Diazepane substituted compounds as orexin receptor antagonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

 

Description

Orexin (hypocretin) include two neuropeptide produced in the hypothalamus: orexin AND (OH -) (protein consisting of 33 amino acids) and orexin IN (OH -) (protein consisting of 28 amino acids) (Sakurai T et al., Cell, 1998, 92, 573-585). It was found that orexin stimulate food intake in rats, thus suggesting a physiological role of these proteins as mediators of feedback mechanism that regulates feeding behavior (Sakurai T et al., Cell, 1998, 92, 573-585). Orexin regulate States of sleep and wakefulness, opening new possibilities of therapeutic approaches to the treatment of patients with narcolepsy or insomnia. (Chemelli R. et al., Cell, 1999, 98, 437-451). It was also shown that orexin are important in arousal, reward, learning and memory (Harris et al., Trends Neurosci., 2006 29(10), 571-577). In mammals have been cloned and characterized two rexinoid receptor. They belong to the superfamily of receptors associated with G-protein (Sakurai T et al., Cell, 1998, 92, 573-585): receptor orexin-1 (OH or OX1R) is selective for OH -, and receptor orexin-2 (OH or OX2R) is able to bind both OH-and OH-Century, it Is believed that the physiological actions that are part of orexin through one or both OF receptor and AH receptor, as well as two subtypes rexinoid receptors.

Orex the new receptors found in the brain of mammals, and they can take many involved in pathologies such as depressive syndrome; fear; dependence; syndrome obsessive-compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; delimitable disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirious syndrome; dementia; severe mental retardation and dyskinesia, such as Huntington's disease and Tourette Syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; dependency on food intake; eating/purging; cardiovascular disease; diabetes; disorders of appetite/taste sensations; nausea; vomiting; motion sickness; asthma; cancer; Parkinson's disease; syndrome/Cushing's disease; basophilic adenoma; prolactinoma; hyperprolactinemia; tumor/pituitary adenoma; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcer; fröhlich syndrome; disease adenohypophysis; disease of the pituitary gland; hypothyroidism of adenohypophysis; school of adenohypophysis; hypothalamic hypogonadism; kallman syndrome (loss of smell, loss of sense of smell); functional or psychogenic amenorrhea; hypopituitarism is m; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; violation of the biological and cardiac rhythms; sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome; lung and heart diseases, acute and congestive heart failure; hypotension; hypertension; delay urinary tract; osteoporosis; angina pectoris; myocardial infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal failure; the violation of the mechanism of absorption of glucose; migraine; hyperalgesia; pain; enhanced or increased sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; pain sports injuries; pain related to infection e.g. HIV, pain after chemotherapy; pain after stroke, pain after operations; neuralgia; nausea; the Orsk disease; vomiting; pathological conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; incontinence of the bladder, such as emergency incontinence; immunity to anesthesia or withdrawal of narcotics; sleep disorders; temporary cessation of breathing during sleep; narcolepsy; insomnia; parasomnia; syndrome of de-physiological cycles after transmeridional flights; and neurodegenerative diseases, including nosological forms, such as complex disinhibition-dementia-parkinsonism-amyotrophy; pallido-ronto-nigrina degeneration; seizures; epilepsy and other diseases related to General dysfunction Aracinovo system.

Some antagonists Aracinovo receptor described in PCT publications patents WO 99/09024, WO 99/58533, WO 00/47576, WO 00/47577, WO 00/47580, WO 01/68609, WO 01/85693, WO 01/96302, WO 2002/044172, WO 2002/051232, WO 2002/051838, WO 2002/089800, WO 2002/090355, WO 2003/002559, WO 2003/002561, WO 2003/032991, WO 2003/037847, WO 2003/041711, WO 2003/051368, WO 2003/051872, WO 2003/051873, WO 2004/004733, WO 2004/026866, WO 2004/033418, WO 2004/041807, WO 2004/041816, WO 2004/052876, WO 2004/083218, WO 2004/085403, WO 2004/096780, WO 2005/060959, WO 2005/075458, WO 2005/118548, WO 2006/067224, WO 2006/110626, WO 2006/127550, WO 2007/019234, WO 2007/025069.

The present invention is directed to diazepinone compounds that are antagonists rexinoid receptors and which are suitable for treatment or prevention never the logical and psychiatric disorders and diseases, involving Aracinovo receptors.

The present invention is directed to compounds of the formula I:

where:

R1is phenyl, substituted R1a, R1band R1c;

R2is heteroaryl, substituted R2a, R2band R2c;

R1a, R1b, R1c, R2a, R2band R2cindependently selected from the group consisting of

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) -(C=O)m-On-C1-6of alkyl, where m is 0 or 1, n is 0 or 1 (if m is 0 or n is 0, then there is a connection), where adjacent R2aand R2bor R2band R2ccan be joined together with formation of cycloalkenes or cycloalkane ring, and where the alkyl is unsubstituted or substituted by one or more substituents selected from R13,

(5) -(C=O)m-On-C3-6cycloalkyl where cycloalkyl is unsubstituted or substituted by one or more substituents selected from R13,

(6) -(C=O)m-C2-4alkenyl, where alkenyl is unsubstituted or substituted by one or more substituents selected from R13,

(7) -(C=O)m-C2-4the quinil where quinil is unsubstituted or substituted by one or more substituents selected from R13,

(8) -(C=O)sub> m-On-phenyl or -(C=O)m-On-naphthyl, where phenyl or naphthyl is unsubstituted or substituted by one or more substituents selected from R13,

(9) -(C=O)m-On-heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected from R13,

(10) -(C=O)m-NR10R11where R10and R11independently selected from the group consisting of

(a) hydrogen,

(b) (C1-6of alkyl, which is unsubstituted or substituted by one or more substituents selected from R13,

(C)3-6alkenyl, which is unsubstituted or substituted by one or more substituents selected from R13,

(d) cycloalkyl, which is unsubstituted or substituted by one or more substituents selected from R13,

(e) phenyl, which is unsubstituted or substituted by one or more substituents selected from R13and

(f) heterocycle, which is unsubstituted or substituted by one or more substituents selected from R13,

(11) -S(O)2-NR10R11,

(12) -S(O)q-R12where q is 0, 1 or 2 and where R12choose from the group of definitions for R10and R11,

(13) -CO2N

(14) -CN,

(15) -NO2,

(16) =O and

(17)- (OH)2

provided that at least one of R2a, R2bor R2cis halogen or1-6the alkyl or where adjacent R2aand R2bor R2band R2ccan be joined together with formation of cycloalkenes or cycloalkane ring, and where the alkyl, cycloalkyl or cycloalkane is unsubstituted or substituted by one or more substituents selected from R13;

R3represents-C1-6alkyl or-C3-6cycloalkyl, which are unsubstituted or substituted by one or more substituents selected from R13;

R13selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -(C=O)m-On-C1-6of alkyl, where alkyl is unsubstituted or substituted by one or more substituents selected from R14,

(4) -On-(C1-3)perfluoroalkyl,

(5) -(C=O)m-On-C3-6cycloalkyl where cycloalkyl is unsubstituted or substituted by one or more substituents selected from R14,

(6) -(C=O)m-C2-4alkenyl, where alkenyl is unsubstituted or substituted by one or more substituents selected from R14,

(7) -(C=O)m-On-phenyl or -(C=O)m-On-naphthyl, where phenyl or naphthyl is unsubstituted or substituted one or several and deputies, selected from R14,

(8) -(C=O)m-On-heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected from R14,

(9) -(C=O)m-NR10R11,

(10) -S(O)2-NR10R11,

(11) -S(O)q-R12,

(12) -CO2N

(13) -CN

(14) =O and

(15) -NO2;

R14selected from the group consisting of

(1) hydroxyl,

(2) halogen,

(3) (C1-6of alkyl,

(4) -C3-6cycloalkyl,

(5) -O-C1-6of alkyl,

(6) -O(C=O)-C1-6of alkyl,

(7) -NH-C1-6of alkyl,

(8) phenyl,

(9) heterocycle,

(10) -CO2N

(11) -CN;

or its pharmaceutically acceptable salt.

Variant implementation of the present invention includes compounds of formula Ia:

where R1, R2and R3are as defined above; or their pharmaceutically acceptable salts.

Variant implementation of the present invention includes compounds of formula Ib:

where R1, R2and R3are as defined above;

or their pharmaceutically acceptable salts.

Variant implementation of the present invention includes compounds of formula Ic:

where R1a, R1b, R1c, R2and R3are t is Kimi, as defined above; or their pharmaceutically acceptable salts.

Variant implementation of the present invention includes compounds of formula Id:

where R1a, R1b, R1cand R2are as defined above;

or their pharmaceutically acceptable salts.

Variant implementation of the present invention includes compounds of formula Ie:

where R1a, R1b, R1cand R2are as defined above;

or their pharmaceutically acceptable salts.

Variant implementation of the present invention includes compounds where R1represents phenyl, which is unsubstituted or substituted by one or more substituents selected from the

(1) halogen,

(2) hydroxyl,

(3) -On-C1-6the alkyl where n is 0 or 1 (where if n is 0, then there is a link) and where the alkyl is unsubstituted or substituted by one or more substituents selected from R13,

(4) -On-phenyl, where phenyl is unsubstituted or substituted by one or more substituents selected from R13,

(5) -heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected from R13,

(6) -NR10R11where R10and R11 is independently selected from the group consisting of

(a) hydrogen,

(b) (C1-6of alkyl, which is unsubstituted or substituted by one or more substituents selected from R13,

(7) -S(O)2-NR10R11,

(8) -CO2N

(9) -CN,

(10) -NO2and

(11) IN(OH)2.

Variant implementation of the present invention includes compounds where R1represents phenyl, which is unsubstituted or substituted by one or more substituents selected from methyl, -CF3, halogen, -OCF3, -OCH3, -OCH2CH3, -CO2CH3, -CN, -N(CH3), -NH(CH2CH3), -NO2, -B(OH)2, triazolyl or phenyl.

Variant implementation of the present invention includes compounds where R1represents phenyl, which is unsubstituted or substituted by one or more substituents selected from methyl, -CF3, fluorine, -OCF3, -OCH3, -CO2CH3, -B(OH)2, triazolyl or phenyl.

Variant implementation of the present invention includes compounds where R1selected from the group consisting of

(1) phenyl,

(2) biphenyl,

(3) 2,6-acid,

(4) 2,4-dichlorphenol,

(5) 2,6-dichlorophenyl,

(6) 2,3-dipthera,

(7) 2,4-dipthera,

(8) 2,6-dipthera,

(9) 2-methoxy-4-methylphenyl,

(10) 3-methoxybiphenyl,

(11) 3-methylbutan the La and

(12) 5-methyl-2-triazolylmethyl.

Variant implementation of the present invention includes compounds where R1represents phenyl, which is unsubstituted or substituted by one or more substituents selected from methyl or triazolyl. Variant implementation of the present invention includes compounds where R1is phenyl. Variant implementation of the present invention includes compounds where R1is triazolylmethyl or triazolyl(methyl)phenyl. Variant implementation of the present invention includes compounds where R1is 5-methyl-2-triazolylmethyl.

Variant implementation of the present invention includes compounds where R2is heteroaryl, which is unsubstituted or substituted by one or more substituents selected from the

(1) halogen,

(2) hydroxyl,

(3) -On-C1-6the alkyl where n is 0 or 1 (where if n is 0, then there is a connection), and where the alkyl is unsubstituted or substituted by one or more substituents selected from R13,

(4) -On-phenyl, where phenyl is unsubstituted or substituted by one or more substituents selected from R13,

(5) -heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected and the R 13,

(6) -NR10R11where R10and R11independently selected from the group consisting of

(a) hydrogen,

(b) (C1-6of alkyl, which is unsubstituted or substituted by one or more substituents selected from R13,

(7) -S(O)2-NR10R11,

(8) -CO2N

(9) -CN, and

(10) -NO2,

provided that at least one Deputy is halogen or1-6acellam or where two adjacent substituent joined together with formation of cycloalkyl rings.

Variant implementation of the present invention includes compounds where R2is heteroaryl, substituted with halogen or1-6acellam, and optionally substituted hydroxyl group, -O-C1-6acellam or phenyl.

Variant implementation of the present invention includes compounds where one of R2a, R2band R2cis halogen or1-6the alkyl and the other of R2a, R2band R2care hydrogen. Under this option, the implementation of the present invention includes compounds where one of R2a, R2band R2cis chlorine, fluorine or stands and the other of R2a, R2band R2care hydrogen. Variant implementation of the present invention includes compounds where two of R2a, R2band R2cconnected to the place with the formation With 1-6alkyl ring, and the other of R2a, R2band R2care hydrogen. Under this option, the implementation of the present invention includes a compound where two of R2a, R2band R2cjoined together to form with1-6alkyl ring which is substituted by =O, and the other of R2a, R2band R2care hydrogen.

Variant implementation of the present invention includes compounds where R2selected from the group consisting of

(1) benzimidazolyl,

(2) benzothiazolyl,

(3) benzoxazolyl,

(4) cyclopentylpropionyl,

(5) digitalcamerareview,

(6) dihydroquinoline,

(7) properidine,

(8) pyrazolopyrimidine,

(9) pyridinyl,

(10) pyridopyrimidines,

(11) pyrimidinyl,

(12) hintline,

(13) hineline,

(14) khinoksalinona,

(15) tetrahydroquinazoline,

(16) thiadiazolyl and

(17) thienopyrimidine,

which is substituted by halogen or C1-6the alkyl and optionally substituted hydroxyl group, -O-C1-6the alkyl, keto, -NH2or phenyl.

Variant implementation of the present invention includes compounds where R2selected from the group consisting of

(1) 1,3-benzoxazol-2-Il,

(2) 2-(6,7-dihydro-5H-cyclopent[d]pyrimidine)silt,

(3) 2-(7,8-dihydroquinoline-5(6N)-he)silt,

(4) 2-(furo[2,3]pyrim the Dean)silt,

(5) 2-(pyrazolo[3,4]pyrimidine)silt,

(6) 2-pyridinyl,

(7) 2-(pyrido[2,3-d]pyrimidine-7(8H)-one)silt,

(8) 2-pyrimidinyl,

(9) 2-hintline,

(10) 2-khinoksalinona,

(11) 2-(5,6,7,8-tetrahydroquinazolin)silt,

(12) 2-(thieno[2,3-d]pyrimidine)silt and

(13) 2-(thieno[2,3]pyrimidine-4-amine)silt,

which replaced the stands, chlorine or fluorine.

Variant implementation of the present invention includes compounds where R2selected from the group consisting of

(1) 1,3-benzoxazol-2-Il,

(2) 2-pyrimidinyl,

(3) 2-hintline,

(4) 2-khinoksalinona and

(5) 2-(thieno[2,3]pyrimidine-4-amine)silt,

which replaced the stands, chlorine or fluorine.

Variant implementation of the present invention includes compounds where R2is benzoxazolium, replaced by stands, chlorine or fluorine.

Variant implementation of the present invention includes compounds where R2is pyrimidinium, replaced by stands, chlorine or fluorine.

Variant implementation of the present invention includes compounds where R2is hinazolinam, replaced by stands, chlorine or fluorine.

Variant implementation of the present invention includes compounds where R2is khinoksalinona, replaced by stands, chlorine or fluorine.

Variant implementation of the present invention includes compounds where R2is (is ieno[2,3]pyrimidine-4-amine)silt, replaced by stands, chlorine or fluorine.

Variant implementation of the present invention includes compounds where R2is not 6-chlorobenzothiazole.

Variant implementation of the present invention includes compounds where R3represents-C1-6alkyl, which is unsubstituted or substituted by one or more substituents selected from R13.

