated by the neuromodulatory effect of mGluR2 allosteric modulators, particularly positive mGluR2 allosteric modulators.

Furthermore, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment or prevention, amelioration, control or reduction of risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including a human, wherein said treatment or prevention is affected or facilitated by the neuromodulatory effect of mGluR2 positive allosteric modulators.

Where the present invention is directed to the use of a compound or composition of the present invention in the manufacture of a medicament for, e.g., the treatment of a mammal, it is to be understood that such use is to be construed as a method of, e.g., treating a mammal in certain jurisdictions comprising administering to a mammal in need of such, e.g., treatment, an effective amount of a compound or composition of the present invention.

In particular, neurological or psychiatric disorders associated with glutamate dysfunction include one or more of the following conditions or diseases: acute neurological and psychiatric disorders such as brain deficits secondary to heart bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord contusion, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, dementia (including aids-induced dementia), alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive disorders, idiopathic and drug-induced parkinson's disease, muscle spasms and disorders associated with muscle rigidity including tremors, epilepsy, convulsions, migraine (including migraine (miganieheadache), urinary incontinence, substance tolerance (substention tolerance), substance withdrawal (substention with nicotine) (including substances such as opioids, tobaccos, tobacco products, alcohols, benzodiazepines, cocaine, sedatives, hypnotics and the like), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, 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, cerebral edema, pain (including acute and chronic states, severe pain, refractory pain, neuropathic pain and post-traumatic pain), tardive dyskinesia, sleep disorders (including lethargy), attention deficit/hyperactivity disorder, and conduct disorder.

In particular, the condition or disease is a central nervous system disorder selected from: anxiety disorders, psychiatric 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 consisting of: agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia, and other phobias.

Preferably, the central nervous system disorder is a psychiatric disorder selected from: schizophrenia, delusional disorders, schizoaffective disorders, schizophreniform disorders, and substance-induced psychotic disorders.

Preferably, the central nervous system disorder is a personality disorder selected from: obsessive-compulsive personality disorder and schizoid (schizoid), schizotypal (schizotypal) disorder.

Preferably, the central nervous system disorder is a substance-related disorder selected from the group consisting of: alcohol abuse, alcohol dependence, 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: anorexia nervosa and bulimia nervosa.

Preferably, the central nervous system disorder is a mood disorder selected from the group consisting of: bipolar disorder (type I and type II), cyclothymia, 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: generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial seizure epilepsy with or without impairment of consciousness, infantile spasms, partial status epilepticus, 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: delirium, substance-induced persisting delirium, 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 above disorders, the treatment of anxiety, schizophrenia, migraine, depression and epilepsy is of particular importance.

Currently, the diagnostic & Statistical Manual of Mental Disorders (DSM-IV), 4 th edition of the American society for Mental Disorders, provides a diagnostic tool for determining the conditions described herein. Those skilled in the art recognize that alternative nomenclature, disease taxonomies and classification systems exist for the neurological and psychiatric disorders described herein, and that they evolve with medical and scientific progress.

Because these positive allosteric modulators of mGluR2, comprising compounds of formula (I), enhance the response of mGluR2 to glutamate, the methods of the present invention advantageously utilize endogenous glutamate.

Because positive allosteric modulators of mGluR2 comprising a compound of formula (I) enhance the response of mGluR2 to agonists, it will be appreciated that the present invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by administering an effective amount of a mGluR2 positive allosteric modulator comprising a compound of formula (I) in combination with an mGluR2 agonist.

The compounds of the present invention may be used in combination with one or more other drugs for the treatment, prevention, control, amelioration, or lessening the risk of a disease or condition for which the compound of formula (I) or the other drug may have utility, wherein the combination of the drugs is safer or more effective than either drug alone.

Pharmaceutical composition

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 of the invention, in particular a compound of 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 of the present invention, in particular the compounds of 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, or any subgroup or combination thereof, may be formulated for administration purposes in a variety of pharmaceutical forms. All compositions generally used for systemic administration of drugs can be employed as long as the composition is suitable.

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 ideally in unit dosage form, in particular suitable for oral, rectal, transdermal, parenteral injection or administration by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, sugar alcohols, oils, alcohols and the like (in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions); or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like (in the case of powders, pills, capsules and tablets). Solid pharmaceutical carriers are obviously employed in this case because of the convenience of administration in tablets and capsules, which represent the most advantageous oral dosage unit form. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients, such as those to increase solubility, may also be included. For example, injection solutions can 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 which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable wetting agent, and optionally in combination with a minor proportion of suitable additives of any nature which do not cause significant deleterious effects on the skin. The additives may facilitate application to the skin and/or may aid in the preparation of the desired composition. These compositions may be administered in various ways, for example as a transdermal patch, as a spot-on, as an ointment.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form 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 product pouches (powder packets), wafers (wafers), suppositories, injectable solutions or suspensions, and the like, as well as segregated multiples thereof. Since the compounds of the present invention are effective orally administrable dopamine antagonists, pharmaceutical compositions for oral administration comprising said compounds are particularly advantageous.

It has been mentioned that the present invention relates to a pharmaceutical composition comprising a compound of the invention and one or more other drugs for the treatment, prevention, control, amelioration or reduction of the risk of a disease or condition for which a compound of formula (I) or said other drugs may have utility, and to the use of such a composition in the manufacture of a medicament.

The following examples are intended to illustrate the invention without limiting its scope.

Experimental part

Several methods for preparing the compounds of the present invention are illustrated in the following examples. All starting materials were obtained commercially and used without further purification unless otherwise indicated.

In particular, the following abbreviations may be used throughout the examples and the description:

AcOEt (Ethyl acetate)	M (mole)
		AcOH (acetic acid)	MeOH (methanol)
BBr3(boron tribromide)	mg (milligrams)
		BINAP (+ -) -1, 1' -bis (2-naphthol)	MgSO4(magnesium sulfate)
Br2(bromine)	MHz (megahertz)
		CDCl3(deuterated chloroform)	min (minutes)
CCl4(carbon tetrachloride)	μ l (microlitre)
		DCM (dichloromethane)	ml (milliliter)
MCPBA (3-chloro)Perbenzoic acid)	mmol (millimole)
		DEAD (diethyl azodicarboxylate)	m.p. (melting point)

DIBAL (diisobutylaluminum hydride)	NaBH(OAc)3(sodium triacetoxyborohydride)
		DME (dimethoxyethane)	Na2CO3(sodium carbonate)
DMF (dimethylformamide)	NaH (sodium hydride)
		DMSO (dimethyl sulfoxide)	NaHCO3(sodium bicarbonate)
Dppf (1, 1' -bis (diphenylphosphinyl) ferrocene)	NaHMDS (sodium hexamethyldisilazane)
		EDCI. HCl (1-3 (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride)	NaI (sodium iodide)
Et3N (Triethylamine)	NaOtBu (sodium tert-butoxide)
		Et2O (diethyl ether)	Na2SO4(sodium sulfate)
EtOH (ethanol)	NBS (N-bromosuccinimide)
		g (gram)	NH4Cl (ammonium chloride)
1H (proton)	NH4OH (ammonium hydroxide)
		H2(Hydrogen)	NMR (nuclear magnetic resonance)
HCl (hydrochloric acid)	Pd2(dba)3(dibenzylidene acetone palladium (II))
		HPLC (high pressure liquid phase)Chromatography method	PdCl2(dppf)2(bis (diphenylphosphinyl) ferrocene palladium (II) dichloride)
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(Phosphorylbromide)
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 spectrometry)	Tf2O (trifluoromethanesulfonic anhydride)
		LiAlH4(lithium aluminum hydride)	Xantphos (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene)

Whenever reference is made to saline, it is meant a saturated aqueous solution of NaCl. All temperatures are expressed in degrees Celsius (C.), unless otherwise indicated. All reactions were carried out under a non-inert atmosphere at room temperature unless otherwise indicated.

In a single mode reactor: emrys^TMAn optizer microwave reactor (personal chemistry a.b.,now Biotage) (description of the instrument can be found inwww.personalchemistry.com)And in a multimodal reactor: MicroSYNTHLabstation (Milestone, Inc.) (the instrument description can be found inwww.milestonesci.com) In (3) performing a microwave-assisted reaction.

A.Preparation of intermediate compounds

A1.Intermediate compound 1

Intermediate compound 1

Reaction in N₂The reaction is carried out under an atmosphere. To a commercially available solution of 4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (1.00g, 6.60mmol, 1 eq) in acetonitrile (45ml) was added K₂CO₃(2.73g, 19.8mmol, 3 equiv.) and isoamyl bromide (441mg, 8.65mmol, 1.3 equiv.). The resulting solution was heated at 100 ℃ for 12 hours. The reaction was then cooled to room temperature and filtered through a layer of celite. The filtrate was then concentrated in vacuo. The crude residue thus obtained is then passed through flash chromatography (SiO)₂Gradient elution with 0-2% MeOH in DCM) to give intermediate compound 1 as a creamy solid (82%, 5.40 mmol).

A2.Intermediate Compounds 2 and 2'

Intermediate compound 2

A solution of intermediate compound 1(1.5g, 6.81mmol) in aqueous NaOH (0.1N, 75ml) and THF (20ml) was heated to 100 deg.C for 1 hour. The reaction was cooled to 0 ℃ and acidified by addition of 1M HCl, adjusting the pH to about 3, at which time a white solid precipitated out. The solid was filtered and dried under vacuum to give N-isoamyl substituted intermediate compound 2(1.3g, 6.30mmol) as a white solid. The N-N-butyl substituted intermediate compound 2' was prepared in an equivalent manner.

A3.Intermediate compounds 3, 3' and 3 "

Intermediate compound 3

Reaction in N₂The reaction is carried out under an atmosphere. To a solution of intermediate compound 2(2.00g, 9.66mmol, 1 eq) in DMF (10ml) was carefully added P (═ O) Br₃(5.54g, 19.0mmol, 2 equiv.) the resulting solution was then heated in a sealed tube at 100 ℃ for 2 hours. The reaction was then cooled to room temperature and washed with H₂O (30ml) was diluted and the resulting solution was extracted with AcOEt (3X 30 ml). Mixing the organic layer with Na₂SO₄Dried and concentrated under vacuum to give an oil. By flash chromatography (SiO)₂Eluting with DCM) to afford N-isoamyl substituted intermediate compound 3(2.13g, 82%, 7.92mmol) as a creamy solid. The N-N-butyl substituted intermediate compound 3' and the N-methylcyclopropyl substituted intermediate 3 "were prepared in the same manner.

A4.Intermediate compound 4

Intermediate compound 4

To a round bottom flask containing intermediate compound 2(100mg, 0.48mmol) in DCM (5ml) was added 3 equivalents of pyridine (0.118ml, 1.44 mmol). The mixture was cooled to-78 ℃ and Tf was added slowly₂O (0.217ml, 0.528 mmol). The solution was warmed to room temperature and stirred for 1/2 hours. The mixture was hydrolyzed with cold water, extracted with DCM (3X 10ml), washed twice with brine and Na₂SO₄Drying, filtration and evaporation under reduced pressure gave intermediate 4(133mg)。

A6.Intermediate compound 6

Intermediate compound 6

The reaction was carried out under nitrogen atmosphere. To a solution of N- (2-bromo-benzyl) -acetamide (468mg, 2.02mmol) in acetonitrile (45ml) were added di-tert-butyl dicarbonate (1.34g, 6.15mmol) and N, N-dimethylaminopyridine (501mg, 4.1 mmol). The reaction mixture was then stirred at room temperature for 20 minutes, then diluted with AcOEt (40ml) and saturated NaHCO₃Solution (2X 40ml) and saturated NH₄Washed with a solution of Cl (3X 40 ml). The organic layer was then washed with Na₂SO₄Dried and concentrated under vacuum to give a crude solid. By short open column chromatography (SiO)₂Eluting with 2% MeOH in DCM) to afford intermediate compound 6 as a yellow oil (590.00mg, 89%, 1.79 mmol).

A7.Intermediate compound 7

Intermediate compound 7

To a solution of intermediate compound 6(200mg, 0.61mmol) in DMSO (4ml) were added bis (pinacolato) diboron (232mg, 0.913mmol) and potassium acetate KOAc (180mg, 1.83mmol), the solution was degassed with a stream of nitrogen, and then to the reaction mixture was added 1, 1 '-bis (diphenylphosphino) ferrocene palladium (II) dichloride (1, 1' -bis (diphenylphosphino) ferrocenepalladium (II) dichloride), DCM (20.0mg, 0.0183 mmol). The reaction mixture was then heated at 110 ℃ for 16 hours under nitrogen atmosphere. The reaction was then cooled to room temperature and diluted with AcOEt (30ml), and the resulting solution was washed with water (3X 15ml) and then Na₂SO₄The organic fraction was dried and concentrated under vacuum to give the desired compound. The product was passed through short open column chromatography (SiO)₂Eluting with DCM) to give intermediate compound 7(149.0mg, 89%, 0.054mmol) as a yellow oil.

