TW201029987A - Novel compounds - Google Patents

Abstract

The present application discloses novel benzimidazole derivatives and their use as modulators of the GABAA receptor complex. In other aspects the application discloses the use of these compounds, in a method for therapy and to pharmaceutical compositions comprising these compounds.

Description

201029987 6. Description of the Invention: [Technical Field] The present invention relates to novel benzimidazole derivatives, pharmaceutical compositions containing such humans, and methods of using the same. The compounds of the invention are useful in the treatment of central nervous system diseases and conditions that modulate GABAa receptor complexes' and are particularly useful for combating eschar and related diseases. [Prior Art] A regulatory site on the GABAa receptor complex (such as a benzodiazepine call site) is the target of an anxiolytic agent such as the classical anxiolytic benzodiazepine. However, 'classic anxiolytic benzodiazepines and a variety of adverse characteristics. There are a plurality of isomeric isomers of the GABAA receptor; each receptor is a pentameric complex comprising a subunit of the η γ 丨-3, δ, ... subunit isomeric isomers. Classic anxiolytic benzodiazepines do not exhibit subtype selectivity. A key element of the classical benzodiazepine disadvantages (such as sedation, dependence, and cognitive impairment) has been shown to be associated with the alpha 1 subunit of the GABAa receptor. Therefore, compounds which are expected to have selectivity to the heart and/or α3 subunits greater than the selectivity to the d subunits have improved side effect characteristics. Therefore, there is an urgent need for a combination of the best pharmacological characteristics, and it is urgent to find that there is no correlation with the non-five people of the existing characters...-w c°mp°und. An effective compound for the side effects of human beings. SUMMARY OF THE INVENTION In a first aspect of the invention, the invention provides a formula [compound: 201029987]

HO

Or a nitrogen oxide, any stereoisomer thereof, or any mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is as defined below. In a second aspect of the invention, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or an oxynitride thereof, any isomer thereof, or any mixture thereof, or a pharmaceutical thereof An acceptable salt and at least one pharmaceutically acceptable carrier, excipient or diluent. In another aspect, the invention provides the use of a compound of the invention, or an oxynitride thereof, any stereoisomer thereof, or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, for use in the manufacture. A pharmaceutical composition for treating, preventing or ameliorating a disease or condition or condition in a mammal, including a human, which is responsive to modulation of a GABAa receptor complex. In another aspect, the invention relates to a method of treating, preventing or ameliorating a disease or condition or condition of a living subject, including a human, which response to modulation of a GABAa receptor complex, The method comprises the steps of administering to the active subject in need thereof a therapeutically effective amount of a compound of the invention or an oxynitride thereof, any stereoisomer thereof, or any mixture thereof, or pharmaceutically acceptable thereof Salt. Other objects of the present invention will become apparent to those skilled in the art from the following detailed description and embodiments. [Embodiment] Substituted Benzimidazole Derivative 1 In the first aspect of the present invention, the present invention provides a formula:

Or an oxynitride, any isomer thereof, or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein R represents phenyl; the phenyl group is optionally selected from one or more The substituents of the following group are substituted: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, hydroxyalkyl and alkoxy. In a specific example of the compound of the formula (I), R represents a phenyl group substituted by one or more substituents independently selected from the group consisting of a functional group, a cyano group, a hydroxyalkyl group and an alkoxy group. . In another specific example of the compound of formula (I), R represents 5 201029987

Wherein R1, R2, R3, R4 and R5 independently of each other represent hydrogen, a dentyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a transalkyl group or an alkoxy group. In another embodiment, R1 represents hydrogen. In another embodiment, R1 represents a cyano group. In another embodiment, R1 represents a halo group, such as a gas. In another embodiment, R1 represents an alkoxy group, such as methoxy. In another embodiment, R2 represents hydrogen. In another embodiment, r2 represents a cyano group. In another embodiment, R2 represents a hydroxyalkyl group such as a hydroxyethyl group such as 1-hydroxy-ethyl. In another embodiment, R2 represents a halo group such as fluorine. In another embodiment, R3 represents hydrogen. In another embodiment, R3 represents a halo group such as fluorine or gas. In another embodiment, R4 represents hydrogen. In another embodiment, R4 represents a halo group such as fluorine. In another embodiment, R4 represents an alkoxy group, such as a decyloxy group. In another embodiment, R4 represents a cyano group. In another specific example of the compound of formula (I), R represents

Wherein R1 represents a halogen group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. 201029987 In another embodiment, R1 represents a cyano group. In another specific example of the compound of formula (I), R represents

Wherein R2 represents a halogen group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, a alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. In another embodiment, R2 represents a cyano group. In another embodiment, R2 represents 1-hydroxy-ethyl. In another specific example of the compound of the formula (I), the ruler represents

Wherein R1 and R2 independently of each other represent a functional group, a trifluoromethyl group, a trifluorodecyloxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. In another embodiment, Ri represents a cyano group. In another example, R2 represents a letter, such as said.

❹ wherein R and R3 independently of each other represent a halo group, a trifluoroindolyl group, a trifluoroindolyl group, a cyano group, a nitro group, a county group 1, a decyl group or an alkoxy group. In another embodiment, R1 4 represents a cyano group. In another embodiment, R1 represents a halo group, such as a gas. 7 201029987 In another embodiment, R3 represents a halogen group, such as fluorine or gas. In another embodiment of the compound of formula (I), R represents W t

