Imidaqzolo-5-yl-2-anilinopyrimidines as agents for inhibition of cell proliferation, method for their preparing (variants), using, pharmaceutical composition and method for producing

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

 

The present invention relates to pyrimidine derivatives or their pharmaceutically acceptable salts or their esters, gidrolizuyutza in vivo, which have inhibitory activity against cell cycle, and accordingly are suitable for use due to their activity against cell proliferation (e.g., cancer) and for this reason are suitable for use in methods of treatment of the human or animal. The present invention also relates to a method of obtaining the above pyrimidine derivatives, to pharmaceutical compositions containing them and to their use for producing medicaments used for the production of effect against proliferation of cells in a warm-blooded animal such as man.

A family of intracellular proteins called cyclename, plays a Central role in cell cycle. Synthesis and degradation of tsiklonov tightly controlled, so that their level of ekspressirovali fluctuates during the cell cycle. Cycline associated with cyclin-dependent serine/threonin kinases (CDK), and this binding is essential for CDK activity (such as CDK1, CDK2, CDK4 and/or CDK6) in the cell. Although specific details on how each of these factors combined for regulating the activity of cdks, Vlada obscure, the balance between the two dictates whether the cell to develop within the cell cycle or not.

Recent studies of the convergence of oncogene and suppressor gene tumor identify the entry in the cell cycle as a key point to control mitogenesis tumors. Moreover, CDK, apparently, are in the cycle after a number of signaling pathways oncogene. Rasagulla CDK activity by positive regulation of tsiklonov and/or erasing of endogenous inhibitors, apparently, is an important axis between mitogenic signalling pathways and proliferation of tumor cells.

Accordingly, it was found that the inhibitor of cell cyclacenes, in particular inhibitors of CDK2, CDK4 and/or CDK6 (which are in S-phase and G1-S and G1-S phase, respectively), should represent the value as an inhibitor of cell proliferation, such as cancer cell growth in mammals.

The present invention is based on the discovery of the fact that certain pyrimidine compounds unexpectedly inhibit exposure of the cell cyclacenes, demonstrating selectivity for CDK2, CDK4 and CDK6, and thus have properties directed against cell proliferation. Such properties, as expected, are of value in the treatment of painful conditions associated with abnormalities in the cells is cnyh cycles and cell proliferation such as cancers (solid tumors and various types of leukemia), fibroproliferative and differentiationin disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma,acute and chronic neuropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and diseases of the eye with the proliferation of retinal vessels.

Accordingly, the present invention provides a compound of formula (I):

where:

R1represents halogen, nitro, cyano, hydroxy, amino, carboxy, carbarnoyl, mercapto, C1-6alkyl,C1-6alkoxy, C2-6alkenyl or C2-6quinil;

p is 0-4; where the values of R1may be the same or different;

R2represents sulfamoyl or group, Ra-Rb-;

q is 0-2; where the values of R2may be the same or different; and where p + q = 0-5;

R3represents halogen, nitro, cyano, hydroxy, trifluoromethyl, triptoreline, amino, carboxy, carbarnoyl, mercapto, sulfamoyl, C1-3alkyl, C2-3alkenyl, C2-3quinil, C1-3alkoxy, C1-3alkanoyl, N-(C1-3alkyl)amino, N,N-(C1-3alkyl)2amino, C1-3alkanolamine, N-(C1-3alkyl)carbarnoyl, N,N-(C1-3alkyl) 2carbarnoyl, C1-3S(O)andwhere a is 0-2, N-(C1-3alkyl)sulfamoyl or N,N-(C1-3alkyl)2sulfamoyl; where R3may be optionally substituted on a carbon atom by one or more Rc;

n is 0-2, where the values of R3may be the same or different;

R4represents hydrogen, C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-8cycloalkyl, phenyl or heterocyclic group associated with carbon; where R4may be optionally substituted on a carbon atom by one or more Rd; and where, if said heterocyclic group contains residue-NH-, its nitrogen may be optionally substituted by a group selected from Rn;

R5and R6are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, triptoreline, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanolamine, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6S(O)andwhere a is 0-2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulfamoyl, N,N-(C1-6alkyl)2sulfamoyl, C1-6alkylsulfate is ylamino, C3-8cycloalkyl or 4-7 membered saturated heterocyclic group; R5and R6independently from each other may be optionally substituted on a carbon atom by one or more Re; and where, if the specified 4-7 membered saturated heterocyclic group contains residue-NH-, its nitrogen may be optionally substituted by a group selected from Rf;

Rais selected from C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, heterocyclic group, panels1-6of alkyl or (heterocyclic group)C1-6of alkyl; Ramay be optionally substituted on a carbon atom by one or more Rg; and where, if said heterocyclic group contains residue-NH-, its nitrogen may be optionally substituted by a group selected from Rh;

Rbrepresents-C(O)-, -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or-N(Rm)SO2-; where Rmrepresents hydrogen or C1-6alkyl, optionally substituted by one or more Riand r is 1-2;

Rd, Rgand Riare independently selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6 of alkyl, C2-6alkenyl, C2-6the quinil, C1-6alkoxy, C1-6alkoxyl1-6alkoxy, C1-6alkoxyl1-6alkoxyl1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanolamine, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6S(O)andwhere a is 0-2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulfamoyl, N,N-(C1-6alkyl)2sulfamoyl, C1-6alkylsulfonyl, C3-8cycloalkyl, phenyl, heterocyclic group, panels1-6alkyl-R°-, (heterocyclic group)C1-6alkyl-R°-, phenyl-R°or (heterocyclic group)-R°-; where Rd, Rgand Riindependently from each other may be optionally substituted on a carbon atom by one or more Rj; and where, if said heterocyclic group contains residue-NH-, its nitrogen may be optionally substituted by a group selected from Rk;

Raboutrepresents-O-, -N(Rp)-, -C(O)-, -N(Rp)C(O)-, -C(O)N(Rp)-, -S(O)S-, -SO2N(Rp)- or-N(RP)SO2-; where Rprepresents hydrogen or C1-6alkyl, and s is 0-2;

Rf, Rh, Rkand Rnare independently selected from C1-4of alkyl, C1-4alkanoyl, C 1-4alkylsulfonyl, C1-4alkoxycarbonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; where Rf, Rh, Rkand Rnindependently from each other may be optionally substituted on a carbon atom by one or more Rl; and

Rc, Re, Rland Rjare independently selected from halogen, nitro, cyano, hydroxy, triptoreline, trifloromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbazole, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbazole, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesila, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl, N-ethylsulfonyl, N,N-dimethylsulphamoyl, N,N-diethylcarbamoyl or N-methyl-N-ethylsulfonyl; or their pharmaceutically acceptable salt or ester, hydrolisis in vivo.

In another aspect the present invention provides a compound of formula (I):

where:

R1represents halogen, nitro, cyano, hydroxy, amino, carboxy, carbarnoyl, mercapto, C1-6 alkyl, C1-6alkoxy, C2-6alkenyl or C2-6quinil;

p is 0-4; where the values of R1may be the same or different;

R2represents sulfamoyl or group, Ra-Rb-;

q is 0-2; where the values of R2may be the same or different; and where p + q = 0-5;

R3represents halogen, nitro, cyano, hydroxy, trifluoromethyl, triptoreline, amino, carboxy, carbarnoyl, mercapto, sulfamoyl, C1-3alkyl, C2-3alkenyl, C2-3quinil, C1-3alkoxy, C1-3alkanoyl, N-(C1-3alkyl)amino, N,N-(C1-3alkyl)2amino, C1-3alkanolamine, N-(C1-3alkyl)carbarnoyl, N,N-(C1-3alkyl)2carbarnoyl, C1-3S(O)andwhere a is 0-2, N-(C1-3alkyl)sulfamoyl or N,N-(C1-3alkyl)2sulfamoyl; where R3may be optionally substituted on a carbon atom by one or more Rc;

n is 0-2, where the values of R3may be the same or different;

R4represents hydrogen, C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-8cycloalkyl, phenyl or heterocyclic group associated with carbon; where R4may be optionally substituted on a carbon atom by one or more Rd; and where, if said heterocyclic group contains residue-NH-, and his is from may be optionally substituted by a group selected from Rn;

R5and R6are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, triptoreline, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanolamine, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6S(O)andwhere a is 0-2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulfamoyl, N,N-(C1-6alkyl)2sulfamoyl, C1-6alkylsulfonyl, C3-8cycloalkyl or 4-7-membered saturated heterocyclic group; R5and R6independently from each other may be optionally substituted on a carbon atom by one or more Re; and where, if the specified 4-7-membered saturated heterocyclic group contains residue-NH-, its nitrogen may be optionally substituted by a group selected from Rf;

Rais selected from C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, heterocyclic group, panels1-6of alkyl or (heterocyclic group)C1-6of alkyl; Ramay be optionally substituted on ATO is e carbon one or more R g; and where, if said heterocyclic group contains residue-NH-, its nitrogen may be optionally substituted by a group selected from Rh;

Rbrepresents-C(O)-, -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -SO2N(Rm)- or-N(Rm)SO2-;

where Rmrepresents hydrogen or C1-6alkyl, optionally substituted by one or more Riand r is 1-2;

Rd, Rgand Riare independently selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanolamine, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6S(O)andwhere a is 0-2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulfamoyl, N,N-(C1-6alkyl)2sulfamoyl, C1-6alkylsulfonyl, C3-8cycloalkyl, phenyl, heterocyclic group, phenyl-R°or (heterocyclic group)-R°-; where Rd, Rgand Riindependently from each other may be optionally substituted on a carbon atom by one or more Rj; and where, if said heterocyclic group contains residue-NH-,its nitrogen may be optionally substituted by a group selected from Rk;

Raboutrepresents-O-, -N(Rp)-, -C(O)-, -N(Rp)C(O)-, -C(O)N(Rp)-, -S(O)s-, -SO2N(Rp)- or-N(Rp)SO2-; where Rprepresents hydrogen or C1-6alkyl, and s is 0-2;

Rf, Rh, Rkand Rnare independently selected from C1-4of alkyl, C1-4alkanoyl, C1-4alkylsulfonyl, C1-4alkoxycarbonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; where Rf, Rhand Rkindependently from each other may be optionally substituted on a carbon atom by one or more Rl; and

Rc, Re, Riand Rjare independently selected from halogen, nitro, cyano, hydroxy, triptoreline, trifloromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbazole, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbazole, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesila, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl, N-ethylsulfonyl, N,N-dimethylsulphamoyl, N,N-diethylcarbamoyl or N-methyl-N;

or their pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

In the present description, the term "alkyl" includes an alkyl group with a straight or branched chain, but references to individual alkyl groups such as "propyl", point only to the variant with a straight chain. For example, "C1-6alkyl" includes C1-4alkyl, C1-3alkyl, propyl, isopropyl and tert-butyl. However references to individual alkyl groups such as "propyl", point only to the variant with a straight chain, and references to individual alkyl groups branched chain, such as "isopropyl", point only to the version of branched chain. A similar condition applies to other radicals, for example "panels1-6alkyl includes panels1-4alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halogen" refers to fluorine, chlorine, bromine and iodine.

There, where the optional substituents are selected from one or more" groups, you need to understand that this definition includes all substituents selected from only one of these groups or substituents selected from two or more of the following groups.

"Heterocyclic group" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of the which, at least one atom is chosen from nitrogen, sulphur or oxygen, which, if not stated otherwise, may be associated with the carbon atoms or nitrogen, where the group-CH2- can optionally be replaced by-C(O)-, a ring nitrogen atom may optionally bear on yourself C1-6alkyl group to form a Quaternary compound or a ring nitrogen atom and/or sulfur may optionally be oxidized, with the formation of N-oxides and/or S-oxides. The examples and the corresponding values of the term "heterocyclic group" is morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolin, indolyl, hinely, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinil, diazolidinyl, pyrrolidinyl, thiomorpholine, pyrrolidyl, homopiperazine, 3,5-dioxopiperazinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrole, 4-pyridone, 1-isohedron, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. Preferably the "heterocyclic group" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms, of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, if not stated otherwise, to be bound with the carbon atoms or nitrogen, the group-CH2- may not necessarily be replacing the a-C(O)-, and a ring sulphur atom may be optionally oxidized with the formation of the S-oxides. More preferably the "heterocyclic group" is tetrahydrofuryl, pyridyl, pyrrolidinyl, morpholino, imidazolyl, piperidinyl or pyrrolidinyl. In particular, the "heterocyclic group" is tetrahydrofuryl or morpholino. In another aspect of the present invention, in particular, the "heterocyclic group" represents a tetrahydrofuran-2-yl, 2-oxopyrrolidin-1-yl, furan-2-yl, oxazolyl, morpholino, piperidinyl, thiazolyl, pyrazinyl, isoxazolyl, tetrahydropyran, pyridyl, isoxazolyl, isothiazolin, 1,2,5-thiadiazolyl, phthalimido.

"A 4-7-Membered saturated heterocyclic group" is a saturated monocyclic ring containing 4 to 7 atoms, of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, if not stated otherwise, to be bound with the carbon atoms or nitrogen, where the group-CH2- can optionally be replaced by-C(O)-, and the sulfur atom may be optionally oxidized with the formation of the S-oxides. The examples and the corresponding values of the term "heterocyclic group" is morpholino, piperidyl, 1,4-dioxane, 1,3-dioxolane, 1,2-oxathiolane, imidazolidinyl, pyrazolidine, piperazinil, diazolidinyl, pyrrolidinyl, thiomorpholine, piperazine and tetrahydropyranyl.

Example "C1-6alkanoyloxy represents acetoxy. Examples of "C1-6alkoxycarbonyl" include C1-4alkoxycarbonyl, methoxycarbonyl, etoxycarbonyl, n - and tert-butoxycarbonyl. Examples of "C1-6alkoxy" include C1-4alkoxy, C1-3alkoxy, methoxy, ethoxy and propoxy. Examples of "C1-6alkanolamine include formamido, acetamido, propionamido. Examples of "C1-6S(O)andwhere a is 0 to 2" include C1-6alkylsulfonyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methil and ethylsulfonyl. Examples of "C1-6S(O)rwhere r is 1-2" include methylsulfinyl, ethylsulfinyl, methil and ethylsulfonyl. Examples of "C1-6alkanoyl" include C1-6alkanoyl, propionyl and acetyl. Examples of "N-C1-6alkylamino" include methylamino, ethylamino. Examples of "N,N-(C1-6alkyl)2amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "C2-6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C2-6the quinil" are ethinyl, 1-PROPYNYL and 2-PROPYNYL. Examples of "N-(C1-6alkyl)sulfamoyl" are N-(methyl)sulfamoyl and N-(ethyl)sulfamoyl. Examples of "N-(C1-6alkyl)2sulfamoyl" are N,N-(dimethyl)sulfamoyl and N-(methyl)-N-(ethyl)sulfamoyl. Examples of "N(C 1-6alkyl)carbamoyl" are N-(C1-4alkyl)carbarnoyl, methylaminomethyl and ethylaminoethanol. Examples of "N,N-(C1-6alkyl)2carbamoyl" are N,N(C1-4alkyl)2carbarnoyl, dimethylaminoethyl and methylaminoethanol. Examples of "C3-8cycloalkyl" are cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl. Examples of "(heterocyclic group)C1-6of alkyl" include pyridylmethyl, 3-morpholinopropan and 2-pyrimid-2-ileti. Examples of "C3-8cycloalkyl1-6of alkyl" represents cyclopropylethyl, cyclobutylmethyl, 2-cyclopropylethyl and cyclohexylethyl.

Suitable for use pharmaceutically acceptable salt of the compound of the present invention is, for example, an acid additive salt of the compound of the present invention which is sufficiently basic, for example, an acid additive salt, for example, inorganic or organic acids, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric or maleic acid. Also suitable for use pharmaceutically acceptable salt of the compound of the present invention which is sufficiently acidic is an alkali metal salt, for example, sodium salt or potassium salt SEL cinselligi metal, for example, a salt of calcium or magnesium, ammonium salt or a salt of organic bases, which give physiologically acceptable cation, for example, salt of methylamine, dimethylamine, trimethylamine, piperidine, research or Tris-(2-hydroxyethyl)amine.

Ester, hydrolisis in vivo, the compounds of formula (I)containing a carboxy or a hydroxy-group represents, for example, pharmaceutically acceptable ester which is hydrolysed in the human or animal with the receipt of the original acid or alcohol. Suitable for use pharmaceutically acceptable esters for carboxy include C1-6alkoxymethyl esters, for example, methoxymethyl, C1-6alkanoyloxy esters, for example, pivaloyloxymethyl, telegrafie esters, C3-8cycloalkylcarbonyl1-6alkalemia esters, for example, 1-cyclohexyloxycarbonyloxy; 1,3-dioxolan-2-animecrave esters, for example 5-methyl-1,3-dioxolan-2-animationy; and (C1-6alkoxycarbonylmethyl esters, for example, 1-methoxycarbonylmethylene, and can be formed at any carboxypropyl in the compounds of the present invention.

Ester, hydrolisis in vivo, the compounds of formula (I)containing a hydroxy-group, includes Neorganicheskie the esters, such as phosphate esters, and α-aryloxyalkyl ethers and related compounds which as a result of the hydrolysis of ester in vivo break up with getting the original hydroxy-group. Examples α-aryloxyalkanoic ethers include acetoxymethyl and 2,2-dimethylphenylacetate. The choice of groups, forming esters, gidrolizuacy in vivo, hydroxy, includes alkanoyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl, alkoxycarbonyl (obtaining alkalicarbonate esters), dialkylamino and N-(dialkylaminoalkyl)-N-allylcarbamate (obtaining carbamates), dialkylaminoalkyl and carboxyethyl. Examples of the substituents on the benzoyl include morpholine, piperazine derivatives, associated with a ring nitrogen atom via a methylene group in the 3 - or 4-position sensornogo rings.

Some compounds of formula (I) may have chiral centres and/or geometric isomeric centres (E-and Z-isomers), and it should be understood that the present invention encompasses all such optical isomers, diastereoisomers and geometric isomers that possess inhibitory activity against CDK.

The present invention relates to any tautomeric form of the compounds of formula (I), which have inhibitory activity against CDK, and all ingesta. In particular, the person skilled in the art will notice that where R4represents hydrogen, imidazole ring represented by the formula (I)may tautomerization.

It should also be understood that certain compounds of formula (I)can exist in solvated, and resolutional forms, for example, in such forms as hydrated forms. You should understand that the present invention covers all of solvated forms which possess inhibitory activity against CDK.

Preferred values of R1, R2, R3, R4, R5, R6, n, p, and q are as follows. Such values can be used, where necessary, together with any of the definitions, claims or embodiments defined above or below.

Preferably R1represents halogen, amino, C1-6alkyl or C1-6alkoxy.

More preferably R1represents halogen, C1-4alkyl or C1-4alkoxy.

Specifically, R1represents chlorine, C1-3alkyl or C1-3alkoxy.

More specifically, R1represents chlorine.

In another aspect of the present invention, R1preferably represents halogen, amino, C1-6alkyl or C1-6alkoxy.

In another aspect of the present invention, R1more preferably represents chlorine, amino, methyl or methoxy.

Preferably p is 0-2; where the values of R1may be the same or different.

More preferably p is 0 or 1.

In one aspect of the present invention preferably p is 0.

In another aspect of the present invention preferably p is 1.

Preferably, when p is 1, R1represents a group that is in the meta - or para-position relative to the-NH-group of the aniline of the formula (I).

More preferably, when p is 1, R1located in the meta-position relative to the-NH-group of the aniline of the formula (I).

Preferably R2represents sulfamoyl or group, Ra-Rb-; where

Rais selected from C1-6of alkyl, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, heterocyclic group, panels1-6of alkyl or (heterocyclic group)C1-6of alkyl; Ramay be optionally substituted on a carbon atom by one or more Rg;

Rbrepresents-N(Rm)C(O)-, -C(O)N(Rm)-, -SO2N(Rm)-or-N(Rm)SO2-; where Rmrepresents hydrogen;

Rgis selected from halogen, hydroxy, amino, carbamoyl, C1-6the alkyl or C1-6alkoxy; and

R jis selected from halogen or hydroxy.

More preferably R2represents sulfamoyl or group, Ra-Rb-; where

Rais selected from C1-6of alkyl, C3-8cycloalkyl1-6of alkyl, panels1-6of alkyl or (heterocyclic group)C1-6of alkyl; Ramay be optionally substituted on a carbon atom by one or more Rg;

Rbrepresents-N(Rm)SO2-; where Rmrepresents hydrogen;

Rgis selected from halogen, hydroxy, carbamoyl or C1-6alkoxy; and

Rjis selected from hydroxy.

Specifically, R2represents sulfamoyl, N-(tetrahydrofuran-2-ylmethyl)sulfamoyl, N-[3-(2-oxopyrrolidin-1-yl)propyl]sulfamoyl, N-(3-methoxypropyl)sulfamoyl, N-(4-terbisil)sulfamoyl, N-(cyclopropylmethyl)sulfamoyl, N-propylsulfonyl, N-(2,3-dihydroxypropyl)sulfamoyl, N-[2-(2-hydroxyethoxy)ethyl]sulfamoyl, N-(furan-2-ylmethyl)sulfamoyl, N-(2-hydroxyethyl)sulfamoyl or N-(carbamoylmethyl)sulfamoyl.

In another aspect of the present invention R2preferably represents sulfamoyl or group, Ra-Rb-; where

Rais selectedfrom C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, phenyl rigmarolish group; where Ramay be optionally substituted on a carbon atom by one or more Rg;

Rbrepresents-N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or-N(Rm)SO2-; where Rmrepresents hydrogen or C1-6alkyl, and r is 2;

Rgis selected from halogen, hydroxy, amino, cyano, carbamoyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6alkoxy, C1-6alkoxyl1-6alkoxyl1-6alkoxy, N,N-(C1-6alkyl)2amino, C1-6S(O)andwhere a is 2, C3-8cycloalkyl, phenyl, heterocyclic group, panels1-6alkyl-Raboutor (heterocyclic group)-Rabout-; where Rgmay be optionally substituted on a carbon atom by one or more Rj;

Raboutrepresents-O-; and

Rjis selected from halogen, hydroxy, methyl or methoxy.

In another aspect of the present invention R2more preferably represents sulfamoyl or group, Ra-Rb-; where

Rais selected from methyl, ethyl, propyl, tert-butyl, penttila, 1,1-dimethylpropyl, 2,2-dimethylpropyl, allyl, 2-PROPYNYL, cyclopropyl, cyclobutyl, phenyl or oxazolyl; where Ramay be optionally substituted on the atom is carbon one or more R g;

Rbrepresents-N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)2-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or-N(Rm)SO2-; where Rmrepresents hydrogen or methyl;

Rgis selected from fluorine, hydroxy, amino, cyano, carbamoyl, methyl, methoxy, ethoxy, isopropoxy, ethoxyethoxy, toxicokinetics, N,N-dimethylamino, mesila, cyclopropyl, phenyl, tetrahydrofuranyl, 2-oxopyrrolidin, 1,3-DIOXOLANYL, morpholino, piperidinyl, furan, thiazolyl, pyrazinyl, isoxazolyl, tetrahydropyrane, pyridyl, benzyloxy, isoxazolidine, isothiazolinone, 1,2,5-thiadiazolidine, where Rgmay be optionally substituted on a carbon atom by one or more Rj; and

Rjis selected from fluorine, hydroxy, methyl or methoxy.

