TW200838865A - New thieno [2,3-b] pyridine compounds - Google Patents

Abstract

Novel compounds of formula (I) and the use thereof in the treatment of mGluR1 and mGluR5 receptor-mediated disorders wherein X represents a group selected from SO, SO2; Y represents a group selected from (CH2)n, NH, NHCH2; n is an integer of 0 to 1; Z is H or monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; R1 is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is an optionally substituted phenyl, heterocyclyl, or NR3R4 group wherein R3 and R4 are independently selected from the group of hydrogen and an optionally substituted alkyl, or R3and R4 together with the N atom to which they are attached form an optionally substituted C5-7 heterocyclyl group, containing one or more heteroatom(s), or NH-CO-NR5R6 group, wherein R5 and R6 are independently selected from the group of hydrogen and an optionally substituted alkyl, or R5 and R6 together with the N atom.

Description

200838865 (1) IX. INSTRUCTIONS OF THE INVENTION • TECHNICAL FIELD OF THE INVENTION The present invention relates to novel ligands of the novel mGluR1 and mGluR5 receptor subtypes of the formula (I) and/or salts thereof and/or hydrated And/or solvates, and pharmaceutical compositions thereof, and their use in the treatment and/or prevention of conditions requiring modulation of the mGluR1 and mGluR5 receptors. [Prior Art] The main excitatory neurotransmitter in the mammalian central nervous system (CNS) is a glutamate molecule that binds to neurons and thus activates cell surface receptors. These receptors fall into two main categories based on the structural characteristics of the receptor protein, the way the receptor transduction signal is to the cell, and the pharmacological profile: ion channel and metabolic glutamate receptors. " Metabolic glutamate receptors (mGluRs) are G-protein-coupled φ bodies that activate a variety of intracellular second message systems after glutamate binding. Activation of mGluRs in undamaged mammalian neurons induces one or more of the following reactions: activation of phospholipase C; increased hydrolysis of inositol phospholipids (PI); intracellular calcium release; activation of phospholipase D; adenosine cyclase Activation or inhibition; increase or decrease the formation of cyclic adenosine monophosphate (cAMP); activation of guanosine quinone cyclase; increase formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increase release of peanut oleic acid And increase or decrease the activity of voltage-gated and ligand-gated ion channels. (Trends Pharmacol · Sci., 1993, 14, 13; -6- (2) 200838865

Neurochem. Int ·, 199 4, 24? 43 9; Neuropharmacology, 1995, 34, 1; Prog. N eurobiol., 1 999, 59, 55; Berl. 2 005, 179, 4) 〇

Eight mGluR subtypes, named mGluRl to mGluR8, have been identified by molecular selection 1994, 13, 1031; Neuropharmacology, 1995, 34, 1; J. Med·C he m., 1995, 38, 1417 ). Further receptor variability occurs through the spliced form of certain mGluR subtypes (PiV/S, 992, 89, 1 03 3 1 ; BBRC, 1 994, 199, 113 6; J. Neurosci., 1 995, 15, 3970) 代谢 According to the amino acid sequence homology, the second message system used by the receptor, and its pharmacological characteristics, the metabolic glutamate receptor subtypes can be divided into three groups. , Group I, Group II, and Group III mGluRs. Group I mGluR includes mGluRl, mGluR5 and its diverse cut variants. The physiological role of Group I mGluRs suggests that activation of these receptors induces neuronal excitation. Evidence suggests that this excitability is due to direct activation of postsynaptic mGluRs, but it has also been suggested to increase neurotransmitter release due to activation of postsynaptic mGluRs. P/zarmaco/. S ci ·, 1992, 15, 92; Neurochem. Int., 1994, 24, 439;

Neuropharmacology, 1 9 9 5, 34, 1; Trends Pharmacol. Sc i ·, 1 9 9 4,1 5,3 3 ) ° It has been pointed out that metabolic glutamate is involved in some of the normal development of mammalian CNS. It has been shown that activation of mGluRs is required to induce long-term potentiation of hippocampus and long-term cerebellar depression 1993, 363, 347; iVaiwre, (3) 200838865 1 994, 368, 740; Cell, 1 994, 79, 3 65 ; Cell, 1 994, 79, 377). About the role of mGluR activation in pain perception and analgesia Φ Ε ^ Λ {Neuroreport, 1 993, 4, 879 ; Brain Res·, 1999, 871, 223) 〇

Group I metabolic glutamate receptors, and in particular mGluR5, have been suggested to be involved in a variety of physiological 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, obesity And gastroesophageal reflux disease (GERD) {Schoepp et al., Trends Pharmacol. Sci. 19 9 3, 14:13;

Cunningham et al., Life Sci. 1994, 54: 135; Ho liman et al., Ann. Rev. Neurosci. 19 94, 1 7:31; Pin e t al.,

Neuropharmacology 19 9 5, 34:1; Knopf el et al., J. Med·C hem. 19 9 5, 38:141 7; Spoor en et al., Trends Pharmacol. Sci·2001, 22:331; G asp Ar ini et al. Curr. Opin. Pharmacol· 2 0 02, 2:43; Neugebauer Pain 2002, 98:1, SI as si et al.,

Curr Top Med Chem. 2 0 0 5; 5 (9) : 8 9 7 - 91 1 ) 〇MGluR5_ Selective compound such as 2-methyl-6-(phenylethynyl)-pyridine ("MPEP") , effective in animal models of mood disorders (including depression and depression) (Spooren et al. y J. Pharmacol. Exp. Ther. 2000, 295:1267; Tatar czynska et a L, Br. J Pharmacol. 2 0 01, 13 2:1423;

Klodzynska et al., Pol J. Pharmacol, 2001, 132: 1423,. Most of the pathology of these conditions is thought to be due to excessive glutamate-induced excitability of CNS neurons. Based on Group I mGluRs, the glutamate-salt-mediated neuronal excitation is increased via synaptic 200838865 (4) post-mechanism and enhanced presynaptic glutamate release, the activation of which is pathologically Contributed. Preferably, the selective antagonist of Group I mGluR receptor is therapeutically effective, and is particularly useful as a neuroprotective, analgesic or anti-caries agent. Most of the pathology of these conditions is thought to be due to excessive glutamate-induced excitability of CNS neurons. Based on Group I mGlURs (mGluRl and mGUR5), glutamate-mediated neuronal excitation is increased via post-synaptic mechanisms and enhanced release of presynaptic glutamate φ, which is activated on pathological lines. Contributed. Therefore, selective antagonists of Group I mGluR receptors are therapeutically effective and are particularly useful as neuroprotective, analgesic or anti-caries agents. International Patent Application WO 09739000 describes that novel thienopyridine sulfonamide derivatives are useful for inhibiting the binding of endothelin peptide to ETA or ETB and for the treatment of hypertension, cardiovascular disease, asthma, eye diseases, renal failure, wounds Healing, endotoxin shock, immediate allergies and bleeding #sexual shock. Japanese Patent JP 070765 86 describes furopyridine and thienopyridine as bone resorption inhibitors for the treatment of osteoporosis. The thienopyridine derivative is used as a blood-supplying agent, an anti-tumor agent, and an immunostimulant as described in the JP 0705 3 5 62 patent application. According to E. Zeinab et al. (Jrd Phrm, 1992, 325(5), 3 〇 1), thienopyridine and thienopyrimidine derivatives have been synthesized and their mycotoxin inhibitor activity has been evaluated. Some of these compounds inhibit the growth of mycotoxins and molds. -9- (5) 200838865 International Patent Application WO 02/0875 84 describes that thienopyridinium organisms act as *proenzyme inhibitors in formulations which also contain cyclooxygenase-2 inhibitors. The above documents do not claim or suggest that the compounds are active at the receptor. SUMMARY OF THE INVENTION The present invention relates to novel ligands of the novel mGluRl and mGluR5 of formula (1): D-derivative aldose and mGluR receptor sub-

Wherein X is a group selected from the group consisting of so and so2; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is a fluorene or a single occurrence of an alkyl group, a nitro group, Halogen, alkoxyfluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethylaminomethyl, dialkylaminomethyl, hydroxy, alkanesulfonylamino;

Ri is a selective substituted alkyl group, a cycloalkyl group, a phenyl group, a bicyclic group; a group, a triyl group, an alkylphenyl group, a-10-(6) 200838865 R2 is a selective substituted phenyl group, a heterocyclic group, Or a NR3R4 group, wherein R3 and R4 are independently selected from the group consisting of hydrogen and a selective substituted group, or 113 and R4 together with the attached N atom form a selectively substituted C5_7 heterocyclic group, which comprises One or more heteroatoms, or NH-CO-NR5R6 based, where! ^5 and r6 are independently selected from the group consisting of hydrogen and a group selected to replace the substituent, or r5 and r6 form a selective substituted C5_7 heterocyclic group with the attached N atom, which comprises one or more And a hydrate or/or solvate thereof and/or a pharmaceutically acceptable salt thereof formed with an acid or a base. Another aspect of the invention provides a method of synthesizing a compound of formula (I). Another aspect of the invention pertains to intermediates in the preparation process. Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as an active ingredient and/or a mirror image isomer thereof and/or a racemate and/or a non-image isomer and / or salts and / or hydrates or solvates, and pharmaceutically acceptable diluents, excipients and / or inert carriers. In another aspect, the use of a compound of formula (I) for preventing and/or treating a disorder of the mGuR5 receptor vector, particularly a neurological disorder, a mental disorder, acute and chronic, is provided. Pain and lower urinary tract neuromuscular dysfunction and gastrointestinal disorders. Another aspect of the invention provides the use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of a disorder of the mGluR5 receptor vector, in particular a neurological disorder, a mental disorder Acute and chronic pain and lower urinary tract neuromuscular dysfunction and gastrointestinal disorders. -11 - (7) 200838865 [Embodiment] DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel ligands of the novel mGluRl and mGluR5 receptor subtypes of formula (I):

Wherein X is a group selected from the group consisting of so and so2; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer from 〇 to 1; Ζ is a Η or a single occurrence of an alkyl group, a nitro group, Halogen, alkoxy, trifluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxy, alkanesulfonamide base;

Ri is a selectively substituted alkyl, cycloalkyl, phenyl, biphenyl or heterocyclic group; L is a selectively substituted phenyl group, a heterocyclic group, or an NR3 group, wherein I and FU are independently selected A group derived from a hydrogen- and optionally substituted subgroup, or 1 and I together with a N atom to which they are attached, form a substituted substituted Cl? heterocyclic group containing one or more heteroatoms, or NH_C〇_NR5R6 a group wherein R5 and r0 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl group, or Rs and Re are bonded to the attached N atom to form a selective substituted C^ A heterocyclic group which comprises one or more heteroatoms 'and/or hydrates and/or solvates thereof and/or pharmaceutically acceptable salts thereof formed with an acid or a base. More preferred embodiments of the invention are compounds of formula (I)

Wherein X is a group selected from the group consisting of so and so2; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is a fluorene or a single occurrence of an alkyl group, a nitro group, Halogen, alkoxy, trifluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxy, alkanesulfonamide base;

Ri is an alkyl or C3-1G cycloalkyl group, optionally substituted with one or more substituents selected from the group consisting of alkoxy, trifluoromethyl, amine, alkylamino, dialkylamino, amine a group, an alkylaminomethyl group, a dialkylaminomethyl group, a decylamino group, a cyano group, a halogen, or a phenyl or biphenyl group, optionally substituted with one or more substituents selected from the group consisting of alkyl groups, Methoxy, trifluoromethyl, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, decylamino, -13- 200838865 (9 Alkanesulfonyl, alkanesulfonyl, cyano, halogen, or - saturated or unsaturated, containing from 1 to 4 heteroatoms selected from ruthenium, osmium or S. Monocyclic or bicyclic heterocyclic groups, such as D-based, urinyl, thioxyl, piperidinyl, morpholyl, tetrahydroquinolyl, oxazolyl, isoxazolyl, furylthiophene, triazolyl, pyrrolidine ring, selective Substituted by one or more of the following groups: hydroxy, alkyl hydroxy, alkyl, alkoxy, trifluoromethyl, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, φ dialkylaminomethyl, a mercaptoamino group, a cyano group, a halogen or a ketone group; R 2 is a phenyl group, optionally substituted by one or more substituents selected from the group consisting of alkyl, methoxy, trifluoromethyl, amine, alkylamino , dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, decylamino, alkanesulfonyl, alkanesulfonyl, cyano, halogen, or 1 - 4 a saturated or unsaturated monocyclic or bicyclic C5_7 heterocyclic group selected from hetero atoms of hydrazine, N or S, such as pyridyl, quinolyl, thiazolyl, 'piperidinyl, morpholyl, tetrahydroquine a morphyl group, an oxazolyl group, a oxazolyl group, a furylthiophene, a triazolyl group, a pyrrolidine ring, optionally substituted by one or more of the following groups; a radical, a lx; a base, a base, a hospital Oxy, trimethyl, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, decylamino, cyano, halogen or keto Or an NR3R4 group, wherein R3 and R4 are independently selected from the group consisting of hydrogen and alkyl, the alkyl group being optionally substituted with one or more substituents selected from the group consisting of alkoxy, trifluoromethyl, amine, alkylamine Dialkylamine , an aminomethyl group, an alkylaminomethyl group, a dialkylaminomethyl group, a mercaptoamino group, a cyano group, a halogen, or a combination of 3 and R 4 together with the attached N atom to form a C5-7 heterocyclic group, Containing one or more-14-200838865 (10) heteroatoms selected from hydrazine, N or S, the selectivity of which is substituted by one or more of the following groups: hydroxy, alkyl hydroxy, alkyl, alkoxy, Trifluoromethyl, amine., alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, decylamino, cyano, halogen or keto, or a group of NH-CO-NRsR6 wherein 115 and r6 are independently selected from the group consisting of hydrogen and alkyl, the alkyl group being optionally substituted with one or more substituents selected from the group consisting of alkoxy, trifluoromethyl, amine, Alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, monoamine methyl, decylamino, cyano, halogen, or R5 and R6 together with the attached N atom form C5_7 a heterocyclic group comprising one or more heteroatoms selected from the group consisting of hydrazine, N or S, optionally substituted with one or more of the following groups: hydroxy, alkyl hydroxy, alkyl, alkoxy, trifluoromethyl Base, amine base, hospital Amino-amino-amino-amine, aminomethyl, polyaminomethyl, monoamine methyl, decylamino, cyano, halogen or keto, and/or hydrates and/or solvates and / or a pharmaceutically acceptable salt thereof formed with an acid or a base. Φ With respect to Z and the substituents Ri, R2, R3, R4, r5 and r6, the alkyl group means a straight or branched alkyl group having 1 to 4 carbon atoms, except when 1 is a cycloalkyl group, wherein a cycloalkane The base moiety contains from 3 to 10 carbon atoms.

In Ri and/or R3 and/or R4 and/or R5 and/or r6, the alkyl group may be optionally substituted by one or more substituents selected from the group consisting of alkoxy, trifluoromethyl, amine, decylamine. Base, second compound amine group, aminomethyl group, polyaminomethyl group, dialkylaminomethyl group, mercaptoamine group, cyano group, fluorine group, chlorine group, bromine group. When Ri represents a cycloalkyl group, the cycloalkyl moiety contains 3 to 10 carbon atoms and may be a monocyclic, bicyclic or tricyclic group such as a cyclohexyl or adamantyl group, and the -15-200838865 (11) naphthenic group The group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, -methoxy, trifluoromethyl, amine, alkylamino, dialkylamino, aminomethyl, alkylamine Methyl, dialkylaminomethyl, mercaptoamine, cyano, fluoro, chloro, molybdenum. When 1^ and/or R2 represents phenyl or R! is a biphenyl group, the phenyl or biphenyl group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, methoxy, trifluoro. Methyl, amine, alkylamino, dialkylamino, aminomethyl, φ alkylaminomethyl, dialkylaminomethyl, decylamino, alkanesulfonyl, alkanesulfonylamino, Cyano, fluoro, chloro, bromo. When Ri and/or R2 represents (:5-7 heterocyclic group, the heterocyclic ring may be a saturated or unsaturated monocyclic or bicyclic ring containing 1-4 hetero atoms selected from hydrazine, N or S, such as pyridyl, quinine Lolinyl, thiazolyl, piperidinyl, morpholinyl, tetrahydroquinolyl, oxazolyl, isoxazolyl, furylthiophene, triazolyl, pyrrolidinyl ring. R2 when a ring containing a hetero atom Without aromatic character, it must contain at least one basic nitrogen atom and the heterocyclic group is bonded to the thienopyridine φ oxime by the nitrogen atom. The heterocyclic group may be optionally substituted by one or more of the following groups : hydroxy, alkyl hydroxy, alkyl, methoxy, trifluoromethyl, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydrazine Alkyl, cyano, fluoro, chloro, bromo or keto. The compound of formula (I) can form a salt with an acid. The invention also relates to a salt of a compound of formula (I) with an acid, particularly a salt formed by a pharmaceutically acceptable acid. Even if the compound of formula (1) is not separately indicated, it means a free base or a salt. Both organic and inorganic acids can be used to form an acid. Addition salts. Suitable inorganic-16-200838865 (12) Acids, for example, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. Representative of monovalent organic acids • Examples are, for example, formic acid, acetic acid, propionic acid and different butyric acid, Valeric acid and caproic 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 may also be Such as hydroxy acids, such as citric acid, or aromatic carboxylic acids, such as benzoic acid or salicylic acid, and aliphatic and aromatic sulfonic acids, such as methanesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid. Acid addition salts The particularly valuable class is the acid itself which is physiologically acceptable and has no therapeutic effect at the dosage used or does not adversely affect the active ingredient. These acid addition salts are pharmaceutically acceptable acids. Addition salts. The reason for not being a pharmaceutically acceptable acid addition salt but an acid addition salt in the present invention is that in a given case, it is purified or isolated from the desired compound. Favorable. Solvates and/or hydrates of the compounds of formula (I) also include Within the scope of the invention. • A particularly important compound of the formula (I) of the present invention is shown below: Φ 2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2 ,3-b]pyridin, 2-(4-chloro-phenylsulfinyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridinidine, 3- ( 4-chloro-phenyl)-2-(4-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridinium, 3-(4-chloro-phenyl)-2-(toluene- 4-sulfonyl)-thieno[2,3-b]pyridine, 4-[3-(4-chloro-phenyl)-thieno[2,3 4]pyridine-2-sulfonyl benzene -17- 200838865 (13) Nitrile, • 2-Benzenesulfonyl-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine, • 3-[3-(4-Chloro- Phenyl)-thieno[2,3_b]pyridine-2-sulfonyl]-benzonitrile, 3 _(4-chloro-phenyl)-2-(pyridine-3-sulfonyl)-thieno[ 2,3-b]pyridin, 2-(butane-1-sulfonyl)_3-(4-chloro-phenyl)-thieno[2,3-b]pyridin-3-(4-chloro- Benzo)-2-(2,4· _*methyl-indol-5-minesayl)-indolo[2,3-b]pyridine, 3-(4-chloro-phenyl)-2 -(thiophene-2-sulfonyl)-thieno[2,3-b]pyridin, 3-(4-chloro-phenyl)-indeno[2,3-b]la D疋-2 - mineral acid (4-chloro-phenyl)_ guanamine, 3-(4-Chloro-phenyl)-2-phenylmethanesulfonyl-thieno[2,3-b]pyridine 10, 2-(3-chloro-phenylsulfonyl)-3-( 4-chloro-phenyl)-thieno[2,3-b]pyridinium, 2-(4-chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-6-chloro-thiophene [2,3-b] 〇 ratio D, 2-(3-fluoro-phenylsulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine, 2 -(3-cyano-benzenesulfonyl)-3-(3-fluoro-phenyl)-thieno[2,3-b]pyridin, -18- (14) 200838865 2-(4-chloro -Benzenesulfonyl)-3-(4-chloro-phenyl)-6-fluoro-thieno[2,3-b]pyridine, 2-(4-amino-bennic acid)-3-(3 -Chloro-bens)-Mercapto[2,3-b], D-, 2-(3-cyano-benzenesulfonyl)-3-(3-methyl-piperidinyl)-thieno[ 2,3-b ] P is more than D,

