4-phenylpyrimidine-2-carbonitrile derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-phenylpyrimidine-2-carbonitrile of formula

(values of R, R1, R2 are given in the formula of invention) or their pharmaceutically acceptable salts which have inhibition properties towards catepsin K and catepsin S. The invention also relates to use of derivatives of formula I for treating catepsin K and catepsin S related disorders, as well as to a pharmaceutical composition containing the said derivative.

EFFECT: improved properties of derivatives.

9 cl, 151 ex

 

The invention relates to derivatives of 4-phenylpyrimidine-2-carbonitrile to contain their pharmaceutical compositions and to the use of these derivatives to obtain drugs for the treatment of cathepsin K and cathepsin S-related diseases such as atherosclerosis, bone disease such as osteoporosis, inflammatory and immune disorders such as rheumatoid arthritis and multiple sclerosis, and chronic pain, such as neuropathic pain.

Cysteinate are a class of peptidases, characterized by the presence of a cysteine residue in the catalytic site of the enzyme, and these proteases are associated with normal decomposition and protein processing. Many pathological disorders or diseases are the result of abnormal activity of cysteinate, such as overexpression or enhanced activation. Cysteine cathepsins, such as cathepsin B, K, L, S, V, F, represent a class of lysosomal enzymes that are involved in various disorders, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors, coronary disease, atherosclerosis, autoimmune diseases and infectious diseases.

Cathepsin K has a strong collagenolytic, elastase and gelatinase activity (Bromme et al., J. Biol, Chem, 271, 2126-2132, 1996) and is expressed predominantly in the East is aclasta (Bromme et Okamoto, Biol. Chem. Hopp-Seyler, 376, 379-384, 1995). He breaks down the key proteins of the bone matrix, including collagen types I and II (Kaffienah et al., Biochem. J. 331, 727-732, 1998), gelatin, osteopontin and osteonectin, and also participates in the metabolism of extracellular matrix, necessary for normal growth and repair of bones (Bossard et al., J. Biol. Chem. 271, 12517-12524, 1996). Inhibition of cathepsin K should lead to a reduction mediated by osteoclast bone resorption.

Inhibitors of cathepsin K may therefore represent a new therapeutic agent for the treatment of painful conditions in humans, such as osteoporosis.

Sukhova et al (J. Clin. Invest. 102, 576-583, 1998) demonstrated that cells (macrophages), which migrate and accumulate in the developing atherosclerotic plaques in humans, also synthesize potent elastase cathepsin K and S.

Degradation of the matrix, especially in the fibrous cap of such plaques is a critical process in the destabilization of atherosclerotic lesions. Thus, the metabolism of extracellular matrix components, collagen and elastin, which give the tightness of the fibrous cap of the lesion, can critically affect the clinical manifestations of atherosclerosis, such as thrombosis of the coronary artery as a result of destruction of atherosclerotic plaques. Inhibition of cathepsins K and/or S at sites of plaque, sklan the x break, it may thus be an effective way to prevent such events.

As cathepsin K, cathepsin S also has a strong alactolyticus (Arch. Biochem. Biophys., 299, 334-339, 1992; J. Biol. Chem., 267, 7258-7262, 1992) and collagenolytic activity (Biochem. J., 256, 433-440, 1998). Diseased human arteries superexpression cathepsin K and S and show mutual deficit cystatin C, the most common endogenous inhibitor of cysteinate (J. Clin. Invest. 102, 576-583, 1998; J. Clin. Invest. 104, 1191-1197, 1999). Sukhova et al (J. Clin. Invest. 111, 897-906, 2003) demonstrated that a deficiency of cathepsin S reduces atherosclerosis in mice with deficiency of LDL receptors. Bromme et al (Biochem. Biophys. Research Comm. 312, 1019-1024, 2003) also demonstrated that cathepsin K and S degradable HDL3 and free from lipids apoA-I in vitro. This further indicates cathepsin K and S as a therapeutic target for atherosclerosis.

It is shown that cathepsin S is a key enzyme involved in the invariant processing chain in antigen presenting cells of human and mouse (J. Clin. Invest. 110, 361-369, 2002). This invariant processing circuit regulates the function of class II MHC and is associated with inflammatory and autoimmune disorders. Saegusa et al (J. Clin. Invest. 110, 361-369, 2002) demonstrated that inhibition of cathepsin S in vivo alters the view of autoantigen and development organospecific the autoimmunity.

In the International patent Application WO 03/020287 also revealed that mRNA for cathepsin S is activated in animal models of chronic pain and that the introduction of inhibitors of cathepsin S causes a reversal of the mechanical hyperalgesia in these animals.

Derivatives of 4-aminopyrimidine-2-carbonitrile have been described as inhibitors of cathepsins K and/or S in the International patent application WO 03/020278 (Novartis Pharma GMBH), whereas the structurally related derivatives of 4-aminopyrimidine-2-carbonitrile were recently disclosed in WO 04/000819 (ASTRAZENECA AB) as inhibitors of cathepsin S. Pyrrolopyrimidine were similarly disclosed as inhibitors of cathepsin K and/or S in WO 03/020721 (Novartis Pharma GMBH) and WO 04/000843 (ASTRAZENECA AB).

Presently discovered that derivatives of 4-phenylpyrimidine-2-carbonitrile having a General formula I

in which R denotes 1-3 possible substituent, independently selected from (C1-6)alkyl (if necessary substituted by one or more Halogens), (C1-6)alkyloxy (if necessary substituted by one or more halogen, cyano, halogen, hydroxy, nitro, (C3-6)cycloalkyl, CO(C1-6)alkyl, S(C1-6)alkyl, SO(C1-6)alkyl, SO2(C1-6)alkyl, SO2NH(C1-6)alkyl, SO2NH2, NHCO(C1-8)alkyl and CO2H; or 2 substituent R in the related provisions of the place indicate OCH 2O, OCH2CH2O or CH2CH2O;

R1represents H or (C1-6)alkyl;

R2means (C2-6)alkyl, if necessary, replaced IT, (C1-4)alkyloxy, (C6-10)aryloxy, (C6-10)aryl(C1-4)alkyloxy, one or more atoms of halogen, NR3R4, CO2H or CONR6R7;

R3and R4independently represent H, (C1-8)alkyl [if necessary substituted by one or more halogen atoms, (C1-4)alkyloxy or (C6-10)aryloxy], (C3-8)cycloalkyl [if necessary substituted by one or more halogen atoms], (C1-4)alkyl, substituted 4-8 membered saturated heterocycle, including a heteroatom selected from O, S and NR5, 4-8-membered saturated a heterocycle, including a heteroatom selected from O, S and NR5, (C6-10)aryl, (C2-9)heteroaryl [if necessary substituted by 1-3 substituents selected from halogen, CF3, (C1-4)alkyl and (C1-4)alkyloxy], (C6-10)aryl(C1-4)alkyl or (C2-9)heteroaryl(C1-4)alkyl; or

R3and R4together with the nitrogen to which they are bound, form a 4-8-membered saturated the heterocycle and, if necessary substituted by one or more Halogens or CONR8R9and which may optionally include 1 or more heteroa the Ohm, selected from O, S and NR5; or

R3represents H or (C1-4)alkyl; and R4means (C1-4)alkyl, substituted CONR8R9, COOR10, NR8, R9, NR8COR9or NR8CONR9R10;

R5denotes H, (C1-4)alkyl [if necessary substituted (C3-8)cycloalkyl, (C6-10)aryl or (C2-5- heteroaryl], (C3-8)cycloalkyl, (C6-10)aryl or (C2-5)heteroaryl;

R6and R7independently represent H, (C1-4)alkyl or 4-to 8-membered saturated a heterocycle, including a heteroatom selected from O, S and NR5; or

R6and R7together with the nitrogen to which they are bound, form a 4-8-membered saturated the heterocycle and, if necessary substituted by one or more halogen, and which may optionally include 1 or more heteroatoms selected from O, S and NR5;

R8and R9independently represent H or (C1-4)alkyl; or

R8and R9together with the atoms to which they are linked, form a 4-8-membered saturated a heterocycle, which may optionally include 1 or more heteroatoms selected from O, S and NR5;

R10represents H or (C1-4)alkyl;

or their pharmaceutically acceptable salts are inhibitors of cathepsin K and cathepsin S and can therefore use the I to obtain drugs for the treatment of cathepsin K and cathepsin S-associated disorders, such as, for example, atherosclerosis, bone diseases such as osteoporosis, inflammatory and immune disorders such as rheumatoid arthritis and multiple sclerosis, and chronic pain such as neuropathic pain.

Another aspect of the invention relates to derivatives of 4-phenylpyrimidine-2-carbonitrile having a General formula I

the formula I

in which

R denotes 1-3 possible substituent, independently selected from (C1-6)alkyl [if necessary substituted by one or more halogen], (C1-6)alkyloxy [if necessary substituted by one or more halogen], cyano and halogen;

R1represents H or (C1-6)alkyl;

R2means (C2-6)alkyl, if necessary, replaced IT, (C1-4)alkyloxy, one or more halogen atoms or NR3R4;

R3and R4independently represent H, (C1-8)alkyl [if necessary substituted by one or more halogen], (C3-8) cycloalkyl [if necessary substituted by one or more halogen], 4-8-membered saturated a heterocycle, including a heteroatom selected from O, S and NR5, (C6-10)aryl, (C2-9)heteroaryl, (C6-10)aryl(C1-4)alkyl or (C2-9)heteroaryl-(C1-4)alkyl; or

R3and R4together with the nitrogen to which which they are associated, form a 4-8-membered saturated the heterocycle and, if necessary substituted by one or more halogen, and which may optionally include 1 or more heteroatoms selected from O, S and NR5;

R5denotes H, (C1-4)alkyl [if necessary substituted (C3-8) cycloalkyl, (C6-10)aryl or (C2-5) heteroaryl], (C3-8)cycloalkyl, (C6-10)aryl or (C2-5)heteroaryl; or their pharmaceutically acceptable salts.

The term (C1-6)alkyl as used in the definition of formula I means a branched or unbranched alkyl containing 1-6 carbon atoms, such as hexyl, pentyl, 3-methylbutyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

The term (C2-6)alkyl similarly means a branched or unbranched alkyl containing 2-6 carbon atoms, such as hexyl, pentyl, 3-methylbutyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl and ethyl. Preferred (C2-6)alkyl as used in the definition of R2in the formula I is n-propyl.

The term (C1-4)alkyl means a branched or unbranched alkyl containing 1-4 carbon atoms, such as butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

The term (C1-8)alkyl means a branched or unbranched alkyl, sod is Rashi 1-8 carbon atoms, such as octyl, heptyl, hexyl, pentyl, 3-methylbutyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

The term (C3-6) cycloalkyl means cycloalkyl containing 3-6 carbon atoms, such as cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term (C3-8) cycloalkyl similar means cycloalkyl containing 3-8 carbon atoms, such as cyclooctyl, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term (C6-10)aryl means a radical derived from an aromatic group containing 6 to 10 carbon atoms, such as, for example, phenyl and naphthyl.

The term (C6-10)aryl(C1-4)alkyl means a (C1-4)alkyl, substituted (C6-10)aryl, such as benzyl.

The term (C2-9)heteroaryl means 5 - or 6-membered cyclic aromatic radical containing 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, and which may be attached to another 5 - or 6-membered (hetero)aromatic ring. Examples of such heteroaryl groups are pyridyl, imidazolyl, pyrazolyl, pyrimidinyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, thienyl, oxadiazolyl, hinely, ethanolic, benzothiazolyl, benzimidazolyl etc. Preferred heteroaryl are 2-pyridyl and 3-pyridyl.

The term (C2-5)heteroaryl means 5 - what if 6-membered cyclic aromatic radical, containing 1-3 heteroatoms selected from nitrogen, oxygen or sulfur. Examples of such heteroaryl groups are pyridyl, imidazolyl, pyrazolyl, pyrimidinyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, thienyl, oxadiazolyl etc. Preferred heteroaryl are 2-pyridyl and 3-pyridyl.

The term (C2-9)heteroaryl(C1-4)alkyl means a (C1-4)alkyl, substituted (C2-9)heteroaryl, such as, for example, pyridine-4-ylmethyl.