In another aspect of the present invention, specifically, R2represents sulfamoyl, N-(tert-butoxycarbonyl)sulfamoyl, N-(tetrahydrofur-2-ylmethyl)sulfamoyl, N-(cyclopropylmethyl)sulfamoyl, N-(FSD-2-ylmethyl)sulfamoyl, N-(cyanomethyl)sulfamoyl, N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)sulfamoyl, N-(carbamoylmethyl)sulfamoyl, N-methylcarbamoyl, N-(4-terbisil)sulfamoyl, N-(pyridine-2-ylmethyl)sulfamoyl, N-(pyridine-3-ylmethyl)sulfamoyl, N-(4-methylthiazole-2-yl)sulfamoyl, N-(3-methylisoxazol-5-ylmethyl)sulfamoyl, N-(tetrahydrate the EN-2-ylmethyl)sulfamoyl, N-(2-methylpyridin-5-yl)sulfamoyl, N-[2-(2-hydroxyethoxy)ethyl]sulfamoyl, N-(2-hydroxyethyl)sulfamoyl, N-(2,2,2-triptorelin)sulfamoyl, N-(2-methoxyethyl)sulfamoyl, N-(2-methylethyl)sulfamoyl, N-(2-benzyloxyethyl)sulfamoyl, N-(2,2-dimethoxymethyl)sulfamoyl, N-[2-(N,N-dimethylamino)ethyl]sulfamoyl, N-(2-piperidine-1-retil)sulfamoyl, N-[2-(methoxyethoxy)ethyl]sulfamoyl, N-ethylsulfonyl, N-[2-(2-methoxyethoxy)ethyl]sulfamoyl, N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulfamoyl, N-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl)sulfamoyl, N-(2-pyridin-2-retil)sulfamoyl, N-(2-pyridin-4-retil)sulfamoyl, N-(2-isoxazol-3-Eloxatin)sulfamoyl, N-(2-isothiazol-3-Eloxatin)sulfamoyl, N-(2-1,2,5-thiadiazole-3-Eloxatin)sulfamoyl, N-methyl-N-(2-methoxyethyl)sulfamoyl, N-[3-(2-oxopyrrolidin-yl)propyl]sulfamoyl, N-(3-methoxypropyl)sulfamoyl, N-propylsulfonyl, N-(2,3-dihydroxypropyl)sulfamoyl N-(3-morpholinopropan)sulfamoyl, N-[3-(N,N-dimethylamino)propyl]sulfamoyl, N-(3,3,3-cryptochromes)sulfamoyl, N-(2,2-dimethyl-3-hydroxypropyl)sulfamoyl, N-(3-hydroxypropyl)sulfamoyl, N-(3-ethoxypropan)sulfamoyl, N-(2-hydroxypropyl)sulfamoyl, N-(3-isopropoxyphenyl)sulfamoyl, N-(3-isopropoxy-2-hydroxypropyl)sulfamoyl, N-(3-isoxazol-3-roxiprin)sulfamoyl, N-(3-isothiazol-3-roxiprin)sulfamoyl, N-(3-1,2,5-thiadiazole-3-roxiprin)sulfamoyl, N-(1,1-dimethylpropyl)sulfamoyl, N-methyl-N-(3-what morpholinopropan)sulfamoyl, N-butylsulfonyl, N-tert-butylsulfonyl, N-(2-hydroxybutyl)sulfamoyl, N-methyl-N-tert-butylsulfonyl, N-intercultural, N-(5-hydroxyphenyl)sulfamoyl, N-(4,5-dimethyloxazole-2-yl)sulfamoyl, N-(cyclopropyl)sulfamoyl, N-(cyclobutyl)sulfamoyl, N-(3-triptoreline)sulfamoyl, N-arylsulphonyl, N-(2-PROPYNYL)sulfamoyl, N-methylcarbamoyl, acetamido, methylamino or mesyl.

In another aspect of the present invention more specifically, R2represents N-(cyclopropylmethyl)sulfamoyl, N-(2,2,2-triptorelin)sulfamoyl, N-(2-methoxyethyl)sulfamoyl, N-(3-methoxypropyl)sulfamoyl, N-(cyclopropyl)sulfamoyl or N-(cyclobutyl)sulfamoyl.

Preferably q is 0 or 1.

In one aspect of the present invention preferably q is 0.

In another aspect of the present invention preferably q is 1.

Preferably, when q is 1, R2is meta - or para-position relative to the-NH-group of the aniline of the formula (I).

More preferably, when q is 1, R2located in the para-position relative to the-NH-group of the aniline of the formula (I).

Preferably p + q = 0-3.

More preferably p + q is 0-2.

Specifically, p + q is 0 or 1.

In one aspect of the present invention preferably p + q is equal to 0.

In another aspect of the present invention preferably p + q is 1.

Before occhialino R 3represents a halogen.

More preferably R3represents bromine.

In another aspect of the present invention preferably R3represents bromine or chlorine.

Preferably n is 0 or 1.

In one aspect of the present invention more preferably n is 0.

In another aspect of the present invention more preferably n is 1.

Preferably, when n is 1, R3is a 5-position pyrimidine ring.

Preferably R4represents hydrogen, C1-6alkyl, C2-6alkenyl, C2-6quinil; where R4may be optionally substituted on a carbon atom by one or more Rd; where Rdis such as defined here below.

More preferably R4represents hydrogen or C1-6alkyl; R4may be optionally substituted on a carbon atom by one or more Rd;

Rdis selected from amino, C1-6alkoxy, C1-6alkanolamine, C1-6alkylsulfonyl, phenyl, heterocyclic group, or (heterocyclic group)-R°-; where Rdmay be optionally substituted on a carbon atom by one or more Rj;

R° represents-C(O)N(Rp)-; where Rprepresents hydrogen; and

R jrepresents a halogen.

Specifically, R4represents hydrogen or C1-6alkyl; R4may be optionally substituted on a carbon atom by one or more Rd;

Rdis selected from amino, C1-6alkoxy, phenyl or heterocyclic group.

More specifically, R4represents hydrogen, methyl, ethyl, benzyl, 2-phthalimidomethyl, 2-amino-ethyl or 2-methoxyethyl.

Specifically preferred R4represents methyl or ethyl.

In another aspect of the present invention preferably R4represents hydrogen, C1-6alkyl or C2-6alkenyl; where R4may be optionally substituted on a carbon atom by one or more Rd; where

Rdis selected from halogen, amino, C1-6alkoxy, C1-6alkanolamine, C1-6alkylsulfonyl, phenyl or heterocyclic group.

In another aspect of the present invention more preferably R4represents hydrogen, methyl, ethyl, isopropyl or 3-butenyl; where R4may be optionally substituted on a carbon atom by one or more Rd; where

Rdis selected from fluorine, amino, methoxy, acetamido, methylamino, phenyl or phthalimido.

In another aspect of the present invention, specifically, R represents hydrogen, methyl, ethyl, isopropyl, 3-butenyl, benzyl, 2-phthalimidomethyl, 2-amino-ethyl, 2-methoxyethyl, 2-acetamidophenyl, 2-methylaminomethyl or 2,2,2-triptorelin.

In another aspect of the present invention more specifically, R4represents methyl, ethyl or isopropyl.

Preferably R5and R6are independently selected from hydrogen or C1-6the alkyl.

More preferably R5and R6are independently selected from hydrogen or methyl.

Specifically, R5is selected from hydrogen or methyl, and R6represents hydrogen.

In another aspect of the present invention preferably R5and R6are independently selected from hydrogen or C1-6of alkyl; R5and R6independently from each other may be optionally substituted on a carbon atom by one or more Re; where

Reis selected from halogen or methoxy.

In another aspect of the present invention more preferably R5and R6are independently selected from hydrogen, methyl, ethyl or isopropyl; R5and R6independently from each other may be optionally substituted on a carbon atom by one or more Re; where

Reis selected from fluorine or methoxy.

In another TSA is regarding subsection of the present invention more preferably R 5and R6are independently selected from hydrogen, methyl, ethyl, isopropyl, trifloromethyl or methoxymethyl.

In another aspect of the present invention more preferably R5represents methyl or isopropyl, and R6represents hydrogen.

For this reason, in another aspect, the present invention provides a compound of formula I (as shown above) where:

R1represents chlorine;

p is 0 or 1;

R2represents sulfamoyl or group, Ra-Rb-;

Rais selected from C1-6of alkyl, C3-8cycloalkyl1-6of alkyl, panels1-6of alkyl or (heterocyclic group)C1-6of alkyl; Ramay be optionally substituted on a carbon atom by one or more Rg;

Rbrepresents-N(Rm)SO2; where Rmrepresents hydrogen;

Rgis selected from halogen, hydroxy, carbamoyl or C1-6alkoxy;

Rjis selected from hydroxy;

q is 0 or 1;

p + q is 0 or 1;

n is 0;

R4represents hydrogen or C1-6alkyl; R4may be optionally substituted on a carbon atom by one or more Rd;

Rdis selected from amino, C1-6alkoxy, phenyl or heterocy the symbolic group; and

R5and R6are independently selected from hydrogen or C1-6of alkyl; or pharmaceutically acceptable salt or ester, hydrolisis in vivo.

For this reason, in a further aspect the present invention provides a compound of formula (I) (as depicted above), where:

R1represents chlorine;

p is 0 or 1; and when p is 1, R1located in the meta-position relative to the-NH-group of the aniline of the formula (I);

R2represents sulfamoyl, N-(tetrahydrofuran-2-ylmethyl)sulfamoyl, N-[3-(2-oxopyrrolidin-1-yl)propyl]sulfamoyl, N-(3-methoxypropyl)sulfamoyl, N-(4-terbisil)sulfamoyl, N-(cyclopropylmethyl)sulfamoyl, N-propylsulfonyl, N-(2,3-dihydroxypropyl)sulfamoyl, N-[2-(2-hydroxyethoxy)ethyl]sulfamoyl, N-(furan-2-ylmethyl)sulfamoyl, N-(2-hydroxyethyl)sulfamoyl or N-(carbamoylmethyl)sulfamoyl;

q is 0 or 1; and when q is 1, R2located in the para-position relative to the-NH-group of the aniline of the formula (I);

p + q is 1;

n is 0;

R4represents methyl or ethyl; and

R5is selected from hydrogen or methyl, and R6represents hydrogen; or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

For this reason, in a further additional aspect of the present invention pre is seen as a compound of formula (I) (as depicted above), where:

R1represents halogen, amino, C1-6alkyl or C1-6alkoxy;

p is 0-2; where the values of R1may be the same or different;

R2represents sulfamoyl or group, Ra-Rb-; where

Rais selected from C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, phenyl or heterocyclic group; Ramay be optionally substituted on a carbon atom by one or more Rg;

Rbrepresents-N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or-N(Rm)SO2-; where Rmrepresents hydrogen or C1-6alkyl, and r is 2;

Rgis selected from halogen, hydroxy, amino, cyano, carbamoyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6alkoxy, C1-6alkoxyl1-6alkoxyl1-6alkoxy, N,N-(C1-6alkyl)2amino, C1-6S(O)andwhere a is 2, C3-8cycloalkyl, phenyl, heterocyclic group, panels1-6alkyl - Raboutor (heterocyclic group)-R°-; where Rgmay be optionally substituted on a carbon atom by one or more Rj;

Raboutrepresents-O-;

Rjis selected from halogen, hydroxy, methyl or IU is hydroxy;

q is 0 or 1;

R3is a halogen;

n is 0 or 1;

R4represents hydrogen, C1-6alkyl or C2-6alkenyl; where R4may be optionally substituted on a carbon atom by one or more Rd; where

Rdis selected from halogen, amino, C1-6alkoxy, C1-6alkanolamine, C1-6alkylsulfonyl, phenyl or heterocyclic group; and

R5and R6are independently selected from hydrogen or C1-6of alkyl; R5and R6independently from each other may be optionally substituted on a carbon atom by one or more Re; where

Reis selected from halogen or methoxy,

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

For this reason, in another further additional aspect of the present invention provides a compound of formula (I) (as depicted above), where:

R1represents chlorine, amino, methyl or methoxy,

p is 0-2; where the values of R1may be the same or different;

R2represents sulfamoyl, N-(tetrahydrofur-2-ylmethyl)sulfamoyl, N-(cyclopropylmethyl)sulfamoyl, N-(FSD-2-ylmethyl)sulfamoyl, N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)sulfamoyl, N-(cyanomethyl)sulfamoyl, N-(ka is samoloty)sulfamoyl, N-methylcarbamoyl, N-(4-terbisil)sulfamoyl, N-(pyridine-2-ylmethyl)sulfamoyl, N-(pyridine-3-ylmethyl)sulfamoyl, N-(4-methylthiazole-2-yl)sulfamoyl, N-(3-methylisoxazol-5-ylmethyl)sulfamoyl, N-tetrahydropyran-2-ylmethyl)sulfamoyl, N-(2-methylpyridin-5-yl)sulfamoyl, N-[2-(2-hydroxyethoxy)ethyl]sulfamoyl, N-(2-hydroxyethyl)sulfamoyl, N-(2,2,2-triptorelin)sulfamoyl, N-(2-methoxyethyl)sulfamoyl, N-(2-methylethyl)sulfamoyl, N-(2-benzyloxyethyl)sulfamoyl, N-(2,2-dimethoxymethyl)sulfamoyl, N-[2-(N,N-dimethylamino)ethyl]sulfamoyl, N-(2-piperidine-1-retil)sulfamoyl, N-[2-(methoxyethoxy)ethyl]sulfamoyl, N-ethylsulfonyl, N-[2-(2-methoxyethoxy)ethyl]sulfamoyl, N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulfamoyl, N-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl)sulfamoyl, N-(2-pyridin-2-retil)sulfamoyl, N-(2-pyridin-4-retil)sulfamoyl, N-(2-isoxazol-3-Eloxatin)sulfamoyl, N-(2-isothiazol-3-Eloxatin)sulfamoyl, N-(2-1,2-5-thiadiazole-3-Eloxatin)sulfamoyl, N-methyl-N-(2-methoxyethyl)sulfamoyl, N-[3-(2-oxopyrrolidin-1-yl)propyl]sulfamoyl, N-(3-methoxypropyl)sulfamoyl, N-propylsulfonyl, N-(2,3-dihydroxypropyl)sulfamoyl, N-(3-morpholinopropan)sulfamoyl, N-[3-(N,N-dimethylamino)propyl]sulfamoyl, N-(3,3,3-cryptochromes)sulfamoyl, N-(2,2-dimethyl-3-hydroxypropyl)sulfamoyl, N-(3-hydroxypropyl)sulfamoyl, N-(3-ethoxypropan)sulfamoyl, N-(2-hydroxypropyl)sulfamoyl, N-(3-isopropoxyphenyl)su is efamol, N-(3-isopropoxy-2-hydroxypropyl)sulfamoyl, N-(3-isoxazol-3-roxiprin)sulfamoyl, N-(3-isothiazol-3-roxiprin)sulfamoyl, N-(3-1,2-5-thiadiazole-3-roxiprin)sulfamoyl, N-(1,1-dimethylpropyl)sulfamoyl, N-methyl-N-(3-morpholinopropan)sulfamoyl, N-butylsulfonyl, N-tert-butylsulfonyl, N-(2-hydroxybutyl)sulfamoyl, N-methyl-N-tert-butylsulfonyl, N-intercultural, N-(5-hydroxyphenyl)sulfamoyl, N-(4,5-dimethyloxazole-2-yl)sulfamoyl, N-(cyclopropyl)sulfamoyl, N-(cyclobutyl)sulfamoyl, N-(3-triptoreline)sulfamoyl, N-arylsulphonyl, N-(2-PROPYNYL)sulfamoyl, N-methylcarbamoyl, acetamido, methylamino or mesyl;

q is 0 or 1;

R3represents a bromine or chlorine;

n is 0 or l;

R4represents hydrogen, methyl, ethyl, isopropyl, 3-butenyl, benzyl, 2-phthalimidomethyl, 2-amino-ethyl, 2-methoxyethyl, 2-acetamidophenyl, 2-methylaminomethyl or 2,2,2-triptorelin;

R5and R6are independently selected from hydrogen, methyl, ethyl, isopropyl, trifloromethyl or methoxymethyl;

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

In another aspect of the present invention preferred compounds of the present invention are any connection of the examples presented, or its pharmaceutically acceptable salt, or ester, hydrolysis in vivo.

In another aspect of the present invention, preferred compounds of the present invention are compounds obtained in examples 25, 37, 42, 43, 53, 67, 121, 122, 123 and 136.

Preferred aspects of the present invention are those aspects that relate to the compound of formula (I) or its pharmaceutically acceptable salt.

Another aspect of the present invention provides a method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salt or its complex ether, gidrolizuyushchie in vivo, this method (where R1, R2, R3, R4, R5, R6n, p and q, unless otherwise indicated, are as defined in formula (I)), consists of:

Method (a) interaction of a pyrimidine of formula (II):

where L is a replaceable group; with an aniline of formula (III):

or

Method b) interaction of the compounds of formula (IV):

with the compound of the formula (V):

where T represents O or S; Rxmay be the same or different, and are selected from C1-6of alkyl;

Method (c) for compounds of formula (I), where R2represents sulfamoyl or group, Ra-Rb-, and Rba small town is a place-NHSO 2-; interaction pyrimidine of formula (VI):

where X is a replaceable group; with an amine of formula (VII):

Method (d) for compounds of formula (I); the interaction between the pyrimidine of formula (VIII)

with the compound of the formula (IX):

where Y is a replaceable group;

and after that, if necessary:

i) converting compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) formation of pharmaceutically acceptable salts or complex ester, gidrolizuyushchie in vivo.

L is a replaceable group, usable values for L are, for example, halogen or sulfonyloxy, for example chlorine, bromine, methansulfonate or toluene-4-sulfonyloxy.

X is a replaceable group, usable values for X are, for example, the group of fluorine or chlorine. Preferably X represents fluorine.

Y is a replaceable group, usable values for Y are, for example, halogen or sulfonyloxy group, for example, bromine, iodine or triftormetilfullerenov. Preferably Y made the focus of an iodine.

Specific reaction conditions for the above reactions are as follows.

Method a) Pyrimidines of formula (II) and anilines of formula (III) can interact together:

i) in the presence of an appropriate solvent, e.g. a ketone, such as acetone, or alcohol, such as ethanol or butanol or an aromatic hydrocarbon such as toluene or N-methylpyrrolidine, optionally in the presence of an appropriate acid, for example, inorganic acids such as hydrochloric acid or sulfuric acid, or organic acids such as acetic acid or formic acid (or the corresponding Lewis acid and at a temperature in the range of 0°C to the boiling point, preferably at the boiling point; or

ii) under standard Buchwald conditions (for example, see SOC., 118, 7215; SOC., 119, 8451; J.Org.Chem., 62, 1568 and 6066), for example, in the presence of palladium acetate, in an appropriate solvent, for example, in an aromatic solvent such as toluene, benzene or xylene, with an appropriate base, e.g. an inorganic base such as cesium carbonate, or organic base, such as tert-butoxide, in the presence of an appropriate ligand, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and at a temperature in the range from 25 to 80°C.

Pyrimidines Faure the uly (II), where L represents a chlorine, can be prepared according to scheme 1:

Scheme 1

Anilines of formula (III) are commercially available compounds or they are known from the literature, or they are prepared using standard methods known in this field.

Method b) Compounds of the formula (IV) and compounds of formula (V) interact together in an appropriate solvent, such as N-methylpyrrolidinone or butanol, at a temperature in the range of 100-200°C, preferably in the range of 150-170°C. the Interaction is preferably conducted in the presence of an appropriate base, such as sodium hydride, sodium methoxide or potassium carbonate.

The compounds of formula (V) can be prepared according to scheme 2:

Scheme 2

The compounds of formula (IV) and (Va) are commercially available compounds or they are known from the literature, or they are prepared using standard methods known in this field.

Method c) Compounds of the formula (VI) and amines of formula (VII) can interact together in the presence of an inert solvent, such as N-methylpyrrolidone or pyridine, in the presence of a base, for example, inorganic bases such as cesium carbonate, or n is outstay organic bases, such as the excess of (VII), and at a temperature in the range from 25 to 80°C.

The compounds of formula (VI) (where X represents chlorine) can be prepared according to scheme 3:

Scheme 3

The compounds of formula (VIa) can be prepared in accordance with method a, method b or d, where q is 0.

Method d) Compounds of the formula (VIII) and amines of formula (IX) can interact together under standard Buchwald conditions, as described in method A.

The synthesis of compounds of formula (VIII) is described in scheme 1.

The compounds of formula (IX) are commercially available compounds or they are known from the literature, or they are prepared using standard methods known in this field.

Amines of formula (VI) are commercially available compounds or they are known from the literature, or they are prepared using standard methods known in this field.

Some of the various ring substituents in the compounds of the present invention can be introduced using standard reactions of aromatic substitution or they can be generated using a conventional modifications of functional groups, either before or directly after the processes described above, and, as such, are included in the aspect of the method of the present invention. Such cooperation is interacted and modifications include, for example, introduction of a substituent by reaction of aromatic substitution, recovery of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for such procedures are well known in the field of chemistry. Specific examples of reactions of aromatic substitution include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, allhelgona and Lewis acid (such as trichloride aluminum) in the conditions of the Friedel -; introduction of an alkyl group using alkylhalogenide and Lewis acid (such as trichloride aluminum) in the conditions of the Friedel -; and the introduction of the group of halogen. Specific examples of modifications include the restoration of the nitro group to the amino group, for example, by catalytic hydrogenation using a Nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfanyl or alkylsulfonyl.

You might also notice that some of the reactions discussed here, it may be necessary/desirable to protect any sensitive groups in the compounds. Cases where protection is necessary or desirable, and appropriate ways to protect well-known is the illusion in this area. Can be used conventional protective groups in accordance with standard practice (see illustration in T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reagents include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions considered here.

Suitable for use by protective group for amino or alkylamino represents, for example, acyl group, for example, alkanoyloxy group, such as acetyl, alkoxycarbonyl group, for example, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, arylethoxysilanes group, for example, benzyloxycarbonyl or arilou group, for example, benzoyloxy. Conditions unprotect the above protective groups optionally vary depending on the choice of protective groups. So, for example, acyl group, such as alcoolica or alkoxycarbonyl group, or arolina group may be removed, for example, by hydrolysis with a suitable base, such as alkali metal hydroxide, e.g. lithium hydroxide or sodium. Alternatively, the acyl group, such as tert-butoxycarbonyl group may be removed, for example, by treatment with the appropriate acid, Taco is as hydrochloric, sulfuric or phosphoric acid, or triperoxonane acid, and armletaccessory group, such as benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal, or by treatment with a Lewis acid for example, bortis(triptoreline). The corresponding alternative protective group for a primary amino group is, for example, palolo group which can be removed by treatment with alkylamine, for example, dimethylaminopropylamine, or with hydrazine.

Appropriate protective group for the hydroxy-group is, for example, acyl group, for example, alkanoyloxy group, such as acetyl, arilou group, for example, benzoyloxy, or arylmethyl group, for example, benzyl. Conditions for removing protection from the above protective groups will vary depending on the choice of protective groups. So, for example, acyl group, such as alcoolica or arolina group may be removed, for example, by hydrolysis with a suitable base, such as alkali metal hydroxide, e.g. lithium hydroxide or sodium. Alternatively, allmerica group such as benzyl group may be removed, for example, by hydrogenation over a catalyst such ka is palladium-on-charcoal grill.

Appropriate protective group for carboxypropyl represents, for example, aeriferous group, for example methyl or ethyl group, which may be removed, for example, by hydrolysis using a base such as sodium hydroxide, or, for example, tert-boutelou group that can be removed, for example by treatment with acid, for example, organic acids such as triperoxonane acid, or, for example, benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal grill.

Protective groups can be removed at any convenient stage of the synthesis using conventional techniques, well known in this field.

