Compounds and compositions as itpkb inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole derivatives of general formula I

and pharmaceutically acceptable salts thereof, where n equals 1 or 2, m equals 0, 1 or 2, A contains in the ring a group selected from -CR1=, -CR2=, -CR3=, -CR4= and -CR5=, where 0 or 1 in these groups is replaced with N, R1, R2, R3, R4 and R5 are independently selected from a group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6 heterocycloalkyl-C0-alkyl, where the said heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, C5heteroaryl-(C0-C4)alkyl, where the said heteroaryl contains 1-4 heteroatoms selected from nitrogen atoms, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12; -XN(XOR12)2, -XNR11XC(O)OR12 -XNR11XNR11C(O)R12 -XNR11XNR11R12, -XNR11C(O)R12, where each X is independently selected from a group comprising a chemical bond and C1-C4alkylene, each R11 is selected from a group comprising hydrogen and C1-C6alkyl, and R12 is selected from a group comprising hydrogen, C1-C6alkyl and phenyl, or R11 and R12 together with a nitrogen atom to which R11 and R12 are bonded form C6heterocycloalkyl. Said heteroaryl or heterocycloalkyl in R1, R2, R3, R4 or R5 optionally contains one substitute selected from a group comprising hydroxyl, cyano, C1-C6alkyl, hydroxyl(C1-C6)alkyl and carboxy, R6 and R7 independently denote hydrogen, R8 is selected from a group comprising C1-C6alkyl, halogen(C1-C3)alkyl, -CH2OR8a and -COOR8a or two R8 groups bonded to different carbon atoms, together form a (C1-C2)alkyl bridge, or two R8a groups bonded to one carbon atom form a (C3-C8)cycloalkyl group, where R8a is selected from a group comprising hydrogen and C1-C6alkyl, R9 is selected from a group comprising phenyl and C6heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen atoms, and C9heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, where the said phenyl or heteroaryl in R9 is optionally substituted with 1-2 substitutes independently selected from a group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14, where each of R13 and R14 is independently selected from a group comprising hydrogen and C1-C6alkyl, R10 denotes hydrogen, Y and Z are independently selected from a group comprising CR20 and N, where R20 denotes hydrogen, provided that compounds of formula I do not include compounds of formula II, which are described in claim 1, and provided that compounds of formula I do not include compounds which are: 1-(4-fluorophenyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)piperazine, 1- ((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(4-(trifluoromethyl)-(pyridin-2- yl)piperazine, 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)-(pyridin-2-yl)piperazine and 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-fluoropyridin-2-yl)piperazine. The invention also relates to specific compounds obtained.

EFFECT: novel pyrazole derivatives which can be used in treating diseases or disorders which are mediated by disrupted activation of the said compound are obtained.

8 cl, 1 tbl, 4 ex

 

Reference to related applications

This application claims earlier priority based on provisional application U.S. ser. room 60/832681 registered on July 21, 2008, and provisional application U.S. ser. room 60/893874 registered 08 March 2007 Full descriptions of these applications are included in the description of the present application by reference in full.

Background of invention

The scope of the invention

The invention proposes a new class of compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or impaired activity In cells, particularly diseases or disorders that are associated with abnormal activation of the Inositol-1,4,5-trisphosphate-3-kinase B (ITPKb).

Background of invention

Protein kinases represent a large family of proteins which play a Central role in the regulation of many cellular processes and control cellular functions. A partial list of such kinases includes, without limitation, protein-nonspecific kinase, such as IPTKb, receptor tyrosine kinase, such as receptor kinase platelet growth factor (PDGF-R), growth factor receptor nerve tissue, trkB, Met and receptor fibroblast growth factor FGFR3, preceptory tyrosine kinase, such as Abl and hybrid kinase BCR-Abl, Lck, Csk, Fes, Bmx and c-src, and serine/trionychinae, such as b-RAF, c-RAF, sgk, MAP kinase (e.g., MCC, MCC etc) and SAPK2α, SAPK2β and SAPK3. Impaired kinase activity is observed in many pathological conditions, including benign and malignant proliferative disorders and diseases associated with abnormal activation of the immune and nervous systems.

The new compounds of the present invention inhibit the activity IPTKb and, therefore, can be used to treat IPTKb-related diseases.

A brief description of the invention

One object of the present invention are the compounds of formula I:

where

n is chosen from 0, 1, 2 and 3

m is chosen from 0, 1, 2 and 3

And in the cycle contains up to three groups selected from the group including CR1=, -CR2=, -CR3=, -CR4= - CR5=replaced by N,

R1, R2, R3, R4and R5independently selected from the group comprising hydrogen, hydroxy, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, C3-C8heteroseksualci(C0-C4)alkyl, C1-C10heteroaryl(C0-C4)alkyl, -XSO2R11 , -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12, -XN(XOR12)2, -XNR11XC(O)OR12, -XNR11XNR11R12, -XNR11XNR11C(O)R12, -XNR11C(O)R12where each X is independently selected from the group comprising a chemical bond With1-C4alkylen, each R11selected from the group including hydrogen and C1-C6alkyl, a R12selected from the group including hydrogen, C1-C6alkyl and C6-C10aryl, or R11and R12together with the nitrogen atom to which R11and R12attached, form a3-C8heteroseksualci, and the specified heteroaryl or heteroseksualci R1, R2, R3, R4or R5optionally substituted by 1-3 substituents, independently selected from the group comprising halogen, hydroxy, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl and carboxy,

R6and R7independently selected from the group including hydrogen, C1-C3alkyl, or R6and R7together with the carbon atom, to the mu they are attached, form3-C7cycloalkyl,

R8selected from the group including1-C6alkyl, halogen(C1-C3)alkyl, C1-C6alkoxy, -CH2OR8a-COOR8aand C2-C6alkenyl, or two groups R8attached to different carbon atoms, together form the alkyl bridge, or two groups R8attached to the same carbon atom, form a group With3-C8cycloalkyl or carbonyl group, where R8aselected from the group including hydrogen and C1-C6alkyl,

R9selected from the group including6-C10aryl and C1-C10heteroaryl where specified aryl or heteroaryl R9optionally substituted by 1-3 substituents, independently selected from the group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, cyano(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14where each R13and R14independently selected from the group including hydrogen and C1-C6alkyl,

R10selected from the group including hydrogen, C1-C6alkyl, -NR15R16, -NR15C(O)R16and-C(O)NR15R16where each R15and R16independently selected from the group including hydrogen, C1-C6alkyl, C 6-C10aryl, C1-C10heteroaryl,3-C12cycloalkyl and C3-C8heteroseksualci where specified aryl, heteroaryl, cycloalkyl and heteroseksualci optionally substituted by 1-3 substituents, independently selected from the group comprising halogen, hydroxy, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy,

Y and Z independently are selected from the group including CR20and N, where R20selected from the group including hydrogen and C1-C4alkyl,

and their pharmaceutically acceptable salts, provided that the compounds of formula I include compounds of formula II and N-oxides, prodrugs, substituted derivatives, individual isomers and mixture of isomers, pharmaceutically acceptable salt and solvate (e.g., hydrates) of such compounds.

The second object of the present invention is a pharmaceutical composition comprising a compound of formula I or its N-oxide, individual isomers and mixture of isomers, or pharmaceutically acceptable salt in a mixture with one or more suitable excipients.

The third object of the present invention is a method of treating disease in an animal in which inhibition of kinase activity, primarily ITPKb activity, prevents, inhibits or Smage the pathological condition and/or symptoms moreover, this method includes the introduction of the animal a therapeutically effective amount of the compounds of formula I or its N-oxide, individual isomers and mixture of isomers or a pharmaceutically acceptable salt.

The fourth object of the present invention is the use of compounds of formula I to obtain a medicinal product intended for the treatment of a disease in an animal in which kinase activity, primarily ITPKb activity, contributes to the development of pathological conditions and/or symptoms.

The fifth object of the present invention is a method of obtaining compounds of formula I and their N-oxides, prodrugs, substituted derivatives, individual isomers and mixtures of isomers and pharmaceutically acceptable salts.

Detailed description of the invention

Definitions (terms)

"Alkyl" as a group or as a structural element of other groups, such as halogenated and alkoxy means a hydrocarbon residue with a straight or branched chain. With1-C4alkoxy includes methoxy, ethoxy etc. Halogenated includes trifluoromethyl, pentafluoroethyl etc.

"Aryl" means a monocyclic or condensed bicyclic aromatic system containing a cycle from six to ten carbon atoms. For example, aryl means phenyl or naphthyl, prepact the positive phenyl. "Allen" means the divalent radical formed aryl group.

"Heteroaryl" is a saturated, unsaturated or partially saturated monocyclic system containing a cycle of 5-7 atoms selected from C, O, N and S, including, for example, pyridyl, indolyl, imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, morpholino, pyrrolidinyl, pyrrolidinyl-2-it, piperazinil, piperidinyl, piperidinyl etc.

The term "bridged or condensed bicyclic system containing 8 to 14 atoms selected from atoms of C, O, N and S (which is a saturated, unsaturated or partially saturated), includes, for example, indazoles, honokalani, chinoline, benzofuranyl, benzopyranyl, benzothiophene, benzo[1, 3]dioxol, benzimidazolyl, 1,4-dioxa-8 azaspiro[4.5]Dec-8-yl, etc.

