TW201307301A - Metabotropic glutamate receptor modulators - Google Patents

Abstract

The invention relates to heterocyclic derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are mGluR5 modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

Description

Metabotropic glutamine receptor modulator

The present invention relates to a heterocyclic derivative which can be used as a novel metabotropic glutamate receptor (mGluR) modulator, a synthetic method thereof, and a derivative thereof for treating and/or preventing various diseases and A condition (including a neurological condition).

Neuronal stimulation is transmitted by the central nervous system (CNS) via the interaction of neurotransmitters released by neurons, which have a specific effect on the neuroreceptors of another neuron. L-glutamic acid is considered to be the major excitatory neurotransmitter in the mammalian central nervous system and therefore plays a key role in a number of physiological processes. The glutamate-dependent stimulating receptors are divided into two major groups. The first group contains ligand-controlled ion channels, while the other group contains a metabotropic glutamate receptor (mGluR). The metabotropic glutamate receptor is a subfamily of G protein coupled receptors (GPCRs). There is increasing evidence of ionic and ubiquitous glutamate receptors in peripheral roles outside the central nervous system (eg, in chronic pain states).

Currently, these metabotropic glutamate receptors (mGluR) are known to have eight different members. These eight receptors can be divided into three groups based on structural parameters such as sequence identity, second messenger systems utilized by these receptors, and their different affinities for low molecular weight compounds. mGluR1 and mGluR5 belong to Group I, which is coupled positively to phospholipase C and whose activity results in the flow of intramolecular calcium ions. MGluR2 and mGluR3 belong to Group II, and mGluR4, mGluR6, mGluR7, and mGluR8 belong to Group III, both of which are negatively coupled to adenosine cyclase, that is, their activation results in a decrease in second messenger cAMP, thereby inhibiting neuronal activity.

mGluR5 modulators have been shown to modulate the effects of presynaptic released neurotransmitter glutamate via postsynaptic transduction (receptors). Moreover, because these modulators can be both positive and/or negative mGluR5 modulators, such modulators can increase or inhibit the effects mediated by these metabotropic glutamate receptors.

The modulator is a negative mGluR5 modulator that reduces the effect of mediation via the metabotropic glutamate receptor. Since the various pathophysiological processes and disease states affecting the central nervous system are thought to be involved in abnormal glutamate nerve conduction, and the mGluR5 receptor has been shown in many regions of the central nervous system and peripheral nervous system, regulation of these receptors The agent can medically treat diseases involving the central nervous system and the peripheral nervous system.

Thus, mGluR5 positive or negative modulators can be administered to provide neuroprotective and/or disease amelioration in the following acute or chronic pathological conditions or to provide symptomatic effects on the following conditions: Alzheimer's disease, Cuija Syndrome/Cuija's disease, mad cow disease (BSE), Purkinin-related infection, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tau protein disease, Down's syndrome, liver Encephalopathy, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, repair Gram's syndrome, neuronal waxy lipofacia, neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's dementia, light Cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, boxer dementia, vascular and frontal dementia, cognitive impairment, learning disabilities, eye injuries , eye disease, eye disease, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma, hypoglycemia, hypoxia, hypoxia during perinatal period, ischemia, due to cardiac arrest Or ischemia or paralysis caused by stroke or bypass surgery, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury, inner ear injury of tinnitus, tinnitus, sound- or drug-induced inner ear injury, Sound- or drug-induced tinnitus, hyperesthesia, L-dopa-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dyskinesia, dyskinesia in Huntington's disease , drug-induced dyskinesia, antipsychotic drugs-induced dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced dyskinesia, chorea, Dyton's chorea, dysthymia, dystonia, stereotypic, twitching, tardive dyskinesia, antipsychotic-induced dyskinesia, tic disorder, spastic torticollis, eyelids, local and general Insufficiency, nystagmus, hereditary cerebellar dysmotility, cortical basal ganglia degeneration, trembling, idiopathic trembling, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse , opium addiction, opium abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), lack of attention Hyperactivity disorder (ADHD), Attention Deficit Syndrome (ADS), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Disease Dementia, dementia of Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain lesions, AIDS brain lesions, AIDS Dementia syndrome, AIDS-related dementia, severe depression, severe depression, depression, depression caused by Borna virus infection, severe depression caused by Borna virus infection, double Polar bipolar disorder, drug tolerance, drug tolerance to opioids, dyskinesia, fragile X syndrome, intestinal tract (IBS), migraine, multiple sclerosis (MS), muscle cramps, pain, Chronic pain, acute pain, inflammatory pain, neuralgia, diabetic neuropathic pain (DNP), pain associated with rheumatoid arthritis, hyperalgesia, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD) ), schizophrenia, schizophrenia positive or cognitive or negative symptoms, spasticity, turdy, urinary incontinence, vomiting, pruritus, pruritus, sleep disorder, frequent urination, lower urinary tract Meat disease, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disease, dyspepsia, nausea, respiratory infection, neurological eclipse, chronic laryngitis, asthma, reflux Asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorder, square phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, Phobia, substance-induced anxiety, paranoia, schizophrenia, schizophrenia, substance-induced psychosis, or paralysis, diabetes, hyperammonemia and liver failure, and sleep disorders.

mGluR5 negative or positive regulators can also be administered to provide inhibition weeks Tumor cell growth, migration, invasion, adhesion, and toxicity of the lateral tissues, peripheral nervous system, and central nervous system. mGluR5 modulators can also be administered to provide medical intervention in tumor formation, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), Lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue tumor, glioma, malignant glioma, astroglioma, glioma , neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial tumor, lymphoma, myeloma, Hodgkin's disease, Burkitt's Lymphoma, leukemia, thymoma, and other tumors.

mGluR5 positive or negative modulators can also be administered to provide improved disease and/or provide symptomatic effects on the following conditions: diabetes, hyperammonemia, and liver failure.

Further indications for mGluR5 negative or positive modulators include those indications in which a particular condition does not necessarily exist, but wherein certain physiological parameters may be improved by administration of the compound, including cognitive enhancement, learning disabilities, and/or Neuroprotection.

Positive modulators are particularly useful for the treatment of positive and negative symptoms of schizophrenia, as well as cognitive impairment in various forms of dementia and mild cognitive impairment.

Furthermore, the mGluR modulator can be active when administered in combination with other substances that exhibit neurological effects via different machines.

Simultaneous administration of Group I mGluR modulators with NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (Zieminska et al. Acta Neurobiol . Exp ., 2006 , 66 , 301-309; Zieminska et al. Neurochemistry International , 2003 , 43 , 481-492; and Zieminska et al. Neurochemistry International , 2006 , 48 , 491-497).

Simultaneous administration of Group I mGluR modulators with compounds such as L-DOPA, dopamine mimetic, and/or antipsychotics can be used to treat a variety of conditions including dyskinesia, antipsychotic-induced dyskinesia, haloperidol (haloperidol)-induced dyskinesia, dopamine mimetic-induced dyskinesia.

Some types of mGluR5 modulators have been described in the literature.

It has now been discovered that certain heterocyclic derivatives are potent mGluR5 modulators. Thus, these materials are medically advantageous for the treatment of conditions involving abnormal glutamate neurotransmission or where modulation of the mGluR5 receptor can lead to medical benefits. These materials may be administered in the form of a pharmaceutical composition in which they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.

Purpose of the invention

The object of the present invention is to provide a novel pharmaceutical compound which is a mGluR5 modulator and a pharmaceutical composition thereof. A further object of the present invention is to provide a treatment, elimination, and subtraction by using a compound of the present invention or a pharmaceutical composition containing the same Light, alleviate, improve, or ameliorate undesirable central nervous system disorders involving abnormal glutamate nerve conduction, and/or provide symptomatic effects.

A further object of the invention is to provide a process for the manufacture of heterocyclic derivatives.

Summary of invention

Therefore, the inclusion of the invention can be summarized in the following words: a compound selected from the formula I Wherein X represents CH ₂ or C=O; Y represents CR ⁶ R ⁷ , NR ⁸ , O or S; R ¹ represents H, C _1-6 alkyl, or F; R ² represents H, C _1-6 alkyl Or F; or R ¹ and R ² together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two selected from the group consisting of sulfur and oxygen. And a hetero atom of nitrogen and wherein the ring is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, _C1-6 alkyl, _C1-6 alkoxy, amine a substituent substituted with a hydroxyl group, a cyano group, a decyl group, a C _1-6 alkylamino group, a bis-(C _1-6 alkyl)amino group, a C _1-6 alkylcarbonylamino group, and a pendant oxy group; ³ represents H, C _1-6 alkyl, or F; R ⁴ represents H, C _1-6 alkyl, or F; or R ³ and R ⁴ together with the carbon atom to which they are attached form a 3-7 member ring , which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen, and wherein the ring may optionally be subjected to one or more selected from the group consisting of halogen and trifluoromethyl. group, a trifluoromethoxy group, C _1-6 alkyl, C _1-6 alkoxy, amino, hydroxy, cyano, acyl, C _1-6 alkylamino, di - (C _1-6 alkyl ) Amino, C _1-6 alkylcarbonyl group, and the oxo substituent; R ⁵ represents a group selected aryl, heteroaryl, C _3-6 cycloalkyl group, a heterocyclic group, and the monocyclic a moiety; R ⁶ represents H, C _1-6 alkyl, or F; R ⁷ represents H, C _1-6 alkyl, or F; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form 3- a 7-membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen, and wherein the ring is optionally freed from one or more selected from the group consisting of halogens, Trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino, di-(C ₁ Substituted with a substituent of a _-6 alkyl)amino group, a C _1-6 alkylcarbonylamino group, and a pendant oxy group; R ⁸ represents an H, C _1-6 alkyl group (which may optionally be selected from one or more Substituents for halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and bis-(C _1-6 alkyl)amine Substituted), C _3-6 cycloalkyl, C _1-6 alkylcarbonyl (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy Amine, Group, C _1-6 alkoxy group, and two - (C _1-6 alkyl) amino group substituted with the substituents), C _3-6 cycloalkylcarbonyl, C _1-6 alkoxycarbonyl group (which may be optionally One or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and di-(C _1-6 alkane Substituted by a substituent of an amine group, an aminocarbonyl group, an N- C _1-6 alkylaminocarbonyl group (wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoro a substituent of a methoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group), N,N -di- (C _1-6 alkyl)aminocarbonyl (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine a substituent of a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group; and optical isomers, prodrugs, pharmaceutically acceptable salts thereof, hydrates thereof a solvate, and a polymorph; wherein the compound of formula (I) is not representative: 2-((2,4-dichlorophenyl)amino)-7-methyl-7,8-dihydroquinazoline- 5(6 H )-ketone, 2-((2,4-dimethylphenyl) Amino)-7-methyl-7,8-dihydroquinazolin-5( 6H )-one, 2-((2-methoxyphenyl)amino)-7,7-dimethyl -7,8-Dihydroquinazolin-5(6 H )-one, 2-((2-methoxyphenyl)amino)-7-methyl-7,8-dihydroquinazoline- 5(6 H )-keto, 2-((3-trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((3, 4-xylyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one, 2-((3,5-dimethoxyphenyl)amino group -7,7-Dimethyl-7,8-dihydroquinazolin-5( 6H )-one, 2-((4-ethylphenyl)amino)-7,7-dimethyl- 7,8-Dihydroquinazolin-5(6 H )-one, 2-((4-ethylphenyl)amino)-7-methyl-7,8-dihydroquinazoline-5 (6 H )-keto, 2-((4-fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6 H )-one, 2-((4) -fluorophenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((4-fluorophenyl)amino)-7-methyl-7,8- Dihydroquinazoline-5(6 H )-one, 2-((4-methoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5 ( 6 H )-keto, 2-((4-methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((4-methoxybenzene) Amino)-7-methyl-7,8-dihydroquinazolin-5( 6H )-one, 2-(cyclopentylamino)-7,7-di Methyl-7,8-dihydroquinazolin-5( 6H )-one, 2-(cyclopropylamino)-7,7-dimethyl-7,8-dihydroquinazoline-5 (6 H )-ketone, 2-(meta-tolylamino)-7,8-dihydroquinazolin-5(6 H )-one, 2-(anilino)-7,8-dihydroquinazoline Porphyrin-5(6 H )-one, 2-(p-tolylamino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2- ((3-(Trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2-((4-benzene) Oxyphenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2-(meta-tolylamino)-7,8 -dihydroquinazoline-5(6 H )-one, 7,7-dimethyl-2-(anilino)-7,8-dihydroquinazolin-5(6 H )-one, 7- Methyl-2-((4-phenoxyphenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 7-methyl-2-(p-tolyl) Amino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2-(p-tolylamino)-7,8-dihydroquinazoline Porphyrin-5(6 H )-one, 7-methyl-2-(anilino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((3,5-xylene) Amino)-7,8-dihydroquinazolin-5(6 H )-one, 7-methyl-2-(meta-tolylamino)-7,8-dihydroquinazoline -5(6 H )-one, or 7-methyl-2-(3 -(Trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one.

A further aspect of the invention relates to a compound of formula I , wherein X represents CH ₂ and Y represents CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ each represent H.

A further aspect of the invention relates to compounds of formula I , wherein X represents C=O and Y represents CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ each represent H.

A further aspect of the invention relates to a compound of formula I , wherein R ³ and R ⁴ each represent H or C _1-6 alkyl or R ³ and R ⁴ together with the carbon atom to which they are attached form a saturated 3-7 membered ring.

A further aspect of the invention relates to a compound of formula I , wherein X represents C=O and Y represents CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ each represent a C _1-6 alkyl group.

A further aspect of the invention relates to compounds of formula I , wherein X represents C=O and Y represents NR ⁸ , wherein R ⁸ represents C _1-6 alkyl.

A further aspect of the invention relates to a compound of formula I , wherein R ⁵ represents optionally one or more selected from the group consisting of halogen, cyano, C _1-6 alkoxy, trifluoromethoxy, C _1-6 alkyl, C _{1 a} phenyl group substituted with a substituent of a ₆ -alkylthio group, a difluoromethyl group, and a difluoromethoxy group; optionally one or more selected from the group consisting of halogen, C _1-6 alkyl, amine group, C _1-6 alkane group, and a cyano substituent of the substituted pyridyl; C _1-6 alkyl substituted by free of pyrimidinyl; free of C _1-6 alkyl substituted cyclohexyl group; or by random or C _1-6 alkyl C _1-6 alkylcarbonyl substituted piperidinyl.

A further aspect of the invention relates to a compound of formula I selected from formula IA Wherein R ^{1 to} R ⁷ are as defined in the above formula I , and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

The compound of formula IA , wherein R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

The compound of formula IA , wherein R ¹ -R ⁴ , R ⁶ , and R ⁷ each represent H and R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

The compound of formula IA , wherein R ¹ -R ⁴ , R ⁶ , and R ⁷ each represent H and R ⁵ represents a phenyl group optionally substituted with one or more halogen atoms.

A further aspect of the invention relates to a compound of formula I selected from formula IB Wherein R ^{1 to} R ⁷ are as defined in the above formula I , and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

The compound of the formula IB , wherein R ⁵ represents a monocyclic moiety selected from the group consisting of an aryl group, a heteroaryl group, a cyclic C _3-6 alkyl group, and a heterocyclic group.

A compound of the formula IB , wherein R ¹ , R ² , R ⁶ and R ⁷ each represent H; R ³ and R ⁴ each represent H or C _1-6 alkyl (for example methyl or ethyl) or R ³ and R ^{4 is} combined to form a 3-7 membered ring (e.g., a cyclopropane ring); and R ⁵ represents a monocyclic moiety selected from the group consisting of an aryl group, a heteroaryl group, a cyclic C _3-6 alkyl group, and a heterocyclic group.

A compound of the formula IB , wherein R ¹ , R ² , R ⁶ and R ⁷ each represent H; R ³ and R ⁴ each represent H or C _1-6 alkyl (for example methyl or ethyl) or R ³ and R ⁴ to form a 3-7 membered ring (eg, a cyclopropane ring); and R ⁵ represents optionally one or more selected from the group consisting of halogen, cyano, C _1-6 alkoxy, trifluoromethoxy, C _{1- a} phenyl group substituted with a substituent of a ₆ alkyl group, a C _1-6 alkylthio group, a difluoromethyl group, and a difluoromethoxy group; optionally one or more selected from the group consisting of halogen, C _1-6 alkyl, and amine group , C _1-6 alkoxy, and cyano substituent of the substituted pyridyl; the optionally substituted by C _1-6 alkyl pyrimidinyl; the optionally substituted by C _1-6 alkyl cyclohexyl group; or by random C _{a 1-6} alkyl or C _1-6 alkylcarbonyl substituted piperidinyl group.

The compound of the formula IB , wherein R ^{1 -} R ⁴ each represent H; R ⁶ and R ⁷ each represent a C _1-6 alkyl group (e.g., methyl); and R ⁵ represents a monocyclic moiety selected from the group consisting of an aryl group and a heteroaryl group. .

The compound of the formula IB , wherein R ^{1 -} R ⁴ each represent H; R ⁶ and R ⁷ each represent a C _1-6 alkyl group (e.g., methyl); and R ⁵ represents optionally one or more selected from C _1-6 A phenyl group substituted with a substituent of an alkyl group and a halogen.

A compound of the formula IB , wherein R ¹ and R ² each represent a C _1-6 alkyl group (e.g., methyl); R ^{4 -} R ⁷ each represent H; and R ⁵ represents a monocyclic moiety selected from the group consisting of an aryl group and a heteroaryl group. .

A further aspect of the invention relates to a compound of formula I selected from formula IC Wherein R ^{1 to} R ⁵ and R ⁸ are as defined in the above formula I , and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

A compound of the formula IC , wherein R ⁸ represents a C _1-6 alkyl group (e.g., methyl); and R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

A compound of the formula IC , wherein R ⁸ represents a C _1-6 alkyl group (e.g., methyl); and R ⁵ represents optionally one or more selected from C _1-6 alkyl, cyano, C _1-6 alkoxy. And a phenyl or pyridyl group substituted with a substituent of a halogen.

