TWI329635B - Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors - Google Patents

Description

1329635 (1) IX. INSTRUCTIONS OF THE INVENTION [Technical Field of the Invention] Field of the Invention The present invention relates to a novel metabolic glutamate receptor (mGluR) modulator, a method of synthesizing the same, and by administering such substances and/or Or prevent neurological diseases. [Prior Art] BACKGROUND OF THE INVENTION Neuronal stimulation is transmitted by the interaction of neurotransmitters released by neurons by the central nervous system (C N S ), which has a specific influence on the neuroreceptors of other neurons. L-glutamic acid is considered to be the major excitatory neurotransmitter in mammalian c N S and as a result plays an important role in many physiological processes. The glutamate-dependent stimulating receptors are divided into two main groups. The first group contains ligand-controlled ion channels and the second group contains metabolic glutamate receptors (mGluR). The metabolic glutamate receptor is a subfamily of G-protein coupled receptors (GPCRs). Evidence for the role of both ionic and metabolic glutamate receptors in peripheral roles outside of C N S, for example, in chronic pain states.

Currently, eight different members of these mGURs are known. Root structure parameters such as sequence homology, the second messenger system utilized by these receptors, and their different affinities for low molecular weight compounds, the eight receptors can be divided into three groups: · mGluRl and mGluR5 belong to the Group I (2) 1329635, which is coupled to phospholipase C and whose activity results in intracellular calcium ion activity. Both mGluR2 and mGluR3 belong to Group II and mGluR4, mGluR6, mGluR7 and mG1 uR8 belong to the 丨π group, which is coupled to adenylate cyclase and whose activity causes a decrease in the first messenger cAMP and likewise causes neurons Inhibition of activity.

Group I mGluR modulators have been shown to modulate the effects of the neurotransmitter glutamate released presynaptic via the postsynaptic mechanism. Moreover, because these modulators can be both positive and/or negative Group I mGluR modulators, such modulators can increase or inhibit the effects of these metabolic receptors. Because various pathophysiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate nerve conduction and it is known that Group I mGluR is shown to be expressed in a region of the CNS, modulators of these receptors are involved in CNS disease. There is a therapeutic benefit in the treatment. Thus, Group I mGluR modulators can be administered to provide acute and chronic pathological conditions such as neuroprotection such as: AIDS-related dementia, Alzheimer's disease, human giku syndrome (Creutzfeld-Jakob's) Syndrome), bovine spongiform encephalopathy (BSE) or other prion-related infections, diseases involving mitochondrial dysfunction, /3 -amyloidosis and/or Diseases of tauopathy such as Down's disease, hepatic encephalopathy, Huntington's disease, motor neuropathy such as amyotrophic lateral sclerosis (ALS), multiple (3) 1329635 primary sclerosis (MS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's disease Dementia, mild cognitive impairment, boxer

Dementia, vascular and frontal dementia, dysfunction, ocular trauma or disease (eg glaucoma, retinopathy, macular degeneration), head and spinal cord trauma / trauma, hypoglycemia, anoxia (eg perinatal) ), ischemia (eg due to cardiac arrest, stroke, bypass surgery or transplantation), sputum, glioma and other tumors, inner ear damage (eg tinnitus, sound or medication), L-dopa drug-induced and delayed Sexual dyskinesia (tardive dyskinesia) ° Other indications in this article include symptoms of the following conditions: addiction (nicotine, alcohol, opiates, cocaine, amphetamines, obesity, and others), amyotrophic lateral cord Amyotrophic lateral sclerosis (ALS), anxiety and panic disorder, attention deficit hyperactivity disorder (ADHD), restless leg syndrome (restless leg syndrome) and hyperactivity Children, autism, convulsions/epilepsy, dementia (eg Alzheimer's disease, Cossack's psychosis) (Korsakoff syndrome), vascular dementia, HIV infection) 'major depressive disorder or depression (including causes)

Borna virus infection) and bipolar manic depressive disorder, drug resistance such as opioids, movement disorders, dystοnia, dyskinesia (4) 1329635

(dyskinesia) (eg, L-dopa drug-induced tardive dyskinesia or Huntington's disease), X chromosome fragility (fragiie x_syndr〇me), Huntington dance (Huntington's chorea), irritable bowel syndrome (IBS), migraine 'multiple sclerosis, muscle spasm, pain (chronic and acute, such as inflammatory pain, neuropathic pain, allodynia, feeling) Hyperalgesia, ηociceptive Pain, Parkinson's disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), convulsions, tinnitus, and ritual Tourette's syndrome, urinary incontinence and vomiting, itching (eg pruritus), sleep disorders, urinary disorders, neuromuscular disorders of the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter ( Lower esophageal sphincter ) ( LES ), gastrointestinal tract

Functional gas trointestinal disorders, dyspepsia, nausea, respiratory infections, bulimia nervosa, laryngitis, asthma (eg reflux-related asthma), lung disease, eating disorders, obesity And obesity-related diseases. Another indication of Group I mGUR modulators includes those indications in which no particular conditions are present but wherein certain physiological parameters (e.g., cognitive enhancement) can be improved by administration of the compounds of the invention. 5) 1329635 Positive modulators are particularly useful for the treatment of positive and negative symptoms of schizophrenia and cognitive impairment and mild cognitive impairment of various forms of dementia. Among the Group I mGluR modulators, those of particular interest are those showing a regulatory effect on the ♦mGluR5 receptor and such conditions or diseases that may affect the function of the mGluR5 receptor. In addition to the use of mGluR5 modulators in the prevention and/or treatment of the above conditions or diseases, mGluR5 φ positive modulators or activators are particularly useful for the prevention and/or treatment of mGluR5 receptors. Situation or disease. mGluR5 modulators and in particular mGluR5 positive regulators or activators are particularly useful for the prevention and/or treatment of addiction, neuropathic pain, L-dopa drug-induced and tardive dyskinesia, ALS, X Fragile X-syndrome, Parkinson's disease, anxiety, epilepsy, positive and/or negative symptoms of schizophrenia, dynamism, or for cognitive enhancement and neuroprotection. SUMMARY OF THE INVENTION In the present invention, we have determined certain vinyl-substituted tetrahydroquinolinones in the class of compounds disclosed in International Patent Application No. PCT/GB2005/0007, which is incorporated herein by reference. Group I mGluR modulators and in particular mGluR5 modulators. Thus, these materials may be therapeutically beneficial in the treatment of conditions involving abnormal glutamate neurotransmission or in which modulation of Group I mGluR receptors produces therapeutic benefit. These materials are preferably administered in the form of a pharmaceutical composition -9 - (6) 1329635 where they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients. OBJECT OF THE INVENTION One object of the present invention is to provide a novel pharmaceutical compound which is a tetrahydroquinolinone Group I mGIuR modulator and a pharmaceutical composition. Another object of the present invention is to provide a novel method for treating, eliminating, alleviating, alleviating, or ameliorating a poor CNS disease involving abnormal glutamate transmission by using the compound of the present invention or a pharmaceutical composition containing the same. A further object of the invention is to provide a process for the preparation of tetrahydroquinolinone activity principles. Further objects will become apparent hereinafter, and additional objects will be apparent to those skilled in the art. DISCLOSURE OF THE INVENTION We therefore believe that the inclusion of our invention may specifically include the following words: a compound of formula I, η

Wherein R1 represents aryl or heteroaryl; -10-(7)(7)1329635 R2 and R3, which may be the same or different, represent hydrogen or hydrazine 6; R4 and R5' may be the same or different, Represents hydrogen or Ci66^; 'aryl" denotes an unsubstituted phenyl ring or 5 substituents = phenyl ring, # may be phase (d) different, and its substituent (IV) is free to pass one or more fluorine Any of the q 6 alkyl groups substituted with a chlorine or bromine atom, substituted by one or more fluorine, chlorine or bromine atoms; (alkoxy, ring q, base, F, C1, Br, !, CN, Nitro, amphoteric amine 2, N-cycloCm alkyl_N_Ci 6 alkylamino, nitrogen, pyrrolidinyl, hexahydropyridinyl, morpholinyl, 4-Ci d alkyl-hexahydropyridyl Group of morphine, tetrazolyl, oxazolyl, furyl, pyrrole s, thiophenyl, isoxazolylthiazolyl imidazolyl, oxadiazolyl' pyridyl, pyrimidinyl and phenyl; Aryl represents a (hetero)aromatic 5-, 6 or 7-membered ring having from 丨 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring is unsubstituted or warp. , 2 or 3 substituents substituted, which can be phase Or different 'substituents are selected from C alkoxy' ring substituted by any C,-6 alkyl group substituted by one or more fluorine, chlorine or desert atoms, optionally substituted by one or more fluorine, chlorine or bromine atoms C312 alkyl, hydroxy, F, cl, Br, i, CN, nitro, di-CV6 compound amine 'N-cyclo C3_12 alkyl-Ν·〇ΐ 6 alkylamino group, nitrogen sulfonyl group, pyrrolidinyl group, Hexahydropyridyl, morpholinyl, 4_Ci 6 alkyl hexahydropyrrole, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, picol, thiazolyl, imidazolyl a group consisting of oxadiazolyl, pyridyl, chewing, and phenyl; -11 - (8) 1329635 and the compound of formula I is not representable: 2-phenylethynyl-7,8-dihydro-6H-quin Porphyrin-5-one 2-pyridyl-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-m-tolylvinyl- 7,8-dihydro-6H-quinolin- 5-keto 2-(3-hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-methoxy-phenylethynyl)-7,8- Dihydro-6H-quinolin-5-one 2-(3-fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one

2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-bromo-phenylethynyl)-7,8-dihydro-6H- Quinoline-5-one 3-(5-keto-5,6,7,8-tetrahydro-salin-2-ylethynyl)-benzonitrile 2-thiazol-5-ylethynyl-7, 8-dihydro-6H-quinolin-5-one 2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-dimethyl-2-pyridine 3--3-ethynyl-7,8-dihydro-6H-quinoline-5-7,7-dimethyl-2-m-tolylvinyl-7,8-dihydro-6H-quinoline-5 -keto φ 2-( 3-hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-salrosolin-5-one 2-(3-methoxy-benzene Ethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-fluoro-phenylethynyl)-7,7-dimethyl-7 ,8-Dihydro-6H-quinolin-5-one 2-(3-chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quino-12-(9)1329635 oxolin-5-one 3-(7,7- Dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 7.7-dimethyl-2-thiazol-5-ylethynyl-7 ,8-Dihydro-6H-quinoline-5-one 7.7-dimethyl-2-oxazol-5-ylacetylene 7,8 - dihydro - 6H - saliva Lin - 5-one

2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one or 2-(2-phenyl-thiazol-5-ylethynyl) -7,8-Dihydro-6H-salrin-5-indole and its optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs. Compounds of the formula I, wherein R2 and R3, which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl or tert-butyl and R4 and R5 represent hydrogen. Compounds of the formula I, wherein R2 and R3 represent hydrogen and R4 and R5, which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl or tert-butyl. Compounds of the formula I, wherein R2, R3, R4 and R5, which may be the same or different, represent hydrogen, methyl or ethyl. 1-13- (10) 1329635 A compound of the formula I wherein R1 represents an aryl group; it is to be understood that aryl represents an unsubstituted phenyl group or a phenyl group which is substituted by the same or different or di-substituted, which substituent Selected as methyl, ethyl, ., 2-propyl, n-butyl, tert-butyl, hydroxy, methoxy, yl, n-propoxy, isopropoxy, n-butoxy, third Butoxy φ CF3, CH2F, CH2F, C2F5, OCF3, OC2F5, F, C1 ' > CN, hexahydropyridyl, morpholinyl, tetrazolyl, oxazolyl, guanidinothiophenyl, isoxazole A group consisting of a thiazolyl group, an imidazolyl group, an oxadiazolyl group, a benzyl group, a pyrimidinyl group, and a phenyl group. A compound of the formula I, wherein aryl represents a mono- or di-substituted phenyl group having an unsubstituted benzene having a substituent at a meta position. A compound of formula I of the formula wherein the phenyl ring is at the meta position and the substituent is different. • A compound of the formula I wherein the substituent is selected from the group consisting of F, CN, .syl, tetrazolyl and unsubstituted phenyl. A compound of the formula I, wherein R1 represents a heteroaryl; it should be understood that: heteroaryl represents pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, D5-yl, thiazol-5-yl, Each of these rings may be unsubstituted or substituted, methyl 'ethyl, n-propyl, 2-propyl, n-butyl, tert-butoxy, methoxy, ethoxy, n-propoxy, iso Propyloxy, n-mono-mono-n-propylethoxy, Br, i-based, pyridine:- or-substituted π-deazolazole - phenyl, butoxy-14-(11) 1329635, second-butoxy Base, CF3, CH2F, CH2F, C2F5, OCF3, OC2P5, F, Cl 'Br, CN, hexahydropyridyl, morpholinyl, tetrazolyl, fluorenyl, furyl, thiophenyl, isoxazole A thiazolyl, imidazolyl-oxazolyl' pyridyl or pyrimidinyl mono- or disubstituted. A compound of the formula I, wherein @S$年: unsubstituted heteroaryl or a mono- or di-substituted heteroaryl ring having a substituent at the meta position.