In the definitions in the formula I R3and R4and/or R6and R7and/or R8and R9may, together with the nitrogen to which they are bound, form a 4-8-membered saturated a heterocycle, such as anzeigen, pyrrolidine, piperidine or 1H-azepin. Such rings may contain 1 or more additional heteroatoms selected from O, S or NR5with the formation of such rings, as morpholine, thiomorpholine, hexahydro-1,4-oxazepine, piperazine, homopiperazine, imidazolidin or tetrahydrothieno.

The term "halogen" means F, Cl, Br or I. When the halogen is a substituent in the alkyl group, preferred is F. the Preferred halogen-substituted alkyl is trifluoromethyl.

Preferred according to the invention derivatives of 4-phenylpyrimidine-2-carbonitrile according to the formula I are those in which R2means (C2-6)alkyl, alseny HE (C1-4)alkyloxy, one or more halogen or NR3R4.

Other preferred compounds are compounds in which R2denotes propyl, substituted in position 3 by a group NR3R4.

More preferred are the derivatives of the formula I, in which 4-phenyl includes tripterocalyx Deputy in metaprogram.

Especially preferred derivatives of 4-phenylpyrimidine-2-carbonitrile according to the invention are:

- 4-(3-hydroxy-1-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-(3-(piperidine-1-yl)-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(1-ethylpropylamine)-propyl]-6-(3-triptoreline)-pyrimidine-carbonitrile;

- 4-[3-(4-methyl-[1,4]diazepin-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-(3-cyclohexylamino)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-{3-[methyl-(1-methylpiperidin-4-yl)-amino]-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(4-methylpiperazin-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-(3-isopropylaminomethyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(4-pyridin-2-yl-piperazine-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(carbamoylmethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(ka is oxymethylene)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(2-diethylaminoethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(2-acetylaminofluorene)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-{3-[2-(2-Oxymetazoline-1-yl)-ethylamino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-(3,4-dimetilfenil)-6-[3-(methylcarbamoylmethyl)-propyl]-pyrimidine-2-carbonitrile;

- 4-[3-(2-acetylaminofluorene)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile;

- 4-(3,4-dimetilfenil)-6-{3-[2-(2-Oxymetazoline-1-yl)-ethylamino]-propyl}-pyrimidine-2-carbonitrile;

- 4-[3-(3-dimethylaminopropylamine)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile;

- 4-(3,4-dimetilfenil)-6-{3-[2-(1-methylpyrrolidine-2-yl)-ethylamino]-propyl}-pyrimidine-2-carbonitrile;

- 4-(3-cyclopropylamino-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(1-(S)-methyl-2-methoxyethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(1-(S)-carbamoylethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(1-(R)-carbamoylethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(1-ethyl-1-methylpropylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(1-methylcyclopropyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(2-hydroxyethylamino)-propyl]-6-(3-triptoreline)-pyrim the DIN-2-carbonitrile;

- 4-[3-(1-carbarnoyl-1 methylethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;

- 4-[3-(2-oxopyrrolidin-3-(S)-ylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile; or their pharmaceutically acceptable salt.

The invention relates in the following aspect to pharmaceutical compositions comprising a derivative of 4-phenylpyrimidine-2-carbonitrile having the General formula I, or its pharmaceutically acceptable salt, in a mixture with pharmaceutically acceptable excipients.

Derivatives of 4-phenylpyrimidine-2-carbonitrile General Formula I can be obtained as depicted in Scheme 1, the condensation of a derivative of acetophenone having the formula (II)in which R has the meaning as defined above, with a complex ester of the formula R'-OC(O)R2in which R' represents a (C1-6)alkyl, and R2shall have the meaning given above, to obtain the derived 1,3-dione of formula (III). If necessary, the group R1can be introduced by alkylation derived 1,3-dione in the presence of a base such as potassium carbonate and a suitable solvent, for example THF or acetone, when heated, to obtain the derivative of 2-alkyl-1,3-dione having the formula (IV). The cyclization of 1,3-dione (IV) with urea in the presence of acid, for example, concentrated aqueous hydrochloride in a suitable dissolve the e, for example ethanol, with heating gain derived 2-hydroxy-4-phenylpyrimidine formula (V). Treatment of compounds of formula (V) POCl3at high temperature leads to a derivative of 2-chloro-4-phenylpyrimidine formula (VI), which cyanidation cyanide copper in a solvent, for example dimethylformamide or N-methylpyrrolidinone, and using microwave heating leads to the derived 4-phenylpyrimidine-2-carbonitrile General Formula I.

Stage cyanidation can also be implemented using cyanide zinc as a reactant with a catalyst based on a transition metal, such as tetrahetarenoporphyrazines, in a suitable solvent, for example dimethylformamide, dimethoxyethane or N-methylpyrrolidinone.

Scheme 1

In an alternative method, as shown in figure 2, is derived 1,3-dione of the formula (IV) is treated with S-methyl isothiouronium in a suitable solvent, for example isopropanol, and a suitable base, such as triethylamine, getting derived 2-methylsulfanyl-4-phenylpyrimidine formula (VII). Oxidation derivative of the formula VII monopersulfate potassium (Oxone) or m-chloroperbenzoic acid (MCPBA) in a suitable solvent, for example methanol, water, chloroform, or mixtures thereof, leads to the derived 2-methanesulfonyl-4-phenyl what rimidine formula (VIII), which treatment with sodium cyanide in a suitable solvent, for example dimethyl sulfoxide, leads to derivatives of 4-phenylpyrimidine-2-carbonitrile General Formula I.

Scheme 2

In another method, as shown in figure 3, derived β-complex keto-ester of formula (IX)in which R2shall have the meaning given above, is condensed with thiourea in the presence of sodium methylate, getting derived 2-mercapto-4-hydroxypyrimidine formula (X), which, in the S-methylation of iodomethane in the presence of a base, for example potassium hydroxide, leads to the derived 2-methylsulfanyl-4-hydroxypyrimidine formula (XI). Treatment of compounds of formula XI POCl3gives the derivative 2-methylsulfanyl-4-chloropyrimidine formula (XII), oxidation of which with the use of MCPBA leads to the derived 2-methanesulfonyl-4-chloropyrimidine formula (XIII).

Scheme 3

The reaction of the combination of compound XIII with phenylboronate acids using a catalyst based on a transition metal derivative gives 2-methanesulfonyl-4-phenylpyrimidine formula (VII), which can subsequently be converted to derivatives of 4-phenylpyrimidine-2-carbonitrile General Formula I by treatment with sodium cyanide in a suitable solvent, such as dimethylsulfate the de.

In an alternative method, depicted in figure 4, for the introduction of a phenyl group in position 4 of the pyrimidine, a compound having the formula XIII (see scheme 3)may be introduced into reaction with hexamethylbenzene, to obtain the derived 2-methanesulfonyl-4-trimethylenediamine formula (XIV), in which the reaction with sodium cyanide in dimethyl sulfoxide leads to a derivative of 2-cyano-4-trimethylenediamine formula (XV). As a result of the combination by Stille the compounds of formula XV with arylhalides using a catalyst based on a transition metal as described in the General literature, receive the derived 4-phenylpyrimidine-2-carbonitrile General Formula I.

Scheme 4

Derivatives of 4-phenylpyrimidine-2-carbonitrile General Formula I, in which R2means (C2-6)alkyl substituted by a group NR3R4can be derived from the corresponding alcohol derivative, as depicted in scheme 5 for the compounds according to the invention, in which R2designate a Deputy representing 3-OH-propyl.

Oxidation of a suitable alcohol derivative of the formula (I) periodontal dessa-Martin, or using the alternative procedure of oxidation, receive a corresponding derived aldehyde according to formula (XVI), which is then the outdoor the comfort with the amine of the formula HNR 3R4under conditions of reductive amination, getting these derivatives 4-phenylpyrimidine-2-carbonitrile according to the invention.

Scheme 5

Derivatives of 4-phenylpyrimidine-2-carbonitrile General Formula I, in which R2means (C2-6)alkalicarbonate acid or carboxamide, can be derived from the corresponding alcohol derivative as shown in scheme 6, compounds according to the invention, in which R2denotes a Deputy representing 3-OH-propyl.

Oxidation of a suitable alcohol derivative of the formula (I) with the use of sodium chlorite and sodium hypochlorite in the presence of TAMRA as a catalyst to obtain the corresponding acid (XVIII). The reaction mix of this acid with primary or secondary amines with different combination of reagents, such as EDCI, PyBOP, HBTU, etc. receive appropriate carboxamide (XIX) as the reaction product.

Scheme 6

In another way, as depicted in scheme 7 for the introduction of the phenyl in position 4 of the pyrimidine, a compound having formula XV (see scheme 4), is treated with iodine, receiving a derivative of 2-cyano-4-godparenting formula (XX). Then, using a combination of type Stille or Suzuki or Negishi compounds of formula XX with arylboronic acids or other and the target akrilovye compounds of metals with the use of a catalyst based on a transition metal, as described in the General literature, get derivatives of 4-phenylpyrimidine-2-carbonitrile General Formula I.

Scheme 7

In another method, as shown in figure 8, for the introduction of R2and phenyl in position 6 and 4, respectively, pyrimidine, reaction of a combination of compound XXI with arylhalides with the transition metal as a catalyst, followed by removal of the protective group is benzyl get the compound of General formula I, where R2denotes 3-hydroxypropyl, which can be further derivatization according to scheme 5 with obtaining compounds with different R2and phenyl in positions 6 and 4 of the pyrimidine.

Scheme 8

Compound XXI can be synthesized according to scheme 3 and scheme 4 with β-ketefian with R2as a 4-benoxaprofen (XXIV), which can be synthesized as depicted in scheme 9. The reaction of 4-benzenemethanol acid with acid Melodrama in the presence of isopropylcarbamate with DMAP as base get acylated derivative of the acid of Melodrama, which is then converted into the XXIV ethanolism with acid. Alternatively, compound XXIV can also be synthesized from ethyl - or methylacetoacetate (XXV) through the widely documented chemistry double anion with 3-benzeneethanamine (XXVI) as the alkylating agent.

In the doctrine of derivative 4-phenylpyrimidine-2-carbonitrile General Formula I, in which the group R2contains the nitrogen atom of the primary amine (in the form NR3R4or NR5), the nitrogen must be temporarily protected, for example, protective groups for labile to acid tert.-butyloxycarbonyl (Vos). Other suitable protective groups for functional groups that must be temporarily protected during synthesis known in the prior art, for example, Wuts, P. G.M. and Greene, T. W.: Protective Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

Scheme 9

Compounds according to the invention, which may be in free base form, can be separated from the reaction mixture in the form of pharmaceutically acceptable salts.

Pharmaceutically acceptable salts can also be obtained by treating the free base of formula I with organic or inorganic acid, such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, triperoxonane acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonate acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.

Compounds according to the invention may exist in solvated, and resolutional forms, including the Aya hydrated forms. In General, the solvated forms are equivalent nonsolvated forms and are within the scope of the present invention.

Compounds according to the present invention can exist as amorphous forms, but also possible and many crystalline forms. In General, all physical forms are equivalent for applications processed in accordance with the present invention, and are within the scope of this invention.

Derivatives of 4-phenylpyrimidine-2-carbonitrile according to the invention and their salts may contain a center of chirality in one or more side chains R, R1-R10and can therefore be obtained in the form of a pure enantiomer or as a mixture of enantiomers or as a mixture containing diastereomers. Methods of asymmetric synthesis, through which the pure stereoisomers are known in the prior art, for example the synthesis of chiral induction or conducted on the basis of chiral intermediates, enantioselective enzymatic conversion, separation of stereoisomers or enantiomers using chromatography on chiral environments. Such methods are, for example, described in Chirality in Industry (edited by A. N. Collins, G. N. Sheldrake and J. Crosby, 1992; John Wiley).

It was found that the compounds according to the invention are inhibitors of human cathepsin K and cathepsin S and can therefore, in the following aspect of izaberete the Oia, be used in therapy and, in particular, to obtain drugs for the treatment of osteoporosis, atherosclerosis and related cathepsin K and cathepsin S-dependent disorders, such as inflammatory and immune disorders such as rheumatoid arthritis, chronic pain, such as neuropathic pain, and other disorders associated with abnormal bone resorption, such as Paget's disease, osteoarthritis, osteolytic bone cancer and metastatic bone disease.

