Derivatives of substituted triazoldiamine, pharmaceutical composition based on thereof and method for its preparing

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

 

The technical field

The present invention relates to a derivative of the substituted triazolinone and their use as selective inhibitors of one or two types of kinases. In particular, the present invention relates to derivatives of substituted 1,2,4-triazole-3,5-diamine and their use as selective inhibitors of one or two kinases, as well as to a method of treatment or attenuation of symptoms mediated by one or two selective kinase.

Background of the invention

In the patent application WO 99/21845 described (i) derivatives of 4-aminothiazole following formula intended for use as inhibitors of cyclin-dependent kinases:

where:

R1means substituted or unsubstituted group that represents C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl); C1-6alkenyl; C1-6quinil; C1-6alkoxyl; C1-6alcohol; carbocyclic or heterocyclic cycloalkyl, which can be monocyclic, condensed or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), or heteroseksualci, which can be monocyclic, condensed or unfused polycyclic (e.g., PIR is original, piperidinyl, morpholinyl); carbocyclic or heterocyclic, monocyclic, condensed or unfused polycyclic aryl (e.g. phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, chinoline, ethenolysis, acridines, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene or benzofuran); carbonyl (for example, carboxyl, ester, aldehyde or ketone); a simple ether; (C1-6alkyl)carbonyl; (C1-6alkyl)aryl; (C1-6alkyl)cycloalkyl; (C1-6alkyl)(C1-6alkoxyl); aryl(C1-6alkoxyl); simple tiefer (for example, aryl-S-aryl, cycloalkyl-S-aryl, cycloalkyl-S-cycloalkyl or diallylsulfide); thiol and sulfonyl; and R2means substituted or unsubstituted, carbocyclic or heterocyclic, monocyclic, condensed or unfused polycyclic ring structure; where each optional Deputy for R1and R2independently represents halogen (e.g. chlorine, iodine, bromine or fluorine), oxygen (=O); halogenated (e.g., trifluoromethyl); C1-6alkyl, C1-6alkenyl; C1-6quinil; hydroxyl; C1-6alkoxyl; a carbocyclic cycloalkyl, which can be monocyclic, condensed or decondense ofanim polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heteroseksualci, which can be monocyclic, condensed or unfused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinil, morpholinyl or triazinyl); carbocyclic or heterocyclic, monocyclic, condensed or unfused polycyclic aryl (e.g. phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, chinoline, ethenolysis, acridines, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene or benzofuran); an amino group (primary, secondary or tertiary); nitro; thiol; a simple thioether; Imin; cyano; amido; phosphonate; phosphine; carboxyl, thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde or ester; (ii) pharmaceutically acceptable salts of the compounds of the above formula and (iii) prodrugs and pharmaceutically active metabolites of compounds of the above formula or its pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.

In the patent application WO 01/09106 described diamino-1,2,4-triazolinone acid and its derivatives of the formula (I)intended for use as inhibitors of GSK-3 (protein kinase):

g is e:

R3CZ-piece can be attached to the nitrogen atom in position 1 or in position 2;

R1means hydrogen, alkyl, aryl, aralkyl, aralkyl or alicyclic group; R2means hydrogen, alkyl, aryl, aralkyl, aralkyl or alicyclic group, or R1and R2with the nitrogen atom to which they are attached, form a heterocyclic ring which may be substituted or substituted; R3means alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q denotes O or S, aralkyl, alicyclic group, heteroaryl, heteroalkyl, arylcarboxylic, electrially, giarelli or NR6R7; R4means hydrogen, alkyl, aryl, aralkyl, aralkyl or alicyclic group; R5means hydrogen, alkyl, aryl, aralkyl, aralkyl or alicyclic group, or R4and R5together with the nitrogen atom to which they are attached, form a heterocyclic ring which may be substituted or substituted; R6means hydrogen, aryl or alicyclic group; R7means hydrogen, aryl or alicyclic group, and Z denotes oxygen or sulphur. R1may represent hydrogen, unsubstituted or substituted phenyl, and the substituents for the phenyl group independently selected from one to three groups, including C1-C6alkyl, C1-C6alkoxy, C1 -C6alkoxy(C1-C6)alkyl, aryl, aryloxy, halogen, hydroxy, carboxy, cyano and nitro. R1preferably means phenyl which may be substituted or is substituted by one to three groups such as methyl, methoxy or chlorine. R2may represent hydrogen, unsubstituted or substituted phenyl, and the substituents for the phenyl group independently selected from one to three groups, including C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6)alkyl, aryl, aryloxy, halogen, hydroxy, carboxy, cyano and nitro. R2preferably means hydrogen. R3may represent unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted benzyl, unsubstituted or substituted thienylmethyl, unsubstituted or substituted phenylthiomethyl, unsubstituted or substituted naphthylmethyl, unsubstituted or substituted fullerenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted pyridyl, unsubstituted or substituted indolylmethane, unsubstituted or substituted phenylcarbonylamino, unsubstituted or substituted cyclopentadienyl, unsubstituted or substituted phenylpropyl, unsubstituted or substituted diphenylether, and the substituents for the aryl groups of R3chosen from- (CH2)nO-, where n is equal is 1-3, or from one to three groups including halogen, aryl, PERFLUORO(C1-C6)alkyl, nitro, arylcarbamoyl, aryloxy, C1-C6acyl; or R3is NR6R7where R6and R7independently mean hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted C1-C6alicyclic group, and the substituents for the groups R6and R7independently selected from one to three groups including halogen, aryl, aryloxy, alkyl, nitro and alkoxy. R3preferably means phenyl which may be substituted or is substituted by one to three groups, including chlorine, bromine, phenyl, trifluoromethyl, nitro, benzoyl, phenoxy, acetyl or 3,4-och2O-; naphthyl; benzyl which may be substituted or is substituted by one to three groups, including phenyl or fluoro; 2-thienylmethyl; phenylthiomethyl 2-naphthyl-methyl; cyclohexyl; 3-pyridyl; 3-indoleacetic; phenylcarbonylamino; cyclopent-2-animetal; phenylpropyl; 2,2-diphenylether; 2-furylidene; or NR6R7where R6and R7independently denote hydrogen, phenyl, which may be substituted or is substituted by one to three groups, including chlorine, phenyl, phenoxy, methyl, bromine, nitro or methoxy; cyclohexyl or 1-naphthyl. In case R4may represent hydrogen. In case R5may represent hydrogen. In convenient when you learn R 6may represent unsubstituted or substituted aryl, unsubstituted or substituted alicyclic group. R6preferably means cyclohexyl, naphthyl or phenyl, which may be substituted or is substituted by one to three groups, including chlorine, bromine, phenyl, methyl, phenoxy, nitro or methoxy. R7may represent hydrogen.

In U.S. patent No. 5750545 described triazole derivatives of the formula (I) and formula (III), intended for use as drugs for the prevention and treatment of immune diseases:

where:

X means an oxygen atom or a sulfur atom; W means-NR4R5or-SR6; R1means a hydrogen atom, a lower alkyl, -NR10R11, -N=, R13or a group of formula (II)

where:

Y means a hydrogen atom, lower alkyl, lower alkoxy, halogen, cyano, nitro, lower alkyl substituted by halogen, -NR14R15, tetrazolyl, optionally substituted phenyl, hydroxy or carboxyl, L is the direct (immediate) bond, an oxygen atom, a sulfur atom, alkylene, vinile or ethynylene, and n is an integer from 1 to 3 provided that when n is 2 or 3, Y may be the same or different values; R2and R3have identical or different meanings and represent an atom of water is entering or lower alkyl; R4and R5have identical or different meanings and represent a hydrogen atom, optionally substituted lower alkyl, cycloalkyl, phenyl or -(CH2)mCOOR16where R16means a hydrogen atom or lower alkyl, m is an integer from 1 to 6, R6means lower alkyl, R10and R11have identical or different meanings and represent a hydrogen atom, optionally substituted benzoyl, optionally substituted phenyl, lower alkylsulphonyl or COCOOR17where R17means lower alkyl, R13means optionally substituted methylene, R14and R15have identical or different meanings and represent a hydrogen atom, a lower alkyl, -COCOOR17or CSNHR18where R18means lower alkyl, or their pharmaceutically acceptable salts.

The object of the present invention are derivatives of substituted triazolinone and their use as selective inhibitors of one or two kinases. In particular, an object of the present invention are derivatives of substituted 1,2,4-triazole-3,5-diamine, their use as selective inhibitors of one or two kinases and the way to cure or ameliorate disease symptoms mediated by one or two selective kinase.

A brief statement of the substance of the invention

The present invention relative to the tsya to the compound of formula (I):

where:

R1selected from the group including C1-8alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl {and heterocyclyl optionally substituted by 1-2 hexosaminidase; and cycloalkyl, heterocyclyl, aryl and heteroaryl replaced by Deputy chosen from the group including:

C1-8alkyl (optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl);

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-SO2-(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (with am is but substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl) and heteroaryl)},

cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; heterocyclyl optionally substituted by 1-2 hexosaminidase; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted Deputy chosen from the group comprising C1-8alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl)}};

R2selected from the group including hydrogen, C1-8alkyl, C2-8alkenyl, C2-8quinil and hydroxy(C1-8)alkyl;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3choose from a group including:

C1-8alkyl, C2-8alkenyl, C2-8quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (and the aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},

cycloalkyl, heterocyclyl, aryl, heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group including:

C1-8alkyl, C2-8alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently researched is isimo selected from the group comprising hydrogen and C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH)(C1-8)alkyl, C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-C(O)(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl))},

-NH-SO2-(C1-8)alkyl,

cycloalkyl, heterocyclyl (optionally substituted by 1-2 hexosaminidase), aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (and cycloalkyl, aryl and heteroaryl optional is entrusted substituted by 1-5 substituents, independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};

and its pharmaceutically acceptable salts.

One of the embodiments of the present invention relates to a method of treatment or attenuation of symptoms mediated by one or two selective kinase.

Another variant of implementation of the present invention relates to a method for producing compounds according to this invention, pharmaceutical compositions and medicaments.

Detailed description of the invention

Some embodiments of the present invention pertain to compounds of formula (I)in which R1preferably chosen from the group comprising C1-4alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl replaced by Deputy chosen from the group including:

C1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-4)alkyl, -CO2H, -CO2(C1-4)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (g is lågen) 1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl);

C1-4alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-4)alkyl, -CO2H, -CO2(C1-4)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-SO2-(C1-4)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl, -C1-4alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl) and heteroaryl)},

cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; heterocyclyl optionally substituted by 1-2 hexosaminidase; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted Deputy, select the m group, including C1-4alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-4alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl)}}.

More preferably R1selected from the group including C1-4alkyl and aryl {and aryl substituted Deputy chosen from the group including:

C1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano,

(halogen)1-3, hydroxy and nitro),

C1-4alkoxy,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-SO2-(C1-4)alkyl);

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl, -C1-4alkylamino (where the amino is substituted by two substituents, not avisio selected from the group comprising hydrogen and C1-4alkyl) and heteroaryl)},

heterocyclyl (and heterocyclyl optionally substituted with 1-2 substituents independently selected from the group including C1-4alkyl and oxo), and heteroaryl}.

Most preferably R1selected from the group including C1-4alkyl and phenyl (which phenyl is substituted by the Deputy chosen from the group including:

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-SO2-(C1-4)alkyl);

-SO2- {substituted by one Deputy, selected from the group including piperidinyl and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl, -C1-4alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl), and pyridinyl)}, and

piperazinil (optionally substituted by 1-2 substituents, represents C1-4alkyl), imidazolidinyl, isothiazolinones (and imidazolidinyl and isothiazolinones optionally substituted by 1-2 hexosaminidase), imidazolyl and triazolyl}.

Some embodiments of the present invention pertain to compounds of formula (I)in which R2preferably selected from the group including hydrogen,

C 1-4alkyl, C2-4alkenyl, C2-4quinil and hydroxy(C1-4)alkyl.

More preferably R2selected from the group including hydrogen, C1-4alkyl.

Most preferably R2represents hydrogen.

Some embodiments of the present invention pertain to compounds of formula (I)in which X is preferably chosen from the group comprising-C(O)-, -C(S)- and-SO2-.

Some embodiments of the present invention pertain to compounds of formula (I)in which R3preferably chosen from the group including:

C1-4alkyl, C2-4alkenyl, C2-4quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-4)alkyl, -CO2H, -CO2(C1-4)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (and the aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-4alkyl, cyano, halogen, (halogen)1-3(C1-4)alkyl, (halogen)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)},

cycloalkyl, gets recycler, aryl, heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group including:

C1-4alkyl, C2-4alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-4)alkyl, -CO2H, -CO2(C1-4)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH)(C1-4)alkyl,

C1-4alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-4)alkyl, -CO2H, -CO2(C1-4)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-C(O)(C1-4)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl),

-SO2- {substituted one for what estealam, selected from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-C1-4alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl))},

-NH-SO2-(C1-4)alkyl,

cycloalkyl, heterocyclyl (optionally substituted by 1-2 hexosaminidase), aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl, cycloalkyl, aryl and heteroaryl (and cycloalkyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-4alkyl, cyano, halogen, (halogen)1-3(C1-4)alkyl, (halogen)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)}.

More preferably R3choose from a group including:

C1-4alkyl, C2-4alkenyl, C2-4quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (PR is what aryl and heteroaryl optionally substituted by 1-5 substituents, independently selected from the group including C1-4alkyl, cyano, halogen, (halogen)1-3(C1-4)alkyl, (halogen)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)},

cycloalkyl, heterocyclyl, aryl, heteroaryl {and cycloalkyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group including:

C1-4alkyl, C2-4alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-CO2H, -CO2(C1-4)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH)(C1-4)alkyl,

C1-4alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-4)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-C(O)-(C1-4 )alkyl),

aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl and aryl (which aryl optionally substituted by 1-5 substituents independently selected from the group including C1-4alkyl, cyano, halogen, (halogen)1-3(C1-4)alkyl, (halogen)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)}.

Most preferably R3choose from a group including:

C1-4alkyl, C2-4alkenyl, C2-4quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy, nitro, phenyl and thienyl (and phenyl and thienyl optionally substituted with 1-2 substituents independently selected from the group including C1-4alkyl, cyano, halogen, hydroxy and nitro)},

cyclopentyl, cyclohexyl, cycloheptyl, benzo[b]thienyl, phenyl, furyl, thienyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridinyl {and cyclohexyl and phenyl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cyclohex the silt and phenyl optionally substituted with 1-2 substituents, independently selected from the group including:

C1-4alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy and nitro),

-CH(OH)(C1-4)alkyl,

C1-4alkoxy,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl),

thienyl and thiazolyl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, thienyl and thiazolyl optionally substituted with 1-2 substituents independently selected from the group including:

C1-4alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-CO2H, -CO2(C1-4)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy and nitro),

C1-4alkoxy,

-C(O)(C1-4)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-C(O)(C1-4)alkyl),

pyrrolyl and pyridinyl;

and Tyagi who was Salil optionally substituted by one Deputy, selected from the group including C1-4alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group including:

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-4alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl),

cyano, halogen, hydroxy and nitro}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl and phenyl (which phenyl optionally substituted by 1-5 substituents independently selected from the group including C1-4alkyl, cyano, halogen, hydroxy and nitro)}.

Some embodiments of the present invention pertain to compounds of formula (I)representing the compound of formula (Ia):

where:

R4choose from a group including:

C1-8alkyl {optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl};

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-SO2-(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl) and heteroaryl)},

cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group, Lucaya hydrogen and C 1-8alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, halogen, hydroxy and nitro; and heterocyclyl optionally substituted by 1-2 hexosaminidase)};

R2selected from the group including hydrogen, C1-8alkyl, C2-8alkenyl, C2-8quinil and hydroxy(C1-8)alkyl;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3choose from a group including:

C1-8alkyl, C2-8alkenyl, C2-8quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (and the aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},

cycloalkyl, heterocyclyl, aryl, heteroaryl {and cycloalkyl, heterotic the sludge, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group including:

C1-8alkyl, C2-8alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH)(C1-8)alkyl,

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C(O)(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy, selected from the group consisting of heterocycle and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl))},

-NH-SO2-(C1-8)alkyl,

cycloalkyl, heterocyclyl (optionally substituted by 1-2 hexosaminidase), aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (and cycloalkyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};

and its pharmaceutically acceptable salts.

Some embodiments of the present invention pertain to compounds of formula (I)representing the compound of formula (Ib):

where:

R4choose from a group including:

C1-8alkyl {optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from GRU the dust, comprising hydrogen and C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl};

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-SO2- (C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl) and heteroaryl)},

cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising amino (replacing the military two alternates, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, halogen, hydroxy and nitro; and heterocyclyl optionally substituted by 1-2 hexosaminidase};

R2selected from the group including hydrogen, C1-8alkyl, C2-8alkenyl,2-8quinil and hydroxy(C1-8)alkyl;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3choose from a group including:

C1-8alkyl, C2-8alkenyl,2-8quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (and the aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},

cycloalkyl, heterocyclyl, aryl, heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group including:

C1-8alkyl, C2-8alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH)(C1-8)alkyl,

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C(O)(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl), -SO2- {substituted one mandated the holder selected from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl))},

-NH-SO2-(C1-8)alkyl,

cycloalkyl, heterocyclyl (optionally substituted by 1-2 hexosaminidase), aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (and cycloalkyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};

and its pharmaceutically acceptable salts.

Some embodiments of the present invention pertain to compounds of formula (I)representing the compound of formula (Ic):

where:

R4selected from the group comprising:C1-8alkyl {optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO 2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl};

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-SO2-(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl) and heteroaryl)},

cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl (the alkyl optionally is Ameen at the end carbon atom Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, halogen, hydroxy and nitro; and heterocyclyl optionally substituted by 1-2 hexosaminidase};

R2selected from the group including hydrogen, C1-8alkyl, C2-8alkenyl,2-8quinil and hydroxy(C1-8)alkyl;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3choose from a group including:

C1-8alkyl, C2-8alkenyl,2-8quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (and the aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydro is C(C 1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},

cycloalkyl, heterocyclyl, aryl, heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group including:

With1-8alkyl, C2-8alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH) (1-8)alkyl,

With1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C(O)(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected and from the group comprising hydrogen and1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group comprising hydrogen and C1-8alkyl))},

-NH-SO2-(C1-8)alkyl,cycloalkyl, heterocyclyl (optionally substituted by 1-2 hexosaminidase), aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (and cycloalkyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};

and its pharmaceutically acceptable salts.

Some embodiments of the present invention pertain to compounds of formula (Ic)in which R4preferably chosen from the group including:

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-SO2-(C1-4)alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-4alkyl and-C1-4alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-4alkyl) and heteroaryl)},

heterocyclyl (optionally substituted by 1-2 substituents independently selected from the group including C1-4alkyl and oxo), and heteroaryl.

Some embodiments of the present invention pertain to compounds of formula (I)representing the compound of formula (Id):

where:

R4choose from a group including:

C1-8alkyl {optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl};

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO 2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-SO2-(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl) and heteroaryl)},

cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, halogen, hydroxy and nitro; and heteros CLIL optionally substituted by 1-2 hexosaminidase};

R2selected from the group including hydrogen, C1-8alkyl, C2-8alkenyl, C2-8quinil and hydroxy(C1-8)alkyl;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3choose from a group including:

C1-8alkyl, C2-8alkenyl, C2-8quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (and the aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},

cycloalkyl, heterocyclyl, aryl, heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group on the responses:

C1-8alkyl, C2-8alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH)(C1-8)alkyl,

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C(O)(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl))},

-NH-SO2-(C1-8 )alkyl,

cycloalkyl, heterocyclyl (optionally substituted by 1-2 hexosaminidase), aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (and cycloalkyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};

and its pharmaceutically acceptable salts.

Some embodiments of the present invention pertain to compounds of formula (I)representing the compound of formula (Ie):

where:

R1selected from the group including C1-8alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl {and heterocyclyl optionally substituted by 1-2 hexosaminidase; and cycloalkyl, heterocyclyl, aryl and heteroaryl replaced by Deputy chosen from the group including:

C1-8alkyl (optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group of the s, comprising hydrogen and C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl);

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl and-SO2-(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl) and heteroaryl)},

cycloalkyl, heterocyclyl, aryl and heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; heterocyclyl optionally substituted by 1-2 hexosaminidase and, in addition, cycloalkyl, heterocyclyl, aryl and GE is Eroare optionally substituted Deputy selected from the group including C1-8alkyl (which alkyl optionally substituted at the terminal carbon atom by a Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl)}};

R3choose from a group including:

C1-8alkyl, C2-8alkenyl, C2-8quinil {and alkyl, alkenyl and quinil optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, aryl and heteroaryl (and the aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},

cycloalkyl, heterocyclyl, aryl, heteroaryl {and cycloalkyl, heterocyclyl, aryl and heteroaryl neo is Astelin substituted by 1-3 substituents, independently selected from the group consisting of cyano, halogen, hydroxy and nitro; and, in addition, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with 1-2 substituents independently selected from the group including:

C1-8alkyl, C2-8alkenyl (and the alkyl and alkenyl optionally substituted at the terminal carbon atom by a Deputy chosen from the group comprising-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl, amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl), cyano, (halogen)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),

-CH(OH)(C1-8)alkyl,

C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy chosen from the group including halogen)1-3and hydroxy),

-C(O)H, -C(O)(C1-8)alkyl, -CO2H, -CO2(C1-8)alkyl,

amino (substituted with two substituents, independently selected from the group including hydrogen, C1-8alkyl, -C(O)(C1-8)alkyl),

-C(O)amino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl),

-SO2- {substituted by one Deputy chosen from the group comprising heterocyclic and amino (amino substituted with two substituents, n is dependent selected from the group including hydrogen, C1-8alkyl and-C1-8alkylamino (where the amino is substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl))},

-NH-SO2-(C1-8)alkyl,

cycloalkyl, heterocyclyl (optionally substituted by 1-2 hexosaminidase), aryl and heteroaryl}

amino {substituted by two substituents, independently selected from the group including hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (and cycloalkyl, aryl and heteroaryl optionally substituted by 1-5 substituents independently selected from the group including C1-8alkyl, cyano, halogen, (halogen)1-3(C1-8)alkyl, (halogen)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};

and its pharmaceutically acceptable salts.