Variant implementation of the present invention includes compounds where R3represents-C1-6alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -C1-6of alkyl,

(4) -(C1-3)perfluoroalkyl,

(5) -O-(C1-3)perfluoroalkyl,

(6) -C3-6cycloalkyl and

(7) -C2-4alkenyl.

Variant implementation of the present invention includes compounds where R3is-C1-6the alkyl. Under this option, the implementation of the present invention includes compounds where R3selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile, isopentyl, neopentyl and hexyl. Under this option, the implementation of the present invention includes compounds where R3is stands.

Specific options for OSA is estline of the present invention includes compounds which is selected from the group consisting of the compounds which are subjects of the following examples, or their pharmaceutically acceptable salts.

Compounds of the present invention may contain one or more asymmetric centers and thus can be present in the form of racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers. Depending on the nature of the various substituents of the molecule may be additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers and it is intended that all possible optical isomers and diastereomers in mixtures and pure or partially pure compounds included in the scope of the present invention. It is anticipated that this invention includes all such isomeric forms of these compounds. Formula I shows the structure of a class of compounds without a definite stereochemistry.

Independent synthesis of diastereomers or their chromatographic separation can be achieved, as is well known in this area, through appropriate modifications described in this description of the methodology. Their absolute stereochemistry can be determined by x-ray analysis of crystalline products or Cree is a metallic intermediate products, are modified, if necessary, a reagent containing an asymmetric center is known absolute configuration. If necessary, racemic mixtures of compounds can be separated in such a way as to highlight the individual enantiomers. The separation may be conducted by well-known methods in this field, such as the binding of racemic mixtures of compounds with enantiomerically pure compound with formation of a mixture of diastereomers followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction are often the formation of salts using enantiomerically pure acids or bases. Then diastereomeric derivatives can be converted into pure enantiomers by removal of added chiral residue. Racemic mixture of compounds can also be separated directly by chromatographic methods, which are well known in the field using a chiral stationary phase. In addition, any enantiomer of a compound can be obtained in the stereoselective synthesis using optically pure starting compounds and reagents of known configuration by means known in the field of methods.

Ka is obvious to a person skilled in this field, as used in this description, the term halogen or halo is intended to include fluorine, chlorine, bromine and iodine. Similarly With1-6as, for example, in C1-6the alkyl, defines the group, which have 1, 2, 3, 4, 5 or 6 carbon linear or branched chain, so1-6alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl, pentyl and hexyl. Groups, which are indicated as independently substituted by substituents may be independently substituted many of these substituents. Used in this description, the term "heterocycle" includes both unsaturated and saturated heterocyclic residues, where unsaturated heterocyclic residues (i.e. "heteroaryl") include benzoimidazolyl, benzimidazolinyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzotriazolyl, benzothiophene, benzoxazepin, benzoxazolyl, carbazolyl, carbolines, cinnoline, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazoles, isobenzofuranyl, isoindolyl, ethanolic, isothiazolin, isoxazolyl, naphthyridine, oxadiazole, oxazole, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyrimidines, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, hintline, hinely, honokalani, tetrazolyl, tetrasulphides, thiadiazolyl, thiazolyl, thienyl, triazolyl and their N-hydroxy is s and where saturated heterocyclic residues include azetidine, 1,4-dioxane, hexahydroazepin, piperazinil, piperidinyl, pyridine-2-oeil, pyrrolidinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothieno, and their N-oxides.

The term "pharmaceutically acceptable salts" means salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric salt, salt, ferrous iron, lithium, magnesium, salts of trivalent manganese, salts of divalent manganese, potassium, sodium, zinc, etc. Specific options include ammonium, calcium, magnesium, potassium and sodium salts. Salt in solid form can exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucose is, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine, etc.

If the connection of the present invention is a base, the salts can be derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutaminase, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, muzinovy, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acid, etc. Specific options for implementation include citric, Hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acid. It should be understood that, as used in this description, references to the compounds of formula I also mean the inclusion of pharmaceutically acceptable salts.

An example of the invention is the use of compounds described in the examples and in this specification. Specific compounds within the present invention include a compound which is selected from the group consisting of compounds, op is sledding in the following examples, and their pharmaceutically acceptable salts and individual enantiomers and diastereomers.

The considered compounds are suitable in the method, the calling antagonism activity Aracinovo receptor in patients, such as mammals, in need of such inhibition, comprising introducing an effective amount of the compounds. The present invention is directed to the use described in this description of the compounds as antagonists activity Aracinovo receptor. In addition to primates, in particular humans, according to the methods of the present invention can be conducted in the treatment of various other mammals. The present invention is directed to a compound of the present invention or its pharmaceutically acceptable salt for use in medicine. Also the present invention is directed to the use of compounds of the present invention or its pharmaceutically acceptable salt for a drug that causes antagonism activity Aracinovo receptor or for treatment of the above in this description of disorders or diseases of humans and animals.

Usually the subject of impact in these ways is a mammal such as a human male or a female. The term "therapeutically effective amount" means the amount in question is the first connection, which will cause the biological or medical response of a tissue, system, animal or human that is being hunted by a researcher, veterinarian, medical doctor or other practitioner. It is established that the person skilled in the art can affect neurological and psychiatric disorders through treatment of the patient affected by the disease, an effective amount of the compounds of the present invention. Used in this description, the terms "processing" and "processing" refers to all processes that may slow the violation, suppression, control or halt the progression described in this description of neurological and psychiatric disorders, but not necessarily leading to the complete elimination of all symptoms of the disorders, as well as preventive therapy of the above pathological conditions, particularly in patients prone to such disease or disorder. The term "introduction" compound should be understood as meaning the provision of a compound of the invention or a prodrug compound of the invention in need of it individual.

Used in this description, the term "composition" is intended to include a product containing certain ingredients in certain quantities. The term p is towards the pharmaceutical composition is designed to activate the product containing the active ingredient(s) and the inert ingredient(s), which is the media, as well as any other product, which is formed, directly or indirectly, from combination, complexation or aggregation of any two or more ingredients, or by dissociation of one or more ingredients, or through other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical composition of the present invention include any composition obtained by mixing the compounds of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" is meant the carrier, diluent or excipient, which must be compatible with other ingredients of the composition and must not have a harmful influence on the recipient.

Useful properties of the compounds according to the present invention as OX1R antagonists and/or OX2R receptors can be easily determined without the laborious research by means well known in the field of methodology, including FLIPR Ca2+flow analysis" (Okumura et al., Biochem. Biophys. Res. Comm. 280:976-981, 2001). In the standard experiment was established antagonistic activity of the compounds of the present invention receptor OH and OH. For intracellular changes the value of calcium were grown cells Chinese hamster ovary (Cho), expressing the receptor orexin-1 rats or receptor orexin 2 people, in the environment of Dulbecco modified by the method of Claim containing 2 mm L-glutamine, 0.5 g/ml G418, 1% hypoxanthineguanine Supplement, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% heat activated fetal calf serum (FCS). Cells were cultivated at 20,000 cells/well in black 284-hole sterile tablets Becton-Dickinson with a transparent bottom, coated with poly-D-lysine. All reagents from GIBCO-Invitrogen Corp. Sowed the plates were incubated over night at 37°C and 5% CO2. As the agonist was preparing the original solution Ala-6.12 orexin people in a 1 mm solution in 1% bovine serum albumin (BSA) and diluted in buffer for analysis (balanced salt Hanks solution containing 20 mm HEPES, 0.1% of BSA and 2.5 mm probenecid, pH 7.4) for use in the analysis at a final concentration of 70 PM. The investigated compounds were received as 10 mm initial solution in DMSO, then diluted in 384-well tablets first DMSO, then buffer for analysis. The day of the test cells were washed 3 times with 100 μl of buffer for analysis, and then incubated for 60 min (37°C, 5% CO2in 60 μl of buffer for analysis containing 1 μm ester of Fluo-4AM, 0,02% pluranguloj acid and 1% BSA. Then the solution containing the dye was aspirated and cells were washed 3 times with 100 ál bufreads analysis, leaving in each well 30 μl of this buffer. Inside fluorometric imaging tablet reader (FLIPR, Molecular Devices) to the tablet was added to the compounds in a volume of 25 μl, incubated for 5 minutes and at the end was added 25 μl of agonist. Fluorescence was measured for each well with 1 second intervals for 5 minutes and the height of each peak fluorescence was compared with the height of the peak fluorescence induced 70 PM Ala-6.12 orexin with buffer instead of the antagonist. For each antagonist was determined value IC50(the concentration of compound necessary for inhibiting 50% of the agonist response). Through these analyses can be defined the true activity of the antagonist Aracinovo receptor for compounds that can be used in the present invention.

In particular, the compounds of the following examples have activity to anlagenservice receptor orexin-1 rats and/or receptor orexin 2 people in the above analyses mainly with IC50less than about 50 microns. Many of the compounds of the present invention have activity to anlagenservice receptor orexin-1 rats and/or receptor orexin 2 people in the above analyses with IC50less than about 100 microns. These results show the true activity of the compounds when using such is the firmness of the antagonists of the receptor orexin-1 and/or receptor orexin-2. The present invention also includes compounds included in the scope of the invention, which have activity as agonists of the receptor orexin-1 and/or receptor orexin-2. In relation to other diazepamum the compounds of the present compounds exhibit unexpected properties, for example, in relation to increased bioavailability, metabolic stability, time-dependent inhibition and/or selectivity with respect to other receptors.

Aracinovo receptors involved in many different biological functions. This suggests a possible role of these receptors in various pathological processes in humans and in other species. Compounds of the present invention are useful in the treatment, prevention, the improvement of controlling or reducing the risk of various neurological and psychiatric disorders associated with alexanonyme receptors, including one or more of the following pathological conditions or diseases: insomnia, sleep disorders, including an increase in the quality of sleep, improve sleep quality, increase the efficiency of sleep, increased duration of sleep; increasing the value, which is calculated from the time that a subject sleeps divided by the time during which the subject is attempting to sleep; the improvement of the initial stage of sleep; poniz is the latent sleepiness or sudden onset of sleep (time, want to fall asleep); the reduction of difficulty in falling asleep; the increase in the duration of sleep; a decrease in the number of awakenings during sleep; a decrease in the number of intermediate awakenings during sleep; decreased night activity; reducing time spent after you Wake up until the next onset of sleep; an increase in the total amount of sleep; reduced separation sleep; changing the time mode, frequency or duration of the stages of REM sleep; changing the time mode, frequency or duration of stages of slow wave sleep (i.e. stages 3 or 4); increase the number and percentage of sleep stages 2; activation of slow wave sleep; increases in EEG Delta activity during sleep; a decrease in the number of night awakenings, especially revivals in the early morning; increase alertness during the day, reduce sleepiness during the day; the treatment or reduction of excessive sleepiness during the day; increased satisfaction from a deep sleep; increased duration of sleep; idiopathic insomnia, sleep problems; insomnia; hypersomnia idiopathic hypersomnia, repetitive hypersomnia, hereditary hypersomnia, narcolepsy, sleep interrupted, the temporary cessation of breathing during sleep, insomnia, nocturnal myoclonus, interrupt REM sleep, upset biorhythms in connection with the flight through several is like time zones, sleep disorders from working the night shift, dyssomnia, nightmares, insomnia associated with depression, nervous disorders/mood disorder, Alzheimer's disease or cognitive impairment, as well as sleepwalking and enuresis, and sleep disorders associated with aging; in the evening the confusion of Alzheimer's disease; conditions associated with diurnal rhythms, as well as mental and physical disorders associated with travel across time zones and with a rolling schedule, a pathological condition in which the medicinal product is called as side effects reduction of the fast stage of sleep; fibromyalgia; syndromes manifested as nevosstanovlenie sleep and muscle pain or temporary cessation of breathing during sleep, is associated with respiratory failure during sleep; pathological condition resulting from a decrease in sleep quality; increased learning; improving memory; increasing memory retention; eating disorders associated with excessive food intake and related complications, such as compulsive eating disorders, obesity (both genetic and caused by external conditions), diseases associated with obesity, including neurogenic bulimia, hypertension, diabetes, increased insulin concentration in the plasma of crovie insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate and colon cancer, osteoarthritis, obstructive temporarily stop breathing, cholelithiasis, gallbladder stone, heart disease, abnormal heart rhythm and arrhythmia myocardial infarction, congestive heart failure, ischemic heart disease, sudden death, stroke, polycystic ovary, craniopharyngioma, Prader-Willi syndrome, fröhlich syndrome, growth hormone deficiency, normal variant of dwarfism, Turner syndrome and other pathological conditions showing reduced metabolicheskoi activity or decrease in the expenditure of the remaining energy as a percentage of total fat-free mass for example, children with acute lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, disorders associated with sex hormones, sexual and reproductive dysfunction, such as impaired fertility, infertility, immaturity of the reproductive system in men and excessive hairiness in women, the defects associated with obesity of the mother, gastrointestinal diseases, such as obesity, associated with gastroesophageal reflux disease, respiratory disorders, such as hypoventilation syndrome due to obesity (Pickwickian syndrome), who disca, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, kidney cancer, increased anesthetic risk, lowering the risk of secondary effects of obesity, such as reducing the risk of left ventricular hypertrophy; diseases and disorders that cause abnormal oscillatory activity in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders for which there is abnormal adhesion activity, in particular, with the involvement of the thalamus; the improvement cognitive function; improving memory; increasing memory retention; enhancement of immune response; strengthening immune function; paroxysmal sensation of heat; night sweats; extension of time of life; schizophrenia; diseases associated with muscles that are controlled by the rhythms of the excitation/relaxation, asked the natural system, such as heart rate and other diseases of the cardiovascular system; pathological conditions associated with cell proliferation, such as dilation of blood vessels or the narrowing of blood vessels, and blood pressure; cancer; cardiac arrhythmia; increased cu is reentered the pressure; congestive heart failure; pathological conditions of the urinary system; disorders of sexual and reproductive functions; adequate kidney function; sensitivity to anesthetics; mood disorders, such as depression or more particularly depressive disorders, for example single or repeated large depressive disorder and estimatesa disorder or bipolar disorder, for example bipolar disorder type I, bipolar II disorder and cyclothymic disorder, mood disorders due to a General medical condition and mood disorders caused by medication; anxiety disorders including acute stress, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, acute anxiety the state with the reaction of panic, panic disorder, post-traumatic stress disorder, separation anxiety, social phobia, specific phobia, an anxiety disorder caused by medication, and fear due to a General medical condition; acute neurological and psychiatric disorders, such as cerebral insufficiency after cardiac bypass surgery and grafting, stroke, ischemic stroke, ischemia mo is ha spinal-cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronales damage; Huntington's chorea; amyotrophic lateral sclerosis; multiple sclerosis; eye damage; retinopathy; cognitive disorders; diopsittaca and due to the action of medicines for Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV, Parkinson's disease, Huntington's disease, a disease of Peak disease of Creutzfeldt-Jakob disease, perinatal hypoxia other General medical conditions or drug dependence); delirious syndrome, amnestic disorders or cognitive impairment associated with age; schizophrenia or psychosis including schizophrenia (paranoid, erratic, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusion disorder, brief psychotic disorder, separated psychotic disorder, psychotic disorder due to General medical condition, and psychotic disorder caused premonitoring means; disorders caused by the use of the substance, and the behavior detecting a propensity for drug use (including by taking substances delirious syndrome, prolonged dementia, long-lasting disorder that causes memory loss, psychotic disorder or anxiety disorder; immunity, the use of the substance that causes addiction, dependence or abstinence from substances including alcohol, amphetamines, marijuana, cocaine, hallucinogens, inhalant, nicotine, opioid, phenylcyclidine, sedatives, sleep AIDS, or tranquilizers); violation of movements, including paralysis and akineticalkie-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, a syndrome of progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, complex Parkinson's disease-amyotrophic lateral sclerosis and calcification of the basal nuclei of the brain), chronic fatigue syndrome, fatigue, including fatigue, Parkinson's, fatigue in multiple sclerosis, fatigue caused by sleep disorders or disturbances circadian rhythms, parkinsonism caused by the drug (such as parkinsonism caused by tranquilizers, neuroleptic malignant syndrome caused by tranquilizers on the three upset tone, caused by tranquilizers acute akathisia caused by tranquilizers late dyskinesia and drug-induced postural tremor), the syndrome of Gilles de La Tourette's, epilepsy and dyskinesia [including tremor (such as tremor during rest, essential tremor and intentsionnogo tremor), horey (e.g., chorea of Sydenham, Huntington's disease, benign congenital chorea, neuroacanthocytosis, symptomatic chorea, chorea caused by medication, and hemiballism), myoclonus (including myoclonus and focal myoclonus), tics (including light teak, complex tics and symptomatic tics), restless legs syndrome and dystonia (including General dystonia, such as idiopathic dystonia, dystonia caused by medication, symptomatic dystonia and paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic graphospasm, hemiplegic dystonia); attention deficit disorder with hyperactivity (ADHD); a conductive disorder; migraine (including headache); involuntary urination; immunity to certain substances; refraining from certain substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzol azepine, cocaine, sedatives, sleep AIDS, etc); psychosis; schizophrenia; anxiety (including General anxiety disorder, panic disorder and obsessive-compulsive disorder); mood disorder (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus; neuronale damage, including eye damage; retinopathy; macular degeneration of the eye; vomiting; swelling of brain; pain, including acute and chronic pain condition, severe pain, uncontrollable pain, inflammatory pain, neuropathic pain, post traumatic pain, bone pain and the joints (osteoarthritis), repetitive pain at movement, toothache, pain and cancer pain, myofascial pain (damage muscles, fibromyalgia), perioperative pain (General surgery, gynecological), chronic pain, neuropathic pain, pain after injury, trigeminal neuralgia, migraine and headache.