Wherein R1 and R4 independently of each other represent a halogen group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. In another specific example, the 'R1' represents a functional group such as gas. In another embodiment, R1 represents an alkoxy group, such as a decyloxy group. In another embodiment, R4 represents a functional group, such as fluorine. In another 1 : an example shows an alkyloxy group such as a methoxy group. In another embodiment, R is not a base. In another embodiment, R1 represents (d), such as chaos' and R4 represents cyano. In another specific example of the compound of the formula (I), r represents 2_"gas-phenyl, 4-chloro-2-hydrogen-phenyl, 2-nitrox-4-phenylene, 2-gas巧_methoxy-styl '2-cyano-phenyl, 3-yl-phenyl-phenyl, 2-cyano small fluoro-phenyl, 5-fluoro-2-indolyl-phenyl or 3-((丨_Hydroxy-ethyl) _ phenyl. In another embodiment, 'the compound of the invention is 2-(tetra)·(1-trans-U-fluorenylethyl)-benzo]m-based}- Nitrile; 3-{6-[5-(1-hydroxy-1-indolyl-ethylbenzopyrene); and *"基一_ 2-U-{6-[3-(W Paint B Base) phenyl]_. ratio. 士士基b ih_benzoxazol-5-yl)-propan-2-ol; 201029987 2-{1_[6 benzene-5-methoxy phenyl) , pyridine winter base]_ιη_ stupid and microphone. Sodium-5-yl}-propan-2-ol; '2 {1 [6-(5-fluoro-2-methoxy-phenyl)_〇比唆_2 base]_ιη笨和米峻-5_ 2-{1-[6-(2-Ga-4-fluorophenyl)_npyridin-2-yl]_1Η•benzoxazole_5_yl}-propan-2- Alcohol; 4-gas-3-{6-[5♦ mercapto]•methyl_ethyl)-benzene (tetra) saliva < pyridin-2-yl}- benzoic nitrile; 2-peak peak [5-( 1-hydroxysuccinyl-ethyl)-benzimidazole small acridine-2-yl}-benzonitrile; 5-gas-2-{6-[5-(1-carbylmethyl-ethyl) _Benziminyl succinylpyr bromide-2-yl}-stupole carbonitrile; 2-[1-[6-(2-phenylphenyl)_2_Dtb dimethyl]benzo-. Or a nitrogen oxide, any stereoisomer or mixture thereof, a basket structure or a pharmaceutically acceptable salt thereof. It is considered that two or more of the above specific examples are within the scope of the invention. The definition of the terms in this statement is as specified in this specification and the accompanying patent application. The following terms are used to scare the term “r-alkyl, branched or straight-chain _ Α "" Atomic and sulfhydryl groups of the atom, for example, c] 3 alkyl, phenyl, C 2.6 alkyl, c -7 -formyl, C 丨 6 arcane, and the like. Representative examples are Yinji, 201029987 ethyl, propyl (eg, $^w^prop-1-yl, prop-2-yl (or isopropyl is 'butyl) such as 2-methylpropan-2-yl Γ讳筮 _ _, butyl, sec-butyl, butyl-1-yl, butyl-2-yl, pentyl (eg pent-1-yl, quinone 9 ^ -pent-2-yl, Pentyl-3-yl), 2-methylbutanyl, 3-methylbut-1-yl, hexyl (eg hex-1-yl), heptyl (eg hept-1-yl), octyl (例士辛1基), thiol (such as 壬-1 -yl) and the like. The ridge or hal〇gen means fluorine, gas, desert or angstrom The term "radical J" shall mean the group -CN. The term "shawyl" shall mean the group -N〇2. The term 1 group shall mean the group -OH. The term "hydroxyalkyl" as used herein. • * -i Ά , 4 Substituted by a radical — or multiple U radicals. Representative examples are methyl, ethyl (e.g., ethyl, 2, ethyl) and the like. The term "alkoxy" as used herein refers to a group of 6 alkyl groups. Representative examples are methoxy, ethoxy, propoxy (eg i- Oxyl, Woxy), Butanyl (e.g., !·butoxy, 2·butoxy, 2_fluorenyl-2-propoxy), pentamidine (1-pentamethylene, 2·pentyloxy) , hexyloxy U-hexyloxy, 3-hexyloxy) and the like. The term "optionally substituted" as used herein means that the group in question, substituted or substituted with one or more specified substituents. When the group in question is substituted with a substituent above the substituent, the substituents may be the same or different. ^ Some defined terms may appear more than once in the structural formula, and when more than one occurrence occurs, the terms should be defined independently of each other. The term "treatment" as used herein means the management and care of a patient for the purpose of combating a disease, condition 201029987 or condition. The term is intended to include delaying the progression of a disease, condition or condition, slowing or alleviating symptoms and complications and/or healing or eliminating the disease, condition or condition. The patient to be treated is preferably a mammal, especially a human. As used herein, the terms "disease", "condition ((3) is raised)" and "disorder" are used interchangeably to refer to a state in which a patient is not in a normal physiological state.

The term "drug" as used herein means a pharmaceutical composition suitable for administering a pharmaceutically active compound to a patient. The term "pharmaceutically acceptable" as used herein means suitable for normal medical applications, i.e., does not cause adverse events in a patient, and the like. The term "effective amount" as used herein means a dose sufficient to effect treatment of a patient as compared to no treatment. As used herein, the term "therapeutically effective amount" of a compound means summer which is sufficient to cure, slow or partially arrest the clinical manifestations of a given disease and its complications. The amount sufficient to achieve this is intended to be a "therapeutically effective amount." The effective amount for each purpose will depend on the severity of the disease or injury and the weight of the individual: the general condition. It will be appreciated that routine experimentation can be used to determine the appropriate dose from the matrix of the constructive values and the test matrix, all within the general skill of the trained physician or veterinarian. _ pharmaceutically acceptable salts The compounds of the invention may be provided in any form suitable for the desired compound, including the compounds of the invention. Appropriate salt and prodrug form. ^乐予上 (i.e., Physiological Magic 201029987) Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic acids and organic acid addition salts, such as hydrochloride derived from hydrochloric acid, derived from Hydrobromide of hydrobromic acid, nitrate derived from nitric acid, peroxyacid salt derived from peroxyacid, phosphate derived from phosphoric acid, sulfate derived from sulfuric acid, formate derived from formic acid, derived from Acetate from acetic acid, aconitate derived from acinic acid, ascorbate derived from ascorbic acid, besylate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamon derived from cinnamic acid An acid salt, a citrate derived from citric acid, an enpot acid salt derived from en-poic acid, a heptanoate derived from heptanoic acid, a fumarate derived from a counter-butyl succinic acid, derived from A glutamic acid glutamate, a glycolate derived from glycolic acid, a lactate derived from lactic acid, a maleate derived from cis-butyl diacid, and a malonate derived from malonic acid , derived from mandelic acid of mandelic acid, derived from methane sulfonate Acid methanesulfonate, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, phthalic acid salt derived from phthalic acid, salicylate derived from salicylic acid, a sorbate derived from sorbic acid, a stearate derived from stearic acid, a succinate derived from succinic acid, a tartrate derived from tartaric acid, and a p-toluene derived from p-toluenesulfonic acid ◎ Acid salts and the like. These salts can be formed by procedures well known and described in the art. Other acids which may not be considered pharmaceutically acceptable, such as oxalic acid, may also be suitable for the preparation of the compounds of the present invention. And pharmaceutically acceptable salts of the intermediates of the acid addition salts. Examples of pharmaceutically acceptable cationic salts of the compounds of the invention include, but are not limited to, sodium salts of the compounds of the invention containing anionic groups , potassium 12 201029987 salt, calcium salt, magnesium salt, zinc salt, aluminum salt, lithium salt, choline salt, lysinium sait salt and ammonium salt and the like. These cationic salts can be used by this technology The process of knowing and interpreting is formed in the present invention. The "salt salt" of the nitrogen-containing compound is also a pharmaceutically acceptable salt. Preferred "onium salt" includes alkyl rust salts: cycloalkyl phosphonium salts and cycloalkyl alkyl phosphonium salts. Examples of prodrug forms of the compounds include examples of suitable prodrugs of the materials of the invention 'comprising compounds modified at the parent compound or at a plurality of reactive or derivatable groups. Modification of the group, hydroxyl or amine group Compounds of interest are of interest. Examples of suitable derivatives are vinegar or awake amine. The compounds of the invention may be provided in a soluble form or insoluble form together with a pharmaceutically acceptable solvent such as water, ethanol and the like. Soluble forms may also include hydrated forms such as monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like. Generally, for the purposes of the present invention, soluble forms are considered to be etc. Works in an insoluble form. Stereoisomers It will be appreciated by those skilled in the art that the compounds of the invention may be in the form of different stereoisomers, including enantiomers, diastereomers and cis and trans isomers. The present invention includes all such stereopsis. Isomers and any mixtures thereof (including racemic mixtures). The optical isomer resolution methods known to those skilled in the art can be used, and these methods are common to the museum. It will be obvious to each technician. These methods include J. Jaques, A. C〇Uet « Q "r . t and S. Wilen, "Enantiomers,