"The compounds of formula II are compounds selected from the group comprising 1-(2-ethoxyphenyl)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine, 1-(2-methoxyphenyl)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine, 1-(4-forfinal)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine, 1-(2-ethoxyphenyl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine, 1-(2-methoxyphenyl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine, 1-(2-ethoxyphenyl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine, 1-(5-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-methoxyphenyl)-1H-pee the azole-4-yl)methyl)piperazine, 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine, 1-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)-4-(pyridin-2-yl)piperazine, 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine, 1-((3-phenyl-1H-pyrazole-4-yl)methyl)-4-(pyridin-2-yl)piperazine, 1-(2-ethoxyphenyl)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine, 1-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)-4-(2-methoxyphenyl)piperazine, 1-(4-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine, 1-(5-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine, 1-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine, 1-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)-4-(pyridin-2-yl)piperazine and 1-(4-forfinal)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic, condensed bicyclic or associated bridge connection polycyclic system containing a loop a specified number of atoms. For example, With3-C10cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

"Heteroseksualci" means cycloalkyl specified in the bid, in which up to three carbon atoms in the cycle is replaced by a group selected from C(O)NR30, O, S(O)0-2where R30choose from the groups hydrogen and C -C6alkyl. Heteroseksualci includes imidazolidin, pyrrolidine, piperidine, etc. Group3-C8heteroseksualci(C0-C4)alkyl used in the description of the application to describe the substituents R1-R5includes pyrrolidinyl, where methyl is a place of connection, for example, to cycle A.

"Halogen" preferably means chlorine or fluorine, and bromine, or iodine.

"Treatment" means a method of reducing or diminishing the intensity of the disease and/or its attendant symptoms.

Detailed description of preferred embodiments of the invention.

The present invention provides compounds, compositions and methods for the treatment of kinase associated diseases, primarily IPTKb-associated diseases. For example, these are autoimmune diseases, especially diseases associated with cells, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), immune thrombocytopenic purpura (ITP) and hemolytic anemia.

In one embodiment, the compounds of the formula I n is 1 or 2, m is 0, 1 or 2, and contains in a loop up to three groups selected from-CR1=, -CR2=, -CR3=, -CR4= - CR5=replaced by N.

In another embodiment, R2, R3and R4independently selected from the group comprising hydrogen, hydroxy, Galaga is, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, C3-C8heteroseksualci(C0-C4)alkyl, C1-C10heteroaryl(C0-C4)alkyl, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)OR11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12, -XN(XOR12)2, -XNR11XC(O)OR12, -XNR11C(O)R12where each X is independently selected from the group comprising a chemical bond and C1-C4alkylen, each R11selected from the group including hydrogen and C1-C6alkyl, a R12selected from the group including hydrogen, C1-C6alkyl and C6-C10aryl, and specified heteroaryl or heteroseksualci R1, R2, R3, R4or R5optionally substituted by 1-3 substituents, independently selected from the group comprising halogen, hydroxy, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl and carboxy.

In another embodiment, R1, R5, R6and R7mean hydrogen, a R8you who eraut from the group include1-C2alkyl, halogen(C1-C3)alkyl, C1-C6alkoxy, -CH2OR8a, -COOR8aand C2-C6alkenyl, or two groups R8attached to different carbon atoms, together form the alkyl bridge, or two groups R8attached to the same carbon atom, form a group With3-C8cycloalkyl or carbonyl group, and R8aselected from the group including hydrogen and C1-C6alkyl.

In another embodiment, R9selected from the group including6-C10aryl and C1-C10heteroaryl where specified aryl or heteroaryl R9optionally substituted by 1-3 substituents, independently selected from the group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, cyano(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14where each R13and R14independently selected from the group including hydrogen and C1-C6alkyl, and R10means hydrogen.

In another embodiment, Y represents a nitrogen atom, and contains in a loop up to three groups selected from the group including CR1=, -CR2=, -CR3=, -CR4= - CR5=, replaced by a nitrogen atom.

In another embodiment, R2, R3and R4independently selected from a group is s, including hydrogen, hydroxy, cyano, cyanomethyl, fluorine, chlorine, bromine, iodine, aminocarbonyl, aminocarbonylmethyl, tetrazolyl, amidino, methylcarbamyl, 1-(hydroxyimino)ethyl, aminomethyl, dimethylaminomethyl, N-ethylformate, methylaminomethyl, dimethylamino, carboxymethyl, methylaminorex, ethyleneoxy, imidazolyl, pyrazolyl, 3 amiloride, isopropylaminocarbonyl, phenyleneoxy, hydroxycarbonylmethyl, 2-hydroxyethoxy, 2-hydroxypropylamino, aminocarboxyl, hydroxyethylamino, pyrrolidinyl substituted by a carboxy group, isoxazolyl, 2-hydroxyethylpyrrolidine-1-yl, 3-hydroxypyrrolidine-1-Il, 3-hydroxyazetidine-1-yl, pyrrolyl, optionally substituted by cyano group, methylaminomethyl, methylsulphonyl, methylcarbamoylmethyl, carboxy, tetrazolyl, tetrazolyl, dihydroxyethylene, oxazolyl, imidazolyl, optionally substituted by a methyl group, pyrazolyl and 1,2,4-triazolyl.

In another embodiment, R8selected from the group comprising methyl, ethyl, methoxycarbonyl, carboxy, trifluoromethyl and vermeil, or two groups R8attached to the same carbon atom, form a group cycloalkyl, or two groups R8together form the alkyl bridge, for example, methyl, ethyl or propyl, comprising divalent radical, such as (a), (b) or (C), respectively

In another embodiment, R9selected from the group comprising phenyl, pyridinyl, pyrazinyl, pyrimidinyl and furo[3,2-C]pyridine-4-yl, where the specified phenyl, pyridinyl, pyrazinyl, pyrimidinyl or furo[3,2-C]pyridine-4-yl optionally substituted by 1-3 substituents, independently selected from the group comprising trifluoromethyl, cyano, bromo, chloro, hydroxymethyl, methylcarbamyl, methyl, aminocarbonyl, nitro, iodine, fluorine, methoxycarbonyl, hydroxy, amino, carboxy and methoxy.

In another embodiment, the compounds of formula I is chosen from the group comprising 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether methylcarbamyl acid, 4-[3-(4-imidazol-1-ylphenyl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine, 4-[3-(6-chloropyridin-3-yl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(4-triptoreline)piperazine, 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinamide, 1-(5-bromopyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(5-chloropyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, (6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyridine-3-yl)methanol, 1-(6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyridine-3-yl)Etalon, 1-(3,5-dihl pyridin-4-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinamide, 1-(6-chloropyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}-4-cryptomaterial, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(6-methylpyridin-2-yl)piperazine, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyrimidine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(5-triptorelin-2-yl)-[1,4]diazepan, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-2,6-dimethyl-4-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-pyridine-2-reparation, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(3-triptorelin-2-yl)piperazine, 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinamide, 4-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}furo[3,2-C]pyridine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(5-nitropyridine-2-yl)piperazine, 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 1-{3-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazole-4-ylmethyl}-4-(5-triptorelin-2-yl)piperazine, N-hydroxy-4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 1-(4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)Etalon, oxime 1-(4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)e is the anon, methyl ester of 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzoic acid, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(5-iodopyridine-2-yl)piperazine, 1-(4-chloro-3-triptoreline)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(3-triptoreline)piperazine, 1-(4-bromophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 4-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}phenol, 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyridine-3-ylamine, 1-(3, 4-dimetilfenil)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2-forfinal)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinic acid, 4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-2-methyl-4-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(5-methylpyridin-2-yl)piperazine, 1-(3-chloropyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}isonicotinamide, 2-fluoro-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 2-fluoro-5-{4-[4-(5-triptorelin-2-yl)-piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 4-{4-[4-(5-triptorelin-2-yl)-[1, 4]diazepan-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 2-fluoro-5-{4-[4(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzylamine, (2-fluoro-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzyl)dimethylamine, N-(2-fluoro-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzyl)formamide, 1-(4-chlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(4-methoxyphenyl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-pair-tailpipes, 1-(3-chlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,4-differenl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(3,4-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,3-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(3,5-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,3-dimetilfenil)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,4-dimetilfenil)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 4-{4-[4-(5-chloropyridin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 2-{4-[3-(4-cyanophenyl)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}isonicotinamide, 4-{4-[4-(4-chloro-3-triptoreline)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[4-(3,4-dimetilfenil)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(4-methylpyridin-2-yl)piperazine, 1-(2,4-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(4-chloro-2-forfinal)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 2-cyano-5-{4-[4-(5-trifluoromethyl what iridin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 2-cyano-5-{4-[4-(5-triptorelin-2-yl)[1,4]diazepan-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 2-cyano-N-methyl-5-{4-[4-(5-triptorelin-2-yl)-[1,4]diazepan-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[2-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[5-(5-triptorelin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[2-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[3,5-dimethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenol, 1-[3-(4-bromophenyl)-1H-pyrazole-4-ylmethyl]-4-(5-triptorelin-2-yl)piperazine, 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether ethylcarbamate acid, 1-[3-(4-imidazol-1-ylphenyl)-1H-pyrazole-4-ylmethyl]-4-(5-triptorelin-2-yl)piperazine, 2-methyl-4-{3-[4-(1H-pyrazole-4-yl)phenyl]-1H-pyrazole-4-ylmethyl}-1-(5-triptorelin-2-yl)piperazine, 4-{4-[3,3-dimethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[2,5-dimethyl-4-(triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether ethylcarbamate acid, 4-{4-[3-ethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 1-ethyl-3-(4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)urea, 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether methylcarbamyl acid, (4-{4-[3-methyl-4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)acetonitrile, 2-(4-{4-[3-methyl-4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)acetamide", she dimethyl(5-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}pyridine-2-yl)amine, (4-{4-[3-methyl-4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)acetic acid, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether isopropylcarbamate acid, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether phenylcarbinol acid, 5-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}pyridine-2-carbonitrile, 6-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}nicotinamide, 2-(5-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}-pyridine-2-yl)ndimethylacetamide, 5-{4-[3-methyl-4-(5-t is attorneypages-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}pyridine-2-silt ether Karabanovo acid, (S)-methyl 4-((3-(4-cyanophenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine-2-carboxylate, (S)-4-((3-(4-cyanophenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine-2-carboxylic acid, (S)-4-(4-((3-(methoxymethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-2-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenylamino)ethanol, (R)-5-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenyl)isoxazol, (R)-4-((3-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridine-2-yl)piperazine, (R)-2-methyl-4-((3-(4-(methylsulphonyl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-N-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenylsulfonyl)ndimethylacetamide, (R)-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzoic acid, (R)-4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-4-((3-(4-((1H-tetrazol-5-yl)methyl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridine-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)ethanol, (R)-2,2'-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-alazander)diethanol, (S)-4-(4-((3-(tripto is methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-4-{4-[3-trifluoromethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, (S)-4-(4-((2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-4-(4-((2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-4-(4-((2-(permitil)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (S)-4-(4-((2-(permitil)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((4-(5-(trifluoromethyl)pyridine-2-yl)piperidine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-5-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenyl)oxazol, (R)-4-((3-(4-(1H-pyrazole-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-4-((3-(4-(1H-1,2,4-triazole-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenylamino)acetic acid, (R)-N-methyl-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzosulfimide, (R)-1-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenyl)-1H-pyrrol-2-carbonitrile, 4-(4-((3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-is)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((8-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]Octan-3-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-2-methyl-4-((3-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridine 2-yl)piperazine, (R)-2-methyl-4-((3-(4-(5-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-methyl-4-((3-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-N-(2-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)ethyl)ndimethylacetamide, (R)-N1-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)ethane-1,2-diamine, (R)-4-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)morpholino, (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)-N-(2-(piperidine-1-yl)ethyl)pyridin-2-amine, (R)-4-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridine-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)piperazine-2-(R)-2-hydroxy-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzoic acid, 1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)pyrrolidin-3-ol, 4-(4-((7-(5-(trifluoromethyl)pyridin-2-yl)-4,7-diazaspiro[2.5]Octan-4-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)-4,7-diazaspiro[2.5]Octan-7-yl)IU who yl)-1H-pyrazole-3-yl)benzonitrile, 1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)propan-2-ol, (S)-1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)pyrrolidin-2-yl)methanol, (R)-1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)propan-2-ol, (S)-1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)propan-2-ol, (R)-2-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yloxy)ethanol and (R)-1-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)azetidin-3-ol.