Thus, in specific embodiments, the implementation of the present invention provides methods of improving sleep quality; increased duration of sleep, increased REM sleep and stage; increase stage 2 sleep; reducing the fragmentation of the sleep modes; the treatment of insomnia, improve learning, increase memory retention; treatment or control of obesity; treatment or pin is aerovane depression; treatment, control, improve the quality of life or reduce the risk of epilepsy, including absence epilepsy; treatment or control of pain, including neuropathic pain; treating or controlling Parkinson's disease; treatment or control of psychosis, treatment, control, improve the quality of life or reduce the risk of schizophrenia in vulnerable patients mammals, which include the introduction to the patient a therapeutically effective amount of the compounds of the present invention.

The considered compounds are also suitable for a method of prevention, treatment, control, improve the quality of life or reduce the risk referred to in this description of the diseases, disorders and pathological conditions. The dosage of the active ingredient in the compositions of the present invention can vary, but it is necessary that the amount of active ingredient sufficient to obtain a suitable dosage forms. The active ingredient can be introduced requiring it to patients (animals or human) at dose levels that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, the route of administration and duration of application. From patient to patient dose will vary hung is on the nature and severity of the disease, the weight of the patient, special diet of the patient, concurrent drug therapy, and other factors that will be considered by the person skilled in the art. Basically, to achieve effective antagonism rexinoid receptors in the day, the patient is given dosage of from 0.0001 to 10 mg/kg of body weight, for example the elderly dosage generally will vary from about 0.5 mg to 1.0 g per patient per day, which can be entered as single or multiple doses. In one embodiment, the dosage will vary from about 0.5 mg to 200 mg per patient per day; in another embodiment from about 0.5 mg to 200 mg per patient per day; and the following embodiment, from about 5 mg to 50 mg per patient per day. The pharmaceutical compositions of the present invention can be provided in the form of a solid dosage form containing about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg of the active ingredient. For oral administration the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient depending on the symptoms dosage for the patient to be treated. Connections can be entered in the mode is from 1 to 4 times a day, for example, one or twice a day.

Compounds of the present invention can be used in combination with one or more other drugs in the treatment, prevention, control, and improvement of quality of life or reduction of risk of diseases or pathological conditions for which compounds of the present invention or other drugs may be useful where the joint combination drug is safer or more effective than each drug separately. Such other drug(s) may be entered by and in the amount, which for him is usually applied, simultaneously or sequentially with the compound of the present invention. While using the compounds of the present invention with one or more other drugs, a pharmaceutical composition in unit dosage form contains such other drugs and the necessary connection of the present invention. However, combination therapy may also include therapies in which the compound of the present invention and one or more other drugs injected into various overlapping modes of application. It is also assumed that when used to is Binali with one or more other active ingredients compounds of the present invention and other active ingredients can be used at lower dose levels compared with the use of each separately. Thus, the pharmaceutical compositions of the present invention include compositions which in addition to the compound of the present invention contain one or more active ingredients. The above combinations include combinations of compounds of the present invention not only one other active compound, but also with two or more other active compounds.

Similarly, the compounds of the present invention can be used in combination with other drugs that are used for prevention, treatment, control, improve quality of life or reduce the risk of diseases or pathological States for which suitable compounds of the present invention. Such other drugs may be entered by and in the quantity that is usually applied simultaneously or sequentially with the compound of the present invention. Thus, the pharmaceutical compositions of the present invention include compositions which in addition to the compound of the present invention also contain one or more active ingredients.

The mass ratio of the compounds of the present invention to the second active ingredient may vary and will depend upon the effective dose of each is about the ingredient. Mainly will be used effective dosage of each component. Thus, for example, if the connection of the present invention combined with another agent, then the mass ratio of the compounds of the present invention to another agent mainly will vary from about 1000:1 to about 1:1000, for example from about 200:1 to about 1:200. Combinations of the compounds of the present invention and other active ingredients will generally be in the aforementioned range, but in each case shall apply effective dosage of each active ingredient. In combinations of the compound of the present invention and other active ingredients can be introduced separately or together. In addition, the introduction of one element may be prior to, simultaneously with or after administration of other agent(s).

Compounds of the present invention can be introduced in combination with other compounds, which, as is well known in this area, are suitable for improving sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, sleeping pills, anxiolytics, neuroleptics, sedatives, antihistamines, benzodiazepines, barbiturates, cyclopyrrolone, GABA agonists, antagonists of 5-HT2, including antagonists of 5-HT-2A and anti nesty 5-HT-2A/2C, antagonists of histamine, including H3 antagonists histamine, inverse agonists of the histamine H3, imidazopyridine, mild tranquilizers, agonists and antagonists of melatonin on melatonergic funds, other antagonists of orexin, agonists orexin, agonists and antagonists prokineticin, pyrazolopyrimidine, calcium channel antagonists of T-type, triazolopyridine and the like, for example: adinazolam, allobarbital, econimic, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, capromorelin, capured, carbocloro, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, claparede, clorazepate, clarett, clozapine, clonazepam, lprazepam, desipramine, exclama, diazepam, dichloralphenazone, divalproex, diphenylhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, postepu, gaboxadol, glutetimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midfur midazolam, modafinil, nefazodone, NGD-2-73, Nizamabad, nitrazepam, nortriptyline, oxazepam, paraldehyde is recommended, paroxetine, PE is cobarbital, perlapi, perphenazine, phenelzine, phenobarbital, diazepam, promethazine, propofol, protriptyline, kwazepam, ramelteon, reclusiam, related, secobarbital, sertraline, supraglan, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranilcipromin, trazadon, triazolam, crepidam, triatomid, triclofos, triptorelin, trimeton, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem and their salts, and combinations thereof, and the like, or compounds of the present invention can be introduced together with the application of physical methods such as with light therapy or electrical stimulation.

In another embodiment, the compounds being considered can be applied in combination with other compounds that are known in this field that can be entered separately or in the same pharmaceutical compositions, including, but not limited to: insulin sensitizers including (i) PPARγ antagonists, such as glitazone (for example, ciglitazone; darglitazone; englitazone; Eagleton (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and the like); (ii) biguanides, such as Metformin and phenformin; (b) insulin or insulin mimetics, such as biota, LP-100, Novorapid, insulin detemir, insulin lispro, insulin glargine, zinc suspension insulin (tape and ultralente); insulin is Ispra, GLP-I (73-7) (insulin, according to); and GLP-I (7-36)-NH2); (c) sulfonylureas such as acetohexamide; chlorproma; diabinese; glibenclamide; glipizide; gliburid; glimepiride; gliclazide; ClientID; glikvidon; glycolipid; tolazamide and tolbutamide; (d) inhibitors of α-field of glycosidase inhibition, such as acarbose, adipsin; camiglibose; emiglitate; miglitol; voglibose; progenitin-Q; substation; CKD-711; MDL-25,637; MDL-73,945, and MOR 14, and the like; (e) lowering cholesterol agents, such as (i) inhibitors of HMG-COA reductase inhibitor (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, mevastatin, rosuvastatin, simvastatin and other statins), (ii) absorbents bile acids/airing, such as cholestyramine, holestipol, dialkylaminoalkyl derivatives Poperechnaya dextran; Colestid®; LoCholest®, and the like, (ii) nicotinebuy alcohol, nicotinic acid or a salt thereof, (iii) α ognisty receptor activation, proliferation, such as derivatives fenofibrinova acid (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol intake, such as esters of stanol, beta-sitosterol, Sterol glycosides such as tiqueside; and azetidinone, such as ezetimibe and the like, and inhibitors (acetyl CoA:cholesterol transferase (ACAT)), such as avasimibe and melinamide, (v) antioxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; (f) PPARα agonists such as clofibrate, bensaf the brother, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other derivatives fibroeva acid, such as Atromid®, Lopid® and Tricor®, and the like, and PPARα agonists described in WO 97/36579 Glaxo; (g) PPARδ agonists; (h) PPAR α/δ agonists, such as muraglitazar and compounds described in US 6414002; and (i) anti-obesity, such as (1) means, amplifying secretion of growth hormone agonists/antagonists of the receptor, enhances the secretion of growth hormone, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and L-163,255; (2) inhibitors of protein tyrosine phosphatase-1B (PTP-1B); (3) ligands cannabinoides receptor, such as antagonists or inverse agonists cannabinoides of the CB1 receptor, such as rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) serotonergic anti-obesity, such as fenfluramine, dexfenfluramin, phentermine, and sibutramine; (5) agonists, β3 adrenergic receptors, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, trekkin, Zeneca D7114, SR 59119A; (6) inhibitors of pancreatic lipase, such as orlistat (Xenical®), Triton WRl 339, RHC80267, lipstatin, tetrahydrolipstatin, teaspoon, diethylaminopropyl; (7) antagonists of the neuropeptide Y1 such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (8) antagonists of neuropeptide Y5, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-16070, SR-120562A, SR-120819A and JCF-104; (9) antagonists of the receptor for melanin-concentrating hormone (MCH); (10) 1 antagonists of the receptor for melanin-concentrating hormone (MCH1R), such as T-226296 (Takeda); (11) agonists/antagonists 2 receptor for melanin-concentrating hormone (MCH2R); (12) antagonists rexinoid receptors, such as SB-334867-A and described in the patent publications listed in this description; (13) reuptake inhibitors SSRIs, such as fluoxetine, paroxetine, sertaline; (14) agonists melanocortin, such as Melanotan II; (15) other agonists, Mc4r (melanocortin receptor 4), such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14 (Palatin); (16) agonists 5HT-2; (17) agonists 5HT2C (serotonin receptor 2C), such as BVT933, DPCA37215, WAY161503, R-1065; (18) antagonists Galanina; (19) CCK agonists; (20) agonists, CCK-a (cholecystokinin-A), such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613; (22) antagonists of corticotropin-releasing factor; (23) the modulators of the histamine 3 receptor (H3); (24) antagonists/inverse agonists of the histamine 3 receptor (H3), such as typename, 3-(1H-imidazol-4-yl)propyl N-(4-pentyl)carbamate, closedprofit, jodieproffit, impressive, GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]carbamate; (25) inhibitors of β-hydroxy steroid dehydrogenase-1 (β-HSD-1); 26) a phosphodiesterase inhibitor, such as Tefillin, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilomilast; (27) inhibitors of phosphodiesterase-3B (PDE3B); (28) inhibitors transfer NE (norepinephrine), such as GW 320659, despiramine, talsupram and nomifensine; (29) receptor antagonists (ghrelin; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) derived leptin; (32) BRS3 agonist (subtype receptor bombezin 3), such as [D-Phe6,beta-Ala11,Phe13,Nlel4]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide, and compounds disclosed in Pept. Sci. 2002 Aug; 8(8): 461-75); (33) CNTF (ciliary neurotrophic factors)such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), Buchbinder, PD 170,292 and PD 149164 (Pfizer); (34) CNTF derivatives, such as axokine (Regeneron); (35) reuptake inhibitors monoamine oxidase, such as sibutramine; (36) activators UCP-1 (uncoupling protein-1), 2 or 3, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenylbenzene acid (TTNPB), retinoic acid; (37) β agonists thyroid hormones, such as KB-2611 (KaroBioBMS); (38) inhibitors of FAS (fatty acid synthase), such as cerulenin and S; (39) inhibitors DGAT1 (diacylglycerol, acetyltransferase 1); (40) inhibitors DGAT2 (diacylglycerol, acetyltransferase 2); (41) inhibitors of ACC2 (acetyl-COA-carboxylase-2); (42) glucocorticoid antagonists; (43) acyl-estrogens, such as oleoyl-astral described del Mar-Grasa, M. et al., in Obesity Research, 9:202-9 (2001); (44) inhibitors is dipeptidylpeptidase IV (DP-IV), such as solarindustrie, validperiod, NVP-DPP728, LAF237, MK-431, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, assuming your 274-444; (46) inhibitors vector in primary forms; (47) inhibitors vectors glucose; (48) inhibitors vectors phosphate; (49) Metformin (Glucophage®); and (50) Topiramate (Topimax®); and peptide YY, PYY 3-36, analogs, derivatives and fragments of peptide YY, such as BIM 43073D, BIM-43004C (Olitvak, D.A. et al., Dig. Dis. Sci. 44(3):643-48 (1999)); (51) agonists of the receptor neuropeptide Y2 (NPY2), such as NPY3-36, N acetyl [Leu(28,31)]NPY24-36, TASP-V and cyclo-28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) agonists of the receptor neuropeptide Y4 (NPY4), such as pancreatic peptide (PP), and other Y4 agonists, such as 1229U91; (54) inhibitors of cyclooxygenase-2, such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, TIRExB or JTE522, ABT963, CS502 and GW406381, and their pharmaceutically acceptable salts; (55) antagonists of neuropeptide Y1 (NPY1), such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) opioid antagonists such as nalmefene (Revex ®), 3-methoxyestradiol, naloxone, naltrexone; (57) inhibitors of 11β HSD-1 (11-beta hydroxysteroid dehydrogenase type 1), such as BVT 3498, BVT 2733; (58) Aminorex; (59) amphora; (60) amphetamine; (61) benzphetamine; (62) chlorphentermine; (63) clobenzorex; (64) klotrix; (65) glominerals; (66) clortermine; (67) cilexetil; (68) dextroamphetamine; (69) diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72) finarex; (73) vanprapar the COP; (74) fluorex; (75) glominerals; (76) furfurylmercaptan; (77) levamfetamine; (78) levorotatory; (79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83) pentrex; (84) phendimetrazine; (85) phenmetrazine; (86) pillories; (87) Vitapharm 57 (88) zonisamide.