Specific compounds of formula I within the scope of the invention include, but are not limited to, the following compounds: N -phenyl-5,6,7,8-tetrahydroquinazolin-2-amine, N- (4-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-2-amine, N- (3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine, N - (4-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine, 2-((3-fluorophenyl)amino)-7,8-dihydroquinazoline- 5(6 H )-keto, 2-((3-chlorophenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((4-chlorophenyl) Amino)-7,8-dihydroquinazolin-5(6 H )-one, 3-((5-o-oxy-5,6,7,8-tetrahydroquinazolin-2-yl) Amino)benzonitrile, 4-((5-o-oxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, 2-((3-methoxy) Phenyl)amino)-7,8-dihydroquinazolin-5( 6H )-one, (racemic)-2-((3-fluorophenyl)amino)-7-methyl- 7,8-Dihydroquinazolin-5(6 H )-one, (racemic)-2-((3-chlorophenyl)amino)-7-methyl-7,8-dihydroquinazoline -5-( 6H )-one, (racemic)-2-((4-chlorophenyl)amino)-7-methyl-7,8-dihydroquinazoline-5( 6H )- Ketone, (racemic)-2-((4-bromophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-3 -((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazoline Phenyl-2-yl)amino)benzonitrile, (racemic)-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl) Amino)benzonitrile, (racemic)-7-methyl-2-((4-(trifluoromethoxy)phenyl)amino)-7,8-dihydroquinazolin-5 ( 6 H )-keto, (racemic)-3-fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amine Benzocarbonitrile, (racemic)-7-methyl-2-(pyridin-3-ylamino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic) -2-((6-Chloropyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-7-A 2-((6-methylpyridin-3-yl)amino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-2-((6-amine) Pyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5( 6H )-one, (racemic)-2-((4-chlorophenyl)amine -7-ethyl-7,8-dihydroquinazolin-5( 6H )-one, 2-((3-fluorophenyl)amino)-7,7-dimethyl-7, 8-Dihydroquinazoline-5(6 H )-one, 2-((4-chlorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5 ( 6 H )-ketone, 4-((7,7-dimethyl-5-o-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, 2 '-((4-Chlorophenyl)amino)-6',8'-dihydro-5' H -spiro[cyclopropane-1,7'-quinazoline]-5' -ketone, 2-((3-chlorophenyl)amino)-8,8-dimethyl-7,8-dihydroquinazolin-5(6 H )-one, 8,8-dimethyl -2-(meta-tolylamino)-7,8-dihydroquinazolin-5(6 H )-one, 8-methyl-2-(anilino)-7,8-dihydropyridine And [2,3-d]pyrimidine-5(6 H )-one, 2-((3-fluorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3- d]pyrimidine-5(6 H )-one, 2-((3-chlorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidine-5 ( 6 H )-keto, 3-((8-methyl-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)amino)benzene Formonitrile, 8-methyl-2-(meta-tolylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one, 2-((3) -Methoxyphenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one, 4-((5'-side oxygen) -6',8'-dihydro-5' H -spiro[cyclopropane-1,7'-quinazolin]-2'-yl)amino)benzonitrile, 2-((3-methylsulfide) Phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-2-((4-(difluoromethyl)phenyl)amino) -7-Methyl-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-2-((4-(difluoromethoxy)phenyl)amino)-7 - methyl-7,8-dihydro-quinazolin -5 (6 H) - one, (rac) -2 - ((6-methoxy- 3-yl) amino) -7-methyl-7,8-dihydro-quinazolin -5 (6 H) - one, (rac) -7-methyl-2 - ((4- Cyclohexyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-2-((1-isopropylpiperidin-4-yl)amino) -7-Methyl-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-2-((1-ethylhydrazinopiperidin-4-yl)amino)-7 -methyl-7,8-dihydroquinazolin-5( 6H )-one, (racemic)-2-((5-chloropyridin-2-yl)amino)-7-methyl- 7,8-Dihydroquinazolin-5(6 H )-one, (racemic)-6-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazoline) Phenyl-2-yl)amino)nicotinonitrile, (racemic)-7-methyl-2-((5-methylpyridin-2-yl)amino)-7,8-dihydroquinazoline- 5(6 H )-keto, (racemic)-2-fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl) Amino)benzonitrile, (racemic)-7-methyl-2-((2-methylpyrimidin-5-yl)amino)-7,8-dihydroquinazolin-5 (6 H -ketones, and their optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs.

Furthermore, the present invention relates to a compound of the formula I as defined above, or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate thereof, and a polymorph thereof, for the treatment and/or prophylaxis with abnormal glutamic acid A condition or disease associated with nerve conduction, including a condition or disease affected or aided by modulation of the mGluR5 receptor, including a condition or disease selected from those described earlier.

In a further aspect, the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for use in the treatment and/or prevention of a central nervous system disorder. Furthermore, the present invention relates to a compound of the formula I as defined above, or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate thereof and a polymorph thereof, for the treatment and/or prevention of abnormal glutamate nerves Conduction. The invention further relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for modulation of the mGluR5 receptor. Furthermore, the invention relates to such compounds for the treatment, prevention and or modulation of a condition or disease selected from those described in the earlier description. The invention is further directed to such compounds for the treatment, prevention or modulation of physiological parameters, such as cognitive conditions (whether or not there is a particular identifiable condition).

A further aspect of the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for use in the treatment and/or prophylaxis of aberrant glutamate A condition associated with conduction or modulation of the mGluR5 receptor therein may result in a medical benefit. The conditions that can be treated are as described above. These conditions and indications include:

a) mGluR5 modulator: chronic pain, neuralgia, diabetic neuropathic pain (DNP), cancer pain, pain associated with rheumatoid arthritis, inflammatory pain, L-dopa-induced dyskinesia, dopamine mimetic - induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dopamine mimetic-induced dyskinesia in Parkinson's disease therapy, tardive dyskinesia, Parkinson's disease, Anxiety disorder, panic disorder, coke Considering panic disorder, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorder, obesity, binge eating disorder, Huntington's disease, epilepsy, Alzheimer's disease, Positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disease, gastroesophageal reflux disease (GERD), migraine, intestinal fistula (IBS), or enhanced cognitive function and/or neuroprotection.

b) Negative regulation of mGluR5 can be used especially for: chronic pain, neuralgia, diabetic neuropathic pain (DNP), cancer pain, pain associated with rheumatoid arthritis, inflammatory pain, L-dopa-induced exercise Obstruction, dopamine mimetic-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dopamine mimetic-induced dyskinesia in Parkinson's disease therapy, tardive dyskinesia, Parkinson's disease, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorder, obesity, binge eating disorder, migraine, intestinal fistula Syndrome (IBS), functional gastrointestinal disease, gastroesophageal reflux disease (GERD), Huntington's disease and/or epilepsy.

c) Positive regulation of mGluR5 may be particularly useful for: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.

A further aspect of the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for the treatment of bulimia.

The invention further relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for use in the manufacture or prevention of abnormal glutamate nerve conduction The medical use of a condition or disease. Such uses include the use of the compounds in the manufacture of a medicament for the prevention and/or treatment of a condition or disease in an animal, including a human, which is affected or aided by modulation of the mGluR5 receptor.

Furthermore, the present invention relates to the treatment or prevention of a condition or disease associated with abnormal glutamate nerve conduction, including a condition or disease affected or assisted by modulation of the mGluR5 receptor, including from those described earlier in the description. Method of disease or disease).

Further, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, at least one compound of the formula I as defined above, or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate thereof, and a polymorph, together with One or more pharmaceutically acceptable excipients.

Furthermore, the mGluR modulators as described above are expected to have high activity when used in combination with other substances that exhibit neurological effects via different machines.

In still a further aspect, the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, and at least one NMDA receptor antagonist A combination such as memantine for neuroprotection and/or for cognitive function enhancement.

A further aspect of the invention relates to a pharmaceutical composition comprising at least two different active ingredients, comprising at least one compound selected from formula I as defined above, in addition, at least one NMDA-antagonist, one or more pharmaceutically acceptable Excipients. These compositions are useful for the treatment of central nervous system-related diseases, cognitive enhancement, and neuroprotection. The invention further provides a composition comprising at least two different active ingredients, including at least one compound selected from formula I as defined above, in addition, at least one NMDA-antagonist, for the treatment of any of the conditions indicated herein, Including central nervous system-related diseases, cognitive function enhancement and neuroprotection.

The invention also relates to pharmaceutical compositions comprising a combination of a compound of formula I as described above and an NMDA receptor antagonist, including wherein the NMDA receptor antagonist is, for example, memantine and pharmaceutically acceptable thereof a composition of salts, polymorphs, hydrates, and solvates.

The invention also relates to a pharmaceutical composition comprising at least two different active ingredients, including at least one compound selected from formula I as defined above, and additionally, at least one selected from the group consisting of L-dopa, other dopamine mimetic drugs (such as anti-Bakin Sjogren's dopamine mimetic, including bromocriptine, caberolin, ropinirole, pramipexole, pergolide, rotigotine Rotigotine)), and antipsychotic drugs (such as traditional antipsychotic drugs, including haloperidol (haloperidol), perphenazin (perphenazin), chlorpromazine, metoclopramide) .

The invention also provides a method of neuroprotection of a living animal, including a human, comprising the step of administering a medically effective amount of a composition as described above to a living animal, including a human.

Furthermore, the present invention also provides the use of a composition as described above for the manufacture of a medicament for providing neuroprotection in animals, including humans.

The invention also relates to the synthesis or preparation of a compound of formula IA' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ⁵ is as defined above in Formula I , wherein cyclohexanone of formula II is Reaction with 1-tributoxy- N,N,N',N' -tetramethylmethanediamine of formula III at elevated temperature Compound of formula IV React with formula V That is, the compound of the formula IA' can be converted into an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, or a polymorph, if necessary.

The invention also relates to the synthesis or preparation of a compound of formula IA' Or a method of optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, wherein R ⁵ is as defined above in Formula I , wherein Formula IV is prepared according to the above method Compound Treated with guanidine hydrochloride to give compound of formula V With a compound of formula VI which is reacted under palladium catalyzed coupling conditions of R ⁵ -Hal VI, i.e., formula IA 'compound, if necessary, can be converted to optically acceptable isomers, prodrugs, pharmaceutically a salt, hydrate, solvate, or polymorph.

The invention also relates to the synthesis or preparation of a compound of formula IA' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ⁵ is as defined above in Formula I , wherein Formula V is prepared according to the above method Compound Conversion to the aryl halide of formula VII R ⁵ -NH ₂ VIII is then treated with an amine of formula VIII to provide a compound of formula IA' which , if desired, can be converted into optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, Solvate, or polymorph.

The invention also relates to the synthesis or preparation of a compound of the formula IB' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ³ and R ⁴ represent a methyl group and R ⁵ is as defined above in Formula I , wherein Substituting cyclohexane-1,3-dione of formula IX Treated with dimethylformamide dimethyl acetal to give compound of formula X Then react it with the formula V That is, the compound of the formula IB' can be converted into an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, or a polymorph, if necessary.

The invention also relates to the synthesis or preparation of a compound of the formula IB' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ³ and R ⁴ represent a methyl group and R ⁵ is as defined above in Formula I , wherein a compound of formula X prepared according to the above method Treated with guanidine hydrochloride to give a compound of formula XI With a compound of formula VI which is then palladium - R ⁵ -Hal VI reacted under catalytic coupling conditions, i.e., formula IB 'compound, if necessary, can be converted to the optical isomer, prodrug, pharmaceutically Accepted salts, hydrates, solvates, or polymorphs.

The invention also relates to the synthesis or preparation of a compound of the formula IB' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ³ and R ⁴ represent a methyl group and R ⁵ is as defined above in Formula I , wherein a compound of formula XI prepared according to the above method Conversion to aryl halide of formula XII R ⁵ -NH ₂ VIII is then treated with an amine of formula VIII to give the formula IB' , which can be converted to optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, if desired , solvate, or polymorph.

The invention also relates to the synthesis or preparation of a compound of formula IB" or IB"'

Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein R ¹ -R ² and R ⁶ -R ⁷ represent a methyl group and R ⁵ is as above I defined by the substitution of cyclohexane-1,3-dione of formula XII Treated with dimethylformamide dimethyl acetal to give a compound of formula XIV Then react it with the formula V A mixture of IB" and IB" compounds can be isolated (for example, by preparative HPLC) to obtain a compound of formula IB" and IB"' , which can be converted to an optical isomer, if desired. Prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.

The invention also relates to the synthesis or preparation of a compound of the formula IC' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ⁵ is as defined above for Formula I and R ⁸ represents methyl, wherein Formula XV Compound Subjecting to cyclization conditions (eg, using a strong base such as sodium hydride or sodium butoxide) to give a compound of formula XVI Let it undergo a decarboxylation condition (for example, treatment with trifluoroacetic acid) to obtain a compound of formula XVII Then treating it with meta-chloroperbenzoic acid to obtain the corresponding sulfonyl intermediate, and then reacting with the amine of formula VIII , R ⁵ -NH ₂ VIII , to obtain the compound of formula IC' , if necessary It is converted into an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, or a polymorph.

The invention also relates to the synthesis or preparation of a compound of the formula IC' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein R ⁵ is as defined above for formula I and R ⁸ represents methyl, wherein The formula XVI compound Conversion to XVIII compound Converting this compound to a compound of formula XIX (eg, via treatment with phosphonium chloride) R ⁵ -NH ₂ VIII is then treated with an amine of formula VIII to give a compound of formula IC' which , if desired, can be converted into optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, Solvate, or polymorph.

The invention also relates to the synthesis or preparation of a compound of the formula IC' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein R ⁵ is as defined above for formula I and R ⁸ represents methyl, wherein Compound of formula XVII Conversion to XVIII compound Converting this compound to a compound of formula XIX (eg, via treatment with phosphonium chloride) R ⁵ -NH ₂ VIII is then treated with an amine of formula VIII to give a compound of formula IC' which , if desired, can be converted into optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, Solvate, or polymorph.

Detailed description of the invention

For the purposes of the present invention, in the compounds of formula I , the carbon atom content of the various different hydrocarbon-containing moieties is represented by the minimum and maximum number of carbon atoms indicated in the prefix in the moiety, ie, the prefix C _ij means a part (inclusive) of an integer "i" to an integer "j" carbon atoms. Thus, for example, (C _1-3 )alkyl means an alkyl group of one to three carbon atoms (i.e., 1, 2 or 3 carbon atoms), contained (i.e., methyl, ethyl, propyl, and iso-) Propyl), in its straight or branched form, ( _C1-6 ), for example, means a radical of one to six carbon atoms (i.e., 1, 2, 3, 4, 5 or 6 carbon atoms).

As used herein, the following definitions apply unless otherwise indicated. The term " _C1-6 alkyl" denotes a straight or branched alkyl group. Examples of such an alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, butyl, and t-butyl groups.

The term "C _2-6 alkenyl" represents a straight or branched alkenyl group.

The term " _C1-6 alkoxy" represents a straight or branched -OC _1-6 alkyl group. Examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, and an isopropoxy group, a butoxy group, and a third butoxy group.

The term "mercapto" denotes C _1-6 alkylcarbonyl, trifluoroethenyl, hydroxy-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, C _1-6 alkoxy-C _1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C _3-12 alkane Carbocarbonyl, aryl-C _1-6 alkylcarbonyl, heteroaryl-C _1-6 alkylcarbonyl, arylamino-C _1-6 alkylcarbonyl, heteroarylamino-C _1-6 alkylcarbonyl And a heterocyclic carbonyl group and a heterocyclic group -C _1-6 alkylcarbonyl group.

The term " _{cycloC 3-12} alkyl" represents a monocyclic or bicyclic, or tricycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantane. a group optionally substituted by one or more (e.g., 1, 2, 3, 4 or 5), which may be the same or different, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _{1- 6} alkyl, C _2-6 alkenyl, C _1-6 alkoxy, amine, hydroxy, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkylamino, and di-(C _{1- 6} alkyl)amino, C _1-6 alkylcarbonylamino, pendant oxy, C _1-6 alkoxyimino, N -C _1-6 alkylaminocarbonyl, N,N -di- Substituent substitution of a (C _1-6 alkyl)aminocarbonyl group, an aryl C _1-6 alkoxycarbonyl group, and a C _1-6 alkylenedioxy group.

The term "cyclo C _3-6 alkyl" represents a monocyclic alkyl group, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, optionally at one or more (eg 1, 2, 3, 4 or 5) independently or differently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, amino, hydroxy, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyl, C _1-6 alkylamino, and two - (C _1-6 alkyl) amino, C _1-6 Alkylcarbonylamino, pendant oxy, C _1-6 alkoxyimino, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl Substituted with an aryl C _1-6 alkoxycarbonyl group and a C _1-6 alkylenedioxy group.

The term "aryl" denotes phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally independently selected by one or more (eg 1, 2, 3, 4 or 5) which may be the same or different From halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkyl, amine, hydroxy, nitro, cyano, formyl , C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonyloxy C _1-6 alkyl, C _1-6 alkylamino , bis-(C _1-6 alkyl)amino, cyclo C _3-12 alkylamino, C _1-6 alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N- C _1-6 alkane Aminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cyclo C _3-12 alkyl, pyridyl, And a substituent of a C _1-6 alkylenedioxy group.