A8.Intermediate compound 8

Intermediate compound 8

Reaction in N₂The reaction is carried out under an atmosphere. To a mixture of 1, 4-dioxane (5.88ml) and DMF (0.12ml) was added 4-bromobenzeneboronic acid pinacol cyclic ester (300mg, 1.06mmol), N-acetylethylenediamine (0.155ml, 1.59mmol), Xantphos (123mg, 0.21mmol) and Cs at room temperature₂CO₃(518mg, 1.59mmol) with N₂The mixture was purged for 5 minutes. Addition of Pd (OAc)₂(24mg, 0.1mmol) and the mixture in the sealed tube was irradiated under microwave conditions at 170 ℃ for 10 minutes. The reaction was then cooled to room temperature and filtered through a layer of celite. The volatiles were evaporated under vacuum and the residue thus obtained was subjected to short open column chromatography (SiO)₂In DCM/MeOH (NH)₃) Elution) to give intermediate compound 8(80 mg).

A9.Intermediate compound 9

Intermediate compound 9

To a solution of 4-pyridinethiol (149mg, 1.35mmol) in dimethylformamide (5ml) was added K₂CO₃(186mg, 1.35 mmol); the resulting solution was stirred for 12 minutes, and then 2- (4-bromomethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2-is added thereto]A solution of dioxolane (400mg, 1.35mmol) was stirredThe solution was allowed to stand for 2 hours. The mixture was then diluted by addition of water (30ml) and extracted with AcOEt (3 × 15 ml); the organic layer was then washed with Na₂SO₄Dried and concentrated under vacuum to give the crude product. The crude reaction mixture was then purified by Biotage purification (eluting with DCM) to give intermediate compound 9(406.0mg, 1.24mmol, 92%).

A10.Intermediate compound 10

Intermediate compound 10

Commercially available 4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (4.70g, 31.29mmol, 1 eq), 4- (trifluoromethoxy) benzyl bromide (5.44ml, 32.86mmol, 1.05 eq) and K₂CO₃(12.9g, 93.8mmol, 3 equiv.) are combined in acetonitrile (200 ml). The mixture was heated in a sealed tube at 140 ℃ for 16 hours. The reaction was then cooled to room temperature and the solvent was evaporated under vacuum. The resulting residue was dissolved in DCM and filtered through a celite layer. The filtrate was then concentrated under vacuum. The white solid thus obtained was then triturated with ether to give intermediate compound 10(9.20g, 91%) as a white solid.

A11.Intermediate compound 11

Intermediate compound 11

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

A12.Intermediate compound 12

Intermediate compound 12

Intermediate compound 11(6.57g, 21.19mmol, 1 eq) and P (═ O) Br were added₃(12.15g, 42.39mmol, 2 equiv.) are mixed in DMF (125ml) and the resulting mixture is heated at 110 ℃ for 1 hour. The reaction was then cooled to room temperature and washed with H₂O (200ml) was diluted and the resulting solution was then extracted with AcOEt (3X 75 ml). The organic layer was washed with MgSO₄Dried and concentrated under vacuum. By flash chromatography (SiO)₂Eluting with DCM) to afford intermediate compound 12(6.75g) as a white solid. Intermediate compound 12' was prepared in an analogous manner, wherein the para position of the phenyl moiety was substituted with a fluoro instead of a trifluoromethoxy moiety.

A13.Intermediate compound 13

Intermediate compound 13

To PPh of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (500mg, 2.27mmol), N- (2-hydroxyethyl) morpholine (330.8mg, 2.72mmol) and polymer linkage (loading 2.15mmol/g) at 0 deg.C₃(2.11g, 4.54mmol) to a mixture of azodicarboxylic acid di-tert-butyl ester (784.0mg, 3.40mmol) in dry DCM (30ml) was added. The reaction mixture was stirred at room temperature for 2 hours. The resin was then filtered off, washed with DCM and the filtrate concentrated in vacuo. The residue (756.45mg) was used in the next reaction step without further purification.

A14.Intermediate compound 14

Intermediate compound 14

Intermediate compound 3(200mg, 0.74mmol), 1-tert-butoxycarbonylpiperazine (151mg, 0.81mmol), K were reacted at room temperature₃PO₄(236mg, 1.1mmol) and catalyst [577971-19-8]CAS (10mg) was mixed in 1, 4-dioxane (3 ml). The corresponding mixture was heated in a sealed tube at 85 ℃ for 16 hours. The mixture was cooled to room temperature, filtered through a layer of celite and washed with DCM. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to give intermediate compound 14(200mg, 72%).

A16.Intermediate compound 16

Intermediate compound 16

A mixture of 5- (4-bromophenyl) -1, 3-oxazole (220mg, 0.98mmol), bis (pinacolato) diboron (372mg, 1.47mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (24mg, 0.0294mmol), KOAc (288mg, 2.93mmol) in DMSO (7ml) was heated at 110 ℃ for 16 hours. The mixture was cooled to room temperature, diluted with AcOEt (30ml) and washed with water (3X 15 ml). The combined organic layers were washed with Na₂SO₄Dried and evaporated in vacuo, and the residue thus obtained (200mg) was used in the next reaction step without further purification.

A17.Intermediate compound 17

Intermediate compound 17

Commercially available 4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (4.0g, 0.0266mol), beta-bromophenylether (5.62g, 0.0279mol) and K₂CO₃(11.0g, 0.0799mol) in CH₃The solution in CN (150ml) was heated at reflux for 16 h. The reaction mixture was then filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized from ether to give intermediate compound 17(7g, 97%).

A18.Intermediate compound 18

Intermediate compound 18

To a solution of intermediate compound 17(7.0g, 0.0259mol) in MeOH (100ml) was added aqueous NaOH (0.1N, 200 ml). The reaction mixture was heated to 100 ℃ for 3 hours. The reaction was then cooled to room temperature and MeOH was evaporated under vacuum. The resulting basic aqueous phase was acidified by addition of 2N HCl and the pH was adjusted to about 3 at which time a white solid precipitated out. The solid was collected using a sintered funnel, washed with ether and dried under vacuum to give intermediate compound 18(5.78g, 87%) as a white solid.

A19.Intermediate compound 19

Intermediate compound 19

Intermediate compound 18(7.10g, 0.027mol) and P (═ O) Br₃(15.886g, 0.055mol) was mixed in DMF (150ml) and the resulting mixture was heated at 110 ℃ for 3 h. The reaction was then cooled to room temperature and diluted with water (100ml) and the resulting solution was extracted with AcOEt (3 × 150 ml). Mixing the organic layer with Na₂SO₄Dried and concentrated under vacuum. Subjecting the crude product to flash chromatography (SiO)₂Eluting with DCM) to give intermediate compound 19(7.67g, 89%).

A20.Intermediate compound 20

Intermediate compound 20

To 3- (trifluoromethyl) benzaldehyde ([454-89-7 ]) contained in DCE (20-30ml)]CAS) (0.872ml, 0.0065mol) and 4-piperidinemethanol (0.5g, 0.0043mol) and a few drops of AcOH in a round-bottomed flask were added NaBH (OAc)₃(2.2g, 0.0107 mol). The mixture was stirred at room temperature overnight, then with saturated NaHCO₃The solution was washed and extracted with DCM. The combined organic layers were passed over Na₂SO₄Dried and concentrated under vacuum. The crude product was purified by flash chromatography to afford intermediate compound 20(0.610g, 56%).

A23.Intermediate compound 23

Intermediate compound 23

To a round bottom flask containing methyl 4-formylbenzoate (5.6g, 0.034mol) and morpholine (2g, 0.023mol) in DCE (20ml) was added a few drops of AcOH and molecular sieve (4A). The reaction mixture was stirred at room temperature for 40 minutes and NaBH (OAc) was added₃(5g, 0.023 mol). The mixture was stirred at room temperature overnight and then an additional equal amount of NaBH (OAc) was added₃(5g, 0.023 mol). The mixture was stirred at room temperature for 5 hours, then washed with HCl (1N) and extracted with DCM. Finally saturated NaHCO is used₃The solution cleans the organic layer. The combined organic layers were passed over Na₂SO₄Dried and concentrated under vacuum. Passing the crude product through a flash colorSpectrum (DCM/MeOH (NH)₃) Mixture) to yield intermediate compound 23(3g, 60%).

A24.Intermediate compound 24

Intermediate compound 24

In N₂The reaction was carried out under an atmosphere. To a solution of intermediate compound 23(2g, 0.0085mol) in THF (12ml) was slowly added lithium aluminum hydride (1M in THF) (17ml, 0.017 mol). The reaction mixture was stirred at room temperature for 2 hours. Then, saturated NaHCO was carefully added₃The solution was extracted with DCM. The combined organic layers were passed over Na₂SO₄Dried and concentrated in vacuo to afford intermediate compound 24(1.75g, 100%) which was used in the next reaction step without further purification.

A28.Intermediate compound 28

Intermediate compound 28

Intermediate compound 3(250mg, 0.93mmol), tributyl (vinyl) tin (0.325ml, 1.11mmol) and Pd (PPh)₃)₄A mixture (22mg, 0.0186mmol) in degassed toluene (10ml) was microwaved at 130 ℃ for 25 minutes. The mixture was then cooled to room temperature and the solvent was evaporated under vacuum. The residue was purified by flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield intermediate compound 28(100mg, 50%) as a pale yellow solid.

A29.Intermediate compound 29

Intermediate compound 29

To a solution of 4-pyridylcarbinol (15g, 137.4mmol) in DCM (200ml) was added thionyl chloride (43.6ml), and the resulting reaction mixture was stirred at room temperature for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue was diluted with DCM and saturated NaHCO₃And (4) cleaning with the solution. The combined organic layers were passed over Na₂SO₄Dried and concentrated in vacuo to afford intermediate compound 29(17.18g, 99%).

A30.Intermediate compound 30

Intermediate compound 30

To a mixture of NaH (60% in mineral oil) (0.718g, 17.96mmol) in THF (20ml) was added dropwise a solution of 5-bromoindole (2.34g, 11.8mmol) in THF (17 ml). The resulting mixture was stirred at room temperature for 1 hour. Intermediate compound 29(1.81g, 14.2mmol) was then added and the mixture was heated at 80 ℃ overnight. Cooling the reaction mixture with H₂O washes and extracts with AcOEt. The combined organic layers were passed over Na₂SO₄Dried and evaporated under vacuum. The residue was purified by flash chromatography (SiO)₂DCM/MeOH mixture) to afford intermediate compound 30(2.73g, 80%).

A31.Intermediate compound 31

Intermediate compound 31

To a solution of intermediate compound 30(2.73g, 9.5mmol) in DMSO (27ml) was added bis (pinacolato) diboron (2).414g, 9.5mmol) and KOAc (2.8g, 28.5 mmol). The solution was then degassed using a nitrogen stream and 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.23g, 0.28mmol) was added to the reaction mixture. The reaction mixture was then heated at 110 ℃ under nitrogen overnight. The reaction was then cooled to room temperature and an additional amount of bis (pinacolato) diboron) (1.63g, 6.4mmol), KOAc (1.89g, 19.2mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride and DCM (0.155g, 0.19mmol) were added and the mixture was heated at 130 ℃ overnight. The cooled reaction mixture was diluted with AcOEt, filtered through a layer of celite and the filtrate was washed with water. The combined organic layers were passed over Na₂SO₄Dried and concentrated in vacuo to give intermediate compound 31(4.5g, quantitative), which was used in the next reaction step without further purification.

A32.Intermediate compound 32

Intermediate compound 32

To (N-tert-butoxycarbonyl) -1, 2, 3, 6-tetrahydropyridine-4-boronic acid pinacol ester ([286961-14-6 ]]CAS) (1.5g, 4.8mmol) to a mixture of 1, 4-dioxane (8ml) and DMF (2ml) was added 4-chloro-2-methylpyridine (0.308g, 2.4mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.293g, 0.36mmol) and potassium carbonate (0.993g, 7.2 mmol). The mixture was then degassed with a nitrogen stream and then microwaved for 90 minutes at 160 ℃. The cooled reaction mixture was filtered through a layer of celite and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield intermediate compound 32(0.5g, 38%).