Compounds according to the invention can be introduced interline or parenterally to humans, preferably in a daily dose of 0.001-100 mg / kg body weight, preferably 0.01 to 10 mg per kg of body weight. Mixed with pharmaceutically suitable auxiliary means, for example, as described in the standard reference, Gennaro et al., Remington''s Pharmaceutical Sciences, (20th ed., Lippincott Williams & Wilkins, 2000, see, in particular, Part 5: Pharmaceutical Manufacturing), compounds can be extruded in solid dosage forms such as pills, tablets, or treated with obtaining capsules or suppositories. By pharmaceutically suitable liquids the compounds can also be used in the form of solution, suspension, emulsion, for example, for use as drugs for injection or in the form of a spray, for example for use as a nasal spray.

To obtain drugs is the R forms, for example pills, you can use the usual additives such as fillers, dyes, polymeric binder, etc. In General, may be any pharmaceutically acceptable additive, which does not disturb the function of the active compounds.

Suitable carrier materials, which compositions can be administered, include lactose, starch, cellulose derivatives, etc. or mixtures thereof, in the right quantities.

The invention is further illustrated by the following examples.

Methods

General chemical procedures. All reagents were either purchased from common commercial sources or synthesized according to the literature procedures using commercial sources. Data proton NMR (1H NMR) were obtained on a spectrometer Bruker DPX 400 and attributed to internal TMS. Mass spectra were recorded on a Shimadzu LC-8A (HPLC) PE Sciex API 150EX LCMS. Analytical analysis IHMS reverse phase was performed on a column LUNA C18 (5µ; 30×4.6 mm) in a gradient from 90% water/0.1% of formic acid to 90% acetonitrile/0.1% of formic acid) at a flow rate of 4 ml/min

Abbreviations

Dimethylformamide (DMF), N-methylpyrrolidinone (NMP), dichloromethane (DCM), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), high performance liquid chromatography (HPLC), diisopropylethylamine (DIPEA), triethylamine (the EA), extended (br), singlet (s), doublet (d), triplet (t), triperoxonane acid (TFA), tert.-butyloxycarbonyl (Vos), 1-(3-dimethylaminopropyl)-3-ethyl of carbodiimide HCl (EDCl), 1-hydroxybenzotriazole (HOBt), 2,2,6,6-tetramethyl-1-piperidinyloxy (TAMRA).

EXAMPLE 1

4-Propyl-6-(3-triptoreline)-pyrimidine-2-carbonitrile

A: 3-hydroxy-1-(3-triptoreline)-Gex-2-EN-1-he

To a stirred suspension of sodium amide (0,78 g) in ether (40 ml), under nitrogen atmosphere, was added 3-trifurcation (1,52 ml). The mixture was stirred for 5 minutes, then slowly added ethyl butyrate (1,32 ml). The resulting mixture was heated under reflux overnight, cooled to room temperature and extinguished with water (20 ml). The ether layer was removed and the aqueous layer was acidified with HCl (5M), then was extracted with simple ether (3 x 20 ml). The organic layers were combined, washed with water (20 ml), dried over sodium sulfate and evaporated under reduced pressure to give crude product in the form of oil. Flash chromatography on silica gel was obtained 3-hydroxy-1-(3-triptoreline)-Gex-2-EN-1-it is in the form of oil (0.74 g).

1H NMR (CDCl3) δ: 8,12 (s, 1H), of 8.06 (d, 1H), to 7.77 (d, 1H), to 7.59 (t, 1H), to 6.19 (s, 1H), 3,88 (ush. s, 1H), 2,44 (t, 2H), 1,69-to 1.79 (m, 2H), 1,01 (t, 3H).

B: 6-propyl-4-(3-triptoreline)-1 H-pyrimidine-2-he

Stir a mixture of 3-hydroxy-1-(3-triptoreline who yl)-Gex-2-EN-1-it (259 mg), urea (90 mg), HCl (0.15 ml, 5M) and ethanol (5 ml) was heated under reflux for 16 hours. Added an additional amount of urea (60 mg) and HCl (0.15 ml, 5M) and the reflux was continued for 24 hours. The mixture was allowed to cool and the solvent evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (20 ml) and water (20 ml), the organic layer was separated and then washed with saturated solution of sodium carbonate (20 ml), then water (20 ml). The ethyl acetate extract was dried over sodium sulfate and evaporated under reduced pressure, obtaining 6-propyl-4-(3-triptoreline)-1H-pyrimidine-2-it looks like a solid brown color (204 mg). MS m/z 283,0 (M+1), 100%.

C: 2-chloro-4-propyl-6-(3-triptoreline)-pyrimidine

A mixture of 6-propyl-4-(3-triptoreline)-1H-pyrimidine-2-she (204 mg) and acid chloride phosphoric acid (3 ml) was stirred and heated under reflux for 72 hours, then left to cool, then poured into a mixture of ice/simple ether (20 ml). The ether layer was separated, washed with saturated solution of sodium carbonate (20 ml), dried over sodium sulfate and evaporated under reduced pressure, obtaining 2-chloro-4-propyl-6-(3-triptoreline)-pyrimidine in the form of a dark brown oil (239 mg).

MS m/z 301,3 (M+1), 100%.

D: 4-propyl-6-(3-triptoreline)-pyrimido the-2-carbonitril

To a solution of 2-chloro-4-propyl-6-(3-triptoreline)-pyrimidine (50 mg) in 1-methyl-2-pyrrolidinone (2 ml) was added copper cyanide (I) (60 mg). The suspension was heated in a microwave oven at 200°C for 20 minutes, then was poured into a mixture of ethyl acetate (10 ml) and aqueous ammonia (5 ml). The organic layer was separated, washed with water (10 ml), dried over sodium sulfate and evaporated under reduced pressure. Preparative HPLC was obtained target compound 4-propyl-6-(3-triptoreline)-pyrimidine-2-carbonitrile in the form of a brown resin (4,1 mg).

1H NMR (CDC13) δ: 8,27-of 8.37 (m, 2H), 7,82 (d, 1H), 7,34 (s, 1H), 7,68 (t, 1H), 2,88 (t, 2H), 1,78 is 1.91 (m, 2H), of 1.03 (t, 3H). MS m/z 292,0 (M+1), 100%.

EXAMPLE 2

5-Methyl-4-propyl-6-(3-triptoreline)-pyrimidine-2-carbonitrile

A: 2-methyl-1-(3-triptoreline)-hexane-1,3-dione

To a stirred suspension of potassium carbonate (596 mg) in acetone (7 ml) was added 3-hydroxy-1-(3-triptoreline)-Gex-2-EN-1-he (190 mg), then iodomethane (0.45 ml). The mixture was heated under reflux for 6 hours, cooled to room temperature and the solvent was evaporated under reduced pressure. The resulting oil was dissolved in ethyl acetate (20 ml), washed with water (3×20 ml), dried over sodium sulfate and evaporated under reduced pressure to give crude product in the form of oil.

Flash chromatog what afia on silica gel was obtained 2-methyl-1-(3-triptoreline)-hexane-1,3-dione in the form of oil (102 mg).

1H NMR (CDC13) δ: 8,14 (s, 1H), of 8.06 (d, 1H), to 7.77 (d, 1H), 7,56 (t, 1H), to 4.41 (q, 1H), 2,29-2,48 (m, 2H), 1,46-of 1.55 (m, 2H), 1,40 (d, 3H), 0,78 (t, 3H).

B: 5-methyl-6-propyl-4-(3-triptoreline)-1 H-pyrimidine-2-he

Stir a mixture of 2-methyl-1-(3-triptoreline)-hexane-1,3-dione (102 mg), urea (45 mg), HCl (0.10 ml, 5M) and ethanol (4 ml) was heated under reflux for 16 hours. Added an additional amount of urea (30 mg) and HCl (0.10 ml, 5M) and the reflux was continued for 24 hours. The mixture was allowed to cool and the solvent evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (10 ml) and water (10 ml), the organic layer was separated and then washed with saturated solution of sodium carbonate (10 ml), then water (10 ml). The ethyl acetate extract was dried over sodium sulfate and evaporated under reduced pressure, obtaining 5-methyl-6-propyl-4-(3-triptoreline)-1H-pyrimidine-2-it is in the form of a yellow oil (64 mg).

MS m/z 297,4 (M+1), 100%.

C: 2-chloro-5-methyl-4-propyl-6-(3-triptoreline)-pyrimidine

A mixture of 5-methyl-6-propyl-4-(3-triptoreline)-1H-pyrimidine-2-she (64 mg) and acid chloride phosphoric acid (3 ml) was stirred and heated under reflux for 24 hours, then left to cool and poured into a mixture of ice/simple ether (20 ml). The ether layer was separated, washed with saturated solution of CT is onata sodium (10 ml) and water (10 ml), dried over sodium sulfate and evaporated under reduced pressure, obtaining 2-chloro-5-methyl-4-propyl-6-(3-triptoreline)-pyrimidine in the form of an oil (64 mg).

MS m/z 315,0 (M+1), 100%.

D: 5-methyl-4-propyl-6-(3-triptoreline)-pyrimidine-2-carbonitrile

To a solution of 2-chloro-5-methyl-4-propyl-6-(3-triptoreline)-pyrimidine (50 mg) in dimethylformamide (1 ml) was added cyanide zinc (II) (16 mg) and tetrakis(triphenylphosphine)-palladium (0) (16 mg). The suspension was heated in a microwave oven at 150°C for 5 minutes, then was poured into ethyl acetate (50 ml) and washed with water (2×10 ml). The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. Preparative HPLC was obtained 5-methyl-4-propyl-6-(3-triptoreline)-pyrimidine-2-carbonitrile in the form of a yellow resin (11 mg).1H NMR (CDC13) δ: 7,63-7,81 (m, 4H), 2,87 (t, 2H), 2,39 (s, 3H), 1,80-1,90 (m, 2H), with 1.07 (t, 3H). MS m/z 306,4 (M+1), 100%.

EXAMPLE 3

4-(3-hydroxy-1-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

A: 1,3-dioxo-6-hydroxy-1-(3'-tryptophanyl)-hexane

To a stirred suspension of sodium hydride (60% in paraffin oil, 20 g) in diethyl ether (1 l) at 0°C was added ethanol (1 ml). To this mixture was added gamma-butyrolactone (18 g), then for 30 minutes was added dropwise a solution of simple diethyl ether (100 ml) of 3'-triftoratsetofenona (38 g). A mixture of astable and for mixing at room temperature for 72 hours. Was added ethanol (20 ml)to destroy excess sodium hydride, and then an aqueous solution of ammonium chloride (20 g in 300 ml water). The organic layer was separated and washed with diluted hydrochloric acid (0.1 N., 500 ml), then water (2×200 ml). The ether layer was dried over sodium sulfate, the solvent was removed under reduced pressure. The residue was passed through a column of silica gel using petroleum ether and ethyl acetate (1:1) as eluent, obtaining 1,3-dioxo-6-hydroxy-1-(3'-tryptophanyl)-hexane (32 g).1H NMR (CDC13) δ: 8,1 (s, 1H), 8,04 (d, 1H), 7,76 (d, 1H), 7,55 (DD, 1H), 6,2 (s, 1H), 3,74 (t, 2H), 2,61 (t, 2H), of 1.97 (m, 2H). MS m/z 275 (M+1), 100%.

B: 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3-triptoreline)pyrimidine

To a solution of 1,3-dioxo-6-hydroxy-1-(3'-tryptophanyl)-hexane (32 g) in isopropanol (30 ml) was added S-methylisothiourea (34 g). The mixture was heated at 110°C for 4 hours. After cooling to room temperature was added triethylamine (45 ml) and methanol (50 ml) and the mixture was heated under reflux with an oil bath at 85°C for 6 hours. After removal of the solvent and triethylamine under reduced pressure, the residue was placed in ethyl acetate (500 ml) and water (500 ml). The organic layer was separated, then washed with diluted hydrochloric acid (0.1 N., 500 ml), then water (2×300 ml). The organic layer was dried, the solvent was removed under reduced pressure. Estato is passed through a column of silica gel, using petroleum ether and ethyl acetate (1:1) as eluent, obtaining 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3-triptoreline)pyrimidine (18 g).1H NMR (CDCl3) δ: 8,3 (s, 1H), of 8.25 (d, 1H), 7,76 (d, 1H), 7,58 (DD, 1H), 7,28 (s, 1H), 3,74 (t, 2H), 2,92 (t, 2H), 2,65 (s, 3H), 2,03 (m, 2H). MS m/z 329 (M+1), 100%.