2-(3-cyano-benzenesulfonyl)-3-(4-methyl-piperidinyl)-thieno[2,3-b], 2-(3-cyano-benzenesulfonate) 3-(4-tolyl)-thieno[2,3-b]pyrrole, 2-(3-amino-benzoinsyl)-3-(3-methoxy-phenyl)-indole Phenomenon [2,3_ b ] _ steep, 2-(3-methoxy-branched)-3-(4-chloro-phenyl)-indeno[2,3_b] _ steep, 2- (3-cyano-5-fluoro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]H is more than D, 2-(3-pro-4- Methyl-benzene ore-branched)-3-(4- gas-phenyl)-deutero[2,3_b]D is more than H, 2-(3,4-dimethyl-benzenesulfonyl) -3-(4-fluoro-phenyl)-thieno[2,3-b]pyridine, 2-(3-cyano-benzenesulfonyl)-3-(4-fluoro-phenyl)-6- Chloro-thieno[2,3-b ], 2-(3-amino-5-gas-benzene ortho)-3-(4-per-benzyl)-嚷-[2,3_ b ]卩定, -19- 200838865 (15) 2-(3-Cyano-phenylsulfonyl)-3-(4-fluoro-phenyl)-6-fluoro-thieno[2,3-b] Steep ratio, 2-(4-bromo-phenylsulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridinium, 5-amino-2-(4 -Chloro-based ore-based)-3-(4-chloro-yl)-deutero[2,3_b] _ steep, 2-(3,4-dichloro-benzene Acyl) -3- (4-chloro - phenyl) - thieno [2,3-b]

2-(3-Ga-4-methyl-benzoic acid)-3-(4-oxo-phenyl)-indeno[2,3-b]-deep, 2-(3-amino-ben Ore-based)-3-(2-chloro-benyl)-exposed benzo[2,3-b]tI ratio U, 2-(3-tap-5-pro-mineral)-3 -(4-chloro-phenyl)-6-a-puro[2,3-b]pyridine, 2-(3-fluoro-4-methoxy-phenylsulfonyl)-3-(4- Chloro-phenyl)-thieno[2,3-b]pyridine, 2-(4-chloro-benzenesulfonyl)-3-(4-methyl-piperidinyl)-thieno[2,3- b] lit steep, 2-(3-indolyl-5-3⁄4-benzene ornidyl)-3-(4-methyl-a-D-based)-exposed benzo[2,3-b]pyridine, 2- (4-chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-5-fluoro-thieno[2,3-b], D, 2-(4-chloro-benzenesulfonate 3-(4-chloro-phenyl)-5-chloro-thieno[2,3-b]pyridine, -20- (16) 200838865 2-(4-chloro-phenylsulfonyl)-3 -(4-chloro-phenyl-bu- 4-chloro-thieno[2,3-b]pyridine, 2-(4-chloro-phenylsulfonyl)-3_(4-chloro-phenyl)_4_fluoro-thiophene And [2,3-b]pyridine, 5-amino-2-(4-chloro-benzenesulfonyl)-3-(4-methyl-piperidinyl)-thieno[2,3_b]pyridine,

2-(3-cyano-5-fluoro-benzenesulfonyl)-3-(3-fluoro-phenyl)-thieno[2,3-b] ladenidine, 5-amino-2-(2- 4-chloro-benzenesulfonyl)-3-(3-fluoro-phenyl)-thieno[2,3-b]呖, 2_(4-chloro-phenylsulfonyl)_3_(4-methyl -piperidinyl)_6_chloro-thieno[2,3 - b ] D is more than 2-, 3-(3-fluoro-4-methoxybenzosulfonyl)-3-(4-fluoro-benzene ))-thieno[2,3-b]pyridine, 2-(3-fluoro-4-yl-phenylsulfonyl)_3_(3-fluoro-phenyl)-thieno[2,3-b] 11 Shi π, 2_( 3 · cyano-5-fluoro-benzenesulfonyl)-3-(2-fluoro-phenyl)-thieno[2,3-b ] U ratio D, 2-( 3-cyano-5-fluoro-benzenesulfonyl)-3-(3-chloro-phenyl)_thieno[2,3_b] Π is more than B. The present invention also relates to a compound of the formula (I) and/or a physiologically acceptable salt thereof and/or a hydrate and/or a solvate thereof as an active ingredient, and a physiological organ or a physiological compound A pharmaceutical composition of an acceptable carrier. The compound of the formula (I) and/or its physiologically acceptable salts and/or hydrates and/or solvates may be administered by conventional methods, for example, orally, parenterally (including subcutaneous, intramuscular and intravenous). , buccal, sublingual, nasal, rectal, or transdermal administration, and the pharmaceutical composition is adjusted according to the route of administration. The compound of the formula (I) and/or its physiologically acceptable salts and/or hydrates and/or solvates are active when formulated into an oral dosage form which may be in the form of a liquid or a solid, for example, a syrup , suspensions or emulsions, tablets, capsules and lozenges. Liquid formulations of the compounds of the formula (I) and/or their physiologically acceptable salts and/or hydrates and/or solvates are generally derived from the compounds of the formula (I) and/or their physiologically acceptable salts and/or Or a suspension or solution of a hydrate and/or solvate in a suitable liquid carrier such as an aqueous solvent such as water and ethanol or glycerol, or a non-aqueous solvent such as polyethylene glycol or oil. The formulation may also contain a suspending agent, preservative or dye. The composition of the solid form of the Φ tablet can be prepared using any suitable pharmaceutical carrier for the preparation of the solid formulation. Examples of solid carriers include lactose, white clay, sucrose, talc, gelatin, amaranth, pectin, acacia, magnesium stearate, stearic acid and the like. Alternatively, the tablets may be coated with standard aqueous or non-aqueous techniques. The solid form of the capsule can be prepared by a conventional encapsulation process. For example, a drug containing the active ingredient can be prepared as a standard carrier and then loaded into a hard gelatin capsule; or, using any suitable pharmaceutical carrier, such as an aqueous gelatin, cellulose, citrate or oil, to prepare a dispersion or Suspension, -22- 200838865 (18) The dispersion or suspension is then placed in a soft gel capsule. - a typical parenteral composition acceptable from a compound of formula (I) and/or its physiologically acceptable salts and/or hydrates and/or solvates in a sterile aqueous carrier or parenteral administration A solution or suspension in oil, the sterile aqueous carrier or parenterally acceptable oil being, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent prior to administration. φ for the nasal administration of the composition of the invention comprising the compound of the formula (I) and/or its physiologically acceptable salts and/or hydrates and/or solvates, which can be formulated into aerosols, droplets, colloids And powder. The aerosol formulations of the present invention typically comprise a solution or fine of a compound of formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate in a physiologically acceptable aqueous or non-aqueous solvent. The suspension, and often in a single or multiple dosage form in sterile form in a sealed container, may be in the form of a medicinal sputum or in a refilled form using an atomizing device. Alternatively, the sealed container can be a single dispensing device, such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve for emptying the contents of the container at one time. If the dosage form comprises an aerosol dispenser, it will contain a propellant which may be a compressed gas such as compressed air or an organic propellant such as a chlorofluorocarbon. The aerosol dosage form can also be in the form of a pump-atomizer. Compositions of the invention comprising a compound of formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate are suitable for buccal or sublingual administration, including tablets, lozenges and tablets The active ingredient is formulated with gum arabic, Tragacons gum or gel, glycerin and the like. -23- (19) 200838865 The composition of the present invention comprising a compound of the formula (1) and/or a physiologically acceptable salt thereof and/or a hydrate and/or a solvate thereof for rectal administration often comprises a conventional suppository In the form of a suppository of the matrix, the suppository base such as cocoa butter and other materials commonly used in the art. Preferably, the suppository is formed by first mixing the composition with a softened or melted carrier followed by cooling and shaping in a mold.

Compositions of the invention comprising a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for transdermal administration include ointments, gels and patches. The composition of the present invention comprising a compound of the formula (I) and/or a physiologically acceptable salt thereof and/or a hydrate and/or a solvate is preferably in the form of a unit dosage form such as a tablet, a capsule or an ampoule. The unit dosage for oral administration of the present invention preferably comprises 0.1 to 5 mg of the compound of the formula (I) and/or a physiologically acceptable salt thereof and/or a hydrate and/or a solvate thereof, calculated as a free base. The unit dosage for parenteral administration of the present invention preferably comprises from 1 to 500 mg of the compound of the formula (I) and/or a physiologically acceptable salt thereof and/or a hydrate and/or a solvate thereof, freely Base calculation. The compound of the formula (I) and/or its physiologically acceptable salts and/or hydrates and/or solvates can be administered in accordance with the principle of administration of a daily dosage form. In the treatment of disorders of mGluRl and mGluR5 mediated media, such as schizophrenia, depression, depression, panic disorder, bipolar disorder, and circadian disorder or chronic and acute pain disorders, the dose is about 0_01mg per day. /kg body weight to about MOmg/kg body weight or about 0. 5 mg to about 7 g per patient per day. -24 - 200838865 (20) The amount of active ingredient combined with the carrier material to produce a single dosage form depends on the individual being treated and the particular route of administration. For example, a formulation for oral administration to humans will conveniently comprise from about 5 to about 95% of the total composition of a carrier comprising from about 5 mM to about 5 amps of active ingredient. The unit dosage form will usually contain from about 1 mg to about 1000 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 250-300 mg '400 mg, 500 mg, 60 Omg, 800 mg or 1000 mg 〇φ. The exact dose for a particular patient will depend on a variety of factors, including age, weight, state of health, sex, foraging, time of administration, route of administration, rate of excretion, combination of drugs, and the severity of the particular condition being treated. For medical use, it has been found that the compound of the formula (I) and/or its physiologically acceptable salts and/or hydrates and/or solvates of the present invention exhibit biological activity at the mGluR1 and mGluR5 receptors, and can be used for the treatment of mGluRl and mGluR5 vectors. The disorder. It has been found that the compounds of the invention or salts thereof exhibit high potency and selectivity in the individual metabolic glutamate receptor (mGluR) subtypes. In particular, the compounds of the invention are potent and selective for mGluRl and mGluR5 systems. Therefore, the compounds of the present invention are expected to be useful for preventing and/or treating disorders associated with excitatory activation of the mGluR1 and mGluR5 receptors and for inhibiting neuronal damage caused by excitatory activation of the mGluR1 and mGlUR5 receptors. The compounds of the invention are useful for producing the inhibitory effects of mGluRl and mGluR5 in mammals, including human-25-(21) 200838865. • Therefore, the compounds of the invention are expected to be useful in the prevention and/or treatment of disorders of the mGluRl and mGluR5 receptor mediators, such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders, and lower urinary tract neuromuscular dysfunction And gastrointestinal disorders. The dosage required for the treatment or prevention of a particular disorder will depend on the individual being treated and the route of administration. Φ The present invention relates to a compound of formula (I), as defined above, for therapeutic use. The present invention relates to the use of a compound of formula (I), as defined above, for the prevention and/or treatment of disorders of the mGluRl and mGluR5 receptor mediators. The invention relates to the use of a compound of formula (I), as defined above, for the prevention and/or treatment of a neurological disorder. The invention relates to the use of a compound of formula (I), as defined above, for the prevention and/or treatment of a psychotic disorder. • The invention relates to the use of a compound of formula (1), as defined above, for the prevention and/or treatment of chronic and acute disorders. The present invention relates to the use of a compound of formula (I), as defined above, for the prevention and/or treatment of lower urinary tract neuromuscular dysfunction and gastrointestinal disorders. The present invention relates to the use of a compound of formula (I), as defined above, for the prevention and/or treatment of pain: migraine, inflammatory pain, neuropathic pain disorders (eg diabetic neuropathy, arthritis and rheumatoid diseases) ), lower back pain, post-operative pain and various conditions, including colic, colic, kidney or cramps, menstrual pain, migraine and gout. -26- 200838865 (22)

The present invention relates to a compound of the formula (I), as defined above, for the prevention and/or treatment of the following conditions: Alzheimer's disease, Alzheimer's disease, AIDS, induced dementia, Parkinson's disease, muscular atrophic spinal cord side Sclerosing, Huntington's disease, migraine, epilepsy, schizophrenia, depression, depression, acute depression, obesity, obsessive-compulsive disorder, ocular disorders (such as retinopathy, diabetic retinopathy, fluoroscopy), Auditory neuropathic disorders (such as tinnitus), chemotherapy-induced neuropathy, post-herpetic neuralgia and trigeminal dysmenorrhea, tolerance, dependence, X chromosome fragility, autism Mental retardation, schizophrenia and Down's syndrome. The present invention relates to the use of a compound of formula (I), as defined above, for the prevention and/or treatment of stroke, head trauma, hypoxic and ischemic injuries, hypoglycemia, cardiovascular disease and epilepsy. The compounds of the invention are also suitable for the treatment of neuromuscular dysfunction of the lower urinary tract such as urgency, overactive bladder, frequent urination, reduced urinary compliance, cystitis, urinary incontinence, enuresis and # dysuria . Furthermore, the compounds of the invention are also suitable for the treatment of gastrointestinal disorders such as transient lower esophageal sphincter relaxation (TLESR), gastrointestinal reflux, and intestinal cramps. 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 disorders of the mGlxxR1 and mGluR5 receptor mediators and for the above disorders. The present invention also provides a method for preventing and/or treating a disorder having or at risk of mGluR1 and mGluR5 receptor mediators and the above-mentioned disorder, -27-200838865 (23), which includes effective administration to a patient A compound of the formula (I) as defined above. In the present specification, the name "therapy" includes treatment and prevention unless otherwise stated. The name "therapeutic" is "therapeutically" and is interpreted in the same way. In this specification, the term "antagonist", unless otherwise indicated, refers to a compound that can partially or completely block a transduction pathway that results in a ligand reaction. The term "disorder", unless otherwise indicated, refers to any condition or disease associated with metabolic glutamate receptor activity. Preparation Methods Abbreviations The meanings of the abbreviations used here are as follows. Abbreviations not shown in the lower φ have conventional meanings unless otherwise stated. DMF N,N-dimethylformamide TEA triethylamine THF tetrahydrofuran ^ DMSO dimethyl hydrazine According to the invention, a process for the preparation of formula (1 a): -28- 200838865 (24)

Wherein X is a group selected from the group consisting of SO and so2; Y is a group selected from (CH2)n, NH, NHCH2; • η is an integer from 0 to 1; Ζ is a fluorene or a single occurrence of an alkyl or nitro group. , R! is optionally substituted alkyl, cycloalkyl, ##, phenyl, biphenyl; R2 is phenyl, optionally substituted by alkyl or halogen; by acting as a solvent Compound of formula (III) in the presence of m & μ 卞 sodium methoxide in dimethylformamide:

• 0 wherein Α is a substituent defined by R 2 in formula (la), Ζ is a hydrazine or a single occurrence of an alkyl or nitro group, and is reacted with a compound of formula (VII):

HlgCH2SOYRi (VII) -29 - 200838865 (25) wherein Hlg is a chloro or bromo group, and Y and Ri are as described above in formula (Ia) or reacted with a compound of formula (VIII):

HlgCH2S〇2YR1 (VIII) wherein Hlg is a chloro or bromo group, Y and Ri are as described above in the formula (la), to obtain a compound of the formula (la), and then selectively forming a salt of the compound of the formula (Ia) And / or hydrates and / or solvates (flow chart). Flowchart 1 Ο 0

(la) a·S0C12' Ph-A (compound of formula (VI), wherein a is a substituent of R2 in formula (la)), catalytic amount dmF, 80-1 30 ° C, 2-3 hours b· A1CM3, 8〇43 (rc, 5 8 hours; C• thiourea, water 7 ethanol, reflux, 20-24 hours; -30- (26) 200838865 d. HlgCH2SOYRi M HlgdSC^YRi (respectively VII) and a compound of formula (VIII) wherein Hlg is chloro or bromo), NaOCH3, DMF, 70-150 ° C, 2-6 hours. Mercapto chloride from appropriate 2-chloro-nicotinic acid Or 5-nitro-2-chloronicotinic acid is prepared by reacting sulfinium chloride with a suitable 4-monosubstituted benzene derivative in the presence of A1C13. The reaction is via a conventional method suitable for Friedel-Crafts reaction. This is carried out using a suitable benzene derivative as a solvent.

The product (II) is purified by crystallization and reacted with thiourea under reflux in a mixture of water and ethanol according to the J. Katritzky method (see J. & C., 1 95 8, 3 6 1 0). The resulting compound of formula (III) is in crystalline form. S-hoofing and ring closure were carried out by the method of F. Guerrera (Farmaco Ed Sci, 1 976, 31, 21). The compound of the formula (III) is reacted with a different halomethylhydrazine, halomethylguanidine or halomethylsulfonamide derivative in the presence of a base such as NaOMe, Cs2C〇3 or KOH. The halomethyl hydrazine derivative can be obtained from the appropriate halomethyl sulfide and m-chloro-perbenzoic acid by the method of G. Letts et al. (J. Mec/. Chm., 2003, 465). The halomethyl maple derivative is commercially available or can be synthesized by a known method such as Y. Yinfa et al. (Synth. C o mm un., 20 04, 34, 1 3? 2443). The halomethylsulfonamide derivative can be obtained by the method 200, 57, 5009) of K · W o j c i e c h o w s k i e t a 1. According to the invention, a method for preparing a compound of formula (lb): -31 - 200838865 (27)

X \ Y—Ri where x is a so, so2; Y is a group selected from (CH2)n, NH, NHCH2; n is an integer from 〇 to 1; Ζ is a fluorene or a hospital; R! is a selective substitution An alkyl group, a cycloalkyl group, a phenyl group, a biphenyl group, a heterocyclic group; R 2 is a phenyl group or an aromatic heterocyclic group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, Trifluoromethyl, amine, amphoteric, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, decylamino, cyano, fluoro, chloro, bromo a compound of the formula (XI): in the presence of sodium methoxide in the dimethylformamide as a solvent:

-32- (XI) 200838865 (28) Reacts with the compound of formula (VII):

HlgCH2SOYRi (VII) wherein Hlg is a chloro or bromo group, γ is as described above in formula (Ib), or is reacted with a compound of formula (VIII):

HlgCH2S02YRi (VIII) wherein η 1 g is a chloro or bromo group, γ and R1 are as described above in the formula (1 b), and the compound of the formula (IV) is prepared =

X \ Y-Ri wherein 1^ is reacted with copper bromide (Π) and butyl nitrite in acetonitrile as described in the above formula (lb); and in the presence of a base and a catalyst in a solvent, Combine the prepared formula (V)

-33- 200838865 (29) wherein R1 is as described in the above formula (lb), reacting with a compound of formula (IX) · R2-B(OH)2 • (IX) wherein R2 is as in formula (lb) above Said, a compound of formula (lb), and subsequently a salt and/or hydrate and/or solvate of the compound of formula (lb) are selectively formed (Scheme 2). ® Flowchart 2

a· HlgCHdOYRi or HlgCHdC^YRi (compounds of formula (VII) and formula (VIII), respectively, wherein Hlg is chloro or bromo), DMF or butanol, 70-150 〇C, 13 hours; b CuBr2, tert-butyl nitrite, CH3CN, 6〇-80°C, 1-3 hours; c, R2-B(OH)2 (compound of formula (IX), wherein R2 is in the above formula (lb) Definition, Na2C03, ethanol-toluene, or dimethoxyethane, pd(PPh3) 4, 1-5 hours, 20-ll〇t:; The compound of formula (IV) is derived from 2-hydrothio-nicotine A Nitrile and corresponding formula -34- 200838865 (30) (VIII) The halomethyl-oxime compound is prepared by the method of F. Guerrera (i^armae (? £, 5,., 1, 976, 3 1, 21). The amine-thienopyridine derivative of the formula (IV) thus obtained is converted into a bromine derivative of the formula (V) by a similar method described in the document HCWals (e.g., 1 98 8, 44, 592 1). The use of butyl nitrite or isoamyl nitrite and Cu(II) salt (such as CuBr2) in acetonitrile is carried out at a temperature of 60-80 ° C. The compound of formula (lb) is a conventional method by Suzuki coupling reaction. Use appropriate boric acid or borate, base and palladium catalyst (described in A) · Suzuki & H. C Brown: Organzc i/ze5*es Vol. 1-3). According to the present invention, a method for preparing a compound of the formula (Ic):

Wherein X represents S〇2; Y represents a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is Η or alkyl;

Ri is a selective substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic group; -35- (31) 200838865 R2 is NRsR4, wherein Rs and r4 are independently selected from hydrogen and selectively substituted A group of alkyl groups, or R3 and r4, together with the N atom to which they are attached, form a substituted C5-7 heterocyclic group containing one or more heteroatoms, by a compound of formula (V):

Y-Rj (V) wherein 1 is reacted with a compound of the formula (XVI) as described in the above formula (Ic): HNR3R4 (XVI) wherein R3 and R4 are as described in the above formula (Ic), and a formula (1〇) is obtained. a compound, and then selectively forms a salt of the formula lc〇ft# and/or a hydrate and/or a solvate (flowchart 3) ° Flowchart 3

a. HNR3R4, 70-200〇C,

(Ic) hours, acetonitrile or DMF or micro-36-200838865 (32) wave-assisted reaction. • The above reaction was carried out by a simple method of Kirscli. G. (reira/^i/ron 55, 27, 7P99, . 65/7). The corresponding bromine compound (V) is advantageously heated with an appropriate amine (HNR3R4) in a suitable solvent (acetonitrile, DMF or water) at a temperature of from 70 to 200 °C. In certain cases, sealed tubes or microwave assisted reactions and higher temperatures are used in this preparation. According to the invention, a process for the preparation of a compound of formula (Id):

Wherein X represents so2; Y represents a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is Η or alkyl;

Ri is a selectively substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic group; R 2 is 1 < [11-(^04113114, wherein R6 is independently selected from hydrogen or selectively substituted a radical group, or R3 and R4, together with the N atom to which they are attached, form a selectively substituted c5_7 heterocyclyl group containing one or more heteroatoms, in the presence of phosgene or diphosgene , compound of formula (IV): -37- 200838865 (33)

Wherein R i is reacted with a compound of formula (XIII) as described above in formula (I d ):

HNR3R4 (XIII) wherein R3 and R4 are as described in the above formula (Id), to obtain a compound of the formula (Id), and thereafter a salt and/or a hydrate and/or a solvate which selectively form a compound of the formula (Id) ( Flow chart 4).