A33.Intermediate compound 33

Intermediate compound 33

A solution of intermediate compound 32(0.5g, 1.82mmol) in 20% TFA in DCM (10ml) was stirred at room temperature for 4h, then the solvent was evaporated. The residue (0.5g) was used in the next reaction step without further purification.

A35.Intermediate compound 35

To a solution of intermediate compound 2' (1.5g, 7.8mmol) in acetonitrile (13ml) was added pinacol ester of (4-bromomethylphenyl) boronic acid (3.0g, 9.76mmol) ([ 138500-85-3-85)]CAS) and cesium carbonate (5.92g, 15.6 mmol). The reaction mixture was subjected to microwave treatment at 160 ℃ for 30 minutes. The solvent was then evaporated under vacuum and the residue was purified by flash chromatography (SiO)₂DCM/MeOH mixture) to afford intermediate compound 35(2.93g, 92%).

A36.Intermediate compound 36

Intermediate compound 36

Reacting intermediate compound 3(0.366g, 1.361mmol),(Compound described in US2005187277A 1) (0.436g, 1.63mmol), Pd (PPh)₃)₄(0.157g, 0.136mmol) in 1, 4-dioxane (2ml) and saturated Na₂CO₃The mixture of solutions (2ml) was treated with microwaves at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and the filtrate was evaporated under vacuum. The residue was then passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield intermediate compound 36(0.55g, 98%).

A39.Intermediate compound 39

Intermediate compound 39

To 4-Aminomethylphenylboronic acid pinacol ester (CAS138500-88-6) (1.2g, 5.14mmol) and Et at room temperature₃To a stirred solution of N (1.42ml, 10.28mmol) in DCM (50ml) was added di-tert-butyl dicarbonate (1.68g, 7.72 mmol). The mixture was stirred at room temperature for 2 hours. Evaporation of the solvent under vacuum gave a residue which was treated with diethyl ether to give intermediate compound 39(1.7g, solid, 99%) which was used in the next reaction step without further purification.

A40.Intermediate compound 40

Intermediate compound 40

To intermediate compound 39(1.7g, 5.14mmol) in 1, 4-dioxane (3ml) and saturated Na₂CO₃To a solution in solution (3ml) was added intermediate compound 3(1.15g, 4.28 mmol). The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added thereto₃)₄(485.0mg, 0.42 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and the filtrate was concentrated under vacuum. The crude reaction mixture was then passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃)9:1) to yield intermediate compound 40(1.3g, 77%).

A41.Intermediate compound 41

Intermediate compound 41

To a solution of intermediate compound 40(0.125g, 0.316mmol) in DMF (anhydrous, 5ml) at 0 deg.C was added NaH (60%, mineral oil; 0.019mg, 0.474 mmol). The resulting suspension was stirred at 0 deg.C (nitrogen atmosphere) for 30 minutes. 3-Fluorobenzyl bromide (0.059ml, 0.474mmol) was then 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 saturated NaCl solution. The combined organic layers were passed over Na₂SO₄And (5) drying. The crude reaction mixture was then passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃)9:1) to yield intermediate compound 41(0.082g, 51%) as a yellow oil.

A42.Intermediate compound 42

Intermediate compound 42

To a mixture of 4-bromo-2-fluoroaniline (0.6g, 3.15mmol), tetrahydro-4H-pyran-4-one (0.68g, 6.31mmol) and NaBH (OAc)₃(0.96g, 4.72mmol) to a mixture in DCE (20ml) was added molecular sieves (4A) (1 g). The mixture was stirred at room temperature for 16 hours. Then an additional amount of tetrahydro-4H-pyran-4-one (0.34g, 3.15mmol) and NaBH (OAc) was added₃(0.66g, 3.15mmol), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then filtered through a layer of celite and washed with DCM. The filtrate was concentrated in vacuo to give intermediate compound 42(0.86g, quantitative), which was used in the next reaction step without further purification.

A43.Intermediate compound 43

Intermediate compound 43

To a solution of intermediate compound 42(0.86g, 3.15mmol) in DMSO (3ml) were added bis (pinacolato) diboron (0.80g, 3.15mmol) and KOAc (0.93g, 9.45 mmol). The solution was then degassed with a stream of nitrogen and then 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.07g, 0.09mmol) was added to the reaction mixture. The reaction mixture was then heated at 120 ℃ under nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature and diluted with water (50ml), the resulting solution extracted with AcOEt, then the organic fraction was passed over Na₂SO₄Dried and concentrated in vacuo to afford intermediate compound 43(1.01g, 100%) which was used in the next reaction step without further purification.

A44.Intermediate compound 44

Intermediate compound 44

To a solution of NaH (60% in mineral oil) (0.13g, 3.25mmol) in DMF (5ml) was added commercially available 4-bromophenol (0.50g, 2.89mmol) and the reaction was stirred at room temperature for 10 min. 4-chloro-2-methylpyridine (0.30g, 2.40mmol) was then added and the resulting reaction mixture was then subjected to microwave treatment at 150 ℃ for 10 minutes. After cooling, the mixture was diluted with water and Et₂And (4) extracting. The combined organic layers were passed over Na₂SO₄Dried and concentrated under vacuum. The resulting residue was purified by flash chromatography (DCM) to give intermediate compound 44(0.52g, 81%).

A45.Intermediate compound 45

Intermediate compound 45

To a solution of intermediate compound 44(0.50g, 1.89mmol) in DMSO (5ml) was added bis (pinacolato) diboron (0.72g, 2.84mmol) and KOAc (0.56g, 5.68 mmol). The solution was then degassed with a stream of nitrogen and then 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.05g, 0.06mmol) was added to the reaction mixture. The reaction mixture was then heated at 110 ℃ under nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature and diluted with water, the resulting solution was extracted with AcOEt, the organic fraction was passed over Na₂SO₄Dried and concentrated in vacuo to afford intermediate compound 45(0.58g, 100%) which was used in the next reaction step without further purification.

B.Preparation of the Final Compounds

B1.Final Compounds 1-110

Final Compound 1-110 to 3, 4-Dimethoxyphenylboronic acid (740.0mg, 4.08mmol) in 1, 4-dioxane (14ml) and NaHCO₃To a solution in a saturated solution (14ml) was added intermediate compound 3(1.00g, 3.70 mmol). The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added thereto₃)₄(641.0mg, 0.55 mmol). The reaction was then treated with microwaves in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and the filtrate was concentrated under vacuum. The crude reaction mixture was then purified by flash chromatography (eluting with a 0-2% solvent gradient of MeOH in DCM) to afford the desired compound. The compound was then recrystallized from ether to give the final compounds 1-110(940.0mg, 2.88mmol, 78%).

B2.Final Compounds 1-179

Final Compounds 1-179

Intermediate compound 4(150mg, 0.44mmol) and 4- (acetamidomethyl) phenyl-boronic acid (129mg, 0.67mmol) in 1, 4-dioxane (5ml) and Et at room temperature₃Mixing with N (0.12ml, 0.89mmol), and adding N₂The mixture was rinsed for 5 minutes. Adding Pd (PPh)₃)₄(77mg, 0.067mmol) and the resulting mixture was heated at 90 ℃ for 2 hours. The mixture was cooled to room temperature and diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3X 20 ml). The combined organic layers were passed over Na₂SO₄Dried and evaporated in vacuo, and the residue obtained is subjected to column chromatography (SiO)₂DCM/AcOEt) to yield 16mg of the final compound 1-179 as a white solid.

B3.Final Compounds 1-114

Final Compounds 1-114

Intermediate compound 4(150mg, 0.44mmol), 3-fluoro-4-methoxyphenylboronic acid (110mg, 0.67mmol) in 1, 4-dioxane (5ml) and Et at room temperature₃N (0.12ml, 0.89mmol) and mixing with N₂The mixture was rinsed for 5 minutes. Adding Pd (PPh)₃)₄(77mg, 0.067mmol) and the resulting mixture was heated at 90 ℃ for 2 hours. The mixture was cooled to room temperature and diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3X 20 ml). The combined organic layers were passed over Na₂SO₄Dried and evaporated in vacuo, and the residue obtained is subjected to column chromatography (SiO)₂DCM/AcOEt) to yield 43mg of the final compound 1-114 as a yellow solid.

B4.Final Compound 1-095

Final Compound 1-095

Intermediate compound 4(150mg, 0.44mmol), 4- (3-hydroxypropyl) -phenylboronic acid (120mg, 0.67mmol) in 1, 4-dioxane (5ml) and Et at room temperature₃N (0.12ml, 0.89mmol) and mixing with N₂The mixture was rinsed for 5 minutes. Adding Pd (PPh)₃)₄(77mg, 0.067mmol) and the resulting mixture was heated at 90 ℃ for 2 hours. The mixture was cooled to room temperature and diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3X 20 ml). The combined organic layers were passed over Na₂SO₄Dried and evaporated in vacuo, and the residue obtained is subjected to column chromatography (SiO)₂DCM/AcOEt) to yield 40mg of final compound 1-095 as a white solid.

B5.Final Compounds 1-103

Final Compounds 1-103

Intermediate compound 4(150mg, 0.44mmol), 4- (methoxymethyl) -phenylboronic acid (110mg, 0.67mmol) in 1, 4-dioxane (5ml) and Et at room temperature₃N (0.12ml, 0.89mmol) and mixing with N₂The mixture was rinsed for 5 minutes. Adding Pd (PPh)₃)₄(77mg, 0.067mmol) and the resulting mixture was heated at 90 ℃ for 2 hours. The mixture was cooled to room temperature and diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3X 20 ml). The combined organic layers were passed over Na₂SO₄Dried and evaporated in vacuo, and the residue obtained is subjected to column chromatography (SiO)₂DCM/AcOEt) to give 52mg of the final compound 1-103 as a white solid.

B6.Final Compounds 1-178

Final Compounds 1-178

To intermediate compound 7(220.0mg, 0.58mmol) in 1, 4-dioxane (6ml) and saturated Na₂CO₃To a solution in solution (6ml) was added intermediate compound 3(173mg, 0.65 mmol). The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added thereto₃)₄(101.0mg, 0.088 mmol). The reaction was then microwaved at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and the filtrate was concentrated under vacuum. The crude reaction mixture was then purified by preparative HPLC to give pure final compounds 1-178(51mg, 0.15mmol, 26%).

B7.Final Compound 1-097

Final Compound 1-097

To 4-hydroxyphenylboronic acid (336mg, 2.44mmol) in 1, 4-dioxane (20ml) and saturated NEt₃To a solution in solution (0.615ml, 4.43mmol) was added final compound 5-052(750mg, 1.79 mmol). The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added thereto₃)₄(384mg, 0.33 mmol). The reaction was heated in a sealed tube at 90 ℃ for 2 hours. The resulting reaction mixture was cooled to room temperature, diluted with water and brine and extracted with AcOEt. Through Na₂SO₄The organic layer was dried and concentrated under vacuum. Then by flash chromatography (SiO)₂Eluting with a mixture of heptane/AcOEt) to give final compound 1-097(230mg, 45%).

B8.Final Compounds 1-274

Final Compounds 1-274

To a solution of phenol (0.042ml, 0.48mmol) in dry THF (3ml) was added NaH (60% in mineral oil, 13.83mg, 0.96mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. Final compound 5-052(100mg, 0.24mmol) was added. The mixture was microwaved in a sealed tube at 80 ℃ for 10 minutes. The mixture was cooled to room temperature, the solvent was evaporated in vacuo and the residue thus obtained was purified by column chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to give 55mg of final compound 1-274 as a white solid.

B9.Final Compounds 1-298

Final Compounds 1-298

Mixing intermediate compound 3(100mg, 0.371mmol), aniline (0.067ml, 0.743mmol), and K₃PO₄(158mg, 0.745mmol) and catalyst [577971-19-8]CAS (10mg) was mixed at room temperature in 1, 4-dioxane (15 ml). The corresponding mixture was stirred in a sealed tube at 80 ℃ (oil bath temperature) for 12 hours. The mixture was cooled to room temperature and AcOEt (30ml) and NaHCO were added to the reaction mixture₃(10ml, saturated aqueous solution). The layers were separated and the organic layer was passed over Na₂SO₄And (5) drying. The solvent was evaporated in vacuo and the residue thus obtained was purified by flash chromatography to give final compound 1-298(50 mg).