Compounds of the formula I wherein the heteroaryl ring system is di-substituted and the substituents are different at the meta position. A compound of the formula I of the formula wherein the substituent is selected from the group consisting of F, CN, pyridyl, tetrazolyl and unsubstituted phenyl. And a method of treating a living animal (including a human) associated with abnormal glutamate neurotransmission or wherein the modulation of a Group I mGluR receptor results in a therapeutic benefit or disease, comprising selecting a quantity selected from Formula I Group I roGluR modulators are administered to live animals (including humans),

Wherein R1 represents aryl or heteroaryl; R2 and R3, which may be the same or different, represent hydrogen or C, 6 alkyl; R4 and R5' may be the same or different and represent hydrogen or C, 6 alkyl; -15- (12) 1329635 mjm aryl represents an unsubstituted phenyl ring or a phenyl ring substituted with L 2 ό 4 or 5 substituents which may be the same or different, the substituents being alkyl, a hydroxy group, an N-cycloC hexahydropyridyl group, a decyl group, an imidazolyl group; a C16 alkyl group y optionally substituted with one or more fluorine, chlorine or bromine atoms, optionally or a plurality of fluorine or chlorine Or a bromine atom substituted Ci6 alkoxy group, cyclogalan F' Cl' Br' 1' CN> - N nitro, -C16 alkylamine 2 fluorenyl-NC, .6 guanamine, nitrogen sulfonyl, pyrrole Pyridyl, morpholinyl, 4-C,.6 alkyl-hexahydropyridyl D-tetrazofuryl, pyrrolyl, thiophenyl, isoxazolyl, thiazinidine, shaziridyl A heteroaryl group consisting of a pyrimidinyl group and a phenyl group means a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, Wherein the ring is unsubstituted or substituted by i, 2 or 3 Substituent, which may be the same or different 'substituent is selected from c 6 - 6 alkyl substituted by any one or more fluorine, chlorine or bromine atoms, optionally substituted with one or more fluorine, chlorine or bromine atoms Cm, alkoxy, cyclo c3.12 alkyl, hydroxy, F, Cl, Br, I, CN, nitro, ~alkylamino, N-cyclo C3.12 alkyl-NC, .6 alkylamino, Nitrogen B-denyl, zzaridyl, hexahydropyridyl, oxabulinyl, 4 _ c 1 j alkyl-hexaazinyl, tetrazolyl, oxazolyl 'furanyl, pyrrolyl, thiobenzene a group consisting of thiol, thiazolyl, imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl and phenyl: and 1 optical isomer, pharmaceutically acceptable salt, hydrate, solvent Compounds, and polymorphs; -16- (13) 1329635 which is effective in alleviating the condition or disease or enhancing knowledge.

Such a method in which the abnormal glutamate nerve conduction is involved or in which the modulation of the Group I mGluR receptor causes therapeutic benefit or the disease is selected from the group consisting of: AIDS-related dementia, Alzheimer's disease ), human Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion-related infections, diseases involving mitochondrial dysfunction Diseases involving /5-splash-like disease and/or tauopathy such as Down's disease, hepatic encephalopathy, Huntington's disease, motor neuropathic diseases such as Amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (post-operative cognitive deficit) P〇CD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, boxing dementia, blood vessels Sexual and frontal dementia, dynaminos, ocular trauma or disease (eg glaucoma, retinopathy, macular degeneration), head and spinal cord trauma / trauma, hypoglycemia, anoxia (eg birth), ischemia ( For example, due to cardiac arrest, stroke, bypass surgery or transplantation), sputum, glioma and other tumors, inner ear damage (such as tinnitus, sound or drug-induced), L-dopa drug-induced and tardive dyskinesia (tardive) Dyskinesia ), addiction (nicotine, alcohol, opiates, cocaine, -17- (14) 1329635

Amphetamine, obesity and others), anxiety and panic disorder, attention deficit hyperactivity disorder (ADHD), restless leg syndrome and overactive children, autism, convulsions/ Epilepsy, dementia (such as Alzheimer's disease, Korsakoff syndrome, vascular dementia, sputum IV infection), major depressive disorder or depression (including from Borna) Bipolar manic depressive disorder, drug resistance such as opioids, movement disorders, dystonia, dyskinesia (eg L-dopa drugs are late) Tardive dyskinesia or Huntington's disease, X chromosome

Fragile X-syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle cramps, pain (chronic and acute, for example Inflamed pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain, Parkinson's disease, post traumatic stress disorder, schizophrenia And negative symptoms), sputum, sputum syndrome (T〇ureUe, s syndrome), urinary incontinence and vomiting, itching (such as itching), sleep disorders, urinary disorders, neuromuscular disorders of the lower urinary tract, stomach Gastroesophageal reflux disease (GER D ), lower esophageal sphincter (LES), gastrointestinal -18- (15) 1329635 functional gastrointestinal disorders

Malnutrition, nausea, respiratory infections, bulimia nervosa, laryngitis, asthma (eg reflux-related asthma), lung disease, eating disorders, obesity and obesity-related diseases , Wilderness phobia 'Generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post traumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, emotion Schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, sputum, or for cognitive enhancement and/or neuroprotection 'wherein the compound is administered in the form of a pharmaceutical composition comprising a compound of formula I and one or more pharmaceutically acceptable excipients or carriers. Further, the use of at least one compound of formula I,

Wherein R1 represents aryl or heteroaryl; R2 and R3, which may be the same or different, represent hydrogen or q6 alkyl; -19-(16) 1329635 R4 and R5' may be the same or different and represent hydrogen or C, 6 alkyl; It should be understood that: aryl represents an unsubstituted phenyl ring or a phenyl ring substituted with 1, 2, 3, 4 or 5 substituents, which may be the same or different, and the substituents thereof Optional free of any alkyl group substituted by one or more fluorine, chlorine or bromine atoms, any Ci 6 alkoxy group substituted by one or more fluorine, chlorine or bromine atoms, ring c; , C1, Br,! , CN, nitro, bis(6-alkylamino), N-cycloC^2 alkyl _N_Ci.6 alkylamino, nitrogen sulfonyl, pyrrolidinyl, /, hydropyridyl, morpholinyl, 4 C t -6 alkyl-hexahydropyridin; yl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenylisoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridylpyrimidine a group consisting of a phenyl group and a phenyl group; a heteroaryl group means a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, Wherein the ring is unsubstituted or substituted by 1, 2 or 3 substituents, which may be the same or different, the substituents being selected from Cl_6 alkane substituted by any one or more fluorine 'chloro or bromine atoms. Substituted, optionally substituted by one or more fluorine, chlorine or bromine atoms. Cw alkoxy, ring C3.12, hydroxyl, F, Cl, Br, I, CN, nitro, di-CU6 alkylamino , N-ring C3.12 alkylalkylamine, nitrogen block, pyrrolidinyl, hexahydropyridyl, morpholinyl, 4-Ci 6 alkyl-hexahydropyrrole, tetrazolyl, oxazolyl, Furanyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, a group consisting of oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvents-20-(17) 1329635 and many more a body for the manufacture and use of a medicament for the prevention and/or treatment of a condition or disease in an animal including humans. The condition or disease is produced or promoted by a modulatory effect of a Group I mGIuR1, particularly mGluR5, a modulator. . The compound of formula I used in the manufacture of a medicament according to the invention has been found to be a modulator of the Group I mGluR receptor. In particular, these compounds are modulators of the mGluR5 receptor. Surprisingly, they have been shown to exhibit at least partial actuation or positive regulation of m(31uR5 receptor). As a result, one aspect of the invention is the use of one or more compounds of formula I,

Wherein I R1 represents an aryl or heteroaryl group; R2 and R3, which may be the same or different, represent hydrogen or a Ci 6 substituent: R4 and R5' may be the same or different and represent hydrogen or Ci6 alkyl; It is understood that: aryl represents an unsubstituted phenyl ring or a phenyl ring substituted with 1, 2, 3, τ· per ζ 5 substituent, which may be the same or different, and the substituents are selected from any one or a Ci 1 alkyl group substituted with a plurality of fluorine, chlorine or bromine atoms, any of -21 - (18) 1329635, one or more fluoroalkyl groups, a hydroxyl group, a F group, an N-ring C 3-12 , a chlorine or a bromine atom Substituted c, -6 alkoxy, ring c3.1: , Cl, Br, I, CN, nitro, di-Ci 6 alkylamine-based N-Cm alkylamino, nitrogen-based, pyrrolidinyl, Hexahydropyridyl 'nofolinyl' 4_Ci 6 alkyl hexahydropyridinyltetrazolyl chewing oxime, furyl, pyrrolyl, thiophenyl, isoxazolyl 'thiazolyl, misoyl, dioxin a group consisting of azolyl, pyridyl, pyrimidinyl and phenyl; heteroaryl represents a (hetero)aromatic 5...6- or 7-membered ring having from 丨 to 4 heteroatoms independently Selected from oxygen nitrogen and sulfur, wherein the ring is unsubstituted or 1, 2 or 3 substituents which may be the same or different 'substituent selected from hydrazine substituted by any one or more fluorine, chlorine or bromine atoms, -alkyl group, any warp- or more Ci-6 alkoxy, cyclo C3_12 alkyl, hydroxy, F, Cl, Br, I, CN, nitro, di-(^.6 alkylamino, N-ring c3 i2 substituted with fluorine, chlorine or bromine atoms Alkyl_n_Ci 6 alkylamino, nitrogen, pyrrolidinyl, hexahydropyridyl, morpholinyl, 4-Ci 6 alkyl-hexahydropyrrole, tetrazolyl, oxazolyl, furyl, pyrrole a group consisting of thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl and phenyl; and optical isomers, pharmaceutically acceptable salts thereof, hydrated , solvates, and polymorphs; for the prevention and/or treatment of AIDS-related dementia, Alzheimer's disease, human Jaku syndrome (C reutzfe 1 d - J akob ' ssyndrome ), bovine spongiform encephalopathy (BSE) or other -22-(19)1329635

Prion-associated infections, diseases involving mitochondrial dysfunction, diseases involving /3 -amyloidosis and/or tauopathy such as Down's syndrome, hepatic encephalopathy ( Hepatic encephalopathy ), Huntingt ο η ' sdisease , motor neuropathy such as amyotrophic lateral sclerosis ( ALS ) , multiple sclerosis ( MS ) , withdrawal of nucleus Bridge cerebral atrophy (olivopontocerebellar atrophy), postoperative cognitive impairment (post-operative

Relationship deficit ) ( POCD ), Parkinson's disease, Parkinson's disease, mild cognitive impairment, boxing dementia, vascular and frontal dementia, dysfunction, eye trauma or disease (eg glaucoma, retina Lesions, macular degeneration), head and spinal cord trauma/trauma, hypoglycemia, anoxia (eg, maternity), ischemia (eg, due to cardiac arrest, stroke, bypass surgery, or transplantation) '痉挛, neuroglioma And other tumors, inner ear injuries (such as tinnitus, sound or drug-induced), L-dopa drug-induced and tardive dyskinesia, addiction (nicotine, alcohol, opiates, cocaine, amphetamines, Obesity and other), anxiety and panic disorder, attention deficit hyperactivity disorder (ADHD), restless leg syndrome and hyperactive children, autism, paralysis/epilepsy, Dementia (eg Alzheimer's disease, Korsakoff syndrome, vascular dementia, ΗIV sensation) ), Major depression (major depressive disorder) or depression (including due to -23- (20) 1329635

Borna virus infection) and bipolar manic depressive disorder, drug resistance such as sputum tablets, movement disorders, dystοnia, dyskinesia (eg L-dopa) Drug-induced tardive dyskinesia or Huntington's disease, Fragi丨eX syndrome, Huntington's chorea, intestinal irritation syndrome (irritable bowel syndrome) (IBS), migraine, multiple sclerosis, muscle spasm, pain (chronic and acute, such as inflammatory pain, neuropathic pain, allodynia, hyperalgesia, involuntary pain) Nociceptive pain )), Parkinson's disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), sputum, Tourette's syndrome, urinary incontinence and vomiting, itching Situation (eg itching), sleep disorders, urinary disorders, neuromuscular disorders of the lower urinary tract, stomach Gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES) 'functional gastrointestinal disorders, dyspepsia, nausea' respiratory tract infection, bulimia nervosa, chronic Laryngitis, asthma (eg reflux-related asthma), lung disease, eating disorders, obesity and obesity-related diseases, wild phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder Post traumatic stress disorder, Society-24- (21) 1329635 phobia, substance-induced anxiety, delusional disorder, schizoaffective disorder , schizophreniform disorder, substance-induced psychotic disorder, sputum, or medicine for cognitive enhancement and/or neuroprotection.