As stated above, the compounds defined in the present invention have activity against cell proliferation, such as anticancer activity, which is expected to occur in connection with the inhibitory activity of compounds against CDK. These properties can be estimated, for example, using the procedures below:

Tests

The following abbreviations are used:

HEPES is a N-[2-hydroxyethyl]piperazine-N'-[2-econsultancy acid]

DTT is dithiothreitol

PMSF is phenylmethylsulfonyl

With the unity investigated using analysis of kinase activity in vitro in 96-hole format using Scintillation Proximity Assay (SPA - obtained from Amersham) for measuring enable [γ-33-P]-ATP in the analyzed substrate (retinoblastoma protein - GST; GST-Rb). Each well is placed connection subject to study (diluted in DMSO and in water, to adjust concentrations), and in the control wells or roscovitine as inhibitory control, or DMSO as a positive control.

To each well add approximately 0.2 μl of partially purified enzyme CDK2/cyclin E (the number depends on the activity of the enzyme), diluted in 25 μl incubation buffer, and then 20 μl of a mixture of GST-Rb/ATP/ATP33 (containing 0.5 μg GST-Rb and 0.2 μm ATP, and 0.14, McCue [γ-33-P]-ATP in the incubation buffer), and the resulting mixture was gently shaken and then incubated at room temperature for 60 minutes.

Then to each well was added 150 μl of stop solution containing (0.8 mg/hole beads Protein A-PVT SPA (Amersham)), 20 gr/hole antiglycation transferase, rabbit IgG (obtained from Molecular Probes), 61 mm EDTA and 50 mm HEPES, pH 7.5, containing 0.05% of sodium azide.

Tablets sealed using seals to tablets Topseal-S, leave for two hours, and then centrifuged at 2500 rpm, HD within 5 minutes. Produce samples tablets on the Topcount, 30 seconds on each hole.

The incubation buffer used for dilution of mixtures of enzyme and substrate, contains 50 mm HEPES, pH 7.5, 10 mm MnCl2, 1 mm DTT, 100 μm sodium Vanadate, 100 mm NaF, 10 mm glycerol sodium, BSA (final concentration 1 mg/ml).

The analyzed substrate

This analysis is only part of the retinoblastoma protein (Science 1987 Marl3;235(4794):1394-1399; Lee W.H., Bookstein R, Hong f, Young L.J., Shew J.Y., Lee DURING), fused with GST tag. Perform PCR with the retinoblastoma gene, encoding amino acids 379-928, (obtained from plasmid retinoblastoma ATCC pLRbRNL), and the sequence is cloned into a vector merge pGEx 2T (Smith, D.B. and Johnson, for K.S. Gene 67, 31 (1988): which contains the tac promoter for inducible expression, gene lac Iqfor use in any cell of the host E. coli, and the coding region for thrombin cleavage (obtained from Pharmacia Biotech), which is used for amplification of amino acids 792-928. This sequence is again cloned in pGEx 2T.

The sequence 792-928 retinoblastoma, thus obtained, is expressed in E. coli cells BL21 (DE3) pLysS), using methods of induced expression, and purified as follows.

Pasta E.coli re-suspended in 10 ml/g of NETN buffer (50 mm Tris, pH 7.5, 120 mm NaCl, 1 mm EDTA, 0,5% V/V NP-40, 1 mm PMSF, 1 μg/ml leupeptin, 1 μg/ml Aprotinin and 1 μg/ml of pepstatin) and treated with ultrasound for 2 x 45 seconds per 100 ml of homogenate. After centrifugation the supernatant is loaded into 10 ml of glutathione in the colon is at Sepharose (Pharmacia Biotech, Herts, UK) and washed with NETN buffer. After washing kinase buffer (50 mm HEPES, pH 7.5, 10 mm MgC12, 1 mm DTT, 1 mm PMSF, 1 μg/ml leupeptin, 1 μg/ml Aprotinin and 1 μg/ml of pepstatin), protein elute with 50 mm restored glutathione in kinase buffer. Fractions containing GST-Rb (792-927), harvested and subjected to dialysis during the night with kinase buffer outside. The final product analyzed by gel electrophoresis (polyacrylamide gel), using sodium dodecyl sulfate (SDS), using gels based on 8-16% Tris-glycine (Novex, San Diego, USA).

CDK2 and cyclin E

Open reading frames CDK2 and cyclina E allocate using PCR with reverse transcriptase using mRNA in HeLa cells and activated T lymphocytes as templates and clone into expression vector insects pVL1393 (get from Invitrogen 1995, the number prospectus: V1392-20). Then CDK2 and cyclin E dual Express [using the standard technique of joint Baculogold virus infection] in the cellular system in SF21 insect cells Spodoptera Frugiperda derived from ovarian tissue Fall Army Worm is commercially available).

Example production cycline E/CDK2

The following example lists the details of the production cycline E/CDK2 in SF21 cells (TC100 + 10% FBS(TCS) is + 0.2% Pluronic), received a dual infection with MOI 3 each virus, cyclin E and CDK2.

The SF21 cells grown in culture in rotations is usamsa vial to the number of 2.33 x 10 6cells/ml, and used for inoculation of 10 x 500 ml rotating flasks at 0.2 x 106cells/ml Rotating flasks are incubated on a rotating rack in a 28°C.

After 3 days (72 hours), calculate cells, and the average value for 2 bottles, as found, is to 1.86 x 106cells/ml (99% viable). Then culture infected dual viruses at MOI of 3 for each virus.

Viruses are mixed together before addition to the cultures, and cultures of return on a rotating rack in a 28°C.

After 2 days (48 hours) after infection collect 5 liters of culture. The total number of cells in the collection 1.58 x 106cells/ml (99% viability). Cells are centrifuged at 2500 rpm, 30 min, 4C, Heraeus Omnifuge 2,0 RS, portions of 250 ml. of the Supernatant is poured.

Partial joint cleaning CDK2 and cyclina E

The SF21 cells re-suspended in lyse buffer (50 mm Tris, pH of 8.2, 10 mm MgCl2, 1 mm DTT, 10 mm glycerol, 0.1 mm of orthovanadate sodium, 0.1 mm NaF, 1 mm PMSF, 1 μg/ml leupeptin and 1 μg/ml Aprotinin) and homogenized for 2 minutes in 10 ml Dounce homogenizer. After centrifugation, the supernatant is loaded into anion-exchange column Poros HQ/M 1,4/100 (PE Biosystems, Hertford, UK). CDK2 and cyclin E together suiryudan at the beginning of the passage 0-1M NaCl gradient (carried out in lytic buffer minus protease inhibitors), the 20 column volumes. Joint elution is monitored by Western blotting using antibodies against CDK2, and against Zilina E (Santa Cruz Biotechnology, California, US).

By analogy can be constructed tests, designed to assess inhibition of CDK4 and CDK6. CDK2 (no access EMBL X62071) can be used together with cyclin A or cyclin E (see EMBL, the access number M73812), and further details of these analyses are contained in International PCT publication No. WO99/21845, the relevant sections of the Biochemical and Biological Evaluation of which are included here as a reference.

Although the pharmacological properties of the compounds of formula (I) vary with structural change, in General, activity possessed by compounds of the formula (I)may be demonstrated at concentrations or doses IC50in the range from 250 μm to 1 nm.

In the study in the above analysis of in vitro inhibitory activity of CDK2 from example 14 measured as IC50= 0,146 microns.

The activity in vivo of the compounds of the present invention can be assessed using standard techniques, for example, by measuring inhibition of cell growth and evaluation of cytotoxicity.

Inhibition of cell growth can be measured by staining cells with sulforhodamine B (SRB), a fluorescent dye, which stains the proteins, and as a result, the AET an estimate of the amount of protein (i.e. cells) in the hole (see Boyd, M.R.(1989) Status of the NCI preclinical antitumour drug discovery screen. Prin. Prac Oncol 10:1-12). Thus, when measuring the inhibition of cell growth provides the following details:

Cells in an appropriate medium in a volume of 100 μl are placed in a hole 96 tablets; environment are modified, Dulbecco eagle medium for MCF-7, SK-UT-1B and SK-UT-1. The cells give the possibility to attach overnight, then add the inhibitory compounds at various concentrations, with a maximum concentration of 1% DMSO (vol/vol). Control tablet is analyzed to obtain values for the number of cells before the dosage. Cells are incubated at 37°C (5% CO2within three days.

At the end of three days, in tablets add TCA to a final concentration of 16% (volume/volume). Then the tablets incubated at 4°C for 1 hour, the supernatant removed, and the tablets are washed in tap water. After drying, add 100 μl of SRB dye (of 0.4% SRB in 1% acetic acid)for 30 minutes at 37°C. Excess SRB remove and tablets washed in 1% acetic acid. SRB associated with the protein, solubilizers in 10 mm Tris, pH 7.5, and shaken for 30 minutes at room temperature. The OD values recorded at 540 nm, and the concentration of inhibitor which causes 50% inhibition of growth is determined on a semi-log graph of the concentration of the inhibitor to the function of the absorption coefficient. The concentration of a compound that reduces the optical density is lower than that obtained when cells are placed in the tablet at the beginning of the experiment, gives the value for toxicity.

Typical values IC50for compounds of the present invention, when they are examined in the analysis using the SRB are in the range from 1 mm to 1 nm.

In accordance with a further aspect of the present invention provides a pharmaceutical composition, which contains a pyrimidine derivative of the formula (I)or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, as defined above, in combination with a pharmaceutically acceptable diluent or carrier.

The composition may be in a form suitable for use by oral administration, for example, in the form of a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion)as a sterile solution, suspension or emulsion, for topical administration, in the form of ointment or cream or for rectal administration, in the form of a suppository.

Generally, the above compositions can be prepared in the usual way, using conventional diluents.

The compound of formula (I), as a rule, can be introduced warm the blood of an animal; at a unit dose within 5-5000 mg per square meter body surface of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically effective dose. A unit dosage form such as a tablet or capsule, should, as a rule, contain, for example, about 1-250 mg of the active ingredient. Preferably used daily dose in the range of 1-50 mg/kg, But the daily dose if necessary will vary depending on the treated subject, the specific route of administration and the severity of the disease that is being treated. In accordance with this optimal dose can be determined by the attending physician who treats the patient.

In accordance with a further aspect of the present invention creates a compound of formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, as defined above, for use in a method of treatment of the human or animal-assisted therapy.

The authors found that the compounds defined in the present invention, or their pharmaceutically acceptable salt or ester, hydrolisis in vivo, are effective inhibitors of the cell cycle (agents against cell proliferation), as expected, this property arises because of their properties relative what about the inhibition of CDK. Accordingly, the compounds of the present invention, as expected, are suitable for use in the treatment of diseases or medical conditions mediated fully or partially, the CDK enzymes, i.e. the compounds may be used to exert inhibitory effects on CDK warm-blooded animal in need of such treatment. Thus, the compounds of the present invention provide a method of treating the proliferation of malignant cells characterised by inhibition of CDK enzymes, that is, these compounds can be used to provide protivovrashchatelnogo effects, mediated fully or partially by inhibition of CDK. Such a connection of the present invention, as expected, has a broad range of anticancer properties, as CDK involved in the development of many common cancer in humans, such as leukemia and cancers of the breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary. Thus, it is expected that the compound of the present invention will possess anticancer activity against this cancer. In addition, it is expected that the compound of the present invention will possess activity against several leukemia, malignant is the deseases of the lymphatic system and solid tumors, such as carcinomas and sarcomas, in tissues such as liver, kidney, prostate and pancreas. Specifically, such compounds of the present invention, as expected, predominantly slow the growth of primary and secondary solid tumors, for example, colon, breast, prostate, lungs and skin. More particularly such compounds of the present invention or their pharmaceutically acceptable salt, or ester, hydrolisis in vivo, is expected to inhibit the growth of those primary and secondary solid tumors, which are associated with cancers, especially those tumors which are significantly dependent on CDK during their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, female external genital organs and skin.

In addition, it is expected that the compound of the present invention will possess activity against other diseases associated with cell proliferation in a wide range of other painful conditions, including various types of leukemia, fibroproliferative and differentiationin disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic neuropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone disease and diseases of the eye with proliferat what she retinal vessels.

Thus, in accordance with this present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt or its complex ether, gidrolizuemye in vivo, as defined above, for use as a medicinal product; and the use of the compounds of formula (I) or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo, as defined above, to obtain medicines for producing inhibitory effects on the cell cycle (against cell proliferation) in a warm-blooded animal such as man. In particular, the inhibitory effect by preventing entry or development in the S phase by inhibiting CDK2, CDK4 and/or CDK6, in particular CDK2.

In accordance with a further feature of the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt, or a complex ether, gidrolizuemye in vivo, as defined here above for obtaining a medicinal product intended for the treatment of cancers (solid tumors and various types of leukemia), fibroproliferative and differentiationin disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic neuropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune the disease, acute and chronic inflammation, bone diseases and diseases of the eye with the proliferation of retinal vessels, in particular, in the treatment of cancer.

In addition, the present invention relates to a method for producing inhibitory effects on the cell cycle (against cell proliferation) in a warm-blooded animal, such as man, in need of such treatment, which includes the introduction of a specified animal an effective amount of a compound as defined directly above. In particular, the inhibitory effect by preventing entry or development in the S phase by inhibiting CDK2, CDK4 and/or CDK6, in particular CDK2.

The present invention also relates to a method for producing inhibitory effects on the cell cycle (against cell proliferation) in a warm-blooded animal, such as man, in need of such treatment, which includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo, as defined here above. In particular, the inhibitory effect by preventing entry or development in the S phase by inhibiting CDK2, CDK4 and/or CDK6, in particular CDK2.

Moreover, the present invention apply the method of treatment of cancers (solid tumors and various types of leukemia), fibroproliferative and differentiationin disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic neuropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and diseases of the eye with the proliferation of retinal vessels in warm-blooded animals such as man, in need of such treatment, which includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo, as defined here above.

In particular, it is provided a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment, which includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo, as defined here above.

In a further aspect the present invention provides a pharmaceutical composition which contains a compound of the formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, as defined here above, in combination with a pharmaceutically acceptable diluent or novtel is m, suitable for producing inhibitory effects on the cell cycle (against cell proliferation) in a warm-blooded animal such as man.

In a further aspect the present invention provides a pharmaceutical composition which contains a compound of the formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, as defined here above, in combination with a pharmaceutically acceptable diluent or carrier suitable for the treatment of cancers (solid tumors and various types of leukemia), fibroproliferative and differentiationin disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic neuropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and diseases of the eye with the proliferation of retinal vessels in a warm-blooded animal such as man.

Further, the present invention relates to a pharmaceutical composition which contains a compound of the formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, as defined here above, in combination with a pharmaceutically acceptable diluent or carrier suitable for the treatment of cancer in a warm-blooded animal is, such as people.

Prevention of DNA synthesis cells by inhibiting the main initiating activities with the entry into S phase, such as initiation CDK2, can also be useful in protecting normal cells from toxicity cycloparaffinic pharmaceutical agents. Inhibition of CDK2 or 4 will prevent progression of the cell cycle in normal cells, which could limit the toxicity cycloparaffinic pharmaceutical agents that act in S phase, G2 phase or mitosis. Such protection can lead to the prevention of hair loss, usually associated with the use of these agents.

For this reason, in a further aspect the present invention provides a compound of formula (I)as defined above, or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, for use as an agent for protection of cells.

For this reason, in a further aspect the present invention provides a compound of formula (I)as defined here above, or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, for use in the prevention of hair loss occurring in the treatment of malignant conditions using pharmaceutical agents.

Examples of pharmaceutical agents for the treatment of malignant the s States, which are known to cause hair loss include alkylating agents such as ifosfamide and cyclophosphamide; antimetabolites, such as methotrexate, 5-fluorouracil inside the body, gemcitabine and cytarabine; vinca alkaloida and analogues, such as vincristine, vinblastine, vindesine, vinorelbine; taxanes such as paclitaxel and docetaxel; inhibitors of topoisomerase I, such as irinotecan and topotecan; citaxin antibiotics such as doxorubicin, daunorubicin, mitoxantrone, actinomycin D and mitomycin; and others, such as etoposide and tretinoin.

In another aspect of the present invention the compound of formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, can be administered in combination with one or more of the above pharmaceutical agents. In this case, the compound of formula (I) can be entered using a system or non-system assets. In particular, the compound of formula (I) can be entered using a non-system means, for example, local injection.

Therefore, the present invention relates to a method of preventing hair loss during treatment of one or more malignant conditions in a warm-blooded animal, such as man, using pharmaceutical agents, including the introduction of a specified animal an effective amount of the compounds of formula (I) Riego pharmaceutically acceptable salt or in vivo hydrolyzable ester.

In addition, the invention concerns a method of preventing hair loss during treatment of one or more malignant conditions in a warm-blooded animal, such as man, pharmaceutical agents, by introducing a specified animal an effective amount of the compounds of formula (I)or its pharmaceutically acceptable salt or its complex ether, gidrolizuyushchie in vivo, with an effective quantity of a specified pharmaceutical agent, with the simultaneous, sequential or separate administration.

In accordance with a further aspect of the present invention provides a pharmaceutical composition suitable for preventing hair loss, arising in connection with the treatment of malignant conditions using pharmaceutical agents, which contains a compound of the formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, and this pharmaceutical agent in combination with a pharmaceutically acceptable diluent or carrier.

In accordance with a further aspect of the present invention provides a kit containing the compound of formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, and a pharmaceutical agent for the treatment of malignant conditions, which is known to cause rubbed the hair.

In accordance with a further aspect of the present invention provides a kit containing:

a) a compound of formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, in the first standard dosage form;

b) a pharmaceutical agent for the treatment of malignant conditions, which is known to cause hair loss; in the second standard dosage form; and

c) a container to hold the above first and second dosage forms.

In accordance with another feature of the present invention provides the use of compounds of formula (I) or its pharmaceutically acceptable salt or its complex ether, gidrolizuyushchie in vivo, in the manufacture of a medicinal product for preventing hair loss during treatment of malignant conditions using pharmaceutical agents.

In accordance with a further aspect of the present invention provides a combination treatment to prevent hair loss, comprising introducing an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or its complex ether, gidrolizuyushchie in vivo, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction efficiency is active amount of a pharmaceutical agent for the treatment of malignant conditions warm-blooded animal, such as people.

As mentioned above, the size of the dose required for therapeutic or prophylactic treatment of specific diseases associated with cell proliferation, the need will vary depending on the object of treatment, method of administration and the severity of the disease treated. Assume the standard dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg

Inhibitory activity against CDK defined above, can be applied as a sole therapy or may involve, in addition to the compound of the present invention one or more other substances and/or treatments. This combined treatment can be achieved by simultaneous, sequential or separate introduction of individual components of the treatment. In the field of medical Oncology, the normal practice is to use a combination of various treatment modalities for the treatment of each patient with cancer. In medical Oncology the other component (components) of such a combined treatment in addition to treatment with inhibition of cell cycle defined above, can be surgery, radiation therapy or chemotherapy. Such chemotherapy may include three main categories of therapeutic Agay is that:

(i) other agents that inhibit the cell cycle, which work on the same mechanisms as described above, or other;

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, idoxifene), POCs (for example, megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, orasol exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), agonists and LHRH antagonists (for example goserelin acetate, leuprolide), inhibitors of testosterone 5α-dihydroorotase (for example, finasteride), antiinvasive agents (for example, inhibitors of metalloproteinases, such marimastat, and inhibitors activator receptor function urokinase plasminogen) and inhibitors of the function of a growth factor (such growth factors include, for example, a growth factor derived from platelets and growth factor hepatocyte, such inhibitors include antibodies, growth factors, antibodies, receptors, growth factors, inhibitors of tyrosine kinase and inhibitors of serine/threonin kinase); and

(iii) medicines against proliferation of tumors and their combinations, which are used in medical Oncology, such as antimetabolites (for example, antifolate such as methotrexate, ftorpirimidinu similar to 5-Ferraz the Lu, analogues of purine and adenosine, cytosine arabinoside); antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubitsina, mitomycin-C, dactinomycin, mithramycin); platinum compounds (e.g. cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosamine, thiotepa); antimitoticescoe agents (for example Vinca alkaloids like vincristine, and taxoid, like Taxol, Taxotere); topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan). In accordance with this aspect of the present invention provides a pharmaceutical product containing the compound of formula (I)as defined above, and the additional anticancer agent, as defined above, for the combined treatment of cancer.

In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of systems studies in vitro and in vivo to assess the impact of inhibitors on the activity relative to the cell cycle in laboratory animals such as cats, dogs, rabbits, obesa is s, rats and mice, as part of the study of new therapeutic agents.

For the above-mentioned another pharmaceutical composition, method, process, use and characteristics of the production of medicines, also claimed alternative and preferred embodiment of the compounds of the present invention, are described here.

EXAMPLES

Now the invention will be illustrated using the following non-limiting examples in which, unless approved otherwise:

(i) temperatures are given in degrees Celsius (°C); operations are carried out at room temperature or ambient temperature, that is at a temperature in the range 18-25°C;

(ii) organic solutions are dried over anhydrous magnesium sulfate; evaporation of solvent is carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5 to 30 mm Hg)with a bath temperature of up to 60°C;

(iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) carried out on plates coated with silica gel;

(iv) as a rule, after the reactions, produce TLC and reaction times are given for illustration only;

(v) final products are of satisfactory spectra of proton nuclear magnetic resonance (NMR) and/or mass spectra

(vi) the outputs are given for illustration only, and are not necessarily those which can be obtained by careful design of the way; if you want more material, making repeat;

(vii) when given, NMR data are given in the form of Delta values for major diagnostic protons, they are given in ppm (ppm) relative to tetramethylsilane was (TMS)as internal standard, determined at 300 MHz using predatory dimethyl sulfoxide (DMSO-d6) as solvent unless otherwise indicated;

(viii) chemical symbols have their usual meanings; used units and symbols SI;

(ix) the relationship of the solvents are given in volume/volume (vol./vol.); and

(x) mass spectra were obtained when the electron energy 70 EV, chemical ionization (CI)using the direct exposure of the sample; where indicated ionization is performed using electron impact (EI), fast atom bombardment (FAB) or elektrorazpredelenie (ESP); values are given for m/z; usually reported only ions which indicate the original mass; and if not approved by the other ion comparison is a (MH)+;

(xi) unless approved otherwise compounds containing an asymmetrically substituted carbon atom and/or sulfur, are not permitted;

(xi) there where a synthesis is described as similar to that described in the previous example, the quantities used are the millimolar equivalents relations in relation to those used in the previous example.

(xvi) the following abbreviations are used:

THF tetrahydrofuran;

DMF N,N-dimethylformamide;

DMFDMA dimethylformamide, dimethylacetal;

EtOAc ethyl acetate;

MeOH methanol;

EtOH ethanol;

DCM dichloromethane; and

DMSO dimethyl sulfoxide.

xvii) where mentioned column Isolute SCX-2, this means "ionoobmennye" extraction cartridge for adsorption of basic compounds, i.e. a polypropylene tube containing a strong cation-exchange sorbent on the basis of benzosulfimide acid used in accordance with the manufacturers instructions obtained from International Sorbent Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan, UK, CF82 7RJ;

xviii) where mentioned amine Isolute column, it means "ionoobmennye" extraction cartridge for adsorption of acidic compounds, i.e. a polypropylene tube containing aminosilane, covalently linked to the particles of the silicon dioxide used in accordance with the manufacturers instructions obtained from International Sorbent Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan, UK, CF82 7RJ;

xix) where mentioned Chemelut column, this means the extraction cartridge to remove water is, i.e. a polypropylene tube containing diatomaceous earth used in accordance with manufacturer's instructions, obtained from Varian, Harbor City, California, USA.