(Id) b. phosgene or triphosgene, NHR3R4 (compound of formula (XIII)), base, (_) 5 ° C - room temperature The method of preparing the compound of formula (Id) is to convert the amine of formula (IV) in situ. The isocyanate derivative is formed and the latter is reacted with an amine of the formula (XIII). The above reaction can be carried out by a conventional method. Conversion of the amine (IV) to its isocyanate derivative is carried out in an aprotic solvent (such as tetrahydrofuran, chlorinated hydrocarbon) using a suitable carbonic acid derivative (such as phosgene or triphosgene) in a base such as triethylamine. In progress, there is -38- 200838865 (34) The temperature is carried out at a temperature between -5 °C and room temperature. ^ According to the invention, a method for preparing a compound of the formula (Ie):

Wherein X is a group selected from the group consisting of SO and S02; γ is a group selected from (CH2)n, NH, NHCH2; η is an integer of 0 to 1; hydrazine is an amine group, alkanesulfonylamino group, halogen;

Ri is a selective substituted alkyl group, a cycloalkyl group, a phenyl group, a biphenyl group, a heterocyclic group;

R 2 is phenyl, optionally substituted by alkyl or halogen; by compound of formula (la):

X \ Y -Ri wherein X is a group selected from SO, S02; -39 - 200838865 (35) Y is a group selected from (CH2)n, NH, NHCH2; n is an integer from 0 to 1; Nitra; I is a selective substituted alkyl, cycloalkyl, phenyl, biphenyl heterocyclyl; R2 is a phenyl group, optionally substituted by an alkyl group or a halogen, and reacted with a suitable reducing agent to prepare a formula ( Ie) compound

Wherein Z is an amine group; and X, Y, n, Ri and r2 are as described above for the formula (Ie), and thereafter selectively forming a salt and/or a hydrate and/or a solvate of the obtained amine derivative. Or a. selectively producing the amine derivative of the formula (Ie) (wherein z is an amine group; X, Y, η, Ri and R2 are as defined in the above formula (le)) and sodium nitrite in hydrochloric acid And reacting with copper (I) iodide or copper (I) chloride or copper (I) bromide or sodium tetrafluoroborate to obtain a compound of the formula (Ie) wherein Z is a halogen; X, Y, η, Ri and R2 are as defined in the above formula (Ie)), and then selectively form salts and/or hydrates and/or solvates of the halogen derivative of the formula (Ie) obtained, or b. selectively An amine derivative of the formula (Ie) (wherein Z is an amine group; X, Y, η, R! and R2 are as defined in the above formula (Ie)) and an alkylsulfonium-40 - 200838865 (36) chlorine The derivative is reacted to obtain a compound of the formula (Ie) (wherein Z is alkanesulfonamide-based; X, Y, n, Ri and R2 are as defined in the above formula (Ie)), and then selected. Salts and/or hydrates of the alkylenesulfonylamino derivatives of the formula (Ie) And / or solvate (flow chart 5).

flow chart

Y-Ri b c

Y-Ri a. SnCl2 or Fe powder / HC1 b. NaN02, concentrated HC1, Cu(I)I or Cn(I)Cl or Cu(I)Br or NaBF4; c. alkyl S02C1, base, 0-80° C;

A compound of the formula (la) wherein Z is a nitro group; X, Y, n, Ri and R2 are as defined in the above formula (Ie) is used as a starting point for the preparation of the 5-substituted thienopyridine of the formula (Ie) Things. The appropriate nitro compound shown in Scheme 5 is selectively reduced, such as by FD Bellamy's method {Tetrahedron Lett. f 2 5, W, 1984) for stannous chloride in ethyl acetate and heated, or The combination of iron and HC1 is used by the method described in the following literature: Org·

Co//, 5, 3 M, 1 9 73 . This reaction produces a compound of the formula (Ie) wherein Z is an amine group; X, Y, η, Ri and R2 are as described above for the formula (Ie), which is optionally via It〇, after S. et al. Conventional Sandmeyer chemistry techniques for diazotization (Bull · C hem. So c. Jpn ., 4 9,1 9 2 0, \ 97 6. The -41 - 200838865 (37) reaction using concentrated nitrous acid in hydrochloric acid Sodium is carried out in the presence of copper (I) iodide or copper (I) chloride or copper (I) bromide, advantageously at a temperature of (-) 5 - ( + 5) ° C. In the preparation of the corresponding fluorine compound In this case, an aryl diazonium salt is obtained by using sodium tetrafluoroborate at the same temperature, and the salt is decomposed by heating to 1600-200 ° C. By the preparation method, a halogen derivative of the formula (Ie) is obtained. (wherein Z is a halogen; X, Y, η, Ri and R2 are as defined in the above formula (Ie).) Alternatively, a compound of the formula (Ie) wherein Z is an amine group; X, Y, η, I and R2 are as defined above Conversion of the formula (Ie) to a sulfonamide derivative is carried out by using the corresponding sulfonium chloride in the presence of a suitable base such as pyridine or triethylamine at a temperature of from 0 to 80 ° C. Invention, a preparation formula (If) Method The compound:

Wherein X represents S〇2; γ represents a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is an amine group, alkanesulfonylamino group, halogen;

Ri is a selective substituted alkyl, cycloalkyl, phenyl, biphenyl, -42-200838865 (38) heterocyclic group; • R2 is a selective substituted phenyl group, a heterocyclic group, or an NR3R4 group, • The R3 and L groups are independently selected from hydrogen or a selectively substituted alkyl group, or I and R4 together with the attached N atom form a selective substituted c5_: heterocyclic group containing one or more Heteroatom, by formula (v) compound··

» wherein R1 and Y are as described in the above formula (I f), reacted with an appropriate oxidizing agent, and the N-oxide derived from the formula (X) is obtained.

# Br wherein R! and Y are reacted with an aqueous solution of nitric acid in acetic acid as described in the above formula (If), and then the obtained nitro derivative of the formula (XI): -43- 200838865

Wherein Ri and Y are as described in the above formula (If), the (XII) amine group is derivatized with a suitable reducing agent, and the resulting formula is prepared.

Object:

Wherein Ri and Y are as described in the above formula (If), a· and the compound of the formula (IX) are present in the base and the catalyst R2_B(OH)2 (IX) wherein R2 is a selective substituted phenyl group or a heterocyclic ring a compound (wherein z is an amine group; R2 is a selective substituted Y and Ri is as described in the above formula (If)), and thereafter a salt and/or a hydrate of the amine derivative of the formula, and Substituting in a solvent to obtain a phenyl group or a heterocyclic group, which is selectively formed and/or solvated - 44- 200838865 (40) (i) selectively, prepared (If) an amino derivative (wherein Z is an amine group; R 2 is a selectively substituted phenyl group, a heterocyclic group, Y and Ri are as described in the above formula (If)), and sodium nitrite is hydrochloric acid and iodinated Reaction of copper (I) or copper (I) chloride or copper (I) bromide or sodium tetrafluoroborate to obtain a compound of the formula (If) wherein Z is a halogen; R 2 is a selective substituted phenyl group, a heterocyclic group, γ and Ri are as described in the above formula (If), and then selectively form a salt and/or a hydrate and/or a solvate of the halogen derivative of the formula (I f) obtained, Or (ii) selectively, prepared If) an amino derivative (wherein Z is an amine group; R 2 is a selectively substituted phenyl group, a heterocyclic group, and Y and Ri are as described in the above formula (If)), and an alkanesulfonyl chloride derivative is reacted, Producing a compound of the formula (If), and then selectively forming a salt and/or a hydrate and/or a solvate of the alkanesulfonylamino derivative of the formula (If), or b. and formula (XIII) The compound is reacted at 70-200 ° C··········· The R2 group is as described in the above formula (If), and thereafter selectively forms a salt and/or a hydrate and/or a solvate of the obtained amine derivative of the formula (If), or (i) Optionally, the amine derivative of the formula (If) is prepared (wherein Z is an amine group; Y, Ri and the R2 group of the NR3R4 group are as described in the above formula (If)) and sodium sulfite in hydrochloric acid and The reaction of copper (I) or copper (I) chloride or copper (I) bromide or sodium tetrafluoroborate to obtain a compound of the formula (If) wherein Z is a halogen; Y, Ri and NR3R4 are R2 is as described in the above formula (If), -45- 200838865 (41) and thereafter selectively forming a salt and/or a hydrate and/or a solvate of a halogen derivative of the formula (If), or (ii) selectively producing an amine derivative ( Wherein Z is an amine group; Y, Ri and is NR3; and the FU group of R2 is as described in the above formula (If)) is reacted with a sulfonyl chloride derivative to obtain a compound of the formula (If) (wherein the Z alkane) Sulfonamide; Y, Ri and R2 of the NR3R4 group are as described in the above formula (if), and then selectively form salts of the obtained alkanesulfonylamino derivative of the formula (If) and / or hydrate and / or solvate (flow chart 6).

Flow chart 6

a. 3-Chloro-peroxybenzoic acid, 〇°C-room temperature, CHC13, 1-3 days, b HN〇3-acetic acid aqueous solution, 1 00- 1 30 ° C, 2-10 hours, c SnCl2 Or Fe powder, ethyl acetate or concentrated HC1, d R2-B(OH)2 (compound of formula (IX) wherein R2 is a selective substituted phenyl, heterocyclic group); Na2C〇3, ethanol, toluene or two Methoxyethane, Pd(PPh3)4, 1 5 hours, 2 0 -1 1 0 〇C, -46- 200838865 (42) e· NHR3R4 (a compound of formula (XIII), wherein R3 and R4 are as defined above (If)), 70-200 ° C, 1-5 hours, acetonitrile or DMF, f NaN02, concentrated HC1, Cu(I)I or Cu(I)Cl or Cu(I)Br or NaBF4,

g alkyl S02C1, base, 0-80 ° C

The compound of formula (X) is synthesized starting from the compound of formula (V) by the method described in the P0501 1 66 patent. The conversion of the corresponding bromine derivative to the N-oxide of formula (X) with an m-chloroperoxybenzoic acid in an aprotic solvent (e.g., a chlorinated hydrocarbon) is advantageously carried out at a low temperature, between 01 and room temperature. The N-oxide of the formula (X) is prepared by selective nitration using an aqueous solution of nitric acid to prepare a compound of the formula (XI). The reaction is carried out in a solution of Klemm, L.H. (J. Ckm., 7, 970, 81) in acetic acid at a temperature of from 100 to 130 °C. The conversion rate is about 20% 'unchanged starting materials can be recycled. The methods used in the subsequent reaction steps (c ' d ' e ' f and g) were carried out in the manner described above (see Schemes 2, 3 and 5). According to the invention, a process for the preparation of a compound of formula (1 g):

Wherein X represents S Ο 2 ; -47- 200838865 (43) Y is a group selected from (CH2)n, nh, NHCH2; n is an integer from 0 to 1; ζ is an amine group, a bromo group, a chloro group, Base, methoxy, amine group;

Ri is a selectively substituted alkyl, cycloalkyl, phenylheterocyclyl; R2 is a selectively substituted phenyl, heterocyclyl, or NR3R4 group wherein R3 and R4 are independently selected from a hydrogen-substituted alkyl group. a group, or R3 and R4, optionally substituted by a C 5 ·7 heterocyclyl group, which comprises one or more hetero-compounds of a compound of formula (X): mono- or di-alkane, biphenyl, Or selective mesons together form an atom,

Wherein Ri and Y are reacted as described in the above formula (Ig), and the compound of the formula (IX) is present in a solvent in a base and a catalyst R2-B(OH)2 (IX) wherein R2 is selective A compound of the formula (XIV) is prepared by substituting a phenyl group or a heterocyclic group: -48- (44) (44) 200838865

Wherein R 2 is a selective substituted phenyl or heterocyclic group, and R i and Y are as described in the above formula (Ig) or reacted with a compound of (XIII): NHR3R4 (XIII) wherein R 3 and R 4 are as defined above A compound of the formula (XIV) wherein R2 is a NRsR4 group, wherein R3 and R4 are independently selected from a hydrogen or a selectively substituted alkyl group, or R3 and R4 are bonded thereto, as described in (Ig) The N atoms together form a selectively substituted c5-7 heterocyclic group comprising one or more heteroatoms; and a compound of formula (XIV) wherein R], R2 and Y are as described in formula (Ig) above, and trifluoro The acetic anhydride is reacted in a solvent to obtain a compound of the formula (XV):

Wherein Ri, R2 and Y are as described in the above formula (Ig); and -49-200838865 (45) a compound of the formula (XV) wherein l, R2 and Y are as described in the above formula (Ig), • a. reacting with phosphorus bromide (ΠΙ) to obtain a compound of formula (Ig) wherein z is a bromo group, and X, Υ, η, γ, and R 2 are as described in the above formula (ig), and thereafter Selectively forming a salt and/or a hydrate and/or a solvate of the bromo derivative of the formula (Ig); or (i) a bromine derivative of the formula (Ig) (wherein Z is a bromo group; X, Y, η, Ri and R2 are reacted with potassium fluoride in DMSO according to the above formula (Ig) to obtain a compound of the formula (4) (wherein 2 is a fluorine group, and further, ¥, 11, 111 and 112 are as The above formula (Ig)), and thereafter selectively forming salts and/or hydrates and/or solvates of the obtained fluorochemical derivative of the formula (Ig); or b· with phosphorus oxychloride ( III) a reaction to obtain a compound of the formula (Ig) wherein Z is a chloro group, X, Y, η, Ri and R2 are as described in the above formula (Ig), and then selectively forms the obtained formula ( Ig) a salt and/or a hydrate and/or a solvate of a chlorine derivative; or (1) a chlorine derivative of the formula (Ig) (wherein Z is a chlorine group; R2 is as described in the above formula (Ig)) is reacted with potassium fluoride in DMSO to obtain a compound of the formula (Ig) wherein Z is a fluorine group, X, Y, η, L and R2 are as described in the above formula (Ig)), and thereafter selectively form salts and/or hydrates and/or solvates of the obtained fluoroglycan derivatives. Or 'c. reacting with methyl iodide in the presence of silver carbonate in a solvent to obtain a compound of the formula (Ig) wherein Z is a methoxy group, and X, Y, η, Ri and R2 are as defined in the above formula (Ig) And optionally forming a salt and/or a hydrate and/or a solvate of the obtained methoxy derivative of the formula (18); or -50-200838865 (46) d. with trifluoromethane The sulfonic anhydride is reacted in a solvent and then reacted with ammonia or mono-* and dialkylamine to obtain a compound of the formula (Ig) wherein Z is an amine group or a monoalkylamino group or a dialkylamino group, X, γ, η, Ri and R2 are as described in the above formula (Ig), and thereafter selectively form salts and/or hydrates and/or solvates of the obtained methoxy derivative of the formula (Ig). (Flowchart 7). Flowchart 7 Br

(X) S Y-Ri

(XIV) S Y-

a. R2-B(OH)2 (a compound of formula (IX) wherein R2 is a selective substituted phenyl, heterocyclic group); Na2C03, ethanol, toluene or dimethoxyethane, Pd(PPh3)4, 1 - 5 hours, 2 0 -1 1 0 °C; b· NHR3R4 (a compound of the formula (XIII), wherein 113 and R4 are as described in the above formula (If)), 70-200 ° C, for 5 hours, Acetonitrile or DMF; c. Polonovsky type reaction (CF3C0) 20, DMF, 0 ° C - room temperature; d. POBr3, DMF, 80-1 30 ° C, then selective KF, DMSO, 100-150 〇C; e· P0C13, DMF, 80-1 30 ° C, then selective KF, DMSO, 100-150 〇C; -51 - 200838865 (47) f· iodomethane, AgC〇3, dichloromethane - DMF, 0 °C-room temperature; * g·i·(CF3S〇2)2〇, dichloromethane, pyridine; 〇_5°C, - ii·nh3 or mono- or dialkylamine, 0°C-room temperature. The compound of the formula (Ig) which contains a Z substituent (amino group, amphoteric amine group, methoxy group and halogen) is usually synthesized by a conversion of a cyclic amide group of the formula (XV). The synthesis of the compounds of the formulae (XIV) and (XV) is described in the Hungarian patent application HU/P050 1 1 66. φ Starting from the N-oxide of formula (X) wherein the N-oxide of formula (X) is synthesized by the method described above, the compound of formula (Ig) is prepared by the following method: in dimethyl The compound of formula (XIV) is treated with acetic anhydride or trifluoroacetic anhydride at a temperature of 0-25 t in decylamine using the Hartling, R. method (J. Het. Chem., 13, 976, / /97). Polonovsky type reaction. A compound of the formula (Ig) wherein Z is a chloro group or a bromo group can be prepared from the corresponding formula (XV) pyridone. A variety of methods are described in the art, including variations of this reaction. Here, the Dennis W. method (J. Org. Ckm, / 60, Φ 72, 995, 3750) is used with phosphorus oxychloride or phosphorus bromide in a suitable solvent (preferably DMF) at 80-1 The reaction was carried out at a temperature of 30 °C. A compound of the formula (Ig) wherein Z is a fluoro group can be prepared from a chloro or bromo compound of the formula (ig) using the simple method of DolleF. 11, 2003, 5333). The reaction is carried out at a temperature of from 100 to 15 ° C with potassium fluoride in DM SO. In the case where Z of the formula (Ig) is a methoxy group, the compound of the formula (XV) is reacted with methyl iodide in a halogenating solvent such as dichloromethane or chloroform (sometimes using 10-20% DMF to improve solubility) The reaction is carried out in the presence of silver carbonate at room temperature as -52-200838865 (48) as follows: Ned Α· method {J. Org·Chem. 26' . 2004, 9215) 〇 (Ig) 6 An amine or 6-substituted amino compound in which hydrazine is an amine group or a mono- or dialkylamino group, using the method of Hi say ο I· et al. (5horg. Md. ZeH., /3, 5 , 2003, 973) was prepared from a compound of formula (XV) via a two-step process. First, the guanamine functional group is converted to trifluoromethanesulfonic acid using a trifluoromethanesulfonic anhydride in a dry halogenated solvent such as dichloromethane or chloroform at a temperature of 0-5 ° C in the presence of a pyridyl group. salt. The crude product is reacted with ammonia in methanol or DMSO or mono- or dialkylamine in DMSO at a temperature of 〇-25 °C. According to the invention, a process for the preparation of a compound of formula (Ih): 7

Wherein X represents so2; γ represents a group selected from (CH2)n, NH, NHCH2; " η is an integer from 〇 to 1; - Ζ is an amine group, a hydroxyl group, a bromo group, a chloro group, a fluorine group, a methoxy group Base, mono or dialkylamine group;