C: 2-methanesulfonyl-4-(3-hydroxypropyl)-6-(3-triptoreline)pyrimidine

To a solution of 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3-triptoreline)pyrimidine (7,8 g) in a mixed solvent of methanol and water (200 ml, 10:1) was added OXONE (34 g). The mixture was stirred at room temperature for 3 hours, then was diluted with ethyl acetate (500 ml). The mixture was washed with water (3×500 ml). The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, obtaining 2-methanesulfonyl-4-(3-hydroxypropyl)-6-(3-triptoreline) pyrimidine (8,9 g) as a crude product, which was used for the next stage without further purification.1H NMR (CDCl3) δ: 8,3 an 8.4 (m, 2H), 7,8-7,87 (m, 2H), 7,68 (DD, 1H), of 3.77 (t, 2H), 3.43 points (s, 3H), 3,10 (t, 2H), 2,10 (m, 2H).

D: 4-(3-hydroxypropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

To a stirred solution of 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3-triptoreline)pyrimidine (200 mg) in dimethyl sulfoxide (5 ml) was added sodium cyanide (27 mg). The mixture was stirred at room temperature for 45 minutes, then poured in e is ylacetic (50 ml) and washed with water (2×50 ml). The organic layer was dried over sodium sulfate, evaporated under reduced pressure and was purified preparative HPLC. Allocated 4-(3-hydroxypropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile in the form of resin (78 mg).

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 7,83 (d, 1H), 7,80 (s, 1H), 7,69 (t, 1H), of 3.77 (t, 2H), 3,05 (t, 2H), 2,07 and 2.13 (m, 2H). MS m/z 308,3 (M+1), 100%.

EXAMPLE 4a

4-(3-piperidine-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

A: 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

Periodical dessa-Martin (104 mg) was added to a solution of 4-(3-hydroxypropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (50 mg) in dichloromethane (5 ml) and the resulting suspension was stirred at room temperature for 45 minutes the Mixture was washed with water (3×10 ml), dried over sodium sulfate and evaporated under reduced pressure, obtaining 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile in a solid brown color (70 mg). MS m/z 306,1 (M+1), 100%.

B: 4-(3-piperidine-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

To a suspension of macroporous cyanoborohydride (102 mg, of 2.35 mmol/g) in acetonitrile (0.5 ml) was added piperidine (19 l), acetic acid (0.1 ml) and a solution of 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (49 mg) in acetonitrile (0.5 ml). The mixture was heated in a microwave oven etc is 150°C for 10 minutes, was filtered through a glass filter using the device for multifiltrate Vacmaster, and was purified preparative HPLC. Allocated 4-(3-piperidine-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile in the form of a transparent resin (12 mg).

1H NMR (CDCl3) δ: 8.34 per (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,79 (s, 1H), 7,68 (t, 1H), 2,93 (t, 2H), 2,32 is 2.44 (m, 5H), 1,97-2,05 (m, 2H), 1,49 is 1.60 (m, 4H), 1,37-of 1.45 (m, 2H), 1,23-to 1.38 (m, 1H). MS m/z 375,3 (M+1), 85%.

The procedure described above, was further applied, using the appropriate amine derivative, to obtain the following compounds:

4b: 4-(3-Morpholine-4-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,28-to 8.34 (m, 2H), 7,82 (d, 1H), 7,78 (s, 1H), 7,69 (t, 1H), 3,68 (t, 4H), 2,96 (t, 2H), 2,38-2,48 (m, 6H), 1,98-2,07 (m, 2H). MS m/z 377,4 (M+1), 100%.

4c: 4-[3-(1,4-Deformability-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31-of 8.33 (m, 2H), 7,83 (d, 1H), 7,76 (s, 1H), 7,69 (t, 1H), 2.95 and (t, 2H), 2,55 (ush. t, 4H), 2,48 (t, 2H), 1,92-2,05 (m, 6H). MS m/z 411,3 (M+1), 100%.

4d: 4-(3-(4-Methylpiperazin-1-yl)-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31-of 8.33 (m, 2H), 7,82 (d, 1H), 7,78 (s, 1H), 7,69 (t, 1H), equal to 2.94 (t, 2H), 2,30-2,60 (ush. m, 10H), and 2.26 (s, 3H), 1,98-2,05 (m, 2H). MS m/z 390,1 (M+1), 100%.

4e: 4-(3-Cyclohexylamino)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31-to 8.34 (m, 2H), 7,82 (d, 1H), 7,78 (s, 1H), 7,68 (t, 1H), 2,97 (who, 2H), a 2.71 (t, 2H), 2,35 at 2.45 (m, 1H), 1,92-2,03 (m, 2H), 1,79 is 1.91 (m, 2H), 1,65-to 1.77 (m, 2H), 1,54-of 1.65 (m, 1H), 0,96-1,32 (m, 5H). MS m/z 389,3 (M+1), 100%.

4f: 4-(3-isopropylaminomethyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31-8,35 (m, 2H), 7,82 (d, 1H), 7,78 (s, 1H), 7,68 (t, 1H), 2,98 (t, 2H), 2,80 (kV, 1H), 2,69 (t, 2H), 1,95-2,02 (m, 2H), of 1.05 (d, 6H). MS m/z 349,5 (M+1), 83%.

4g: 4-[3-(benzylmethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: with 8.33 (s, 1H), 8,28 (d, 1H), 7,82 (d, 1H), 7,69 (s, 1H), to 7.67 (t, 1H), 7,20-7,29 (m, 5H), 3,49 (s, 2H), equal to 2.94 (t, 2H), 2.40 a-2,50 (ush. t, 2H), of 2.23 (s, 3H), 1,97-of 2.08 (m, 2H). MS m/z 411,3 (M+1), 100%.

4h: 4-(3-isobutylamino)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8.34 per (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,78 (s, 1H), 7,68 (t, 1H), 2,98 (t, 2H), 2,69 (t, 2H), 2,42 (d, 2H), 1,95-2,05 (m, 2H), 1,66-of 1.78 (m, 1H), of 0.91 (d, 6H). MS m/z 363,3 (M+1), 98%.

4i: 4-{3[(Pyridine-4-ylmethyl)-amino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,54 (d, 2H), 8.34 per (s, 1H), 8.30 to (d, 1H), 7,83 (d, 1H), of 7.75 (s, 1H), 7,68 (t, 1H), 7.24 to 7,27 (m, 2H), 3,82 (s, 2H), 3.00 for (t, 2H), by 2.73 (t, 2H), 2,00-2,09 (m, 2H). MS m/z 398,0 (M+1), 100%.

4j: 4-(3-Pyrrolidin-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,79 (s, 1H), 7,68 (t, 1H), 2,97 (t, 2H), 2,44-of 2.56 (m, 6H), 2.00 in 2,07 (m, 2H), 1,74-to 1.79 (m, 4H). MS m/z 361,1 (M+1), 100%.

4k: 4-(3-azepin-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1 H NMR (CDCl3) δ: 8.34 per (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,78 (s, 1H), 7,68 (t, 1H), equal to 2.94 (t, 2H), 2,58-2,61 (m, 4H), of 2.53 (t, 2H), 1,94 is 2.01 (m, 2H), 1,54-to 1.67 (m, 8H). MS m/z 389,3 (M+1), 100%.

4l: 4-[3-(azacyclonol-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), to 7.77 (s, 1H), 7,68 (t, 1H), 2,98 (t, 2H), 2,48-of 2.58 (m, 6H), 1.91 a is 2.00 (m, 2H), 1,51-1,72 (m, 10H). MCm/z 403,5 (M+1), 100%.

4m: 4-(3-Cyclopentylmethyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: at 8.36 (s, 1H), 8.30 to (d, 1H), 7,81-to 7.84 (m, 2H), to 7.67 (t, 1H), 3,48 (ush. t, 1H), is 3.08-3,20 (ush. m, 2H), 3.04 from (t, 2H), 2.26 and is 2.33 (m, 2H), 2.00 in to 2.13 (m, 2H), 1,71-of 1.84 (m, 4H), 1,57 by 1.68 (m, 2H). MS m/z 375,3 (M+1), 100%.

4n: 4-(3-Cycloheptylmethyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,79 (s, 1H), 7,68 (t, 1H), 2,97 (t, 2H), to 2.67 (t, 2H), 2,58-of 2.64 (m, 1H), 1,95-2,02 (m, 2H), 1,24-of 1.84 (m, N). MS m/z 403,5 (M+1), 100%.

A: 4-[3-(cyclohexylethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,78 (s, 1H), 7,68 (t, 1H), 2,97 (t, 2H), 2,68 (t, 2H), 2,43 (d, 2H), 1,96-2,04 (m, 2H), 0,85-to 1.77 (m, 11N). MS m/z 403,5 (M+1), 100%.

4p: 4-(3-tert.-Butylaminoethyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,79 (s, 1H), 7,68 (t, 1H), 2,99 (t, 2H), 2,66 (t, 2H), 1,94 is 2.01 (m, 2H), 1,11 (s, 9H). MS m/z 363,3 (M+1), 100%.

4q: 4-[3-(2,2-dimethylpropylene)-propyl]-6-(3-tripto who were)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: (a 8.34 (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,78 (s, 1H), 7,68 (t, 1H), 2,99 (t, 2H), 2,69 (t, 2H), 2,34 (s, 2H), 1,97-2,04 (m, 2H), of 0.90 (s, 9H). MS m/z 377,5 (M+1), 100%.

4r: 4-[3-(1-Ethylpropylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), 7,79 (s, 1H), 7,68 (t, 1H), 2,99 (t, 2H), 2,66 (t, 2H), 2,33-2,39 (kV, 1H), 1,95-2,02 (m, 2H), of 1.35 to 1.47 (m, 4H), to 0.88 (t, 6H). MS m/z 377,5 (M+1), 100%.

4s: 4-{3-[Methyl-(1-methylpiperidin-4-yl)-amino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8.34 per (s, 1H), 8,32 (d, 1H), 7,82 (d, 1H), to 7.77 (s, 1H), 7,68 (t, 1H), 2,87-2,95 (m, 4H), of 2.51 (t, 2H), 2,29-is 2.37 (m, 1H), of 2.25 (s, 6H), 1,88 is 2.01 (m, 4H), 1,53 is 1.70 (m, 4H). MS m/z 418,3 (M+1), 58%.

4t: 4-[3-(2,2,2-Triptoreline)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (MeOD) δ: 8,51 (s, 1H), 8,48 (d, 1H), 8,24 (s, 1H), to $ 7.91 (d, 1H), 7,79 (t, 1H), 3,92 (kV, 2H), 3,21 (t, 2H), is 3.08 (t, 2H), 2.21 are to 2.29 (m, 2H). MS m/z 389,1 (M+1), 58%.

4u: 4-[3-(4-methyl-[1,4]diazepan-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,32-to 8.34 (m, 2H), 7,82 (d, 1H), 7,79 (s, 1H), 7,69 (t, 1H), equal to 2.94 (t, 2H), 2,68-a 2.71 (m, 4H), 2,53-2,62 (m, 6H), was 2.34 (s, 3H), 1,94-2,02 (m, 2H), 1,76-to 1.82 (m, 2H). MS m/z 404,5 (M+1), 100%.

4v: 4-(3-[1,4]oxazepan-4-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,39 (s, 1H), 8,31 (d, 1H), 7,86 (s, 1H), 7,83 (d, 1H), 7,68 (t, 1H), of 3.97 (t, 2H), a 3.87 (t, 2H), 2,07-of 3.77 (m, N). MS m/z to € 391.1 (M+1), 100%.

4w: 4-(3-Phenylaminopropyl)-6-(3-trif ermatinger)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31 (s, 1H), compared to 8.26 (d, 1H), 7,81 (d, 1H), 7,72 (s, 1H), 7,66 (t, 1H), 7,16 (t, 2H), 6,70 (t, 1H), 6,60 (d, 2H), 3.72 points ush. s, 1H), 3.27 to (t, 2H), 3,03 (t, 2H), 2,15-2,19 (m, 2H). MS m/z 383,1 (M+1), 58%.