In another embodiment, the compounds being considered can be used in combination with antidepressant or anti-anxiety agents, including inhibitors of reuptake of norepinephrine (including tricyclic tertiary tricyclic amines and secondary amines), inhibitors of serotonin reuptake (SSRI), monoamine oxidase inhibitors (MAOI), reversible inhibitors of monoamine oxidase (RIMA), reuptake inhibitors of serotonin and norepinephrine (SNRI), antagonists of the corticotropin-releasing factor (CRF)antagonists, α-adrenoreceptor antagonists of receptors neirokinina-1, atypical antidepressants, benzodiazepines, agonists or antagonists of 5-HT1A, in particular partial agonists 5-HT1A antagonists of the corticotropin-releasing factor (CRF). Specific agents include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline; fluoxetine, paroxetine, sertaline, isocarboxazid, phenelzine, tranilcipromin and selegiline; moclobemide; venlafaxine; apropiat; bupropion, lithium, nefasto is and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and their pharmaceutically acceptable salts.

In another embodiment, the compounds being considered can be used in combination with agents against Alzheimer's disease; inhibitors of beta-secretase; inhibitors of gamma-secretase; enhancing the secretion of growth hormone means; recombinant growth hormone; inhibitors of HMG-CoA reductase inhibitor; NSAIDs, including ibuprofen; vitamin E; anti-amyloid remedy antibodies; antagonists of CB-1 receptors or inverse agonists of CB-1 receptors; antibiotics, such as doxycycline and rifampin; receptor antagonists N-methyl-D-aspartate (NMDA), such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil and taken; enhancing the secretion of growth hormone means, such as ibutamoren, mesilate ibutamoren and capromorelin; antagonists of the histamine H3; AMPA agonists; inhibitors of PDE IV; reverse GABAA agonists or agonists of the neuronal nicotinic.

In another embodiment, the compounds being considered can be used in combination with sedatives, hypnotics means, anxiolytics, neuroleptics, soothing agents, cyclopyrrolones, imidazopyridines the mi, pyrazolopyrimidines, minor tranquilizers, agonists and antagonists of melatonin on melatonergic agents, benzodiazepines, barbiturates, 5HT antagonists-2 and the like, such as: adinazolam, allobarbital, econimic, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capured, carbocloro, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, claparede, clorazepate, clarett, clozapine, lprazepam, desipramin, exclama, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, postepu, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midfloor, midazolam, nefazodone, Nizamabad, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapi, perphenazine, phenelzine, phenobarbital, diazepam, promethazine, propofol, protriptyline, kwazepam, reclusiam, related, secobarbital, certain, supraglan, temazepam, thioridazine, tracazolate, tranilcipromin, trazodone, triazolam, crepidam triatomid, triclofos, trifluoperazine, trimeton, trimipramine, medazepam, the SNRIs venlafaxine is in, zaleplon, zolazepam, zolpidem and their salts, and combinations thereof, and the like, or the considered compounds may be introduced together with the used physical methods such as with light therapy or electrostimulating.

In another embodiment, the compounds being considered can be used in combination with levodopa (with or without a selective extracerebral inhibitor carboxylase, such as carbidopa or benserazide), anticholinergic means, such as biperiden (optionally as its hydrochloride or lactate salt) and hydrochloride of trihexyphenidyl (benzhexol), inhibitors of COMT, such as entacapone, inhibitors MOA-B, antioxidants, antagonists of adenosine A2a receptors, cholinergic agonists, NMDA receptor antagonists, antagonists of serotonin receptors and agonists of dopamine receptors, such as alenamy, parlodel, fenoldopam, lisuride, exagrid, pergolid and pramipexol. It should be borne in mind that dopamine agonists can be in the form of pharmaceutically acceptable salts, for example the hydrobromide of alentemol, nelfinavir bromocriptine, nelfinavir fenoldopam, hydrochloride nakagaito and nelfinavir e.g. and pramipexole, and are typically used in nesolenyh forms.

In another embodiment, the compounds being considered can be used in combination : the AI with acetophenazine, alentemol, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, Fiorentina, haloperidol, levodopa with benserazida, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindone, nakagaito, olanzapine, pergolid, perphenazine, pimozidom, pramipexol, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene or trifluoperazine.

In another embodiment, the compounds being considered can be used in combination with compounds selected from fenotiazina, thioxanthene, heterocyclic benzodiazepines, butyrophenones, difenilbutilpiperidina and neuroleptic agent class of indoles. Suitable examples fenotiazinas include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a benzodiazepine is clozapine. Example butyrophenones is haloperidol. Example difenilbutilpiperidina is pimozide. An example of indole is malindalo. Other neuroleptic agents include loxapine, sulpiride and risperidone. It should be borne in mind that neuroleptic agents, when used in combination with the considered compounds, can p is be in the form of pharmaceutically acceptable salts, for example, chlorpromazine hydrochloride, besilate mezoridazina, thioridazine hydrochloride, maleate acetophenazine, hydrochloride fluphenazine, anatta fluphenazine, decanoate of fluphenazine, thiothixene hydrochloride, haloperidol decanoate, succinate of loxapine and hydrochloride molindone. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are typically used in mesolevel form.

In another embodiment, the compounds being considered can be used in combination with anorectics agent such as Aminorex, amphora, amphetamine, benzphetamine, chlorphentermine, clobenzorex, klotrix, glominerals, clortermine, cilexetil, dexfenfluramin, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, penetrex, fenproporex, fluorex, luminares, furfurylmercaptan, levamfetamine, levofacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, phenterex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, pillories and sibutramine; inhibitors of serotonin reuptake (SSRI); halogenated derivatives amphetamine, including chlorphentermine, klotrix, clortermine, dexfenfluramin, fenfluramin, pillories and sibutramine, and their pharmaceutically acceptable salts.

In another embodiment, rassm drivebye compounds can be used in combination with an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of lipoxygenase-5, an inhibitor of cyclooxygenase, such as an inhibitor of cyclooxygenase-2, an inhibitor of interleukin, such as an inhibitor of interleukin-1, a NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or a cytokine-suppressive anti-inflammatory agent, for example such compounds, such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, Ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesics, Sufentanil, sulindac, tenidap and the like. Similarly, the compounds being considered can be put together with a painkiller; potentiating agent, such as caffeine, an H2-antagonist, simethicone, aluminum hydroxide or magnesium; anti-edema agent, such as phenylephrin, phenylpropanolamine, pseudovirion, Oxymetazoline, epinephrine, nafazolina, Xylometazoline, propylhexedrine or left-desoxyephedrine; antitussive agent, such as codeine, hydrocodone, caramiphen, carbetapentane or dextramethorphan; a diuretic; and somnolency or nesomnennym antihistaminic drug.

Compounds of the present invention can be injected oral, parenteral (for example, intramuscularly, intraperitoneally, intravenously, via ICV introduction the Oia, by intracisternal injection or infusion, by subcutaneous injection, or implant), through inhalation spray, nazalnam, vaginal, rectal, sublingual or topical routes of administration and can be formulated (alone and together) into a suitable dosage form containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and fillers for each route of administration. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use by people.

Pharmaceutical compositions for administration of the compounds of the present invention can be easily presented in the form of dosage forms and can be obtained using well-known methods of the pharmaceutical industry. All methods include the stage of mixing the active ingredient with the carrier which comprises one or more accessory ingredients. Typically, the pharmaceutical compositions are produced by homogeneous and tight mixing the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired drug. In the pharmaceutical composition the active compound is included in the amount is as, sufficient to provide the desired effect in disease processes or conditions. Used in this description, the term "composition" is intended to include a product containing certain ingredients in certain amounts, as well as any product that is obtained, directly or indirectly, in the combination of ingredients in specific amounts.

Pharmaceutical compositions intended for oral administration can be obtained according to any known method for the production of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavors, colorants and preservatives, to provide the best pharmaceutical elegance and giving the structure a pleasant taste. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. For example, these excipients may be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and grinding agents such as corn starch or alginic acid; binding agents such as starch, gelatin, gum, and lubricants, such as stearate MAGN what I stearic acid or talc. Tablets may be uncoated or may be coated by known methods for slow disintegration and absorption in the gastrointestinal tract, thereby ensuring prolonged action over a longer period of time. Compositions for oral administration can also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active substance in a mixture with excipients suitable for receiving water suspensions. Oil suspensions can be obtained by suspension of the active ingredient in a suitable oil. Can also be used in emulsions of the type water-in-oil. Dispersible powders and granules suitable for obtaining an aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. The pharmaceutical compositions of the present invention can be in the form of a sterile aqueous or oily suspension for injection. is soedineniya of the present invention can also be introduced in the form of suppositories for rectal administration. For local application can be used in creams, ointments, jellies, solutions or suspensions, etc. containing compounds of the present invention. Compounds of the present invention can also be obtained for administration by inhalation. Compounds of the present invention can also be obtained for introduction via transdermal skin patches well known in this field means.

In the following examples and the following diagrams illustrate some of the ways to obtain the compounds of the present invention. Educt get under known in this field techniques or as shown in this description. In this specification, the following abbreviations are used: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; THF: tetrahydrofuran; DEAD: diethylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide; EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; HOBT: hydroxybenzotriazole; Boc: tert-butoxycarbonyl; Et3N: triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovine serum albumin; TFUCK: triperoxonane acid; DMF: N,N-dimethylformamide; MTBE: tert-butyl ether; SOCl2: thionyl chloride; CDI: carbonyldiimidazole; CT: room temperature; HPLC: high performance liquid chromatography. Compounds of the present invention can be obtained once the ranks of ways.

In some cases the final product may be further modified, for example, by manipulation of substituents. Such manipulations may include, but are not limited to, reaction, recovery, oxidation, alkylation, acylation and hydrolysis, which are usually well-known specialist in this field. In some cases, for carrying out the above reaction schemes can be modified to facilitate reactions and to avoid unwanted reaction products. The following examples are given in order that the invention can be understood in more detail. These examples are illustrative only and should not be construed as limiting the invention in any way.

Scheme And

2-(2H-1,2,3-triazole-2-yl)benzoic acid (a-1)

A solution of 2-identying acid (3.0 g, 12,09 mmol) in DMF is treated (1.5 g, and 21.7 mmol) of 1,2,3-triazole, was 7.08 g (21,7 mmol) CsCO3, 114 mg (0,60 mmol) CuI and 310 mg (2,17 mmol) of TRANS-N,N'-dimethylcyclohexane-1,2-diamine. The mixture is heated at 120°C for 10 minutes in a microwave reactor. The reaction mixture is cooled to room temperature, diluted with EtOAc and filtered through celite. The residue is purified by gradient elution on SiO2(MeOH in DCM with 0.1% Asón), obtaining the desired quickly loireau 2-(2H-1,2,3-triazole-2-yl)benzoin the Yu acid, A-1.

Data for compounds a-1:1H NMR (500 MHz, DMSO-d6) δ of 13.05 (users, 1H), 8,12 (s, 2H), 7,81-7,52 (m, 4H) ppm

Unwanted 2-(1H-1,2,3-triazole-2-yl)benzoic acid eluted second.

2-(2H-1,2,3-triazole-2-yl)-5-methylbenzoic acid (a-2)

A solution of 2-iodine-5-methylbenzoic acid (4.0 g, of 15.3 mmol) in DMF (10 ml) is treated with 1,2,3-triazole (2.1 g, 30,5 mmol), CsCO3(9.95 g, 30,5 mmol), CuI (0,145 g, from 0.76 mmol) and TRANS-N,N'-dimethylcyclohexane-1,2-diamine (0,43 g of 3.05 mmol). The mixture is heated at 120°C for 10 minutes in a microwave reactor. The reaction mixture is cooled to room temperature, diluted with water and washed with EtOAc. The aqueous phase is acidified with 1N. HCl and extracted with EtOAc. The organic layer is dried over Na2SO4filter and concentrate. The residue is purified by gradient elution on SiO2(MeOH in DCM with 0.1% Asón), getting quickly loireau 2-(2H-1,2,3-triazole-2-yl)-5-methylbenzoic acid a-2 with subsequent undesirable regioisomer, 2-(1H-1,2,3-triazole-2-yl)-5-methylbenzoic acid.

Data for compound a-2:1H NMR (500 MHz, DMSO-d6) δ 12,98 (users, 1H), 8,04 (s, 2H), 7,72 was 7.45 (m, 3H), 2,41 (s, 3H) ppm

5-Bromo-2-(2H-1,2,3-triazole-2-yl)benzoic acid (a-3)

A solution of 5-bromo-2-identying acid (10.0 g, of 30.6 mmol) in DMF is treated (2,11 g of 30.6 mmol) of 1,2,3-triazole, 14,09 g (61,2 mmol) K3PO4·H2O and 583 mg (a 3.06 mmol) of CuI. A mixture of n is grebaut at 60°C for 3 hours with stirring in an atmosphere of N 2. The reaction mixture is cooled to room temperature, diluted with water and acidified with 1N. HCl. The mixture three times the share in EtOAc. The organic layers collected, washed with saturated salt solution, dried over Mg2SO4filter and concentrate. The residue is purified column chromatography (EtOAc in hexane, 1% Asón buffer)to give the desired quickly loireau 5-bromo-2-(2N-1,2,3-triazole-2-yl)benzoic acid, And-3.

Data for compound a-3:1H NMR (500 MHz, DMSO-d6) δ 13,4 (users, 1H), 8,12 (m, 2H), 7,94-7,88 (m, 2H), 7,78-7,73 (m, 1H) ppm

Junk 5-bromo-2-(1N-1,2,3-triazole-2-yl)benzoic acid eluted second.

Circuit

2-(Diputaciones)-4-fluoro-1-nitrobenzene (1)

A solution of 5-fluoro-2-nitrobenzaldehyde (75 g, 443 mmol), monohydrate paratoluenesulfonyl (8,4 g, 44,3 mmol) and n-butanol (122 ml of 1.33 mol) is refluxed in toluene (630 ml) using nozzles Dean-stark for 15 hours. The reaction mixture is cooled, concentrated and partitioned between water (1 l) and EtOAc (1 l). The organic layer was washed with water (1 l) and saturated salt solution (1 l), dried over Na2SO4and concentrate. The crude reaction mixture was purified column chromatography (EtOAc in hexane, 1% triethylamine buffer)to give compound B-1 in the form of oil.

Data link is In-1 1H NMR (500 MHz, CDCl3) δ a 7.92 (DD, J=8,5, and 4.5 Hz, 1H), 7,54 (DD, J=9,0, 3.0 Hz, 1H), 7,15-7,11 (m, 1H), equal to 6.05 (s, 1H), 3,67-to 3.52 (m, 4H), 1,63-of 1.57 (m, 4H), 1,43-of 1.35 (m, 4H), 0,94-of 0.91 (m, 6H) ppm;

mass spectrometry low resolution (ICSD) (M+H) m/z=169,8 found, 300,3 calculated loss is observed acetal).