Illustrative compounds of the present invention include a compound of formula (I)representing the compound of formula (Ic):

The compound of formula (Ic), in which X, R2, R3and R4interdependent selected from the following groups:

td align="center"> 4-CH3-cyclohexyl 113
ConnectionXR2R3R4
1C(Oh)N(2,6-F2)Ph 4-SO2-NH2
2C(Oh)N(2,6-F2-3-CH3)Ph4-SO2-NH2
3C(Oh)N(2,4,6-F3)Ph4-SO2-NH2
4C(Oh)N(2-F)Ph4-SO2-NH2
5C(Oh)N(2,4-F2)Ph4-SO2-NH2
6C(Oh)N(2-F-6-CF3)Ph4-SO2-NH2
7C(Oh)N(2,6-Cl2)Ph4-SO2-NH2
8C(Oh)N(2,4,6-Cl3)Ph4-SO2-NH2
9C(Oh)N(2-NO2)Ph4-SO2-NH2
10C(Oh)N[2,6-(OCH3)2]Ph4-SO2-NH2
11C(Oh)N[2,4,6-(CH3)3]Ph4-SO2-NH2
12C(Oh)NPh4-SO2-NH2
13C(the) N(2,6-F2)Ph4-SO2-1-N-piperidine-1-yl
14C(Oh)N2-thienyl4-SO2-NH2
15C(Oh)N(3-CH3)2-thienyl4-SO2-NH2
16C(Oh)N(3-F)2-thienyl4-SO2-NH2
17C(Oh)N(3-Cl)2-thienyl4-SO2-NH2
18C(Oh)N(3-och2CH3)2-thienyl4-SO2-NH2
19C(Oh)N(3-NHCOCH3)2-thienyl4-SO2-NH2
20C(Oh)N(5-CH3)2-thienyl4-SO2-NH2
21C(Oh)N(5-Br)2-thienyl4-SO2-NH2
22C(Oh)N(5-PINES3)2-thienyl4-SO2-NH2
23C(Oh)N2-thienyl4-SO2-1-N-piperidine-1-yl
24C(Oh)the (3-CH3)2-thienyl4-SO2-1-N-piperidine-1-yl
25C(Oh)N2-furyl4-SO2-NH2
26C(Oh)N5-isoxazolyl4-SO2-NH2
27C(Oh)N2-pyridinyl4-SO2-NH2
28C(Oh)N3-pyridinyl4-SO2-NH2
29C(Oh)N4-pyridinyl4-SO2-NH2
30C(Oh)N3-thienyl4-SO2-NH2
31C(Oh)N3A,7a-dihydrobenzo[b]-Tien-2-yl4-SO2-NH2
32C(Oh)N(5-CH2CH3)2-thienyl4-SO2-NH2
33C(Oh)N[3,5-(CH3)2]2-thienyl4-SO2-NH2
34C(Oh)N[2,4-(CH3)2]5-thiazolyl4-SO2-NH2
35C(Oh)N (3-Br)2-thienyl4-SO2-NH2
36C(Oh)N4-(CH3)-1,2,3-thiadiazole-5-yl4-SO2-NH2
37C(Oh)N1,2,3-thiadiazole-4-yl4-SO2-NH2
38C(Oh)Ncyclopentyl4-SO2-NH2
39C(Oh)Ncyclohexyl4-SO2-NH2
40C(Oh)N2-thienyl-CH24-SO2-NH2
42C(Oh)N2-thienyl-(CN)24-SO2-NH2
43C(Oh)N(2,6-F2)-Ph-CH24-SO2-NH2
44C(Oh)N(2,6-F2)Ph(CH)24-SO2-NH2
45C(Oh)Ncycloheptyl4-SO2-NH2
46C(Oh)N4-CH3-cyclohexyl4-SO2-NH2
47C(Oh)N4-SO2-NH2
48C(Oh)N4-(CH2)3CH3-cyclohexyl4-SO2-NH2
49C(Oh)N5-(2-pyridinyl)2-thienyl4-SO2-NH2
50C(Oh)N3-(1H-pyrrol-1-yl)2-thienyl4-SO2-NH2
51C(Oh)N5-[C(CH3)3]2-thienyl4-SO2-NH2
52C(Oh)N5-[(CH)2C(O)-OC(CH3)3]2-thienyl4-SO2-NH2
53C(Oh)NPh(C)24-SO2-NH2
54C(Oh)N(2,6-F2-3-NO2)Ph4-SO2-NH2
55C(Oh)N(2,6-F2-3-NH2)Ph4-SO2-NH2
56C(Oh)N[2,6-(CH3)2]Ph4-SO2-NH2
57C(Oh)N(2-CH3)Ph4-SO2-NH2
58C(Oh)N[2,6-F2-3-CH(OH)CH3]Ph4-SO2-NH2
59C(Oh)N(2,6-F2)Ph4-SO2-NH2
60C(Oh)N(2,6-F2-3-CH3)Ph4-SO2-NH2
61C(Oh)N(2,6-F2)PhN
62C(Oh)NPhN
63C(Oh)N(2,6-F2)Ph3-Cl
64C(Oh)NPh3-Cl
65C(Oh)N-NH(Ph)H
66C(S)N-NH[(2,6-F2)Ph]4-SO2-NH2
67C(Oh)N-NH[(2,6-F2)Ph]4-SO2-NH2
68SO2N(2,6-F2)Ph4-SO2-NH2
69C(Oh)N(2-Cl-3-CH3-6-F)Ph4-SO2-NH2
70 C(Oh)N(2-Cl-6-F)Ph4-SO2-NH2
71C(Oh)N(2,6-F2)Ph4-(4-CH3-1,4-H-piperazine-1-Il)
72C(Oh)N(2,6-F2-3-CH3)Ph4-(4-CH3-1,4-N-piperazine-1-Il)
73C(Oh)N(3-CH3)2-thienyl4-(4-CH3-1,4-N-piperazine-1-Il)
74C(Oh)N[3,5-(CH3)2]2-thienyl4-(4-CH3-1,4-N-piperazine-1-Il)
75C(Oh)N(5-CH2CH3)2-thienyl4-(4-CH3-1,4-N-piperazine-1-Il)
76C(Oh)N(2,6-F2)Ph4-SO2-NH(CH2CH3)
78C(Oh)N(2,6-F2-5-Cl)Ph4-SO2-NH2
80C(Oh)N(2,6-F2)Ph4-SO2-NH(CH3)
81C(Oh)N(2,6-F2-3-CH3)Ph4-SO2-NH(CH3)
82C(Oh)N(3-CH3)2-Anil 4-SO2-NH(CH3)
83C(Oh)N[3,5-(CH3)2]2-thienyl4-SO2-NH(CH3)
84C(Oh)N(5-CH2CH3)2-thienyl4-SO2-NH(CH3)
85C(Oh)N[3,5-(CH3)2]2-thienyl4-SO2-N(CH3)2
86C(Oh)N(5-CH2CH3)2-thienyl4-SO2-N(CH3)2
87C(Oh)N(3-CH3)2-thienyl4-SO2-N(CH3)2
88C(Oh)N(2,6-F2-3-CH3)Ph4-SO2-N(CH3)2
89C(Oh)N(2,6-F2)Ph4-SO2-N(CH3)2
90C(Oh)N(5-CH2CH3)2-thienyl4-(1-H-imidazol-1-yl)
91C(Oh)N(3-CH3)2-thienyl4-(1-H-imidazol-1-yl)
92C(Oh)N[3,5-(CH3)2]2-thienyl 4-(1-H-imidazol-1-yl)
93C(Oh)N(2,6-F2)Ph4-(1-H-imidazol-1-yl)
94C(Oh)N(2,6-F2-3-CH3)Ph4-(1-H-imidazol-1-yl)
95C(Oh)N(2,6-F2-3-CH3)Ph4-(1-H-1,2,4-triazole-1-yl)
96C(Oh)N(2,6-F2)Ph4-(1-H-1,2,4-triazole-1-yl)
97With(About)N(5-CH2CH3)2-thienyl4-(1-H-1,2,4-triazole-1-yl)
98C(Oh)N[3,5-(CH3)2]2-thienyl4-(1-H-1,2,4-triazole-1-yl)
99C(Oh)N(3-CH3)2-thienyl4-(1-H-1,2,4-triazole-1-yl)
100C(Oh)N(2,6-F2)Ph4-(1-N-1,3,4-triazole-1-yl)
101C(Oh)N(2,6-F2-3-CH3)Ph4-(1-N-1,3,4-triazole-1-yl)
102C(Oh)N(3-CH3)2-thienyl4-(1-N-1,3,4-triazole-1-yl)
103C(Oh)N(5-CH2SN 3)2-thienyl4-SO2NH[(CH2)2N(CH3)2]
104C(Oh)N(3-CH3)2-thienyl4-SO2NH[(CH2)2N(CH3)2]
105C(Oh)N(2,6-F2-3-CH3)Ph4-SO2NH[(CH2)2N(CH3)2]
106C(Oh)N(2,6-F2)Ph4-SO2NH[(CH2)2N(CH3)2]
107C(Oh)N[3,5-(CH3)2]2-thienyl4-SO2NH[(CH2)2N(CH3)2]
108C(Oh)N[3,5-(CH3)2]2-thienyl4-NH-SO2-CH3
109C(Oh)N(3-CH3)2-thienyl4-NH-SO2-CH3
110C(Oh)N(5-CH2CH3)2-thienyl4-NH-SO2-CH3
111C(Oh)N(2,6-F2)Ph4-NH-SO2-CH3
112C(Oh)N(2,6-F2-3-CH3)Ph4-NH-SO2-CH3
C(Oh)N(3-CH3)2-thienyl4-(2-imidazolidinone)
114C(Oh)N(2,6-F2-3-CH3)Ph4-(2-imidazolidinone)
115C(Oh)N(2,6-F2)Ph4-(2-imidazolidinone)
116C(Oh)N(3-CH3)2-thienyl4-(1,1-dioxido-2-isothiazolinone)
117C(Oh)N(2,6-F2)Ph4-(1,1-dioxido-2-isothiazolinone)
118C(Oh)N(2,6-F2)Ph4-SO2-NH-2-pyridinyl
119C(Oh)N(5-CH2CH3)2-thienyl4-SO2-NH-2-pyridinyl
120C(Oh)N[3,5-(CH3)2]2-thienyl4-SO2-NH-2-pyridinyl
121C(Oh)N(3-CH3)2-thienyl4-SO2-NH-2-pyridinyl

and its pharmaceutically acceptable salts.

Illustrative compounds of the present invention include a compound of formula (I)representing the compound of formula (Id):

where X, R3and R4interdependent selected from the following groups:

ConnectionXR3R4
122With(About)(2,6-F2)Ph4-SO2-NH2
123With(About)(2,6-F2-3-CH3)Ph4-SO2-NH2
124With(About)(2,6-F2)PhH
125With(About)PhH
126With(About)(2,6-F2)Ph3-Cl
127With(About)Ph3-Cl
128C(S)-NH[(2,6-F2)Ph]4-SO2-NH2

and its pharmaceutically acceptable salts.

Illustrative compounds of the present invention include a compound of formula (I)representing the compound of formula (Ie):

where R1and R3interdependent selected from the following groups:

ConnectionR1R3
79CH3(3-CH3)Teenel

and its pharmaceutically acceptable salts.

Compounds of the present invention may also be in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts" (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997 (Jan), 66, I, 1). However, other salts may be useful for producing compounds according to this invention or their pharmaceutically acceptable salts. Typical organic or inorganic acids include, but are not limited to, hydrochloric, Hydrobromic, idiscovered, perchloro, sulphuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, almond, methansulfonate, hydroxyethanesulfonic, benzosulfimide, oxalic acid, pambou, 2-naphthalenesulfonate, p-toluensulfonate, cyclohexanesulfamic, salicylic, some saccharine or triperoxonane acid. Typical organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine, procaine, aluminum salts, calcium, lithium, magnesium, potassium, sodium and zinc.

In the scope of the present invention includes prodrugs of the link is on this invention. Such prodrugs are typically containing functional group derivatives of these compounds, which are easily converted in vivo into the required compound. Thus, in the treatment methods of the present invention, the term "introduction" means the treatment of various diseases specifically described or not described by a compound which is converted to the desired compound in vivo after administration to a needy person. Conventional methods of selecting and obtaining acceptable derivative prodrugs described, for example, in the publication "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

Compounds according to this invention, having at least one chiral center may exist as enantiomers. Compounds having two or more chiral centers may additionally exist as diastereomers. If the implementation of the methods for producing compounds according to this invention is formed of a mixture of stereoisomers, these isomers can be divided by the usual methods, in particular preparative chromatography. These compounds can be obtained in the form of racemic mixtures or individual enantiomers may be obtained by standard methods known to the person skilled in the art, for example using enantioselective synthesis or separation, the creation of diastereomeric pairs by the formation of a salt using the receiving optically active acid, subsequent execution fraktsionirovannoe crystallization and recovery of the free base. Connections can also select by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary center. Alternative connection can be shared by using the columns for chiral HPLC. It should be noted that all of these isomers and mixtures are included in the scope of the present invention and, in addition, the term "compound of formula X" means the enantiomers, the diastereomers and the similar form of connection.

Except where otherwise indicated, the term "alkyl" means a saturated group with a straight or branched chain consisting only of 1-8 replaced by hydrogen carbon atoms, preferably 1-6 substituted with hydrogen, carbon atoms and most preferably 1-4 replaced by hydrogen atoms of carbon. The term "alkenyl" means a partially unsaturated alkyl group with straight or branched chain, having at least one double bond. The term "quinil" means a partially unsaturated alkyl group with straight or branched chain, having at least one triple bond. The term "alkoxy" means-O-alkyl, where alkyl has the above values.

The term "cycloalkyl" means a saturated or casticin the unsaturated cyclic alkyl ring, having 3-8 replaced by hydrogen atoms of carbon. Examples of such groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "heterocyclyl" means a saturated or partially unsaturated five-membered ring, in which at least one member is a N atom, O or S and which optionally contains one additional atom or one, two or three additional N atom; a saturated or partially unsaturated six-membered ring in which one, two or three members are a N atom; a saturated or partially unsaturated bicyclic devotione ring, in which at least one member is a N atom, O or S and which optionally contains one, two or three additional N atom; and rich or partially unsaturated bicyclic desatino ring, in which one, two or three members represent the atom N. Examples of such groups include, but are not limited to, pyrrolyl, pyrrolidinyl, DIOXOLANYL, imidazolines, imidazolidinyl, pyrazolyl, pyrazolidine, piperidine, morpholine or piperazinil.

The term "aryl" means an aromatic monocyclic ring system containing 6 substituted by hydrogen carbon atoms, an aromatic bicyclic ring system containing 10 substituted by hydrogen atoms or aromatic carbon is articlecheck ring system, containing 14 substituted by hydrogen atoms of carbon. Examples of such groups include, but are not limited to, phenyl, naphthalenyl or anthracene.

The term "heteroaryl" means an aromatic monocyclic five-membered ring system in which at least one member is a N atom, O or S and which optionally contains one, two or three additional N atom, an aromatic six-membered monocyclic ring in which one, two or three members are a N atom, an aromatic bicyclic devotione ring, in which at least one member is a N atom, O or S and which optionally contains one, two or three additional N atom, and bicyclic aromatic desatino ring, in which one, two or three members represent the atom N. Examples of such groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazoles, chinoline or ethenolysis.

The term "halogen" means fluorine atom, chlorine, bromine or iodine.

The term "independently" means that when the group is substituted by more than one Deputy, these substituents may be the same or different values. The term "dependent" means that the substituents defined suitable is the combination of structural elements.

One of the embodiments of the invention is a pharmaceutical composition or pharmaceutical preparation containing pharmaceutically acceptable carrier and any of the above compounds. In an example embodiment of the invention can result in a pharmaceutical composition or pharmaceutical preparation obtained by mixing any of the above compounds and a pharmaceutically acceptable carrier. In another example embodiment of the invention it is possible to lead the way to obtain the pharmaceutical composition or the medicinal product, comprising mixing any of the above compounds and a pharmaceutically acceptable carrier. In another embodiment, the present invention can result in a pharmaceutical composition or pharmaceutical preparations containing one or more compounds according to this invention in combination with pharmaceutically favourable media.

Used here is the term "composition" means a product that contains the appropriate ingredients in certain amounts, as well as any product obtained directly or indirectly as a result of unification of certain ingredients in certain amounts.

Compounds of the present invention are selective inhibitors of one or DV is x kinases, suitable for use in the treatment or attenuation of symptoms mediated by one or two kinases. In particular, this kinase is cyclin-dependent kinase or tyrosinekinase. More specifically, the kinase is a cyclin-dependent kinase 1, cyclin-dependent kinase-2, cyclin-dependent kinase-4, the receptor-2 endothelial growth factor vascular endothelial receptor and growth factor receptor-2 epidermal growth factor (human).

Inhibitors of cyclin-dependent kinases play an important role in the regulation of development of eukaryotic cells throughout the life cycle of the cells due to the fact that they are associated with protein complexes formed by cyclename and cyclin-dependent kinases, and thus weaken the activity of cyclin-dependent kinases. Route of metabolism involving inhibitors of cyclin-dependent kinases, are often destroyed in tumor cells, causing improper regulation of the life cycle of cells. Overexpression of inhibitors of cyclin-dependent kinase inhibits cell growth in one of the control points in the life cycle of cells. Therefore, the use of inhibitors of cyclin-dependent kinase seems to be very attractive for the treatment of tumors, since these kinases contribute to tumor growth. Suppression or control unregulated Pro is operacii cells can give positive results in the case of some species angiopathy, the growth of benign tumors, leukemias and related diseases. Especially good target for inhibitor of cyclin-dependent kinase (CDK) in the creation of anticancer agents is the receptor CDK-1. This protein controls the final control point in the life cycle of cells between the G2 phase and m

The second protein target, which is able to facilitate the process of destruction of the tumor, is the receptor endothelial growth factor vascular (VEGF) tyrosine kinase. This protein is involved in both normal and pathological angiogenesis. The VEGF receptors are tripartite and include extracellular legendbase.ui domain, a transmembrane domain and an intracellular tyrosine kinase domain. Currently, there are two known receptor VEGF: (1) VEGF-R2 (KDR/Flk1/VEGF-R2 receptor, mediating the biological activity of mitogenesis and proliferation of endothelial cells; and (2) VEGF-R1 (Flt1/VEGF-R1) receptor, mediating functions such as adhesion of endothelial cells. It is established that inhibition of signaling VEGF-R2 inhibits the development of blood vessels. Inhibitors of the specified receptor seems useful for the regulation or restriction of angiogenesis.

Many cytotoxic cancer treatments cause the destruction of rapidly dividing epithelial hair follicle, which leads to alopecia (hair loss). Ing the repression of cyclin-dependent kinase prevents caused by chemotherapy alopecia due to the delay of the life cycle of cells and reduce the sensitivity of epithelial cells to anticancer means (Davis S.T., et al., Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors, Science, 2001, (Jan 5), 291, 5501, 25-6). Local use is not causing apoptosis of CDK inhibitors represents a potentially effective approach to the prevention caused by chemotherapy alopecia in cancer patients.

Although plastic coronary artery is a very effective remedy occlusion of a coronary artery, the success of this treatment in the long term is limited to high rates of restenosis. Restenosis after plastic operations on vessels largely due to the activation, migration and proliferation of smooth muscle cells of blood vessels (Ross, R., Nature, 1993, 362, 801-809). Recent studies have shown that CDK2 very quickly activated after Dendarii endothelial cells in a model of carotid artery restenosis in rats (Wei, G.L., et al., Circ. Res., 1997, 80, 418-426). Therefore, the treatment, the vast proliferation of cells, which purposefully affects cyclin-dependent kinase or other components of the mechanism that determines the life cycle of cells, may be a promising approach to the treatment of these diseases.

Some embodiments of the present invention relate to a method of treatment or attenuation of symptoms mediated by one or two selective kinases, which includes an introduction to the needy subject of therapeutic the ski effective amount of the compounds or pharmaceutical compositions according to this invention. A therapeutically effective amount of compounds of formula (I)used in the implementation of this method, is from about 0.001 mg/kg/day to about 300 mg/kg/day.

Some embodiments of the present invention relate to the use of compounds of formula (I) to obtain a drug to cure or ameliorate disease symptoms mediated by one or two kinases, the need of the subject.

In accordance with the methods of the present invention compounds of the present invention or containing pharmaceutical compositions can be entered separately at different times throughout the course of treatment or simultaneously in separate or common forms. Therefore, the scope of the present invention includes all such methods of simultaneous or alternating treatment and the term "introduction" must have a corresponding value.

Some embodiments of the present invention relate to a compound or its containing pharmaceutical composition introduced into a profitable combination with other drugs intended to cure or ameliorate disease symptoms mediated by one or two kinases. Combination therapy involves co-administration of compounds of formula (I) or its containing pharmaceutical the composition and additional medicines to cure or ameliorate disease symptoms, mediated by one or two kinases, the sequential introduction of the compound of formula (I) or its containing pharmaceutical compositions and additional medicines to cure or ameliorate disease symptoms mediated by one or two kinases, the introduction of a pharmaceutical composition comprising a compound of formula (I) or its containing pharmaceutical composition and an additional tool to cure or ameliorate disease symptoms mediated by one or two kinases, or essentially simultaneous introduction of separate pharmaceutical compositions containing a compound of the formula (I), and a separate pharmaceutical composition containing an additional drug, to treat or ameliorate symptoms of the disease, mediated by one or two kinases.

The term "other drugs" means, without limitation, tools, inhibit the development of blood vessels, antineoplastic agents, cytotoxic tools, inhibitors of cell proliferation and the like. The term "treating or relieving symptoms" means, without limiting this definition, destruction and suppression of the development or activation of stasis malignant tumors. For example, the inhibitor of the two kinases CDK1-VEGF-R of the present invention, the overwhelming development of ravenskih vessels, you can type in accordance with the scheme of drug treatment with other cytotoxic compound, such as a DNA alkylating agent. Preferred antineoplastic agents selected from the group including cladribine (2-chloro-2'-deoxy(beta)-D-adenosine), chlorambucil (4-[bis(2-chloroethyl)amino]basaburua acid), DTIC-house (5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide), platinum and neputyovye chemotherapeutic agents. Containing platinum anti-cancer agents include, but are not limited to, cisplatin (CIS-dichlorodiammineplatinum). Not containing platinum anti-cancer agents include, but are not limited to, cyclophosphamide, fluorouracil, epirubicin, methotrexate, vincristine, doxorubicin, bleomycin, and etoposide. Any antitumor agent is administered in a therapeutically effective amount, which varies depending on the means used, the type of malignant disease, subject to treat or reduce the symptoms, and other conditions, by methods well known in the field.

The term "subject" used herein is meant an animal, preferably a mammal, most preferably a human, which is the object of treatment, observation or experiment.

The term "therapeutically effective amount" is used here in the meaning of the AI denotes the number of active compound or pharmaceutical means, which causes the biological or medicinal response in a tissue system, animal or person that wishes to obtain the researcher, veterinarian, doctor or other Clinician, and which includes relieving symptoms be the treatment of diseases or disorders.

The widespread nature of the kinase isoforms and their role in physiology require the creation of highly selective inhibitors of the kinase. On the basis of evidence of the relationship of certain isoforms with specific diseases, we can assume that inhibiting compounds that selectively affect one or two isoforms (compounds selectively acting on at least two isoforms of cyclin-dependent kinase or tyrosine kinase, referred to as inhibitors of two kinases) or only one of the isoforms relative to the other isoforms or other kinases are excellent therapeutic agents. Such compounds shall have a higher efficiency and less toxicity due to its specificity. Therefore, the person skilled in the art should appreciate that the compound of formula (I) is therapeutically effective for the treatment of diseases mediated defined, one or two, kinases, through selective inhibition of one or two kinases. Connection Yes is this invention have activity of selective inhibitors of one or two kinases with a new combination of structural elements X, R3and R4optimally substituted in the field of triazole. The suitability of the compounds of formula (I) as a selective inhibitor of one or two kinases can be determined by methods described in this description of the invention, the volume of such fitness allows you to use the specified connection for treating one or more diseases, mediated by one or two kinases.