B10.Final Compounds 1-267

Final Compounds 1-267

The reaction was carried out under nitrogen atmosphere. Intermediate compound 3(150mg, 0.557mmol), phenylacetylene (0.064ml, 0.580mmol), PdCl₂(PPh₃)₂(19.6mg，0.028mmol)、PPh₃(3.7mg, 0.014mmol) and NEt₃(0.078ml, 2.23mmol) were mixed in THF (6ml) at room temperature and N was used₂The mixture was purged for 5 minutes. CuI (1.3mg, 0.007mmol) was added and the resulting mixture was heated in a sealed tube at 90 deg.C (oil bath temperature) for 10 hours. The reaction mixture was cooled to room temperature and Na was added₂S₂O₄Aqueous solution (saturated solution). DCM (30ml) was added and the layers were separated. The organic layer was washed with NaHCO₃Washing with aqueous solution (saturated solution), passing over Na₂SO₄Dried and concentrated in vacuo. The residue thus obtained is passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to give final compound 1-267(57 mg).

B11.Final Compounds 1-260

Final Compounds 1-260

To a solution of final compound 1-267(45mg, 0.155mmol) and 1, 4-cyclohexadiene (0.22ml, 2.32mmol) in MeOH (5ml) was added 10% Pd/C (10mg) at room temperature. The resulting mixture was stirred in a sealed tube for 12 hours. The catalyst was filtered off and the solvent was evaporated under vacuum. The resulting residue was taken up in MeOH (15ml) and 10% Pd/C (10mg) was added. The resulting mixture was hydrogenated with hydrogen (20psi) for 3 hours. The catalyst was filtered off and the solvent was evaporated. The residue thus obtained is passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) and then purified by reverse phase HPLC chromatography to give final compound 1-260(1.63mg) as a white solid.

B12.Final Compounds 1-182

Final Compounds 1-182

To intermediate compound 8(80mg, 0.62mmol) in 1, 4-dioxane (1ml) and saturated Na₂CO₃To a solution in solution (1ml) was added intermediate compound 3(64.34mg, 0.239 mmol). The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added to the solution₃)₄(41.4mg, 0.035 mmol). The reaction was then microwaved at 140 ℃ for 5 minutes. The resulting reaction mixture was then filtered through a layer of celite and AcOEt (10ml) was added. Addition of H₂O (10ml) and the layers were separated. The organic layer is coated with Mg₂SO₄Dried and concentrated in vacuo. The residue obtained is then passed through column chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to afford pure final compound 1-182(28mg) as a bright yellow solid.

B13.Final Compounds 1-258

Final Compounds 1-258

To intermediate compound 9(121mg, 0.371mmol) in 1, 4-dioxane (3ml) and saturated NaHCO₃To a solution in solution (3ml) was added intermediate compound 3(100g, 3.71 mmol). The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added to the solution₃)₄(64.0mg, 0.056 mmol). The reaction was then microwaved at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and the filtrate was concentrated under vacuum. The crude reaction mixture was then purified by HPLC to give the final compound 1-258(13.0mg, 0.034mmol, 10%).

B14.Final Compounds 1-239

Final Compounds 1-239

Intermediate compound 4(150mg, 0.44mmol) and 4- (3-methyl propionate) phenyl-boronic acid (140mg, 0.67mmol) in 1, 4-dioxane (5ml) and Et at room temperature₃Mixing with N (0.12ml, 0.89mmol), and adding N₂The mixture was rinsed for 5 minutes. Adding Pd (PPh) to the mixture₃)₄(77mg, 0.06mmol) and the resulting mixture was heated at 90 ℃ for 2 hours. The mixture was cooled to room temperature and diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3X 20 ml). The combined organic layers were passed over Na₂SO₄Drying, evaporating under vacuum and passing the residue thus obtained through column chromatography (SiO)₂DCM/AcOEt) gave 63mg of the final mixture 1-239 as a yellow solid.

B15.Final Compounds 1-240

Final Compounds 1-14

To the final compound 1-239(20mg, 0.057mmol) in THF/H at 0 deg.C₂To a solution of O1:1(4ml) was added lithium hydroxide (24mg, 0.57 mmol). The reaction mixture was stirred for 30 minutes and the solution was concentrated. The pH was adjusted to pH 2 with 1N HCl solution and the precipitate thus formed was filtered off and dried to yield 10mg of final compound 1-240 as a white solid.

B16.Final Compound 2-043

Final Compound 2-043

The intermediate compound is reacted at room temperature12(300mg, 0.804mmol), 1- (2-phenylethyl) piperazine (0.176ml, 0.964mmol), K₃PO₄(341mg, 1.60mmol) and catalyst [577971-19-8]CAS (10mg) was mixed in 1, 4-dioxane (6 ml). The corresponding mixture was heated in a sealed tube at 110 ℃ for 16 hours. The mixture was cooled to room temperature, filtered through a layer of celite and washed with AcOEt. The filtrate was concentrated in vacuo and the residue thus obtained was filtered by flash chromatography to give final compound 2-043(349mg, 90%) as a pale yellow solid.

B17.Final Compound 1-037

Final Compound 1-037

Intermediate compound 12(350mg, 0.938mmol) and intermediate compound 13(375mg, 1.12mmol) were added to 1, 4-dioxane (3ml) and saturated Na₂CO₃The solution (3ml) was mixed. The resulting solution was degassed with a nitrogen stream, and Pd (PPh) was added thereto₃)₄(108.3mg, 0.093 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and washed with AcOEt. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to give final compound 1-037(305.6mg, 65%).

B18.Final Compound 2-022

Final Compound 2-022

The final compound, 2-056(150mg, 0.55mmol), 3-chloro-4- (trifluoromethoxy) benzyl bromide (0.16ml, 0.55mmol) and K₂CO₃A mixture of (150mg, 1.1mmol) in DMF (2ml) was stirred at room temperature overnight. Then mixing the obtainedThe reaction mixture was filtered through a layer of celite and washed with AcOEt. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to give the desired compound. The compound was then recrystallized from ether to give final compound 2-022(170mg, 64%).

B19.Final Compounds 1-250

Final Compounds 1-250

Intermediate compound 3(198mg, 0.74mmol) and intermediate compound 16(200mg, 0.74mmol) were added to 1, 4-dioxane (5ml) and saturated Na₂CO₃The solution (5ml) was mixed. The resulting solution was degassed with a nitrogen stream, and Pd (PPh) was added thereto₃)₄(128mg, 0.115 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and washed with AcOEt. The filtrate was concentrated in vacuo, and the residue thus obtained was purified by flash chromatography to give the final compounds 1-250(63.9mg, 26%, yield calculated based on the subsequent two-step reaction).

B20.Final Compounds 1-223

Final Compounds 1-223

Intermediate compound 3(727mg, 2.70mmol) and commercially available 4- (morpholinyl) phenylboronic acid (560mg, 2.70mmol) in 1, 4-dioxane (10ml) and saturated Na₂CO₃The solution (10ml) was mixed. The resulting solution was degassed with a nitrogen stream, and Pd (PPh) was added thereto₃)₄(468mg, 0.405 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. Then mixing the obtainedThe reaction mixture was filtered through a layer of celite and the filtrate was washed with water (10 ml). The combined organic layers were passed over Na₂SO₄Dried and evaporated under vacuum. The crude reaction mixture was then purified by flash chromatography to afford the desired compound. The compound was then recrystallized from ether to give final compounds 1-223(620mg, 65%).

B21.Final Compounds 1-049

Final Compounds 1-049

Intermediate compound 19(250mg, 0.783mmol)) and 3-chloro-4-isopropoxy-phenylboronic acid (159mg, 0.86mmol) in 1, 4-dioxane (2.5ml) and saturated NaHCO₃The solution (2.5ml) was mixed. The resulting solution was degassed with a nitrogen stream, and Pd (PPh) was added thereto₃)₄(130mg, 0.11 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and the filtrate was evaporated under vacuum. The crude reaction mixture was then purified by flash chromatography to afford the desired compound. The compound was then recrystallized from ether to give final compound 1-049 as a white solid (65mg, 21%).

B22.Final Compound 4-020

Final Compound 4-020

Intermediate compounds 3(100mg, 0.37mmol), 4- (3-trifluoromethylbenzyloxy) -piperidine (115.11mg, 0.444mmol), K were reacted at room temperature₃PO₄(150mg, 0.70mmol) and catalyst [577971-19-8]CAS (10mg) was mixed in 1, 4-dioxane (5 ml). The corresponding mixture was added in a sealed tube at 85 ℃The heat was applied for 16 hours. The mixture was cooled to room temperature and filtered through a layer of celite. The filtrate was concentrated in vacuo and the residue thus obtained was purified by flash chromatography to give final compound 4-020 as a white gummy solid (90mg, 55%).

B23.Final Compound 4-044

Final Compound 4-044

Intermediate compound 3(150mg, 0.406mmol), 4- (phenylpiperidin-4-yl) -morpholine (113.3mg, 0.46mmol), K were reacted at room temperature₃PO₄(200mg, 0.94mmol) and catalyst [577971-19-8]CAS (10mg) was mixed in 1, 4-dioxane (4 ml). The corresponding mixture was heated in a sealed tube at 85 ℃ for 36 hours. The mixture was cooled to room temperature and filtered through a layer of celite. The filtrate was concentrated in vacuo and the residue thus obtained was purified by preparative HPLC to give final compound 4-044(123mg, 51%) as a pale yellow solid.

B24.Final Compound 2-028

Final Compound 2-028

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

B25.Final Compound 3-009

Final Compound 3-009

A mixture of intermediate compound 20(0.223g, 0.00081mol, 1.1 equiv.) and NaH (60% dispersed in mineral oil, 0.035g, 0.00088mol, 1.2 equiv.) in DME (1.5ml) was stirred at room temperature for 10 minutes. Intermediate compound 3(0.20g, 0.00074mol, 1 eq) was then added slowly. The resulting reaction mixture was treated with microwaves at 130 ℃ for 20 minutes. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue was suspended in DCM, filtered and the filtrate concentrated in vacuo. The crude reaction mixture was then purified by flash chromatography to give final compound 3-009(146mg, 47%).

B26.Final Compound 3-008

Final Compound 3-008

To the final compound 3-016(346mg, 1.19mmol) and 3- (trifluoromethyl) benzaldehyde ([454-89-7 ]]CAS) (262mg, 1.5mmol) in DCE (40ml) was added NaBH (OAc) in portions₃(760mg, 3.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. Then, with NH₄The mixture was quenched with aqueous Cl. The combined organic layers were concentrated under vacuum. The crude product was purified by flash chromatography to afford the final compound 3-008 as a light brown solid (370 mg).

B27.Final Compounds 1-271

Final Compounds 1-271

To intermediate Compound 11(200mg, 0.64mmol), intermediate Compound 24(267mg, 1.28mmol) and PPh₃(309mg, 1.15mmol) to a mixture of di-tert-butyl azodicarboxylate (279mg, 1.21mmol) in THF (5ml) was added. The reaction mixture was subjected to microwave treatment at 120 ℃ for 20 minutes. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography (10-20% DCM/MeOH (NH)₃) Solvent gradient elution of (c) to give final compounds 1-271(219.7mg, 70%).

B28.Final Compound 3-014

Final Compound 3-014

To the final compound 3-018(191mg, 0.70mmol) and 3- (trifluoromethyl) benzaldehyde ([454-89-7 ]]CAS) (174mg, 1mmol) in DCE (16ml) was added NaBH (OAc) in portions₃(443mg, 2.1 mmol). The mixture was stirred at room temperature for 3 hours, after which saturated NH was used₄It was quenched with Cl solution. The combined organic layers were passed over Na₂SO₄Dried and concentrated under vacuum. The crude product was purified by flash chromatography to give final compound 3-014(270mg, 89%) as a white solid.

B29.Final Compound 2-036

Final Compound 2-036

To intermediate compound 2(0.2g, 0.971mmol), K₂CO₃To a mixture of (0.268g, 1.942mmol) and NaI (catalytic amount) in acetonitrile (12ml) was added 1- (2-chloroethyl) -4-pyridin-2-yl-piperazine (0.393g, 1.748 mmol). Will be provided withThe reaction mixture was subjected to microwave treatment twice at 150 ℃ for 10 minutes. DCM was then added and the mixture was filtered. With saturated NaHCO₃The filtrate was washed with the solution. The combined organic layers were passed over Na₂SO₄Dried and concentrated under vacuum. The residue was purified by flash chromatography (DCM/MeOH (NH)₃) Mixture) to yield final compound 2-036(152.5mg, 40%) as a near white solid.