6-fluoro-2-chlorination (3)

To a solution of compound B-1 (26,1 g, 87 mmol) in EtOAc (350 ml) under nitrogen atmosphere at 25°C. added Pd-C (10% wt., 2.3 g) and the reaction mixture is placed in an atmosphere of hydrogen (1 ATM). The reaction mixture is stirred for 12 hours, filtered through celite and concentrated. The residue is again dissolved in THF (350 ml) and cooled to 0°C. To the resulting solution was added triethylamine (45,0 ml, 323 mmol) and dropwise triphosgene (8.6 g, of 29.1 mmol) in THF (60 ml). The reaction mixture is stirred for 10 minutes and add ammonia in methanol (46,1 ml, 323 mmol, 7M solution). The reaction mixture was stirred at 0°C for 10 minutes and quickly warmed to room temperature. After 15 minutes at room temperature, the reaction mixture was acidified with 4M HCl in dioxane (120 ml) to pH 2. The reaction mixture was stirred at room temperature for 1 hour and immediately concentrate. The residue is subjected to azeotropic distillation with toluene and methanol, receiving the connection-2 as a yellow solid residue. Data connection-2: mass spectrometry low resolution (M+H) m/z=164,9 found; 165,1 vicis is prohibited. The solid yellow residue is dissolved in pure phosphorus oxychloride (130 ml) and refluxed (120°C) for 1 hour. The reaction mixture is cooled and the excess solvent is removed in vacuum. The crude reaction mixture mixed with EtOAc (600 ml) and slowly quenched with water (500 ml) at 0°C. the Aqueous phase is extracted with EtOAc (2×200 ml), the combined organic phases are dried over Mg2SO4and concentrate. The crude reaction mixture was purified column chromatography (EtOAc/dichloromethane)to give compound b-3 in the form of not-quite-white solid.

Data connection-3:1H NMR (500 MHz, CDCl3) δ 9,29 (s, 1H), 8,04 (DD, J=9,0, 5.0 Hz, 1H), to 7.77-7,72 (m, 1H), to 7.59 (DD, J=7,5, 2.5 Hz, 1H) ppm;

mass spectrometry low resolution (M+H) m/z=183,2 found, USD 183.0 calculated.

Scheme

4-Methyl-1,3-benzoxazol-2-thiol (s-1)

A solution of 2-amino-m-cresol (4.0 g, 32.5 mmol) and ethylxanthate potassium (10.4 g, 65,0 mmol) in 30 ml of EtOH is refluxed for 3 hours. The solvent is removed on a rotary evaporator, the residue is dissolved in about 50 ml of water and add acetic acid to pH ~5. The resulting solid is separated by filtration and dried in vacuum, obtaining the compound C-1 as a white solid. Data for compound C-1: LC-MS: retention time=1,67 mine is; m/z (M+H)=166,0 found; 166,0 calculated.

4-Methyl-2-chloro-1,3-benzoxazol (p-2)

To a suspension of compound s-1 (1.6 g, 9.7 mmol) in POCl3(4,5 ml of 48.4 mmol) is added PCl5(2.2 g, 10.6 mmol) and approximately 10 ml of CH2Cl2. After stirring overnight the solvent is removed by evaporation on a rotary evaporator, the residue is partitioned between CH2Cl2and 5% aqueous Na2CO3. After separation of the layers the organic layer washed with water, dried over Na2SO4and concentrate. The residue is purified by chromatography on silica gel (EtOAc/hexane)to give compound 2 as a white solid. Data for compound C-2: LC-MS: retention time=2.28 min; m/z (M+H)=168,0 found; 168,0 calculated.

Scheme D

2,5-Dichloro-1,3-benzoxazol (D-1)

To a suspension of 2-mercapto-5-chlorobenzoxazole (5.0 g, 26.9 mmol) in POCl3(of 12.6 ml, 135 mmol) is added PCl5(6.2 g, of 129.6 mmol) and about 20 ml of CH2Cl2. After stirring for 5 days, the solvents are removed by evaporation on a rotary evaporator and the residue partitioned between EtOAc and saturated aqueous NaHCO3. After separation of the layers the organic layer was washed with saturated salt solution, dried over Na2SO4and concentrate. The residue is dissolved in a minimum amount of CHCl3add hexane and small if estvo solids filtered off. The filtrate is concentrated, obtaining the compound D-1 in the form of a white solid. Data for compound D-1: LC-MS: retention time=2.38 min; m/z (M+H)=188,0 found; 188,0 calculated.

Scheme E

The ketone (S-1)

A solution of BOC-Ethylenediamine (20,0 g, 125 mmol) in 250 ml of Et2O dropwise process of 10.2 ml (125 mmol) and methyl vinyl ketone are left to mix for 24 hours. Then the reaction mixture was cooled to 0°C and add to 22.6 ml (162 mmol) of triethylamine followed by the addition of 19.6 ml (137 mmol) of benzylchloride. The reaction mixture was left to slowly warm to room temperature with stirring overnight. The reaction mixture was diluted with EtOAc, washed with aqueous 10% citric acid solution, then with saturated NaHCO3and then a saturated solution of salt. The organic phase is dried over Na2SO4, filtered and concentrated, obtaining the compound E-1 in the form of a pale yellow oil. Data for compound E-1: LC-MS: retention time=2.22 min; m/z (M+H)=265,2 found; 365,2 calculated (observed loss of the BOC-group).

Benzyl-5-methyl-1,4-diazepan-1-carboxylate (E-2)

A solution of 39.0 g (107 mmol) of compound E-1 in 300 ml of EtAc is saturated with HCl (gas), the flask was closed and stirred for 2 hours. The solvents are removed on a rotary evaporator, the residue is dissolved in 1M HCl, washed with Et 2O, alkalinized with NaOH and extracted three times with 2:1 CHCl3/EtOH. The combined organic phases are washed with saturated salt solution, concentrated, dissolved in CH2Cl2and filtered, obtaining of 19.2 g of brown oil. The resulting substance was dissolved in 200 ml of CH2Cl2and to it add 5 ml of the SPLA. After stirring for 2 hours add 23.1 g (109 mmol) of Na(OAc)3VN and the resulting mixture is stirred for 48 hours at room temperature. A certain amount of the solvent is removed on a rotary evaporator and the residue is transferred into a separating funnel containing a saturated solution of NaHCO3and 2:1 CHCl3/EtOH. The layers are separated and the aqueous layer was twice extracted with CHCl3/EtOH. The combined organic layers washed with a minimum quantity of saturated salt solution, concentrated, dissolved in CH2Cl2, filtered and concentrated, obtaining the compound E-2 in the form of a brown oil. Data for compound E-2: LC-MS: retention time=1.12 min; m/z (M+H)=249,1 found; 249,2.

1-Benzyl-4-tert-butyl-5-methyl-1,4-diazepan-1,4, in primary forms (E-3)

To a solution of 23.8 g (96 mmol) of compound E-2 in 200 ml of CH2Cl2add to 26.7 ml (192 mmol) of triethylamine and 25.1 g (115 mmol) dicret-BUTYLCARBAMATE. After stirring over night at room temperature the reaction mixture was diluted with CH2 Cl2and transferred into a separating funnel, washed with a saturated solution of NaHCO3, dried over Na2SO4and concentrate. The residue is purified by chromatography on silica gel (EtOAc/hexane)to give compound E-3 in the form of a colorless oil. Data for compound E-3: LC-MS: retention time=2.64 min; m/z (M+H)=249,2 found; 349,4 calculated (observed loss of the BOC-group).

1-Benzyl-4-tert-butyl(5R)-5-methyl-1,4-diazepan-1,4, in primary forms (E-4) and 1-benzyl-4-tert-butyl(5S)-5-methyl-1,4-diazepan-1,4, in primary forms (E-5)

The enantiomers of compound E-3 preparative share in column (10 cm×50 cm Chiralpak AD when the isocratic elution with 60% EtOH and 40% hexane (containing 0.1% diethylamine) at a flow rate of 175 ml/min. In these conditions, in a single pass may be separated by about 6 g of compound E-3. Analytical analysis is performed on the column and 0.46 cm×25 cm Chiralpak AD with 60% EtOH and 40% hexane (containing 0.1% diethylamine) at a flow rate of 1 ml/min. First eluruumis enantiomer (E-4), considered as (R)-enantiomer is desired isomer and has a retention time of 4.12 minutes. It is a colourless resin >98% EE. Second eluruumis enantiomer (E-5), considered as (S)-enantiomer, is a minor isomer and has a retention time 4,82 minutes. It is a colourless resin ~90%.

Scheme F

Benzyl(5R)-5-methyl-1,4-diazepan-1-carboxylate (F-1)

A solution of 15 g (43,0 mmol) of compound E-4 in 350 ml of EtOAc saturated with HCl (gas), the flask was closed and stirred for 15 minutes. The solution is again saturated with HCl (gas), the flask was closed and stirred for 30 minutes, then volatiles removed on a rotary evaporator, getting 13,0 g cleaners containing hydrochloride salt of compound F-1 in the form of a colourless resin. Data for compound F-1: LC-MS: retention time=1.10 min; m/z (M+H)=249,2 found; 249,3 calculated.

Benzyl(5R)-5-methyl-4-[2-(2H1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-carboxylate (F-2)

To a solution of 12.0 g (of 42.3 mmol) cleaners containing hydrochloride salt of compound F-1, 8.8 g (with 46.6 mmol) of compound a-1, 6,92 g (50.8 mmol) of 1-hydroxy-7-isobenzofuranone and 18.6 ml (169 mmol) of N-methylmorpholine in 200 ml of DMF added 12.2 g (63.5 mmol) EDC and the reaction mixture was stirred over night at room temperature. The reaction mixture was partitioned between EtOAc and 10% aqueous KHSO4, washed with water, saturated solution of NaHCO3, water, saturated salt solution, dried over MgSO4and concentrate on a rotary evaporator. Previous acidic and basic layers extracted using EtOAc. The organic extracts are washed with saturated salt solution, dried, concentrated and combined with the above organic residue. The entire residue purified by chromatography on silica gel(EtOAc/hexane), receiving a connection F-2 as a colorless oil. Data for compound F-2: LC-MS: retention time=2.25 min; m/z (M+H)=420,3 found; 420,5 calculated.

(7R)-7-Methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan (F-3)

A round bottom flask containing a solution of 12.2 g (29,0 mmol) of compound F-2 in 250 ml EtOAc, pumped under reduced pressure and rinsed three times with N2. Then in the flask add to 20.4 g of 20% Pd(OH)2on carbon. The flask is again pumped under reduced pressure, rinsed three times with N2and then three times H2. The reaction mixture was stirred in an atmosphere of H2during the night, then filtered through a loose layer of celite, washed with EtOAc and then the Meon. The filtrate is concentrated, obtaining the compound F-3 as a colorless solid. Data for compound F-3: LC-MS: retention time=0,81 minute and 1.01 min (in these conditions, there is two conformer); m/z (M+H)=of 286.2 found; 286,3 calculated.

2-{(5R)-5-Methyl-4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6-perinatales (F-4)

To 3.0 g (10.5 mmol) of compound F-3 in 50 ml of DMF add 4,40 ml (to 31.5 mmol) of triethylamine and 1.92 g (10.5 mmol) of compound b-3 and the mixture is heated on an oil bath at 75°C for 4 hours, the bath temperature is reduced to 50°C and the reaction mixture is stirred overnight at this temperature. After cooling to room temperature, reacciona the mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, water, saturated salt solution and dried over MgSO4. After concentration on a rotary evaporator the residue is purified column flash chromatography (hexane/EtOAc)to give compound F-4 as a yellow solid. Data for compound F-4: LC-MS: retention time=1.88 minutes and 1.95 minutes (in these conditions, there is two conformer); m/z (M+H)=432,1949 found; 432,1943 calculated.

Scheme G

Benzyl(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,3-diazepan-1-carboxylate (G-1)

To a solution of 22.3 g (78 mmol) cleaners containing hydrochloride salt of compound F-1, 15.9 g (78 mmol) of compound a-2, 12.8 g (94 mmol) of 1-hydroxy-7-isobenzofuranone and 43.1 ml (392 mmol) N-methylmorpholine in 300 ml of DMF added to 22.5 g (118 mmol) EDC and the reaction mixture was stirred over night at room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrate on a rotary evaporator. The residue is purified column chromatography on silica gel (EtOAc/hexane)to give compound G-1 in the form of a colourless resin. Data for compound G-1: LC-MS: retention time=2.22 min; m/z (M+H)=434,2 found; 434,2 calculated.

(7R)-7-Methyl-1-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-Diaz is an (G-2)

A round bottom flask containing a solution of 29.6 g (68,3 mmol) of compound G-1 and 200 ml Meon, pumped under reduced pressure and rinsed three times with N2. Then the flask was added 2.4 g of 20% Pd(OH)2on carbon. The flask is again pumped under reduced pressure, rinsed three times with N2and then three times H2. The reaction mixture was stirred in an atmosphere of H2for three days, then filtered through a loose layer of celite, washed with EtOAc and then the Meon. The filtrate is concentrated, obtaining the compound G-2 as a white foam. Data for compound G-2: LC-MS: retention time=0.96 minutes and 1.13 minutes (in these conditions, there is two conformer); m/z (M+H)=300,0 found; to 300.2 calculated.

5-Chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol (G-3)

To 21,0 g (70,1 mmol) of compound G-2 in 250 ml of DMF type of 29.3 ml (210 mmol) of triethylamine and 13.2 g (70,1 mmol) of compound D-1 and the mixture is heated on an oil bath at 75°C for 2 hours. After cooling the bath to room temperature, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, water, saturated salt solution and dried over MgSO4. After concentration on a rotary evaporator the residue is purified column flash chromatography (hexane/EtOAc)to give the resin. The resin is stirred in a mixture of 250 ml of EtOAc and 300 ml of hexane for the eyes. After filtration obtain compound G-3 as a white solid. Data for compound G-3: LC-MS: retention time=to 2.29 min; m/z (M+H)=451,1 found; 451,2 calculated; mass spectrometry high-resolution chemical ionization at atmospheric pressure) [msvr (APCI)] m/z (M+H)=451,1631 found; 451,1644 calculated.

Scheme N

Benzyl(5R)-4-[5-bromo-2-(2N-1,2,3-triazole-2-yl)benzoyl]-5-methyl-1,4-diazepan-1-carboxylate (N-1)

To a solution of 2.5 g (8,8 mmol) cleaners containing hydrochloride salt of compound F-1, 2.35 g (8,8 mmol) of compound a-3, 1,43 g (10.5 mmol) of 1-hydroxy-7-isobenzofuranone and a 4.83 ml (43,9 mmol) N-methylmorpholine in 35 ml of DMF add 2,52 g (13,2 mmol) EDC and the reaction mixture was stirred over night at room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrate on a rotary evaporator. The residue is purified column chromatography on silica gel (EtOAc/hexane)to give compound N-1 in the form of a white solid. Data for compound H-1: LC-MS: retention time=2.28 minutes and 2,34 minutes (in these conditions, there is two conformer); m/z (M+H)=498,1 found; 498,1 calculated.

Benzyl(5R)-4-[5-(methoxycarbonyl)-2-(2N-1,2,3-triazole-2-yl)benzoyl]-5-methyl-1,4-diazepan-1-carboxylate (N-2)

Chere is C the solution 2,63 g (5.3 mmol) of the compound N-1, 118 mg (of 0.53 mmol) of palladium (II)acetate, 218 mg (of 0.53 mmol) of 1,3-bis(diphenylphosphino)propane and of 2.21 ml (15.8 mmol) of triethylamine in 20 ml of methanol and 10 ml of DMSO at 80°C for 10 minutes bubbled carbon monoxide. Then the reaction mixture is connected to the container with carbon monoxide and stirred over night at 80°C. the Reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrate on a rotary evaporator. The residue is purified column chromatography on silica gel (EtOAc/hexane)to give compound N-2 in the form of a colourless resin. Data for compound H-2: LC-MS: retention time=2.10 minutes and a 2.36 minutes (in these conditions, there is two conformer); m/z (M+H)=478,1 found; 478,2 calculated.