Other compounds according to the invention is described in detail in the examples and table.

Pharmacology and industrial applicability

Compounds of the invention modulate the activity IPTKb and as such are used for the treatment of diseases or disorders in which impaired activity IPTKb contributes to the pathology and/or symptoms of diseases.

By suppressing the activation and development of cells inhibitors ITPKb of the present invention have various therapeutic applications. Inhibition of ITPKb pharmacological means is a method of suppressing an impaired function In cells under pathological conditions. For example, glue the key play a pathological role in chronic graft rejection and autoimmune diseases (for example, rheumatoid arthritis, SLE, ordinary erythematosus and the like), psoriasis, allergies (asthma, rhinitis, COPD, dermatitis) and others, including anaphylaxis and many diseases, oposredovannyi complement. Compounds according to the invention, inhibiting ITPKb, can be effective agents for the treatment of these diseases, where ITPKb initiates the pathogenesis.

Other diseases and conditions that can be treated with these compounds include diseases associated or mediated by an abnormal proliferation, e.g., lymphoma In cells. In addition, such diseases include other disorders mediated by antibodies, such as allergies, systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and idiopathic thrombocytopenic purple (ITP). In addition to treatment of the above diseases or conditions inhibitors ITPKb of the present invention can also be used for preventing or modulating the development of such diseases or disorders in a subject (including humans and animals such as other mammals), the suspected presence of a disease or predisposed to such diseases or disorders. Modulators In cells that can be used in the methods of treatment according to the invention, include specific inhibitors ITPKb described below in the examples and shown in the table.

In the invention t is the train features a method of modulating the development and function of lymphocytes In the subject (human or other mammal) for treating autoimmune diseases includes introduction to the subject of the compounds of formula I or pharmaceutical compositions in amounts effective to modulate kinase activity or cellular level ITPKb (thus, as shown in in vitro), thereby modulating the differentiation and function of b-lymphocytes in the body of the subject. Connections can reduce the cellular level of ITPKb through inhibition of kinase activity ITPKb.

In accordance with the foregoing, the present invention also offers a method of preventing, treating and/or reducing the intensity of any symptoms of the above diseases or disorders in a subject in need of such treatment, and this method lies in the fact that the specified subject is administered a therapeutically effective amount (see below in the section introduction Methods and pharmaceutical compositions) of the compounds of formula I or its pharmaceutically acceptable salt. The compounds of formula I can lower the cellular level ITPKb through inhibition of kinase activity ITPKb thus, as described below in the in vitro tests. If any of the above apply the required dose can vary depending on the method of administration, the particular condition to be treated, and expected actions.

Methods of administration and pharmaceutical compositions

In the General case, the AE, compounds according to the invention is administered in therapeutically effective quantities of any of the usual and acceptable by known methods, separately or in combination with one or more therapeutic agents. Therapeutically effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the activity of the used connections and other factors. In General satisfactory results are achieved with systemic administration of daily doses of from about 0.03 up to 2, 5 mg/kg of body weight. For the larger mammal, e.g. humans, prescribed daily dose of from approximately 0.5 mg to approximately 100 mg, which you can enter, for example, single doses up to four times a day or in a form with delayed release. Suitable standard dosage forms for oral administration comprise from about 1 to 50 mg of active ingredient.

Compounds according to the invention can be introduced in the form of pharmaceutical compositions by any acceptable method, first of all enterline, for example, by oral way, for example, in the form of tablets or capsules, or parenterally way, for example, in the form of injection solutions or suspensions, local way, for example, in the form of lotions, gels, ointments or creams, or intran the hall way, or in the form of suppositories. Pharmaceutical compositions comprising the compound of the present invention in free form or in the form of pharmaceutically acceptable salts in a mixture with at least one pharmaceutically acceptable carrier or diluent, get in the normal way using the processes of mixing, granulating or coating. For example, the oral composition may be a tablet or gelatin capsules comprising the active ingredient in a mixture with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) an oil, such as silicon dioxide, talc, stearic acid, its calcium or magnesium salt and/or polyethyleneglycol, and tablets can also be included) binders, for example magnesium silicate/aluminum, starch paste, gelatin, tragakant, methylcellulose, Na-carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if necessary g) dezintegriruetsja agents, for example starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be an aqueous isotonic solutions or suspensions, and suppositories are obtained from fatty emulsions or suspensions. Song mo is but to sterilize and/or they may contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, contributing to the dissolution agents, salts for regulating osmotic pressure and/or buffer substances. In addition, they can contain other therapeutically valuable compounds. Suitable formulations for transdermal application include an effective amount of the compounds of the present invention in a mixture with a carrier. The media may include absorbable pharmacologically acceptable solvents to provide suction through the skin of the patient. For example, systems for percutaneous introduction represent a bandage comprising a base, a reservoir containing the compound optionally in a mixture with a carrier, optionally a membrane that regulates the delivery of compounds to the skin surface at a given speed for a long time, and the layer for holding the device on the skin surface. You can also use matrix percutaneous formulations. Suitable formulations for topical application, for example, on the skin and eyes, preferably are aqueous solutions, ointments, creams or gels known in this field. Such compositions may contain solubilizing, stabilizing, toning agents, buffering agents and preservatives.

Compounds according to the invention can be introduced in a therapeutically effective the positive quantities in combination with one or more therapeutic agents (pharmaceutical combination). For example, a synergistic effect is achieved by using a combination with other immunomodulatory or anti-inflammatory substances, for example, when used in combination with cyclosporine, rapamycin or ascomycin, or immunodepressants analogs, e.g. cyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or similar compounds, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, Leflunomide, mizoribine, mycophenolate acid, mycophenolate mofetil, 15-desoxypeganine, immunodepressants antibodies, especially monoclonal antibodies to receptors of leukocytes, such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, or other immunomodulatory compounds, such as CTLA41g. If the compounds according to the invention is administered in conjunction with other therapeutically active agents, doses in conjunction input connections vary depending on the type of the jointly-used drug, from a particular drug, the condition to be treated, etc.

The invention also relates to pharmaceutical combinations, for example, the set including a) a first agent which is a compound according to the invention specified above, in free form or in the form of a pharmaceutically acceptable with the Lee, and b) at least one second agent. The kit includes instructions for administration of medicines.

The terms "co-administration" or "combined introduction" or similar terms used in the description means the introduction of selected therapeutic agents to a single patient, as well as the course of treatment, according to which the agents are not necessarily entered at the same time and in the same way.

The term "pharmaceutical combination", as used in the description of the application, means the product which is formed by mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula I and collateral agent, are administered to a patient simultaneously in the form of a single product or dose. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula I and collateral agent, are administered to the patient separately, simultaneously, together or sequentially, without time limits, and this introduction provides achieve therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to the combined treatment solutions, for example, to the introduction of three or more active in the of Reventon.

Methods for producing compounds according to the invention

The present invention also includes methods for producing compounds according to the invention. In the above reactions it is necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxypropyl, if they must be present in the final product. The introduction of protective groups allows to exclude the participation of such functional groups in the ongoing reactions. Appropriate protective groups are used in accordance with accepted practice, for example, see T.W.Greene and .G.M.Wuts, "Protective Groups in Organic Chemistry", John Wiley and Sons (1991).

