TW200838853A - New quinoline derivatives - Google Patents

Abstract

Novel compounds of formula (I) and the use thereof in the prevention and/or treatment of mGluR5 receptor-mediated disorders wherein R1 and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amino group or saturated heterocyclyl group, wherein the heteroatom is N; R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted aryl group having at least one substituent selected from the group of hydrogen, halogen, alkyl, alkoxy group, or R3 and R4 together with the N atom to which they are attached can form C5-7 heterocyclyl group, containing 1 or 2 heteroatom(s) selected from the group of N, O, which may be optionally substituted by the groups selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkyloxycarbonyl, aminocarbonyl, -OCH2CH2O-, benzyl and substituted phenyl group; R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano group, or R6 and R7 together with the atoms to which they are attached can form an unsaturated heterocyclyl group.

Description

200838853 IX. INSTRUCTIONS OF THE INVENTION [Technical Field] The present invention relates to a novel compound, a process for preparing the same, an intermediate of the preparation method, a pharmaceutical composition containing the same, and a mGluR5 receptor thereof for preventing and/or treating The use of an intermediary disorder. [Prior Art] A major excitatory neurotransmitter in the mammalian central nervous system (CNS) is the glutamate molecule, which binds to neural crest and thus activates cell surface receptors. These receptors can be divided into two broad categories based on the structural properties of the receptor protein: ionotropic glutamate receptors and metabotropic glutamate receptors. Metabolic glutamine Receptor classes (mGliiRs) are receptors that are coupled to G proteins that, upon binding to glutamate, activate a variety of intracellular second messenger systems. Activation of niGluRs in intact mammalian neurons triggers one or more of the following reactions: activation of phospholipase C; increased hydrolysis of phosphoinositide (PI); release of intracellular calcium; activation of phospholipase D; Activation or inhibition of adenyl cyclase; increase or decrease of cyclic adenosine monophosphate (cAMP) formation; activation of guanyiy cyclase (guanyiy1 cyclase); increase of circular birds Formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increase of release of arachidonic acid; and increase or decrease of potential-gated and ligand-gated type 200838853, ion channel Activity. Zheng Zheng., P/zflrmco/. 5Ή· 199 3, 14:13 ; Schoepp, Neurochem. Int. 1994, 24:439,

Pi^ W Λ ., Neuropharmacology 1995, 34:1; Bor di and

Ugolini} Prog. Neurobiol. 199 9, 59:55) There are eight different mGluR subtypes called mGluRl to mGluR8 that have been identified by molecular selection (iV β A: awis /n_, TV ewr α π 7 9 9 4, 13:1031; Pin et al., N e ur o ph ar mac ο lo gy 1 9 9 5, 3 4 :1;

Knopfel et al., J. Med. Chem. 1995, 38: 141 7) Further receptor diversity occurs through the expression of selected mGluR subtypes (Ρζ·«争乂·, 尸7992 , Hua A., BBRC 1994, 199:1136; Joly J. Neurosci. 1995, 1 5 : 397 0. The metabolic glutamate receptor subtype can be based on the amino acid sequence identity and the receptor The two messenger systems, and their pharmacological properties, are subdivided into three groups: Group I, Group III, and Group III mGluRs. Group I mGluR includes mGluRl, mGluR5, and other types of selected junctions. Attempts to mGluRs physiological roles have shown that activation of these receptors causes neuronal excitation. Evidence suggests that this excitability is due to direct activation of mGluRs after the catapult, but it has also been shown that activation of mGluRs before the occurrence of pre-triggering leads to an increase in neurotransmitter release. (Ph 乂 乂., Neuropharmacology 199 5, 34:1; Watkins Debate, Trends

Pharmacol. Sci. 19 9 4, 15:33). Metabolic glutamate receptors are thought to be involved in a variety of normal procedures in mammalian CNS, and activation of mGluRs is necessary for inducing long-term hippocampal gain for 200838853 V - / long-term potentiation and long-term cerebellar depression {Bashir Et al., Nature 1993, 363:347; Bortolotto et al., Nature 1994, 3 68: 740; Aiha φ Λ Cell 1994, 79:365; 莩乂·, Ce// 79:377). The role of mGluR activation in nociception and analgesia has also been confirmed (Me//er et al., Neuroreport 1 9 9 31 4: 879; Bor di and U golini,

Brain Res. 19 9 9, 871:223, ° % Group I metabolic glutamate receptors (especially mGlnR5) have been considered to play a considerable role in a variety of pathophysiological processes and disorders affecting the CNS. These include stroke, head trauma, hypoxic and ischemic injuries, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's, acute and chronic pain, drug abuse and withdrawal syndrome, Obesity, as well as gastroesophageal reflux {GEKT>) {S cho epp # Λ ·, Trends Pharmacol. S ci · 1993, 14:13; Cunningham et al., Life S ci · 1994, 54:135;

Ho liman et al., Ann. Rev. Neurosci. 19 9 4, 1 7:31; Pin et al., Neuropharmacology 19 9 5, 34:1; Knopf el et al.” J · Me d. C he m. 19 9 5, 38:141 7; Spo or en Hua Wei., Trends Pharmacol· S ci · 2 001, 22:331; G asp ar ini Debate. Curr.

Op in. Pharmacol. 2 0 0 2, 2:43; Neugebauer Pain 2002, 9 8:1, SI as si Nightmare ·, Curr Top Med C hem. 2005; 5(9): 897-97/). mGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)-pyridine ("MPEP") are effective in animal model trials of emotional disorders including anxiety and depression (9) ren contend., /· PAarmaco/.五叮. The r. 2 0 0 0, 295: 1267; T at ar czynska et al. Br. J. 200838853

Pharmacol. 2 0 01,13 2:1423; Klodzynska argues., Pol. J. Pharmacol, 2 0 0 i , 73 2 ·. J ). Many of the pathologies in these conditions are thought to be caused by excessive excitation of CNS neurons triggered by glutamate. Since group I mGlixRs appear to increase glutamate-mediated neuronal excitation via post-thalotic mechanisms and increased presynaptic glutamate release, activation may contribute to this pathology. Therefore, selective antagonists of Group I mGhR receptors may be medically advantageous, especially as neuroprotective agents, analgesics, or anticonvulsants. A variety of compound derivatives having the above pharmacological activities are mentioned in the literature. International Patent Application WO 02/20489 is directed to novel quinoline derivatives and methods for the treatment of cGMP related conditions, cardiovascular disorders, sexual dysfunction, diabetes, and gastrointestinal disorders. These compounds are indicated to be particularly potent and selective inhibitors of cGMP PDE-5. International Patent Application WO 03 /0805 80 proposes novel quinoline compounds and their use in the treatment of anxiety, depression, obesity, and cognitive memory disorders. These compounds are indicated to be useful as 5-HT6 receptor antagonists for the treatment of neurological diseases and conditions. International Patent Application WO 05/05 8 83 4 relates to the treatment of diseases mediated by the liver X receptor (LXR) (especially multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and atherosclerosis) Novel quinoxaline derivatives that inhibit the production of Th-Ι lymphokine, resulting in increased HDL levels and cholesterol metabolism. However, there is still a need for novel compounds and compositions that are active at the mGUR5 receptor in metabolic glutamate receptors (mGluRs), particularly 200838853. SUMMARY OF THE INVENTION The compounds of the present invention are represented by formula (I):

() among them

Ri and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N; R3 and R4 are independently selected from hydrogen, alkane a substituted aryl group having at least one substituent selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, or R3 and R4 together with an N atom to which it is bonded may form a core. a Cs-7 heterocyclic group of a hetero atom optionally selected from the group consisting of hydrogen, halogen, alkyl, alkylalkyl, alkyloxycarbonyl, aminocarbonyl, hydrazineCH2CH20-, benzyl and substituted phenyl Substituted; R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, or

Re and R7 together with the atom to which they are attached may form an unsaturated heterocyclic group; and/or its mirror image isomers and/or racemates and/or non-image areomers and/or their formation with an acid or a base A pharmaceutically acceptable salt. Another aspect of the invention provides a process for the synthesis of a compound of formula (I) - 200838853 A further aspect of the invention is an intermediate relating to the process. A further aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and/or its mirror image isomer and/or racemate and/or non-image isomer and/or salt thereof And/or hydrates or solvates as active ingredients, as well as pharmaceutically acceptable diluents, excipients, and/or inert carriers. φ In another aspect of the invention provides a compound of formula (I) for the prevention and/or treatment of mG1UR5 receptor-mediated disorders (especially neurological disorders, psychiatric disorders, acute and chronic pain, lower urinary neuromuscular dysfunction, And the use of gastrointestinal disorders). A further aspect of the invention provides the use of a compound of formula (I) for the manufacture of a condition for the prevention and/or treatment of a disorder mediated by the mGluR5 receptor (especially neurological disorders, psychiatric disorders, acute and chronic) Medicine for pain, lower urinary neuromuscular dysfunction, and gastrointestinal disorders. • A further aspect of the invention provides a method of using a compound of formula (1) for the prevention and/or treatment of a condition mediated by the mGluR5 receptor, which means administering an effective amount of the invention to a mammal, including a human, to be treated The compound of formula (I) itself or as a medicine. The above aspects and other aspects of the invention are detailed in the text. [Embodiment] The compound of the present invention is represented by the formula (I): -11 _ 200838853 \· /

(I) where

Ri and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, amine substituted or substituted heterocyclic group, wherein the hetero atom is N; R3 and R4 are independently selected from hydrogen, An alkyl group having a substituted aryl group having at least one substituent selected from the group consisting of hydrogen, halogen, fluorenyl, and anthraceneoxy, or R3 and IU together with an N atom attached thereto may form 1 or 2 selected from n, a Cm heterocyclic group of a hetero atom which is optionally selected from the group consisting of hydrogen, halogen, alkyl, hydroxyalkyl, alkyloxy forged, aminocarbyl, -〇ch2ch2o-, benzyl and substituted Substituted by a phenyl group; R5, R6, R7 and Rs are independently selected from the group consisting of ammonia, halogen, affiliary, alkoxy, cyano, or R6 and R7 together with an atom to which they are attached may form an unsaturated heterocyclic group; And/or its mirror image isomers and/or racemates and/or non-image areomers and/or pharmaceutically acceptable salts thereof formed with acids or bases. Preferred compounds of the invention include those of the formula (I) having the following definitions: 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, Ci-4 alkyl, Cw alkoxy, cyano, optionally substituted amine, Or a saturated heterocyclic group wherein the hetero atom is N, R3 and R4 are independently selected from hydrogen, Cw alkyl, and have at least one substituent selected from the group consisting of hydrogen-12-200838853, halogen, Cw alkyl, Cw alkoxy Substituting an aryl group, or R3 and R4 together with an N atom attached thereto may form a Cyheterocyclic group containing 1 or 2 hetero atoms selected from ruthenium and osmium, which may be optionally selected from hydrogen, halogen, Cw alkyl , Cw hydroxyalkyl, alkyloxycarbonyl, aminocarbonyl, -OCH2CH2 〇-, benzyl and substituted phenyl (which may be optionally selected from 1 or 2 selected from hydrogen, halogen, Cw alkyl, C1M alkane) Substituted by the base of the oxy group; φ is substituted; R5, R6, R7, and r8 are independently selected from hydrogen, halogen, Cl_4 alkyl, Ci-4 decyloxy, cleavage' or R6 and R7 The atom may form an unsaturated 5 to 7 membered heterocyclic group containing 1 or 2 germanium atoms; and/or its mirror image isomer and/or racemate and/or non-image isomer and / or a pharmaceutically acceptable salt thereof formed with an acid or a base. Another preferred embodiment comprises a compound of formula (I) having the following definitions: R1 and r2 are independently selected from the group consisting of hydrogen, chloro, fluoro, c" alkyl, Cu alkoxy, fluorenyl, or fluorene; R3 and IU are independently selected from hydrogen, Cl 2 alkyl, benzyl substituted by 1 or 2 independently selected from the group consisting of hydrogen, halogen, C^4 alkyl, Clj alkoxy, R3 and R4 together with The N atom may form a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, or a piperidinyl group, which may be optionally selected from the group consisting of hydrogen, halogen, Cm alkyl, hydroxymethyl, alkyloxycarbonyl. , an aminocarbonyl group, and a group of -ocha^o-), or a piperidinyl group (which may be selected from the group consisting of a Ci4k group, a fluorenyl group, a phenyloxy carbon group, and Phenyl groups (they may be selected from -13 to 200838853, substituted by one or two substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy); R5 'R6, R7, and R8 are independent Selected from hydrogen, chlorine, fluorine, Ch2 alkyl, Ci_2 alkoxy, cyano, or R6 and R7 together with an atom to form 2,3-dihydro-[1,4]dioxane or 2, 5-dihydro-furan ring; and/or its mirror image isomers and/or Cyclones and/or non-image isomers and φ / or a pharmaceutically acceptable salt thereof formed with an acid or a base. The following is a list of definitions used to illustrate the description of the invention and the various terms used in the claims. Doubt, to be understood, when the specification refers to a certain definition of "basic definition" or "defined above" ("hereinbefore defined", "defined hereinbefore", or "defined above"), the basic system covers The first and most broad definitions, as well as the various and all other definitions mentioned in this section. For the avoidance of doubt, it is to be understood that "Ci_4" in this specification means having 1, 2, 3, or 4 Carbon-containing linear or branched groups of carbon atoms. As used herein, "alkyl" and other radicals having the radical "alk", such as alkoxy, mean a carbon chain which may be linear or branched or a combination thereof. Examples of the group include methyl, ethyl, propyl, isopropyl, butyl, secondary butyl and tertiary butyl, pentyl, hexyl, heptyl, and the like. "hetero" Contains one or A plurality of 0 or N atoms. For example, a heterocyclic ring system containing one or more ruthenium or N atoms (including a mixture of such atoms) in the ring. A hetero atom replaces a carbonogen -14 - 200838853]). Examples of the heterocyclic ring include pyrrolidinyl, piperidinyl, piperidinyl, morpholinyl, and piperidin-2-one. The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. The term "amino", unless specified otherwise, includes _NH2 groups and radicals derived from primary or secondary amines, which may also include aromatic amines. "Selectively substituted" or "optionally substituted" ("optionally substituted") is intended to have both substituted and unsubstituted φ. The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Among the salts formed with alkalis, those which are particularly important are metals (such as sodium, potassium), alkaline earth metals (such as fishing, clocks), and salts of ammonia or organic amines. The latter bases may have a substituent such as a hydroxyl group or an amine group which may affect, for example, the solubility and handleability of the product. Both organic acids and Φ inorganic acids can be used to form acid addition salts. Suitable inorganic acids can be, for example, hydrochloric acid, sulfuric acid, and phosphoric acid; representative examples of monovalent organic acids can be, for example, formic acid, acetic acid, trifluoroacetic acid, and C. The acid, and various different butyric acid, valeric acid, and citric acid; representative examples of the divalent organic acid may be, for example, oxalic acid, malonic acid, maleic acid, fumaric acid, and succinic acid. Other organic acids can also be used, such as hydroxy acids (such as citric acid, tartaric acid) or aromatic carboxylic acids (such as benzoic acid or salicylic acid), as well as aliphatic and aromatic sulfonic acids (such as methanesulfonic acid and p-toluenesulfonic acid). ). Particularly preferred among these acid addition salts are those in which the acid component itself has no effect at the dose administered, or which has no adverse effect on the active ingredient 15-200838853(R). These acid addition salts are pharmaceutically acceptable acid addition salts. Acid addition salts which are not pharmaceutically acceptable acid addition salts are within the scope of the invention in that they are advantageous in the purification and isolation of the desired compounds in the intended case. The compounds described herein may contain one or more asymmetric centers and may therefore have non-image isomers and optical isomers. The present invention includes all such possible non-image isomers and racemic mixtures thereof and substantially pure mirror image structures thereof. Of particular importance among the compounds of formula (I) of the present invention are those shown below: 3_(3,4-Dimethyl-phenylsulfonyl)-4-(tyrosolin-4-yl)quinoline; 3-(4 -methyl-benzenesulfonyl)_4_(3-methyl-piperidinyl-bu)-quinoline; 3-(3,4-methyl-phenylsulfonyl)-4-(4-methyl -piperidinylbuquinoline; 3-(4-methyl-benzenesulfonyl)-4-(4-methyl-piperidine-fluorenyl)-quinoline; 3-phenylsulfonyl-4 (piperidin-1-yl)-quinoline; 3-(4-methyl-benzenesulfonyl)-4-(piperidin-1-yl)-quinolin; ® 4_cleavylamino- 3- ( 4-methyl-benzenesulfonyl-yl)-quinoline; 6·ethyl-4-(4-methyl-piperidinyl-1-yl)·3-(4-methoxy-benzenesulfonyl)- Quinoline; 6-fluoro-3-(4-methyl-benzenesulfonyl)_4·(4-methyl-piperidin-bupybuquinoline; 6-ethoxy-3-(4-chloro- Benzenesulfonyl)-4-(4-fluoro-benzylaminoquinoline; 4-(azepine-1-yl)-3-(4-methyl-benzenesulfonyl)-quinoline D; 4 ·(N-indol-1-yl)-3-(4-chloro-benzenesulfonyl)-quinoline; 6-methyl- 3-(4-methyl-phenylsulfonyl)_4-(4-A Benzyl-piperidine-diyl)_16-2008388532) Quinoline; 4-(4-methyl-warm-U-l-yl)-3------------- - piperidine-1- -8--Benzenesulfonyl-2,3-dihydro-[1,4]dioxo[2,3_g]quinoline; 6-ethyl-4-(4-ethyloxyfluorenyl) -暧D疋-1-yl)-3-(4-chloro-benzene ore)-嗤琳; 4 - __•ethylamino-3-(4-methyl-benzoic acid)-Land Lin