Therefore, the term "disease mediated by one or two kinases in value used here include, but are not limited to, compounds capable of inhibiting one or more kinases, the kinase inhibition refers to cancer, abnormal cell proliferation, tumor growth, tumor vascularization, and angiopathy, angiogenesis caused by chemotherapy alopecia and restenosis.

Compounds according to this invention suitable for use as an aid to a number of chemotherapeutic agents recommended for treatment of specific types of cancer. For example, it was found that compounds according to this invention can be used in combination therapy with at least one chemotherapeutic agent for treatment of a number of different cancers, making it possible to reduce the dose of chemotherapeutic river is recommended for the treatment of a particular cancer type or violation of, associated with cell proliferation. Therefore, it is expected that the compounds according to this invention can be used in accordance with the treatment scheme prior to the introduction of certain chemotherapeutic drugs, recommended for the particular type of cancer, during the administration of a chemotherapeutic drug, or after administration of certain chemotherapeutic agents.

The pharmaceutical compositions according to this invention can be obtained by conventional methods used in pharmacology. The composition of this invention can contain a pharmaceutically acceptable carrier. The above composition can be obtained in different forms depending on the form of a medicinal product, including, but not limited to, forms, intended for intravenous (bolus and infusion), oral, nasal, percutaneous, local (with or without occlusion), intraperitoneal, subcutaneous, intramuscular or parenteral administration, and all such forms are well known specialista in the field of pharmacology. Upon receipt of the compositions in dosage forms for oral administration can be used one or more conventional pharmaceutical carriers, such as water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, syrups and the like, in the case of liquid preparations DL the oral administration (for example, suspensions, elixirs and solutions), or devices such as starches, sugars, diluents, granulating tools, lubricants, binders, disintegrating agents and the like, in the case of the production of solid preparations for oral administration (for example, powders, capsules and tablets).

As is well known in this field, these compounds can enter parenterally in the form of injectable preparation containing the active ingredient, dissolved in an inert liquid medium. Injectable preparation may contain the active ingredient mixed with acceptable inert liquid carrier. Acceptable liquid carriers include vegetable oils such as peanut oil, cottonseed oil, sesame oil and the like, and organic solvents, such as solketal, glycerol formal, and the like. Alternatively, you can also use aqueous preparations for parenteral administration. For example, acceptable aqueous solvents include water, ringer's solution and isotonic aqueous saline solution. In addition, as a solvent or suspending agent in aqueous drug usually use sterile non-volatile oil. These drugs receive dissolving or suspending the active ingredient in the liquid carrier in an amount to provide a content of 0.005 to 1 wt.% the active ingredient in the final product. You can use other additives, including preservatives, agents for isotonic solution, a solubilizer, a stabilizer and a painkiller.

In addition, the compounds of the present invention can be used in a form for injection into the nose through local application of acceptable nasal carriers or form for percutaneous introduction representing percutaneous stickers (patches), well known to specialists in this field. The use of the system for percutaneous delivery of drugs provides a scheme of medical treatment with the constant introduction of the required dose, in contrast to the intermittent injection.

Because of the ease of introduction, the preferred dosage form for oral administration are tablets and capsules, which used solid pharmaceutical carriers. If desired, the tablets by standard methods can be applied sugar or intersolubility floor.

When receiving a liquid form, the active drug component can be combined with aromatherapy suspendresume or dispersing agents such as the synthetic and natural gums, including, for example, tragakant, Arabian gum, methylcellulose and the like. Other usable dispersing substances VK is ucaut glycerin and the like homestudy of the present invention can also be introduced in the form of liposomal systems for delivery, such as small single-layer vesicles, large single bubbles and multi-layered vesicles. Delivery system containing liposomes are well known in this field, obtained using different phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Pharmaceutical compositions of this invention typically contain a single dosage form (such as a tablet, capsule, powder, injection solution, the drug is packaged in the amount of a teaspoon, and the like) from about 0.001 to about 100 mg/kg In one embodiment of the invention the pharmaceutical composition contains in a single dosage form, from about 0.01 to about 50 mg/kg compound, preferably from about 0.05 to about 20 mg/kg In this area known methods of determining therapeutically effective dose for a particular pharmaceutical composition. Therapeutically effective amount required to introduce the person, it is possible to determine, for example, mathematically based on the results of animal studies.

Abbreviations

CSCl2-thiophosgene

DIC - diisopropylcarbodiimide

DMF - N,N-dimethylformamide

EDCI - ethyldiethanolamine

HOBI - hydroxybenzotriazol

NH2NH2-hydrazine

Pd - palladium(II)

Ph phenyl

TBAF is tetrabutylammonium fluoride

TFU - triperoxonane acid

THF - tetrahydrofuran

Nomenclature

The names assigned to the compounds correspond to the nomenclature, are well known in the art; an example of the name of the connection using the numbering of the rings to the following:

4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

Names can be assigned using the nomenclature system based on the above example, or can be created using commercial software assigning chemical names, such as ACD/Index Name (Advanced Chemistry Development, Inc., Toronto, Ontario).

General synthesis methods

Typical compounds of the present invention can be synthesized by the General methods of synthesis described below and illustrated in the diagrams. Because the schemes are illustrative only, the scope of the invention is not limited presents the chemical reactions and conditions. Methods of obtaining different starting substances used on these circuits are well known to specialists in this field.

Scheme And

A method of obtaining compound A3 (described in the article Jenardanan, G.C., Francis, M., Deepa, S., and Rajaskekharan, NR, Synthetic Communications, 1997, 27, 19, 3457-3462) is that the isocyanate representing the connection A1 (recip the TES method, described in article R.L.McKee and R.W. Bost, J. Am. Chem. Soc., 1946, 68, 2506-2507) (where R1has the above values) are dissolved in appropriate solvent and combined with a suspension of compound A2 and potassium hydroxide in a solvent. The mixture is heated and stirred, after which the product representing the connection A3, isolated by precipitation in cold water.

A method of obtaining compound A5 (Reiter, J., Pongo, L. and Dvortsak, P., J. Heterocyclic Chemistry, 1987, 24, 127-142) is that the connection A3 dissolved in appropriate solvent and subjected to interaction with hydrazine. Then the solvent is evaporated and the residue compounds A3 heated under reflux in an alcohol solvent to form solids, representing the connection A4. Connection A4 are dissolved in appropriate solvent and subjected to interaction with R3CO2H, or R3COCl (where R3has the above values) and agent combinations, such as DIC (diisopropylcarbodiimide) or EDCl (ethyldimethylammonium), thus obtaining the target compound A5

Schema

The alternate connection B3 is produced by a method described in the scientific literature (Webb, R.L., Eggleston, D.S. and Labaw, C.S., J. Heterocyclic Chemistry, 1987, 24, 275-278). In accordance with the method presented in CX is IU And, compound B3 is subjected to interaction with hydrazine education target intermediate compound A4.

Scheme

Connection C1 (CAS No. 1455-77-2) dissolved in appropriate solvent and subjected to interaction with R3CO2H, or R3COCl (where R3has the above values) and agent combinations, such as DIC or EDCI, with the formation of compound C2. Connection C2 purified, dissolved in appropriate solvent and subjected to interaction in an inert atmosphere with R1-halogen (where R1and the halogen have the above values; in addition to halogen, R1may be associated with other acceptable removed by the group) in the presence of a base such as potassium carbonate and a catalyst such as a palladium complex. Product representing the connection A5, isolated by conventional methods.

Scheme D

The alternate connection D1 (CAS No. 24807-56-5) dissolved in appropriate solvent and subjected to interaction with R1NH2in the presence of a base such as potassium carbonate and a catalyst such as a palladium complex, with the formation of compound D2. Connection D2 purified, dissolved in appropriate solvent and subjected to catalytic hydrogenation, thus obtaining the compound A4. Connection A4 can use the ü for other target compounds in this invention in accordance with the scheme A.

Scheme E

Compound A3 is dissolved in a solvent and subjected to interaction with a protective group such as substituted benzylamine (for example, 4-methoxybenzylamine), in the presence of a base (such as potassium carbonate) formation of compound E1. Connection E1 purified, dissolved in appropriate solvent and subjected to interaction with R2-halogen (where R2and the halogen have the above values; in addition to halogen, R2may be associated with other suitable removable group) in the presence of a base (such as potassium carbonate), thus obtaining the compound E2. Connection E2 treated with a suitable reagent, such as triperoxonane acid, and when heated will receive E3 connection. Compound 3 is dissolved in a suitable solvent and subjected to interaction with R3CO2H, or R3COCl (where R3has the above values) and agent combinations, such as DIC or EDCI, while receiving the target connection E4. Product representing the connection E4, purified by conventional methods.

The alternate connection E4 receive dissolving compound A5 in an acceptable solvent and subjecting the interaction with R2-halogen (where R2and the halogen have the specified vychutnajte; in addition to halogen, R2may be associated with other suitable removable group) in the presence of a base (such as potassium carbonate).

Specific examples of synthesis

A specific characteristic of the compounds according to this invention receives in accordance with the following examples and sequences of reactions; examples and diagrams showing the sequence of reactions shown as illustrations for a better understanding of the invention and should not limit the scope of the invention set forth in the accompanying claims. Described intermediate agents can also be used in the following examples, additional compounds of the present invention. The yields of products obtained by performing the described reactions are not optimized. The person skilled in the art should know how to increase the yields of products as a result of change of time of reaction, temperature, solvents and/or reagents.

Spectra1H and13With NMR obtained in the spectrometer Bruker AC-300 (300 MHz) using as internal standards, respectively tetramethylsilane and DMSO. Elemental analyses are performed in the company of Quantitative Technologies Inc. (Whitehouse, New Jersey), and the results obtained differ from the calculated values are within 0.4% except where otherwise stated. The fact is the melting temperature determined in open capillary tubes using the apparatus Mel-Temp II (Laboratory Devices Inc.) without correction of the obtained values. Mass spectra with elektrorazpredelenie (MS-ES) obtained in the spectrometer Hewlett Packard 59987A.

Example 1

4-[[5-amino-1-(2,6-differentail)-1H-1,2,4-triazole-

3-yl]amino]benzosulfimide (compound 1)

A suspension of 1-amidino-3,5-dimethylbenzonitrile, representing a compound 1C (2,012 g, 10 mmol), and powdered potassium hydroxide (0,561 g, 10 mmol) in DMF (8 ml) at 0°added to a solution (3 ml) isocyanate, representing a compound 1B (derived from sulfanilamide, representing the connection 1A, and thiophosgene the method described in the article R.L McKee and R.W. Bost, J. Am. Chem. Soc., 1946, 68, 2506-2507), in DMF. The reaction mixture is heated to 50-60°C, stirred for 1 hour and poured into 250 ml of a mixture of ice water. The resulting yellow solid is filtered, washed with water and dried under vacuum, thus obtaining an intermediate compound 1D as a yellow powder (2,5513 g); other 69-80°C (decomposition).1H NMR (300 MHz, CD3OD) δ of 7.90 (m, 4H), equal to 6.05 (s, 1H), 2,22 (s, 3H), of 2.20 (s, 3H); (CDCl3) δ is 10.75 (s, wide, 1H), 8,35 (s, wide, 1H), of 7.90 (kV, 4H), 7,65 (c, width, 2H), 5,95 (s, 1H), 5,00 (c, width, 2H); MS (ESI) m/z: 353 (M+H+).

Hydrazine (1,845 g, 57,58 mmol) are added to a solution of intermediate 1D (1.88 g, 5.33 mmol) in THF (60 ml). The reaction mixture is intensively stirred at 50-60°C for 2-3 hours and evaporated in vacuum. The residue is heated under reflux in methanol (60 ml) and the cooling gap is up to room temperature. The resulting solid is collected by filtration and washed with methanol, thus obtaining an intermediate compound 1E as a gray solid (0,8722 g, 64%); other 291-296°C (decomposition);1H NMR (300 MHz, (CD3)2SO) δ to 9.20 (s, 1H), 7,60 (m, 4H), 7,00 (s, 2H), 5,90 (s, 2H); MS (ESI) m/z: 255 (M+H+), 277 (M+Na+).

2,6-Differentiald, representing a compound 1F (41,4 μl, 0.33 mmol), are added to a solution of intermediate compound 1E (63,6 mg, 0.25 mmol) in anhydrous pyridine (2.5 ml) in a bath with a mixture of water with ice. The resulting reaction mixture was stirred at room temperature for 6 hours and evaporated in vacuum to dryness. The residue is purified by chromatography using 10% methanol/methylene chloride and recrystallized from THF/methylene chloride, thus obtaining the compound 1 (50.2 mg, 51%) as a white powder, etc. 149-155°C (decomposition);1H NMR (300 MHz, CD3OD) δ the 7.65 (m, 3H), at 7.55 (d, 2H), 7,18 (t, 2H); ((CD3)2SO) δ 9,86 (s, 1H), 8,03 (s, 2H), 7,72 (m, 1H), 7,58 (d, J=8,9 Hz, 2H), 7,46 (d, J=8,9 Hz, 2H), 7,35 (t, J=8,3 Hz, C), 7,11 (s, 2H);13With NMR (300 MHz, (CD3)2SO) δ 160,4, 159,7, 158,9, 157,9, 157,1, 157,0, 156,6, 144,0, 135,6, 133,9, 127,0, 116,3, 112,9, 112,5, 112,3; MS (ESI) m/z: 395 (M+H+), 417 (M+Na+). Elemental analysis. Calculated for C15H12F2N6O3S: C 45,69; H OF 3.07; N 21,31. Found: 45,29; H 3.04 From; N 20,89.

The following compound is obtained by acylation of the intermediate soedineniya 1E method of example 1, using the indicated starting material instead of compound 1F and the appropriate reagent (reagent):

5
ConnectionName > dataThe original substance
24-[[5-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,80 (c, 1H), 7,78-of 7.55 (m, 5H), 7,52 (s, 2H), 7,12 (t, 2H), 6,38 (s, 2H), 2,22 (s, 3H); MS (ESI) m/z: 409 (M+H+), 431 (M+Na+)
2,6-debtor-3-methylbenzoate in anhydrous pyridine
34-[[5-amino-1-(2,3,6-triterpenoid)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ cent to 8.85 (s, 1H), 7,78 is 7.50 (m, 7H), 7,32 (m, 1H), 6,38 (s, 2H); MS (ESI) m/z: 413 (M+H+), 435 (M+Na+)
2,3,6-triterpenoid in anhydrous pyridine
44-[[5-amino-1-(2-perbenzoic)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ of 8.90 (s, wide, 1H), 8,00 (cm, 2H), 7,82 (t, 1H), 7,78-7,20 (m, 7H), 6.35mm (cm, 2H); MS (ESI) m/z: 377 (M+H+), 399 (M+Na+)
2-perbenzoate in anhydrous pyridine
4-[[5-amino-1-(2,4-differentail)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,88 (s, 1H), 7,95 (s, 2H), 7,78-7,58 (m, 4H), of 7.48 (s, 2H), 7,35-to 7.77 (m, 2H), 6,38 (s, 2H); MS (ESI) m/z: 395 (M+H+), 417 (M+Na+)
2,4-deformatiessailing in anhydrous pyridine
64-[[5-amino-1-[2-fluoro-6-(trifluoromethyl)benzoyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,86 (s, 1H), of 8.06 (s, 2H), a 7.85 (m, 3H), 7,54 (d, J=8,9 Hz, 2H), 7,40 (d, J=8,9 Hz, 2H), to 7.09 (s, 2H); MS (ESI, m/z: 445 (M+H+), 467 (M+Na+)
2-fluoro-6-(trifluoromethyl)benzoyl chloride in THF
74-[[5-amino-1-(2,6-dichlorobenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,82 (s, 1H), 7.68 per was 7.45 (m, 9H), 6.35mm (s, 2H); (CD3OD) of 7.60 (d, 2H), 7,55 (m, 3H), 7,38 (d, 2H); MS (ESI) m/z: 428 (M+H+), 450 (M+Na+)
2,6-dichlorobenzophenone in anhydrous pyridine
84-[[5-amino-1-(2,4,6-trichlorobenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,88 (s, 1H), 7,78 (s, 2H), 7,75-of 7.48 (m, 6H), 6,38 (s, 2H); MS (ESI) m/z: 462 (M+N+), 484 (M+Na+)
2,4,6-trichlorobenzoyl in anhydrous pyridine
94-[[5-amino-1-(2-nitrobenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide
/br> 1H NMR (300 MHz, CD3OD) δ of 8.28 (d, 2H), 8,95 is 7.85 (m, 3H), a 7.62 (d, 2H), 7,35 (d, 2H); MS (ESI) m/z: 404 (M+N+), 426 (M+Na+)
2-nitrobenzanthrone in anhydrous pyridine
104-[[5-amino-1-(2,6-dimethoxybenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,65 (s, wide, 1H), 7,68 (m, 4H), to 7.50 (d, 1H), 7,30 (cm, 2H), 6,72 (d, 1H), of 6.68 (DD, 1H), 6.35mm (cm, 2H), 3,92 (s, 3H), 3,85 (s, 3H); MS (ESI) m/z: 419 (M+H+), 441 (M+Na+)
2,6-dimethoxybenzoate in anhydrous pyridine
114-[[5-amino-1-(2,4,6-trimethylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,78 (s, 1H), 7,78 (s, 2H), 7,72-the 7.43 (m, 5H), 7,75-of 6.78 (m, 3H), 6.35mm (s, 2H), 2,38-of 2.16 (m, 9H); MS (ESI) m/z 401 (M+H+), 423

(M+Na+)
2,4,6-trimethylbenzoyl in anhydrous pyridine
124-[(5-amino-1-benzoyl-1H-1,2,4-triazole-3-yl)amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,80 (s, 1H), 8,28 (d, 2H), 7,80-7,58 (m, 7H), 7,52 (s, 2H), 6,38 (s, 2H); MS (ESI) m/z: 359 (M+H+), 381 (M+Na+)
the benzoyl chloride in anhydrous pyridine
144-[[5-amino-1-(2-thienylboronic)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ of 8.92 (s, 1H), 8,40 (DD, 1H), 8,12 (DD, 1H), 7,88 (kV, 4H), to 7.50 (s, 2H), 7,32 (m, 1H), 6,45 (C, H); MS (ESI) m/z: 365 (M+H+), 387 (M+Na+)
thiophene-2-carboxylic acid associated DIC/HOBt (1-hydroxybenzotriazole)in anhydrous DMF
154-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

so 280-284°;1H NMR (300 MHz, (CD3)2SO) δ 9,88 (s, 1H), with 8.05 (d, 1H), 7,88 (c, 2H), 7,78 (kV, 4H), to 7.15 (m, 3H), 2,62 (s, 3H);

(CD3)2CO) δ of 8.92 (s, 1H), 7,98 (d, 1H), of 7.90 (kV, 4H), 7,45 (c, 2H), 7,15 (d, 1H), 6.42 per (s, 2H), 2,68 (s, 3H);

13C NMR (300 MHz, (CD3)2SO) δ 160,6, 157,9, 157,4, 157,2, 150,9, 143,9, 136,0, 135,5, 131,8, 127,3, 124,3, 116,3, 18,1; MS (ESI) m/z: 379 (M+H+), 401 (M+Na+)
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
164-[[5-amino-1-[(3-fluoro-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,92 (s, wide, 1H), 8,18 (t, 1H), 7,92 (cm, 2H), 7,78 (kV, 4H), 7,25 (d, 1H), 7,18 (cm, 2H); MS (ESI) m/z: 383 (M+H+), 405 (M+Na+)
3-fortifed-2-carboxylic acid (obtained by the method described E.C. Taylor and P. Zhou, Org. Prep. Proced. Int., 1997, 29, 221)associated DIC/HOBt in anhydrous DMF
174-[[5-amino-1-[(3-chloro-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,92 (s, wide, 1H), of 8.25 (d, 1H), 7,95 (cm, 2H), 7,78 (kV, 4H), 7,32 (d, 1H), 7,18 (cm, 2H); MS (ESI) m/z: 99 (M+H +), 421 (M+Na+)
3-chlorothiophene-2-carboxylic acid related EDCI/HOBt in anhydrous DMF
184-[[5-amino-1-[(3-ethoxy-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,85 (s, wide, 1H), 8,08 (d, 1H), 7,85 to 7.75 (m, 6H), 7,28 (d, 1H), 7,15 (cm, 2H); MS (ESI) m/z: 409 (M+H+), 431 (M+Na+)
3-ethoxythiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
19N-[2-[[5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-1H-1,2,4-triazole-1-yl]carbonyl]-3-thienyl]ndimethylacetamide