Example 1

2-(3-Chloroanilino)-4-(2-Mei-5-yl)pyrimidine

Sodium hydride (45 mg, 60% suspension in mineral oil, 1.12 mmol) is added to a stirred suspension of 5-(3-dimethylaminopropyl-2-EN-1-oil)-2-methylimidazole (100 mg, of 0.56 mmol) and 3-chlorophenylalanine (95 mg, 0,56 mmol) in dry 1-butanol (4.0 ml) under nitrogen atmosphere. The mixture was stirred at ambient temperature for 15 minutes, then heated at 126°C for 26 hours. The reaction mixture allow to cool and volatile products are removed by evaporation. The residue is suspended in water (20 ml), and add acetic acid (67 ml)and the solution extracted with DCM (3 x 20 ml). The extracts are combined, dried (Na2SO4), and the solvent is removed by evaporation. The residue is purified by column chromatography, elwira DCM/MeOH (100:0 increasing in polarity to 92:8), obtaining specified in the connection header, 33 mg (21%), in the form of a solid product. NMR: 2,35 (s, 3H), 6,95 (d, 1H), 7.23 percent (d, 1H), 7,30 (m, 1H), to 7.67 (s, 1H), 7,72 (s, 1H), with 8.05 (s, 1H), 8,43 (d, 1H), 9,62 (s, 1H), 12,15 (s, 1H); m/z: 286.

Example 2

2-(3-(Chloroanilino)-4-(1,2-dimethylimidazole-5-yl)pyrimidine

5-(3-Dimethylaminopropyl-2-EN-1 oil)-1,2-dimethylimidazole (method 1; 111 mg, of 0.58 mmol who) and 3-chlorpheniramine (97 mg, of 0.58 mmol) is treated as described in example 1, obtaining specified in the connection header, 51 mg (29%), in the form of a solid product. NMR: 2,40 (s, 3H), of 3.97 (s, 3H), 6,98 (d, 1H), 7,15 (d, 1H), 7,30 (m, 1H), 7,58 (d, 1H), to 7.67 (s, 1H), of 7.97 (s, 1H), 8,40 (d, 1H), 9,68 (s, 1H); m/z: 300.

Example 3

2-Aniline-(2-Mei-5-yl)pyrimidine

Sodium hydride (167 mg, 60% suspension in mineral oil, 4,18 mmol) is added to a stirred suspension of 5-(3-dimethylaminopropyl-2-EN-1-oil)-2-methylimidazole (250 mg, of 1.39 mmol) and fenilaniny bicarbonate (275 mg, of 1.39 mmol), suspended in dry 1-butanol (10 ml), under nitrogen atmosphere and the mixture is stirred and heated in nitrogen atmosphere, at 126°C for 18 hours. The reaction mixture allow to cool, and then add fenilaniny bicarbonate (275 mg, of 1.39 mmol) and sodium hydride (111 mg, 60% suspension in mineral oil, 2,78 mmol) and the mixture is stirred and heated at 126°C for additional 20 hours. Then the reaction mixture is extracted as described in example 1, obtaining specified in the connection header 159 mg (46%) as a solid product. NMR: of 2.33 (s, 3H), 6,92 (t, 1H), 7,18 (d, 1H), 7,27 (t, 2H), to 7.67 (s, 1H), 7,80 (d, 2H), at 8.36 (d, 1H), 9,37 (s, 1H), 12,12 (s, 1H); m/z: 252.

Example 4

4-(2-Mei-5-yl)-2-(4-sulfamerazine)pyrimidine

Thionyl chloride (2.0 ml) are added to 2-aniline-4-(2-Mei-5-yl)pyrimidine (example 3; 98 mg, 0,39 mmol), cooled at 0�B0; C, in nitrogen atmosphere. Added chlorosulfonic acid (104 μl, 1.56 mmol)and the mixture stirred at 0°C for 30 minutes. The excess thionyl chloride is removed by evaporation and the residue is treated with a mixture of THF (4.0 ml) and concentrated aqueous ammonia (1.0 ml). The mixture is stirred for 15 minutes and the volatile products are removed by evaporation. The residue is triturated with water and the precipitated solid product is collected by filtration, washed with distilled water and dried in vacuum to obtain specified in the connection header, 62 mg (48%). NMR: of 2.33 (s, 3H), 7,10 (s, 2H), 7,24 (d, 1H), 7,72 (m, 3H), 7,95 (d, 2H), 8,43 (d, 1H), 9,83 (s, 1H); m/z: 331.

Example 5

2-Aniline-4-(1,2-dimethylimidazole-5-yl)pyrimidine

5-(3-Dimethylaminopropyl-2-enoyl)-1,2-dimethylimidazole (method 1; 314 mg, of 1.62 mmol) and fenilaniny bicarbonate (321 mg, of 1.62 mmol) is treated as described in example 1, obtaining specified in the connection header, 113 mg (26%), in the form of a solid product. NMR: is 2.37 (s, 3H), 3,93 (s, 3H), 6,95 (t, 1H), was 7.08 (d, 1H), 7,28 (m, 2H), to 7.59 (s, 1H), 7,69 (d, 2H), 8,35 (d, 1H), 9,43 (s, 1H); m/z: 266.

Example 6

4-(1,2-Dimethylimidazole-5-yl)-2-(4-sulfamerazine)pyrimidine

Thionyl chloride (2.0 ml) are added to 2-aniline-4-(1,2-dimethylimidazole-5-yl)pyrimidine (example 5; 94 mg, 0.36 mmol), cooled at 0°C, in nitrogen atmosphere. Added chlorosulfonic acid (94 μl, 1.56 mmol) and the mixture peremeshivayte 0° C for 30 minutes, then allow to warm up and stirred for two hours at ambient temperature, and then heated at 90°C for one hour. The excess thionyl chloride is removed by evaporation and the residue azeotrope is distilled off with toluene. The resulting crude sulphonylchloride is treated with a mixture of THF (4.0 ml), water (2.0 ml) and concentrated aqueous ammonia (1.0 ml). The mixture is stirred for 15 minutes and the volatile products are removed by evaporation. The residue is triturated with water (5 ml) and the precipitated solid product is collected by filtration, washed with distilled water and dried in vacuum. The crude product is then suspended and stirred in DCM (10 ml)containing a few drops of MeOH. The solid product is collected by filtration, washed with DCM and dried in vacuum to obtain specified in the connection header, 67 mg (54%). NMR: of 2.38 (s, 3H), of 3.96 (s, 3H), 7,13 (s, 2H), 7,20 (m, 1H), 7,63 (s, 1H), 7,73 (d, 2H), 7,88 (d, 2H), 8,43 (d, 1H), 9,88 (s, 1H); m/z: 345.

Example 7

4-(1-Benzyl-2-Mei-5-yl)-2-(3-chloroanilino)pyrimidine

The sodium methoxide cases (36.8 mg, of 0.68 mmol) is added to a stirred suspension of 1-benzyl-5-(3-dimethylaminopropyl-2-EN-1-oil)-2-methylimidazole (method 5; 153 mg, or 0.57 mmol) and 3-chlorophenylalanine (106 mg, of 0.62 mmol) in dry 1-butanol (1.0 ml) in nitrogen atmosphere. The reaction mixture is heated under reflux during 4 hours, then give her a chance to cool off. Volatile products are removed by evaporation and the residue partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase is separated, dried and the solvent is removed by evaporation. The residue is purified by column chromatography, elwira DCM and 7M methanolic solution of ammonia (97:3), obtaining specified in the connection header, 73 mg (34%). NMR: 2,35 (s, 3H), 5,78 (s, 2H), 6,84-7,00 (m, 5H), 7,07 (t, 1H), 7,15-7,30 (m, 4H), 7,56-the 7.65 (m, 2H), 8,29 (d, 1H); m/z 374.

Example 8

2-(3-Chloroanilino)-4-[1-(2-methoxyethyl)imidazol-5-yl]pyrimidine hydrochloride

Triftormetilfullerenov anhydride (0.16 ml, of 0.93 mmol) are added to a solution of 2-methoxyethanol (73,7 ml, 0.88 mmol) and diisopropylethylamine (0,20 ml of 1.17 mmol) in DCM (1 ml), at -20°C, and the solution is stirred for 30 minutes. Then this mixture is added to a solution of 2-(3-chloroanilino)-4-(1-triphenylimidazole-4-yl)pyrimidine (method 2; 300 mg of 0.58 mmol) in DCM (5 ml) at -20°C, and the reaction mixture was allow to warm up and stirred for 2 hours at ambient temperature. The mixture is partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase is separated, dried and volatile products are removed by evaporation. The residue is purified by column chromatography, elwira DCM and 7M methanolic solution of ammonia (for 99.5:0.5, and the increase is of the polarity to 96:4). The purified product is dissolved in a simple ether and treated with ethereal solution of hydrogen chloride. The precipitate is collected by filtration, washed with simple ether and dried to obtain specified in the connection header, 132 mg (69%). NMR: 3,17 (s, 3H), 3,63 (t, 2H), 4,96 (t, 2H), 5,86 (users, 1H),? 7.04 baby mortality (d, 1H), 7,28-7,44 (m, 2H), 7,60 (d, 1H), 7,88 (s, 1H), 8,56 (s, 1H), 8,64 (d, 1H), 9.28 are (s, 1H), 10.0 g (s, 1H); m/z: 330.

Example 9

2-(3-Chloroanilino)-4-(imidazol-5-yl)pyrimidine

A mixture of 2-(3-chloroanilino)-4-(1-triphenylimidazole-4-yl)pyrimidine (method 2; 256 mg, 0.5 mmol) in MeOH (3 ml) and 2M hydrochloric acid (1 ml) is stirred for 15 minutes. Volatile products are removed by evaporation, and the residue partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer is separated, dried and the solvent is removed by evaporation. The residue is purified by column chromatography, elwira DCM and 7M methanolic solution of ammonia (for 99.5:0.5, and with increasing polarity to 93:7), obtaining specified in the connection header, 102 mg (75%), in the form of a solid product. NMR: to 6.95 (DD, 1H), 7,25-7,33 (m, 2H), 7,73 (DD, 1H), 7,81 (d, 2H), of 8.06 (s, 1H), 8,46 (d, 1H), 9,68 (s, 1H), 12,48 (users, 1H); m/z: 270.

Example 10

2-(3-Chloroanilino)-4-[1-(2-phthalimidomethyl)imidazol-5-yl]pyrimidine

2-Phthalimidomethyl (660 mg, 2.04 mmol) are added to a solution of 2-(3-chloroanilino)-4-(1-triphenylimidazole-4-yl)pyrimidine (method 2;1,00 g, 1,95 mmol) in DCM (5 ml)and the reaction mixture is stirred for 4 hours. The solvent is removed by evaporation and to the residue add MeOH (6 ml) and 2M hydrochloric acid (1.5 ml). The mixture is stirred for 5 minutes, the volatile products are removed by evaporation and the residue partitioned between EtOAc and saturated aqueous sodium bicarbonate. The resulting precipitate is collected by filtration, washed with water and EtOAc and dried to obtain specified in the connection header, 350 mg (40%), in the form of a solid product. NMR: 3,81-of 3.96 (m, 2H), 4,77 to 4.92 (m, 2H), 6,98 (d, 1H), 7,06 (d, 1H), 7,31 (m, 1H), 7,37 (d, 1H), 7,63-7,80 (m, 6H), 7,92 (s, 1H), 8,27 (d, 1H), 9,50 (s, 1H); m/z: 443.

Example 11-12

The following compounds are prepared using a method analogous to that described in example 10, using the appropriate starting materials1but when extracting the organic layer is separated, dried, the solvent is removed by evaporation and the residue purified by column chromatography, elwira DCM and 7M methanolic solution of ammonia (for 99.5:0.5, and with increasing polarity to 93:7).

Etc.ConnectionNMRm/z
112-(3-Chloroanilino)-4-(1-ethylimidazole-5-yl)pyrimidineof 1.26 (t, 3H), 4,56 (kV, 2H), 7,00 (d, 1H), 7,21 (d, 1H), 7,30 (m, 1H), EUR 7.57 (d, 1H), 7,87-to $ 7.91 (m, 1H) 8,44 (d, 1H), 9,62 (s, 1H)300
122-(3-Chloroanilino)-4-(1-Mei-5-yl)pyrimidinea 4.03 (s, 3H), 6,95-7,10 (m, 2H), 7,15-7,38 (m, 3H), 7,45-of 7.60 (m, 2H), 7,65 (s, 1H), 7,87 (s, 1H), scored 8.38 (d, 1H)286
1In the case of example 12 used triflates source material is trimethylsilylmethyl triplet

Example 13

4-[1-(2-amino-ethyl)imidazol-5-yl]-2-(3-chloroanilino)pyrimidine

Hydrazine hydrate (54 ml, at 1.73 mmol) are added to a suspension of 2-(3-chloroanilino)-4-[1-(2-phthalimidomethyl)imidazol-5-yl]pyrimidine (example 10; 163 mg, and 0.37 mmol) in EtOH (5 ml) and the mixture heated under reflux for 2 hours. The mixture allow to cool, volatile products are removed by evaporation and the residue purified by column chromatography, elwira DCM and 7M methanolic solution of ammonia (90:10) to obtain specified in the connection header, 69 mg (59%), in the form of a solid product. NMR: 1,41 (users, 2H), 2,99 (t, 2H), 4,55 (t, 2H), 7,00-to 7.09 (m, 2H), 7,22-7,35 (m, 3H), 7,65-of 7.70 (m, 2H), 7,73 for 7.78 (m, 1H), 8,39 (d, 1H); m/z: 315.

Example 14

2-Aniline-4-(1-Mei-5-yl)pyrimidine

The sodium methoxide (2,63 g of 48.7 mmol) are added to a solution of 5-(3-dimethylaminopropyl-2-EN-1-oil)-1-methylimidazole (method 4; only 2.91 g, 16.2 mmol) and fenilaniny bicarbonate (3,52 g of 17.9 mmol) in 2-propanol (14 ml) and the reaction mixture is heated with education is the principal fridge for 3 hours. The reaction mixture allow to cool and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase is separated, dried and the solvent is removed by evaporation. The residue is purified by column chromatography, elwira DCM and 7M methanolic solution of ammonia (97:3) to obtain specified in the header connection to 2.57 g (64%), in the form of a solid product; m/z: 252.

Example 15

4-(1-Mei-5-yl)-2-(4-sulfamerazine)pyrimidine

Chlorosulfonic acid (0,48 ml, 7,16 mmol) are added to a suspension of 2-aniline-4-(1-Mei-5-yl)pyrimidine (example 14; 449 mg, to 1.79 mmol) in thionyl chloride (9 ml), cooled at 0°C. the Mixture allow to warm to ambient temperature, then heated under reflux for 30 minutes. Volatile products are removed by evaporation and the residue is dried inhigh vacuum. To the residue add 7M methanolic solution of ammonia (30 ml) and the mixture is stirred for 10 minutes. Volatile products are removed by evaporation to obtain specified in the connection header, 360 mg (61%) as a solid product. NMR: Android 4.04 (s, 3H), 7,15 (s, 2H), 7,27 (d, 1H), 7,73 (d, 2H), 7,84-to $ 7.91 (m, 3H), of 8.06 (s, 1H), and 8.50 (d, 1H), 9,92 (s, 1H); m/z: 331.

Example 16

2-{4-[N-(3-Methoxypropyl)sulfamoyl]aniline}-4-(1-Mei-5-yl)pyrimidine

Chlorosulfonic acid (0,22 ml, 3,18 mmol) DOB is given to a suspension of 2-aniline-4-(1-Mei-5-yl)pyrimidine (example 14; 200 mg, 0.80 mmol) in thionyl chloride (4 ml), cooled at 0°C. the Mixture allow to warm to ambient temperature, stirred for 15 minutes, then heated under reflux for 20 minutes. Volatile products are removed by evaporation and the solid residue dried in high vacuum. The residue is suspended in pyridine (3 ml), cooled to -20°C, and add diisopropylethylamine high (0.56 ml, 3,98 mmol)and then 3-methoxypropylamine (0.16 ml, to 1.60 mmol). The reaction mixture allow to warm to ambient temperature and stirred for 30 minutes. Add EtOAc (15 ml) and the mixture was washed with saturated aqueous sodium bicarbonate (15 ml)and then with saturated salt solution (15 ml). The solvent is removed by evaporation and the residue purified by column chromatography, elwira DCM and 2M methanolic solution of ammonia (100:0 increasing in polarity to 85:15) to obtain specified in the connection header, 89 mg (28%), in the form of a solid product. NMR of 1.75 (m, 2H), was 2.76 (q, 2H), 3,14 (s, 3H), 3,22-3,30 (m, 2H), 4,01 (s, 3H), 7,25 (d, 1H), 7,34 (t, 1H), of 7.70 (d, 2H), to 7.77 (s, 1H), 7,83 (s, 1H), to $ 7.91 (d, 2H), of 8.47 (d, 1H), 9,92 (s, 1H); m/z: 403.

Examples 17-25

The following compounds are prepared in a manner analogous to that described in example 16, using the appropriate intermediates.

Example 26

4-(1,2-Dimethylimidazole-5-yl)-2-(4-{N-[3-(pyrrolidin-2-on-1-yl)propyl]sulfamoyl}aniline)pyrimidine

The ethereal solution of hydrogen chloride (1 ml of 1M solution, 1.0 mmol) are added to a solution of 4-{N-[3-(pyrrolidin-2-on-1-yl)propyl]sulfamoyl}aniline (method 13, 300 mg, 1.0 mmol) in MeOH (minimum volume). Volatile products are removed by evaporation and to the residue is added cyanamide (50 mg, 1.2 mmol), and then dimethylacetamide (0.5 ml). The mixture is heated to 100°C for 30 minutes. Add 5-(3-dimethylaminopropyl-2-enoyl)-1,2-dimethylimidazole (method 1; 180 mg of 0.93 mmol) and sodium methoxide (110 mg, 2.0 mmol) and the mixture heated under reflux for one hour. The mixture allow to cool and partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer is separated, washed with saturated salt solution, dried (Na2SO4) and volatile products are removed by evaporation. The residue is purified by column chromatography, elwira DCM and 7M methanolic solution of ammonia (96:4), obtaining specified in the connection header, 220 mg (50%). NMR: 1,48 is 1.58 (m, 2H), 1,79-1,89 (m, 2H), and 2.14 (t, 2H), is 2.37 (s, 3H), 2,68 (kV, 2H), 3,10 (t, 2H), 3,21 (t, 2H), 3,95 (s, 3H), 7,19 (d, 1H), 7,34 (t, 1H), 7,63 (s, 1H) of 7.69 (d, 2H), 7,92 (d, 2H) 8,43 (d, 1H), 9,92 (s, 1H); m/z: 470.

Example 27

The following compound is prepared in a manner analogous to that described in example 26, with the use the of the corresponding intermediate compounds.

Etc.ConnectionNMR, DMSO-d6, 300MHz @ 303,1km/z
274-(1,2-Dimethylimidazole-5-yl)-2-{4-[N-(2-tetrahydrofuranyl)sulfamoyl]aniline}

the pyrimidine
1,45-of 1.56 (m, 1H), 1,68-of 1.88 (m, 3H), is 2.37 (s, 3H), of 2.75 (t, 2H), 3,51-to 3.58 (m, 1H), 3,63-3,70 (m, 1H), of 3.73-3,82 (m, 1H), 3,95 (s, 3H), 7,19 (d, 1H), 7,46 (t, 1H), 7,63 (s, 1H), of 7.70 (d, 2H), to $ 7.91 (d, 2H), 8,43 (d, 1H), 9,90 (s, 1H)429

Example 28

2-Aniline-4-(1-ethyl-2-Mei-5-yl)pyrimidine

5-(3-Dimethylaminopropyl-2-EN-1-oil)-1-ethyl-2-Mei (method 16; 2,10 g, 10.1 mmol), fenilaniny bicarbonate (2.2 g, 11.1 mmol) and sodium methoxide (1.2 g, of 22.2 mmol) suspended in anhydrous DMA (15 ml), and the mixture is heated at 110°C for 18 hours. The reaction mixture allow to cool to ambient temperature and poured into water (50 ml). The solution is extracted with EtOAc (2 x 50 ml). The combined extracts washed with water (2 x 50 ml)and then with saturated salt solution (2 x 50 ml), dried and volatile products are removed by evaporation. The residue is triturated with simple ether, collected by filtration and air-dried, obtaining specified in the title compound (1.48 g, 53%) as a reddish brown solid product. NMR: 1,17 (t, 3H), of 2.38 (s, 3H), to 4.52 (q, 2H), 6,93 (t, 1H), was 7.08 (d, 1H), 7,27 (t, 2H), 7,60 (s, 1H), 7.62mm (d, 2H), 8,35 (d, 1H), 9,35 (s,1H); m/z 280.

Examples 29-33

The following compounds are synthesized analogously to the method of example 28.

Example 34

4-(1,2-Dimethylimidazole-5-yl)-2-(4-methylenedianiline)pyrimidine

Methanesulfonanilide (by 0.055 ml, 0.71 mmol) are added to a solution of 4-(1,2-dimethylimidazole-5-yl)-2-(4-aminoaniline)pyrimidine (example 165; 0.18 g, 0.64 mmol) and pyridine (0,052 ml, 0.64 mmol) in DCM (2.0 ml), cooled at 4°C. the Mixture allow to warm to ambient temperature. The mixture is partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic layer is separated, volatile products is evaporated and the residue purified by column chromatography on silica gel, elwira DCM/7M methanolic solution of ammonia (96:4), obtaining specified in the title compound (0.15 g, 65%) as a solid product. NMR: a 2.36 (s, 3H), 2,90 (s, 3H), 3,91 (s, 3H), 7,06 (d, 1H), 7,14 (d, 2H), EUR 7.57 (s, 1H), to 7.64 (d, 2H), with 8.33 (d, 1H), 9,37 (users, 1H), 9,42 (s, 1H); m/z 359.

Example 35

4-(1,2-Dimethylimidazole-5-yl)-2-{4-[N-(2-methoxyethyl)sulfamoyl]aniline}pyrimidine

Sodium tert-piperonyl (1.04 g, the 10.8 mmol) is added to a degassed solution of 2-amino-4-(1,2-dimethylimidazole-5-yl)pyrimidine (method 26; 567 mg, 3 mmol), N-(2-methoxyethyl)-4-identicaland (method 40; 1.54 g, 4.5 mmol), Tris(dibenzylideneacetone)diplegia(0) (72 mg, 0.15 mmol) and 2,2'-bis(diphenylphosphino is about)-1,1'-binaphthyl (102 mg, 0.15 mmol) in dioxane (36 ml), and the mixture is heated at 80°C during the night. The reaction mixture is cooled to room temperature, and added MeOH (5 ml), and the mixture is then poured into the column Isolute SCX-2, elwira first MeOH (10 x 30 ml), and then elute the product with 2% methanolic solution of ammonia (10 x 30 ml). The solvent is removed by evaporation and the residue is dissolved in EtOAc (100 ml), washed with water (3 x 100 ml)and then with saturated salt solution (100 ml), dried and the solvent removed by evaporation to obtain specified in the connection header (1,0l g, 84%) as a foam. NMR: 2,40 (s, 3H), of 3.07 (q, 2H), 3,20 (s, 3H), 3,38 (t, 2H), 3,86 (s, 3H), 5,00 (t, 1H), 6,95 (d, 1H), 7,47 (s, 2H), 7,71 (m, 4H), at 8.36 (d, 1H); m/z 403.

Examples 36-72

The following compounds are synthesized analogously to the method of example 35.

