Phenylaminopyrimidine compounds and uses thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula Ia

where in the formula Ia
Q and Z independently are selected from N and CR1;
R1independently selected from hydrogen, halogen, R2, OR2HE, R4, OR4CN, CF3, (CH2)nN(R2)2where n is 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3and OR5R4; or
two Deputy R1together with the carbon atoms to which they are attached, form an unsaturated 5 - or 6-membered heterocycle containing from 1 to 4 N atoms;
R 2represents a C1-4alkyl;
R3is an R2With2-4alkenyl or phenyl;
R4represents NH2, Other2N(R1)2substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted, thiomorpholine-1-oxide, substituted or unsubstituted, thiomorpholine-1,1-dioxide, substituted or unsubstituted piperazinil, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted, imidazolyl, substituted or unsubstituted tetrahydrofuranyl and substituted or unsubstituted tetrahydropyranyl;
R5represents a C2-4alkylen;
R6-R9independently selected from H, RXCN, halogen, substituted or unsubstituted With1-4the alkyl, OR1, CO2R1N(R1)2, NO2and CON(R1)2and at least one of R6-R9is an RXCN;
RXrepresents a substituted or unsubstituted C1-6alkylen, where up to 2 carbon atoms may be substituted or not substituted groups, NSO2R1, NRY, CONRY, SO, SO2or;
Yrepresents H or substituted or unsubstituted With1-4alkyl; and
R11is selected from H, halogen, substituted or unsubstituted With1-4the alkyl, OR2, CO2R2, CN, CON(R1)2and CF3,
where the substituents are selected from the group consisting of C1-4of alkyl, C3-6cycloalkyl,2-6alkenyl,2-6the quinil, C1-6alkylaryl, phenyl, unsaturated 5 - or 6-membered heterocycle containing from 1 to 4 N atoms, halogen, halogenfree, unsaturated 5-or 6-membered gallogermanate containing from 1 to 4 N atoms, hydroxy-group, hydroxymethyl,1-4alkoxygroup, fenoxaprop, carboxypropyl, amino, C1-6alkyls, fenalco, alluminare, alloctype,1-6alcoholfree, phenylsulfonyl and ceanography, or its pharmaceutically acceptable salt.

2. The compound of formula Ia according to claim 1, in which R1represents hydrogen, morpholinyl, CH2morpholinyl,1-4alkoxygroup, thiomorpholine, 3-hydroxypyrrolidine, iodine, fluorine, HE, 4-hydroxypiperidine, 4-hydroxyethylpiperazine, N-methylpiperidine, 3-hydroxypiperidine, carbonyl-4-pyrrolidinylcarbonyl, hydroxy-4-piperidinyl, 4-methylcarbamoylmethyl, 4-methylpiperazine, CH3SO2NN-piperidinyl, imidazolyl, CON(R1)2, CF3or R2OR 3.

3. The compound of formula Ia according to claim 1, in which R6represents H or methyl.

4. The compound of formula Ia according to claim 1, in which R7represents H, methyl, methoxy group, halogen or hydroxy-group.

5. The compound of formula Ia according to claim 1, in which R8represents H, RxCN, such as CONHCN, CH2NHCOCN, CONHC(CH3)2CN, NCNSO2CH3, SO2NHCH2CN or NH(SO2CH3)CH2CN, IT, CO2CH2CH3, CON(R1)2N(R1)2or CO2R1where Rxand R1meet the definition in claim 1.

6. The compound of formula Ia according to claim 1, in which R9represents H, RxCN, where Rxcorresponds to the definition in claim 1, a methoxy group, halogen, OCF3or CF3.

7. The compound of formula Ia according to claim 1, in which R11represents H, halogen, substituted or unsubstituted With1-4alkyl, OR2, CO2R2CN or CF3.

8. The compound of formula Ia according to claim 7, in which R11represents H, methyl, methoxy group, Cl, Br, F or CO2R2where R2corresponds to the definition in claim 1.