1H NMR (300 MHz, (CD3)2SO) δ 11,0 (s, wide, 1H), 9,92 (s, wide, 1H), 8,18 (kV, 2H), 7,85 (cm, 2H), 7,78 (kV, 4H), 7,15 (cm, 2H), measuring 2.20 (s, 3H); MS (ESI) m/z: 421 (M+H+), 444 (M+Na+)
3-(acetylamino)thiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
204-[[5-amino-1-[(5-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,92 (s, wide, 1H), 8,15 (d, 1H), 7,85 (cm, 2H), 7,78 (kV, 4H), 7,20 (cm, 2H), was 7.08 (d, 1H), 2,62 (c, 3H); MS (ESI) m/z: 379 (M+H+)
5-methylthiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
214-[[5-amino-1-[(5-bromo-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,98 (with the IR 1H), with 8.05 (d, 1H), 7,95 (c, width, 2H), 7,78 (kV, 4H), of 7.48 (d, 1H), 7,20 (cm, 2H); MS (ESI) m/z 444 (M+N+)
5-bromothiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
224-[[1-[(5-acetyl-2-thienyl)carbonyl]-5-amino-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 10,02 (c, width, 1H), 8,28 (d, 1H), 8,02 (d, 1H), 7,95 (c, width, 2H), 7,75 (kV, 4H), 7,20 (cm, 2H), 2,65 (c, 3H); MS (ESI) m/z: 407 (M+H+), 429 (M+Na+)
5-acetylthiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
254-[[5-amino-1-(2-fornicator)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,87 (s, 1H), to 8.20 (d, 1H), 8,02 (DD, 1H), 7,85 (kV, 4H), of 7.48 (c, 2H), to 6.88 (DD, 1H), 6.42 per (s, 2H); MS (ESI) m/z: 349 (M+H+), 371 (M+Na+)
2-frailcare in anhydrous pyridine
264-[[5-amino-(5-isoxazolidinone)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,95 (s, wide, 1H), of 8.92 (d, 1H), 8,00 (c, width, 2H), 7,78 (m, 2H), 7,68 (m, 3H), 7,15 (cm, 2H); MS (ESI) m/z: 350 (M+H+), 372 (M+Na+)
isoxazol-5-carboxylic acid associated DIC/HOBt in anhydrous DMF
274-[[5-amino-1-(2-pyridylcarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ of 9.75 (s, 1H),8,72 (d, 1H), 8,00 (m, 2H), of 7.90 (s, Shir, 2H), 7.68 per-of 7.48 (m, 5H), 7,10 (cm, 2H); MS (ESI) m/z: 360 (M+H+), 382 (M+Na+)
picolina acid associated DIC/HOBt in anhydrous DMF
284-[[5-amino-1-(3-pyridylcarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,82 (s, 1H), which 9.22 (d, 1H), 8,78 (DD, 1H), 8,45 (DD, 1H), 7,92 (c, width, 2H), 77,62 (kV, 4H), 7,15 (cm, 2H); MS (ESI) m/z: 360 (M+H+), 382 (M+Na+)
nicotinic acid associated DIC/HOBt in anhydrous DMF
294-[[5-amino-1-(4-pyridylcarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,80 (s, 1H), 8,82 (d, 2H), 8,00-of 7.90 (m, 4H), 7,60 (kV, 4H), 7,12 (cm, 2H); MS (ESI) m/z: 360 (M+H+), 382 (M+Na+)
isonicotinoyl acid associated DIC/HOBt in anhydrous DMF
304-[[5-amino-1-(3-thienylboronic)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ the remaining 9.08 (d, 1H), cent to 8.85 (s, wide, 1H), 7,98 (DD, 1H), 7,82 (kV 4H), a 7.62 (DD, 1H), of 7.48 (s, wide, 1H), 6,45 (cm, 2H); MS (ESI) m/z: 365 (M+H+), 387(M+Na+)
thiophene-3-carboxylic acid associated DIC/HOBt in anhydrous DMF
314-[[5-amino-1-(benzo[b]Tien-2-ylcarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,95 (s, wide, 1H), cent to 8.85 (who, 1H), 8,15 (DD, 2H), 8,02 (cm, 2H), 7,85 (kV, 4H), 7,55 (m, 2H), 7,18 (cm, 2H); MS (ESI) m/z: 415 (M+H+)
benzo[b]thiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
344-[[5-amino-1-[(2,4-dimethyl-5-thiazolyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,88 (s, wide, 1H), of 7.90 (c, width, 2H), 7,78 (kV, 4H), 7,15 (cm, 2H), 2,78 (c, 6N); MS (ESI) m/z: 394 (M+H+), 416 (M+Na+)
2,4-dimethylthiazol-5-carboxylic acid associated DIC/HOBt in anhydrous DMF
354-[[5-amino-1-[(3-bromo-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,95 (c, 1H), 8,23 (d, J=5,31H), of 7.95 (s, 2H), to 7.77 (s, 4H), 7,39 (d, J=5,3 1H), 7,16 (s, 2H); MS (ESI) m/z: 444,9 (M+H), 466,9 (M+Na+)
3-bromothiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
364-[[5-amino-1-[(4-methyl-1,2,3-thiadiazole-5-yl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 10,07 (s, 1H), 8,09 (s, 2H), 7,86 (d, J=8,8, 2H), 7,72 (d, J=8,9, 2H), 7,21 (s, 2H), 3,02 (c, 3H); MS (ESI) m/z: 381,0 (M+H), 403,0 (M+Na+)
4-methyl-1,2,3-thiadiazole-5-carboxylic acid associated DIC/HOBt in anhydrous DMF
374-[[5-amino-1-(1,2,3-thiadiazole-4-ylcarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 M is C, (CD3)2SO) δ 10,18 (s, 1H), to 9.93 (s, 1H), with 8.05 (s, 2H), 7,76 (d, J=8,8, 2H), 7,63 (d, J=8,8, 2H), 7,16 (s, 2H); MS (ESI) m/z: 367,0 (M+H), 389,0 (M+Na+)
1,2,3-thiadiazole-4-carboxylic acid associated DIC/HOBt in anhydrous DMF
384-[[5-amino-1-(cyclopentanecarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,73 (s, 1H), 7,69 (s, 4H), 7,65 (s, 2H), 7,13 (c, 2H), 1,78 (m, 3H), of 1.65 (m, 6H); MS (ESI) m/z: 351,0 (M+H), 373,0 (M+Na+)
cyclopentanecarbonyl acid associated DIC/HOBt in anhydrous DMF
394-[[5-amino-1-(cyclohexylcarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,76 (s, 1H), 7,69 (s, 4H), 7,66 (s, 2H), 7,13 (c, 2H), 1,98 (c, 2H), 1,80 (c, 2H), 1.69 in (d, 1H), 1,36 (m, 6N); MS (ESI) m/z: 365,0 (M+H), (387,1 (M+Na+)
cyclohexanecarbonyl acid associated DIC/HOBt in anhydrous DMF
404-[[5-amino-1-(2-titilate)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,80 (s, 1H), 7,73 (d, J=1,2, 4H), 7,69 (s, 2H), 7,45 (DD, J=1,5, 1H), 7,16 (s, 2H), was 7.08 (d, J=2,7, 1H), 7,01 (t, J=5,1, 1H), to 4.52 (s, 2H);

MS (ESI) m/z: 379,0 (M+H), 400,9 (M+Na+)
2-thiophenoxy acid associated DIC/HOBt in anhydrous DMF
424-[[5-amino-1-[(2E)-1-oxo-3-(2-thienyl)-2-propenyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1/sup> H NMR (300 MHz, (CD3)2SO) δ 9,82 (s, 1H), 7,92 (d, J=8,3, 1H), 7,72 (s, 4H), 7,35 (d, J=15,8, 2H), 7,26 (d, J=19,5, 3H), 7,15 (s, 2H), 6,26 (c, 1H); MS (ESI) m/z: 391,0 (M+H), 412,9 (M+Na+)
3-(2-thienyl)acrylic acid associated DIC/HOBt in anhydrous DMF
434-[[5-amino-1-[(2,6-differenl)acetyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,81 (s, 1H), 7,69 (s, 6H), 7,44 (t, J=16,6, 1H), 7,16 (s, 3H), 4,37 (s, 2H); MS (ESI) m/z: 409,0 (M+H), 431,0 (M+Na+)
2,6-dipertanyakan acid associated DIC/HOBt in anhydrous DMF
444-[[5-amino-1-[(2E)-3-(2,6-differenl)-1-oxo-2-propenyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,86 (s, 1H), a 7.85 (d, J=4,7, 2H), 7,71 (s, 4H), 7,31 (m, 4H), 7,16 (s, 2H), of 6.31 (s, 1H); MS (ESI) m/z: 421,0 (M+H), byr442.9 (M+Na+)
2,6-littoraria acid associated DIC/HOBt in anhydrous DMF
454-[[5-amino-1-(cyclohexylcarbonyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ of 9.75 (s, 1H), 7,69 (c, 4H), 7,66 (c, 2H), 7,12 (c, 2H), 2,00 (d, J=11,7, 2H), 1.77 in (d, J=10,5, 2H), 1,40 (m, 3H), of 1.07 (m, 2H), of 0.91 (d, J=6,4, 4H); MS (ESI) m/z: 254, 379,0 (M+H), 401,0 (M+Na+)
cycloheptanone acid associated DIC/HOBt in anhydrous DMF
464-[[5-amino-1-[(4-methylcyclohexyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]b is solarpanel

1H NMR (300 MHz, (CD3)2SO) δ of 9.75 (s, 1H), 7,69 (s, 4H), 7,66 (s, 2H), 7,12 (c, 2H), 2,00 (d, J=11,7, 2H), 1.77 in (d, J=10,5, 2H), 1,40 (m, 3H), of 1.07 (m, 2H), of 0.91 (d, J=6,4, 4H); MS (ESI) m/z: 254, 379,0 (M+H), 401,0 (M+Na+)
TRANS-4-methyl-1-cyclohexanecarbonyl acid associated DIC/HOBt in anhydrous DMF
474-[[5-amino-1-[(2-methylcyclohexyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ of 9.75 (s, 1H), 7,68 (c, 4H), 7,66 (s, 2H), 7,13 (c, 2H), 1.55V (m, 9H), of 0.85 (d, J=6,0, 4H); MS (ESI) m/z: 254, 379,0 (M+H), 401,0 (M+Na+)
2-methyl-1-cyclohexanecarbonyl acid associated DIC/HOBt in anhydrous DMF
484-[[5-amino-1-[(4-butylcyclohexyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ of 9.75 (s, 1H), 7,68 (s, 4H), 7,66 (c, 2H), 7,12 (c, 2H), 2,02 (d, J=11,3, 2H), 1,82 (d, J=9,9, 2H), 1,40 (d, J=11,3, 2H), 1,25 (s, 7H), of 1.02 (m, 4H), 0,87 (s, 4H); MS (ESI) m/z: 254, 435,1 (M+H), (457,1 (M+Na+)
TRANS-4-butyl-1-cyclohexanecarbonyl acid associated DIC/HOBt in anhydrous DMF
494-[[5-amino-1-[[5-(2-pyridinyl)-2-thienyl]carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,98 (s, 1H), 8,65 (d, 1H), of 8.25 (d, 1H), 8,08 (d, 1H), 8,02 to 7.75 (m, 8H), 7,42 (DD, 1H), 7,20 (s, 2H); MS (ESI) m/z: 442 (M+H+), 464 (M+Na+)
5-(2-pyridyl)thiophene-2-carboxylic acid, wired is I DIC/HOBt, in anhydrous DMF
504-[[5-amino-1-[[3-(1H-pyrrol-1-yl)-2-thienyl]carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,85 (c, 1H), 8,18 (d, 1H), 7,85-of 7.70 (m, 6H), 7,32 (d, 1H), 7,18 (s, 2H), 7,12 (t, 2H), 6,20 (t, 2H); MS (ESI) m/z: 430 (M+H+)
3-(1H-pyrrol-1-yl)thiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
514-[[5-amino-1-[[5-(1,1-dimethylethyl)-2-thienyl]carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ

of 8.95 (s, 1H), of 8.25 (d, 1H), 7,95 (d, 2H), a 7.85 (d, 2H), 7,50 (s, 2H), 7,18 (d, 1H), 6.48 in (s, 2H), of 1.55 (s, 9H); MS (ESI) m/z: 421 (M+H+), 443 (M+Na+)
5-tert-butylthiophene-2-carboxylic acid associated DIC/HOBt in anhydrous DMF
521,1-dimethylethylene ester of 3-[5-[[5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-1H-1,2,4-triazole-1-yl]carbonyl]-2-thienyl]-(2E)-2-propanolol acid

1H NMR (300 MHz, (CD3)2SO) δ 9,95 (s, 1H), they were 8.22 (d, 1H), 7,95 (s, 2H), 7,82-to 7.68 (m, 6H), to 7.15 (s, 2H), of 6.52 (d, 1H), of 1.52 (s, 9H); MS (ESI) m/z: 491 (M+H+), 513 (M+Na+)

5-(2-tert-butoxycarbonylamino)thiophene-2-carboxylic acid (intermediate compound)1H NMR (300 MHz, (CD3)2CO) δ 7,80-70 (m, 2H), of 7.48 (d, 1H), 7,32 (d, 1H), 1,50 (s, N), MS (ESI) m/z: 253 (M-H+), 209 (M-H+-CO2)
5-(2-tert-butoxycarbonylamino)thiophene-2-carboxylic Ki the lot (obtained using the Heck reaction, running between 5-bromothiophene-2-carboxylic acid and tert-butyl acrylate)associated DIC/HOBt in anhydrous DMF
534-[[5-amino-1-[[5-(phenylethynyl)-2-thienyl]carbonyl]1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,98 (s, 1H), to 8.20 (d, 1H), 7,95 (s, 2H), 7,78 (m, 4H), 7.62mm (m, 2H), 7,60 (d, 1H), 7,45 (m, 3H), 7,18 (s, 2H); MS (ESI) m/z: 465 (M+H+), 487 (M+Na+)

5-fenretinide-2-carboxylic acid (intermediate compound)

1H NMR (300 MHz, (CD3)2CO) δ 7,98 (d, 1H), 7,58 (m, 2H), 7,45 (m, 3H), 7,35 (d, 1H); MS (ESI) m/z: 229 (M+H+)
5-fenretinide-2-carboxylic acid (intermediate compound obtained by oxidation of 5-fenretinide-2-carboxaldehyde)associated DIC/HOBt in anhydrous DMF
544-[[5-amino-1-(2,6-debtor-3-nitrobenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ of 8.90 (s, 1H), 8,55 (m, 1H), 7,75 is 7.50 (m, 7H), and 6.25 (s, 2H); MS (ESI) m/z: 440 (M+H+), 462 (M+Na+)
2,6-debtor-3-nitrobenzoic acid associated DIC/HOBt in anhydrous DMF
554-[[5-amino-1-(3-amino-2,6-differentail)-1H-1,2,4-triazole-3-yl]-amino]benzosulfimide

1H NMR (300 MHz, CD3OD) δ to 7.68 (d, 2H), 7,45 (d, 2H), 6,95 (m, 1H), 6,85 (m, 1H); MS (ESI) m/z: 410 (M+H+), 432 (M+Na+)
catalytic Hydra is the formation of compound 54 in methanol using catalysis 10%palladium on coal
564-[[5-amino-1-(2,6-dimethylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ

is 8.75 (s, 1H), 7,65-7,28 (m, 7H), to 7.15 (d, 2H), 6,32 (s, 2H, in), 2.25 (s, 6H); MS (ESI) m/z: 387 (M+H+), 409 (M+Na+).
2,6-dimethylbenzoic acid associated DIC/HOBt in anhydrous DMF
574-[[5-amino-1-(2-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ is 8.75 (s, 1H), 7,72-7,25 (m, 10H), 6.35mm (s, 2H), of 2.45 (s, 3H); MS (ESI) m/z: 373 (M+H+), 395 (M+Na+).
2-methylbenzoate in anhydrous pyridine
665-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-differenl)-1H-1,2,4-triazole-1-carbothioamide

1H NMR (300 MHz, (CD3)2CO) δ the 10.40 (s, 1H), of 8.90 (s, 1H), 8,15 (s, 2H), a 7.85 (d, 2H), of 7.75 (d, 2H), 7,40 (m, 1H), 7,15 (m, 2H), 6.35mm (s, 2H), of 5.75 (s, 2H); MS (ESI) m/z: 426 (M+H+), 448 (M+Na+)
2,6-differentiational in anhydrous pyridine
675-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-differenl)-1H-1,2,4-triazole-1-carboxamide

1H NMR (300 MHz, (CD3)2CO) δ to 9.15 (s, 1H), 8,80 (s, 1H), 7,80 (d, 2H), of 7.70 (d, 2H), 7,42 (m, 1H), 7,15 (m, 2H), 7,00 (s, 2H), 6.35mm (s, 2H); MS (ESI) m/z: 410 (M+H+), 432 (M+Na+)
2,6-differentiational in anhydrous DMF
684-[[5-amino-1-[2,6-differenl)sulfonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2CO) δ 8,80 (s, 1H), a 7.85 (m, 1H), of 7.75 (d, 2H), 7,65 (d, 2H), 7,30 (m, 2H), 6,95 (s, 2H), 6.35mm (s, 2H); MS (ESI) m/z: 431 (M+H+), 453 (M+Na+)
2,6-differentialalgebraic in anhydrous pyridine
694-[[5-amino-1-(2-chloro-6-fluoro-3-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,85 (s, 1H), 8,05 (c, 2H), of 7.64-of 7.55 (m, 3H), 7,45-7,35 (m, 3H), 7,10 (c, 2H), of 2.38 (s, 3H); MS (ESI) m/z: 425 (M+H+), 447 (M+Na+)
2-chloro-6-fluoro-3-methylbenzoate in anhydrous pyridine
704-[[5-amino-1-(2-chloro-6-perbenzoic)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,87 (s, 1H), with 8.05 (s, 2H), 7.68 per-7,63 (m, 1H), EUR 7.57-to 7.50 (m, 3H), of 7.48-7,42 (m, 3H), 7,09 (c, 2H); MS (ESI) m/z 411 (M+H+), 433 (M+Na+)
2-chloro-6-perbenzoate in anhydrous pyridine
784-[[5-amino-1-(3-chloro-2,6-differentail)-1H-1,2,4-triazole-3-yl]-amino]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,89 (c, 1H), 8,07 (c, 2H), 8,00-a 7.92 (t, 1H), to 7.59 (d, 2H), 7,49-7,44 (m, 3H), 7,12 (s, 2H); MS (ESI) m/z: 429 (M+H+)
3-chloro-2,6-differentia acid associated DIC/HOBt in anhydrous DMF
1224-[[3-amino-1-(2,6-differentail)-1H-1,2,4-triazole-5-yl]amino]benzosulfimide

(minor isomer provisions Conn is in 1)

1H NMR (300 MHz, CD3CN) δ for 9.90 (s, 1H), of 7.90 (kV, 4H), 7,60 (m, 1H), 7,15 (t, 2H), 5,62 (s, 2H), around 4.85 (s, 2H); MS (ESI) m/z: 395 (M+H+), 417 (M+Na+)
2,6-differentiald in anhydrous pyridine
1234-[[3-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-5-yl]amino]benzosulfimide

(minor isomer position of the joint 2)

1H NMR (300 MHz, (CD3)2SO) δ 10,0 (c, 1H), 8,00 (d, 2H), 7,78 (d, 2H), 7,50 (m, 1H), 7,20 (s, 2H), 7,15 (t, 2H), and 6.25 (s, 2H), 2,28 (s, 3H); MS (ESI) m/z: 409 (M+H+), 431 (M+Na+)
2,6-differentiald in anhydrous pyridine
1283-amino-5-[[4-(aminosulfonyl)-phenyl]amino]-N-(2,6-differenl)-1H-1,2,4-triazole-1-carbothioamide

(minor isomer position of the joint 66)

1H NMR (300 MHz, (CD3)2CO) δ

12,10 (s, 1H), 10,28 (8,1H), a 7.85 (m, 4H), 7,45 (m, 1H), 7,20 (m, 2H), 6,45 (s, 2H), of 5.75 (s, 2H);

MS (ESI) m/z: 426 (M+N+), 448 (M+Na+)
-

Example 2

1-(2,6-Differentail)-N3-[4-(1-piperidinylcarbonyl)phenyl]-1H-1,2,4-triazole-3,5-diamine (compound 13)

1-Amidino-3,5-dimethylpyrazole representing the connection 1C, is subjected to the interaction with 1-(4-isothiocyanatobenzene)piperidine, representing the connection 2B, the method according to example 1, thus obtaining the compound 2C.1H NMR (300 MHz, CD3CN) δ 10,75 (c, width, 1H), 8,40 (s,Shir, 1H), 7,95 (s, wide, 1H), 7,55 (kV, 4H), 5,95 (s, 1H), 3,00 (m, 4H), of 2.25 (s, 6N), by 1.68 (m, 4H), of 1.45 (m, 2H); MS (ESI) m/z: 421 (M+H+).

Compound 2C is subjected to interaction with hydrazine, thus obtaining the compound 2D.1H NMR (300 MHz, CD3CN) δ 10,75 (c, width, 1H), 7,65 (s, wide, 1H), 7,55 (kV, 4H), to 5.85 (s, Shir, 2H), 2,82 (m, 4H), of 1.55 (m, 4H), 1,32 (m, 2H); MS (ESI) m/z: 323 (M+H+).

Compound 2D acelerou 2,6-debtor-3-methylbenzothiazol, representing a compound 1F in anhydrous pyridine, while receiving compound 13 (yield 85%).1H NMR (300 MHz, CDCl3): δ 7,60 is 7.50 (m, 3H), 7,42 (d, 2H), 7,18 (t, 2H), 6,98 (s, wide, 1H), 6,55 (cm, 2H), 2,98 (m, 4H), of 1.65 (m, 4H), of 1.42 (m, 2H); MS (ESI) m/z: 363 (M+H+), 485 (M+Na+).

The following compound is obtained by acylation of the intermediate 2D method according to example 3, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > dataThe original substance
23N3-[4-(1-piperidinylcarbonyl)phenyl]-1-(2-thienylboronic)-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 10,02 (s, wide, 1H), 8,40 (DD, 1H), 8,18 (DD, 1H), 7,92 (c, width, 2H), 7,88 (d, 2H), 7,58 (d, 2H), 7,32(t, 1H), 2,88 (m, 4H), of 1.55 (m, 4H), of 1.35 (m, 2H); MS (ESI) m/z: 433 (M+H+), 455 (M+Na+)
thiophene-2-carboxylic acid associated DIC/HOBt in DMF
241-[(3-methyl-2-thienyl)carbonyl]-N3-[4-(1-piperidinylcarbonyl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 10,02 (s, wide, 1H), 8,02 (d, 1H), 7.95 is-7,80 (m, 4H), to 7.68 (d, 2H), 7,18 (d, 1H), 2,88 (m, 4H), 2,68 (c, 3H), of 1.55 (m, 4H), of 1.35 (m, 2H); MS (ESI) m/z: 447 (M+H+), 469 (M+Na+)
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF

Example 3

4-[[5-Amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide (compound 32)

Hydrazine monohydrate (0,97 ml, 1,019 mol) and potassium hydroxide (1.12 g, 20 mmol) are added to a solution of 5-acetylthiophene-2-carboxylic acid (1.70 g, 10 mmol) in diethylene glycol (20 ml) and water (1 ml). The reaction mixture is stirred at an oil bath at 110°C for 16 hours, cooled to room temperature, acidified with 2 N. HCl solution and extracted with methylene chloride (4×50 ml). The organic layers are combined, dried, concentrated and separated by chromatography on silica gel (producing elution with a mixture of 10% methanol/methylene chloride), thus obtaining 3-ethylthiophen-2-carboxylic acid, representing a compound 3A as a pale yellow solid (1,161 g, 74%).1H NMR (300 MHz, CD3OD) δ to 7.59 (d, J=3,7, 1H), 6.87 in (q, j =3,7, 1H), 2,88 (kV, J=7,5, 1H), 1,32 (t, J=7,5, 3H); MS (ESI) m/z: 155 (M-H+).

Compound 1E acelerou connection 3A, by means of DIC/HOBt in anhydrous DMF by the method of example 1, thus obtaining the compound 32 (yield 59%).1H NMR (300 MHz, (CD3)2CO) δ of 8.90 (s, wide, 1H), of 8.25 (d, 1H), 7,88 (kV, 4H), 7,45 (cm, 2H), 7,10 (d, 1H), 6,45 (c, width, 2H), 3,05 (kV, 2H), of 1.42 (t, 3H); MS (ESI) m/z: 393 (M+H+), 415 (M+Na+).

Example 4

4-[[5-Amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide (compound 33)

2.2 equivalent of a 2.0 M solution of LDA in heptane/THF/ethylbenzene (0,97 ml, 1,019 mol) are added to a solution of 3-methylthiophene-2-carboxylic acid (1.42 g, 10 mmol) in anhydrous THF (20 ml) at 0°C. the Reaction mixture was stirred at 0°C for 1.5 hours and then add methyliodide (1.4 ml, 22 mmol). The resulting mixture was stirred at 0°another 2 hours, acidified with 2 N. HCl solution and extracted with methylene chloride (4×50 ml). The organic layers combine, concentrate, and separate HPLC, while receiving a 3.5-dimethylthiophene-2-carboxylic acid, representing a compound 4A as a white powder.1H NMR (300 MHz, CD3OD) δ 6,72 (s, 1H), 2,43 (s, 3H), of 2.46 (s, 3H); MS (ESI) m/z: 155 (M-H+).