Such medicines, in which the medicine is used for the prevention and/or treatment of addiction, neuropathic pain, L-dopa drug-induced and tardive dyskinesia, ALS, X chromosome fragility (fragiie χ. syndrome) ), Parkinson's disease, anxiety, epilepsy, positive and/or negative symptoms of schizophrenia, dynamism, or for cognitive enhancement and/or neuroprotection. Further, a pharmaceutical composition comprising a compound of the formula I, together with one or more pharmaceutically acceptable excipients or carriers,

Wherein R1 represents an aryl or heteroaryl group; R2 and R3' may be the same or different and represent a hydrogen or a C16 building group: R4 and R5' may be the same or different and represent hydrogen or a Ci 6 building; it is understood that: -25- (22) 1329635 An aryl group means an unsubstituted phenyl ring or a phenyl fluorene substituted by i'2'3, 4 or 5 substituents which may be the same or different, the substituents being selected from Any Cm alkyl group substituted by one or more fluorine, chlorine or bromine atoms,

a Cl, Br, I, CN, C, .6 alkoxy group substituted by one or more fluoroalkyl, hydroxy, F chloro or bromine atoms, ring c3.1: nitro, di-Cu alkylamino group, N-ring C3.12 base - N- Ci.6 guanylamino, nitrogen-resistant pyrrolidinyl,

Hexahydropyridyl, morpholinyl, 4-Cl.6 alkyl. hexahydromethylene, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, A group heteroaryl group consisting of imidazolyl, oxazolyl, pyridyl, pyrimidinyl and phenyl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms, the hetero atom Independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring is unsubstituted or substituted with i, 2 or 3 substituents, which may be the same or different, the substituents being selected from any one or more fluorines, C, substituted by a chlorine or bromine atom, substituted by one or more fluorine, chlorine or bromine atoms • Cl.6 alkoxy, cyclo C3.i2 alkyl, hydroxy, F, C1, Br , j, CN, .nitro, bis-Cl.6 alkylamino, oxime ring C3. 丨2 alkyl-N_Ci 6 alkylamino, nitrogen sulfonyl, pyrrolidinyl, hexahydropyridyl, morpholin , 6-alkylhexahydropyrazine, tetrazolyl, oxazolyl, furyl, pyrrolylthiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl and Group of phenyl groups: and compounds of formula I It can be expressed as follows: 2-propenylethynyl-7,8-dihydro-6H-quinolin-5-one 2· pyridine-4-ylethynyl-7,8-dihydro-6H-quinoline-5_ Ketone-26-(23)1329635 2-m-tolylvinyl-7,8-dihydro-6H-quinolin-5-one 2-(3-hydroxy-phenylethynyl)-7,8-dihydro - 6H-quinoline-5-one 2-(3-methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-fluoro-phenylethynyl -7,8-Dihydro-6H-quinolin-5-one 2-(3-chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2- (3- Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one

3-(5-keto-5,6,7,8-tetrahydroquinolin-2-ylethynyl)-benzonitrile 2-thiazol-5-ylethynyl-7,8-dihydro-6H -quinolin-5-one 2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7.7-dimethyl-2-pyridin-3-ylethynyl-7 ,8-Dihydro-6H-quinolin-5-one 7.7-dimethyl-2-m-tolylvinyl-7,8-dihydro-6H-quinolin-5-one 2-(3-hydroxy- Phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one

2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-fluoro-phenylethynyl) -7,7-Dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-chloro-phenylethynyl)-7,7-dimethyl-7,8-di Hydrogen-6H-quinolin-5-one 2-(3-bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 3- (7) ,7-Dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile-27- (24) (24) 1329635

7.7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinoline-5-one 7.7-dimethyl-2-oxazol-5-ylethynyl-7 8-Dihydro-6H-quinoline-5-one 2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinoline-5-one or 2-( 2-phenyl-thiazol-5-ylethynyl-7,8-dihydro-6H-quinoline-5- and its optical isomers, pharmaceutically acceptable salts, hydrates, solvates and more Form. Specific compounds of formula I within the present invention include, but are not limited to, 6,6-dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinoline-5-one 2-( 3-fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-chloro-phenylethynyl)-6,6- Dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-methoxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H -quinoline-5-one 2-(3-hydroxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 3- (6,6- Dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 6,6-dimethyl-2-thiazol-5-ylethynyl -7,8-dihydro-6H-quinoline-5--28-(25)1329635 ketone 6,6-monomethyl-2-(3-/, gas B ratio-1-base-benzyl Block base)-7,8-dihydro-6H-quinolin-5-one 7,7-dimethyl-2-(3-hexahydropyridin-1-yl-phenylethynyl)-7,8- Dihydro-6H-quinolin-5-one 2-(3-hexahydropyridin-1-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one

2-(3-norfosine-4-yl-phenylethyl carbyl)-7,8--chloro-6H-salin-5-one 7,7-dimethyl-2-(3-? Benzo-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 6.6-monomethyl-2-( 3-fofolin-4-yl-phenyl b -7,8-monohydro-6H-quinoline _5 ketone 6.6-dimethyl-2-[3-(111-tetrazol-5-yl)-phenylethynyl]-7,8-di Chlorine-6H -Salina-5-嗣

7.7-Dimethyl-2-[3-(11tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-salin-5-one 2-[3-(1Η- Tetrazolium-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one 2-[3-fluoro-5-(11"1-tetrazol-5-yl) -Phenylethynyl]-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-[3-fluoro-5-(111-tetrazol-5-yl)- Phenylethynyl]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-[3-fluoro-5-(1H-tetrazol-5-yl)-benzene Ethyl acetyl]-7,8·dihydro- -29- (26) 1329635 6H-quinolin-5-one 2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro- 6 Η-quinolin-5-one 7,7-dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-one 6, 6-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-one

7,7-Dimethyl-2-phenylethynyl-7,8-dihydro-6Η-quinolin-5-one 6,6-dimethyl-2-phenylethynyl-7,8-di Hydrogen-6Η-quinolin-5-one 2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one 7,7-dimethyl- 2-(4-Methyl-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one 6,6-dimethyl-2-(4-methyl-thiazole- 2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one

2-(4-Fluoro-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one 2-(4-fluoro-thiazol-2-ylethynyl)-7,7 -Dimethyl-7,8-dihydro-6Η-quinolin-5-one 2-(4-fluoro-thiazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro -6Η-quinolin-5-one 2·(2-phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6Η-quinoline 5-2-(5-fluoro-pyridine-3 -ylethynyl)-7,8-dihydro-6y-quinolin-5-one 3-fluoro-5- (7,7-dimethyl-5-keto-5,6,7,8-tetra Hydrogen-quinolin-2-yl-30-(27)1329635 ethynyl)-benzonitrile 2-(4·fluoro-5-phenyl-oxazol-2-ylethynyl)-7,8-dihydro - 6H-quinoline-5-one 2-(4- gas-5-disgust-3-yl-chew-2-ylethyl)-7,8-mono-6H-quinolin-5-one 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one

2-(4-Fluoro-5-pyridin-3-yl-oxazole-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6Η-quinolin-5-one 7, 7-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6Η-quinolin-5-one 2-pyridin-2-ylethynyl-7,8-dihydro-6Η Quinoline-5-嗣6,6-dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6Η-sialin-5

6.6- Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one 7.7-dimethyl-2-(4- Methyl-oxazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one 2-(4-fluoro-5-pyridin-3-yl-1Η-imidazol-2-yl Ethynyl)-7,8-dihydro-6Η-quinolin-5-one 2-(4-fluoro-5-pyridin-3-yl-1Η-imidazol-2-ylethynyl)-7,7-di Methyl-7,8-dihydro-6Η-wortho-5-one 2-(4-fluoro-5-pyridin-3-yl-1Η-imidazol-2-ylethynyl)-6,6-dimethyl Base-7,8-dihydro-6Η-salostani-5-one-31 - (28)1329635 6,6-dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl -7,8-Dihydro-6H-quinolin-5-one 7,7-dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-di Hydrogen-6H-quinolin-5-one 2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-thiazole-2 -ylethynyl- 7,8-dihydro-6H-quinolin-5-one

2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-[1,3,4]oxadiazol-2-yl Ethynyl-7,8-dihydro-6H-quinolin-5-one 2-(1H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 6.6- Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-611-quinolin-5-one 7.7-dimethyl-2-[1,3 , 4] thiadiazol-2-ylethynyl-7,8-dihydro-611-salostani-5-one

7.7-Dimethyl-2-(111-tetrazol-5-ylethynyl)-7,8-dihydro-611-quinoline-5-oxime 6.6-dimethyl-2-(111-tetrazole- 5-ylethynyl)-7,8-dihydro-611-quinolin-5-one 6.6-dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinoline - 5-keto-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 6,6-dimethyl-2-oxazol-2-ylethynyl-7 ,8-dihydro-6H-quinoline-5-7,7-dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinoline-5

(S-32-(29)1329635 Ketone 6.6-Dimethyl-2-m-tolylvinyl-7,8-dihydro-6H-quinolin-5-one 7,7-dimethyl-2- ( 2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 6.6-dimethyl-2-(2-phenyl-oxazole-5-yl Ethynyl)-7,8-dihydro-6H-quinolin-5-one

7,7-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-Salina-5-嗣6.6-dimethyl-2-(5 -phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(5-fluoro-pyridin-3-ylethynyl)-7,7-dimethyl -7,8-dihydro-6H-quinolin-5-one 2-(5-fluoro-pyridin-3-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H- Quinoline-5-one 3-fluoro-5-(5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzene

Formaldehyde 3-(6,6-dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-5-fluoro-benzonitrile 2- (4 -fluoro-5-phenyl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-diox-6H-嗤琳-5-嗣2- (4-fluoro-5- Phenyl-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 6.6-dimethyl-2-(5-pyridine-3 -yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-salin-5-one-33- (30) (30)1329635 7,7- Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 2- (5-Pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one and its optical isomers, pharmaceuticals Acceptable salts, hydrates, solvates, and polymorphs. DETAILED DESCRIPTION OF THE INVENTION For the purposes of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by the prefix of the smallest and largest digits of the carbon atoms in the specified portion, that is, the prefix Ci.j indicates the inclusion of the integer "i" to The fraction of the integer "j" carbon atom. Thus, for example, (alkyl refers to an alkyl group containing one to three carbon atoms, (ie, methyl 'ethyl, propyl, and isopropyl), in both straight and branched form. The term "C,_6 alkyl" embraces a straight or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group may be unsubstituted and includes, for example, methyl, Further, the n-propyl group, the 2-propyl group, the n-butyl group, the third butyl group. Further, these alkyl groups may be optionally substituted by one or more fluorine, chlorine and/or bromine atoms; Examples include -CF3, -C2F5, -CBr3, and -CC1" the term "(^.6 alkoxy)" includes a straight or branched -OC μ alkyl group, wherein "(^_6 alkyl, as previously Definitions of giving. Examples of alkyl" include methoxy, ethoxy, n-propoxy, isopropoxy. C, -6 alkoxy may optionally be subjected to one or more fluorine, chlorine and/or bromine atoms. Substituting, thereby forming, for example, -〇CF3, -OC2F5, -CBr3. The term "ring-34-(31)(31)1329635 C3_12 alkyl" means having 3, 4, 5, 6, 7, 8, 9 , 10, 1 1 price of a carbon atom Ring, bicyclic or tricyclic, and includes cyclopropyl, tert-butyl, cyclopentyl, cyclohexyl, bicyclo[2 _2.1]heptyl and adamantyl. C 3 . Substituting one or more fluorine, chlorine and/or bromine atoms as used in the context of the present invention, the term 'di-C, alkylamino, means that the nitrogen atom of the amine group is as defined above. The same or different C16-based substituted amino moiety. Examples of the di-c,-6 alkylamino group include dimethylamino, -S oximino and N-methyl-N-isopropylamine. The term "N" -C ring C312 alkyl-N_c -6-6 alkylamino" includes an amine group in which the nitrogen atom of the amine group is substituted by a Cl6 alkyl group and an N-ring Cm group. Cm yard group and N-ring 〇 3.12 yard base Both are as defined above. The term "4-C,·6 alkyl-hexahydropyrrolidine, a six-position nitrogen atom at the 4-position of the hexahydropyridinium ring has a Ci 6 alkyl moiety Hydropyridinyl 'the 'C,-6 alkyl' has the same meaning as previously given. The term "(hetero)aromatic 5-, 6- or 7-membered ring" means having up to 4 in the ring a heterocyclic ring of oxygen, nitrogen and/or sulfur atoms, which comprises 5, 6 or 7 carbons and heteroatoms which are aromatic ring systems. Examples of such (hetero)aromatic 5-, 6- or 7-membered rings include unsubstituted or appropriately substituted scorpions , B steroids, thiophenes, furans, isoxazoles, imidazoles, oxins, oxadiazoles, thiazoles, imidazolines, pyrazoles, oxazolidines, isoxazolidines , thiazole steep, pyridine, sorghum, sorghum, scorpion, nitrogen, and the term "halogen" means fluoro, chloro, bromo and bowl. The compounds of the invention are named according to the IUPAC or CAS nomenclature system. Abbreviations known to those skilled in the art can be used (e.g., "ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hours, and "rt" -35 - (for 32) 1329635

For room temperature). The term "analog" or "derivative" is used in the conventional medical sense to mean that the reference is structurally similar to a reference molecule (eg, 7,8-dihydroindol-5-one), but is replaced by standard and controlled means. A molecule of one or more specific substituents of a substituent, thereby producing a molecule that resembles a reference molecule. Synthesis and delineation of analogs (eg, structural and/or biochemical analysis), identifying positive changes in known compounds 'which may have improved or biased characteristics (high potency and/or specific target receptor types) The selectivity, the ability to better blood-brain disorders in dairy animals, lower side effects, etc.) are known drug design approaches in medicinal chemistry. In addition, methods known to those skilled in the art have improved therapeutic efficacy in controlling dementia, i.e., higher or selective, larger or lower penetrants of a particular target receptor type. An analog of a compound of the invention that has the ability of a blood-brain barrier (eg, a higher or lower blood-brain rate), fewer side effects, and the like. The phrase "pharmaceutically acceptable", as used in reference to the present invention, refers to molecular entities and other components of such compositions that are physiologically tolerable and typically not when administered to a mammal (eg, a human). Annoying reaction. Preferably, as used herein, the term "pharmaceutical" means to be used by a federal or state government regulatory agency or other commonly recognized pharmacopeia in the United States for use in mammals, and more in humans. Used in the phase of the -6H-quino reference structure, using micro-repair, for example, more penetrating, in the form of a female force and / / breast-feeding wall penetration and derivation of the composition to feed on the numbness of the pharmacopoeia or special -36-(33)1329635 The pharmaceutically acceptable salt of the compound of the present invention in the form of a pharmaceutically acceptable salt means the biological effect of the parent compound and it is not a biological or undesirable salt. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired I.

It will be understood by those skilled in the art that a compound having a chiral center can exist and be isolated from optically active and racemic forms of the compound to exhibit homomorphic morphology. It is to be understood that any of the racemic, optically active, polymorphic, tautomeric forms or mixtures thereof of the compounds of the invention, which have the usefulness described herein, are described in Scheme 1 below. preparation. The materials are prepared by procedures well known in the art of the procedures described in the schemes, organic chemistry, or are commercially available. All of the present compounds are prepared by the procedures described in this scheme or by analogous procedures well known to those of ordinary skill in the art. All variables in the process are as defined below or in the scope of the patent application. A synthetic step towards 2-substituted-vinyl-7,8-diquinolin-5-ones of the general formula I is given to Scheme 1. Appropriately functional hexane·1,3-dione derivative 1 and ammonium acetate/acetic acid in benzene correspond to 3-amino-cyclohex-2-enone derivative 2. Compound 2 then oxime is chemically reacted with an acid alkyl ester and cyclized at elevated temperatures to form quinoline-2,5 3 . Subsequent reaction with phosphonium chloride produces 2-chloro-substituted quinoline-5. Substitution of a chloro-substituent with a suitable acetylene derivative in the presence of a palladium (0) catalyst base produces a compound of formula I. . "Medical I and sex k determine i-li-t---"Most or stand-up "The most popular person: the L-6H-; the ring: the production of propyne-diketone- Ketone-derived at -37-(34)1329635 Scheme 1 2 - Substitution of vinyl·7,8-dihydro-6H-quinolin-5-one

It will be apparent to those skilled in the art that the synthetic steps described are merely representative of the nature and alternative synthetic steps are well known to those of ordinary skill in the art of organic chemistry. [Embodiment] Experimental Examples The compounds of the present invention and the preparation thereof will be better understood by the following examples which are intended to be illustrative and not intended to limit the scope of the invention. Hereinafter, "DMF" is defined as N,N-dimethylformamide, "HCr" is defined as hydrochloric acid, "D1VISO" is defined as dimethyl sulfoxide and "TMS" is defined as tetramethyl hexane. -38- (35 ) 1329635 Preparation 1 3-Amino-5,5-dimethylcyclohex-2-en-1-one

The title compound was prepared according to (Baraldi, P. G.; Simoni, D.; M an f r e d i n i, S. ; Synthesis 1 9 8 3, (1 1 ) 902-903), a colorless solid in 76% yield.

Similar to (Pettit, GR; Fleming, WC; Paull, KDJ Org. Chem. 1 968, 33 (3) 1089-1092), 3-amino-5,5-dimethylcyclohex-2-ene- The 1-ketone was reacted with ethyl propiolate to give the title compound as a pale brown solid in 78.5% yield. The physical properties are as follows: Ή NMR (CDC13 ' TMS ) δ 1 .14 > 2.42 > 2.82 > 6.47, and 8.04. -39- (36)1329635 Preparation 3 2-Chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one

Cl

Similar to (Shanazarov, AK; Kuzovkin, V. Α·; Chistjakov, VV; Granik, VG Khim. Geterotsikl. Soedin. 1991, (1) 86-92.) Treatment with phosphonium chloride (p〇ci3) 7,7 -Dimethyl-7,8-dihydro-1H,6H-quinolin-2,5-dione to give the title compound as a grey solid in 60% yield. The physical properties are as follows: 1H NMR (CDC13, TMS) δ 1 _ 1 1,2 · 54, 3.01, 7.30, and 8.30.

Preparation of 4 3-Amino-5-Ethylcyclo-2-ene-1-one

NH2 is very similar (Baraldi, Ρ·G_; Simoni, D.; Manfredini. S·; Synthesis 1 983, (1 1) 902-903) to 5-ethylcyclohexane-1,3-di-40 (37) 1329635 Ketone was reacted with ammonium acetate to give the title compound. The physical properties are as follows: Ή NMR ( CDC13 ' TMS ) δ : 0.93 ( t, 6.5 Hz, 3H ); 1.42 ( m, 2H ) ; 1.88 -2.44 (m, 5H) ; 4.62 ( br s, 2H ) and 5.23ppm ( s, lH). Preparation 5

3-amino-6-propylcyclohex-2-en-1-one

Nh2 is very similar (Baraldi, P_G.; Simoni, D.; Manfredini, S.; Synthesis 1 983, (1 1 ) 902-903) 4-propylcyclohexane-1,3-dione and acetic acid The ammonium is reacted to give the title compound as a colorless solid. • Physical properties are as follows: Ή NMR ( CDC13 5 TMS ) δ : 0.91 ( t, 7 Hz, 3H ); 1.25-1.90 ( m, 5H ) ; 1.98-2.18 ( m, 2H) ; 2.35 (t, 6 Hz, 2H ; 4.50 (1^8, 211) and 5.19?? 111 (8, 11 〇. Preparation 6 3-Amino-5·isopropylcyclohex-2-en-1-one-41 - (38) 1329635

Similar to (B araldi, Ρ·G.; S im ο ni, D _; M anf redini, S.; Synthesis 1 983, (1 1) 902-903) to give 5-isopropylcyclohexane-1, The 3-dione is reacted with ammonium acetate to give the title compound as a colorless solid. The physical characteristics are as follows:

'H NMR ( CDC13, TMS ) δ 0.91 ( d, 6.5 Hz ); 1.48 -1.65 (m, 1 H) ; 1.84 -2.39 ( m. 5H ) ; 5.04 ( brs, 2H) and 5.22 ppm ( s, 1H) . Preparation of 7 3-Amino-6,6-dimethylcyclohex-2-en-1-one

Nh2 is similar to (Baraldi, P. G.; Simoni, D.; Manfredini, S.;

Synthesis 1 983, (1 1) 902-903) The 4,4-dimethylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid. The physical characteristics are as follows:

Mp 153-154 - °C ; NMR (DMSO-D6 > TMS) δ : 0.94 ( s, 6H ) ; 1.64 ( t, 6.5 Hz, 2H ) ; 2.28 ( t, 6.5 Hz, 2H) ; 4.79 ( s, 1H) and 6.58 ppm (brs, 2H). -42- 8 (39) 1329635 Preparation of 3-amino-6-ethyl-6-methylcyclohex-2-en-1-one

S y nt 1,3- 3 Η ) (m 5.14

1.73 (c, preparation of 2-benzene similar to (Baraldi, PG; Simoni, D.; Manfrei thesis 1 983, (1 1 ) 902-903) to react 4-ethyl-4-methyldione with ammonium acetate The colorless solid physical properties of the title compound were as follows: - NMR (CDC13, TMS) <5: 0.83 (t, ; 1.06 (s, 3H); 1.40 - 1.80 (m, 3H); 1 , 1 Η ); 2.35 ( t, 6.5 Hz, 2H); 4.3 1 ( br s. ppm ( s, 1H) . Mp 99- 100 ° C ; *H NMR (CDC13 > TMS) δ , 2_45 , 2.79 , 3.91 , and 8.33 ; analysis 7Η21Ν30 ) (%): C, 71_6; H, 7.5; N, 14 " 9 ethynyl-7,8-dihydro-6H-salin-5-one iini, S.; cyclohexane-body. 6 · 5 Η ζ, .85-2.00 2Η) and: 1.08, found 値-43- (40) 1329635 Ο

Adding cerium (triphenylphosphine) palladium (0.02 g, molar) to 2-chloro-7,8-dihydro-6Η-porphyrin-5-one (0.2 gm) and block B under argon pressure A solution of benzene (0.17 g, 1.6 mmol) in three mL). The mixture was heated under reflux for 3 h. The mixture was concentrated under reduced pressure and the residue compound (0.04 g, 15%) was purified on hydrazine gel by column chromatography.

NMR NMR (CDC13 > TMS) (2H); 2.68 ( 2H ) ; 3.17 ( 2H ) ; 7.22-7.38 ( 7.46 ( 1H ) ; 7.60 ( 2H ) ; 8.24 ( 1H ); (M+ 1) Preparation of l〇2-pyridin-3-ylethynyl-7,8-dihydro-6H·quinolin-5-one 0.062 mM, 1 · 1 mM ethylamine (7 I later produced the standard δ at d : 2.20 3Η ); MS 248 Ο

Similar to the procedure described in Preparation 9, a medium yield of title compound - 44 - (41) 1329 625 (120 mg, 15%, MP: 120-122.1 ° C) was obtained. Preparation of 11,7,7-dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one

The title compound (50 mg, 12%, MP: 108 - 109.2 ° C) was obtained in a medium yield. Preparation of 12 2 -m-tolylvinyl-7,8-dihydro-6H-quinolin-5-one oxime

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 13 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one -45- (42) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 14 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 15 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-one

-46- (43)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Preparation of 1 6 2-(3-chloro-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 17 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6Η-salin-5-one -47- (44)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Preparation 18 3-(5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. 9 Preparation 19 2-thiazol-5-ylethynyl-7,8-dihydro-6Η-quinolin-5-one

-48 - (45)1329635 Ο

The procedure was similar to the procedure described in Preparation 9. Medium yield heading

-ketone

The compound was obtained similarly to the procedure described in Preparation 9. Heading in medium yield Preparation of 21-6-quinoline-5-one 2_(2-phenyl-oxazole-5-ylethynyl)-7,8-di

-49- (46) 1329635 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Preparation 22 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation of 23,7-7-dimethyl-2-m-tolylvinyl-7,8-dihydro-6H-quinolin-5-one oxime

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 24 -50-(47)1329635 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation of 25 2-(3-methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 26 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-611-quinoline-5--51 - (48)1329635 ketone oxime

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield of 27 2-(3-chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6-quinoquine. Porphyrin- 5-ketone

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 28 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6Η-quinolin-5-one * «3Η -52- (49)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 29 3-(7,7-Dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Preparation 30 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6Η-quinolin-5-嗣-53- (50)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 1 6,6-Dimethyl, 2-phenylethynyl-7,8-dihydro-611-quinolin-5-one 0

-54- (51) 1329635 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 2 6,6-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 3 6,6-Dimethyl-2-m-tolylvinyl-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 4 -55- (52) (52) 1329635 2-(3-methoxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one

Compound. Example 5 2-(3-Fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 6 2-thiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 〆 «=< -56- (53)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 7 2-(4-Methyl-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one oxime

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 8 7,7-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one -57- (54)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. 6,6-Dimethyl-2-(4-methyl-thiazol-2-ylethyl)-7,8-dihydro-6Η-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 10 2-(4-Fluoro-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one -58- (55)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. 2-(4-Fluoro-thiazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6Η-salrogin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 12 2-(4-Fluoro-thiazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6Η-quinolin-5-one -59- (56) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 13 2-(5-Fluoro-pyridin-3-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one oxime

类似于 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 1 4 3-Fluoro-5-(7,7-dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile t «= >· -60- (57) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 1 5 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 16 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,8-dihydro-6 Η-quinolin-5-one-61 - (58) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 1 7 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6Η-quinoline-5- ketone

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 18 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6Η-quinolin-5-one -62- (59) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 19 7,7-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-611-quinolin-5-one oxime

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 20 2 -Pyridin-2-ylethynyl-7,8-dihydro-6Η-quinolin-5-one oxime

〆 «Λ . -63- (60) 1329635 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 21 2-(3-Chloro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 22 2-(3-Hydroxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one oxime

Similar to the procedure described in Preparation 9, the title was obtained in medium yield '-S, -64- (61) 1329635

Example 23 3-(6,6-Dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)benzonitrile

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 24

6,6-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-salin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. -65- (62) 1329635 Example 25 6,6-Dimethyl-2-(3-hexahydropyridin-1-yl-phenylethynyl)-7,8-dihydro-6H-quinoline-5- Ketone 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 26 7,7-Dimethyl-2-(3-hexahydropyridin-1-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 27 2-(3-Hexahydropyridine·1-yl-phenylethynyl)-7,8-dihydro-6H-quinoline 5--66-(63)1329635 ketone

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 28 2-(3-norfosolin-4-yl-phenylethynyl)-7,8-dihydro-6H-salin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 29 7,7-Dimethyl-2-(3-hofosolin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one-67- (64) 1329635

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

6,6-monomethyl-2-(3-norfos-4-yl-phenylethyl)-7,8-monoamino-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 31 6,6-Dimethyl-2-[3-(111-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-sormine-5-one oxime s= · -68- (65)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 32 7,7-Dimethyl-2-[3-(111-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6Η-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 33 2-[3-( 1Η-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6Η-quinoline-5-one-69-(66) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 34 2-[3-Fluoro-5-(1Η-tetrazol-5-yl)-phenylethynyl]-6,6-dimethyl-7,8-dihydro-6Η-quinoline-5- ketone

Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 35 2-[3-Fluoro-5-(1Η-tetrazol-5-yl)-phenylethynyl]-7,7-dimethyl-7,8-di-gas-6H-quinoline-5-嗣-70- (67)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 3 6 2-[3-Fluoro-5-(1Η-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6Η-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 3 7 2-(3-Trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one

-71 - (68) 1329635 ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

7,7-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 3 9 6,6-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-嗣, *>·. -72 - (69)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Analogously to the procedure described in Preparation 9, the title compound was obtained in a medium yield of 41,6-dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6-quinoline-5 -ketone oxime

-73- (70) 1329635 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 4 2 6,6-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 43 7,7-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one oxime

-74- (71) 1329635 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 44 2-(4-Fluoro-5-pyridin-3-yl-1H-imidazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 45

2-(4-fluoro-5-pyridin-3-yl-^-imidazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the titled 〆··· X^)-75-(72)1329635 was obtained in a medium yield. Example 4 6 2-(4-Fluoro-5-pyridin-3-yl-111-imidazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-611-quinoline-5 -ketone

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 47

6,6-Dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-salin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. -76-(73)1329635 Example 48 7,7-Dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinoline-5 -ketone 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 49 2-(4-Pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinoline-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 5 0 2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one -77- (74) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 51 2-[1,3,4]oxadiazol-2-ylethynyl-7,8-dihydro-6Η-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 52 2-(1Η-tetrazol-5-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one 0

-78- (75) 1329635 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 53 6,6-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-611-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. 7,7-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-61 quinolin-5-one 0

Similar to the procedure described in Preparation 9, the titled -79- (76) 1329 625. Example 55 7,7-Dimethyl-2-(111-tetrazol-5-ylethynyl)-7,8-dihydro-611-quinolin-5-one

A

N~N Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 56 6,6-Dimethyl-2-(111-tetrazol-5-ylethynyl)-7,8-dihydro-611-quinoline-

0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. -80-(77)1329635 Example 5 7 6,6-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0

D />

N

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 5 8 2 -oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 5 9 6,6-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 〆 «=· -81 - (78)1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 6 0 7,7-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6Η-salin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 61 7,7-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6Η-quinolin-5-one

-82 - (79) 1329635 Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 6 2 6,6-dimethyl-2-(2-phenyl-oxazole-5-yl Ethynyl)-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield.

Example 63 7,7-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0

Similar to the procedure described in Preparation 9, obtaining a medium yield heading

'*· J -83- (80) 1329635. Example 64 6,6-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 6 5 2-( 5-Fluoro-pyridin-3-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quin

Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. < S ) -84- (81) 1329635 Example 66 3 -Fluoro-5·( 5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 0

N. Similar to the procedure described in Preparation 9, the title compound was obtained in medium yield. Example 6 7 3-(6,6-Dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-5-fluoro-benzonitrile

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 6 8 -85- (82) 1329635 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-diaza-6H-indole琳-5-嗣 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 69 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 70 6,6-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-〆«ΕΧ ' . -86- (83) 1329635 7,8-Dihydro-6H-quinolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 7 1 7,7-Dimethyl-2-(5.pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-611-saliva Porphyrin-5-one

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. Example 72 2-(5-Pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one-87- ( 84) 1329635 Ο

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. 7,7-Dimethyl-2-phenylethynyl-78-dihydro-6^1_salolin-5-one 0

Similar to the procedure described in Preparation 9, the title compound was obtained in a medium yield. The pure stereoisomeric forms of the compounds and intermediates of the invention can be obtained by the procedures known in the art. The non-imagewise isomers can be separated by physical methods such as selective crystallization and chromatographic techniques, such as liquid chromatography using chiral stationary phases. The mirror image isomers can be separated from each other by the selective crystallization of their non-mirromeric isomer salts with optically active acids. Alternatively, the mirror image isomers can be separated by chromatographic techniques using chiral stationary phases. Such pure stereoisomeric forms can also be derived from the corresponding pure isomer forms of the appropriate starting materials, provided that the reaction selectivity occurs. The stereoisomer form of Formula I is clearly intended to be included in the scope of the present invention. Addition salt

For therapeutic use, the salts of the compounds of formula I are those in which the relative ions are pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of acids and bases can also be found, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts, whether or not pharmaceutically acceptable, are included within the scope of the invention. A pharmaceutically acceptable salt as described above means a therapeutically active non-toxic salt form which is capable of forming a compound of formula I. The latter may be used by using such suitable acids as inorganic acids, such as hydrohalic acids such as hydrochloric acid, hydrobromic acid, etc.; sulfuric acid; nitric acid; phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, Glycolic acid, 2-hydroxypropionic acid, ketopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1, 2, 3 - propane tricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, And similar to the acid treatment of the base. Conversely, the salt form can be converted to the free base form by treatment with a base. Pharmaceutical Compositions The active ingredients of the present invention, together with one or more conventional adjuvants, carriers, or diluents, can be placed in a pharmaceutical composition and unit dosages thereof, and can be solid, such as coated, in such form. Uncoated tablets or gargles, or liquids, such as solutions, suspensions, lotions, elixirs, or capsules filled with them are all used orally; in suppositories for rectal administration -89 - (86) 1329635

It can be used in the form of a capsule or in the form of a sterile injectable solution for parenteral use, including intravenous or subcutaneous. The pharmaceutical compositions and unit dosage forms thereof can be included in conventional or specific proportions of conventional or novel ingredients, with or without additional active ingredients or principles, and such unit dosage forms can contain any <RTIgt; A suitable amount of the active ingredient in the same amount. Tablets containing from one (1) to one hundred (100) milligrams, or more, from five (5) to five hundred (500) milligrams of active ingredient per sharp are therefore suitable representative unit dosage forms. The term "carrier" as applied to the pharmaceutical composition of the invention refers to a diluent, excipient or carrier with which the active compound is administered. Such pharmaceutical carriers may be sterile liquids such as water, aqueous saline solution, aqueous dextrose, aqueous glycerol and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are disclosed in E. W. Martin, 18th Edition, "Remington's Pharmaceutical Sciences". Methods of Treatment Due to their high activity and their low toxicity, the principles of activity of the present invention can be administered to individuals in need thereof, such as living animals (including humans) for treating, alleviating or ameliorating, alleviating or removing them. A sensitive indication or condition 'or representative of the indication or condition described in the application' is preferably synergistic, simultaneous or together with one or more pharmaceutically acceptable excipients, carriers, or diluents 'Special and preferably in the form of an effective amount of a pharmaceutical composition' whether by oral, rectal, or parenteral

ί «a. ··· K. 3 J -90- (87) (87) 1329635 (including intravenous or subcutaneous) or in some cases even localized. The appropriate dosage range is 1-1000 mg per day, preferably 10-500 mg per day, and especially 50-500 mg, usually depending on the correct mode of administration, the form of administration, the indication for which it is administered, and the individual involved The weight of the individual involved and the preferred choice and experience of the doctor or veterinarian. The term "therapeutically effective," as applied to a dose or amount, refers to an amount of a compound or pharmaceutical composition that, when administered to a living subject in need thereof, is sufficient to produce the desired activity. The active agents of the present invention may comprise conventional non-toxic pharmaceuticals. Dosage unit formulations of acceptable carriers are administered orally, topically, parenterally or mucosally (e.g., by buccal, by inhalation, or rectally). Oral routes are generally desired. The active agents can be capsules, lozenges, Orally administered in the form of a similar person (see Remington: The Science and Practice of

Pharmacy, 20th E d i t i ο n ( 2 0 0 0 ) , Philadelphia, PA). Oral administration of the drug can be time-controlled release carrier, including diffusion-control systems, osmotic devices, dissolution-control matrices, and erodable/degradable matrices. For oral administration in the form of a recording or capsule, the active pharmaceutical ingredient can be combined with non-toxic pharmaceutically acceptable excipients such as binders (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethyl) Cellulose): fillers (eg 'lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulphate, or calcium sulphate); lubricants (eg, hard fat) Magnesium, talc, or vermiculite, stearic acid, sodium stearyl carboxylate, glyceryl behenate, calcium stearate, etc.; -91 - (88) 1329635

a disintegrant (for example, potato starch or sodium starch glycolate); or a wetting agent (for example, sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (eg gum arabic, yellow) Silicone or alginate), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Oral administration of a liquid form of the 'pharmaceutical ingredient can be combined with a non-toxic pharmaceutically acceptable inert carrier (eg, 'ethanol, glycerol, water), a suspending agent (eg, sorbitol syrup, cellulose derivative or hydrogenated edible fat), Emulsifier (for example, lecithin or gum arabic), non-aqueous carrier (for example, almond oil, oil ester, ethanol or fractionated vegetable oil), preservative (for example, methyl or propyl-p-hydroxybenzoic acid or sorbic acid) , and so on. Stabilizers such as antioxidants (BHA, BHT, gallic acid, sodium sulphate, sodium citrate, citric acid) may also be added to stabilize the dosage form. Tablets can be coated by methods known in the art. The composition of the present invention can also be introduced into microspheres or microcapsules, for example, from polyglycolic acid/lactic acid (PGLA). The liquid formulations for oral administration can be in the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented as a dry powder which is recovered with water or other vehicle before use. Oral administration can be suitably formulated to produce controlled or delayed release of the active compound. The effective drug can also be administered in the form of a liposome delivery system, such as a single layer of small vesicles, a single layer of large vesicles, and multiple layers of vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or lecithin, as is known. The medicament of the present invention can also be delivered by using individual antibodies as individual molecules to which the compound molecules can be attached. Effective drugs are also available as alignable -92- (89) 1329635

Soluble polymer linkage of the drug carrier. The polymers may include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or palmitoyl Residue-substituted polyethoxylated poly-lysine. In addition, the effective drug can be linked to a class of biodegradable polymers that can be used to achieve controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, poly-ankyl Crosslinked or amphiphilic block copolymers of butyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and hydrogels. For administration by inhalation, the treatment according to the invention may be in the form of an aerosol spray formulation from a pressurized pack or nebulizer, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethylene. Ethane, carbon dioxide, or other suitable gas is conventionally delivered. In the case of a pressurized aerosol, the dosage unit can provide a valve measurement that delivers a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Formulations of the invention may be administered parenterally, i.e., intravenously (iv.), intraventricular (icv), subcutaneous (sc), intraperitoneal (intestine), intramuscular (im), subdermal ( Sd), or intradermal (i_d_) administration, by direct injection, delivery via, for example, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with added preservatives. The composition may be in the form of, for example, an oil or water carrier, -93- (90) (90) 1329635, a suspension 'solution, or an emulsion, and may contain a formulation such as suspension, stability, and/or Dispersant. Alternatively, the active ingredient may be in a powder form for recovery with a suitable carrier, for example, sterile non-pyrogenic water, prior to use. The compositions of the present invention may also be formulated for rectal administration, e.g., as a suppository or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides). The composition may be present in a package or dispenser device which may comprise one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to aid in the titration of the dosage, if desired. The package may, for example, comprise a metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration, as well as compositions of the invention formulated in a compatible pharmaceutical carrier, placed in a suitable container and labeled with the condition indicated by the treatment. As disclosed herein, the dosage of the component in the compositions of the invention is determined to ensure that the dosage administered continuously or intermittently will not exceed the amount determined after consideration of the results of the individual conditions of the test animal and the patient. The specific dose is naturally varied depending on the dosage step, the condition of the patient or target animal such as age, weight, sex, sensitivity, feed, dosage cycle, drug used in combination, severity of the disease. Under certain conditions, the appropriate dosage and dosage time can be determined by the above-mentioned index but can be determined by the test and according to the judgment of the practitioner and according to the standard clinical technique of each patient's environment (age, general condition, serious symptoms) Sex, Sex, etc.) Finally, the toxicity and therapeutic efficacy of the compositions of the present invention can be determined in experimental animals by standard pharmaceutical procedures, for example, by measuring LD5D (a dose that kills 50% of the population) and ED5. (The dose ratio between the dose-treatment of 94% (91) 1329635 and the toxic effect of the effective treatment of 50% of the population is expressed as the therapeutic index and it can be expressed as ED5〇/LD5°. The composition showing the large therapeutic index is preferred. Examples of sexual medicine compositions

It can be processed into tablets, film-coated tablets, capsules, drip solutions, suppositories, injections and infusion preparations, etc. by means of commonly used solvents, auxiliaries and carriers, and can be orally, rectally, parenterally, and Additional routes are administered therapeutically. Representative pharmaceutical compositions are as follows. (a) Lozenges containing the active ingredient suitable for oral administration can be prepared by conventional ingot techniques. (b) For suppositories, any of the usual suppository bases which are solid at room temperature but melt at about body temperature, such as polyethylene glycol, can be used in the usual steps of the active ingredient.

(c) For enteral (including intravenous and subcutaneous) sterile solutions, use a confining active ingredient in combination with conventional ingredients such as, for example, sodium chloride and double distilled water, 'according to known procedures' such as filtration' Aseptically filled into ampoules or IV-drop bottles, and autoclaved for sterilization. Other suitable pharmaceutical compositions are immediately apparent to those skilled in the art. Provisioning Examples The following examples are given again by way of illustration and are not made. • 95· (92) 1329635 Example 1 Lozenge Formulations Suitable formulations of tablets containing 10 mg of the active ingredient are as follows. mg Active ingredient 10 Lactose 6 1 Microcrystalline cellulose 25 Talc 2 Magnesium stearate 1 Colloidal cerium oxide 1

Example 2 Lozenge Formulations Other suitable formulations containing 1 mg of lozenge are as follows: -96 - (93) 1329635 mg active ingredient 100 crosslinked polyvinylpyrrolidone 10 potato starch 20 polyvinylpyrrolidone 19 Magnesium stearate 1 microcrystalline cellulose 50 film coating and coloring. The film coating material consists of the following: Hypromellose 10 microcrystalline cellulose 5 Talc 5 Polyethylene glycol 2 Color pigment 5

• Example 3 _ Capsule formulation The appropriate formulation for a capsule containing 50 mg of the active ingredient is as follows: -97- (94) 1329635 mg active ingredient 50 corn starch 26 calcium hydrogen phosphate 50 talc 2 colloidal cerium oxide 2 Gelatin capsules. Example 4 Injectable solution The appropriate formulation of the injectable solution is as follows: Active ingredient mg 10 Sodium chloride mg q. s. Water for injection ML to 1. 〇

Example 5 Liquid Oral Formulations The appropriate formulation for a 1 liter oral solution containing 2 mg of the active ingredient in one milliliter of the mixture is as follows: -98 - (95) 1329635 ____________ _____ mg 2 250 300 150 10 q. s. Add to 1 0 0 0 ml

Active Ingredients Sucrose Glucose Sorbitol Orange Taste Colorant Pure Water Example 6 Liquid Oral Formulation Other suitable formulations for a 1 liter liquid mixture containing 20 mg of active ingredient in 1 ml of the mixture are as follows: gram active ingredient 20.00 tragacanth 7.00 Glycerin 50.00 Sucrose 400.00 Methylparaben 0.50 propylparaben 0.05 Black raisin flavor 10.00 Soluble red pigment 0.02 Pure water added to 1000 ml-99- (96) 1329635 Example 7 Liquid oral formulation Other used A suitable formulation of a 1 liter liquid mixture containing 2 mg of active ingredient in 1 ml of the mixture is as follows:

Active ingredient 2 sucrose 400 bitter orange peel 20 sweet orange peel 15 pure water added to 1 000 ml Example 8 Aerosol formulation 180 g aerosol solution containing gram active ingredient 10 oleic acid 5 ethanol 8 1 pure water 9 tetraoxane B-75-100- (97) 1329635 15 ml of the solution was filtered in an aluminum aerosol can, covered with a metering valve, and rinsed with 3.0 bar. Example 9 TDS Formulation 100 g of solution contains: grams of active ingredient 10.0 ethanol 57.5 propylene glycol 7.5 dimethyl yam 5.0 hydroxyethyl cellulose 0.4 pure water 19.6

A 1.8 ml solution was placed on the batt covered with a backing foil. The system is closed with a suitable protective liner that is removed prior to use. Example 1 Tenon Nanoparticle Formulation 10 g of polybutylcyanoacrylate nanoparticle contained: r -101 - (98) 1329635 grams of active ingredient 1.00 poloxamer (Ρ ο 1 ο X amer ) 0.10 cyanide Acrylate 8.75 mannitol 0.10 sodium chloride 0.05

Polybutylcyanoacrylate vinegar nanoparticles are prepared by emulsion polymerization using a water/〇1 N HC1/ethanol mixture as a polymerization medium. Finally, the nanoparticle in the suspension is freeze-dried under vacuum. Pharmacology - The principle of activity of the present invention, and the pharmaceutical composition thereof and the therapeutic method therewith are characterized by unique and advantageous properties. The claim "the whole of the subject" is not significant. In the standard acceptable reliable test procedure, 'compounds and their pharmaceutical compositions exhibit the following properties and characteristics of valuable oxime: The method is used to characterize the binding properties of MGLUR5 antagonist properties and bind to the membrane permeability of the mGluR5 receptor in the cortical membrane. Preparation of [3H]MPEP(2-methyl-6-(phenylethynyl)pyridine) mouse cortical membrane at position-adjusted position: -102- (99) (99)1329635

The Sprague-Dawley male (200-250 g) daggers and quickly removes its brain. The anatomical cortex and a glass Teflon homogenizer were homogenized to 20 volumes of cooled 0.32 sucrose. The homogenate was centrifuged at 1000 10 8 for 10 minutes. Nine pellets and supernatant were discarded and centrifuged at 20, 〇〇〇 xg for 20 minutes. The resulting nine pellets were resuspended in 20 volumes of distilled water and centrifuged at 8 OOOxg for 20 minutes. The supernatant and the buffy coat were then centrifuged at 48,000 xg for 20 minutes in the presence of 50 mM Tris-HCl, pH 8.0. Then, nine pellets were resuspended and centrifuged at 48,000 x g for 20 to more than three times in the presence of 50 mM Tris-HCl 'pH 8.0. All centrifugation steps were carried out at 4 °C. After resuspending in 5 volumes of 50 mM Tris-HCl, pH 8.0, the conjunctival suspension was rapidly frozen at -80 °C. On the day of analysis, the membrane was thawed and washed four times by resuspending in 50 mM Tris-HCl, pH 8.0 and centrifugation at 48,000 xg for 20 minutes. And finally resuspended in 50 mM Tris-HCl, pH 7.4. The amount of protein in the final film formulation (25 〇 - 500 ng/ml) was determined according to the method of Lowry (Lowry Ο. Η. et al. 1951. J. Biol Chem. 193, 256-275). [3H]MPEP analysis culture line by (3H-MPEP (50.2 Ci/mole, 5nM,

Tocris) was added to a vial with 125-250 micrograms of protein (total volume 0.5 milliliters) and various concentrations of reagents. Incubate at room temperature for 6 minutes (equalize under the conditions used). Non-specific binding lines & Add unlabeled MPEP (10 uM) definition. The culture was terminated using a Millipore filtration system. The sample was rinsed with 4 ml of ice-cold assay buffer under a fixed vacuum through a glass fiber--103-(100) 1329635 filter (Schleicher & Schuell). After separation and washing, the filter was placed in a scintillation liquid (5 ml Ultima Gold) and the radioactivity remaining on the filter was measured using a conventional liquid scintillation counter (Hewlett Packard, liquid scintillation analyzer). .

The specific binding is extremely high, which is normally > 8 5 % and is essentially independent of buffer (Tris or HEPES oth 50 mM) and pH (6.8-8.9). The selected protein concentration (250-500 μg/ml) with clear saturation protein dependence and for subsequent analysis is within the linear portion of this dependence. The cold MPEP replacement has an IC5 of 18.8 ± 4.1 nM. Thermal ligand. The Kd of (3H)-MPEP of 13_6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of the displacer Kd 値 ( ICs of cold MPEP equal to Ki of 13·7 nM). Bmax is 0-56 pm/mg protein. The specific affinity of the membrane-regulating position of the mGLuR5 receptor is shown in the cortex/meningeal preparation of the compound of the present invention. Functional Analysis of the MGLUR5 Receptor Materials and Methods Astrocyte Culture Primary astrocyte culture lines were prepared from the cortex of neonatal rats as described by Booher and Sensenbrenner U972). Briefly, Sprague_ Dawley pups (2_4 days old) were decapitated and dissected to neocortex-104-(101)1329635 (neocortices), decomposed using a resistance filter (pore size 80 μm) and carefully honed. The cell suspension was flattened on a poly-D- lysine pre-coated flask (Costar) and supplemented with 10% heat-passivated fetal bovine serum (FCSi, Sigma), 4 mM branamine (Biochrom) and 50 μg /ml only gentamycin (Biochrom) Dulbecco's modified eagle medium (D MEM,

Invitrogen) was incubated at 37 ° C in a humidified atmosphere of 5% CO 2 / 95 % air for 7 days and the medium was exchanged on day 2.

After 7 DIV, the cells were shaken overnight at 250 rpm to remove oligodendrocytes and microglia. On the next day, the astrocytes were washed twice with CMF-PBS, trypsinized and leveled at a density of 40,0〇〇-45,000 cells/well in a poly-D-lysine pre-coated 96-well plate. (Becton Dickinson #6516 or #6640). 24 hours after the establishment of secondary culture, astrocytes were washed with PBS+ + and DMEM containing lxG5-supplement (InVitrogen), 微5 μg/ml heparan sulfate (Sigma), Astrocytic-defined medium (ADM) consisting of 1.5 μg/ml fibronectin (Sigma) (Miller et al., 1 99 3) was fed. After 3 days, the medium was exchanged and the cells were cultured for another 2-3 days so that the astrocytes were 14-15 DIV at the time of the experiment. Immunocytochemistry Immunostaining is performed to determine the presence of classical star-shaped cell markers such as GFAP which also expresses the mGluR5 receptor. -105- (102) 1329635 [3H]-phosphoinositol accumulation

After 12 days of astrocyte culture, remove ADM and add inositol-DMEM (MP Biomedicals) supplemented with [3 Η] my 〇-inositol (〇·5 u C i / well; P erki η E1 mer ), and ADM Chemicals. After 4 hours, the medium was replaced with 100 μl of Locke's buffer (plus 20 mM Li+, pH 7.4) and incubated at 37 ° C for 15 minutes before replacing the Locke's buffer with the activator/antagonist. The culture was terminated by replacing the Locke's solution with 100 μl of 〇_1 M HC1 (10 minutes on ice) (45 minutes at 37 ° C). At this stage the 96 well plate was frozen at -20 °C until further analysis. Separation of labeled phosphoinositides using a resin exchange column (AG1-X8 Biorad, 140-14444) manufactured by Home using 1 ml of 1 M ammonium formate/0.1 Μ formic acid in 24-well visiplates (Perkin Elmer) . The scintillation fluid (UltimaFlow AF, Perkin Elmer) was added and the plate was closed and rotated before measuring the radioactivity of the perintegration per minute (DPM) per minute using a conventional liquid phase flash count (Microbeta, Perkin Elmer). The FLIPR study showed that the astrocytes cultured as shown by immunostaining exhibited the mGluR5 receptor. Cells were stimulated with mGluR5 agonist DHPG or L-hypo-synthesis using a Fluorometric Imaging Plate Reader (FLIPR) and a Ca-pack (both Molecular Devices, CA) Increase in internal calcium «=· -106- (103) (103) 1329635 plus. Prior to the addition of the agonist or antagonist, the medium was aspirated and reconstituted with sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride at 150 μL at RT. Loading buffer consisting of (1.8 mM), D-glucose (15 mM), and HEPES (20 mM) Ca-sensitive dye (MD # R8033), pH 7·3 was loaded for 2 h. Subsequently, the disk was transferred to FLIP.R to add the measured DHPG (300 ^ Μ) or L-calcinate (100 ηΜ) as a fluorescent unit (RFU) to detect calcium increase. If the antagonist is tested, these compounds are pre-incubated for 10 minutes at RT prior to the addition of the individual agonist. For positive modulators, the concentration response curve for the presence of the kalucinate is present with or without the 10 VM conditioner to determine the extent to which the potentiation/activator potency is increased. Thereafter, a concentration reaction curve of a positive regulator in the presence of a kwitterite salt in a maximum window (normally 10-30 η Torr) showing a synergistic effect at a fixed concentration was carried out. Data Analysis The increase in fluorescence signal after the addition of the agonist reflects the increase in intracellular calcium. The inconsistency in the number of cells per well is corrected by the spatial uniformity of the FLIPR software. Calculate the average of the copy timing data (η = 5) and use it for graphical representation. For pharmacological evaluation, the maximum sputum reduction (MaxMin) is used to calculate the calcium change in the various concentrations of the agonist or antagonist. All reactions (DPM- or RFU-値) were determined as a percentage of the control group (=maximal reaction of the kyaninate at 100 ηΜ). According to the use -107- (104) (104) 1329635

Calculation of the logic equations for GraFit 5.0 (Erithacus Software) EC50 and IC50 〇 Chemicals All chemicals were purchased from Sigma unless otherwise indicated. references

Booher and Sensenbrenner (1972) Neurobiology 2(3): 97-105 Miller et al. (1993) Brain Res. 618(1): 175-8. The compounds of the invention have an EC50 range of from about 0.5 nM to about 100; zM. Conclusion In conclusion, it will be apparent from the foregoing that the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention comprising the principles of activity according to the present invention, as well as pharmaceutical compositions thereof and methods for their preparation and use thereof Treatment, all have the characteristics and benefits explicitly listed above. The high activity of the active agents of the compounds of the invention and their compositions, as evidenced by the reporter test, is indicative of their availability in terms of their valuable activity in humans and in lower animals. However, the clinical evaluation of humans has not yet been completed. It should be clearly understood that the distribution and sale of any compound or composition that is within the scope of the present invention for humans will of course be determined prior to the approval of the government agency responsible for the issue, such as the US Food and Drug Administration. . -108- (105) 1329635 The present vinyl-substituted tetrahydroquinolinone derivative represents a novel class I group mGluR modulator. They are especially useful as positive regulators or activators for mGluR 5 . Given their effectiveness, they will be an effective treatment for a wide range of CNS disorders involving abnormal glutamate-induced stimuli.