Ri is a selective substituted alkyl, cycloalkyl, phenyl, biphenyl heterocyclyl; R2 is a selective substituted phenyl, heterocyclic, or -53-200838865 (49) NR sR4, wherein R3 And R4 is independently selected from the group consisting of hydrogen or a selectively substituted alkyl group, or R3 and R4 together with the attached N atom form a selectively substituted C5-7 heterocyclic group containing one or more heteroatoms By compound of formula (XIV):

Wherein Ri, R2 and Y are as described in the above formula (Ih), a· reacting with phosphorus (III) oxychloride or phosphorus pentachloride to obtain a compound of the formula (Ih) wherein Z is a chloro group, X, Y , n, Ri and R2 are as described above in the formula (Ih), or b. are reacted with phosphorus (III) oxybromide to obtain a compound of the formula (Ih) wherein Z is a chloro group, X, Y, η, Ri And R2 are as described above in the formula (Ih), and thereafter selectively form a salt and/or hydrate and/or solvate of the obtained chlorine or bromo derivative of the formula (Ih) wherein Z is chlorine Or a bromo group; X, Y, n, Ri and R2 are as described above in the formula (Ih); or (i) a chloro or bromo derivative of the formula (Ih) wherein Z is a chloro or bromo group; X, Y, η, Ri and R2 are reacted with potassium fluoride in DMSO according to the above formula (Ih) to obtain a compound of the formula (Ih) (wherein Z is a fluorine group, X, Y, η, Ri and R2 is as defined in the above formula (Ih)), and thereafter selectively forms a salt and/or hydrate and/or solvate of the obtained fluorine-based derivative of the formula (Ih); or -54- 200838865 (50) (ii) a chloro or bromo derivative of the formula (Ih) wherein Z is a chloro or bromo group; X, Y, η, Ri R2 is reacted with sodium methoxide in methanol as described above in the formula (Ih) to obtain a compound of the formula (Ih) wherein Z is a methoxy group, and X, Y, η, Ri and R2 are as defined above (Ih) And optionally forming a salt and/or a hydrate and/or a solvate of the obtained methoxy derivative of the formula (Ih), or (iii) a chloro or bromo group of the formula (Ih) a derivative (wherein Z is a chloro or bromo group; X, Y, η, Ri and R2 are as described above in the formula (Ih)) and sodium acetate is reacted in acetic acid to obtain a compound of the formula (Ih) wherein Z is The hydroxyl group, X, Y, η, Ri and R2 are as described above in the formula (Ih), and then selectively form salts and/or hydrates and/or solvents of the obtained hydroxyl derivative of the formula (Ih). a compound, or (iv) a chloro or bromo derivative of the formula (Ih) (wherein Z is a chloro or bromo group; X, Y, η, Ri and R2 are as described above in the formula (Ih)) and trifluoromethane The sulfonic anhydride is reacted in a solvent and then reacted with ammonia or a mono- and dialkylamine to obtain a compound of the formula (Ih) (wherein Z is an amine group or a monoalkylamino group or a \dialkylamino group, respectively, X, Y, η, Ri and R2 are as in the above formula (Ih) And then selectively forming salts and/or hydrates and/or solvates of the obtained methoxy derivative of the formula (Ih) wherein Z is an amine group or a monoalkylamino group or a dialkylamino group, respectively Or (v) a chloro or bromo derivative of the formula (Ih) (wherein Z is a chloro or bromo group; X, Y, η, Ri and R2 are as described above in the formula (Ih)) and sodium azide Reacting in DMF and water to obtain a compound of the formula (Ih) (wherein Z is an azide group, X, Y, η, Ri and R2 are as described above in the formula (Ih)), and then 55-200838865 (51) The obtained azido derivative is reacted with sodium borohydride in a solvent to obtain a compound of the formula (Ih): wherein z is an amine group, and X, Y, η, R! and R2 are as defined in the above formula (Ih). And then selectively forming salts and/or hydrates and/or solvates of the amine derivative of formula (Ih) produced (Scheme 8).

a· P0C13, POBr3, PC15, 50-15〇t:, pure or in DMF;

b. KF, DMSO or DMF, 1 0 0 - 1 5 0 °C

c. NaOCH3, methanol, 0_60 ° C

d· CH3COONa, C H3 C Ο Ο H,8 0 -1 0 0 〇C e· NH3 or single- or one-house amine or DMF, 100-150 °C, sealed tube or

Microwave assisted reaction

Fi NaN3 , DMF-water, 80- 1 00 ° C, ii. NaBH 4 , methanol 0-30 ° C Compound of formula (Ih) wherein Z is a chloro or bromo group, which is an N-oxide from formula (XIV) The derivative was prepared by the method of Sakamoto et al. (CAem. Phrm. 5w//. 36; 1 98 8; 22#). The reaction is carried out with a phosphorus reagent containing a suitable halogen or a phosphorus reagent in a suitable solvent such as DMF at a temperature of from 50 to 150 °C. This process produces a dihalo isomer at positions 4 and 6 of the thienopyridine ring which can be separated by crystallization or chromatography -56-200838865 (52). Compounds of formula (Ih) 4-substituted by halogen (chloro or bromo) can be used in the process of Fujimoto et al. (Pharm 5w//, 2, 1 954, /37) using acetic acid and sodium acetate at 80-100. The reaction is carried out at a temperature of ° C to convert into a 4-hydroxy derivative. The compound of formula (Ih) having a 4-amino functional group is prepared via a two-step process: first, a compound of formula (Ih) wherein Z is a chloro or bromo group, is reacted with sodium azide to produce formula (Ih) An azide derivative of the compound wherein Z is an azide group which is reduced to the corresponding amine derivative with a suitable borohydride such as sodium borohydride in methanol or ethanol. A compound of the formula (Ih) wherein Z is an amine group or a monoalkyl group or a dialkyl group substituted amine group, and another method is as follows: Gawley R. E., etc. is used for the 4-halogen derivative of the formula (Ih) The method of human (Tetrahedron Lett., 45, 4, 2004, 757) and Prem·S. S. (Synth Comm. 34, 1 6, 2 0 0 4, 2 9 2 5) is ammonia, monosubstituted or Treated with a disubstituted amine or dimethylformamide. The process is carried out in some cases in a sealed tube or microwave assisted manner at a temperature of from 1 to 10 °C. A compound of the formula (Ih) wherein Z is a methoxy group can be produced by a conventional method described by Neumann K. (Chem Ber; 48, 1915, 961). The compound of the formula (Ih) wherein Z is a chloro group or a bromo group is reacted with sodium methoxide in methanol at a temperature of from 0 to 60 °C. The fluorination reaction starting from the corresponding (Ih) chloro or bromo compound is as follows: using a suitable solvent such as DMF or DMS hydrazine, potassium fluoride in the application of Hochberg R. Med at a temperature of 100-150 ° C · A simplified method of Chem.; 45, -57-200838865 (53) 2 0 02, 5 3 97) to produce a 4-fluoro compound of formula (Ih). The treatment of all reaction mixtures can be carried out in different ways as is conventional in synthetic chemistry. The product can be purified by crystallization or by column or flash chromatography. Biological test method MGluRl receptor binding assay The MGluRl receptor binding assay was performed according to the improved method of Lavreysen et al. (Mol. Pharm, 2003 '63, 108 2). Based on the high homology of the human and murine mGluRl receptors, murine cerebellum formulations were used to measure the binding properties of reference compounds and novel compounds to murine mGluRl. Non-specific binding was measured in the presence of ΙμΜ R214127 using the radioligand [3H]R2 14127 (3 nM). The IC-50 oxime was converted from the substitution curve by nonlinear regression analysis to the Ki 値 via the Cheng and Prusoff formula (Biochem. Pharmacol., 1 973, 22, 3 099). MGUR5 receptor binding assay MGluR5 receptor binding was measured according to the modified Gasparini et al. method (Bioorg Med Med. Lett. 2000, 12: 407-409). The rat brain cortex formulation was used to measure the binding properties of the reference compound and the novel compound for murine mGluRl. The A1 8 cell strain expressing hmGluR5a (purchased from Euro screen) was used to measure the binding characteristics of the compound to the human mGluR5a receptor. The radioligand [3Η]·Μ-ΜΡΕΡ (2 nM) was used. Non-specific binding was measured in the presence of 10 μΜ -58- 200838865 (54) M-MPEP. Evaluation of Functional Activity The efficacy of cultures of the native mouse mGluR5 and mGluRl receptors on the native murine mGluR5 and mGluRl receptors was performed using a 17-day-old Charles River mouse embryonic neonatal cortical cell culture and from 4 days. The original cerebellar cell culture φ of the Wistar rat is measured. (For details on the preparation of the neural cell culture, see Johnson, MI;

Bunge, RP (1 9 9 2): Primary cell cultures of peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedoroff, S.; Richardson A., The Humana Press Ine., 51-77) . After isolation, the cells were seeded in a standard 96-well plate and the culture was maintained at 37 ° C with a 95% air-5% CO 2 atmosphere. Neocortex and cerebellar cultures were used for calcium measurements at 5-7 days and 3-4 days, respectively. # Cell culture for recombinant human mGluR5a receptor Chinese hamster ovary (CH0) cells stably expressing recombinant human mGluR5a receptor (CHO-mGluR5a, purchased from Euroscreen) containing 10% FCS > 1% antibiotic antimycotic solution, Cultured in F12 medium of 400 pg/ml G418, 250 pg/ml zeocin, 5 pg/ml puromycin. Fine cells were cultured in a humidified incubator at 37 ° C in a 5% CO 2 /95% air atmosphere and inoculated 3 times per week. Cells were plated at 2.5-3.5 x 104 cells/well in standard 96-well plates and receptor expression was induced by the addition of 600 ng/ml doxycycline every other day. Calcium measurements were taken 24 hours after the addition of the inducer at '16--59-200838865 (55). Measurement of cytosolic calcium concentration by fluorescence measurement Measurement of cytosolic calcium concentration ([Ca2 + ]i) was performed on primitive neocortical and cerebrospinal cultures and on CHO-mGluR5a cells stably expressing the human mGluR5a receptor. The cells were grown in standard 96-well plates and loaded with fluorescent Ca2+-sensitive dye, fluorine-4/AM (2 μΜ) before measurement: the nerve culture system was loaded in its growth medium, and the CHO-mGluR5a system was loaded in the analysis buffer. (145 mM NaCl, 5 mM KC1, 2 mM MgCl2, 2 mM CaCl2, 10 mM HEPES, 20 mM D-glucose, 2 mM probenecid, ρΗ = 7.4), the assay buffer was supplemented with 2 mM acetone Sodium and 30 pg/ml glutamate-pyruvate transaminase (in the case of CHO-mGlnR5a cells, these supplements are also present during the [Ca2+]i measurement). The load was carried out by incubating the cells with a dye solution of 100 μΐ/well at 37 ° C in a humidified incubator under a 5% CO 2 /95% air atmosphere. The cells were washed twice with analytical buffer to stop the dye loading. After washing, various concentrations of test compound (diluted in assay buffer in DMSO or dimethylformamide (DMF), final DMSO/DMF concentration < 0.1%) or buffer were added to each well depending on the experimental setup. . In the case of neocortical cultures, the assay buffer also contained TTX (0.5 μΜ) to inhibit the spontaneous vibration of [Ca2+]i, and in the case of cerebellar culture, the probenecid was taken with safinpirone ( Substituting sulfinpyrazone) (0.25 mM). Incubate at 37 ° C for 10-20 minutes. Each column was measured with a fluorescence reader (FlexStation II, Molecular Devices) -60- (56) (56) 200838865 [Ca2 + ]i baseline and agonist-induced changes. The excitation and detection of the launch is performed from the bottom of the disc. All measurement procedures were performed at 37 ° C and controlled by conventional software. The inhibitory efficacy of the test compounds was assessed by measuring the decrease in agonist-induced [Ca2+]i-rise in the presence of different concentrations of the compound. The DHPG line was used as an agonist for the three cultures at concentrations of 20 and 100 μM in the neocortical and cerebellar culture lines, respectively. In the case of CHO-mGluR5a cells, the DHPG line was used at an EC 80 concentration derived from the daily dose-response curve measured. The fluorescence data is expressed as an F/F (fluorescent change calibrated with the baseline). The processing of all holes in a single disc is measured. The data obtained for the wells treated in the same manner were averaged and the average obtained was used for analysis. Inhibitory efficacy at a single concentration point is expressed as % inhibition of agonist response. Data (from at least three independent experiments) were fitted with a S-shaped concentration-inhibition curve, IC 50 値 is the concentration of the compound used to produce one-half of the maximum inhibition. Analysis was performed using Soft Max Pro (Molecular Devices) to calibrate the fluorescence data and curve fitting with GraphPad Prism. Results The compounds of the formula (I) of the present invention exhibited affinity for murine and human mGluR1 and mGluR5 receptors, and were confirmed to be functional antagonists, which inhibited the functional response induced by stimulation of the mGluR5 receptor. -61 - 200838865 (57) Table

Miscellaneous numbering structure (Μ+Η)+ or ινΓ mGlu 5 Ki inM) mGlul Ki (_ 'hnmr mm 1 C1 421,2 氺•kitit (300 MHz, DMSO- and, 30 °C): 8.82 (dd, J = 4.6, 1.7 Hz? lH); 7.82 (dd, J = 8.3, 1.7 Hz, 1H); 7.63-7.50 (m, 7H); 7.32-7.23 (m, 2H). 2 α ζΕ^Οα 405,1 * (500 MHz, CDC13, 30 °C): 8.64 (dd5J = 4.6, 1.6 Hz, 1H); 7.89 (dd5 J=8.2, 1.6 Hz? 1H); 7.59-7.55 (m, 2H); 7.54-7.50 ( m, 2H); 7.50-7.43 (m5 4H); 7.35 (dd, J=8.2, 4.6 Hz, 1H).

-62- 200838865 (58)

3 Cl O^H> 404,1 * itieic (300 MHz, CDC13, 30 0C) 8.72 (dd5 J=4.6, 1.7 Hz? 1H); 7.70 (dd, /=8.3, 1.7Hz? 1H); 7.59-7.50 (m, 2H); 7.48-7.41 (m, 2H); 7.34 (dd, J = 8.3, 4.6 Hz, 1H); 7.21-7.14 (m? 2H); 7.07-6.97 (m, 2H). 4 CI 400 , 2 is ** (300 MHz, DMSO-do, 30 〇C): 8.79 (dd, J = 4.6, 1.6 Hz, 1H); 7.80 (dd, /=8.3, 1.6 Hz, 1H); 7.60-7.52 ( m,3H); 7.47-7.41 (m, 2H); 7.36-7.29 (m, 2H); 7.28-7.22 (m, 2H); 2.36 (s, 3H). 5 Cl 3 445.0 *** (300 MHz, DMSO, 30 °C): 10.39 (s5 1H); 8.79 (dd5 J = 4.6, 1.6 Hz, 1H); 7.80 (dd?J= 8.3, 1.6 Hz, 1H); 7.71-7.63 (m? 2H) 7.60-7.50 (m, 3H); 7.50-7.43 (m, 2H); 7.32-7.24 (m, 2H); 2.08 (s, 3H). 6 Cl Cl 421, 2 icit (300 MHz, DMSO-^5 30 ° C): 8.84 (dd, J = 4.6, 1.7 Hz, 1H); 7.84 (dd? J = 8.3, 1.7 Hz, 1H); 7.69-7.61 (m, 1H); 7.60-7.53 (m5 3H); 7.40-7.35 (m, 2H); 7.32 (ddd, J = 8.1, 7.4, 1.3 Hz, 1H); 7.17-7.09 (m, 2H). 7 Cl Qc^-O- 411,2 it (300 MHz, CDC13 , 30 〇C): 8.75 (dd5 J=4.5, 1.6 Hz? 1H); 7.72 (dd, J=8.2, 1.6 Hz, 1H); 7.67-7.61 (m, 4H); 7.5 0-7.43 (m, 2H); 7.36 (dd, J = 8.2, 4.5 Hz, 1H); 7.21-7.13 (m, 2H). 8 Cl 386,0 * *** (300 MHz, CDC13, 30 0C) : 8.71 (dd, J = 4.6, 1.7 Hz, m); 7.68 (dd, J = 8.2, 1.7 Hz, 1H); 7.58-7.48 (m, 3H); 7.45-7.39 (m, 2H); 7.38-7.29 (m, 3H); 7.18-7.12 (m, 2H). 9 a CN 411,2 * * (300 MHz, CDCI3, 30 °C): 8.75 (dd3 7=4.6, 1.6 Hz, 1H); 7.80-7.75 (m, 2H); 7.72 (dd, J = 8.3, 1.6 Hz, 1H); 7.69-7.66 (m5 1H); 7.55-7.45 (m, 3H); 7.36 (dd, "7=8,3, 4, 5 7.20-7.13 (m,2H). -63- (59)200838865

10 CI 387,2 ie *** (500 MHz, DMSO-do, 25 0C): 8.85-8.80 (m, 2H); 8.58 (dd, J = 2.5, 0.6 Hz, 1H); 7.97 (ddd, J= 8.2? 2.5, 1.6 Hz, 1H); 7.83 (dd? J = 8.3, 1.6 Hz, iH); 7.59-7.52 (m5 4H); 7.30-7.26 (m5 2H). 11 d' ch3 366,2 ieie (300 MHz, CDC13, 30 °C): 8.77 (dd5y=4.651.7 Hz, 1H); 7.82 (dd5J= 8.3, L7 Hz, 1H); 7.56-7.51 (m, 2H); 7.48-7.43 (m5 2H); 7.40 (dd5 J= 8.3? 4.6 Hz? 1H); 2.97-2.87 (m5 2H); 1.70-1.57 (m5 2H); 1.38-1.20 (m, 2H); 0.81 (t5 J = 7.3 Hz, 3H). 12 Cl o^H^CH3 h3c 421,2 ** icicic (300 MHz, DMSO-do, 30 °C): 8.83 (dd, J= 4.6, 1.6 Hz, 1H); 7.83 (dd5J= 8.3, 1.6 Hz, 1H 7.62-7.53 (m,3H); 7.38-7.31 (m, 2H); 2.59 (s5 3H); 2.25 (s, 3H). 13 Cl 391,9 ** (300 MHz, DMSO-do, 30 T ): 8.81 (dd5 7=4.6, 1.6 Hz, 1H); 8.10 (dd, 1 = 5.0, 1.4 Hz, 1H); 7.84 (dd5 7=8.3, 1.6 Hz? 1H); 7.63-7.58 (m, 2H) ; 7.56 (dd? J = 8.3, 4.6 Hz, 1H); 7.45 (dd5J = 3.9, 1.4 Hz, 1H); 7.41-7.34 (m? 2H); 7.15 (dd, J= 5.0, 3.9 Hz, 1H). 14 Cl is h3c 405,2 ★ ★it (500 MHz, DMSO- and, 25 0C): 8.84 (dd5J= 4.6, 1.6 Hz, 1H); 7.83 (dd, J = 8.3, 1.6 Hz, 1H); 7.64-7.60 (m, 2H); 7.58 (dd?J = 8.3, 4.6 Hz, 1H); 7.40-7.35 (m , 2H); 2.20 (s5 3H); 2.05 (s, 3H). 15 JM Cl ** • kit it (300 MHz, DMSO-^, 30 °C): 10.74 (s? 1H); 8.76 (dd5 J = 4.6, L6Hz? 1H); 7.77 (dd?J = 8.3, 1.6 Hz, 1H); 7.56-7.48 (m5 3H); 7.31-7.21 (m5 4H); 7.01-6.93 (m, 2H). -64- 200838865 (60)