Racemates, and Resolutions , T u . ", John Wiley and Sons, New 13 201029987

The method discussed in York (1981). Optically active compounds can also be prepared from optically active starting materials. Nitrogen Oxide In the case of the present invention, nitrogen oxides represent tertiary amines (including aromatic nitrogen heterocyclic compounds, non-aromatic nitrogen heterocyclic compounds, trialkylamines and tri-glycosylamines f atoms) t-oxidative derivatives Things. For example, the nitrogen oxide of the pyridyl group-containing compound may be an oxy-pyridine-2-yl group, a 3-based group and a 4-based derivative. The nitrogen oxides of the compounds of the present invention can be prepared by oxidizing a corresponding nitrogen base in the presence of an acid such as acetic acid at an elevated temperature using a conventional oxidizing agent such as hydrogen peroxide, or by using a suitable solvent ( For example, a compound which is reacted with a peracid (such as peracetic acid) or a reaction of oxime 3 - gas oxybenzoic acid in a gas-like or dichlorosilane, for example, in the form of dichloromethane, ethyl acetate or methyl acetate. The compound can be used in its labeled or unlabeled form. In the context of the present invention, one or more atoms of the labeled compound differ from the atomic mass or mass number of atoms typically found in nature by atomic mass or mass number. Labeling will allow the compound to be readily quantified.