Example 73

4-(1,2-Dimethylimidazole-5-yl)-2-(4-{N-[2-(2-methoxyethoxy)ethyl]sulfamoyl}aniline)pyrimidine hydrochloride

1M Ethereal solution of hydrogen chloride (4 ml) are added to a solution of 4-(1,2-dimethylimidazole-5-yl)-2-(4-(N-tert-butoxycarbonyl)-N-[2-(2-methoxyethoxy)ethyl]sulfamoyl)of aniline)pyrimidine (method 55; 77 mg, 0.14 mmol) in anhydrous dioxane (2 ml)and the mixture stirred at ambient temperature for 5 days. Volatile products are removed by vepari the project and the residue triturated c simple ether, collected by filtration, washed with simple ether (2 x 10 ml) and dried to obtain specified in the title compound (65 mg (96%)in the form of a yellow solid product. NMR: 2,70 (s, 3H), of 2.86 (m, 2H), 3,18 (s, 3H), 3,36 (m, 4H), 3,42 (m, 2H), 4,08 (s, 3H), 7,38 (d, 1H), 7,58 (s, 1H), 7,74 (d, 2H), to 7.93 (d, 2H), 8,40 (s, 1H), 8,69 (d, 1H), of 10.25 (s, 1H); m/z 447.

Examples 74-75

The following compounds are synthesized analogously to the method of example 73.

Etc.ConnectionNMRm/zSM
744-(1,2-Dimethylimidazole-5-yl)-2-[4-(N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulfamoyl) aniline]pyrimidine hydrochloride2,63 (s, 3H), 2,84 (m, 2H), 3,20 (s, 3H), 3,40 (m, 10H)4,08 (s, 3H), 7,38 (d, 1H), of 7.48 (m, 1H), 7,73 (d, 2H), of 7.90 (d, 2H), scored 8.38 (s, 1H), 8,66 (d, 1H), 10,22 (s, 1H)491FPIC. 56
754-(1,2-Dimethylimidazole-5-yl)-2-{4-(N-(2-{2-[2-(2-methoxyethoxy) ethoxy]ethoxy}ethyl) sulfamoyl]aniline} pyrimidine hydrochlorideof 2.68 (s, 3H), 2,85 (m, 2H), 3,20 (s, 3H), 3,40 (m, 14H), 4,08 (s, 3H), 7,32 (d, 1H), 7,46 (m, 1H), 7,73 (d, 2H), 7,89 (d, 2H), 8,40 (s, 1H), to 8.62 (d, 1H), 10,22 (s, 1H)535FPIC. 57

Example 76

4-(1,2-Dimethylimidazole-5-yl)-2-{4-[N-(2-methylethyl)sulfamoyl]aniline}pyrimidine

4-Dimethylaminopyridine (3 mg, of 0.025 mmol) and 2-(methylsulphonyl)ethanamine (200 μl, 2 mmol) are added to a solution of 4-(1,2-dimethy is imidazol-5-yl)-2-(4-(persulfonic)of aniline)pyrimidine (method 59; 87 mg, 0.25 mmol) in NMP (1 ml) and the mixture is heated at 100°C for 18 hours. The mixture allow to cool to ambient temperature and the solvent is removed by evaporation. The residue is purified using preparative LC-MS (constant flow of 5% V/V (35% NH3in the Meon) with the gradient of H2O: CH3CN) (5:95, with the increase in polarity to 95:5) for a period of 7.5 min), with specified title compound (91 mg, 81%) as a solid product. NMR: of 2.38 (s, 3H), of 2.97 (s, 3H), 3,11 (m, 2H), 3,21 (m, 2H), 3,95 (s, 3H), 7,20 (m, 1H), to 7.61 (s, 1H), to 7.75 (m, 3H), 7,95 (d, 2H), 8,43 (d, 1H), 9,95 (s, 1H); m/z 451.

Examples 77-79

The following compounds are synthesized analogously to the method of example 76.

Example 80

4[1-(2-Methoxyethyl)-2-Mei-5-yl]-{4-[N-(tetrahydrofur-2-ylmethyl)sulfamoyl]aniline}pyrimidine

A mixture of 4-[1-(2-methoxyethyl)-2-Mei-5-yl]-2-N-(4-forconvenience)pyrimidine (method 60; 200 mg, 0.51 mmol) and dimethylaminopyridine deposited on polystyrene (800 mg, 1.6 mmol/g resin) in 1-methyl-2-pyrrolidone (4 ml) is stirred for 10 minutes at ambient temperature. Add tetrahydrofurfurylamine (258 mg, 2.55 mmol) and the reaction mixture is heated at 90°C for 40 hours, then at 100°C for 48 hours. Volatile products are removed by evaporation, and the residue purified by using a column of chromatogra the AI on silica gel, elwira DCM/MeOH (99:1, with increasing polarity to 96:4)to obtain purifiedproduct (120 mg), triturated with simple ether, collected by filtration and dried at 80°C in vacuum to obtain specified in the title compound (55 mg, 23%). NMR: 1.52m (m, 1H), 1.70 to a 1.88 (m, 3H), 2,39 (s, 3H), of 2.75 (m, 2H), 3,10 (s, 3H), 3,49 (t, 2H), 3,55 (m, 1H), to 3.67 (m, 1H), 3,78 (m, 1H), 4,74 (t, 2H), 7.23 percent (d, 1H), 7,49 (t, 1H), of 7.70 (d, 3H), a 7.85 (d, 2H), 8,42 (d, 1H), 9,79 (s, 1H); m/z 473.

Examples 81-82

The following compounds are synthesized analogously to example 80.

Etc.ConnectionNMRm/z
8114-[1-(2-Methoxyethyl)-2-Mei-5-yl]-2-{4-[N-(cyclopropylmethyl) sulfamoyl]aniline} pyrimidine0,06 (m, 2H), 0,34 (m, 2H), 0,79 (m, 1H), 2.40 a (s, 3H), 2,62 (t, 2H), 3,11 (s, 3H), 3,50 (t, 2H), amounts to 4.76 (t, 2H), 7,24 (d, 1H), 7,50 (t, 1H), 7,69 (s, 1H), of 7.70 (d, 2H), 7,87 (d, 2H), 8,42 (d, 1H), 9,79 (s, 1H)443
8224-[1-(2-Methoxyethyl)-2-Mei-5-yl]-2-{4-[N-(3-methoxypropyl) sulfamoyl]aniline} pyrimidineto 1.60 (m, 2H), 2.40 a (s, 3H), 2,77 (ushort, 2H), 3,12 (s, 3H), 3.15 in (s, 3H), of 3.28 (m, 2H), 3,52 (t, 2H), 4,74 (t, 2H), 7,24 (d, 1H), was 7.36 (users, 1H), of 7.70 (d, 3H), 7,88 (d, 2H), 8,40 (d, 1H), 9,80 (s, 1H)461
1Purified by column chromatography, elwira DCM/MeOH (98:2 increasing in polarity to 90:10).
2Purified by column chromatography, elwira DCM/MeOH (98:2 increasing in polarity to 95:5).

Example 83

4-(1-Ethyl-2-Mei-5-yl)-2-(4-(N-(hydroxyethyl)sulfamoyl)of aniline)pyrimidine

Chlorosulfonic acid (150 μl, of 2.16 mmol) is added dropwise to a solution of 2-aniline-4-(1-ethyl-2-Mei-5-yl)pyrimidine (example 28; 150 mg, 0.54 mmol) in thionyl chloride (3 ml), cooled at 0°C and the mixture was stirred at 0°C for 10 minutes, then heated at 90°C for 90 minutes. Volatile products are removed by evaporation and the residue is dried in high vacuum (<2 mm Hg) for 1 hour. The obtained solid product is placed in a nitrogen atmosphere and add a solution of ethanolamine (494 mg, 8.1 mmol) in MeOH (3 ml). The mixture is stirred for 30 minutes and volatile products is evaporated in vacuum. Add water (20 ml) and the precipitated solid product is collected by filtration, washed with water (2 x 10 ml) and simple ether (2 x 10 ml) and dried in vacuum at 60°C obtaining specified in the title compound (177 mg, 81%) as a beige solid product. NMR: 1,22 (t, 3H), 2,41 (s, 3H), 2,80 (s, 2H), 3,38 (kV, 2H), 4,63 (m, 3H), 7,20 (m, 1H), was 7.36 (s, 1H), to 7.77 (s, 1H), 7,82 (d, 2H), to $ 7.91 (d, 2H), 8.34 per (d, 1H), 9,85 (s, 1H); m/z 403.

Examples 84-125

The following compounds are synthesized analogously to the method of example 83.

Example 126

4-(1-Ethyl-2-Mei-5-yl)-2-(4-{N-[2-(2-hydroxyethoxy)ethyl]sulfamoyl}aniline)pyrimidine

Chlorosulfonic acid (150 μl, of 2.16 mmol) is added dropwise to a solution of 2-aniline-4-(1-ethyl-2-Mei-5-yl)pyrimidine (example 28; 150 mg, 0.54 mmol) in thionyl chloride (3 ml), cooled to 0°C, and the mixture is stirred for 10 minutes at 0°C, then heated at 90°C for 90 minutes. Volatile products are removed by evaporation and the resulting solid product is placed in a high vacuum (<2 mm Hg) for 1 hour. The obtained solid product is placed in a nitrogen atmosphere, and cautiously add a solution of 2-(2-amino-ethyl)ethanol (114 mg, of 1.08 mmol) and Diethylenetriamine in MeOH (3 ml). The solution is stirred for 30 minutes and volatile products is evaporated. Add water (20 ml) and the precipitated solid product is collected by filtration and washed with water (2 x 10 ml). The residue is dissolved in MeOH (5 ml) and loaded into the amine Isolute column, elute MeOH (30 ml), and the fractions containing the product is evaporated to obtain specified in the title compound (190 mg, 79%) as a beige solid product. NMR: of 1.18 (t, 3H), 2,39 (s, 3H), 2,89 (t, 2H), 3.15 in (m, 7H), to 4.38 (q, 2H), 7,21 (d, 1H), 7,71 (m, 3H), 7,89 (d, 2H), to 8.41 (d, 1H), 9,82 (s, 1H); m/z 447.

Examples 127-144

The following compounds are synthesized analogs is ichno way of example 126.

Example 145

5-Bromo-4-(1,2-dimethylimidazole-5-yl)-2-{4-[N-(2-methoxyethyl)sulfamoyl]aniline}pyrimidine

Bromine (8 μl, 0.14 mmol) are added to a solution of 4-(1,2-dimethylimidazole-5-yl)-2-{4-[N-(2-methoxyethyl)sulfamoyl]aniline}pyrimidine (example 35; 52 mg, 0.13 mmol) in glacial acetic acid (2 ml), heated to 60°C. the Mixture is heated at 60°C for 4 hours, then the solvent is removed by evaporation. The residue is dissolved in DCM (20 ml), washed with saturated aqueous sodium bicarbonate (20 ml), dried (Chemelut column1005) and purified using flash chromatography elwira DCM/2% methanolic solution of ammonia (100:0 increasing in polarity to 97:3) to obtain the specified title compound (37 mg, 60%) as a white foam. NMR: 2,40 (s, 3H), 3,06 (kV, 2H), 3,20 (s, 3H), on 3.36 (t, 2H), 3,68 (s, 3H), 5,00 (t, 1H), 7,56 (s, 1H), to 7.67 (d, 2H), 7,73 (d, 2H), 7,80 (s, 1H), 8,53 (s, 1H); m/z 483.

Examples 146-148

The following compounds are synthesized analogously to the method of example 145.

Example 149

5-Chloro-4-(1-ethyl-2-Mei-5-yl)-2-{4-[N-(2-methoxyethyl)sulfamoyl]aniline}pyrimidine

N-Chlorosuccinimide (80 mg, 0.6 mmol) are added to a solution of 4-(1-ethyl-2-Mei-5-yl)-2-{4-[N-(2-methoxyethyl) sulfamoyl]aniline}pyrimidine (example 37; 208 mg, 0.5 mmol) in glacial acetic acid (5ml) and the mixture is heated at 60° C for 3 hours. The solvent is evaporated and the residue is dissolved in DCM (30 ml), washed with saturated aqueous sodium bicarbonate (20 ml), the aqueous layer was extracted with DCM (20 ml). The DCM extracts in unite, dried (Chemelut column 1005) and the solvent is evaporated. The residue is purified using flash chromatography on silica gel, elwira DCM/2% methanolic solution of ammonia (100:0 increasing in polarity to 97:3) to obtain the specified title compound (110 mg, 44%) as a white foam. NMR: 1,24 (t, 3H), of 2.45 (s, 3H), to 3.09 (q, 2H), or 3.28 (s, 3H), 3,40 (t, 2H), 4,32 (t, 2H), 4.92 in (t, 1H), 7,40 (s, 1H), 7,72 (d, 2H), 7,83 (d, 2H), 7,88 (s, 1H), 8,49 (s, 1H); m/z 451.

Examples 150-153

The following compounds are synthesized analogously to the method of example 149.

Etc.ConnectionNMRm/zSM
1505-Chloro-4-(1,2-dimethylimidazole-5-yl)-2-{4-[N-(2-methoxyethyl) sulfamoyl]aniline} pyrimidineof 2.50 (s, 3H), 3.15 in (kV, 2H), 3,26 (s, 3H), 3,42
(t, 2H), of 3.78 (s, 3H), 4.92 in (t, 1H), 7,43 (s, 1H), 7,71 (d, 2H), 8,01 (d, 3H), 8,07 (s, 1H), 8,61 (s, 1H)437PR
15115-Chloro-4-(1-ethyl-2-Mei-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulfamoyl] aniline}pyrimidineto 1.24 (t, 3H), 1,50 (m, 1H), of 1.84 (m, 3H), 2,48 (3H), 2,90 (m, 1H), 3,12 (m, 1H), to 3.73 (m, 2H), 3,94 (m, 1H), 4,37 (kV, 2H), a 4.83 (t, 1H), was 7.36 (s, 1H), of 7.70 (d, 2H), 7,81 (d, 2H), 7,89 (s, 1H), 8,44 (s, 1H)477PR
15215-Chloro-4-(1-ethyl-2-Mei-5-yl)-2-[4-(N-cyclopropylamino) aniline]pyrimidineof 0.60 (m, 4H), 1,25 (t, 3H), 2,31 (m, 1H), 2,53 (s, 3H), 4,39 (kV, 2H), 4,96 (users, 1H), 7,37 (s, 1H), 7,71 (d, 2H), a 7.85 (m, 3H), to 8.45 (s, 1H)433PR
15315-Chloro-4-[1-(2-methoxyethyl)-2-Mei-5-yl]-2-{4-(N-(2-methoxyethyl) sulfamoyl]aniline} pyrimidineof 2.44 (s, 3H), 2,87 (kV, 2H), 3,03 (s, 3H), 3.15 in (s, 3H), 3,29 (m, 2H), 3,38 (m, 2H), 4,60 (m, 2H), 7,50 (ushort, 1H), to 7.64 (s, 1H), 7,72 (d, 2H), 7,83 (d, 2H), 8,63 (s, 1H), 10,10 (s, 1H)481PR
1Purified by column chromatography, elwira DCM/MeOH (98:2 increasing in polarity to 96:4).

Example 154

4-(1,2-Dimethylimidazole-5-yl)-2-{4-[N-(2,3-dihydroxypropyl)sulfamoyl]aniline}pyrimidine

Water (0.5 ml), and then TFU (2.5 ml), added to a solution of 4-(1,2-dimethylimidazole-5-yl)-2-{4-[N-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)sulfamoyl]aniline}pyrimidine (example 38,119 mg, 0.26 mmol) in DCM (2 ml) and the mixture was stirred at ambient temperature for 1 hour. The solvent is evaporated and to the residue add 1M ethereal solution of hydrogen chloride (5 ml) and ether (20 ml). Received prezi the ITAT collected by filtration and dried in vacuum. The solid product is suspended in MeOH (2 ml), add 1M aqueous solution of lithium hydroxide (2 ml) and the mixture is stirred for 1 hour at ambient temperature. The reaction mixture was poured into a column Isolute SCX-2, washed with MeOH (10 x 15 ml) and elute the product with 2% methanolic solution of ammonia (5 x 15 ml). The solvent is removed by evaporation to obtain specified in the title compound (66 mg, 61%) as a white solid product. NMR: of 2.38 (s, 3H), 2,60 (m, 1H), and 2.83 (m, 1H), 3,25 (m, 2H), 3.43 points (m, 1H), 3,95 (s, 3H), 4,48 (t, 1H), 4,70 (d, 1H), 7,20 (m, 2H), 7.62mm (s, 1H), 7,69 (d, 2H), of 7.90 (d, 2H), to 8.41 (d, 1H), 9,90 (s, 1H); m/z 419.

Example 155

5-Chloro-4-(1,2-dimethylimidazole-5-yl)-2-(4-sulfamerazine)pyrimidine

A mixture of 5-chloro-4-(1,2-dimethylimidazole-5-yl)-2-{4-[N-(tert-butyl)sulfamoyl]aniline}pyrimidine (example 60; 116 mg, 0,267 mmol), triperoxonane acid (2.7 ml), water (0.3 ml) and anisole (145 μl, of 1.34 mmol), stirred at ambient temperature for 72 hours. The mixture is then concentrated by evaporation and the residue is treated with water and ether. The precipitated solid product is collected by filtration, washed with water and simple ether and dried to obtain specified in the title compound (87 mg, 86%) as a white solid product. NMR: 2,4 (s, 3H), of 3.78 (s, 3H), 7,15 (s, 2H), 7,65 (s, 1H), 7,73 (d, 2H), 7,83 (d, 2H), and 8.6 (s, 1H), 10,11 (s, 1H); m/z 378 (M-H)-.

Example 156

The following compounds are synthesized similar what about the method of example 155.

Etc.ConnectionNMRm/zSM
1565-Chloro-4-(1,2-dimethylimidazole-5-yl)-2-[4-(N-methylsulfonyl) aniline]pyrimidineof 2.38 (d, 3H), 2,43 (s, 3H), of 3.78 (s, 3H), 7,2 (1H, HF), to 7.67 (m, 3H), 7,87 (d, 2H), 8,63 (s, 1H), 10,17 (s,1H)391 (M-H)-PR

Example 157

5-Bromo-4-(1-Mei-5-yl)-2-(4-sulfamerazine)pyrimidine

Bromine (75,5 mg, 0.47 mmol) are added to a solution of 4-(1-Mei-5-yl)-2-(4-sulfamerazine)pyrimidine (example 15; 0.14 g, 0.42 mmol) and sodium acetate (41.7 mg, 0.51 mmol) in acetic acid (4 ml), and the mixture is stirred for 1 hour. Volatile products are evaporated and the residue partitioned between EtOAc and saturated aqueous potassium bicarbonate. The organic phase is separated and dried. The remainder of the pre-adsorb on silica gel and purified by column chromatography on silica gel, elwira DCM/2% methanolic solution of ammonia (9:1) to obtain the specified title compound (91 mg, 52%). NMR: 10,14 (s, 1H), up 8.75 (s, 1H), of 7.90-of 7.69 (m, 4H), 7,17 (s, 2H), of 3.84 (s, 3H); m/z 409.

Example 158

2-(3-Chloroanilino)-4-[1-(2-acetamidomethyl)imidazol-5-yl]pyrimidine

Acetic anhydride (0,58 μl, 1.0 mmol) are added to a solution of 2-(3-chloroanilino)-4-[1-(2-amino-ethyl)imidazol-5-yl]pyrimidine (example is 13; 0,30 g to 0.63 mmol) in pyridine (2 ml) at 0°C. the Mixture allow to warm to ambient temperature and stirred for 2 hours. Add 7M methanolic solution of ammonia (0.5 ml) and the mixture was diluted with EtOAc (10 ml). The precipitate is removed by filtration and the filtrate pre-adsorb on silica gel, and purified by column chromatography on silica gel, elwira DCM/2% methanolic solution of ammonia (11:1) to obtain the specified title compound (88 mg, 39%) as a white solid product. NMR: 9,68 (s, 1H), 8,43 (d, 1H), 8,03-of 7.96 (m, 2H), 7,81 (s, 1H), 7,79 (s, 1H), 7,60 (DD, 1H), 7,33 (t, 1H), 7,12 (d, 1H), 6,98 (DD, 1H), 4,56-to 4.46 (m, 2H), 3,44-3,37 (m, 2H), 1,80 (s, 3H); m/z 357.

Example 159

The following compound is synthesized analogously to the method of example 158, using the appropriate sulphonylchloride instead of acetic anhydride.

Etc.ConnectionNMRm/zSM
1592-(3-Chloroanilino)-4-[1-(2-methylaminomethyl) imidazol-5-yl]pyrimidine9,41 (s, 1H), 8,43 (d, 1H), to 7.93 (m, 1H), 7,83 (s, 2H), EUR 7.57 (DD, 1H), 7,33 (t, 1H), 7,24 (d, 1H), 7,22-7,17 (m, 1H), 7,00 (DD, 1H), with 4.64-of 4.57 (m, 2H), 3,29-up 3.22 (m, 2H), 2,78 (s, 3H)393,395PR

Example 160

4-(1,2-Dimethylimidazole-5-yl)-2-[4-[N-methylsulfonyl)aniline]pyrimidine

N-Methyl-4-am is robinsonshouse (method 110; 250 mg, 1.3 mmol) dissolved in MeOH, and (3 ml) and add 1M HCl in ether (1.3 ml, 1.3 mmol). Add cyanamide (68 mg, 1.6 mmol) with DMA (0.5 ml). The mixture is heated to 100°C within 30 minutes there was added 5-(3-dimethylaminopropyl-2-EN-1 oil)-1,2-dimethylimidazole (method 15; 230 mg, 1.2 mmol) and sodium methoxide (150 mg, 2.6 mmol) and heated to 180°C for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate solution, and the resulting solid product is collected. The solid product triturated with hot DMF and filtered. The filtrate is evaporated in vacuo and purified using flash chromatography on silica gel, elwira DCM/2% methanolic solution of ammonia (100:0 increasing in polarity to 85:15) to give white solid product, which digeridoo with acetonitrile to obtain specified in the connection header in the form of a solid product (84 mg, 20%). NMR: 2,38 (d, 6H), of 3.95 (s, 3H), 7,19 (d, 2H), 7,63 (s, 1H), 7,68 (d, 2H), to 7.93 (d, 2H), 8,43 (d, 1H), to 9.91 (s, 1H); m/z 359.

Examples 161-164

The following compounds are synthesized analogously to the method of example 160.

Etc.ConnectionNMRm/zSM
1614-(1,2-Dimethylimidazole-5-yl)-2-[2-methoxy-4-(N-methylsulfonyl)-5-methylaniline]pyrimidineof 2.36 (s, 3H), 2,41 (d, 3H), 3,88 (s, 3H), 3,90 (s, 3H), 7,20 (m, 1H), 7,30 (userc,1H), 7,37 (s, 1H), to 7.64 (s, 1H), 8,16 (s, 1H), of 8.27 (s, 1H), 8,40 (d, 1H)403Spot
1624-(1,2-Dimethylimidazole-5-yl)-2-{4-[N-(4,5-dimethyloxazole-2-yl) sulfamoyl]aniline} pyrimidineat 1.91 (s, 3H), 2,02 (s, 3H), is 2.37 (s, 3H), of 3.94 (s, 3H), 7,16 (d, 1H), 7.62mm (s, 1H), of 7.75 (d, 2H), 7,83 (d, 2H), to 8.41 (d, 1H), 9,82 (s, 1H)440Spot
1634-(1,2-Dimethylimidazole-5-yl)-2-[4-(N-methylcarbamoyl) aniline]pyrimidineof 2.36 (s, 3H), was 2.76 (d, 3H), of 3.95 (s, 3H), 7,14 (d, 1H), to 7.61(s, 1H), to 7.77 (s, 4H), 8,20 (userc, 1H), 8,40 (d, 1H), 9,71 (s, 1H)323Spot
1644-(1,2-Dimethylimidazole-5-yl)-2-(4-acetamidophenyl) pyrimidinea 2.00 (s, 3H), of 2.35 (s, 3H), 3,90 (s, 3H), 7,02 (d, 1H), 7,47 (d, 2H), EUR 7.57 (m, 3H), 8,31 (d, 1H), was 9.33 (s, 1H), made up 9.77 (s, 1H)323Spot

Example 165

4-(1,2-Dimethylimidazole-5-yl)-2-(4-aminoaniline)pyrimidine

Sodium hydroxide (1.2 g, 3.0 mmol) are added to a solution of 4-(1,2-dimethylimidazole-5-yl)-2-(4-acetamidophenyl)pyrimidine (example 164; 1,25 g, 3.88 mmol) in isopropanol (12 ml) and water (0.5 ml) and the mixture heated under reflux for 90 minutes. The mixture allow to cool and partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic layer is separated and volatile products is evaporated. The residue is purified using column chromate is graphy on silica gel, elwira DCM/7M methanolic solution of ammonia (96:4) to obtain the specified title compound (0.75 g, 69%) as a brown solid product. NMR: of 2.33 (s, 3H), 3,85 (s, 3H), 4.75 in (users, 2H), 6,51 (d, 2H), 6,92 (d, 1H), 7,22 (d, 2H), 7,51 (s, 1H), they were 8.22 (d, 1H), of 8.90 (s, 1H); m/z 28.