The term "heteroaryl" denotes an aromatic 5-6 membered ring containing one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or 5-6 containing one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. And a bicyclic group fused to a benzene ring or a 5-6 membered ring containing one to four heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the heteroaryl group is optionally subjected to one or more (eg, 1, 2, 3, 4 or 5) may be the same or different independently selected from the group consisting of halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoro Methoxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, amine, hydroxy, nitro, cyano, C _1-6 alkane Carbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkoxycarbonyloxy group, C _1-6 alkylamino group, and di-(C _1-6 alkyl)amino group, ring C _3-12 alkane Amino, C _1-6 alkylcarbonylamino, aminocarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-C _1-6 alkylaminocarbonyl, pyrrolidinyl, piperidine Substituents of pyridine, morpholinyl, cyclo C _3-12 alkyl, C _1-6 alkylenedioxy, aryl, and pyridyl are substituted. Representative heteroaryl groups include furyl, thienyl, pyrrolyl, Azolyl, different Azyl, isothiazolyl, Diazolyl, pyrazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, Diazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, fluorenyl, benzofuranyl, benzothienyl, fluorenyl, pyridazinyl, isoindole Mercapto, dihydroindenyl, carbazolyl, benzimidazolyl, benzo Azolyl, benzothiazolyl, quinolyl, quinazolinyl, quin Alkyl, porphyrin, naphthyridyl, isoquinolyl, quinazolyl, pyridazinyl, and pteridinyl.

The term "heterocyclyl" denotes a saturated or unsaturated, non-aromatic 3 to 12 membered ring containing one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and one to six heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. a saturated or unsaturated non-aromatic bicyclic ring system having from 3 to 12 members, wherein the heterocyclic ring or ring system may optionally be the same or different via one or more (eg 1, 2, 3, 4 or 5) Independently selected from the group consisting of halogen, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy Amino, hydroxy, nitro, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyl, C _1-6 alkylamino, and di-(C _1-6 alkyl)amine, C _1-6 alkylcarbonylamino, pendant oxy, C _1-6 alkoxyimino, N -C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl Substituting a substituent of an aminocarbonyl group, an aryl C _1-6 alkoxycarbonyl group, and a C _1-6 alkylenedioxy group; examples of the heterocyclic group include piperidinyl, morpholinyl, thio? a phenyl group, an imidazolinyl group, an imidazolidinyl group, a pyrazolinyl group, a pyrazolidinyl group, a pyrrolinyl group, a pyrrolidinyl group or a piperazinyl group, wherein the heterocyclic ring or ring The system is optionally attached to the group to which it is attached via a nitrogen or carbon atom.

The term "halogen" stands for fluorine, chlorine, bromine and iodine.

The compounds of the invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations that are well known to those skilled in the art can be used (eg "Ph" is phenyl, "Me" is methyl, "Et" is ethyl, "min" is minutes, "h" is hour, and "rt" is Room temperature).

Memantine, also known as 1-amino-3,5-dimethyladamantane, is disclosed in U.S. Patent Nos. 4,122,193, 4,273,774, and 5,061,703, the disclosures of each of reference.

Memantine is a non-competitive NMDA receptor antagonist with a systemic activity of moderate affinity for the receptor. It exhibits strong voltage-dependent properties and rapid closure and deblocking dynamics (see, for example, Görtelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42: 904-913; Winblad et al., Int. J. Geriat. Psychiatry, 1999, 14: 135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al., Curr. Pharm. Des., 2002, 8: 835-43; Jirgensons et. al. Eur. J. Med. Chem., 2000, 35: 555-565).

The term "analog" or "derivative" is used herein in the conventional pharmaceutical concept to mean a molecule that is structurally similar to a reference molecule, but with targeting and A controlled manner is modified to replace one or more specific substituents in the reference molecule with an alternate substituent, thereby producing a molecule that is structurally similar to the reference molecule. Synthesis and screening of analogs (eg, using structural and/or biochemical assays) to identify slightly modified versions of known compounds that may have improved or biased characteristics (such as higher potency under specific targeted receptor formats and/or Or selective, with a greater ability to penetrate the blood-brain barrier, less side effects, etc.) is a detailed drug design method in pharmaceutical chemistry.

In addition, methods known to those skilled in the art can be used to create improved medical efficacy (i.e., greater potency and/or selectivity in specific targeted receptor formats, with greater or lower penetration). Analogs and derivatives of the compounds of the invention that are capable of breast-blood-brain barrier (eg, higher or lower blood-brain barrier penetration), fewer side effects, and the like.

The term "prodrug" is used herein in the conventional pharmaceutical concept to mean a molecule that undergoes a transformation (eg, an enzyme or chemical transformation) in vivo to release the active parent drug. The prodrugs of the compounds of formula I of the present invention can be prepared by chemical modification of functional groups present in the compounds of formula I , whereby the chemically modified compounds can undergo transformation (e.g., enzymatic hydrolysis) in vivo to provide compounds of formula I. Examples of functional groups present in the compounds of formula I which may be modified to produce prodrugs include carboxyl groups, hydroxyl groups, amine groups, and sulfur groups. The prodrugs of the compounds of the formula I according to the invention can be prepared according to conventional techniques which have been described in the art (for example Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007 ).

The phrase "pharmaceutically acceptable" in relation to the present hair composition means that the molecular entity and other components of the composition are physiologically tolerable and When administered to a mammal, such as a human, it does not typically produce an adverse reaction. The term "pharmaceutically acceptable" may also mean approved by the regulatory agency of the federal or state government or listed in the United States Pharmacopoeia or other recognized pharmacopoeia for mammals, particularly humans.

The compounds of the invention may be in the form of a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt" means a salt thereof which has the biological utility and properties of the parent compound and which is not biologically or otherwise undesirable. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.

Those skilled in the art will appreciate that the compounds of the invention having a chiral center may exist and be resolved in optically active and racemic forms. Some compounds can exhibit polymorphism. It is to be understood that the invention encompasses any racemic, optically active, polymorphic, tautomeric or stereoisomeric forms of the compounds of the invention, or mixtures thereof, having the useful properties described herein.

The following reactions Figures 1-4 illustrate the preparation of the compounds of formula I of the present invention. All raw materials can be prepared by the steps described in these reaction diagrams, by well-known steps of organic chemists, or commercially available. All of the final compounds of the present invention can be prepared by the procedures described in the figures or by analogous procedures known to those skilled in the art of organic chemistry. All variables used in Reaction Schemes 1-4 are as defined below or as defined in the scope of the patent application. Compounds containing one or more chiral centers can be prepared as racemates or mixtures of various stereoisomers and then isolated. However, they may also be prepared by a special enantioselective synthesis method. In some chiral compounds, the pharmacological activity of the enantiomers is different.

Reaction Scheme 1 - Synthesis of a compound of formula IA' .

Cyclohexanone 1 and 1-t-butoxy- N,N,N',N' -tetramethylmethanediamine ( 2 ) are reacted under temperature to obtain a dimethylmethylene derivative 3 , and then treated with substituted 胍4 , the compound IA' is obtained. Alternatively, intermediate 3 can be reacted with guanidine hydrochloride to give 5,6,7,8-tetrahydroquin-2-amine ( 5 , which is also commercially available), and palladium catalyzed directly with halide 6 . The coupling reaction is either converted to the compound IA' by conversion to the aryl halide 7 (for example, by the Sandmeyer reaction) followed by reaction with the corresponding one of the amines 8 .

Reaction Scheme 2 - Synthesis of a compound of formula IB' .

The 5-substituted cyclohexane-1,3-dione 9 is converted to the dimethylaminomethylene derivative 10 by dimethylformamide dimethyl acetal (DMF-DMA). Condensation with substituted hydrazine 4 gives compound IB' . Further, the arylamine 11 can be formed from the intermediate 10 and guanidine hydrochloride. The palladium-catalyzed coupling reaction with the halide 6 is followed by the compound IB' . The third synthetic route of the compound of formula IB' begins with intermediate 11 , which is converted to the corresponding aryl halide 12 (for example, via the Sandmeyer reaction), which in turn reacts with the primary amine 8 That is, the compound IB' is obtained.

Reaction Scheme 3 - Synthesis of the formula IB" and IB"' compounds.

The 6,6- and 8,8-dimethylated derivatives IB" and IB"' can be similar to the synthetic route described in the reaction scheme of Figure 2 , using 4-substituted cyclohexane-1,3-dione 13 as Raw materials are obtained. In the final step, two possible regioisomers are formed which can then be separated (e.g., by preparative HPLC).

Reaction Scheme 4 - Synthesis of the compound of formula IC' .

Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate ( 18 ) and ethyl 3-(methylamino)propionate ( 20 ) were synthesized according to the procedure described elsewhere (see Palenki , Et al., Bioorganic & Medicinal Chemistry Letters, 2000 , 10(15), 1645-1648 and Dyck, et al., Journal of Medicinal Chemistry, 2005 , 48(12), 4100-4110). The cyclization of ester 22 to pyridopyrimidinone 23 is accomplished by a strong base such as sodium hydride. After decarboxylation with trifluoroacetic acid, the resulting 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one ( 24 ) Treatment with meta-chloroperbenzoic acid followed by coupling with the corresponding amine 8 is converted to the compound IC' . Alternatively, intermediate 23 can be converted to the corresponding chloride 26 via hydroxy derivative 25 . The resulting aryl chloride 26 can then be reacted with amine 8 to provide the compound IC' .

It will be appreciated that in the above transitions, it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.

The pure stereoisomeric forms (including optical isomers) of the compounds and intermediates of the invention can be obtained by the application of procedures known in the art. Diastereomers can be separated by physical separation methods such as selective crystallization and chromatographic techniques (e.g., liquid chromatography using a chiral stationary phase). Enantiomers (optical isomers) can be separated from one another by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, the enantiomers can be separated by chromatographic techniques using a chiral stationary phase.

Pure stereoisomeric forms can also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively. Stereoisomer forms of formula I are included within the scope of the invention.

Compounds of formula I which are labeled with a radioactive atom can be obtained using procedures known in the art. Typical compounds include one or more of which are replaced by deuterium wherein one or more of ¹² C are substituted by ¹⁴ C wherein one or more of the fluorine atoms are replaced by ¹⁸ F or other isotopes. These can be used to treat diseases such as cancer but are also for diagnostic purposes. The radioactive atoms exchanged in the molecule are typically isotopes of carbon, hydrogen, halogen, sulfur or phosphorus. Compounds of formula I which are labeled with a radioactive atom are included within the scope of the invention.

Addition salt

For medical use, the salts of the compounds of formula I are those in which the counterion is pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases are also found, for example, for use in the preparation and purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are within the scope of the invention. A pharmaceutically acceptable salt as defined above is meant to comprise a medically active, non-toxic salt form, which is a formable compound of formula I. The latter may conveniently be in the form of a base with a suitable acid such as a mineral acid such as a hydrohalic acid such as hydrochloric acid, hydrobromic acid or the like; sulfuric acid; nitric acid; phosphoric acid or the like; or an organic acid such as acetic acid, propionic acid, glycolic acid, 2 -hydroxypropionic acid, oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid It is obtained by treating an acid such as acid, ethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid or 4-amino-2-hydroxybenzoic acid. Conversely, the salt form can be converted to the free base form by treatment with a base.

Pharmaceutical composition

The active ingredient of the compound of the present invention may be placed in the form of a pharmaceutical composition, unit dose or dosage form together with one or more excipients such as adjuvants, carriers, or diluents. The pharmaceutical composition may be in a solid dosage form such as a powder, granule, pill, coated or uncoated tablet or filled capsule, or a liquid dosage form such as a solution, suspension, latex, or a capsule filled with it, or a semi-solid dosage form. Used in the form of gels, creams and ointments. The dissolution and release profiles of the active ingredients of the pharmaceutical dosage form can vary from seconds to months.

Pharmaceutical compositions are designed for use by animals and humans and can be applied via application routes. The ideal application path is the oral path, the skin path, the lung path, the nasal path, the rectal path, and the parenteral path. The pharmaceutical composition and unit dosage form thereof may contain conventional or novel ingredients in conventional or specific proportions, with or without additional active compounds or ingredients, and the unit dosage form may contain any suitable effective amount of A daily dose range commensurate with the active ingredient. Tablets containing from one (1) to one hundred (100) milligrams of active ingredient or (more broadly) from five (0.5) to five hundred (500) milligrams of active ingredient per tablet are suitably representative unit dosage forms.

The term "carrier" as used in the pharmaceutical compositions of the invention means a diluent, excipient, or carrier with which the active compound is administered. The pharmaceutical carrier can be a sterile liquid such as water, a saline solution, an aqueous dextrose solution, an aqueous glycerin solution, and an oil, including petroleum, animal, plant or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. . A.R. Gennaro (20th edition) at "Remington: The Science and Practice of Pharmacy" Suitable pharmaceutical carriers are described.

treatment method

Due to its high activity and low toxicity, and exhibiting the most favorable medical index, the active ingredient of the present invention can be administered to patients with such needs, such as living animals (including humans), for treatment, alleviation, or improvement. , mitigating, or eliminating the indications or conditions that are susceptible to it, or representative indications or conditions presented elsewhere in this application, preferably simultaneously, simultaneously, with one or more pharmaceutically acceptable excipients , a carrier, or a diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether orally, orally, or parenterally (including intravenously and subcutaneously) or, in some cases, even partially effective The amount of investment. The appropriate dosage range is 1-1000 mg per day, optionally 10-500 mg per day, and optionally 50-500 mg per day, as usual, according to the exact mode of administration, the form of the application, and the application. The indications, the patients involved and the weight of the patients involved, as well as the preferences and experience of the physician or veterinarian.

The term "treating" as used herein means to relieve or alleviate at least one symptom of a disease in a patient. In the definition of the invention, the term "treatment" also means to arrest, delay the onset (i.e., the time prior to the clinical manifestation of the disease) and/or reduce the risk of developing or worsening the disease.

The term "combination" as used herein is defined as a single pharmaceutical composition (formulation) comprising a compound of the invention and a second active ingredient (eg, an NMDA receptor antagonist, L-DOPA, a dopamine mimetic, or an antipsychotic). In a formulation known in the art; or two individual pharmaceutical compositions (formulations), A formulation comprising a compound of the invention as formulated above and comprising a second active ingredient (eg, an NMDA receptor antagonist, L-DOPA, a dopamine mimetic, or an antipsychotic) in a formulation known in the art for administration clothes.

The term "consistently administered" in the definition of the present invention is used to mean a compound of the present invention and a second active ingredient (for example, an NMDA receptor antagonist, L-DOPA, a dopamine mimetic, or an antipsychotic) in a composition. In the middle of the investment, or in different compositions to simultaneously vote, or continue to vote. Successive administration is considered to be "linked", however, the fact that the compound of the invention and the NMDA receptor antagonist must be administered separately at intervals may still allow the mammal to achieve a beneficial effect. For example, a compound of the invention and an NMDA receptor antagonist must be administered on the same day (eg, each - once or twice daily), including within one hour of each other, and including synchronization.

The term "medically effective amount" as applied to a dose or amount means the amount of the compound or pharmaceutical composition sufficient to result in the desired activity after administration to an animal in need thereof.

The compounds of the invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectal) in a dosage unit formulation containing a conventional non-toxic pharmaceutically acceptable carrier. It is often desirable to use an oral path. Active agents may be capsules, tablets and the like for oral administration server (see "Remington: The Science and Practice of Pharmacy, 20 th Edition" pharmaceutical composition via the mouth may hurl the time - in the form of controlled-release carriers, including. Diffusion-control systems, osmotic devices, dissolution-control matrices, and erosive/degradable matrices.

In the case of oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient of the formula I can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (for example pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl). Methylcellulose); fillers (eg lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (eg hard Magnesium oleate, talc, or vermiculite, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrant (eg potato starch or sodium carboxymethyl starch) And/or wetting agents (such as sodium lauryl sulfate), coloring and fragrances, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginate), buffer salts, A combination of carboxymethyl cellulose, polyethylene glycol, wax, and the like. For oral administration in liquid form, the pharmaceutical component 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 food). Fat), emulsifier (such as lecithin or acacia), non-aqueous carrier (such as almond oil, oily ester, ethanol or fractionated vegetable oil), preservative (such as methyl or propyl paraben or sorbate) Acid), and so on. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

Tablets can be coated by methods well known in the art. The compositions of the invention containing a compound of formula I as an active compound can also be incorporated (for example, from polyglycolic acid/lactic acid (PGLA)) in beads, microspheres or microcapsules. Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented in the form of a dry product for reconstitution with water or other suitable vehicle before use. Oral formulations can be formulated to control or delay the release of the active compound.

The compounds of the invention may also be delivered 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. The vesicles can be formed from a variety of well-known phospholipids, such as cholesterol, stearic acid amine or choline.

The compounds of the invention may also be delivered by the use of monoclonal antibodies (on which the compound molecules are coupled) as individual carriers. The active drug can also be coupled to a soluble polymer that is a targetable drug carrier. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or substituted with palmitoyl residues Polyethylene oxide-polylysine. Furthermore, the active ingredient may be coupled to a biodegradable polymer for the purpose of controlled release of the drug, such as polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, poly-ε-caprolactone, A cross-linking or amphiphilic block copolymer of polyhydroxybutyric acid, polyorthoester, polyacetal, polyhydropyran, polycyanoacrylate, and hydrogel.

In the case of administration by inhalation, the medical agent according to the invention containing the compound of the formula I as the active compound can be conveniently employed in a pressurized pack or spray, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, Delivery in the form of an aerosol spray of dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a quantitative 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.

The formulation containing the compound of the present invention may be parenteral, that is, intravenous (iv), intraventricular (icv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), subdermal (sd), Or intradermal (id) administration, by direct injection, delivered via, for example, bolus injection or continuous infusion. The injectable formulation can be presented in unit dosage form, for example in an ampoule or in a multi-dose container (with a preservative added). The composition may take the form of an excipient, suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active agent can be in powder form for reconstitution with a suitable carrier, such as sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated, for example, in the form of a medicated or retained enema (e.g., containing a conventional medicinal base such as cocoa butter or other glycerides) for rectal administration.