4-(4-benzyl-piperazin-1-yl)-3-(4-chloro-benzenesulfonyl)-quinoline; 4-(azepine-1-yl)-3-phenylsulfonyl- Quinoline; 3-(3-indolyl-benzene ortho-yl)-6-oxo-4-(4-methyl-a-D-1,4-yl)-porphyrin; 6-fluoro-3-(4- Methoxy-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 6-fluoro-3-(3-methoxy-benzenesulfonyl)-4- (4-methyl-piperidin-1-yl)-quinoline; • 6·fluoro-3-(3,4-dimethyl-benzenesulfonyl)-4-(4-methyl-piperidine- 1-yl)·quinoline; 3·(3-chloro-4-methoxy-benzenesulfonyl)-6-fluoro-4-(4-methyl-piperidin-1-yl)-indene, 3-(3-chloro-4-win-the present-branched)-6-gas-4-(4-methyl-indole D-l-yl)-quinoline; 3-(3,4-dichloro -Benzenesulfonyl)-6-fluoro-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3-chloro- ortho-branched)-6-par-4- 4-methyl-pula D-1,4-yl)-嗟琳; -17- 200838853 3-(4-Chloro-phenylsulfonyl)-6-methyl-4-(4-methyl-piperidine- 1-yl)-quinoline; 3-(3-fluoro-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3- Methoxy-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3,4- _^^methyl-bens -6-methyl-4-(4-methyl-峨D疋-1·yl)-嗤琳 3-(3-chloro-4-methoxy-benzenesulfonyl)-6-methyl 4-(4-Methyl-piperidin-1-yl)-indole, 3-(3-chloro-phenylsulfonyl)-6-methyl-4-(4-methyl-piperidine-1 -yl)-quinoline; 3-(3-fluoro-4-methyl-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidin-1-yl)-quinoline; -(3-chloro-4-methyl-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidin-1-

3-(3-chloro-4-fluoro-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3,4-dichloro -Benzenesulfonyl)-7-fluoro-4-(4-methyl-piperidin-1-yl)-quinoline; 7-fluoro-3-(3-cyano-benzenesulfonyl)-4- (4-methyl-piperidin-1-yl)-quinoline; 7-gas-3-(4-aminobenzoene)-4-(4-methyl-cyclidine-1-yl) -Porphyrin; -18- 200838853t) 3-(3-Chloro-4-methyl-brown base)-7-in-one 4-(4-methyl-indole D-1 -m)-quinoline 7-fluoro-3-(3-methoxy-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3,4-difluoro-benzene Sulfhydryl)-7-fluoro-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3-chloro-4-fluoro-phenylsulfonyl)-7-fluoro- 4 -(4-methyl-piperidin-1-yl)-

7-Chloro-3-(3,5-dichloro-benzenesulfonyl)-4-(4-methylpiperidin-1-yl)-quinoline; 7-Chloro-3 (3,5- Difluoro-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 7-chloro-3-(3-cyano-benzenesulfonyl)-4-(4 -methyl-piperidin-1-yl)-quinolin; 7-chloro·3_(4-methyl-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quin

7-Chloro-3-(4-Terminal-branched)-4-(4-Methyl-暧D疋-1-yl)-嗟琳; 3-Benzenesulfonyl-7-chloro-4- (4-methyl-piperidin-1-yl)-quinoline; 7-gas-3-(4-chloro-branched)-4-(4-methyl-indol-1-yl) -Salina; 7-Chloro-3-(3,4-I-methoxy-benzoic acid)-4-(4-methyl-a-D-1,4-yl)-嗤琳, 7-Chlorine - 3- (3-3⁄4 -Benzene ortho)-4-(4-methyl-maid-D--1-yl)-Salina 7_Chloro-3_(3-methoxy-phenylsulfonyl) 4-(4-methyl-piperidin-1-yl)--19- 9 200838853;) quinoline; 7-chloro-3-(3-chloro-4-methoxy-benzenesulfonyl)- 4-(4-Methyl-piperidin-1-yl)-indenyl, 7-chloro-3-(3- gas-methicic acid)-4 - (4-methyl-y-D疋-1 - Base)-Lu Lin, 7-chloro-3-(3-chloro-4-fluoro-phenylsulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 6-chloro- 3-(3,5-difluoro-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quin

6-Chloro-3-(4-methyl-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 6-chloro-3-(4-chloro-benzenesulfonate Mercapto)-4-(4-methyl-piperidin-1-yl)-quinoline; 8-fluoro-3-(3-fluoro-4-methyl-phenylsulfonyl)-4-(4- Methyl-piperidin-1-yl)-quinoline; 8-fluoro-3-(4-methyl-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline B ; 3-(3,4- _•chloro-benzoic acid)-8-Rear-4-(4-methyl-H-H-1,4-yl)-porphyrin; 3-(3-chloro-4 - sharp-benzene extended base)-8 - per-4-(4-methyl-decyl-1-yl)-quinoline; 3-(3,4-fluoropropane/-benzoic acid) -8-pro- 4-(4-methyl-峨D疋-1-yl)-porphyrin; 3 - present orthoke-6-methyl- 4- (味琳-1-yl)-Salina ; 3-(3-chloro-benzenesulfonyl)-6-methoxy-4-(zurryloline-1-yl)-quinoline; 3-phenylsulfonyl-6-fluoro-4-(s-phenyl -1·yl)-quinoline; -20- 200838853 6-Chloro-3-(4-chloro-benzenesulfonyl)-4-(sodium benzo-i-yl)-quinoline; 3-(3-chloro -4-methyl-benzenesulfonyl)-7-fluoro-4-(isolin-1-yl)-quinoline; 3-(3,4-dichloro-benzenesulfonyl)-7-fluoro- 4-(picolin-1-yl)·quinoline; 7-chloro-3-(3,5- _•chloro-ben 5 yellow-branched)-4 -(味琳-1·基)-嗟7-Chloro-3-(3,4-dimethyl-benzenesulfonyl)-4-(tyrosolin-1-yl)-quinoline; 7-chloro-3-(3-chloro-benzenesulfonate) -4-(sodium porphyrin·ι_yl)·quinoline; 7-chloro-3-(3-chloro-4-methyl-benzenesulfonyl)· 4 -(glyphos-1 -yl)-quin Phenanthroline; φ 7-chloro-3-(3,4-dichloro-benzenesulfonyl)-4-(tyrosolin-1-yl)-quinoline; 7-chloro- 3·(3-chloro-4- Atmosphere - this 5 shell brewing base) -4 - (味琳-1 - base) - Salina. Pharmaceutical Formulations Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula (I) and/or a mirror image isomer thereof and/or a racemate and/or a non-image isomer and/or a pharmaceutically acceptable Salts and/or hydrates and/or solvates are accepted as active ingredients, together with one or more pharmaceutically acceptable carriers. • The compound of the formula (I) and/or its mirror image isomer and/or racemate and/or non-image isomer and/or pharmaceutically acceptable salt and/or hydrate and/or solvate may be cast by any conventional method. And, for example, oral, parenteral (including subcutaneous, intramuscular, and intravenous), buccal, sublingual, nasal, rectal, or transdermal administration, and the pharmaceutical composition is adjusted accordingly . Orally-administered compounds of formula (I) and/or their mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or The solvates can be formulated into liquids or solids such as syrups, suspensions or emulsions, lozenges, capsules, and snails. -21 - 200838853,) a compound of the formula (I) and/or its mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates Liquid blends usually consist of a compound of the formula (I) and/or its mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates. A suspension or solution formed in a suitable liquid carrier such as an aqueous solvent such as water, ethanol or glycerol; or a non-aqueous solvent such as polyethylene glycol or oil. This blend may also contain a suspending agent, preservative, flavouring agent, or coloring agent. The composition in the form of a tablet solid can be prepared by any suitable pharmaceutical carrier conventionally used in the preparation of solid compositions. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, arabic gum, magnesium stearate, stearic acid and the like. Alternatively, the tablet can be applied by standard aqueous or non-aqueous techniques. Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally using one or more accessory ingredients or adjuvants. Compressed tablets may be optionally mixed with a binder, a lubricant, an inert diluent, a surfactant, or a dispersing agent in a suitable machine in the form of a free-flowing form (such as a powder or granule). Made by compression. Compositions in the form of capsules can be prepared using routine encapsulation procedures. For example, nine capsules containing the active ingredient can be made using standard carriers and then incorporated into hard gelatin capsules; or, using any suitable pharmaceutical carrier (eg, aqueous gums, cellulose, sulphate, or oil) Prepare a dispersion or suspension and then pour the dispersion or suspension -22-200838853 into a soft gelatin capsule. Typical parenteral compositions are compounds of the formula (I) and/or their mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or Or a solvate consisting of a solution or suspension formed in a sterile aqueous carrier or a parenterally acceptable oil such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with the appropriate solvent just prior to administration. The composition of the present invention for nasal administration can be conveniently prepared by containing a compound of the formula (I) and/or its mirror image isomer and/or racemate and/or a non-mironomer and/or a salt thereof. Aerosols, drops, gels, and powders. The aerosol blends of the invention typically comprise a compound of formula (I) and/or its mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or a solution or fine suspension of a solvate in a pharmaceutically acceptable aqueous or non-aqueous solvent, and usually in a single or multiple doses in a sterile form in a sealed container. The 匣 form or the refilled form is used in conjunction with the atomizing device. Alternatively, the sealed container can be a single dispensing device such as a single dose nasal inhaler or aerosol dispenser fitted with a metering valve that can be disposed of when the contents of the container are used up. If the dosage form contains an aerosol dispenser, it will contain a propellant which may be a compressed gas (e.g., compressed air) or an organic propellant (e.g., a chlorofluorocarbon). Aerosol formulations are also available in the form of a pump atomizer. Containing a compound of the formula (I) and/or its mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvents-23-200838853)) The composition of the present invention is suitable for buccal or sublingual administration, including "tablets, lozenges, and pastilles, wherein the active ingredient is associated with a carrier (such as sugar and gum arabic, yellow). Silicone, or gelatin, glycerin, etc.) blended. Containing a compound of the formula (I) and/or its mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates for rectal administration The compositions of the present invention administered may conveniently be presented as a suppository containing a conventional suppository base such as cocoa butter and other materials conventional in the art. These suppositories can be conveniently formed by first mixing the composition with a softened or melted carrier, cooling and shaping in a mold. Containing a compound of the formula (I) and/or its mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates for transdermal purposes The compositions of the invention administered include ointments, gels, and patches. Compositions of the invention comprising a compound of formula (I) and/or its mirror image isomers and/or racemates and/or or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates The dosage should be in unit dosage form, such as tablets, capsules, or ampoules. Compounds of the formula (I) and/or their enantiomers and/or racemates and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates thereof for oral administration of the dosage unit of the invention. And/or the solvate is calculated as a free base, preferably (K1 to 50 0 mg ° for the parenterally administered compound of formula (I) and/or its mirror image isomers and/or contained in each dosage unit of the invention. Or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates, calculated as free base, preferably from 0.1 to 500 mg. Pharmaceutically acceptable compounds of the formula (I) and/or their enantiomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates may each The daily dose is administered in principle. In the treatment of mGluR5-mediated conditions such as schizophrenia, anxiety, depression, panic, bipolar disorder, and circadian disorders or chronic and acute pain disorders, the daily dose ranges from about 0.01 mg/kg body weight to about 140 mg/kg body weight is useful, or from about 0.5 mg to about 7 g per patient per day. The amount of active ingredient that can be combined with the carrier material to make a single dosage form will vary depending on the subject and the mode of administration. For example, a formulation for oral administration to humans may conveniently contain from about 5 mg to about 5 g of the active agent in admixture with a suitable and convenient amount of carrier material which may be from about 5% to about 95% of the total composition. Unit dosage forms usually contain from about 1 mg to about 1 000 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 25-3 00 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, however, it is important to understand that the specific dose level used for any particular patient depends on a number of factors, including age, weight, general health, surname, diet, time of administration, route of administration, rate of excretion. The situation of combined medication, and the severity of specific diseases for medical treatment. Medical use of the compounds of the formula (I) according to the invention and/or their mirror image isomers and/or racemates and -25 - 200838853, / or non-image isomers and / or pharmaceutically acceptable salts and / or hydrates and / or solvates have been found to be biologically active at the mGluR5 receptor and are therefore expected to be useful in the treatment of mGluR5 mediated diseases. The compounds of the invention or salts thereof have been found to have a high degree of potency and selectivity for individual metabolic glutamate receptor (mGluR) subtypes; in particular, compounds of the invention are potent and selective for the mGluR5 receptor Sex. Therefore, the compounds of the present invention are expected to be useful for preventing and/or treating conditions associated with excitatory activation of mGluR 5 receptor 0 and for inhibiting neural crest damage caused by excitatory activation of the mGluR5 receptor. These compounds are useful for the production of mGluR5 inhibition in mammals, including humans. Thus, it is expected that the compounds of the invention are well suited for use in the prevention and/or treatment of conditions which are mediated by the mGluR5 receptor, such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders. The compounds of the invention are also well suited for the treatment of lower urinary neuromuscular dysfunction, such as urgency, overactive bladder, frequent urination, reduced urinary compliance, cystitis, incontinence, enuresis And dysuria. The dosage required to treat or prevent a particular condition will necessarily vary depending on the patient being treated and the route of administration. The invention relates to a compound of the formula (I) as defined above and/or its mirror image isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts and/or hydrates and/or Or solvate for medical use. The invention relates to a compound of formula (I) as defined above for use in the prevention and/or treatment of a condition mediated by the mGluR5 receptor. -26- 200838853,) The present invention relates to a compound of formula (1) as defined above for use in the prevention and/or treatment of neurological disorders. The present invention relates to a compound of the formula (1) as defined above for use in the prevention and/or treatment of psychiatric disorders. The present invention relates to a compound of formula (1) as defined above for use in the prevention and/or treatment of chronic and acute pain conditions. The present invention relates to a compound of the formula (1) as defined above for use in the prevention and/or treatment of urinary tract neuromuscular dysfunction and gastrointestinal disorders. The present invention relates to a compound of the formula (1) as defined above for use in the prevention and/or treatment of pain associated with migraine, inflammatory pain, neuropathic pain conditions such as diabetic neuropathy, arthritis and rheumatoid Disease, lower back pain, post-operative pain, and pain associated with various conditions including angina/sore sore, renal colic or biliary colic, menstruation, migraine, and gout. The present invention relates to a compound of the formula (I) as defined above for use in the prevention and/or treatment of Alzheimer's disease, Alzheimer's disease, dementia caused by AIDS, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obesity, obsessive-compulsive and obsessive-compulsive conditions, ophthalmic conditions such as retinopathy, diabetic retinopathy, glaucoma, auditory neuropathy Tinnitus, chemotherapy-induced neuropathy, post-herpetic neuralgia and trigeminal neuralgia, tolerance, dependence, fragile X-chromosomal syndrome (Fragile X), loneliness/autism, mental retardation, schizophrenia And Down's syndrome. The present invention relates to a compound of formula (I) as defined above for use in the prevention and/or treatment of stroke, head trauma, hypoxic and ischemic injury, hypoglycemia, cardiovascular disease, and -27-200838853 And epilepsy. These compounds are also well-suited for the treatment of lower urinary neuromuscular dysfunction, such as urgency, overactive bladder, frequent urination, reduced urinary compliance, cystitis, incontinence, enuresis, and Urinary dysfunction. These compounds are also well suited for the treatment of gastrointestinal disorders such as transient φ sphincter sphincter relaxation (TLESR), gastrointestinal reflux disease, and irritable bowel syndrome. The invention also relates to the use of a compound of formula (I) as defined above for the manufacture of a medicament for the prevention and/or treatment of a condition mediated by the mGluR5 receptor and any of the conditions listed above. The invention also provides a method for preventing and/or treating a disorder mediated by a mGluR5 receptor and a disorder or a risk thereof, comprising administering to the patient an effective amount such as the above A compound of formula (I) as defined. # In the context of this manual, the word "therapy" includes treatment and prevention unless otherwise specified; and "therapeutic" and "therapeutically" should be interpreted accordingly. As used herein, unless otherwise indicated, the term "antagonist" means a compound that partially or completely blocks, in any way, a transduction pathway that results in a ligand-reactive reaction. The term "condition" means any condition or disease associated with metabolic glutamate receptor activity unless otherwise indicated. -28 - 200838853, v— / Preparation Methods Abbreviations The abbreviations used in the text have the definitions listed below. Abbreviations not listed below have their usual meanings unless otherwise specified. DMF N,N-dimethylformamide i-BuOH 2-methyl-2-propanol