9. The compound of formula Ia according to claim 1, in which at least one of R7, R8and R9is an RXCN.

10. The compound of formula Ia according to claim 1, in which Rxrepresents-C(O)NHCH2; -NHC(O)CH2CH 2NHCH2C(O)NHC(CH3)2, -C(O)N(CH3)CH2, -N(SO2CH3)CH2, -CH2NHC(O)CH2, NHCH2C(O)NHCH2C(O)NHCH2.

11. The compound according to claim 1, which compound of formula Ib

where Z is independently selected from N and CH;
R1independently selected from H, halogen, HE, CONHR2, CON(R2)2, CF3, R2OR2CN, research, thiomorpholine, thiomorpholine-1,1-dioxide, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinil, imidazolyl, substituted or unsubstituted pyrrolidinyl and C1-4alkylene, where the carbon atoms on the choice of substituted or not substituted NRYand/or possibly substituted morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinil, imidazolyl, substituted or unsubstituted pyrrolidinyl;
R2represents a C1-4alkyl;
RYrepresents H or substituted or unsubstituted With1-4alkyl;
R8is an RxCN;
Rxrepresents a substituted or unsubstituted With1-4alkylen, where up to 2 carbon atoms may be substituted or not substituted groups, NSO2R1, NRY, CONRY, SO, SO2or;
R11pre is is N or C 1-4alkyl, where the substituents are selected from the group consisting of C1-4of alkyl, C3-6cycloalkyl,2-6alkenyl,2-6the quinil,1-6alkylaryl, phenyl, unsaturated 5 - or 6-membered heterocycle containing from 1 to 4 N atoms, halogen, halogenfree, unsaturated 5 - or 6-membered gallogermanate containing from 1 to 4 N atoms, hydroxy-group, hydroxymethyl,1-4alkoxygroup, fenoxaprop, carboxypropyl, amino, C1-6alkyls, fenalco, alluminare, alloctype, C1-6alcoholfree, phenylsulfonyl and ceanography,
or its pharmaceutically acceptable salt.

12. Connection by claim 11, in which R8represents-CONHCN, -CONHCH2CN, -CONHC(CH3)2CN, -CONHCH2CONHCH2CN, -CH2NHCOCN, -NHCOCH2CN, -NCNSO2CH3, -SO2NHCH2CN, or-NH(SO2CH3)CH2CN.