If desired, compositions containing a compound of formula I can be presented in a package or dispenser device which may contain one or more unit dosage forms containing the active ingredient and/or may contain various dosage levels to aid in the titration of the dosage. The package may, for example, comprise a metal foil or a plastic film, such as a blister pack. The packaging or dispenser device can be completed by a service instruction. The compositions of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled for treatment in a condition.

As disclosed herein, the dosage of the components of the compositions of the present invention is determined to ensure that the continuous or intermittent dose will not exceed the amount determined after considering the results of the test animal and the individual condition of the patient. The specific dose is naturally dependent on the dosage step, the condition of the patient or animal patient such as age, weight, sex It varies depending on the sensitivity, the meal, the period of administration, the drug used in the combination, and the severity of the disease. The appropriate dosage and timing of administration under certain conditions may be determined on the basis of the above index, but may be further honed, and ultimately based on the judgment of the physician and the condition of each patient (age, general condition, symptom severity, Gender, etc.) is determined according to standard clinical techniques.

Toxicity and efficacy of the compositions of the present invention may by the standard experimental animal in pharmaceutical procedures, e.g., by measuring LD ₅₀ (lethal to 50% of the dose groups) and the ED ₅₀ (the dose therapeutically effective in having 50% of the group) to give know. The dose ratio between the medical effect and the toxic effect is the medical index and it can be expressed as the LD ₅₀ /ED ₅₀ ratio. It is preferred to present a composition of a large medical index.

The present invention provides novel and useful uses and uses of the compounds of the present invention, which comprise the active ingredients according to the present invention, as well as novel pharmaceutical compositions thereof, methods for their preparation, and treatment therewith, as apparent from the examples described herein below. method.

The higher order activity of the active agents and compositions thereof (as evidenced by the reported assays) is shown to be based on their usefulness in humans and in lower animals. The clinical assessment of humans is not yet complete. It is expressly understood that the distribution and sale of any compound or composition for human use within the scope of the invention must of course be based on the prior approval of the government agency responsible for and authorizing the case.

The compound of formula I represents a novel mGluR5 modulator. In view of their efficacy, they will be a useful treatment for a wide range of conditions involving excessive glutamate-induced stimuli, especially central nervous system disorders.

Therefore these compounds are found in the treatment of active objects (especially humans) As with the application of the condition shown earlier in the description.

These compounds have also been found to be useful in the treatment of indications for active objects, particularly humans, where specific conditions are not necessarily present, but where specific physiological parameters can be improved by administration of the present compound, including enhancement of cognitive function.

Neuroprotective effects and cognitive enhancement can also be achieved by administering a combination of the present compound and an NMDA receptor antagonist such as memantine.

The method of treating a moving subject with a compound of the invention to inhibit the progression of the selected mild disease or alleviating the mild disease is by any generally accepted pharmaceutical route, as described above, using a selected effective agent to alleviate the particular mild disease desired to be alleviated. The dose is reached. The compounds of the present invention are useful in the manufacture of a medicament for the treatment of a living animal to inhibit the progression of a selected mild disease or condition or to alleviate the mild disease or condition, particularly a mild disease or condition susceptible to treatment with a Group I mGluR modulator. The use is carried out in a conventional manner, comprising the steps of mixing an effective compound of the present invention with a pharmaceutically acceptable diluent, excipient, or carrier, a method of treatment, a pharmaceutical composition, and a compound of the present invention for the manufacture of a medicament. use.

Representative pharmaceutical compositions prepared by combining the active ingredient with suitable pharmaceutically acceptable excipients, diluents, or carriers include tablets, capsules, injection solutions, liquid oral formulations, aerosol formulations, TDS formulations And nanoparticle formula, so that it can be used for oral, injection, or skin use, and also according to the aforementioned medicine.

Experimental part

The compounds of the present invention and their preparation will be more apparent from the following examples, which are intended to be illustrative, not limiting.

Hereinafter, "ACN" is defined as acetonitrile, "Boc" is a third butoxycarbonyl group, "DAST" is diethylaminosulfur trifluoride, "DCM" is dichloromethane, "DEE" is diethyl ether, "DIPEA" Is N,N -diisopropylethylamine ( N -ethyl-N-isopropylpropan-2-amine), "DMF" is N,N -dimethylformamide, and "DMF-DMA" is N,N -dimethylformamide dimethyl acetal, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "MeOH" is methanol, and "MTBE" is methyl tertiary butyl ether (or 2 -Methoxy-2-methylpropane), "PdCl ₂ (dppf) ^* DCM" is the error of 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride and methylene chloride "Pd ₂ dba ₃ " is ginseng (dibenzylideneacetone) dipalladium (0), "TEA" is triethylamine, and "XanthPhos" is (9,9-dimethyl-9 H -oxa Indole-4,5-diyl)bis(diphenylphosphine), and "THF" is tetrahydrofuran.

General procedure 1 - Preparation of substituted steroids

An aqueous nitric acid solution (67%, d = 1.4) was then added to the stirred solution of the appropriate amine in ethanol at 20 °C. The resulting solution was stirred at reflux for 4-8 hours. The mixture was then cooled to 15 ° C and diethyl ether was added to induce the product to crystallize. The resulting suspension was stirred at 20 ° C for 15 minutes or overnight. The precipitate was filtered, washed with a mixture of diethyl ether and ethyl ether (3:1).

General step 2 - ring closure reaction to give 2-amino-7,8-dihydroquinazolinone derivatives

Optionally substituted 2-((dimethylamino)methylene)cyclohexane-1,3-dione (1.0 mmol), corresponding hydrazine (1-1.4 equivalent) and triethylamine (0.3 The mixture of ethanol (6 ml) in ml) was refluxed for 3-24 hours. The progress of the reaction was monitored by TLC or HPLC. The resulting mixture was cooled to room temperature and diluted with water. The precipitate formed is filtered off, washed with water, and recrystallized from methanol or other suitable solvent to give the final compound.

If the product did not precipitate after dilution with water, the reaction mixture was extracted with dichloromethane or ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced vacuum. The resulting precipitate is then purified by flash column chromatography or preparative HPLC.

Preparation 1 2-((dimethylamino)methylene)cyclohexane-1,3-dione

Cyclohexane-1,3-dione (22.40 g, 200 mmol), N,N -dimethylformamide dimethyl acetal (47.7 g, 400 mmol) and acetonitrile (200 ml) The mixture was stirred at room temperature overnight and concentrated in vacuo. The mixture was then triturated with EtOAc (EtOAc)EtOAc.

Preparation 2 2-((Dimethylamino)methylene)-5-methylcyclohexane-1,3-dione

5-methylcyclohexane-1,3-dione (18.50 g, 146.0 mmol), N,N -dimethylformamide dimethyl acetal (34.90 g, 293.0 mmol) and A mixture of ethyl acetate (150 mL) was evaporated. The mixture was then triturated with EtOAc (EtOAc)EtOAc.

Preparation 3 2-((Dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione

The title compound was obtained from 5,5-dimethylcyclohexane-1,3-dione (4.91 g, 35.0 mmol), N,N -dimethylformamide as described in Preparation 2 . Prepared in dimethyl acetal (8.34 g, 70.0 mmol) and acetonitrile (35 mL) to give 4.72 g (yield: 69%)

Preparation 4 2-((Dimethylamino)methylene)-4,4-dimethylcyclohexane-1,3-dione

The title compound was obtained from 4,4-dimethylcyclohexane-1,3-dione (4.91 g, 35.0 mmol), N,N -dimethylformamide as described in Preparation 2 . Prepared in dimethyl acetal (8.34 g, 70.0 mmol) and acetonitrile (35 mL) to give 2.71 g (39%) of y.

General Step 3 - N - arylation to give 2-amino-7,8-dihydropyrido[2,3-d]pyrimidinone derivatives General procedure 3a - starting from 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

The meta-chloroperbenzoic acid is added to the stirred 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d] at a temperature below 30 °C. The solution of the pyrimidine-5( 6H )-one in toluene (5-10 ml) was stirred at the same temperature for 0.5 hour. The appropriate amine and N,N -diisopropylethylamine are added at a temperature below 30 ° C, and the mixture is stirred at room temperature for 2 hours. Then, toluene (5 ml) and isopropyl alcohol (8 ml) were added, and the mixture was washed with 1N aqueous sodium hydroxide solution (4 ml) and 15% aqueous sodium chloride solution (4 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting precipitate was purified by column chromatography (EtOAc EtOAcEtOAcEtOAc

Alternatively, the oxidized intermediate 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-5 can be used prior to reaction with the corresponding amine. 6 H )-ketone was isolated.

General procedure 3b - starting from 2-chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

The N -arylation reaction can also be carried out starting from 2-chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one, 2-chloro group -8-Methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one is obtained from 8-methyl-2-(methylthio)-5- in two steps. Ethyloxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester and the corresponding decarboxylated analog 8-methyl-2-(methylthio)- The 7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one is obtained via a 2-hydroxy derivative.

Adding an aqueous 1N hydrochloric acid solution to 2-chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one and the appropriate amine (1 equivalent) - Butanol suspension. The resulting solution was heated at 90 ° C for 1 hour. The mixture was cooled to rt, EtOAc (EtOAc)EtOAc. The layers were separated and EtOAc (EtOAc)EtOAc. The residue is then purified by column chromatography (gum, gradient 30% to 60% ethyl acetate / heptane) to give the final compound.

The reaction can also be carried out in N,N -dimethylformamide at 120 ° C for 4 hours. After cooling to room temperature, the crude product was precipitated by adding saturated sodium bicarbonate solution. The formed precipitate was filtered, washed with water (2×20 ml), dried, and purified by column chromatography (EtOAc, methylene chloride/ethyl acetate, 5:1).

Preparation 5 Ethyl 4-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(methylthio)pyrimidine-5-carboxylate

Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10.00 g, 43.0 mmol), ethyl 3-(methylamino)propanoate (7.00 g, 53.4 mmol) A mixture of triethylamine (8.00 mL, 57.3 mmol) in acetonitrile (120 mL) was refluxed for 16 hr, cooled to room temperature and concentrated in vacuo. The residue was purified by EtOAc EtOAcjjjjjjj

Preparation 6 8-methyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

Sodium hydride (60% oil, 2.31 g, 57.8 mmol) dissolved in the first Tributyl alcohol (30 ml). Then 4-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (12.55 g, 38.3 mmol) A solution of the toluene (200 ml) of the ear was added at room temperature. The reaction solution was refluxed for 0.5 hour, cooled to room temperature, and neutralized with a 5% aqueous hydrochloric acid solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting elut elut elut elut elut

Preparation 7 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

8-methyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (10.50 g , 37.3 millimolar) and 1N sodium hydroxide solution (75 ml, 75 mmol) in ethanol (40 ml) mixture was refluxed for 4 hours, cooled to room temperature, diluted with water (200 ml), then 1N water Neutralize with hydrochloric acid solution. The mixture was then extracted with dichloromethane (2×400 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The title compound (3.50 g, 45%) was obtained as a pale yellow solid.

Preparation 8 2-hydroxy-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

Add 1N sodium hydroxide solution (107 mL) to 8-methyl-2-(methylthio)-5-sideoxy-5,6,7,8-tetrahydropyrido[2,3-d] Pyrimidine-6-carboxylic acid ethyl ester (6.82 g, 21.33 mmol) in ethanol (100 ml) suspension and the mixture was stirred at 90 ° C for 16 h. The reaction mixture was concentrated to dryness. The suspension was filtered and EtOAc EtOAc m.

8-Methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one can also be used as a starting material to provide the title compound.

Preparation 9 2-Chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

2-Hydroxy-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one (3.56 g, 13.51 mmol) of phosphonium chloride (50 ml) The suspension was heated at 80 ° C for 64 hours. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The residue was partitioned between ethyl acetate (500 mL) and sat. After stratification, the organic layer was washed with brine (500 mL) dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut

Example 1 N -phenyl-5,6,7,8-tetrahydroquinazolin-2-amine

Barium carbonate (133 mg, 0.41 mmol), PdCl ₂ (dppf) ^* DCM (20 mg, 0.03 mmol), 2-bromo-5,6,7,8-tetrahydroquinazoline (58 A suspension of milligrams (0.27 mol) and aniline (35 mg, 0.38 mmol) in toluene (1 mL) was heated at 100 ° C under argon for 6 h then cooled to room temperature and evaporated. The residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound (22 mg, 36%).

¹ H NMR (CDCl ₃ ), δ _H , 1.78-1.92 (m, 4H), 2.63 (t, 2H), 2.75 (t, 2H), 6.95-7.02 (m, 2H), 7.31 (t, 2H), 7.62 (d, 2H), 8.11 (s, 1H).

LC/MS (M+H) ⁺ =226

Example 2 N- (4-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine

Barium carbonate (138 mg, 0.42 mmol), PdCl ₂ (dppf) ^* DCM (23 mg, 0.028 mmol), 2-bromo-5,6,7,8-tetrahydroquinazoline (60) Millimeter, 0.28 moles, and a suspension of 4-fluoroaniline (50 mg, 0.39 mmol) in toluene (1 mL) at 100 ° C under argon for 16 h, then cooled to room temperature, then evaporation. The residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound (10 mg, 15%) was obtained eluting eluting eluting eluting

¹ H NMR (CDCl ₃ ), δ _H , 1.78-1.92 (m, 4H), 2.62 (t, 2H), 2.74 (t, 2H), 6.96-7.06 (m, 3H), 7.51-7.60 (m, 2H) ), 8.09 (s, 1H).

LC/MS (M+H) ⁺ =244

Example 3 N- (3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine

1-Tributoxy- N,N,N'N '-tetramethylmethanediamine (522 mg, 3.00 mmol) was added dropwise to cyclohexanone at room temperature under an argon atmosphere ( 306 mg, 3.00 mmol). The reaction mixture was stirred at room temperature for 24 hours and then at 110 ° C for 1 hour. The resulting mixture was concentrated under reduced pressure to give crude ethyl 2-((dimethylamino)methylene)cyclohexanone (280 mg) as a brown oil. .

Crude 2-((dimethylamino)methylene)cyclohexanone (270 mg, ca. 1.74 mmol), 1-(3-chlorophenyl)indole nitrate (404 mg, 1.74 mmol) The mixture of triethylamine (0.6 ml) in ethanol (6 ml) was refluxed for 6 hours, cooled to room temperature and then diluted with water. The formed precipitate was collected by filtration, washed with water and then crystallised from methanol to give the title compound (100 mg,

¹ H NMR (D ₆ -DMSO), δ _H , 1.63-1.83 (m, 4H), 2.53-2.63 (m, 2H), 2.63-2.73 (m, 2H), 6.88 (d, 1H), 7.22 (dd , 1H), 7.63 (d, 1H), 7.95 (s, 1H), 8.19 (s, 1H), 9.51 (br s, 1H).

LC/MS (M+H) ⁺ = 260,262.

Example 4 N- (4-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine

Barium carbonate (138 mg, 0.42 mmol), PdCl ₂ (dppf) ^* DCM (23 mg, 0.028 mmol), 2-bromo-5,6,7,8-tetrahydroquinazoline (60) Mg, 0.28 mol), and a suspension of 4-chloroaniline (50 mg, 0.39 mmol) in toluene (1 mL) at 100 ° C under argon for 16 h then cooled to room temperature. evaporation. The residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound (26 mg, 35%) was obtained eluting eluting eluting eluting

¹ H NMR (CDCl ₃ ), δ _H , 1.81-1.92 (m, 4H), 2.63 (t, 2H), 2.75 (t, 2H), 7.10 (br.s, 1H), 7.23 - 7.27 (m, 2H) ), 7.57 (d, 2H), 8.11 (s, 1H).

LC/MS(M+H) ⁺ =260,262

Example 5 2-((3-fluorophenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)cyclohexane-1,3-dione is reacted with 1-(3-fluorophenyl) hydrazine to obtain a beige solid The title compound (132 mg, 51%).

¹ H NMR (CDCl ₃ ), δ _H , 2.01-2.11 (m, 2H), 2.56 (t, 2H), 2.92 (t, 2H), 6.83 (t, 1H), 7.33 (dd, 1H), 7.54 ( d, 2H), 7.80 (d, 1H), 8.82 (s, 1H), 10.38 (br s, 1H).

LC/MS (M+H) ⁺ =258

Example 6 2-((3-chlorophenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)cyclohexane-1,3-dione is reacted with 1-(3-chlorophenyl) hydrazine to obtain a pale yellow solid. The title compound (185 mg, 68%).

_{^{1 H NMR (D 6 -DMSO)}} , δ H, 2.01-2.11 (m, 2H), 2.56 (t, 2H), 2.91 (t, 2H), 7.06 (d, 1H), 7.32 (t, 1H), 7.72 (d, 1H), 7.96 (s, 1H), 8, 82 (s, 1H), 10.33 (br s, 1H).

LC/MS (M+H) ⁺ =274,276

Step 7 2-((4-chlorophenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)cyclohexane-1,3-dione is reacted with 1-(4-chlorophenyl) hydrazine to obtain a beige solid The title compound (199 mg, 73%).

_{^{1 H NMR (D 6 -DMSO)}} , δ H, 1.99-2.09 (m, 2H), 2.54 (t, 2H), 2.88 (t, 2H), 7.35 (d, 2H), 7.81 (d, 2H), 8.79 (s, 1H), 10.33 (br s, 1H).

LC/MS (M+H) ⁺ =274,276

Example 8 3-((5-Sideoxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile

According to general procedure 2, let 2-((dimethylamino)methylene)cyclohexane- The 1,3-diketone was reacted with 1-(3-cyanophenyl)oxime to give the title compound (147 mg, 56%).

_{^{1 H NMR (D 6 -DMSO)}} , δ H, 2.01-2.11 (m, 2H), 2.57 (t, 2H), 2.93 (t, 2H), 7.45 (d, 1H), 7.52 (t, 1H), 8.05 (d, 1H), 8.26 (s, 1H), 8.84 (s, 1H), 10.47 (br s, 1H).