AcOH acetic acid THF tetrahydrofuran According to the invention, the compound of formula (I) is prepared

() among them

Ri and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N; R3 and R4 are independently selected from hydrogen, alkane a substituted aryl group having at least one substituent selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, or R3 and R4 together with an N atom attached thereto may form 1 or 2 selected from the group consisting of ruthenium and osmium. a C5_7 heterocyclic group of a hetero atom optionally selected from the group consisting of hydrogen, halogen, alkyl, hydroxyalkyl, alkyloxycarbonyl, aminocarbonyl, -CH 2 CH 20 -, benzyl 29- 20 0 8 3 8 8 5 35) The base and the base of the 彳10# I + # κ base are replaced;

Rs R6 'heart and system are independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, or the atoms to which R6 and R7 are bonded to form an unsaturated heterocyclic group; and/or its mirror image isomerism And/or a racemate and/or a non-image isomer and/or a pharmaceutically acceptable salt thereof formed with an acid or a base, comprising: a) a compound of formula (VI)

(VI) (wherein Rl, r2, r5, R6, R?, and r8 are as defined above for the compound of formula (1)) are converted to a compound of formula (VII)

(wherein X is selected from the group consisting of halogen, benzenesulfonyloxy or trifluoromethanesulfonyloxy, and R!, R2, R5, R6, R7, and R8 are as defined above for the compound of formula (1)), and then The resulting compound of formula (VII) is combined with formula (VIII) -30- 200838853 R4\ sound 3

N Η (VIII) (wherein 3 and r4 are as defined above for the definition of the compound of formula (I)) to give a compound of formula (I) which selectively forms a mirror image isomer and/or racemate thereof / or a non-image isomer and / or a pharmaceutically acceptable salt; or b ·) a compound of formula (XV) R4 \ sound 3

Br Rg (xv)

(wherein R3, r4, r5, R6, R7, and r8 are as defined above for the compound of formula (1)) and a compound of formula (π I)

M+S

R2 (HI) (wherein M is selected from the group consisting of alkali or alkaline earth metals, and I and 1^2 are as described above, 31 to 200838853), and the formula (i) is reacted to obtain the formula (XVI) Compound K, R3 r5 n

k (XVI) (wherein Ri, R2, R3, R4, R5, R6, R7, and R8 are as defined above for the compound of formula (I)) and then oxidizing the compound of formula (XVI) to give formula (XVII) Compound

(XVII) (wherein Ri, R2, R3, R4, R5, R6, R7, and Rs are as defined above for the compound of formula (I)) and then oxidizing the compound of formula (xvn) to give formula (I) a compound, and optionally a mirror image isomer and/or a racemate thereof and/or a non-mironomer and/or a pharmaceutically acceptable salt; or C.) a compound of formula (I) wherein Ri, R2, R3 , R4, R5, R6, R7, and R8 are as defined above for the compound of formula (1). Interconversion 32-200838853 is a compound of formula (I) wherein Ri, R2, R3, R4, R5, R6 , R7, and r8 are as defined above for the compound of formula (1); where appropriate, the compound of formula (I) wherein R2, R3, R4, R5, R6, R7, and R8 are Separating the mirror image isomers and/or racemates and/or non-image isomers of the definitions provided by the compounds of formula (I) above; and then selectively forming salts and/or salts of the compounds of formula (I) Hydrate and / or Φ solvate. Preparation of a compound of formula (VI)

(VI) where

Ri and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N; R5, R6, R7 and R8 are independently selected From hydrogen, halogen, alkyl, alkoxy, cyano, or R6 and 117 together with an atom to which they are attached may form an unsaturated heterocyclic group; and/or its mirror image isomers and/or racemates and/or The method of the non-image isomer and/or its pharmaceutically acceptable salt with an acid or a base comprises: a) a compound of formula (II) -33 - 20083 8853)}

Br (Π) (wherein R5, R6, R7, and r8 are as defined above for the compound of formula (1)) and a compound of formula (III)

Ri m+sSZ/(ill) (wherein the lanthanide is selected from an alkali metal or an alkaline earth metal, and 1 and the r2 system are as defined above for the compound of formula (I)) to give a compound of formula (IV) r5 oh

R8 (IV) (wherein Ri, R2, R5, R6, R7, and R8 are as defined above for the compound of formula (I)), and then oxidizing the compound of formula (IV) to give compound (V)-34 - 200838853])

(wherein Ri, R2, R5, R6, R7, and R8 are as defined above for the compound of formula (I)), and then oxidizing the compound of formula (V) to give compound of formula (VI) #, and selectively forming a mirror image isomer and/or racemate and/or a non-mironomer and/or a pharmaceutically acceptable salt; or b.) a compound of formula (IX)

φ (wherein 1 and R2 are as defined above for the compound of formula (I)) and α-halogen-acetate of formula (X)

Hlg-CH2-COOR9 (X) (wherein Hlg is a halogen, r9 is an ethyl group or a methyl group) is reacted to obtain a compound of the formula (XI)-35-200838853υ SO2-CH2-COOR9 (XI) (wherein Ri and R2 are as The above definition of the compound provided by the formula (1) and R9 is as defined above for the compound of the formula (X); the compound of the formula (XI) and the trial of the trialkyl orthoformate of the formula (xn)

CH(〇R10)3 (XII) (wherein Ri is ethyl or methyl) is reacted to give a compound of formula (XIH)

So2-c-coor9 CH—〇一 Ri〇 (XIII)

(wherein and R2 are as defined above for the definition of the compound of formula (I) 'R9 is as defined above for the compound of formula (X), and Rig is as defined above for the compound of formula (XII); Compound of formula (XIΠ) and aniline derivative of formula (XIV)

-36 - (XIV) 200838853!) (wherein R5, R6, r7, and the definitions given above for the compound of formula (1) are reacted to give a compound of formula (VI)' and selectively form its mirror image And/or racemate and/or non-image isomer and/or pharmaceutically acceptable salt according to the reaction scheme la, formula (II) 3-bromo-derivative can be used as the thiophenol alkali metal of formula (III) The salt or thiophenolic alkaline earth metal salt (e.g., sodium salt) is substituted to produce a compound of formula (IV) (see Bioorg. Med. Chem. Lett. 2001, 9, 11 4 1 - φ i 7 44). Advantageously, the substitution reaction can be catalyzed by palladium and carried out under microwave conditions. In order to shorten the reaction time 'Pd-catalytic and/or microwave irradiation is required. The oxidation reaction of 3-arylhydrocarbylthio-4-hydroxyquinoline of formula (IV) can be achieved by hydrogen peroxide in a suitable acid (such as trifluoroacetic acid) to obtain the formula (V) and the formula (VI, respectively). ) Hey. The reaction of converting a 4-hydroxyquinoline derivative of the formula (VI) into a compound of the formula (VII) can be carried out by a known halogenation method using an appropriate reagent (e.g., pocl3, SOCl2, PC15, POBr3, PBr3) ® or using, for example, benzene Sulfoonyl chloride or trifluoromethanesulfonic anhydride is carried out by known deuteration methods. The reaction of the compound of the formula (VII) can also be carried out by halogenation or deuteration of the (V) 4-hydroxyquinoline derivative, followed by oxidation of the obtained compound by a known method or by the above method. The compound of the formula (I) can be produced by an aromatic nucleophilic substitution reaction of a compound of the formula (VII) with a compound of the formula (VIII) or a secondary amine. -37- 2〇〇8388530 Reaction Flowchart 1 a

According to the reaction scheme lb, another method for preparing the compound of the formula (1) by passing the intermediate of the formula (VI) is to react the compound of the formula (IX) with the α-halogen-acetate of the formula (X) in a suitable solvent (such as DMF, water). In the reaction. The compound of the formula (m) can be obtained by a known method or can be obtained by a known method from a suitable benzenesulfonyl chloride derivative (refer to, for example, 5卩7. The compound of the formula (XIII) can be derived from the compound of the formula (XI) and the formula (XII). a compound which is obtained by reacting with acetic anhydride. [Im. Org·c/zem. 别,1 6(7), 127 5-12 78 ; Zh. Org. Khimt 1980, 1 6(7), 1483 - /#7). An aniline derivative of a compound of the formula (XIII) and a compound of the formula (XIV) can give a phenylsulfonyl-phenylamino-acrylate [eg /. & g. Chm. USSR (Engl. Transl., 1980, 16 ( 7), 12 75-1278; Zh. Org· -38 - 200838853,)

Diw, 7), which can be converted in situ to the 4-hydroxy-quinoline derivative of formula (VI) (see 丄C/ze, c. 7>aw. 7,/99 ((to 7-392) A similar reaction in the above). To obtain the compound of the formula (I), the same preparation procedure as described in the above Reaction Scheme 1a can be employed.

Hig-CH2-COOR9 CH(OR10)3

a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), and/or its mirror image isomers and/or racemates and/or non-image isomers and/or The pharmaceutically acceptable salt formed with the acid or base is a novel substance. According to the reaction scheme 2, 4-amino-3-bromoquinoline of the formula (XV) can be produced by a known method (··· Meyi C/zem. 0, 4 (567-4 (577). According to the reaction Scheme 2, formula (XV) 4 -amino-3-bromoquinoline can be substituted with, for example, the sodium thiophenolate salt of formula (III) to give a compound of formula (XVI). Advantageously, this aromatic nucleophilic reaction can be utilized Palladium catalyst and/or under microwave conditions - 39-200838853) The oxidation of 4-amino-3-arylthioquinoline of formula (XVI) can be carried out by known methods, preferably with a suitable acid. (such as acetic acid), under the reaction of potassium permanganate, to obtain the formula (XVII) 4-amino-3-arylsulfinyl quinoline or in a suitable acid (such as acetic acid or trihydrate) The fluoroacetic acid is reacted with aqueous hydrogen peroxide to obtain a compound of the formula (I), and the compound of the formula (XVII) is subjected to an oxidation reaction, which can be carried out by a known method, preferably a suitable acid (e.g., ethylene sulphuric acid). In the reaction, the reaction with potassium permanganate is carried out at 〇-5 ° C. Reaction Scheme 2 .