The labeled compounds of the invention are useful as diagnostic tools, radiotracers or monitors in a variety of diagnostic methods and are suitable for in vivo receptor imaging. The labeled isomers of the invention preferably contain at least one radionuclide as a label. All positron-emitting radionuclides are available candidates. In the case of the present invention, the radioactive nucleus is preferably selected from the group consisting of 2H(4), J 201029987, and the physical method of the isomer is selected from the positron emission tomography method (ΡΕτ). , single photon imaging computed tomography (SPECT), magnetic resonance spectroscopy (mrs), magnetic resonance imaging (Gu) and computerized axial tomography or a combination thereof. The preparation method can be used to cut off the water supply by a conventional method of chemical synthesis (for example, the method described in the examples). The starting materials used in the methods described in this application are known or *5Γ 4丨丨m qsi m 1 π 耵 and are readily prepared from commercially available chemicals by conventional methods. A compound of the invention may also be converted to another compound of the invention by conventional methods. The end products of the reactions described herein can be separated using conventional techniques (e.g., extraction, crystallization, distillation, chromatography, etc.). The compounds of the invention may be in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. As usual, for the purposes of the present invention, the solvated form is considered equivalent to the V unsolvated form. 'Biological activity The compounds of the invention are capable of modulating the GABAa receptor complex. The ability of these compounds to bind to GABAa receptor complexes, including their specific subunits, can be tested. Therefore, the compound of the present invention (a ligand of a benzodiazepine binding site on the gabaa receptor) is suitable for the treatment and/or prevention of various central nervous system diseases and disorders outside the central nervous system. Thus, in another aspect, the compound of the present invention is considered to be useful for treating, preventing or ameliorating diseases, disorders that modulate gabAa steroid complexes, particularly GABAa receptor complexes in the middle sacral nervous system. Or condition. In another embodiment, the compound of the invention is a ligand for a GABAa receptor complex external to the central nervous system. In a specific example, 'the compound of the invention is considered to be suitable for treating, preventing or ameliorating anxiety; panic disorder with or without phobia; phobia without history of panic disorder; phobia; animal phobia; social phobia; Obsessive-compulsive disorder (OCD); generalized anxiety disorder; substance-induced anxiety disorder; stress disorder; post-traumatic stress disorder, parting anxiety disorder; acute stress disorder; sleep disorder; memory disorder; neuropathy; spasticity disorder; epilepsy; (seizure); 痉挛; child enthusiasm; affective disorder; depression; bic〇lar disorder; depression; major depression; single episode of major depression; recurrent major depression; Dis〇rder ); bipolar disorder; mania; type II hyperpolar disorder (bipolar ϊ manic disorder); delirium type hypermania; circulatory affective disorder; psychosis; schizophrenia; cognitive disorder Insufficient learning; memory loss and dysfunction; dementia; lack of attention; attention deficit hyperactivity disorder (ADHD); Down's syndrome; Tourette's syndrome; Alzheimer's disease; Parkinson's disease; Huntington's disease; Pick's disease; Creutzfeldt-Jakob disease; cognitive impairment; schizophrenia s lack of tolerance 'plucking ticks; stuttering; systemic tic disorder; muscle tightness 201029987 barriers; cerebral ischemia; stroke; head trauma; Blood-induced neurodegeneration; pain consisting of acute pain, chronic pain, mild pain, moderate or severe pain, postoperative pain, neuropathic pain, central neuropathic pain, and diabetic neuropathy, postherpetic neuralgia, Peripheral nerve injury, prosthetic pain, muscle fiber pain, pain associated with chronic regional pain syndrome, somatic pain, visceral pain or skin pain, pain caused by inflammation or infection, and osteoarthritis, rheumatoid arthritis ❹related pain, neuronal hyperexcitability, peripheral nerve hyperexcitability, chronic headache, migraine, head Related conditions, tension headache; pain irritating vomiting; acute, delayed and expected vomiting; specific vomiting induced by chemotherapy or radiation; motion sickness; postoperative nausea; vomiting; eating disorders, eating disorders; Weight gain; anorexia nervosa; bulimia nervosa 'Healthy food obsessive-compulsive disorder (0rth0rexia nervosa); binge eating disorder (BED), menstrual syndrome; neuralgia; trigeminal neuralgia; muscle spasm; Drug spillover or dependence; alcohol withdrawal; ❿ ❿, circadian rhythm disorder; individual circadian rhythm disorder caused by jet lag or shift; diabetes; type i diabetes; type 2 diabetes; hyperinsulinemia, Dyslipidemia; hyperlipidemia; inflammatory disease or autoimmune disorder. In another embodiment, the compound is considered to be useful for treating or slowing down, considering, for example, anxiety, panic disorder with or without fear, panic disorder without panic disorder, phobia, animal phobia, social fear Symptoms, obsessive-compulsive disorder, generalized anxiety disorder, substance-induced anxiety, stress disorder, post-traumatic stress disorder, parting anxiety disorder, acute stress disorder or sleep disorder. In another embodiment, the compound is considered to be suitable for treating or slowing anxiety. In another embodiment, the compound is considered to be useful for treating or slowing pain, such as acute pain 'chronic pain, mild pain 'moderate or severe pain, neuropathic pain, central pain' and diabetic neuropathy, post-herpetic nerve Pain, pain associated with peripheral nerve injury, somatic pain, visceral pain or skin pain, pain caused by inflammation or infection, postoperative pain, prosthetic pain, excessive hyperesthesia of the nerves, excessive excitation of the peripheral nerves, chronic headache, Migraine, migraine-related illness or tension-type headache. In another embodiment, the compound is considered to be useful for treating or slowing pain. In another embodiment, the compound is considered to be useful for treating or slowing schizophrenia, cognitive disorders, lack of learning, memory loss and dysfunction, therapy, lack of attention, attention deficit hyperactivity disorder (ADHD), Down syndrome, Tourette's syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, cognitive impairment, cognitive deficits in schizophrenia, plucking, Oral fistula, systemic tic disorder, muscle tone disorder, cerebral ischemia, stroke head trauma, neurodegeneration caused by cerebral ischemia. In another specific embodiment, the compounds are considered to be useful for treating or slowing schizophrenia. Further, the compounds of the present invention are useful as radioligands in assays for detecting compounds capable of binding to human GABAa receptors. It is now contemplated that a suitable dose of the active pharmaceutical ingredient (API) is from about 1 mg to about 10 mg of API per day, more preferably from about 1 mg to about 5 mg Api per day, and from about 30 mg to about 1 day for the best mother. Within the range of 〇mg API, however, the appropriate dosage will depend on the precise mode of administration, the form of administration, the indications being considered, the weight of the individual involved, and especially the individual involved, and the preferences and experience of the attending physician or veterinarian 18 201029987. Pharmaceutical Compositions In another aspect, the invention provides a novel pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. ❹ ❹ Although the compound of the invention for use in therapy A can be administered as a raw compound, preferably with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical auxiliaries. The active ingredient in the form of a physiologically acceptable salt is optionally introduced in the form of a pharmaceutical composition. In a preferred embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, and - or a plurality of pharmaceutically acceptable carriers, and optionally Other therapeutic and/or prophylactic ingredients known and used in the art. The carrier must be "acceptable" to mean that it is compatible with the other ingredients of the formulation and not deleterious to the recipient. μ The pharmaceutical composition of the present invention may be suitable for oral, transrectal, bronchial, nasal, transpulmonary, phlegm, and uterine.卩 (including buccal and sublingual), percutaneous (plus... leg 1), transvaginal or parenteral (including eutaneous, subcutaneous, intramuscular, intraperitoneal, intra-membranous, intra-venous, arterial) Internal, intracerebral, intraocular, or infusion) pharmaceutical composition administered, (d) suitable for inhalation or inhalation 1: (including powder and liquid aerosol administration... continuous release system The solid of the compound of the present invention is only a semi-permeable matrix of a polymer of ruthenium, and the matrix such as ruthenium may be in the form of a shaped article such as a film or a microcapsule. Therefore, the compound of the present invention can be formulated into a medicine together with the compound of the present invention. Composition of the form 1 彳 or thinner 珉 form and its unit dosage form. These forms include 201029987 solid 'and especially for tablets, filled capsules, powders and granules, and liquids', especially aqueous or non-aqueous solutions, Suspensions, emulsions, ugly agents and filled capsules thereof, all of which are used orally; suppositories for rectal administration; and sterile injectable solutions for parenteral use. The dosage form may contain conventional ingredients in the conventional proportions (with or without other active compounds or ingredients), and such unit dosage forms may contain any suitable effective amount of active ingredient commensurate with the intended daily dosage range to be employed. A variety of oral and parenteral dosage forms can be administered. It will be apparent to those skilled in the art that the following dosage forms may comprise a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention as an active ingredient. The pharmaceutically acceptable carrier can be a solid or a liquid. The solid form preparation includes a powder, a lozenge, a pill, a capsule, a cachet, a test, and a dispersible granule. The solid carrier can be a Or a plurality of substances which can also act as a diluent, a flavoring agent, a solubilizing agent, a monthly/salt agent, a suspending agent, a binder, a preservative, a key disintegrating agent or a capsule. For a powder, the carrier is a fine powder. a fine powder in which the active ingredient is mixed. For a tablet, the active ingredient is mixed with a carrier having the necessary binding ability in a suitable ratio and pressed into a desired shape. And the size of the powder and the lozenge preferably containing 5% or 10% to about 70% of the active compound suitable for the carrier of magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, cellulose, Starch, gelatin, tragacanth, decyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. The term "preparation" is intended to include the active compound and the carrier as a carrier. A formulation of a sealant that provides an active ingredient (with or without a carrier) in a capsule surrounded by a carrier, such that the carrier is combined with the active component. Similarly, it includes a flat gel and a mouth-containing bond. A key, a powder Capsules, pills, cachets and buccal preparations can be used in solid form suitable for oral administration. In the preparation of suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and The active ingredient is dispersed therein by scrambling. The molten homogeneous mixture is then poured into a mold of suitable size to cool and solidify. Compositions suitable for vaginal administration may be in the form of a pessary (p y y), tampon, cream, gel, paste, in addition to the active ingredient, as well as suitable carriers known in the art. , foam or spray. The liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solution, and 5, a solution for parenteral injection of a liquid preparation in an aqueous solution of a glycol. The compound of the present invention can be formulated for parenteral administration (for example,, for example, rapid injection or continuous infusion), and can be supplied to the ampule in unit dosage form with the humic agent. Pre-filled infusion or multi-dose preparation Φ 'small volume agent in the barrier. The composition may be used in the following oily or aqueous vehicle, such as L solution, solution or emulsion, and may contain a chemical agent, such as a suspending agent, a compounding agent, and/or a stabilizer. Dispersant. Alternatively, the active ingredient may be obtained by sterile separation of sterile solids or by the use of a suitable vehicle for the preparation of a suitable medium (e.g., sterile pyrogen-free water). "Set the original powder 21 201029987 An aqueous solution suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable coloring agents, flavoring agents, stabilizers and thickening agents as needed. Aqueous suspensions suitable for oral use can be obtained by the finely divided active ingredient with viscous f (such as natural or synthetic gums, resins, methylcellulose, sodium methacrylate or other well known suspending agents) - The starting point (4) is prepared in water. Also included are solid form preparations which are intended to be converted to liquid form preparations for oral administration shortly before use. These liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, preparations such as & may also contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents and the like. For topical administration to the epidermis, the compounds of the invention may be formulated as ointments, creams or lotions or as a transdermal patch. For example, ointments and creams may be added with a suitable thickening agent and/or gum (iv) m aqueous or oily matrix. The lotion may be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersing agents, materials, additives, or colorants.组合 Compositions suitable for topical administration in the mouth include: buccal tablets containing the active π' in a flavoring base (usually sucrose and gum arabic or tragacanth) which are included in the inert group # (such as gelatin and glycerin or Severe sugar and: active ingredients in the evening; and mouthwashes, which are contained in a suitable liquid carrier. The solution or suspension is applied directly to the nasal cavity by conventional means, for example, using a dropper, pipette or spray. The composition may be provided in a single form. The early human agent summer form or multiple doses 22 201029987 Administration to the respiratory tract may also be achieved by means of an aerosol formulation, wherein the active ingredient is combined with a suitable propellant (such as a gas fluorocarbon (), for example _ chlorodifluoromethane: 3⁄4, tri-fluorofluoromethane or di-tetrafluoroethane; carbon dioxide: or other suitable gas to be supplied in pressurized packaging. Aerosols also contain ^ surfactants (such as (d) lipid drug dose Alternatively, the active ingredient may be provided in the form of a dry powder, for example, a compound in a suitable powder base (such as lactose, starch, starch derived & (such as hydroxypropyl) The powder mixed in the cellulose) and the polyethylene (IV)_(PVP) are preferably formed into a gel in the nasal cavity. The powder composition may be in a unit dosage form: for example, gelatin can be administered by means of an inhaler, for example, gelatin. In a capsule or cartridge or blister pack. For compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size, for example about 5 microns or less. The diameter can be obtained, for example, by micronization, as is known in the art. For example, a composition suitable for providing sustained release of the active ingredient can be used. The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a package preparation containing discrete quantities of preparations, such as those included in the retort, capsules and vials or ampoules. The unit dosage form may be a capsule, a lozenge, a flat gel or a mouth-containing tablet itself, or it may be any suitable unit dosage form in the form of a sentence. 23 201029987 In one embodiment, the invention provides a lozenge or capsule for oral administration. In another embodiment, the invention provides a liquid for intravenous administration and continuous infusion. Additional details regarding the formulation and administration techniques can be found in new