16 Cl 0^-0 392,2 itisis ick-k (300 MHz5 CDC13j 30 °C): 8.75 (dd5 J=4.5, 1.6 Hz, 1H); 7.80 (dd, J=8.3, L6Hz, 1H); 7.55- 7.48 (m, 2H); 7.46-7.40 (m5 2H); 7.39 (dd5J = 8.3, 4.5 Hz, 1H); 2.68 (tt5 J = 12.0, 3.4 Hz, 1H); 1.98-1.72 (m, 4H); 1.70 -1.36 (m, 3H); 1.20-0.96 (m? 3H). 17 times itit itieit (300 MHz DMSO-do, 30 0C): 8.81 (dd, J= 4.5, 1.6 Hz, 1H); 7.86 (dd, J = 8.3, 1.6 Hz, 1H); 7.60-7.54 (m, 3H); 7.37-7.26 (m? 5H); 7.16-7.11 (m5 2H); 4.61 (s, 2H). 18 Cl o^-oc 462, 1 ititic (300 MHz, CDC13? 30 °C): 8.71 (dd5J=4.651.7Hz5lH); 7.69 (dd, J=8.3? 1.7 Hz, 1H); 7.63-7.50 (m,6H); 7.50-7.38 (m , 5H); 7.32 (dd, J= 8.3, 4.6 Hz, 1H); 7.22-7.15 (m, 2H). 19 Cl Cl 421,2 it Λ* Λ (300 MHz, DMSO-i/6? 30 °C ): 8.83 (dd, J = 4.6, 1.6 Hz, lH); 7.83 (dd5 J=8.3, 1.6 Hz, 1H); 7.75 (dt5 J = 7.2, 2.0 Hz, 1H); 7.62-7.51 (m, 5H) ; 7.29-7.21 (m, 3H). 20 Cl 〇^<>cH3 (300 MHz, DMSO-admin, 30 0C): 8.79 (dd, /=4.6, 1.6 Hz, 1H); 7.84 (dd, J = 8.3, 1.6 Hz, lH); 7.64-7.50 (m, 5H); 3.42-3.28 (m, 2H); 2 .54-2.39 (m,2H); 1.63-1.49 (m,2H); 1.44-1.22 (m,1H); 1.06-0.86 (m,2H); 0.82 (d,y=6.6Hz? 3H). 21 Cl *** (300 MHz, DMSO-*, 30 0C): 8.77 (dd, J = 4.6, 1.6 Hz, lH); 8.72-8.55 (brm, 1H), 7.83 (dd5 J = 8.3, 1.6 Hz, 1H 7.63-7.56 (m, 2H); 7.54 (dd, J = 8.3? 4.6 Hz, 1H); 7.52-7.46 (m, 2H); 7.36-7.28 (m, 2H); 7.23-7.16 (m? 2H) ); 4.02 (s, 2H). -65- 200838865(61)

22 400, 2 * 23 F ς φ. CH3 Cl 418,2 ★ 24 FQ^02-^CH3 ch3 397,5 * 25 Cl MS(EI) 463 ★ 26 ch3 0>^CH3 380,2 ie 27 ch3 〇^-〇~ch3 380,2 ★ 28 MS(EI) 453 * *** -66 - 200838865(62)

29 ό . ζΧ^. 2·^ 395,2 * 30 ό , F MS (El): 412 ★ (500 MHz, DMSO-hand, 25 °C): 8.84 (dd5 J=4.5, 1.6 Hz, 1H); 8,23-8.19 ( m,1H); 7.83 (dd, J = 8.3, 1.6 Hz, 1H); 7.64-7.59 (m, 2H); 7.57 (dd5 J = 8.3, 4.5 Hz, 1H); 7.37-7.31 (m5 2H); 7.31 -7.26 (m5 2H). 31 C1 ό F ζι>δ02^ 404,1 * 32 Γ^\^€η3 Ν" CN 〇d-so^ MS(EI) 397 * 33 α q^s〇2^> _c1 Cl 455,1 •kk 34 O^cf F 472,1 * -67- 200838865(63)

35 ch3 C〇-s〇2-cvci 400,2 * kisit 36 ch3 cn 〇C/S〇2^ MS(FIB) 398 it it 37 ch3 ό c, 〇C>S0^ 400,2 ύ 38 aci CN 411 , 2 ή ★ 39 Cl ό F 418,2 it 40 Cl ό F ζχ>8〇2-<4 CN 429,1 * ** -68- 200838865 (64)

41 α ζΧ^8〇2^3-α 456,1 it 42 crcx ζΧ>8〇2-〇~εΝ 411,2 it 43 α 456,0 it 44 α ch3 414,2 * 45 471,9 k 46 ο QC^sQ-CVa MS(EI) 394 * 47 ch3 464,1 ★ it -69- 200838865 (65)

48 Cl Φ Q^S〇2^3-〇CH3 416,2 is * 49 Cl 0 H2NX^s. 2 servant 1 436,6 it 50 Cl ch3 435,1 •k 51 Cl 〇x^〇2-q CN 446,2 52 CN 395,2 it * 53 Or^ 〇i^Q CN MS(EI) 390 it is -k 54 0 c, 404,3 * -70- 200838865 (66) 55 FJ 384,0 ie ό Oc N Guang>so factory〇-ch; 56 ζϊ h3c 428,2 57 Cl Λ 456,0 * • Cl ά w - 58 X Cl X/-s〇2-〇~ci (FAB) 438 (500 MHz, DMSO-do, 25 °C): 7.99 (dd, J= 8.8, 7.5 Hz, 1H); 7.61-7.51 (m, 6H); 7.35 (dd? J = 8.8, 1.4 Hz, 1H); 7.31-7.24 (m5 2H). - 59 ch3 MS(FIB) 391 * * 0 CN 60 C>cl 421,1 ie 0 C /-s〇2-〇~ci -71 - 200838865 (67)

61 〇^^CH3 384,0 ★ 62 Cl Q^〇2_Q_CH3 ch3 MS(EI) 413 •k 63 Cl 〇vs〇2^Q~CH3 Cl MS(EI) 433 ie 64 Cl CH3X^°^ CN 441,2 4e 65 Cl X^so^ CN 429,2 it (300 MHz, DMS0-i4 30 °C): 8.14 (ddd? J = 7.7, 1.5, 1.1 Hz, 1H); 8.00 (dd, J= 8.8, 7.5 Hz3 1H); 7.86 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H); 7.75-7.65 (m5 2H); 7.59-7.51 (m5 2H); 7.36 (dd5J= 8.8, 1.6 Hz, 1H); 7,27 -7.19 (m,2H). 66 Or- 〇cfs〇2^ CN MS(FIB) 402 it -72- 200838865(68)

67 /^V-〇ch3 O^〇2~<^, CN MS(FIB) 407 •k ie 68 Cl 〇^O~CT3 454,2 is 69 CN CN(EI) 401 * 70 Cl 6 丫och3 Ovs〇2 w 416,2 ★ 71 Cl cxy-^><: 429,2 72 Cl 0 N°XX^〇i 466,1 ** 73 〇>CN Cx^s〇2^ MS(EI) 377 -73- (69)200838865

74 F ό CN Cl into N person S N-=/ MS(EI) 428 it 75 MS (El): 412 * ieieit (500 MHz, DMS0' 25 °C): 8.13 (dm, J = 7.9 Hz, 1H) ; 7.99 (dd, /=8.8, 7.6 Hz, 1H); 7.82 (dm, J = 8.1 Hz, 1H); 7.72-7,66 (m,2H); 7.36 (dd, J = 8.8, 1.4 Hz5 1H) 7.36-7.29 (m,2H); 7.29-7.22 (m,2H). 76 a clX^so^ MS(EI) 437 ieis 77 Cl MS(E1) 421 ή 78 F 388,2 * *** 79 Cl 2 X)^〇2^3-ci MS (El) 434 ★ it (300 MHz, CDCIb, 30 °C): 8.38-8.27 (brm, 1H); 7.50-7.38 (m, 4H); 7.36-7.28 ( m, 2H); 7.19-7.09 (m5 2H); 6.96-6.87 (brm,1H); 2·52 (vbrs, 2H). -74- 200838865 (70)

80 Cl Φ Q^so2^^C1 Cl 455,9 * it-k 81 Cl F MS(EI) 451 * 82 FQ^〇2_^Q_CH3 幸承氺★ it it it 83 CN 411,2 * 84 h3c, 0 Q^〇2~Q, CN MS(FIB) 407 ★ 85 514,2 * -75- 200838865(71)

S6 Cl ό . F MS (El): 462 it (500 MHz, DMS0' 25 °C): 8.22 (ddd, J = 8.4, 2.3, 1.3 Hz, 1H); 7.88 (d, J= 8.7 Hz, 1H) ; 7.67-7.61 (m, 3H); 7.59-7.54 (m, 2H); 7.27-7.22 (m5 2H). 87 Cl F 422,2 88 Cl O^H: 428,1 * 89 Cl X^s〇2 -<^m F MS (El): 435 • k (500 MHz, DMSO-do, 25 °C): 7.99 (dd, J=8.7, 7.6 Hz, 1H); 7.60-7.55 (m, 2H); 7.45 (t, J = 7.7 Hz, 1H); 7·35 (dd, J= 8,7, L3 Hz, 1H); 7·30 (dd, J = 8.0, 1.8 Hz, 1H); 7.29-7.25 ( M5 2H); 7.12 (dd, J = 9.0, 1.8 Hz, 1H); 2.27 (d5J = 1.5 Hz, 3H). 90 Cl 0 CN Xms〇^ f MS (El): 446 * (500 MHz, DMSO-do , 25 ° C): 8.23 (dm, J = 8.4 Hz, 1H); 8.03 (dd, J = 8.8, 7.5 Hz, 1H); 7.67-7.61 (m, 2H); 7.59-7.54 (m, 2H); 7.38 (dd, J = 8.8, 1.4 Hz, 1H); 7.28-7.22 (m, 2H). -76- 200838865 (72)

91 MS (El): 433 is ** (500 MHz, DMSO-admin, 25 °C): 8.84 (dd, J= 4.5, 1.6·1, 1H); 8.23-8.19 (m, 1H); 7.83 (dd5 J = 8.3, 1.6 Hz? 1H); 7.64-7.59 (m, 2H); 7.57 (dd5 J = 8.3, 4.5 Hz5 1H); 737-7.31 (m, 2H); 7.31-7, 26 (m, 2H) 3.90 (s, 3H). 92 6 Q^S02^Q-C1 MS(EI) 460 ★ 93 6 Q^s〇2^Q_ci MS(EI) 417 itit 94 ch3 ύ ζ^δ〇2^^α MS (EI) 406 head 95 ch3 Cl ch3 496,2 it* -77- (73) 200838865 (73)

96 ch3 NJ CN ods〇2^4 F 416,1 * (500 MHz, DMSO, 25 0C): 8.77 (dd, V= 4.5, 1.5 Hz, 1H); 8.55 (dd5/=8.4, 1.5 Hz, 1H); 8.36-8.29 (m5 2H); 8.19 (ddd5 J = 7.8, 2.4, 1.6 Hz, 1H); 7.54 (dd, V= 8·4, 4·5 Hz, 1H); 3.27-3.18 (m5 2H) 3.03-2.95 (m, 2H); 1.65-1.49 (m, 3H); 1.10-0.99 (m5 2H); 0.96 (d?J=6.4 Hz, 3H). 97 Cl MS (FAB): 453 * ( 500 MHz, CDC13? 25 °C): 8.38 (d? J= 2.3 Hz? 1H); 7.64 (d? J=2.3 Hz? 1H); 7.50-7.41 (m, 4H); 7.36-7.30 (m5 2H) 7.19-7.13 (m? 2H). 98 r>OH 〇^s°2^〇-ci MS(EI) 408 ★ 99 OH 0 Q^s〇2_^cl MS(EI) 408 100 ch3 , n-ch3 ζΧ^^〇·α 353,1 * 101 H3C-0 OC^s〇2-〇-ci 451,2 * -78- 200838865(74)

102 Cl , ό (^)^so2^3-c. (500 MHz, DMSO-4 25 0C): 8.83 (dd, J=7.4? 5.4 Hz, 1H); 7.61-7.55 (m, 2H); 7.52- 7.44 (m,4H); 7.44 (dd, "/ = 11.2, 5.4 Hz, 1H); 7.28-7.23 (m? 2H). 103 Cl o„0 ^j^s〇2^fy.a 437,2 104 Ch3 H2N ό XjC^s〇2^3~c, 422,2 4c 105 °^ch3 0 〇Ss〇2-^ya MS(Fffi) 436 ie^eit 106 CHb 0 MS(EI) 407 ieit 107 ch3 ό ΗΟχχ ^-^ 423,2 it 108 so2ch3 464,1 it it * -79- (75)200838865

109 CrF 404,1 it 110 ςτ CN o^s°2~<4 F MS (FAB): 412 it (400 MHz, DMSCM6, 25 °C): 8.85 (dd5J= 4.6, 1.5 Hz, 1H); 8.24 (ddd, J = 8.5, 2.4, 1.3 Hz, 1H); 7.86 (dd5J= 8.3, 1.5 Hz, 1H); 7,69-7.65 (m, 1H); 7.63 (ddd, J = 7.7, 2.4, 1.7 Hz , 1H); 7.60-7.51 (m? 2H); 7.46-7.38 (m? 1H); 7.13- 7.05 (m, 2H)· 111 ch3 NH 0 NH QC^s°2〇-〇ch3 378,2 ieick 112 Ch3 NH 0 NH 382,1 *** 113 421,3 it 114 Q^-〇-a 404,1 it -80- (76) 200838865 115 ςτ 419,1 ★ Morning 2Νχχ>--<>^ • n ( ^ ^ ^ C C C - 〇^s〇2~〇-ci 119 MS it (400 MHz, DMSO-do, 25 (FAB): °C): 8.51 (d,./=8.7Hz5 1H); - rC 440 8.02-7.94 (m , 2H); 7.78-7.70 (m, 2H); 7.59 (d, J = 8.7 Hz, • 0 c, X^S〇2"^C1 1H); 3.23-3.11 (m5 2H); 3.06-2.96 (m , 2H); 1.63-1.43 (m, 3H); L18-1.03 (m, 2H); 0.95 * (d, 7=6.3 Hz, 3H). -81 - (77) 200838865 (77)

120 H3Y^ k/N 〇 NH Q^S02-Q^0CH3 446,3 121 〇y° 〇C^^Q~cl 436,2 icicis 122 ^丫. Q^so2hQ-ci 451,2 isitie 123 Cl X^s〇2~^a MS (El): 437 ★ NMR (500 MHz, CDC135 25 0C): 8.62 (dd, J= 2.8, 0.8 Hz, 1H); 7.49-7.42 (m, 4H); 7.40 (dd, J= 8.4, 2.8 Hz, 1H); 7.35-7.30 (m, 2H); 7.18-7.14 (m, 2H). 124 Cl cn^-Γ 0 472, 3 125 Cl nh2 φΤ)-δ〇2-^α 436,1 is 126 F 〇φ〇2{^_·3 418,2 it -82- 200838865 (78)

127 F 418,2 * 128 Crcx Q^S02^^0CH3 F 434,2 ie 129 Q cx^s〇2^y~a MS(EI) 378 * 130 F 〇C/s〇2^IVc, 422,1 * 131 H2NX)^o- 419,2 it 132 o&f F 413,2 ie 133 Q^s〇2^J_cl MS(EI) 376 -83- 200838865(79)

134 (5 N ^ CX^s〇2-€Vc, MS(EI) 428 135 464,2 ** 136 αα. ζΧ>8〇2^4 F 429,2 * 137 f φτ XX>s〇2-€ Vc, 422,1 * 138 ςτ, CIxxhl^4 F 447,2 •k 139 c^F - F 431,1 •k 140 Qci-S〇2-〇-Ci 423,4 * -84- 200838865 (80)

* Kj <500nM ** 500nM<Ki< 1500nM *** Ki>1500nM

1H NMR spectra were obtained from a Varian Unity Inova 300, a Varian Unity Inova 500 or from a Varian V-400 spectrometer. Chemical shifts are expressed in ppm from TMS. The invention is further illustrated by the following non-limiting examples. EXAMPLES Example 1 (4-Chloro-phenyl)-(2-chloro-indole ratio 0-but-3-yl)-Kelly intermediate (II) Thionine dichloride (15 ml, 0.2 mol) and DMF (0.5 ml) was added dropwise to a suspension of 2-chloro-nicotinic acid (31.5 g, 0,2 mol) in chlorobenzene (100 ml), and the mixture was stirred at 120 ° C for 4 hours. Aluminum chloride (33 g, 0.25 mol) was added to the reaction mixture at 0 ° C and allowed to boil for 6 hours. The reaction mixture was poured into ice (100 ml) and ethyl acetate (100 ml). The mixture was stirred at room temperature for half an hour. The pH was adjusted to 8 by an aqueous sodium hydroxide solution (40%). The resulting emulsion was filtered, and the filtrate was separated and ethyl acetate (2x 50 ml). The organic phase was washed with water (100 ml) dried over Na2ss The crude product was crystallized from isopropanol (20 ml) eluted eluted eluted eluted elute • Start the same reaction with 2-chloro-5-nitro-nicotinic acid (Klunder, J. M. et al. J. Med. C hem. 1 992, 35, 1 8 8 7.) Example 2 (4 _Chloro-phenyl)-(2-Homothio-pyridin-3-yl)-methanone hydrochloride thiourea (15.6 g, 0,200 mmol) in water (50 ml) and ethanol (25

The solution in ml) was added dropwise to a suspension of (4-chloro-phenyl)-(2-chloro-pyridin-3-yl)-methanone (7.65 g, 30 mmol) in ethanol (20 m 1) . The reaction mixture was heated for 24 hours, then cooled to 〇 ° C and stirred for 2-3 hours. The precipitate was filtered off, washed with water, and stirred with NaOH solution (2·5 g NaOH in 60 mL of water) at room temperature for one hour. The mixture was filtered off and the filtrate was adjusted to pH 1 with 6N aqueous hydrochloric acid. The product was filtered off and washed with water to give crystallites. Example 3 General procedure for the preparation of a compound of formula (la) by 2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine to (4-chloro (4-Chloro-phenyl) is added to a solution of phenyl)-(2-hydrothio-pyridin-1-yl)-methanone hydrochloride (0.7 g, 2.4 mmol) in DMF (15 mL) -Chloromethyl maple (0·7 g, 3.0 mmol) and NaOMe (0·28 g, 5.0 mmol). The reaction mixture was maintained at a temperature of 1 2 0 - 130 ° C for 2 hours, followed by evaporation under vacuum. Water (15 ml) was added to the residue and extracted with dichloromethane (3×20 ml). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was purified from the crystals of ethyl acetate containing 10% methylene chloride. </ RTI> 71 g of the title compound 〇 compound 1-14, 16, 17, 18, 19, 22 &gt; 23 &gt; 24, 26- 3 1 33 1-35, 37, 39-41, 44, 4 5, 48, 54-56, 59, 61- 63 Λ 68, 70, 72, 78, 80, 82, 87 &gt; 88 and 9 1 j Prepared in the same reaction. Different chloromethyl hydrazine reagents can be purchased by the buyer or by the method of Y. Yinfa et al. {Synth. Communication. , 2004, 34, 13, 2 4 4 3)

preparation. Example 4 3-(4-Chlorophenyl)-thieno[2,3-b]pyridine-2-sulfonic acid (4-chloro-phenyl)-decylamine (Compound 15) N-(4-Chloro-Benzene Sulfhydramide (〇·265 g, 1.1 mmol) (intermediate A), (4-chloro-phenyl)-(2-hydrothio-pyridin-3-yl)-methanone hydrochloride A mixture of the salt (0·29 g, 1 mmol) (Example 2) and Na.sub.3.sub.3 (0.12 g, 2.2 mmol) in DMF (5 ml). The solvent was then removed under vacuum, water (15 ml) was added to the residue, and the mixture was extracted three times with chloroform (15-15 ml). The organic phase is dried and concentrated. The residue was honed in n-hexane (1 〇ml). After the hexane was poured off, the oily product was purified by column chromatography (Kieselgel 60, eluent: chloroform:methanol = 98:2) to yield oxime. .225 g (52%) of the title compound. N_(4-Chloro-phenyl)-chloromethanebeline-87-200838865 (83) (Intermediate A) to 4-chloroaniline (0.65 g; 5.0 mmol) in dichloromethane (10 ml) The solution was added to TEA (1.4 m Bu 1 mmol). The resulting solution was cooled to 5 ° C, and a solution of chloromethyl sulfonyl chloride (〇 9 m 1, 10 mmol) in dichloromethane (5 ml) was added dropwise, and the temperature was maintained at 5 ° C. . After the addition was completed, the reaction mixture was stirred at 1 ° C for 30 minutes, and then stirred at ambient temperature for 20 hours. The reaction mixture was evaporated to dryness <~~~~~~~ The solution was then neutralized to pH = 7 with an aqueous solution of HCl and extracted three times with ethyl acetate (3 0 - 0 0 ml). The organic phase is dried and concentrated. The crude product was purified by column chromatography eluting elut elut elut elut elut eluting Melting point: 1 0 2 · 1 0 4 °C. Example 5 φ 3-(4-Chlorophenyl)-thieno[2,3-b]pyridine-2-sulfonic acid 4-chloro-benzyl decylamine (Compound 2 1) The title compound is from &gt;^-( 4_Chloro-benzyl)-chloromethane_sulfonamide (intermediate A) and (4-chloro-phenyl)-(2-hydrothio-pyridine-yl)-methanone hydrochloride (example) 2) Prepared according to the method described in Example 4. The crude product was purified by EtOAc EtOAc (EtOAc) -88- 200838865 (84) N-(4-Chloro-benzyl-)-chloromethanelineamine (Intermediate A) The title compound (Intermediate A) is from 4-chlorobenzylamine and chlorodecanesulfonyl. Chlorine was prepared according to the procedure described in Example 4. The obtained compound was purified by column chromatography to give (5 4%) of crystal product. Melting point: 91-92 °C. Example 6 3-(4-Chlorophenyl)-2-(4-methyl-piperidin-1-sulfonyl)-thieno[2,3-b]pyridine (Compound 20) The title compound is from 1- Methyl chlorosulfonyl-4-methylpiperidine (intermediate A) and (4-chlorophenyl)-(2-hydrothio-pyridin-1-yl)-methanone hydrochloride (Example 2) Prepared according to the method described in Example 3. The crude product was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) 1-chloromethanesulfonyl-4-methylpiperidine (Intermediate A) to 4-methylpiperidine (0.6 mi; 1 〇mmol) in chloroform (1 〇ml) with stirring solution added to tea (1.4 m Bu 1〇mmo1). The resulting solution was cooled to 5 ° C, and a solution of chloromethanesulfonyl chloride (0·4 ml, 4·4 mmol) in dichloromethane (5 ml) was added dropwise, and the temperature was maintained at 5 °C. After the addition was completed, the reaction mixture was stirred at 1 ° C for 30 minutes, then -89-200838865 (85) and stirred at ambient temperature for 4 hours. The reaction mixture was diluted with dichloromethane (1 〇 ml) - and washed twice with EtOAc (5-10 mL) and then water. The organic phase is dried and concentrated. The crude product was crystallized from n-hexane (5 ml), then crystallised from EtOAc (3:1). Melting point: 9 0 - 9 2 °C.