Methyl-3-{[(7R)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2N-1,2,3-triazole-2-yl)benzoate (H-3)

A round bottom flask containing a solution of 750 mg (1.57 mmol) of compound H-2 in 100 ml of EtOAc and 20 ml Meon, pumped under reduced pressure and rinsed three times with N2. Then the flask was added 1.1 g of 20% Pd(OH)2on carbon. The flask is again pumped under reduced pressure, rinsed three times with N2and then three times H2. The reaction mixture was stirred in an atmosphere of H2within 24 hours, then filtered through a loose layer of celite, washed with EtOAc and then the Meon. Filtration is at focus, receiving a connection H-3 in the form of a colourless resin. Data for compound H-3: LC-MS: retention time=1.01 minutes and 1.13 minutes (in these conditions, there is two conformer); m/z (M+H)=344,1 found; 344,2 calculated.

Methyl-3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2N-1,2,3-triazole-2-yl)benzoate (N-4)

To 540 mg (1.57 mmol) of compound H-3 in 10 ml of DMF added to 0.22 ml (1.57 mmol) of triethylamine and 310 mg (1,65 mmol) of compound D-1 and the mixture is heated on aluminum fuser at 50°C during the night. After cooling to room temperature the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, water, saturated salt solution and dried over MgSO4. After concentration on a rotary evaporator the residue is purified column flash chromatography (hexane/EtOAc)to give compound N-4 as a white solid. Data for compound H-4: LC-MS: retention time=2,24 minutes; m/z (M+H)=495,1 found; 495,2 calculated; mass spectrometry high-resolution chemical ionization at atmospheric pressure) m/z (M+H)=495,1561 found; 495,1542 calculated.

3-{[(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2N-1,2,3-triazole-2-yl)benzoic acid (N-4)

To a solution of 120 mg (0.25 mmol) of the compound N-4 in the Meon/THF/H2Oh, each of 20 ml, add 1,94 ml (1.94 mmol) of 1M aqueous RA the creators of sodium hydroxide and the mixture is stirred over night at room temperature. Removal of organic solvents, the reaction mixture was concentrated, then diluted with EtOAc three times washed with 1M NaOH. The aqueous layers are acidified with 1M HCl, three times washed with EtOAc, the organic layers combined, washed with water, saturated salt solution and dried over MgSO4. After concentration on a rotary evaporator, the residue suspended in a mixture of Et2O/hexane and concentrated, obtaining the compound H-5 as a white solid. Data for compound H-5: LC-MS: retention time=1,94 minutes; m/z (M+H)=481,1 found; 481,1 calculated; mass spectrometry high-resolution chemical ionization at atmospheric pressure) m/z (M+H)=481,1409 found; 481,1386 calculated.

Scheme I

[3-{[(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2N-1,2,3-triazole-2-yl)phenyl]methanol (I-1)

To 400 mg (0.81 mmol) of the compound N-4 in 10 ml of DMF add to 0.70 ml of 1.62 mmol) of 2,3M solution lydialydia in THF and the mixture is stirred for 30 minutes at room temperature. The reaction mixture was quenched with water, then diluted with EtOAc, washed with 1M HCl, water, saturated salt solution and dried over MgSO4. After concentration on a rotary evaporator the residue is purified column flash chromatography (hexane/EtOAc), concentrated, suspended in Et2O/hexane and again concentrate, receiving soy is inania I-1 in the form of a white solid. Data for compound I-1: LC-MS: retention time=1.86 min; m/z (M+H)=467,1 found; 467,1 calculated; mass spectrometry high-resolution chemical ionization at atmospheric pressure) m/z (M+H)=467,1623 found; 467,1593 calculated.

Scheme J

2-Chloro-6,7-diphthongisation (J-1)

A solution of 4,5-debtor-1,2-phenylenediamine (3 g, 20,82 mmol) in EtOH (100 ml) is treated with Glyoxylic acid (2,34 ml, 21,02 mmol, 50 wt%. in water) and heated at boiling for 3 hours. The mixture is cooled to 0°C. and the solid is separated by filtration. The resulting material was diluted with POCl3(29,1 ml, 312 mmol) and stirred at the boil under reflux for 1 hour. The refrigerator is removed and is blown through the mixture of N2that leads to concentration. The residue was diluted with DCM, cooled to 0°C and slowly add 5% aqueous solution of NaHCO3. The mixture was poured into a separating funnel and separated layers. The organic phase is washed with 5% aqueous solution of NaHCO3, dried over Na2SO4filter and concentrate. The crude substance was dissolved in CHCl3handle 12 g of silica gel and concentrated to a fine powder. Powder loaded onto silica gel and purified by the isocratic elution (10% EtOAc in DCM)to give compound J-1 in the form of not-quite-white solid.

Data for compound J-1 1H NMR (500 MHz, CDCl3) δ of 8.8 (s, 1H), 7,9 (m, 1H), 7,8 (m, 1H) ppm

6,7-Debtor-2-{(5R)-5-methyl-4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}cinoxacin (J-2)

To 711 mg (2.5 mmol) of compound F-3 in 10 ml of DMF add the 1.04 ml (7.5 mmol) of triethylamine and 500 mg (2.5 mmol) of the compound J-1, and the mixture is heated on aluminum fuser at 75°C for 5 hours. After cooling to room temperature the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, water, saturated salt solution and dried over MgSO4. After concentration on a rotary evaporator the residue is purified column flash chromatography (hexane/EtOAc), concentrated, suspended in a mixture of Et2O/hexane and again concentrate, receiving the compound J-2 as a yellow solid. Data for compound J-2: LC-MS: retention time=2.20 min; m/z (M+H)=450,0 found; 450,2 calculated; mass spectrometry high-resolution chemical ionization at atmospheric pressure) m/z (M+H)=450,1862 found; 450,1848 calculated.

SCHEME TO

5-Methyl-2-chlorothieno[2,3-d]pyrimidine (K-1)

To 1.5 g (10.9 mmol) of 2-amino-4-methylthiophene-3-carbonitrile in acetonitrile (9 ml) is added 2.0 ml (16.3 mmol) of diphosgene and the mixture is heated in a sealed tube at 100°C for 15 hours. After cooling to room temperature the reaction mixture IU is slowly poured into water and partitioned between water and EtOAc. The organic phase is washed with a saturated solution of NH4Cl, dried over MgSO4and concerts. The obtained yellow solid was dissolved in ethanol (30 ml), the resulting suspension add 2.4 g (36,1 mmol) of zinc dust and 3.1 ml (22,6 mmol) of ammonium hydroxide and the reaction mixture heated at 78°C for 1 hour. After cooling the reaction mixture to room temperature the mixture is filtered through celite, partitioned between EtOAc and water and extracted with EtOAc (2×100 ml). The organic phase is dried over MgSO4, concentrated and the residue purified column flash chromatography (EtOAc/hexane)to give compound K-1 in the form of not-quite-white solid. Data for compound K-1: LC-MS: retention time=2,03 minutes; m/z (M+H)=185,1 found; to 185.0 calculated.

5-Methyl-2-{(5R)-5-methyl-4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine (K-2)

To 27 mg (0.15 mmol) of 5-methyl-2-chlorothieno[2,3-d]pyrimidine and 42 mg (0.15 mmol) of compound F-3 in DMF (1.0 ml) is added 0.1 ml (0.73 mmol) of triethylamine and the mixture is heated at 90°C for 15 hours. After cooling to room temperature the reaction mixture was poured into water and partitioned between water and EtOAc. The organic phase is washed with a saturated solution of NH4Cl, dried over MgSO4and concerts. The residue is purified column flash chromatography (EtOAc/hexane)to give the compounds is of K-2 in the form of not-quite-white foamy solid. Data for compound K-2: LC-MS: retention time=2.68 min; m/z (M+H)=of 434.1 found; 434,2 calculated; mass spectrometry high-resolution m/z (M+H)=434,1769 found; 434,1764 calculated.

Scheme L

2,4-Dichloro-5,6,7,8-tetrahydroquinazolin (L-1)

To 10.0 g (58.8 mmol) of ethyl-2-oxocyclohexanecarboxylate in ethanol (200 ml) is added to 19.4 ml (118 mmol) of sodium methoxide and 4.6 g (76 mmol) of urea and the mixture is heated at 80°C for 15 hours. After cooling to room temperature, the white solid is filtered off and washed several times with cold diethyl ether. After drying in high vacuum, a white solid is dissolved in pure phosphorus oxychloride (77 ml) and heated at 120°C for 1 hour. The reaction mixture is cooled to room temperature and the excess phosphorus oxychloride is removed by evaporation on a rotary evaporator. The residue is partitioned between EtOAc (400 ml) and water (200 ml) and the organic phase is successively washed with a saturated solution of NaHCO3(200 ml) and saturated salt solution (200 ml). The organic phase is dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give compound L-1 in the form of a slightly yellow solid. Data for compound L-1: LC-MS: retention time=2.49 min; m/z (M+H)=203,1 found; 203,0 calculated.

2-Chloro-5,6,8-tetrahydroquinazolin (L-2)

4.7 g (23,1 mmol) of compound L-1 dechlorinate similar to that described for compound K-1, when receiving the connection L-2 as a white solid. Data for compound L-2: LC-MS: retention time=1,92 minutes; m/z (M+H)=169,2 found; 169,1 calculated.

2-{(5R)-5-Methyl-4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazolin (L-3)

284 mg (1,68 mmol) of compound L-2 and 400 mg (1,40 mmol) of compound F-3 is subjected to a combination similar to that described for compound K-2, when receiving the connection L-3 as a white solid. Data for compounds L-3: LC-MS: retention time=1,73 minutes; m/z (M+H)=418,1 found; 418,2 calculated; mass spectrometry high-resolution m/z (M+H)=418,2348 found; 418,2355 calculated.

SCHEME M

2,4-Dichloro-6,7-dihydro-5N-cyclopent[d]pyrimidine (M-1)

To 10.0 g (64,0 mmol) ethyl-2-oxocyclopentanecarboxylate in ethanol (130 ml) is added to 0.80 ml (9.6 mmol) of concentrated HCl and 5.8 g (96 mmol) of urea and the mixture is heated at 80°C for 4 hours. After cooling to room temperature the solid is filtered off and washed several times with cold diethyl ether. After drying in high vacuum, a white solid was dissolved in 1N. NaOH (100 ml) and heated at 110°C for 1 hour. The reaction mixture is cooled to room temperature and acidified with 3n. HCl to pH 2 the solid is separated by filtration. The solid is washed with cold diethyl ether and dried in high vacuum overnight (slightly modified method ofEur. J. Med. Chem.1980,15, 317-322). After drying in high vacuum, the solid is dissolved in pure phosphorus oxychloride (55 ml) and heated at 120°C for 1 hour. The reaction mixture is cooled to room temperature and the excess phosphorus oxychloride is removed by evaporation on a rotary evaporator. The residue is partitioned between EtOAc (400 ml) and water (200 ml) and the organic phase is successively washed with a saturated solution of NaHCO3(200 ml) and saturated salt solution (200 ml). The organic phase is dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give compound M-1 in the form of a white solid. Data for compound M-1: LC-MS: retention time=2.40 min; m/z (M+H)=189,1 found; 189,0 calculated.

2-Chloro-6,7-dihydro-5N-cyclopent[d]pyrimidine (M-2)

of 4.2 g (of 22.2 mmol) of compound M-1 dechlorinate similar to that described for compound K-1, when receiving the connection M-2 in the form of a white solid. Data for compound M-2: LC-MS: retention time=1,22 minutes; m/z (M+H)=155, 1mm found; 155,0 calculated.

2-{(5R)-5-Methyl-4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5N-cyclopent[d]pyrimidine (M-3)

of 32.5 mg (0.21 mmol) of the is placed M-2 and 30 mg (0,105 mmol) of compound F-3 is subjected to a combination similar to that described for compound K-2, receiving connection M-3 as a white solid. Data for compound M-3: LC-MS: retention time=1.88 min; m/z (M+H)=404,4 found; 404,2 calculated; mass spectrometry high-resolution m/z (M+H)=404,2204 found; 404,2199 calculated.

Scheme N

2-Chloro-7,8-dihydroquinoline-5(6N)-he (N-1)

To 200.0 mg (1,23 mmol) 7,8-dihydroquinoline-2,5(1N,6N)-dione in acetonitrile (6,1 ml) is added to 1.14 ml (12.3 mmol) of phosphorus oxychloride and the mixture is heated at 65°C for 3 hours. The reaction mixture is cooled to room temperature and the excess phosphorus oxychloride is removed by evaporation on a rotary evaporator. The residue is partitioned between EtOAc (400 ml) and water (200 ml) and the organic phase is successively washed with a saturated solution of NaHCO3(200 ml) and saturated salt solution (200 ml). The organic phase is dried over MgSO4and concentrate, receiving the compound N-1 in the form of a beige solid. Data for compounds N-1: LC-MS: retention time=1,54 minutes; m/z (M+H)=182,1 found; 182,0 calculated.

2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-7,8-dihydroquinoline-5(6N)-he (N-2)

of 36.4 mg (0.21 mmol) of the compound N-1 and 50 mg (0,105 mmol) of compound G-2 is subjected to a combination similar to that described for compound K-2, receiving the compound N-2 as a white solid. Data for the compounds is s N-2: LC-MS: retention time=1.88 min; m/z (M+H)=445,1 found; 445,2 calculated; mass spectrometry high-resolution m/z (M+H)=445,2357 found; 445,2352 calculated.

Scheme About

2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}pyrido[2,3-d]pyrimidine-7(8N)-he (1)

To 670 mg (3,47 mmol) of 2-(methylthio)pyrido[2,3-d]pyrimidine-7(8N)-it (synthesized according to the method found inJ. Med. Chem.2000,43, 4606-4616) in CH2Cl2(17 ml) was added 1.55 g (6,93 mmol)mCPBA and the mixture is stirred at room temperature for 1 hour. Directly, the reaction mixture was concentrated and re-dissolved in dioxane (10 ml). To the resulting solution was added 675 mg (2.25 mmol) of compound G-2 and 2.4 ml (17.3 mmol) of triethylamine. The reaction mixture is heated at 100°C for 6 hours. The reaction mixture is cooled to room temperature, quenched with saturated solution of NH4Cl and extracted with EtOAc (4×20 ml). The organic phase is dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give compound O-1 in the form of solids. Data for compound O-1: LC-MS: retention time=2.01 min; m/z (M+H)=445,4 found; 445,2 calculated.

6-Chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}pyrido[2,3-d]pyrimidine-7(8N)-he (2)

660 mg (1,49 mmol) of the compound O-1V DMF (7.4 ml) is added 347 mg (2,60 mmol) N-chlorosuccinimide (NCS) and 108 mg (0.45 mmol) of benzoyl peroxide and the mixture is stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (75 ml) and washed with water (4×30 ml). The organic phase is dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give compound O-2 as a white solid. Data for compound O-2: LC-MS: retention time=2.19 min; m/z (M+H)=479,1 found; 479,2 calculated; mass spectrometry high-resolution m/z (M+H)=479,1748 found; 479,1710 calculated.

Scheme P

5-Methyl-2-chlorothieno[2,3]pyrimidine-4-amine (P-1)

To a solution of 5-methyl-2,4-dichlorethene[2,3]pyrimidine (0.20 g, 0.9 mmol) in 5 ml THF added ammonium hydroxide (0,57 g, 4.5 mmol) and stirred at room temperature for two days. Then the system is partitioned between EtOAc and water, dried over MgSO4concentrate and purify by chromatography normal phase (0→75% EtOAc/hexane)to give compound R-1 in the form of powder color bone. Data for compound R-1: LC-MS: retention time=1.48 min; m/z (M+H)=200,1 found; 200,1 calculated.