4x: 4-[3-(4-Pyridin-2-yl-benzylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,68 (d, 1H), 8.34 per (s, 1H), 8,27 (d, 1H), 7,94 (d, 2H), 7,63-7,81 (m, 5H), 7,41 (d, 2H), 7,21-of 7.23 (m, 1H), 3,86 (s, 2H), 2,99 (t, 2H), 2,74 (t, 2H), 2.00 in 2,07 (m, 2H). MS m/z 474,1 (M+1), 42%.

4y: 4-[3-(4-phenylpiperazin-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (MeOD) δ: 8,51 (s, 1H), of 8.47 (d, 1H), 8,24 (s, 1H), of 7.90 (d, 1H), to 7.77 (t, 1H), 7,21 (t, 2H), 6,93 (d, 2H), 6,83 (t, 1H), 3,11-3,15 (m, 4H), to 2.99 (t, 2H), 2,63 of 2.68 (m, 4H), of 2.53 (t, 2H), is 2.05 and 2.13 (m, 2H). MS m/z 452,1 (M+1), 100%.

4z: 4-[3-(4-benzylpiperazine-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31-to 8.34 (m, 2H), 7,82 (d, 1H), 7,78 (s, 1H), to 7.67 (t, 1H), 7,25-to 7.32 (m, 5H), of 3.48 (s, 2H), with 2.93 (t, 2H), 2,38 is 2.55 (m, 10H), 1,97-2,05 (m, 2H). MS m/z 466,0 (M+1), 100%.

4a': 4-[3-(4-Pyridin-2-yl-piperazine-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,32 (d, 1H), 8,18 (d, 1H), 7,82 (d, 1H), 7,80 (s, 1H), 7,68 (t, 1H), 7,47 (t, 1H), 6,60-of 6.65 (m, 2H), 3,51-of 3.53 (m, 4H), 2,98 (t, 2H), 2,54-to 2.57 (m, 4H), 2,48 (t, 2H), 2,03-2,11 (m, 2H,). MS m/z 453,0 (M+1), 100%.

EXAMPLE 5a

4-(3-isopropylphenyl)-6-propylpyrimidine-2-carbonitril

A:2-mercapto-6-propylpyrimidine-4-ol

Sodium (4.6 g) was added by portions at 0°C to methanol (150 ml The mixture was stirred at room temperature until dissolution. After cooling to 0°C, was added parts of the thiourea (11,0 g) and the mixture was stirred until dissolution. Ethyl butyrylacetate (15,8 g) in methanol (200 ml) was added dropwise at 0°C for 30 minutes. The mixture was heated under reflux for 9 h, then concentrated under reduced pressure. The residue was dissolved in water. After acidification with acetic acid to pH 6 and stirring for 1 hour, the mixture was filtered. The precipitate was sequentially washed with water and isopropanol, and then dried under reduced pressure, obtaining 2-mercapto-6-propylpyrimidine-4-ol (14,1) in the form of white crystals (So pl.=220°C).

1H NMR (DMSO-d6) δ: 12,2 (ush. s, 2H); of 5.68 (s, 1H); 2,32 (t, J=7 Hz, 2H); 1.60-to 1,50 (m, 2H); from 0.88 (t, J=7 Hz, 3H).

B: 2-methylsulfanyl-6-propylpyrimidine-4-ol

1H. a solution of potassium hydroxide in methanol (110 ml) was added dropwise at 0°C to a suspension of 2-mercapto-6-propylpyrimidine-4-ol (17.0 g) in methanol (220 ml). The mixture was stirred at room temperature for 15 minutes. After cooling to 0°C for 15 minutes was added dropwise iodomethane (6.8 ml).

The mixture was stirred at room temperature for 6 hours, then filtered. The first precipitate is then washed with methanol, water, isopropanol, and then dried under reduced pressure. The filtrate was concentrated under reduced is the t, triturated with water, filtered. The second precipitate is then washed with methanol, water, isopropanol, and then dried under reduced pressure. Both sediment United, getting a 2-methylsulfanyl-6-propylpyrimidine-4-ol (15.5 g) as white crystals (So pl.=158°C).

1H NMR (DMSO-d6) δ: to 5.93 (s, 1H); 2,47 (s, 3H); 2,45 to 2.35 (m, 2H); 1,65-of 1.55 (m, 2H); to 0.89 (t, J=7 Hz, 3H).

C: 4-chloro-2-methylsulfanyl-6-propylpyrimidine

A suspension of 2-methylsulfanyl-6-propylpyrimidine-4-ol (15.5 g) in the acid chloride phosphoric acid (160 ml) was heated under reflux for 6 hours. The solvent is kept at reduced pressure. The residue was diluted with dichloromethane and poured into ice. The layers were separated, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, obtaining 4-chloro-2-methylsulfanyl-6-propylpyrimidine (17.5 g, 100%) as an orange oil.

1H NMR (CDCl3) δ: 6,85 (s, 1H); 2,7-2,6 (m, 2H); 2.57 m (s, 3H); to 1.8-1.7 (m, 2H); to 0.97 (t, J=7 Hz, 3H).

D:4-chlor-2-methanesulfonyl-6-propylpyrimidine

M-chloroperbenzoic acid (65.0 g, 378 mmol) was added in portions over 15 minutes to a solution of 4-chloro-2-methylsulfanyl-6-propylpyrimidine (17.5 g, 84 mmol) in DCM (350 ml) at 0°C. the Mixture was stirred at room temperature for 24 hours, then filtered. Precipitate the latter is subsequently washed with a small amount of DCM, aqueous solution of sodium metabisulfite, water and triturated with saturated sodium bicarbonate solution, filtered, then washed with water, dried under reduced pressure, obtaining 4-chloro-2-methanesulfonyl-6-propylpyrimidine (18,3 g, 93%) as a solid off-white color (So pl.=73°C).

1H NMR (CDCl3) δ: the 7.43 (s, 1H); 3,37 (s, 3H); 2,87 (t, J=7 Hz, 2H); 1.9 to 1,7 (m, 2H); of 1.02 (t, J=7 Hz, 3H).

E: 4-(3-isopropylphenyl)-2-methanesulfonyl-6-propylpyrimidine

Potassium carbonate (0,850 g, 6 mmol), water (1 ml) and tetrakis(triphenylphosphine)palladium (0,695 g, 0.6 mmol) was sequentially added under nitrogen atmosphere to a mixture of 4-chloro-2-methanesulfonyl-6-propylpyrimidine (1,17 g, 5 mmol) and 3-isopropylaniline acid (0,984 g, 6 mmol) in dimethoxyethane (40 ml). The mixture was heated under reflux for 18 hours, then concentrated under reduced pressure. The residue was separated between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 7/3)to give a yellow oil, which was led in pentane. After filtering was obtained 4-(3-isopropylphenyl)-2-methanesulfonyl-6-propylpyrimidine (0,380 g) as a solid off-white color (That is l=82°C).

1H NMR (CDCl3) δ: 8,0-7,9 (m, 2H); 7,71 (s, 1H); of 7.5 to 7.4 (m, 2H); 3.43 points (s, 3H); of 3.1 to 3.0 (m, 1H); 2.95 and-to 2.85 (m, 2H); 1,95-of 1.85 (m, 2H); to 1.32 (d, J=7 Hz, 6H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 319,1 (M+1). HPLC (200-400 nm): 99,3%.

F: 4-(3-isopropylphenyl)-6-propylpyrimidine-2-carbonitril

Sodium cyanide (65 mg, of 1.32 mmol) was added at room temperature to 4-(3-isopropylphenyl)-2-methanesulfonyl-6-propylpyrimidine (211 mg) in dimethyl sulfoxide (2 ml). The mixture was stirred at room temperature for 2 hours, then was divided between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 7/3)to give a pink oil, which was led in pentane. After filtering was obtained 4-(3-isopropylphenyl)-2-cyano-6-propylpyrimidine (164 mg) as a solid off-white color (So pl.=64°C).

1H NMR (CDCl3) δ: 7,98 (s, 1H); of 7.90-a 7.85 (m, 1H); 7,71 (s, 1H); of 7.5 to 7.4 (m, 2H); 3,10-2,95 (m, 1H); 2,85 is 2.75 (m, 2H); 1,90 and 1.80 (m, 2H); to 1.32 (d, J=7 Hz, 6H); of 1.02 (t, J=7 Hz, 3H). MS m/z: 266,1 (M+1). HPLC (200-400 nm): 98.5 per cent.

Specified, the procedure described above was then applied, using appropriate derivative Bronevoy acid, to obtain the following compounds:

5b: 4-Phenyl-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,15-with 8.05 (m, 2H); 7,71 (s, 1H); 7,60 was 7.45 (m, 3H); 2,90 is 2.80 (m, 2H); 1,90 and 1.80 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 224,1 (M+1). HPLC (200-400 nm): 97.1 per cent.

5c: 4-(3-isopropyl-6-methoxyphenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,01 (s, 1H); to $ 7.91 (s, 1H); to 7.35 (d, J=8 Hz, 1H); 6,97 (d, J=8 Hz, 1H); 3,90 (s, 3H); of 3.1 and 2.9 (m, 1H); 2,85 is 2.75 (m, 2H); 1.85 to about 1.75 (m, 2H); of 1.28 (d, J=7 Hz, 6H); a 1.01 (t, J=7 Hz, 3H). MS m/z: 296,2 (M+1). HPLC (200-400 nm): 98,3%.

5d: 4-(3-Trifloromethyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: with 8.05 (d, J=8 Hz, 1H); 7,98 (s, 1H); 7,71 (s, 1H); 7,58 (t, J=8 Hz, 1H); 7,42 (d, J=8 Hz, 1H); 2,9-2,8 (m, 2H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 308,1 (M+1). HPLC (200-400 nm): 97.1 per cent.

5e: 4-(4-fluoro-3-were)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 7,99 (d, J=8 Hz, 1H); 7,95-of 7.90 (m, 1H); the 7.65 (s, 1H); to 7.15 (t, J=8 Hz, 1H); 2,9-2,8 (m, 2H); is 2.37 (s, 3H); 1.9 to 1.8 m (m, 2H); of 1.02 (t, J=7 Hz, 3H). MS m/z: 256,1 (M+1). HPLC (200-400 nm): 97.1 per cent.

5f: 4-(2,3-dimetilfenil)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 7,40-7,35 (m, 1H); 7.3 to a 7.1 (m, 3H); 2,85 is 2.75 (m, 2H); to 2.35 (s, 3H); of 2.25 (s, 3H); 1.85 to about 1.75 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 252,3 (M+1). HPLC (200-400 nm): 99,6%.

5g: 4-(3-chloro-4-forfinal)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,21 (d, J=8 Hz, 1H); for 8.1 to 8.0 (m, 1H); 7,66 (s, 1H); 7,35-7,20 (m, 1H); 2,9-2,8 (m, 2H); 1,90 is 1.75 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 276/278 (M+1). HPLC (200-400 nm): 93,3%.

5h: 4-(3,5-dichlorophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,00 (s, 2H); 7,68 (s, 1H); 7.5 (a, 1H); 2,9-2,8 (m, 2H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 292/294 (M+1). HPLC (200-400 nm): 93,7%.

5i: 4-(3-were)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 7,94 (s, 1H); 7,88 (d, J=8 Hz, 1H); 7,71 (s, 1H); 7,45-7,35 (m, 2H); 2,9-2,8 (m, 2H); 2,47 (s, 3H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 238,2 (M+1). HPLC (200-400 nm): 99,1%.

EXAMPLE 6a:

4-(3,5-bis-triptoreline)-6-propylpyrimidine-2-carbonitril

A: 2-methanesulfonyl-4-propyl-6-trimethylaniline

Tetrakis(triphenylphosphine)palladium (2,48 g, 2.1 mmol) and hexamethylditin (20 g, to 61.4 mmol) was sequentially added under nitrogen atmosphere to a mixture of 4-chloro-2-methanesulfonyl-6-propylpyrimidine (12.8 g, to 54.5 mmol), lithium chloride (2.8 g, 66 mmol) and 2,6-di-tert.-butyl-4-METHYLPHENOL (0.18 g, 0.82 mmol) in dioxane (240 ml). The mixture was heated under reflux for 3 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 8/2)to give 2-methanesulfonyl-4-propyl-6-trimethylsilylacetamide (9.5 g, 48%) as a yellow oil.

1H NMR (CDCl3) δ: 7,51 (s, 1H); 3,39 (s, 3H); of 2.81 (t, J=7 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.02 (t, J=7 Hz, 3H); 0,44 (s, 9H).