The compounds of formula I in which Y represents N, a R6and R7both signify hydrogen, receive, as shown in figure 1.

Scheme 1 n, m, A, R1, R2, R3, R4, R5, R8, R9and R10have the meanings specified in section a Brief description of the invention.

The compound of the formula I get in the interaction of the compounds of formula 3 with a compound of formula 4 in the presence of a suitable solvent (for example, DHM) and an appropriate reducing agent (e.g., NaCNBH3). The compound of formula 3 get the reaction of the compounds of formula 2 with complex POCl3/DMF, followed by addition of an appropriate base (such as NaOH).

Detailed examples of sin is ESA the compounds of formula I are given below in the Examples section below.

Additional methods for producing compounds according to the invention

The connection according to the invention can be obtained in the form of a pharmaceutically acceptable acid additive salts by the reaction of the free base compounds with pharmaceutically acceptable inorganic or organic acid. In another embodiment, a pharmaceutically acceptable basic additive salt of the compounds according to the invention can be obtained by reaction of the free acid of the compound with a pharmaceutically acceptable inorganic or organic base.

In another embodiment, the salts of the compounds according to the invention can be obtained by using salts of the starting materials or intermediate compounds.

Free acid or free base of the compounds according to the invention are obtained from the corresponding primary additive salt or acid salt additive, respectively. For example, the connection according to the invention in the form of an acid additive salt can be converted into the corresponding free base by treatment appropriate base (for example, a solution of ammonium hydroxide, sodium hydroxide and the like). The connection according to the invention in the form of a basic additive salts can be converted into the corresponding free acid in the processing of the appropriate acid (e.g. hydrochloric acid, and the like).

Compounds according to the invention in non-oxidized form which can be obtained from N-oxides of the compounds according to the invention in the processing of regenerating agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, trichloride phosphorus, tribromide phosphorus or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at a temperature from 0°C to 80°C.

Prodrugs of the compounds according to the invention receive known methods (for example, see Saulnier and others, Bioorganic and Medicinal Chemistry Letters, 4, 1985 (1994)). For example, appropriate prodrugs can be obtained by the interaction of unmodified compounds according to the invention with suitable carbamimidoyl agent (for example, 1,1-aryloxyalkanoic, para-nitrophenylarsonic or the like).

Compounds according to the invention containing a protective group, can be obtained by the known methods. Detailed description of methods of introducing protective groups and their removal can be found in the monograph T.W.Greene, "Protecting Groups in Organic Chemistry", 3rd ed., John Wiley and Sons, Inc., (1999).

Compounds according to the invention can be obtained, including the method according to the invention, in the form of a solvate (e.g. hydrate). Hydrates of the compounds of the present invention is obtained by recrystallization from a mixture of water/organic solvent, such as dioxane, tetrahydrofuran or methanol.

Compounds according to the invention can be obtained in the form of an individual stereoisomer in the interaction of racemic mixtures of compounds with pricheski active separating agent with the formation of pairs diastereoisomeric compounds, separation of the diastereomers and the allocation of optically pure enantiomers. Although the separation of enantiomers carried out using covalent diastereomeric derivatives of the compounds according to the invention, preferred are dissociable complexes (e.g., crystalline diastereomeric salt). Diastereomers have different physical properties (e.g. melting point, boiling point, solubility, reactivity, etc. and because of this they can be separated by simple means. The diastereomers separated by chromatography, or preferably by the method based on the difference in solubility. Then optically pure enantiomer is isolated using a separating agent in any way, excluding racemization. A more detailed description of the methods used for the separation of stereoisomers of the compounds present in the form of racemic mixtures can be found in the monograph by Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc. (1981).

In the end, the compounds of formula I can be obtained by the method, which is that:

(a) conducting a reaction as shown in scheme 1, and

(b) does not necessarily make the connection according to the invention in pharmaceutically acceptable salt,

(in) does not necessarily make the salt of the compounds according to the invention in mesolevel (free) fo the mu,

(g) optional turn oxidized form of the compounds according to the invention in a pharmaceutically acceptable N-oxide,

d) optional transform N-oxide compounds according to the invention in its unoxidized form,

(e) optional allocate individual isomer of the compounds according to the invention from a mixture of isomers,

(g) optional turn unmodified compound according to the invention in a pharmaceutically acceptable prodrug, and

(C) does not necessarily make the prodrug compounds in unmodified form.

Obtaining starting materials is not described in detail, since the compounds are known or can be obtained by the known methods or as described below in the Examples section below.

For the person skilled in the art it is obvious that the above syntheses and modifications are provided to illustrate methods for obtaining compounds of the present invention, and that you can get them using other known methods.

Examples

The present invention is illustrated, without limitation, the following examples of the preparation of compounds of the formula I according to the invention.

Example 1

4-{4-[4-(5-Triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl)benzonitrile

Stage 1

In a solution of sodium acetate (51,5 g, 381 mmol) and hydrochloride of Semik is based (23 g, 207 mmol) in water (50 ml) was added a solution of 4-acetylbenzoate (25 g, 173 mmol) in ethanol (35 ml) and the reaction mixture is boiled under reflux for 3 hours Then the mixture was cooled to room temperature, the resulting crystalline substance was separated by filtration and dried under vacuum, to receive 4-acetylpenicillamine in a solid white color.

1H-NMR (400 MHz, d-DMSO): δ a 9.60 (s, 1H), of 8.06 (d, 2H, J is 8.8 Hz), 7,81 (d, 2H, J is 8.8 Hz), 6,50 (s, user., 2H), 3,41 (s, user., 1H), measuring 2.20 (s, 3H).

Stage 2

The complex phosphorus/dimethylformamide received at slow addition of phosphorus oxychloride (of 10.25 ml, 110 mmol) at temperatures less than 5°C in dimethylformamide (25 ml, 220 mmol). In the complex of phosphorus/dimethylformamide with stirring portions was added 4-acetylbenzoate (10.1 g, 50 mmol) and the reaction mixture was heated at 65°C for 4 h the Mixture was poured into ice cooled and neutralized by adding sodium hydroxide solution (20 g in 80 ml water). Then the mixture was heated at 55°C for 10 min, cooled, acidified using conc. hydrochloric acid, and incubated over night. A solid substance was separated by filtration and dried under vacuum, thus received the product in a solid dark yellow (3.4 g). The filtrate was extracted three times EtOAc (50 ml), the combined organic extracts were washed with water and Sol is the best solution and dried over MgSO 4. The residue was fractionally rapid chromatography on a column (eluent: EtOAc/hexane, 2:5), the received 4-(4-formyl-1H-3-yl)benzonitrile in a solid yellow color (2.0 g).

1H-NMR (400 MHz, d-DMSO): δ to 9.93 (s, 1H), to 8.70 (s, 1H), 8,12 (d, 2H, J 8 Hz), 7,92 (d, 2H, J 8 Hz).

Stage 3

A solution of 4-(4-formyl-1H-3-yl)benzonitrile (60 mg, 0, 3 mmol), 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (34.7 mg, 0 15 mmol) and glacial acetic acid (25 μl) in methanol (5 ml) was stirred at room temperature for 30 minutes the mixture was added one portion of triacetoxyborohydride sodium (127 mg, 0.6 mmol), the mixture was heated at 40°C for 1 h, and then was cooled to room temperature. The crude residue was fractionally by the method of preparative GHUR. The resulting triptorelin neutralized conc. aqueous sodium bicarbonate solution, was obtained 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile in a solid white color.

1H-NMR (400 MHz, CDCl3): δ 8,32 (s, 1H), 7,98 (d, 2H, J 8,4 Hz), the 7.65 (d, 2H, J 8,4 Hz), 7,56-rate of 7.54 (m, 2H), 6,56 (d, 1H, J is 8.8 Hz), 3,59 of 3.56 (m, 4H), 3,44 (s, 2H), 2,52-of 2.50 (m, 4H).

Example 2

Getting 4-(4-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-yl)phenyl ether methylcarbamyl acid

Stage 1

A mixture of 1-(4-hydroxyphenyl)ethanone ((3), 544 mg, 4 mm is l) and methylisocyanate (500 mg, 8,8 mmol) in toluene (5 ml) was stirred in a sealed tube. Then to the mixture was added triethylamine (404 mg, 4 mmol) and the mixture was heated at 100°C for 2 h, and the data LC/MS indicated complete consumption of the starting compound (3). The reaction was stopped by adding a saturated solution of sodium bicarbonate and the mixture was extracted with EtOAc (20 ml ×5). The combined organic phase was dried over sodium sulfate and concentrated. The crude product was purified Express chromatography, was obtained 4-acetildenafil ether methylcarbamyl acid (4) in the form of a solid white color. 100% (ELSD), m/e 194 (M+1).

Stage 2

A mixture of 4-acetylphenyl ether methylcarbamyl acid ((4), 750 mg) of the hydrochloride of semicarbazide (669 mg, 6 mmol) was stirred in ethanol (10 ml). Then to the mixture was added a catalytic amount of acetic acid (0.1 ml) and the reaction mixture is boiled under reflux for 3 hours the Mixture was cooled to room temperature, the resulting crystalline substance was separated by filtration and dried under vacuum, was obtained 4-(1-semicarbazides)phenyl ether methylcarbamyl acid (5) in a solid white color. 100% (ELSD), m/e 251 (M+1).

1H-NMR (400 MHz, d-methanol): δ 7,84-7,81 (m, 2H), 7,13-7,11 (m, 2H), and 2.79 (s, 3H), 2,24 (s, 3H).