LC/MS (M+H) ⁺ =265

Example 9 4-((5-Sideoxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile

According to the general procedure 2, 2-((dimethylamino)methylene)cyclohexane-1,3-dione is reacted with 1-(4-cyanophenyl) hydrazine to obtain a beige solid The title compound (167 mg, 63%).

¹ H NMR (D ₆ -DMSO), δ _H , 2.03-2.13 (m, 2H), 2.58 (t, 2H), 2.94 (t, 2H), 7.75 (d, 2H), 8.01 (d, 2H), 8.86 (s, 1H), 10.64 (br s, 1H).

LC/MS (M+H) ⁺ =265

Example 10 2-((3-methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)cyclohexane-1,3-dione is reacted with 1-(3-methoxyphenyl) hydrazine to obtain a white solid. The title compound (31 mg, 12%).

¹ H NMR (D ₆ -DMSO), δ _H , 2.01-2.11 (m, 2H), 2.55 (t, 2H), 2.89 (t, 2H), 3.22 (s, 3H), 6.62 (d, 1H), 7.20(t,1H), 7.34(d,1H), 7.52(s,1H), 8.79(s,1H), 10.15(br s,1H).

LC/MS (M+H) ⁺ =270

Example 11 (racemic)-2-((3-fluorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with 1-(3-fluorophenyl) hydrazine to obtain The title compound (206 mg, 71%).

¹ H NMR (CDCl ₃ ), δ _H , 1.18 (d, 3H), 2.25-2.45 (m, 2H), 2.60-2.76 (m, 2H), 2.96-3.06 (m, 1H), 6.79 (dd, 1H) ), 7.18-7.34 (m, 2H), 7.49 (br s, 1H), 7.75 (d, 1H), 8.96 (s, 1H).

LC/MS (M+H) ⁺ =272

Example 12 (racemic)-2-((3-chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with 1-(3-chlorophenyl) hydrazine to obtain The title compound was obtained as a pale yellow solid (191 mg, 61%).

¹ H NMR (CDCl ₃ ), δ _H , 1.17 (d, 3H), 2.25-2.45 (m, 2H), 2.60-2.77 (m, 2H), 2.96-3.06 (m, 1H), 7.07 (d, 1H) ), 7.25 (dd, 1H), 7.45 (d, 1H), 7.53 (br s, 1H), 7.86 (s, 1H), 8.95 (s, 1H).

LC/MS(M+H) ⁺ =288,290

Example 13 (racemic)-2-((4-chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with 1-(4-chlorophenyl) hydrazine to obtain The title compound (199 mg, 73%).

¹ H NMR (CDCl ₃ ), δ _H , 1.16 (d, 3H), 2.25-2.45 (m, 2H), 2.60-2.77 (m, 2H), 2.93-3.04 (m, 1H), 7.31 (d, 2H) ), 7.52 (br s, 1H), 7.61 (d, 2H), 8.93 (s, 1H).

LC/MS(M+H) ⁺ =288,290

Example 14 (racemic)-2-((4-bromophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with 1-(4-bromophenyl)oxime to obtain The title compound (175 mg, 48%).

¹ H NMR (D ₆ -DMSO), δ _H , 1.08 (d, 3H), 2.24 - 2.42 (m, 2H), 2.53-2.61 (m, 1H), 2.65 - 2.77 (m, 1H), 2.85 - 2.95 (m, 1H), 7.49 (d, 2H), 7.78 (d, 2H), 8.79 (s, 1H), 10.34 (br s, 1H).

LC/MS (M+H) ⁺ =332,334

Example 15 (racemic)-3-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with 1-(3-cyanophenyl) hydrazine to obtain The title compound was obtained as a white solid (135 mg, 45%).

¹ H NMR (D ₆ -DMSO), δ _H , 1.09 (d, 3H), 2.25-2.45 (m, 2H), 2.54-2.62 (m, 1H), 2.69-2.79 (m, 1H), 2.90-3. (m, 1H), 7.46 (d, 1H), 7.53 (dd, 1H), 8.06 (d, 1H), 8.28 (s, 1H), 8.84 (s, 1H), 10.52 (s, 1H).

LC/MS (M+H) ⁺ =279

Example 16 (racemic)-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with 1-(4-cyanophenyl) hydrazine to obtain The title compound (257 mg, 85%).

¹ H NMR (CDCl ₃ ), δ _H , 2.26-2.46 (m, 2H), 2.63-2.80 (m, 2H), 2.97-3.00 (m, 1H), 7.59 (br s, 1H), 7.63 (d, 2H), 7.83 (d, 2H), 8.99 (s, 1H).

LC/MS (M+H) ⁺ =279

Example 17 (racemic)-7-methyl-2-((4-(trifluoromethoxy)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and 1-(4-(trifluoromethoxy)phenyl) The title compound (54 mg, 14%) was obtained as a white solid.

¹ H NMR (D ₆ -DMSO), δ _H , 1.07 (d, 3H), 2.24 - 2.42 (m, 2H), 2.53-2.61 (m, 1H), 2.63 - 2.75 (m, 1H), 2.85 - 2.95 (m, 1H), 7.30 (d, 2H), 7.88 (d, 2H), 8.79 (s, 1H), 10.36 (br s, 1H).

LC/MS (M+H) ⁺ =338

Example 18 (racemic)-3-fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with guanidine hydrochloride to obtain the intermediate 2-amino-7. -Methyl-7,8-dihydroquinazolin-5( 6H )-one. This intermediate was combined with 4-bromo-3-fluorobenzonitrile (240 mg, 1.2 mmol), cesium carbonate (652 mg, 2.0 mmol), palladium acetate (16 mg, 0.07 mmol) XanthPhos (58 mg, 0.1 mmol) and tetrahydrofuran (2 ml) were reacted under microwave irradiation at 100 ° C for 1 hour under microwave irradiation, cooled to room temperature, and passed through a silicone pad (purified with tetrahydrofuran). Filtered in. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting elut elut elut elut elut

¹ H NMR (D ₆ -DMSO), δ _H , 1.07 (d, 3H), 2.24 - 2.44 (m, 2H), 2.53-2.61 (m, 1H), 2.65 - 2.75 (m, 1H), 2.85 - 2.95 (m, 1H), 7.67 (d, 1H), 7.85 (d, 1H), 8.13 (dd, 1H), 8.80 (s, 1H), 10.16 (br s, 1H).

LC/MS (M+H) ⁺ =297

Example 19 (racemic)-7-methyl-2-(pyridin-3-ylamino)-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with 1-(pyridin-3-yl) hydrazine to obtain The title compound was obtained as a white solid (156 mg, 57%).

¹ H NMR (CDCl ₃ ), δ _H , 1.17 (d, 3H), 2.27-2.45 (m, 2H), 2.62-2.76 (m, 2H), 2.96-3.06 (m, 1H), 7.31 (br, 1H) ), 7.60 (br, 1H), 8.23 (d, 1H), 8.37 (br, 1H), 8.83 (br, 1H), 8.96 (s, 1H).

LC/MS (M+H) ⁺ =255

Example 20 (racemic)-2-((6-chloropyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and 1-(6-chloropyridin-3-yl) The title compound (153 mg, 49%).

¹ H NMR (D ₆ -DMSO), δ _H , 1.07 (d, 3H), 2.25-2.42 (m, 2H), 2.53-2.61 (m, 1H), 2.65-2.77 (m, 1H), 2.86-2.96 (m, 1H), 7.44 (d, 1H), 8.26 (d, 1H), 8.77 (s, 1H), 8.80 (s, 1H), 10.48 (br s, 1H).

LC/MS (M+H) ⁺ =289,291

Example 21 (racemic)-7-methyl-2-((6-methylpyridin-3-yl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is cleavable from 1-(6-methylpyridin-3-yl) The title compound (107 mg, 36%) was obtained.

¹ H NMR (D ₆ -DMSO), δ _H , 1.07 (d, 3H), 2.24 - 2.42 (m, 2H), 2.42 (s, 3H), 2.53-2.61 (m, 1H), 2.63-2.75 (m) , 1H), 2.85-2.95 (m, 1H), 7.19 (d, 1H), 8.06 (d, 1H), 8.67 (s, 1H), 8.77 (s, 1H), 10.23 (br s, 1H).

LC/MS (M+H) ⁺ =269

Example 22 (racemic)-2-((6-Aminopyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione is reacted with guanidine hydrochloride to obtain the intermediate 2-amino-7. -Methyl-7,8-dihydroquinazolin-5( 6H )-one. This intermediate (266 mg, 1.5 mmol), di-Boc-protected 5-bromopyridin-2-amine (700 mg, 1.9 mmol), cesium carbonate (978 mg, 3.0 mM) A mixture of palladium acetate (24 mg, 0.1 mmol) and Xanth Phos (87 mg, 0.15 mmol) in tetrahydrofuran (5 ml) was stirred under a argon atmosphere at 90 ° C for 2 hours under microwave irradiation. Cool to room temperature and filter. The filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, ammonium hydroxide/ethanol/dichloromethane, 1:3:100) to give oily bis-Boc-protected 2-((6-amino) Pyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5( 6H )-one (190 mg, 37%), dissolved in dichloromethane (4 mL) It was treated with trifluoroacetic acid (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 4 hr then concentrated over vacuo. The residue was purified by preparative EtOAc (EtOAc) elute

¹ H NMR (D ₆ -DMSO), δ _H , 1.07 (d, 3H), 2.24 - 2.42 (m, 2H), 2.53-2.61 (m, 1H), 2.63 - 2.75 (m, 1H), 2.85 - 2.95 (m,1H), 3.39 (br, 2H+H ₂ O), 6.95 (d, 1H), 7.62 (br, 2H), 8.06 (d, 1H), 8.44 (s, 1H), 8.78 (s, 1H) ), 10.29 (s, 1H).

LC/MS (M+H) ⁺ =270

Example 23 (racemic)-2-((4-chlorophenyl)amino)-7-ethyl-7,8-dihydroquinazolin-5(6 H )- ketone

N,N -dimethylformamide dimethyl acetal (0.51 g, 4.28 mmol) was added to 5-ethylcyclohexane-1,3-di (0.40 g, 2.85 mmol) In a suspension of anhydrous benzene (5 ml), the mixture was heated under reflux for 4 hours and then evaporated to give 2-((dimethylamino)methylene)-5-ethylcyclohexane-1,3- Dione. This intermediate was dissolved in absolute ethanol (5 mL) and then 1-(4-chlorophenyl)indole (0.48 g, 2.85 mmol). The mixture was heated under reflux for 8 hours. After chilling, the title compound was crystalljjjjjjjjjj .

¹ H NMR (CDCl ₃ ), δ _H , 1.00 (t, 3H), 1.53 (q, 2H), 2.01-2.40 (m, 2H), 2.59-2.79 (m, 2H), 3.03 (dd, 1H), 7.32 (d, 2H), 7.53 (s, 1H), 7.62 (d, 2H), 8, 94 (s, 1H).

LC/MS (M+H) ⁺ =302

Example 24 2-((3-fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione is reacted with 1-(3-fluorophenyl)anthracene. The title compound (57 mg, 20%) was obtained as white solid.

_{^{1 H NMR (D 6 -DMSO)}} , δ H, 1.05 (s, 6H), 2.48 (s, 2H), 2.85 (s, 2H), 6.84 (dd, 1H), 7.34 (dd, 1H), 7.56 ( d, 1H), 7.82 (d, 1H), 8.83 (s, 1H), 10.40 (br s, 1H).

LC/MS (M+H) ⁺ =286

Example 25 2-((4-Chlorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione is reacted with 1-(4-chlorophenyl)anthracene. The title compound (112 mg, 37%) was obtained as a white solid.

_{^{1 H NMR (D 6 -DMSO)}} , δ H, 1.04 (s, 6H), 2.47 (s, 2H), 2.83 (s, 2H), 7.36 (d, 2H), 7.83 (d, 2H), 8.80 ( s, 1H), 10.32 (br s, 1H).

LC/MS(M+H) ⁺ =302,304

Example 26 4-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile

According to general procedure 2, 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione is reacted with 1-(4-cyanophenyl)anthracene. The title compound (123 mg, 42%) was obtained as pale yellow solid.

¹ H NMR (D ₆ -DMSO), δ _H , 1.05 (s, 6H), 2.50 (s, 2H), 2.88 (s, 2H), 7.77 (d, 2H), 8.03 (d, 2H), 8.87 ( s, 1H), 10.69 (br s, 1H).

LC/MS (M+H) ⁺ =293

Example 27 2'-((4-Chlorophenyl)amino)-6',8'-dihydro-5' H -spiro[cyclopropane-1,7'-quinazoline Porphyrin-5'-ketone

(1-ethoxycyclopropoxy)trimethylnonane (7.58 g, 43.5 mmol), 1-(triphenylphosphine)propan-2-one (18 g, 56.5 mmol) and Bit-toluenesulfonic acid (0.75 g, 4.35 mmol) was dissolved in 1,2-dichlorobenzene (50 ml), and the mixture was heated to 100 ° C for 4 hours, then cooled to room temperature and then passed on a silicone This was carried out by flash column chromatography (eluent eluted with petroleum ether then dichloromethane) to afford intermediate 1-cyclopropylpropan-2-one (2.67 g, 64%).

Sodium hydride (0.7 g, 80% in toluene suspension) was washed twice with benzene and then resuspended in tetrahydrofuran (35 ml). Dimethyl malonate (1.74 g, 13.2 mmol) was added, after which 1-cyclopropylidenepropan-2-one (1.15 g, 12.0 mmol) was added slowly. The mixture was heated under reflux for 4 hours. A solution of potassium hydroxide (1.54 g, 27.5 mmol) in water (10 mL) was then added and the mixture was refluxed for one hour. The mixture was cooled and treated with aqueous hydrochloric acid to adjust pH to 1 and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated, and the residue was purified by flash column chromatography to afford oily snail [2.5] octane-5,7-dione (1.3) Gram, 54%).

Spirulina [2.5] octane-5,7-dione (390 mg, 2.82 mmol) dissolved in ethyl acetate (20 mL), then N,N -dimethylformamide dimethyl Aldehyde (503 mg, 4.22 mmol) was added. The mixture was refluxed for 12 hours and then evaporated to dryness to give an intermediate enamine. 180 mg (0.93 mmol) of this intermediate was dissolved in absolute ethanol together with 1-(4-chlorophenyl)indole (157 mg, 0.93 mmol) and triethylamine (470 mg, 4.66 mmol). (94 ml) in. The mixture was heated under reflux for 72 hours and then cooled. The resulting precipitate was filtered, washed with EtOAc EtOAc EtOAc

¹ H NMR (CDCl ₃ ), δ _H , 0.52 (s, 4H), 2.49 (s, 2H), 2.81 (s, 2H), 7.31 (d, 2H), 7.61 (d, 2H), 7.64 (s, 1H), 8.99 (s, 1H).

LC/MS (M+H) ⁺ =300

Example 28 2-((3-Chlorophenyl)amino)-8,8-dimethyl-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-4,4-dimethylcyclohexane-1,3-dione is reacted with 1-(3-chlorophenyl)anthracene. . The two regioisomers formed were separated by column chromatography to give the title compound (240 mg, 20%).

¹ H NMR (D _{6 -} DMSO), δ _H , 1.38 (s, 6H), 1.99 (t, 2H), 2.61 (t, 2H), 7.08 (d, 1H), 7.36 (t, 1H), 7.70 ( d, 1H), 8.11 (s, 1H), 8.83 (s, 1H), 10.37 (br s, 1H).

LC/MS(M+H) ⁺ =302,304

Example 29 8,8-Dimethyl-2-(meta-tolylamino)-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-4,4-dimethylcyclohexane-1,3-dione is reacted with 1-(meta-tolyl) . Will be shaped The title compound (218 mg, 19%) was obtained as a pale yellow solid.

_{^{1 H NMR (D 6 -DMSO)}} , δ H, 1.36 (s, 6H), 1.98 (t, 2H), 2.31 (s, 3H), 2.59 (t, 2H), 7.21 (t, 1H), 6.87 ( d, 1H), 7.60 (d, 1H), 7.68 (s, 1H), 7.79 (s, 1H), 10.07 (br s, 1H).

LC/MS (M+H) ⁺ =282

Example 30 8-methyl-2-(anilino)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

According to general procedure 3a, 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one (209 mg, 1.00 mmol) Ear) with meta-chloroperbenzoic acid (297 mg, 1.72 mmol), N,N -diisopropylethylamine (0.523 ml, 3.00 mmol) and aniline (0.103 g, 1.11 mmol) The title compound (72 mg, 28%) was obtained as white solid.

¹ H NMR (CDCl ₃ ), δ _H , 2.68 (t, 2H), 3.22 (s, 3H), 3.58 (t, 2H), 7.08 (t, 1H), 7.34 (t, 2H), 7.48 (br s , 1H), 7.63 (d, 2H), 8.65 (s, 1H).

LC/MS (M+H) ⁺ =255

Example 31 2-((3-fluorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

According to general procedure 3a, 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one (418 mg, 2.0 mmol) Ear) and meta- chloroperbenzoic acid (594 mg, 3.4 mmol), N,N -diisopropylethylamine (1.046 ml, 6.0 mmol) and 3-fluoroaniline (246 mg, The title compound (25 mg, 5%) was obtained as a white solid.

¹ H NMR (CDCl ₃ ), δ _H , 2.69 (t, 2H), 3.23 (s, 3H), 3.60 (t, 2H), 6.76 (dd, 1H), 7.15 (d, 1H), 7.25 (dd, 1H), 7.48 (br s, 1H), 7.73 (d, 1H), 8.64 (s, 1H).