B30.Final compound 5-007

Final Compounds 1-131

To a solution of intermediate compound 28(35mg, 0.161mmol) in DCM (6ml) was added one drop of TFA. N- (methoxymethyl) -N- (trimethylsilylmethyl) -benzylamine (46mg, 0.193mmol) was then added slowly and the resulting reaction mixture was stirred at room temperature for 2 hours. The solvent was then evaporated under vacuum and the residue was purified by flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield final compounds 1-131(6mg, 10%).

B31.Final Compounds 2-055

Final Compounds 2-055

A mixture of intermediate compound 12' (250mg, 0.81mmol), 1- (2-pyridyl) -piperazine (0.129ml, 0.85mmol) and diisopropylethylamine (0.416ml, 2.4mmol) in acetonitrile (5ml) was microwaved at 160 ℃ for 30 min. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue thus obtained is passed through flash chromatography (SiO)₂DCM/MeOH mixture) to give final compound 2-055(192mg, 61%) as a white solid.

B32.Final Compound 5-020

Final Compound 5-020

Intermediate compound 3(0.6g, 2.20mmol) and intermediate compound 31(3.69g, 3.79mmol) were added to 1, 4-dioxane (7ml) and saturated Na₂CO₃The solution (6ml) was mixed. The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added thereto₃)₄(0.39g, 0.33 mmol). The reaction was then microwaved in a sealed tube at 140 ℃ for 5 minutes. The resulting reaction mixture was then diluted with AcOEt, filtered through a layer of celite and the filtrate was washed with water (10 ml). The combined organic layers were passed over Na₂SO₄Dried and evaporated under vacuum. The crude reaction mixture was then purified by flash chromatography to afford the desired compound. The compound was then recrystallized from ether to give the final compound 5-020(0.39g, 44%).

B33.Final Compound 4-047

Final Compound 4-047

A mixture of intermediate compound 3 "(0.3 g, 1.18mmol), 4-phenylpiperidine (0.286g, 1.77mmol) and diisopropylethylamine (0.615ml, 3.54mmol) in acetonitrile (5ml) was microwaved at 150 ℃ for 20 minutes. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue thus obtained is passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield the desired compound. The compound was then recrystallized from ether to give the final compound 4-047(0.29g, 73%).

B34.Final Compounds 4-003

Final Compounds 1-196

A mixture of final compound 5-054(0.37g, 1.05mmol) and palladium (10% on charcoal) (catalytic amount) in EtOH (10ml) was stirred under a hydrogen atmosphere at 50psi for 3 hours. The catalyst was then filtered off and the filtrate was evaporated under vacuum. The residue thus obtained is passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield the final compound 4-003(0.21g, 57%).

B35.Final Compounds 1-306

Final Compounds 1-306

Intermediate compound 35(0.25g, 0.61mmol) and commercially available 2-bromo-6-methylpyridine (0.158g, 0.92mmol) in 1, 4-dioxane (2ml) and saturated NaHCO₃The solution (2ml) was mixed. The resulting solution was degassed with a nitrogen stream and Pd (PPh) was added thereto₃)₄(0.10g, 0.09 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was filtered through a layer of celite and the filtrate was washed with water (10 ml). The combined organic layers were passed over Na₂SO₄Dried and evaporated under vacuum. The crude reaction mixture was then purified by flash chromatography to afford the final compounds 1-306(0.078g, 34%).

B36.Final Compounds 5-015

Final Compounds 5-015

To a solution of final compound 5-014(0.04g, 0.130mmol) and diisopropylethylamine (0.068ml, 0.392mmol) prepared by reaction pathway B1 in DCM (2ml) was added acetyl chloride (0.014ml, 0.196 mmol). The reaction mixture was stirred at room temperature for 12 hours. The solvent is then evaporated under vacuum and the residue thus obtained is passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield final compound 5-015(0.045g, 99%).

B37.Final Compounds 1-198

Final Compounds 1-198

To a solution of intermediate compound 41(0.082mg.0.163mmol) in DCM (10ml) was added TFA (5 ml). The resulting solution was stirred at room temperature for 3 hours. The solvent was then evaporated under vacuum and the residue was dissolved in DCM as NaHCO₃And a NaCl saturated solution. The combined organic layers were passed over Na₂SO₄Dried and concentrated under vacuum. The residue was purified by flash chromatography (DCM/MeOH (NH)₃) Mixture) to yield final compound 1-198 as a white solid (17mg, 26%).

B38.Final Compounds 1-185

Final Compounds 1-185

To a mixture of final compounds 1-308(0.2g, 0.533mmol) in 1, 4-dioxane (10ml) was added N-methyl-2-methoxyethylamine (0.0711mg, 0.8mmol), palladium diacetate (0.0118mg, 0.053mmol) and Xantphos (0.0616mg, 0.8 mmol). The reaction mixture was stirred in a sealed tube at 120 ℃ for 16 hours. The resulting reaction mixture is then passed over siliconThe algal soil layer was filtered and washed with AcOEt. The filtrate was washed with saturated NaCl solution. The combined organic layers were passed over Na₂SO₄Dried and concentrated under vacuum. The residue was purified by flash chromatography (DCM/MeOH9:1) to afford final compounds 1-185 as yellow solids (24mg, 12%).

B39.Final Compounds 1-226

Final Compounds 1-226

To a solution of final compound 1-224(0.147mg, 0.385mmol) in DCM (20ml) at 0 deg.C was added BBr₃(0.182ml, 1.92 mmol). The resulting solution was warmed to room temperature and stirred for 16 hours. Then NH is added₄An aqueous OH solution. The resulting aqueous solution was extracted with dichloromethane and washed with saturated NaCl solution. The combined organic layers were passed over MgSO₄Dried and concentrated under vacuum. The residue was purified by flash chromatography (DCM/MeOH (NH)₃)9:1) to yield final compound 1-226(28mg, 20%) as a yellow solid.

B40.Final Compounds 5-052

Final Compounds 5-052

The reaction is carried out in N₂The reaction is carried out under an atmosphere. Intermediate compound 4(26mg, 0.077mmol) was dissolved in pyridine (1ml, 12.26 mmol). The resulting solution was heated at 40 ℃ for 1 hour. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue thus obtained was treated with 1, 4-dioxane to give a white solid, which was filtered and dried under vacuum to identify final compound 5-052(25 mg; white solid).

B41.Final Compound 2-056

Final Compound 2-056

A solution of intermediate compound 14(200mg, 0.53mmol) in a TFA/DCM mixture (20%) (5ml) was stirred at room temperature overnight. By adding K₂CO₃(saturated solution) the mixture was basified. The organic layer was then passed over MgSO₄Dried and concentrated under vacuum. The residue was identified as final compound 2-056(150mg), which was used in the next reaction step without further purification.

B42.Final Compound 3-015

Final Compound 3-015

To a mixture of 1-tert-butoxycarbonyl-4-hydroxypiperidine (447mg, 2.22mmol) in DME (8ml) was added NaH (60% in mineral oil), and the reaction mixture was stirred at room temperature for 5 minutes. Intermediate compound 3(500mg, 1.85mmol) was then added and the resulting reaction mixture was microwaved at 130 ℃ for 30 minutes. The reaction was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give final compound 3-015(460mg) as a brown oil.

B43.Final Compound 3-016

Final Compound 3-016

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

B44.Final Compound 5-053

Final Compound 5-053

Intermediate compound 3(1g, 3.71mmol), (N-tert-butoxycarbonyl) -1, 2, 3, 6-tetrahydropyridine-4-boronic acid pinacol ester (1.26g, 4.08mmol) and Pd (PPh)₃)₄(0.642g, 0.556mmol) in 1, 4-dioxane (6ml) and saturated NaHCO₃The mixture in solution (6ml) was treated with microwaves at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and the filtrate was evaporated under vacuum. The crude reaction mixture was then passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to yield final compound 5-053(0.57g, 41%) as a white solid.

B45.Final compound 3-017

Final compound 3-017

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

B46.Finalization ofCompound 3-018

Final Compounds 3-018

To a solution of final compound 3-017(540mg, 1.44mmol) in MeOH (50ml) was added amberlyst-15 (4.6 mmol/g loading) (1g, 4.6 mmol). The resulting mixture was shaken at room temperature for 12 hours. The resin was then filtered off and the solvent discarded. Suspend the resin in MeOH/NH₃(50ml) 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 3-018 as a yellow oil (198 mg).

B47.Final Compound 5-054

Final Compound 5-054

A mixture of intermediate compound 3' (0.34g, 1.33mmol), intermediate compound 33(0.5g, 1.73mmol) and diisopropylethylamine (0.925ml, 5.32mmol) in acetonitrile (3ml) was treated with microwaves at 150 ℃ for 20 minutes. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue thus obtained is passed through flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to give final compound 5-054(0.37g, 79%).

B48.Final Compounds 1-307

Final Compounds 1-307

To a solution of intermediate compound 36(0.55mg, 1.76mmol) in DCM (20ml) was added TFA (10 ml). The resulting solution was allowed to stand at room temperatureStirred for 2 hours. The solvent was then evaporated under vacuum and the residue was dissolved in DCM as NaHCO₃And a saturated solution wash of NaCl. The combined organic layers were washed with Na₂SO₄Drying and concentration under vacuum gave final compounds 1-307(0.310g, 74%) which were used in the next reaction step without further purification.

B49.Final Compounds 1-308

Final Compounds 1-308

To a suspension (0 ℃) of copper (II) bromide (0.2g, 0.89mmol) and tert-butyl nitrite (0.178ml, 1.48mmol) in acetonitrile (29ml) was added dropwise final compound 1-307(0.31g, 0.99mmol) at 0 ℃ over 5 minutes. The mixture was stirred at 0 ℃ for 1 hour, then warmed to room temperature and gradually heated at 65 ℃ for 1 hour. The resulting reaction mixture was then filtered through a layer of celite, washed with acetonitrile and the filtrate evaporated under vacuum to give the final compounds 1-308(0.464g), which were used in the next reaction step without further purification.

B50.Final Compounds 1-190

Final Compounds 1-190

Intermediate compound 43(0.30g, 1.11mmol) and intermediate compound 3(0.43g, 1.33mmol) were added to 1, 4-dioxane (3ml) and saturated Na₂CO₃The solution (3ml) was mixed. The resulting solution was degassed with a nitrogen stream, and Pd (PPh) was added thereto₃)₄(0.12g, 0.1 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and washed with AcOEt. The filtrate was washed with brine.The combined organic layers were passed over MgSO₄Dried and concentrated under vacuum. The residue thus obtained was purified by preparative HPLC to give final compounds 1-190(0.04g, 9%).

B51.Final Compound 1-064

Final Compound 1-064

Intermediate compound 3(0.48g, 1.89mmo) and intermediate compound 45(0.59g, 1.89mmol) were added to 1, 4-dioxane (4ml) and saturated NaHCO₃The solution (4ml) was mixed. The resulting solution was degassed with a nitrogen stream, and Pd (PPh) was added thereto₃)₄(0.22g, 0.19 mmol). The reaction was then microwaved in a sealed tube at 150 ℃ for 10 minutes. The resulting reaction mixture was then filtered through a layer of celite and washed with AcOEt. The filtrate was washed with brine. The combined organic layers were passed over MgSO₄Dried and concentrated under vacuum. The residue thus obtained was purified by flash chromatography (DCM/MeOH mixture) to give final compound 1-064(0.16g, 25%).

The final compounds in the following table have been synthesized according to the preceding examples, which are shown in the column labeled "examples no. The compounds marked with an asterisk are exemplified in the examples.

Table 1A:a compound wherein L is a covalent bond.

Table 1B:wherein L is a saturated or unsaturated alkaneA compound of a radical chain.

Table 1C:compounds wherein L comprises an O atom.

Table 1D:compounds wherein L comprises an N atom.

TABLE 2: a compound prepared according to the examples wherein a is piperazinyl.

TABLE 3: a compound prepared according to the example wherein a is 4-piperidinyl.

TABLE 4: a compound prepared according to the example wherein a is 1-piperidinyl.

TABLE 5: other compounds prepared according to the examples where a is an N-containing heterocycle.

a- -A- -b: a is R⁴One side of the portion; b is one side of the L moiety

TABLE 6: according to the formula wherein R²The compound prepared in the examples is not hydrogen.

C. Physical and chemical data

LCMS-method:

LCMS-general procedure A

The HPLC gradient was provided by Alliance2795XE and included a quaternary pump with degasser, autosampler, column oven, photodiode array detector (PDA2996) and column as described in detail in the methods below. The effluent of the column was split into MS detectors. The MS detector was equipped with an electrospray ionization source. Nitrogen was used as the atomizing gas. A mass spectrum of 50 to 600 was acquired in 0.5 seconds. The capillary pinhole voltage (needle voltage) was 3.5kV, and the source temperature was maintained at 140 ℃. And acquiring data by using a Waters-Micromass MassLynx-Openlynx data system.