Preparation of starting materials:

Starting materials for the examples above are either commercially available or are readily prepared using standard methods from known materials. For example, the following reactions represent an illustration, but not limitation, some of the original materials used in the above reactions.

Method 1

5-(3-Dimethylaminopropyl-2-enoyl)-1,2-dimethylimidazole

5-(3-Dimethylaminopropyl-2-enoyl)-2-Mei (350 mg, of 1.95 mmol) is suspended in DMFDMA (14 ml) and the mixture is stirred and heated at 100°C for 56 hours. Excess DMFDMA removed by evaporation and the residue purified via chromatography elwira DCM/MeOH (94:6) to obtain specified in the connection header 111 mg (29%) as a solid product. NMR (CDCl3): is 2.40 (s, 3H), of 3.00 (s, 6H), 3,88 (s, 3H), of 5.50 (d, 1H), 7,47 (s, 1H), 7,65 (d, 1H); m/z: 194.

Method 2

2-(3-Chloroanilino)-4-(1-triphenylimidazole-4-yl)pyrimidine

4-(3-Dimethylaminopropyl-2-EN-1-oil)-1-triphenylimidazole (method 3) is treated with 3-khlorfenilalanina under conditions similar to those that describe the Xia in example 7, obtaining specified in the title compound; m/z: 514.

Method 3

4-(3-Dimethylaminopropyl-2-EN-1-oil)-1-triphenylimidazole

A suspension of 4-acetyl-1-triphenylimidazole (method 6; 11.9 g, to 33.9 mmol) in DMFDMA (30 ml) is heated under reflux for 24 hours. The solution is allowed the opportunity to cool and the precipitate collected by filtration to obtain specified in the connection header 10.7 g, (78%). M/z: 408.

Ways 4-5

The following compounds are prepared using the procedure of method 3.

FPIC.ConnectionM/z
45-(3-Dimethylaminopropyl-2-EN-1-oil)-1-Mei180
51-Benzyl-5-(3-dimethylaminopropyl-2-EN-1-oil)-2-Mei270

Method 6

4-Acetyl-1-triphenylimidazole

A solution of 4-(1-hydroxyethyl)-1-triphenylimidazole (method 10; 30.5 g, 86 mmol) in dioxane (500 ml) is heated to 100°C. Add manganese dioxide (63,6 g, 0.73 mol) in parts, so it is supported by reasonable delegacia. The mixture should be allowed the opportunity to cool a little and inorganic solids are removed by filtration. Volatile products are removed from the filtrate by evaporation to obtain specified in the header Conn is the link to 30.3 g, (99%) as a solid product. NMR: to 2.55 (s, 3H),? 7.04 baby mortality-7,40 (m, 15H), the 7.43 (s, 1H), EUR 7.57 (s, 1H).

Ways 7-8

The following compounds are prepared using the procedure of method 6.

FPIC.ConnectionDATA
75-Acetyl-1-MeiM/z: 125
85-Acetyl-1-benzyl-2-MeiNMR: of 2.38 (s, 3H), of 2.44 (s, 3H), ceiling of 5.60 (s, 2H), 6,99 (d, 2H), 7,22-7,31 (m, 3H), to 7.77 (s, 1H)

Method 9

5-(1-Hydroxyethyl)-1-Mei

Methylanisole (100 ml, 3M solution in diethyl ether, 0.30 mol) is added dropwise to a solution of 5-formyl-1-methylimidazole (14.5 g, 0.13 mol) in THF (750 ml), cooled to -20°C in such a way that the reaction temperature is maintained below 3°C. the Mixture allow to warm to ambient temperature and carefully add water (150 ml). The aqueous mixture was continuously extracted with EtOAc. Extract into EtOAc, dried, and volatile products are removed by evaporation to obtain specified in the connection header of 14.4 g (88%) as a solid product. NMR: of 1.41 (d, 3H), 4,65-of 4.77 (m, 1H), 4,96-5,11 (m, 1H), 6,72 (s, 1H), 7,47 (s, 1H).

Ways 10-11

The following compounds are prepared using the procedures of method 9.

FPIC. ConnectionDATA
104-(1-Hydroxyethyl)-1-triphenylimidazoleNMR: of 1.28 (d, 3H), 4,58 (m, 1H), a 4.83 (d, 1H), 6,65 (s, 1H), 7.03 is-7,10 (m, 6H), of 7.23 (d, 1H), 7,33-the 7.43 (m, 9H)
111-Benzyl-5-(1-hydroxyethyl)-2-MeiM/z: 217

Way 12

1-Benzyl-5-formyl-2-Mei

Benzylbromide (21,4 ml, 0.18 mol) is carefully added to a mixture of 4-formyl-2-methylimidazole (18,1 g, 0.16 mol) and potassium carbonate (45,0 g, 0.33 mol) in DMF (100 ml) at 0°C and the reaction mixture was allow to warm to ambient temperature. The mixture is then partitioned between EtOAc and saturated aqueous sodium bicarbonate, the organic phase is separated and dried. Volatile products are removed by evaporation to obtain specified in the connection header in the form of a crude mixture of regioisomers of 32.0 g (99%). M/z: 201.

Way 13

4-{N-[3-(Pyrrolidin-2-on-1-yl)propyl]sulfamoyl}aniline

Sulfanilamide (6.5 g, 37,1 mmol), 3-(pyrrolidin-2-on-1-yl)Propylamine (5,79 g and 40.8 mmol) and triethylamine (5,69 ml of 40.8 mmol) in n-butanol (15 ml) is heated under reflux for 10 hours. The mixture allow to cool, add the silica and volatile products is evaporated. The residue is purified using chromatography, elwira DCM/MeOH (100:0), increasing polarity to (90:10), with the decree of the tion in the connection header. M/z: 297.

Way 14

The following compound is prepared using the procedure of method 13.

FPIC.Connectionm/z
144-[N-(2-Tetrahydrofuranyl)sulfamoyl]aniline257

Way 15

5-(3-Dimethylaminopropyl-2-EN-1 oil)-1,2-dimethylimidazole

2-Methyl-4-acetylimidazole (129 g, 1.04 mol) is dissolved in a mixture of DMF (900 ml) and .DMA (1.5 l) and the mixture heated under reflux in nitrogen atmosphere for 18 hours. The reaction mixture allow to cool to ambient temperature, the product crystallizes. The solid product is collected by filtration, washed with DMF, DMA, and then a simple ether and dried in vacuum at 40°C obtaining specified in the connection header (115 g, 57%) as pale-brownthe crystalline solid product. NMR: 2,13 (s, 3H), 2.95 and (s, 6H), of 3.78 (s, 3H), 5.56mm (d, 1H), 7,50 (d, 1H), 7,53 (s, 1H); m/z 94.

How 16-25

The following compounds are synthesized in a manner analogous to the way 15.

Method 26

2-Amino-4-(1,2-dimethylimidazole-5-yl)pyrimidine

5-(3-Dimethylaminopropyl-2-EN-1 oil)-1,2-dimethylimidazole (method 15; 2.8 g, 14.5 mmol) and guanidine hydrochloride (3.5 g, 36,3 mmol) suspended in 1-butanol is (30 ml). The sodium methoxide (3.1 g, 58 mmol) is added at once and the mixture is heated under reflux, under nitrogen atmosphere, for 18 hours. The reaction mixture allow to cool to ambient temperature, pre-adsorb on silica gel and purified by column chromatography on silica gel, elwira DCM/2% methanolic solution of ammonia (100:0 increasing in polarity to 95:5) to obtain the specified title compound (2.3 g, 84%). NMR of 2.16 (s, 3H), 3,93 (s, 3H), of 6.52 (s, 2H), 6,80 (d, 1H), 7,47 (s, 1H), 8,17 (d, 1H); m/z 190.

How 27-32

The following compounds are synthesized by a method similar to method 26.

Etc.ConnectionNMRm/zSM
272-Amino-4-(1-ethyl-2-Mei-5-yl)pyrimidineto 1.24 (t, 3H), 2.40 a (s, 3H), and 4.40 (q, 2H), 4,88 (s, 2H), 6,78 (d, 1H), 7,41 (s, 1H), 8,14 (d, 1H)204Spot
2812-Amino-4-[1-(2-methoxyethyl)-2-Mei-5-yl]pyrimidineof 2.35 (s, 3H), 3,14 (s, 3H), to 3.58 (t, 2H), with 4.64 (t, 2H), of 6.49 (users, 2H), 6,83 (d, 1H), 7,51 (s, 1H), 8,11 (d, 1H)234Spot
2922-Amino-4-[1-(1-butene-4-yl)-2-Mei-5-yl]pyrimidineof 2.50 (s, 5H), of 4.54 (t, 2H), 4,94 (d, 1H), 4,99 (d, 1H), 5,80 (m, 1H), of 6.49 (users, 2H), 684 (d, 1H), 7,51 (s, 1H), 8,13 (d, 1H)230FPIC. 18
3032-Amino-4-(1-methyl-2-ethylimidazole-5-yl)pyrimidineto 1.38 (t, 3H), was 2.76 (d, 2H), of 3.94 (s, 3H), of 5.00 (s, 2H), 6,83 (d, 1H), 7,51 (s, 1H), 8,12 (d, 1H)204Spot
3132-Amino-4-(1-methyl-2-isopropylimidazole-5-yl)pyrimidineof 1.40 (d, 6H), of 3.13 (m, 1H), 3,98 (s, 3H), of 5.00 (s, 2H), 6,83 (d, 1H), 7,50 (s, 1H), they were 8.22 (d, 1H)218Spot
3242-Amino-4-(1-methyl-2-cryptomaterial-5-yl)pyrimidineof 4.16 (s, 3H), 5,13 (s, 2H), 6.87 in (d, 1H), 7,53 (s, 1H), 8,35 (d, 1H)244Spot
1The reaction mixture is heated under reflux for 2 hours 40 minutes, the Reaction mixture is evaporated, water is added and the mixture extracted with EtOAc. The extract is washed with saturated salt solution, dried and evaporated.
2The reaction mixture is evaporated in vacuum. Add water and extracted into EtOAc. The extract is washed with saturated salt solution, dried and evaporated.
3Purified by column chromatography on silica gel, elwira EtOAc/MeOH (100:0 increasing in polarity to 50:50).
4Purify via column chromatographing silica gel, elwira EtOAc/MeOH (100:0 increasing in polarity to 70:30).

Method 33

1-(Triphenylmethyl)-2-methyl-4-(2-hydroxyethyl)imidazole

Triphenylmethylchloride (24.5 g, 88 mmol) in DMF (100 ml) is added dropwise during 1 hour to a solution of 2-methyl-4-(2-hydroxyethyl)imidazole (10 g, 80 mmol) and triethylamine in DMF (100 ml). The reaction mixture was stirred at ambient temperature for 18 hours and then the volatile products are removed by evaporation. The obtained solid product fray with water (3 x 500 ml) and ether (200 ml), collected by filtration and dried in vacuum at 60°C obtaining specified in the connection header (23.7 g, 80%) as a pale-yellow solid product. NMR was 1.43 (d, 3H), of 1.62 (s, 3H), 2,53 (s, 1H), 4,80 (kV, 1H), 6,59 (s, 1H), 7,13 (m, 6H), 7,37 (m, 9H); m/z 369.

Method 34

1-(Triphenylmethyl)-2-methyl-4-acetylimidazole

1-(Triphenylmethyl)-2-methyl-4-(2-hydroxyethyl)imidazole (method 33; 23.7 g, 64 mmol) is suspended in chloroform (180 ml) under nitrogen atmosphere. Activated manganese oxide(IV) (27.8 g, 320 mol) is added at once and the mixture is heated under reflux for 3 hours. The reaction mixture allow to cool, then filtered through a pad of diatomaceous earth and the pad washed thoroughly with chloroform. The filtrate is evaporated to obtain specified in the connection header (23,4 g, 100%) as a pale yellow powder. NMR 1,71 (s, H), of 2.53 (s, 3H), 7,13 (m, 6H), 7,37 (m, 9H), 7,52 (s, 1H); m/z 367.

Method 35

1-Ethyl-2-methyl-5-acetylimidazole

Tiltepec (11 ml, or 83.2 mmol) is added dropwise during 15 minutes to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (method 34; and 23.4 g, 64 mmol) in DCM (300 ml) and the mixture is stirred for 5 hours at ambient temperature. The solution was diluted with DCM (100 ml) and extracted with 1M aqueous citric acid solution (5 x 75 ml). Water extracts combined solid product is alkalinized with sodium bicarbonate and extracted with DCM (5 x 75 ml). The organic extracts are combined, dried and evaporated to obtain specified in the connection header (8,59 g, 88%) as a pale yellow oil. NMR of 1.32 (t, 3H), 2,41 (s, 6H), the 4.29 (q, 2H), 7,68 (s, 1H); m/z 153.

Method 36

1-(2-Methoxyethyl)-2-methyl-5-acetylimidazole

A solution of 2-methoxyethylamine (prepared in the amount of 6 mmol of 2-methoxyethanol and triftormetilfullerenov anhydride using the method published in Synthesis198285) in DCM (20 ml) is added dropwise to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (method 34; 1.5 g, 4 mmol) in DCM (5 ml), and the mixture is stirred for 40 hours at ambient temperature. Volatile products are removed by evaporation to obtain a solid product (2.4 g)which is purified using flash chromatography on silica gel, elwira DCM/MeOH (100:0, with increasing p is arnosti to 95:5), obtaining specified in the title compound (660 mg, 88%) as a solid product. NMR (CDC13) is 1.31 (s, 3H), 1,49 (s, 3H), 2,02 (s, 3H), 2,43 (m, 2H), and 3.31 (m, 2H), 6.87 in (s, 1H); m/z 183.

Method 37

1-(1-Butene-4-yl)-2-methyl-5-acetylimidazole

Specified in the title compound synthesized in a manner analogous to the method 36, using the triflate derived from cyclopropanemethanol. Specified in the header connection receive in the form of an oil after flash chromatography on silica gel, elwira DCM/MeOH (100:0 increasing in polarity to 96:4). NMR (CDC13) 2,43 (m, 8H), 4,32 (t, 2H), 5,02 (m, 1H), 5,08 (s, 1H), 5,74 (m, 1H), 7,69 (s, 1H); m/z 179.

Method 38

{N-[2-(Methoxyethoxy)ethyl)]carbamoyloxymethyl}phenyl

Chloromethylation simple ether (5 ml, 65 mmol) is carefully added to a solution of [N-(2-hydroxyethyl)carbamoyloxymethyl] phenyl (6,45 g, 33 mmol) and diisopropylethylamine (12 ml, 70 mmol) in DCM (50 ml) and the reaction mixture stirred at ambient temperature for 4 hours. Volatile products are removed by evaporation and the residue is dissolved in EtOAc (100 ml), washed with 1M aqueous citric acid solution (2 x 50 ml), saturated aqueous sodium bicarbonate (50 ml)and then with saturated salt solution (50 ml), dried and evaporated to obtain specified in the connection header (of 7.64 g, 97%) as a colourless oil. NMR to 3.34 (s, 3H), 3,42 (kV, 2H), 3,61 (t, 2H), 4,60 (s, 3H), 5,14 (m, 3H), 7,34 (m, H); m/z 262 (M+Na)+.

Method 39

N-[2-(Methoxyethoxy)etil-4-identicaland

A suspension of {N-[2-(methoxyethoxy)ethyl)]carbamoyloxymethyl}phenyl (method 38, 2.4 g, 10 mmol) and 10% palladium on coal (300 mg) in THF (20 ml) stirred in an atmosphere of hydrogen at ambient temperature for 18 hours. The catalyst is removed by filtration and the filtrate placed in a nitrogen atmosphere. Add triethylamine (1 ml, 7.5 mmol) and 4-iodanishvili (1,82 g, 6 mmol) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of EtOAc (30 ml) and 1M aqueous citric acid solution (30 ml). The phases are separated and the aqueous phase washed with EtOAc (30 ml). The organic extracts are combined washed with 1M aqueous citric acid solution (2 x 30 ml), saturated salt solution (30 ml), dried and volatile products are removed by evaporation to obtain specified in the connection header (2,18 g, 98%) as a waxy solid product. NMR of 3.15 (q, 2H), and 3.31 (s, 3H)and 3.59 (t, 2H), 4.53-in (s, 2H), 4,96 (t, 1H), 7,58 (d, 2H), of 7.90 (d, 2H); m/z 370 (M-H)-.

The method 40

N-(2-Methoxyethyl)-4-identicaland

A solution of 4-iodinecolored (of 3.64 g, 12 mmol) in DCM (30 ml) is added dropwise to a solution of 2-methoxyethylamine (1.3 ml, 15 mmol) and triethylamine (2 ml, 15 mmol) in DCM (60 ml), cooled in an ice bath to 0°C. the mixture is allowed the opportunity to warm to ambient temperature, and stirred for 1 hour. The solvent is removed by evaporation and the resulting oil was dissolved EtOAc (100 ml) and washed with 1 N. aqueous solution of citric acid (2 x 100 ml), saturated salt solution (100 ml) and dried. Volatile products are removed by evaporation to obtain specified in the title compound (4.1 g, 100%) as a clear oil. NMR: 3,12 (2H, HF), or 3.28 (3H, s), 3,44 (2H, t), of 4.90 (1H, t), EUR 7.57 (2H, d), 7,81 (2H, d); m/z: 342.

How 41-53

The following compounds are synthesized in a manner analogous to the method 40.

Etc.ConnectionNMRm/z
41N-(Cyclopropylmethyl)-4-identicaland0,01 (m, 2H), 0,32 (m, 2H), 0,76 (m, 1H), 2,60 (t, 2H), 7,47 (d, 2H), 7,72 (t, 3H),336
to $ 7.91 (d,2H)
42N-(2,2-Dimethyl-1,3-dioxolane-4-ylmethyl)-4-identicalandof 1.20 (s, 3H), 1,25 (s, 3H), 2.91 in (m, 1H), 3,12 (m, 1H), 3,60 (m, 1H), 3,92 (m, 1H), 4,13 (m, 1H), 4,71 (t, 1H), 7,52 (d, 2H), 7,80 (d, 2H)396
431N-(2-Benzyloxyethyl)-4-identicalandof 3.12 (q, 2H), 3,42 (m, 2H), 4,35 (s, 2H), 4,80 (m, 1H), 7,25 (m, 5H), of 7.48 (d, 2H), 7,79 (d, 2H)418
44N-(2,2-Dimethoxymethyl)-4-iadanza sulfonamid of 3.00 (t, 2H), or 3.28 (s, 6H), 4,24 (t, 1H), with 4.64 (t, 1H), 7,51 (d, 2H), 7,80 (d, 2H)370
45N-(Tetrahydrofur-2-ylmethyl)-4-identicaland1,50 (m, 1H), 1,80 (m, 3H), of 2.81 (m, 1H), 3,10 (m, 1H), 3,65 (m, 2H), 3,84 (m, 1H), 4,89 (t, 1H), 7,49 (d, 2H), 7,80 (d, 2H)368
46N-(3-Methoxypropyl)-4-identicalandby 1.68 (m, 2H), to 3.02 (q, 2H), 3,21 (s, 3H), 3,38 (t, 2H), 5,10 (s, 1H), 7,51 (d, 2H), 7,80 (d, 2H)356
47N-(Cyclopropyl)-4-identicaland0,60 (4H, d), and 2.27 (1H, m), is 4.85 (1H, s), 7,60 (2H, d), of 7.90 (2H, d)322 (M-H)-
48N-(4-Methylthiazole-2-ylmethyl)-4-identicaland2,22 (s, 3H), 4.26 deaths (d, 2H), 7,11 (s, 1H), 7,53 (d, 2H), 7,94 (d, 2H), at 8.60 (t, 1H)395
49N-(3-Methylisoxazol-5-ylmethyl)-4-identicaland2,11 (s, 3H), 4,16 (d, 2H), 6,02 (s, 1H), of 7.48 (d, 2H), to 7.93 (d, 2H), 8,43 (t, 1H)377 (M-H)-
50N-(1,4-Dioxane-2-ylmethyl)-4-identicaland2,82 (m, 1H), to 3.02 (m, 1H), 3,60 (m, 7H), of 4.83 (t, 1H), 7,51 (d, 2H), 7,83 (d, 2H)382 (M-H)-
512N-Propyl-4-identicalandof 0.9 (t, 3H), 1.5 a (kV, 2H), 2,93 (kV, 2H), 4,45 (t, 1H), EUR 7.57 (d, 2H), 7,87 (d, 2H)324 (M-H)-
522N-(tert-Butyl)-4-th is benzosulfimide of 1.07 (s, 9H), at 7.55 (m, 3H), of 7.93 (d, 2H)338

(M-H)-
53N-Allyl-4-identicaland3,20 (t, 2H), 5,00 (d, 1H), 5,10 (d, 1H), to 5.66 (m, 1H), 7,52 (d, 2H), a 7.85 (t, 1H), of 7.96 (d, 2H)322
1The source material is prepared according to JACS 1966; vol 88,2302.
2The triethylamine replace excess interacting Amin.

Method 54

N-tert-Butoxycarbonyl-4-identicaland

A solution of di-tert-butyl dicarbonate (10 g, 46 mmol) in DCM (80 ml) is added dropwise within 15 min to a stirred solution of 4-identicaland (11.3 g, 40 mmol), 4-dimethylaminopyridine (488 mg, 4 mmol) and triethylamine (6.2 ml, 44 mmol) in DCM (50 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then the solvent is removed by evaporation. The residue is dissolved in EtOAc (240 ml), washed with 1M aqueous citric acid solution (2 x 160 ml), saturated salt solution (160 ml), and dried to remove the solvent by evaporation to obtain an orange solid product. The crude product is recrystallized from EtOAc/isohexane, collected by filtration, washed twice with isohexane and dried to obtain specified in the connection header (of 10.25 g, 67%) as white crystals. NMR of 1.40 (s, 9), 7,71 (d, 2H), of 7.90 (d, 2H); m/z 382 (M-H)-.