LC/MS (M+H) ⁺ =273

Example 32 2-((3-Chlorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

According to general procedure 3a, 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one (418 mg, 2.0 mmol) Ear) with meta-chloroperbenzoic acid (594 mg, 3.4 mmol), N,N -diisopropylethylamine (1.046 mL, 6.0 mmol) and 3-chloroaniline (282 mg, The title compound (57 mg, 10%) was obtained as a white solid.

¹ H NMR (CDCl ₃ ), δ _H , 2.69 (t, 2H), 3.23 (s, 3H), 3.60 (t, 2H), 7.04 (d, 1H), 7.23 (dd, 1H), 7.32 (d, 1H), 7.48 (br s, 1H), 7.95 (s, 1H), 8.64 (s, 1H).

LC/MS (M+H) ⁺ =289,291

Example 33 3-((8-Methyl-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)amino)benzonitrile

According to general procedure 3b, 2-chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one (140 mg, 0.7 mmol) was The title compound (110 mg, 55%) was obtained as a pale yellow solid.

¹ H NMR (CDCl ₃ ), δ _H , 2.71 (t, 2H), 3.25 (s, 3H), 3.62 (t, 2H), 7.33 (d, 1H), 7.41 (dd, 1H), 7.60 (br s , 1H), 7.62 (d, 1H), 8.28 (s, 1H), 8.64 (s, 1H).

LC/MS (M+H) ⁺ =280

Example 34 8-methyl-2-(meta-tolylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

According to general procedure 3b, 2-chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one (100 mg, 0.51 mmol) The title compound (79 mg, 58%) was obtained as a pale yellow solid.

¹ H NMR (CDCl ₃ ), δ _H , 2.37 (s, 3H), 2.70 (t, 2H), 3.24 (s, 3H), 2.60 (t, 2H), 6.91 (d, 1H), 7.22-7.26 ( m, 1H), 7.40 (br s, 1H), 7.46-7.48 (m, 2H), 8.64 (s, 1H).

LC/MS (M+H) ⁺ =269

Example 35 2-((3-Methoxyphenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one

According to general procedure 3b, 2-chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5( 6H )-one (100 mg, 0.51 mmol) The title compound (77 mg, 54%) was obtained from m.

¹ H NMR (CDCl ₃ ), δ _H , 2.70 (t, 2H), 3.26 (s, 3H), 2.61 (t, 2H), 3.83 (s, 3H), 6.63-6.66 (m, 1H), 7.07- 7.09 (m, 1H), 7.22-7.26 (m, 1H), 7.41 (br s, 1H), 7.47-7.48 (m, 2H), 8.65 (s, 1H).

LC/MS (M+H) ⁺ =285

Example 36 4-((5'-Phenoxy-6',8'-dihydro-5' H -spiro[cyclopropane-1,7'-quinazoline]-2'-yl)amino)benzonitrile

Spirulina [2.5] octane-5,7-dione (390 mg, 2.82 mmol) dissolved in ethyl acetate (20 mL), then N,N -dimethylformamide dimethyl Aldehyde (503 mg, 4.22 mmol) was added. The mixture was refluxed for 12 hours and then evaporated to dryness to give an intermediate enamine. 165 mg (1.1 mmol) of this intermediate was dissolved in dry ethanol (8.5 mL) with 1-(4-cyanophenyl)indole (175 mg, 1.1 mmol). The mixture was heated under reflux for 30 hours and then cooled. The formed precipitate was filtered, washed with diethyl ether then dried

¹ H NMR (CDCl ₃ ), δ _H , 0.55 (s, 4H), 2.52 (s, 2H), 2.86 (s, 2H), 7.63 (d, 2H), 7.85 (d, 2H), 7.93 (s, 1H), 9.04 (s, 1H).

LC/MS (M+H) ⁺ =291

Example 37 2-((3-Methylthio)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to the general procedure 2, 2-((dimethylamino)methylene)cyclohexane-1,3-dione is reacted with 1-(4-(methylthio)phenyl) hydrazine. The title compound (260 mg, 76%).

¹ H NMR (CDCl ₃ ), δ _H , 2.11-2.20 (m, 2H), 2.51 (s, 3H), 2.60-2.67 (m, 2H), 2.92-2.98 (m, 2H), 7.02 (d, 1H) ), 7.26 (dd, 1H), 7.37 (d, 1H), 7.44 (br s, 1H), 7.73 (s, 1H), 8.98 (s, 1H).

LC/MS (M+H) ⁺ =286

Example 38 (racemic)-2-((4-(difluoromethyl)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

2-Amino-7-methyl-7,8-dihydroquinazolin-5( 6H )-one (531 mg, 3.00 mmol) (based on general procedure 2, from 2-(( Dimethylamino)methylene)-5-methylcyclohexane-1,3-dione (18.10 g, 0.10 mol) and guanidine hydrochloride (12.35 g, 0.13 mol) in triethylamine ( (50.50 g, 0.50 mol) and ethanol (200 ml), (4-bromophenyl)methanol (617 mg, 3.00 mmol), Pd ₂ dba ₃ (137 mg, 0.15 mmol) ), XanthPhos (116 mg, 0.20 mmol), palladium carbonate (1.950 g, 6.00 mmol), and two A mixture of the alkane (10 ml) was stirred under argon for 20 hrs, cooled to room temperature, diluted with dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude intermediate 2 - ((4-hydroxymethyl) phenyl) amino) -7-methyl-7,8-dihydro-quinazolin -5 (6 H The ketone was diluted with dichloromethane (30 mL). Pyridinium chlorochromate (800 mg, 3.69 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (EtOAc, EtOAc/hexanes: 1:3) to yield 4-((7-methyl-5-s-oxy)- 5,6,7,8-Tetrahydroquinazolin-2-yl)amino)benzaldehyde (197 mg, 23% in 2 steps).

Add DAST (0.13 ml, 1.01 mmol) to 4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzene A solution of formaldehyde (190 mg, 0.68 mmol) in dichloromethane (10 mL). A second portion of DAST (0.13 mL, 1.01 mmol) was then added and the mixture was stirred at room temperature for 4 days, diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulfate and concentrated EtOAc. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc:

¹ H NMR (CDCl ₃ ), δ _H , 1.09 (d, 3H), 2.30-2.43 (m, 2H), 2.53-2.60 (m, 1H), 2.68-2.77 (m, 1H), 2.90-2.97 (m) , 1H), 6.92 (t, 1H), 7.50 (d, 1H), 7.92 (d, 1H), 8.81 (s, 1H), 10.40 (br s, 1H).

LC/MS (M+H) ⁺ =304

Example 39 (racemic)-2-((4-(difluoromethoxy)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and 1-(4-(difluoromethoxy)phenyl) The title compound (210 mg, 66%) was obtained as a white solid.

¹ H NMR (CDCl ₃ ), δ _H , 1.09 (d, 3H), 2.24-2.40 (m, 2H), 2.52-2.60 (m, 1H), 2.62-2.71 (m, 1H), 2.86-2.93 (m) , 1H), 7.09 (t, 1H), 7.13 (d, 1H), 7.80 (d, 1H), 8.79 (s, 1H), 10.21 (br s, 1H).

LC/MS (M+H) ⁺ =320

Example 40 (racemic)-2-((6-methoxypyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

Mercuric chloride (3.830 g, 14.10 mmol) was added to 6-methoxypyridin-3-amine (1.364 g, 11.0 mmol) and triethylamine (5.5 mL) at 0 °C with vigorous stirring. 39.6 mmoles, and a mixture of N',N" -di-Boc-thiourea (3.630 g, 13.2 mmol) in dichloromethane (45 ml). The reaction mixture was stirred at room temperature for 18 hr. Then, it was filtered through Celite. The filtrate was washed with water. The organic phase was dried over magnesium sulfate and concentrated, and then the residue was purified by column chromatography. /dichloromethane/hexane, 1:5:5), purified, washed with cold hexane, and dried to give N',N" -di-Boc-protected 1-(6-methoxy) as a white solid. Pyridin-3-yl)indole (3.520 g, 87%), then trifluoroacetic acid (12 mL) dichloromethane (30 mL) Trifluoroacetate (2.512 g, 66%).

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and 1-(6-methoxypyridin-3-yl)anthracene The title compound (109 mg, 35%) was obtained as a white solid.

¹ H NMR (CDCl ₃ ), δ _H , 1.18 (d, 3H), 2.23 - 2.44 (m, 2H), 2.58-2.76 (m, 2H), 2.91-3.00 (m, 1H), 3.95 (s, 3H) ), 6.78 (d, 1H), 7.30 (br s, 1H), 7.93 (d, 1H), 8.39 (s, 1H), 8.92 (s, 1H).

LC/MS (M+H) ⁺ =285

Example 41 (racemic)-7-methyl-2-((4-methylcyclohexyl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and trans-1-(4-methylcyclohexyl)phosphonium salt The title compound (80 mg, 29%) was obtained as a white solid.

¹ H NMR (CDCl ₃ ), δ _H , 0.88 (d, 3H), 0.95-1.10 (m, 2H), 1.03 (d, 3H), 1.21-1.38 (m, 3H), 1.63-1.74 (m, 2H) ), 1.81-1.92 (m, 2H), 2.18-2.29 (m, 2H), 2.40-2.60 (m, 2H), 2.68- 2.80 (m, 1H), 3.72-3.87 (m, 1H), 7.82 (br s, 1H), 8.55-8.67 (2 br s, 1H).

LC/MS (M+H) ⁺ =274

Example 42 (racemic)-2-((1-isopropylpiperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

1-isopropylpiperidin-4-amine (1.420 g, 10.00 mmol), 1 H -pyrazole-1-carboxamidine hydrochloride (1.480 g, 10.00 mmol), and N,N - A mixture of diisopropylethylamine (1.65 ml, 10 mmol) of N,N -dimethylformamide (5.5 ml) was stirred at 60 ° C for 15 hours, cooled to room temperature and diluted with diethyl ether. Stir at room temperature to complete the crystallization. The obtained solid was collected by filtration, washed with diethyl ether (3×20 ml), and then evaporated to dryness to give 1-(1-isopropylpiperidin-4-yl)indole hydrochloride as a white solid (1.910) Gram, 86%).

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and 1-(1-isopropylpiperidin-4-yl) The title compound (94 mg, 14%) was obtained as a yellow solid.

¹ H NMR (CDCl ₃ ), δ _H , 1.04 (d, 6H), 1.13 (d, 3H), 1.50-1.60 (m, 2H), 2.03-2.10 (m, 2H), 2.21-2.39 (m, 4H) ), 2.49-2.59 (m, 1H), 2.61-2.68 (m, 1H), 2.70-2.79 (m, 1H), 2.80-2.90 (m, 3H), 3.92-4.02 (m, 1H), 5.50 (br s, 1H), 8.83 (br s, 1H).

LC/MS (M+H) ⁺ =303

Example 43 (racemic)-2-((1-ethylhydrazinopiperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

1-(4-Aminopiperidin-1-yl)ethanone (1.42 g, 10.00 mmol), 1 H -pyrazole-1-carboxamidine hydrochloride (1.48 g, 10.00 mmol), And a mixture of N,N -diisopropylethylamine (1.65 ml, 10 mmol) of N,N -dimethylformamide (5.5 ml) was stirred at 60 ° C for 15 hours and cooled to room temperature. It was diluted with diethyl ether and stirred at room temperature for 10 minutes. The ether solution was then decanted and discarded. The resulting slurry was milled in a mixture of diethyl ether / acetonitrile (3:2). The solid formed was collected by filtration, washed with diethyl ether (3×20 ml), and then evaporated to dryness to give 1-(1-ethylhydrazinopiperidin-4-yl)phosphonium salt as a pale beige solid. Acid salt (1.71 g, 77%).

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and 1-(1-ethylhydrazinopiperidin-4-yl) The title compound (65 mg, 21%) was obtained as a white solid.

H NMR (CDCl ₃ ), δ _H , 1.03 (d, 3H), 1.30-1.52 (m, 2H), 1.76-1.94 (m, 2H), 2.00 (s, 3H), 2.20-2.30 (m, 2H) , 2.44-2.66 (m, 2H), 2.68-2.85 (m, 2H), 3.10-3.20 (m, 1H), 3.74-3.83 (m, 1H), 4.03-4.12 (m, 1H), 4.22-4.29 ( m, 1H), 8.01 (br s, 1H), 8.62 (2 br s, 1H).

LC/MS (M+H) ⁺ =303

Example 44 (racemic)-2-((5-chloropyridin-2-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione (18.10 g, 0.10 mol) and guanidine hydrochloride (12.35 g, 130 The reaction was carried out in ethanol (200 ml) under reflux for 10 hours. The reaction mixture was then cooled to room temperature. The solid formed was collected by filtration, washed with methyl tert-butyl ether (2×150 ml), and dried at 60 ° C to give the white product 2-amino-7 as a white solid. - methyl-7,8-dihydro-quinazolin -5 (6 H) - one (10.98 g, 62%).

2-Amino-7-methyl-7,8-dihydroquinazolin-5( 6H )-one (490 mg, 2.77 mmol), 5-chloro-2-iodopyridine (862) Mg, 3.60 mmol, cesium carbonate (1.81 g, 5.54 mmol), palladium acetate (44 mg, 0.20 mmol), and Xanth Phos (162 mg, 0.28 mmol) anhydrous The mixture of alkane (8 ml) was stirred at 90 ° C under argon for 6 hours, cooled to room temperature and filtered. The solid residue was washed with hot methanol (3×5 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified with EtOAc (EtOAc m.

¹ H NMR (D ₆ -DMSO), δ _H , 1.10 (d, 3H), 2.30-2.45 (m, 2H), 2.60 (d, 1H), 2.70-2.81 (m, 1H), 2.92-3.01 (m) , 1H), 7.90 (dd, 1H), 8.33 (s, 1H), 8.35 (d, 1H), 8.85 (s, 1H), 10.35 (s, 1H).

LC/MS (M+H) ⁺ =289,291

Example 45 (racemic)-6-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino) nicotinonitrile

2-Amino-7-methyl-7,8-dihydroquinazolin-5( 6H )-one was prepared according to the procedure described in Example 44 .

The 2-amino-7-methyl-7,8-dihydro-quinazolin -5 (6 H) - one (170 mg, 1.00 mmol), 6-bromo-nicotinonitrile (360 mg, 2.00 mmol Mohr), cesium carbonate (970 mg, 3.00 mmol), palladium acetate (22 mg, 0.10 mmol), and Xanth Phos (110 mg, 0.20 mmol) The mixture of the alkane (10 ml) was stirred under a argon atmosphere at 80 ° C under microwave irradiation for 2 hours in a sealed vessel, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc

¹ H NMR (CDCl ₃ ), δ _H , 1.21 (d, 3H), 2.31-2.49 (m, 2H), 2.69-2.82 (m, 2H), 3.06-3.16 (m, 1H), 7.95 (d, 1H) ), 8.65-8.72 (m, 2H), 8.89 (s, 1H), 9.10 (s, 1H).

LC/MS (M+H) ⁺ =280

Example 46 (racemic)-7-methyl-2-((5-methylpyridin-2-yl)amino)-7,8-dihydroquinazolin-5(6 H )-one

2-Amino-7-methyl-7,8-dihydroquinazolin-5( 6H )-one was prepared according to the procedure described in Example 44 .

2-Amino-7-methyl-7,8-dihydroquinazolin-5( 6H )-one (340 mg, 2.00 mmol), 2-bromo-5-methylpyridine (680) Mg, 4.00 mmol, cesium carbonate (1.95 g, 6.00 mmol), palladium acetate (44 mg, 0.20 mmol), and XanthPhos (220 mg, 0.40 mmol) The mixture of the alkane (25 ml) was stirred under a argon atmosphere at 80 ° C under microwave irradiation for 2 hours in a sealed vessel, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc

¹ H NMR (CDCl ₃ ), δ _H , 1.19 (d, 3H), 2.27-2.44 (m, 2H), 2.32 (s, 3H), 2.63-2.77 (m, 2H), 3.00-3.11 (m, 1H) ), 7.53 (m, 1H), 8.20 (s, 1H), 8.35 (d, 1H), 8.47 (s, 1H), 9.02 (s, 1H).

LC/MS (M+H) ⁺ =269

Example 47 (racemic)-2-fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile

2-Amino-7-methyl-7,8-dihydroquinazolin-5( 6H )-one was prepared according to the procedure described in Example 44 .

2-Amino-7-methyl-7,8-dihydroquinazolin-5( 6H )-one (340 mg, 2.00 mmol), 4-bromo-2-fluorobenzonitrile (800 mg, 4.00 mmol), cesium carbonate (1.95 g, 6.00 mmol), palladium acetate (44 mg, 0.20 mmol), and XanthPhos (220 mg, 0.40 mmol) The mixture of the alkane (25 ml) was stirred under a argon atmosphere at 80 ° C under microwave irradiation for 2 hours in a sealed vessel, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc

¹ H NMR (CDCl ₃ ), δ _H , 1.20 (d, 3H), 2.29-2.48 (m, 2H), 2.66-2.81 (m, 2H), 3.03-3.12 (m, 1H), 7.32 (d, 1H) ), 7.55 (dd, 1H), 7.66 (s, 1H), 8.06 (d, 1H), 9.01 (s, 1H).

LC/MS (M+H) ⁺ =297

Example 48 (racemic)-7-methyl-2-((2-methylpyrimidin-5-yl)amino)-7,8-dihydroquinazolin-5(6 H )-one

According to general procedure 2, 2-((dimethylamino)methylene)-5-methylcyclohexane-1,3-dione and 1-(2-methylpyrimidin-5-yl) The title compound (62 mg, 10%) was obtained.

¹ H NMR (CDCl ₃ ), δ _H , 1.18 (d, 3H), 2.29-2.42 (m, 2H), 2.62-2.74 (m, 2H), 2.73 (s, 3H), 2.96-3.05 (m, 1H) ), 7.34 (s, 1H), 8.97 (s, 1H), 9.01 (s, 2H).