Stage 3

The complex phosphorus/dimethylformamide received the ri slow addition of phosphorus oxychloride (0,41 ml, 4.5 mmol) at temperatures less than 5°C in dimethylformamide (of 0.71 ml, 9.0 mmol). In the complex of phosphorus/dimethylformamide with stirring portions was added 4-(1-semicarbazides)phenyl ether methylcarbamyl acid (5,330 mg of 1.32 mmol) and the reaction mixture was heated at 65°C for 4 h the Mixture was poured into ice cooled and neutralized by adding sodium hydroxide solution (20 g in 80 ml water). Then the mixture was heated at 55°C for 10 min, cooled, acidified using conc. hydrochloric acid three times and was extracted with EtOAc (50 ml). The combined organic layers were washed with water, brine and dried over MgSO4. The residue was fractionally rapid chromatography on a column (eluent: EtOAc/hexane, 2:5), the received 4-(4-formyl-1H-pyrazole-3-yl)phenyl ether methylcarbamyl acid in a solid yellow color. 96% (ELSD). m/e 246 (M+1).

Stage 4

A solution of 4-(4-formyl-1H-pyrazole-3-yl)phenyl ether methylcarbamyl acid ((6), 35 mg, 0,142 mmol), (R)-1-(5-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine ((7), 34 mg, 0.14 mmol) and glacial acetic acid (17 μl) in DHM (5 ml) was stirred at room temperature for 30 minutes Then the mixture was added one portion of triacetoxyborohydride sodium (120 mg, 0.6 to mmol), the mixture was heated at 40°C for 4 h and cooled to room temperature. The crude residue fracc who was onorevoli by the method of preparative GHUR (eluent: acetic acid), it was obtained 4-(4-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-yl)phenyl ether methylcarbamyl acid in a solid white color. 100 (ELSD), m/e 475 (M+l).

1H-NMR (400 MHz, d-methanol): δ of 8.25 (s, 1H), to 7.67 (d, 2H, J 8.0 Hz), 7,63 (m, 1H), 7,12 (d, 2H, J 8,4 Hz), 7,74 (d, 1H J 9,2 Hz), to 4.62 (m, 1H), 4,19 (m, 1H), 3,78 (s, 2H), 3,10 (t, 2H, J 12 Hz), 2,97 (m, 1H), 2,70 (s, 3H), of 2.56 (s, 3H, mixture of acetate eluent when conducting IHVR), 2,52 (m, 1H), 2,32 (m, 1H), 1.14 in (d, 3H, J 6.8 Hz).

Example 3

4-[3-(4-Imidazol-1-ylphenyl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine

Stage 1

To a solution of tert-butyl ester 3-methyl-4-(5-triptorelin-2-yl)piperazine-1-carboxylic acid ((9), 200 mg, 0, 58 mmol) in dichloromethane (3 ml) was added TFU (1 ml) and the reaction mixture was stirred at room temperature for 1 h the Solvent was removed in vacuum and the residue was dissolved in 1,2-dichloroethane (3 ml). To the solution was added 3-(4-bromophenyl)-1H-pyrazole-4-carboxaldehyde (132 mg, of 0.53 mmol) and triacetoxyborohydride sodium (223 mg, 1.05 mmol) and the reaction mixture was heated at 50°C during the night. The mixture is then cooled, the reaction was stopped by adding a saturated solution of NH4Cl was extracted with AcOEt, the extract was dried (NaSO4) and concentrated. The product was purified by TLC (eluent: Et3N/MeOH/CH2Cl2, 3:5:92), it was obtained 4-[-(4-bromophenyl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine.

Stage 2

Dried in a drying Cabinet flask Slanka, equipped with a magnetic stirrer, a few times was evacuated and filled with dry and pure argon. Then the flask was placed Cu2O (2.1 mg, 0.01 mmol), hydrazone salicylic aldehyde (7.9 mg, 0.06 mmol), imidazole (30 mg, 0.44 mmol), Cs2CO3(171 mg, 0.52 mmol) and 4-[3-(4-bromophenyl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine (140 mg, 0, 29 mmol), the flask was evacuated and filled with argon. Then to the mixture was added anhydrous and degassed acetonitrile (1 ml) in an argon atmosphere, the flask was tightly closed under the pressure of the argon and the mixture was heated at 85°C for 2 days. The reaction mixture was cooled to room temperature, diluted with AcOEt, suspensio was filtered through a layer of celite and the filtrate was concentrated. The crude residue was fractionally by the method of preparative GHUR. The obtained Sol TFU was neutralized with aqueous NaHCO3when this was received (R)-4-[3-(4-imidazol-1-ylphenyl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine.

1H-NMR (400 Hz, MeOH-d4): δ 8,24 (s, 1H), 8,17 (s, 1H), 8,02 (d, 2H, J is 8.8 Hz), 7,62-7,56 (m, 5H), 7,13 (s, 1H), 6,72 (d, 2H, J 9,2 Hz)to 4.52 (s, 1H), 4,07 (d, 1H, J 12,8), to 3.41 (s, 2H), is 3.08 (td, 1H, J 12,8, J 3,2), 2,96 (d, 1H, J 11,2), and 2.83 (d, 1H, J 11,2), of 2.21 (dd, 1H, J 11,2, J 4,0), 2,02 (td, 1H, J 11,2, J 3,2)and 1.15 (d, 3H, J 6,4).

Example 4

4-[3-(6-Chloropyridin-3-yl)-1H-pyrazole-4-ylmethyl]-2-(R)-methyl-1-(5-triptorelin-2-yl)p is perusin

Stage 1

To a solution of 5-acetyl-2-bromopyridine (1 g, 5 mmol) in anhydrous ethanol (20 ml) were added hydrochloride semicarbazide (0,61 g, 5.5 mmol) and acetic acid (1 ml) and the reaction mixture is boiled under reflux for 3 hours the Mixture was cooled to room temperature, the precipitate was separated by filtration and dried under vacuum, to receive 5-acetyl-2-broneerimistasuta. MS: m/e 257 (M+1).

Stage 2

DMF (0.54 ml, 7 mmol) and POCl3(0,65 ml, 7 mmol) was separately cooled at 0°C, and then POCl3was added dropwise to DMF. In the resulting reaction mixture was slowly added a solution of 5-acetyl-2-broneerimistasuta (600 mg, of 2.33 mmol) in DMF (5 ml). The resulting suspension was heated to room temperature and then at 70°C for 3 hours the Mixture was cooled to room temperature, poured into ice and podslushivaet solution of Na2CO3. Then the mixture was heated at 60°C for 10 min, cooled and was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4, was filtered and was evaporated. The residue was fractionally Express chromatography (eluent: EtOAc/hexane, 1:1), was obtained 3-(6-chloropyridin-3-yl)-1H-pyrazole-4-carbaldehyde. MS: m/e 208 (M+1).

Stage 3

A solution of 3-(6-chloropyridin-3-yl)-1H-pyrazole-4-carbaldehyde (110 mg, of 0.53 mmol), 2-(R)-methyl-1-(5-triform terpyridine-2-yl)piperazine (120 mg, 0.49 mmol) and glacial acetic acid (0.2 ml) in anhydrous 1,2-dichloroethane (3 ml) was stirred at 50°C for 30 minutes Then the mixture was added triacetoxyborohydride sodium (210 mg, 1 mmol) and the resulting mixture was heated at 50°C for 3 hours the Mixture was cooled to room temperature, added to ice water and the solution was extracted with CH2Cl2. The combined organic extracts were washed with water, dried over Na2SO4, was filtered and was evaporated. The residue was fractionally by molecular-sieve GHUR. The resulting triptorelin was neutralized with sodium carbonate solution, was obtained 4-[3-(6-chloropyridin-3-yl)-1H-pyrazole-4-ylmethyl]-2-(R)-methyl-1-(5-triptorelin-2-yl)piperazine. MS: m/e 437 (M+1).1H-NMR (400 MHz, CD3OD): δ 9,0 (s, 1H), 8,45 (d, 1H, J 8.0 Hz), with 8.33 (s, 1H), 7,74 (s, 1H), of 7.70 (d, 1H, J 8.0 Hz), 7,53 (d, 1H, J 8.0 Hz), for 6.81 (d, 1H, J 8 Hz), 4,62 (user., 1H), 4,20 (user., d, 1H), 3,6-2,8 (m, 5H), 2,4-2,0 (m, 2H), of 1.16 (d, 3H, J 7 Hz).

The compounds of formula I, shown in the table was obtained according to the methods described in the above examples, from the appropriate starting materials.

Methods of analysis

Compounds of the present invention were analyzed for ability to inhibit ITPKb by the following method.

Cleaning ITPKb

The DNA sequence that encodes a fragment of ITPKb mouse (amino acids 640-942), amplified from full-length construct in an expression vector mammalian pKDNZ PCR. The sequence of the 3'primer included a stop codon and the exposed site, the available restriction enzyme PacI, the Product is hydrolyzed by the enzyme PacI before embedding in plasmid MN, which was obtained by hydrolysis enzymes PmlI and PacI. When cloning in plasmid MN to the N-terminal site of the field of broadcast was annexed sequence MGSDKIHHHHHH. Mutant enzymes were obtained site-specific mutagenesis using a set of reagents Stratagene Quikchange.