Remington s Pharmaceutical Sciences (Maack Publishing, Easton, PA). The dose to be administered must of course be carefully adjusted according to the following factors: the age, weight and condition of the individual to be treated, as well as the route of administration, dosage form and regimen, and the desired result' and the precise dose should of course be determined by the physician. The actual dosage will depend on the nature and severity of the condition being treated, and can be judged by the physician and can be varied by dose titration of the particular conditions of the invention to produce the desired therapeutic effect. However, it is contemplated that each additional dose will comprise a pharmaceutical composition comprising from about 0.1 mg to about 500 mg, preferably from about 1 mg to about 1 mg, optimally from about 1 mg to about 1 mg of the active ingredient, suitable for therapeutic treatment. The active ingredient can be administered in one or several doses per day. In some cases, satisfactory results can be obtained with doses as low as 0.1/kg (intravenous) and i Mg/kg (orally). It is currently believed that the upper limit of the dose range is about i〇mg/kg (intravenous) and 1〇〇mg/kg (oral). The preferred range is from about 〇.丨 to about 10 mg/kg per day (intravenous) and about every day. 1 gg/kg to about ι〇〇 (oral). The present invention provides, in another aspect, a method of treating, preventing or ameliorating a disease or condition or condition of a living subject, including a human, the disease, 24 201029987 receptor complex reacting, and the method package (Including humans) administering an effective amount of a condition or condition to a compound that modulates GABAa to the desired active object. It is now expected that a suitable dosage range is from 1 mg per 至 to 10 to 500 奎 每日 日 日 Α Α 克 克 克 尤其 尤其 尤其 尤其 尤其 尤其 , , , , , 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此The form of the form of music, the indications for which the drug is administered, the individual and the individual iW bottle involved, and the preferences and experience of the attending physician or veterinarian. 实施 Embodiments The present invention is further described with reference to the following examples, The examples are not intended to limit the scope of the claimed invention in any way. General All reactions involving air sensitive reagents or intermediates are carried out under nitrogen and in anhydrous solvents. Use magnesium sulfate or sodium sulfate as dehydration in the treatment procedure. Drying agent and evaporating the solvent under reduced pressure.