13. The connection section 12, in which R8represents-CONHCH2CN.

14. Connection by claim 11, in which R1represents morpholine.

15. Connection by claim 11, in which Z represents CH.

16. The compound according to claim 1, selected from the following compounds: N-(cyanomethyl)-3-(2-(4-martindemello)pyrimidine-4-yl)benzamide; N-(cyanomethyl)-4-(2-(4-martindemello)pyrimidine-4-yl)benzamide; N-(cyanomethyl)-3-methyl-4-(2-(4-martindemello)pyrimidine-4-yl)Bentham is d;
N-(cyanomethyl)-2-methyl-4-(2-(4-martindemello)pyrimidine-4-yl)benzamide;
2-cyano-N-(3-(2-(4-martindemello)pyrimidine-4-yl)benzyl)ndimethylacetamide;
2-(3-(2-(4-martindemello)pyrimidine-4-yl)benzylamino)acetonitrile;
2-cyano-N-(3-(2-(4-martindemello)pyrimidine-4-yl)phenyl)ndimethylacetamide;
2-(3-(2-(4-martindemello)pyrimidine-4-yl)phenylamino)acetonitrile;
N-(cyanomethyl)-4-(2-(3,4,5-trimethoxybenzylamine)pyrimidine-4-yl)benzamide;
N-(2-cyanoprop-2-yl)-4-(2-(4-martindemello)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(3-martindemello)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-thiomorpholine)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-itfinally)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-N-(4-(2-(4-martindemello)pyrimidine-4-yl)phenyl)methanesulfonamide;
N-(cyanomethyl)-4-(2-(4-(morpholinomethyl)phenylamino)pyrimidine-4-yl)benzamide;
N-(2-(cyanomethylene)-2-oxoethyl)-4-(2-(4-martindemello)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(4-hydroxypiperidine-1-yl)phenylamino)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(4-(hydroxymethyl)piperidine-1-yl)phenylamino)-5-methylpyrimidin-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(4-(hydroxymethyl)piperidine-1-yl)phenylamino)pyrimidine-4-yl)benzamide;
2-cyano-N-(2-methoxy-4-(2-(4-martindemello)pyrimidine-4-yl)phenyl)ndimethylacetamide;
N-(cyanomethyl)-4-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimi the Jn-4-yl)benzamide;
N-(cyanomethyl)-2-methoxy-4-(2-(4-martindemello)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(3-hydroxypiperidine-1-yl)phenylamino)-5-methylpyrimidin-4-yl)benzamide;
N-(cyanomethyl)-2-methoxy-4-(5-methyl-2-(4-martindemello)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(5-methoxy-2-(4-martindemello)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenylamino)pyrimidine-4-yl)benzamide;
4-(2-(4-(1-benzylpiperidine-4-yloxy)phenylamino)pyrimidine-4-yl)-N-(cyanomethyl)benzamide;
N-(cyanomethyl)-4-(2-(6-morpholinopropan-3-ylamino)pyrimidine-4-yl)benzamide;
4-(5-chloro-2-(4-martindemello)pyrimidine-4-yl)-N-(cyanomethyl)benzamide;
2-cyano-N-(2-methoxy-4-(5-methyl-2-(4-martindemello)pyrimidine-4-yl)phenyl)ndimethylacetamide;
4-(2-(4-(4-acetylpiperidine-1-yl)phenylamino)pyrimidine-4-yl)-N-(cyanomethyl)benzamide;
N-(cyanomethyl)-4-(5-methyl-2-(4-(4-(methylsulfonyl)piperidine-1-yl)phenylamino)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(4-hydroxypiperidine-1-yl)phenylamino)-5-methylpyrimidin-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(piperidine-4-yloxy)phenylamino)pyrimidine-4-yl)benzamide;
ethyl 4-(4-(cyanomethylene)phenyl)-2-(4-martindemello)pyrimidine-5-carboxylate;
4-(4-(4-(cyanomethylene)phenyl)pyrimidine-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-martindemello)pyridine-4-yl)benzamide;
-(5-bromo-2-(4-martindemello)pyrimidine-4-yl)-N-(cyanomethyl)benzamide;
5-(4-(4-(cyanomethylene)phenyl)pyrimidine-2-ylamino)-N,N-dimethyl-2-martinbentley;
N-tert-butyl-5-(4-(4-(cyanomethylene)phenyl)pyrimidine-2-ylamino)-2-martinbentley;
5-(4-(4-(cyanomethylene)phenyl)pyrimidine-2-ylamino)-N-ethyl-2-martinbentley;
N-(cyanomethyl)-4-(2-(3-fluoro-4-martindemello)pyrimidine-4-yl)benzamide;
N-(2-chloro-4-(2-(4-martindemello)pyrimidine-4-yl)phenyl)-2-cyanoacetamide;
2-cyano-N-(4-(2-(4-martindemello)pyrimidine-4-yl)-2-(triptoreline)phenyl)ndimethylacetamide;
N-(cyanomethyl)-4-(2-(4-morpholino-3-(trifluoromethyl)phenylamino)pyrimidine-4-yl)benzamide;
5-(4-(4-(N-(cyanomethyl)methylsulfonylamino)phenyl)pyrimidine-2-ylamino)-N-(2-(dimethylamino)ethyl)-2-martinbentley;
N-(cyanomethyl)-N-(4-(2-(4-morpholine-3-(trifluoromethyl)phenylamino)pyrimidine-4-yl)phenyl)methanesulfonamide;
N-(cyanomethyl)-4-(2-(3-(propoxymethyl)phenylamino)pyrimidine-4-yl)benzamide;
2-cyano-N-(4-(2-(4-martindemello)pyrimidine-4-yl)-2-(trifluoromethyl)phenyl)ndimethylacetamide;
4-(2-(1H-indazol-5-ylamino)pyrimidine-4-yl)-N-(cyanomethyl)benzamide;
4-(2-(3-(allyloxymethyl)-4-martindemello)pyrimidine-4-yl)-N-(cyanomethyl)benzamide;
N-(cyanomethyl)-4-(2-(4-(1-ethylpiperazin-4-yloxy)phenylamino)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-N-(4-(2-(3-fluoro-4-martindemello)pyrimidine-4-yl)phenyl)methanesulfonamide;
N-(4-(2-(3-cyano-4-martindemello)pyrimidine-4-yl)phenyl)-N-(cyanomethyl)meta is a sulfonamide;
2-cyano-N-(4-(2-(4-martindemello)pyrimidine-4-yl)phenyl)ndimethylacetamide;
5-(4-(4-(N-(cyanomethyl)methylsulfonyl)phenyl)pyrimidine-2-ylamino)-2-morpholinomethyl acid;
N-(cyanomethyl)-4-(2-(4-(3-(diethylamino)propoxy)phenylamino)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-(4-(2-morpholinoethoxy phenylamino)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(2-{[4-(1,1-dioxo-1λ6,4-thiomorpholine-4-yl)phenyl]amino}pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-[2-({4-[(1,1-dioxo-1λ6,4-thiomorpholine-4-yl)methyl]phenyl}amino)pyrimidine-4-yl]benzamide;
N-(cyanomethyl)-N-methyl-4-(2-(4-morpholinothio)pyrimidine-4-yl)benzamide;
N-(cyanomethyl)-4-(5-methyl-2-(4-martindemello)pyrimidine-4-yl)benzamide; and
N-(cyanomethyl)-4-(5-fluoro-2-(4-martindemello)pyrimidine-4-yl)benzamide and their pharmaceutically acceptable salts.