LCMS-general procedure B

HPLC gradients were provided by Agilent Technologies HP1100, including pumps with degasser (quaternary or binary), autosampler, column oven, Diode Array Detector (DAD) and columns as described in detail in the methods below. The effluent of the column was split into MS detectors. The MS detector was equipped with an electrospray ionization source. Nitrogen was used as the atomizing gas. The source temperature was maintained at 140 ℃. And acquiring data by using MassLynx-Openlynx software.

ICMS-general method C

LC gradients were supplied by Acquity UPLC (Waters) system, including binary pump, sample organizer (sample organizer), column heater (set at 55 deg.C.), and Diode Array Detector (DAD). The effluent of the column was split into MS detectors. The MS detector was equipped with an electrospray ionization source. Mass spectra from 100 to 1000 were acquired by scanning in 0.18 seconds using a retention time (dwell time) of 0.02 seconds. The capillary pinhole voltage was 3.5kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the atomizing gas. And acquiring data by using a Waters-MicromassMassLynx-Openlynx data system.

Method 1

In addition to general method A, reverse phase HPLC was performed using a Zorbax-C18 column (cartridge) (3.5 μm, 4.6X 50mm) from Agilent Technologies at a flow rate of 1 ml/min. The column oven was set at 25 ℃. Two mobile phases (mobile phase a: water + 0.5% formic acid; mobile phase B: acetonitrile + 0.5% formic acid) were used. First, 95% a and 5% B were performed for 0.1 min. The gradient was then adjusted to 100% B at 5 minutes, held to 6.0 minutes, and equilibrated to the initial condition at 6.5 to 7.0 minutes. A typical injection volume of 5-20. mu.L was used. Data for positive and negative ionization modes were acquired using an ES MS detector. For positive ionization mode, the cone hole voltage is 30V; for the negative ionization mode, the cone voltage is 63V.

Method 2

In addition to general method A, reverse phase HPLC was performed using a Zorbax-C18 column (1.8 μm, 4.6X 30mm) from Agilent Technologies at a flow rate of 1.5 ml/min. The column oven was set at 30 ℃. Two mobile phases (mobile phase a: water + 0.05% formic acid; mobile phase B: acetonitrile + 0.05% formic acid) were used. The gradient conditions used were: from 90% a and 10% B to 100% B at 3.5, held to 3.7 minutes, equilibrated to initial conditions at 3.8 to 4.5 minutes. A typical injection volume of 5-20. mu.L was used. Data for positive and negative ionization modes were acquired using an ES MS detector. For positive ionization mode, the cone hole voltage is 30V; for the negative ionization mode, the cone voltage is 63V.

Method 3

In addition to general method B, reversed phase HPLC was performed using an ACE-C18 column (3.0 μm, 4.6X 30mm) from Advanced chromatography technologies at 40 ℃ and a flow rate of 1.5 ml/min. The gradient conditions used were: equilibrate to initial conditions at 7.5 to 9.0 minutes from 80% A (0.5g/l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C, to 100% B at 7 minutes in 6.5 minutes. The injection volume was 5. mu.l. High resolution mass spectra (time of flight, TOF) from 100 to 750 were acquired by scanning in positive ionization mode only in 0.5 seconds with a retention time of 0.1 second. For the positive ionization mode, the capillary pinhole voltage was 2.5kV and the cone voltage was 20V. Leucine-enkephalin is the standard substance for lock mass calibration (lock mass calibration).

Method 4

The same procedure as in 3 was followed except for general procedure B, except that a sample volume of 10. mu.L was used.

Method 5

In addition to general method B, reversed phase HPLC was performed using an ACE-C18 column (3.0 μm, 4.6X 30mm) from Advanced chromatography technologies at 40 ℃ and a flow rate of 1.5 ml/min. The gradient conditions used were: equilibration to initial conditions at 7.5 to 9.0 minutes was from 80% A (0.5g/l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, 100% B at 7 minutes. The injection volume was 5. mu.l. Low resolution mass spectra from 100 to 1000 were acquired by scanning in 1.0 second with a retention time of 0.3 second (ZQ detector, quadrupole). The capillary pinhole voltage was 3 kV. The cone voltage is 20V and 50V for the positive ionization mode and 20V for the negative ionization mode.

Method 6

In addition to general procedure C, reverse phase UPLC was performed using a bridged ethylsiloxane/silica (BEH) C18 column (1.7 μm, 2.1X 50mm) at a flow rate of 0.8 ml/min. Two mobile phases were used (mobile phase A: 0.1% formic acid in H)₂O/methanol 95/5; mobile phase B: methanol) under gradient conditions: from 95% a to 5% a, 95% B over 1.3 minutes and for 0.2 minutes. A sample volume of 0.5. mu.l was used. The cone voltage was 10V and 20V for positive and negative ionization modes, respectively.

Method 7

In addition to general method B, reversed phase HPLC was carried out using an Agilent XDB-C18 column (1.8 μm, 2.1X 30mm) at 60 ℃ and a flow rate of 1 ml/min. The gradient conditions used were: equilibrate to initial conditions at 7.5 to 9.0 minutes from 90% A (0.5g/l ammonium acetate solution), 5% B (acetonitrile), 5% C (methanol) to 50% B and 50% C, to 100% B at 7 minutes in 6.5 minutes. The injection volume was 2. mu.l. With a retention time of 0.1 second, high resolution mass spectra (time of flight, TOF) from 100 to 750 were acquired by scanning only with positive ionization in 0.5 seconds. The pinhole voltage of the capillary tube is 2.5kV, and the pinhole voltage of the taper hole is 20V. Leucine-enkephalin is the standard substance for lock-in mass correction.

Method 8

In addition to general method B, reversed phase HPLC was carried out using an Agilent XDB-C18 column (1.8 μm, 4.6X 30mm) at 60 ℃ and a flow rate of 1.5 ml/min. The gradient conditions used were: from 80% A (0.5g/l ammonium acetate solution), 20% B (acetonitrile/methanol mixture, 1/1), to 100% B over 6.5 minutes, held for 7 minutes, equilibrated to the initial conditions at 7.5 to 9.0 minutes. The injection volume was 5. mu.l. Low resolution mass spectra from 100 to 1000 were acquired by scanning in 1.0 second with a retention time of 0.3 second (ZQ detector, quadrupole). The capillary pinhole voltage was 3 kV. The cone voltage is 20V and 50V for the positive ionization mode and 20V for the negative ionization mode.

Method 9

In addition to general method B, reversed phase HPLC was performed using an ACE-C18 column (3.0 μm, 4.6X 30mm) from Advanced chromatography technologies at 40 ℃ and a flow rate of 1.5 ml/min. The gradient conditions used were: equilibrate to initial conditions at 7.5 to 9.0 minutes from 80% A (0.5g/l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C, to 100% B at 7 minutes in 6.5 minutes. The injection volume was 5. mu.l. High resolution mass spectra (time of flight, TOF) from 100 to 750 were acquired by scanning within 0.5 seconds with a retention time of 0.3 seconds. The capillary pinhole voltage was 2.5kV and 2.9kV for the positive and negative ionization modes, respectively. The cone voltage was 20V for both positive and negative ionization modes. Leucine-enkephalin is the standard substance for lock-in mass correction.

Melting point determinations were performed in open capillaries or on Buchi B-540 or Mettler FP 62.

TABLE 7: physicochemical data of the compounds. For the salt form, [ MH +for the free base is reported]。

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS 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	Pale yellow solid
1-008	148	299	4.59	Method 1	White solid
						1-009	149	293	4.43	Method 3	Yellow solid
1-010	Decomposition of	336	5.00	Method 5	Yellow solid
						1-011	60	323	4.43	Method 3	Yellow solid
1-012	Decomposition of	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 body
1-016		331	2.56	Method 2	Pale yellow solid
						1-017		331	2.60	Method 2	Light brownColored solid

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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	Pale 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	Pale 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	Pale 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 body
						1-046	185	362	3.96	Method 1	White solid
1-047		317	4.09	Method 3	Pale yellow solid

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						1-048	188	347	4.20	Method 4	White solid
1-049	Decomposition of	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	Decomposition of	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	Light 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	Decomposition of	414	4.67	Method 7	Near white solid
						1-069		414	4.40	Method 7	Near white solid
1-070		380	4.10	Method 7	Near 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	Near 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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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	Decomposition of	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	Near white solid
1-094	131	343	3.03	Method 2	Pale 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	Pale yellow solid
						1-103	91	311	4.22	Method 1	White solid
1-104		311	4.52	Method 3	Cream colored solid

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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	Pale yellow solid
1-108		313	3.51	Method 3	Cream colored 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	Pale 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	Decomposition of	339	3.68	Method 3	White solid
						1-119	Decomposition of	333	4.39	Method 5	Cream colored 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	Decomposition of	353	4.08	Method 5	Cream colored 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 colored 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

Chemical combinationArticle number	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						1-133		337	4.72	Method 7	White solid
1-134	294	371	5.40	Method 3	Cream colored solid
						1-135		351	5.33	Method 4	White solid
1-136		397	4.64	Method 5	Cream colored solid
						1-137		411	4.78	Method 3	White solid
1-138		441	4.70	Method 3	Cream colored solid
						1-139		396	3.95	Method 3	Light 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	Near white solid
1-156	139	360	4.09	Method 3	Near white solid
						1-157	162	374	4.36	Method 5	White solid
1-158	142	374	4.23	Method 5	Cream colored solid
						1-159	171	374	4.25	Method 5	White solid
1-160		374	4.18	Method 3	Cream colored solid

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						1-161		378	4.17	Method 3	White solid
1-162	156	392	4.21	Method 3	Light 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 colored solid
						1-167		404	4.05	Method 3	White solid
1-168	Decomposition of	364	3.27	Method 5	Lyophilized
						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	Decomposition of	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	Light brown solid
						1-187		322	4.52	Method 3	Yellow colour

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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	Decomposition of	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 colored 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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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	Decomposition of	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	Decomposition of	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	Decomposition of	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	Near white solid

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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 colored 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	Near 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	Colorless 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	Decomposition of	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 colored 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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						1-272		401	4.78	Method 3	White solid
1-273		347	4.15	Method 7	White solid
						1-274	Decomposition of	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 colour
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	Light 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	Near white solid
1-297		350	4.78	Method 7	Pale yellow solid
						1-298	Decomposition of	282	3.97	Method 3	Cream colored solid
1-299		296	4.00	Method 3	Light brown oil

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						1-300	Decomposition of	367	3.91	Method 3	White solid
1-301	Decomposition of	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	Near 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	Decomposition of	401	4.66	Method 3	Beige solid
2-016		409	4.33	Method 3	White solid
						2-017		379	4.55	Method 3	Light brown solid
2-018		391	4.75	Method 3	Light yellow oil
						2-019		413	4.49	Method 3	Yellow glue
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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						2-023		366	3.32	Method 3	Yellow glue
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	Near white solid
2-028		353	3.56	Method 3	Light cream colored solid
						2-029	155	421	4.71	Method 3	Light 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 glue
2-034	Decomposition of	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	Near 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	Decomposition of	365	3.38	Method 3	Light brown solid
2-042	Decomposition of	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	Decomposition of	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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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	Near 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	Light brown solid
3-009	117	462	5.20	Method 3	Near white solid
						3-010	187				White solid
3-011	Decomposition of	351	2.55	Method 3	White solid
						3-012		432	4.60	Method 3	Cream colored 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 colored solid
4-005		353	3.87	Method 3	Cream colored 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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						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	Decomposition of	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 colloidal solid
						4-021	Decomposition of	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 colourSolid body
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	Light brown solid
4-035		389	4.93	Method 3	Pale yellow solid
						4-036		405	5.29	Method 3	Brown colloidal 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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						4-040	113	412	4.91	Method 3	Light cream colored solid
4-041		418	4.82	Method 3	Light brown solid
						4-042	Decomposition of	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	Near white solid
4-049	138	497	4.89	Method 3	White solid
						4-050	Decomposition of	491	4.20	Method 3	White solid
4-051	Decomposition of	509	4.88	Method 3	Light brown solid
						4-052		499	4.39	Method 7	Light brown solid
4-053		485	3.85	Method 7	Yellow solid
						4-054					Cream colored solid
4-055	155	435	3.85	Method 3	Cream colored solid
						4-056		431	4.16	Method 3	Cream colored solid
4-057	242	449	4.54	Method 3	Cream colored solid
						4-058		499	5.05	Method 3	White solid
4-059	157	475	5.27	Method 3	White solid
						4-060	96				Near white solid
4-061	175	447	4.20	Method 3	Cream colored solid
						4-062	139	454	5.06	Method 3	White solid
4-063		471	3.56	Method 7	Near 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	Decomposition of	384	3.31	Method 3	Near white solid