Method 55

4-(1,2-Dimethylimidazole-5-yl)-2-(4-{N-(tert-butoxycarbonyl)-N-[2-(2-methoxyethoxy)ethyl]sulfamoyl}aniline)pyrimidine

2-(2-Methoxyethoxy)ethanol (50 μl, 0.4 mmol), and then diisopropyl azodicarboxylate (0.1 ml, 0.4 mmol), added to stir a solution of 4-(1,2-dimethylimidazole-5-yl)-2-{4-[N-(tertbutoxycarbonyl)sulfamoyl]aniline}pyrimidine (example 36; 90 mg, 0.2 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in anhydrous THF (4 ml), under nitrogen atmosphere, at 0°C. the Reaction mixture allow to warm to ambient temperature and stirred for 1 hour. The mixture is then poured directly into the column Isolute SCX-2, elute first, MeOH (8 x 15 ml), and then elute the product with 2% methanolic solution of ammonia (6 x 15 ml). The solvent is evaporated and the residue is dissolved in EtOAc (25 ml), washed with saturated aqueous sodium bicarbonate (2 x 25 ml), dried and the solvent is evaporated to obtain specified in the title compound (77 mg, 71%) as a yellow oil. NMR: to 1.38 (s, 9H), 2.49 USD (s, 3H), 3,38 (s, 3H), of 3.56 (m, 2H), 3,68 (m, 2H), 3,76 (t, 2H), 3.96 points (s, 3H), 4,06 (t, 2H), 7,03 (d, 1H), 7,49 (s, 1H), 7,58 (s, 1H), 7,78 (d, 2H), to 7.93 (d, 2H), 8,40 (d, 1H); m/z 547.

How 56-57

The following compounds are synthesized in a manner analogous to the way 55.

Etc.ConnectionYAM is m/zSM
564-(1,2-Dimethylimidazole-5-yl)-2-[4-(N-(tert-butoxycarbonyl)-N-{2-[2-(2-methoxyethoxy) ethoxy]ethyl}sulfamoyl)aniline]pyrimidineto 1.38 (s, 9H), 2,48 (,591Etc.
3H), 3,37 (s, 3H), of 3.56 (m, 2H), 3,65 (m, 8H), with 3.79 (t, 2H), 3.96 points (s, 3H), Android 4.04 (t, 2H), 7,01 (d, 1H), 7,41 (s, 1H), 7,56 (s, 1H), 7,79 (d, 2H), 7,92 (d, 2H), 8,40 (d, 1H)36
574-(1,2-Dimethylimidazole-5-yl)-2-{4-[N-(tert-butoxycarbonyl)-[N-(2-{2-[2-(2-methoxyethoxy) ethoxy]ethoxy}ethyl) sulfamoyl]aniline} pyrimidineto 1.38 (s, 9H), 2,48 (s, 3H), 3,37 (s, 3H), of 3.56 (m, 2H), 3,65 (m, 12H), with 3.79 (t, 2H), 3.96 points (s, 3H), Android 4.04 (t, 2H), 7,01 (d, 1H), 7,41 (s, 1H), 7,56 (s, 1H), 7,79 (d, 2H), 7,92 (d, 2H), 8,40 (d, 1H)635PR

Method 58

4-Identicallurdered

18-crown-6 (0.5 g) and potassium fluoride (11.6 g, 200 mmol) are added to a solution of identicalchlorine (30,3 g, 100 mmol) in acetonitrile (100 ml) and the suspension stirred for 18 hours at ambient temperature. Insoluble products are removed by filtration and the solvent removed from the filtrate by evaporation. The residue is dissolved in EtOAc (300 ml), washed with water (2 x 150 ml), saturated salt solution (100 ml), dried and the solvent is evaporated to obtain specified in the connection header (27,54 g, 96%) as a white solid fuel is Dogo product. NMR of 7.70 (d, 2H), 8,01 (d, 2H); m/z 286.

Method 59

4-(1,2-Dimethylimidazole-5-yl)-2-[4-(persulfonic)aniline]pyrimidine

The cesium carbonate (2.3 g, 7.2 mmol) is added to a degassed solution of 2-amino-4-(1,2-dimethylimidazole-5-yl)pyrimidine (method 26; 756 mg, 4 mmol), 4-itsunparalleled (method 58; 1.50 g, 5.2 mmol), Tris(dibenzylideneacetone)diplegia(0) (92 mg, 0.18 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (124 mg, 0.18 mmol) in dioxane (36 ml) under nitrogen atmosphere. The mixture is heated at 80°C for 18 h, and then allowing to cool to ambient temperature. The mixture was poured into water (50 ml) and extracted with DCM (2 x 50 ml). The organic extracts are combined, washed with saturated salt solution (50 ml), dried and the solvent is evaporated. The remainder of the pre-adsorb on silica gel and purified by column chromatography on silica gel, elwira DCM/2% methanolic solution of ammonia (100:0 increasing in polarity to 97:3) to obtain specified in the connection header (984 mg, 71%) as a pale-yellow solid product. NMR of 2.38 (s, 3H), of 3.96 (s, 3H), 7,28 (d, 1H), 7,65 (s, 1H), 8,00 (d, 2H), 8,13 (s, 2H), of 8.47 (d, 1H), 10,32 (s, 1H); m/z 348.

The method 60

4-[1-(2-Methoxyethyl)-2-Mei-5-yl]-2-N-(4-forconvenience)pyrimidine

Specified in the title compound synthesized from a compound of method 28, in a manner analogous to the method of 59, except t the th, that reaction mixture is evaporated before removing the aqueous phase and extraction of EtOAc. The crude product is purified by column chromatography on silica gel, elwira DCM/MeOH (98:2 increasing in polarity to 96:4). NMR: (CDC13) 2,52 (s, 3H), of 3.27 (s, 3H), 3,61 (t, 2H), and 4.68 (t, 2H), 7,11 (d, 1H), 7,52 (s, 1H), to 7.61 (s, 1H), 7,89 (d, 2H), of 7.96 (d, 2H), to 8.41 (d, 1H); m/z 392.

Method 61

2-Amino-5-bromo-4-(1,2-dimethylimidazole-5-yl)pyrimidine

Specified in the title compounds are synthesized from fashion link 26, in a manner analogous to the method of example 145, except that the reaction mixture is heated at 60°C for 1.5 h, diluted with water and alkalinized 2M aqueous solution of sodium hydroxide. The obtained solid product is collected by filtration and dried in vacuum at 60°C. NMR: of 2.38 (s, 3H), and 3.72 (s, 3H), at 6.84 (s, 2H), 7,55 (s, 1H), scored 8.38 (s, 1H); m/z 269.

Method 62

N-(2-Methoxyethyl)-N-methyl-4-identicaland

Sodium hydride (144 mg, 3.6 mmol) is added in portions to a solution of N-(2-methoxyethyl)-4-identicaland (method 40, 1 g, 3 mmol) in THF (10 ml) and the mixture was stirred at ambient temperature for 15 minutes. Add logmean (230 μl, 3.6 mmol) and the reaction mixture stirred for 18 hours. Carefully add water (30 ml) and the mixture extracted with ether (40 ml). The combined organic layers washed with saturated salt solution (50 ml), dry the t and evaporated volatile products. The residue is purified using flash chromatography on silica gel, elwira isohexane/EtOAc (100:0 increasing in polarity to 10:1) to obtain the specified title compound (730 mg, 69%) as a clear oil. NMR: 2,78 (s, 3H), and 3.16 (t, 2H), up 3.22 (s, 3H), of 3.45 (t, 3H), 7,42 (d, 2H), 7,80 (d, 2H); m/z 356.

How 63-64

The following compounds are synthesized in a manner analogous to the way 62.

Etc.ConnectionNMRm/zSM
63N-(3-Morpholinopropan)-N-methyl-4-identicalandto 1.77 (m, 2H), 2,41 (m, 6H), to 2.75 (s, 3H), 3,11 (t, 2H), 3,69 (m, 4H), of 7.48 (d, 2H), 7,87 (d, 2H)425Spot
64N-(tert-Butyl)-N-methyl-4-identicaland(CDCl3): of 1.35 (s, 9H), 2,96 (s, 3H), 7,53 (d, 2H), 7,83 (d, 2H)n/aSpot

Method 65

4-Methylpropanol

To a solution of 4-bromothioanisole (22,3 g, 11 mmol) in DCM (250 ml) in 10 g add m-chloroperoxybenzoic acid (40 g, 23 mmol). The precipitate is removed by filtration and washed with DCM. The filtrate is evaporated in vacuo and the resulting solid product is recrystallized from EtOH (180 ml) to obtain the specified title compound as colourless crystals of 11.7 g (45%). TPL 103-106°C.

Way 66/p>

N-(3-Morpholinopropan)-4-identicaland

4-Iodanishvili (3.03 g, 10 mmol) in DCM (30 ml) added dropwise over 15 minutes to a solution of 4-(3-aminopropyl)of the research (1.75 ml, 12 mmol) and triethylamine (1.7 ml, 12 mmol) in DCM (50 ml), cooled in an ice bath. The mixture allow to warm to ambient temperature and stirred for 15 minutes. Add water (50 ml) and the phases are separated. The organic layer was washed with water (50 ml) and saturated salt solution (50 ml), dried (Chemelut column 1010) and evaporated to obtain specified in the connection header (4,10 g, 100%) as a beige solid product. NMR: 1,70 (m, 2H), 2,43 (m, 6H), 3,14 (t, 2H), 3,71 (m, 4H), was 7.08 (s, 1H), 7,58 (d, 2H), a 7.85 (d, 2H); m/z 411.

Method 67

1-[3-[N,N-Dimethylamino)propylthio]-4-Brabanthal

3-(Dimethylamino)propylchloride hydrochloride (3,48 g, 22 mmol) in parts added to a suspension of 4-bromothiophene (of 3.78 g, 20 mmol) and potassium carbonate (5,52 g, 40 mmol) in DMF (40 ml) and the reaction mixture heated to 60°C for 15 minutes. The mixture allow to cool to ambient temperature, poured into water (100 ml) and extracted with EtOAc (2 x 100 ml). The extracts are combined, washed with saturated salt solution (3 x 100 ml), dried (Chemelut column 1010) and evaporated to obtain specified in the connection header (5,25 g, 96%) as a pale yellow oil. NMR: 1,76 (m, 2H), measuring 2.20 (s, 6H), to 2.35 (t, 2H), with 2.93 (t, 2H), 7,18 (who, 2H), 7,38 (d, 2H); m/z 276.

Method 68

1-(3,3,3-Cryptosporidia)-4-Brabanthal

3-Bromo-1,1,1-tryptophan (640 μl, 6 mmol) are added to a mixture of 4-bromothiophene (945 mg, 5 mol) and potassium carbonate (760 mg, 5.5 mmol) in DMF (5 ml) and the reaction mixture is heated at 40°C for 1 hour. The mixture allow to cool to ambient temperature, poured into water (50 ml) and extracted with EtOAc (2 x 30 ml). The extracts are combined, washed with saturated salt solution (3 x 30 ml), dried (Chemelut column 1010) and evaporated to obtain specified in the connection header (1,36 g, 95%) as a pale yellow oil. NMR: 2,56 (m, 2H), 3,13 (t, 2H), 7,31 (d, 2H), 7,51 (d, 2H); m/z 285 (M+).

Method 69

1-(1-Butylthio)-4-Brabanthal

Specified in the title compounds are synthesized in a manner analogous to the way 68. NMR of 0.85 (t, 3H), of 1.38 (m, 2H)and 1.51 (m, 2H), 2,96 (t, 2H), 7.23 percent (d, 2H), 7,46 (d, 2H); m/z 244 (M+).

The method 70

1-[3-(N,N-Dimethylamino)propylsulfonyl]-4-Brabanthal

Oxon (14 g, 23 mmol) are added to a solution of 1-[3-(N,N-dimethylamino)propylthio]-4-bromine benzol (method 67; of 5.24 g of 19.1 mmol) in MeOH (150 ml) and water (30 ml) and the mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was poured into a column Isolute SCX-2, washed with MeOH (6 x 40 ml) and elute the product with 2% methanol solution ofammonium (10 x 40 ml). The solvent is evaporated and the residue purified using flash chromate is graphy on silica gel, elwira DCM/2% methanolic solution of ammonia (100:0 increasing in polarity to 94:6), obtaining specified in the title compound (4.68 g, 80%) as a pale yellow oil. NMR: of 1.62 (m, 2H), 2,03 (s, 6H), 2,19 (t, 2H), 3,32 (m, 2H), 7,81 (m, 4H); m/z 306.

Method 71

1-(3,3,3-Triphosphorylation)-4-Brabanthal

Oxon (3.7 g, 6 mmol) are added to a solution of 1-(3,3,3-cryptosporidia)-4-bromine benzol (method 68, 1,36, of 4.75 mmol) in MeOH (25 ml) and water (5 ml) and the mixture was stirred at ambient temperature for 18 hours. MeOH is evaporated, add water (20 ml) and the mixture extracted with DCM. The extracts are dried (column Chemelut CE1005), and the solvent is removed by evaporation to obtain specified in the connection header (1,43 g, 95%) as a white solid product. NMR: 2,62 (m, 2H), to 3.67 (m, 2H), 7,86 (s, 4H); m/z 316 (M+).

Method 72

1-(1-Butylsulfonyl)-4-Brabanthal

Specified in the title compound is synthesized from compound according to the method 69 the same way 71. NMR: 0,80 (t, 3H), 1,31 (m, 2H), 1,47 (m, 2H), 3,29 (t, 2H), 7,78 (d, 2H), 7,86 (d, 2H); m/z 276 (M+).

Method 73

3-Methoxy-1-propenolatomethyl

Methanesulfonanilide (1.75 ml, 22 mmol) are added to a solution of 3-methoxy-1-propanol (1,81 g, 20 mmol) and triethylamine (3,35 ml, 24 mmol) in DCM (40 ml), cooled in an ice bath, and the mixture was stirred at ambient temperature for 18 hours. Add DCM (25 ml) is water (50 ml), and the phases are separated and the aqueous layer was extracted with DCM (25 ml). The extracts are combined, washed with water (50 ml) and saturated salt solution (50 ml), dried (Chemelut column CE1010) and evaporated to obtain specified in the connection header 3.25 g (97%) as a pale yellow oil. NMR: 2,00 (m, 2H), 3,01 (s, 3H), at 3.35 (s, 3H), 3,49 (t, 2H), to 4.38 (t, 2H).

Method 74

1-(3-Methoxypropylamine)-4-Brabanthal

Potassium carbonate (2.8 g, 20 mmol) are added to a solution of 3-methoxypropan-1-yl of methansulfonate (method 73; 3.25 g, and 19.3 mmol) and 4-bromothiophene (3,48 g, 18.4 mmol) in DMF (30 ml) and the mixture is heated at 40°C for 4 hours. The mixture allow to cool to ambient temperature, poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The extracts are combined, washed with saturated aqueous sodium bicarbonate solution (50 ml) and saturated salt solution (2 x 50 ml), dried (Chemelut column CE1010) and remove volatile products by evaporation. The residue is dissolved in MeOH (150 ml) and parts of water is added (30 ml) and axon (13,4 g, 21.6 mmol). The mixture was stirred at ambient temperature for 18 hours. MeOH is evaporated, water is added (50 ml) and the solution extracted with DCM (3 x 50 ml). The extracts are combined, washed with saturated salt solution (50 ml), dried (Chemelut column CE1010) and evaporated. The residue is purified using flash chromatography on silica gel, elwira isohexane:EtOAc (100:0, increasing the Olanesti to 90:10) to obtain specified in the connection header (3,32 g, 62%) as a colourless oil. NMR: 1,95 (m, 2H), 3,19 (m, 2H), 3,26 (s, 3H), 3,41 (t, 2H), of 7.70 (d, 2H), 7,78 (d, 2H).

Method 75

3-Hydroxyethoxy

Hydroxylamine hydrochloride (35 g, 0.5 mol) are added to a solution of sodium hydroxide (58 g of 1.45 mol) in water (580 ml). Add MeOH (600 ml), and then in parts add ethylpropyl (38 ml of 0.37 mol) and the resulting solution was stirred at ambient temperature for 6 days. The mixture is acidified to pH 2 with concentrated hydrochloric acid and then saturated sodium chloride. The solution is extracted with DCM (8 x 500 ml), the extracts combined, dried and the solvent evaporated. The solid residue is washed with hot isohexane (3 x 300 ml) of the final suspension allow to cool and the resulting solid product is collected by filtration, dried in vacuum, obtaining specified in the connection header (11,16 g, 35%) as a crystalline white solid product. NMR: 6,04 (s, 1H), 8,43 (s, 1H), 11,16 (s, 1H); m/z 85 (M+).

Method 76

3-Oxo-2,3-dihydrothiazolo

Glycinamide. HCl (1 mol) are suspended in DMF (500 ml) and added dropwise SO2Cl2(300 ml) for 1.5 hours with cooling, keeping the reaction temperature between 5 and 10°C. the Reaction mixture is stirred at 10-15°C for 6 hours, at this moment carefully add water (500 ml). The solid product is removed put the m filtration and the filtrate is extracted with simple ether (2 l). The ether solution is washed with saturated salt solution (200 ml) and evaporated in vacuo to obtain a pale yellow solid product (132 g). the Aqueous layer was extracted with DCM (2 x 600 ml). Portions of DCM are combined and washed with ether and water. The organic layer was washed with saturated salt solution and evaporated in vacuum to obtain a cream solid (18 g) - B. A and B merge, dissolve in ether, dried and added activated charcoal. The solution is filtered and the filtrate is evaporated in vacuum to obtain a pale yellow solid product (104,3 g). This solid product is ground with isohexane obtaining specified in the connection header (of 91.3 g, 90%). TPL: 102-105°C.

Method 77

Atenololbuy

To liquid ammonia (300 ml) for 2 hours add methylpropionate (52,4 g of 0.62 mol), maintaining the temperature at -70°C. the Ammonia give an opportunity to evaporate and the reaction mixture is evaporated in vacuum to obtain specified in the title compound (43 g), which is used without further purification. TPL: 54-55°C.

Method 78

3-Oxo-2,3-dihydro-1,2,5-thiadiazole

To a stirred solution of tinykernel (method 77; 43 g of 0.62 mol) in water (310 ml), cooled in an ice bath, at a time add ammonium thiosulfate (92,35 g of 0.62 mol). The reaction mixture allow to warm to room te is the temperature for 5 hours. To the reaction mixture quickly, within 10 minutes, add a solution of iodine (79,2 g, 0.31 mol) in MeOH (1 l) to give a dark solution. Add ammonium thiosulfate, until then, until you get a yellow solution. The solvent is evaporated to about 400 ml and the mixture is extracted with simple ether (3 x 300 ml). The ether solution is washed with saturated salt solution (100 ml), passed through the paper to separate the phases and evaporated in vacuum to obtain specified in the title compounds as a pale orange solid product (32,8 g, 52%). TPL: 70-71°C.

Method 79

3-[2-(tert-Butoxycarbonylamino)ethoxy]isoxazol

Diisopropylethylamine (1.1 ml, 5.5 mmol) is added dropwise to a solution of 2-(tert-butoxycarbonylamino)ethanol (850 μl, 5.5 mmol), 3-hydroxycarbazole (method 75; 425 mg, 5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) in THF (20 ml) and the mixture was stirred at ambient temperature for 18 hours. The solvent is evaporated and the residue purified using flash chromatography on silica gel, elwira isohexane:EtOAc (100:0 increasing in polarity to 4:1) to obtain the specified title compound (506 mg, 44%) as a white solid product. NMR: USD 1.43 (s, 9H), of 3.56 (m, 2H), 4,32 (m, 2H), 4,90 (s, 1H), 5,98 (s, 1H), 8,16 (s, 1H); m/z 229.

How 80-84

The following compounds are synthesized in a manner analogous to the method of 79, with the use according to the corresponding amine and heterocycle as starting materials.

Etc.ConnectionNMRm/zSM
803-[2-(tert-Butoxycarbonylamino) ethoxy]isothiazolto 1.38 (s, 9H), 3,30 (m, 2H), 4,24 (t, 2H), of 6.71 (d, 1H), 6,93 (m, 1H), 8,81 (d, 1H)245Spot
813-[2-(tert-Butoxycarbonylamino) ethoxy]-1,2,5-thiadiazoleto 1.38 (s, 9H), and 3.31 (m, 2H), 4.16 the (t, 2H), of 6.96 (m, 1H), 8,35 (s, 1H)246Spot
823-[3-(tert-Butoxycarbonylamino) propoxy]isoxazolof 1.36 (s, 9H), of 1.80 (m, 2H), 3.04 from (q, 2H), 4,17 (t, 2H), 6,24 (s, 1H), 6,83 (m, 1H), 8,61 (s, 1H)243Spot
833-[3-(tert-Butoxycarbonylamino) propoxy]isothiazolof 1.36 (s, 9H), of 1.80 (m, 2H), 3.04 from (q, 2H), 4,17 (t, 2H), of 6.71 (d, 1H), 6,80 (m, 1H), 8,82 (d, 1H)259Spot
843-[3-(tert-Butoxycarbonylamino) propoxy]-1,2,5-thiadiazoleof 1.36 (s, 9H), of 1.80 (m, 2H), 3.04 from (q, 2H), 4,17 (t, 2H), to 6.80 (m, 1H), at 8.36 (s, 1H)260Spot

Method 85

3-(2-Aminoethoxy)isoxazol hydrochloride

4M hydrogen Chloride in dioxane (10 ml) are added to a solution of 3-[2-(tert-butoxycarbonylamino)ethoxy]isoxazol (method 79; 500 mg, 2.2 mmol) in dioxane (10 ml)and the mixture is PE is amerivault at ambient temperature for 3 days. The obtained solid product is collected by filtration, washed with ether and dried to obtain specified in the title compound (298 mg, 83%) as a white solid product. NMR 3,20 (m, 2H), 4,39 (t, 2H), 6,13 (s, 1H), 8.30 to (s, 3H), 8,69 (s, 1H); m/z 129.

How 86-90

The following compounds are synthesized in a manner analogous to the way 85.

Etc.ConnectionNMRm/zSM
863-(2-Aminoethoxy) isothiazole hydrochloride3,19 (m, 2H), 4,46 (t, 2H), 6,76 (d, 1H), 7,28 (s, 1H), 8,40 (s, 3H), 8,87 (d, 1H)145Spot
873-(2-Aminoethoxy)-1,2,5-thiadiazole hydrochloride3,20 (m, 2H), 4,58 (t, 2H), at 8.36 (m, 4H)146Spot
883-(3-Aminopropoxy) isoxazol hydrochloride2,02 (m, 2H), and 2.83 (m, 2H), 4,24 (t, 2H), 6,29 (s, 1H), 8,20 (s, 3H), 8,61 (s, 1H)143Spot
893-(3-Aminopropoxy) isothiazole hydrochloride2,02 (m, 2H), and 2.83 (m, 2H), 4,36 (t, 2H), 6,78 (d, 1H), 8,10 (s, 3H), 8,81 (d, 1H)159Spot
903-(3-Aminopropoxy)-1,2,5-thiadiazole hydrochloride2,02 (m, 2H), and 2.83 (m, 2H), 4,43 (t, 2H), 8,10(s,3H), 8,39 (s, 1H)160Spot

<> How 91-94

The following compounds are synthesized using the procedure as described in JOC 1987, 2714-2716.

MethodConnection
915-Methyl-4-(methylamino)isoxazol hydrochloride
925-Acetyl-2-(trifluoromethyl)imidazol
935-Acetyl-2-(methoxymethyl)imidazol
94N-(5-Methyl-4-isoxazolyl)-2,2,2-triptorelin

How 95-109

The following compounds are prepared using procedures similar to those described in JOC 1987, 2714-2726.