17. The compound according to claim 1, which is N-(cyanomethyl)-4-(2-(4-martindemello)pyrimidine-4-yl)benzamide with below the following structural formula

or its pharmaceutically acceptable salt.

18. The connection 17, which is the monohydrochloride salt of N-(cyanomethyl)-4-(2-(4-martindemello)pyrimidine)-4-yl)benzamide.

19. The compound according to claim 1, which is 1N-(cyanomethyl)-4-(2-(4-(4-hydroxypiperidine-1-yl)phenylamino)-5-methylpyrimidin-4-yl)benzamide or its pharmaceutically acceptable the th Sol.

20. The compound according to claim 1 or 16, which shows the properties of the inhibitor of the JAK kinase.

21. Connection claim 20, where the kinase inhibitor is an inhibitor of JAK2 kinase.

22. The method of obtaining the compounds of formula Ia according to claim 1 or compounds Ib according to claim 11, including the operation of combination reaction of compounds of formula II

where Q and R11meet the definition in claim 1 and X is a leaving group, with compounds of formulas III and IV

n, Z, R1and R6-R9meet the definition in claim 1; and
M is a derivative of boron or a derivative of metal.

23. The method of obtaining connection 17, which includes the following operations: (a) the combination of compounds of the following formula:

with a compound of the following formula:

obtaining compounds of the following formula:

(b) the combination of the compounds obtained in operation (a), with the compound of the following formula:

obtaining compounds of the following formula:

(C) reaction of the compound obtained in operation (b), with

24. The pharmaceutical composition exhibiting the properties of an inhibitor of JAK kinase, comprising a therapeutically effective quantity the quantity of compounds according to claim 1 or 16, and a pharmaceutically acceptable filler.

25. The compound according to claim 1 or 16 for use in the stent.

26. A method of treating immunological or inflammatory, hyperproliferative diseases, metabolic or vascular diseases, including the introduction of an effective amount of a compound according to claim 1 or 16, or the pharmaceutical composition according to paragraph 24 to a subject who needs it.