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						5-002	164.7	398	3.24	Method 3	White solid
5-003	Decomposition of	322	4.33	Method 3	White solid
						5-004		377	4.2	Method 3	Light cream color glue
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	Colorless 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	Light 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	Decomposition of	306	3.93	Method 3	Light brown solid
5-017	Decomposition of	306	3.84	Method 3	Light 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 colored solid
5-021	Decomposition of	307	3.31	Method 3	Pulp and its production process
						5-022		307	2.93	Method 3	Beige solid
5-023	Decomposition of	384	3.51	Method 3	Cream colored solid
						5-024	284	398	3.53	Method 3	Cream colored solid
5-025		398	3.72	Method 3	Cream colored solid
						5-026	Decomposition of	338	4.43	Method 5	Bright yellow solid
5-027	Decomposition of	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

Compound numbering	Melting Point (. degree.C.)	[MH+]	RT (minutes)	LCMS method	Physical form
						5-030		324	4.4	Method 3	Cream colored 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	Light cream colored 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 colored solid
						5-038	141				Cream colored solid
5-039	276	361	4.52	Method 3	White solid
						5-040	111	393	4.87	Method 3	Cream colored solid
5-041	130	362	4.85	Method 3	White solid
						5-042		412	5.73	Method 3	Light yellow
5-043	Decomposition of	365	4.57	Method 3	Pale yellow solid
						5-044		395	4.51	Method 3	Brown colloidal 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	Colorless 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

Decomposition-decomposition of the product during the measurement

D. Pharmacological examples

The compounds provided by the present invention are positive allosteric modulators of mGluR 2. These compounds appear to enhance glutamate responses by binding to allosteric sites that differ from glutamate binding sites. The response of mGluR2 to glutamate concentrations is enhanced when compounds of formula (I) are present. The compounds of formula (I) are expected to exert their effect at mGluR2 essentially by their ability to potentiate receptor function. The following are used to identify the compounds, more specifically the compounds according to formula (I), as shown in Table 4³⁵S]The GTP γ S binding assay measures the properties of positive allosteric modulators on mGluR 2.

[ ³⁵ S]GTP γ S binding assay

[³⁵S]GTP γ S binding is a membrane-based functional assay for the determination of the introduced non-hydrolyzable form of GTP, i.e., 2³⁵S]GTP γ S (guanosine 5' -triphosphate, with gamma-ray emission)³⁵S-tag) to study the function of G protein-coupled receptors (GPCRs). G protein alpha subunit by guanosine triphosphate(GTP) catalyzes the conversion of guanosine 5' -diphosphate (GDP) and when the GPCR is activated by an agonist³⁵S]GTP γ S is introduced and cannot be cleaved to continue the conversion cycle (Harper (1998) Current Protocols in Pharmacology2.6.1-10, John Wiley&Sons, Inc.). Radioactivity [ alpha ]³⁵S]The amount of GTP γ S bound is a direct measure of G protein activity and therefore the agonist activity can be determined. The mGluR2 receptor was shown to be preferentially coupled to G.alpha.i protein, preferably for use in this method, and therefore it was widely used to study receptor activation of mGluR2 receptor in recombinant cell lines and 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). Herein, we describe [ 2]³⁵S]Use of a GTP γ S binding assay to detect Positive Allosteric Modulation (PAM) properties of a compound of the invention³⁵S]The GTP γ S binding assay utilizes and is modulated by a cell membrane from transfection with the human mGluR2 receptor, and the assay is from Schaffhauser et al ((2003) Molecular Pharmacology 4: 798-810).

Preparation of the film

CHO cells were cultured to pre-confluency (pre-confluency), stimulated with 5mM butyrate for 24 hours before washing in PBS, and then harvested by disruption (scrap) in homogenization buffer (50mM Tris-HCl buffer, pH7.4, 4 ℃). The cell lysate was briefly homogenized (15 seconds) using an ultra-turrax homogenizer. The homogenate was centrifuged at 23500 Xg for 10 minutes and the supernatant discarded. The pellet was resuspended in 5mM Tris-HCl (pH7.4) and centrifuged again (30000 Xg, 20 min, 4 ℃). The final pellet was resuspended in 50mM HEPES (pH7.4) and stored in appropriate aliquots at-80 ℃ prior to use. Protein concentration was determined by the Bradford method (Bio-Rad, USA) using bovine serum albumin as a standard.

[³⁵S]GTP γ S binding assay

Frozen membranes (pre-incubation in 96-well microplates (15. mu.g/test well, 30 min, 30 ℃ C.) followed by thawing and brief homogenization) were used in test bufferLiquid (50mM HEPES pH7.4, 100mM NaCl, 3mM MgCl)₂50 μ M GDP, 10 μ g/ml saponin) in a membrane containing human mGluR2, wherein the buffer contains increasing concentrations of positive allosteric modulator (from 0.3nM to 50 μ M) or minimal predetermined concentrations of glutamic acid (PAM method) or no glutamic acid. For the PAM process, the membrane is brought into contact with EC₂₅Glutamate at a concentration (i.e. that giving 25% of the maximal response) was previously incubated and was in agreement with published data (Pin et al (1999) Eur. J. Pharmacol.375: 277-294). In addition³⁵S]After GTP γ S (0.1nM, f.c.) to reach a total reaction volume of 200 μ l, the plate is briefly shaken and further incubated to allow introduction at activation (30 min, 30 ℃)³⁵S]GTP γ S. Rapid vacuum filtration was performed by using a 96-well plate cell collector (Filtermate, Perkin-Elmer, USA) on glass fiber filter plates (Unifilter96 well GF/B filter plates, Perkin-Elmer, Downers Grove, USA) microplates, followed by washing with 300. mu.l of frozen wash buffer (Na₂PO₄.2H₂O10mM，NaH₂PO₄.H₂O10mM, pH7.4) was washed three times to stop the reaction. The filters were then air dried and 40. mu.l of liquid scintillation cocktail (Microscint-O) was added to each well and membrane bound was determined on a 96-well scintillation plate reader (Top-Count, Perkin-Elmer, USA)³⁵S]GTP γ S. Measurement of nonspecific value in the presence of 10. mu.M of cold GTP³⁵S]GTP γ S binding. Each curve was created at least once using duplicate samples of each data point at 11 concentrations.

Data analysis

In the presence of added EC₂₅mGluR2 agonist glutamate to determine Positive Allosteric Modulation (PAM), concentration-response curves of representative compounds of the invention were generated using Prism GraphPad (Graph Pad Inc, San Diego, USA) software. The curves were fit to a four parameter logistic equation (Y ═ bottom + (top-bottom)/(1 +10^ ((LogEC))₅₀-X) Hill slope) so that EC can be determined₅₀The value is obtained.

Table 8.Pharmacological data for the Compounds of the invention

At a predetermined EC₂₅All compounds were tested for positive allosteric modulation (GTP γ S-PAM) in the presence of the mGluR2 agonist glutamate at concentration. The values shown are the average of pairs of values from 11 concentration response curves from at least one experiment. All compounds showed pEC greater than 5.0₅₀Values, from 5.1 (weak activity) to 7.6 (very high activity). For a single experiment, pEC₅₀The measurement error of the values is estimated to be about 0.3 log units.

Compound numbering	GTPgS-hR2PAMpEC50
		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

The "active ingredient" (a.i.) used in all these examples refers to the final compound of formula (i), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof, a quaternary ammonium salt thereof and a prodrug thereof.

Typical examples of formulations of the present invention are as follows:

1. tablet formulation

5-50 mg of active ingredient

Dicalcium phosphate 20mg

Lactose 30mg

Talc 10mg

Magnesium stearate 5mg

Adding potato starch to 200mg

In this example, the active ingredient may be replaced with the same amount of any compound of the present invention, in particular the same amount of any of the exemplified compounds.

2. Suspension formulation

Aqueous suspensions for oral administration are prepared containing 1-5 mg of an active compound, 50mg of sodium carboxymethylcellulose, 1mg of sodium benzoate, 500mg of sorbitol and water (up to 1ml) per 1 ml.

3. Injection preparation

Parenteral compositions are prepared by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume of propylene glycol and water.

4. Ointment

5-1000 mg of active ingredient

Stearyl alcohol 3g

Lanolin 5g

White Vaseline 15g

Adding water to 100g

In this example, the active ingredient may be replaced with the same amount of any compound of the present invention, in particular 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 to those skilled in the art that the invention thus described may be varied in a number of ways.

Claims (34)

1. A compound of 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 content of the first and second substances,

V¹selected from covalent bonds and divalent saturated or unsaturated, straight chain or branched chain alkyl groups with 1-6 carbon atoms;

M¹selected from hydrogen, ring C_3-7Alkyl, aryl, alkylcarbonyl, alkoxy, aryloxy, arylalkoxy, arylcarbonyl, hexahydrothiopyranyl, furanyl and Het¹；

L is selected from the group consisting of a covalent bond, -O-, -OCH₂-、-OCH₂CH₂-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-、-S-、-NR⁷-、-NR⁷CH₂-、-NR⁷Ring C_3-7、-NR⁷CH₂CH₂-、-OCH₂CH₂N(R⁷)CH₂-、-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-C.ident.C-, -C ═ O-, and-C (R)⁸)＝C(R⁹) -, wherein each R⁷Independently of one another, from hydrogen and C_1-3Alkyl radical, wherein R⁸And R⁹Independently of one another, from hydrogen, halogen and C_1-3An alkyl group;

R²and R³Each independently of the others, hydrogen, halogen or alkyl;

a is selected from piperazinyl and piperidinyl, wherein each group is optionally substituted with n groups R⁴Wherein n is an integer equal to 0, 1, 2 or 3;

R⁴selected from the group consisting of halogen, cyano, hydroxy, oxo, formyl, acetyl, carboxy, nitro, thio, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylalkoxy, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, polyhalo C_1-3Alkylthio, alkylsulfonyl, Het³、Het³-alkyl, Het³-oxy, Het³-oxyalkyl, Het³-alkoxy, Het³-oxoxy radical, Het³-carbonyl, Het³-carbonylalkyl, Het³Thio, Het³-thioalkyl, Het³-sulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkenyl, arylcarbonylalkyl, arylsulfaneRadical, arylsulfonyl, -NR^aR^balkyl-NR^aR^bO-alkyl-NR^aR^b、-C(＝O)-NR^aR^b-C (═ O) -alkyl-NR^aR^bAnd O-alkyl-C (═ O) -NR^aR^bWherein R is^aAnd R^bSelected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkoxyalkyl, Het³、Het³-alkyl, alkylsulfonyl, alkyl-NR^cR^dAnd C (═ O) alkyl-NR^cR^dWherein R is^cAnd R^dSelected from hydrogen, alkyl and alkylcarbonyl;

or two radicals R⁴Can combine to form a divalent group-X¹-C_1-6-X²-, in which C_1-6Is a saturated or unsaturated, straight-chain or branched-chain hydrocarbon group of 1 to 6 carbon atoms, and X¹And X²Each independently is O or NH; wherein the divalent group is optionally substituted with one or more groups selected from: halogen, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl and acetyl;

Het¹selected from tetrahydropyranyl and pyridinyl, wherein each group is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl and C_1-3An alkoxy group;

Het³selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolyl, pyrrolidinyl, piperazinyl, triazolyl, tetrazolyl, indolyl, thienyl, furyl, tetrahydropyranyl, tetrahydrothiopyran-1, 1-dioxide, thiazolyl, thiadiazolyl, isothiazolyl, thiazolyl, and mixtures thereof,Azolyl, morpholinyl, oxazolyl, morpholinyl, oxazolyl, oxazol,Oxadiazolyl, isoxazolylAzolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzoOxazolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzomorpholinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, thionaphthyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzo [1, 3 ] yl]IIAlkyl and quinazolinyl; wherein each group is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C_1-6Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono (alkyl) amino and di (alkyl) amino, and C_1-3An alkoxy group;

aryl is naphthyl, phenyl or biphenyl, wherein each group is optionally substituted with 1, 2 or 3 substituents independently from each other selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, hydroxy, amino, oxo, carboxy, nitro, thio, formyl, acetyl, ethoxycarbonyl and C_1-3An alkoxy group;

the alkyl is a saturated straight chain or branched chain alkyl with 1-6 carbon atoms, or a saturated cyclic alkyl with 3-7 carbon atoms, or a saturated alkyl with 4-12 carbon atoms, and comprises at least one saturated straight chain or branched chain alkyl with 1-6 carbon atoms and at least one saturated cyclic alkyl with 3-7 carbon atoms; wherein each carbon atom may be optionally substituted by one or more groups selected from: halogen, polyhalo C_1-3Alkyl, cyano, hydroxy,Amino, oxo, carboxy, nitro, thio, formyl, acetyl, carbamoyl, phenyl and a divalent radical-OCH₂CH₂O-; and

alkenyl is alkyl which additionally contains one or more double bonds.