3

25 6 201029987 Synthesis of 4-(6-bromo-pyridin-2-ylamino)-3-nitro-benzoic acid methyl ester (3) Stirring 2-amino group in anhydrous THF (50 ml) at 〇 ° C -6-bromopyridine 2 (3 g ' 17.3 mmol) and 60% NaH (1 g, 26 mmol) for 1 hour, and then dropwise addition of 4-fluoro-3-nitro-benzoic acid decyl ester 1 (3.4 g) , 17.3 mmol) in anhydrous THF (50 ml). The resulting cold solution was allowed to reach room temperature and stirred overnight to complete the reaction. LCMS showed complete conversion to the product and the reaction was quenched by the addition of iPrOH and HzO. A precipitate formed and the precipitate was taken out to dryness under reduced pressure to give a yield (yield: 74%) of 3 (4.5 g) as an orange solid. The product identity was confirmed by NMR and LCMS and the next step was carried out. ❻ Synthesis of 3-amino-4-(6-light-) butyl-2-ylamino)-benzoic acid oxime (4) 4-(6-Bisbi-2-ylamino)-3 -Nitro-benzoic acid A | 2 g, 5·6 mmol) dissolved in EtOH (50 ml) with the addition of Raney-nickel (0.2 g, 1.5 mmol) and subsequently in jj2 atmosphere The nitriding was carried out for 6 hours. LCMS showed complete conversion and the reaction mixture was passed through a bed of celite to remove the catalyst. The mixture was washed thoroughly with EtOH and then evaporated under reduced pressure to give a white solid. 65 g ; 9 〇 %. The product identity was confirmed by NMR and LCMS, and the next step was carried out. 〇 Synthesis of 1-(6-bromo-pyridin-2-yl)-1 hydrazine-benzimidazole _5• formic acid methyl vinegar (5 Dissolving 3-amino-4-(6-bromo-pyridin-2-ylamino)- benzoic acid oxime 4 (9 〇g, 279 mmol) in 1 mL of dry THF, B, * , τ and adding tridecyl ortho-decanoate (44 g, 419 mmol) and p-toluenesulfonic acid (27 2, s (4) mmol), heating the reaction mixture to reflux for 4 hours. LCMS exhibition; Conversion, and the reaction is stopped with an aqueous solution of sodium hydrogencarbonate, and the resulting solution is filtered out. Drying under pressure. The product is not pure, and therefore G 1遒 is then subjected to column chromatography using 26 201029987 CH^WMeOH/NH—. (95:5:0.1%) as the mobile phase. Solid material. η. η is placed at 43 g; 46 〇/P is known by NMR and HPLC. The compound is sufficiently pure to carry out the next step. Synthesis of 2-[1-(6-bromo-pyridin-2-yl)·1Η _Benzimidazole _s group] propyl _2_ leaven (4) Dissolve methyl 1-(6-bromo-pyridin-2-yl)-1 quinone-benzimidazole _5-carboxylate 5 (12 g, 36 mmol) in 120 Ml anhydrous THF and cooled to _1 () C &gt; c. Me To this solution was added MeMgBr (3 Μ, 36 nU, 1 〇 8 mmol) dropwise, after the end of the addition, the reaction mixture was allowed to reach room temperature and in the environment The mixture was stirred overnight. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Chromatography (2% MeOH/CHCl3) <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> </RTI> ❹ Method A · Suzuki Coupling General procedure A solution of compound 6 (1 equivalent) and aryl boronic acid (1·5 equivalent) or the corresponding oleic acid vinegar is dissolved/suspended in DME/H20/1,3 - propylene glycol or dioxane / HsO / EtOH, and added Na2CO 2 (about 3 equivalents). Adding catalyst

(Ph3P) 2PdCl2 (5 m〇i%) or (ph3p)4Pd (5 mol%), and the reaction mixture was stirred overnight at 9 (TC. Cool the reaction mixture to room temperature, dilute with water) and extract with ethyl acetate. Na2S04 was dehydrated and concentrated under reduced pressure. Using a hexane solution (gradient) or 27 201029987 CH/h/MeOH/NH- (95:5: 〇.丨%) The mobile phase purified the crude product to give the title compound 7a-7i.

OH

6

OH

P(Ph3&gt;4 or (Ph3P)2PdCI2 Na2C03 DME/H20/l,3-^^_g|

- Mouth simmering / chanting / EtOH 90 ° C The following compounds were prepared using the protocol described above for Suzuki coupling.

Compound starting material R1 XYZ 7a 6 CN CH CH 7 7 6 C C-CN CH CH 7c 6 H C-CHOHCH3 CH CH 7d 6 G1 CH CH C-OMe 7e 6 OMe CH CH CF 7f 6 Cl CH CF CH 7g 6 Cl CH CH C-CN 7h 6 CN CF CH CH 7i 6 CN CH-Cl CH 3_ 6 Cl CH CH CH 2- {6-[5-(1-hydroxy-1-indolyl-ethyl)-stupid LC-ESI-HRMS of imidazol-1-yl]pyridin-2-yl}-benzonitrile 7a [M + H] + shows 355.1551 Da. Calculated as 355.155886 Da with a deviation of -2.2 ppm 3-{6-[5-(l-hydroxy-1-methyl-ethyl)-benzimidazol-1-yl]pyridin-2-yl}-benzene LC-ESI-HRMS of carbonitrile 7b [M+H] + shows 355.1567 Da. Calculated as 355.155886 Da' deviation is 2.3 ppm 201029987 2-(1-{6-[3-(1-hydroxy-ethyl)-phenyl]-(1pyridin-2-yl}-111-benzimid嗤-5-yl)-propan-2-ol 7c 2-{l-[6-(2-chloro-5-methoxy-phenylpyridin-2-yl]-1H-benzopyrene LC-ESI-HRMS of 5-amino}-propan-2-ol 7d [M+H] + shows 394.1309 Da. Calculated value is 3 94.131685 Da, deviation is -2 ppm 2-{l-[6-(5- Fluoro-2-methoxy-phenyl)_»bipyridin-2-yl]-1H-stuppymi-5-yl}-propan-2-ol 7e © [M+H] + LC- ESI-HRMS shows 378.1626 Da. The calculated value is 378.161235 Da with a deviation of 3.6 ppm 2-{l-[6-(2-gas-4-gas-phenyl)-»bybiti-2-yl]-1H-benzene LC-ESI-HRMS of mersin-5-yl}-propan-2-ol 7f [M+H] + shows 382.1123 Da. Calculated value is 3 82.111698 Da, deviation is 1.6 ppm 4-gas-3-{6 -[5-(1·hydroxy-1-methyl-ethyl)-benzimidazole-1·yl;]_吼吼_2-yl}-benzonitrile 7g [M+H] + LC-ESI -HRMS shows 389.1 166 Da. Calculated as 3 89.1163 69 Da with a deviation of 0.6 ppm 2-fluoro-6-{6-[5-(l-hydroxy-1_methyl-ethyl)_benzimidazole_ι _基]_吼 bit-2-yl}-benzoquinone guess 7h [Μ十H] + LC-ESI-HRMS 373, 1469196 Da. Calculated as 373.145919 Da' deviation is 2.7 ppm 5-chloro-2-{6-[5-(l-hydroxy-1-methyl-ethyl)_benzimidazole-丨-kib Bibi-2-yl}-benzonitrile 7i 29 201029987 [M+H] + LC-ESI-HRMS shows 373.1469196 Da. Calculated as 373.145919 Da with a deviation of 2.7 ppm 2-[l-[6-( LC-ESI-HRMS of 2- gas phenyl)-2-acridinyl]benzimidazol-5-yl]propan-2-ol 7j [M+H] + 364.12084 Da» Calculated as 364.121 12 Da, The deviation is -0.8 ppm. The test method can be used to test the in vitro effects, pharmacokinetic properties and in vivo effects of the compounds of the present invention using standard pharmacological procedures of cell culture or laboratory animals. Such procedures as Mirza NR et al., NS11394 ❹ ([ 3'-[5-(1 - Hydroxy -1 -methyl-ethyl)-benzoimidazol-1 -yl]-bip henyl-2-carbonitrile]), a unique subtype-selective GABAa receptor positive modulator: In vitro actions, pharmacokinetic properties And in-vivo anxiolytic efficacy; Journal of Pharmacology And Experimental Therapeutics FaW For (4) first published on September 12, 2008; DOI: 10.1124/jpet.108.138859 The person. Test Method 1 抑制 Inhibition of 3H-fluunitrazepain (3H-FNM) in vitro The gab A recognition site and the benzodiazepine regulatory unit can be selectively labeled with 3H-flunitrazepam. Tissue preparation Unless otherwise stated 'otherwise in 〇_4. (: Perform preparation under. Use