LC/MS (M+H) ⁺ =270

Examples of representative pharmaceutical compositions

In combination with commonly used solvents, excipients, adjuvants and carriers, the present compounds can be formulated into tablets, coated tablets, capsules, drops, medicines, injections and infusion preparations, etc., and can be taken orally, rectal Medical, non-enteral, and other routes for medical applications. Representative pharmaceutical compositions according to the invention are as follows:

(a) Tablets containing the active ingredient suitable for oral administration can be prepared by conventional tableting techniques.

(b) In terms of medicine, any commonly used drug base may be incorporated by a usual step of the active ingredient, such as polyethylene glycol, which is solid at room temperature, but at or near body temperature. melt.

(c) For parenteral (including intravenous and subcutaneous) sterile solutions, the active ingredient is used together with conventional amounts of conventional ingredients, such as appropriate amounts of sodium chloride and double distilled water (according to conventional procedures such as filtration, aseptic filling) Ann In a bottle or IV-drop bottle, autoclave).

Other suitable pharmaceutical compositions will be immediately understood by those skilled in the art.

Recipe example

Again, the examples provided below are for illustrative purposes only and are not to be construed as limiting.

Example 1 Tablet formula

The appropriate formulation of a tablet containing 10 mg of the active ingredient is as follows:

Example 2 Tablet formula

Another suitable formula for tablets containing 100 mg is as follows:

Example 3 Capsule formula

The appropriate formulation of capsules containing 50 mg of active ingredient is as follows: Fill in gelatin capsules.

Example 4 Injection solution

The appropriate formulation for the injection solution is as follows:

Example 5 Liquid oral formula

A suitable formulation of 1 liter of oral solution containing 2 mg of the active ingredient in one ml of the mixture is as follows:

Example 6 Liquid oral formula

Another suitable formulation of a 1 liter liquid mixture containing 20 mg of the active ingredient in one ml of the mixture is as follows:

Example 7 Liquid oral formula

Another suitable formulation of a 1 liter liquid mixture containing 2 mg of the active ingredient in one ml of the mixture is as follows:

Example 8 Aerosol formula

180 grams of aerosol solution contains:

15 ml of this solution was filled into an aluminum aerosol can, covered with a dosing valve, and purged at 3.0 bar.

Example 9 TDS (transdermal drug delivery system) formula

100 grams of solution contains:

1.8 ml of this solution was placed on the pile fabric covered by the backing adhesive foil. The system is sealed with a protective liner and the protective liner is removed prior to use.

Example 10 Nanoparticle formula

10 g of polybutyl cyanoacrylate nanoparticles contain:

The polybutylcyanoacrylate nanoparticles are obtained by performing a latex polymerization reaction in a water/0.1N hydrochloric acid/ethanol mixture as a polymerization medium. Finally, the nanoparticles in the suspension are lyophilized under vacuum.

Example 11 Suspension formula

1.0 g suspension contains:

The hydroxypropyl methylcellulose was uniformly dispersed in water with a high speed mixer/blender. After the hydroxypropyl methylcellulose was subjected to a hydration time of about one hour, the active ingredient was uniformly blended into a hydroxypropylmethylcellulose solution. The viscosity of the suspension can be adjusted by the amount of hydroxypropyl methylcellulose, resulting in a very stable suspension with very slow particulate precipitation and particulate agglomeration.

Example 12 Injection solution

The 1.0 ml solution contains:

The active ingredient was dissolved in dimethyl hydrazine by stirring and heating (solution 1). The mannitol was dissolved in water for injection (solution 2). After cooling to room temperature, solution 1 and solution 2 were mixed by continuous stirring. The solution is then sterilized by filtration or by means of thermal compression.

Pharmacology

The active ingredients of the present invention, as well as the pharmaceutical compositions containing them, and the methods of treatment thereof, are characterized by unique and advantageous properties. The compounds and their pharmaceutical compositions exhibit (in the standard accepted and reliable test procedure) the following useful properties and characteristics.

method Combined analysis method for characterization of mGluR5 antagonistic properties [ ³ H]MPEP (2-methyl-6-(phenylethynyl)pyridine) binds to the transmembrane atopic regulation of the mGluR5 receptor in the cortex Preparation of rat cortical membrane

Sprague-Dawley rats (200-250 g) were decapitated and their brains were quickly removed. The cortex was dissected and homogenized in 20 volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate was centrifuged at 1,000 x g for 10 minutes. The precipitate was discarded, and the supernatant was centrifuged at 20,000 x g for 20 minutes. The resulting precipitate was resuspended in 20 volumes of distilled water and centrifuged at 8,000 x g for 20 minutes. The supernatant and buffy coat were then centrifuged at 48,000 x g for 20 minutes in the presence of 50 mM Tris-HCl, pH 8.0. Then will The pellet was resuspended in the presence of 50 mM Tris-HCl, pH 8.0 and centrifuged at 48,000 x g for another two to three times. All centrifugation steps were carried out at 4 °C. After resuspending in 5 volumes of 50 mM Tris-HCl, pH 8.0, the membrane suspension was rapidly frozen at -80 °C.

On the day of analysis, the membrane suspension was thawed, washed four times by resuspending in 50 mM Tris-HCl, pH 8.0, and then centrifuged at 48,000 x g for 20 minutes, and finally resuspended in 50 mM Tris-HCl, pH 7.4. The amount of protein in the final membrane preparation (500-700 μg/ml) was determined according to the Lowry method (Lowry O. H. et al. 1951. J. Biol. Chem. 193, 256-275).

[ ³ H]MPEP analysis

The cultivating department started by adding [ ³ H]MPEP (50.2 Curie/mole, 5 nM, Tocris, GB) to a vial containing 125-250 micrograms of protein (total amount 0.25 ml) and various concentrations of the drug. . Further, the analysis was carried out using [ ³ H]MMPEP (2-(3-methoxyphenylethynyl)-6-methylpyridine hydrochloride) as a radioactive ligand. The incubation was allowed to continue at room temperature for 60 minutes (equalization was achieved under the conditions used). Non-specific binding was defined by the addition of unlabeled MPEP (10 μM). The incubation was terminated using a Millipore filter system. The samples were rinsed twice on a glass fiber filter (Schleicher & Schuell, Germany) under constant vacuum with 4 ml ice-cold assay buffer. After separation and rinsing, the filter was placed in a scintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) and the retained radioactivity retained on the filter was measured using a conventional liquid scintillation counter (Canberra Packard, Germany).

Characterization

The specificity of binding is extremely high, ie >85% and is essentially independent of buffer (50 mM for Tris or HEPES) and pH (6.8-8.9). The apparently saturable protein dependence and the protein concentration (500-700 [mu]g/ml) selected for subsequent analysis is within the linear portion of this dependence. Cold MPEP replacement IC heat Ligand ₅₀ 11.2 ± 0.64nM. The K _d of [ ³ H]MPEP is 13.6 nM and is measured by the Scatchard analysis method and used to calculate the affinity of the displacer according to the K _d value according to the Cheng Prusoff correlation (IC of cold MPEP) _{50 is} equivalent to 8.2 nM of K _i ). _Bmax is 0.56 pm/mg protein.

Functional analysis of mGluR5 receptor Study on calcium in cytosol of cells transfected with stable cells

Chinese hamster ovary cells (CHO-K1 cells) (transfected with diazepam for inducible expression of the human metabotropic glutamate receptor mGluR5) were seeded at a density of 35.000 cells per well to a 96-well black clear bottom. In the tray. The standard growth medium used (Dulbecco's modified Eagle Medium, DMEM plus L-proline) contains the appropriate inducer isopropyl-β-D-thiogalactopyranoside ( IPTG) to achieve optimal receptor performance. One day after the inoculation, the growth medium was changed to Ca-Kit (Molecular Devices, USA) and incubated for an additional hour. Ca-Kit is contained in 20 mM HEPES pH 7.4, glutamic acid-pyruvate transamin The enzyme, pyridoxal phosphate and sodium pyruvate were reconstituted in assay buffer in Hank's balanced salt solution (HBBS). Compounds that are agonistic to the receptor can trigger an increase in calcium in the cytosol, which can be seen by an increase in the fluorescence signal measured using a fluorescent imaging reader (Molecular Devices). To analyze the potency of their regulation of calcium-reaction, the test compound (dissolved in 0.5% of the final dimethyl hydrazine concentration) at the receptor agonist (at a concentration that provides about 80% of the maximum signal) Gentamic acid was added in 5 minutes before the connection.

Stellate cell culture

Primary stellate cell culture was prepared from the cortex of neonatal rats as described by Booher and Sensenbrenner (1972, Neurobiology 2(3): 97-105). Briefly, Sprague-Dawley pups (2-4 days old) were decapitated and the new cortex was dissected, lysed with a nylon filter (pore size 80 microns) and carefully milled. The cell suspension was applied to a pre-coated poly-D-lysine flask (Costar, Netherlands), followed by the addition of 10% fetal bovine serum (FCS, Sigma, Germany), 4 mM branamide and 50 micrograms. /ml statin (both Biochrom, Germany) in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany) at 37 ° C in 5% carbon dioxide / 95% air The culture was carried out for 7 days in a humidified atmosphere, and the medium was changed on the 2nd and 6th days.

After 7 days of in vitro culture (7 DIV), the cells were shaken overnight at 250 rpm to remove oligodendrocytes and microglial cells. On the next day, the stellate cells were washed twice with CMF-PBS (phosphate buffered saline without calcium and magnesium, Biochrom, Germany), trypsinized, and coated at a density of 40,000 cells/well. It was precoated with a poly-D-lysine 96-well plate (Greiner, Germany). 24 hours after the establishment of the subculture, the stellate cells were rinsed with PBS ⁺⁺ (phosphate buffered saline, Biochrom, Germany), and then put into the sulfuric acid containing 1 × G5-additive (Invitrogen, Germany), 0.5 μg / ml A stellate cell-determined medium consisting of acetaminophen and 1.5 mg/ml fibronectin (all Sigma, Germany) DMEM (Miller et al., (1993) Brain Res. 618(1): 175- 8). After 3 days, the medium was replaced and the cells were incubated for another 2-3 days so that the stellate cells at the time of the experiment were 14-15 DIV.

Immunocytochemistry

Immunostaining is performed to confirm the presence of stellate cell markers such as glial fibrillary acidic protein (GFAP) and to monitor the performance of the mGluR5 receptor.

Study on calcium in cytosol of stellate cells

The increase in calcium in the cytosol caused by mGluR5 agonist L-suppressed with succinate was measured using a fluorescence imaging plate reader (FLIPR) and Ca-Kit (both Molecular Devices). The medium was aspirated prior to the addition of the agonist or antagonist, and the cells were loaded at room temperature with sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8). mM), D-glucose (15 mM), and HEPES (20 mM), 150 μl of loading buffer of calcium-sensitive dye reconstituted in pH 7.3 for 2 hours . The disk was then transferred to FLIPR to detect an increase in calcium (measured relative to fluorescent units (RFU)) with the addition of L-telluronate (100 nM). If an antagonist is detected, these compounds are pre-incubated for 10 minutes at room temperature prior to addition to the individual agonist.

In the case of a positive modulator, the concentration-response curve of the gentisylamine was performed in the presence and absence of a 10 μM modulator to determine the extent of potentiation/agonist potency increase. Thereafter, the concentration-response curve of the positive regulator is carried out in the presence of a gentamic acid salt at a fixed concentration (typically 10-30 nM) exhibiting a maximum synergistic window.

data analysis

The increase in fluorescence signal after the addition of the agonist reflects an increase in calcium in the lysate. The inconsistency in the amount of cells in each well was normalized using the spatial uniformity correction of the FLIPR operating software Screenworks. Calculate the average of the replicated time data (n=3-5) and use it for graphical representation. To assess pharmacology, changes in calcium due to different concentrations of agonist or antagonist are measured using MaxMin calculations.

All reactions (RFU-values) are expressed as a percentage of the control (=maximum response). EC ₅₀ and IC ₅₀ were calculated according to the Logistic equation using GraFit 5.0 (Erithacus software, GB) or Prism 4.0 (GraphPad software, USA). Compounds of the invention have a potency (IC ₅₀₎ range from about 0.5 nM to 100 μM range.

The results of representative compounds of the invention are shown in Table A1.

In summary, it will be apparent from the foregoing that the present invention provides novel and useful applications and uses of the compounds of the present invention, the compounds comprising the active ingredients according to the present invention, as well as novel pharmaceutical compositions thereof, and methods for their preparation and treatment thereof method.

The higher order activity of the active agents and compositions thereof (as evidenced by the reported assays) is shown to be based on their usefulness in humans and in lower animals. The clinical assessment of humans is not yet complete. It is expressly understood that the distribution and sale of any compound or composition for human use within the scope of the invention must of course be based on the prior approval of the government agency responsible for and authorizing the case.

The compound of formula I represents a novel mGluR5 modulator. In view of their efficacy, they will be a useful treatment for a wide range of conditions involving excessive glutamate-induced stimuli, especially central nervous system disorders.

These compounds are therefore found to be useful in the treatment of active objects, particularly humans, as well as those exhibited earlier in the description.

These compounds have also been found to be useful in the treatment of indications for active objects, particularly humans, where specific conditions are not necessarily present, but where specific physiological parameters can be improved by administration of the present compound, including enhancement of cognitive function.

Neuroprotective effects and cognitive enhancement can also be achieved by administering a combination of the present compound and an NMDA receptor antagonist such as memantine.

The method of treating a moving subject with a compound of the invention to inhibit the progression of the selected mild disease or alleviating the mild disease is by any generally accepted pharmaceutical route, as described above, using a selected effective agent to alleviate the particular mild disease desired to be alleviated. The dose is reached. The compounds of the present invention are useful in the manufacture of a medicament for the treatment of a living animal to inhibit the progression of a selected mild disease or condition or to alleviate the mild disease or condition, particularly a mild disease or condition susceptible to treatment with a Group I mGluR modulator. Uses are carried out in a conventional manner, and include the compounds of the present invention which are effective A step of mixing a pharmaceutically acceptable diluent, excipient, or carrier, a method of treatment, a pharmaceutical composition, and the use of a compound of the present invention in the manufacture of a medicament.

Representative pharmaceutical compositions prepared by combining the active ingredient with suitable pharmaceutically acceptable excipients, diluents, or carriers include tablets, capsules, injection solutions, liquid oral formulations, aerosol formulations, TDS formulations And nanoparticle formula, so that it can be used for oral, injection, or skin use, and also according to the aforementioned medicine.

****

The scope of the invention is not limited by the specific embodiments described herein. In fact, various modifications of the invention in addition to those described herein will be understood by those skilled in the art.

All patents, applications, publications, test methods, documents, and other materials cited herein are hereby incorporated by reference.

Claims (15)