27. The method according to p in which immunological or inflammatory disease associated with organ transplant.

28. The method according to p in which the hyperproliferative disease is cancer or myeloproliferative disease.

29. A method of inhibiting JAK kinase in the cell, including the contact of the cells with a therapeutically effective amount of a compound according to claim 1 or 16.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates organic chemistry and specifically to novel pyridine amide derivatives of general formula I where n equals 1; R1 and R2 together denote a residue selected from a group consisting of -CH=N-NH- and -CH=CH-N=CH-, which is bonded in any desirable direction to the parent structure or R2 and R3 together denote a residue selected from a group consisting of -CH=N-NH-; -CR28=N-NH-; -S-C(=S)-NH-; -S-CR29=N-; -N=CR30-O-; -N=CH-NH-; -N=N-NH-; -O-CH2-O-; -CH2-CH2-CH2-NH, -O-CH2-CH2-O-; -N=CH-CH=N-; -CH=CH-CH=N-, which is bonded in any desirable direction to the parent structure, or R3 and R4 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, or R4 and R5 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, and the rest of the residues R1, R2, R3, R4 and R5, mutually independently, in each case denote H; where R28 denotes F; Cl; Br or I; R29 and R30, mutually independently, in each case denote -NH-C(=O)-R31; -NH2; -NH-S(=O)2-R32; -NH-C(=O)-O-R33; -S-R34; where R31, R32, R33 and R34, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R6 denotes H or denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R7 denotes hydrogen or -OH; R denotes -CF3; or denotes an unsubstituted tert-butyl residue; T denotes C-R35 and U denotes C-R36, V denotes N and W denotes C-R38; where R35 and R36 denote H; where R38 denotes -NR40R41; -OR42 or -SR43; where R40, R41, R42 and R43, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; or denote a saturated, unsubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-member cycloaliphatic residue, or where R40 and R41 in each case together with a nitrogen atom as a ring member which binds them together, form a saturated 6-member heterocycloaliphatic residue, optionally substituted with one R57 residue, where R57 denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; in each case in form of corresponding physiologically acceptable salts. The invention also relates to a method of producing a compound of formula I, a medicinal agent based on the compound of formula I and use of the compound of formula I.

EFFECT: obtaining novel amide derivatives of pyridine, useful in treating vanilloid receptor 1 mediated diseases.

25 cl, 1 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method for preparing N-(1,5,3-dithiazocynan-3-yl)amides of formula , wherein R=p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c), which can find application as biologically active compounds, selective sorbents and precious metal extractants. Substance of the method consists in the reaction of N1,N1,N7,N7 - tetramethyl-2,5-dithiaheptane-1,7-diamine with hydrazides RC(O)NHNH2 in the presence of the catalyst samaric nitrate crystallohydrate Sm(NO3)3·6H2O at temperature 65-75°C for 20-26 h.

EFFECT: what is developed is a method for preparing new high-selectivity N-(1,5,3-dithiazocynan-3-yl)amides.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I , in which X1, X2, X3, X4 and X5 independently denote -CH- or N; or X3, X4 and X5 independently denote -CH- or N, and X1 and X2 independently denote C and are part of an additional 6-member aromatic ring; in which R1 denotes methyl or ethyl, or R1 denotes hydrogen; R2 denotes methyl, ethyl, propyl, tert-butoxy carbonylmethyl, allyl, difluoromethyl, ethylbenzene, methylbenzene, butenyl, hydroxyethyl, tolyl, pentenyl, methoxyethyl, butynyl, propynyl, methylcarbonyloxy, cyclopentyl, each of which can be substituted with one or more identical or different substitutes selected from R5; or R2 denotes hydrogen; R3 denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, halogenalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy or alkoxyalkyl, each of which can be substituted with one or more identical or different substitutes selected from R6; or R3 denotes hydrogen, -CH2-C(O)-heterocycloalkyl or -CH2-C(O)NR9-R12; R11 denotes one or more identical or different substitutes selected from hydrogen, halogen, cyano, amino, alkyl, methylthionyl, methylsulphonyl, amino, cyano or alkoxy; where R5, R6, R9, R12 are as indicated in claim 1, under the condition that R1, R2 and R3 cannot be methyl at the same time; under the condition that when R2 and R3 both denote hydrogen, R1 cannot be methyl or hydrogen; under the condition that when R1 denotes methyl or hydrogen, R2 denotes methyl and R3 denotes hydrogen when ring B cannot be phenyl; and pharmaceutically acceptable salts and N oxides thereof. The invention also describes a pharmaceutical composition for use in case of skin diseases, said composition containing a compound of formula I, and use of said compound in preparing a medicinal agent for preventing conditions associated with skin wounds.