Ri

The pharmaceutically acceptable salt of a compound of the formula (XVI) with a compound of the formula (XVII), and/or a mirror image isomer thereof and/or a racemate and/or a non-mironomer and/or an acid or a base thereof is New substance. Some of the compounds of formula (I) may also be mirror image isomers, racemates, non-mirror isomers. These stereoisomers can be selectively isolated, for example, by palm column chromatography or by the use of knots -40-200838853, crystallography (in the case of non-image isomers). Pure mirror image isomers and/or racemates and/or non-mirromeric isomers of the compounds of formula (I) can also be prepared from stereochemically pure precursors and/or geometrically pure precursors. The compound of the formula (I) containing a basic functional group can be converted into a salt thereof by an acid, and/or can be released from the obtained acid addition salt by treatment with a base. The compound of formula (I) can be converted to a hydrate and/or solvate. The compounds of formula (I) can be optionally converted into different compounds of formula (I) by conventional methods. Biological test methods mGluR5 receptor binding assay The mGluR5 receptor binding is based on a modified method by Gasparini et al. (Bioorg. Med. Chem. Lett., 2000, 12, ¥07). Based on the high degree of identity between human and rat mGluR5 receptors, rat cortical membrane preparations were used to determine the binding properties of reference compounds and novel compounds to rat mGluR5. The binding properties of the compound to the human mGluR5a receptor were determined by an A18 cell strain capable of expressing hmGluR5a (purchased from Euroscreen). Non-specific binding was determined with [3H]-M_MPEP (2 nM) as radiolabeled ligand' in the presence of 10 μM M-MPEP. Evaluation of Functional Activity Against Cell Culture of Natural Rat mGluR5 Receptor - 41 - 200838853,) Evaluation of the native rat mGluR5 receptor using a primary neocortical cell culture obtained from a 17-day-old Charles River rat embryo. Functional potency (for details on preparation of neural cell cultures, please refer to MI; Bunge, RP (19 9 2): Primary cell cultures 〇f peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedoroff, S.; Richardson A., //wm (four) a Prew /nc·, 57-77). After separation, the cells were coated on a standard 96-well microplate and the culture was maintained at 37 ° C, 95% air - 5 % <:02 atmosphere. After 5-7 days, in vitro calcium measurements were made using neocortical cultures. Cell culture of recombinant human mGluR5a receptor, Chinese hamster ovary (CHO) cells capable of stably expressing recombinant human mGluR5a (CHO-mGluR5a, Euroscreen) receptor in 10% FCS, 1% antibiotic antifungal solution Cultured in F 12 medium of 400 gg/ml Lu G418, 250 pg/ml zeocin, 5 pg/ml puromycin. The cells were maintained in a humidified incubator at 37 ° C, 5% CO 2 /95% air atmosphere and passaged three times a week. The cells were coated with 2.5-3·5χ104 cells/well on a standard 96-well microplate, and the receptor expression was induced by adding 600 ng/ml of doxycycline the next day. Calcium measurements were taken 1 to 24 hours later. Fluorescence measurement of cytosolic calcium concentration Measurement of cytosolic calcium concentration ([Cah],) was performed on primary neocortical cell cultures and CHO-mGluR5a cells capable of stably expressing human-42-200838853 mGluR5a receptor. The cells were grown in standard 96-well microplates and loaded with fluorescent Ca2+-sensitive dye fluo-4/AM (2 μΜ) in the cells prior to measurement: the neural culture was loaded in its growth medium. Dye, while CHO-mGluR5a cells are supplemented with 2 mM Na-pyruvate and 30 Rg/ml glutamate-pyruvate transaminase assay buffer (145 mM NaCl,

5 mM KC1, 2 mM MgCl2, 2 mM CaCl2, 10 mM HEPES, 20 mM D-glucose, 2 mM probenecid, pH = 7.4) were loaded with dye (if CHO-mGlnR5a cells, the aforementioned The supplement is also present during the [Ca2+h measurement process). Dye loading was achieved by incubating the cells with a 100 μΐ/well dye solution in a humidified incubator at 37 ° C for 40 - 1 20 minutes in an atmosphere of 5% CO 2 / 95% air. To stop dye loading, wash the cells twice with assay buffer. After washing, various concentrations of test compound (diluted in assay buffer from DMSO or dimethylformamide (DMF) stock solution, final DMSO/DMF concentration <0.1%) or buffer were added to each well. Depending on the experimental configuration. In the case of a new cortical culture, the assay buffer also contained cesium (0.5 μΜ to inhibit [Ca2+; spontaneous oscillation of h). After incubation for 10-20 minutes at 37 ° C, the baseline and agonist-induced changes in [Ca 2 + ]i were measured tube by tube using a plate reader fluorimeter (FlexStation II, Molecular Devices), luminescence Excitation and detection are performed from the bottom of the disc. The entire measurement process is carried out at 37 ° C and controlled by custom software. The inhibitory potency of the test compound was evaluated by measuring the degree of decrease in Ca2 + h rise caused by the agonist -43-200838853)). DHPG was used as an agonist of the two cultures at a concentration of 20 μM in neocortical cultures. In the case of CHO-mGluR5a cells, the shellfish U D Η P G system was administered at a concentration of E C 80 . E C 8 0 値 is obtained from the daily dose-response curve. Fluorescence data is expressed in AF/F (fluorescent change normalized to baseline). All processing on a single disk is measured in a number of wells, the data from the same process is averaged from the same well, and the average enthalpy is used for analysis. The inhibitory potency of a compound at a single concentration point is expressed as a hundred percent inhibition of the control agonist response, the sigmoidal concentration-inhibition curve is applied to these data (from at least three independent experiments), and the compound is determined to be 1 C50 値 ( Produces a compound concentration that is half the maximum inhibition). The raw fluorescence data was analyzed by Soft Max Pro (Molecular Devices), and the curve of the nest [] was completed with GraphPad Prism. Results The compound of the formula (I) of the present invention exhibited affinity for both rat and human niGluR5 receptors, and was confirmed to be a functional antagonist, i.e., they inhibited the functional response caused by the stimulation of the mGluR5 receptor. The invention is further illustrated by the following non-limiting examples. All operations were carried out at room temperature (ie, a temperature range of 18-25 °C) unless otherwise specified. After the reaction, thin layer chromatography (TLC) was carried out and the reaction time provided was for illustrative purposes only. The structures of all intermediates and final products are illustrated by IR, NMR, and MS spectroscopy; the yields provided are for illustrative purposes only. The NMR data is the use of the specified solvent for the main -44 - 200838853]) to identify the proton relative to the internal standard of tetramethyl decane (TMS), expressed in parts per million (ppm) delta ( 5) 値 form. The shape of the signal is represented by abbreviations. EXAMPLES All starting materials can be obtained by purchase or can be synthesized by a variety of known methods as described in the literature. Example 1 3- (3,4- _methyl-mineral base)_4-(味琳-4-yl)-嗤琳 Table I Compound 1 4- (Momoline-4-yl)-quinoline In a microwave reactor, a mixture of porphyrin (〇. 8 6 m 1 , 9.9 mmol) and 4-chloroquinoline (0.74 g, 4.5 mmol) was heated up to 195 ° C during 60 seconds. The reaction mixture was allowed to cool to 150 ° C and maintained at this temperature for 10 minutes Φ. The mixture was dissolved in dichloromethane (40 ml). Yield: 94%. !H NMR (3 00 MHz, DMSO-heart, 30 〇C): 3 · 1 9 - 3 · 2 7 (m, 4H); 3·95-4·04 (ιη, 4H); 7.02 (d, 1H, /=5.0 Hz); 7.49 (ddd, 1H, J=8.4, 6·9, 1.3 Hz); 7.67 (ddd, 1H, J=8.4, 6.9, 1.5 Hz); 8.03 (ddm, 1H, "7 = 8.4, 1.5 Hz); 8.07 (ddm, 1H, J = 8.4, 1.3 Hz); 8.76 (d, 1H, J = 5.0 Hz) · 200838853,) MS(EI)M + = 214. 3 -Bromo-4 -(tyrosolin-4-yl)-quinoline dissolves 4 -(morpholin-4-yl)-carboline (2 · 8 g, 13 mm ο 1) in 〇 - 5 °C a mixture of bromine (0.7 ml, 13.6 mmol) in dichloromethane (3.5 ml) and acetic acid (7·ml) in a mixture of acetic acid (26 mL) and dichloromethane (9 ml) The solution formed in the solution was added dropwise over a period of 3 hours. The reaction mixture was stirred at 〇 5 • C for 2 hours. The residue was dissolved in ethyl acetate (200 ml). The solvent was evaporated, and the title compound was obtained from mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 7 4 %. lR NMR (3 00 MHz, DMSO-rf^ 30 °C): 3 · 2 0 - 3 . 5 7 (brm, 4 H ); 3.80-3.91 (m5 4H); 7.65 (ddd9 1H, 8.4, 6.9, 1.4 Hz); • 7.79 (ddd, 1H, J=8.4, 6.9, 1.4 Hz); 8.01 (ddm, 1H9 J=8.45 1.4 Hz); 8.29 (ddm, 1H5 J=8.49 1.4 Hz); 8.8 4 (s, 1 H) · MS (EI): M + = 292 (79Br). 3-(3,4-Dimethyl-phenylthio)-4-(tyrosolin-4-yl)-quinoline hydrochloride 3- 3-bromo-4-(morpholin-4-yl)-quin Porphyrin (293 mg, 1 mmol), 3,4·dimethylsulfide (0.27 ml, 1.9 5 mmol), sodium tert-butoxide (187 mg, 1.95 mmol), 肆-(triphenylphosphine) (230 mg, 0.2 mmol) and tri-46-200838853, a mixture of grade butanol (0.7 ml) or DMF (0.7 ml) was heated in a microwave reactor at 143 for 2 hours. The solvent was evaporated in vacuo and the residue was crystallisjjjjjjjjjjjjjjj The residue was purified by gradient flash chromatography (40 g, EtOAc, EtOAc: EtOAc: EtOAc: This crude product was dissolved in ethyl acetate (5 ml) and ethyl acetate (0.5 ml, EtOAc, The precipitate was filtered, washed with ethyl acetate and dried Yield: 64%. JH NMR (3 00 MHz, DMSO-J6, 30 ° C): 2.18 (s, 3H); 2.19 (s, 3H); 3.70-3.87 (m? 8H); 6.98 (dd, 1H, J = 7.9, 2.1 H 9); 7.0 9 _ 7 · 1 7 (m, 2 H); 7.78 (ddd, 1H, J = 8.6, 7.0, 1.1 Hz); 8.01 (ddd, 1H, *7=8.5, 7.0, 1 . 1 Hz);

8.23 (dd? 1H, «7=8.5, 1.1 Hz); 8.30 (dd, 1H, *7=8.6, 1.1 Hz); 8.74 (s, 1H). MS(EI): M + = 350 3-(3,4-dimethyl-phenylsulfinyl)-4-(glylin-4-yl)-quinoline hydrochloride 3-(3,4 -Dimethyl-phenylthio)-4-(tyrosolin-4-yl)-quinoline hydrochloride (280 mg, 0.8 mmol) in acetic acid (6 ml) and water at 0-5 °C (22 ml) in the mixture. An aqueous potassium permanganate solution (c = 0.1 Torr, 1.65 ml, 0.165 mmol) was added dropwise to the mixture at 〇 5 ° C for 3 hours. Order -47- 20083 8853i} The reaction mixture was stirred at 0 to 5 ° C for 1 hour, and water (30 ml), methylene chloride (30 ml), and potassium carbonate (10 g) were added to the solution. The aqueous phase was extracted with dichloromethane (2 x 40 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained crude product was purified by gradient flash chromatography (1 00 g EtOAc, hexanes: hexane: chloroform = 3:7, lys. B: chloroform), and the purified product was dissolved in acetic acid. Ethyl acetate (1 ml) and a solution of hydrogen chloride in ethyl acetate (0.4 ml, c = 1.6 Μ, 0.64 mmol). After the precipitate was filtered, EtOAc (EtOAc m. lH NMR (300 MHz? DMSO-J^3 0 °C): 2.26 (s9 6H); 3.31-3.44 (m, 2H); 3.61-3.72 (m? 2H); 3.72-3.83 (m5 2H); 3.84- 3.95 (m, 2H); 7.34 (d, 1H5 J = 7.8 Hz); 7.43 (dd, 1H5 J = 7.8, 2.1 Hz); 7.54 (d, 1H9 J = 2.1 Hz); 7.78 (ddd, 1H, /= 8.6, 7.0, 1.3 Hz);

8.02 (ddd? 1H, J=8.5, 7.0, 1.3 Hz); 8 · 1 7 - 8 · 2 8 (m, 2 H ); 9.06 (s, 1H). MS (EI): M + = 3 66. 3-(3,4-Dimethyl-benzenesulfonyl)-4-(tyrosolin-4-yl)-quinoline Table I Compound 1 3-(3,4-Dimethyl-benzenesulfinamide The base 4-(zurolin-4-yl)-quinoline hydrochloride (322 mg, 0.8 mmol) was dissolved in a mixture of acetic acid (7 ml) and water (25 ml). An aqueous solution of potassium permanganate (c = 0.1 -48 - 200838853, Μ, 4 ml, 4 mmol) was added dropwise to the mixture at 〇-5 °C for 4 hours. The reaction mixture was stirred at 0-5 t for 1 hour, and water (30 ml), dichloromethane (30 ml), and potassium carbonate (= 10 g) were added to the solution. The aqueous phase was extracted with methylene chloride (2×40 ml), the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated, and the crude product was subjected to gradient flash chromatography (100 g 矽 , , A A: hexane: chloroform = 3 : 7. The solution B was purified by chloroform to give the title compound.