Compound 1E acelerou connection 4A, by means of DIC/HOBt in anhydrous DMF by the method of example 1, thus obtaining the compound 33 (yield 73%).1 H NMR (300 MHz, (CD3)2SO) δ 9,88 (s, wide, 1H), 7,85 (c, width, 2H), 7,78 (kV, 4H), 7,18 (cm, 2H), 6,92 (s, 1H), 2,58 (c, 3H), by 2.55 (s, 3H); MS (ESI) m/z: 393 (M+H+), 415 (M+Na+).

Example 5

4-[[5-Amino-1-[2,6-debtor-3-(1-hydroxyethyl)benzoyl]-1H-1,2,4-triazole-3-yl]amino]benzosulfimide (compound 58)

2',4'-Defloration (5 g, 32 mmol) is subjected to interaction with sodium borohydride (1,21 g) in THF (20 ml) and methanol (10 ml) for 1 hour. The resulting mixture was evaporated to dryness and distributed between methylene chloride and water. The organic layer is separated, dried and evaporated, thus obtaining 1-(2',4'-differenl)ethanol as a colourless oil (a 4.86 g, 96%).1H NMR (300 MHz, CDCl3) δ of 7.48 (m, 1H), 6,85 (m, 1H), 6.75 in (m, 1H), 5,15 (kV, 1H), 2,0 (s, 1H), and 1.5 (d, 3H).

1-(2',4'-Differenl)ethanol (5,384 g, 34 mmol), tert-butyldimethylsilyloxy (6,148 g and 40.8 mmol) and imidazole (5,567 g, 81,8 mmol) in DMF (60 ml) are combined and stirred at room temperature overnight. The resulting mixture was evaporated to dryness in vacuo and the residue is distributed between methylene chloride and water. The organic layer is separated, dried and evaporated, thus obtaining 1-(2',4'-differenl)ethyl-tert-butyldimethylsilyloxy ester as a white solid (6,88 g, 74%).1H NMR (300 MHz, CDCl3) δ 7,45 (kV, 1H), 6.75 in (m, 1H), 6,62 (m, 1H), of 5.05 (q, 1H), 1,32 (d, 3H), from 0.88 (s, 9H), 0.05 and 0.01 (both singlet, both 3H).

1.6 M RA is creative n ' utility in hexane (3.75 ml, 6 mmol) are added dropwise to a solution of 1-(2',4'-differenl)ethyl-tert-butyldimethylsilyl ether (1,362 g, 5 mmol) in THF (60 ml) at -50°C and stirred at the same temperature for 3 hours. The reaction mixture was poured onto dry ice and evaporated to dryness. The residue is distributed between methylene chloride and water and acidified with acetic acid. The organic layer is separated, dried and evaporated, thus obtaining 2,6-debtor-3-(1-tert-butyldimethylsilyloxy)benzoic acid, representing a compound 5A as a white solid (1.57 in g, 99%).1H NMR (300 MHz, CDCl3) δ 7,70 (kV, 1H), 7,00 (t, 1H), 6,00 (W, 1H), 5,15 (kV, 1H), 1,40 (d, 3H), of 0.90 (s, 9H), 0.12 and 0.05 for both singlet, both 3H).

Compound 1E acelerou compound 5A associated DIC/HOBt, in bezwoda DMF by the method of example 1, thus obtaining 4-[[5-amino-1-(2,6-debtor-3-(1-tert-butyldimethylsilyloxy)benzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide representing the connection 5V (yield 46%).1H NMR (300 MHz, CDCl3) δ 7,72 (m, 3H), 7,38 (d, 2H), 7,02 (t, 1H), 6,80 (s, 1H), 6,45 (s, 2H), 5,15 (kV, 1H), and 4.68 (s, 2H)and 1.15 (d, 3H), of 0.92 (s, 9H), of 0.10 (s, 3H), of 0.02 (s, 3H); MS (ESI) m/z: 553 (M+H+), 575 (M+Na+).

From the reaction mixture there is also 4-[[5-amino-2-(2,6-debtor-3-(1-tert-butyldimethylsilyloxy)benzoyl)-2H-1,2,4-triazole-3-yl]amino]benzosulfimide (minor isomer provisions) (192 mg, 34%).1H NMR (300 MHz, CDCl3): δ 10,00, 1H), 7,92 (d, 2H), 7,82 (d, 2H), 7,70 (kV, 1H), 7,02 (t, 1H), 5,18 (kV, 1H), 4,82 (s, 2H), 4,32 (c, 2H), of 1.42 (d, 3H), of 0.92 (s, 9H), of 0.10 (s, 3H), 0,02 (c, 3H); MS (ESI) m/z: 553 (M+H+), 575 (M+Na+).

0.7 ml of 1.0 M solution of TBAF in THF are added to a solution of 4-[[5-amino-1-(2,6-debtor-3-(1-tert-butyldimethylsilyloxy)benzoyl)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide representing the connection 5V (193 mg, 0.35 mol)in THF (10 ml). The reaction solution was stirred at room temperature for 1 hour and evaporated to dryness. The resulting residue is subjected to chromatography on a column of silica gel, producing elution with a mixture of 20% methanol/methylene chloride, thus obtaining the product representing the connection 58, in the form of a white foam (90 mg, 59%).1H NMR (300 MHz, (CD3)2SO) δ 9,85 (s, 1H), 8,00 (s, 2H), to 7.75 (m, 1H), 7,55 (m, 2H), 7,45 (m, 2H), 7,30 (m,1H), 7,10 (s, 2H), 6,80 (s, 1H), of 5.55 (d, 1H), 5,00 (m, 1H), 1,38 (d, 3H); MS (ESI) m/z: 421 (M+N+-H2O), 439 (M+H+), 461 (M+Na+).

Example 6

4-[[5-Amino-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]benzolsulfonat acid (compound 59)

Sodium salt of 4-selfoptimization, representing a compound 6B (obtained by the method in example 1), is subjected to the interaction with 1-amidino-3,5-dimethylpyrazole representing the connection 1C, with the formation of compound 6C, which is subjected to interaction with chitrasena, while receiving soedinenie 6D.1H NMR (300 MHz, (CD3)2SO) δ 11,1 (s, 1H), up 8.75 (s, 1H), and 7.3 (m, 4H), to 5.85 (s, 2H); MS (ESI) m/z: 256 (M+H+).

Compound 6D acelerou 2,6-differentiaion, representing a compound 1F in anhydrous pyridine, while receiving the connection 59 (4%).1H NMR (300 MHz, (CD3)2SO) δ a 9.35 (s, 1H), 7,95 (s, 2H), 7,82 (m, 2H), 7,45-7,25 (m, 5H); MS (ESI) m/z: 396 (M+H+).

The following compound is obtained by acylation of the intermediate soedineniya 6D the method according to example 6, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > dataThe original substance
604-[[5-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]benzolsulfonat acid

1H NMR (300 MHz, CD3OD) δ a 7.62 (d, 2H), 7,50 (m, 1H), 7,38 (d, 2H), 7,05 (m, 1H), 2,30 (s, 3H); MS (ESI) m/z: 410 (M+H+).
2,6-debtor-3-methylbenzoate in anhydrous pyridine

Example 7

1-(2,6-Differentail)-N3-phenyl-1H-1,2,4-triazole-3,5-diamine (compound 61)

3-Aniline-5-amino-1,2,4-triazole, representing a compound 7A (obtained by the way what about the example 1), acelerou 2,6-differentiaion, representing a compound 1F in anhydrous pyridine, while receiving compound 61 as a white solid (yield 61%).1H NMR (300 MHz, CDCl3) δ 7,80 (s, 1H), 7,45 (m, 1H), 7,30-to 7.15 (m, 4H), 7,05-6,85 (m, 5H), 6,70 (s, 2H); MS (ESI) m/z: 316 (M+H+), 338 (M+Na+).

The following compound is obtained by acylation of compounds 7A the method according to example 7, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > dataThe original substance
621-benzoyl-N3-phenyl-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, CDCl3) δ 8,30 (s, 2H), 7,65-7,40 (m, 5H), 7,28 (d, 2H), 7,00 (t, 1H), 6,80 (s, 1H), 6,70 (s, 2H);

MS (ESI) m/z: 280 (M+H+), 302 (M+Na+)
the benzoyl chloride in anhydrous pyridine
655-amino-N-phenyl-3-(phenylamino)-1H-1,2,4-triazole-1-carboxamide

1H NMR (300 MHz, (CD3)2CO) δ 9,20 (c, 1H), to 8.20 (s, 1H), of 7.70 (m, 4H), 7,35 (m, 2H), 7,25 (m, 2H), 7,15 (t, 1H), 7,98 (s, 2H), to 6.88 (t, 1H); MS (ESI) m/z: 295 (M+H+), 317 (M+Na+).
phenylisocyanate in anhydrous DMF
1241-(2,6-differentail)-N5-phenyl-1H-1,2,4-triazole-3,5-diamine

(minor isomer in which ogene connection 61)

1H NMR (300 MHz, CDCl3) δ 9,80 (c, 1H), 7,65 (d, 2H), 7,60-to 7.32 (m, 3H),

7,25-7,00 (m, 3H), and 4.40 (s, 2H); MS (ESI) m/z: 316 (M+H+), 338 (M+Na+)
-
1251-benzoyl-N5-phenyl-1H-1,2,4-triazole-3,5-diamine

(minor isomer connection locations 62)

1H NMR (300 MHz, CDCl3) δ and 10.20 (s, 1H), 8,18 (d, 2H), 7,72-7,30 (m, 7H),

to 7.15 (t, 1H), 4,30 (s, 2H); MS (ESI) m/z: 280 (M+H+), 302 (M+Na+)
-

Example 8

N3-(3-Chlorophenyl)-1-(2,6-differentail)-1H-1,2,4-triazole-

3,5-diamine (compound 63)

3-(3-Chloroanilino)-5-amino-1,2,4-triazole, representing a compound 8A (obtained by the method in example 1), acelerou 2,6-differentiaion, representing a compound 1F in anhydrous pyridine, while receiving the connection 63 in the form of a pale yellow solid (yield 66%).1H NMR (300 MHz, CDCl3) δ 7,6-to 7.50 (m, 2H), 7,15-to 6.80 (m, 6H), 6,60 (s, 2H); MS (ESI) m/z: 350 (M+H+), 372 (M+Na+).

The following compound is obtained by acylation of the intermediate 8A the method according to example 8, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > dataThe original substance
641-entail-N 3-(3-chlorophenyl)-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2CO) δ 8,58 (s, 1H), 8.30 to (d, 2H), 8,00 (m, 1H), 7,75-7,25 (m, 6H), 6.90 to (d, 1H); MS (ESI) m/z: 314 (M+H+), 336 (M+Na+)
the benzoyl chloride in anhydrous pyridine
126N5-(3-chlorophenyl)-1-(2,6-differentail)-1H-1,2,4-triazole-3,5-diamine (minor isomer position of the joint 63)

1H NMR (300 MHz, CDCl3) δ for 9.90 (s, 1H), of 7.90 (s, 1H), 7,58-to 6.95 (m, 7H), 4,35 (s, 2H); MS (ESI) m/z: 350 (M+H+), 472 (M+Na+)
-
1271-benzoyl-N5-(3-chlorophenyl)-1H-1,2,4-triazole-3,5-diamine

(minor isomer position of the joint 64)

1H NMR (300 MHz, (CD3)2CO) δ 10,30 (s, 1H), to 8.20 (d, 2H), 8,15 (m, 1H), 7,70-of 7.60 (m, 2H),

at 7.55 (t, 2H), 7,35 (m, 1H), 7,10 (d, 1H), ceiling of 5.60 (s, 2H); MS (ESI) m/z: 314 (M+H+), 336 (M+Na+)
-

Example 9

1-(2,6-Differentail)-N3-[4-(4-methyl-1-piperazinil)phenyl]-1H-1,2,4-triazole-3,5-diamine (compound 71)

4-(4-Methylpiperazine)phenylisothiocyanate subjected to interaction with 1 equivalent of nitrate 3,5-dimethylpyrazol-1 carboxamidine and 1.1 equivalent of tert-butoxide potassium in DMSO at 55°C for 4 hours. Add 10 equivalents of hydrazine and stirred at 55°C for 4 hours. Reaktsionnuyu the mixture is concentrated, dissolved in methanol, filtered impurities will contentresult, while receiving 3-(4-methylpiperazine)of aniline-5-amino-1,2,4-triazole, representing a compound 9A (yield 87%).1H NMR (400 MHz, (CD3)2SO) δ 9,05 (c, 1H), 8,60 (c, 1H), 7,35 (d, 2H), 6,77 (d, 2H), 5,70 (s, 2H), 2,97 (m, 4H), 2,48 (m, 4H), of 2.23 (s, 3H); MS (ESI) m/z: 274 (M+H+).

3-(4-Methylpiperazine)of aniline-5-amino-1,2,4-triazole, representing the connection 9A, acelerou 2,6-differentiaion, representing a compound 1F in anhydrous pyridine, while receiving the connection 71 (30%yield).1H NMR (300 MHz, (CD3)2SO) δ 9,07 (s, 1H), 7,88 (s, 1H), 7,72-7,66 (m, 1H), 7,32 (m, 1H), 7,25-7,17 (m, 2H), 6,97-6,92 (m, 1H), of 6.71 (d, 1H), 3,39-to 3.35 (m, 2H), 3,17 (s, 3H), 3.00 and-of 2.97 (m, 4H), of 2.51 is 2.46 (m, 4H); MS (ESI) m/z: 414 (M+H+).

The following compound is obtained by acylation of the intermediate 9A the method according to example 9, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > dataThe original substance
721-(2,6-debtor-3-methylbenzoyl)-N3-[4-(4-methyl-1-piperazinil)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,05 (c, 1H), 7,87 (s, 1H), to 7.59-7,51 (m, 1H), 7.24 to to 7.18 (m, 2H), 6,72 (d, 2H), 3,35 (s, 2H), 2,99-2,96 (m, 4H), 2,45-to 2.42 (m, 4H), of 2.28 (s, 3H); MS (ESI) m/z: 428 (M+N+).
2,6-debtor-3-methylbenzoate in b is Sodnom pyridine
73N3-[4-(4-methyl-1-piperazinil)phenyl]-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,13 (s, 1H), to 7.77 (c, 1H), 7,58-of 7.55 (m, 2H), 7,38-7,26 (m, 1H), 6,92 (d, 2H), 3,17 (c, 3H), 3,09-of 3.07 (m, 4H), 2,62 (s, 4H), to 2.35 (s, 3H); MS (ESI) m/z: 398 (M+H+)
3-methyl-2-thiencarbazone acid associated DIC/HOBt in anhydrous DMF
741-[(3,5-dimethyl-2-thienyl)carbonyl]-N3-[4-(4-methyl-1-piperazinil)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,11 (s, 1H), 7,73 (s, 2H), to 7.59-rate of 7.54 (m, 2H), 7,38-7,26 (m, 1H), 6,94 (d, 2H), 3,16-3,13 (m, 4H), 2,80-2,78 (m, 4H), of 2.56 (s, 3H), 2,53 (c, 3H), of 2.46 (s, 3H); MS (ESI) m/z: 412 (M+H+)
3,5-dimethyl-2-thiencarbazone acid associated DIC/HOBt in anhydrous DMF
751-[(5-ethyl-2-thienyl)carbonyl]-N3-[4-(4-methyl-1-piperazinil)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,17 (s, 1H), 7,78 (s, 1H), 7,51 (d, 2H), 7,35-7,24 (m, 3H), was 7.08 (d, 2H), 3,14-of 3.12 (m, 4H), 2,96 (kV, 2H), was 2.76-by 2.73 (m, 4H), 2,43 (s, 3H), of 1.34 (t, 3H); MS (ESI) m/z: 412 (M+H+)
5-ethyl-2-thiencarbazone acid associated DIC/HOBt in anhydrous DMF

Example 10

4-[[5-Amino-1-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]-N-ethylbenzylamine (compound 76)

Compound 1 (100 mg, 0,254 mmol) is subjected to interaction with 1.2 equivalent ethyltryptamine unsulfonated (Et-TFMS) (40 μl, 0,305 mmol) and 1.5 equivalents of tert-butoxide potassium (K-t-BO) (0.38 mmol, 381 μl of 1.0 M solution in THF) in THF (5 ml) at 50°, stirring the mixture for 16 hours. The reaction mixture is purified by chromatography on a column of producing elution with a mixture of 10% methanol/methylene chloride, and get the product that represents the connection 76 (27,1 mg, yield 25%).1H NMR (400 MHz, (CD3)2SO) δ 9,87 (s, 1H), 8,00 (s, 2H), 7,76-to 7.68 (m, 1H), 7,55-of 7.48 (m, 4H), 7,34 (t, 2H), 7,22 (m, 1H), 2,73-to 2.67 (m, 2H), were 0.94 (t, 3H); MS (ESI) m/z: 423 (M+H+).

Example 12

N3-Methyl-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine (compound 79)

3,5-Diamine-1,2,4-triazole, representing the connection 12A, acelerou 3-methylthiophene-2-carboxylic acid, representing the connection 12V associated DIC/HOBt in anhydrous DMF by the method of example 1, thus obtaining the compound 41 (yield 72%).1H NMR (300 MHz, (CD3)2SO) δ 7,88 (d, J=4,5, 1H), to 7.59 (s, 2H), 7,05 (d, J=4,8, 1H), 5,78 (s, 2H), by 2.55 (s, 3H); MS (ESI) m/z: 224,1 (M+H+), 245,9 (M+Na+).

Compound 41 (0.45 mmol, 100 mg) is subjected to interaction with 3 equivalents of iodomethane (1,34 mmol, 84 μl) and 1.1 equivalent of tert-butoxide potassium (0.49 mmol, 493 μl of 1.0 M solution in THF) in THF (5 ml), stirring the mixture for 16 hours at 25°C. the Reaction mixture is purified by chromatography on a column (elution with a mixture of 10% methanol/dichloromethane)to give the product of the t, representing the connection 79 (7.7 mg, yield 7%).1H NMR (400 MHz, (CD3)2SO) δ 9,80 (s, 1H), 7,60 (d, 1H), of 6.96 (d, 1H), 6,17 (s, 2H), 3,47 (c, 3H), 2.40 a (s, 3H); MS (ESI) m/z: 238 (M+H+), 260 (M+Na+).

Example 13

4-[[5-Amino-1-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]-N-methylbenzenesulfonamide (compound 80)

Tert-BuOK (23.1 ml, 1.0 M solution in tert-BuOH, and 23.1 mmol) are added dropwise to a solution of 4-isothiocyanato-N-methylbenzenesulfonamide, representing a compound 13B (obtained by the method of example 1) (4.8 g, 21,0 mmol), and nitrate 2.5-dimethylpyrazol-1-carboxamidine, representing a compound 1C (4,2 g, 21,0 mmol)in DMF (20 ml). The mixture is heated to 60°C for 2 hours and poured on ice. The precipitate is collected by filtration, washed with water and subjected to air drying, thus obtaining 4-[3-(3,5-dimethylpyrazol-1-illuminometer)touraid]-N-methylbenzenesulfonamide representing the connection 13C, in the form of a yellow solid (7,3 g, yield 95%).1H NMR (300 MHz, (CD3)2SO) δ 8,01 (c, 1H), 7,71 (m, 4H), x 6.15 (s, 1H), 2.40 a (c, 3H), 2,22 (s, 6H); MS (ESI) m/z: 367 (M+H+).

Hydrazine (3.3 grams, 110,0 mmol) is added at 0°to a suspension of 4-[3-(3,5-dimethylpyrazol-1-illuminometer)touraid]-N-methylbenzenesulfonamide, representing a compound 13C (2.0 g, 5.5 mmol)in THF (20 ml). The mixture is heated to 60°C for 2 cha is offering, and poured on ice. The precipitate is collected by filtration, washed with water and CH2Cl2and subjected to air drying, thus obtaining the compound 13D in the form of a white solid (1.3 g, yield 87%).1H NMR (300 MHz, (CD3)2SO) δ 11,36 (s, 1H), 9,31 (s, 1H), 7,63 (kV, 4H), 7,09 (kV, 1H), equal to 6.05 (s, 2H), 2,39 (d, 3H); MS (ESI) m/z: 269 (M+H+).

Compound 13D acelerou 2,6-differentiaion, representing a compound 1F in anhydrous pyridine by the method of example 1, thus obtaining the compound 80 (yield 80%).1H NMR (300 MHz, CD3OD) δ to 7.64 (m, 1H), 7,63 (d, 2H), 7,53 (d, 2H), 7,15 (t, 2H), 2,43 (s, 3H); MS (ESI) m/z: 409 (M+H+).

The following compound is obtained by acylation of the intermediate 13D method of example 13, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > dataThe original substance
814-[[5-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]-N-methylbenzenesulfonamide

1H NMR (300 MHz, CD3OD) δ at 7.55 (d, 2H), of 7.48-7,44 (m, 1H), 7,46 (d, 2H), 2,42 (s, 3H), of 2.25 (s, 3H); MS (ESI) m/z: 423 (M+H+)
2,6-debtor-3-methylbenzoate in anhydrous Piri is ine
824-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-methylbenzenesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ 9,92 (s, 1H), 8,03 (d, 1H), 7,81 (d, 2H), 7,69 (d, 2H), 7,14 (m, 2H), 2,62 (c, 3H), by 2.55 (s, 3H); MS (ESI) m/z: 393 (M+H+)
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
834-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-methylbenzenesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ of 9.89 (s, 1H), of 8.09 (d, 1H), 7,74 (d, 2H), 7,63 (d, 2H), 7,02 (d, 1H), equal to 2.94 (q, 2H), 2,32 (s, 3H), of 1.33 (t, 3H); MS (ESI) m/z: 407 (M+H+)
3,5-dimethylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
844-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-methylbenzenesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ 9,65 (c, 1H), to 7.64 (d, 1H), 7,50 (d, 2H), 7,69 (d, 2H), 6,66 (s, 1H), 2,36 (c, 3H), of 2.34 (s, 3H), 2,12 (s, 3H); MS (ESI) m/z: 407

(M+H+)
5-ethylthiophen-2-carboxylic acid associated DIC/HOBt in DMF

Example 14

1-[(3,5-Dimethyl-2-thienyl)carbonyl]-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (compound 85)

4-Isothiocyanato-N,N-dimethylbenzenesulfonamide, representing a compound 14C (obtained by the method of example 1) (1.8 g, 7.4 mmol), subjected to interaction with nitrate 2.5-dimethylpyrazol-1-carboxamidine,representing a compound 1C (1.5 g, 7.4 mmol), and tert-BuOK (7,4 ml, 1.0 M solution in tert-BuOH, 7.4 mmol), thus obtaining 4-[3-(3,5-dimethylpyrazol-1-illuminometer)touraid]-N,N-dimethylbenzenesulfonamide representing the connection 14C, in the form of a yellow solid (2.5 g, yield 89%).1H NMR (300 MHz, (CD3)2SO) δ of 10.05 (s, 1H), 8,91 (c, 1H), to 7.67 (m, 4H), 6,15 (c, 1H), 2.57 m (c, 6N), 2,18 (c, 6N); MS (ESI) m/z: 381 (M+N+).

Compound 14C (2.5 g, 6.6 mmol) is subjected to interaction with hydrazine (4,2 g, 132,0 mmol), thus obtaining 1.7 g (90%) of compound 14D in the form of a white solid.1H NMR (300 MHz, (CD3)2SO) δ for 9.47 (s, 1H), 7,81 (d, 2H), of 7.75 (d, 2H), 6,10 (c, 1H), 2,67 (C, 6N); MS (ESI) m/z: 283 (M+H+).

Compound 14D acelerou 3,5-dimethylthiophene-2-carboxylic acid, representing a compound 1F associated DIC/HOBt in DMF, while receiving the connection 85 (yield 52%).1H NMR (300 MHz, (CD3)2SO) δ to 9.93 (s, 1H), 7,88 (d, 2H), a 7.85 (s, 1H), 7,65 (d, 2H), 6.90 to (s, 1H), 2,60 (C, 6N), of 2.56 (s, 3H), of 2.54 (s, 3H); MS (ESI) m/z: 421 (M+H+).

The following compound is obtained by acylation of the intermediate 14D method of example 14 using the specified starting material instead of compound 14 and the appropriate reagent (reagent):

Connected is e Name > dataThe original substance
864-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N,N-dimethylbenzenesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ there is a 10.03 (s, 1H), 8,13 (d, 1H), to $ 7.91 (s, 1H), 7,86 (d, 2H), 7,66 (d, 2H), 7,10 (d, 2H), 2.95 and (q, 2H), has 2.56 (s, 6H), of 1.32 (t, 3H); MS (ESI) m/z: 421 (M+H+)
5-ethylthiophen-2-carboxylic acid associated DIC/HOBt in DMF
874-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N,N-dimethylbenzenesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ 10,01 (c, 1H), with 8.05 (d, 1H), 7,86 (d, 3H), of 7.69 (d, 2H), 7,13 (d, 1H), 2.63 in (s, 3H), by 2.55 (s, 6H); MS (ESI) m/z: 407 (M+H+)
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
884-[[5-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]-N,N-dimethylbenzenesulfonamide

1H NMR (300 MHz, CDCl3) δ 7,79 (s, 1H), 7,55 (d, 2H), 7,40 (d, 2H), 7,35 (m, 1H), 6,95 (s, 2H), 6,92 (m, 1H), 2,65 (s, 6H), and 2.27 (s, 3H); MS (ESI) m/z: 437 (M+H+)
2,6-debtor-3-methylbenzoate in anhydrous pyridine
894-[[5-amino-1-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]-N,N-dimethylbenzenesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ 9,74 (s, 1H), to 7.77 (c, 2H), 7,50-7,40 (m, 1H), 7,30-7,20 (m, 4H), 7,10 (m, 2H, in), 2.25 (s, 6H), MS (ESI) m/z: 423 (M+H+)
2,6-differentielle the ID in anhydrous pyridine

Example 15

1-[(5-Ethyl-2-thienyl)carbonyl]-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (compound 90)

Using the method described in the scientific literature (Webb et al., J. Heterocyclic Chem., 1987, 24, 275-278), 4-imidazol-1-ranelin (0.50 g, 3.14 mmol), diphenylcyanoarsine (0.75 g, 3.14 mmol) and THF (30 ml) are combined in a nitrogen purged flask. The mixture is heated under reflux for 2 hours, cooled to the temperature of the ice and added dropwise hydrazine (of 31.4 ml, 1.0 M solution in THF, to 31.4 mmol). Then the mixture is again heated under reflux for 2 hours. The precipitate was filtered, collected, washed with ethyl acetate and subjected to air drying, thus obtaining an intermediate compound 15A (0,60 g, 79%).1H NMR (300 MHz, (CD3)2SO) δ of 11.15 (s, 1H), cent to 8.85 (s, 1H), 8,05 (c, 1H), EUR 7.57 (s, 1H), of 7.48 (d, 2H), 7,35 (d, 2H),? 7.04 baby mortality (s, 1H), 5,85 (c, 2H); MS (ESI) m/z: 242 (M+H+).

Compound 15A acelerou 5-ethylthiophen-2-carboxylic acid, representing the connection 15V associated DIC/HOBt in DMF by the method of example 1, thus obtaining the compound 90 (yield 59%).1H NMR (300 MHz, (CD3)2SO) δ 9,63 (s, 1H), 8,14 (d, 1H), 7,85-of 7.70 (m, 7H), 7,56-7,53 (m, 2H), 7,07 (d, 2H), 2.95 and (q, 2H), 1,33 (t, 3H); MS (ESI) m/z: 380 (M+H+).

The following compound is obtained by acylation of the intermediate 15A the method according to example 15, using the specified recognize the substance instead of connecting 15V and the respective reagent (reagent):

ConnectionName > dataThe original substance
91N3-[4-(1H-imidazol-1-yl)phenyl]-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,62 (s, 1H), of 7.97 (d, 1H), 7,92 (c, 1H), 7,82-7,72 (m, 5H), 7,56-7,53 (m, 2H), 7,11 (d, 1H), 2,61 (s, 3H); MS (ESI) m/z: 366 (M+H+).
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
921-[(3,5-dimethyl-2-thienyl)carbonyl]-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2CO) δ of 9.51 (s, 1H), 8,15 (s, 1H), to 7.75 (m, 4H), to 7.61 (c, 1H), 7,53 (d, 2H), 7,05 (s, 1H), 6,85 (s, 1H), 2,53 (s, 3H), 2,52 (s, 3H); MS (ESI) m/z: 380 (M+H+)
3,5-dimethylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
931-(2,6-differentail)-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,52 (s, 1H), of 8.06 (s, 1H), to 7.93 (s, 1H), of 7.70 (t, 1H), EUR 7.57 (s, 1H), 7,45 (d, 2H), was 7.36 (d, 2H), 7,30 (m, 2H), 7,01 (s, 1H); MS (ESI) m/z: 382 (M+H+)
2,6-differentiald in anhydrous pyridine
941-(2,6-debtor-3-methylbenzoyl)-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ

9,52 (s, 1H), 8,08 (s, 1H), to 7.93 (s, 1H), EUR 7.57 (s, 1H), 7,53 t, 1H), 7,42 (d, 2H), 7,35 (d, 2H), 7,18 (t, 1H), 7,02 (s, 1H, in), 2.25 (s, 3H); MS (ESI) m/z: 396
2,6-debtor-3-methylbenzoate in anhydrous pyridine

Example 16

1-(2,6-Debtor-3-methylbenzoyl)-N3-[4-(1H-1,2,4-triazole-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (compound 95)

4-(1,2,4-Triazole-1-yl)aniline (0.35 g, to 2.18 mmol), diphenylcyanoarsine (0.52 g, to 2.18 mmol) and hydrazine (21,8 ml, 1.0 M solution in THF, to 21.8 mmol) is subjected to interaction by the method according to example 15, thus obtaining the compound 16D (0.40 g, yield 78%) as a white solid.1H NMR (300 MHz, (CD3)2SO) δ 11,21 (s, 1H), 9,06 (s, 1H), of 8.92 (s, 1H), 8,13 (s, 1H), to 7.61 (m, 4H), by 5.87 (s, 2H); MS (ESI) m/z: 243 (M+H)+.

Compound 16D acelerou 2,6-debtor-3-methylbenzothiazol representing the connection 16B, in anhydrous pyridine by the method of example 1, thus obtaining the compound 95 (51%yield).1H NMR (300 MHz, (CD3)2SO) δ 9,62 (s, 1H), 9,11 (s, 1H), 8,12 (s, 1H), to $ 7.91 (s, 1H), 7,56 (d, 2H), 7,60-7,50 (kV, 1H), 7,45 (d, 2H), 7,16 (t, 1H, in), 2.25 (s, 3H); MS (ESI) m/z: 397 (M+H+).

The following compound is obtained by acylation of the intermediate 16A the method according to example 16, using the specified starting material instead of compound 16B and the appropriate reagent (reagent):

ConnectionName > dataOriginal substances, the
961-(2,6-differentail)-N3-[4-(1H-1,2,4-triazole-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ being 9.61 (s, 1H), 9,05 (s, 1H), 8,07 (s, 1H), 7,85 (s, 2H), 7,63 (p, 1H), 7,53 (d, 2H), 7,41 (d, 2H), 7,30 (m, 2H), 7,29 (m, 2H); MS (ESI) m/z: 383 (M+H+).
2,6-differentiald in anhydrous pyridine
971-[(5-ethyl-2-thienyl)carbonyl]-N3-[4-(1H-1,2,4-triazole-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,72 (s, 1H), 9.15, with (s, 1H), 8,17 (s, 1H), 8,16 (d, 1H), 7,78 (s, 2H), to 7.77 (d, 2H), 7,72 (d, 2H),? 7.04 baby mortality (d, 1H), 2,96 (kV, 2H), 1,33 (t, 3H); MS (ESI) m/z: 381 (M+H+).
5-ethylthiophen-2-carboxylic acid associated DIC/HOBt in DMF
981-[(3,5-dimethyl-2-thienyl)carbonyl]-N3-[4-(1H-1,2,4-triazole-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,67 (s, 1H), 9.15, with (s, 1H), 8,18 (c, 1H), to 7.75 (m, 6H), 6.89 in (s, 1H), 2,52 (s, 3H), of 2.51 (s, 3H); MS (ESI) m/z: 381 (M+H+).
3,5-dimethylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
991-[(3-methyl-2-thienyl)carbonyl]-N3-[4-(1H-1,2,4-triazole-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,68 (s, 1H), 9,13 (s, 1H), 8,16 (s, 1H), to 7.99 (d, 1H), to 7.77 (m, 6H), 7,12 (d, 1H); MS (ESI) m/z: 367 (M+H+).
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF

The use of the 17

1-(2,6-Differentail)-N3-[4-(4H-1,2,4-triazole-4-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (compound 100)

4-(1,3,4-Triazole-1-yl)aniline (1.35 g, 8,43 mmol), diphenylcyanoarsine (2.00 g, 8,43 mmol) and hydrazine (84,3 ml, 1.0 M solution in THF, of 84.3 mmol) is subjected to interaction by the method according to example 15, thus obtaining the compound 17A (1.10 g, yield 77%) as a white solid.1H NMR (300 MHz, (CD3)2SO) δ 8,90 (c, 2H), a 7.62 (d, 2H), was 7.36 (d, 2H), of 5.82 (s, 2H); MS (ESI) m/z: 243 (M+H+).

Compound 17A acelerou 2,6-differentiaion, representing a compound 1F in anhydrous pyridine by the method of example 1, thus obtaining the compound 100 (yield 36%).1H NMR (300 MHz, (CD3)2SO) δ being 9.61 (s, 1H), 8,98 (c, 2H), of 7.96 (c, 2H), to 7.67 (t, 1H), 7,47 (d, 2H), 7,42 (d, 2H), 7,32 (m, 2H); MS (ESI) m/z: 383 (M+N+).

The following compound is obtained by acylation of the intermediate 17D method of example 17, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > DataThe original substance
1011-(2,6-debtor-3-methylbenzoyl)-N3-[4-(4H-1,2,4-triazole-4-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ being 9.61 (s, 1H), to 8.94 (s, 2H), to $ 7.91 (s, 2H), 7,55(kV, 1H), 7,43 (kV, 4H), 7,18 (t, 1H); MS (ESI) m/z: 397 (M+N+).
2,6-debtor-3-methylbenzoate in anhydrous pyridine
1021-[(3-methyl-2-thienyl)carbonyl]-N3-[4-(4H-1,2,4-triazole-4-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 10,22 (s, 1H), 9,04 (s, 2H), 7,95 (m, 3H), to 7.67 (d, 2H), 7,07 (d, 1H), 6,13 (s, 2H); MS (ESI) m/z: 367 (M+N+)
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF

Example 18

4-[[5-Amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-[2-(dimethylamino)ethyl]benzosulfimide(compound 103)

4-Amino-N-(2-dimethylaminoethyl)benzosulfimide (2.00 g, by 8.22 mmol), diphenylcyanoarsine (2.00 g, by 8.22 mmol) and hydrazine (82,3 ml, 1.0 M solution in THF, to 82.3 mmol) is subjected to interaction by the method according to example 15, thus obtaining the compound 18A (1.35 g, yield 50%) as a white solid.1H NMR (300 MHz, (CD3)2SO) δ which 9.22 (s, 1H), 8,43 (s, 1H), 7,55 (m, 4H), 7,02 (s, 1H), 5,91 (s, 2H), 2,71 (t, 2H), 2,15 (t, 2H), 2.05 is (s, 6H); MS (ESI) m/z: 326 (M+N+).

Compound 18A acelerou 5-ethylthiophen-2-carboxylic acid, representing the connection 15V associated DIC/HOBt in DMF by the method of example 1, thus obtaining the compound 103 (yield 40%).1H NMR (300 MHz, (CD3)2SO) δ 10,02 (s, 1H), 8,13 (d, 1H), 7,88 (s, 1H), of 7.75 (d, 2H), 7,71 (d, 2H), 7,07 (d, 1H), 7,01 (s, 2H), 2.95 and (q, 2H), 2,75 (t, 2H), measuring 2.20 (t, 2H), 2,04 (s, 6H), of 1.35 (t, 3H); MS (ESI) m/z 464 (M+N +).

The following compound is obtained by acylation of the intermediate 18A the method according to example 18, using the specified starting material instead of compound 15V and the respective reagent (reagent):

ConnectionName > DataThe original substance
1044-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-[2-(dimethylamino)ethyl]benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ of 9.89 (s, 1H), 8,04 (d, 1H), 7,83 (s, 1H), 7,79 (d, 2H), 7,71 (d, 2H), 7,15 (s, 2H), was 7.08 (d, 1H), was 2.76 (t, 2H), 2,61 (s, 3H), of 2.21 (t, 2H), 2,07 (s, 6H); MS (ESI) m/z: 450 (M+N+).
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
1054-[[5-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]-N-[2-(dimethylamino)ethyl]benzosulfimide

1H NMR (300 MHz, CD3OD) δ EUR 7.57 (d, 2H), 7,45 (m, 3H), of 7.00 (t, 1H), 2,86 (t, 2H), 2,32 (t, 2H, in), 2.25 (s, 3H), 2,11 (s, 6H); MS (ESI) m/z: 480 (M+N+)
2,6-debtor-3-methylbenzoate in anhydrous pyridine
1064-[[5-amino-1-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]-N-[2-(dimethylamino)

ethyl]benzosulfimide

1H NMR (300 MHz, CD3OD) δ of 7.60 (m, 1H), 7,55 (d, 2H), 7,45 (d, 2H), 7,11 (t, 1H), 2,87 (t, 2H), 2,32 (t, 2H), 2,12 (s, 6H); MS (ESI) m/z: 466 (M+the +)
2,6-differentiald in anhydrous pyridine
1074-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-[2-(dimethylamino)ethyl]

benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ of 9.89 (s, 1H), 7,81 (m, 4H), 7,71 (d, 2H), 7,22 (s, 1H), 6,86 (c, 1H), and 2.79 (t, 2H), 2.63 in (s, 3H), 2,61 (s, 3H), of 2.21 (t, 6H), to 2.06 (s, 6H); MS (ESI) m/z: 464 (M+N+)
3,5-dimethylthiophene-2-carboxylic acid associated DIC/HOBt in DMF

Example 19

N-[4-[[5-Amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]phenyl]methanesulfonamide (compound 108)

N-(4-AMINOPHENYL)methanesulfonamide (2.00 g, 10,70 mmol), diphenylcyanoarsine (2,60 g, 10,70 mmol) and hydrazine (107,0 ml, 1.0 M solution in THF, 107,0 mmol) is subjected to interaction by the method according to example 15, thus obtaining the compound 19A (1,30 g, yield 45%) as a white solid.1H NMR (300 MHz, (CD3)2SO) δ 8,80 (c, 1H), 8,55 (s, 1H), 7,43 (d, 2H), of 6.96 (d, 2H), of 5.75 (s, 2H), 2,82 (s, 3H); MS (ESI) m/z: 269 (M+N+).

Compound 19A acelerou 3,5-dimethylthiophene-2-carboxylic acid, representing the connection of the 19th century, associated DIC/HOBt in DMF by the method of example 1, thus obtaining the compound 108 (yield 11%).1H NMR (300 MHz, (CD3)2SO) δ of 9.30 (s, 1H), 9,25 (s, 1H), of 7.70 (s, 1H), to 7.61 (d, 2H), 7,12 (d, 2H), 6,83 (s, 1H), 2,87 (s, 3H), of 2.50 (s, 3H); MS (ESI) m/z: 407 (M+N+).

Below is the following compound is obtained by acylation of the intermediate 19A by way of example 19, using the specified starting material instead of compound 14 and the appropriate reagent (reagent):

ConnectionName > DataThe original substance
109N-[4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]phenyl]methanesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ

9,35 (c, 1H), of 9.30 (s, 1H), 8,01 (d, 1H), of 7.75 (s, 1H), 7.62mm (d, 2H), 7,12 (m, 3H), 6,83 (s, 1H), 2,89 (s, 3H), at 2.59 (s, 3H); MS (ESI) m/z: 393 (M+N+)
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF
110N-[4-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]phenyl]methanesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ 9,37 (s, 1H), of 9.30 (s, 1H), 8,12 (d, 1H), 7,74 (s, 1H), 7.62mm (d, 2H), 7,12 (d, 2H), 7,03 (d, 1H), 2.95 and (q, 2H), 2,89 (s, 3H), of 1.35 (t, 3H); MS (ESI) m/z: 407 (M+N+)
5-ethylthiophen-2-carboxylic acid associated DIC/HOBt in DMF
111N-[4-[[5-amino-1-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]phenyl]methanesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ to 9.32 (s, 1H), of 9.21 (s, 1H), 7,88 (s, 2H), to 7.64 (t, 1H), 7,25 (m, 4H), 6,92 (d, 2H), 2,82 (s, 3H); MS (ESI) m/z: 409 (M+N+)
2,6-differentiald in anhydrous pyridine
112N-[4-[[5-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-3-the l]amino]phenyl]methanesulfonamide

1H NMR (300 MHz, (CD3)2SO) δ

was 9.33 (s, 1H), 7,88 (s, 2H), 7,54 (kV, 1H), 7,25 (d, 2H), 7,16 (t, 1H), 6,92 (d, 2H), 2,82 (s, 3H), of 2.25 (s, 3H); MS (ESI) m/z: 423 (M+N+)
2,6-debtor-3-methylbenzoate in anhydrous pyridine

Example 20

1-[4-[[5-Amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]phenyl]-2-imidazolidinone (compound 113)

1-(4-AMINOPHENYL)imidazolidin-2-he (0.24 g, 1.35 mmol), diphenylcyanoarsine (0.32 g, 1.35 mmol) and hydrazine (13,5 ml, 1.0 M solution in THF, 13.5 mmol) is subjected to interaction by the method according to example 15, thus obtaining the compound 20A (0.28 g, 80%) as a white solid.1H NMR (300 MHz, (CD3)2SO) δ 11,05 (s, 1H), 8,42 (s, 1H), 7,35 (d, 2H), 7,24 (d, 2H), 6,65 (s, 1H), 5,78 (c, 2H), 3,74 (t, 2H), 3,32 (t, 2H); MS (ESI) m/z: 260 (M+N+).

Compound 20A acelerou 3-methylthiophene-2-carboxylic acid, representing the connection of the 20th century, associated DIC/HOBt in DMF by the method of example 1, thus obtaining the compound 113 (yield 41%).1H NMR (300 MHz, (CD3)2SO) δ of 9.21 (c, 1H), 8,01 (d, 1H), 7,68 (s, 1H), 7,55 (d, 2H), 7,43 (d, 2H), 7,11 (d, 1H), of 6.71 (c, 1H), 3,83 (kV, t), 3,37 (kV, 2H), 2.63 in (s, 3H); MS (ESI) m/z: 384 (M+N+).

The following compound is obtained by acylation of the intermediate 20A method of example 20, using the specified starting material instead of compound 20B and the appropriate reagent (reagent):

ConnectionName > DataThe original substance
1141-[4-[[5-amino-1-(2,6-debtor-3-methylbenzoyl)-1H-1,2,4-triazole-3-yl]amino]phenyl]-2-imidazolidinone

1H NMR (300 MHz, (CD3)2SO) δ 9,12 (s, 1H), 7,82 (s, 2H), 7,50 (m, 1H), 7,21 (m, 4H), 7,20 (m, 1H), 6,70 (s, 1H), and 3.72 (t, 2H), 3,28 (t, 3H), of 2.21 (s, 3H); MS (ESI) m/z: 414 (M+N+)
2,6-debtor-3-methylbenzoate in anhydrous pyridine
1151-[4-[[5-amino-1-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]phenyl]-2-imidazolidinone

1H NMR (300 MHz, (CD3)2SO) δ

9,16 (c, 1H), 7,87 (s, 2H), 7,63 (m, 1H), 7,19 (m, 6H), 6,74 (s, 1H), and 3.72 (t, 2H), 3,28 (t, 3H); MS (ESI) m/z: 400 (M+N+)
2,6-differentiald in anhydrous pyridine

Example 21

N3-[4-(1,1-Dioxido-2-isothiazolinone)phenyl]-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine (compound 116)

4-(1,1-Dioxothiazolidine-2-yl)phenylamine (0,92 g, 4,36 mmol), diphenylcyanoarsine (1.10 g, 4,36 mmol) and hydrazine (43,6 ml, 1.0 M solution in THF, was 43.6 mmol) is subjected to interaction by the method according to example 15, thus obtaining the compound 21A (1.2 g, 95%) as a white solid.1H NMR (300 MHz, (CD3)2SO) δ 11,05 (s, 1H), 8,58 (c, 1H), 7,47 (d, 2H), 7,05 (d, 2H), 5,78 (s, 1H), 3,55 (t, 2H), 3,32 (t, 2H), 2,30 (p, 2H); MS (ESI) m/z: 295 (M+N+).

Compound 21A acelerou 3-methylthiophene-2-carbon is howling acid, representing the connection 20V associated DIC/HOBt in DMF by the method of example 1, thus obtaining the compound 116 (yield 48%).1H NMR (300 MHz, (CD3)2SO) δ 9,38 (s, 1H), 8,01 (d, 1H), 7,73 (s, 2H), a 7.62 (d, 2H), 7,15 (d, 2H), was 7.08 (d, 1H), to 3.67 (t, 2H), 3,42 (t, 2H), 2,58 (s, 3H), 2,35 (p, 2H); MS (ESI) m/z: 419 (M+N+).