5-Methyl-2-(4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3]pyrimidine-4-amine (P-2)

To a solution of compound P-1 (0.09 g, 0.49 mmol) and compound F-3 (0.15 g, 0.54 mmol) in 2 ml of DMF added triethylamine (0.25 g, 2.5 mmol) and the system is heated in a microwave oven at 185°C for 40 minutes. The system is partitioned between EtOAc and water, dried over MgSO4to whom will centerour and purified by chromatography normal phase (EtOAc/hexane), getting the connection to R-2 as a white foam. Data for compound P-2: LC-MS: retention time=1.45 min; m/z (M+H)=449,1 found; 449,2 calculated; mass spectrometry high-resolution m/z (M+H)=449,1869 found; 449,1867 calculated.

Scheme Q

2-Amino-4-methyl-3-furonitrile (Q-1)

To a solution of hydroxyacetone (1.0 g, 13.5 mmol) in 45 ml of Meon add solution malonitrile (0.9 g, 13.5 mmol) in tea (1,36 g, 13.5 mmol) and 10 ml of the Meon. After stirring over night at room temperature the solvent is removed on a rotary evaporator, receiving the connection Q-1 as a brown semi-solid substance.

Data for compound Q-1:1H NMR (500 MHz, CDCl3) δ a 2.01 (s, 3H), 4,71 (users, 2H), to 6.57 (s, 1H).

5-Methyl-2-chlorpro[2,3]pyrimidine (Q-2)

To a solution of compound Q-1 (1.6 g, 13,1 mmol) in 13 ml of FCN in a sealed tube add diphosgene (3,9 g and 19.6 mmol) and heated at 95°C during the night. The system is cooled to room temperature and composition partitioned between EtOAc/DCM and water, dried over MgSO4and concentrate, getting a brown oil. To a solution of the obtained oil (1.0 g, 4.9 mmol) in 30 ml of EtOH added zinc dust (2.6 g, to 39.4 mmol), ammonium hydroxide (3.0 g, 24.6 mmol) and heated to 78°C for 0.5 hours. Then the system is cooled and filtered through a loose layer of celite. Then the filtrate is partitioned between EtOAc and water, dried over MgSO4 concentrate and purify by chromatography normal phase (EtOAc/hexane)to give compound Q-2 as a yellow crystalline substance. Data for compound Q-2: LC-MS: retention time=1.65 min; m/z (M+H)=169,0 found; 169,0 calculated.

5-Methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3]pyrimidine (Q-3)

To a solution of compound Q-2 (0.02 g, 0.14 mmol) and compound G-2 (0.04 g, 0.14 mmol) in 2 ml of DMF added triethylamine (0.07 g, 0.71 mmol) and the system heated by a microwave oven at 120°C for 25 minutes. The reaction mixture was filtered and purified under conditions of reversed phase (5%→95% 0.1% TFUK in water: 0.1% TFUK in ACN) with subsequent conversion to the free base using saturated sodium carbonate, receiving compound Q-3 foam color bone. Data for compound Q-3: LC-MS: retention time=2,55 minutes; m/z (M+H)=432,3 found; 432,4 calculated; mass spectrometry high-resolution m/z (M+H)=432,2144 found; 432,2143 calculated.

Scheme R

5,6-Dimethyl-2-chlorpro[2,3]pyrimidine (R-2) and 2-chloro-4-ethoxy-5,6-dimethylfuran[2,3]pyrimidine (R-3)

To a solution of 2-amino-4,5-dimethyl-3-furonitrile (1.0 g, 7,3 mmol) in 7 ml of ACN in a sealed tube add diphosgene (3,9 g and 19.6 mmol) and heated at 95°C during the night. The system is cooled to room temperature and the contents are distributed between EOAc/DCM and water, dried over MgSO4concentrate and purify by chromatography normal phase (0→100% EtOAc/hexane)to give compound R-1 in the form of a pink solid. To the obtained substance (0,23 g, 1.0 mmol) in 8 ml EtOH added zinc dust (0.56 g, 8.6 mmol), ammonium hydroxide (0,67 g, 5.4 mmol) and heated at 78°C during the night. The system is cooled and filtered through a loose layer of celite. Then the filtrate is partitioned between EtOAc and water, dried over MgSO4and concentrate, receiving a mixture of compound R-2 and compound R-3 in the form of a reddish solid, which is used as such. Data for compound R-2: LC-MS: retention time=2,04 minutes; m/z (M+H)=USD 183.0 found; USD 183.0 calculated; Data for compound R-3: LC-MS: retention time=3.19 min; m/z (M+H)=227,1 found; 227,0 calculated.

Scheme S

5-Amino-1,3-dimethylpyrazol-4-carbonitrile (S-1)

To a solution of (1-amoxicilian)malonitrile (4.0 g, 29.4 mmol) in 75 ml Meon add methylhydrazine (1.3 g, 29.4 mmol) and the system stirred at 65°C for 2 hours. The reaction mixture was poured into a flask containing 1H. HCl. After stirring over night at room temperature the solvent is removed on a rotary evaporator, getting a brown semi-solid substance. The resulting material partitioned between EtOAc and water, dried over MgSO4and concentrate, receiving the connection is s S-1 in the form of a reddish powder.

Data for compound S-1:1H NMR (500 MHz, CDCl3) δ of 2.21 (s, 3H), 3,55 (s, 3H),4,13 (users, 2H).

1,3-Dimethyl-6-chloropyrazole[3,4]pyrimidine (S-2)

To a solution of compound S-1 (1.0 g, 7,3 mmol) in 7 ml of ACN in a sealed tube add diphosgene (2.1 g, 11.0 mmol) and heated at 95°C during the night. The system is cooled to room temperature and the contents are distributed between EtOAc/DCM and water, dried over MgSO4concentrate and purify by chromatography normal phase (EtOAc/hexane)to give white crystalline powder. To a solution of the obtained white crystalline powder (from 0.37 g, 1.7 mmol) in 12 ml of EtOH added zinc dust (0.9 g, a 13.9 mmol), ammonium hydroxide (1.1 g, 8,7 mmol) and heated at 78°C for 0.5 hours. The system is cooled and filtered through a loose layer of celite. Then the filtrate is partitioned between EtOAc and water, dried over MgSO4and concentrate, receiving a mixture of compound S-2 as a yellow solid. Data for compound S-2: LC-MS: retention time=1.31 min; m/z (M+H)=183,1 found; USD 183.0 calculated.

The T

5-Bromo-1,3-benzoxazol-2-thiol (T-1)

To a solution of 2-amino-4-Grafenau (3.0 g, 15.9 mmol) in 45 ml of EtOH add ethylxanthate potassium (5,1 g, 31.9 per mmol) and the system was stirred at 80°C for 3 hours, cooled to room temperature and stirred over night. The solvent is removed vacuume, then dissolved in water and acidified with acetic acid, which leads to the formation of sludge. The obtained precipitate was separated by filtration, giving the compound T-1 in the form of a grayish-white powder. Data for compound T-1: LC-MS: retention time=2.17 min; m/z (M+H)=230,0 found; 230,0 calculated.

5-Bromo-2-chloro-1,3-benzoxazol (T-2)

To a solution of compound T-1 (1.8 g, 7.8 mmol) in 6 ml of DCM added phosphorus oxychloride (6.0 g, 39,1 mmol), then pentachloride phosphorus (2.4 g, 11.7 mmol) and the system is stirred over night at room temperature. The solvent is removed in vacuum and the reaction mixture was partitioned between DCM and saturated with sodium bicarbonate solution and water. The organic layer is dried over Na2SO4concentrate and purify by chromatography normal phase (EtOAc/hexane)to give compound T-2 as a white solid. Data for compound T-2: LC-MS: retention time=2.37 min; m/z (M+H)=232,9 found; 232,9 calculated.

Scheme U

4-(Allyloxy)-2-(methylthio)-5-vinylpyridin (U-1)

To 3.0 g (12.9 mmol) of ethyl-2-(methylthio)-4-chloropyrimidine-5-carboxylate THF (65 ml) was added 1.12 g (to 19.3 mmol) of allyl alcohol and of 6.45 ml (12.9 mmol, 2M in THF) NaHMDS. The reaction mixture was stirred at room temperature for 2 hours and quenched by adding a saturated solution of salt. The aqueous phase extragere the t EtOAc (4×20 ml), dried over MgSO4and concentrate. The crude reaction mixture was again dissolved in THF (50 ml) and of 38.7 ml (38,7 mmol, 1M in THF) and at room temperature add diisobutylaluminum. After about 45 minutes the reaction mixture was quenched with a saturated solution of potassium sodium tartrate. The aqueous phase is extracted with EtOAc (4×50 ml), dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give oil. The oil obtained is dissolved in chloroform (31 ml) and the resulting solution was added 4.1 g (4.7 mmol) MnO2. The reaction mixture was stirred at room temperature for 4 hours, filtered through celite and concentrated, obtaining a clear oil. The oil obtained in THF (10 ml) are added to a suspension of 8.3 ml (16,7 mmol, 2M in THF) NaHMDS and 6.8 g (19.0 mmol) of methyltriphenylphosphonium in THF (40 ml) and the reaction mixture is stirred for 2 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (4×50 ml). The combined organic phases are dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give oil. Data for compound U-1: LC-MS: retention time=2,87 minutes; m/z (M+H)=208,9 found; 209,1 calculated.

(5R)-1-[4-(Allyloxy)-5-vinylpyridin-2-yl]-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan (U-2)

To 500 mg (2,40 mmol) of the compound U-1 in CH2Cl2 (12.0 ml) is added 1.08 g (4.8 mmol)ofmCPBA and the mixture is stirred at room temperature for 1 hour. Directly, the reaction mixture was concentrated and the residue is dissolved in DMF (10 ml). To the resulting solution was added to 1.67 ml (12,0 mmol) of triethylamine and 1.44 g (4.8 mmol) of compound G-2 and the reaction mixture is heated to 100°C. After 4 hours the reaction mixture is cooled and partitioned between EtOAc and water. The combined organic extracts dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give compound U-2 as a foamy solid. The connection information for U-2: LC-MS: retention time=2.30 min; m/z (M+H)=460,3 found; 460,2 calculated.

2-{(5R)-5-Methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-7N-pyrano[2,3-d]pyrimidine (U-3)

To 500 mg (1,09 mmol) of the compound U-2 in degassed 1,2-dichloroethane (5,4 ml) is added 0.12 g (4.8 mmol) of the catalyst Jean 1b and the mixture is stirred at room temperature for 15 hours. The reaction mixture was partitioned between EtOAc and water and the combined organic extracts dried over MgSO4and concentrate. The residue is purified column flash chromatography (EtOAc/hexane)to give compound U-3 in the form of a foamy solid. The connection information for U-3: LC-MS: retention time=1.69 min; m/z (M+H)=432,2 found; 432,2 calculated; m is SS spectrometry high-resolution m/z (M+H)=432,2155 found; 432,2143 calculated.

2-{(5R)-5-Methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5N-pyrano[2,3-d]pyrimidine (U-4)

To 420 mg (0.97 mmol) of the compound U-3 in degassed ethyl acetate (9.7 ml) is added 68 mg of 20% of the mass. of palladium hydroxide and the reaction mixture is placed in an atmosphere of hydrogen at room temperature. After 2 hours the reaction mixture was filtered through celite and concentrated. The residue is purified column flash chromatography (EtOAc/hexane)to give compound U-4 in the form of a foamy solid. Data for compound U-4: LC-MS: retention time=1,63 minutes; m/z (M+H)=434,2 found; of 434.1 calculated; mass spectrometry high-resolution m/z (M+H)=434,2312 found; 434,2299 calculated.

Scheme V

5-Methyl-2-chloro-4-[(1E)-prop-1-EN-1-yl]pyrimidine (V-1)

To 1.5 g (9.2 mmol) of 5-methyl-2,4-dichloropyrimidine in DMF (35 ml) is added 1.5 g (10.1 mmol) of alitretinoin potassium, 150 mg (0.18 mmol) PdCl2(dppf)·DCM and 1.54 ml (11 mmol) of triethylamine. The reaction mixture was stirred at 100°C for 15 hours. The reaction mixture was diluted with EtOAc (60 ml), washed with water, saturated sodium bicarbonate solution and saturated salt solution and concentrated. The residue is purified column flash chromatography (EtOAc/hexane)to give oil. Data for compound V-1: LC-MS: retention time=to 2.06 min; m/z (M+H)=169,1 n is Geno; 169,6 calculated.

5-Methyl-4-propyl-2-chloropyrimidine (V-2)

To 550 mg (3,26 mmol) of compound V-1 in ethanol (10 ml) was added 100 mg of 10% platinum on carbon and the mixture is stirred at room temperature under the pressure of the balloon of hydrogen gas for 15 hours. The reaction mixture was filtered through celite and concentrated, obtaining oil. Data for compound V-2: LC-MS: retention time=2.04 min; m/z (M+H)=RUB 171.1 found; 171,6 calculated.

(5R)-5-Methyl-1-(5-methyl-4-propylpyrimidine-2-yl)-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan (V-3)

A mixture of 289 mg (0.97 mmol) of compound G-2, 165 mg (0.97 mmol) of compound V-2 and 674 μl (a 4.83 mmol) of triethylamine in DMF (5 ml) was stirred at 100°C. for 15 hours. The reaction mixture was diluted with EtOAc (60 ml), washed with water, saturated sodium bicarbonate solution and saturated salt solution and concentrated. The residue is purified column flash chromatography (EtOAc/hexane)to give foamy solid. Data for compound V-3: LC-MS: retention time=2.30 min; m/z (M+H)=434,2 found; 434,5 calculated; mass spectrometry high-resolution m/z (M+H)=434,2667 found; 434,2663 calculated.

Scheme W

(5R)-1-[4-Chloro-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[5-methyl-1,2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan (W-1)

A mixture of 100 mg (0.33 mmol) of compound G-2, 87 mg (0.4 mmol) of 2,4-dichlor-(trifluoromethyl)pyrimidine and 233 μl (1,67 mmol) of triethylamine in DMF (2 ml) was stirred at 100°C. in microwave oven for 30 minutes. The reaction mixture was diluted with EtOAc (60 ml), washed with water, saturated sodium bicarbonate solution and saturated salt solution and concentrated. The residue is purified column flash chromatography (EtOAc/hexane)to give foamy solid. Data for compound W-1: LC-MS: retention time=2,63 minutes; m/z (M+H)=480,1 found; 480,9 calculated.

(5R)-5-Methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1-[4-methyl-5-(trifluoromethyl)pyrimidine-2-yl]-1,4-diazepan (W-2)

A mixture of 30 mg (0,063 mmol) of compound W-1, 22 mg (0.125 mmol) of trimethylamine, 5 mg (0.006 mmol) PdCl2(dppf) and 26 mg (of 0.625 mmol) of LiCl in DMF (1.5 ml) was stirred at 130°C for 30 minutes. Added 22 mg (0.125 mmol) of trimethylamine and the reaction mixture is stirred for another hour. The reaction mixture was diluted with EtOAc (60 ml), washed with saturated sodium bicarbonate solution and saturated salt solution and concentrated. The residue is purified column flash chromatography (EtOAc/hexane)to give foamy solid. The connection information for W-2: LC-MS: retention time=3,48 minutes; m/z (M+H)=460,0 found; 460,5 calculated; mass spectrometry high-resolution m/z (M+H)=460,2090 found; 460,2067 calculated.