Yield: 3.8%. lH NMR (5 00 MHz, DMSO-J5? 30 °C): 2.28 (s5 3H); 2.30 (s, 3H); 3.05-3.13 (m? 4H); 3.45 -3.52 (m? 4H); 7.39 (d , 1H, *7=7.9 Hz); 7.64 (dd, 1H, /=7.9, 1.9 Hz); 7.6 7 (d ? 1H, /=1.9 Hz); 7.74 (ddd, 1H, "7=8.6, 6.9, 1.2 Hz); 7.96 (ddd, 1H, J=8.5, 6.9, 1.2 Hz); 8.20 (dd, 1H, 7=8.5, 1.2 Hz); 8.32 (dd, 1H? /=8.6, 1.2 Hz); 9.39 ( s, 1H). MS (FAB): [M + H] + = 383 3-(3,4-dimethyl-benzenesulfonyl)-4-(morpholin-4-yl)-quinoline hydrochloride 3-- 3,4-Dimethyl-benzenesulfonyl)-4-(morpholin-4-yl)-quinoline (80 mg, 0.21 mmol) dissolved in ethyl acetate (3 ml) Ethyl ester solution (c = 1.6 Torr, 0.28 ml, 0.45 mmol) was added dropwise to the solution. The solid was filtered, washed with ethyl acetate and dried title crystal Yield: 8 6 %. -49 - 2008388535) lB NMR (300 MHz, DMSO-J^ 30 °C): 2.29 (s? 3H); 2.30 (s? 3H); 3.13-3.23 (m5 4H); 3,48 -3.5 7 (m9) 4H); 7.40 (d, 1H, J=8.0 Hz); 7.67 (dd, 1H, "7=8.0, 2.1 Hz); 7.70 (d? 1H, "7=2.1 Hz); 7.77 (ddd, 1H, J = 8.6, 6.9, 1.3 Hz); 7.99 (ddd? 1H, J = 8.5, 6.9, 1.3 Hz); 8.22 (dd, 1H, *7 = 8.5, 1.3 Hz); 8.33 (dd, 1H? /= 8.6, 1.3 Hz); 9.39 (s, 1 H).

MS (FAB): [M + H] + = 3 83. Example 2 3-(4-Methyl-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline Table I Compound 2 3-(4-Methylphenylthio) -4-hydroxy-quinoline 3 - bromo-4-yl phenyl porphyrin (0.448 g, 2 mmol; J·dm· kc 7229-7237), 4-methylbenzenethiol (〇·30 g, 2 a mixture of 4 mmol), 肆-(triphenylphosphine)palladium (0.115 §, 0.1 mmol), sodium tert-butoxide (0.23 g, 2.4 mmol) and DMF (2.0 ml) in an 8-ml microwave vial Stir at 1 42 ° C and light for 3 hours. After evaporating the solvent in vacuo, EtOAcqqqqqqqqqq Yield: 61%. 4 NMR (5 00 MHz, DMSO-4 2 5 0 C): 2.23 (s, 3H); 7.04-7.09 (m, 4H); 7.39 (ddd, 1H, /=8·1,7·〇, 1.1 Hz) ; -50- 2008388535) 7.61 (ddm, 1H, "7=8.4, 1.1 Hz); 7.70 (ddd, 1H, "7=8.4, 7.0, 1.5 Hz); 8.12 (ddm, 1H, J=8.1, 1.5 Hz) 8.30(s,1H); 12.23(brs,1H) o M + (EI) = 267. 3-(4-methyl-benzenesulfonyl)-4-quinoline

3-(4-Methyl-phenylthio)-4-hydroxyquinoline (0.25 g, 0.936 mmol) was dissolved in trifluoroacetic acid (5.0 ml), and trifluoro hydrogen peroxide was added dropwise at room temperature. The acetic acid solution (c = 3.0 M, 3.7 ml) was added to the reaction mixture over a period of 8 hours, and then the mixture was filtered and evaporated to dryness. Yield: 8 7 %. 4 NMR (500 MHz, DMSO-heart, 25 〇C): 2 · 3 7 (s, 3 Η ); 7.34-7.4 〇 (m, 2H); 7.44 (ddd, 1H, J = 8.1, 7.0, 1.2 Hz 7.69 (ddm, 1H, J=8.4, i.2 Hz); 7.76 (ddd5 1H? J=8.4, 7.05 1.5 Hz); 7.8 8 -7.95 (m9 2H); 8.05 (ddm, 1H, J= 8.1 1.5 Hz); 8.74 (d, 1H, /=6.8 Hz); 12.75 (d, 1H, J = 6.8 Hz). MS (FAB): [M + H] + = 3 00. 4-Chloro-3-(4-methyl-benzenesulfonyl)-quinoline 3-(4-methyl-phenylsulfonyl)-4-hydroxyquinoline (〇·24) at 135 °C g, 0.8 mmol) was mixed with phospholyl chloride (15 ml) -51 - 200838853, and the mixture was stirred for 5 hours. After the phosphonium chloride was distilled off, the residue was poured onto ice. The resulting slurry was stirred at 0 to 5 ° C for 2 hours, then was then neutralized with sodium carbonate and then extracted with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate. Yield: 91%. lE NMR (5 00 MHz, CDC13, 25 〇C): 2.42 (s, 3H); 7.31-7.36 (m, 2H); 7.72 (ddd, 1H, J = 8.6, 6.9, 1.1 Hz);

7.91 (ddd, 1H, J = 8.5, 6.9, 1.4 Hz); 7.92-7.96 (m, 2H); 8.21 (dm, 1H? J = 8.5 Hz); 8.33 (ddm, 1H, J = 8.6, 1.4 Hz) ; 9.63 (s, 1H). MS (EI) [M + H] + = 285 (35C1). 3-(4-Methyl-phenylsulfonyl)-4-(4-methyl-piperidin-1-yl)quinoline Compound I of Table I 2 4-Chloro-3-(4-methyl-benzenesulfonate) Base quinoline (0.25 mmol, 79 mg) dissolved in acetonitrile (0.5 ml), and added 4-methylpiperidine (63 μί, 0.55 mm ο 1); and the reaction mixture was stirred at 50 ° C. Hour, then stir at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified mjjjjjjj Yield: 8 7 %. !H NMR (5 00 MHz, DMSO-^5? 25 °C): 0.92 (d, 3H? J = 6.6 Hz); 0.92-1.04 (m? 2H); 1.38- 1.47 (m, 2H); 1.47- 1.61(m,1H); 2.39(s,3H); 2.83 -2.93 (m? 2H); 3.26-3.34(m9 2H); 7.39-7.45(m5 2H); -52- 200838853 η 7.71(ddd,1Η, J 8.6, 7.0, 1.2 Hz); 7.72-7.78 (m, 2H); 7.9 3 (ddd 5 1H, J=8.4, 7.0, 1.2 Hz); 8.16 (dd, 1H, «7=8.4, 1.2 Hz) ; 8.28 (dd, 1H, J = 8.65 1.2 Hz); 9.3 5 (s ? 1H). MS (EI): M + = 3 80.

3-(4-methyl-phenylsulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline hydrochloride 3-(4-methyl-phenylsulfonyl)-4 -(4-Methyl-piperidin-1-yl)-quinoline (40 mg, 0.105 mmol) was dissolved in ethyl acetate (0.5 ml), then ethyl hydrogen chloride in ethyl acetate (c = 1.6 M, 65 ΐ , 0.105 mmol) was added dropwise to the solution. The solvent was removed in vacuo to give the title compound. Yield: 100%. lU NMR (5 00 MHz? DMSO-J^ 25 °C): 0.93 (d, 3H, J = 6.5 Hz); 1.08- 1.20 (m9 2H); 1.48- 1.57 (m, 2H); 1.5 7- 1.68 ( m,1H); 2.4 1 (s 3H); 3.19-3.29 (m? 2H); 3.32-3.42 (m5 2H); 7.42-7.49 (m? 2H); 7.77 (ddd, 1H, J= 8.6, 7.0 , 1.2 Hz); 7 · 8 1 7 · 8 6 (m, 2 H); 8.01 (ddd, 1H, J=8.5, 7.0, ! .2 Hz); 8.19 (dd, 1H5 J=8.59 1.2 Hz); 8.29 (dd, 1H, J = 8.6, 1.2 Hz); 9.37 (s, 1H). MS (EI) M + = 3 80. Example 3 3-(3,4-Methyl-benzoic acid)-4-(4-methyl-yt-D--1-yl)-Salina-53-200838853 Table I Compound 3 3 -(3,4-Dimethyl-phenylthio)-4-hydroxyquinoline This title compound was used for the preparation of 3-(4-methyl-phenylthio)-4-hydroxyquine as described in Example 2. The method of porphyrin is prepared from 3-bromohydroxyquinoline and 3,4-dimethylthiophenol. Yield: 580%. 4 NMR (5 00 MHz, DMSO·^, 2 5 0 C): 2.14 (s, 3H);

2.15(s? 3H); 6.90 (dd? 1H5 J=7.8? 2.0 Hz); 6.98-7.0 4(m, 2H); 7.38 (ddd, lH, /=8.1, 7·0,1·2 Hz); 7, 60 (ddm, 1H, /=8.4, 1.2 Hz); 7.69 (ddd? 1H, J two 8.4, 7.0, 1.5 Hz); 8.11 (ddm, 1H, J = 8.1, 1.5 Hz); 8.2 5 (s , 1 H); 12.18 (brs, 1 H) MS (EI) M + = 281. 3-(3,4-Dimethyl-benzenesulfonyl)-4-hydroxyquinoline The title compound was used to give 3-(4-methyl-phenylsulfonyl) as described in Example 2. The method of 4-hydroxyquinoline gave a yield of 89%. 4 NMR (5 00 MHz, DMSO·^, 2 5 0 C): 2.30 (s, 3H); 2.32 (s, 3H); 7.27 (d, 1H? 8.5 Hz); 7.39 (ddd, 1H, "7=8.1 , 7.0, 1.2 Hz); 7.62 (ddm, 1H, J=8.4, 1.2 Hz); 7.68 (ddd? 1H, J=8.4, 7.0? 1.5 Hz); 7.78-7.82(m, 2H); 54- η 200838853 8.15 (ddm,1Η, J=8.1, 1.5 Hz); 8.66(s,1H); 12.63(brs, MS(FAB): [M + H] + = 3 14 4-chloro-3-(3,4- Dimethylbenzenesulfonyl)-quinoline The title compound was obtained according to the procedure used for the preparation of 4-chloromethylbenzenesulfonyl)-quinoline as described in Example 2. Yield: 92%. NMR (5 00 MHz, CDC 1 3 5 2 5 ° C): 2.32 (s? 3H); 2.33 (s9 3H); 7.32 (d? 1H? J = 8.1 Hz); 7.77 (d? 1H? J=2A Hz); 7.82 (dd? 1H5 J=8.15 2.1 7.85 (ddd, 1H, J-8.6, 7.0, 0.9 Hz); 8.05 (ddd, 1H, J=8.5, 7.0, 1.3 Hz); 8.3 9-8.46 (m , 9.66 (s, 1H) MS (EI) M + = 3 3 1 (3 5 C1) 3-(3,4-dimethylphenylsulfonyl)-4-(4-methyl-piperidine -1-yl)-quinoline The title compound was obtained according to the procedure used for the preparation of the compound of formula 2 as described in Example 2. Yield: 8 7 %. lH NMR (5 00 MHz, DMSO-t/^ 2 5 °C): 〇.91 (d, 3H, /=6.5 Hz); 0.92-1.03 (m, 2H); 1.3 8- 1.46 (m, 2H); 1.47-1.61 (m, 1H); 2.29 ( s,3H); 2.30(s9 3H); 2.82-2.91(m, 2H); 3 · 2 8 - 3.3 6 (m, 2 H); 1H) 1-(4- Hz); 2H); -

200838853,) 7.36 (d? 1H, "7=8.1 Hz); 7.54 (dd, 1H, J=8.1, 2.0 7.6 7 (d ? 1H, J = 2.0 Hz); 7.70 (ddd, 1H, "7=8.5 , 6.9, 1.2 7.93 (ddd, 1H, J=8.5, 6.9, 1.2 Hz); 8.16 (dd, 1H, /=8.5, 1.2 Hz); 8.27 (dd? 1H, J=8.55 1.2 9.3 5 (s , 1 H) MS(EI)M + = 3 94. 3-(3,4·Dimethyl-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline salt The compound was obtained according to the procedure described in Example 2 for the preparation of the hydrochloride salt of the compound of formula I. Yield: 1 0 0 % lU NMR (5 00 MHz, DMSO-i/^, 25 ° C) : 0.93(d,3H? /=6.5 Hz); 1.03-1. 1 6(m, 2H); 1.46- 1 .5 5 (m? 2H); 1.5 5 - 1.67(m,1H); 2.30(s , 3H); 2.3 1 (s, 3H); 3 . 1 0-3.20(m, 2H); 3.3 2-3.42(m9 2H); 7.3 9 (d, 1H? J=8. 1 Hz); 6 1 (dd, 1 H,8 · 1, 2 · 0 7.72 (d9 1H, J=2.0 Hz); 7.75 (ddd9 1H, J=8.6, 7.0, 1.2 7.99 (ddd, 1H, /=8.6, 7.0, 1.2 Hz); 8. 1 8 (dd, 1H, *7=8.6, 1.2 Hz); 8.28 (dd? 1H, J=8.6? 1.2 9.36(s, 1H). MS(EI)M + = 3 94. Example 4

Hz); Hz); Hz); hydrochloric acid

Hz); Hz); Hz); -56- 200838853,) 3-(4-methyl-phenylsulfonyl)-4-(3-methyl-piperidinyl-bu)-quinoline Table I Compound 4 The title compound was obtained according to the procedure used for the preparation of Compound 2 of Table I as described in Example 2 from 4-chloro-3-(4-methyl-phenylsulfonyl)-quinoline. Yield: 90%. ]H NMR (500 MHz, DMSO-c/^ 25 °C): 〇.67 (d, 3H, /= 6.7 Hz); 0.99-1 · 1 l (m, 1H); • 1.28-I41 (m, 2H); 1.41-1.52 (m, 1H); 1.63_1.74 (m, 1H); 2.39 (s, 3H); 2.70_2.79 (m, 1H); 2.81-2.96 (m, 2H); 3.20- 3.29 (m, 1H); 7.39-7.44 (m, 2H); 7.71 (ddd, 1H? J=8.5, 6.9? 1.2 Hz); 7.72-7.77 (m? 2H); 7.93 (ddd5 1H, /=8.4, 6.9, 1.2 Hz); 8.16 (dd, 1H, "7=8.4, 1.2 Hz); 8.28 (dd, 1H, /=8.5, 1.2 Hz); 9.36 (s, 1H). MS (EI) M + = 380. • Example 5 7-Chloro-3-(4-chloro-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline Table I Compound 195 (4-Chloro-benzenesulfonate a mixture of methyl bromoacetate (11.25 ml, 116 mmol) and sodium 4-chloro-benzenesulfinate (25.2 g, 116 mmol) in DMF (120 ml). Stir and heat for 2 hours at C. The solution was diluted with water (3 60 ml), and the separated oil was extracted with chloroform (200 ml), and then washed with water (3×80 ml), -57-200838853, and the organic phase was evaporated in vacuo. The yield was 2 2.4 g (7 7.7 %). MS (EI) M + = 249. The following compounds were prepared using the above procedure: such as (3-chloro-phenylsulfonyl)-methyl acetate (MS(EI)M + = 249); (3,4-dichloro-benzenesulfonyl)-methyl acetate (MS(EI)M + = 284); (4-methoxy-phenylsulfonyl)-methyl acetate (MS(EI)M + = 245); (3-chloro-4-fluoro-benzenesulfonate) Methyl acetate - MS (EI) M + = 267). 2-(4-Chloro-benzenesulfonyl)-3-ethoxy-methyl acrylate methyl (4-chloro-benzenesulfonyl)-acetate (22.4 g, 90 mmol), triethyl orthoformate A mixture of (33.2 ml, 216 mmol) and acetic anhydride (19.1 ml, 203 mmol) was refluxed for 3 hours while simultaneously distilling ethanol, triethyl orthoformate, and acetic anhydride, and then evaporated to dryness. The obtained crude material (22.7 g, 82.8%) was used in the next step without purification. MS (EI) M + = 3 05. 0 Using the above procedure, the following compounds were prepared: such as 2-(3-chloro-benzenesulfonyl)-3-ethoxy-methyl acrylate (MS(EI)M + = 3 05); 2-(3-chloro- 4-fluoro-benzenesulfonyl)-3-ethoxy-methyl acrylate (MS(EI)M + = 3 23); 2-(3,4·dichloro-phenylsulfonyl)-3-B Oxy-methyl acrylate (MS(EI)M + = 340); 2-(4-gas-benzene ore)-3·ethoxy-propionic acid methyl vinegar (MS(EI)M + = 289 7-Chloro-3-(4-chloro-phenylsulfonyl)-4-hydroxyquinoline 2-(4-chloro-benzenesulfonyl)-3-ethoxy-methyl acrylate (7.62 g, -58- 200838853,) 25 mmol) of a mixture of 3-chloroaniline (3.19 g, 25 mmol) in diphenyl ether (20 ml) After cooling, the precipitate was filtered and washed with diethyl ether to yield 4.25 g (48.%). MS (EI) M + = 3 5 5 .