These compounds are therefore found in the treatment of active subjects, especially humans, in the following diseases: AIDS-related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongy Bovine spongiform encephalopathy (BSE) or other prion-related infections, diseases involving mitochondrial dysfunction, and amyloidosis and/or tauopathy Diseases such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuropathy such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment ), boxing dementia, vascular and frontal dementia, dysfunction, eye trauma or Disease (eg glaucoma, retinopathy, macular degeneration), head and spinal cord trauma/trauma, hypoglycemia, anoxia (eg perintal), ischemia (eg due to cardiac arrest, stroke, bypass surgery) Or transplant), 痉re·· 3 > -109- (106) 1329635 挛, glioma and other tumors 'inner ear damage (eg tinnitus, sound or drug-induced), L-dopa drug-induced and delayed movement Obstacle (tardive dyskinesia) °

These compounds have also been found in the treatment of active objects, especially in humans: addiction (nicotine, alcohol, opiates, coca, amphetamines, obesity and others), amyotrophic lateral Sclerosis), anxiety and panic disorder, attention deficit hyperactivity Disorder (ADHD), restless leg syndrome and hyperactivity, autism, paralysis/epilepsy Dementia (eg Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infection), major depressive disorder or depression (including caused by Borna virus) Bipolar manic depressive disorder, drug resistance such as opioids, movement disorders, dystonia, dyskinesia (eg L-dopa drugs) Sexual dyskinesia or Huntington's disease, X-staining Breakable body disease (fragi 1 e

Xsyndrome), Huntington's chorea, irritable bowel syndrome (IBS) 'Migraine, multiple sclerosis, muscle spasms, pain (chronic and acute, such as inflammatory pain, neuropathic pain, Touch pain (allodynia), hyperalgesia, involuntary pain (nociceptive * V. -110- (107) J329635 pain), Parkinson's disease, p0St traumatic stress disorder, schizophrenia (positive and negative symptoms), squatting, tinnitus, Tourette's syndrome, urinary incontinence and vomiting, itching (such as itching), sleep disorders, urinary dysfunction - disease, lower urinary tract muscles Sexual disorders, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES), gastrointestinal dysfunction, dyspepsia, nausea, respiratory infection Bulimia nervosa, chronic laryngitis, asthma (eg countercurrent) f 1 u x )-related asthma, lung disease, eating disorders, obesity and obesity-related diseases. These compounds are also found in the use of therapeutically active agents, particularly human indications, where no particular circumstances exist but wherein specific physiological parameters (including cognitive enhancement) can be improved by administration of the compounds of the invention. 'Methods of treating a moving subject with a compound of the invention, for the suppression of progression, or for the reduction of a minor disease thereof, as described above, by any generally accepted medical route, the use of an effective mitigation of the particular ailment to be alleviated dose. The compounds of the invention are useful in the inhibition of progression or in the selection of minor diseases or conditions in the manufacture of therapeutic actives, in particular in the use of Group I mGluR modulators, in particular mGluR5 modulators, especially mGluR5 positive regulators or activators The use of a medicament for the treatment of a susceptible ailment or condition is carried out by the step of comprising a compound of the invention in an amount effective in combination with a pharmaceutically acceptable diluent, excipient, or carrier. The usual manner, and methods of treatment, pharmaceutical compositions, and the use of the compounds of the invention in the manufacture of a medicament. Representative pharmaceutical compositions are prepared by mixing active ingredients with suitablepharmaceutically acceptable diluents, excipients, or carriers, including lozenges, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS Formulations, and nanoparticle formulations, which are prepared for oral, injectable, or dermatological use, are also consistent with the foregoing.本 氺 氺 * The present invention is not limited to the scope of the specific embodiments described herein. Indeed, various modifications of the invention will become apparent to those skilled in the <RTIgt; All patents 'applications, publications' test methods, documents, and other materials cited herein are hereby incorporated by reference.

-112-

Claims (1)