ITPKb expressed in Escherichia coli (strain NT). Typically, a batch of cells with a volume of 4 l was cultured in LB medium containing ampicillin (0.1 mg/ml)at 30°C to a density of 0.5 a600and then what was ndesirable L-arabinose (0,02%) within 6 hours The cells were collected by centrifugation, the precipitate resuspendable in 50 ml of buffer solution of the following composition: 50 mm Tris, pH 8, 100 mm NaCl, 1 mm TSAR and 0.1 mg/ml lysozyme containing one tablet of complete set of protease inhibitors (firm Roche). Cells were destroyed when the sonication and debris was removed by centrifugation at 35000 g for 40 minutes

Initial purification was performed using three series-connected columns filled with Ni-separate (Hi-Trap HP, the volume of 1 ml, the firm Amersham). After applying supernatants column was washed with buffer (20 mm Tris, pH 8.0, 20 mm imidazole, 10% vol. glycerol and 1 mm TSER), and then suirable product concentration gradient of imidazole (to final concentration of 200 mm).

The fractions containing ITPKb, identified by electrophoresis in LTOs/PAG, fractions a-e, containing the purified product was concentrated using columns centriprep 20 (15 kDa) was replaced with buffer solution to the solution of the following composition: 20 mm Tris, pH 8, 200 mm KCl, 5 mm MgCl2, 0.5 mm DTT, 10% glycerol, 1 μm IP3and 20 μm ATP, while the final protein concentration was 7 mg/ml

The definition of ITPKb activity biochemical methods

The ITPKb activity was assessed by the reduction of ATP levels using a set of reagents Kinase-Glo, Promega). The reaction was carried out in a buffer solution of the following composition: 50 mm Tris, R is 8,0, 100 mm NaCl, 1 mm DTT, 10% glycerin, 5 mm MgCl2, 1 μm ATP and 10 μm RZ (firm Alexis Biochemicals). In the reaction mixture by volume of 40 μl was added to 50 ll of inhibitor solution, and then 10 μl of a solution of purified kinase ITPKb (final concentration of 60 nm). The reaction mixture was incubated at room temperature for 60 min and the reaction was stopped by adding equal volume of reagent Kinase-Glo, Promega). Luminescence was measured on a luminometer (company Molecular Devices Acquest).

According to the results of inhibition of phosphorylation of IP3 compounds of formula I preferably are characterized by the values of the IC50less than 500 nm, preferably less than 250 nm, more preferably less than 100 nm.

Measurement of intracellular IP3, IP4 and IP5 method GHUR

The Jurkat cells were obtained from the collection of ATS (clone E6-1) (www.ATCC.org Cat#TIB-152). A suspension of 10 cells in 1 ml of medium RP Ml-1640, containing Inositol, incubated in prisutstvie 3H-myoinositol (15 µci) in Inositol at 37°C for 6 hours and Then the cell suspension was diluted in 4 ml of RPMI-1640 medium containing 10% ETS, and incubated overnight at 37°C. cell Suspension was concentrated, cells resuspendable in 1 ml of RPMI-1640 medium containing 10% ETS, and added 1 μl of inhibitor solution in DMSO. Then added 50 µg OCT and 10 µg anti-SW-person (company BD Pharmingen, clone CD28.2), and incubated for 5 min at 37°C. cell Suspension was concentrated ireally stopped when resuspending cells in 100 µl FSB 350 mm HCl. Then the extracts were centrifuged to remove proteins and cellular debris. The content in extracts labeled Inositol-polyphosphate was determined by the method GHUR (column Partisphere SAX, 15 cm×4.6 mm, eluent: gradient from buffer A (10 mm (NH4)H2PO4+H3PO4pH 3,35)to the buffer solution In (1.7 M (NH4)H2PO4pH at 3.35, +H3PO4), according to the following program: 0-100% (0-12 .5 min), 100% (12-5-25 min, 0-100% (25-30 min), 100% (30-45 min). Radioactivity was determined on a flow detector β-Ram system IN/US.

According to the results of inhibition of the conversion of IP3 to IP4 compounds of the formula I preferably are characterized by the values of the IC50less than 1 micron, more preferably less than 500 nm.

Is understood that the examples and embodiments of the invention are provided for illustration only, and various modifications or changes within the entity and the amount of the specified application and the attached claims are obvious to a person skilled in this field. All publications, patents and applications cited in the description, included in the description by reference in full.

1. The compound of the formula I

where n is chosen from 1 and 2
m is chosen from 0, 1 and 2
And contains in the cycle group selected from-CR1=, -CR2=, -CR3=, -CR4= - CR5=, where 0 or 1 is C these groups are replaced by N,
R1, R2, R3, R4and R5independently selected from the group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6heteroseksualci-C0-alkyl, where the specified heteroseksualci includes 1-2 heteroatoms selected from nitrogen atoms and oxygen, With5heteroaryl-(C0-C4)alkyl, where the specified heteroaryl comprises 1-4 heteroatoms selected from nitrogen atoms, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)ORl1, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12, -XN(XOR12)2, -XNR11XC(O)OR12, -XNR11XNR11C(O)R12, -XNR11XNR11R12, -XNR11C(O)R12where each X is independently selected from the group comprising a chemical bond With1-C4alkylen, every R11selected from the group including hydrogen, C1-C6alkyl, a R12selected from the group including hydrogen, C1-C6alkyl and phenyl, or R11and R12together with the nitrogen atom to which R11and R12attached, form a6heteroseksualci, and the specified heteroaryl or heteroseksualci R1, R2, R3, R4/sub> or R5optionally contains one Deputy, selected from the group comprising hydroxy, cyano, C1-C6alkyl, hydroxy(C1-C6)alkyl and carboxy,
R6and R7independently mean hydrogen,
R8selected from the group including1-C6alkyl, halogen(C1-C3)alkyl, -CH2OR8aand-COOR8aor two groups R8attached to different carbon atoms, together form a (C1-C2)alkyl bridge, or two groups R8attached to the same carbon atom form the group (C3-C8)cycloalkyl, where R8aselected from the group including hydrogen and C1-C6alkyl,
R9selected from the group comprising phenyl and C6heteroaryl where specified heteroaryl includes 1-2 heteroatoms selected from nitrogen atoms, and C9heteroaryl where specified heteroaryl includes 1-2 heteroatoms selected from nitrogen atoms and oxygen, with the specified phenyl or heteroaryl R9optionally substituted with 1-2 substituents independently selected from the group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14where each R13and R14independently selected from the group including hydrogen and C1-C6/sub> alkyl,
R10means hydrogen,
Y and Z independently are selected from the group including CR20and N, where R20means hydrogen,
and their pharmaceutically acceptable salts, provided that the compounds of formula I include compounds of formula II, which are
1-(2-ethoxyphenyl)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine,
1-(2-methoxyphenyl)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine,
1-(4-forfinal)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine,
1-(2-ethoxyphenyl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine,
1-(2-methoxyphenyl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine,
1-(2-ethoxyphenyl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine,
1-(5-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine,
1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)piperazine,
1-((3-(4-methoxyphenyl)-1H-pyrazole-4-yl)methyl)-4-(pyridin-2-yl)piperazine,
1-(2-ethoxyphenyl)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine,
1-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)-4-(2-methoxyphenyl)piperazine,
1-(4-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine,
1-(5-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine,
1-(4-(forfinal)-4-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)piperazine,
1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-((3-(4-forfinal)-1H-pyrazole-4-and the)methyl)piperazine,
1-((3-phenyl-1H-pyrazole-4-yl)methyl)-4-(pyridin-2-yl)piperazine,
1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine and
1-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)-4-(pyridin-2-yl)piperazine,
provided that the compounds of formula I do not include compounds that are
1-(4-forfinal)-4-((3-phenyl-1H-pyrazole-4-yl)methyl)piperazine,
1-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)-4-(4-(trifluoromethyl)-(pyridine-2-yl)piperazine,
1-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)-4-(5-(trifluoromethyl)-(pyridine-2-yl)piperazine and
1-((3-(4-forfinal)-1H-pyrazole-4-yl)methyl)-4-(5-herperidin-2-yl)piperazine.

2. The compound according to claim 1, in which
R2, R3and R4independently selected from the group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6heteroseksualci-C0-alkyl, where the specified heteroseksualci includes 1-2 heteroatoms selected from nitrogen atoms and oxygen, With5heteroaryl-(C0-C4)alkyl, where the specified heteroaryl comprises 1-4 heteroatoms selected from nitrogen atoms, -XSO2Rl1, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)ORl1, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12, -XN(XOR12)sub> 2, -XNR11XC(O)OR12, -XNR11XNR11C(O)R12, -XNR11XNR11R12, -XNR11C(O)R12where each X is independently selected from the group comprising a chemical bond With1-C4alkylen, each R11selected from the group including hydrogen and C1-C6alkyl, a R12selected from the group including hydrogen, C1-C6alkyl and phenyl, or R11and R12together with the nitrogen atom to which R11and R12attached, form a6heteroseksualci, and the specified heteroaryl or heteroseksualci R1, R2, R3, R4or R5optionally contains one Deputy, selected from the group comprising hydroxy, cyano, C1-C6alkyl, hydroxy(C1-C6)alkyl and carboxy,
R1and R5mean hydrogen,
R8selected from the group including1-C2alkyl, halogen(C1-C3)alkyl, -CH2OR8aand-COOR8a; or two groups R8attached to different carbon atoms, together form a (C1-C2)alkyl bridge, or two groups R8attached to the same carbon atom, form a group With3-cycloalkyl, where R8aselected from the group including hydrogen and C1-C6alkyl.

3. The compound according to claim 2, in which Y represents N, and contains a group, SEL is annoy from-CR 1=, -CR2=, -CR3=, -CR4= - CR5=replaced by N.