The following compounds were prepared by the above procedure: such as 8-chloro-3-(4-chloro-benzenesulfonyl)-4-hydroxyquinoline (MS(EI)M + = 3 5 5 ); 6-chloro-3-( 4-fluoro-benzenesulfonyl)-4-hydroxyquinoline (MS(EI)M + = 338); 6-cyano-3-(4-fluoro-phenylsulfonyl)-4 hydroxyquinoline (MS ( EI)M + = 329); 8-chloro-3·(3,4-dichloro-benzenesulfonyl)-4-hydroxyquinoline (MS(EI)M + = 390); 8 -ethyl- 3 -(4-Chloro-benzenesulfonyl)-4-hydroxyquinoline (MS(EI)M + = 3 48). 3-(4-Chloro-benzenesulfonyl)-4,7-dichloroquinoline 7-chloro-3-(4-chloro-benzenesulfonyl)-4-hydroxyquinoline (4.25 g, 12 mmol) After refluxing the mixture formed in phosphorous (III) oxychloride (5.6 ml, 60 mmol) for 3 hours, the reaction mixture was poured into water (50 ml) and basified with 5 M sodium hydroxide solution. . After cooling, the precipitate was filtered off and washed with water. The yield was 3.8 g (8 5.0%). MS (EI) M + = 3 73. Using the above procedure, the following compounds were prepared: such as 3-(3-chloro-benzenesulfonyl)-4,6-dichloroquinoline (MS(EI)M + = 3 73 ); 3-(4-chloro-benzenesulfonate) 4,8-dichloroquinoline (MS (EI)M + = 3 73); 4-chloro-6-cyano-3-(4-fluoro-benzenesulfonyl)-quinoline (MS (EI) M+ = 3 47); 4-chloro-3-(4-chloro-benzenesulfonyl)-6-fluoro-quinoline (MS(EI)M + = 3 57). -59- 2008388535) 7-Chloro-3-(4-chloro-phenylsulfonyl)· 4 - (4 ·methyl-piperidin-1 yl)-quinoline Table I Compound 195 3-(4- Chlorine-based, 4,7-dichloroindene (186 mg, 0*5 mmol), 4-methylpiperidine (71 μΐ, 〇·6 mm〇l), and DBU (90 μΐ, The mixture formed in 0.6 mmol) in DMF (6 ml) was at 80. After stirring for 1 hour under stirring, water (30 ml) was added after cooling, and the solid was filtered and crystallized from methanol. The yield was 167 mg (76.6 ° / 〇).

MS (EI) M + = 43 6. Specific examples of the compound of the formula (I) and their affinity for the rat mGluR5 receptor are shown in the following table.

-60- 200838853

Table I

Compound No. Structure (M+H)+ Ki(nM) 1 [:]. . 383 Half-book 2 6〇0 381 氺氺氺 3 6〇0 394 *氺氺 4 α. 〇ysta 381 氺氺氺 5 0. . 353 氺氺 6 0. . 〇yvca 367 氺氺氺 7 ca^o 415 氺 8 ft, 功"a〇 470 * -61 - 200838853〇

9 U〇〇 389 氺氺氺 10 r 〇. . 434 氺 11 9 ΝΗ 439 439 氺 12 399 * 13 Ρ 功 SO 462 氺 14 A. Work 399 氺氺 15 i φ%. . XX 431 * -62- 200838853 200838853

24 1 °{ . Public. . 435 氺 25 l. . 〇ysta 393 氺 26 l. . 423 氺 27 r? Public H. . 〇5^ 433 氺28 9 403 氺29 NH 〇n 421 * 30 451 氺-64- 200838853D) 31 〇/ NH 〇π 439 * 32 air χχ 381 氺** 33 Fxx^sxx 399 氺34 〇0 〇yu 401氺* 35 367 氺36 383 氺37 c,O0rsO 373 氺38 〇. . Clwxx 417 氺 39 403 氺 -65- 200838853,) 40 C0TXX 389 * 41 0〇o 381 氺 42 a. 425 氺 43 a. 387 氺 44 413 氺 45 381 氺 46 6〇0 ^ysta 395 氺氺氺 47 6〇0 α^Ό 367 氺氺* 48 6〇0 cxxysto 425 氺** 66 - 2008388532)

49 on. Merchandise 381 * 50 1 φ%. . Interview XX 411 * 51 425 氺氺氺 52 466 氺 53 487 氺氺氺 54 0 丫 0 O〇0 oVsta 439 * 55 °Y°^ 6〇0 FO^sta 457 氺 -67- 200838853,)

56 0" c^° IV C0TXX 439 * 57 0" c/0 453 氺 58 ,〇i: Work sxx 469 氺 59 h2n 丫. Work sxx 424 氺60 0〇o 03⁄43⁄4 411 * 61 ό 402 氺62 r ϋ χ v° 430 氺-68- 200838853t) 63 r 泰 410 氺64 P ΟότΌ 444 氺65 ΰ 472 * 66 472 氺67 9 462 氺68 Gong SO 476 氺-69- 200838853,

69 pc 488 氺 70 0 〇6^ 472 氺 71 〇>〇 464 氺 72 Φ α^χχ 482 氺 73 A xx 476 * 74 A 〇>〇 〇yxx 474 * -70- 2〇〇8388530

75 ο〆 Φ Ο,, Interview XX 508 氺 76 c^tx 355 氺氺 77 9 NH 〇 n ay'xx 389 氺氺 78 78 Λ. . Xx y y y y y y y y y y y y y y y y 85 9 417 氺86 0. 395 氺 87 9 NH 〇 419 419 氺 88 6〇0 / 功 sta? 427 * -72- 2008388533)

89 〇o 063⁄4 367 氺氺 90 0 458 氺 91 1 Φ%. 411 * 92 6〇0 〇〇ysta 439 氺 93 o〇0 401 * 94 〔χό"χχ 427 * 95 0. . ¢0^3⁄4 425 * 96 0〇o 〇oirsta 395 氺 -73- 200838853})

97 0〇〇 〇ysta 425 Umbrella 98 \^〇 丫0 0〇〇 483 氺 99 ΐ %〇 功 sxx 457 氺 100 功stx 496 * 101 〔. 〕 IV ο^α 369 * 102 441 * 103 NH 〇 〇 /〇xxy\x 437 氺 -74- 200838853])

104 0〇o 383 * 105 wtXc, 417 * 106 Work SXX 508 氺 107 0〇o FOC^O 371 * 108 6〇0 C, XX^SO 401 氺 109 1 Φ%. Work SO 397 氺 110 i Vl〇 385 * 111 P °T〇ysx) 474 氺 -75- 200838853丨)

112 Q, 431 * 113 〇 〇 003⁄4 405 氺 114 ,. Interview with Ok 425 氺 115 9 co^o 488 氺 116 6〇0 ^〇yst〇 411 * 117 ^〇irsXX 506 氺 118 0. . FX^rsO 385 * -76- 200838853,) 119 ^wsxx 425 氺 120 Ο,, 407 * 121 Visit XX 433 氺 122 功 sOl. 1 453 * 123 9 gong ul 478 氺 124 u〇0 359 氺 125 429 * 126 ft, coi^a 441 氺 -77- 2008388535)

111 Λ 1 426 氺 128 1 〔N〕 / Power 398 氺 129 0 丫 460 氺 130 φ I 435 * 131 〇 丫 〇\^ Λ 474 氺氺 132 0 丫0ν Λ 功 454 * 133 lnjo 393 * 134 泰. / 411 氺 135 ΟΟ^Ό 411 氺 -78- 200838853)

136 ά. 385 * 137 ό 419 氺氺 138 ό xx^V C1 454 氺氺 139 ό" F 421 氺 140 xii^ CN 410 氺*氺 141 6 403 氺氺氺 142 χό^α. % 415 氺氺氺 143 ό. . wV- OCH3 445 氺氺 -79- 200838853⁄4

144 6 ϋ F 403 氺氺 145 6 och3 415 146 6 ch3 413 氺 氺 147 Cl 449 氺氺氺 148 6V Cl 419 氺氺氺 149 6 FO0rV Cl 454 氺氺* 150 6 410 氺氺 -80- 200838853⁄4

151 6 ch3 413 氺氺氺 152 What? F 421 氺本氺 153 0 HXX^V Cl 450 氺氺 154 6 H3COC^V F 417 氺氺 155 6 CN 406 氺 156 6 399 *氺* 157 6 ϋΗ3 411 氺氺 -81 - 200838853^

158 415 415 氺氺 159 ό F 399 氺氺氺 160 ό ό H3Cx) ifvV och3 411 氺氺氺 161 6 ch3 409 氺氺氺 162 ό H5COc5V Cl 445 氺氺氺 163 6 Cl 415 氺氺 164 6 Cl 450 *氺氺-82- 200838853

165 XX7^XCH3 F 413 *氺氺166 H3CxxyuN 406 氺氺167 6 "XliV Cl 429 氺氺氺168 ό H3 read V ch3 409 169 ό Cl 434 氺氺* 170 6 x^v F 421 *氺171 0"Fxx7"aCH3 399 氺氺氺172 6 403 *氺»83- 200838853"

173 6 385 氺氺氺 174 ό. . 419 氺氺氺175 6 Rain och3 415 氺氺氺176 ό χχ^α Cl 454 氺氺氺177 ό FX^V Cl 454 **氺178 ό" F 417 氺氺氺179 ό CN 410 氺** -84- 200838853))

180 0. . 410 氺氺氺 181 ό. . 434 氺氺 182 ό. . Och3 445 氺氺氺 183 ch3 413 氺氺氺 184 6 ch3 413 氺氺 185 6 xrfvXl, ^0(:Η3 415 氺氺氺 186 6〇. χό^χ F 421 氺氺氺 -85- 200838853丨)

187 ό. . rXXjVF Cl 437 氺氺氺188 όν Cl 471 氺氺氺189 6V F 437 氺氺氺190 ό ϋ CN 426 氺氺氺191 ό j〇9vXI 415 *氺* 192 ό ϋ 419 193 ό xrfvxi , ^^och3 431 氺氺194 6 401 氺本本-86- 2008388532)

195 A 436 氺氺氺196 όν C1XXJ^, och3 461 氺*氺197 6,/0 joyp F 419 氺氺氺198 ό .雨och3 431 氺氺氺199 ch3 429 氺本氺200 ό ^Y^OCH3 Cl 466氺氺氺201 6 Cl 436 氺氺* 202 6V Cl 471 氺氺* -87- 200838853

203 όν clO0r^CHj F 434 氺氺 umbrella 204 426 氺氺 205 Cl 450 氺氺氺 206 0. . F 437 氺氺氺 207 όν Cl 454 氺** 208 ό〇ν〇 Χόν Cl 471 氺*氺 209 C,X^V F 437 *氺氺 210 ό CN 426 氺氺氺 -88 - 200838853^

211 415 415 氺氺氺 212 ό 419 氺氺氺 213 ό 436 氺氺氺 214 F 419 氺氺 215 0 c, Oc! rvV och3 431 氺氺氺 216 6 Cl 436 氺 217 F 434 氺氺 218 ό 426 氺 - 89 - 2008388535)

219 Cl 450 ** 220 6 ch3 429 氺氺氺 221 k. Cl 466 氺 222 ό F 437 氺* 223 0 Cl 471 氺氺氺 224 ό Read V5 ch3 429 Umbrella 225 6V och3 461 氺氺 226 ό QC?V 1 F Cl 454 氺氺氺 -90- 200838853⁄4

227 Φ. , /. Σό'ν F F 421 氺 228 όν F 403 氺 229 ό. . F 415 氺氺 230 0 F 385 氺 231 0 ςχί%, F 419 氺氺氺 232 ό Rain F F 403 氺氺 233 ό F F 417 氺氺氺 234 ό ςχϊ%. F 410 氺氺氺 -91 - 200838853,)

235? F 399 氺氺氺236 6 Rain. F Cl 454 氺氺氺237 6 Rain FF Cl 437 238 6 FF 421 氺氺氺239 ό H5C〇XlirV Cl 466 Native 240 H5C0XI^VF 433 * 241 0 415 氺242 6 HiC〇OC^V och3 457 氺-92- 2008388533)

243 ό HiC〇Xlir^) F 415 ** 244 όν och3 427 * 245 What /. Read sc9u Cl 461 氺246 ό H5C〇xtfvV Cl 432 氺247 6〇v〇F 429 ** 248 0 Cl 445 氺氺* 249 6 H5tx^V Cl 466 Book 氺250 6V HicoOcy^ ch3 425 氺氺-93- 20083 88539)

251 όν CN 432 氺氺氺252 0 ncX)^vX1f 410 氺氺253 χφ°ν° Cl 471 *氺254 0 fb 369 氺氺氺255 0 H;xr^VF 405 氺256 0 H3CXxir^ CN 394 氺氺257 0 H3WvXXf 387 氺258 0. . XXX Xa〇CH3 399 * 259 0 H5XtfYi F 387 * -94- 200838853⁄4

260 0 och3 399 氺氺261 0 H5CO0rV Cl 433 氺氺262 0 Cl 438 *氺263 0 Cl 403 * 264 0 H5CO^V Cl 438 ** 265 0 ϋ 394 氺266 〇Cl 417 氺氺267 0 F 401 氺268 0 H5CxtfV F 405 氺-95- 200838853,)