J^^35 Em X. Application for patents [W sub-component 3Α [Patent No. 95 1 3 0667] Chinese patent application scope is replaced by the amendment of the Republic of China on May 1st, 1999. 1 · A compound of formula I, Wherein R1 represents aryl or heteroaryl; R2 and R3, R4 and R5, it is understood that: they may be the same or different and represent hydrogen or Ci6 alkyl; they may be the same or different and represent hydrogen or Ci6 alkyl; The radical means an unsubstituted phenyl ring or a benzyl ring substituted by 1, 2, 3, 4 or 5 substituents, which may be the same or different, the substituents being selected from any one or more fluorines, Ci6 alkyl substituted by chlorine or bromine atom, Cl6 alkoxy substituted by one or more fluorine, chlorine or bromine atoms, ring c3. J2 alkyl, hydroxyl, F, CM, Br, I, CN, nitro 'Di-Cu alkylamino group, N-ring C: 3 ·, 2 alkyl-N-Cm alkylamino group, nitrogen sulfonyl group, pyrrolidinyl group, hexahydropyridyl group, morpholinyl group, 4-Cu alkyl group - hexahydropyridinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl and phenyl a group [S 丄: group; heteroaryl]; + _ race represents a (hetero)aromatic 5-, 6- or 7, Changyi _/~ ring having from 1 to 4 heteroatoms independently selected from the group consisting of Oxygen, nitrogen and sulfur, The ring is unsubstituted or substituted with 1, 2 or 3 substituents, which may be the same or different, and the 〇* /, substituent is selected from any one or more fluorine, chlorine or bromine atoms m; Ft ^ Γ 1 ·6 alkyl, any Ci-6 oxime substituted by one or more fluorine, chlorine or bromine atoms, ring c3.12 alkyl, hydroxy, F, Cl, Br, I, CN, nitrate -'-Cu alkylamino, N-cyclo c3 i2 alkyl_N_Ci 6 alkylamino, nitrogen H danyl, pyrrolidinyl, hexahydropyridyl, morpholinyl, 4 _ c ι -6 alkyl -hexahydropyridinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl and phenyl And the compound of formula I is not represented by: 2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one 2-pyridin-3-ylethynyl-7,8-dihydrogen - 6H-quinoline-5-one 2 - m-tolylethyl 8 - _ ammonia - 6H - 嗤 -5 - 5 - steel 2- ( 3 - hydroxy-phenylethynyl)-7,8 - dihydro - 6H-quinoline-5-one 2-(3-methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-fluoro-phenylethynyl) -7,8 - two Hydrogen-嗤琳-5-嗣2-(3-chloro-phenylethynyl)-7,8-dihydro-6Η-quinolin-5-one 2-(3-bromo-phenylethynyl)-7 ,8-Dihydro-6Η-quinolin-5-one 3-( 5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 2-thiazole- 5-ylethynyl-7,8-dihydro-6Η-quinolin-5-one 2-oxazol-5-ylethynyl-7,8-dihydro-6Η-quinolin-5-one-2 - 1329635 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7.7-dimethyl-2-m-tolylvinyl- 7 ,8-Dihydro-6H-quinolin-5-one 2-(3-hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-chloro-phenylethynyl)-7 ,7-Dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro- 6H-quinolin-5-one 3-(7,7-dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 7.7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinoline-5-one 7,7-dimethyl-2-oxazol-5-ylethynyl- 7,8-Dihydro-6H-quinoline-5-one 2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinoline-5 ketone or 2 - (2-phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinoline- 5- And optical isomers and pharmaceutically acceptable salts thereof. 1329635 2. A compound according to claim 1 wherein R2 and R3, which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl or t-butyl and R4 and R5 represent hydrogen. 3. A compound according to claim 1 wherein R2 and R3 represent hydrogen and R4 and R5, which may be the same or different and represent methyl, ethyl, n-propyl, 2-propyl, n-butyl or Third butyl. 4. A compound according to claim 1 wherein R2 'R3, R4 and R5, which may be the same or different, represent hydrogen, methyl or ethyl. The compound according to any one of claims 1 to 4, wherein R1 represents an aryl group; it should be understood that: aryl means unsubstituted phenyl or mono- or di-substituted with the same or different substituents. a phenyl group, the substituents being selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropyl Oxygen, n-butoxy, tert-butoxy, CF3, CH2F, CH2F, C2F5, OCF3, OC2F5 'F, Cl, Br, CN, hexahydropyridyl, morpholinyl, tetrazolyl, oxazole A group consisting of a furyl group, a furyl group, a thiophenyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidinyl group, and a phenyl group. 6. A compound according to claim 5, wherein the 1329635 aryl group represents an unsubstituted phenyl group or a mono- or di-substituted phenyl group having a substituent at a meta position. 7. A compound according to any one of claims 1 to 4 wherein R1 represents a heteroaryl group. Heteroaryl represents pyridine-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol-5-yl, thiazol-5-yl, wherein each of these rings may be unsubstituted or phenyl, A Base, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, third Butoxy, CF3, CH2F, CH2F, C2F5, OCF3, OC2F5, F, Cl, Br, CN, hexahydropyridyl D, morpholinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, Isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridyl or pyrimidinyl mono- or di-substituted. 8. A compound according to claim 1 of the patent application, which is selected from the group consisting of: 6,6- _methyl-2-pyrene than U疋-3-ylethylidene - 7,8 - qi - 6H - 嗤琳- 5-keto, 2-(3-fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-chloro-benzene Ethyl ethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-methoxy-phenylethynyl)-6,6-dimethyl Base-7,8-dihydro-6H-quinolin-5-one, 2-(3-hydroxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quino- 5- 1329635 Lin-5-keto, 3-(6,6-dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile, 6.6-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinoline-5-one, 6,6-dimethyl-2-(3-hexahydropyridine-1 -yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 7.7-dimethyl-2-(3-hexahydropyridin-1-yl-phenylethynyl)- 7,8-dihydro-6H-quinolin-5-one, 2-(3-hexahydropyridin-1-yl-phenylethynyl)-7,8-dihydro-6H-quino-5-oxime , 2-( 3 -orfos-4'-yl-benyl),-7,8 - _ gas - 6H -pyrene _ 5-ketone, 7.7- _methyl-2- (3 -Noflavin-4-yl-phenylethyl carbyl)-7,8--hydro-6H-quinolin-5-one, 6.6-dimethyl-2-(3-morpholine-4-yl -phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 6.6-dimethyl-2-[3-(1-tetrazol-5-yl)-phenylethynyl ]-7,8-Dihydro-6H-quinolin-5-one' 7.7-dimethyl-2-(3-(1Η-tetrazol-5-yl)-phenylethynyl]-7,8- Dihydro-6H-quinoxazol-5-one, 2-[3-(1Η-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one, 2-[3-Fluoro-5-(111-tetrazol-5-yl)-phenylethynyl]-6,6-dimethyl-6- 1329635 base-7,8-dihydro-6H-quinoline- 5-keto, 2-[3-fluoro-5-(1}1-tetrazol-5-yl)-phenylethynyl]-7,7-dimethyl-7,8-dihydro-6H-quin Porphyrin-5-one, 2-[3-fluoro-5-(1^tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-嗤琳-5-嗣, 2- (3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinoline-5-one, 7,7-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 6.6-dimethyl-2-(3 -trifluoromethyl-phenylethynyl)-7,8-dihydro-6 Η-quinoline·5-one, 7.7-dimethyl-2-phenylethynyl-7,8-dihydro-6Η -quinolin-5-one, 6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6Η-quinolin-5-one, 2-(4-methyl-thiazole-2 -ylethynyl)-7,8-dihydro-6y-quinoline-5-one, 7,7-dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8 -Dihydro-6Η-quinolin-5-one, 6,6-dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinoline- 5-keto, 2-(4-fluoro-thiazol-2-ylethynyl)-7,8-dihydro-6Η-quinoline-5-one, 2-(4-fluoro-thiazol-2-ylethynyl) -7,7-Dimethyl-7,8-dihydro-6Η-quinolin-5-one, 2-(4-fluoro-thiazol-2-ylethynyl)-6,6-dimethyl- 7,8-dihydro-1329635 6H-quinolin-5-one, 2-(2-phenyl-thiazol-5-ylethynyl)-7,8-dihydro-611-quinolin-5-one, 2-(5-fluoro-pyridin-3-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 3-fluoro-5-(7,7-dimethyl-5-one 5-,6,7,8-tetrahydro-quinoline -2-ylethynyl)-benzonitrile, 2-(4-fluoro-5-phenyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-sialolin-5-one, 2-( 4 -Gas-5-indole 卩疋-3 -yl-Boxan-2-ylethenyl)-7,8 - one gas-6H-quinolin-5-one, 2- (4- Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-fluoro -5-pyridin-3-yl-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinoxadol-5-one, 7,7-dimethyl -2 -pyridin-2-ylethynyl-7,8-dihydro-6H-quinoline-5-one, 2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinoline-5 -ketone, 6.6-methyl-2-ladenidine-2-ylethyl fast radical- 7,8--gas- 6H-wowlin- 5-ketone, 6.6-dimethyl-2-(4-methyl -oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 7.7-dimethyl-2-(4-methyl-oxazol-2-ylethynyl) -7,8-dihydro-6H-嗤琳-5-嗣, -8- 1329635 2-(4-fluoro-5-pyridin-3-yl-1H-imidazol-2-ylethynyl)-7, 8-diamino- 6H-嗤琳-5-嗣, 2-(4-fluoro-5-pyridine-3-yl-1H-imidazol-2-ylethynyl)-7,7-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 2- ( 4 -fluoro-5-pyridin-3-yl-1H-imidazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 6.6-Dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 7.7-dimethyl-2- (4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-pyridin-3-yl-imidazole-bu-acetylene ,7,8-dihydro-6H-quinolin-5-one, 2-thiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-[1, 3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6^1-quinolin-5-one, 2-[1,3,4]oxadiazol-2-ylethynyl -7,8-Dihydro-6H-quinoline-5-one, 2-(1H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 6.6- Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-611-quinolin-5-one, 7.7-dimethyl-2-[1, 3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6^嗤琳-5-嗣, 7.7-dimethyl-2-(111-tetrazol-5-ylethynyl) -7,8-dihydro-61·!-嗤琳-5-ketone, -9- 1329635 6.6-dimethyl-2-(111-tetrazol-5-ylethynyl)-7,8-dihydro -611-Lusong-5-keto, 6.6-dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-oxazole-2- Ethynynyl-7,8-dihydro-6H-quinolin-5-one, 6.6-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-salin-5-one, 7,7-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinoline-5-one, 6.6-dimethyl-2-m-tolylvinyl- 7 ,8-Dihydro-6H-quinoline-5-one, 7.7-dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinoline -5-keto, 6.6-dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-salben-5-oxime, 7.7-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 6,6-dimethyl-2-( 5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-(5-gas-D than Π定-3-ylethyl)- 7,7-monomethyl-7,8--gas-6H-quinolin-5-one, 2-(5-fluoropyridin-3-ylethylidene)-6,6-monomethyl- 7,8 - monogas-6H-quinolin-5-one, 3-fluoro-5-(5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzene- 10-,1) 1329635 carbonitrile, 3-(6,6-dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-5-fluoro- Benzoonitrile, 2-(4-fluoro-5-phenyl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-quinoline-5 -ketone, 7,7-dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6Η-quin Porphyrin-5-one, 2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl-7,8-dihydro-6Η-quinolin-5-one , and its optical isomers and pharmaceutically acceptable salts. 9. A medicament comprising at least one compound of formula I R1 wherein R1 represents a non-aryl or anthracene group; R2 and R3, which may be the same or different, represent hydrogen or Cl.6 alkyl; R4 and R5, which may be the same or different, represent hydrogen or Ci-6 -11 - 1329635 It should be understood that aryl represents an unsubstituted phenyl ring or a phenyl ring substituted with 1, 2, 3, 4 or 5 substituents which may be the same or different and the substituents thereof Any of the Ci 6 alkoxy groups optionally substituted by one or more fluorine, chlorine or bromine atoms, optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloalkyl, hydroxy, F, Cl , Br, I, CN, nitro, bis-Ci 6 amine, N-ring Cm, N-Ci_6, amine, nitrogen, thiophene, hexahydropyridyl, morpholine , 4 - C !·6 alkyl-hexahydropyridinium, tetradecyl, oxazolyl 'furanyl, pyrrolyl, thiophenyl, isoxazolyl, thioxyl, imidazolyl, oxadi a group consisting of azolyl, pyridyl, pyrimidinyl and phenyl; heteroaryl means a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms independently selected From oxygen, nitrogen and sulfur, where the ring is not Substituted or substituted by 1, 2 or 3 substituents, which may be the same or different 'the substituents are selected from any of the -6 alkyl groups substituted by one or more fluorine, chlorine or bromine atoms, any one or C!-6 alkoxy, cyclo C3-12 alkyl, hydroxy, F, Cl, Br, I, CN, nitro, di-Cu alkylamino, N-ring substituted with a plurality of fluorine, chlorine or bromine atoms C3.12 alkyl-N-Cu alkylamino, nitrogen-based, pyrrolidinyl, hexahydropyridyl, morpholinyl, 4-(^-6-alkylhexahydropyrryl, tetrazolyl, a group consisting of oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl and phenyl; and optical isomers thereof a pharmaceutically acceptable salt; and the following compounds and their optical isomers and pharmaceutically acceptable salts except -12- 1329635: 2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one-2-pyridyl-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-inter Tolylvinyl-7,8-dihydro-6H-quinolin-5-one 2-(3-hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2- (3-methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-fluoro-phenylethynyl)-7,8-dihydro-6H- Quinoline-5-one 2-(3-chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-bromo-phenylethynyl)-7,8 -Dihydro-6H-quinolin-5-one 3-(5-keto-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 2-thiazole-5- Ethynynyl-7,8-dihydro-6H-quinolin-5-one-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-di Methyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinoline-5-one 7,7-Dimethyl-2-m-tolylvinyl-7,8-dihydro-6H-quinolin-5-one 2-(3-hydroxy-phenylethynyl)-7,7-dimethyl Base-7,8-dihydro-6H-quinolin-5-one 2-(3-methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quin Porphyrin-5-one 2-(3-fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-indole 2-(3-chloro-phenyl Ethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-bromo-phenylethynyl)-7,7-dimethyl-7, 8-dihydro^^quinoxa-13- 1329635 oxalyl-5-one 3-(7,7-dimethyl-5-keto-5,6,7,8-tetrahydro-quinolin-2-yl Ethynyl)-benzonitrile 7,7-dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinoline-5-one 7,7-dimethyl-2 Oxazol-5-ylethynyl-7,8-dihydro-6H-quinoline-5-one 2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H - quinoline-5-one and 2-(2-phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one. 10. Application of a compound of formula I, r\ Wherein R1 represents an aryl or heteroaryl group; R2 and R3, which may be the same or different, represent hydrogen or C!-6 alkyl; R4 and R5, which may be the same or different, represent hydrogen or CL6 alkyl; It is understood that an aryl group means an unsubstituted phenyl ring or a phenyl ring substituted by 1, 2, 3, 4 or 5 substituents, which may be the same or different, and the substituent is selected -14- 1329635 Free radicals substituted with one or more fluorine 'chlorine or bromine atoms substituted with one or more fluorine, chlorine or bromine atoms substituted by 12 alkyl, hydroxyl, F, (M, Br, ί, CN, nitrate Base group, N-ring C3·&quot;alkyl·N_Ci 6 alkylamino group, nitrogen hexyl hexahydroxanthyl group, morpholinyl group, 4_Ci 6 alkyl-hexahydro group, decyl group, furyl group, pyrrole a group, a thiophenyl group, an iso-yl group, an imidazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidinyl group, and a group; a heteroaryl group 7K having from 1 to 4 hetero atoms (6- or 7-membered ring, the hetero The atoms are independently selected from the group consisting of oxygen, nitrogen, and are unsubstituted or substituted with 1, 2 or 3 substituents, different 'substituents are selected from C u 6 alkyl substituted by any one or more fluorines, any - or a plurality of fluorine, chlorine or Cu alkoxy groups, a ring C3.12, a base group, a F, a C1, a nitro group, a bis(^.6 alkylamino group, an N-ring C3.12 alkyl-NC Thiophene, pyrrolidinyl, hexahydropyridyl, morpholinyl, hydroquinone thiol, tetradecyl, D oxime, fluorenyl, indolyl oxazolyl, thiazolyl, imidazolyl a group consisting of oxadiazolyl, pyridyl and phenyl; and its light Isomers and pharmaceutically acceptable salts; which are used in the manufacture of a medicament for the prevention and/or treatment of a condition or disease in an animal, the condition or the regulating effect of the disease agent being produced or promoted. Application of Patent Application No. 10, C 1 -6, oxy, cyclo c3., di-Cu alkylamine, pyrrolidinyl, pyridinyl, tetrazolyloxalyl, thiazolyl a group of aromatic 5-, sulfur, wherein the ring may be the same or a chlorine or bromine atom substituted by a bromine atom, Br, I, CN, I-6 amine, nitrogen 4-〇丨-6 · The use of a hexa-, thiophenyl, pyridyl, pyrimidinyl group in a human, including mGluR5, wherein mGluR5 [£ -15- modulator is a positive mGluR5 modulator or mGluR5 mobilizes I2. Wherein R1 represents an aryl or heteroaryl group; R2 and R3' may be the same or different and represent hydrogen or R4 and R5' which may be the same or different and represent hydrogen or should be understood: Labor: phenyl represents unsubstituted benzene A phenyl ring substituted with a base ring or a substituent of 1, 2, 2, which may be the same or different, freely substituted or substituted with a plurality of fluorine, chlorine or bromine atoms, meaning one or more fluorine, chlorine or bromine Atomic substituted C16 institute 12 alkyl, hydroxy, F, Cl, Br, I ' CN, nitro, yl N-cyclo C3-12 fluorenyl-N-Ci.6 compound amine, nitrogen hexamethylene hexahydroanthracene Pyridyl, morpholinyl, 4-C, -6-alkyl-hexahydro, oxazolyl, furyl, pyrrolyl, thiophenyl, isoyl' imidazolyl, oxadiazolyl, pyridyl, Pyrimidinyl and group; heteroaryl denotes a 6- or 7-membered ring having from 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and 1-6 alkyl; e 1 - 6 alkyl 3, 4 or 5 ################################################################################################ a group of thiazolyl phenyl groups) aromatic 5_, sulfur, wherein the ring -16- 1329635 is unsubstituted or substituted by i, 253 substituents which may be the same or different, the substituents being selected from CKe alkyl optionally substituted by one or more fluorine 'chloro or bromine atoms Ch-yard oxy group, ring C3.12 alkyl group, hydroxyl group, F, cl, Br, Bu CN substituted by one or more fluorine, chlorine or bromine atoms Nitro-alkylamino, N-cyclo c3.12 alkyl_N_Cl 6 alkylamino, nitrogen-n-pyrrolidinyl, hexahydropyridyl, morpholinyl, 4-Ci 6 alkyl-hexahydropyramyl a group consisting of tetrazolyl, oxazolyl, furyl, pyrrolylthiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl and phenyl; and optical Isomers and pharmaceutically acceptable salts; for the manufacture of a AIDS-related dementia, Alzheimer's disease, human Jakub's syndrome (Creutzfeld-Jakob's) Syndrome), bovine spongiform encephalopathy (BSE) or other priori-related infections, diseases involving mitochondrial dysfunction, involving amyloidosis and/or tau Diseases of tauopathy such as Down's disease, hepatic encephalopathy, Huntington's disease, motor neuropathy such as amyotrophic lateral sclerosis (amy〇tr〇phic) Lateral sclerosis) ( ALS) , multiple sclerosis (MS), olivopontocerebellar atrophy ' post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild dysfunction (mild Cognitive impairment), boxing home -17- 1329635 dementia, vascular and frontal dementia, dysfunction' ocular trauma or disease (eg glaucoma, retinopathy, macular degeneration), head and spinal cord trauma / trauma, hypoglycemia, Hypoxia (eg, delivery), ischemia (eg due to cardiac arrest, stroke, bypass surgery or transplantation), sputum, glioma and other tumors, inner ear damage (eg tinnitus, sound or medication-induced), L - Dopa drug-induced and tardive dyskinesia, addiction (nicotine, alcohol, opiates, cocaine, amphetamines, obesity, and others) 'Anxiety and panic disorder, attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD), restiess leg syndrome, and hyperactive children' autism , 痉挛/epileptic dementia (such as Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infection), major depressive disorder or depression (including Caused by Borna virus infection) and bipolar manic depressive disorder, drug resistance such as opioids, m〇vement disorders, dystonia, dyskinesia (eg L-multi Bacao-induced tardive dyskinesia or Huntington's disease, X-chromosome fragility (Fragiie_x syndr〇me), Huntington's chorea, intestinal irritation Irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasm, pain (chronic and acute, such as inflammatory pain, neuropathic pain, allodynia, hyperalgesia -18-1329635 (hyperalgesia) , traumatic nociceptive pain, Parkinson's disease, post-traumatic stress disorder (post traumatic st Ress disorder), schizophrenia (positive and negative symptoms), sputum, Tourette's syndrome, urinary incontinence and vomiting, itching (eg itching), sleep disorders, urinary problems, lower urinary tract Neuromuscular disorders, gastroesophageal reflux disease (GERD), lower esophagus Lower esophageal sphincter (LES), gastrointestinal disorders, dyspepsia, nausea, respiratory infections, bulimia nervosa, chronic laryngitis, asthma (eg reflux) - related asthma), lung disease, eating disorders, obesity and obesity-related diseases, wild phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post traumatic stress disorder, social Social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder , 谵妄, or medicine for cognitive enhancement and/or neuroprotection. 1 3 According to the application of the scope of claim 12, wherein the medicine is used for the prevention and/or treatment of addiction, neuropathic pain, L-dopa drug-induced and tardive dyskinesia, ALS, X Fragile-X syndrome 'Parkinson's disease, anxiety, -19-1329635 epilepsy, positive and/or negative symptoms of schizophrenia, dynamism, or for cognitive enhancement and / or neuroprotective § Cui. I4, a pharmaceutical composition which comprises, as an active ingredient, a compound according to claim 1 and one or more pharmaceutically acceptable excipients or carriers. -20