Etc.ConnectionNMRm/zSM
955-Methyl-4-(N-methyl-N-propionamido) isoxazolof 1.09 (t, 3H), 2,08 (kV, 2H), of 2.38 (s, 3H), and 3.16 (s, 3H), 8,16 (s, 1H)169Spot
961-Methyl-2-ethyl-5-acetylimidazoleof 1.36 (t, 3H), 2,41 (s, 3H), of 2.72 (q, 2H), 3,82 (s, 3H), 7,72 (s, 1H)153Spot
975-Methyl-4-(N-methyl-N-isobutylamino) isoxazolof 1.03 (d, 6H), a 2.36 (s, 3H), 2,48 (m, 1H), and 3.16 (s, 3H), to 8.20 (s, 1H)183Spot
981-Methyl-2-isopropyl-5-acetylimidazole of 1.36 (d, 6H), 2,42 (s, 3H), 3,10 (m, 1H), 3,84 (s, 3H), of 7.75 (s, 1H)167Spot
994-(Isopropylamino)-5-methylisoxazolCDCl3of 1.12 (d, 6H), is 2.30 (s, 3H), 3,21 (1H, septuplet), 8,01 (s, 1H)1414-amino-5-methyl-isoxazol
1005-Methyl-4-[N-isopropylacrylamide) isoxazolCDCl31,02 (users, 6H), of 1.80 (s, 3H), of 2.38 (s, 3H), 4,99 (1H, septuplet), of 8.09 (s, 1H)183Spot
1015-Acetyl-1-isopropyl-2-Meiof 1.40 (d, 6H), of 2.38 (s, 3H), 2,42 (s, 3H), 5,08 (osirm, 1H), 7,81 (s, 1H)167Spot
1023,5-Dimethyl-4-aminoethoxy2,04 (s, 3H), 2,19 (s, 3H), of 3.78 (s, 2H)112
103N-(2,2,2-Triptorelin)-5-methyl-4-aminoethoxy(CDCl3) 2,32 (s, 3H), 2,80 (s, 1H), 3,52 (kV, 2H), of 8.06 (s, 1H)181Spot
1043,5-Dimethyl-4-formalizationof 2.08 (s, 3H), of 2.23 (s, 3H), 8,10 (s, 1H), 9,50 (s, 1H)140Spot
1053,5-Dimethyl-4-methylaminoethanolof 2.08 (s, 3H), of 2.30 (s, 3H), 2,60 (d, 3H), of 3.84 (s, 1H)n/aSpot
1063,5-Dimethyl-4-(N-methylacetamide) isocs is angry of 1.75 (s, 3H), of 2.16 (s, 3H), of 2.30 (s, 3H), of 3.00 (s, 3H)168Spot
107l,2,4-Trimethyl-5-acetylimidazoleof 2.26 (s, 3H), of 2.38 (s, 6H), of 3.65 (s, 3H)152Spot
108N-(2,2,2-Triptorelin)-N-(5-methyl-4-isoxazolyl) ndimethylacetamideis 1.82 (s, 3H), is 2.37 (s, 3H), 4,36 (kV, 2H), to 8.62 (s, 1H)223Spot
1091-(2,2,2-Triptorelin)-2-methyl-5-acetylimidazoleof 2.38 (s, 6H), 5,31 (kV, 2H), of 7.96 (s, 1H)207Spot

The method 110

N-Methyl-4-aminobenzenesulfonamide

4-Aminobenzenesulfonate (200 mg, to 1.14 mmol) is dissolved in a solution of methylamine in EtOH (3 ml, excess) and heated to 80°C for 45 minutes, then cooled to room temperature and left to mix overnight. The solvent is evaporated in vacuum and the azeotrope is distilled off together with ether to obtain specified in the connection header in the form of a solid product (160 mg, 75%). NMR: 2,12 (s, 3H), of 5.85 (s, 2H), 6,59 (d, 2H), 7,37 (d, 2H); m/z 187.

The method 111

2-Amino-4-(1,2-dimethylimidazole-5-yl)-5-chloropyrimidine

2-Amino-4-(1,2-dimethylimidazole-5-yl)pyrimidine (method 26; 378 mg, 2 mmol) and N-chlorosuccinimide (267 mg, 2 mmol) is dissolved in glacial acetic acid (7 ml) under nitrogen atmosphere. The reaction mixture is heated at 5° C for 18 hours, while adding additional N-chlorosuccinimide (89 mg, 0.66 mmol)and the reaction mixture heated at 65°C for an additional 2 hours. Volatile products are removed by evaporation and the residue is dissolved in water (10 ml). The pH of the solution was adjusted to 11-12 by adding 40% aqueous sodium hydroxide solution. The precipitated solid product is collected by filtration and carefully washed with water, dried in vacuum at 60°C obtaining specified in the title compound (344 mg, 77%) as a yellow solid product. NMR of 2.35 (s, 3H), of 3.75 (s, 3H), of 4.83 (s, 2H), 7,53 (s, 1H), of 8.27 (s, 1H); m/z 224.

Example 166

The following further illustrates the most common pharmaceutical dosage forms containing the compound of formula (I) or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo (hereinafter, the compound X), for therapeutic or prophylactic use in humans:

(a)Tablet Img tablet
Connection X100
Lactose Heb. Pharm.182,75
Sodium, croscarmelloseto 12.0
The paste of corn starch

(5% wt./about. paste)
2,25
Magnesium stearate3,0
(b): Tablet IImg tablet
Connection X50
Lactose Heb. Pharm.223,75
Sodium, croscarmellose6,0
Corn starch15,0
Polyvinylpyrrolidone

(5% wt./about. paste)
2,25
Magnesium stearate3,0
(c): Tablet IIImg tablet
Connection X1,0
Lactose Heb. Pharm.93,25
Sodium, croscarmellose4,0
The paste of corn starch

(5% wt./about. pasta
0,75
Magnesium stearate1,0
(d): Capsulemg/capsule
Connection X10
Lactose Heb. Pharm.488,5
Magnesium stearate1,5
(e): Injection I(50 mg/ml)
Connection X5,0% mass/volume
1M sodium hydroxide solution15,0% volume/volume
0,1M Hydrochloric acid (to bring the pH to 7.6)
The polyethylene glycol 4004,5% mass/volume
Water for injectionsup to 100%
(f)Injection II10 mg/ml
Connection X1,0% mass/volume
Sodium phosphate Brit. Pharm.3, 6% weight/volume
0,1M sodium hydroxide solution15,0% volume/volume
Water for injectionsup to 100%
(g): Injection III(1 mg/ml, pH 6, with

buffer)
Connection X0,1% weight/volume
Sodium phosphate Brit. Pharm.of 2.26% mass/volume
Citric acid0,38% mass/volume
The polyethylene glycol 4003.5% mass/volume
Water for injectionsup to 100%

Comments

The above preparations can be obtained by conventional procedures well known in the pharmaceutical field. The tablets (a)-(c) can be provided with a coating for enteral absorption by conventional means, for example, by a coating of azettftalat pulp.

1. The compound of formula (I)

where R1represents halogen, amino, C1-6alkyl, C1-6alkoxy;

p is 0-4, where the values of R1may be the same or different;

R2represents sulfamoyl or group, Ra-Rb-;

q is 0-2, where the values of R2may be the same or different, and where p+q=0-5;

R3represents halogen or cyano;

n is 0-2, where the values of R3may be the same or different;

R4represents hydrogen, C1-6alkyl, C1-6alkenyl,3-8cycloalkyl or heterocyclic group associated with carbon, where R4may be optionally substituted on a carbon atom by one or more Rd;

R5and R6are independently selected from hydrogen, halogen, C1-6of alkyl, C2-6alkenyl or3-8cycloalkyl, where R5and R6independently from each other may be optionally substituted on a carbon atom by one or more Re;

Rais selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl,3-8cycloalkyl1-6of alkyl, phenyl, heterocyclic group, panels1-6of alkyl or (heterocyclic group)1-6of alkyl, where Randmaybe n is necessarily substituted on a carbon atom by one or more R gand where, if said heterocyclic group contains residue-NH-, its nitrogen may be optionally substituted by a group selected from Rh;

Rbrepresents-N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or-N(Rm)SO2-where Rmrepresents hydrogen or C1-6alkyl and r is 1-2;

Rdand Rgare independently selected from halogen, cyano, hydroxy, amino, carboxy, carbamoyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6alkoxy, C1-6alkoxyl1-6alkoxyl1-6alkoxy, N,N-(C1-6alkyl)2amino, C1-6alkanolamine,1-6alkyl-S(O)andwhere a is 0-2, C1-6alkoxycarbonyl, C1-6alkylsulfonamides,3-8cycloalkyl, phenyl, heterocyclic group, panels1-6alkyl-Rabout-, (heterocyclic group)1-6alkyl-Rabout-, phenyl -, Roor (heterocyclic group)-Rabout-,

where Rdand Rgindependently from each other may be optionally substituted on a carbon atom by one or more Rj;

Raboutrepresents-O-;

Rhselected from C1-6the alkyl or benzyl and

Reand Rjare independently selected from halogen, hydroxy, methoxy, this is C, ethylamino, dimethylamino, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl and ethylsulfonyl;

moreover, the heterocyclic group is a saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom selected from nitrogen, sulfur or oxygen, and which may be associated with the carbon atoms or nitrogen, where the group-CH2- can optionally be replaced by-C(O)-group;

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

2. The compound of formula (I) according to claim 1 where R is 0-2, where the values of R1may be the same or different, or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

3. The compound of formula (I) according to any one of claims 1 and 2, where R2represents sulfamoyl or group, Ra-Rb-where Rais selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil,

With3-8cycloalkyl, phenyl or heterocyclic group, where Ramay be optionally substituted on a carbon atom by one or more Rg;

Rbrepresents-N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or-N(Rm)SO2-where Rmrepresents hydrogen or C1-6alkyl which r is 2;

Rgis selected from halogen, hydroxy, amino, cyano, carbamoyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6alkoxy, C1-6alkoxyl1-6alkoxyl1-6alkoxy, N,N-(C1-6alkyl)2amino, C1-6alkyl-S(O)andwhere a is equal to 2, p3-8cycloalkyl, phenyl, heterocyclic group, panels1-6alkyl-Roor (heterocyclic group)-Ro-where Rgmay be optionally substituted on a carbon atom by one or more Rj;

Rorepresents-O - and

Rjis selected from halogen, hydroxy, methyl or methoxy;

moreover, the heterocyclic group is a saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom selected from nitrogen, sulfur or oxygen, and which may be associated with the carbon atoms or nitrogen, where the group-CH2- can optionally be replaced by-C(O)-group;

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

4. The compound of formula (I) according to claim 1, where q is 0 or 1, or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

5. The compound of formula (I) according to claim 1, where q is 1 and R2located in the para-position relative to the-NH-group is E. aniline of the formula (I), or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

6. The compound of formula (I) according to claim 1, where R3represents halogen, or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

7. The compound of formula (I) according to claim 1, where n is 0 or 1, or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

8. The compound of formula (I) according to claim 1, where R4represents hydrogen, C1-6alkyl or C2-6alkenyl, where R4may be optionally substituted on a carbon atom by one or more Rdwhere Rdis selected from halogen, amino, C1-6alkoxy, C1-6alkanolamine, C1-6alkylsulfonyl, phenyl or heterocyclic group,

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

9. The compound of formula (I) according to claim 1, where R5and R6are independently selected from hydrogen or C1-6of alkyl, where R5and R6independently from each other may be optionally substituted on a carbon atom by one or more Rewhere Reis selected from halogen or methoxy,

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

10. The compound of formula (I) according to claim 1, where

R represents chlorine, amino, methyl or methoxy;

R is 0-2, where the values of R1may be the same or different;

R2represents sulfamoyl, N-(tetrahydrofur-2-ylmethyl)sulfamoyl, N-(cyclopropylmethyl)sulfamoyl, N-(FSD-2-ylmethyl)sulfamoyl, N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)sulfamoyl, N-(cyanomethyl)sulfamoyl, N-(carbamoylmethyl)sulfamoyl, N-methylcarbamoyl, N-(4-terbisil)sulfamoyl, N-(pyridine-2-ylmethyl)sulfamoyl, N-(pyridine-3-ylmethyl)sulfamoyl, N-(4-methylthiazole-2-yl)sulfamoyl, N-(3-methylisoxazol-5-ylmethyl)sulfamoyl, N-(tetrahydropyran-2-ylmethyl)sulfamoyl, N-(2-methylpyridin-5-yl)sulfamoyl, N-[2-(2-hydroxyethoxy)ethyl]sulfamoyl, N-(2-hydroxyethyl)sulfamoyl, N-(2,2,2-triptorelin)sulfamoyl, N-(2-methoxyethyl)sulfamoyl, N-(2-methylethyl)sulfamoyl, N-(2-benzyloxyethyl)sulfamoyl, N-(2,2-dimethoxymethyl)sulfamoyl, N-[2-(N,N-dimethylamino)ethyl]sulfamoyl, N-(2-piperidine-1-retil)sulfamoyl, N-[2-(methoxyethoxy)ethyl]sulfamoyl, N-ethylsulfonyl, N-[2-(2-methoxyethoxy)ethyl]sulfamoyl, N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulfamoyl, N-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl)sulfamoyl, N-(2-pyridin-2-retil)sulfamoyl, N-(2-pyridin-4-retil)sulfamoyl, N-(2-isoxazol-3-Eloxatin)sulfamoyl, N-(2-isothiazol-3-Eloxatin)sulfamoyl, N-(2-1,2,5-thiadiazole-3-Eloxatin)sulfamoyl, N-methyl-N-(2-methoxyethyl)sulfamoyl, N-[-(2-oxopyrrolidin-1-yl)propyl]sulfamoyl, N-(3-methoxypropyl)sulfamoyl, N-propylsulfonyl, N-(2,3-dihydroxypropyl)sulfamoyl, N-(3-morpholinopropan)sulfamoyl, N-[3-(N,N-dimethylamino)propyl]sulfamoyl, N-(3,3,3-cryptochromes)sulfamoyl, N-(2,2-dimethyl-3-hydroxypropyl)sulfamoyl, N-(3-hydroxypropyl)sulfamoyl, N-(3-ethoxypropan)sulfamoyl, N-(2-hydroxypropyl)sulfamoyl, N-(3-isopropoxyphenyl)sulfamoyl, N-(3-isopropoxy-2-hydroxypropyl)sulfamoyl, N-(3-isoxazol-3-roxiprin)sulfamoyl, N-(3-isothiazol-3-roxiprin)sulfamoyl, N-(3-1,2,5-thiadiazole-3-roxiprin)sulfamoyl, N-(1,1-dimethylpropyl)sulfamoyl, N-methyl-N-(3-morpholinopropan)sulfamoyl, N-butylsulfonyl, N-tert-butylsulfonyl, N-(2-hydroxybutyl)sulfamoyl, N-methyl-N-tert-butylsulfonyl, N-intercultural, N-(5-hydroxyphenyl)sulfamoyl, N-(4,5-dimethyloxazole-2-yl)sulfamoyl, N-(cyclopropyl)sulfamoyl, N-(cyclobutyl)sulfamoyl, N-(3-triptoreline)sulfamoyl, N-arylsulphonyl, N-(2-PROPYNYL)sulfamoyl, N-methylcarbamoyl, acetamido, methylamino or mesyl;

q is 0 or 1;

R3represents a bromine or chlorine;

n is 0 or 1;

R4represents hydrogen, methyl, ethyl, isopropyl, 3-butenyl, benzyl, 2-phthalimidomethyl, 2-amino-ethyl, 2-methoxyethyl, 2-acetamidophenyl, 2-methylaminomethyl or 2,2,2-triptorelin;

R5and R6are independently selected from hydrogen, IU the sludge, ethyl, isopropyl, trifloromethyl or methoxymethyl,

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

11. The compound of formula (I)chosen from:

2-{4-[N-(cyclopropylmethyl)sulfamoyl]aniline}-4-(1,2-dimethylimidazole-5-yl)pyrimidine;

4-(1-ethyl-2-Mei-5-yl)-2-{4-[N-(2-methoxyethyl)sulfamoyl]aniline}pyrimidine;

4-(1-ethyl-2-Mei-5-yl)-2-{4-[N-(3-methoxypropyl)sulfamoyl]aniline}pyrimidine;

4-(1-ethyl-2-Mei-5-yl)-2-{4-[N-(cyclopropylmethyl)sulfamoyl]aniline}pyrimidine;

4-(1-ethyl-2-Mei-5-yl)-2-[4-[N-cyclopropylmethanol)aniline]pyrimidine;

4-(1-methyl-2-isopropylimidazole-5-yl)-2-{4-(N-(cyclopropylmethyl)sulfamoyl]aniline}pyrimidine;

4-(1,2-dimethylimidazole-5-yl)-2-[4-(N-cyclopropylamino)aniline]pyrimidine;

4-(1,2-dimethylimidazole-5-yl)-2-[4-(N-cyclobutylmethyl)aniline]pyrimidine;

4-(1,2-dimethylimidazole-5-yl)-2-{4-[N-2,2,2-triptorelin)sulfamoyl]aniline}pyrimidine;

and

4-(1-isopropyl-2-Mei-5-yl)-2-[4-(N-cyclobutylmethyl)aniline]pyrimidine,

or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo.

12. Pharmaceutical composition having inhibitory cell cycle activity, selective against CDK-2, CDK-4 and CDK-6, and p is docurama the growth of cancer cells, which contains a compound of the formula (I)or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo according to any one of claims 1 to 11 in combination with a pharmaceutically acceptable diluent or carrier.

13. The compound of formula (I)or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo according to any one of claims 1 to 11, suitable as pharmaceuticals.

14. The compound of formula (I)or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo according to any one of claims 1 to 11, with inhibitory cell cycle activity, selective against CDK-2, CDK-4 and CDK-6 to obtain the drug.

15. Method of producing inhibitory effects on the cell cycle (against cell proliferation) in a warm-blooded animal, such as man, which comprises the introduction of a specified warm-blooded animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo according to any one of claims 1 to 11.

16. The pharmaceutical composition which contains a compound of the formula (I)or its pharmaceutically acceptable salt, or ester, hydrolisis in vivo, indicated in paragraph 12, in combination with a pharmaceutically acceptable diluent or carrier suitable for producing inhibiting the effects on the cell cycle (against cell proliferation) in a warm-blooded animal, such as people.

17. The method of obtaining the compounds of formula (I)or its pharmaceutically acceptable salt or in vivo hydrolyzable ester according to claim 1, where R1, R2, R3, R4, R5, R6, n, p, q defined in claim 1, including the interaction of the compounds of formula (IV)

with the compound of the formula (V)

where T is O or S;

Rxmay be the same or different and selected from C1-6the alkyl and,

if necessary, the subsequent conversion of compounds of formula (I) into another compound of formula (I);

remove any protective group;

education pharmaceutically acceptable salt or in vivo hydrolyzable ester.

18. The method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salt or in vivo hydrolyzable ester according to claim 1, where R1, R2, R3, R4, R5, R6, n, p, q defined in claim 1, where R2is sulfamoyl the group or the group Ra-Rband Rbrepresents a group NHSO2-involving the interaction of a pyrimidine of formula (VI)

where X is a substituted group,

with an amine of formula (VII)

if necessary, subsequent pre the treatment of compounds of formula (I) into another compound of formula (I);

remove any protective group;

education pharmaceutically acceptable salt or in vivo hydrolyzable ester.

19. The method of obtaining the compounds of formula (I)or its pharmaceutically acceptable salt or in vivo hydrolyzable ester according to claim 1, where R1, R2, R3, R4, R5, R6, n, p, q defined in claim 1, including the interaction of a pyrimidine of formula (VIII)

with the compound of the formula (IX)

where Y is a substituted group,

and, if necessary, subsequent conversion of compounds of formula (I) into another compound of formula (I);

remove any protective group;

education pharmaceutically acceptable salt or in vivo hydrolyzable ester.

20. The use of the compounds of formula (I)or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo according to any one of claims 1 to 11, in the manufacture of drugs suitable for the treatment of cancer.

21. The use of the compounds of formula (I)or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo according to any one of claims 1 to 11, in the manufacture of drugs suitable for the treatment of leukemia and cancer of the breast, lung, colon, rectum, stomach, prostate, bladder, pancreas shall elez and ovarian cancer.

22. The use of the compounds of formula (I)or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo according to any one of claims 1 to 11, in the manufacture of drugs suitable for the treatment of leukemia, lymphoid malignancies and solid tumors, such as carcinoma and sarcoma tissues, such as liver, kidney, prostate and pancreas.

23. The use of the compounds of formula (I)or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo according to any one of claims 1 to 11, in the manufacture of medicines, suitable for slowing the growth of primary and recurrent solid tumours of, for example, colon, breast, prostate, lungs and skin.

24. The use of the compounds of formula (I)or its pharmaceutically acceptable salt, or a complex ester, gidrolizuyushchie in vivo according to any one of claims 1 to 11, in the manufacture of medicines, suitable for inhibiting the growth of primary and retidiviruuschem solid tumors, for example, certain tumours of the colon, breast, prostate, lung, vulva and skin.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

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

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, virology.

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

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

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

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

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

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

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

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

5 cl, 2 tbl, 581 ex

FIELD: pharmaceutical chemistry, medicine.

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

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

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

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

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

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of amide of the general formula (I)

wherein X means -CH; Y means -CH or nitrogen atom (N); m = 1 or 2; R1 means (C1-C6)-alkyl, (C1-C)-alkoxy-group, N,N-di-[(C1-C6)-alkyl]-amino-group, heterocyclyl-(C1-C6)-alkyl wherein heterocyclyl represents piperazinyl or homopiperazinyl; n = 3; R2 means halogen atom, (C1-C6)-alkyl; R3 means hydrogen atom; Q means phenyl optionally substituted with cyano-group, or pyridyl optionally substituted with morpholino-group, or their pharmaceutically acceptable salts, to methods for synthesis of indicated compounds, pharmaceutical compositions containing thereof and their using in treatment of diseases or states mediated by cytokines.

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

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to anthranylamide derivative selected from compound of formula I or N-oxides thereof, wherein R1 represents methyl, F, Cl, Br; R2 represents F, Cl, Br, I, CF3; R3 represents CF3, Cl, Br, OCH2CF3; R4a represents C1-C4-alkyl; R4b represents H, CH3; and R5 represents Cl, Br, and agriculturally acceptable salt thereof. Also disclosed are composition for pest controlling containing biologically effective amount of formula I and at least one additional component selected from group comprising surfactants, solid and liquid diluents; composition for invertebrate insect controlling containing biologically effective amount of formula I and at least one additional biologically active compound or agent. Also disclosed are method for insect controlling as well as intermediates such as benzoxazinone and parasolocarboxylic acid derivatives.

EFFECT: compounds with insecticide activity, useful in insect controlling.

20 cl, 16 tbl, 33 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 2-morpholyl-6-piperidyl-4-[(4'-(ethoxycarbonyl-5'-1',2',3'-triazol)-1'-yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance allows significant increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: improved and valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, virology.

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

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

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention describes a new compound 4,6-bis-(morpholyl)-2-[(2'-ethoxyacetyltetrazolyl)-5'-yl]-1,3,5-triazine of the formula: that represents an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on germinating sunflower seeds and seedlings.

EFFECT: valuable properties of compound.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

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

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

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

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

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to derivatives of piperazine and piperidine of the formula (I): wherein ---Z represents =C or -N; Q means benzyl or 2-, 3- or 4-pyridylmethyl that can be substituted with one or more substitutes taken among group comprising halogen atom, cyano-group, (C1-C3)-alkoxy-group, CF3, OCF3, SCF3, (C1-C4)-alkyl, (C1-C3)-alkylsulfonyl and their salts, and to a method for their preparing also. It has been found that these compounds elicit valuable pharmacological properties owing to combination of (partial) agonism with respect to members of dopamine receptors subtype and affinity with respect to corresponding serotonin and/or noradrenergic receptors and can be useful in preparing compositions used in treatment of fear and/or depression or Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 3 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

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