269 0 H3C0Ocivb 385 270 0 ϋ 419 氺氺氺 271 0 Cl 454 氺 272 0 H3C〇XliV F 421 氺 273 0 CN 410 * 274 0 Cl 419 氺 275 0 ϋ 403 * 276 〔:〕. . XXJ^X- Cl 433 氺 277 0 Ci 449 氺 -96- 200838853

278 0 HiC〇OC^V. Cl 454 氺 279 0 T 〇\ /0 373 氺氺氺 280 〇 xtfV1 Cl 442 * 281 0 CN 398 * 282 0 ϋ 403 氺 283 0 Fxxisv och3 403 氺 284 0. . wV〇CH3 Cl 437 氺 285 0 Cl 407 * 286 [λ. Cl 442 氺氺 -97- 200838853⁄4

287 0 F 405 氺288 0 Cl 422 氺氺289 0 FxtfVH3 ch3 401 氺290 0 Cl 425 氺氺291 0 389 氺292 0 403 氺氺氺293 0 c,OciV Cl 459 * 294 〇cwvy F 425 * 295 0 424氺-98- 200838853^

296 0 C rain och3 419 * 297 0 cwvx^ Cl 424 氺298 〇c'OC^V Cl 459 氺氺299 0 cwv^) CN 414 * 300 0 αΌ0^Χ3 Cl 438 ** 301 0 clxtfV^ CI 454 氺302 0 c1W^xf Cl 442 氺 303 0. . 387 氺 -99- 200838853⁄4

304 0 373 氺 305 Cl xvyxic1 407 氺 306 0 Rain och3 403 氺氺 307 0 Cl 437 氺氺 308 〇 XxjV' Cl 442 氺氺 309 〔:〕. . F 405 氺* 310 0 F 409 氺 311 0 CN 398 氺氺 312 〔:〕. . FwV Cl 421 本氺氺 -100- 2008388533)

313 〔:〕. . 403 氺 314 0 CH3 401 Bearing 315 0 F 409 氺氺 316 0 Fxx^V, Cl 442 氺氺 umbrella 317 0 401 氺氺 318 〔:〕. . Cl 459 319 0 JO^V F 425 氺氺 320 0 ϋ CN 414 氺氺 321 0. . clwvxxF 407 氺 322 0. . C, WVXI0CH3 419 * -101 - 20083 8853r)

-102- 200838853⁄4

332 〔:〕. . c,XXj"pLcl Cl 459 本氺氺 333 0 ch3 417 * 334 〔:〕. . c,xxjV Cl 441 本氺氺 335 0 ςτ^νψα F Cl 441 336 0 F F 409 337 0 F 391 氺 338 0. . F 403 氺339 0 1 °v° ςτ^χχ. F 407 氺氺340 0 Rain FF 391 氺-103- 200838853, 341 0 FF 405 氺氺342 八ς^χχΗ3 F 387 氺343 0 Rain FFF 409 氺氺344 0 Rain FF Cl 425 *氺氺345 〇v F Cl 442 氺** 346 398 氺氺347 Φ^χχ Cl 459 氺氺348 441 氺氺-104- 200838853^ 349 6 CI 437 氺氺350 6. aWXIF 435 氺氺 351 6" F 453 本氺

* * * Ki<200nM

* * 200 nM < Ki < 5 00 nM 500 nM < Ki Example 6 Preparation of pharmaceutical composition: α) Lozenge: 0.01-50% active ingredient of formula (I), 15-50% lactose, 15-50% potato starch, 5-15% polyvinylpyrrolidone, 1-5% talc, 0.01-3% magnesium stearate, 1-3% colloidal cerium oxide, and 2-7% ultra-amylopectin mixed, then It is granulated by a wet granulation method and pressed into a tablet. -105- 200838853]" Drago s, coating film I: The tablet prepared by the above method is coated with a layer composed of an enteric solvent film or a gastric solvent film or by a sugar and A layer consisting of talc, the sugar-coated ingot is polished with a mixture of bee and carnuba wax. ~ Capsule: 0.011-50% of the active ingredient of formula (I), 1-5% sodium lauryl sulfate, 15-50% starch, 15-50% lactose, 1-3% colloidal cerium oxide, and 0.01-3 % magnesium stearate are thoroughly mixed, and the mixture is passed through a sieve and rubbed into a hard gelatin capsule. Saturated suspension: Composition: 0.01-15 % formula (I) active ingredient, 0.1-2% sodium hydroxide, 0.1-3% citric acid, 0.05_0·2% nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02 % nipasol, 0·01-0·5 % carbopol (polyacrylic acid), 0.1-5% 96% ethanol, 0.1-1% flavoring agent, 20-70% sorbitol (70% aqueous solution), and 30 - 50% distilled water. In a solution formed of nipagin and citric acid in 20 ml of distilled water, carbopol was added in small portions with vigorous stirring, and the solution was allowed to stand for 10-12 hours. With stirring, add a solution of sodium hydroxide in iml distilled water, an aqueous solution of sorbitol, and finally a raspberry flavor containing ethanol. The active ingredient is added to the carrier in small amounts and suspended in an immersed homogenizer. 'Finally, the suspension is made up with distilled water to the desired -106-200838853] 2) The final volume, and then the suspension syrup is passed through the colloid milling equipment. e) Suppository: For each suppository, 0.01-15% of the formula (I) The active ingredient and 1-20% lactose are thoroughly mixed, then 50-95% adeps pro suppository (such as Witepsol 4) is melted, cooled to 35 ° C, and then a mixture of the active ingredient and lactose is mixed with a homogenizer. The resulting mixture is molded into a cooled form. Freeze-dried powder ampule composition: A solution of 5% mannitol or lactose is prepared by double-distilled water for injection, and the solution is filtered to form a sterile solution. It is also prepared by double-steamed water for injection. 0 · 0 1 - 5 % of the solution of the active ingredient of formula (I), and then filtering the solution into a sterile solution. Mix the two solutions under aseptic conditions, dilute into the ampoule in an amount of 1 ml, and put the ampoule into the ampoule. The contents were freeze-dried and sealed under nitrogen for a ° ° before administration. Dissolve the contents of the ampoule in sterile water or • 0.9% (physiological) sterile sodium chloride solution.

Claims (1)