2. A compound according to claim 1, characterised in that V is¹Selected from covalent bonds, -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-。

3. A compound according to any one of claims 1 to 2, characterised in that M is¹Selected from hydrogen, ring C_3-7Alkyl, phenyl, biphenyl, phenoxy, benzyloxy, furyl, and pyridyl; wherein any one of said benzene-based groups is optionally substituted with 1 to 3 groups selected from: halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, and C_1-3An alkoxy group; and the ring C_3-7Alkyl optionally substituted by one or more halogens or polyhalogens C_1-3Alkyl groups are substituted.

4. A compound according to any one of claims 1 to 2, characterised in that V is¹-M¹Is selected from-CH₂-CH₂-CH₂-CH₃、-CH₂-CH(CH₃)-CH₃、-CH(CH₃)-CH₂-CH₂-CH₃、-CH₂-CH(CH₃)CH₂-CH₃、-CH₂-CH₂-CH(CH₃)-CH₃(ii) a Or V¹Selected from covalent bondingBond, -CH₂-、-CH₂-CH₂-、-CH₂-CH₂-CH₂-and-CH₂-CH ═ CH —; and M¹Selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, phenoxy, benzyloxy, furyl, and pyridyl; wherein each benzene-based group M¹Optionally substituted with 1 to 3 groups selected from: halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy and C_1-3An alkoxy group.

5. A compound according to any one of claims 1 to 2, wherein R²And R³Each independently hydrogen or methyl.

6. A compound according to any one of claims 1 to 2, characterized in that L is selected from the group consisting of a covalent bond, -O-, -OCH₂-、-OCH₂CH₂-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-、-NR⁷-、-NR⁷CH₂-、-NR⁷Ring C_3-7、-OCH₂CH₂N(R⁷)CH₂-、-CH₂CH₂-, -C.ident.C-, -C ═ O-and-CH ═ CH-, in which each R is identical to the other⁷Independently of one another, from hydrogen and C_1-3An alkyl group.

7. A compound according to any one of claims 1 to 2, characterized in that R⁴Selected from the group consisting of halogen, cyano, hydroxy, acetyl, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylalkoxy, polyhaloC_1-3Alkyl, polyhalo C_1-3Alkoxy, polyhalo C_1-3Alkylthio, alkylsulfonyl, Het³、Het³Alkyl, Het³-oxy, Het³-oxyalkyl, Het³-alkoxy, Het³-oxoxy radical, Het³-carbonyl, Het³-sulfanyl radicalAryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkenyl, arylcarbonylalkyl, arylsulfonyl, -NR^aR^balkyl-NR^aR^bO-alkyl-NR^aR^b、-C(＝O)-NR^aR^b-C (═ O) -alkyl-NR^aR^bAnd O-alkyl-C (═ O) -NR^aR^bWherein R is^aAnd R^bSelected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkoxyalkyl, Het³、Het³-alkyl, alkylsulfonyl, alkyl-NR^cR^dAnd C (═ O) alkyl-NR^cR^dWherein R is^cAnd R^dSelected from hydrogen, alkyl and alkylcarbonyl;

or two radicals R⁴Can combine to form a divalent group-X¹-C_1-6-X²-, in which C_1-6Is a saturated or unsaturated, straight-chain or branched-chain hydrocarbon group of 1 to 6 carbon atoms, and X¹And X²Each independently is O.

8. A compound according to any one of claims 1 to 2, characterized in that two radicals R⁴Can combine to form a compound selected from-CH₂CH₂-O-、-O-CH₂-O-and-O-CH₂CH₂A divalent group of-O-.

9. Compound according to claim 1, characterised in that Het¹Selected from tetrahydropyranyl and pyridinyl, wherein each group Het¹Optionally substituted by 1, 2 or 3 polyhalogens C_1-3Alkyl substituents.

10. Compound according to any one of claims 1 to 2, characterised in that Het³Selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolyl, tetrahydropyranyl, tetrahydrothiopyran-1, 1-dioxide, thiazolyl, and mixtures thereof,Azolyl, morpholinyl, oxazolyl, morpholinyl, oxazolyl, oxazol,Oxadiazolyl, imidazolyl, benzoAzolyl, benzothienyl, benzofuranyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, indolyl, indolinyl, phthalazinyl and benzo [1, 3 ]]IIAn alkyl group; wherein each group is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, C_1-6Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, oxo, acetyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono (alkyl) amino and di (alkyl) amino, and C_1-3An alkoxy group.

11. A compound according to claim 1, characterized in that:

V¹selected from covalent bonds, -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-；

M¹Selected from hydrogen, ring C_3-7Alkyl, phenyl, biphenyl, phenoxy, benzyloxy, furyl, and pyridyl; wherein each M is based on phenyl¹Optionally substituted with 1 to 3 groups selected from: halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy andC_1-3an alkoxy group; and the ring C_3-7Alkyl optionally substituted by one or more halogens or polyhalogens C_1-3Alkyl substituted;

l is selected from the group consisting of a covalent bond, -O-, -OCH₂-、-OCH₂CH₂-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-、-NR⁷-、-NR⁷CH₂-、-NR⁷Ring C_3-7、-OCH₂CH₂N(R⁷)CH₂-、-CH₂CH₂-, -C.ident.C-, -C ═ O-and-CH ═ CH-, in which each R is identical to the other⁷Independently of one another, from hydrogen and C_1-3An alkyl group;

R²and R³Independently of one another, hydrogen, halogen or alkyl;

a is selected from piperazinyl and piperidinyl groups, wherein each of said groups is optionally substituted with n groups R⁴Wherein n is an integer equal to 0 or 1;

R⁴selected from the group consisting of halogen, cyano, hydroxy, acetyl, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylalkoxy, polyhaloC_1-3Alkyl, polyhalo C_1-3Alkoxy, polyhalo C_1-3Alkylthio, alkylsulfonyl, Het³、Het³-alkyl, Het³-oxy, Het³-oxyalkyl, Het³-alkoxy, Het³-oxoxy radical, Het³-carbonyl, Het³-sulfanyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkenyl, arylcarbonylalkyl, arylsulfonyl, -NR^aR^balkyl-NR^aR^bO-alkyl-NR^aR^b、-C(＝O)-NR^aR^b-C (═ O) -alkyl-NR^aR^bAnd O-alkyl-C (═ O) -NR^aR^bWherein R is^aAnd R^bSelected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkoxyalkyl, Het³、Het³-alkyl, alkylsulfonyl, alkyl-NR^cR^dAnd C (═ O) alkyl-NR^cR^dWherein R is^cAnd R^dSelected from hydrogen, alkyl and alkylcarbonyl; or two radicals R⁴Can combine to form a compound selected from-CH₂CH₂-O-、-O-CH₂-O-and-O-CH₂CH₂-a divalent radical of O-;

Het¹selected from tetrahydropyranyl and pyridinyl, wherein each group Het¹Optionally substituted by 1, 2 or 3 polyhalogens C_1-3Alkyl substituents;

Het³selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, piperazinyl, triazolyl, tetrahydropyranyl, tetrahydrothiopyran-1, 1-dioxide, thiazolyl, and mixtures thereof,Azolyl, morpholinyl, oxazolyl, morpholinyl, oxazolyl, oxazol,Oxadiazolyl, imidazolyl, benzoAzolyl, benzothienyl, benzofuranyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, indolyl, indolinyl, phthalazinyl and benzo [1, 3 ]]IIAn alkyl group; wherein each group is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C_1-6Alkyl, polyhalo C_1-3Alkyl, cyano, hydroxy, oxo, acetyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono (alkyl) amino and di (alkyl) amino, and C_1-3An alkoxy group;

aryl is phenyl or biphenyl, wherein each group is optionally substituted with 1, 2 or 3 substituents independently from each other selected from halogen, C_1-3Alkyl, polyhalo C_1-3Alkyl, polyhalo C_1-3Alkoxy, cyano, nitro,Ethoxycarbonyl and C_1-3An alkoxy group; and

the alkyl is a saturated straight chain or branched chain alkyl with 1-6 carbon atoms, or a saturated cyclic alkyl with 3-7 carbon atoms, or a saturated alkyl with 4-12 carbon atoms, and comprises at least one saturated straight chain or branched chain alkyl with 1-6 carbon atoms and at least one saturated cyclic alkyl with 3-7 carbon atoms; wherein each carbon atom may be optionally substituted by one or more groups selected from: cyano, hydroxy, carboxy, carbamoyl, phenyl and a divalent radical-OCH₂CH₂O-。

12. The compound according to claim 1, wherein the compound is selected from the group consisting of:

(Compound 2-006), and

-3-cyano-1-cyclopropylmethyl-4- (4-phenyl-piperidin-1-yl) -pyridin-2 (1H) -one

(Compound 4-047).

13. A compound according to claim 1 or 12, which exists as an optical isomer, wherein the compound is a racemic mixture or a single optical isomer.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament.

16. Use of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment or prevention of a condition in a mammal, including a human, wherein the treatment or prevention is affected by the neuromodulatory effect of mGluR2 positive allosteric modulators.

17. Use of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment or prevention, amelioration, control or reduction of risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including a human, wherein said treatment or prevention is affected by the neuromodulatory effect of positive allosteric modulators of mGluR 2.

18. Use according to any one of claims 16 and 17, wherein the condition or disease is a central nervous system condition selected from: anxiety disorders, psychiatric disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia.

19. Use according to claim 18, wherein the central nervous system disorder is an anxiety disorder selected from the group consisting of: phobias, Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD).

20. The use according to claim 19, wherein the phobias are selected from the group consisting of agoraphobia and social phobia.

21. Use according to claim 18, wherein the central nervous system disorder is a psychiatric disorder selected from: schizophrenia, delusional disorders, schizoaffective disorders, schizophreniform disorders, and substance-induced psychotic disorders.

22. Use according to claim 18, wherein the central nervous system disorder is a personality disorder selected from: obsessive-compulsive personality disorder and schizophreniform, schizotypal disorder.

23. Use according to claim 18, wherein the central nervous system disorder is a substance-related disorder selected from the group consisting of: alcohol abuse, alcohol dependence, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal.

24. Use according to claim 18, wherein the central nervous system disorder is an eating disorder selected from: anorexia nervosa and bulimia nervosa.

25. Use according to claim 18, wherein the central nervous system disorder is a mood disorder selected from: bipolar disorders type I and II, cyclothymia, depression, dysthymic disorder and substance-induced mood disorder.

26. Use according to claim 18, wherein the central nervous system disorder is migraine.

27. Use according to claim 18, wherein the central nervous system disorder is epilepsy or a convulsive disorder selected from: generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, partial status epilepticus.

28. Use according to claim 18, wherein the childhood disorder is attention deficit/hyperactivity disorder.

29. Use according to claim 18, wherein the central nervous system disorder is a cognitive disorder selected from: delirium, dementia and mild cognitive impairment.

30. Use according to claim 29, wherein the central nervous system disorder is a cognitive disorder selected from: substance-induced persisting delirium, dementia due to HIV disease, dementia due to huntington's disease, dementia due to parkinson's disease, dementia of the alzheimer's type and substance-induced persisting dementia.

31. Use according to claim 18, wherein the central nervous system disorder is selected from anxiety, schizophrenia, migraine, depression and epilepsy.

32. Use according to any one of claims 16 to 17, wherein the mGluR2 positive allosteric modulator has an EC₅₀Is 1. mu.M or less.

33. Use of a compound according to claims 1 to 13 in the manufacture of a tracer for imaging mGluR2 receptors.

34. Use of a compound according to any one of claims 1 to 13 in combination with an mGluR2 orthoagonist in the manufacture of a medicament for the treatment or prevention of a condition as cited in any one of claims 16 to 29 in a mammal, including a human, wherein said treatment or prevention is effected by the neuromodulatory effect of mGluR2 allosteric modulators.