4. The compound according to claim 3 in which R2, R3and R4independently selected from the group comprising hydrogen, hydroxy, cyano, cyanomethyl, fluorine, chlorine, bromine, iodine, aminocarbonyl, aminocarbonylmethyl, tetrazolyl, methylcarbamyl, 1-(hydroxyimino)ethyl, aminomethyl, dimethylaminomethyl, N-ethylformate, methylaminomethyl, dimethylamino, carboxymethyl, methylaminorex, ethyleneoxy, imidazolyl, pyrazolyl, 3 amiloride, isopropylaminocarbonyl, phenyleneoxy, hydroxycarbonylmethyl, 2-hydroxypropylamino, aminocarboxyl, hydroxyethylamino, pyrrolidinyl substituted by a carboxy group, isoxazolyl, 2-hydroxyethylpyrrolidine-1-yl, 3-hydroxypyrrolidine-1-yl 3-hydroxyazetidine-1-yl, pyrrolyl, optionally substituted by cyano group, methylaminomethyl, methylsulphonyl, methylcarbamoylmethyl, carboxy, tetrazolyl, tetrazolyl, dihydroxyethylene, oxazolyl, imidazolyl, optionally substituted by a methyl group, pyrazolyl and 1,2,4-triazolyl.

5. The compound according to claim 4, in which R8selected from the group comprising methyl, ethyl, methoxycarbonyl, carboxy, trifluoromethyl and vermeil, or two groups R8together form a methyl or ethyl bridge, or two groups R8attached to the same carbon atom form the group cyclopropyl.

6. The compound according to claim 5, in which R9selected from the group comprising phenyl, pyridinyl, pyrazinyl, pyrimidinyl and furo[3,2-C]pyridine-4-yl, where the specified phenyl, pyridinyl, pyrazinyl, pyrimidinyl or furo[3,2-C]pyridine-4-yl optionally substituted with 1-2 substituents independently selected from the group comprising trifluoromethyl, cyano, bromo, chloro, hydroxymethyl, methylcarbamyl, methyl, aminocarbonyl, iodine, fluorine and hydroxy.

7. The compound according to claim 1, selected from the group comprising 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl} benzonitrile, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether methylcarbamyl acid, 4-[3-(4-imidazol-1-ylphenyl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine, 4-[3-(6-chloropyridin-3-yl)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(4-triptoreline)piperazine, 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinamide, 1-(5-bromopyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(5-chloropyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, (6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyridine-3-yl)methanol, 1-(6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyridine-3-yl)Etalon, 1-(3,5-dichloropyridine-4-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine,4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinamide, 1-(6-chloropyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}-4-cryptomaterial, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(6-methylpyridin-2-yl)piperazine, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyrimidine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(5-triptorelin-2-yl)-[1,4]diazepan, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-2,6-dimethyl-4-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-pyridine-2-reparation, 1 -[3-(4-fluoro-phenyl)-1H-pyrazole-4-ylmethyl]-4-(3-triptorelin-2-yl)piperazine, 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinamide, 4-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}furo[3,2-C]pyridine, 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 1-{3-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazole-4-ylmethyl}-4-(5-triptorelin-2-yl)piperazine, N-hydroxy-4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 1-(4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)Etalon, oxime 1-(4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)ethanone, methyl ester 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzoic acid, 1-[3-(4-forfinal)-1H-pyrazole-4-and the methyl]-4-(5-iodopyridine-2-yl)piperazine, 1-(4-chloro-3-triptoreline)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(3-triptoreline)piperazine, 1-(4-bromophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 4-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1H-yl}phenol, 1-(3,4-dimetilfenil)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2-forfinal)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-2-methyl-1-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-2-methyl-4-(5-triptorelin-2-yl)piperazine, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(5-methylpyridin-2-yl)piperazine, 1-(3-chloropyridin-2-yl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 2-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}isonicotinamide, 2-fluoro-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 2-fluoro-5-{4-[4-(5-triptorelin-2-yl)-piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 4-{4-[4-(5-triptorelin-2-yl)-[1,4]diazepan-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 2-fluoro-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzylamine, (2-fluoro-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzyl)dimethylamine, N-(2-fluoro-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzyl)formamide, 1-(4-chlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazin, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-pair-tailpipes, 1-(3-chlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,4-differenl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(3,4-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,3-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(3,5-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,3-dimetilfenil)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(2,4-dimetilfenil)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 4-{4-[4-(5-chloropyridin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 2-{4-[3-(4-cyanophenyl)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}isonicotinamide, 4-{4-[4-(4-chloro-3-triptoreline)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[4-(3,4-dimetilfenil)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(4-methylpyridin-2-yl)piperazine, 1-(2,4-dichlorophenyl)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 1-(4-chloro-2-forfinal)-4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine, 2-cyano-5-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 2-cyano-5-{4-[4-(5-triptorelin-2-yl)[1,4]diazepan-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 2-cyano-N-methyl-5-{4-[4-(5-triptorelin-2-yl)[1,4]diazepan-1-ylmethyl]-1H-pyrazole-3-yl}benzamide, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}be sonitrol, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[2-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[5-(5-triptorelin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[2-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[3,5-dimethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[4-(5-trifluoromethyl-pyridine-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenol, 1-[3-(4-bromophenyl)-1H-pyrazole-4-ylmethyl]-4-(5-triptorelin-2-yl)piperazine, 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether ethylcarbamate acid, 1-[3-(4-imidazol-1-ylphenyl)-1H-pyrazole-4-ylmethyl]-4-(5-triptorelin-2-yl)piperazine, 2-methyl-4-{3-[4-(1H-pyrazole-4-yl)phenyl]-1H-pyrazole-4-ylmethyl}-1-(5-triptorelin-2-yl)piperazine, 4-{4-[3,3-dimethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[2,5-dimethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether ethylcarbamate acid, 4-{4-[3-ethyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl} benzonitrile, 1-ethyl-3-(4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)urea, 4-{4-[4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether methylcarbamyl acid, (4-{4-[3-methyl-4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)acetonitrile, 2-(4-{4-[3-methyl-4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)acetamide", she dimethyl(5-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}pyridine-2-yl)amine, (4-{4-[3-methyl-4-(6-triptorelin-3-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl)acetic acid, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether isopropylcarbamate acid, 4-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}phenyl ether phenylcarbinol acid, 5-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}pyridine-2-carbonitrile, 6-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}nicotinamide, 2-(5-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}-pyridine-2-yl)ndimethylacetamide, 5-{4-[3-methyl-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}pyridine-2-silt ether Karabanovo acid, (S)-methyl 4-((3-(4-cyanophenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine-2-carboxy is at, (S)-4-((3-(4-cyanophenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine-2-carboxylic acid, (S)-4-(4-((3-(methoxymethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-2-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenylamino)ethanol, (R)-5-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenyl)isoxazol, (R)-4-((3-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-methyl-4-((3-(4-(methylsulphonyl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-N-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenylsulfonyl)ndimethylacetamide, (R)-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzoic acid, (R)-4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-4-((3-(4-((1H-tetrazol-5-yl)methyl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)ethanol, (R)-2,2'-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-alazander)diethanol, (S)-4-(4-((3-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-4-{4-[3-Tr is formetal-4-(5-triptorelin-2-yl)piperazine-1-ylmethyl]-1H-pyrazole-3-yl}benzonitrile, (S)-4-(4-((2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-4-(4-((2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-4-(4-((2-(permitil)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (S)-4-(4-((2-(permitil)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-5-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenyl)oxazol, (R)-4-((3-(4-(1H-pyrazole-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-4-((3-(4-(1H-1,2,4-triazole-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-(4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenylamino)acetic acid, (R)-N-methyl-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzosulfimide, (R)-1-(4-(4-((-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)phenyl)-1H-pyrrol-2-carbonitrile, 4-(4-((3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]Octan-8-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((8-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]OK the EN-3-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, (R)-2-methyl-4-((3-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-methyl-4-((3-(4-(5-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-2-methyl-4-((3-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrazole-4-yl)methyl)-1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, (R)-N-(2-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)ethyl)ndimethylacetamide, (R)-N1-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)ethane-1,2-diamine, (R)-4-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)morpholino, (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)-(2-(piperidine-1-yl)ethyl)pyridin-2-amine, (R)-4-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)piperazine-2-(R)-2-hydroxy-4-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)benzoic acid, 1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)pyrrolidin-3-ol, 4-(4-((7-(5-(trifluoromethyl)pyridin-2-yl)-4,7-diazaspiro[2.5]Octan-4-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 4-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)-4,7-diazaspiro[2.5]Octan-7-yl)methyl)-1H-pyrazole-3-yl)benzonitrile, 1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)IU who yl)-1H-pyrazole-3-yl)pyridine-2-ylamino)propan-2-ol, ((S)-1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)pyrrolidin-2-yl)methanol, (R)-1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridine 2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)propan-2-ol, (S)-1-(5-(4-(((R)-3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-ylamino)propan-2-ol and (R)-1-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yl)azetidin-3-ol.