EFFECT: novel compounds which can be useful in treating skin diseases are obtained and described.

19 cl, 304 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds, which represent (4,5-dihydrooxazol-2-yl)-(5,6,7,8-tetrahydroquinoxylan-5-yl)-amino and (4,5-dihydrooxazol-2-yl(-(5,6,7,8-tetrahydroquinolin-5-yl)-amino or their pharmaceutically acceptable salt. Said compounds are applied in methods of intraocular pressure reduction and treatment of pain in mammals who require it.

EFFECT: obtaining compounds, which are alpha-adrenergic agonists.

3 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole- 2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, where R means hydrogen; R1 means phenyl, substituted with 1, 2 or 3 substitutes, each of them is independently selected from a group containing halogen, cyano, C1-4alkyl, perfluoroC1-4alkyl and perfluoroC1-4alkoxy; R2 means hydrogen or C1-4alkyl; R3 means hydrogen, trifluoromethyl or cyano; X means N or CR4, where R4 is trifluoromethyl. Also the invention relates to a pharmaceutical composition containing compounds of the formula as an active ingredient. The following derivatives are presented: derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole-2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) representing quick-dissociating antagonists of dopamine 2 receptors and used as medicinal agents for treatment or prevention of central nervous system.

EFFECT: improved properties of compounds.

7 cl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic 5-nitropyridin-2-yl-thioalkenyl-4-dithiocarbamate derivatives of general formula (I) or pharmaceutically acceptable acid- or base addition salts thereof. The compounds have antifungal activity even in case of deep, subcutaneous and surface mycoses in humans, caused by strains (including those resistant to existing drugs) of mycosis causative agents. In general formula , R denotes nitro, cyano, halide-substituted C1-C6 alkyl group, n=1, 2 or 3. The invention also relates to use of compounds of formula (I), a method of producing said compounds, a pharmaceutical composition and a method for treatment using said compounds.

EFFECT: improved method.

12 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to nitro-derivatives of polycyclic heterocyclic compounds, more specifically to a heterocyclic compound containing two nitrofurazan rings, directly bonded to a furazan ring, and specifically to 3,4-bis(4-nitrofurazan-3-yl)-furazan .

EFFECT: 3,4-bis(4-nitrofurazan-3-yl)-furazan as an energy-rich compound.

1 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula (I) wherein A, R1, R2, R3, R4, R5, R6 and R7 are presented in the description, preparing and using them as pharmaceutically active compounds possessing SP1/EDG1 receptor agonist activity.

EFFECT: using the declared compounds or pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for preventing or treating the diseases or disorders associated with the activated immune system.

13 cl, 76 ex, 2 tbl

Azole compounds // 2493154

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to antibacterial compounds of formula (I) , where one or two of U, V, W and X represent N, the remaining ones represent CH or, in case X, can also represent CRa, where Ra represents fluorine; R1 represents alcoxygroup, halogen or cyanogroup; R2 represents H, CH2OH, CH2N3, CH2NH2, alkylcarbonylaminomethyl or triazol-1-ylmethyl; R3 represents H or, when n=1, R3 can also represent OH, NH2, NHCOR6 or triazol-1-yl; A represents CR4; K represents O, NH, OCH2, NHCO, NHCH2; CH2NH5 CH2CH2, CH=CH, CHOHCHOH or CHR5; R3 represents H or together with R5 forms bond, or R4 can also represent OH, when K is not O, NH, OCH2 or NHCO; R5 represents OH or together with R4 forms bond; R6 represents alkyl; m=0 or 1 and n=0 or 1; and G is specified in i.1 of the formula; and to salt of such compound.

EFFECT: obtaining antibacterial compounds.

19 cl, 1 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

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