B: 4-propyl-6-trimethylsilylacetamide-2-carbonitril

Sodium cyanide (0,63 g, 12.9 mmol) was added at room temperature to 2-methanesulfonyl-4-propyl-6-trim is illinoispayday (2,34 g, 6.5 mmol) in dimethyl sulfoxide (23 ml). The mixture was stirred at room temperature for 2 hours, then was divided between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 9/1)to give 4-propyl-6-trimethylsilylacetamide-2-carbonitrile (1,53 g, 76%) as a solid off-white color (So pl.=62°C).

1H NMR (CDCl3) δ: 7,47 (s, 1H); 2,80-to 2.65 (t, J=7 Hz, 2H); to 1.8-1.7 (m, 2H); 0,99 (t, J=7 Hz, 3H); 0,41 (s, 9H).

C: 4-(3,5-bis-triptoreline)-6-propylpyrimidine-2-carbonitril

Bis(triphenylphosphine)palladium dichloride (34 mg, 0.05 mmol) was added under nitrogen atmosphere to a mixture of 4-propyl-6-trimethylsilylacetamide-2-carbonitrile (155 mg, 0.50 mmol) and 3,5-bis-triftormetilfullerenov (0.10 ml, of 0.58 mmol) in dimethylformamide (3 ml). The mixture was heated under reflux for 4 hours, then concentrated under reduced pressure. The residue was separated between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: DC), receiving solid, which raster is and pentane. After filtering was obtained 4-(3,5-bis-triptoreline)-6-propylpyrimidine-2-carbonitrile (63 mg, 35%) as a solid off-white color (So pl.=112°C).

1H NMR (CDCl3) δ: 8,56 (s, 2H); 8,07 (s, 1H); 7,80 (s, 1H); 2,92 (t, J=8 Hz, 2H); 1,95-of 1.85 (m, 2H); of 1.05 (t, J=7 Hz, 3H). MS m/z: 360,3 (M+1). HPLC (200-400 nm): 99,4%.

The above procedure was then applied, using the appropriate derivatives of bromo - or iodophenyl, to obtain the following compounds:

6b: 4-(3-chlorophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,10 (s, 1H); to 7.99 (d, J=8 Hz, 1H); of 7.69 (s, 1H); 7,6 to 7.4 (m, 2H); of 2.86 (t, J=7 Hz, 2H); 1,90 is 1.75 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 258/260 (M+1). HPLC (200-400 nm): 94,9%.

6c: 4-(3,4-dichlorophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,23 (s, 1H); of 7.96 (d, J=8 Hz, 1H); to 7.67 (s, 1H); a 7.62 (d, J=8 Hz, 1H); of 2.86 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 292/294 (M+1). HPLC (200-400 nm): 99,3%.

6d: 4-(4-Chloro-3-triptoreline)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,42 (s, 1H); compared to 8.26 (d, J=8 Hz, 1H); 7,75-the 7.65 (m, 2H); 2,87 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); was 1.04 (t, J=7 Hz, 3H). MS m/z: 326/328 (M+1). HPLC (200-400 nm): 98,9%.

6e: 4-(4-cyano-3-were)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,10 (s, 1H); to 7.99 (d, J=8 Hz, 1H); to 7.77 (d, J=8 Hz, 1H); 7,73 (s, 1H); is 2.88 (t, J=8 Hz, 2H); in 2.68 (s, 3H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 263,2 (M+1). HPLC (200-400 nm): 99,5%.

6f: 4-(3-chloro-4-were)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,11 (s, 1H); to $ 7.91 (d, J=8 Hz, 1H); 7,66 (s, 1H); 7,39 (d, J=8 Hz, 1H); 2,84 (t, J=8 Hz, 2H); 2,47 (s, 3H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 272/274 (M+1). HPLC (200-400 nm): 99,3%.

6g: 4-(4-methyl-3-triptoreline)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: with 8.33 (s, 1H); to 8.20 (d, J=8 Hz, 1H); 7,71 (s, 1H); 7,47 (d, J=8 Hz, 1H); of 2.86 (t, J=7 Hz, 2H); at 2.59 (s, 3H); 1,90 is 1.75 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 306,1 (M+1). HPLC (200-400 nm): 97.8 per cent.

6h: 4-(4-fluoro-3-triptoreline)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: an 8.4 to 8.3 (m, 2H); 7,71 (s, 1H); 7,39 (t, J=9 Hz, 1H); is 2.88 (t, J=7 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 310,1 (M+1). HPLC (200-400 nm): 94,0%.

6l: 4-(3,4-dimetilfenil)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: of 7.90 (s, 1H), 7,82 (d, J=7,6 Hz, 1H), 7,66 (s, 1H), 7,27 (d, J=7,6 Hz, 1H), 2,82 (t, J=7.8 Hz, 2H), is 2.37 (s, 3H), of 2.35 (s, 3H), of 1.84 (Quint, 2H), 1,01 (t, J=7.4 Hz, 3H). MS m/z: 252 (M+1). HPLC (200-400 nm): 99.7 per cent.

6m: 4-(3-fluoro-4-were)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 7,79 (d, 2H), 7,65 (s, 1H), 7,34 (t, J=7.8 Hz, 1H), 2,84 (t, J=7,6 Hz, 2H), is 2.37 (s, 3H)and 1.83 (m, 2H), of 1.02 (t, J=7.2 Hz, 3H). MS m/z: 256 (M+1). HPLC (200-400 nm): 98,9%.

The specified procedure was modified to obtain the following compounds using the appropriate derivatives of bromo - or iodophenyl by heating under reflux with 1,2-dichloroethane instead of DMF as solvent.

6n: 4-(4-chloro-3-forfinal)-6-propylpyrimidine-2-carbonitril the

1H NMR (CDCl3) δ: 8,0-7,9 (m, 1H); 7,86 (d, J=8 Hz, 1H); to 7.67 (s, 1H); and 7.6-7.5 (m, 1H); of 2.86 (t, J=8 Hz, 2H); 1,95 and 1.80 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 276/278 (M+1). HPLC (200-400 nm): 97,6%.

6o: 4-(3-chloro-4-cyanophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,28 (s, 1H); 8,11 (d, J=8 Hz, 1H); a 7.85 (d, J=8 Hz, 1H); 7,73 (s, 1H); 2,89 (t, J=7 Hz, 2H); 1,95 and 1.80 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 283/285 (M+1). HPLC (200-400 nm): 98.1 per cent.

6r: 4-Propyl-6-(3,4,5-tryptophanyl)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 7,81 (m, 2H), 7,63 (s, 1H), 2,87 (t, J=7,6 Hz, 2H), of 1.85 (m, 2H), of 1.03 (t, J=8 Hz, 3H). MS m/z: 278 (M+1). HPLC (200-400 nm): 98,6%.

EXAMPLE 7a

4-[3-(Pyridin-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile hydrochloride

To a solution of 4-(3-oxopropyl)-6-(triptoreline)-pyrimidine-2-carbonitrile (91 mg) in dichloromethane (6 ml) was added acetic acid (36 μl, 2 equiv.) then 2-aminopyridine (1.3 EQ.). The solution was stirred at room temperature for 15 min, then was added triacetoxyborohydride sodium (2 EQ.) and the mixture was stirred for 18 h at room temperature. Added to cold dilute solution of sodium carbonate, and the mixture was stirred for 10 minutes and separated the organic layer. The crude product was chromatographically on a column containing 2 g of silica gel, elwira a mixture of dichloromethane:ethanol 99:1, obtaining 4-[3-(pyridin-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carb the nitrile in the form of a free base. The free base was dissolved in DCM and added HCl (1 M in a simple ether). The solvent was removed under reduced pressure. The residue was re-dissolved in DCM, and the product was besieged by adding a simple diethyl ether to obtain 4-[3-(pyridin-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile in the form of a salt of hydrochloric acid.

1H NMR (CD3OD) δ: 8,51 (s, 1H), 8,48 (d, 1H), 8,28 (s, 1H), of 7.90 (s, 1H), 7,89 (t, 1H), 7,81 (d, 1H), 7,79 (t, 1H), was 7.08 (d, 1H), 6.89 in (t, 1H), 3,51 (t, 2H), 3,12 (t, 2H), 2,31-of 2.20 (m, 2H). MS m/z 384,0 (M+1).

The procedure described above was then applied, using the appropriate amine, to obtain the following compounds in free base form, or a corresponding salt of hydrochloric acid:

7b: 4-[3-(5-Chloropyridin-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: with 8.33 (s, 1H), 8,28 (d, 1H), to 7.99 (s, 1H), to 7.84 (d, 1H), 7,76 (s, 1H), 7,68 (t, 1H), 7,33 (d, 1H), 6,33 (d, 1H), 4,47 (ush. s, 1H), 3,48 is 3.40 (m, 2H), 3,01 (t, 2H), 2,22 and 2.13 (m, 2H). MS m/z 418,1 (M+1).

7c: 4-[3-(4-Methylpyridin-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31 (s, 1H), 8,27 (d, 1H), to $ 7.91 (d, 1H), 7,82 (d, 1H), of 7.75 (s, 1H), 7,66 (t, 1H), 6,38 (d, 1H), x 6.15 (s, 1H), 4,42 (ush. s, 1H), 3,47 is 3.40 (m, 2H), 3,03 (t, 2H), 2,20-to 2.13 (m, 2H), 2,19 (s, 3H). MS m/z 398,1 (M+1).

7d: 4-[3-(1-Methylbenzimidazole-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,31 (s, 1H), and 16 (d, 1H), 7,79 (d, 1H), 7,78 (s, 1H), 7,60 (t, 1H), 7,41 (d, 1H), 7,09-7,02 (m, 1H), 7,02-of 6.96 (m, 2H), to 4.38 (ush. s, 1H), 3,74-3,68 (m, 2H), 3.43 points (s, 3H), of 3.07 (t, 2H), 2,34-of 2.26 (m, 2H). MS m/z 437,1 (M+1).

7e: 4-[3-(4-Triptorelin-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (DMSO-d6) δ: 8,50 (d, 1H), 8,49 (s, 1H), 8,46 (s, 1H), 8,14 (d, 1H), to 7.99 (d, 1H), to 7.84 (t, 1H), 7,11 (t, 1H), only 6.64 (d, 1H), 6,63 (s, 1H), 3.43 points-to 3.36 (m, 2H), 2,97 (t, 2H), 2,12-2,04 (m, 2H). MS m/z 452,1 (M+1).

7f: 4-[3-(isoquinoline-3-yl-amino)-propyl]-6-(3-trifluoromethyl phenyl)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,80 (s, 1H), 8.30 to (s, 1H), to 8.20 (d, 1H), 7,79 (d, 1H), 7,72 (s, 1H), 7,71 (d, 1H), 7,60 (t, 1H), 7,51 (d, 1H), 7,46 (t, 1H), 7,19 (t, 1H), of 6.49 (s, 1H), 4,66 (ush. s, 1H), 3,48-of 3.42 (m, 2H), of 3.07 (t, 2H), 2,29-2,22 (m, 2H). MS m/z 434,3 (M+1).

7g: 4-[3-(3,5-Differencein-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,32 (s, 1H), 8.30 to (d, 1H), 7,83 (d, 1H), 7,79 (d, 1H), to 7.77 (s, 1H), 7,68 (t, 1H), 7,05-6,97 (m, 1H), 4,60 (ush. s, 1H), to 3.58 (q, 2H), to 3.02 (t, 2H), 2,24-of 2.16 (m, 2H). MS m/z 420,0 (M+1).

7h: 4-[3-(1-methyltrifluoroacetamide)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: charged 8.52 (s, 1H), and 8.50 (d, 1H), 8,29 (s, 1H), to $ 7.91 (d, 1H), 7,80 (t, 1H), 4,35-4,24 (m, 1H), 3,42-3,26 (m, 2H), 3,12 (t, 2H), 2.40 a-2,22 (m, 2H), equal to 1.59 (d, 3H). MS m/z 403,1 (M+1).

7i: 4-[3-(2-amino-2-oxoethylidene)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: 8,53 (s, 1H), and 8.50 (d, 1H), of 8.27 (s, 1H), to $ 7.91 (d, 1H), 7,79 t, 1H), 4,01 (s, 2H), 3,37-of 3.31 (m, 2H), is 3.08 (t, 2H), 2,98 (s, 3H), 2,37-of 2.27 (m, 2H). MS m/z 378,3 (M+1).