The Ultra-Turrax homogenizer homogenizes the cerebral cortex of male Wistarrat (15G_2GGg) for 5-10 seconds in 20 ml Tris-HCl (30 mM, pH 7.4) 30 201029987. The suspension was centrifuged at 27, 〇〇〇 xg for 15 minutes, and the pellet was washed three times with buffer (centrifugation at 27, 〇〇〇 xg for a minute). in. The washed centrifugation block was homogenized in 2 ml of buffer and incubated on a water bath (37C) for 30 minutes to remove endogenous GABA and then at 27, 〇〇〇xg for "10 minutes. Then in buffer The centrifugation block was homogenized and centrifuged at 27,00 〇xg for 1 〇 minutes. The final pellet was resuspended in babies w buffer and the preparation was frozen and stored at _2 〇 t: The preparation was thawed and centrifuged for 1 min at 27 〇〇〇Xg. The centrifugation block was washed twice with a mtra-Turrax spumulator 1 2 〇 ml 5 加 · · 摔 (pH 7.1), and at 27 Centrifuge (7) minutes at 〇〇〇xg. Resuspend the final pellet in 50 mM Tris-citrate (pH 7 !) (500 ml buffer per gram of initial tissue) and then use for binding assays. 0.5 ml tissue aliquots were added to 25 μ test solution and 25 y 3H-FNM (1 η Μ, final concentration), mixed and incubated for 4 〇 under 2 。. Use 〇 ze ze ze ze (Cl〇nazepam) (i μΜ, final concentration) to determine non-specific binding. After incubation, add 5 ml of ice-cold buffer to the sample and pour directly under aspiration Whatman GF/C glass fiber filter paper, and immediately washed with 5 ml ice-cold buffer. The amount of radioactivity on the filter paper was determined by conventional liquid scintillation counting. Specific binding for total binding minus non-specific binding 〇 results must be specific The 25_?5% of the sexual combination is calculated before the calculation of the IC5Q value 31 201029987. The test value will be expressed as the ICw value (the concentration of the test substance (/xM) when the specific binding of 3H-FNM is 50%).

iCso = (concentration of test substance administered, μΜ) X 1 (9lVCx where C is the specific binding in the control assay, and cx is the specific binding in the test assay.

(These calculations are assumed to be normal mass-action kinetics). The results of these experiments for a variety of compounds of the invention are shown in Table 1 below. Test compound In-tube binding ICs〇 Value (a Μ ) 7a 0.0019 7b 0.0037 7c 0.0053 7d 0.0016 7e 0.0020 7f 0.0026 7g 0.0013 7h 0.0019 7i 0.0029 7j 0.0021

From the above, it will be understood that, although the specific embodiments of the invention have been described herein for the purpose of illustration, various modifications can be made without departing from the spirit and scope of the invention. Therefore, the present invention is limited only by M. The present invention, the scope of the patent application, and/or the combination of the features in the accompanying drawings, and any combination thereof, may be important to the implementation. [Simple description of the diagram]

[Main component symbol description] None

G 33

Claims (1)