(5R)-1-[4-Methoxy-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan (W-3)

A mixture of 312 mg (of 0.65 mmol) of the compound W-1 and 446 μl (1,95 mmol, 4,n. meta is OLE) sodium stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc (60 ml), washed with water, saturated sodium bicarbonate solution and saturated salt solution and concentrated. The residue is purified column flash chromatography (EtOAc/hexane)to give foamy solid. Data for compound W-3: LC-MS: retention time=3,27 minutes; m/z (M+H)=476,0 found; 476,5 calculated; mass spectrometry high-resolution m/z (M+H)=476,2022 found; 476,2017 calculated.

Scheme X

2-Methyl-6-{5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}nicotinamide (X-1)

A mixture of 50 mg (0,17 mmol) of compound G-2, 34 mg (0.22 mmol) of 2,6-dichloropyridine-3-carboxaldehyde and 116 μl (0.84 mmol) of triethylamine in DMF (3 ml) was stirred at 100°C for 45 minutes. The reaction mixture was diluted with EtOAc (60 ml), washed with water, saturated sodium bicarbonate solution and saturated salt solution and concentrated. The residue is purified column flash chromatography (EtOAc/hexane)to give foamy solid. Data for compound X-1: LC-MS: retention time=1.96 min; m/z (M+H)=419,1 found; 419,5 calculated.

2-Methyl-6-{5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}pyridine-3-yl)methanol (X-2)

A mixture of 30 mg (0,072 mmol) of compound X-1 and 2.7 mg (0,072 mmol) detribalized in methanol (1 ml) was stirred at room temperature during the course the e 10 minutes. The reaction mixture was diluted with EtOAc (60 ml), washed with water, saturated sodium bicarbonate solution and saturated salt solution, dried over sodium sulfate and concentrated, obtaining a solid substance. Data for compound X-2: LC-MS: retention time=1.25 min; m/z (M+H)=UAH 421,2 found; 421,5 calculated; mass spectrometry high-resolution m/z (M+H)=421,2347 found; 421,2347 calculated.

The following compound is obtained using the above methodology, but substituting the appropriate substituted reagents, as described in the above schemes reactions and examples. Required source materials were commercially available, described in the literature or can be easily synthesized by a specialist in the field of organic synthesis without time-consuming experimentation.

Table 1
Connection.StructureNameVRMS m/z (M+H)
1-14-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazolFound 431,2202 calculated 431,2190
1-25-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidineFound 448,1920 calculated 448,1914
1-32-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazolinFound 432,2515 calculated 432,2512
1-42-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5N-cyclopent[d]pyrimidineFound 418,2354 calculated 418,2350

1-55,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3-d]pyrimidineFound 446,2299 calculated 466,2299
1-64 ethoxy-5,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-Diaz is EN-1-yl}furo[2,3- d]pyrimidineFound 490,2559 calculated 490,2561
1-71,3-dimethyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1N-pyrazolo[3,4-d]pyrimidineFound 446,2410 calculated 446,2412
1-85-bromo-2-{(5R)-5-methyl-4-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazolFound 495,1164 calculated 495,1144
1-9(5R)-5-methyl-1-[4-methyl-5-(trifluoromethyl)pyrimidine-2-yl]-4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepanFound 446,1908 calculated 446,1911
1-10(5R)-1-[4-methoxy-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[2-(2N-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepanFound 460,1856 calculated 460,1860

The following compound is obtained using the above methods when replacing the corresponding substituted reagents, as described in the criminal code is mentioned above schemes reactions and examples. Required source materials were commercially available, described in the literature or can be easily synthesized by a specialist in the field of organic synthesis without time-consuming experimentation:

6-fluoro-2-{(5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}hinzelin;

5-chloro-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol;

methyl-3-{[(7S)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazole-2-yl)benzoate;

3-{[(7S)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazole-2-yl)benzoic acid;

[3-{[(7S)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazole-2-yl)phenyl]methanol;

6,7-debtor-2-{(5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}cinoxacin;

5-methyl-2-{(5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;

2-{(5S)-5-methyl-4-[2-(2H-1,2,3-terazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazolin;

2-{(5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopent[d]pyrimidine;

2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-7,8-dihydroquinoline-5(6H)-he;

6-chloro-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}pyrido[2,3-d]pyrimidine-7(8H)-he;

<> 5-methyl-2-(4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3]pyrimidine-4-amine;

5-methyl-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3]pyrimidine;

2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine;

(5S)-5-methyl-1-(5-methyl-4-propylpyrimidine-2-yl)-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;

(5S)-1-[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;

(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1-[4-methyl-5-(trifluoromethyl)pyrimidine-2-yl]-1,4-diazepan;

(5S)-1-[4-methoxy-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;

2-methyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}pyridine-3-yl)methanol;

4-methyl-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol;

5-methyl-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;

2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazolin;

2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopent[d]pyrimidine;

5,6-dimethyl-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1 and the}furo[2,3- d]pyrimidine;

4 ethoxy-5,6-dimethyl-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3-d]pyrimidine;

1,3-dimethyl-6-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1H-pyrazolo[3,4-d]pyrimidine;

5-bromo-2-{(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol;

(5S)-5-methyl-1-[4-methyl-5-(trifluoromethyl)pyrimidine-2-yl]-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;

(5S)-1-[4-methoxy-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan.

Although the invention has been described and illustrated with reference to some specific variations in its implementation, the person skilled in the art will understand that can be made various improvements, changes, modifications, deletions or additions of procedures and protocols without deviating from the essence and scope of the invention.

1. Compound which is selected from the group consisting of
6-fluoro-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}hintline;
5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;
methyl-3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazole-2-yl)benzoate;
3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazole-2-yl)benzoic acid;
[3-{(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazole-2-yl)phenyl]methanol;
6,7-debtor-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl} cinoxacin;
5-methyl-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;
2-{(5R)-5-methyl-4-[2-(2H-1,2,3-terazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazoline;
2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopent[d]pyrimidine;
2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-7,8-dihydroquinoline-5(6N)-she;
6-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}pyrido[2,3-d]pyrimidine-7(8H)-she;
5-methyl-2-{4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3]pyrimidine-4-amine;
5-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3]pyrimidine;
2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine;
(5R)-5-methyl-1-(5-methyl-4-propylpyrimidine-2-yl)-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;
(5R)-1-[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;
(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1-[4-methyl-5-(trifluoromethyl)pyrimidine-2-yl]-1,4-diazepan;
(5R)-1-[4-methoxy-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;
2-methyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}pyridine-3-yl)meta is Ola;
4-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;
5-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;
2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazoline;
2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopent[d]pyrimidine;
5,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-1,4-diazepan-1-yl}furo[2,3-d]pyrimidine;
4 ethoxy-5,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3-α]pyrimidine;
1,3-dimethyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1H-pyrazolo[3,4-d]pyrimidine;
5-bromo-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;
(5R)-5-methyl-1-[4-methyl-5-(trifluoromethyl)pyrimidine-2-yl]-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;
(5R)-1-[4-methoxy-5-(trifluoromethyl)pyrimidine-2-yl]-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan;
or their pharmaceutically acceptable salts.

2. Pharmaceutical composition having antagonist activity Aracinovo receptor containing an inert carrier and a compound according to claim 1 or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or its pharmaceutically acceptable salt for use in medicine.

4. Application with the organisations according to claim 1 or its pharmaceutically acceptable salt for a medicinal product for the treatment or prevention of sleep disorders.

5. The way to improve the quality of sleep in vulnerable patients mammals which comprises administration to the patient a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.

6. Method for the treatment of insomnia in vulnerable patients mammals which comprises administration to the patient a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.

7. A method of treating or controlling obesity in vulnerable patients mammals which comprises administration to the patient a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.

8. The compound 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol or its pharmaceutically acceptable salt.

9. The compound of claim 8 where the compound is 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol.

10. Pharmaceutical composition having antagonist activity Aracinovo receptor containing a pharmaceutically acceptable carrier and the compound 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol or its pharmaceutically acceptable salt.

11. The pharmaceutical composition of claim 10, where the composition comprises 5-chlor-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazol.

12. Method for the treatment of insomnia in people, which includes an introduction to the patient a therapeutically effective amount of a compound of claim 8.

13. Method for the treatment of insomnia in people, which includes an introduction to the patient a therapeutically effective amount of a compound according to claim 9.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of indole with formula (I) or indole pharmaceutically acceptable salts: where: ring A stands for a benzene or a tiofen ring; R1 stands for a C1-.6 alkyl that may be substituted by one or several groups selected from among -OH, - O-C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls; -O-C1-6 alkyl; a halogen; CN; 5-6-membered cyclic amine; n is equal to 0 - 4 and to 0- 2 if ring A is a benzene or a tiofen ring accordingly; R2 stands for -H, -C1-6 alkyl; R3 stands for H, -C1-6 alkyl that may be substituted by phenyl, C3-6 cycloalkyl; R4 stands for C1-6 alkyl that may be substituted by one or several groups selected from among -OH, -O- C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls and 5-6-membered cyclic amine; C3-6 cycloalkyl, phenyl or-OH; X1 stands for -CH2-, -O-, -S-, -CH(R°)-; X2 stands for -C(RA)(RB)-, -O-; X3 stands for -C(RC)(RD)-; m is equal to 1 - 3; R° stands for -H, or R°, together with R4, form C3-6 alkylene; RA, RB, RC and RD are identical or different and stand for -H, C1-6 alkyl where, in case m is equal to 2 or 3, each RC and R° may be identical or different provided 1- methyl-4a-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno [1,2-b] pyridine, 4a-phenyl-2,3,4,4a,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine and 2-(1,2,3,4,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine -4a-yl)-N,N-dimethylethanamine are excluded).

EFFECT: compounds possess antagonistic activity regarding NMDA receptor which enables their usage in pharmaceutical compositions for treatment of Alzheimer disease, vascular dementia, Parkinson disease, chronic depression, attention deficit hyperactivity disorder, migraines etc.

18 cl, 40 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to azabenzothiophenyl compounds of formula I

and salts thereof, where: Z1 denotes CR1; Z2 denotes N; Z3 denotes CR3; Z4 denotes CR4; R1, R3 and R4 are independently selected from H or halogen; W denotes , R5 and R6 denote H; X1 denotes -OR11; X2 denotes phenyl which is optionally substituted with one or two groups selected from halogen or (C1-C3)alkylsulphanyl; R11 denotes (C1-C12) alkyl, substituted by one or two groups independently selected from - (CR19R20)nOR16; n equals 0; R16 denotes H, (C1-C12) alkyl or (C2-C8) alkenyl. The invention also relates to a pharmaceutical composition based on said compounds, which can be used in medicine for treating hyperproliferative disorders.

EFFECT: high efficiency of using said compounds.

11 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: method is realised by treating a compound of formula

with boronic acid or ether thereof of formula

,

in which two OR15 groups together with the boron atom with which they are bonded form a pinacolato boronate ester group in the presence of a Pd catalyst. The invention relates to a method of producing a pharmaceutically acceptable salt of thieno[3,2-d]pyrimidine of formula

.

The invention also relates to a pharmaceutical composition, having phosphatidyl inositol-3-kinase inhibitor activity, containing thieno[3,2-d]pyrimidine of formula (I) as an active ingredient, a method of preparing said composition and use of thieno[3,2-d]pyrimidine of formula (I) or pharmaceutically acceptable salt thereof in producing a medicinal agent for inhibiting phosphatidyl inositol-3-kinase.

EFFECT: use of the derivative as a phosphatidyl inositol-3-kinase inhibitor.

11 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing prasugrel hydrochloride which involves the following stages: (i) chlorination of a compound described by formula (III) by addition of an chlorinating agent, optionally drop-by-drop, in a solvent; (ii) reaction of the prepared compound of formula (IV) and a compound described by general formula (V) where R means a protective group for hydroxyl, or its salt in a solvent in the presence of a base; (iii) acetylation of the prepared compound described by general formula (II) by reaction with an acetylation agent in a solvent in the presence of a base and an acetylation catalyst; and (iv) addition of hydrochloric acid, optionally drop-by-drop, to the prepared compound described by formula (I) in a solvent to produce prasugrel hydrochloride described by formula (1a), and differs by the fact that at the stage (i) temperature during addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C, and reaction temperature after addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C. The invention also concerns a product containing prasugrel hydrochloride and CATP in an amount no more than 0.3 %, to the pharmaceutical composition suitable for prevention or treatment of thrombosis or embolism on the basis of the specified product.

EFFECT: production of low-CATP prasugrel hydrochloride.

31 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method of olanzapine purification which involves mixing olanzapine with an organic acid in an organic solvent or a mixture of organic solvents to prepare acid-additive olanzapine salt, precipitation and isolation of acid-additive olanzapine salt and transforming acid-additive olanzapine salt in olanzapine; the organic acid is carboxylic acid which is selected from the group including oxalic, fumaric and benzoic acid.

EFFECT: invention refers to methods for producing pure olanzapine, intermediate products and acid-additive olanzapine salts which in turn can find application for producing pure olanzapine used for preparing a drug for treating mental disorders and conditions.

38 cl, 1 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 5-(4-oxo-2-thioxo-1,3,4,5-tetrahydro-2H-chromeno [2,3-d] pyrimidin-5-yl)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione of formula

, which involves reaction of thiobarbituric acid with salicylic aldehyde in ethyl alcohol medium with molar ratio of reagents equal to 1:1 at temperature 70-80°C for 30 minutes.

EFFECT: novel method for synthesis of said compounds with high output, which can be used as a intermediate product for preparing medicinal agents for treating Alzheimer's disease.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I)

or pharmaceutically acceptable salts thereof, in which: R1, R2, R3, R4, A and E are as described in the claim, and to pharmaceutical composition containing said compounds, and a method of treating and application in order to treat conditions mediated by antagonistic activity towards acid pump, such as gastrointestinal diseases, gastrooesophageal diseases, gastrooesophageal reflux disease (GERD), laryngopharyngeal reflux disease, peptic ulcers, gastric ulcers, duodenal ulcers, NSAID- induced ulcers, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, nonerosive reflux disease (NERD), viscerogenic pain, cancer, heartburn, nausea, oesophagitis, dysphagia, hypersalivation, disorders of the respiratory channel or asthma.

EFFECT: possibility of using compounds to treat different diseases.

9 cl, 1 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: medicine.

SUBSTANCE: invention refers to new pyridine derivatives or to their pharmaceutically acceptable salts of general formula 1: wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from the group including hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino, C4-C9cycloalkylamino, C4-C9heterocycloalkylamino, C1-C10aralkylamino, arylamino, acylamino, saturated heterocyclyl, acyloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy; X represents oxygen or sulphur atom; Y represents oxygen atom or N-R8, wherein R8 is chosen from the group including hydrogen atom; aforesaid aryl group is chosen from phenyl, naphthyl and condensed phenyl group; aforesaid heteroaryl and saturated heterocyclic groups represent pentagonal or hexagonal heterocyclic ring containing 1 to 2 heteroatoms chosen from oxygen, nitrogen and sulphur atom; or condensed heterocyclic ring; and aforesaid aryl and heteroaryl groups are those that 1 to 4 assistants chosen from group including halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted. And specified compounds or their pharmaceutically acceptable salt of formula 1 are not compounds as follows 6-methyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 5-vinyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 6-methyl-8-furan-2-yl-3,4- dihydropyrano[3,4-c]pyridin-1-one, 3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-8-one and dimethyl ether (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthyridine-3,5-dicarboxylic acids.

EFFECT: compounds possess inhibitory action with respect to formation of cytokines involved in inflammatory reactions, can be used as a therapeutic agent for treatment of inflammatory diseases, immune diseases, chronic inflammations; it provides antiinflammatory and analgesic action.

21 cl, 7 tbl, 144 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

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