7j: 4-[3-(2-methoxy-2-oxoethylidene)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile hydrochloride (highlighted as a side product of the synthesis of 4s' below)

1H NMR (CD3OD) δ: charged 8.52 (s, 1H), 8,49 (d, 1H), of 8.27 (s, 1H), to $ 7.91 (d, 1H), 7,79 (t, 1H), a 4.03 (s, 2H), 3,85 (s, 3H), 3,21 (t, 2H), to 3.09 (t, 2H), 2,32-2,22 (m, 2H). MS m/z 379,1 (M+1).

7k: 4-[3-(pyrimidine-2-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: 8,50 (s, 1H), of 8.47 (m, 2H), 8,24 (s, 1H), of 7.90 (d, 1H), 7,78 (t, 1H), 6,85 (t, 1H)and 3.59 (t, 2H), 3,06 (t, 2H), 2,21 (p, 2H). MS m/z 385,0 (M+1).

7l: 4-[3-(6-methoxypyridine-4-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), of 8.37 (s, 1H), of 8.27 (s, 1H), to $ 7.91 (d, 1H), 7,79 (t, 1H), 6,10 (ush. s, 1H), 4,06 (s, 3H), 3,63 (ush. s, 2H), 3,07 (ush. s, 2H), 2,22 (ush. s, 2H). MS m/z 415,0 (M+1).

EXAMPLE 8a:

4-[3-(Methylcarbamoylmethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

To a stirred solution of 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (50 mg) in methanol (1 ml) was added amide hydrochloride of methylglycine (41 mg) and acetic acid (12 μl). The mixture was stirred for 5 minutes, then add triacetoxyborohydride sodium (42 mg) and stirring continued at room temperature t is the significance of the night. The methanol was removed in vacuo, the resulting residue was dissolved in DCM (20 ml) and washed with saturated sodium bicarbonate and water (1:1, 2 x 20 ml). The organic layer was separated, dried over sodium sulfate and evaporated to give crude product in the form of oil. Purification preparative HPLC was obtained TFA salt of 4-[3-(methylcarbamoylmethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile in a solid white color (13 mg).

1H NMR (MeOD) δ: 8,55 (s, 1H), 8,48 (d, 1H), 8,24 (s, 1H), 7,88 (d, 1H), 7,80 (t, 1H), 3,80 (s, 2H), 3.15 in (t, 2H), is 3.08 (t, 2H), 2,75 (s, 3H), 2,22 (m, 2H). MS m/z 378,4 (M+1), 100%.

The procedure described above was then applied, using the appropriate amine derivative, to obtain the following compounds:

8b: 4-[3-(2-Dimethylcarbamoyl-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,55 (s, 1H), 8,48 (d, 1H), 8,28 (s, 1H), to $ 7.91 (d, 1H), 7,80 (m, 1H)and 4.65 (t, 1H), 3,88 (m, 1H), and 3.31 (m, 2H), up 3.22 (m, 1H), is 3.08 (m, 5H), 3,01 (s, 3H), 2,68 (m, 1H), 2,22 (m, 3H), 2,24 (m, 2H). MS m/z 432,4 (M+1), 100%.

8c: 4-[3-(Carbamoylmethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,55 (s, 1H), 8,48 (d, 1H), 8,28 (s, 1H), to $ 7.91 (d, 1H), 7,80 (t, 1H), 3,85 (s, 2H), 3,18 (t, 2H), is 3.08 (t, 2H), and 2.26 (m, 2H). MS m/z 364,3 (M+1), 100%.

EXAMPLE 9a

4-(3-Piperazine-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt trithorax the red acid

To a stirred solution of 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (50 mg) in dichloromethane (1 ml) was added tert.-butyl-1-piperazine carboxylate (61 mg) and acetic acid (12 l). The mixture was stirred at room temperature for five minutes, then add triacetoxyborohydride sodium (42 mg) and stirring continued over night. The reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated sodium bicarbonate and water (1:1, 2×20 ml). The organic fraction was separated, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The obtained residue was dissolved in diethyl ether (1 ml)was added HCl in simple ether (2M, 72 μl) and the reaction mixture was stirred over night. The mixture was diluted simple ether (10 ml), washed with saturated sodium bicarbonate and water (1:1, 2×10 ml), dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give crude product. Purification preparative HPLC was obtained TFA salt of 4-(3-piperazine-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile.

1H NMR (MeOD) δ: 8,51 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,78 (d, 1H), of 3.56 (m, 4H), 3,30 (m, 6H), is 3.08 (t, 2H), 2,32 (m, 2H). MS m/z 376,4 (M+1), 100%.

The following compound was also obtained in accordance with the same procedure:

9b: 4-(3-[1,4]diazepan-1-yl-impregnated is)-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

To a stirred solution of 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (50 mg) in dichloromethane (1 ml) was added tert.-butyl-1-homopiperazine carboxylate (75 μl) and acetic acid (12 μl). The mixture was stirred at room temperature for five minutes, then add triacetoxyborohydride sodium (42 mg) and stirring continued over night. The reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated sodium bicarbonate and water (1:1, 2×20 ml). The organic fraction was separated, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The obtained residue was dissolved in THF (500 μl) and added triperoxonane acid (100 l). The reaction mixture was stirred at room temperature for 2 hours, then the solvent was removed under reduced pressure to give crude product. Purification preparative HPLC was obtained TFA salt of 4-(3-[1,4]diazepan-1-yl-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile.

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), to $ 7.91 (d, 1H), 7,79 (t, 1H), 3,78 (m, 2H), 3,70 (m, 2H)and 3.59 (m, 2H), 3.45 points (t, 2H), 3,38 (t, 2H), and 3.31 (t, 2H), 2,32 (m, 4H). MS m/z 390,3 (M+1), 100%.

EXAMPLE 10a

4-[3-(Carboxymethylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

To a stirred solution of 4-(3-oxopropyl)-6-(3-triptoreline) pyrim the DIN-2-carbonitrile (50 mg) in methanol (1 ml) was added glycine (25 mg), then water (100 μl) and acetic acid (12 μl). The mixture was stirred at room temperature for five minutes, then add cyanoborohydride on solid media (77 mg, 2.57 mmol/g) and stirring continued over night. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude product. Purification preparative HPLC was obtained TFA salt of 4-[3-(carboxymethylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile.

1H NMR (MeOD) δ: 8,55 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), to $ 7.91 (d, 1H), 7,80 (t, 1H), 3,91 (s, 2H), 3,17 (t, 2H), is 3.08 (t, 2H), 2,28 (m, 2H). MS m/z 365,0 (M+1), 100%.

The procedure described above was then applied, using the appropriate amine derivative, to obtain the following compounds:

10b: 4-[3-(2-Carbamoylethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,51 (s, 1H), of 8.47 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,78 (t, 1H), 3,32 (t, 2H), 3,19 (t, 2H), to 3.09 (t, 2H), 2,70 (t, 2H), and 2.27 (m, 2H). MS m/z 378,3 (M+1), 100%.

10c: 4-[3-Carboxymethylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,55 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), to $ 7.91 (d, 1H), 7,80 (t, 1H), 4,14 (s, 2H), 3,38 (t, 2H), is 3.08 (t, 2H), to 3.02 (s, 3H), 2,35 (m, 2H). MS m/z 378,8 (M+1).

EXAMPLE 11a

4-{3-[2-(1-Methylpyrrolidine-2-yl)-ethylamino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile with the eh triperoxonane acid

To a stirred solution of 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (50 mg) in methanol (1 ml) was added 2-(2-amino-ethyl)-1-methylpyrrolidine (48 μl) and acetic acid (12 μl). The mixture was stirred at room temperature for five minutes, then add cyanoborohydride on solid media (77 mg, 2.57 mmol/g) and stirring continued over night. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude product. Purification preparative HPLC was obtained TFA salt of 4-{3-[2-(1-methylpyrrolidine-2-yl)-ethylamino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile.

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,79 (t, 1H), 3,75 (m, 1H), 3,38 (m, 1H), 3,19 (m, 5H), of 3.12 (t, 2H), 2,96 (s, 3H), 2.40 a (m, 2H), and 2.27 (t, 2H), 2,15 (m, 2H), 2,05 (m, 1H), equal to 1.82 (m, 1H). MS m/z 418,3 (M+1), 100%.

The procedure described above was then applied, using the appropriate amine derivative, to obtain the following compounds:

11b: 4-[3-(2-Pyrrolidin-1-yl-ethylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,51 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,78 (t, 1H), 3,61 (t, 2H), 3,50 (m, 6H), 3,24 (t, 2H), 3,10 (t, 2H), 3,29 (m, 2H), 2.13 in (m, 4H). MS m/z 404,5 (M+1), 100%.

11c: 4-{3-[(1-ethylpyrrolidin-2-yl-methyl)-amino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

sup> 1H NMR (MeOD)δ: 8,51 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,78 (t, 1H), 3,82 (m, 1H), 3,78 (m, 1H), 3,68 (m, 1H), 3,55 (m, 1H), of 3.45 (m, 1H), and 3.31 (m, 1H), 3.27 to (t, 2H), 3,20 (m, 1H), 3,11 (t, 2H), 2,50 (m, 1H), 2,31 (m, 2H), 2,19 (m, 2H), 2.05 is (m, 1H), 1,38 (t, 3H). MS m/z 418,1 (M+1), 100%.

11d: 4-(3-(1-azabicyclo[2.2.2]Oct-3-yl-amino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,51 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,78 (t, 1H), 3,95 (m, 1H), 3,86 (m, 1H), 3,42 (m, 5H), of 3.25 (t, 2H), 3,11 (t, 2H), 2.57 m (m, 1H), 2,32 (m, 2H), measuring 2.20 (m, 2H), 2,05 (m, 2H). MS m/z 416,1 (M+1), 100%.

11e: 4-[3-(2-Morpholine-4-yl-ethylamino)-propyl]-6-(3-triftormetilfullerenov-2-carbonitril salt triperoxonane acid

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,80 (t, 1H), a 3.87 (t, 4H), of 3.45 (t, 2H), 3,23 (m, 4H), 3,10 (t, 6H), 2,28 (m, 2H). MS m/z 420,1 (M+1), 100%.

11f: 4-[3-(2-methoxyethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), 8,24 (s, 1H), of 7.90 (d, 1H), 7,79 (t, 1H), 3,66 (t, 2H), 3,42 (s, 3H), of 3.25 (t, 2H), and 3.16 (t, 2H), is 3.08 (t, 2H), 2,24 (m, 2H). MS m/z 365,0 (M+1), 100%.

11g: 4-{3-[2-(2-Oxymetazoline-1-yl)-ethylamino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,79 (t, 1H), 3,53 (m, 2H), 3.46 in (m, 4H), 3,24 (m, 2H), 3,19 (t, 2H), is 3.08 (t, 2H, in), 2.25 (m, 2H). MS m/z 419,0 (M+1), 100%.

11h: 4-[3-(2-Diethylaminoethylamine)-propyl]-6-(3-triptoreline)pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), 8,28 (s, 1H), to $ 7.91 (d, 1H), 7,80 (t, 1H), 3,54 (s, 4H), of 3.28 (t, 2H), 3,12 (t, 2H), 2,98 (s, 6H), is 2.30 (m, 2H). MS m/z 378,4 (M+1), 100%.

11i: 4-[3-(2-Acetylaminofluorene)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,79 (t, 1H), 3,51 (t, 2H), 3,18 (m, 4H), is 3.08 (t, 2H, in), 2.25 (m, 2H), 1,99 (s, 3H). MS m/z 392,1 (M+1), 100%.