200838853 (1) X. Patent application scope L A compound of formula (I): Wherein Ri and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amino or saturated heterocyclic, wherein the hetero atom is N; R3 and R4 are independently selected from hydrogen, a substituted aryl group having at least one substituent selected from the group consisting of hydrogen, halogen, fluorenyl, and anthraceneoxy, or R3 and R4 together with an N atom attached thereto may form 1 or 2 selected from N, a heterocyclic C5_7 heterocyclic group of 0 which may be optionally selected from the group consisting of hydrogen, halogen, alkyl, hydroxyalkyl, alkyloxycarbonyl, aminocarbonyl, 〇ch2ch2o-, benzyl and substituted phenyl Substituted; R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, or R6 and R7 together with an atom to which they are attached may form an unsaturated heterocyclic group; Or a pharmaceutically acceptable salt thereof, or a mirror image isomer and/or a racemate and/or a non-mironomer and/or an acid or a base thereof. 2. A compound of formula (I): -108- (2) (2) 200838853 Wherein 1 and r2 are independently selected from the group consisting of hydrogen, halogen, CU4 alkyl, alkoxy, cyano, optionally substituted amine, or saturated heterocyclic, wherein the hetero atom is N; R3 and R4 are independently selected from hydrogen, a Cb4 alkyl group, a substituted aryl group having at least one substituent selected from the group consisting of hydrogen, halogen, CL4 alkyl, and CL4 alkoxy, or R3 and R4 together with an N atom attached thereto may form 1 or 2 selected from a C5_7 heterocyclic group of a hetero atom of N, 0 which may be optionally selected from the group consisting of hydrogen, halogen, alkyl, Cm hydroxyalkyl, alkyloxycarbonyl, aminocarbonyl, -och2ch2o-, benzyl and substituted a phenyl group (which may be optionally substituted by 1 or 2 groups selected from the group consisting of hydrogen, halogen, Ci-4 alkyl, and Ch4 alkoxy); R5, R6, R7, and R8 are independently selected from Hydrogen, halogen, Ci-4, Ki-4 alkoxy, cyano, or R6 and R7 together with an atom to which they are attached may form an unsaturated 5 to 7 membered heterocyclic group containing 1 or 2 germanium atoms; And/or its mirror image isomers and/or racemates and/or non-image areomers and/or pharmaceutically acceptable salts thereof formed with acids or bases. 3 ·- A compound of formula (I): 109- 200838853 (3) (l) wherein & and R are independently selected from the group consisting of hydrogen, chlorine, fluorine, Ci_2 alkyl, Ci_2 alkoxy, cyano, or piperidinyl; R3 and R4 are independently selected from hydrogen, Cw alkyl, 1 Or 2 benzyl groups independently selected from the group consisting of hydrogen, halogen, Cw alkyl, Cw alkoxy, and R3 and R4 together with the N atom to which they are attached may form pyrrolidinyl, piperidinyl, morpholinyl Or piperidinyl (which may be optionally substituted with a group selected from the group consisting of hydrogen, halogen, Cl-4 alkyl, hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, and -〇CH2CH20-), or Piperidinyl (which may be selected from Cw alkyl, benzyl, -alkyloxycarbonyl, and phenyl at N(4) (which may be optionally selected from 1 or 2 selected from hydrogen, halogen, Ci_4 alkane) Substituted by a group substituted by a group of alkoxy groups); R5, R6, R7, and R8 are independently selected from hydrogen, chlorine, fluorine, Cu alkyl, Ci-2 alkoxy, cyano, or R6 And R7 together with the atom to which it is attached may form 2,3-dihydro-[1,4]dioxobic or 2,5.dihydro-furan ring; and/or its mirror image isomer and/or racemate And/or non-image isomers and/or their pharmaceutically acceptable forms with acids or bases By salt. 4. The compound 'as claimed in the first paragraph of the patent application' is selected from the following: -110- (4) 200838853 3-(3,4-dimethyl-benzenesulfonyl)-4-(porphyrin- 4-yl)quinoline; 3-(4-methyl-benzenesulfonyl)-4-(3-methyl-piperidin-1-yl)-quinoline; 3-(3,4-dimethyl -Benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline 3-(4-methyl-benzenesulfonyl)-4-(4-methyl-piperidine- 1-yl)-quinoline; 3-phenylsulfonyl-4-(piperidin-1-yl)-quinoline; 3-(4-methyl-benzene ore)-4 -(卩派定定-1 - 基)-嗤琳; 4-decylamino-3-(4-methyl-benzene ore)-嗤琳; 6-ethyl-4-(4-methyl-a-D--1-yl)-3-(4 -methoxy-benzoic acid)-quinoline; 6-gas-3-(4-methyl-benzene ore)-4-(4-methyl-maid-D--1-yl)-lu Phenanthroline; 6-ethoxy-3-(4-chloro-benzenesulfonyl)-4-(4-fluoro-benzylamino)-quinoline 4-(azepine-1-yl)-3-( 4-methyl-benzenesulfonyl)-quinoline; #4_(azepine-1-yl)-3-(4-chloro-benzenesulfonyl)-quinoline; 6-methyl- 3-(4 -methyl-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 4-(4-methylpiperidin-1-yl)-3-benzenesulfonyl -quinoline; 9-(4-methyl-峨D-1,4-yl)-8-benzene ore-branched-2,3 - _* ammonia-[1,4]-^oxoxime [2,3 -g] quinoline; 6-ethyl-4-(4-ethyloxy-anthracepin-l-yl)-3_(4-chloro-benzoic acid)-嗟琳; 4 - _ ^Ethylamino-3 - (4-methyl-branched)-嗟琳, -111 - 200838853 (5) 4-(4-Benzyl-piperazin-1-yl)-3 _(4 -Chloro-benzenesulfonyl)-quinoline; 4-(azain-1-yl)-3-phenylsulfonyl-quinoline; 3-(3-branched-phenylene)--6-win -4-(4-methyl-峨D-1,4-yl)-porphyrin; 6 -fluoro-3-(4-methoxy-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 6-fluoro-3-(3-methoxy- Phenylsulfonyl)-4-(4-methyl-piperidin-1-yl)- 6 - per 3-(3,4 -?-methyl-benzine)-4-(4-methyl-pyridin-1-yl)-quinoline; 3-(3-chloro-4 -Methoxy-本石页基基)-6-Tip-4-(4-Methyl-Vin D-1·yl)-嗤琳, 3-(3-Chloro-4-fluoro-benzenesulfonate 6-fluoro-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3,4-dichloro-benzenesulfonyl)-6-fluoro-4-(4 -methyl-piperidin-1-yl)-quin 3-(3-chlorobenzone)-6-mirr-4-(4-methyl-pyridin-1-yl)-salina 3-(4-chloro-benzenesulfonyl)-6 -methyl-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3-win-benzene ore)_6·methyl-4-(4-methyl-B U-1,4-yl)-salin; 3-(3-methoxy-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidin-1-yl)-quinoline; -112- 200838853 (6) 3-(3,4-Dimethyl-phenylsulfonyl)-6-methyl-4 _ (4-methyl-piperidin-1-yl)-Lu Lin; 3-(3 -chloro-4-methoxy-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidine-1-yl)-indole; 3-(3-chloro-benzenesulfonyl) - 6-methyl-4-(4-methyl-piperidin-1-yl)-quinolin; 3-(3 - per-4-methyl-branched)-6-methyl-4 - (4-methyl-group B疋-1- 3-(3-chloro-4-methyl-benzenesulfonyl)-6-methyl-4-(4-methyl-piperidin-1-yl)-quinoline; 3- (3-Chloro-4-3⁄4-benzene ore)-6-methyl-4-(4-methyl-azetidin-1-yl)-quinoline; 3-(3,4-dichloro- Phenylsulfonyl)-7-fluoro-4-(4-methyl-piperidin-1-yl)-quine; 7-(3-yl-phenylene)-4-() 4-methyl-峨D疋-1-yl)-porphyrin; 7-gas-3-(4-amino-benzoic acid)-4-(4-methyl-indole-1-yl) -Lu Blin; 3-(3-chloro-4-methyl-branched base)-7-win-4 4-(4-methyl-pyridin-1,yl)-indole; 7-fluorine 3-(3-methoxy-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3,4-difluoro-benzenesulfonyl) -7-fluoro-4-(4-methyl-piperidin-1-yl)-quinoline; -113- (7) 200838853 3-(3-chloro-4-fluoro-phenylsulfonyl)-7- Fluorine 4-(4-methyl-piperidin-1-yl)-quinoline; 7-chloro-3-(3,5- _* gas-book ore base)-4-(4-methyl- Warm D疋-1-yl)-salostine; 7-chloro-3-(3,5-a-qi i-benzate)-4-(4-methyl-indol-1-yl) -salrin; 7 - gas - 3- (3-alcohol-based ore-branched)-4-(4-methyl- Cloth D-l-yl) - saliva Porphyrin; 7 · gas - 3- (4-methyl-bensyl)-4 - (4-methyl-cyano-1 -yl)-porphyrin; 7-chloro- 3- (4- Sharp-benzene ore-branched)-4-(4-methyl-indole-1-yl)-lulin-3-bensinate-7-chloro-4 -(4-methyl-oxime -1 -yl)-salina; 7-chloro-3-(4-chloro-benzate)-4-(4-methyl-indole D-l-yl)-嗤琳 7-chloro-3 - (3,4 -1·methoxy-based ortho)-4-(4-methyl-indole D-1,4-yl)-quinoline; 7-chloro-3-(3-c) Styrene)-4-(4-methyl-cyclidine-1-yl)-salina 7-chloro-3-(3-methoxy-benzenesulfonyl)-4-(4-methyl- Piperidin-1-yl)-quinoline; 7-chloro-3-(3-chloro-4-methoxy-branched)-4-(4-methyl-indole D-1_yl)-唾琳, 7-Chloro-3-(3-chloro-bensyl)-4-(4-methyl- 卩疋-1-yl)-Salina-114- (8) 200838853 7-Chlorine 3-(3-chloro-4-fluoro-benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 6·chloro-3-(3,5-difluoro -Benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 6-chloro-3-(4-methyl-benzine)-4-(4-A基-暧D定-1-基)-嗤琳; 6-Gas-3-(4-Gas-Benzyl)--4-(4-Methyl-indole D-l-yl)-嗤琳-8-Fluoro-3-(3-Fluoro-4-A -Benzenesulfonyl)-4-(4-methyl-piperidin-1-yl)-quinoline; 8-fluoro-3-(4-methyl-phenylsulfonyl)-4-(4- Methyl-piperidin-1-yl)-quinoline; 3-(3,4- _-chloro-propenyl)-8 - per- 4- (4-methyl-a-D--1-yl) )-Salostine; # 3-(3-Chloro-4-fluoro-benzenesulfonyl)-8-fluoro-4-(4-methyl-piperidin-1-yl)-quinoline; 3-(3 , 4-—sharp-branched)-8-gas- 4-(4-methyl-cyclidine-1-yl)-porphyrin; 3-phenylsulfonyl-6-methyl-4- (suclide-1-yl)-quinoline; 3 - (3-chloro-bensyl)-6-methoxy-4-(味琳-1 -yl)-嗟琳; 3-phenylsulfonate 5--6-fluoro- 4-(tyrosolin-1-yl)-quinoline; 6-gas-3 _(4-gas-benzoic acid)-4-(味琳-1-yl)-嗤Lin, 3-(3-chloro-4-methyl-extension acid)-7-win-4-(味琳-1-基)-陆琳; -115- 200838853 (9) 3·(3,4- Dichloro-benzenesulfonyl)-7-fluoro-4-(tyrosolin-1-yl)-quinoline; 7-chloro-3-(3,5-dichloro-phenylsulfonyl)-4-( (morpholin-1-yl)-quinoline; 7-chloro-3-(3,4-dimethyl-benzenesulfonyl)-4-(flavor Benzyl-1-yl)-quinoline; 7-chloro-3-(3-chloro-benzene ore)-4-(味琳-1-yl)-salina; 7-chloro-3-(3- Chloro-4-methyl-this stone and brewing base)-4-(味琳-1-yl)-salina' 7-chloro-3-(3,4-dichloro-benzenesulfonyl)-4- (succulent-bu)-quinoline; 7-chloro-3-(3-chloro-4-fluoro-benzenesulfonyl)-4·(sodium -1-yl)-quinoline. 5. A pharmaceutical preparation for the preparation of a compound of the following formula (I) and/or its mirror image isomer and/or racemate and/or non-image isomer and/or its acid or base form Method of accepting salt Wherein Ri and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amino or saturated heterocyclic, wherein the hetero atom is N; R3 and R4 are independently selected from hydrogen, An alkyl group, a substituted aryl group having at least one substituent selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, or R3 and R4 together with an N atom attached thereto may form 1 or 2 selected from N, Ο a heteroatom C5_7 heterocyclic group optionally selected from the group consisting of hydrogen, halogen, alkyl, hydroxyalkyl, alkyloxycarbonyl, aminopyramid, -0CH2CH20-116-200838853 (10), And substituted with a substituted phenyl group; Rs, R6, 117 and r8 are independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, or R6 and R7 together with the atom to which they are attached may form an unsaturated impurity Ring group; this method includes: a.) Compound of formula (VI) (VI) (wherein Ri, R2, R5, R6, R7, and R8 are as defined above for the compound provided by the formula (I)) are converted to a compound of formula (VII) (VII) (wherein X is selected from the group consisting of halogen, benzenesulfonyloxy or trifluoromethyl sulfonyloxy, and R1, R2, R5, R6, R7, and R8 are as defined above for the compound of formula (1) And then the resulting compound of the formula (νΙΪ) and the compound of the formula (VIII)-117-200838853 (11) R4\Acoustic 3 NH (VIII) (wherein R3 and R4 are as defined above for the compound of formula (I)) Reacting to give a compound of formula (I), and optionally forming a mirror image isomer and/or a racemate and/or a non-an image isomer and/or a pharmaceutically acceptable salt; or b.) a formula (XV) Compound (XV) (wherein R3, R4, R5, R6, R7, and 8 are as defined above for the compound of formula (I) • provided by formula) and formula (ΠΓ) compound Ri (wherein the lanthanide is selected from the group consisting of an alkali metal or an alkaline earth metal, and Ri and R2 are reacted as defined above for the compound of the formula (I)) to give a compound of the formula (XVI) -118- 200838853 (12) (XVI) (wherein Ri, R2, R3, R4, R5, R6, R7, and R8 are as defined above for the compound of formula (I)), and then oxidizing the compound of formula (XVI) to give formula (XVII) Compound (XVII) (wherein Ri, R2, R3, R4, R5, R6, R7, and R8 are as defined above for the compound of formula (I)), and then oxidizing the compound of formula (XVII) to provide a compound of formula (I), and Selectively forming a mirror image isomer and/or racemate and/or a non-mironomer and/or a pharmaceutically acceptable salt; or C.) a compound of formula (I) wherein Ri, R2, R3, R4, R5, R6, R7, and R8 are as defined above for the compound of formula (I) wherein R, R2, R3, R4, R5, R6, R7, and R8 are interconverted to each other. As defined above for the compound of formula (1)); where appropriate, the compound of formula (1) wherein R, R2, r3, r4, r5, r6, R7, and R8 are as defined above for formula (i) Extracted from -119- 200838853 (13) for definition) of the mirror image isomers and/or racemates and/or non-image isomers; and then selectively forms salts of the compounds of formula (I) and/or Or hydrates and / or solvates. 6. A pharmaceutically acceptable compound for the preparation of a compound of the following formula (VI) and/or its mirror image isomers and/or racemates and/or non-image isomers and 7 or an acid or base thereof Salt method (VI) wherein R1 and R2 are independently selected from the group consisting of ammonia, halogen, affiliation, alkoxy, oxy, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N; R5, R6, R7 And R8 is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, or R6 and R7 together with an atom to which it is bonded may form an unsaturated heterocyclic group; the method comprises: a)) formula (II) Compound-120- 200838853 (14) Br (II) (wherein R 5 , r 6 , r 7 , and r 8 are as defined above for the compound of formula (1)) and a compound of formula (III) Ri M+S R2 (wherein the lanthanide is selected from an alkali metal or an alkaline earth metal, and 1 is reacted with the r2 system as defined above for the compound of formula (I)) to give a compound of formula (IV) (IV) (wherein L, R2, R5, R6, R7, and R8 are as defined above for the compound of formula (1)) and then the compound of formula (IV) is oxidized to give compound of formula (V) -121 - 200838853 (15) (V) (wherein R!, R2, R5, R6, R7, and R8 are as defined above for the compound of formula (I)), and then oxidizing the compound of formula (V) to give a compound of formula (VI), and Selectively forming a mirror image isomer and/or racemate and/or a non-an image isomer and/or a pharmaceutically acceptable salt thereof; or b) a compound of formula (IX) S02Na (IX) (wherein 1^ and R2 are as defined above for the compound of formula (I)) and α-halogen-acetate of formula (X) Hlg-CH2-COOR9 (X) (wherein Hlg is halogen , R9 is ethyl or methyl) reaction to obtain compound of formula (XI)-122-200838853 (16) So2-ch2-coor9 (XI) (wherein 1 and R2 are as defined above for the compound of formula (1), and R9 is as defined above for the compound of formula (X); Trialkyl orthoformate of formula (XII) Ch(or10)3 (XII) (wherein R1() is ethyl or methyl) to give a compound of formula (XIII) So2-c-coor9 CH-Ο R]〇(XIII) (wherein 1 and R2 are as defined above for the compound of formula (I), and R9 is as defined above for the compound of formula (X), and R1G is as defined above for the compound of formula (XII); a compound of formula (XIII) and an aniline derivative of formula (XIV) -123- (XIV) 200838853 (17) (wherein R5, R6, R7, and R8 are as defined above for the definition of the compound of formula (1)) to give a compound of formula (VI), and selectively form its mirror image And/or racemate and/or non-image isomer and/or pharmaceutically acceptable salt 〇 7. - an intermediate such as formula (IV) (IV) Wherein 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amino or saturated heterocyclic, wherein the hetero atom is N; R5, R6, R7 and R8 are Independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, or R6 and R7 together with an atom to which they are attached may form an unsaturated heterocyclic group; and/or its mirror image isomers and/or racemates and And/or a non-image isomer and/or a pharmaceutically acceptable salt thereof formed with an acid or a base. 8. The intermediate of the formula (V) -124- (18) 200838853 -f-R2 Rs (V) wherein l and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N R5, R6, 117 and R8 are independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, or R6 and R7 together with an atom to which they are attached may form an unsaturated heterocyclic group; A structure and/or racemate and/or a non-image isomer and/or a pharmaceutically acceptable salt thereof formed with an acid or a base. 9. An intermediate of formula (VI) (VI) wherein Ri and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N; Rule 5, R6, R7 And R8 is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, or -125-200838853 (19) R6 and R7 together with an atom to which they are attached may form an unsaturated heterocyclic group; and/or its mirror image Isomers and/or racemates and/or non-image isomers and/or pharmaceutically acceptable salts thereof formed with acids or bases. 10. An intermediate such as formula (VII) (VII) wherein X is selected from the group consisting of halogen, benzenesulfonyloxy or trifluoromethanesulfonyloxy, and 1 and r2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, and optionally substituted An amine or saturated heterocyclic group wherein the hetero atom is N; R5, R6, uldent 7 and R8 are independently selected from the group consisting of hydrogen, halogen, affiliation, alkoxy, cyano, or R6 and R7 The atom may form an unsaturated heterocyclic group; and/or its mirror image isomer and/or racemate and/or non-image areomer and/or a pharmaceutically acceptable salt thereof formed with an acid or a base. 1 1 · An intermediate of formula (XVI) (XVI) -126- 200838853 (20) wherein Ri and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy 'cyano, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N R3 and R4 are independently selected from hydrogen, a substituent group, a substituted aryl group having at least one substituent selected from hydrogen, a halogen, an alkyl group, an alkoxy group, or R3 and R4 together with an N atom bonded thereto may form a C5·7 heterocyclic group containing 1 or 2 hetero atoms selected from N and oxime, which may be optionally selected from the group consisting of hydrogen, halogen, φ alkyl, hydroxyalkyl, alkyloxycarbonyl, aminocarbonyl, - och2ch2o-, a group substituted with a substituted phenyl group; R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, or R6 and R7 The atom may form an unsaturated heterocyclic group; and/or its mirror image isomer and/or racemate and/or non-image areomer and/or a pharmaceutically acceptable salt thereof formed with an acid or a base. 12.—The intermediate of the formula (XV II) R4\ sound 3 R5 Ν Ο II丁克(XVII) wherein 1 and r2 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, optionally substituted amine or saturated heterocyclic group, wherein the hetero atom is N; -127- 200838853 (21) R3 and IU are independently selected from hydrogen, alkyl, substituted aryl having at least one substituent selected from hydrogen, halogen, alkyl, alkoxy, or R3 and iU together with N The atom may form a C5-7 heterocyclic group containing 1 or 2 heteroatoms selected from N, fluorene, which may be optionally selected from the group consisting of hydrogen, halogen, ίτι:, hydroxy, methoxy, and amine. Substituted by a carbonyl group, a 0CH2CH20_, a benzyl group and a substituted phenyl group; R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkyl, alkoxy, φ cyano, or R6 and R7 together with The abutting atoms may form an unsaturated heterocyclic group; and/or its mirror image isomers and/or racemates and/or non-image areomers and/or pharmaceutically acceptable salts thereof formed with an acid or a base. A pharmaceutical composition comprising a medically effective amount of a compound of the formula (I) according to any one of claims 1 to 3 of the patent application as an active ingredient (I) together with one or more pharmaceutically acceptable diluents, excipients, and/or inert carriers. A pharmaceutical composition according to claim 13 of the patent application is for use in the prevention and/or treatment of a condition mediated by the mGluR5 receptor. The pharmaceutical composition according to claim 14, wherein the mGluR5 receptor-mediated disorder is a psychiatric disorder. 16. The pharmaceutical composition of claim 14, wherein the mGluR5 receptor-mediated disorder is a neurological disorder. The pharmaceutical composition according to claim 14, wherein the mGluR5 receptor-mediated condition is a chronic and acute pain condition. 18. The pharmaceutical composition according to claim 14, wherein the disorder mediated by the φ mGluR5 receptor is a lower urinary neuromuscular dysfunction, and a gastrointestinal disorder. 19. Use of a compound of formula (I) according to any one of claims 1 to 3 of the patent application (I) is a medicine for the manufacture of a disorder for the prevention and/or treatment of a mGlnR5 receptor. 20. The use of claim 19, wherein the mGluR5 receptor-mediated condition is a psychiatric condition. 21. The use of claim 19, wherein the mGluR5 receptor-mediated condition is a neurological condition. 22. The use of claim 19, wherein the mGluR5 is chronically and acutely afflicted by the -129.200838853 (23). 23. The use of claim 19, wherein the mGluR5 receptor-mediated disorder is lower urinary neuromuscular dysfunction and gastrointestinal disorder. 130- 200838853 Ming said that there is no simple & U : # is the map of the map element on behalf of the map: refers to the table pattern represents the book without a generation} } 定一指指fv ίχ 八, if the case has a chemical formula, please reveal the best Chemical formula showing the characteristics of the invention: ()