8. A compound selected from the group comprising 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(5-nitropyridine-2-yl)piperazine, 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}pyridine-3-ylamine; 6-{4-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]piperazine-1-yl}nicotinic acid, 1-[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-4-(4-methoxyphenyl)piperazine and (R)-2-(5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)-1H-pyrazole-3-yl)pyridine-2-yloxy)ethanol.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula 1: or its pharmaceutically acceptable salt; in which each R1 and R8 independently represents H or hydroxyl; each R2 and R9 independently represents H or hydroxyl; R5 represents H; each R3, R4, R6, R7, R13 and R14 independently represents H; or R1 and R2, taken together, form =O; or R4 and R5, taken together form double bond; or R5 and R6, taken together form double bond; R10 and R11, taken together form double bond; R12 represents H, alkyl, hydroxyl, aralkyl, halogenalkyl, alcoxyl,- -[(W)- N(R21)C(O)]qR21, -[(W)-N(R21)SO2]qR21, -[(W)-O]qR21 or -[(W)-N(R21)]qR21; where each W independently represent bivalent alkyl or aralkyl radical, and q is equal 1, 2, 3 or 4; each R15, R16 and R17 independently represent H; each R18 and R19 independently represents H; and each R21 independently represents H, alkyl, aryl or aralkyl. Invention also relates to pharmaceutical composition. Claimed invention provides cycloamine analogues which can be applied to counteract phenotypic effects of undesirable activation of Hedgehog pathway, such as acquiring function from Hedgehog, Ptc loss of function or mitigated acquired from function mutations.

EFFECT: compounds by claimed invention are especially applicable in cancer treatment.

19 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds consistent with the general formula (I) or the general formula (II) where: R1 = H; Z = O or S; P1 = CR5R6, P2 = CR7R8, Q = CR9R10; each of R5, R6, R7, R8, R9 and R10 denotes H; Y = CR12R13-CO, where R12, R13 is selected from C0-7-alkyl; C3-6-cycloalkyl or phenyl-C0-7-alkyl; and where the phenyl ring doesn't have to be substituted R19, specified below; in the group (X)0, X = CRI4R15, where R14 and R15 are independently selected from C0-7-alkyl, and o represents a number from zero to three; (W)n, W = O, S, C(O), S(O) or S(O)2 or NR16, where R16 denotes H, and n equals zero or one; (V)m, V = C(O), NHC(O), C(O)NH or CR17R18, where R17 and R18 denotes H, and m represents a number from zero to three, on condition that, when m is more than one, (V)m contains a maximum of one carbonyl group; U = a stable 5-7-member monocyclic or 8-11-member dicyclic ring, which is saturated or non-saturated and which has from zero to four heteroatoms selected from: , where R19 represents: C0-7-alkyl, C3-6-cycloclkyl, Ar-C0-7-alkyl, O-C0-7-aklyl, NH-C0-7-alkyl, N(C0-7-alkyl)2, O-phenyl, S-phenyl; or, as a part of CHR19 or CR19 group, R19 can represent a halogen; where Ar represents a stable 5- or 6- member monocyclic or stable 9- or 10- member dicyclic ring, which is unsaturated as determined earlier for U, and where Ar doesn't have to be substituted R19, which is of importance specified above; C0-7-alkyl represents a stable linear or a branched aliphatic carbon chain, which contains from 0 to 7 carbon atoms, which doesn't have to be substituted with one, two or three halogen atoms and doesn't have to contain one or few heteroatoms selected from O, N and S, where the heteroatom is present only when C0-7-alkyl contains as a minimum one carbon atom; C3-6-cycloalkyl relates to C0-7-alkyl, certainly higher than the additionally contained carboxyl ring, which doesn't have to be substituted with one or more halogens, selected from F, Cl, Br and I or heteroatoms, selected from N, O, S; A represents O; B, D and G are independently selected from: CR19, where R19 is as specified above or N; E represents O or S; J, L, M, R, T, T2, T3 and T4 which are independently selected from: CR19 and N, where R19 is as specified above; T5 represents N; q represents a number from one to three, determining in this way a 5-, 6- or 7- member ring or its salt, hydrate or solvate. The bonds of the general formula (I) or the general formula (II), represent cruzipain inhibitors and inhibitors of other cisteinproteases and can be used as therapeutic agents, for example, in cases of Chagas disease or for confirmation of target oriented therapeutic bonding.

EFFECT: new bonds which posses helpful biological properties have been discovered.

27 cl, 156 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl-isoxazole-4-yl-imidazole derivatives of formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit GABA A α5 receptor binding site activity and selectivity. In general formula I

each of R1-R3 independently represents hydrogen atom or halogen atom; R4 represents hydrogen atom, lower alkyl, C3-C7cycloalkyl, -(CH2)n-O-lower alkyl or hydroxy substituted lowest alkyl; R5 represents -(CH2)m-phenyl or -(CH2)m-(5-6-members heteroaryl with 1-2 heteroatoms independently seected from N, O) which optionally substituted by one or more substitutes selected from a group consisting of halogen atom, cyano, nitro, lower alkyl, lower alkoxy, lower alkylsulphanyl, lower alkyl substituted by halogen atom, -C(O)-lower alkyl, -C(O)-O-lower alkyl, -NH-C(O)-O-lower alkyl or -C(O)-NH-R' where R' represents the lower alkynyl or hydroxy substituted lower alkyl, or represents -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-members heterocyclyl with 1-2 heteroatoms selected from N, O), -(CH2)n-(5-6-members heteroaryl with 1-2 heteroatoms selected from N, O) or -(CH2)n-phenyl optionally substituted by halogen atom; R6 represents hydrogen atom, -C(O)H, -(CH2)n-O-lower alkyl, -C(O)O-lower alkyl, lower alkyl substituted by hydroxy or halogen atom, or represents C3-C7-cycloalkyl, phenyl, or represents -(CH2)n-O-CH2-phenyl optionally substituted by halogen atom or lower alkyl, or represents -(CH2)n-O-CH2-(6-members heteroaryl with 1 heteroatom selected from N) optionally substituted by lower alkyl or lower alkyl substituted by halogen atoms, or represents -(CH2)n-NH-(CH2)o-(6-members heterocyclyl with 2 heteroatoms selected from N; n means 0, 1, 2 or 3; m means 0 or 1; o means 1, 2 or 3.

EFFECT: presented preparation of a drug containing one or more compound of formula I and application of the compounds for preparing the drug.

31 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I ; or to its pharmaceutically acceptable salts where n represents 0, 1 or 2; Y1 represents a bond or a group C(O); Y2, represents a bond, the groups C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, C1-2alkyl; R2 represents hydrogen, halogen, cyano, C1-4alkyl, C1-3alkoxy, halogen-substituted-C1-3alkyl, halogen-substituted-C1-3alkoxyl, C6aryl-C0alkyl, tetrazolyl, C3-6cycloalkyl-C0alkyl, C6-7heterocycloalkyl-C0-4alkyl where 1 or 2 carbon atoms in the ring are substituted by the groups selected from -O-, -NH-, -S(O) and -SO2-; and phenoxy groups; where said aryl and heterocycloalkyl groups R2 can be substituted by 1 or 2 radicals independently selected from C1-6alkyl; R3 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group and a group -NR6aR6b where R6a and R6b are independently selected from hydrogen and C1-4alkyl; R4 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group; R5 represents hydrogen or C1-3alkyl group; L represents a bivalent radical selected from ; ; ; ; ; ; ; ; ; ; ; ; and ; where asterisks the junctions of Y2 and R2; where any bivalent radical L can be substituted by 1 or 2 radicals independently selected from halogen, hydroxy, cyano, C1-4alkyl, C1-4alkyl carbonylamino, C1-4alkoxy, C1-4alkoxycarbonyl, halogen-substituted - C1-4alkyl, C1-3alkylsulfonyl, C1-3alkylsulfonyl-amino, cyano-substituted - C1-4alkyl and halogen-substituted -C1-4alkoxy radicals. Also, the invention refers to a method of Hedgehog path inhibition in a cell and to a method of undesired cell proliferation inhibition which involves the interaction of the compound of formula I and the cell.

EFFECT: new substituted imidazole derivatives which can be effective in treatment of some types of cancer are prepared.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel oxadiazole compounds of formula (1) and pharmaceutically acceptable salts thereof, where R1 and R2 assume values given in the description, Y is a single bond. The invention also relates to use of said compounds as DGAT1 inhibitors, for example for treating obesity and diabetes, and a method of inhibiting.

EFFECT: high treatment efficiency.

13 cl, 65 tbl, 712 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one derivatives of general formula 1, , where 1a R=Br, R'=CH2OCH3, R"=CH3; 1b R=H, R'=CH2, R"=CH3; 1c R=H, R1=CH2OCH3, R"=Ph; 1d R=H, R'=CH3, R"=Ph; 1e R=Br, R=CH3, R" - fur-2-yl, which can be used as potential biologically active substances and intermediate products for synthesis of novel heterocyclic systems. The method of producing 3 -(2-substituted-1,3 -oxazol-4-yl)pyridin-2( 1 H)-ones of general formula I involves formation of a heterocyclic system of 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one as a result of base-catalysed regrouping of 3-acylamino-2-furfurylfuro[2,3-b]pyridines while boiling said compounds in ethanol for 4-20 hours with addition of 6-7 mmol of potassium hydroxide per 1 mol of the initial 3-acylamino-2-furfurylfuro[2,3-b]pyridine.

EFFECT: high yield.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns a combination for tumour cell growth inhibition containing a cytotoxic compound selected from camptothecin compounds; metabolic antagonists; periwinkle alkaloids; taxanes; platinum compounds; topoisomerase 2 inhibitors; and a combination of two or more said types, or a signal transfer inhibitor selected from antibodies a target of which is EGFR receptor; tyrosine kinase EGFR inhibitors; from antibodies a target of which is a VEGF/VEGF receptor system; PDGFR inhibitors; Raf inhibitors and PKB transfer inhibitors in an effective amount and a compound of formula (IV).

, where R1, R2, R11, T, U and g have the values specified in formula.

EFFECT: what is offered is a pharmaceutical composition, a method for tumour cell growth inhibition, a method of treating a malignant growth in a patient and application of the combination for preparing a drug; the new effective combinations for tumour cell growth inhibition are presented.

77 cl, 20 dwg, 7 tbl, 257 ex

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