a compound selected from Formula I Wherein X represents CH ₂ or C=O; Y represents CR ⁶ R ⁷ , NR ⁸ , O or S; R ¹ represents H, C _1-6 alkyl, or F; R ² represents H, C _1-6 alkyl Or F; or R ¹ and R ² together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two selected from the group consisting of sulfur and oxygen. And a hetero atom of nitrogen and wherein the ring is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, _C1-6 alkyl, _C1-6 alkoxy, amine Substituted with a substituent of a hydroxyl group, a cyano group, a decyl group, a C _1-6 alkylamino group, a bis-(C _1-6 alkyl)amino group, a C _1-6 alkylcarbonylamino group, and a pendant oxy group; ³ represents H, C _1-6 alkyl, or F; R ⁴ represents H, C _1-6 alkyl, or F; or R ³ and R ⁴ together with the carbon atom to which they are attached form a 3-7 member ring , which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen, and wherein the ring may optionally be subjected to one or more selected from the group consisting of halogen and trifluoromethyl. Base, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino, bis-(C _1-6 alkane base a substituent substituted with an amine group, a C _1-6 alkylcarbonylamino group, and a pendant oxy group; R ⁵ represents a single ring selected from the group consisting of an aryl group, a heteroaryl group, a cyclic C _3-6 alkyl group, and a heterocyclic group a moiety; R ⁶ represents H, C _1-6 alkyl, or F; R ⁷ represents H, C _1-6 alkyl, or F; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form 3- a 7-membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen, and wherein the ring is optionally freed from one or more selected from the group consisting of halogens, Trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino, di-(C ₁ Substituted with a substituent of a _-6 alkyl)amino group, a C _1-6 alkylcarbonylamino group, and a pendant oxy group; R ⁸ represents an H, C _1-6 alkyl group (which may optionally be selected from one or more Substituents for halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and bis-(C _1-6 alkyl)amine Substituted), C _3-6 cycloalkyl, C _1-6 alkylcarbonyl (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy Amine, Group, C _1-6 alkoxy group, and two - (C _1-6 alkyl) amino group substituted with the substituents), C _3-6 cycloalkylcarbonyl, C _1-6 alkoxycarbonyl group (which may be optionally One or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and di-(C _1-6 alkane Substituted by a substituent of an amine group, an aminocarbonyl group, an N- C _1-6 alkylaminocarbonyl group (wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoro a substituent of a methoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group), N,N -di- (C _1-6 alkyl)aminocarbonyl (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine a substituent of a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group; and optical isomers, prodrugs, pharmaceutically acceptable salts thereof, hydrates thereof a solvate, and a polymorph; wherein the compound of formula (I) is not representative: 2-((2,4-dichlorophenyl)amino)-7-methyl-7,8-dihydroquinazoline- 5 (6 H) - one, 2 - ((2,4-dimethylphenyl) Yl) -7-methyl-7,8-dihydro-quinazolin -5 (6 H) - one, 2 - ((2-methoxyphenyl) amino) -7,7-dimethyl - 7,8-Dihydroquinazolin-5(6 H )-one, 2-((2-methoxyphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5 (6 H )-keto, 2-((3-trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((3,4 -xylyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one, 2-((3,5-dimethoxyphenyl)amino) -7,7-Dimethyl-7,8-dihydroquinazolin-5(6 H )-one, 2-((4-ethylphenyl)amino)-7,7-dimethyl-7 ,8-Dihydroquinazoline-5( 6H )-one, 2-((4-ethylphenyl)amino)-7-methyl-7,8-dihydroquinazoline-5 (6 H )-keto, 2-((4-fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6 H )-one, 2-((4- Fluorophenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((4-fluorophenyl)amino)-7-methyl-7,8-di Hydroquinazoline-5(6 H )-one, 2-((4-methoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazoline-5 (6 H )-keto, 2-((4-methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((4-methoxyphenyl) Amino)-7-methyl-7,8-dihydroquinazolin-5( 6H )-one, 2-(cyclopentylamino)-7,7-di Methyl-7,8-dihydroquinazolin-5( 6H )-one, 2-(cyclopropylamino)-7,7-dimethyl-7,8-dihydroquinazoline-5 (6 H )-ketone, 2-(meta-tolylamino)-7,8-dihydroquinazolin-5(6 H )-one, 2-(anilino)-7,8-dihydroquinazoline Porphyrin-5(6 H )-one, 2-(p-tolylamino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2- ((3-(Trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2-((4-benzene) Oxyphenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2-(meta-tolylamino)-7,8 -dihydroquinazoline-5(6 H )-one, 7,7-dimethyl-2-(anilino)-7,8-dihydroquinazolin-5(6 H )-one, 7- Methyl-2-((4-phenoxyphenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 7-methyl-2-(p-tolyl) Amino)-7,8-dihydroquinazolin-5(6 H )-one, 7,7-dimethyl-2-(p-tolylamino)-7,8-dihydroquinazoline Porphyrin-5(6 H )-one, 7-methyl-2-(anilino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((3,5-xylene) Amino)-7,8-dihydroquinazolin-5(6 H )-one, 7-methyl-2-(meta-tolylamino)-7,8-dihydroquinazoline -5(6 H )-one, or 7-methyl-2-(3 -(Trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one. A compound of claim 1, wherein X represents CH ₂ and Y represents CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ each represent H. A compound of claim 1, wherein X represents C=O and Y represents CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ each represent H. A compound according to claim 3, wherein R ³ and R ⁴ each represent H or C _1-6 alkyl or R ³ and R ⁴ together with the carbon atom to which they are attached form a saturated 3-7 membered ring. A compound of claim 1, wherein X represents C=O and Y represents CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ each represent a C _1-6 alkyl group. A compound of claim 1, wherein X represents C=O and Y represents NR ⁸ , wherein R ⁸ represents C _1-6 alkyl. A compound according to claim 1, wherein R ⁵ represents optionally one or more selected from the group consisting of halogen, cyano, C _1-6 alkoxy, trifluoromethoxy, C _1-6 alkyl, C _{1 a} phenyl group substituted with a substituent of a ₆ -alkylthio group, a difluoromethyl group, and a difluoromethoxy group; optionally one or more selected from the group consisting of halogen, C _1-6 alkyl, amine group, C _1-6 alkane group, and a cyano substituent of the substituted pyridyl; C _1-6 alkyl substituted by free of pyrimidinyl; free of C _1-6 alkyl substituted cyclohexyl group; or by random or C _1-6 alkyl C _1-6 alkylcarbonyl substituted piperidinyl. A compound according to claim 1 which is selected from the group consisting of: N -phenyl-5,6,7,8-tetrahydroquinazolin-2-amine, N- (4-fluorophenyl)-5,6 ,7,8-tetrahydroquinazolin-2-amine, N- (3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine, N- (4-chlorobenzene -5,6,7,8-tetrahydroquinazolin-2-amine, 2-((3-fluorophenyl)amino)-7,8-dihydroquinazoline-5( 6H ) -ketone, 2-((3-chlorophenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, 2-((4-chlorophenyl)amino)-7 , 8-dihydroquinazoline-5(6 H )-one, 3-((5-o-oxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzamide Nitrile, 4-((5-o-oxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, 2-((3-methoxyphenyl)amine ,7,8-dihydroquinazoline-5(6 H )-one, (racemic)-2-((3-fluorophenyl)amino)-7-methyl-7,8-di Hydroquinazoline-5(6 H )-one, (racemic)-2-((3-chlorophenyl)amino)-7-methyl-7,8-dihydroquinazoline-5 (6 H )-keto, (racemic)-2-((4-chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5( 6H )-one, (racemic) )-2-((4-bromophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-3-((7- Methyl-5-o-oxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzamide , (racemic)-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, (racemic) -7-Methyl-2-((4-(trifluoromethoxy)phenyl)amino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-3 -fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, (racemic)-7 -methyl-2-(pyridin-3-ylamino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-2-((6-chloropyridine-3 - yl) amino) -7-methyl-7,8-dihydro-quinazolin -5 (6 H) - one, (rac) -7-methyl-2 - ((6-methylpyridine - 3-yl)amino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic)-2-((6-aminopyridin-3-yl)amino)-7 -methyl-7,8-dihydroquinazolin-5( 6H )-one, (racemic)-2-((4-chlorophenyl)amino)-7-ethyl-7,8- Dihydroquinazoline-5(6 H )-one, 2-((3-fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5 (6 H )-keto, 2-((4-chlorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6 H )-one, 4-((7, 7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, 2'-((4-chlorophenyl)amine ) -6 ', 8'-dihydro -5' H - spiro [cyclopropane -1,7'- quinazolin] -5'-one, 2 - ((3-chlorophenyl) Yl) -8,8-dimethyl-7,8-dihydro-quinazolin -5 (6 H) - one, 8,8-dimethyl-2- (meta - tolyl amino) -7 ,8-Dihydroquinazolin-5(6 H )-one, 8-methyl-2-(anilino)-7,8-dihydropyrido[2,3-d]pyrimidine-5 (6 H )-keto, 2-((3-fluorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one, 2- ((3-Chlorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one, 3-((8-methyl) -5-Sideoxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)amino)benzonitrile, 8-methyl-2-(meta- Tolylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one, 2-((3-methoxyphenyl)amino)-8-A Base-7,8-dihydropyrido[2,3-d]pyrimidin-5(6 H )-one, 4-((5'- pendant oxy-6',8'-dihydro-5' H - spiro [cyclopropane-1,7'-quinazolin]-2'-yl)amino)benzonitrile, 2-((3-methylthio)phenyl)amino)-7,8-di Hydroquinazoline-5(6 H )-one, (racemic)-2-((4-(difluoromethyl)phenyl)amino)-7-methyl-7,8-dihydroquinazoline -5-( 6H )-one, (racemic)-2-((4-(difluoromethoxy)phenyl)amino)-7-methyl-7,8-dihydroquinazoline- 5(6 H )-keto, (racemic)-2-((6-methoxypyridin-3-yl)amino)-7-A Base-7,8-dihydroquinazolin-5( 6H )-one, (racemic)-7-methyl-2-((4-methylcyclohexyl)amino)-7,8-di Hydroquinazoline-5(6 H )-one, (racemic)-2-((1-isopropylpiperidin-4-yl)amino)-7-methyl-7,8-dihydroquine Oxazolin-5(6 H )-one, (racemic)-2-((1-ethylhydrazinopiperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazoline -5(6 H )-keto, (racemic)-2-((5-chloropyridin-2-yl)amino)-7-methyl-7,8-dihydroquinazoline-5 (6 H )-ketone, (racemic)-6-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino) nicotinonitrile, ( Cyclo)-7-methyl-2-((5-methylpyridin-2-yl)amino)-7,8-dihydroquinazolin-5(6 H )-one, (racemic)- 2-fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, (racemic)- 7-Methyl-2-((2-methylpyrimidin-5-yl)amino)-7,8-dihydroquinazolin-5(6 H )-one, and its optical isomers, former Medicaments, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs. A pharmaceutical composition comprising a compound according to any of the preceding claims, together with one or more pharmaceutically acceptable excipients. A compound according to any one of claims 1 to 8 for use in the treatment and/or prevention of abnormal glutamate nerve conduction. A compound according to any one of claims 1 to 8 for use in the treatment and/or prevention of a disease selected from the group consisting of Alzheimer's disease, CJ's syndrome, CJD, BSE, and Protein-associated infections, diseases involving mitochondrial dysfunction, diseases involving beta -amyloid and/or tauopathy, Down's disease, hepatic encephalopathy, Huntington's disease, motor neuron disease, muscle Atrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, repairing granule syndrome, neuronal waxy lipofacia , neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's disease, mild dysfunction, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, boxers Dementia, vascular and frontal dementia, cognitive impairment, learning disabilities, eye damage, eye disease, eye disease, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma ,low Hypoglycemia, hypoxia, hypoxia during perinatal period, ischemia, ischemia due to cardiac arrest or stroke or bypass surgery or transplantation, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury Inner ear injury, tinnitus, sound- or drug-induced inner ear injury, sound- or drug-induced tinnitus, L-dopa-induced dyskinesia, L-dopa-induced in Parkinson's disease therapy Sexual dyskinesia, dyskinesia, dyskinesia in Huntington's disease, drug-induced dyskinesia, antipsychotic-induced dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced Dyskinesia, chorea, Huntington's disease, dysthymia, dystonia, stereotypic, twitching, tardive dyskinesia, tic disorder, spastic torticollis, eyelids, local and systemic muscles Insufficient tension, nystagmus, hereditary cerebellar dysmotility, cortical basal ganglia degeneration, trembling, primary tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol Use, opium addiction, opium abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), attention Insufficient Hyperactivity Disorder (ADHD), Attention Deficit Syndrome (ADS), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Dementia, Corsac Korsakoff syndrome dementia, Korsakoff syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain disease, AIDS brain disease, AIDS dementia syndrome, AIDS-related Dementia, severe depression, severe depression, depression, depression due to Borna virus infection, severe depression due to Borna virus infection, bipolar bipolar disorder, drug tolerance Sex, tolerance to opioids, dyskinesia, fragile X syndrome, intestinal tract (IBS), migraine, multiple sclerosis (MS), muscle cramps, pain, chronic pain, acute pain, inflammation Sexual pain, neuralgia, diabetic god Menstrual pain (DNP), pain associated with rheumatoid arthritis, pain abnormalities, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD), schizophrenia, schizophrenia, positive or cognitive or negative symptoms , sputum status, turdy disease, urinary incontinence, vomiting, pruritus, pruritus, sleep disorder, frequent urination, neuromuscular disease of the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter ( LES) Disorders, functional gastrointestinal disorders, dyspepsia, nausea, respiratory infections, bulimia nervosa, chronic laryngitis, asthma, reflux-associated asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food Addiction, binge eating disorder, square phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, phobia, substance-induced anxiety disorder, delusional disorder, emotional schizophrenic disorder, class Schizophrenia, substance-induced psychosis, or disease or condition of sputum; inhibition of peripheral tissues, peripheral nervous system, and central nervous system Tumor cell growth, migration, invasion, adhesion and toxicity; tumor formation, proliferation, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer , lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue tumor, glioma, malignant glioma, astroglioma, glioma, Neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial tumor, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymph Tumor, leukemia, thymoma, tumor, diabetes, hyperammonemia and liver failure and sleep disorders. a compound as claimed in any one of claims 1 to 8 The use of the substance for the treatment or prevention of a disease selected from the group consisting of Alzheimer's disease, CJ's syndrome/CJ's disease, mad cow disease (BSE), Purin-associated infection, and mitochondrial dysfunction Disease, disease involving β-amyloid and/or tau protein disease, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), olive bridge Cerebellar atrophy, postoperative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, repairing granule syndrome, neuronal waxy lipofuscinosis, neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's dementia, mild dysfunction, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, boxer dementia, vascular and frontal dementia, cognitive impairment , learning disabilities, eye damage, eye disease, eye disease, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma, hypoglycemia, hypoxia, hypoxia during perinatal period Ischemia Ischemia, convulsions, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury, inner ear injury of tinnitus, tinnitus, sound- or drug-inducedness due to cardiac arrest or stroke or bypass surgery or transplantation Inner ear injury, sound- or drug-induced tinnitus, L-dopa-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dyskinesia, dyskinesia in Huntington's disease , drug-induced dyskinesia, antipsychotic drugs-induced dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced dyskinesia, chorea, Huntington's disease, fingerprint Symptoms, dystonia, stereotypics, twitching, tardive dyskinesia, tic disorder, spastic torticollis, eyelids, local and systemic dystonia, nystagmus , hereditary cerebellar dysmotility, cortical basal ganglia degeneration, trembling, primary tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opium addiction, opium Abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), Attention Deficit Syndrome (ADS), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Dementia, Dementia of Korsakoff Syndrome Korsakoff syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain disease, AIDS brain disease, AIDS dementia syndrome, AIDS-related dementia, severe depression, severe depression , depression, depression caused by Borna virus infection, severe depression caused by Borna virus infection, bipolar bipolar disorder, drug tolerance, drugs for opioids Tolerance, transport Disorders, fragile X syndrome, intestinal tract (IBS), migraine, multiple sclerosis (MS), muscle cramps, pain, chronic pain, acute pain, inflammatory pain, neuralgia, diabetic neuropathic pain (DNP) , pain associated with rheumatoid arthritis, hyperalgesia, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD), schizophrenia, schizophrenia positive or cognitive or negative symptoms, paralysis, Toray's disease, urinary incontinence, vomiting, pruritus, pruritus, sleep disorder, frequent urination, neuromuscular disease of the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, Functional gastrointestinal disease, dyspepsia, nausea, respiratory infection, bulimia nervosa, chronic laryngitis, asthma, countercurrent correlation Asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorder, square phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, Phobia, substance-induced anxiety disorder, paranoia, schizophrenia, schizophrenia, substance-induced psychosis, or disease or condition of sputum; tumor cells inhibiting peripheral tissues, peripheral nervous system, and central nervous system Growth, migration, invasion, adhesion and toxicity; tumor formation, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung Adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue tumor, glioma, malignant glioma, astroglia, glioma, neuromuscular Cell tumor, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial tumor, lymphoma, Myeloma, Hodgkin's disease, Burkitt's (Burkitt's) lymphoma, leukemia, thymoma, cancer, diabetes, medicine hyperammonemia and hepatic failure and disorders of sleep. A pharmaceutical composition according to claim 9 for use in the treatment or prevention of a condition or disease associated with abnormal glutamate nerve conduction or for regulating mGluR5 receptor for medical benefit. A pharmaceutical composition according to claim 13 wherein the condition associated with abnormal glutamate nerve conduction, or wherein the mGluR5 receptor is modulated to achieve therapeutic benefit, is selected from the group consisting of: Alzheimer's disease, Cuija Syndrome/Cui's disease, mad cow disease (BSE), Purin-associated infection, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/ Or tau protein disease, Down's disease, hepatic encephalopathy, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), Systemic lupus erythematosus, systemic sclerosis, repairing granule syndrome, neuronal waxy lipofacia, neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's dementia, mild dysfunction, various Cognitive deficits in different forms of mild cognitive impairment, cognitive deficits in various forms of dementia, boxer dementia, vascular and frontal dementia, cognitive impairment, learning disabilities, eye injuries, eye problems, eye diseases , glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma, hypoglycemia, hypoxia, hypoxia during perinatal period, ischemia, due to cardiac arrest or stroke or bypass surgery Or transplantation caused by ischemia, convulsions, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury, inner ear injury of tinnitus, tinnitus, sound- or drug-induced inner ear injury, sound - or drug-induced tinnitus, L-dopa-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dyskinesia, dyskinesia in Huntington's disease, drug-induced Dyskinesia, antipsychotic-induced dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced dyskinesia, chorea, Huntington's disease, finger snoring, muscle tone Incomplete disease, stereotypic, twitching, tardive dyskinesia, tic disorder, spastic torticollis, eyelids, local and systemic dystonia, nystagmus, hereditary cerebellar dysmotility, cortical basal ganglia degeneration, tremor Symptoms, primary tremors, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opium addiction, opium abuse, cocaine Addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADS) ), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Dementia, Korsakoff Syndrome Dementia, Korsakov (Korsakoff) syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain disease, AIDS brain disease, AIDS dementia syndrome, AIDS-related dementia, severe depression, severe depression, depression, Inbo Depression caused by Borna virus infection, severe depression caused by Borna virus infection, bipolar bipolar disorder, drug tolerance, drug tolerance to opioids, dyskinesia , fragile X syndrome, intestinal fistula (IBS), migraine, multiple sclerosis (MS), muscle cramps, pain, chronic pain, acute pain, inflammatory pain, neuralgia, diabetic neuropathic pain (DNP), Pain associated with rheumatoid arthritis Analgesia, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD), schizophrenia, schizophrenia or cognitive or negative symptoms, spasticity, dysplasia, urinary incontinence, vomiting, Itching, pruritus, sleep disorder, frequent urination, neuromuscular disease of the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disease, indigestion, nausea, Respiratory infections, bulimia nervosa, chronic laryngitis, asthma, reflux-associated asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, bulimia, phobia, generalized anxiety Symptoms, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, phobia, Substance-induced anxiety, paranoia, schizophrenia, schizophrenia, substance-induced psychosis, or sputum; inhibition of tumor growth, migration, invasion, adhesion of peripheral tissues, peripheral nervous system, and central nervous system And toxicity; tumor formation, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, care Adenocarcinoma, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue tumor, glioma, malignant glioma, astroglia, glioma, neuroblastoma, glioblastoma , medulloblastoma, skin cell cancer, melanoma, malignant melanoma, epithelial tumor, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumor, Diabetes, hyperammonemia and liver failure and sleep disorders. A pharmaceutical composition comprising at least one combination of a compound according to any one of claims 1 to 8 and at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients.