Amide derivative, pharmaceutical composition and therapeutic agents based on thereof

FIELD: organic chemistry, medicine, oncology, pharmacy, biochemistry.

SUBSTANCE: invention relates to amide derivative represented by the following formula [1]:

in any of the following cases (A) or (B), or its salt. In the case (A) R1 represents 5-7-membered saturated cyclic group comprising 1-2 nitrogen atoms as atom forming cycle (saturated cyclic amino-group can be substituted with 1-3 similar or different substitutes chosen from group consisting of (C1-C10)-alkyl, (C1-C10)-alkoxycarbonyl), mono-(C1-C10)-alkylamino- or di-(C1-C10)-alkylamino-group; R2 represents (C1-C10)-alkyl, halogen atom, halogen-(C1-C10)-alkyl, (C1-C10)-alkoxy-group, (C1-C10)-alkoxycarbonyl, nitro-group, mono-(C1-C10)-alkylcarbamoyl, di-(C1-C10)-alkylcarbamoyl or cyano-group; R3 represents hydrogen atom, halogen atom or (C1-C10)-alkoxy-group; Het1 represents any of the following formulae: [2] , [3] , [4] , [5] , [6] , [7] and [8] ; Het2 represents pyridyl, pyrimidinyl, pyrazinyl or 1,2-dihydropyridazinyl (wherein Het2 can be substituted with 1-3 similar or different substitutes chosen from halogen atom) but except for compound wherein R1 means (i) pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl and each of them can be substituted with 1-3 similar or different substitutes chosen from group consisting of alkyl, alkoxycarbonyl, halogen atom, halogenalkyl, hydroxyalkyl, amino-, monoalkylamino-, dialkylamino-group, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; (ii) monoalkylamino-group, or (iii) dialkylamino-group; Het1 means group of the formula [6], and Het2 means pyrazinyl or pyridyl and each of them can mean a substituted alkyl. In case the (B) R1 represents 4-methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino-group, 4-ethylpiperazin-1-yl, 4-n-propylpiperazin-1-yl, cis-3,5-dimethylpiperazin-1-yl, morpholino-, dimethylamino- or diethylamino-group; R2 represents methyl, halogen atom, trifluoromethyl, methoxy-group, methoxycarbonyl, nitro-group, dimethylcarbamoyl or cyano-group; R3 represents hydrogen atom, bromine atom or methoxy-group; Het1 represents compound of the formula [6]; Het2 represents 3-pyridyl. Invention relates to a pharmaceutical composition possessing inhibitory activity with respect to BCR-ABL tyrosine kinase comprising amide derivative of the formula (I) or its salt as active component and a pharmaceutically acceptable nontoxic and inert carrier. Also, invention relates to BCR-ABL tyrosine kinase inhibitor, therapeutic agents comprising amide derivative of the formula (I) or its salt and, optionally, a pharmaceutically acceptable nontoxic and inert carrier used in treatment of chronic myelogenous leukemia, acute lymphoblast cell leukemia, acute myelogenous leukemia. Invention provides and proposes amide derivative inhibiting activity of BCR-ABL tyrosine kinase.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 83 ex

 

This invention relates to amide derivative or its salts and pharmaceutical compositions containing the amide derivative or its salt as an active ingredient.

Because BCR-ABL-tyrosinekinase (see, for example, non-patent document 1) causes aberrant cell growth, a compound that inhibits its activity, suitable for the prevention or treatment of diseases caused by activity of the BCR-ABL tyrosine kinase, for example, chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myelogenous leukemia (see, for example, non-patent document 2).

BCR is a gene that resides in the human twenty-second chromosome, and ABL is a gene that is ninth in human chromosome, and the Philadelphia chromosome is formed by the translocation of the human twenty-second and ninth chromosome. It is known that the gene product chromosome, BCR-ABL, is a protein with tyrosinekinase activity, and continuously generates a signal rise, which causes aberrant cell growth (see, for example, non-patent document 2).

Therefore, the suppression of activity of the BCR-ABL tyrosine kinase makes it possible suppression of cell growth caused by a kinase and a compound that inhibits the activity suitable for use as a therapeutic agent of diseases such as chronic the Skye myelogenous leukemia, acute lymphoblastic leukemia and acute myelogenous leukemia. Known Gleevec® (Glyvek®) (see, for example, patent document 1) as a drug with a similar action, but other drugs with the same mechanism of action, never came to the market, and thus, it was necessary to develop better medicines.

It is known that patients who have achieved remission in the use of Glivec® BCR-ABL-positive acute lymphocytic leukemia relapse, often in addition to the examples blast crisis chronic myelogenous leukemia (see, for example, non-patent document 3). A study of the leukemic cells of patients suffering from recurrence of the disease, determined the appearance of such an option, as EC (see, for example, non-patent documents 4 to 7). Also in the application of Glivec® in patients with BCR-ABL-positive acute lymphoblastic leukemia registered the emergence of resistant cells, which mainly represent variant EC (see, for example, non-patent document 8). With the increasing use of Glivec® number of resistant patients additionally increases, and, thus, it is necessary to develop a therapy.

Patent document 1:

Japanese Unexamined Patent No. 6-87834

p> Patent document 2:

Pamphlet of International Publication WO 02/22597

Non-patent document 1:

Shtivelman, E., et al.: Nature 1985, 315, 550-554

Non-patent document 2:

Daley, G. Q., et al.: Science, 1990, 247, 824-830

Non-patent document 3:

Druker, B. J., et al.: N. Engi. J. Med., 2001, 344, 1038-1042

Non-patent document 4:

Weisberg, E., et al.: Drug Resist Updat, 2001, 4, 22-28

Non-patent document 5:

Gorre, M. E., et al.: Science, 2001, 293, 876-880

Non-patent document 6:

Blagosklonny, M. V.: Leukemia, 2002, 16, 570-572

Non-patent document 7:

Hochhaus, A., et al.: Leukemia, 2002, 16, 2190-2196

Non-patent document 8:

Hofmann W.-K., et al.: blood, 2002, 99, 1860-1862

Non-patent document 9:

Deninger, W. N., et al.: blood, 2000, 96, 3343-3356

Non-patent document 10:

J.Org.Chem., 1996, 61, 1133-1135

Non-patent document 11:

J.Org.Chem., 2000, 65, 1144-1157

Non-patent document 12:

Recl.Trav.Chim.Pays-Bas., 1950, 69, 673-699

Non-patent document 13:

J.Med.Chem., 2000, 43, 1508-1518

Non-patent document 14:

J.Med.Chem., 1975, 18, 1077-1088

Non-patent document 15:

Bioorg.Med.Chem.Lett., 2001, 11, 2235-2239

Non-patent document 16:

J.Heterocyclic Chem., 2000, 37, 1457-1462

Non-patent document 17:

J.Med.Chem., 2000, 43(8), 1508-1518

Non-patent document 18:

Khim.Geterotsikl.Soedim., 1981, (7), 958-962

Non-patent document 19:

J.Heterocyclic Chem., 1990, 27, 579-582

Non-patent document 20:

Arzneim.-Forsch./Drug Res., 1989, 39(2), 1196-1201

Non-patent document 21:

J.Org.Chem., 1996, 61, 7240-7241

Description of the INVENTION

The objective of the invention t is aetsa creating amide derivative, possessing excellent suppressive BCR-ABL to tyrosinekinase activity, or its salt.

Were conducted intensive research on different connections, and it was found that this object is achieved by using amide derivative in accordance with this invention, and, thus, was completed this invention.

This invention relates to amide derivative of the General formula [1] in any of the following cases [A] and [V] or its salt (hereafter called "compound of this invention").

(A)

R1represents a saturated cyclic amino group (saturated cyclic amino group may be substituted by 1-3 identical or different substituents selected from the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino), monoalkylamines or dialkylamino,

R2represents alkyl, halogen, halogenated, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylamines, dialkylamino, nitro, carbarnoyl, monoalkylammonium, dialkylammonium or cyano,

R3represents hydrogen, halogen or alkoxy,

t1 represents any of groups of the following formulas [2] to [8]:

t2 represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridine (t2 may be substituted by 1-3 identical or different substituents selected from the group consisting of alkyl, halogen and amino).

In addition to the compounds in which R1is (i) pyrrolidinium, piperidinium, piperazinil or morpholinyl, each of which may be substituted by 1-3 identical or different substituents selected from the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino, (ii) monoalkylamines or (iii) dialkylamino, t1 is a group of the formula [6], and t2 is pyrazinium or pyridium, which can be substituted by alkyl;

(In)

R1represents the 4 methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1-yl, CIS-3,5-dimethylpiperazine-1-yl, morpholino, dimethylamino or diethylamino;

R2represents methyl, halogen, trifluoromethyl, methoxy, methoxycarbonyl, nitro, dimethylcarbamoyl or cyano;

R3represents a hydrogen, bromine or methoxy;

t1 represents a group of the formula [6];

t2 is 3-pyridyl.

This invention relates also to pharmaceutical compositions containing the above amide derivative or its salt as an active ingredient, and more specifically, the inhibitor of the BCR-ABL tyrosine kinase containing the above-mentioned amide derivative or its salt as an active ingredient. Specific therapeutic tool for the treatment of diseases includes a therapeutic tool for the treatment of chronic myelogenous leukemia, a therapeutic agent for the treatment of acute lymphoblastic leukemia and therapeutic tool for the treatment of acute myelogenous leukemia.

Examples of preferred amide derivatives and their salts include amide derivatives or their salts.

Amide derivative of the General formula [1], where R1is a saturated cyclic amino group (saturated cyclic amino group may be substituted by 1-3 identical or different substituents selected from the group consisting of alkyl and alkoxycarbonyl), monoalkylamines or dialkylamino,

R2represents alkyl, halogen, halogenated, alkoxy, alkoxycarbonyl, nitro, dialkylamino or cyano,

R3represents hydrogen, halogen or alkoxy,

t1 is any of the groups of the formulae [2]to[8], and

t2 represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridine (t2 may be substituted by 1-3 identical or different halogen atoms), or their salts.

Examples of particularly preferred among the above AMI is different derivatives include amide derivative (1)to(40) or their salts:

(1) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(2) 3-iodine-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(3) 3-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(4) 3-fluoro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(5) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(6) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(7) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(2-pyrazinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(8) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(9) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(10) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(11) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(1,2-dihydropyridin-4-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(12) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(13) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimid the Nile)pyrimidine-2-ylamino]phenyl}benzamide,

(14) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyridine-2-ylamino]phenyl}benzamide,

(15) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide,

(16) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyridine-6-ylamino]phenyl}benzamide,

(17) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)pyridine-5-ylamino]phenyl}benzamide,

(18) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)phenylamino]phenyl}benzamide,

(19) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]phenyl}benzamide,

(20) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[5-(3-pyridyl)-1,2,4-triazine-3-ylamino]phenyl}benzamide,

(21) 3-methyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(22) 4-(4-methylpiperazin-1-ylmethyl)-3-nitro-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(23) 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(24) 3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(25) 3,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(26) 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(27) 3-bromo-4-(4-what teleperson-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(28) 3-bromo-4-[4-(n-propyl)piperazine-1-ylmethyl]-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(29) 3-bromo-4-(N,N-dimethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(30) 3-bromo-4-(N,N-diethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(31) 3-bromo-4-(1-pyrrolidinyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(32) 3-bromo-4-(piperidinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(33) 3-bromo-4-(morpholinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(34) 3-bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(35) 3-bromo-4-(4-methylhexane-1H-1,4-diazepin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(36) 3-bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(37) 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(38) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(39) 3-methoxycarbonyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide and

(40) 3-cyano-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benthami is.

The compound of this invention has a suppressive BCR-ABL to tyrosinekinase activity and are suitable as a therapeutic agent for diseases such as chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myelogenous leukemia (see, for example, non-patent document 9).

The compound of the above formula [1] in the case (B) described in the prior art (see, for example, patent document 1 or 2), but not specifically disclosed in the publication. The compound of the above formula [1] in the case (a) is also not described.

The invention will be further described in detail.

Examples of the saturated cyclic amino group" include a 4-to 8-membered saturated cyclic group, which is saturated cyclic group having at least one nitrogen atom as an atom constituting the cycle, and can have from 1 to 3 identical or different members selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. When an atom constituting the ring of the cyclic amine is a nitrogen atom or a sulfur atom, nitrogen atom or sulfur atom may form the oxide. Examples are pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, hexahydro-1H-1,4-diazepine. These substituents may have a connection in your any location. Specifically, this means that "p is rollitini" includes all of the 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.

"Alkyl" includes linear or branched alkyl group having from 1 to 10 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, n-nonyl and n-decyl. Linear alkyl group having from 1 to 3 carbon atoms, are especially preferred.

The alkyl part of the "halogenoalkane", alkoxycarbonyl", "hydroxyalkyl", "monoalkylamines", "dialkylamino", "monoalkylphenol", "dialkylamino", "alkoxy", alkoxyalkyl" and "hydroxyalkyl" includes the above-mentioned alkyl.

"Halogen" includes, for example, fluorine, chlorine, bromine and iodine.

"Halogenated" includes monohalogenated, dehalogenases and trihalomethyl, and a halogen component "halogenoalkane" includes the above halogen. "Halogenated" includes, for example, trifluoromethyl and 2,2,2-triptorelin.

"Acyl" includes acyl groups having from 1 to 11 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, 1-naphtol and 2-naphtol.

"Pyridyl" includes, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl.

"Pyrimidinyl" includes, for example, 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl.

"Pyrazinyl" includes, for example, 2-pyrazinyl.

"Pyridazinyl" R is t, for example, 3-pyridazinyl and 4-pyridazinyl.

"1,2-dihydropyridines" includes, for example, 1,2-dihydropyridin-3-yl and 1,2-dihydropyridin-4-yl.

The compound of this invention can be obtained from known compounds or intermediate compounds, which can be easily obtained, for example, in the following way. When the connection according to this invention is generally, if the starting material contains reactive substituents, which should not participate in this reaction, it is used already protected by suitable protective groups are essentially known methods, when the original substance have substituents that are not intended for the reaction. After the reaction, the protective group can be removed by known methods.

Process 1

where R1, R2, R3, t1 and t2 defined above.

This reaction is a condensation reaction of compound [9] and the compound [10] and therefore is essentially known methods used for the condensation reaction. The compound [1] can be obtained by reacting carboxylic acids as compounds [10] or its reactive derivative with the amine as compounds [9]. Examples of the reactive derivative of the compound [10] include those compounds which is usually used in the condensation reaction with the formation of amide, for example gelegenheid acid (e.g. carboxylic acid, bromohydrin acid etc), mixed acid anhydride, imidazole and active amide. When using carboxylic acid [10] use a condensing agent (for example, 1,1'-oxalylamino, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethylthiophosphate, diphenylphosphoryl, 2-chloro-1-methylpyridine iodide, etc. and the reaction is carried out at a temperature of from -20 to 100°in the presence or in the absence of a base (e.g. organic bases such as triethylamine, N,N-aminobutiramida-N-ethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and so on). The solvent is not specifically limited because it does not participate in the reaction, and examples include ethers such as tetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane; and mixtures of these solvents. In this case, can also be added additives such as 1-hydroxybenzotriazole, N-hydroxysuccinimide etc). The reaction time varies depending on the types of starting compounds and condensing agent and the reaction temperature, but the pre is respectfully ranges from 30 minutes to 24 hours. The number of compounds [10] and the condensing agent is preferably from 1 to 3 mol per mol of compound [9]. When using gelegenheid acid as the reactive derivative of the compound [10] the reaction is carried out at a temperature of from -20 to 100°using pyridine solvent, such as pyridine or 4-methylpyridine, or the base and the solvent described above. And also as an additive can be used 4-dimethylaminopyridine. The reaction time varies depending on the type of gelegenheid acid and the reaction temperature, but is preferably from 30 minutes to 24 hours.

Connection [9] as an initial matter, where t1 is a group of the formula [6]can be obtained by the method described in patent document 1.

Connection [9] as a starting compound, where t1 is a group of the formula [4], [5] or [7], can be obtained in the following way:

where t1 and t2 have the meanings given above, R4and R5represent alkyl or hydroxy, R6, R7and R8represent alkyl, and X1represents halogen.

Stage 1

This reaction is the reaction cross-connections using connection [11] and organoboron compounds [12] or ORGANOTIN is connected to the I [13] and can be carried out essentially known methods. For example, this reaction is carried out at 20-200°in a suitable solvent in the presence of palladium catalyst. As the palladium catalyst is usually used tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium and dichlorobis(tri-o-tolylphosphino)palladium. The solvent used in the reaction is not specifically limited because it does not participate in the reaction, and examples of it include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene and xylene; organic amines such as pyridine and triethylamine; and mixtures of these solvents. When using connection [12] significant is the addition of a base (e.g. sodium hydroxide, potassium carbonate, translesanas potassium phosphate etc). The reaction time varies depending on the type of the source materials and the reaction temperature, but is preferably from 1 to 48 hours.

Stage 2

This reaction is a reaction for reduction of aromatic nitro compounds [14] to the amino group and therefore is essentially known methods used in the reaction of recovery. This method includes, for example, a method of processing zinc or tin under acidic conditions. In the accordance with the method of catalytic reduction, for example, the hydrogenation can be performed using platinum, Raney-Nickel, platinum-on-coal (Pt), palladium-on-coal (Pd-C) or ruthenium complex as a catalyst. In addition, examples include a method using a sulfide, such as dithionite sodium, and method of recovery by ammonium formate or hydrazine in the presence of a metal catalyst.

Connection [11] as a starting compound, where t1 is a group of the formula [4]can be obtained by reacting 2,4-dichloropyridine (obtained, for example, by the method described in non-patent document 12) 2-methyl-5-nitroaniline, using the method of J. P. Wolfe et al. c a palladium catalyst (see non-patent documents 10 and 11). When t1 is a group of the formula [5], for example, this compound can be obtained by reaction of 1-bromo-3-iodobenzoyl with 2-methyl-5-nitroaniline. When t1 is a group of the formula [7], for example, this compound can be obtained by reaction of 2,6-dichloropyrazine with 2-methyl-5-nitroaniline.

The solvent used in the reaction is not specifically limited because it does not participate in the reaction, and examples of it include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbons, such as benzene, toluene and xylene; and mixtures of these solvents. The reactions is carried out at a temperature from 70 to 100° In the presence of a base. Examples of the palladium catalyst include Tris(dibenzylideneacetone)dipalladium (0), palladium acetate(II) and three(o-tolylphosphino)palladium(0). The amount of palladium is preferably from 0.5 to 4 mol.% from halogenated aryl. As a ligand of palladium catalyst, for example, you can use 1,3-bis(diphenylphosphino)propane, 1,1'-bis(diphenylphosphino)ferrocene and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP; BINAP]. Examples of the base include tert-piperonyl sodium tert-piperonyl potassium, cesium carbonate, potassium carbonate and sodium carbonate. The reaction time varies depending on the source materials and the reaction temperature, but is preferably from 1 to 36 hours.

Connection [11], where t1 is a group [4], can also be obtained by reacting 2,4-dichloropyridine with 2-methyl-5-nitroaniline at 20-200°in a suitable solvent in the presence or in the absence of base. Examples of the base include pyridine, triethylamine, N,N-aminobutiramida-N-ethylamine, potassium carbonate, sodium bicarbonate and potassium hydroxide. The solvent is not specifically limited because it does not participate in the reaction, and examples include ethers such as tetrahydrofuran, disutility ether and 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as Ben the ol and toluene; alcohols, such as ethylene glycol and 2-methoxyethanol; halogenated hydrocarbons such as chloroform and dichloromethane; dimethylsulfoxide and mixtures of these solvents. The reaction time varies depending on the source materials and the reaction temperature, but is preferably from 1 to 24 hours.

Connection [14a] as the starting compound [compound [14], where t1 is a group of the formula [4])can also be obtained in the following way:

where R4, R5, R6, R7, R8, t2 and X1have the meanings given above, and X2represents halogen.

Stage 1

This reaction is the reaction cross-connections using connection [15] and organoboron compounds [12] or ORGANOTIN compounds [13] and can be conducted in the same manner as described above.

Stage 2

The compound [17] get halogenoalkanes compounds [16]. Therefore, this reaction is carried out essentially known methods. This reaction is carried out using phosphorus oxychloride, oxybromide phosphorus, pentachloride phosphorus or pentabromide phosphorus in a solvent or without him. The solvent used in the reaction is not specifically limited because it does not participate in the reaction, and examples of it are simple ether is, such as tetrahydrofuran, disutility ether and 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; and mixtures of these solvents. The reaction is usually carried out at a temperature from room temperature to 130°and the reaction time is preferably from 20 minutes to 24 hours.

Stage 3

Connection [14a] can be obtained by reacting compound [17] with the compound [18] using the above method when using a palladium catalyst (see, for example, non-patent documents 10 and 11).

The compound [9a] [connect [9], where t1 is a group of the formula [4]), can be obtained by reacting compound [17] with the compound [19] using the above method when using a palladium catalyst [see, for example, non-patent documents 10 and 11) to obtain the compound [20] and remove the protection at the connection [20].

where t2 and X2have the meanings given above, and R9represents a protective group.

Stage 1

The original compound [19] can be obtained by protection of 2,4-diaminotoluene with a suitable protective group using essentially known methods. Examples of protective groups include acyl derivatives such as benzoyl,acetyl and formyl; and urethane derivatives type, such as benzyloxycarbonyl, tert-butoxycarbonyl and 2,2,2-trichlorocyanuric. Connection [20] can be obtained by reacting compound [17] with the compound [19], using a palladium catalyst.

Stage 2

The reaction of the removal of protection for connections [20] the protective group of the acyl type is removed by hydrolysis using acid or alkali, or removed using ammonia or hydrazine. Examples of the acid used in the hydrolysis include inorganic acids such as hydrochloric acid and sulfuric acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide. Examples of the solvent used in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and 1,4-dioxane; water and mixtures of these solvents. The reaction temperature is in the range from 0 to 100°and the reaction time is usually from several minutes to 24 hours. When the protective group is derived urethane type, it can be removed by hydrogenation using a palladium catalyst or delete processing hydrochloric acid, triperoxonane acid, trimethylsilylimidazole or boron TRIFLUORIDE, depending on the type of protective group.

The original connection [9], where t1 group is the second formula [8], can be obtained by the method described in comparative example 18, below.

Connection [10] as a starting compound can be obtained in the following way:

where R1, R2and R3have the meanings given above, R10is alkyl, and X3represents a removable group, such as Cl, Br, I, OTs, or OMs.

Stage 1

Connection [23] can be obtained by condensation of compound [21] (which can be obtained, for example, by the method described in non-patent document 13) using amine [22] (where the deleted group X3is this the group that you want as halogen, mesilate or toilet). This reaction is a nucleophilic substitution reaction of alkylhalogenide and amines and is essentially known methods. This reaction is carried out in a suitable solvent using an excess of amine or in the presence of a base. Examples of preferred bases include pyridine, triethylamine, N,N-aminobutiramida-N-ethylamine, potassium carbonate and sodium bicarbonate. The solvent is not specifically limited because it does not participate in the reaction, and examples include ethers such as tetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; coal is the hydrogens, such as benzene and toluene; alcohols such as methanol and ethanol; water and mixtures of these solvents. The reaction temperature usually ranges from 0°to 100°C. the reaction Time varies depending on the source materials and the reaction temperature, but is preferably from 30 minutes to 24 hours.

Stage 2

The compound [10] can be obtained by hydrolysis of compound [23]. The reaction is usually carried out in a suitable solvent in the presence of acid or base. Examples of the acid used in the hydrolysis include inorganic acids such as hydrochloric acid and sulfuric acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide. Examples of the solvent used in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and 1,4-dioxane; water and mixtures of these solvents. The reaction temperature is usually in the range from 0 to 100°and the reaction time is usually from 30 minutes to 24 hours.

Process 2

where R1, R2, R3, t1 and t2 have the definitions given above, X4represents Cl, Br, I or SR11and R11represents alkyl.

The compound [1] can be obtained by the interaction of the compounds [24] with the compound [25]. The reaction is carried out at t is mperature from 20 to 200° With in a suitable solvent in the presence or in the absence of base. Examples of the base include pyridine, triethylamine, N,N-aminobutiramida-N-ethylamine, potassium carbonate, sodium bicarbonate and potassium hydroxide. The solvent is not specifically limited because it does not participate in the reaction, and examples include ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene and toluene; alcohols, such as ethylene glycol and 2-methoxyethanol; halogenated hydrocarbons such as chloroform and dichloromethane; dimethylsulfoxide and mixtures of these solvents. The reaction time varies depending on the source materials and the reaction temperature, but is preferably from 1 to 24 hours.

Connection [24] as the starting material can be obtained by condensation of 2,4-diaminotoluene connection [10] in accordance with a modified process 1.

Connection [25] as the starting material can be obtained by using 2,6-dibromopyridine when t1 is a group of formula [2], 3.5-dibromopyridine when t1 is a group of the formula [3], or 2,4-dichloropyrimidine when t1 is a group of the formula [6] in accordance with the process 4 described below. When t1 is a group of the formula [4], the compound [25] can be also the floor is prohibited method described in the above process 1.

Process 3

where R1, R2, R3and t2 have the meanings given above.

The compound [1b] (compound [1], where t1 is a group of the formula [6]) can be obtained by the interaction of the compounds [26] or its acid additive salt with the compound [27]. This reaction is carried out at a temperature of from 20 to 200°in a suitable solvent. The solvent is not specifically limited because it does not participate in the reaction, and examples include alcohols such as methanol, ethanol, 2-propanol and 2-methoxyethanol. The number of compounds [27] is from 1 to 2 mol, and preferably from 1 to 1.2 mol per mol of compound [26]. The reaction time varies depending on the source materials and the reaction temperature, but is preferably from 30 minutes to 30 hours. The use of acid additive salts of the compounds [26] the reaction can be carried out by adding a suitable base (e.g. potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and so on).

Connection [26] as a starting compound can be obtained in the form of free salt or acid additive salts by reacting the compound [24] with cyanamide according to the method described in the document (see, for example, non-patent document 14).

Link is [27] as the starting material can be obtained, for example, in accordance with the modified method described in patent document 1.

Process 4

where R1, R2, R3, R4, R5, R6, R7, R8, t1 and t2 have the meanings given above, X5represents halogen.

This reaction is the reaction cross-connections using connection [28] and organoboron compounds [12] or ORGANOTIN compounds [13] and can be carried out essentially known methods. For example, this reaction is carried out at a temperature of from 20 to 200°in a suitable solvent in the presence of palladium catalyst. As the palladium catalyst used tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium and dichlorobis(tri-o-tolylphosphino)palladium. The solvent used in the reaction is not specifically limited because it does not participate in the reaction, and examples include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene and xylene; organic amines such as pyridine and triethylamine; and mixtures of these solvents. When using connection [12] significantly, the addition of a base (for example sodium hydroxide, potassium carbonate, translesanas potassium phosphate etc). The reaction time varies depending on the source materials and the reaction temperature, but is preferably from 1 to 48 hours.

Connection [28] as a starting compound can be obtained by reacting compound [24] with 4-hydroxy-2-(methylthio)pyridine, when t1 is a group of the formula [4], or interaction of the compound [24] with 4-hydroxy-2-(methylthio)pyrimidine and processing of the reaction product of the phosphorus oxychloride (see, for example, non-patent document 15), when t1 is a group of the formula [6], or interaction by the method described in the document (see, for example, non-patent document 16) using connection [24] and 2,4-dichloropyrimidine when t1 is a group of the formula [6].

The compound of this invention can be used as a medicine in the form of a free base, but it can also be used in the form of pharmaceutically acceptable salts derived essentially known methods. These salts include salts of mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid, and organic acid salts such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluensulfonate acid, b is zolsulphonate acid and methanesulfonamide acid.

Hydrochloride amide derivative according to this invention, for example, can be obtained by dissolving the amide derivative in an alcohol solution, an ethyl acetate solution or ether solution of hydrogen chloride.

As shown in the examples, the tests described below, the compound of this invention has a high inhibitory activity against BCR-ABL tyrosine kinase in comparison with the pyrimidine derivative described in patent document 1. Therefore, the drug of the present invention is suitable as a preventive or therapeutic agent for the treatment of diseases related to activity of the BCR-ABL tyrosine kinase, such as chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myelogenous leukemia.

When the compound of the present invention is used as a medicine, it can be used to treat mammals, including humans, or by itself, or in the form of pharmaceutical compositions containing this compound and pharmaceutically acceptable non-toxic and inert carrier in a ratio of, for example, 0.1 to 99.5%, or preferably from 0.5 to 90%.

Use one or more of the supporting means for the manufacture of drugs, such as fillers or solid, semi-solid or liquid diluent. It is desirable to apply Pharma is eticheskuyu composition in a standard dosage form. The pharmaceutical composition of this invention can be administered intravenously, orally, directly to the target tissue, topically (e.g., transdermal or rectal. Needless to say, as applicable, dosage form, suitable for any route of administration described above. Preferably administered the drug orally.

It is desirable to set the dosage of the compound as an inhibitor of BCR-ABL tyrosine kinase or a therapeutic agent for the treatment of chronic myelogenous leukemia with regard to the condition of the patient, age, body weight and features and severity of the disease and other factors such as route of administration; but usually for adult patients the dose of a compound of the present invention is a number in the range from 0.1 to 1000 mg per individual per day, and preferably from 1 to 500 mg per individual per day.

In some cases, quite a number below this interval, and, on the contrary, in other cases more. You can enter by dividing the total dose into two or three infusions per day.

The BEST WAY of carrying out the INVENTION

The invention hereinafter will be described in more detail with the help of the comparative examples, examples, examples, tests, and examples of the manufacture of dosage forms of the compounds of this invention, which, however, this invention is much more than knowledge.

Comparative example 1

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

Stage 1

Ethyl 3-bromo-4-methylbenzoate

10,00 g 3-Bromo-4-methylbenzoic acid suspended in 100 ml of ethanol and was added to 2.7 ml of concentrated sulfuric acid and then the mixture was heated under reflux for 22 hours. After the solvent had slipped away under reduced pressure, the residue was mixed with ice water, neutralized with a saturated aqueous solution of sodium bicarbonate (pH 8) and then was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to get 10,99 g of target compound as a brown oily product.

1H-NMR (CDCl3): of 1.39 (3H, t), of 2.45 (3H, s), 4,37 (2H, square), 7,29 (1H, DD), 7,87 (1H, DD), to 8.20 (1H, d).

Stage 2

Ethyl 3-bromo-4-(bromomethyl)benzoate

This compound was obtained by the modified method described in the document (J. Med. Chem., 2000, 43(8), 1508-1518). 10.0 g of Ethyl 3-bromo-4-methylbenzoate obtained in stage 1, was dissolved in 125 ml of carbon tetrachloride and after adding 6,83 g of N-bromosuccinimide and 80 g of benzoyl peroxide solution was heated under reflux under irradiation of light bulbs (1500 watts) for 8 hours. After removal of nearstore the different substances by filtration, the filtrate was diluted with 500 ml of dichloromethane. The solution was washed in turn with water and saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to get 13,02 g of the crude product as a brown oil product.

1H-NMR (CDCl3): of 1.40 (3H, t), of 2.45 (3H, s), 4,37 (2H, square), 4,60 (2H, s), 7,52 (1H, d), of 7.96 (1H, DD), 8,24 (1H, d).

Stage 3

Ethyl 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate

11,40 g of Ethyl 3-bromo-4-(methyl bromide)benzoate obtained in stage 2, was dissolved in 114 ml of anhydrous tetrahydrofuran and after the addition of 5.3 g of potassium carbonate is added dropwise within 10 minutes was added a solution of 2.86 g of N-methylpiperazine in 10 ml of tetrahydrofuran under stirring in an argon atmosphere at room temperature. After stirring at room temperature for 4 hours undissolved matter was removed by filtration and the solvent from the filtrate drove away under reduced pressure. The residue was purified column chromatography on silica gel with getting 7,53 g of target compound as a brown oily product.

1H-NMR (CDCl3): of 1.39 (3H, t), is 2.30 (3H, s), 2,48 (4H, usher.), to 2.57 (4H, usher.), 3,63 (2H, s), to 4.38 (2H, square), EUR 7.57 (1H, d), 7,94 (1H, DD), to 8.20 (1H, d).

Stage 4

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride

,00 g of Ethyl 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate, obtained in stage 3, was dissolved in 40 ml of methanol and after the addition of 8.8 ml of 1 N aqueous sodium hydroxide solution the mixture was heated under reflux for 1 hour. After the solvent is kept off, the residue was dissolved in 40 ml of water. The solution was washed with 40 ml of ether, and the aqueous layer was acidified (pH 2) 1 N hydrochloric acid under ice cooling. After the water drove, the operation of adding 50 ml of toluene to the residue, followed by azeotropic removal of water was repeated three times with the receipt of 2.56 g of the crude product in the form of colorless crystals.

1H-NMR (D2O): totaling 3.04 (3H, S), AND 3.72 (8H, usher.), of 4.66 (2H, s), 7,74 (1H, d), with 8.05 (1H, d), with 8.33 (1H, s).

Stage 5

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

1.50 g of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid obtained in stage 4, suspended in 6.3 ml of thionyl chloride, followed by stirring under heating for 24 hours. The reaction solution was cooled in air and loose precipitated crystals were collected by filtration and then washed with diethyl ether obtaining of 1.34 g of the crude product in the form of a colorless crystalline substance.

Melting point: 229-231°C (decomposition)

1H-NMR (D2O): 3,05 (3H, s), 3,83 (8H, usher.), 4,71 (2H, s), 7,76 (1H, d, 8,07 (1H, DD), of 8.37 (1H, s).

Comparative example 2

3-Iodine-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that 3-iodine-4-methylbenzoic acid was used instead of 3-bromo-4-methylbenzoic acid in stage 1, was obtained pale-yellow crystalline substance.

Melting point: 218-220°C (decomposition)

1H-NMR (D2O): to 3.09 (3H, s), 3,86 (8H, usher.), 4,71 (2H, s), to 7.77 (1H, d), 8,13 (1H, DD), 8,66 (1H, d).

Comparative example 3

3-Chloro-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that 3-chloro-4-methylbenzoic acid was used instead of 3-bromo-4-methylbenzoic acid in stage 1, was obtained colorless crystals.

Melting point: 245-247°C (decomposition)

1H-NMR (D2O): of 3.07 (3H, s), 3,84 (8H, usher.), 4,71 (2H, s), 7,79 (1H, d), of 8.06 (1H, DD), 8,21 (1H, s).

Comparative example 4

3-Fluoro-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that 3-fluoro-4-methylbenzoic acid was used instead of 3-bromo-4-methylbenzoic acid in stage 1, was obtained a colorless crystalline substance.

Temperature is the melting point: 242-244° C (with decomposition)

1H-NMR (D2O): a 3.01 (3H, s), 3,63 (4H, usher.), a-3.84 (4H, usher.), 4,63 (2H, s), to 7.68 (1H, t), 7,89 (2H, t).

Comparative example 5

4-(4-Methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov the dihydrochloride

In the same manner as in comparative example 1, except that 4-methyl-3-triptoreline acid was used instead of 3-bromo-4-methylbenzoic acid in stage 1, was obtained a pale brown crystalline substance.

Melting point: 214-216°C (decomposition)

1H-NMR (D2O): to 3.02 (3H, s), 3,81 (8H, usher.), 4,70 (2H, s), to $ 7.91 (1H, d), 8,32 (1H, d), 8,44 (1H, s).

Comparative example 6

4-Methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline

Stage 1

3-(Dimethylamino)-1-(5-pyrimidinyl)-2-propen-1-he

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). 6,01 g dimethylacetal N,N-dimethylformamide was added 1.54 g of 5-acetylpyridine (Khim. Geterotsikl. Soedim., 1981, (7), 958-962) and the mixture was heated under reflux for 15 hours. After the reaction solution was cooled in air, was added a small amount of diisopropyl ether and precipitated precipitated crystals were collected by filtration to obtain 1.52 g of target compound in the form of reddish-brown cristalli the definition of substance.

Melting point: 133-135°

1H-NMR (CDCl3): 2,98 (3H, s), up 3.22 (3H, s), 5,62 (1H, d), 7,89 (1H, d), 9,17 (2H, s), 9,27 (1H, s).

Stage 2

1-(2-Methyl-5-nitrophenyl)guanidine

To 135 g of nitrate 1-(2-methyl-5-nitrophenyl)guanidine (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was directly added 21 g of sodium hydroxide in 1.0 l of cold water solution, followed by stirring at room temperature for 10 minutes. The crystalline substance was filtered, sufficiently washed with water and then dried with compressed air at 60°to obtain 102 g of the target compound as a pale yellow crystalline substance.

Melting point: 135-142°

1H-NMR (DMSO-d6): of 2.16 (3H, s), 5,31 (4H, usher.), 7,31 (1H, d), of 7.48 (1H, d), to 7.59 (1H, DD).

Stage 3

1-Methyl-4-nitro-2-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]benzene

To 1.51 g of 3-(dimethylamino)-1-(5-pyrimidinyl)-2-propen-1-she received in stage 1, was added 1.66 g of 1-(2-methyl-5-nitrophenyl)guanidine, obtained in stage 2, followed by stirring at 120°C for 2 hours. To the liquid reaction solution was added 2-propanol and the crystalline substance was collected by filtration, and then washed in turn with 2-propanol and diethyl ether to obtain 1,95 g of the target compound as pale-korichnevogo the crystalline substance.

Melting point: 200-203°

1H-NMR (DMSO-d6): 2,43 (3H, s), 7,53 (1H, d), the 7.65 (1H, d), to $ 7.91 (1H, DD), 8,68 (1H, d), 8,77 (1H, d), was 9.33 (2H, s), for 9.47 (2H, s).

Stage 4

4-Methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). 1,95 g of 1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]benzene obtained in stage 3, suspended in 300 ml of methanol and after addition of 0.50 g of 10% palladium-on-coal mixture was first made at 30°at 4 ATM for 18 hours. The catalyst was removed by filtration and the solvent from the filtrate drove away under reduced pressure. The residue was purified column chromatography on silica gel with receipt of 0.60 g of the target compound as a yellow amorphous substance.

1H-NMR (CDCl3): of 2.25 (3H, s)to 3.64 (2H, usher.), to 6.43 (1H, d), of 6.99 (1H, s), 7,01 (1H, d), 7,14 (1H, DD), 7,52 (1H, s), 8,54 (1H, DD), to 9.32 (1H, s), 9,35 (2H, s).

Comparative example 7

4-Methyl-3-[4-(2-pyrazinyl)pyrimidine-2-ylamino]aniline

Stage 1

3-(Dimethylamino)-1-(2-pyrazinyl)-2-propen-1-he

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). To of 5.00 g of 2-acetylpyrazine added lower than the 5.37 g of dimethylacetal N,N-dimethylformamide and the mixture was heated with reverse hall is dildocam for 19 hours. The reaction solution was cooled in air and loose precipitated crystalline substance was dissolved in ethyl acetate and then concentrated under reduced pressure. After adding a small amount of diethyl ether precipitated precipitated crystals were collected by filtration and then washed in turn diethyl ether and diisopropyl ether to obtain 5.20 g of target compound as a brown crystalline substance.

1H-NMR (CDCl3): a 3.01 (3H, s), 3,21 (3H, s), 6,36 (1H, d), 7,95 (1H, d), 8,61 (2H, m), was 9.33 (1H, s).

Stage 2

1-Methyl-4-nitro-2-[4-(2-pyrazinyl)pyrimidine-2-ylamino]benzene

This compound has been modified by the method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). a 2.00 g of 3-(Dimethylamino)-1-(2-pyrazinyl)-2-propen-1-she received at stage 1, and 2,90 g nitrate 1-(2-methyl-5-nitrophenyl)guanidine (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) suspended in 23 ml of 2-propanol and, after the addition of 0.50 g of sodium hydroxide the mixture was heated under reflux for 20 hours. After cooling the reaction solution in the air dropped precipitated crystals were collected by filtration to obtain 3.25 g of the crude crystalline substance. The crude crystalline material was dissolved in chloroform-methanol (2:1) and any insoluble matter was removed by filtration, and the ATEM filtrate was concentrated under reduced pressure to get 1,93 g of target compound in the form of a buff crystalline substance.

Melting point: 207-210°

1H-NMR (DMSO-d6): 2,44 (3H, s), 7,53 (1H, d), 7,74 (1H, d), to $ 7.91 (1H, DD), 8,71 (1H, d), 8,81 (3H, m), 9,34 (1H, s), for 9.47 (1H, s).

Stage 3

4-Methyl-3-[4-(2-pyrazinyl)pyrimidine-2-ylamino]aniline

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). to 1.00 g of 1-methyl-4-nitro-2-[4-(2-pyrazinyl)pyrimidine-2-ylamino]benzene obtained in stage 2, suspended in 50 ml of methanol and after adding 100 mg of 10% palladium-on-coal mixture was first made at room temperature at 3 ATM for 14 hours and then was first made at 3.4 ATM for 4 hours. The catalyst was removed by filtration and the solvent from the filtrate drove away under reduced pressure. The residue was purified column chromatography on silica gel with receipt of 0.49 g of the target compound as a yellow amorphous substance.

1H-NMR (CDCl3): of 2.27 (3H, s), of 3.69 (2H, usher.), to 6.43 (1H, DD), 7,00 (1H, s), 7,02 (1H, d), 7,60 (1H, d), of 7.70 (1H, d), 8,58 (1H, d), 8,67 (2H, m), a 9.60 (1H, s).

Comparative example 8

3-[4-(6-Chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline

Stage 1

5-Acetyl-2-chloropyridin

1.84 g of Ground magnesium chloride suspended in 20 ml of toluene and was added 9.4 ml of triethylamine and of 4.46 g of diethylmalonate. After stirring at room temperature the round for 1.5 hours drops) was added, the suspension 4,84 g of 6-chloronicotinamide in 10 ml of toluene for 20 minutes, followed by stirring at room temperature for 2 hours. After neutralization with 60 ml of 1 N hydrochloric acid aqueous layer was separated. The aqueous layer was additionally extracted with diethyl ether and the organic layers were combined and the solvent is then drove away under reduced pressure. To the obtained crude crystalline substance was added dimethyl sulfoxide-water (25 ml 1 ml) followed by stirring with heating to 150-160°C for 2 hours. The reaction solution was cooled in air and added water, and then precipitated precipitated crystals were collected by filtration. Precipitated precipitated crystalline substance was dissolved in ethyl acetate, and the solution was washed in turn with water and saturated aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate. The crude crystalline substance washed with diisopropyl ether and then collected by filtration to obtain 2,74 g of target compound in the form of a translucent crystalline substance.

Melting point: 101-102°

1H-NMR (CDCl3): of 2.64 (3H, d), was 7.45 (1H, d), to 8.20 (1H, dt), to 8.94 (1H, d).

Stage 2

1-(6-Chloropyridin-3-yl)-3-(dimethylamino)-2-propen-1-he

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). To 2,68 g of 5-acetyl-2-chloropyridine obtained in stage 1, was added and 2.26 g of dimethyl what Catala N,N-dimethylformamide and the mixture was heated under reflux for 12 hours. After air cooling, the reaction solution was directly purified column chromatography on silica gel. The crude crystalline material was washed with diethyl ether and then collected by filtration receipt of 1.87 g of the target compound as a yellow crystalline substance.

Melting point: 122-123°

1H-NMR (CDCl3): 2,96 (3H, s), 3,19 (3H, s), 5,62 (1H, d), 7,37 (1H, d), a 7.85 (1H, d), 8,16 (1H, DD), cent to 8.85 (1H, d).

Stage 3

2-[4-(6-Chloropyridin-3-yl)pyrimidine-2-ylamino]-1-methyl-4-nitrobenzene

To 1,83 g of 1-(6-chloropyridin-3-yl)-3-(dimethylamino)-2-propen-1-she received at stage 2, and 1.69 g of 1-(2-methyl-5-nitrophenyl)guanidine, obtained in stage 2 of comparative example 6, was added 18 ml of 2-propanol and the mixture was heated under reflux for 16 hours. After cooling the reaction solution in the air dropped precipitated crystalline substance was collected by filtration and washed with diethyl ether. The crude crystalline material was purified column chromatography on silica gel with receipt of 0.91 g of the target compound as a pale yellow crystalline substance.

Melting point: 210-212°

1H-NMR (DMSO-d6): to 2.42 (3H, s), 7,52 (1H, d), to 7.59 (1H, d), of 7.70 (1H, d), of 7.90 (1H, DD), 8,53 (1H, DD), 8,64 (1H, d), is 8.75 (1H, d) to 9.15 (1H, d), 9,29 (1H, s).

Stage 4

3-[4-(6-Chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline

To 842 mg of 2-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-1-methyl-4-nitrobenzene, obtained in stage 3, was added 6 ml of concentrated hydrochloric acid and the solution was added 2,78 g of dihydrate of tin chloride (II) in 4 ml of concentrated hydrochloric acid under stirring with heating to 55°C. the Mixture was gradually heated to 100°and was further stirred with heating to 100°C for 15 minutes. The reaction solution was cooled in air and added water, and then podslushivaet 10% aqueous sodium hydroxide solution. After adding chloroform and stirring for some time, insoluble substances were removed by filtration and the aqueous layer was separated. The aqueous layer was additionally extracted with chloroform and the organic layers were combined and after osushivaniya over anhydrous magnesium sulfate, the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel to obtain the crude product. The crude product was led by addition of diethyl ether, and the crystalline substance was collected by filtration to obtain 680 mg of the target compound as a pale yellow crystalline substance.

Melting point: 117-118°

1H-NMR (CDCl3) : of 2.25 (3H, s), 3,63 (2H, usher.), 6.42 per (1H, DD), to 6.95 (1H, s), 7,00 (1H, d), 7,10 (1H, d), was 7.45 (1H, d), 7,54 (1H, s), 8,31 (1H, DD), and 8.50 (1H, d), 9,03 (1H, d).

Comparative example 9

3-[4-(5-Bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline

Stage 1

5-Bromonicotinate

To 5,00 g 5-bromonicotinic acid was added 74 ml of thionyl chloride and the mixture was heated under reflux for 6 hours. After the solvent had slipped away under reduced pressure, the crystalline substance is washed with diisopropyl ether and collected by filtration to obtain 4.09 g of the target compound as a colourless crystalline substance.

Melting point: 72-74°

1H-NMR (CDCl3): 8,51 (1H, t), 8,96 (1H, d), of 9.21 (1H, d).

Stage 2

3-Acetyl-5-bromopyridin

1.24 g of ground magnesium chloride suspended in 13 ml of toluene and was added 6.2 ml of triethylamine and 2.93 g of diethylmalonate. After stirring at room temperature for 1.5 hours drops) was added, the suspension 4,08 g 5-bromonicotinate obtained in stage 1, in 10 ml of toluene for 15 minutes, followed by stirring at room temperature for 2 hours. After neutralization with 40 ml of 1N hydrochloric acid, the aqueous layer was separated. The aqueous layer was extracted with diethyl ether and the organic layers were combined, and then dissolve the spruce drove away under reduced pressure. To the obtained oil product was added dimethyl sulfoxide-water (17 ml, 0.7 ml), followed by stirring under heating up to 150-160°C for 2 hours. The reaction solution was cooled in air and added water, and then precipitated precipitated crystalline substance was collected by filtration. Precipitated precipitated crystalline substance was dissolved in ethyl acetate, washed in turn with water and saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. Added to 0.60 g of activated carbon (Kyoryoku Shirasagi MOIWY433) and after standing for 10 minutes, the activated carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting 0,89 g of target compound as a pale yellow crystalline substance.

Melting point: 87-89,5°

1H-NMR (CDCl3): to 2.65 (3H, s)of 8.37 (1H, t), 8,86 (1H, d), 9,07 (1H, d).

Stage 3

1-(5-Bromopyridin-3-yl)-3-(dimethylamino)-2-propen-1-he

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). To 859 mg of 3-acetyl-5-bromopyridine obtained in stage 2, was added 563 mg of dimethylacetal N,N-dimethylformamide and the mixture was heated under reflux for one hour. After ohla the Denia on the air, the reaction solution was directly purified column chromatography on silica gel. The obtained crude crystalline substance was washed with diethyl ether and then collected by filtration to obtain 860 mg of the target compound as a yellow crystalline substance.

Melting point: 131-131,5°

1H-NMR (CDCl3): 2,98 (3H, s), 3,21 (3H, s), 5,63 (1H, d) 7,87 (1H, d), with 8.33 (1H, t), 8,73 (1H, d), 8,98 (1H, d).

Stage 4

2-[4-(5-Bromopyridin-3-yl)pyrimidine-2-ylamino]-1-methyl-4-nitrobenzene

To 833 mg of 1-(5-Bromopyridin-3-yl)-3-(dimethylamino)-2-propen-1-she received at stage 3, and 634 mg of 1-(2-methyl-5-nitrophenyl)guanidine, obtained in stage 2 of comparative example 6, was added 7 ml of 2-propanol and the mixture was heated under reflux for 17 hours. After the reaction solution was dried in the air, dropped precipitated crystalline substance was collected by filtration and washed with diethyl ether to obtain 823 mg of target compound as a pale yellow crystalline substance.

Melting point: 206-208°

1H-NMR (DMSO-d6): 2,43 (3H, s), 7,52 (1H, d), 7,66 (1H, d), of 7.90 (1H, DD), 8,66 (1H, d), a total of 8.74 (1H, d), 8,80 (1H, d), 8,86 (1H, d), 9,31 (2H, s).

Stage 5

3-[4-(5-Bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline

To 807 mg of 2-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-1-methyl-4-nitrobenzene obtained in stage 4, was added 5 ml koncentrirane the Noah hydrochloric acid was added to a solution of 2.36 g of dihydrate of tin chloride (II) in 3.5 ml of concentrated hydrochloric acid under stirring with heating to 55° C. the Mixture was gradually heated to 100°and was further stirred with heating to 100°C for 15 minutes. The reaction solution was cooled in air and added water, and then podslushivaet 10% aqueous sodium hydroxide solution. After adding chloroform and stirring for some time, insoluble substances were removed by filtration and the aqueous layer was separated. The aqueous layer was additionally extracted with chloroform and the organic layers were combined and after drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel to obtain the crude product. The crude product was led by addition of diethyl ether-ethyl acetate and the crystalline substance was collected by filtration to obtain 528 mg of the target compound as a yellow crystalline substance.

Melting point: 129,5-130°

1H-NMR (CDCl3): of 2.26 (3H, s)to 3.64 (2H, usher.), 6,44 (1H, DD), of 6.99 (1H, s), 7,01 (1H, d), 7,13 (1H, d), to 7.59 (1H, d), 8,53 (2H, m), 8,78 (1H, s)to 9.15 (1H, s).

Comparative example 10

3-[4-(1,2-Dihydropyridin-4-yl)pyrimidine-2-ylamino]-4-methylaniline

Stage 1

4-Acetylpyridine

To 3,55 g of potassium salt of monoethylene ester of malonic acid and of 2.21 g of magnesium chloride was added 12 ml of N,N-dimetil mamita and the mixture was stirred while heating to 60° C for 4 hours, the reaction solution 1). Separately prepared reaction solution (reaction solution 2) mixing 2,07 g of 4-pyridineboronic acid (J. Heterocyclic Chem., 1990, 27, 579-582) and 2.95 g of 1,1'-carbonylbis-1H-imidazole in 12 ml of N,N-dimethylformamide at room temperature for 4 hours and the reaction solution was added to the reaction solution 1, followed by stirring at room temperature for 26 hours. To the reaction solution was added diethyl ether and the mixture is neutralized with 50 ml of 1N hydrochloric acid. The aqueous layer was separated and the aqueous layer was additionally extracted four times with diethyl ether. The organic layers were combined and after drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure. To the obtained oil product was added dimethyl sulfoxide-water (5 ml 0.4 ml) followed by stirring with heating to 150-160°C for 2 hours. The solvent is kept under reduced pressure, and the residue was purified column chromatography on silica gel. The crude crystalline substance washed with diisopropyl ether and then collected by filtration to obtain 429 mg of the target compound as a pale yellow crystalline substance.

Melting point: 66,5-67,5°

1H-NMR (CDCl3): 2,70 (3H, s, 7,87 (1H, DD), 9,49 (1H, DD), 9,62 (1H, t).

Stage 2

3-(Dimethylamino)-1-(4-pyridazinyl)-2-propen-1-he

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). To 410 mg of 4-acetylpyridine obtained in stage 1, was added 440 mg of dimethylacetal N,N-dimethylformamide and the mixture was heated under reflux for one hour. After air cooling, the reaction solution was directly purified column chromatography on silica gel. The obtained crude crystalline substance was washed with diethyl ether and then collected by filtration to obtain 341 mg of the target compound as an orange crystalline substance.

Melting point: 136-138°

1H-NMR (CDCl3): a 3.01 (3H, s), 3,24 (3H, s), 5, 66 (1H, d), a 7.85 (1H, DD), 7,92 (1H, d), to 9.32 (1H, DD), of 9.55 (1H, t).

Stage 3

1-Methyl-4-nitro-2-[4-(4-pyridinyl)pyrimidine-2-ylamino]benzene

To 327 mg of 3-(dimethylamino)-1-(4-pyridazinyl)-2-propen-1-she received at stage 2, and 359 mg of 1-(2-methyl-5-nitrophenyl)guanidine, obtained in stage 2 of comparative example 6, was added 4 ml of 2-propanol and the mixture was heated under reflux for 22 hours. The reaction solution was cooled in air and loose precipitated crystalline substance was collected by filtration, and then turns about ivali 2-propanol and diethyl ether to obtain 437 mg of the target compound as a pale yellow crystalline substance.

Melting point: 243-245°

1H-NMR (DMSO-d6): 2,43 (3H, s), 7,53 (1H, d), 7,73 (1H, d), to 7.93 (1H, DD), 8,29 (1H, DD), 8,73 (2H, m), 9,44 (2H, m), 9,88 (1H, s).

Stage 4

3-[4-(1,2-Dihydropyridin-4-yl)pyrimidine-2-ylamino]-4-methylaniline

To 413 mg of 1-methyl-4-nitro-2-[4-(4-pyridinyl)pyrimidine-2-ylamino]benzene obtained in stage 3, was added 3 ml of concentrated hydrochloric acid and a solution of 1.51 g of dihydrate of tin chloride (II) in 2 ml of concentrated hydrochloric acid under stirring with heating to 55°C. the Mixture was gradually heated to 100°and additionally stirred while heating to 100°C for 25 minutes. The reaction solution was cooled in air and after adding water, the solution was podslushivaet 10% aqueous sodium hydroxide solution. After adding chloroform and stirring for some time, insoluble substances were removed by filtration and the aqueous layer was separated. The aqueous layer was additionally extracted with chloroform and the organic layers were combined and after drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel to obtain 38 g of the target compound as a pale yellow amorphous substance.

1H-NMR (CDCl3): 2,24 (3H, s), 4,96 (2H, s), 6,37 (1H, d is), to 6.58 (1H, DD), was 6.73 (1H, t), 6,79 (1H, s), to 6.80 (1H, d), 6,97 (1H, d), 7,41 (1H, t), of 7.70 (1H, d), of 8.27 (1H, d).

Comparative example 11

4-Methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]aniline

Stage 1

3-(Dimethylamino)-1-(3-pyridazinyl)-2-propen-1-he

This compound was obtained by the modified method described in document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). To 762 mg 3 acetylpyridine (Arzneim.-Forsch./Drug Res., 1989, 39(2), 1196-1201) was added 818 mg of dimethylacetal N,N-dimethylformamide and the mixture was heated under reflux for 1.5 hours. After air cooling, the reaction solution was directly purified column chromatography on silica gel. The crude crystalline substance washed with diisopropyl ether and then collected by filtration to obtain 945 mg of target compound in the form of yellowish-brown crystalline substance.

Melting point: 102-105°

1H-NMR (CDCl3): totaling 3.04 (3H, s), up 3.22 (3H, s), 6,69 (1H, d), to 7.61 (1H, DD), to 7.99 (1H, d), of 8.27 (1H, DD), 9,24 (1H, DD).

Stage 2

1-Methyl-4-nitro-2-[4-(3-pyridinyl)pyrimidine-2-ylamino]benzene

800 mg of 3-(Dimethylamino)-1-(3-pyridazinyl)-2-propen-1-she received at stage 1, and 876 mg of 1-(2-methyl-5-nitrophenyl)guanidine, obtained in stage 2 of comparative example 6, was mixed while heating to 120°C for 3 hours. Hardened the reactions the config solution was led by addition of 2-propanol and then washed in turn with 2-propanol and diethyl ether to obtain 1,21 g of target compound as a dark brown crystalline substance.

Melting point: 275-277°

1H-NMR (CF3COOD): of 2.45 (3H, s), 7,56 (1H, usher.), 8,18 (3H, usher.), to 8.57 (1H, usher.), is 8.75 (2H, usher.), 9,18 (1H, usher.), 9,79 (1H, usher.).

Stage 3

4-Methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]aniline

754 mg of 1-methyl-4-nitro-2-[4-(3-pyridinyl)pyrimidine-2-ylamino]benzene obtained in stage 2, suspended in 40 ml of methanol and added 4,21 g dithionite sodium and 3.05 g of sodium bicarbonate and then the mixture was heated under reflux for 5 hours. After the reaction solution was cooled in air, insoluble substances were removed by filtration and the solvent drove away under reduced pressure. To the residue were added water and chloroform, separating the aqueous layer, and then the aqueous layer was extracted three times with chloroform. The organic layers were combined, washed in turn with water, saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel to obtain 247 mg of the target compound as a yellow oil product.

1H-NMR (CDCl3): of 2.26 (3H, s), the 3.65 (2H, usher.), 6,44 (1H, DD), to 6.95 (1H, usher.), 7,02 (1H, d), 7,54 (1H, d), 7,63 (1H, DD), 8,02 (1H, d), and 8.50 (1H, DD), to 8.62 (1H, d), 9,27 (1H, DD).

Comparative example 12

4-Methyl-3-[4-(3-pyridi is)pyridine-2-ylamino]aniline

Stage 1

2-[(4-Chloro)pyridine-2-ylamino]-1-methyl-4-nitrobenzene

This compound was obtained by the modified method described in the document (J. Org. Chem., 1996, 61, 7240-7241). To 2.00 g of 2,4-dichloropyridine (Recl. Trav. Chim. Pays-Bas., 1950, 69, 673-699), and 2.26 g of 2-methyl-5-nitroaniline, 121 mg of palladium (II)acetate, 336 mg (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP] and 6,16 g of cesium carbonate was added 120 ml of toluene and then the mixture was stirred while heating to 70°C for 23 hours in argon atmosphere. After insoluble matter was removed by filtration, the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel with getting 2,11 g of the crude product. The crude product was washed with diethyl ether to obtain 1.22 g of the target compound as a yellow crystalline substance.

Melting point: 130-133°C.

1H-NMR (CDCl3): of 2.38 (3H, s)6,40 (1H, usher.), 6,74 (1H, d), 6,85 (1H, DD), 7,38 (1H, d), of 7.90 (1H, DD), 8,15 (1H, d), to 8.57 (1H, d).

Stage 2

1-Methyl-4-nitro-2-[4-(3-pyridyl)pyridine-2-ylamino]benzene

To 20 ml desoribing of tetrahydrofuran-water (1:1) were added in turn 264 mg of 2-[(4-chloro)pyridine-2-ylamino]-1-methyl-4-nitrobenzene obtained in stage 1, 162 mg of diethyl(3-pyridyl)borane, 470 mg of potassium carbonate and 173 mg of tetrakis(triphenylphosphine)palladium (0) and a mixture of paramashiva and when heated to 80° With over 44 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate to separate an aqueous layer, and then the aqueous layer was additionally extracted three times with ethyl acetate. The organic layers were combined, washed in turn with water and saturated salt solution and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel to obtain 247 mg of the crude product. The crude product was led by addition of chloroform-methanol and then collected by filtration to obtain 143 mg of the target compound as an orange crystalline substance.

Melting point: 170-173°

1H-NMR (CDCl3): 2,43 (3H, s), of 6.49 (1H, usher.), of 6.99 (1H, s), 7,07 (1H, DD), 7,41 (2H, m), 7,87 (2H, m), of 8.37 (1H, d), 8,68 (1H, DD), 8,69 (1H, s), 8,86 (1H, d).

Stage 3

4-Methyl-3-[4-(3-pyridyl)pyridine-2-ylamino]aniline

To 126 mg of 1-methyl-4-nitro-2-[4-(3-pyridyl)pyridine-2-ylamino]benzene obtained in stage 2, was added 1 ml of concentrated hydrochloric acid and the solution was added 465 mg of the dihydrate of tin chloride (II) in 1 ml of concentrated hydrochloric acid with stirring under heating to 60°C. the Mixture was gradually heated to 100°and additionally stirred while heating to 100°C for 40 minutes. After p is a promotional solution was cooled in air, added water and the solution was podslushivaet 10% aqueous sodium hydroxide solution. The solution was extracted three times with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The crude crystalline material was washed with a small amount of chloroform and then collected by filtration to obtain 93 mg of the target compound as a pale yellow crystalline substance.

Melting point: 183-186°

1H-NMR (CDCl3): 2,19 (3H, s), of 3.60 (2H, usher.), 6,37 (1H, usher.), 6,47 (1H, DD), PC 6.82 (1H, s), to 6.88 (1H, d), 6,91 (1H, DD),? 7.04 baby mortality (1H, d), 7,37 (1H, DD), 7,83 (1H, dt), compared to 8.26 (1H, d), 8,64 (1H, DD), 8,81 (1H, d).

Comparative example 13

4-Methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]aniline

Stage 1

1-Methyl-4-nitro-2-[4-(5-pyrimidinyl)pyridine-2-ylamino]benzene

In the same manner as in comparative example 12 (stage 2), except that the dihydroxy(5-pyrimidinyl)borane was used instead of diethyl(3-pyridyl)borane, received the target connection. The crude crystalline substance, obtained by purification column chromatography on silica gel, washed with diethyl ether.

A yellow crystalline substance.

Melting point: 230-232°

1H-NMR (DMSO-d6): to 2.42 (3H, s), 7,31 (1H, DD), 7,47 (2H, m), and 7.8 (1H, DD), with 8.33 (1H, d), 8,61 (1H, s), to 8.94 (1H, d), 9,19 (2H, s), of 9.30 (1H, s).

Stage 2

4-Methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]aniline

163 mg of 1-Methyl-4-nitro-2-[4-(5-pyrimidinyl)pyridine-2-ylamino]benzene obtained in stage 1, was dissolved in 32 ml of tetrahydrofuran-methanol (1:1) was added 98 mg of 10% palladium-on-charcoal grill. In addition, it was added 284 mg of ammonium formate and the mixture was heated under reflux at a bath temperature of 90°C for 40 minutes. The catalyst was removed by filtration and the solvent from the filtrate drove away under reduced pressure. To the residue were added water and ethyl acetate, separating the aqueous layer. The aqueous layer was additionally extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel to obtain 149 mg of the target compound as a pale yellow crystalline substance.

Melting point: 179-180°

1H-NMR (DMSO-d6): 2,19 (3H, s), 3,62 (2H, usher.), to 6.39 (1H, usher.), of 6.49 (1H, DD), 6,76 (1H, s), 6,83 (1H, d), of 6.90 (1H, DD), 7,06 (1H, d), 8,31 (1H, d), of 8.90 (2H, s), a 9.25 (1H, s).

Comparative example 14

4-Methyl-3-[2-(3-pyridyl)pyridine-6-ylamino]aniline

Stage 1

2-Bromo-6-(3-pyridyl)pyridine

This compound was obtained by the modified method of that described by the document (Chem. Pharm. Bull., 1985, 33(11), 4755-4763). To 40 ml of tetrahydrofuran were added to 1.76 g of diethyl(3-pyridyl)borane, of 5.92 g of 2,6-dibromopyridine, 1,99 g of Tetra-n-butylammonium bromide, 692 mg of tetrakis(triphenylphosphine)palladium (0) and of 1.87 g of crushed potassium hydroxide and the mixture was heated under reflux for three hours in an argon atmosphere. After air cooling, the reaction solution was diluted with ethyl acetate, and insoluble substances were removed by filtration. The solvent from the filtrate drove away under reduced pressure, to the residue was added ethyl acetate and a saturated salt solution with separation of the water layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel to obtain 1.26 g of the target compound as a pale yellow crystalline substance.

1H-NMR (CDCl3): 7,34-7,51 (2H, m), 7,62 to 7.75 (2H, m), a 8.34 (1H, dt), 8,67 (1H, DD), 9,17 (1H, d).

Stage 2

1-Methyl-4-nitro-2-[2-(3-pyridyl)pyridine-6-ylamino]benzene

This compound was obtained by the modified method described in the document (J. Org. Chem., 2000, 65, 1144-1157). To 940 mg of 2-bromo-6-(3-pyridyl)pyridine obtained in stage 1, 730 mg of 2-methyl-5-nitroaniline, 37 mg of Tris(dibenzylideneacetone)diplegia (0), 75 mg (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP] and 1,82 m is cesium carbonate was added 12 ml of toluene and the mixture was stirred while heating to 110° C for 24 hours in an argon atmosphere. After air cooling, the reaction solution was diluted with ethyl acetate and the insoluble substance was removed by filtration. The solvent from the filtrate drove under reduced pressure and the residue was led by addition of diethyl ether. The resulting crystalline substance was collected by filtration and then washed with ethyl acetate-diethyl ether to obtain 646 mg of the target compound as a yellow crystalline substance.

Melting point: 148-150°

1H-NMR (CDCl3): to 2.42 (3H, s), 6,53 (1H, usher.), to 6.80 (1H, d), 7,35 (2H, d), 7,44 (1H, DD), 7,69 (1H, m), 7,83 (1H, DD), 8,44 (1H, dt), 8,65 (1H, DD), which is 9.09 (1H, d), 9,20 (1H, d).

Stage 3

4-Methyl-3-[2-(3-pyridyl)pyridine-6-ylamino]aniline

500 mg of 1-Methyl-4-nitro-2-[2-(3-pyridyl)pyridine-6-ylamino]benzene obtained in stage 2, was dissolved in 10 ml of ethanol and was added to 1.05 g of zinc (powder), 430 mg of ammonium chloride and 0.46 ml of acetic acid and then the mixture was stirred while heating to 80°C for 30 minutes. The catalyst was removed by filtration and the solvent from the filtrate drove away under reduced pressure. To the residue was added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution with separation of the water layer. The aqueous layer three times were extracted with ethyl acetate. The organic layers were combined and dried n the d anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure to obtain 114 mg of the target compound as a pale yellow amorphous substance.

1H-NMR (CDCl3): 2,19 (3H, s), 3,40 (2H, usher.), 6,37 (1H, usher.), of 6.45 (1H, DD), of 6.68 (1H, d), 6,91 (1H, d), 7,03 (1H, d), 7,16 (1H, d), 7,38 (1H, DD), 7,56 (1H, t), 8,29 (1H, dt), to 8.62 (1H, dt), 9,19 (1H, d).

Comparative example 15

4-Methyl-3-[3-(3-pyridyl)pyridine-5-ylamino]aniline

Stage 1

3-Bromo-5-(3-pyridyl)pyridine

In the same manner as in comparative example 14 (stage 1), except that 3,5-dibromopyridin used instead of 2,6-dibromopyridine, received the target connection.

A colorless crystalline substance.

1H-NMR (CDCl3): 7,44 (1H, m), 7,88 (1H, m), of 8.04 (1H, t), 8,68-8,77 (3H, m), 8,84 (1H, DD).

Stage 2

1-Methyl-4-nitro-2-[3-(3-pyridyl)pyridine-5-ylamino]benzene

This compound was obtained by the modified method described in the document (J. Org. Chem., 1996, 61, 7240-7241). To 25 mg (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP] was added 2 ml of toluene and (±)-BINAP was dissolved by stirring under heating to 80°C in argon atmosphere. The solution was cooled to room temperature and was added 6 mg of palladium (II) acetate, stirring for one minute, was added 620 mg of 3-bromo-5-(3-pyridyl)pyridine obtained in stage 1, 482 mg of 2-methyl-5-nitroaniline, ,20 g of cesium carbonate and 2 ml (4 ml) of toluene, followed by stirring at 80° C for 18 hours and further heated to 100°C for 24 hours in an argon atmosphere. After air cooling, the reaction solution was diluted with ethyl acetate and the insoluble substance was removed by filtration. The solvent from the filtrate drove under reduced pressure and the residue was purified column chromatography on silica gel to obtain 108 mg of the target compound as a yellow crystalline substance.

Melting point: 195-198°

1H-NMR (CDCl3): to 2.41 (3H, s), USD 5.76 (1H, usher.), 7,39 (1H, usher.), 7,42 (1H, DDD), 7,54 (1H, DD), 7,83 (1H, DD), 7,88 (1H, m), of 8.09 (1H, d), 8,43 (1H, d), and 8.50 (1H, d), 8,67 (1H, DD), 8,83 (1H, d).

Stage 3

4-Methyl-3-[3-(3-pyridyl)pyridine-5-ylamino]aniline

In the same manner as in comparative example 12 (stage 3), except that 1-methyl-4-nitro-2-[3-(3-pyridyl)pyridine-5-ylamino]benzene obtained in stage 2, was used instead of 1-methyl-4-nitro-2-[4-(3-pyridyl)pyridine-2-ylamino]benzene, received the target connection. The residue obtained by concentration under reduced pressure, not further purified.

Pale brown oily product

1H-NMR (CDCl3): of 2.16 (3H, s)to 3.34 (2H, usher.), 5,78 (1H, usher.), 6,40 (1H, DD), is 6.61 (1H, d), 7,01 (1H, d), 7,33-7,40 (2H, m), 7,81 (1H, dt), of 8.28 (1H, d), 8,30 (1H, d), 8,61 (1H, DD), 8,78 (1H, d).

Comparative example 16

4-Methyl-[3-(3-pyridyl)phenylamino)aniline

Stage 1

2-(3-Brompheniramine)-1-methyl-4-nitrobenzene

This compound was obtained by the modified method described in the document (J. Org. Chem., 2000, 65, 1144-1157). To 1.00 g of 1-bromo-3-yogashala, 591 mg of 2-methyl-5-nitroaniline, 32 mg of Tris-(dibenzylideneacetone)diplegia (0), 66 mg (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP] and 1.61 g of cesium carbonate was added 14 ml of toluene and the mixture was stirred while heating to 100°C for 36 hours in an argon atmosphere. After air cooling, the insoluble matter was removed by filtration and the solvent from the filtrate drove away under reduced pressure. The residue was purified column chromatography on silica gel to obtain 256 mg of the target compound as an orange crystalline substance.

Melting point: 114-116°

1H-NMR (CDCl3): of 2.34 (3H, s)5,52 (1H, usher.), of 6.99 (1H, m), 7,14-7,21 (3H, m), 7,33 (1H, d), to 7.77 (1H, DD), 8,02 (1H, d).

Stage 2

1-Methyl-4-nitro-2-[3-(3-pyridyl)phenylamino]benzene

In the same manner as in comparative example 12 (stage 2), except that 2-(3-brompheniramine)-1-methyl-4-nitrobenzene obtained in stage 1 was used instead of 2-[(4-chloro)pyridine-2-ylamino]-1-methyl-4-nitrobenzene, received the target connection. The obtained product is purified column chromatography on silica gel, was led by addition of ethyl is the Etat.

A yellow crystalline substance.

Melting point: 162 to 165°

1H-NMR (DMSO-d6): a 2.36 (3H, s), 7,17 (1H, d), 7,30 (1H, d), 7,40-of 7.70 (5H, m), 7,93-of 7.95 (2H, m), 8,02 (1H, d), to 8.57 (1H, d), cent to 8.85 (1H, s).

Stage 3

4-Methyl-3-[3-(3-pyridyl)phenylamino]aniline

In the same manner as in comparative example 12 (stage 3), except that 1-methyl-4-nitro-2-[3-(3-pyridyl)phenylamino]benzene obtained in stage 2, was used instead of 1-methyl-4-nitro-2-[4-(3-pyridyl)pyridine-2-ylamino]-benzene, received the target connection. The residue obtained by concentration under reduced pressure, not further purified.

Pale yellow oily product

1H-NMR (CDCl3): 2,17(3H, s), 3,50 (2H, usher.), of 5.48(1H, usher.), 6,33 (1H, DD), only 6.64 (1H, d), 6,97-to 7.15 (4H, m), 7,31-7,39 (2H, m), a 7.85 (1H, dt), to 8.57 (1H, DD), 8,82 (1H, d).

Comparative example 17

4-Methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino)aniline

Stage 1

2-[(2-Chloro)pyrazin-6-ylamino)-1-methyl-4-nitrobenzene

In the same manner as in comparative example 12 (stage 1), except that 2,6-dichloropyrazine was used instead of 2,4-dichloropyridine, received the target connection.

A yellow crystalline substance.

1H-NMR (CDCl3): to 2.42 (3H, s), 6,44 (1H, s), the 7.43 (1H, d), of 7.97 (1H, DD), of 8.09 (2H, d), 8,58 (1H, d).

Stage 2

1-IU the Il-4-nitro-2-[2-(3-pyridyl)pyrazin-6-ylamino]benzene

To 64 ml desoribing of tetrahydrofuran-water (1:1) were added in turn 790 mg of 2-[(2-chloro)pyrazin-6-ylamino]-1-methyl-4-nitrobenzene obtained in stage 1, 406 mg dihydroxy(3-pyridyl)borane, of 1.41 g of potassium carbonate and 520 mg of tetrakis(triphenylphosphine)palladium (0), and the mixture was heated under reflux at a bath temperature of 100°C for 3 hours in argon atmosphere. Added 32 or tetrahydrofuran-water (1:1) and the mixture dopolnitelno was heated under reflux for 3 hours and then allowed to stand at room temperature overnight. Precipitated precipitated insoluble substance was collected by filtration, was extracted and washed with methanol and then the solvent of the filtrate drove away under reduced pressure. To the residue was added diethyl ether and after stirring the crystalline substance was collected by filtration and then washed with methanol to obtain 270 mg of the target compound as an amorphous substance.

1H-NMR (DMSO-d6): of 2.45 (3H, s), 7,51 (1H, d), 7,55 (1H, d), a 7.85 (1H, DD), to 8.45 (1H, d), and 8.50 (1H, s), 8,65 (1H, d), a total of 8.74 (1H, s), 9,04 (1H, s), 9,20 (1H, d), 9,29 (1H, s).

Stage 3

4-Methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]aniline

107 mg of 1-methyl-4-nitro-2-[2-(3-pyridine)pyrazin-6-ylamino]benzene obtained in stage 2, was dissolved in 10 ml of methanol (part did not dissolve and was suspenderbelt) was added 16 mg of 10%palladium-on-charcoal grill. In addition, added 221 mg of ammonium formate, followed by stirring with heating on a water bath with a temperature of 50°C for 15 hours. The catalyst was removed by filtration and the solvent from the filtrate drove away under reduced pressure. To the residue were added water and ethyl acetate, separating the aqueous layer. The aqueous layer was additionally extragonadal with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure to obtain 95 mg of the target compound.

1H-NMR (CDCl3): 2,22 (3H, s), to 6.39 (1H, s), 6.48 in (1H, DD), of 6.99 (1H, d), 7,06 (1H, d), the 7.43 (1H, DDD), 8,10 (1H, s), of 8.28 (1H, DDD), 8,43 (1H, s), 8,68 (1H, DD), 9,23 (1H, DD).

Comparative example 18

4-Methyl-3-[5-(3-pyridyl)-1,2,4-triazine-3-ylamino]aniline

Stage 1

3-Methylthio-5-(3-pyridyl)-1,2,4-triazine

First received (3-pyridyl)glyoxal, the hydrobromide by the modified method described in document (Heterocycles, 1990, 31(12), 2163-2172). to 5.00 g of the hydrobromide 3-(bromoacetyl)pyridine (J. Heterocyclic Chem., 1969, 6(6), 891-900) suspended in 30 ml of methanol and added 3,40 g N-oxide of pyridine under stirring with ice cooling, followed by stirring at room temperature for 26 hours after removal of the ice bath. This connection is used for gradient reaction without isolation. Then received 3-meth is ltio-5-(3-pyridyl)-1,2,4-triazine modified method, described in the document (J. Med. Chem., 1979, 22(6), 671-677). To the above solution was added 4,18 g of the hydrochloride of S-methylthiosemicarbazone (Heterocycles, 1979, 12(6), 745-749) and 1.51 g of sodium bicarbonate with stirring with ice cooling was added 6 ml of water and after slow the temperature returns to room temperature, the mixture was stirred at room temperature for 57 hours. The reaction solution was podslushivaet the addition of cold aqueous saturated solution of sodium bicarbonate, and was twice extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel with receipt of 1.37 g of the crude product. The crude product was washed with warm diisopropyl ether to obtain 1.13 g of the target compound as pale yellowish-green crystalline substance.

Melting point: 98-102°

1H-NMR (CDCl3): to 2.75 (3H, s), 7,52 (1H, DDD), 8,48 (1H, DDD), 8,84 (1H, DD), 9,37 (1H, t), 9,43 (1H, s).

Stage 2

3-Methylsulfinyl-5-(3-pyridyl)-1,2,4-triazine

3.00 g of 3-Methylthio-5-(3-pyridyl)-1,2,4-triazine obtained in stage 1, was dissolved in 50 ml of dichloromethane and added 5,76 g of 70% m-chlorbenzoyl acid under stirring with ice cooling. After stirring under ice cooling in ECENA 20 minutes the temperature was returned to room temperature and was added 1.5 g of magnesium sulfate and 10 g of NH-silica gel (Chromatorex NH-DM1020, produced by Fuji Silysia Chemical Co., Ltd.). After stirring at room temperature for 10 minutes to remove insoluble substances were removed by filtration and the solvent from the filtrate drove away under reduced pressure. The residue was purified column chromatography on silica gel to obtain 1.65 g of the crude product. The crude product was washed with 2-propanol-diethyl ether to obtain 1,07 target compound as a pale brown crystalline substance.

Melting point: 150-152°

1H-NMR (CDCl3) δ: 3,17 (3H, s), 7,58 (1H, DD), 8,67 (1H, DD), 8,97 (1H, DD), for 9.47 (1H, d), 9,85 (1H, s).

Stage 3

N-(5-Amino-2-were)ndimethylacetamide

3.00 g of N-(2-methyl-5-nitrophenyl)ndimethylacetamide (Can. J. Chem., 1984, 62, 1292-1296) suspended in 100 ml of ethanol and was added 600 mg of 10% palladium-on-coal, and then the mixture was first made at room temperature at a pressure of 4 ATM for 3 hours. The catalyst was removed by filtration and the solvent from the filtrate drove under reduced pressure to obtain 2.50 g of the crude product. The crude product was washed with a warm solution of diisopropyl ether to obtain 2.37 g of the target compound as a pale green crystalline substance.

Melting point: 136-139°

1H-NMR (D2O) δ: a 2.00 (3H, s)to 3.38 (3H, s), 4,84 (2H, usher.), of 6.29 (1H, DD), to 6.67 (1H, d), to 6.80 (1H, d), 9,01 (1H, usher.).

Stage 4

4-Methyl-3-[5-(3-pyridyl)-1,2,4-triazine-3-ylamino]aniline

671 mg of N-(5-Amino-2-were)ndimethylacetamide, obtained in stage 3, was dissolved in 40 ml of tetrahydrofuran was added 180 mg of 60% sodium hydride with stirring with ice cooling. After stirring under ice cooling for 5 minutes, the temperature was returned to room temperature, followed by stirring for 30 minutes and was added 900 mg of 3-methylsulfinyl-5-(3-pyridyl)-1,2,4-triazine obtained in stage 2. After stirring at room temperature for 3.5 hours the reaction solution was mixed with ice water, extracted twice with dichloromethane and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel with getting 733 mg of 4-methyl-3-{N-acetyl-N-[5-(3-pyridyl)-1,2,4-triazine-3-yl]amino}aniline as intermediate compounds. The above compound was dissolved in 10 ml of methanol was added 2.0 ml of 1N aqueous sodium hydroxide solution, followed by stirring at room temperature for 45 minutes. The reaction solution was mixed with water, was extracted twice with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel with getting mg target compound as a yellowish brown amorphous substance.

1H-NMR (CDCl3): of 2.27 (3H, s), of 3.5-3.9 (2H, usher.), 6,46 (1H, DD), 7,02 (1H, d), 7,38 (1H, usher.), 7,44-7,51 (2H, m), scored 8.38 (1H, dt), 8,79 (1H, DD), 9,19 (1H, s), to 9.32 (1H, d).

Comparative example 19

3-Methyl-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride hydrochloride

Stage 1

1-(4-Methoxy-2-methylbenzoyl)-4-methylpiperazin

To of 3.32 g of 4-methoxy-2-methylbenzoic acid, 5.75 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and of 4.05 g of 1-hydroxybenzotriazole were added 10 ml of N,N-dimethylformamide. Under stirring at room temperature for queue drops) was added a solution of 2.00 g of N-methylpiperazine in 10 ml of N,N-dimethylformamide and a solution of 1.52 g of triethylamine in 10 ml of N,N-dimethylformamide, followed by stirring at room temperature for 15 hours. After the solvent had slipped away under reduced pressure, to the residue was added a saturated aqueous solution of sodium bicarbonate and the solution was twice extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel with receipt of 4.25 g of the target compound as a pale yellow oily product.

1H-NMR (CDCl3) δ: 2,30 (3H, s), is 2.30 (2H, usher.), 2,31 (3H, s), 2,47 (2H, usher.), of 3.27 (2H, usher.), of 3.80 (3H, s), 3,80 (2H, usher.), of 6.73 (1H, d), of 6.75 (1H, s), to 7.09 (1H, DD).

tadia 2

1-(4-Hydroxy-2-methylbenzoyl)-4-methylpiperazin

4,89 g of 1-(4-Methoxy-2-methylbenzoyl)-4-methylpiperazin obtained in stage 1, was dissolved in 150 ml of dichloromethane and drops solution was added 9,87 g tribromide boron in 100 ml of dichloromethane while cooling with ice. After stirring under ice cooling for one hour, the temperature was returned to room temperature and the mixture was additionally stirred for 15 hours. The reaction solution was cooled with ice and podslushivaet by adding 50 ml of water and 150 ml of a saturated aqueous solution of sodium bicarbonate and then insoluble substances were removed by filtration. The filtrate was extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel to obtain 2.20 g of the target compound as a pale yellow crystalline substance.

Melting point: 167-168°

1H-NMR (CDCl3): to 2.18 (3H, s), 2,32 (3H, s), 2,32 (2H, usher.), of 2.50 (2H, usher.), 3,30 (2H, usher.), a 3.83 (2H, usher.), to 4.17 (1H, usher.), of 6.52 (1H, s), is 6.54 (1H, d), 6,94 (1H, d).

Stage 3

3-Methyl-4-(4-methylpiperazin-1-ylmethyl)phenol

a 1.96 g of 1-(4-Hydroxy-2-methylbenzoyl)-4-methylpiperazine obtained in stage 2, was dissolved in 35 ml of tetrahydrofuran and added MX 0.317 g lydialydia several then what s under stirring with ice cooling. After stirring at room temperature for 4 hours the mixture was again cooled with ice and added MX 0.317 g lydialydia several portions under stirring with ice cooling, followed by stirring at room temperature for 15 hours. The reaction solution was cooled with ice was added tetrahydrofuran and after decomposition of literarymagazine insoluble substances were removed by filtration. The solvent of the filtrate is kept off, and the residue was led by addition of acetone to obtain 1.10 g of the target compound as a colourless crystalline substance.

Melting point: 174-176°

1H-NMR (CDCl3) δ: of 2.28 (3H, s)to 2.29 (3H, s), of 2.51 (8H, usher.), 3,39 (2H, s), 6,50 (1H, DD), is 6.54 (1H, d), 7,03 (1H, d).

Stage 4

3-Methyl-4-(4-methylpiperazin-1-ylmethyl)phenyltrichlorosilane

660 mg of 3-Methyl-4-(4-methylpiperazin-1-ylmethyl)phenol obtained in stage 3, was dissolved in 6.6 ml of pyridine was added 1.86 g of anhydrous triftormetilfullerenov acid under stirring with ice cooling, followed by stirring at room temperature for 12 hours. The reaction solution was mixed with ice water, was extracted three times with ethyl acetate and then washed with water. After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure. The residue was purified is kolonochnoi chromatography on silica gel with getting 535 mg of the target compound as a pale yellow oily product.

1H-NMR (CDCl3): 2,31 (3H, s), of 2.38 (3H, s), 2,47 (8H, usher.), of 3.45 (2H, s),? 7.04 baby mortality (1H, d), 7,06 (1H, s), 7,35 (1H, d).

Stage 5

Methyl 3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoate

705 mg of 3-Methyl-4-(4-methylpiperazin-1-ylmethyl)phenyl triftoratsetata obtained in stage 4, was dissolved in the mixture of solvents from 8,40 ml of dimethyl sulfoxide, 4,96 ml of methanol, 2,68 ml of 1,2-dichloroethane and 0,76 ml of triethylamine, and then added to 62.8 mg of 1,3-bis(diphenylphosphino)propane and 34.2 mg of palladium (II)acetate. Under stirring at room temperature the reaction solution was barbotirovany gaseous carbon monoxide for 5 minutes and the solution was further heated under reflux for one hour while bubbling gaseous carbon monoxide. After air cooling to the reaction solution were added water and ethyl acetate and insoluble substances were removed by filtration and then the filtrate was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel with getting 392 mg of the target compound as a pale yellow oily product.

1H-NMR (CDCl3): to 2.29 (3H, s), 2,39 (3H, s), 2,46 (8H, usher.), to 3.49 (2H, s), 3,90 (3H, s), of 7.36 (1H, d), 7,81 (1H, is), 7,83 (1H, s).

Stage 6

3-Methyl-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride

In the same manner as in comparative example 1 (stage 4), except that methyl 3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoate obtained in stage 5 was used instead of ethyl 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate, received the target connection.

A colorless crystalline substance.

Stage 7

3-Methyl-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1 (stage 5), except that 3-methyl-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride obtained in stage 6 was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid, has been the target connection.

A colorless crystalline substance.

Comparative example 20

4-(4-Methylpiperazin-1-ylmethyl)-3-nitrobenzotrifluoride the dihydrochloride

Stage 1

Ethyl 4-(methyl bromide)-3-nitrobenzoate

In the same manner as in comparative example 1 (stage 1), except that 4-(methyl bromide)-3-nitrobenzoic acid was used instead of 3-bromo-4-methylbenzoic acid, has been the target connection.

Yellow oily product

1H-NMR (CDCl3) δ: of 1.43 (3H, t), 4,48 (2H, square), is 4.85 (2H, s), to 7.67 (1H, d), compared to 8.26 (1H, DD), 8,67 (1H, d).

Stage 2

Ethyl 4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoate

In the same manner as in comparative example 1 (stage 3), except that ethyl 4-(methyl bromide)-3-nitrobenzoate obtained in stage 1 was used instead of 3-bromo-4-(methyl bromide)benzoate, received the target connection.

A yellow crystalline substance.

Melting point: 92-94°

1H-NMR (CDCl3) δ: of 1.42 (3H, t), of 2.28 (3H, s), 2,33-of 2.54 (8H, usher.), a 3.83 (2H, s), 4,42 (2H, square), 7,71 (1H, d), 8,19 (1H, DD), to 8.45 (1H, d).

Stage 3

4-(4-Methylpiperazin-1-ylmethyl)-3-nitrobenzoic acid dihydrochloride

In the same manner as in comparative example 1 (stage 4), except that ethyl 4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoate obtained in stage 2, was used instead of ethyl 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoate, received the target connection.

Pale brown crystalline substance.

Melting point: 180°C (decomposition)

1H-NMR (D2O) δ: is 2.88 (3H, s), 3,30-3,90 (8H, usher.), 4,58 (2H, s), 7,72 (1H, d), 8,24 (1H, DD), 8,66 (1H, d).

Stage 4

4-(4-Methylpiperazin-1-ylmethyl)-3-nitrobenzotrifluoride the dihydrochloride

In the same manner as in comparative example 1 (stage 5), except that 4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzoic acid dihydrochloride, obtained in stage 3, was used instead of dihydrochlor is Yes 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid, received target connection.

Pale brown crystalline substance.

Melting point: 190°C (decomposition)

1H-NMR (D2O)δ: 2,99 (3H, s), 3.25 to 4.00 points (8H, usher.), of 4.66 (2H, s), of 7.75 (1H, d), of 8.28 (1H, d), 8,72 (1H, usher.).

Comparative example 21

3-Methoxy-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1 (stages 2-5), except that methyl 3-methoxy-4-methylbenzoate used instead of ethyl 3-bromo-4-methylbenzoate in stage 2, had been the target connection.

A colorless crystalline substance.

1H-NMR (D2O)δ: is 2.88 (3H, s), of 3.54 (8H, usher.), of 3.80 (3H, s)to 4.41 (2H, s), 7,39 (1H, d), 7,52 (2H, m).

Comparative example 22

3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1 (stages 2-5), except that methyl 3,5-dibromo-4-methylbenzoate used instead of ethyl 3-bromo-4-methylbenzoate in stage 2, had been the target connection.

Pale orange crystalline substance.

1H-NMR (D2O): 2,89 (3H, s), of 3.73 (8H, usher.), to 4.73 (2H, s), 8,19 (2H, s).

Comparative example 23

3,5-Dimethoxy-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that 3,5-dime is hydroxy-4-methylbenzoic acid was used instead of 3-bromo-4-methylbenzoic acid in stage 1, received target connection.

Pale-yellow crystalline substance.

1H-NMR (D2O): 2,92 (3H, s)to 3.58 (8H, usher.), is 3.82 (6H, s), of 4.44 (2H, s), 7,20 (2H, s).

Comparative example 24

3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

Stage 1

Ethyl 3-(N,N-dimethylcarbamoyl)-4-methylbenzoate

This compound was obtained by the modified method described in document (Org. Lett., 2002, 4, 2849-2851). to 1.00 g of ethyl 3-iodine-4-methylbenzoate (intermediate compound of comparative example 2) was dissolved in 30 ml of N,N-dimethylformamide was added 23 mg of Tris(dibenzylideneacetone)diplegia (0). Under stirring at room temperature was added 643 μl of phosphorus oxychloride, followed by stirring with heating to 120°C for 12 hours in an argon atmosphere. The reaction solution was mixed with saturated aqueous sodium bicarbonate, and was twice extracted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel with getting 338 mg of the target compound as a brown oily product.

1H-NMR (CDCl3) δ: to 1.38 (3H, t)to 2.35 (3H, s)2,84 (3H, s)and 3.15 (3H, s), 4,36 (2H, square), 7,29 (1H, d), 7,87 (1H, d), 7,95 (1H, DD).

Stage 2

Ethyl 4-(methyl bromide)-3-(N,N-dimethylcarbamoyl)benzoate

In the same manner as in comparative example 1 (stage 2), except that ethyl 3-(N,N-dimethylcarbamoyl)-4-methylbenzoate obtained in stage 1 was used instead of ethyl 3-bromo-4-methylbenzoate, received the target connection.

Yellow oily product

1H-NMR (CDCl3): to 1.38 (3H, t), only 2.91 (3H, s)3,18 (3H, s), 4,36 (2H, square), 4,60 (2H, s), 7,51 (1H, d), 7,88 (1H, d), 7,98 (1H, DD).

Stage 3

Ethyl 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoate

In the same manner as in comparative example 1 (stage 3), except that ethyl 4-(methyl bromide)-3-(N,N-dimethylcarbamoyl)benzoate obtained in stage 2, was used instead of ethyl 3-bromo-4-bromoethylamine, received the target connection.

Brown oily product

1H-NMR (CDCl3): of 1.39 (3H, t), of 2.28 (3H, s), 2,46 (8H, usher.), of 2.86 (3H, s), of 3.13 (3H, s)to 3.58 (2H, usher.), 4,37 (2H, square), was 7.45 (1H, d), 7,86 (1H, d), of 7.97 (1H, DD).

Stage 4

3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride

In the same manner as in comparative example 1 (stage 4), except that ethyl 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoate obtained in stage 3, was used instead of ethyl 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoe is and has been the target connection.

Pale yellow amorphous substance

1H-NMR (D2O)δ: and 2.83 (3H, s), 2,87 (3H, s), to 3.02 (3H, s), 3,44 (8H, usher.), to 4.28 (2H, s), 7,63 (1H, d), of 7.97 (1H, d), with 8.05 (1H, DD).

Stage 5

3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1 (stage 5), except that 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride obtained in stage 4 was used instead of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride, obtained the target connection.

Pale orange crystalline substance.

1H-NMR (D2O) δ: and 2.83 (3H, s), 2,87 (3H, s), 3,03 (3H, s), 3,47 (8H, usher.), the 4.29 (2H, s), to 7.64 (1H, d), to 7.99 (1H, d), of 8.06 (1H, DD).

Comparative example 25

3-Bromo-4-(4-ethylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that N-ethylpiperazine was used instead of N-methylpiperazine at stage 3, had been the target connection.

Pale brown crystalline substance.

1H-NMR (D2O) δ: of 1.33 (3H, t)to 3.34 (2H, square), to 3.67 (8H, usher.), to 4.73 (2H, s), 7,73 (1H, d), 8,03 (1H, DD), 8,32 (1H, d).

Comparative example 26

3-Bromo-4-[4-(n-propyl)piperazine-1-ylmethyl]the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that the N-(n-propyl)piperazine was used instead of N-methylpiperazine at stage 3, received target connection.

A colorless crystalline substance.

1H-NMR(D2O) δ: of 0.95 (3H, t), of 1.75 (2H, m), 3,23 (2H, m), with 3.79 (8H, usher.), to 4.73 (2H, s), 7,73 (1H, d), with 8.05 (1H, DD), 8,35 (1H, d).

Comparative example 27

3-Bromo-4-(N,N-dimethylaminomethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that dimethylamine was used instead of N-methylpiperazine at stage 3, had been the target connection.

A colorless crystalline substance.

1H-NMR (D2O) δ: 2,80 (6H, d), to 4.41 (2H, s), 7,53 (1H, d), 7,88 (1H, DD), 8,16 (1H, d).

Comparative example 28

3-Bromo-4-(N,N-diethylaminomethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that diethylamine was used instead of N-methylpiperazine at stage 3, had been the target connection.

A colorless crystalline substance.

1H-NMR (D2O) δ: of 1.34 (6H, t), 3,29 (4H, square), to 4.52 (2H, s), the 7.65 (1H, d), to 7.99 (1H, DD), compared to 8.26 (1H, d).

Comparative example 29

3-Bromo-4-(1-pyrrolidinyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that pyrrolidine was used instead of N-methylpiperazine at stage 3, had been the target connection.

Pale brown crystalline substance.

1H-NMR (D2O) δ: 1,95 (4H, m),and 3.16 (2H, m)of 3.46 (2H, m), 4,47 (2H, s), 7,54 (1H, d), 7,88 (1H, d), 8,17 (1H, s).

Comparative example 30

3-Bromo-4-(piperidinomethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that piperidine was used instead of N-methylpiperazine at stage 3, had been the target connection.

A colorless crystalline substance.

1H-NMR (D2O) δ: 1,69 (6H, m), 3,14 (2H, t), 3,53 (2H, d), 4,50 (2H, s), 7,66 (1H, d), of 8.00 (1H, d), 8,29 (1H, s).

Comparative example 31

3-Bromo-4-(morpholinomethyl)of the benzoyl chloride dihydrochloride

In the same manner as in comparative example 1, except that morpholine was used instead of N-methylpiperazine at stage 3, had been the target connection.

Pink crystalline substance.

1H-NMR (D2O) δ: 3,39 (4H, m), of 3.69 (2H, m)to 3.99 (2H, m), 4,51 (2H, s), 7,60 (1H, d), 7,92 (1H, DD), by 8.22 (1H, s).

Comparative example 32

3-Bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)benzoic acid dihydrochloride

In the same manner as in comparative example 1 (stage 1-4), except that CIS-2,6-dimethylpiperazine was used instead of N-methylpiperazine at stage 3, had been the target connection.

A colorless crystalline substance.

1H-NMR (D2O) δ: of 1.25 (6H, d), the 3.11 (2H, t), 3,62 (4H, m), a 4.53 (2H, s), to 4.73 (2H, s), to 7.59 (1H, d), of 7.90 (1H, DD), to 8.20 (1H, d).

Comparative example 33

In the same manner as in comparative example 1 (stage 1-4), except that 4-methylhexane-1H-1,4-diazepin was used instead of N-methylpiperazine at stage 3, had been the target connection.

A yellow crystalline substance.

1H-NMR (D2O) δ: of 2.23 (2H, usher.), is 2.88 (3H, s), of 3.57 (4H, usher.), 3,74 (4H, s), 4,58 (2H, s), to 7.61 (1H, d), of 7.90 (1H, DD), 8,17 (1H, d).

Comparative example 34

3-Bromo-4-(4-(tert-butoxycarbonyl)piperazine-1-ylmethyl)benzoic acid

Stage 1

Ethyl 3-bromo-4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]benzoate

to 1.00 g of Ethyl 3-bromo-4-(methyl bromide)benzoate (intermediate compound of comparative example 1) was dissolved in 10 ml of anhydrous tetrahydrofuran, and after adding 473 mg of potassium carbonate drops added 467 mg of N-(tert-butoxycarbonyl)piperazine under stirring at room temperature in argon atmosphere. After stirring at room temperature for 20 hours, the insoluble matter was removed by filtration and the solvent from the filtrate drove away under reduced pressure. The residue was purified column chromatography on silica gel with getting 918 mg of target compound as a pale yellow oily product.

1H-NMR (CDCl3) δ: of 1.40 (3H, t)of 1.46 (9H, s), 2,47 (4H, t), of 3.45 (4H, m), 3,63 (2H, s), to 4.38 (2H, square), 7,58 (1H, d), of 7.96 (1H, DD), 8,21 (1H, d).

Stage 2

3-Bromo-4-[4-(tert-BU is oxycarbonyl)piperazine-1-ylmethyl]benzoic acid

898 mg of Ethyl 3-bromo-4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]benzoate, obtained in stage 1, was dissolved in 5 ml of methanol and was added to 3.2 ml of 1N aqueous sodium hydroxide solution. After stirring at room temperature for 3 hours the mixture was neutralized by slow addition of 3.2 ml of 1N hydrochloric acid. Precipitated precipitated crystalline substance was collected by filtration, washed with water and then dried under reduced pressure to obtain 796 mg of target compound in the form of a colorless crystalline substance.

Melting point: 204-205°C (decomposition)

1H-NMR (DMSO-d6)δ: of 1.40 (9H, s), is 2.40 (4H, t), to 3.36 (4H, m), 3,61 (2H, s), 7,63 (1H, d), 7,92 (1H, DD), 8,07 (1H, d).

Comparative example 35

4-[4-(tert-Butoxycarbonyl)piperazine-1-ylmethyl]-3-triftorperasin acid

In the same manner as in comparative example 34, excepting that 4-(methyl bromide)-3-triptoreline (intermediate compound of comparative example 5) was used instead of ethyl 3-bromo-4-(methyl bromide)benzoate in stage 1, had been the target connection.

A colorless crystalline substance.

Melting point: 126-134°

1H-NMR (CDCl3)δ: of 1.47 (9H, s)to 2.55 (4H, usher.), of 3.54 (4H, usher.), of 3.84 (2H, s), with 8.05 (1H, d), of 8.25 (1H, d), of 8.37 (1H, s).

Example 1

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-(4-methyl-3-[4-(3-pyridyl)Piri is one-2-ylamino]phenyl)benzamide

0.74 g of 4-Methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was dissolved in 27 ml of anhydrous pyridine and added to 920 mg of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride (comparative example 1), followed by stirring at room temperature for 14 hours. The reaction solution was mixed with ice water and saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel to obtain 1.48 g of the crude product. The crude product was led by addition of chloroform-diethyl ether (1:1) and the crystalline substance was collected by filtration receipt of 1.05 g of the target compound as a colourless crystalline substance.

Melting point: 202-203°C (decomposition)

Elemental analysis (for C29H30BrN7About·0,N2O)

Calculated(%): C, 59,17; N, 5,44; N, 16,65

Found (percent): C, 59,16; N, To 5.21; N, 16,64

Example 2

3-Iodine-4-(4-methylpiperazin-1-ylmethyl)-N-(4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl)benzamide

This compound was obtained in the same manner as in example 1, except that 3-iodine-4-(4-methylpiperazin-1-ilmmilmismiliemi the dihydrochloride (comparative example 2) was used instead of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride, and that the reaction was carried out at room temperature for 24 hours and the resulting the crystalline substance was recrystallized from methanol.

A colorless crystalline substance.

Melting point: 199-200°C (decomposition)

Elemental analysis (for C29H30IN7O)

Calculated(%): C, 56,23; N, 4,88; N, 15,83

Found (percent): C, 56,13; N, 4,94; N, 15,80

Example 3

3-Chloro-4-(4-methylpiperazin-1-ylmethyl)-N-(4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl)benzamide

This compound was obtained in the same manner as in example 1, except that 3-chloro-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride (comparative example 3) was used instead of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride, and that the reaction was carried out at room temperature for 24 hours.

A colorless crystalline substance.

Melting point: 193-194°C (decomposition)

Elemental analysis (for C29H30ClN7About·0,6N2O)

Calculated(%): C, 64,64; N, Of 5.84; N, 18,20

Found (percent): C, 64,62; N, the ceiling of 5.60; N, 18,23

Example 4

3-Fluoro-4-(4-methylpiperazin-1-ylmethyl)-N-(4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl)benzamide

This compound was obtained in the same manner as in example 1, except that 3-fluoro-4-(4-methylpiperazin-1-ylmethyl)of the benzoyl chloride dihydrochloride (comparative example 4 was used instead of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl orida dihydrochloride and that the reaction was carried out at room temperature for 22 hours, and the crude crystalline product is obtained by purification via column chromatography on silica gel, washed with chloroform-diethyl ether (1:1).

A colorless crystalline substance.

Melting point: 197-199°C (decomposition)

Elemental analysis (for C29H30FN7About·0,3H2O)

Calculated(%): C, 67,37; N, 5,97; N, 18,96

Found (percent): C, 67,36; N, 5,96; N, 18,93

Example 5

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-(4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl)benzamide

This compound was obtained in the same manner as in example 1, except that 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov the dihydrochloride (comparative example 5) was used instead of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride, and that the reaction was carried out at room temperature for 22 hours, and the resulting crystalline material was washed with diethyl ether.

A colorless crystalline substance.

Melting point: 182-183°C (decomposition)

Elemental analysis (for C30H30F3N7About·0,3H2O)

Calculated(%): C, 63,55; N, 5,44; N, 17,29

Found (percent): C, 63,43; N, lower than the 5.37; N, 17,29

Example 6

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-(4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl)benzamide

This compounds the s was obtained in the same manner as in example 1, except that 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov the dihydrochloride (comparative example 5)was used instead of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride and 4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (comparative example 6) was used instead of 4-methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]aniline and the reaction was carried out at room temperature for 20 hours, and the crude crystalline substance obtained by the purification column chromatography on silica gel, washed with diethyl ether.

Pale-yellow crystalline substance.

Melting point: 231-233°C (decomposition)

Elemental analysis (for C29H29F3N8About·0,2N2O)

Calculated(%): C, 61,52; N, 5,23; N, 19,79

Found (percent): C, 61,37; N, Of 5.24; N, 19,81

Example 7

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-(4-methyl-3-[4-(2-pyrazinyl)pyrimidine-2-ylamino]phenyl)benzamide

This compound was obtained in the same manner as in example 1, except that 4-methyl-3-[4-(2-pyrazinyl)pyrimidine-2-ylamino]aniline (comparative example 7) was used instead of 4-methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]aniline and the reaction was carried out at room temperature for 18 hours.

Pale-yellow crystalline substance.

Melting point: 213-214�B0; C (with decomposition)

Elemental analysis (for C28H29BrN8O)

Calculated(%): C, 58,64; N, 5,10; N, 19,54

Found (percent): C, 58,41; N, 5,11; N, 19,24

Example 8

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

629 mg of 3-[4-(6-Chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline (comparative example 8) suspended in 7 ml of acetonitrile and then added 24 mg of 4-dimethylaminopyridine and 1.15 ml of N,N-aminobutiramida-N-ethylamine. Under ice cooling was added in five portions 979 mg of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride (comparative example 1), followed by stirring at room temperature for one hour after removal of the ice bath. The reaction solution was mixed with water, was extracted with chloroform and then dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel. The crude crystalline substance were washed with ethyl acetate and diethyl ether and the crystalline substance was collected by filtration to obtain 939 mg of target compound as a pale yellow crystalline substance.

Melting point: 219-222°C (decomposition)

Elemental analysis (for C29H29BrClN7O)

You is isleno(%): C, 57,39; N, 4,82; N, 16,15

Found (percent): C, 57,07; N, Of 4.75; N, 16,09

Example 9

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same manner as in example 8, except that 3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline (comparative example 9) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline, and the crude crystalline substance obtained by the purification column chromatography on silica gel, recrystallized from ethyl acetate-diethyl ether.

Pale-yellow crystalline substance.

Melting point: 194-195°C (decomposition)

Elemental analysis (for C29H29Br2N7About·0,3H2O)

Calculated(%): C, 53,03; N, Of 4.54; N, 14,93

Found (percent): C, 53,07; N, A 4.53; N, 14,70

Example 10

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same manner as in example 8, except that 3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline (comparative example 9) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline, and the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-triftormetilfullerenov (comparative example 5) was used instead on the Sabbath.hydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that oily product, purified column chromatography on silica gel, was led by addition of diisopropyl ether-ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 171-173°C (decomposition)

Elemental analysis (for C30H29BrF3N7About·0,7N2O)

Calculated(%): C, 55,17; N, 4,69; N, 15,01

Found (percent): C, 55,16; N, Of 4.57; N, 14,94

Example 11

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(1,2-dihydropyridin-4-yl)pyrimidine-2-ylamino]-4-were}benzamide

This compound was obtained in the same manner as in example 8, except that 3-[4-(1,2-dihydropyridin-4-yl)pyrimidine-2-ylamino]-4-methylaniline (comparative example 10) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the extraction was carried out with ethyl acetate, and the residue obtained by purification via column chromatography on silica gel, washed with diisopropyl ether.

Pale yellow amorphous substance

Elemental analysis (for C28H31BrN8About·0,8{(CH3)2SN}2O)

Calculated(%): C, 59,94; N, 6,47; N, 17,05

Found (percent): C, To 59.51; H, 6,30; N, Ls 16.80

Example 12

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-m is Tyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]aniline (comparative example 11) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and that the crude crystalline substance, obtained by purification column chromatography on silica gel, washed with ethyl acetate-chloroform.

Pale-yellow crystalline substance.

Melting point: 185-187°C (decomposition)

Elemental analysis (for C28H29BrN8About·0.1 n2O)

Calculated(%): C, 58,28; N, 5,13; N, 19,42

Found (percent): C, 58,24; N, 5,00; N, 19,48

Example 13

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

150 mg of 4-Methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (comparative example 6) was dissolved in 4 ml of N,N-dimethylformamide, and then in turn added 255 mg of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)benzoic acid (comparative example 1) and 109 mg of triethylamine. While stirring the suspension at room temperature were added 106 mg diethylthiophosphate and 55 mg of triethylamine, followed by stirring at room temperature for 3 hours. After the solvent had slipped away under reduced pressure, the residue was mixed with water and saturated aqueous sodium hydrogen carbonate solution and then was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel to obtain 240 mg neocis the frame of the product. The crude product was dissolved in chloroform-methanol and was added 2-propanol, followed by concentration under reduced pressure. Precipitated precipitated crystalline substance was collected by filtration and washed in turn with 2-propanol and diethyl ether to obtain 147 mg of the target compound as a pale yellow crystalline substance.

Melting point: 238-240°C (decomposition)

Elemental analysis (for C28H29BrN8About·0.1 n2O)

Calculated(%): C, 58,46; N, 5,12; N, 19,48

Found (percent): C, 58,21; N, 5,02; N, 19,30

Example 14

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyridine-2-ylamino]aniline (comparative example 12) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and that the crude crystalline substance, obtained by purification column chromatography on silica gel, washed with ethyl acetate-chloroform-methanol.

Pale-yellow crystalline substance.

Melting point: 244-245°C (decomposition)

Elemental analysis (for C30H31BrN6About·0,6N2O)

Calculated(%): C, 61,88; N, To 5.57; N, 14,43

Found (percent): C, 61,71; N, 5,49; N, 14,13

Example 15

3-Bromo-4-4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyrimidinyl)pyridine-2-ylamino]aniline (comparative example 13) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and that the crude crystalline substance, obtained by purification column chromatography on silica gel, washed with ethyl acetate-diethyl ether.

Pale-yellow crystalline substance.

Melting point: 244-246°

Elemental analysis (for C29H30BrN7About·0,2N2About·0,2CH3SOOS2H2)

Calculated(%): C, 60,28; N, 5,43; N, 16,51

Found (percent): C, 60,12; N, Of 5.40; N, 16.28 per

Example 16

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyridine-6-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[2-(3-pyridyl)pyridine-6-ylamino]aniline (comparative example 14) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and that the crude crystalline substance, purified column chromatography on silica gel, additionally not washed.

Pale yellow amorphous substance

Elemental analysis (for C30H31BrN6About·1,5H2O)

Calculated(%): C, 60,20; N, 5,73; N, 14,04

Found (percent): C, 60,39; N, Of 5.55; N, 13,00

FAB-MS(POS.) mz 571, (Negatives) m/z 569

Example 17

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)pyridine-5-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[3-(3-pyridyl)pyridine-5-ylamino]aniline (comparative example 15) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the extraction was carried out with ethyl acetate and the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate-diethyl ether.

Pale-yellow crystalline substance.

Melting point: 139-141°

Elemental analysis (for C30H31BrN6About·1,2H2O)

Calculated(%): C, 60,75; N, Of 5.68; N, 14,17

Found (percent): C, 60,96; N, 5,62; N, 13,98

Example 18

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)phenylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[3-(3-pyridyl)pyridine-5-ylamino]aniline (comparative example 16) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the extraction was carried out with ethyl acetate, and the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate-hexane.

Pale brown crystalline in the society

Melting point: 174-175°

Elemental analysis (for C31H32BrN5O)

Calculated(%): C, 65,26; N, The 5.65; N, to 12.28

Found (percent): C, 65,12; N, 5,73; N, 12,19

Example 19

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]aniline (comparative example 17) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the extraction was carried out with ethyl acetate, and an amorphous substance, purified column chromatography on silica gel, was led by addition of ethyl acetate.

A yellow crystalline substance.

Melting point: 192-193°

Elemental analysis (for C29H30BrN7About·0,25N2O)

Calculated(%): C, 60,37; N, 5,33; N, 16,99

Found (percent): C, 60,58; N, To 5.35; N, 16,76

Example 20

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[5-(3-pyridyl)-1,2,4-triazine-3-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[5-(3-pyridyl)-1,2,4-triazine-3-ylamino]aniline (comparative example 18) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and that amorphous substance, purified column chromatography on silica gel, to which was atallitani the addition of 2-propanol.

A yellow crystalline substance.

Melting point: 219-221°

Elemental analysis (for C28H29BrN8About·1,2H2About·0,1 CH3CH(OH)CH3)

Calculated(%): C, 56,55; N, Of 5.40; N, 18,64

Found (percent): C, 56,58; N, 5,00; N, 18,27

Example 21

3-Methyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-methyl-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride (comparative example 19) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 192-193°

Elemental analysis (for C30H33N7O)

Calculated(%): C, 70,98; N, 6,55; N, 19,31

Found (percent): C, 70,79; N, To 6.67; N, 19,39

Example 22

4-(4-Methylpiperazin-1-ylmethyl)-3-nitro-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-is ethyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 4-(4-methylpiperazin-1-ylmethyl)-3-nitrobenzotrifluoride (comparative example 20) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and the extraction was carried out with ethyl acetate, and the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate-diethyl ether.

Pale-yellow crystalline substance.

Melting point: 184-186°

Elemental analysis (for C29H30N8About3·0,7N2O)

Calculated(%): C, 63,19; N, 5,74; N, 20,33

Found (percent): C, 63,38; N, To 5.57; N, 20,00

Example 23

3-Methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride comparative example 21) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led EXT is the implementation of ethyl acetate and then washed with diethyl ether.

Pale-yellow crystalline substance.

Melting point: 171-172°C (decomposition)

Elemental analysis (for C30H33N7About2·0,6N2O)

Calculated(%): C, 67,42; N, Of 6.45; N, 18,35

Found (percent): C, 67,23; N, 6,36; N, 18,19

Example 24

3,5-Dibromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride 3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride (comparative example 22) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate and then washed with diethyl ether.

Pale-yellow crystalline substance.

Melting point: 227-229°

Elemental analysis (for C29H29Br2N7About·0.1 n2About·0,SN3CO2With2H5)

Calculated(%): C, 53,38; N, 4,72; N, 14,33

Found (percent): C, 53,02; N, 4,74; N, 14,09

Example 25

3,5-Dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-the laminitis]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride 3,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-3-benzoyl chloride (comparative example 23) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

A yellow crystalline substance.

Melting point: 201-214°C (decomposition)

Elemental analysis (for C31H35N7About3·0,5H2O)

Calculated(%): C, 66,17; N, Of 6.45; N, 17,43

Found (percent): C, 65,91; H, 6.42 Per; N, 17,42

Example 26

3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 1, except that the dihydrochloride of 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride (comparative example 24) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Orange crystalline substance.

Melting point: 210-214°C (decomposition)

Elemental analysis (for C32H36N8About2·0,6N2O)

Calculated(%): C, 66,79; N, Of 6.52; N, 19,47

Found (percent): C, 66,41; N, 6,17; N, 19,36

Example 27

3-Bromo-4-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-bromo-4-(4-ethylpiperazin-1-ylmethyl)of benzoyl chloride (comparative example 25) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 202-203°

Elemental analysis (for C30H32BrN7About·0,25N2O)

Calculated(%): C, 60,97; N, 5,54; N, 16,59

Found (percent): C, 60,96; N, 5,54; N, 16,32

Example 28

3-Bromo-4-[4-(n-propyl)piperazine-1-ylmethyl]-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except t the th, 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-bromo-4-[4-(n-propyl)piperazine-1-ylmethyl]benzoyl chloride (comparative example 26) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 204-205°

Elemental analysis (for C31H34BrN7About·0,4H2O)

Calculated(%): C, 61,26; N, 5,77; N, 16,13

Found (percent): C, 61.48 Mass; N, To 5.66; N, 15,79

Example 29

3-Bromo-4-(N,N-dimethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-bromo-4-(N,N-dimethylaminomethyl)of benzoyl chloride (comparative example 27) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led add is the group of ethyl acetate.

A colorless crystalline substance.

Melting point: 154-155°

Elemental analysis (for C26H25BrN6O)

Calculated(%): C, 60,35; N, To 4.87; N, 16,24

Found (percent): C, 60,20; N, equal to 4.97; N, 16,13

Example 30

3-Bromo-4-(N,N-diethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-bromo-4-(N,N-diethylaminomethyl)of benzoyl chloride (comparative example 28) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 172-173°

Elemental analysis (for C28H29BrN6O)

Calculated(%): C, 61,65; N, Are 5.36; N, 15,41

Found (percent): C, 61,35; N, Are 5.36; N, 15,35

Example 31

3-Bromo-4-(1-pyrrolidinyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publicaion (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-bromo-4-(1-pyrrolidinyl)of benzoyl chloride (comparative example 29) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 195-196°

Elemental analysis (for C28H27BrN6O)

Calculated(%): C, 61,88; N, Free 5.01; N, 15,46

Found (percent): C, 61,68; N, 5,12; N, 15,11

Example 32

3-Bromo-4-(piperidinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-bromo-4-(piperidinomethyl)of benzoyl chloride (comparative example 30) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 158-159°

Elements of the analyses (for C 29H29BrN6O)

Calculated(%): C, 62,48; N, Of 5.24; N, 15,07

Found (percent): C, 62,23; N, A 5.25; N, 14,83

Example 33

3-Bromo-4-(morpholinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 8, except that 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) was used instead of 3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-methylaniline and the dihydrochloride of 3-bromo-4-(morpholinomethyl)of benzoyl chloride (comparative example 31) was used instead of the dihydrochloride of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)of benzoyl chloride and that the oily product is purified column chromatography on silica gel, was led by addition of ethyl acetate.

Pale-yellow crystalline substance.

Melting point: 179-180°

Elemental analysis (for C28H29BrN6About2)

Calculated(%): C, 60,11; N, A 4.86; N, 15,02

Found (percent): S, 59,94; N, Is 4.93; N, 14,96

Example 34

3-Bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained by the modified method described in document (Synthesis, 1982, 288-291). To 356 mg of 4-methyl-3-[4-(3-pyridyl)pyridine-2-ylamino]aniline (Japanese Unexamined Patent Publication (Kokai) No. 6-87834) and 770 mg of the dihydrochloride of 3-bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)benthological (comparative example 32) were added to 7 ml of dichloromethane and 715 μl of triethylamine. Under stirring at room temperature was added 446 mg of phenyl N-phenyltetrahydropyridine (Synthesis, 1982, 288-291), followed by stirring at room temperature for 2 hours. The reaction solution was mixed with water and then was extracted twice with chloroform. The extract was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified by queue column chromatography on silica gel and column chromatography on NH-silica gel and the obtained oily product was led from ethyl acetate. The crystalline substance was washed with diethyl ether to obtain 259 mg of the target compound as a pale yellow crystalline substance.

Melting point: 204-205°

Elemental analysis (for C30H32BrN7O)

Calculated(%): C, 61,43; N, 5,50; N, 16,72

Found (percent): C, 61,19; N, Of 5.48; N, 16,49

Example 35

3-Bromo-4-(4-methylhexane-1H-1,4-diazepin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in example 34, except that the dihydrochloride of 3-bromo-4-(4-methylhexane-1H-1,4-diazepin-1-ylmethyl)benzoic acid (comparative example 33) was used instead of the dihydrochloride of 3-bromo-4-(CIS-3,5-dimethylpiperazine--ylmethyl)benzoic acid.

Pale-yellow crystalline substance.

Melting point: 156-157°

Elemental analysis (for C30H32BrN7O)

Calculated(%): C, 61,43; N, 5,50; N, 16,72

Found (percent): C, 61,13; N, 5,43; N, 16,39

Example 36

3-Bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

First 3-bromo-4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-N-(4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl)benzamide was obtained by modification of the method described in document (Synthesis, 1982, 288-291). In the same manner as in comparative example 34, except that 4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (comparative example 6) was used instead of 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline and 3-bromo-4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]benzoic acid (comparative example 34) was used instead of the dihydrochloride of 3-bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)benzoic acid and the extraction was carried out with ethyl acetate and the extract was purified only by column chromatography on silica gel and then used for subsequent reactions without further purification. Then received 3-bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide. To 187 mg of the crude reaction product described above was added 1.5 ml triperoxonane acids is followed by stirring at room temperature for 2 hours. The reaction solution was podslushivaet by adding 10% aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on NH-silica gel and was led by addition of ethyl acetate. Crystalline material was washed with warm ethyl acetate to obtain 49 mg of the target compound as a pale yellow crystalline substance.

Pale-yellow crystalline substance.

Melting point: 225-228°C (decomposition)

Elemental analysis (for C27H27BrN8About·0,3H2O)

Calculated(%): C, 57,41; N, To 4.92; N, 19,84

Found (percent): C, 57,53; N, 5,11; N, 18,92

FAB-MS(POS.) m/z 559

Example 37

4-[4-(Tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

This compound was obtained in the same manner as in comparative example 34, except that 4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]aniline (comparative example 6) was used instead of 4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]aniline and 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-triftorperasin acid (comparative example 35) was used instead of the dihydrochloride of 3-bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)benzoic acid and the extraction was carried out what dilatatum, and the oily product is purified column chromatography on silica gel, was led by addition of ethanol, and then washed in turn with ethanol and diethyl ether.

Pale-yellow crystalline substance.

Melting point: 188-191°

1H-NMR (CDCl3)δ: of 1.47 (9H, s), a 2.36 (3H, s), 2,43 (4H, t), of 3.45 (4H, t), 3,71 (2H, s), to 7.09 (1H, usher.), to 7.18 (1H, d), 7.23 percent (2H, s), 7,95 (1H, d), with 8.05 (2H, d), 8,14 (1H, s), 8,56 (1H, d), 8,65 (1H, usher.), of 9.30 (1H, s), 9,42 (2H, s).

Example 38

4-(1-Piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide

To 1.00 g of 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 37) was added 8 ml triperoxonane acid, followed by stirring at room temperature for 2 hours. The reaction solution was podslushivaet by adding 10% aqueous sodium hydroxide solution was added dichloromethane. Precipitated precipitated crystalline substance was collected by filtration to obtain 530 mg of the crude crystalline substance. The filtrate was extracted twice with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure to obtain 370 mg of the crude crystalline substance. 900 mg of both crude crystalline substances were combined, purified Colo is face-to-face chromatography on NH-silica gel, and then was led by addition of isopropanol. Crystalline material was washed in turn with ethyl acetate and diethyl ether to obtain 258 mg of the target compound as a pale yellow crystalline substance.

Pale-yellow crystalline substance.

Melting point: 208-211°

Elemental analysis (for C28H27F3N8O)

Calculated(%): C, 61,31; N, 4,96; N, 20,43

Found (percent): C, 61,03; N, Free 5.01; N, 20,33

Example 39

3-Methoxycarbonyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

100 mg of 3-Iodine-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide (example 2), 1 mg dichlorobis(triphenylphosphine)palladium (II) and 20 mg of sodium bicarbonate suspended in 5 ml of anhydrous methanol and the suspension was heated under reflux at a bath temperature of 80°C for 2 hours while sparging the reaction solution with gaseous carbon monoxide. After air cooling to the reaction solution were added water and ethyl acetate and insoluble substances were removed by filtration and then the filtrate was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel and cu which were stylizowane the addition of ethyl acetate-diethyl ether to obtain 64 mg of the target compound as a colourless crystalline substance.

Melting point: 159-161°C (decomposition)

Elemental analysis (for C31H33N7About3·0,2N2O)

Calculated(%): C, 67,06; N, The 6.06; N, 17,66

Found (percent): C, 66,77; N, 6,03; N, 17,68

Example 40

3-Cyano-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide

200 mg of 3-Iodine-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide (example 2), 35 mg of tetrakis(triphenylphosphine)palladium (0) and 45 mg of 60% cyanide zinc suspended in 2 ml of anhydrous N,N-dimethylformamide, followed by stirring under heating to 80°C for 24 hours. After air drying the reaction solution was mixed with saturated aqueous sodium bicarbonate and was extracted twice with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel and was led by the addition of ethanol to obtain 34 mg of the target compound as a pale yellow crystalline substance.

Melting point: 191-193°C (decomposition)

Elemental analysis (for C30H30N8About·0,5H2O)

Calculated(%): C, 68,29; N, Of 5.92; N, 21,24

Found (percent): C, 68,05; N, Of 5.99; N, 21,12

Example 41

3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidine is l)pyrimidine-2-ylamino]phenyl}benzamide hydrochloride

to 5.00 g of 3-Bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide (example 13) suspended in 250 ml of 50% aqueous ethanol was added 9,24 ml of 1N hydrochloric acid, followed by stirring with heating in a hot bath at 80°obtaining a homogeneous solution. The reaction solution was filtered under heating and the solvent drove away from the filtrate under reduced pressure. The remainder were released when heated in 30 ml of ethanol and then left to stand at room temperature for one day. Precipitated precipitated crystalline substance was collected by filtration and washed with ethanol to obtain 5,13 g of target compound as a pale yellow crystalline substance.

Melting point: 184-186°C (decomposition)

Elemental analysis (for C28H29BrN8About·1,0l·2,0N2O)

Calculated(%): C, 52,06; N, 5,31; N, of 17.35

Found (percent): C, 51,72; N, To 5.17; N, 17,21

Example 42

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide hydrochloride

This compound was obtained in the same manner as in example 41, except that 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-(4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl)benzamide (example 6) was used instead of 3-bromo-4-(4-methylpiperazin-1 ileti the)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide.

Pale-yellow crystalline substance.

Melting point: 244-246°C (decomposition)

Elemental analysis (for C29H29F3N8About·1,0l·0,8H2O)

Calculated(%): C, 56.78 Has; N, 5,19; N, 18,27

Found (percent): C, 56,80; N, 4,96; N, be 18.49

Example 43

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide hydrochloride

This compound was obtained in the same manner as in example 41, except that 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were)benzamide (example 10) was used instead of 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide.

Pale-yellow crystalline substance.

Melting point: 184-187°

Elemental analysis (for C30H29BrF3N7About·1,0l·1.0 h2O)

Calculated(%): C, 51,85; N, With 4.64; N, 14,11

Found (percent): C, 51,78; N, 4,74; N, 13,92

Example 44

4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide methanesulfonate

of 7.00 g of 4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-(4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl)benzamide (example 6) suspended in 70 ml of methanol and drops solution was added 1.20 g methansulfonate sour is you in 3 ml of methanol, followed by stirring under heating at an oil bath at 50° C for 10 minutes. The reaction solution was mixed with 700 mg of activated charcoal (Kyoryoku Shirasagi MOIWY433) and then heated under reflux for 30 minutes. The reaction solution was filtered under heating and the solvent from the filtrate drove away under reduced pressure. The residue was dissolved by heating in 10 ml of methanol and then left to stand at room temperature for 10 minutes. As a result the entire reaction solution was harden. This solution was led by addition of isopropanol to obtain 7.20 g of the target compound as a pale yellow crystalline substance.

Melting point: 171-173°

Elemental analysis (for C29H29F3N8About·1,SN3SO3N·1.0 h2O)

Calculated(%): C, 53,25; N, To 5.21; N, 16,56

Found (percent): C, 53,04; N, Of 5.39; N, 16,74

The test example 1

Inhibiting cell growth action

Cells C and U937 cells (purchased from American Type Culture Collection) were cultured in medium RPMI-1640 (produced by Sigma)containing 10% (vol./about.) calf fetal serum (FCS; TPP) (produced by Sigma) (RPMI-1640/FCS). Cells C and U937 cells were seeded at a density of 5000 cells/100 μl/cell, respectively. The plate was incubated in thermostat with a high content of CO2throughout the night. The test drug was prepared using dimethyl sulfoxide (DMSO)(produced by Nacalai Tesque) at concentrations 1000 times higher than the concentration of the test (0, from 0.00001 to 1 μm). The resulting solution was diluted 500 times in medium RPMI-1640/FCS and then added 100 ál of diluent into the cell. The plate was incubated in thermostat with a high content of CO2. After 72 hours in each well was added 20 μl of fluid Cell counting Kit-8 (5 mmol/l of WST-8, 0.2 mmol/l 1-methoxy-PMS, 150 mmol/l NaCl) (produced by Dojindo). After the reaction with the color development in thermostat with a high content of CO2within 3 hours was determined by absorption formazan produced by restoring the WST-8 at 450 nm using a multi-level counter ARVOsx (produced by Wallac).

The value of the IC50(PC50) (μm) was calculated by the following formula:

The degree of inhibition of growth of cells =

100 - (absorption cells with drug/absorption cells with 0.1% DMSO)·100

After the log-logistic transformation, which gave 50%degree of inhibition of cell growth, defined as IC50was calculated by the method of least squares. The results are presented in table 1.

As a reference medicinal product used 4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide (see patent document 1).

Table 1

Inga is yousee cell growth action
The test drug substanceCells C (value IC50: mkm)Cells U937

(the value of the IC50,μm)
Attitude

Cells U937/

Cells C
Example 10,00224,802181,8
Example 20,00233,341452,2
Example 30,00465,011089,1
Example 40,03312,40375,8
Example 50,00083,994987,5
Example 60,00055,3910780,0
Example 70,00546,511205,6
Example 90,0017to 1.861094,1
Example 100,0014with 3.272335,7
Example 130,00126,205166,7
Example 140,003>10>3333,3
Example 150,00489,11895,8
Example 19to 0.0602,4040,0
Example 200,0151,82 121,3
Example 210,0053>10>1886,8
Example 220,00326,562050,0
Example 230,0094>10>1063,8
Example 240,00157,294860,0
Example 250,0317566,7
Example 270,000497,1614612,2
Example 280,000656,9710723,1
Example 290,017>10>588,2
Example 300,022>10>454,5
Example 350,00755,22696,0
Example 360,0041--
Example 380,00093--
Example 390,035>10>285,7
Example 400,00544,2777,8
Control chemical compound0,1317,8136,9

As can be seen from the results shown in table 1, the compounds given to the CSOs of the invention have excellent inhibitory activity against BCR-ABL tyrosine kinase. Cells C used in test example 1, were positive for the BCR-ABL cells, which were collected from the pleural effusion of a patient with chronic myelogenous leukemia in late stages, which suffered a sharp transformation. The U937 cells were malignant negative against BCR-ABL cells, which were taken from a patient with histiocytic lymphoma. As can be seen in relation to the inhibition of cell growth (U937 cells/cells C), the compounds of this invention are drugs with higher security than the control drug.

In addition, the compounds of this invention possess inhibiting the growth of cells by the action a few hundred times stronger compared to the control drug, and therefore it can be expected that they will show the corresponding inhibiting cell growth effect not only on the previously known mutant kinase, but also on the mutant kinase, which will be discovered in the future. Accordingly, the compounds of this invention are very useful as a therapeutic agent for the treatment of diseases such as chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myelogenous leukemia.

The test example 2

Inhibitory effect on samopostovanje the Muta is based (EC) BCR-ABL

Cells T (purchased from ATS) were cultured in modified, Dulbecco (Dulbecco) environment, the Needle (produced by Sigma)containing 10% TPP (DMEM/FCS). Cells were seeded in 5 ml coated with poly-L-lysine 6 cm Cup, so you have 1,2·106cells/cell. Cup incubated in thermostat with elevated CO2throughout the night. Using lipofectamine reagent (produced by Invitrogen), 2 μg AC vector expression of mutant bcr-abl gene was transfusional in cells. After 16 hours after transliterowany in each cell was added 5 μl prepared in DMSO (produced by Nacalai tesque) of the tested drugs was thus given concentration 1000 times higher. Cup incubated in thermostat with elevated CO2within 2 hours. After treatment with trypsin, the cells were collected in 15 ml centrifuge tube. The tube was centrifuged at 1000 rpm at room temperature for one minute. After removal of the medium was added 50 μl of solution for lysis of the cells. Cells were subjected to cytolysis by using a mixer. The tube was left to stand at 4°C for 15 minutes and was transferred into a 1.5 ml tube. The tube was centrifuged at 12000 rpm at 4°C for 15 minutes. The cell lysate was collected into another 1.5 ml tube. The concentration of protein was determined by the method of the ICA. Samples of cell lysate containing 5 µl of the protein, analyzed by electrophoresis in polyacrylamide gel with sodium dodecyl sulfate (SDS-PAGE). After eletrophoresis protein was transferred to nylon filter (Hybond-P) using the wet method with 4°With during the night. Nylon filter was subjected to 10 ml FBR(PBS)/0.1% tween-20 containing 0.2 μg/ml of antibodies against phosphorylation tyrosine kinase (RU) (produced by Toyobo) at room temperature for one hour. Nylon filter was washed three times FBFR, and then was subjected to 10 ml FBFR/0.1% tween-20 containing 0.4 µg/ml conjugated with AP against mouse IgG (produced by Cell Signaling) at room temperature for one hour. After the nylon filter was washed FBFR four times, determined samopostovanje R BCR-ABL with giving staining reagent alkaline phosphatase.

The results are presented as follows: +++: an almost complete inhibition of phosphorylation; ++: about half of inhibition; +: weak inhibition; - : no inhibition.

As a reference medicinal product used 4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide (see patent document 1).

Table 2

Inhibitory effect of samopozhervovanija on EC mutant BCR-ABL
Subjects

drug

tools
0.1 µl0,3 ál1 ál3 ál10 ál
Example 1--++++++
Example 2++++++
Example 3-++++
Example 4--+
Example 5+++++++++
Example 6-++++++++++
Example 7-+++++
Example 9++++++
Example 10--++++++++
Example 13-+++++++++
Control chemical compound- ----

As can be seen from the results shown in table 2, the compounds of this invention have an effect of inhibiting samopozhervovanija against EC mutant BCR-ABL tyrosine kinase. Thus, it is possible to inhibit the growth of cells caused by the mutant kinase. In particular, reference medicinal product has no inhibitory effect, and therefore it is obvious that this action is specific to the compounds of the present invention.

In addition, the compounds of this invention possess a strong inhibitory samopostovanje action against EC mutant BCR-ABL tyrosine kinase, which is impossible to exert inhibitory samopostovanje effect some control drugs, and therefore you can expect that they will have adequate inhibitory samopostovanje activity against mutant kinases, which will be discovered in the future. Accordingly, the compounds of this invention are very useful as a therapeutic agent for the treatment of diseases such as chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia.

Sample preparation 1
Tablet (PE the oral pill)
Composition/tablet (80 mg)
Connection example 15.0 mg
Corn starch46.6 mg
Crystalline cellulose24,0 mg
The methylcellulose4.0 mg
Magnesium stearate0.4 mg

Mixed powder of this composition is pressed in the usual way and formed with a receiving oral tablets.

Example product 2
The pill (oral pill)
Composition/tablet (80 mg)
The compound from example 25.0 mg
Corn starch46.6 mg
Crystalline cellulose24,0 mg
The methylcellulose4.0 mg
Magnesium stearate0.4 mg

Mixed powder of this composition is pressed in the usual way and formed with a receiving oral tablets.

INDUSTRIAL APPLICABILITY

As described above, since the compound of the present invention is a compound which has a high inhibitory BCR-ABL to tyrosinekinase activity, formats viteska composition, containing the compound of this invention as the active ingredient, suitable as an inhibitor of BCR-ABL tyrosine kinase. Therapeutic agent for the treatment of chronic myelogenous leukemia, a therapeutic agent for the treatment of acute myelogenous leukemia and therapeutic tool for the treatment of acute lymphoblastic leukemia in mammals, including humans.

1. Amide derivative represented by the following formula [1] in any of the following cases (a) and (b) or its salt

(A) R1represents a 5-7 membered saturated cyclic group having 1-2 nitrogen atom as an atom constituting the cycle (saturated cyclic amino group may be substituted by 1-3 identical or different substituents selected from the group consisting of C1-10of alkyl, C1-10alkoxycarbonyl), Monos1-10alkylamino or dis1-10alkylamino;

R2represents C1-10alkyl, halogen, halogen1-10alkyl, C1-10alkoxy, C1-10alkoxycarbonyl, nitro, mono1-10allylcarbamate, dis1-10allylcarbamate or cyano;

R3represents hydrogen, halogen or1-10alkoxy,

Het1 represents any of groups of the following formulas [2]-[8]

Het2 represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridines [Het2 may be substituted by 1-3 identical or different substituents selected from halogen),

in addition to the compounds in which R1is (i) pyrrolidinium, piperidinium, piperazinil or morpholinyl, each of which may be substituted by 1-3 identical or different substituents selected from the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino, (ii) monoalkylamines or (iii) dialkylamino, Het1 is a group of the formula [6], and Het2 is pyrazinium or pyridium, which can be substituted by alkyl;

(C) R1represents the 4 methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1-yl, CIS-3,5-dimethylpiperazine-1-yl, morpholino, dimethylamino or diethylamino;

R2represents methyl, ha is oven, trifluoromethyl, methoxy, methoxycarbonyl, nitro, dimethylcarbamoyl or cyano;

R3represents a hydrogen, bromine or methoxy;

Het1 represents a group of the formula [6];

Het2 represents 3-pyridyl.

2. Amide derivative according to claim 1 or its salt, in which R1represents a 5-7 membered saturated cyclic group having 1-2 nitrogen atom as an atom constituting the cycle (saturated cyclic amino group may be substituted by 1-3 identical or different substituents selected from the group consisting of C1-10of alkyl, C1-10Alcoceber), Monos1-10alkylamino or dis1-10alkylamino,

R2represents C1-10alkyl, halogen, halogen C1-10alkyl, C1-10alkoxy, C1-10alkoxycarbonyl, nitro, dis1-10allylcarbamate or cyano,

R3represents hydrogen, halogen or1-10alkoxy,

Het1 is a group of formula [2]-[8], and

Het2 represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridine (Het2 may be substituted by 1-3 identical or different halogen atoms).

3. Amide derivative according to claim 1, which is a compound selected from the group consisting of the following compounds (1)to(40), or its salt:

(1) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimi the Jn-2-ylamino]phenyl}benzamide,

(2) 3-iodine-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(3) 3-chloro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(4) 3-fluoro-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(5) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(6) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl) pyrimidine-2-ylamino]phenyl}benzamide,

(7) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(2-pyrazinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(8) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(6-chloropyridin-3-yl)pyrimidine-2-ylamino]-4-were} benzamide,

(9) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were} benzamide,

(10) 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{3-[4-(5-bromopyridin-3-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(11) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{3-[4-(1,2-dihydropyridin-4-yl)pyrimidine-2-ylamino]-4-were}benzamide,

(12) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(13) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-iluminator}benzamide,

(14) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyridine-2-ylamino]phenyl}benzamide,

(15) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyridine-2-ylamino]phenyl}benzamide,

(16) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyridine-6-ylamino]phenyl}benzamide,

(17) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)pyridine-5-ylamino]phenyl}benzamide,

(18) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[3-(3-pyridyl)phenylamino]phenyl}benzamide,

(19) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[2-(3-pyridyl)pyrazin-6-ylamino]phenyl}benzamide,

(20) 3-bromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[5-(3-pyridyl)-1,2,4-triazine-3-ylamino]phenyl}benzamide,

(21) 3-methyl-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(22) 4-(4-methylpiperazin-1-ylmethyl)-3-nitro-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(23) 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(24) 3,5-dibromo-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(25) 3,5-dimethoxy-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(26) 3-(N,N-dimethylcarbamoyl)-4-(4-methylpiperazin-1-ILM is Teal)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(27) 3-bromo-4-(4-ethylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(28) 3-bromo-4-[4-(n-propyl)piperazine-1-ylmethyl]-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(29) 3-bromo-4-(N,N-dimethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(30) 3-bromo-4-(N,N-diethylaminomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(31) 3-bromo-4-(1-pyrrolidinyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(32) 3-bromo-4-(piperidinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(33) 3-bromo-4-(morpholinomethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(34) 3-bromo-4-(CIS-3,5-dimethylpiperazine-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(35) 3-bromo-4-(4-methylhexane-1H-1,4-diazepin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide,

(36) 3-bromo-4-(1-piperazinylmethyl)-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(37) 4-[4-(tert-butoxycarbonyl)piperazine-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(38) 4-(1-piperazinylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidine-2-ylamino]phenyl}benzamide,

(39) 3-methoxycarbonyl-4-(4-methyl who piperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide and

(40) 3-cyano-4-(4-methylpiperazin-1-ylmethyl)-N-{4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl}benzamide.

4. Pharmaceutical composition having inhibitory activity against BCR-ABL tyrosine kinase, containing as the active ingredient amide derivative according to any one of claims 1 to 3, or its salt and a pharmaceutically acceptable non-toxic inert carrier.

5. The inhibitor of the BCR-ABL tyrosine kinase containing the amide derivative according to any one of claims 1 to 3, or its salt as an active ingredient and, optionally, a pharmaceutically acceptable non-toxic inert carrier.

6. Therapeutic agent for the treatment of chronic myelogenous leukemia containing the amide derivative according to any one of claims 1 to 3, or its salt as an active ingredient and, optionally, a pharmaceutically acceptable non-toxic inert carrier.

7. Therapeutic agent for the treatment of acute lymphoblastic leukemia containing the amide derivative according to any one of claims 1 to 3, or its salt as an active ingredient and, optionally, a pharmaceutically acceptable non-toxic inert carrier.

8. Therapeutic agent for the treatment of acute myelogenous leukemia containing the amide derivative according to any one of claims 1 to 3, or its salt as an active ingredient and optionally, FA is matemticas acceptable non-toxic inert carrier.

Priority signs:

Signs relating to R1, R2, R3and Het1 are disclosed in the priority application No. 2002-189269 from 28.06.2002, 2002-305146 from 18.10.2002 and 2002-377937 from 26.12.2002, except the following:

for the case of A

where the sign "R2is the nitrogroup," revealed only in applications No. 2002-305146 from 18.10.2002 and 2002-377937 from 26.12.2002; and then

for the case of A

R1represents a saturated cyclic amino group, substituted C1-10alkoxycarbonyl; R3represents halogen or1-10alkoxygroup, Het1 represents formulas 2-5, 7 and 8;

for the case

R1is 1-pyrrolidinyl, piperidino, 4-ethylpiperazin-1-yl, 4-n-propylpiperazine-1-yl, CIS-3,5-dimethylpiperazine-1-yl, morpholino, dimethylamino or diethylamino;

R2represents methyl, methoxy, methoxycarbonyl, nitro, dimethylcarbamoyl or cyano;

R3represents a hydrogen, bromine or methoxy;

priority date corresponds to the date of filing the application with the Russian patent office.

Sign Het2 (for case A), represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridine, values of 3-pyridyl and 5-pyrimidinyl, pyrazinyl, pyridazinyl or 1,2-dihydropyridine and Het2 may be substituted by 1-3 identical or different substituents selected is passed from halogen revealed in all the priority requests.

The sign "4-pyrimidinyl, which can be substituted by 1-3 identical or different substituents selected from halogen disclosed in application No. 2002-305146 from 18.10.2002 and 2002-377937 from 26.12.2002.



 

Same patents:

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 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

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to a derivative copernicia and their pharmaceutically acceptable salts of General formula I

< / BR>
where R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a methyl group, R4represents a hydrogen atom and X represents a methylene group; R1represents a hydrogen atom, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; or R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a sulfur atom

The invention relates to organic chemistry, namely to new derivatives of benzoperylene

The invention relates to new 2-imidazolin-2-yl)thieno - foroperational compounds, to intermediates used to obtain these compounds, and the way of dealing with these compounds with unwanted annual and perennial plants, namely 6-(2-imidazolin-2-yl)thieno - and furo[2,3-b] and 5-(2-imidazolin-2-yl)thieno - and furo[3,2-b]the pyridine compounds and the corresponding 2,3-dihydrothieno and 2,3-dihydropyrimidine with structural formulas (Ia) and (Ib):

< / BR>
whererepresents a single or double bond; R1represents a C1-C4alkyl; R2represents a C1-C4alkyl or C3-C6cycloalkyl; R1and R2together with the carbon atom to which they are joined, can form WITH3-C6cycloalkyl, optionally substituted stands; And represents СООR3CHO, CH2OH, COCH2HE, CONHCH2CH2OH, CONHOH or

R3hydrogen, C1-C12alkyl, which can be broken od is alkoxy, halogen, hydroxyl, C3-C6cycloalkyl, benzyloxy, fullam, phenyl, furfuryl, galopera, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyla, lower alkoxycarbonyl, cyano, C1-C4alkylthio or three (lower) alkylammonium; C3-C6alkenyl, optionally substituted by one of the following groups:1-C3alkoxy, phenyl, halogen or two WITH1-C3alkoxygroup or two halogen groups; C3-C6cyclooctyl, optionally substituted by one or two1-C3alkyl groups; C3-C10quinil, optionally substituted by phenyl, halogen or CH2IT; or the cation of an alkali metal or alkaline-earth metal (CA, BA) manganese, copper, iron, ammonium, or organic ammonium; RWITHand RDrepresent N or CH3; Represents N; COR4or SO2R5provided that when a represents a COR4or SO2R5and is a СOOR3the radical R3cannot be hydrogen or a salt-forming cation; R4represents a C1-C11alkyl, chloromethyl or phenyl, optionally substituted A5 alkyl or phenyl, optionally substituted one metalno, chloro - or nitro-group; W represents 0 or S; X represents 0, S or whenis a single bond, the group S 0; Y and Y', Z and Z' represent hydrogen, halogen, C1-C6alkyl, C1-C4hydroxy (lower) alkyl, C1-C6alkoxy, C1-C6acyloxy, benzoyloxy, optionally substituted by one or two1-C4alkyl, C1-C4alkoxygroup or halogen; C1-C4alkylthio, phenoxy,1-C4haloalkyl,1-C4haloalkoxy, nitro, cyano, C1-C4alkylamino,1-C4dialkylamino,1-C4alkylsulfonyl or phenyl, optionally substituted by one or more1-C4the alkyl, C1-C4alkoxy, halogen, or any combination of these two groups, where Y and Z are the same provided that Y and Z represent hydrogen, halogen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl; and taken together, Y and Z form a ring in which YZ has the structural formula -(CH2)n- where n являе/www.fips.ru/fullimg/rupat2/19962/004.dwl/2058313-8t.gif" ALIGN="ABSMIDDLE">-=where L, M, Q, and R7each represent hydrogen, halogen, nitro, C1-C4lower alkyl, C1-C4lower alkoxy, methoxy, phenyl, phenoxy, provided that only one of the radicals L, M, Q or R7may have a value different from hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy; or a pyridine-N-oxides, when W represents oxygen or sulfur and a is COOR3; and when R1and R2not the same, the optical isomers of these compounds, except for the case when R3represents a salt-forming cation, their salts kislotoustoichivam

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

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

26 cl, 17 tbl, 221 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to azaindoleoxoacetic derivatives of piperazine of the general formula (I): wherein Q is chosen from the group consisting of the following compounds: ; -W- represents compound of the formula: . Proposed compounds possess antiviral activity both in separate using and in combination with other antiviral, anti-infectious agents, immunomodulating agents or inhibitors HIV entering. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

55 cl, 10 tbl, 169 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

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

SUBSTANCE: invention describes novel derivatives of N-triazolylmethylpiperazine of the general formula (I): , wherein R1 means hydrogen atom or (lower)-alkyl; R2 means (lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, cycloalkyl with 5-6 carbon atoms in cycle, pyridinyl-(lower)-alkyl, possibly bi-substituted phenyl-(lower)-alkyl, phenyloxy-(lower)-alkyl substituted with halogen atom in phenyl ring; R3 means (lower)-alkyl, (lower)-alkyloxycarbonyl-(lower)-alkyl or (C5-C6)-cycloalkyl, or both R2 and R3 in common with nitrogen atom to which they are bound form substituted pyrrolidine ring or cyclic group of the formula (a): , wherein A means nitrogen, oxygen atom, methylene or methylidene group wherein its double bond is formed in common with adjacent carbon atom at position 3 of the group (a), and if A means nitrogen atom then this nitrogen atom has substitute R4', and in this case n means 2 or 3, and R4' means (lower)-alkyl, possibly substituted phenyl-(lower)-alkyl, possibly substituted pyridyl, pyridyl-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, pyrimidyl-(C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(lower)-alkyl or morpholinyl-(lower)-alkyl; R4 and R5 mean hydrogen atom and in all cases n means a whole number from 1 to 2; R4 means hydrogen atom, (lower)-alkyl, (lower)-alkoxy-(lower)-alkyl, (lower)-alkoxycarbonyl, (lower)-alkoxycarbonyl-(lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, phenyl, pyrrolidinyl, pyrrolidinyl-(lower)-alkyl, pyridyl or piperidinyl, cyclohexyl, cyclohexyl-(lower)-alkyl, phenyl-(lower)-alkyl, pyridyl monosubstituted with (lower)-alkyl, phenyl-(lower)-alkyl monosubstituted with (lower)-alkyl, pyrimidyl, pyridyl-(lower)-alkyl, morpholinyl-(lower)-alkyl; R5 means hydrogen atom, (lower)-alkyl or (lower)-alkoxy-(lower)-alkyl, or R4 and R5 taken in common mean spiroethylenedioxy-group bound with carbon atom of the group (a), (C3-C4)-alkylene bound with two adjacent atoms of the group (a) or phenyl anellated by two adjacent carbon atoms of the group (a), and their physiologically acceptable acid-additive salts also. Also, invention relates to methods for synthesis of these compounds, a medicinal agent based on thereof and intermediate compound in synthesis of novel compounds. Novel compounds are antagonists of neurokinin receptors and display effect in peripheral region preferably and can be used in treatment of functional and inflammatory disorders of digestive tract.

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

10 cl, 4 tbl, 4 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I): wherein X means -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO, -SO2; m = 1; A represents a direct bond; R1 means hydrogen atom (H); R2 and R3 are chosen independently from H, (C1-C6)-alkyl, heterocycloalkyl, phenyl, heteroaryl, phenylalkyl, phenylheteroalkyl, heteroarylalkyl, heterocycloalkylalkyl; R4 represents H; R5 represents monocyclic, bicyclic or tricyclic group. Also, invention describes a pharmaceutical composition and using compounds in preparing a medicinal agent for using in treatment of diseases or states mediated by one ore more enzymes representing metalloproteinase. Compounds of the formula (I) are useful as inhibitors of metalloproteinases being especially as inhibitors of MMP12.

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

14 cl, 16 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to piperidine- and piperazine-substituted N-hydroxyformamides of the general formula (I) or their pharmaceutically acceptable salts wherein B represents phenyl group monosubstituted at 3- or 4-position with halogen atom or trifluoromethyl group or bisubstituted at 3- and 4-position with halogen atom (that can be similar or distinct); or B represents 2-pyridyl or 2-pyridyloxy-group monosubstituted at 4-, 5- or 6-position with halogen atom, trifluoromethyl group, cyano-group or (C1-C4)-alkyl; or B represents 4-pyrimidinyl group possibly substituted with halogen atom or (C1-C4)-alkyl at 6-position; X represents carbon or nitrogen atom; R1 represents trimethyl-1-hydantoin-(C2-C4)-alkyl or trimethyl-3-hydantoin-(C2-C4)-alkyl group; or R1 represents phenyl or (C2-C4)-alkylphenyl monosubstituted at 3- or 4-position with halogen atom, trifluoromethyl group, thio-group, (C1-C3)-alkyl or (C1-C3)-alkoxy-group; or R1 represents phenyl-SO2NH-(C2-C4)-alkyl; or R1 represents 2-pyridyl or 2-pyridyl-(C2-C4)-alkyl; or R1 represents 3-pyridyl or 3-pyridyl-(C2-C4)-alkyl; or R1 represents 2-pyrimidine-SCH2CH2; or R1 represents 2- or 4-pyrimidinyl-(C2-C4)-alkyl possibly monosubstituted with one of the following substitutes: halogen atom, trifluoromethyl, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, 2-pyrazinyl possibly substituted with halogen atom, or 2-pyrazinyl-(C2-C4)-alkyl possibly substituted with halogen atom. Also, invention describes a method for synthesis (variants) of compounds of the formula (I) and a pharmaceutical composition. Compounds can be used as inhibitors of metalloproteinases and useful in such morbidity states as inflammatory and allergic ones.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

12 cl, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-hetaryl-substituted derivatives of 1,2-tropolones of the general formula (Ia): wherein R1 and R2 mean (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl, nitro-group; Het means six-membered nitrogen heterocycle condensed with one or two benzyl rings that can be substituted with substitutes chosen from group comprising halogen atom, nitro-group, (C1-C6)-alkyl, oxy-(C1-C6)-alkyl, secondary amino-group chosen from anilino-, substituted anilino-, hydroxyethylamino-group, or tertiary amino-group chosen from morpholino-, piperidino-, piperazino-group, 1H-1-imidazolyl. Also, invention relates to a method for synthesis of 2-hetaryl-substituted derivatives of 1,3-tropolone. Method involves condensation of benzoquinones-1,2 with 2-methylheterocycles at heating in the presence of acetic acid taken in the amount providing its role as both a catalyst and a solvent. Also, invention relates to a pharmaceutical composition with antibacterial effect based on 2-hetaryl-substituted derivatives of 1,3-tropolone.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 5 tbl, 3 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

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