Example 7 General procedure for the preparation of intermediate (IV) by 2-(4-chloro-benzonic acid)-indolo[2,3-b]indolepyrimidin-3-ylamine: 3-aminopyridinium疋-2-thiol (6.8 g, 50 mmol), chloromethyl-(4-chloro-phenyl)-indole (12.3 g, 55 mmol) and sodium methoxide (3.0 g, 55 mmol) in anhydrous N, The solution in N-dimethylformamide (150 ml) was stirred at 1201 for 2 hours. The reaction mixture was cooled to room temperature and water (150 ml) was poured. The solid was filtered, washed (H20) and dried to give 13.7 g (yield: 84%) of the title compound. b] General procedure for the preparation of the intermediate (V) of pyridine: to anhydrous copper (II) bromide (1 1.2 g, 50 mmol) and butyl nitrite (9 · 0 ml, 75 mmol) in anhydrous acetonitrile (100 ml) a mixture of 2-(4-chloro-benzene ore)-嚷-[2,3-b]卩 in the argon atmosphere than B--3-amine (10.7 g &gt; 34 mmol) Substance (IV) was added in portions and maintained at a temperature of -90 - 200838865 (86) at 70 °C. The reaction mixture was maintained at 65 ° C for 1.5 hours and then • cooled to room temperature. The crystalline product was filtered off and washed with acetonitrile to give a pure product (7.7 g, 58.3%). Example 9 2-(3-Cyano-5-fluoro-benzenesulfonyl)-3-(3-fluoro-phenyl)-thieno[2,3-b]pyridine, (Compound 1 1〇)

General procedure for the preparation of compounds of formula (lb): 3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (Example 8) (〇·2 g, 0.5 mmol) was dissolved in toluene (4 ml) and ethanol (4.5 ml) under argon. To a Pd(PPh3)4 solution (28 mg, 0.025 mmol) was added 3-fluorophenylboronic acid (85 mg, 0.6 mmol) and 2M Na.sub.2CO.sub.3 (2.3 mL). The reaction mixture was refluxed for 1.5 to 2 hours, and then the organic solvent was evaporated in vacuo. Water (1 〇 m 1) was added to the residue. The resulting suspension was extracted three times with chloroform (3×10 ml). The organic phase was washed with water (5.0 ml), dried over Na. The crude product was purified by column chromatography eluting elut elut elut elut elut elut Compounds 38, 42, 52, 53, 60, 66, 67, 69, 71, 73, 83, 84, 108-110, 113, 114, 126-128, 130, 132, 1 3 6 and 1 3 7 are based on Prepared as described above. Example 1 2-(3-cyano-benzenesulfonyl)-3-(4-methyl-piperidinyl)-thieno[2,3--91-200838865 (87) b] (Compound 36) General procedure for the synthesis of some compounds of formula (Ic) (Scheme 3a):

3-bromo-2-(3-cyano-benzenesulfonyl)-thieno[2,3-b]pyridine (prepared according to Example 8) (2.18 g, 5.75 mmol) and 4-methyl-piperidine ( 2. 〇ml, 17 mmol) was dissolved in DMF (9 ml) and heated to 1 ° C for 1 hour in argon. The reaction mixture was cooled, water (60 mL) was evaporated and evaporated. The organic layer was washed with water (2 x 20 mL), dried and evaporated in vacuo. The crude product was purified by chromatography (Kieselgel 60, hexane:ethyl acetate = 2:1) to yield 1.64 g (72.4%). The similar compounds prepared were 32, 36, 46, 92-96, 98-100, 106, 116-118, 129, 133, 134, 140 and 141 ° Example 11 N-[2-(4-methoxy- Phenylsulfonyl)-thieno[2,3-b]pyridin-3-yl]-4-methyl-piperidin D-indole-carboxamide (Compound 120) General method for the synthesis of some compounds of formula (Ic) (Scheme 3b): 2-(4-Methoxy-benzenesulfonyl)-thieno[2,3-b]pyridin-3-yl-amine (IV) (prepared according to Example 7) (0.48 g, 1.5 mmol) was suspended in dry tetrahydrofuran, triethylamine (〇·3 ml, 2 mmol) was added, and triphosgene (0.18 g 0.6 mmol) dissolved in tetrahydrofuran was added dropwise. After 1 hour, stir at room temperature, add 4-methyl-acridine (0.36 ml, 3 mm 〇l), and continue stirring for 20 hours. The mixture was evaporated in vacuo and the residue dissolved in dichloromethane, washed with water, dried and evaporated. The title compound (0.43 g, 65%) was obtained. • The following compounds were prepared using the above procedure: 111, 112, 120-122 ° Example 12 2-(4-Chloro-phenylene-branched)-3-(4-chloro-phenyl)-non-pheno[2,3- 1&gt;]卩 ratio|1定-5-ylamine (compound 79) SnCl2 2H20 (2·19 g, 9.7 1 mmol) was added all the time to 2-(4-chloro-phenylsulfonyl)-3- (4-Chloro-phenyl)-5-nitro-thieno[2,3-b]pyridine (Example 3, Compound 72) (0.90 g, 1.93 mmol). The reaction mixture was stirred at 70 ° C for 1 hour. The mixture was poured into an ice-cold flask and neutralized with a NaHC03 solution (10%), then dichloromethane (60 ml) was added and the organic layer was separated. The aqueous phase was extracted with dichloromethane (2 x 30 mL). The organic phase was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was subjected to column chromatography (SiO 2 , cyclohexane: acetone = 7:3) to give 2-(4-chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-thiophene [ 2,3-b]pyridine-5-ylamine (0.46 g, yield: 55%). Example 13 N-[2-(4-Chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]indole; pyridine-5-yl]-methanesulfonate Amine (Compound 85) Methanesulfonyl chloride (〇·〇25 g, 0·22 mmol)—all added to 2-(4-chloro-benzene ore)-3-(4-chloro-phenyl) - 嚷-[2,3-b]D]: t D-1,4-amine-93-200838865 (89) (0.095 g, 0.22 mmol) (Example 12) pyridine solution (2 ml). The reaction mixture was refluxed for 3 hours. The solvent was then evaporated in vacuo and the residue was crystalljjjjjjjj Water (10 ml) was added to the filtrate, and the resulting mixture was extracted with dichloromethane (2×10 ml). The organic phase was collected, dried, filtered and concentrated in vacuo. The crystals were collected, washed with cold methanol and filtered to yield (yield: 73 mg, yield: 65%).

Example 14 5-Chloro-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine (Compound 97) 2-(4-Chlorine -Benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridin-5-ylamine (Example 12) (0·69 g, 1.58 mmol), thick A suspension of HCl (6 ml) and water (4 ml) was cooled to 0 °C, and aq. EtOAc (3 mL, 0.11 g, The mixture was stirred at 〇 ° C for half an hour. It was then cooled and a solution of Cu(I)Cl (0.188 g, 1.9 mmol) in concentrated HCl (4 ml) was added at once. The mixture was warmed to room temperature and then immersed in a 60 ° C oil bath for 1 hour. The cooled mixture was poured into ice (10 g), EtOAc (EtOAc) The organic phase was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAcjjjjjjj Example 15 2-(4-Chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-5-fluoro-thieno[2,3-1)]-94- (90) 200838865 Pyridine (compound) I23) 2-(4-Chloro-phenylene ortho)-3-(4-chloro-phenyl)-indeno[2,3-b]acridin-5-ylamine (0.50 g,1·14 Mmmol) (Example 12), concentrated HC1 (8 ml)

The suspension of water (4 ml) was cooled to 〇 ° C, then NaN02 ice cold water (5 ml, 0.084 g, 1.2 1 mmol) was added. The mixture was stirred at 〇 ° c for half an hour. Then, the aqueous solution of N a B F 4 (〇 · 1 7 6 g '1 · 5 9 m m ο 1) was added all at once. The mixture was stirred at 〇 ° C for half an hour and filtered. The resulting solid was washed with cold water, methanol, and dried overnight. The compound was melted at 179-182 ° C and stirred for a few minutes. Then, the mixture was cooled to room temperature, and subjected to column chromatography (SiO 2 , cyclohexane:acetone = 9:1) to obtain 5-fluorinated compound (0 · 1 2 6 g, 25 %). Example 16 3-Bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyran-N-oxide General procedure for the preparation of intermediate X: to 3 -Bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (3.51 g, 8.8 mmol) in chloroform (130 ml) m-Chloroperoxybenzoic acid (6.08 g, 35 mmol, 77%), and the mixture was stirred at room temperature overnight. The resulting solution was washed with EtOAc (EtOAc (EtOAc)EtOAc. The crude product was purified with EtOAc (EtOAc) -95- 200838865 (91) Example 17 Preparation of intermediate XI from 3-bromo-2-(4-chloro-phenylsulfonyl)-5-nitro-thieno[2,3-b]pyridine-N-oxide General procedure: 3-bromo-2_(4-chloro-benzenesulfonyl)-thieno[2,3-b]pyridine-N-oxide (prepared as described in Example 16) (4.95 g, 12.2 mmol ) Boiling at 70 ° C for 4 hours with 70% nitric acid (0.75 ml, 12 mmol) in acetic acid. The reaction mixture was evaporated and the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjj Example 18 General procedure for the preparation of intermediate XII from 5-amino-3-bromo-2-(4-chloro-benzenesulfonylthiophene[2,3 _b]pyridine: 3-bromo-2-(4-chloro - Benzenesulfonyl nitro-thieno[2,3-13]pyridine-N-oxide (Example 17) (0·8 g, I78 mmol) dissolved in acetic acid U2 ml) and Fe powder (0, 61) g, 10 mm 〇 l). The reaction mixture was stirred at 7 ° C for 30 minutes, then evaporated under vacuum and the residue was purified by chromatography (Kieselgel 60, chloroform, methanol = 5:0.1). Title Compound (0.51 g, 7 1%) 〇 Example 1 9 5-Amino-2-(4-chloro-phenylsulfonyl)-3-(3-fluoro-phenylthieno[2,3-b] Pyridine-96- 200838865 (92) (Compound 115) 5-Amino-3_bromo-2-(4-chloro-benzenesulfonyl)-thieno[2,3_b]pyridine reacted with 3-fluorophenylboronic acid The yield was 20% as described in Example 9. Compound 1 3 1 was prepared according to the same method.

5-Amino-2-(4-chloro-benzenesulfonyl)-3-(4-methyl-piperidinyl)-thieno[2,3_b]pyridine (Compound 104) 5-Amino-3- Bromo-2-(4-chloro-benzenesulfonyl)-thieno[2,3-b]pyridine was reacted with 4-methyl-piperidine as described in Example 1A. Example 21 2-(4-Chloro-benzenesulfonyl)-3-(3-fluoro-phenyl)-5-fluoro-thieno[2,3-b]pyridine (Compound 137) 5-Amino- 2-(( 4-Chloro-benzenesulfonyl)-3-(3-fluoro-phenyl)-thieno[2,3-b]pyridine (Example 19) was treated as described in Example 15 to give 5-fluoro compound . Example 22 Preparation of 2-(3-cyano-5-fluoro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]B than B-N-oxide The general formula of the intermediate XIV (R2 is a phenyl or aromatic heterocyclic group)-97-200838865 (93) Method: 3 - desert - 2- (3-amino-5-win benzene ore) - 嚷The title compound (yield 63%) was obtained by the same procedure as described in Example 9 to give the title compound (yield: 63%). Example 2 3 2-(4-Chloro-phenylsulfonyl)-3-(4-methyl-piperidinyl)·thieno[2,3-b]

General procedure for the preparation of intermediate XIV (R2 is a substituted amine group) by the ratio of n-N-oxide: 3-bromo-2-(4-chloro-benzenesulfonyl)-thieno[2,3-b Pyridine-N-oxide (prepared according to Example 16) was reacted with 4-methyl-piperidine according to the procedure of Example 10 at 8 ° C to give the title compound. Example 24 Preparation of Intermediate for 2-(3-Cyano-5-fluoro-phenylsulfonyl)-3-(4-chloro-phenyl)-7Η-thieno[2,3-b]pyridine-6-one General procedure for XV: 2-(3 - cyano-5-fluoro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine-N-oxide ( 1 .35 g, 3.0 mmol) was treated with trifluoroacetic anhydride (8.6 ml, 61 mmol) in DMF suspension (1 1 ml) at room temperature for 1.5 hours. At the end of the reaction, it became a solution which was concentrated under vacuum to half volume. Water (8,6 ml) was added and the crystalline product was filtered off and washed with water. 0.93 g (68.9%) of the title compound was produced. -98- (94) 200838865 Example 25 2-(4-Chloro-benzenesulfonyl)-3-(4-methylpiperidinyl)-5-hydroxy-thieno[2,3-b]pyridine 2-(4-Chloro-benzenesulfonyl)_3 gas 4-methyl-piperidinyl)-thieno[2,3-b]pyridine-N-oxide (Example 23) was started using the same as described in Example 24. The process was carried out and the title compound was isolated as a minor product (yield 10%). Corresponding ratio of 2-(4-chloro-benzenesulfonyl)-3-(4-methylpiperidinyl)-7H-thieno[2,3-b]pyridine-6-one is 6〇% (Intermediate XV). Example 2 6 2-(3-Amino-5-chloro-benzene ornidyl)-3-(4-chloro-phenyl)-6-chloro-exo[2,3-b]pyridine (Compound 8 6 A general method for preparing a 6-chloro compound of the formula (I), such as compounds 43, 5, 51, 74, 76, 81, 119 and 138. • 2_(3_Cyano-5-fluoro-benzenesulfonyl)-3-(4-chloro-phenyl)-7H-thieno[2,3-1)]1111-6-one (0.92 g, 2·1 mmol) was dissolved in DMF (14 ml), and phosphorus oxychloride (2·〇ml, 21 mmol) was added, and the reaction mixture was heated at 9 〇-1 〇 (rc heating for 2.5 hours) and then cooled. It is quenched with ice (1 〇g) and purified with ammonium hydroxide (25%, 2 · 5 m 1 ). The solid product is filtered off and washed with water and methanol. 〇· 7 3 g (75%) of the title compound. Example 2 7 -99- 200838865 (95) 2-(3-Cyano-5-fluoro-phenylsulfonyl)-3-(4-chloro- Phenyl)-6-fluoro-thieno[2,3-b]pyridine (Compound 90) General procedure for the preparation of a 6-fluoro compound of formula (1), such as 58, 65, 75, 77, 89 &amp ; 139 °

2-(3-Cyano-5-fluoro-benzenesulfonyl)-3-(4-chloro-phenyl)-6-chloro-thieno[2,3-b]pyridine (0·83 g, 1 .8 mmol) was dissolved in DMSO (10 ml), and potassium fluoride (〇·3 g, 5.0 mmol) was added. The reaction mixture was heated to 140 ° C for 1.5 hours. After cooling, water (10 ml) was added, and the crystalline product was filtered and washed with water. Recrystallization from autothermal methanol gave 0.65 g (62.5%) of compound 90. Example 28 2-(3-Cyano-phenylsulfonyl)-3-(4-chloro-phenyl)-6-methoxy-thieno[2,3-b]pyridine (Compound 64) φ 2- (3-cyano-benzenesulfonyl)-3_(4·chloro-phenyl)-7Η·thieno[2,3-b]pyridine·6-one (0.1 1 g, 0·25 mmol) (Example 24 Silver carbonate (I) (95 mg, 0.35 mmol) and Phosphate (0.15 ml, 2.4 mm 〇1) were suspended in dichloromethane (5 ml) and DMF (0.5 ml). The reaction mixture was stirred at room temperature for 24 hours. It was filtered, washed with dichloromethane (2×10 ml), and the filtrate was washed with Na2CO3 (10%, 10 ml) and water (10 ml). The organic solvent was dried and evaporated in vacuo tolulululululululululululululululululu -100- (96) 200838865 Example 29 6-Amino-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine (compound) 4 9)

2-(4-Chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-7Η-thieno[2,3-b]pyridin-6-one (0·30 g, 0.69 mmol) ( Example 24) Dissolved in pure DMF (10 mL), cooled to 0 <0>C, EtOAc (EtOAc: EtOAc (EtOAc) The reaction mixture was maintained at 〇 ° C for 1 hour, then dimethyl chloride (10 ml) and 1N NaHC03 (10 ml) were added. After separation, the organic phase was washed with water (10 ml), dried and evaporated in vacuo. The crude trifluoromethanesulfonate was treated with NH3 (3 ml) saturated methanol at 0-5 °C for 2 h. The reaction mixture was evaporated in vacuo to give crystallite crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal Example 30 2-(4-Chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-6-dimethylamino-thieno[2,3-b]pyridine (Compound 47) 2- (4-Chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-7H-thieno[2,3-b]pyridin-6-one (〇·19 mmol) (Example 24) Example of use Reaction was carried out in the same manner as described in the same procedure, except that the reaction was carried out for 2 hours at room temperature in the presence of TEA (0.49 mmol) in DMSO (2.0 ml) using dimethylamine hydrochloride. The yield was 73.7%. -101 - (97) (97)200838865 Example 31 4-Chloro-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine (Compound 57) 4-Chloro-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridinium (Compound 43) 2 -(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine N-oxide (prepared according to the procedure described in Example 16) (6.4 g, A mixture of 14.7 mmol) and phosphorus oxychloride (ΙΙΙ) (1 〇 2 ml, 109.4 mmol) was stirred and heated at 60 ° C for 3 hours. The resulting solution was poured into ice and basified with 5M sodium hydroxide. After cooling, the precipitate was filtered off and washed with water. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: methylene chloride) to give 4-chloro compound (3.31 g) and 6-chloro-2-(4-chloro-benzenesulfonate). Mercapto)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine (3·03 g) (Compound 43). Example 32 2-(4-Chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-4-dimethylamino-thieno[2,3-b]pyridine (Compound 135) 4- Chloro-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine (100 mg, 0·22 mmol) in DMF (5 ml The solution in the solution was irradiated with a microwave of 300 W at 210 ° C for 1 minute in the reactor. The solvent was evaporated in vacuo -102 - 200838865 (98). The crude product was purified by column chromatography eluting eluting elut elut elut elut elut Example 33 4-Fluoro-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine (Compound 102) 4-Chloro-2- (4-Chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]-deep (454 mg, 1 mmol) and potassium fluoride (174 mg, 3 mmol The mixture in DMF (5 ml) was stirred and heated at 140 ° C for 48 hours. The solvent evaporates in a vacuum. The crude product was purified by EtOAc EtOAcjjjjjjj Example 34 2-(4-Chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-4-methoxy-thieno[2,3-b]pyridine (Compound 1〇1) 4- Chloro-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b] valence D (150 mg, 0.33 mmol) and sodium methoxide (1. 5 g, (27.8 mmol) in MeOH (150 ml), EtOAc EtOAc m. The combined organic layer was dried with EtOAc EtOAc (EtOAc)EtOAc. 2-(4-chlorobenzone)-3-(4-chloro-phenyl)-4-yl-pyrano[2,3-b]pyridine (Compound 103)