The following compound is obtained by acylation of the intermediate 21A by way of example 21, using the specified starting material instead of compound 20B and the appropriate reagent (reagent):

ConnectionName > DataThe original substance
1171-(2,6-differentail)-N3-[4-(1,1-dioxido-2-isothiazolinone)phenyl]-1H-1,2,4-triazole-3,5-diamine

1H NMR (300 MHz, (CD3)2SO) δ 9,31 (s, 1H), 7,80 (s, 2H), 7.62mm (t, 2H), 7,28 (m, 3H), 7,01 (d, 2H), 3,63 (t, 2H), 3,35 (t, 2H), 2,32 (p, 2H); MS (ESI) m/z: 435 (M+N+).
2,6-differentiald in anhydrous pyridine

Example 22

4-[[5-Amino-1-(2,6-differentail)-1H-1,2,4-triazole-3-yl]amino]-N-(2-pyridinyl)benzosulfimide (compound 118)

4-Amino-N-pyridin-2-yl-benzosulfimide (1.48 g, 5,96 mmol), diphenylcyanoarsine (1.42 g, 5,96 mmol) and hydrazine (59,6 ml, 1.0 M solution in THF, to 59.6 mmol) is subjected to interaction by the method according to example 15, while receiving the connection 22 is (0,98 g, 50%) as a white solid.1H NMR (300 MHz, (CD3)2SO) δ which 9.22 (s, 1H), with 8.05 (s, 1H), 7,73 (m, 3H), 7,53 (d, 2H),? 7.04 baby mortality (d, 1H), 6,85 (m, 2H), to 5.85 (s, 2H); MS (ESI) m/z: 332 (M+N+).

The connection 22A acelerou 2,6-differentiaion, representing a compound 1F in anhydrous pyridine by the method of example 1, thus obtaining the compound 118 (yield 61%).1H NMR (300 MHz, (CD3)2SO) δ 9,85 (s, 1H), 8,00-of 7.90 (m, 2H), 7,65 (m, 1H), to 7.59 (d, 2H), 7,35 (d, 2H), 7,25 (m, 2H),? 7.04 baby mortality (d, 1H), for 6.81 (t, 1H), and 3.31 (s, 2H); MS (ESI) m/z: 472 (M+N+).

The following compound is obtained by acylation of the intermediate 22A by way of example 22, using the specified starting material instead of compound 1F and the appropriate reagent (reagent):

ConnectionName > DataThe original substance
1194-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-(2-pyridinyl)benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,87 (s, 1H), 8,11 (d, 1H), 8,01 (s, 1H), of 7.90 (s, 1H), to 7.75 (m, 4H), to 7.68 (d, 2H), 7,63 (t, 1H), 7,07 (m, 2H), 6,85 (m, 1H), 2.95 and (q, 2H), 1,32 (t, 3H); MS (ESI) m/z: 470 (M+N+)
5-ethylthiophen-2-carboxylic acid associated DIC/HOBt in DMF
1204-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-(2-pyridi the Il)benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ

9,84 (s, 1H), 7,98 (s, 1H), to $ 7.91 (s, 1H), 7,74 (m, 4H), 7,71 (d, 2H), 7,63 (t, 1H), 7,07 (m, 1H), 6,85 (m, 2H), 2,53 (s, 3H), 2,52 (s, 3H); MS (ESI) m/z: 470 (M+N+)
3,5-dietitian-2-carboxylic acid associated DIC/HOBt in DMF
1214-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-(2-pyridinyl)benzosulfimide

1H NMR (300 MHz, (CD3)2SO) δ 9,85 (s, 1H), 8,02 (m, 2H), 7,79 (m, 4H), 7,73 (d, 2H), 7,63 (t, 1H), 7,13 (d, 1H), 7,07 (m, 1H), for 6.81 (m, 1H), 2,61 (s, 3H); MS (ESI) m/z: 456 (M+N+)
3-methylthiophene-2-carboxylic acid associated DIC/HOBt in DMF

Biological examples

The suitability of compounds for the treatment or relief of symptoms of diseases mediated by the cyclin-dependent kinase and receptor, determine the methods described below.

Example 1

Screening CDK1

For screening kinase using the reaction mixture containing 50 mm Tris-HCl pH 8, 10 mm MgCl2, 0.1 mm Na3PO4, 1 mm dithiothreitol (DTT), 10 μm ATP, 0,025 µm biotinylated by histone-H1 peptide substrate, and 0.2 µci per well33R-γ-ATP [2000-3000 CI/mmol]. In each well of streptavidin coated tablet FlashPlate™ (catalog No. SMP103, NEN, Boston, MA) dropper-dispenser enter 70 μl of the reaction mixture for screening kinase. Then the wells, add 1 ál of a solution of the test with the unity in 100% DMSO to achieve a final concentration, equal to 1% DMSO in the reaction mixture with a final volume of 100 μl. Protein CDK1:cyclin-diluted in 50 mm Tris-HCl with pH 8.0, containing 0.1% bovine serum albumin (BSA), in a concentration of 1 ng to 1 mm and for the initiation of the reaction in each well add 30 ál of the mixture (30 ng enzyme/well). The reaction mixture is incubated for one hour at 30°C. after an incubation period of 1 hour, the reaction stops, for which the reaction mixture is sucked off from the tablet and the wells washed twice SFR containing 100 mm etc. The peptide substrate, the biotinylated histone-H1, immobilized on the tablet Flashplate™ and measure the contents of the33R-γ-Asia-Pacific, reading the tablet using a scintillation counter. Inhibition of the enzymatic activity of CDK1 measure to reduce33R-γ-ATP contained in the immobilized peptide.

Screening VEGF-R

For screening kinase using the reaction mixture containing 50 mm Tris-HCl pH 8, 10 mm MgCl2, 0.1 mm Na3PO4, 1 mm DTT, 10 μm ATP, of 0.025 μm biotinylated peptide substrate and 0.8 µci per well33R-γ-Asia-Pacific [2000-3000 CI/mmol]. In each well of streptavidin coated tablet FlashPlate™ (catalog No. SMP103, NEN, Boston, MA) dropper-dispenser enter 70 μl of the reaction mixture for screening kinase. Then the wells, add 1 ál of a solution of the test with the unity in 100% DMSO to achieve a final concentration, equal to 1% DMSO in the reaction mixture with a final volume of 100 μl. Soluble to tyrosinekinase rats, containing the label 6HIS at N-end, diluted in 50 mm Tris-HCl with pH 8.0, containing 0.1% BSA to a concentration of 5 ng per µl of a solution, and to initiate the reaction in each well add 30 ál of the mixture (150 ng enzyme/well). The reaction mixture is incubated for one hour at 30°C. after an incubation period of 1 hour, the reaction stops, for which the reaction mixture is sucked off from the tablet and the wells washed twice SFR containing 100 mm etc. The peptide substrate, biotinylated PLC1, immobilized on the tablet FlashPlate™ and measure the contents of the33R-γ-Asia-Pacific, reading the tablet using a scintillation counter. Inhibition of the enzymatic activity of VEGF-R measure to reduce33R-γ-ATP contained in the immobilized peptide.

The data IC50for VEGF-R and CDK are shown in table 1. The values of the IC50listed as >10 or >100, indicate that at the highest tested dose not detected as 50% inhibition, and the maximum inhibition.

No data
Table 1
IC50(µm)
ConnectionCDK1VEGF-RHER2CDK2
10,00640,1062No dataNo data
20,00320,3659No dataNo data
30,00800,3324No dataNo data
40,022320,3866No dataNo data
50,14360,5209No dataNo data
60,03948,144No dataNo data
70,057>10No dataNo data
80,136>100No dataNo data
90,0391,597No dataNo data
100,2520,4907No dataNo data
110,3046>100No dataNo data
120,04540,08406No dataNo data
130,53530,5318No data
140,00450,0267No dataNo data
150,00480,0511No dataNo data
160,00210,0137No dataNo data
170,00250,027No dataNo data
180,0670,058No dataNo data
190,03390,2907No dataNo data
200,00440,031No dataNo data
210,00880,023No dataNo data
220,03180,2334No dataNo data
230,08890,0353No dataNo data
240,28230,0674No dataNo data
250,019530,064No dataNo data
2618,4˜100No dataNo data
27˜100>100No dataNo data
280,981613,25No dataNo data
2970,39˜100No dataNo data
300,0170,0406No dataNo data
310,0300,044No dataNo data
320,00310,0219No dataNo data
330,00320,0234No dataNo data
340,00160,0681No dataNo data
350,00110,0463No dataNo data
361,56118,61No dataNo data
3710,554,98No dataNo data
380,02990,8795 No dataNo data
390,01220,3336No dataNo data
400,194911,06No dataNo data
420,13420,4433No dataNo data
430,08730,6279No dataNo data
440,52232,677No dataNo data
450,01370,3553No dataNo data
460,03580,4527No dataNo data
470,05862,523No dataNo data
482,603˜100No dataNo data
49>1>1>1No data
500,120,190,20No data
510,0070,0190,031No data
520,03 0,111,47No data
53>1>1>1No data
540,5514,06,1No data
550,0220,582,19No data
560,4920,04,17No data
570,0670,191,32No data
580,0140,420,65No data
591,540,927,83No data
601,370,897,46No data
660,0006to 0.032to 0.0600,0005
670,00370,0380,0520,0014
680,665,14No dataNo data
690,0230,690,14No data
700,0350,911,23No data
3,710,431,30No data
721,430,381,49No data
732,200,0290,176No data
740,460,0210,062No data
750,520,033to 0.060No data
760,0120,53˜10,0044
780,00660,420,780,0017
79>100>100>100>100
800,04520,93461,1200No data
810,01780,48221,69900,001
820,00900,02170,1183No data
830,00840,04040,0130No data
840,00380,04320,0516No data
850,41260,1943>1No Dan is s
860,10870,08690,4128No data
870,21710,01680,4357No data
880,31340,9647˜1No data
890,70960,5979˜10No data
90˜1˜0,1˜0,1No data
910,33490,07360,2233No data
920,34930,13360,0558No data
930,45250,7267˜1No data
940,27160,40890,1469No data
950,13870,25980,9138No data
960,37260,8171targeting 1,4080No data
97˜0,1˜0,1˜0,01No data
98>0,1˜0,1˜0,1No data
990,36560,0980,0945No data
1000,34041,10001,2870No data
1010,14260,64980,8195No data
1022,35301,10102,2600No data
1030,00740,04490,22840,001
1040,01560,01560,20330,001
1050,04610,27560,84480,002
1060,12500,559137,2300,001
1070,01380,03240,02970,002
1080,06570,03070,04170,0120
1090,14650,02520,17050,0210
1100,02190,01360,00550,0050
1110,14990,701916,830No data
1120,08700,703916,350There is data
1130,25450,03020,0680No data
1140,22750,3125the mark of 1.3870No data
1150,31340,46661,4420No data
1160,02080,02610,13130,0010
1170,03520,90805,43500,0070
1180,330,397>100,021
1190,06720,0571˜10,0030
1200,2770,0821,00,0090
1210,09970,02720,71690,0030
122of 2.21>10No dataNo data
1232,05of 5.53˜1000,031
1280,0032amount of 0.1180,1110,0033

Example 2

Test the selectivity for protein kinase

Test for inhibition of test compounds different kinases perform methods, which is smiriti the amount of phosphorylation of the biotinylated peptide substrate. When performing analyses used are described in the scientific literature biotinylated peptide substrates corresponding to each assessed enzyme. The activity of kinases analyzed as follows: get a reaction mixture containing 50 mm Tris-HCl pH 8, 10 mm MgCl2, 0.1 mm Na3VO4, 1 mm DTT, 10 μm ATP, 0.25 to 1 μm biotinylated peptide substrate and 0.2 to 0.8 µci per well33R-γ-Asia-Pacific [2000-3000 CI/mmol]. The test conditions are somewhat different for each protein kinase, for example, for measuring the kinase activity of the insulin receptor is necessary 10 mm MnCl2and for measuring the activity of calmodulinzawisimoy protein kinase required calmodulin and 10 mm CaCl2. Such test conditions known in the field. The reaction mixture is injected dropper-dispenser in the wells of streptavidin coated tablet FlashPlate and add 1 ál of a solution of the drug in 100% DMSO to achieve a final concentration of 1% DMSO in the reaction mixture with a final volume of 100 μl. The enzyme was diluted in 50 mm Tris-HCl with pH 8.0, containing 0.1% BSA and added to each well. The reaction mixture is incubated for one hour at 30°C. After one hour the reaction mixture is sucked off from the tablet and the tablet is washed SFR containing 100 mm etc. The tablet reads using Scintilla the ion counter to determine the number of 33R-γ-ATP contained in the immobilized peptide. Compound analyzed twice in 8 concentrations [100 μm, 10 μm, 1 μm, 100 nm, 10 nm, 1 nm, 100 PM, 10 PM]. When performing analysis to determine the maximum and minimum signals on each tablet. The value of the IC50calculated on the basis of the curve depending on the dose, in percent of maximum suppression signal according to the formula [maximum signal - background signal/signal test connection - background signal (100)=% inhibition], building plot of percentage inhibition against the logarithmic concentration of the test compounds. On each plate place is also known for inhibiting compounds for this kinase.

Determination of kinase enzymes and their sources

VEGF-R (receptor-2 growth factor vascular endothelium) is a protein containing polyhistidine tag at N-Terminus, followed by amino acids 786-1343 domain kinase VEGF-R2 rats (no access U93306 in the Bank of genes GenBank). CDK1 (cyclin-dependent kinase 1) was isolated from insect cells expressing the catalytic subunit of human CDK1 and its positive regulatory subunit cyclin B (New England Biolabs, Beverly, MA, catalog No. 6020). Complex with CDK1-cyclin a commercially available (Upstate Biotech, Lake Placid, NY). The CDK4 complex consists of CDK4 protein and mouse protein cycline D1 mouse (baie is OK CDK4 mice receive as a result of genetic fusion with the N-terminal label in the form of a Flag epitope, and protein cycline D1 mouse receive in the merger with N-terminal label in the form of epitope AU-1. Genes encoding these proteins are transferred into the vectors on the basis of baculovirus commercially available. Recombinant complex of CDK4/D1 get conficere commercially available cells are insect viruses bearing these two designs). Kinase of the insulin receptor consists of residues 941-1313 cytoplasmic domain of the beta-subunit of the insulin receptor human (BIOMOL, Plymouth Meeting, PA, catalog No. SE-195). Protein kinase a is the catalytic subunit of camp-dependent protein kinase, isolated from bovine heart (Upstate Biotech, Lake Placid, NY, catalog No. 14-114). RKS (protein kinase-C) represents the gamma or beta isoforms of the human protein produced in insect cells (BIOMOL, Plymouth Meeting, PA, catalog No. SE-143). Caseinline 1 represents a truncation at the amino acid 318 C-terminal part of the Delta isoform W1 rats, produced in E. coli (New England Biolabs, Beverly, MA, catalog No. 6030). Caseinline 2 includes alpha - and beta-subunit protein W2 person produced in E. coli (New England Biolabs, Beverly, MA, catalog No. 6010). Calmodulins (calmodulinzawisimoy protein kinase 2) is a subset of the alpha-subunit protein of the rat produced in insect cells (New England Biolabs, Beverly, MA, catalog No. 6060). Glikogensintetazy-kinase-3 present the focus of the beta-isoform of the enzyme in rabbit produced in E. coli (New England Biolabs, Beverly, MA, catalog No. 6040). MAR-kinase is the isoforms of ERK-2 rabbit containing polyhistidine tag at N-Terminus produced in E. coli and activated by phosphorylation MAC before cleaning (BIOMOL, Plymouth Meeting, PA, catalog No. SE-137). Protein ERK-1 (cleaved in the company Calbiochem), EGFR (the receptor for epidermal growth factor) was isolated from the membranes of cells A431 human (Sigma, St. Louis, MO, catalog No. E). PDGF-R (growth factor receptor isolated from platelets) is a protein containing polyhistidine tag at N-Terminus, followed by nucleotides 1874-3507 domain kinase beta subunit of PDGF-R person (no access M). HER2 receptor-2 epidermal growth factor (human) contains polyhistidine tag at N-Terminus, followed by 24 additional amino acids, and begins at amino acid 676, followed by the remainder of the cytoplasmic domain of HER2.

Peptide substrates

VEGF-R(Biotin)KHKKLAEGSAYEEV-amide
CDK1(Biotin)KTPKKAKKPKTPKKAKKL-amide
CDK2(Biotin)KTPKKAKKPKTPKKAKKL-amide
CDK4(GST)amino acids 769-921 retinoblastoma
EGF-R(Biotin)poly(GT) 4:1
Protein kinase a(Biotin)GRTGRRNSI-amide
RKS(Biotin)RFARKGSLRQKNV-NH2
Caseinline 1(Biotin)KRRRALS(phospho)VASLPGL-amide
Caseinline 2(Biotin)RREEETEEE-amide
Calmodulins(Biotin)KKALRRQETVDAL-amide
GSK-3(Biotin)KRREILSRRP(phospho)SYR-amide
MAR-kinase ERK-1(Biotin)APRTPGGRR-amide
MAR-kinase ERK-2(Biotin)APRTPGGRR-amide
Insolencies(Biotin)TRDIYETDYYRK-amide
FGF-R2(Biotin)poly(GT) 4:1
PDGF-R(Biotin)KHKKLAEGSAYEEV-amide
HER2(Biotin)KHKKLAEGSAYEEV-amide

The data IC50for different kinases are shown in tables 2A-2k. The values of the IC50listed as >10 or >100, indicate that at the highest tested dose in this analysis is not detected as 50% inhibition, and the maximum inhibition. The values given as ˜10, represent the approximate value obtained on the basis of the detected 50% inhibition.

Table 2A

Selectivity for protein kinase
Analysis of kinase (IC50microns)Connection 1Connection 2Connect the imposition of the 14 The connection 15The connection 16
CDK10,0060,0030,00450,00480,021
PKA>100>1005,434.26 deathsno data
Caseinline 111,16>1000,3480,5470,214
Caseinline 2>100>1008,05>100>100
RKSno data>100no datano datano data
ERK1no datano data>100no datano data
ERK219,359,482,145,950,39
Calmodulins 2>100>10060,4410,53>100
EGF-R>10045,81,928,44>100
VEGF-R0,1310,3660,0260,0510,0137
Kinase of the insulin receptor>100 9,81,22,42>100
GSK-30,0410,0310,0030,00180,004
Kinase PDGF-R11,7610,70,1890,0790,1
Kinase FGF-R2no data0,2690,027no datano data

Table 2b

Selectivity for protein kinase
Analysis of kinase (IC50microns)Connection 17The connection 23The connection 30The connection 32The connection 33
CDK10,00250,0890,0170,0030,003
PKAno data>100no data>100>100
Caseinline 10,6430,1131,540,1810.104 g
Caseinline 22,65>1007,60,527>10
ERK21,871,62to 5.930,563 >10
Calmodulins 22,810,588,3>100>10
EGF-R4,13>1009,6>100>100
VEGF-R0,0270,0350,04060,0220,023
Kinase of the insulin receptor2,02>1004,960,1230,316
GSK-30,0090,0160,0140,0030,004
Kinase PDGF-Rof 0.0810,6290,3920,0740,039
Kinase HER2no datano datano data0,0090,005

Table 2C

Selectivity for protein kinase
Analysis of kinase (IC50microns)The connection 34Compound 38Connection 39The connection 51The connection 55
CDK10,0020,0290,0120,0070,020
PKA>100 >100>1000,911>100
Caseinline 1of 0.1826,14,10,2239,6
Caseinline 2>100>100>1001,78>100
ERK2>1024,213,20,92812,9
Calmodulins 2>100>100>1000,813>100
EGF-R>100>100>1001,116,12
VEGF-R0,0680,8800,3340,0190,577
Kinase of the insulin receptor>10>10019,40,077>100
GSK-30,0150,122to 0.1270,0200,040
Kinase PDGF-R0,2926,373,980,19916,18
Kinase FGF-R2no datano datano datano data0,478
Kinase HER2no data no datano data0,0312,19

Table 2d

Selectivity for protein kinase
Analysis of kinase (IC50microns)Connection 57The connection 58The connection 61The connection 62Connection 63
CDK10,0670,0140,180,530,079
CDK2no datano data0,0490,290,056
PKA>100>100no datano datano data
Caseinline 114,011,24no datano datano data
Caseinline 2>100>100no datano datano data
ERK2>10010,7no datano datano data
Calmodulins 2>100>100no datano datadannynic
EGF-R>100>10no datano datano data
VEGF-R0,1910,4190,0720,0640,32
Kinase of the insulin receptor>100>100no datano datano data
GSK-30,0980,0150,0550,0730,073
Kinase PDGF-R4,198,53no datano datano data
Kinase FGF-R2no data0,096no datano datano data
Kinase HER21,320,6540,820,410,15

Table 2E

Selectivity for protein kinase
Analysis of kinase (IC50microns)The connection 64The connection 65Compound 66Connection 69The connection 70
CDK10,210,670,00060,023 0,035
CDK20,200,41no datano datano data
CDK4no datano datano data0,1870,167
PKAno datano data5,1946,634,2
Caseinline 1no datano data2,7516,635,7
Caseinline 2no datano data>100>100>100
ERK2no datano data1,012,519,4
Calmodulins 2no datano data8,99>100>100
EGF-Rno datano data>10>100>100
VEGF-R0,0510,18to 0.0320,6850,911
Kinase of the insulin receptorno datano data>1045,1>100
GSK-3 0,0210,100,1370,1470,22
Kinase PDGF-Rno datano data1,580,116,2
Kinase FGF-R2no datano datano data0,3650,273
Kinase HER20,0760,79to 0.0600,1391,23

Table 2f

Selectivity for protein kinase
Analysis of kinase (IC50microns)Connection 71Connection 81The connection 82Connection 83The connection 84
CDK13,710,0180,0090,0080,004
CDK40,129no datano datano datano data
PKA>100>100>100>1002,2
Caseinline 1>100of 6.960,3540,2750,188
Caseinline 2>100>10 >100>1001,67
ERK2>10011,681,95>1001,22
Calmodulins 260,9>100>100>100>100
EGF-R>10>100>100>100>10
VEGF-R0,430,4820,0220,0400,043
Kinase of the insulin receptor35,329,61,1>100,172
GSK-31,720,0490,0250,0070,019
Kinase PDGF-R277,760,0420,1130,280
Kinase FGF-R20,4410,2680,0890,0220,300
Kinase HER21,301,7amount of 0.1180,0130,052

Table 2g

Selectivity for protein kinase
Analysis of kinase (IC50microns)The connection 92Connected the e 99 Connection 103The connection 104
CDK10,3490,3660,0070,0016
PKA>100no data>100>100
Caseinline 1>10>10,3220,624
Caseinline 2>100>1005,3>100
RKSno data>100no datano data
ERK2>100>1000,845>100
Calmodulins 219,7>100>100>10
EGF-R>100>100>10>10
VEGF-R0,1340,0980,0450,016
Kinase of the insulin receptoris 3.08>1000,1232,09
GSK-30,0210,0300,0130,020
Kinase PDGF-R0,2820,3850,7020,192
Kinase FGF-R20,242 no data0,1700,200
Kinase HER20,0560,0950,2280,202

Table 2h

Selectivity for protein kinase
Analysis of kinase (IC50microns)Connection 105Connection 107The connection 108Connection 109The connection 110
CDK10,0460,014of 0.0660,1470,022
PKA>100>100>100>100>100
Caseinline 14,490,4120,8161,180,192
Caseinline 2>100>10>10>10>5
ERK218,19>102,39>108,75
Calmodulins 2>1003,43>10>100>100
EGF-R9,600,936>100>100>10
VEGF-R0,276 to 0.0320,0300,0250,014
Kinase of the insulin receptor9,850,3110,811was 2.760,053
GSK-30,0820,0150,0230,0390,008
Kinase PDGF-R2,200,1430,2170,4130,285
Kinase FGF-R20,1420,2350,3070,2440,153
Kinase HER20,8450,0300,0420,1700,006