201029987 VII. Patent application scope: 1. A compound of formula I, Or an oxynitride, any stereoisomer thereof, or any mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R represents phenyl; the phenyl group is independently selected by one or more Substituted by a substituent of the group of the following composition: halo, trifluoromethyl 'trifluoromethoxy, cyano, nitro, alkyl, hydroxy, hydroxyalkyl or alkoxy. 2. A compound according to claim 1, wherein the nitrogen oxide is any stereoisomer or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R represents FT ❹ » wherein R1, R2, R3, R4 and R5 independently of each other represent hydrogen, halo, difluorodecyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, hydroxyalkyl or alkoxy base. 3. A compound according to claim 1, wherein the nitrogen oxide, any stereoisomer thereof or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R represents 34 201029987 wherein R1 Represents a halo group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. 4. A compound according to claim 1, wherein the compound is a nitrogen oxide, any stereoisomer thereof or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R represents wherein R2 represents Halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, hydroxyalkyl or alkoxy. 5. A compound according to claim 1, wherein the nitrogen oxide, any stereoisomer thereof or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R represents Wherein R1 and R2 independently of each other represent a dentate group, a trifluoromethyl group, a trifluorodecyloxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. 6. If you apply for a patent range! A compound of the formula, which is an oxynitride, any stereoisomer thereof or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R represents 35 201029987 Wherein R1 and R3 independently of each other represent a halogen group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. 7. A compound according to claim 1 wherein the nitrogen oxide, any stereoisomer thereof or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R represents Wherein R1 and R4 independently of each other represent a halogen group, a trifluoromethyl group, a trifluorodecyloxy group, a cyano group, a nitro group, an alkyl group, a hydroxyl group, a hydroxyalkyl group or an alkoxy group. 8. A compound according to claim 1 which is 2-{6-[5-(1-hydroxy-1-indolyl-ethyl)-benzimidazol-1-yl]-pyridin-2- -yl}-benzonitrile; 〇3-{6-[5-(1-hydroxy-1-indolyl-ethyl)-benzimidazol-1-yl]-D-pyridin-2-ylbenzene Nitrile; 2-(1-{6-[3-(1-)-yl-ethyl)-phenyl]-. Ratio: Benz-2-yl}-1Η-benzoxazol-5-yl)-prop 2-ol; 2-{1-[6-(2-a-5-methoxy-phenyl)-pyridin-2-yl]-1H-benzimidazol-5-yl}-propene- 2-alcohol; 2-{1-[6-(5-fluoro-2-methoxy-phenyl)-. Bipyridin-2-yl]-1H-benzimidazol-5-yl}-propan-2-ol; 36 201029987 2-{1_[6-(2-gas-4-gas-phenyl)" _2_基]_111_benzo-17mazole_5_yl}-propan-2-ol; 4-gas-3_{6_[5♦ thiol+methylethyl) benzoate bite Bite-2-yl}-benzonitrile; 2-fluoro-6-{6·[5♦hydroxymethylethyl)benzimidazole” kibbitide-2-yl}-benzoquinone; 5· Gas ethyl) benzo (tetra) small group] ° - 2 - benzylbenzonitrile; 2-[1-[6-(2-chlorophenyl)·2_. Pyridyl]benzimidazolyl]propan-2-ol; or an oxynitride thereof, any stereoisomer thereof or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, or an oxynitride thereof, any stereoisomer thereof or a stereoisomer thereof Any mixture, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, hydrazine excipient diluent. 10. A compound, or an oxynitride thereof, or any stereoisomer thereof, or any mixture thereof, or a pharmaceutically acceptable compound thereof, according to any one of claims 1-3 The use of salt for the manufacture of a medicament. 11. The use of a pharmaceutical composition for the treatment, prevention or amelioration of a disease or condition or condition comprising a mammalian human, as claimed in claim 10, for the modulation of GABAA The receptor complex reacts. 37 201029987 12. If you apply for a patent scope! The use of item i, which makes the disease, condition or condition an anxiety disorder; panic disorder with or without fear of phobia; fear of a history of panic disorder; phobia; animal phobia; social phobia; obsessive-compulsive disorder OCD); generalized anxiety disorder; substance-induced anxiety disorder; stress disorder; post-traumatic magic syndrome; parting anxiety disorder; acute stress disorder; sleep disorder; memory disorder'·neuropathy; spasticity disorder; epilepsy; seizure (seizure ;;Children's enthusiasm; affective disorder; depression; bipolar disorder; depression; major depression; single episode of major depression; recurrent severe depression; low-grade sputum sensation, bipolar disorder; mania; Type I type of bipolar I manic disorder; type II hyperic disorder; circulatory affective disorder; psychosis; schizophrenia; cognitive disorders; lack of learning; memory loss and dysfunction Dementia; Insufficient Attention; Attention Deficit Hyperactivity Disorder (ADHD), Down's Syndrome; Tourette's Syndrome; Alzheimer's Disease (Alz) Heimer's disease); Parkins〇n, s disease; Huntington's disease; Pick, s disease; Creutzfeldt Jak〇b disease; cognition障碍 disorders; lack of cognition of schizophrenia; plucking; stuttering; systemic tic disorder; muscle tone disorder; cerebral ischemia; stroke; head trauma; neurodegeneration caused by cerebral ischemia; Acute pain, pain, mild pain, moderate or severe pain, postoperative pain, neuropathic pain, central neuropathic pain, and diabetic neuropathy, post-herpetic neuralgia, peripheral nerve injury, prosthetic pain, muscle fibers Pain, pain associated with chronic regional pain syndrome, somatic cell pain, internal 38 201029987 Pain or skin pain, pain caused by inflammation or sensation, related to osteoarthritis, rheumatoid arthritis Pain, hypertonic disorder of the southern nervous system, excessive excitability of the peripheral nerves, chronic headache, partial pain, migraine-related illness, tight Healing headache, irritating vomiting, m ^ Α -, sexual, delayed and expected vomiting; specific vomiting induced by chemotherapy or radiation. 'Medical disease, postoperative heart; sing; diet Obstacles; eating disorders; obesity; weight gain; anorexia nervosa, bulimia nervosa; obsessive-compulsive disorder of healthy food; violence, a pre-existing syndrome; neuralgia; three gods |,; positive, by © to go to the strong . , God left flat, muscle spasm; for example, paraplegic suffering from the production of Xu Xu Zhuang Zhuang, alcohol withdrawal; tinnitus; day and night rhythm disorder; by jet lag or to Lin Tiantian &amp; t ^ mm when the night rhythm, diabetes, Type i diabetes; ^, S ^ 4 diabetes; hyperinsulinemia, abnormal blood stasis, still lipidemia; ^ ^ v ^ human disease or autoimmune disorder. 13. A method of treating, preventing or ameliorating a living animal or a condition or condition comprising a human, a shoulder ... "a disease or condition reacts to a regulation _αα and a complex substance, the method comprising the steps of: The active substance in need thereof is administered a therapeutically effective amount such as φ Α main 蚩 4, the compound of any one of OU patents 帛1 to 8 or its nitrogen oxides Any mixture of stereoisomers or their stereoisomers or pharmaceutically acceptable thereof. 14. A method for use as a medicament, for example, by any of the first to eighth aspects of the patent The compound of the item, any of its three-dimensional items, the ϋ M _ re-substantially the stereoisomer of the object, or the medicinally acceptable human mammals 1 to 8 Any of the above-mentioned stereoisomers for the treatment, prevention or alleviation of a compound, a stereoisomer thereof or a 39 201029987 mixture thereof, as claimed in the first paragraph of the patent application, including a disease or a disease or condition, Or a pharmaceutically acceptable salt thereof, the disease, condition or condition Reacts to regulate the GABAa receptor complex. VIII. Schema · None 40