4-Chloro-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b] ratio D (150 mg, 0.33 mmol) and acetic acid A mixture of sodium (280 mg, 3. 4 mmol) in acetic acid (7 ml) and water (0.1 ml) was stirred and heated at 100 ° C for 48 hours. The solution was diluted with water (25 ml). The precipitate was filtered off, washed with water (3×10 ml) and dried. The crude product was purified from crystals crystals crystals eluted Example 36 4-Amino-2-(4-chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]-l-butyl (Compound 125) 4-Chlorine - 2-(4-Chloro-phenyl)-(4-oxo-phenyl)-indolo[2,3-b]pyridine (400 mg, 0.88 mmol) and sodium azide (3 60 A mixture of mg, 5.5 4 mmol) in DMF (1 1 ml) and water (4 ml) was stirred and heated for 5 hr. The resulting solution was diluted with water (15 ml). The precipitate was filtered off, washed with water (5 X 1 〇 m 1) and dried. The resulting crude 4-azido-2-(4-chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b] P|tu-104· (100 200838865 (400 mg, 0·87 mmol) dissolved in methanol (20 m 1). Sodium borohydride (400 mg, 10.6 mmol) was added to the solution, and the mixture was stirred at ambient temperature for 24 hours. Water (30 ml) was added and the mixture was extracted with chloroform (3×60 ml). The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The crude residue was purified by EtOAcqqqqqq

Example 37 3-(4-Chloro-phenyl)-4-dimethylamino-2-(4-dimethylamino-benzenesulfonyl)-thieno[2,3-b]pyridine (compound) 124) 4-Chloro-2-(4-chlorobenzone)-3-(4-chloro-phenyl)-indeno[2,3-b] mouth steep (100 mg, 0.22 mmol) The solution in DMF (5 ml) was irradiated in a reactor at 300 W microwave at 25 ° C for 1 min. The solvent evaporates in a vacuum. The crude product was purified by EtOAc EtOAcjjjjjjjj All compounds were analyzed by HPLC-MS or MS and 1 H-NMR. The purity of the compound of formula (1) was measured by HPLC method, and all compounds had &gt;95% purity. Example 38 Preparation of a pharmaceutical composition: a) Tablet: -105- 200838865 (101) 0.01-50% of the active ingredient of formula (I), 15-50% lactose, 15-50% horse-sweet potato starch, 5-15 % polyvinylpyrrolidone, 1-5% talc, 0.01-3%. Magnesium stearate, 1-3% colloidal ceria and 2-7% ultraamylopectin are mixed and then made by wet granulation Granules and tablets are tableted. b) Fructose-coated, coated tablets: Tablets prepared according to the method described above are coated with a layer consisting of a casing or a gastric solvent film or φ sugar and talc. The icing is polished with a mixture of candied fruit and palm vine. Ο Capsule: 0.0 1-50% formula (I) active ingredient, 1-5% sodium lauryl sulfate, 15-50% starch, 15-50% lactose, 1-3% colloidal cerium oxide and 0.01-3% hard &quot; Magnesium citrate is thoroughly mixed and the mixture is filled through a sieve to fill the hard gelatin capsules. d) Suspension: 'Ingredients: 0.01-15% of the active ingredient of formula (I), 0.1-2% sodium hydroxide, φ 0.1-3% citric acid, 0.05-0.2% nipagin (4-hydroxybenzene) Sodium methyl formate), 0.005-0.02% propyl paraben, 0.01 - 0.5% carbopol (polyacrylic acid), 0.1-5% 96% ethanol, 0.1-1% flavoring, 20- 70% sorbitol (70% aqueous solution) and 30-50% distilled water. To the solution of Nitrogen and citric acid in 20 ml of distilled water, a small portion of Kappa wave was added in a small portion under vigorous and stirring, and the resulting solution was allowed to stand for 1 0-1 2 hours. Then, a solution of sodium hydroxide in 1 ml of distilled water, an aqueous solution of sorbitol, and an alcoholic raspberry flavoring agent were added while stirring. At this point, the active ingredient is added to a small portion of the carrier and is suspended in an immersion homogenizer -106 - 200838865 (102). Finally, distilled water is added to the suspension to the desired final volume and the resulting suspension syrup is passed through a colloid honing device. e) Suppositories: 0.01-15% of the active ingredients of formula (I) and 1-20% of lactose are thoroughly mixed in each suppository. Then, 50-95 % of a d e p s p r 〇 suppository (e.g., Witepsol 4) is melted, cooled to 35 ° C, and a mixture of the active ingredient and the lactose is mixed with a homogenizer. The resulting mixture was molded in a cooled form. φ f) Lyophilized powder ampule composition: mannitol or lactose is made into a 5% solution with distilled water for injection use. The solution is filtered to obtain a sterile solution. The active ingredient of the formula (I) is also prepared as a 〇·0 0 1 - 5 % solution with steamed water for injection use, and the solution is filtered to obtain a sterile solution. The two solutions were mixed under aseptic conditions and partially filled with 1 mi to the ampoule. The contents of the ampoule were lyophilized and the ampoule was sealed under a nitrogen atmosphere. The contents of the ampoule were dissolved in sterile water or 9%·9% (physiologically) sodium chloride aqueous solution before administration. -107-

Claims (1)