Table 2i

Selectivity for protein kinase
Analysis of kinase (IC50microns)Connection 113The connection 114Connection 115The connection 116Connection 117
CDK10,2540,2280,3130,0210,035
PKA>100>100>100>100>100
Caseinline 10,3182,09,98>113,46
asianchinese 2 >100>100>100>100>100
RKS>100no datano datano datano data
ERK2>10015,8>10>100>100
Calmodulins 2>10>100>100>100>100
EGF-R>10>100>10>100>100
VEGF-R0,0300,3130,4670,0260,908
Kinase of the insulin receptor>10>100>10>100>100
GSK-30,0710,4310,3910,0621,04
Kinase PDGF-R0,37013,8>100,302>100
Kinase HER20,0681,39the 1.440,1315,44

Table 2j

Selectivity for protein kinase
Analysis of kinase (IC50microns)The connection 118Connection 119Connection 120Connection 121Connection 123
CDK10,3300,0670,2770,0992,05
PKA>100>100>100>100>100
Caseinline 1>1000,757>10>10>100
Caseinline 2>100>100>100>100>100
RKSno data>100no datano datano data
ERK2>100>100>100>100>100
Calmodulins 2>100>100>100>100>100
EGF-R>100strength of 0.159>10>10>100
VEGF-R0,3970,0570,0820,0275,52
Kinase of the insulin receptor>1000159 >100>100>100
GSK-3strength of 0.1590,0060,0180,0293,01
Kinase PDGF-R>100>100,8220,394>100
Kinase HER2>101,01,00,717>100

Table 2k

Selectivity for protein kinase
Analysis of kinase (IC50microns)The connection 124Connection 125Connection 126Connection 127Connection 128
CDK12,2>100>100>1000,003
CDK21,77,3>100>100no data
PKAno datano datano datano data>100
Caseinline 1no datano datano datano data8,97
Caseinline 2no datano data no datano data>100
ERK2no datano datano datano data2,07
Calmodulins 2no datano datano datano data13,2
EGF-Rno datano datano datano data>100
VEGF-R4,8>100>100>100amount of 0.118
Kinase of the insulin receptorno datano datano datano data2,65
GSK-33,0>100>100>1000,094
Kinase PDGF-Rno datano datano datano data1,91
Kinase HER20,82>100˜100>1000,11

Example 3

Measurement of inhibition of cell proliferation

The ability of test compounds to inhibit cell proliferation determined by measuring the content of the 14C-labeled thymidine into newly synthesized DNA of cells. When executing the method using the cell line isolated from carcinoma of several tissues, such as cervical adenocarcinoma HeLa (American type culture collection (ATSS), Virginia, catalog No. CCL-2), malignant melanoma A ATS CRL-1619), adenocarcinoma ovarian SK-OV-3 (ATCC HTB-77), carcinoma of the colon HCT-116 (CCL-247), adenocarcinoma of the prostate PC-3 (ATSC CRL-1435) and MDA-MB-231 (Xenogen Corp.). This way you can determine the effect of compounds on cell growth of many phenotypes. Cells treated with trypsin and counted, then in each well of 96-well microplate scintillation CytoStar processed under tissue culture (Amersham No. RPNQ0160)add 3000-8000 cells in complete medium in a volume of 100 μl. Cells incubated for 24 hours in complete medium at 37°C in an atmosphere containing 5% CO2. Then in wells add 1 μl of test compound in 100% DMSO. In the control wells add only DMSO. Cells incubated for 24 hours in complete medium at 37°C in an atmosphere containing 5% CO2. Methyl14With-thymidine in the amount of 56 MCI/mmol (NEN No. NEC568 or Amersham No. CFA532) diluted in complete medium in each well of the tablet CytoStar add 0.2 µci/well in a volume of 20 µl. Tablet incubated with drug environments is the your and 14With-thymidine for 24 hours at 37°With 5% CO2. The tablet then turn and its contents removed in the container for the14With radioactive waste, after which the tablet twice washed with 200 μl SFR. To each well add 200 ál SFR. The upper part of the tablet stick with a transparent device for sealing and tablets on the basis of the tablet impose white fixture for sealing the bottom of the tablet (Packard No. 6005199). Quantitative determination of methyl14With-thymidine produced by means of a counter Packard Top.

Table 3

Inhibition of cell proliferation (IC50nm)
Cell line
ConnectionHeLaHCT-116SK-OV-3MDA-MB-231PC-3A375
1284254750587119447
14550194072775615726460
1591127242550107247
162632132110 no data368942
172153093900no data2944970
2311803761420868859424
3021519305750no data9518240
327126no data13130no data
337227no data17137no data
34707996no data898626no data
35663172no data1140231no data
3845602270no data67602750no data
39271410no data2910625no data
51220no datano data no data57333
5733995no datano datano data113
581861,270no datano data362981
663520no datano datano data92
692181,720no datano data8441
701961,580no datano data111,100
711,920no datano datano data25no data
80880no data16,300no data272no data
81189778348no data251,770
82245no data921no data15no data
122192no datano data12556
84142no data461no data23no data
92269no datano datano data1,120no data
993,350no datano datano data1,690no data
1036275no datano datano data115
10418641no datano datano data108
105626320no datano datano data652
10717795no datano datano data113
10822176no datano datano data259
10947 51no datano data307no

data
110237187no datano datano data239
113242281281no datano datano data
1142,5301,380no datano datano data1,690
115676486no datano datano data529
116380349no datano datano data639
1172,0601,120no datano datano data2,190
1181,9401,170no datano datano data1,620
119146117no datano datano data199
120978 334no datano datano data259
121310608no datano datano data215
12328,5004,140no datano datano data>10,000
128128910no datano datano data968

Example 4

Models in vivo inhibition of tumor growth

The effect of compounds on the growth of human tumor cells in vivo can be defined implantarea tumor cells of human rights in the rear crotch Nude mice with subsequent introduction of the mice of the test compounds. Tumor cells isolated from tumors of different types, such as cells of human melanoma A, implanted subcutaneously in the back groin male Nude mice (Charles River) and watching the growth of tumors in mice within 6-10 days, measuring the tumor with a caliper. Then enter the test compound together with an acceptable carrier in the form of intraperitoneal injection once a day for 30 days. The test compound can be entered in other ways, such as orally, subcutaneously, or in the form of nutrion the CSOs infusion. In this study the size of the tumor was measured every four days and determine the degree of inhibition by comparing the condition of the animals, which is administered medicinal product to animals, which impose only the media.

Using this model we can also determine the synergistic or enhanced activity of conventional chemotherapeutic drug test compound, comparing animals subjected to the usual treatment of animals, which along with the usual treatment is administered the test compound. In the case of synergistic effects caused by the test compound, the tumor growth is set to slow to a greater extent.

Although in the above description of the invention set out the basic principles of the present invention, illustrated by examples, it is obvious that the practice of the invention includes all possible alternatives, adaptations and modifications are included in the scope the following claims and its equivalents.

1. Derivatives substituted triazolinone having the following formula (I):

where R1means C1-4alkyl, phenyl which is not substituted or substituted with halogen, substituted-SO2-(C1-4)alkyl amino group, imidazolyl, 1,2,4-triazolium, imidazolidinone, deoxidization what ladinian, C1-4alkylpiperazine, balance-SO2-replaced, in turn, an amino group, a C1-4alkylaminocarbonyl, C1-4dialkylamino, pyridinylamino, piperidinium, hydroxyl or C1-4dialkylamino-C1-3alkylaminocarbonyl, a R2means hydrogen, or

R1means hydrogen, a R2means phenyl which is not substituted or substituted by halogen or the group-SO2-NH2;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3means phenyl, optionally substituted by 1-3 substituents, independently selected from the group comprising halogen and nitro, or 1-2 substituents independently selected from the group including C1-4alkoxy, hydroxy-C1-4alkyl, amino or C1-4alkyl not substituted or is substituted by 1-3 halogen atoms at the terminal carbon atom;

C3-7cycloalkyl, not substituted or is substituted by 1-2 groups C1-4alkyl;

thienyl, not substituted or substituted with halogen, C1-4the alkyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C2-4alkenyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C1-4alkoxy, pirrallo, pyridinyl or amino, which is itself substituted-C(O)(C1-4)alkyl;

C1-4alkyl, substituted Tien is scrap or phenyl, which, in turn, substituted with halogen;

C2-8quinil, substituted phenyl;

amino, substituted by phenyl, which in turn may be substituted with halogen;

furyl, isoxazolyl, pyridinyl, dihydrobenzofuranyl, thiazolyl or thiadiazolyl, and thiazolyl and thiadiazolyl can be substituted C1-4by alkyl;

or their pharmaceutically acceptable salts.

2. The compound according to claim 1, in which R2represents hydrogen.

3. The compound according to claim 1, in which R3choose from a group including:

phenyl, optionally substituted by 1-3 substituents, independently selected from the group comprising halogen and nitro, or 1-2 substituents independently selected from the group including C1-4alkoxy, hydroxy-C1-4alkyl, amino or C1-4alkyl not substituted or is substituted by 1-3 halogen atoms at the terminal carbon atom;

C3-7cycloalkyl, not substituted or is substituted by 1-2 groups C1-4alkyl;

thienyl, not substituted or substituted with halogen, C1-4the alkyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C2-4alkenyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C1-4alkoxy, pirrallo, pyridinyl or amino, which is itself substituted-C(O)(C1-4)alkyl;

C1-4Ala is l, replaced by tanila or by phenyl which, in turn, substituted with halogen;

C2-4quinil, substituted phenyl;

amino, substituted by phenyl, which in turn may be substituted with halogen;

furyl, isoxazolyl, pyridinyl, dihydrobenzofuranyl, thiazolyl or thiadiazolyl, and thiazolyl and thiadiazolyl can be substituted C1-4the alkyl.

4. The compound according to claim 1, having the following formula (Ia):

where

R4selected from the group comprising substituted-SO2-(C1-4)the alkyl amino group, imidazolyl, 1,2,4-triazolyl, imidazolidine, dioxothiazolidine, C1-4alkylpiperazine, the rest-SO2-replaced, in turn, an amino group, a C1-4alkylaminocarbonyl, C1-4dialkylamino, pyridinylamino, piperidinium or C1-4dialkylamino-C1-4alkylaminocarbonyl;

R2means hydrogen;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3means phenyl, optionally substituted by 1-3 substituents, independently selected from the group comprising halogen and nitro, or 1-2 substituents independently selected from the group including C1-4alkoxy, hydroxy-C1-4alkyl, amino or C1-4alkyl not substituted or is substituted by 1-3 atoms of the halogen at the terminal carbon atom;

C3-7cycloalkyl, not substituted or is substituted by 1-2 groups C1-4alkyl;

thienyl, not substituted or substituted with halogen, C1-4the alkyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C2-4alkenyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C1-4alkoxy, pirrallo, pyridinyl or amino, which is itself substituted-C(O)(C1-4)alkyl;

C1-4alkyl, substituted tanila or by phenyl which, in turn, substituted with halogen;

C2-8quinil, substituted phenyl;

amino, substituted by phenyl, which in turn may be substituted with halogen;

furyl, isoxazolyl, pyridinyl, dihydrobenzofuranyl, thiazolyl or thiadiazolyl, and thiazolyl and thiadiazolyl can be substituted C1-4by alkyl;

or its pharmaceutically acceptable salt.

5. The compound according to claim 1, having the following formula (Ib):

where

R4selected from the group comprising substituted-SO2-(C1-4)the alkyl amino group, imidazolyl, 1,2,4-triazolyl, imidazolidine, dioxothiazolidine, C1-4alkylpiperazine, the rest-SO2-replaced, in turn, an amino group, a C1-4alkylaminocarbonyl, C1-4dialkylamino, pyridinyl what monography, piperidinium or C1-4dialkylamino-C1-3alkylamino group;

R2means hydrogen;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3means phenyl, optionally substituted by 1-3 substituents, independently selected from the group comprising halogen and nitro, or 1-2 substituents independently selected from the group including C1-4alkoxy, hydroxy-C1-4alkyl, amino or C1-4alkyl not substituted or is substituted by 1-3 halogen atoms at the terminal carbon atom;

C3-7cycloalkyl, not substituted or is substituted by 1-2 groups C1-4-alkyl;

thienyl, unsubstituted or substituted with halogen, C1-4the alkyl (which, in turn, can be substituted by-CO2(C1-4by alkyl), C2-4alkenyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C1-4-alkoxy, pirrallo, pyridinyl or amino, which is itself substituted-C(O)(C1-4)alkyl;

C1-4alkyl, substituted tanila or by phenyl which, in turn, substituted with halogen;

C2-8quinil, substituted phenyl;

amino, substituted by phenyl, which in turn may be substituted with halogen;

furyl, isoxazolyl, pyridinyl, dihydrobenzofuranyl, thiazolyl or thiadiazolyl, and thiazolyl and thiadiazolyl be substituted C 1-4by alkyl;

or its pharmaceutically acceptable salt.

6. The compound according to claim 1, having the following formula:

where

R4selected from the group comprising substituted-SO2-(C1-4)the alkyl amino group, 1,2,4-triazolyl, imidazolidine, the rest-SO2-replaced, in turn, an amino group, a C1-4alkylaminocarbonyl, C1-4dialkylamino or C1-4dialkylamino-C1-3alkylaminocarbonyl; and

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3means phenyl, optionally substituted by 1-3 substituents, independently selected from the group comprising halogen and nitro, or 1-2 substituents independently selected from the group including C1-4alkoxy, hydroxy-C1-4-alkyl, amino or C1-4alkyl not substituted or is substituted by 1-3 halogen atoms at the terminal carbon atom;

With3-7cycloalkyl, not substituted or is substituted by 1-2 groups C1-4alkyl;

thienyl, not substituted or substituted with halogen; C1-4the alkyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C2-4alkenyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C1-4alkoxy, or amino, which is itself substituted-C(O)(C1-4)alkyl;

C1-4alkyl, substituted tanila or by phenyl which, in turn, substituted with halogen;

With3-8quinil, substituted phenyl;

or its pharmaceutically acceptable salt.

7. The compound according to claim 1, having the following formula:

where

R4selected from the group including

replaced-SO2-(C1-4)the alkyl amino group

-SO2-replaced, in turn, an amino group, a C1-4alkylaminocarbonyl, C1-4dialkylamino or C1-4dialkylamino-C1-3alkylaminocarbonyl;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3selected from the group including

phenyl, optionally substituted by 1-3 substituents, independently selected from the group comprising halogen and nitro, or 1-2 substituents independently selected from the group including C1-4alkoxy, hydroxy-C1-4-alkyl, amino or C1-4alkyl not substituted or is substituted by 1-3 halogen atoms at the terminal carbon atom;

C3-7cycloalkyl, not substituted or is substituted by 1-2 groups C1-4-alkyl;

thienyl, not substituted or substituted with halogen; C1-4the alkyl (which, in turn, can be substituted by-CO2(C1-4)alkyl), C2-4alkenyl (which, in St. the first phase, may be substituted by-CO2(C1-4)alkyl); C1-4alkoxy; or amino which is itself substituted-C(O)(C1-4)alkyl;

C1-4alkyl, substituted tanila or by phenyl which, in turn, substituted with halogen;

With2-8quinil, substituted phenyl;

or its pharmaceutically acceptable salt.

8. The compound according to claim 1, having the following formula:

where

R4means the rest-SO2-, substituted amino group, a C1-4alkylaminocarbonyl, C1-4dialkylamino, or C1-4-dialkylamino-C1-3-alkylaminocarbonyl;

X is chosen from the group comprising-C(O)-, -C(S)- and-SO2-; and

R3means phenyl, optionally substituted by 1-3 substituents, independently selected from the group comprising halogen and nitro, or 1-2 substituents independently selected from the group including C1-4alkoxy, -CH(OH) (C1-3)alkyl and C1-4alkyl not substituted or is substituted by 1-3 halogen atoms at the terminal carbon atom;

With3-7cycloalkyl, not substituted or is substituted by 1-2 groups C1-4-alkyl;

thienyl, not substituted or substituted with halogen, C1-4alkoxy or C1-4by alkyl;

or their pharmaceutically acceptable salts.

9. The connection according to claim 6, in which X, R3and R interdependent selected from a group including:

XR3R4
With(O)(2,6-F2)Ph4-SO2-NH2
With(O)(2,6-F2-3-CH3)Ph4-SO2-NH2
With(O)(2,4,6-F3)Ph4-SO2-NH2
With(O)(2-F)Ph4-SO2-NH2
With(O)(2,4-F2)Ph4-SO2-NH2
With(O)(2-F-6-CF3)Ph4-SO2-NH2
With(O)(2,6-Cl2)Ph4-SO2-NH2
With(O)(2,4,6-Cl3)Ph4-SO2-NH2
With(O)(2-NO2)Ph4-SO2-NH2
With(O)[2,6-(och3)2]Ph4-SO2-NH2
With(O)[2,4,6-(CH3)3]Ph4-SO2-NH2
With(O)Ph4-SO2-NH2
With(O)2-thienyl4-SO2-NH2
With(O)(3-CH3)2-thienyl 4-SO2-NH2
With(O)(3-F)2-thienyl4-SO2-NH2
With(O)(3-Cl)2-thienyl4-SO2-NH2
With(O)(3-och2CH3)2-thienyl4-SO2-NH2
With(O)(3-NHCOCH3)2-thienyl4-SO2-NH2
With(O)(5-CH3)2-thienyl4-SO2-NH2
With(O)(5-Br)2-thienyl4-SO2-NH2
With(O)3-thienyl4-SO2-NH2
With(O)3A,7a-dihydrobenzo[b]Tien-2-yl4-SO2-NH2
With(O)(5-CH2CH3)2-thienyl4-SO2-NH2
With(O)[3,5-(CH3)2]2-thienyl4-SO2-NH2
With(O)(3-Br)2-thienyl4-SO2-NH2
With(O)1,2,3-thiadiazole-4-yl4-SO2-NH2
With(O)cyclopentyl4-SO2-NH2
With(O)cyclohexyl4-SO2-NH2
With(O)2-thienyl-CH2 4-SO2-NH2
With(O)2-thienyl-(CN)34-SO2-NH2
With(O)(2,6-F2)-Ph-CH24-SO2-NH2
With(O)(2,6-F2)Ph(CH)24-SO2-NH2
With(O)cycloheptyl4-SO2-NH2
With(O)4-CH3-cyclohexyl4-SO2-NH2
With(O)4-CH3-cyclohexyl4-SO2-NH2
With(O)4-(CH2)3CH3-cyclohexyl4-SO2-NH2
With(O)5-(2-pyridinyl)2-thienyl4-SO2-NH2
With(O)3-(1H-pyrrol-1-yl)2-thienyl4-SO2-NH2
With(O)5-[C(CH3)3]2-thienyl4-SO2-NH2
With(O)5-[(SN)2C(O)OC(CH3)3]-2-thienyl4-SO2-NH2
With(O)Ph(C)24-SO2-NH2
With(O)(2,6-F2-3-NO2)Ph4-SO2-NH2
With(O)(2,6-F2-3NH 2)Ph4-SO2-NH2
With(O)[2,6-(CH3)2]Ph4-SO2-NH2
With(O)(2-CH3)Ph4-SO2-NH2
With(O)(2,6-F2)Ph4-SO2-NH2
With(O)-NH[(2,6-F2)Ph]4-SO2-NH2
With(O)-NH[(2,6-F2)Ph]4-SO2-NH2
SO2(2,6-F2)Ph4-SO2-NH2
With(O)(2-Cl-6-F)Ph4-SO2-NH2
With(O)(2,6-F2-5-Cl)Ph4-SO2-NH2

10. The connection according to claim 6, in which X, R3and R4interdependent selected from a group including:

XR3R4
With(O)(2,6-F2)Ph4-SO2-NH2
C(S)-NH[(2,6-F2)Ph]4-SO2-NH2

11. The connection according to claim 6, representing the connection of the formula (I)selected from the group including:

5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-differenl)-1H-1,2,4-triazole-1-carbothioamide

5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-differenl)-1H-1,2,4-triazole-1-carboxamide;

4-[[5-amino-1-(2-chloro-6-perbenzoic)-1H-1,2,4-triazole-3-yl]amino]benzosulfimide;

4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-methylbenzenesulfonamide;

4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]-N-[2-(dimethylamino)ethyl]benzosulfimide;

1-[4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3-yl]amino]phenyl]-2-imidazolidinone.

12. The connection according to claim 6, in which X, R3and R4interdependent selected from a group including:

XR3R4
With(O)(2,6-F2)Ph4-SO2-NH(CH2CH3)
With(O)(2,6-F2)Ph4-SO2-NH(CH3)
With(O)(3-CH3)2-thienyl4-SO2-NH(CH3)
With(O)[3,5-(CH3)2]2-thienyl4-SO2-NH(CH3)
With(O)(5-CH2CH3)2-thienyl4-SO2-NH(CH3)
With(O)[3,5-(CH3)2]2-thienyl4-SO2-N(CH3)2
With(O) (5-CH2CH3)2-thienyl4-SO2-N(CH3)2
With(O)(3-CH3)2-thienyl4-SO2-N(CH3)2
With(O)(2,6-F2)Ph4-SO2-N(CH3)2

13. The connection according to claim 6, in which X, R3and R4interdependent selected from a group including:

XR3R4
With(O)(2,6-F2)Ph4-(1-H-1,2,4-triazole-1-yl)
With(O)(5-CH2CH3)2-thienyl4-(1-H-1,2,4-triazole-1-yl)
With(O)[3,5-(CH3)2]2-thienyl4-(1-H-1,2,4-triazole-1-yl)
With(O)(3-CH3)2-thienyl4-(1-H-1,2,4-triazole-1-yl)
With(O)(2,6-F2)Ph4-(1-N-1,3,4-triazole-1-yl)
With(O)(3-CH3)2-thienyl4-(1-N-1,3,4-triazole-1-yl)

14. The connection according to claim 6, in which X, R3and R4interdependent selected from a group including:

XR3R4
With(O)(5-CH2 CH3)2-thienyl4-SO2NH[(CH2)2N(CH3)2]
With(O)(3-CH3)2-thienyl4-SO2NH[(CH2)2N(CH3)2]
With(O)(2,6-F2)Ph4-SO2NH[(CH2)2N(CH3)2]
With(O)[3,5-(CH3)2]2-thienyl4-SO2NH[(CH2)2N(CH3)2]
With(O)[3,5-(CH3)2]2-thienyl4-NH-SO2-CH3
With(O)(3-CH3)2-thienyl4-NH-SO2-CH3
With(O)(5-CH2CH3)2-thienyl4-NH-SO2-CH3
With(O)(2,6-F2)Ph4-NH-SO2-CH3

15. Pharmaceutical composition having a selective inhibitory activity against cyclin-dependent kinase containing a compound according to claim 1 and a pharmaceutically acceptable carrier.

16. A method of obtaining a pharmaceutical composition, which consists in the fact that the compound according to claim 1 is mixed with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

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