(1) 200838865 X. Patent application scope 1. A 'compound of formula (I)' X is a group selected from the group consisting of so, so2; γ is a group selected from (CH2)n, hydrazine, NHCH2; η is an integer of 〇 to 1; Ζ is a fluorene or a single occurrence of an alkyl group, a nitro group, a halogen , alkoxy, trifluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxy, alkanesulfonylamino Ri is a selectively substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic group; R 2 is a selective substituted phenyl group, a heterocyclic group, or an NR 3 R 4 group, wherein the r 4 system is independently selected from Hydrogen and a selectively substituted group, or R3 and R4 together with the attached N atom form a selectively substituted C5_7 heterocyclic group containing one or more heteroatoms, or NH-CO-NRsR6 groups, Wherein &amp;5 and R6 are independently selected from the group consisting of hydrogen and a selectively substituted alkyl group, or R6 together with the attached N atom form a selectively substituted heterocyclic group containing one or more heteroatoms And/or its hydrates and/or solvates and/or its formation with an acid or a base -108- 200838865 (2) pharmaceutically acceptable salts. ' 2 · - a compound of formula (I), among them X is a group selected from the group consisting of so, so2; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is a fluorene or a single occurrence of an alkyl group, a nitro group, a halogen , alkoxy, trifluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxy, alkanesulfonylamino ; is alkyl or C3-1G cycloalkyl, optionally substituted by one or more substituents selected from alkoxy, trifluoromethyl, amine, alkylamino, dialkylamino, amine a group, an alkylaminomethyl group, a dialkylaminomethyl group, a decylamino group, a cyano group, a halogen, or a phenyl or biphenyl group, optionally substituted with one or more substituents selected from the group consisting of alkyl groups, Methoxy, trifluoromethyl, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, decylamino, k sulfonyl, fluorene Sulfonyl, cyano, halogen, or a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 1 to 4 heteroatoms selected from N, 0 or S, such as pyridyl, quinolyl, thiazolyl, Piperidinyl, morpholyl, tetrahydroquinoline , oxazolyl, isoxazole-109- (3) 200838865, furylthiophene, triazolyl, pyrrolidine ring, optionally substituted by one or more of the following groups: hydroxyl, alkyl hydroxy, alkane Alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl 'diamine aminomethyl, mercaptoamine, cyano, Halogen or keto group; R2 is phenyl, optionally substituted by one or more substituents selected from alkyl, methoxy, trifluoromethyl, amine, alkylamino, dialkylamino, amine Methyl, alkylaminomethyl, dialkylaminomethyl, decylamino, φ alkanesulfonyl, alkanesulfonylamino, cyano, halogen, or a mixture of 4 selected from 0, N or S a saturated or unsaturated monocyclic or bicyclic C5-7 heterocyclic group of a hetero atom such as pyridyl, quinolyl, thiazolyl, piperidinyl, morpholyl, tetrahydroquinolinyl, b. a base, an isoxazolyl, a furylthiophene, a triazolyl, a pyrrolidine ring, optionally substituted with one or more of the following groups: hydroxy, alkyl hydroxy, alkyl, alkoxy, trifluoromethyl, amine base , a hospital amine, a compound amine, an aminomethyl group, a benzylamino group, a benzylaminomethyl group, a arylamino group, a cyano group, a halogen or a ketone group, or a NR3R4 group, wherein R3 and R4 Is independently selected from the group consisting of hydrogen and alkyl, the alkyl group being optionally substituted by one or more substituents selected from the group consisting of alkoxy, H fluoromethyl, amine, alkylamino, dialkylamino, amine a methyl group, an alkylaminomethyl group, a benzylaminomethyl group, a decylamino group, a cyano group, a halogen, or r3, and together with the N atom to be bonded, form a C5 heterocyclic group, which comprises one or more From a hetero atom of hydrazine, N or S, the selectivity of which is substituted by one or more of the following groups: hydroxy, alkyl hydroxy, alkyl, alkoxy, trifluoromethyl, amine, alkylamino, dioxane Amino, aminomethyl, alkylaminomethyl, adamyrylmethyl, decylamino, cyano, halogen or keto, or -110-200838865 (4) NH-CO-NRsR6, wherein Rs and R0 are independently selected from the group consisting of hydrogen and oxime, and the alkyl group is substituted by one or more substituents selected from the group consisting of: a hospital oxygen, a base, a difluoromethyl group, an amine group, a hospital amine group, and a second hospital. Amine, amine a base, a hospital aminomethyl group, a dialkylaminomethyl group, a mercaptoamine group, a cyano group, a halogen, or R5 and R6 together with the attached N atom form a Cl? heterocyclic group, which comprises one or more selected From a hetero atom of hydrazine, N or S, the selectivity of which is substituted by one or more of the following groups: a radical, a phenyl group, a phenyl group, a methoxy group, a trifluoromethyl group, an amine group, a aryl group , a second amine, an aminomethyl group, an amidinomethyl group, a second amino group, a methyl group, a cyano group, a halogen or a ketone group, and/or a hydrate thereof and/or a solvate thereof and/or Or a pharmaceutically acceptable salt thereof formed with an acid or a base. 3. A compound selected from the group consisting of 2-(4-chloro-phenylhydrazinyl)-3-(4-chloro-phenyl)-thieno[2,3-1&gt;]pyridinium, 2- (4-chloro-phenylsulfinyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyrene ratio # D定, 3- (4-chloro-phenyl)-2 -(4-fluoro-benzene ore)-嚷-[2,3-b] pyridine, 3-(4-chloro-phenyl)-2 -(toluene-4-sulfonyl)-thiophene And [2,3 - b ]pyridine, 4-[3-(4-chloro-phenyl)-thieno[2,3-b]pyridine-2_sulfonyl]-benzonitrile, 2- Phenylsulfonyl-3-(4-chloro-phenyl)-thieno[2,3 _b]pyridine, 3-[3-(4-chlorophenyl)-thieno[2,3-b]pyridine -2-sulfonyl]-benzamide•111 - 200838865 (5) nitrile, 3-(4-chloro-phenyl)_2-(pharoazol-3-sulfonyl)-thieno[2,3-b Pyridone, 2-(butane-1-sulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridin, 3-(4-chloro-phenyl )-2-(2,4-dimethyl-thiazol-5-sulfonyl)-thieno[2,3-b]pyridine, φ 3-(4-chloro-phenyl)-2-(thiophene- 2-sulfonyl)-thieno[2,3-b]pyridin, 3-(4-chloro-phenyl)-thieno[2,3-b]pyridine-2-sulfonic acid (4-chloro -phenyl)-guanamine, 3-(4-Chloro-phenyl)-2-phenylmethanesulfonyl-thieno[2,3-b]pyridine, 2-(3-chloro-phenylsulfonyl)-3-(4 -Chloro-phenyl)-thieno[2,3-b]pyrrole, φ 2-(4-chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-6-chloro-thiophene [2,3-b] pyridine, 2-(3-fluoro-phenylsulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridine, 2-(3 -cyano-benzenesulfonyl)-3-(3-fluoro-phenyl)-thieno[2,3-b]pyridinidine, 2-(4-chloro-benzenesulfonyl)-3-( 4-chloro-phenyl)-6-fluoro-thieno[2,3-b] th η, 2-(4-cyano-phenylsulfonyl)-3-(3-chloro-phenyl)- Thieno[2,3-b]pyr-112-(6) 200838865 D-'2-(3-amino-benztal)-3-(3-methyl-indole D-based)-exposure-[ 2,3· b ] Oral ratio, 2-(3-amino-branched-branched)-3-(4-methyl-nuclear D-yl)-嚷-[2,3_b]呖D , 2-(3-cyano-benzenesulfonyl)-3-(4-methylphenyl)-thieno[2,3-b]pyrrole, 2-(3-cyano-benzenesulfonyl)-3-(3-methoxy-phenyl)-thieno[2,3-b]P is more than D, 2-(3-methoxy- Phenylsulfonyl)-3-(4-chloro-phenyl)-thieno[2,3-b]pyridinium, 2-(3-amino-5-per-phenylene acid)-3-(4 -Chloro-phenyl)-oxime [2,3_ b ] Π ratio steep, 2-(3 - per-4-methyl-benzene ortho)-3-(4-chloro-phenyl)-oxime Benzo[2,3_b]pyridine, 2-(3,4-*methyl-bentonyl)-3-(4-o-phenyl)-exposed benzo[2,3-b] Ratio D, 2-(3-cyano-benzenesulfonyl)_3-(4-fluoro-phenyl)-6-chloro-thieno[2,3-b] ratio B, 2-(3 - cleavage-5-gas-benzene ore-branched)-3-(4-3⁄4-phenyl)- fluorenyl[2,3_b], 2-(3-cyano-benzenesulfonyl) -3_(4-fluoro-phenyl)-6-fluoro-thieno[2,3-b] Π ratio D, 2-(4-bromo-phenylsulfonyl)-3-(4-chloro-benzene ))-thieno[2,3-b]pyridin-113- (7) 200838865 D-butyl, 5-amino-2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl )-thieno[2,3- b ] P is more than D, 2-(3,4-dichloro-benzenesulfonyl)-3-(4-chlorophenyl)-thieno[2,3- b] 妣 steep, 2-(3-fluoro-4-methyl-benzenesulfonyl)-3-(4-fluoro-benzene Base)-thieno[2,3-b] 2-(3-cyano-benzenesulfonyl)-3-(2-chloro-phenyl)-thieno[2,3-b]pyrridine, 2-(3-dision-5- per- -3-(4-chloro-yl)-6-chloro-indeno[2,3-b]pyridine, 2-(3 -per-4-methoxy-benzene ore base --3-(4-Chloro-phenyl)-indeno[2,3-b]pyridine, 2-(4-chloro-benzenesulfonyl)_3_(4-methyl-piperidinyl)-thiophene And [2,3-b] th steep, 2-(3 - cleavage-5-mirror-benzene ore)-3-(4-methyl-峨D-based)_嚷-[2,3- b]pyridine, 2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-5-fluoro-thieno[2,3-b] 呖D, 2-(4- Chloro-phenylsulfonyl)-3-(4-chloro-phenyl)-5-chloro-thieno[2,3-b] uridine, 2-(4-chloro-phenylsulfonyl)-3 -(4-chloro-phenyl)-4-chloro-thieno[2,3-b] 妣, 2-(4-chloro-phenylsulfonyl)-3-(4-chloro-phenyl)- 4-fluoro-thieno[2,3-b]-114- (8) 200838865 Oral ratio B, 5-amino-2-(4-chloro-benzenesulfonyl)-3-(4-methyl -piperidinyl)-thieno[2,3-b]pyridine, 2-(3-cyano-5-fluoro-phenylsulfonyl)-3-(3-fluoro-phenyl)-thieno[2 ,3-b]pyridine, 5-amino-2-(4-chloro-propenyl)-3-(3-fluorof-phenyl)-porphin [2,3_ b] ratio D given port, 2-(4-gas-benzate)-3-(4-methyl-indenyl)-6-chloro-indeno[2,3-b]pyridine, 2-(3-fluoro- 4-methoxy-benzenesulfonyl)-3-(4-fluoro-phenyl)-thieno[2,3-b]pyridine, 2-(3-block-4-methyl-benzene-benzene ore) 3-(3-win-phenyl)-indolo[2,3-b]pyridine, 2-(3-cyano-5-fluoro-phenylsulfonyl)-3-(2-fluoro -phenyl)-thieno[2,3-b ] Π ratio D, 2-(3-oxo-5-yl-phenylene carboxylic acid)-3-(3-chloro-phenyl)-porphin And [2,3- b ] H is more than the mouth. 4. A method of preparing a compound of formula (la), X \ Y—Ri (la) wherein X is a group selected from the group consisting of SO and S02; γ is a group selected from (CH 2 ) n, NH, NHCH 2 ; -115- (9) (9) 200838865 η is 0 to An integer of 1; Ζ is a hydrazine or a single occurrence of an alkyl or nitro group, Ri is a selective substituted alkyl group, a cycloalkyl group, a phenyl group, a biphenyl group, a heterocyclic group; R 2 is a phenyl group, a group or a halogen; a compound of the formula (?) by the presence of sodium methoxide in dimethylformamide as a solvent Wherein A is a substituent as defined for R2 in formula (la), Z is a hydrazine or a single occurrence alkyl group or a single occurrence nitro group, and is reacted with a compound of formula (VII): Hlg^SOYRj (VII) wherein Hlg is Chloro or bromo, Y and Ri are as described above in formula (la) or reacted with a compound of formula (VIII): HlgCH2S〇2YRl (VIII) wherein Hlg is a chloro or bromo group, and Y and Ri are as defined above ( The compound of formula (la) is prepared as described in la), and then the salt and/or hydrate and/or solvate of formula (la)-116-200838865 (10) is selectively formed. 5. A method of preparing a compound of formula (lb), X, s, Y-Rl (lb) wherein X represents SO, so2; Φ Y is a group selected from (CH2)n, hydrazine, NHCH2; η is an integer from 0 to 1; Ζ is Η or alkyl; R i is a selective substituted alkyl group, a cycloalkyl group, a phenyl group, a biphenyl group, a heterocyclic group; R 2 is a phenyl group or an aromatic heterocyclic group, and is optionally substituted by one or more substituents selected from the group consisting of : alkyl, alkoxy, trifluoromethyl, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, ® amide, cyanide a compound of the formula (XI): a fluoro group, a chloro group, a bromo group, a hydroxy group, a methylsulfonyl group, by the presence of sodium methoxide in the dimethylformamide as a solvent. CN S -117- (XI) 200838865 (11) Reaction with a compound of the formula (VII): HlgCH2SOYRi (VII) wherein Hlg is a chloro group or a bromo group, and γ and Ri are as described in the above formula (lb), or VIII) Compound Reaction: HlgCH2S02YRi (VIII) Wherein Hlg is a chloro or bromo group, Y and Ri are as described above in the formula (lb), and the compound of the formula (IV) is prepared: Where Ri is as described in the above formula (lb), Reaction with copper bromide (ruthenium) and butyl nitrite in acetonitrile; and compounding of formula (V) in the presence of a base and a catalyst in a solvent Wherein Ri is reacted with a compound of formula (IX) as described above in formula (lb): -118- (12) 200838865 R2-B(OH)2 (IX) wherein R2 is as described above in formula (lb) Compounds of formula (Ib) are obtained, and thereafter salts and/or hydrates and/or solvates of the compounds of formula (Ib) are selectively formed. 6. A method for preparing a compound (1〇 compound: Wherein X represents S02; Y represents a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is Η or alkyl; Ri is a selective substituted alkyl, cycloalkyl, benzene a group, a biphenyl group, a heterocyclic group; R2 is NR3R4, wherein r3 and R4 are independently selected from the group consisting of hydrogen and a selectively substituted alkyl group, or R3 and R4 together with the attached N atom form a selective Substituting a C5_7 heterocyclic group containing one or more heteroatoms, by a compound of formula (V): Br -119- (V) (13) 200838865 wherein Ri is reacted with a compound of formula (XVI) as described above in formula (Ic): HNR3R4 (XVI) wherein R3 and R4 are as described above for formula (Ic), Compounds of formula (Ic), and subsequent salts and/or hydrates and/or solvates of the compounds of formula (Ic) are selectively formed. 7. A method of preparing a compound of formula (Id): Wherein X represents S Ο 2 ; Y represents a group selected from (CH 2 ) n, NH, NHCH 2 ; η is an integer from 0 to 1; Ζ is hydrazine or alkyl; R! is optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic; R2 is NH-CO-NR3R4 based 'wherein R5 and r6 are independently selected from Hydrogen or a selectively substituted alkyl group ' or R3 and r4 together with the attached N atom form a selectively substituted C. 7 heterocyclyl group containing one or more heteroatoms, by phosgene or Compound of formula (IV) in the presence of triphosgene and a base: -120- 200838865 (14) Wherein R i is reacted with a compound of formula (XIII) as described above in formula (I d): HNR3R4 (XIII) Wherein R3 and R4 are as described in the above formula (Id), and a compound of the formula (Id) is obtained, and then a salt and/or a hydrate and/or a solvate of the compound of the formula (Id) is selectively formed. 8. Preparation of a compound of formula (Ie): X is a group selected from SO, S02; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer of 0 to 1; hydrazine is an amine group, alkanesulfonylamino group, halogen; Is optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic; R 2 is phenyl, optionally substituted by alkyl or halogen; by compound of formula (la) '· -121 - 200838865 (15) Wherein X is a group selected from the group consisting of so and so2; Y is not selected from the group of (CH2)n, NH, NHCH2; η is an integer from 0 to 1; hydrazine is a nitro group; is a substituted alkyl group, a cycloalkyl group, a phenyl group, a biphenyl group ; R2 is a phenyl group selectively substituted by a hospital group or a halogen, and reacted with a suitable reducing agent to prepare a compound of the formula (Ie) Ri and R2 are as above (Ie) And optionally forming a salt and/or a hydrate and/or a solvate of the obtained amine derivative, or a. selectively producing an amine derivative of the formula (Ie) wherein the oxime is an amine a group; X, Y, η, R i and R 2 are as defined in the above formula (I e)) with sodium nitrite in hydrochloric acid and copper (I) iodide or copper (I) chloride or copper (I) bromide or The reaction is carried out in the presence of sodium tetrafluoroborate to obtain a compound of the formula (Ie) wherein Z is a halogen, χ, Υ, η, Ri and R2 are as defined in the above formula (le), and then selectively formed. A salt of the halogen derivative of the formula (Ie) and/or a hydrate and/or a solvent -122-200838865 (16), or b. optionally an amine derivative of the formula (Ie) (wherein Z Is an amine group; X, Y, η, Ri and R2 are reacted with an alkylsulfonium chloride derivative as described above in the formula (Ie) to obtain a compound of the formula (Ie) wherein Z is an alkanesulfonylamino group; And hydrazine, 11, 111 and 112 are as defined in the above formula (16), and then selectively form salts and/or hydrates and/or solvents of the obtained alkanesulfonylamino derivative of the formula (Ie). Compound. 9 · A method of preparing a compound of formula (I f): X \ YR! (If) where X is a so2; Y is not selected from the group of (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is an amine group, alkanesulfonylamino group, halogen; Is optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic; R 2 is a selective substituted phenyl, heterocyclic, or NH4 group, wherein R 3 and R 4 are independently selected from hydrogen Or a group optionally substituted with an alkyl group, or R3 and R4 together with the N atom to which they are attached form a selectively substituted Q7 heterocyclic group containing ~ or more heteroatoms, by a compound of formula (V): -123- (17) 200838865 Wherein Ri and Y are reacted with an appropriate oxidizing agent as described in the above formula (If), and the N-oxide of the formula (乂) is produced as a line 1 organism: Br Wherein Ri and Y are reacted with an aqueous solution of nitric acid in acetic acid as described in the above formula (If), and then the nitro derivative of the formula (XI) is prepared: Wherein Ri and Y are reacted with a suitable reducing agent as described in the above formula (If), and the resulting amine derivative is derived from -124 to 200838865. wherein R1 and γ are as defined in the above formula (I f) Said, a · with the compound of formula (IX) in the presence of a base and a catalyst in the solvent (XII) R2-B(OH)2 (IX) wherein R2 is a selectively substituted phenyl group or a heterocyclic group, a compound of the formula (If) is obtained (wherein Z is an amine group; and R2 is a selective substituted phenyl group, a heterocyclic group, Y and Ri are as described in the above formula (If), and thereafter selectively form a salt and/or a hydrate and/or a solvate of the obtained amine derivative of the formula (I f). And (i) selectively producing an amine derivative of the formula (If) wherein Z is an amine group; R 2 is a selective substituted phenyl group, a heterocyclic group, and γ and R 1 are as defined above (If The compound of the formula (If) is prepared by reacting sodium nitrite with hydrochloric acid and copper (I) or copper (I) chloride or copper (I) bromide or sodium tetrafluoroborate. Is a halogen; R 2 is a selectively substituted phenyl group, a heterocyclic group 'Y and Ri are as described in the above formula (If)), and then selectively forms a salt of the halogen derivative of the obtained formula (If) And/or a hydrate and/or a solvate, or (ii) optionally, an amine derivative of the formula (If) wherein Z is an amine group; R 2 is a selective substituted phenyl group, a heterocyclic group , Y and Ri are as above (If The compound of the formula (If) -125-(19) (19)200838865 is prepared by reacting with an alkanesulfonyl chloride derivative, and then selectively forming the obtained alkane sulfonamide of the formula (If) a salt and/or a hydrate and/or a solvate of the base derivative, or b. reacted with a compound of the formula (XIII) at 7 to 200 ° C: NHR3R4 (XIII) wherein R3 and R4 are as defined above (If The compound of the formula (If) wherein Z is an amine group; Y, Ri and the R 2 group of the NR 3 R 4 group are as described in the above formula (If), and then selectively form the obtained formula (If) a salt and/or a hydrate and/or a solvate of an amine derivative, or (i) optionally, an amine derivative of the formula (If) (wherein Z is an amine group; Y, I and R2 of the NR3R4 group are as described in the above formula (If)) and sodium piniumate in hydrochloric acid and copper (I) or copper (I) chloride or copper (I) bromide or tetrafluoroboric acid. The reaction is carried out in the presence of sodium to obtain a compound of the formula (jf) (wherein z is a halogen; Y, R1 and the R2 of the NR3R4 group are as described in the above formula (If)), and then selectively form a formula (If Salts and/or water of halogen derivatives And/or solvate, or (ii) optionally, the amine derivative (wherein Z is an amine group; Y, Ri and the R2 group of the NR3R4 group are as described in the above formula (If)) Reacting with an alkanesulfonyl chloride derivative to obtain a compound of the formula (If) (wherein the Z alkanesulfonylamino group; Y, Ri and the R 2 group which is a NR 3 R 4 group are as described in the above formula (If)), and thereafter Salts and/or hydrates and/or solvates of the alkanesulfonylamino derivative of the formula (If) obtained are formed sexually. 10. A method of preparing a compound of formula (Ig): -126- (20) 200838865 X represents so2; Y is a group selected from (CH2)n, hydrazine, NHCH2; η is an integer from 0 to 1: Ζ is an amine group, a bromo group, a chloro group, an iodine group, a methoxy group, a mono- or dialkylamino group; R 1 is a selectively substituted alkyl group, a cycloalkyl group, a phenyl group, a biphenyl group, a heterocyclic group; R2 is a selectively substituted phenyl, heterocyclic, or NR3R4 group, wherein r3 and r4 are independently selected from a hydrogen or a selectively substituted alkyl group, or R3 and r4 are taken together with the attached N atom. Optionally substituted C5_7 heterocyclyl containing one or more heteroatoms by a compound of formula (X): Br Wherein Ri and lanthanide are reacted with a compound of the formula (IX) in a solvent in the presence of a base and a catalyst as described in the above formula (Ig): RrB(OH)2(IX)-127-(21) 200838865 Wherein R 2 is a selective substituted phenyl or heterocyclic group, and a compound of the formula (XIV) is obtained: (XIV) Wherein R 2 is a selective substituted phenyl group or a heterocyclic group, and Ri and Y are as described in the above formula (I g ) or reacted with a compound of (XIII): NHR3R4 (XIII) wherein R 3 and R 4 are as defined above (Ig), wherein a compound of the formula (XIV) wherein R2 is a NhR4 group, wherein R3 and IU are independently selected from hydrogen or a substituted substituted group, or R3 and R4 are attached thereto The N atoms together form a selectively substituted c5-7 heterocyclic group containing one or more heteroatoms; and a compound of formula (XIV) wherein R!, R2 and γ are as described in formula (Ig) above, and trifluoro Acetic anhydride is reacted in a solvent to obtain a compound of the formula (χν)·· a compound of the formula (XV), wherein Ri, R2 and a lanthanide are as described in the above formula (Ig) -128-200838865 (22), a· is reacted with phosphorus (III) oxybromide to obtain a compound of the formula (Ig), Wherein Z is a bromo group, and X, Y, η, L and R2 are as described in the above formula (ig), and thereafter selectively form salts and/or hydrates of the obtained bromine derivative of the formula (Ig). And/or a solvate; or (i) a bromine derivative of the formula (Ig) (wherein Z is a bromo group; X, Y, η, 1 and R2 are as described in the above formula (Ig)) and potassium fluoride in DMSO In the reaction, a compound of the formula (Ig) wherein Z is a fluorine group, X, Y, n, Ri and R2 are as described in the above formula (Ig), and then selectively formed (Ig) are obtained. a salt of a fluorine derivative and/or a hydrate and/or a solvate; or b. reacting with phosphorus (III) oxychloride to obtain a compound of the formula (Ig) wherein Z is a chloro group, X, Y, η And Ri and R2 are as described in the above formula (Ig)), and thereafter selectively form a salt and/or a hydrate and/or a solvate of the obtained chlorine derivative of the formula (Ig); or (i) a chlorine derivative of the formula (Ig) wherein Z is a chloro group; X, Y, η, Ri and R2 is reacted with potassium fluoride in DMSO according to the above formula (Ig) to obtain a compound of the formula (Ig) (wherein Z is a fluorine group, and X, Y, η, Ri and R2 are as defined above (Ig) And optionally forming a salt and/or hydrate and/or solvate of the obtained fluorine derivative of the formula (Ig); or c. in the presence of methyl iodide in the presence of silver carbonate in the solvent In the reaction, a compound of the formula (Ig) wherein Z is a methoxy group, X, Y, η, Ri and R2 are as described in the above formula (Ig), and then selectively formed (Ig) a salt and/or a hydrate and/or a solvate of a methoxy derivative; or d. reacting with trifluoromethanesulfonic anhydride in a solvent, and then with ammonia or mono--129-200838865 (23) and dioxane By amine reaction, a compound of the formula (Ig) wherein Z is an amine group or a monoalkylamino group or a dialkylamine group, and x, Y, η, R, and r2 are as described in the above formula (Ig), and Thereafter, salts and/or hydrates and/or solvates of the obtained methoxy derivative of the formula (Ig) are selectively formed. 11. A method of preparing a compound of formula (Ih): N〆Y-R| (Ih) wherein X represents so2; Y represents a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is an amine group, a hydroxyl group, a bromo group, a chloro group, a fluorine group, a methoxy group a mono-, mono- or dialkylamino group; R! is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic; R2 is a selective substituted phenyl, heterocyclic, or NR3R4 a group wherein R3 and R4 are independently selected from hydrogen or a selectively substituted group' or R3 and r4 together with the attached N atom form a selectively substituted heterocyclic group containing one or more Atom, by compound of formula (XIV): -130- (24) (24)200838865 a reaction with phosphorus (III) oxychloride or phosphorus pentachloride to obtain a compound of the formula (Ih) wherein Z is a chloro group, and X, Y, n, Ri and R 2 are as described above in the formula (Ih), Or b. reacting with phosphorus (III) oxybromide to obtain a compound of the formula (Ih) wherein Z is a chloro group, hydrazine, ¥, 11, 111 and 2 are as described above in the formula (11) and thereafter Salts and/or hydrates and/or solvates of the obtained (Ih) chloro or bromo derivatives, wherein Z is a chloro or bromo group; X, Y, η, I and R2 are formed sexually. Or (i) a chloro or bromo derivative of the formula (Ih) wherein Z is a chloro or bromo group; X, Y, η, Ri and R2 are as defined above (Ih) Said) reacting with potassium fluoride in DMSO to obtain a compound of formula (Ih) wherein Z is a fluoro group, X, Y, η, Ri and R2 are as described above in formula (Ih), and thereafter selected To form a salt and/or a hydrate and/or a solvate of the obtained fluorine-based derivative of the formula (Ih); or (ii) a chloro or bromo derivative of the formula (Ih) (wherein Z is a chloro group or a bromo group; X, Y, η, Ri and R2 are as described above in the formula (Ih) and sodium methoxide The reaction is carried out in methanol to obtain a compound of the formula (Ih) wherein Z is a methoxy group, X, Y, η, Ri and R2 are as described above in the formula (Ih), and then selectively forms the obtained formula ( Ih) a salt and/or a hydrate of a methoxy derivative and/or a solvate, or (iii) a chloro or bromo derivative of the formula (Ih) wherein Z is a chloro group or a bromo group; X, Y, η, Ri and R2 are reacted as described above in the formula (Ih) with sodium acetate in acetic acid to obtain a compound of the formula (Ih) wherein Z is a hydroxyl group, X, Y, η, R And R2 are as described in the above formula (Ih)), and then selectively form salts and/or hydrates and/or solvates of the obtained hydroxy derivative of the formula (Ih), or (iv) Ih) a chloro or bromo derivative (wherein Z is a chloro or bromo group; X, Y, n, Ri and R2 are as described above in the formula (Ih)) and trifluoromethanesulfonic anhydride are reacted in a solvent, and then Reaction with ammonia or mono- and dialkylamine to obtain a compound of the formula (I h ) wherein Z is an amine group or a single compound amine or a dialkylamine group, and X, Y, η, I and R 2 are as defined above. (Ih) as described in 'and after selectivity Forming the salts and/or hydrates and/or solvates of the methoxy derivatives of the formula (Ih) obtained, wherein Z is an amine group or a monoalkylamino group or a dialkylamino group, respectively; or (v) Ih) a chloro or bromo derivative (wherein Z is a chloro or bromo group; X, Y, η, Ri and R2 are as described above in the formula (Ih)) and reacted with sodium azide in DMF and water. A compound of the formula (Ih) wherein Z is an azide group, X, Y, η, Ri and R2 are as defined in the above formula (Ih), and then the obtained azido derivative and sodium borohydride are used in a solvent The intermediate reaction 'produces a compound of the formula (Ih) (wherein Z is an amine group, X, Y, η, Ri and R2 are as described above in the formula (Ih)), and then selectively forms the obtained formula (Ih) Salts and/or hydrates and/or solvates of amine derivatives. 1 2. A pharmaceutical composition comprising a therapeutically effective amount of the formula (1) -132- 200838865 (26) compound: Wherein X is a group selected from the group consisting of SO and S02; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is a fluorene or a single occurrence of an alkyl group, a nitro group, Halogen, alkoxy, trifluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxy, alkanesulfonamide R; is optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic; R2 is a selective substituted phenyl, heterocyclic, or NR3R4 group, wherein R3 and R4 are independent a group selected from hydrogen and a selectively substituted alkyl group, or R3 and R4 together with the attached N atom form a selectively substituted C5_7 heterocyclic group containing one or more heteroatoms, or NH-CO- a NR5R6 group, wherein 5 and R6 are independently selected from the group consisting of hydrogen and a selectively substituted alkyl group, or R5 and R6 together with the attached N atom form a selectively substituted C5_7 heterocyclic group, which comprises one or a plurality of heteroatoms: and/or hydrates and/or solvates thereof and/or pharmaceutically acceptable salts thereof formed with an acid or a base, and one or more physiologically acceptable dilutions , Excipients and / or inert -133- (27) (27) 200 838 865 of the carrier. A pharmaceutical composition according to claim 12, which is for use in the prevention and/or treatment of disorders of the mGluR1 and mGluR5 receptor mediators. 14. Use of a compound of the following formula (I) for the manufacture of a medicament for the treatment and/or prevention of disorders of the mGluR1 and mGluR5 receptor mediators, X is a group selected from SO, S02; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is a fluorene or a single occurrence alkyl, nitro, halogen , alkoxy, trifluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxy, alkanesulfonylamino Ri is a selectively substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclic group; R2 is a selective substituted phenyl group, a heterocyclic group, or an NR^4 group, wherein R3 and R4 are independent a group selected from hydrogen and a selectively substituted group, or R3 and r4 together with the attached N atom form a selectively substituted C5_7 heterocyclic group containing one or more heteroatoms, or NH-CO- NRsFU group, wherein the ulmen 5 and r6 are independently selected from the group consisting of hydrogen and a selectively substituted group, or Rs and R6 together with the attached n atom -134-200838865 (28) form a selective substituted Cs_7 a cyclic group comprising one or more heteroatoms; and/or a hydrate thereof and/or a solvate thereof and/or a pharmaceutically acceptable salt thereof formed with an acid or a base. 15. The use of the fourth aspect of the patent application, wherein the disorder of the mGluR1 and mGluR5 receptor mediators is a mental disorder. 16. The use of claim 14 wherein the disorders of the mGluRl and mGluR5 receptor mediators are neurological disorders. 17, the use of claim 14 of the scope of the patent, wherein the disorders of the mGluRl and mGluR5 receptor mediators are chronic and acute pain. 18. The use of the fourth aspect of the patent application, wherein the mGluRl and mGluR5 receptor mediator disorders are lower urinary tract neuromuscular dysfunction and gastrointestinal disorders. A pharmaceutical composition for preventing and/or treating a disorder of mGluR1 and mGluR5 receptor media for use in a mammal in need of such prevention and/or treatment comprising a therapeutically effective amount of a compound of formula (I): Wherein X is a group selected from the group consisting of so and so2; Y is a group selected from (CH2)n, NH, NHCH2; η is an integer from 0 to 1; Ζ is a fluorene or a single occurrence of an alkyl group, a nitro group, Halogen, alkoxy, tri-135- 200838865 (29) fluoromethyl, cyano, amine, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl , hydroxy, alkanesulfonylamino; Ri is a selective substituted alkyl, cycloalkyl, phenyl, biphenyl, anthracenyl; R 2 is a selective substituted phenyl, heterocyclic, or nr3r4, Wherein r3 and r4 are independently selected from the group consisting of hydrogen and a selectively substituted alkyl group, or r3 and r4 are taken together with the attached N atom to form a selectively substituted c5-7 heterocyclic group, which comprises one or more a hetero atom, or a NH-CO-NR5R6 group, wherein the quaternary 5 and R6 are independently selected from the group consisting of hydrogen and a selectively substituted alkyl group, or R5 and R6 together with the attached N atom form a selective substituted C5_7 A heterocyclic group containing one or more heteroatoms; and/or a hydrate thereof and/or a solvate thereof and/or a pharmaceutically acceptable salt thereof formed with an acid or a base. 20. The pharmaceutical composition of claim 19, wherein the mammal is a human. 2 1. The pharmaceutical composition according to claim 19, wherein the disorder of the mGUR1 and mGluR5 receptor vectors is a mental disorder. 4 22. The pharmaceutical composition according to claim 19, wherein "the disorder of the mGluRl and mGlnR5 receptor vectors is a neurological disorder. 2 3. The pharmaceutical composition of claim 19, wherein mGluRl And the disorder of the mGluR5 receptor vector is a chronic and acute pain disorder. -136- 200838865 (30) 24. The pharmaceutical composition of claim 19, wherein the mGluRl and mGluR5 receptor mediators are under the disorder Urinary tract neuromuscular dysfunction and gastrointestinal disorders. 137- 200838865 VII. Designation of the representative representative: (1) The representative representative of the case is: None (2) The symbol of the representative figure of this representative figure is simple: None 8. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention = formula (I) X \ Y-R!