EXAMPLE 12

4-(3-Hydroxy-1-propyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile

A: 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3,4-dimetilfenil) pyrimidine

To a stirred suspension of sodium hydride (60% in paraffin oil, 20 g) in diethyl ether (1 l) at 0°C was added ethanol (1 ml). To this mixture was added gamma-butyrolactone (18 g), followed by drop a solution of 3',4'-dimethylacetophenone (29,6 g) in a simple diethyl ether (100 ml) for 30 minutes. The mixture was left for stirring at room temperature for 72 hours. Then was added ethanol (20 ml)to destroy excess sodium hydride, and then added an aqueous solution of ammonium chloride (20 g in 300 ml water). The organic layer was separated and washed with diluted hydrochloric acid (0.1 N., 500 ml), then water (2×200 ml). The ether layer was dried over sodium sulfate, the solvent was removed under reduced pressure. The residue was mixed with S-methylisothiourea (37 g). A mixture of load, the Wali at 130°C for 4 hours. After cooling to room temperature was added triethylamine (45 ml) and methanol (50 ml) and the mixture was heated under reflux using an oil at 85°C for 6 hours. After removal of the solvent and triethylamine under reduced pressure, the residue was taken away by ethyl acetate (500 ml) and water (500 ml). The organic layer was separated, washed with diluted hydrochloric acid (0.1 N., 500 ml), then water (2×300 ml). The organic layer was dried, the solvent was removed under reduced pressure. The residue was passed through a column of silica gel using petroleum ether and ethyl acetate (1:1) as eluent, obtaining 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3,4-dimetilfenil)pyrimidine (17.5 g).

1H NMR (CDCl3) δ: to 7.84 (s, 1H), 7,80 (d, 1H), 7,15-7,25 (m, 2H), and 3.72 (t, 2H), 2,87 (t, 2H), 2.63 in (s, 3H), of 2.34 (s, 3H), 2,32 (s, 3H), 2,03 (m, 2H).

B: 4-(3-hydroxypropyl)-6-(3,4-dimetilfenil)pyrimidine-2-carbonitrile

To a solution of 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3,4-dimetilfenil)pyrimidine (5.8 g) in a mixed solvent consisting of methanol and water (110 ml, 10:1)was added OXONE (35 g). The mixture was stirred at room temperature for 3 hours, then was diluted with ethyl acetate (500 ml). The mixture was washed with water (3 x 500 ml). The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, obtaining 2-methanesulfonyl-4-(3-hydroxypropyl)-6-(3,4-dimetilfenil)Piri is one as a crude product. To a stirred solution of the specified 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3,4-dimetilfenil)pyrimidine in dimethyl sulfoxide (50 ml) was added sodium cyanide (2.9 g). The mixture was stirred at room temperature for 4 hours, then was poured into ethyl acetate (300 ml) and washed with water (2 x 200 ml). The organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, the specified residue was purified flash chromatography on silica gel using a mixture of petroleum ether/EtOAc (1:1) as eluent, obtaining as a product of 4-(3-hydroxypropyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile (4.8 g).

1H NMR (CDCl3) δ: 8,01 (s, 1H), of 7.96 (s, 1H), 7,89 (d, 1H), 7,25 (d, 1H), to 3.64 (t, 2H), with 2.93 (t, 2H), a 2.36 (s, 3H), of 2.34 (s, 3H), 2.0 (m, 2H). MS m/z 268 (M+1), 100%.

EXAMPLE 13a

4-(3,4-Dimetilfenil)-6-[3-(pyridin-2-yl-amino)-propyl]-pyrimidine-2-carbonitrile hydrochloride

A: 4-(3-oxo-1-propyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile

Periodical dessa-Martin (4,2 g) was added to a solution of 4-(3-hydroxypropyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile (2.0 g) in dichloromethane (100 ml) and the resulting suspension was stirred at room temperature for 45 minutes the Mixture was washed with water (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified flash chromatography on silica gel using the mixture of pet is olany ether/EtOAc (2:1), getting 4-(3-oxopropyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile in a solid white color (1.9 grams).

1H NMR (CDCl3) δ: 7,87 (s, 1H), and 7.8 (d, 1H), of 7.75 (s, 1H), 7,25 (d, 1H), and 3.16 (t, 2H), to 3.09 (t, 2H), a 2.36 (s, 3H), of 2.34 (s, 3H). MS m/z 266 (M+1), 100%.

B: 4-(3,4-dimetilfenil)-6-[3-(pyridin-2-yl-amino)-propyl]-pyrimidine-2-carbonitrile hydrochloride

To a solution of 4-(3-oxopropyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile (91 mg) in dichloromethane (6 ml) was added acetic acid (2 equiv.) then 2-aminopyridine (1.3 EQ.). The solution was stirred at room temperature for 15 min, then was added triacetoxyborohydride sodium (2 EQ.) and the mixture was stirred for 18 h at room temperature. Added to cold dilute solution of sodium carbonate, and the mixture was stirred for 10 minutes and separated the organic layer, the solvent was removed under reduced pressure. The crude product was chromatographically on the column with 2 g of silica gel, elwira a mixture of dichloromethane:ethanol (99:1)to give the product in free base form. The free base was dissolved in DCM and added HCl (1 M in a simple ether). The solvent was removed under reduced pressure. The residue was re-dissolved in DCM and the product was besieged by adding a simple diethyl ether to obtain 4-(3,4-dimetilfenil)-6-[3-(pyridin-2-yl-amino)-propyl]-pyrimidine-2-carbonitrile hydrochloride (60 mg).

1H NMR (CD OD) δ: of 8.09 (s, 1H), 8,00 (s, 1H), 7.95 is-7,86 (m, 2H), 7,83 (d, 1H), 7,32 (d, 1H), 7,07 (d, 1H), to 6.88 (t, 1H), 3,48 (t, 2H), 3,05 (t, 2H), 2,29-2,19 (m, 2H). MS m/z 344,1 (M+1).

Using the appropriate amines were obtained the following compounds in the form of either the free bases or the corresponding salt of hydrochloric acid.

13b: 4-(3,4-Dimetilfenil)-6-(3-(4-methylpyridin-2-yl-amino)-propyl]-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: 8,08 (s, 1H), 7,98 (s, 1H), 7,92 (d, 1H), 7,69 (d, 1H), 7,31 (d, 1H), PC 6.82 (s, 1H), 6,74 (d, 1H), 3,37 (t, 2H), 3.04 from (t, 2H), is 2.37 (s, 6H), to 2.35 (s, 3H), 2,28-to 2.18 (m, 2H). MS m/z 358,0 (M+1).

13c: 4-[3-(2-Dimethylamino-l-methylethylamine)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: 8,13 (s, 1H), 8,02 (s, 1H), 7,95 (d, 1H), 7,31 (d, 1H), 3.95 to of 3.80 (m, 1H), 3,65-of 3.48 (m, 1H), 3.25 to 3.15 in (m, 2H), 3,11 totaling 3.04 (m, 2H), 2,98 (s, 6H), is 2.37 (s, 3H), of 2.35 (s, 3H), 2,32-of 2.26 (m, 2H), 1,50 (d, 3H). MS m/z AZN 352.5 (M+1).

13d: 4-(3,4-Dimetilfenil)-6-[3-(1-ethylpyrrolidin-2-methylamino)-propyl]-pyrimidine-2-carbonitrile the dihydrochloride

1H NMR (CD3OD) δ: 8,13 (s, 1H), 8,02 (s, 1H), 7,95 (d, 1H), 7,32 (d, 1H), a 3.87 at 3.69 (m, 2H), 3,68-to 3.50 (m, 2H), 3,50-to 3.38 (m, 1H), 3.27 to is 3.21 (m, 2H), 3,21-3,11 (m, 1H), 3,13 (t, 2H), 2,52-to 2.41 (m, 1H), of 2.38 (s, 3H), of 2.35 (s, 3H), 2,35-of 2.26 (m, 2H), 2,24 is 2.10 (m, 2H), 2,09-of 1.97 (m, 1H), 1,41 (t, 3H). MS m/z 378,5 (M+1).

13e: (S)-4-(3,4-Dimetilfenil)-6-[3-(hinokitiol-3-amino)-propyl]pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: 8,13 (s, 1H), 8,02 (s, 1H), 7,95 (d, 1H), 7,31 (d, 1H), 3,94-of 3.85 (m, 1H), 3,85 (t, 1H), 3,67-of 3.53 (m, 3H), 3.46 in-and 3.31 (m, 2), up 3.22 (t, 2H), of 3.07 (t, 2H), 2.57 m (ush. s, 1H), of 2.38 (s, 3H), of 2.35 (s, 3H), 2,36-of 2.26 (m, 3H), 2,22 is 2.10 (m, 1H), 2,10-1,99 (m, 2H). MS m/z 376,4 (M+1).

13f: 4-(3,4-Dimetilfenil)-6-[3-(prop-2-yl-amino)-propyl]-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: of 7.90 (s, 1H), 7,82 (d, 1H), 7,69 (s, 1H), 7,28 (d, 1H), 2.91 in (t, 2H), 2,84-2,77 (m, 1H), 2,68 (t, 2H), is 2.37 (s, 3H), of 2.35 (s, 3H), 2,02-of 1.93 (m, 2H), 1.06 a (d, 3H). MS m/z 309,4 (M+1).

13g: 4-(3,4-Dimetilfenil)-6-[3-(1-methyltrifluoroacetamide)-propyl]-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: 8,10 (s, 1H), 8,01 (s, 1H), 7,94 (d, 1H), 7,32 (d, 1H), 4,32-is 4.21 (m, 1H), 3,39-to 3.33 (m, 2H), 3,05 (t, 2H), of 2.38 (s, 3H), of 2.36 (s, 3H), 2,35-2,17 (m, 2H), 1.57 in (d, 6H). MS m/z 363,1 (M+1).

13h: 4-(3,4-Dimetilfenil)-6-{3-[2-(morpholine-4-yl)-ethylamino]-propyl}-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: of 8.06 (s, 1H), 8,00 (s, 1H), 7,92 (d, 1H), 7,32 (d, 1H), 3,69 (t, 4H), of 2.93 (t, 2H), 2,75 (t, 2H), 2,70 (t, 2H), 2,52 (t, 2H), 2,50 at 2.45 (m, 4H), of 2.38 (s, 3H), of 2.35 (s, 3H), 2.06 to to 1.98 (m, 2H). MS m/z 380,4 (M+1).

13i: 4-{[3-(3-diethylcarbamoyl)-piperidine-1-yl]-propyl}-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrided

1H NMR (CD3OD) δ: 8,11 (s, 1H), 8,01 (s, 1H), 7,94 (d, 1H), 7,31 (d, 1H), 3,9-2,9 (m, 13H), of 2.38 (s, 3H), of 2.35 (s, 3H), 2,33 (m, 2H), 2,1 to 1.6 (m, 4H), 1,27-of 1.05 (m, 6H). MS m/z 434,4 (M+1).

13j: 4-(3,4-Dimetilfenil)-6-[3-(4-pyridin-2-yl-piperazine-1-yl)-propyl]-pyrimidine-2-carbonitridation

1H NMR (CD3OD) δ: 8,14 (d, d, 1H), 8,12 (s, 1H), 8,10 (d, 1H), 8,02 (s, 1H), 7,95 (d, 1H), 7,46 (d, 1H), 7,32 (d, 1H), 7,14 (t, 1H), 4,42 (ush. s, 2H), 3,80 (ush. s, 4H), to 3.38 (d, d 2H), 3,35 ush. s, 2H), of 3.07 (t, 2H), 2.40 a (m, 2H), of 2.38 (s, 3H), of 2.36 (s, 3H). MS m/z 413,3 (M+1)

EXAMPLE 14a

4-(3,4-dimetilfenil)-6-[3-(2-hydroxy-1,1-dimethylethylamine)-propyl]-pyrimidine-2-carbonitrile salt triperoxonane acid

To a solution of 4-(3-oxopropyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile (50 mg) in acetonitrile (1.5 ml) under stirring was added 2-amino-2-methyl-1-propanol (36 μl), macroporous cyanoborohydride (110 mg, 2.57 mmol/g) and acetic acid (16 μl) and the resulting suspension was stirred at room temperature for 16 hours. The reaction mixture was filtered and purified preparative HPLC, obtaining 4-(3,4-dimetilfenil)-6-[3-(2-hydroxy-1,1-dimethylethylamine)-propyl]-pyrimidine-2-carbonitrile salt triperoxonane acid in a solid white color (10 mg).

1H NMR (MeOD) δ: 8,08 (s, 1H), 8,00 (s, 1H), 7,92 (d, 1H), 7,33 (d, 1H), 3,55 (s, 1H), 3,11 (t, 2H), to 3.02 (t, 2H), 2,38 (s, 1H), 2,36 (s, 1H), 2,16 was 2.25 (m, 2H), of 1.34 (s, 6H). MS m/z 339,1 (M+1), 100%.

14b: 4-(3,4-dimetilfenil)-6-[3, (2 methoxyethylamine)-propyl]-pyrimidine-2-carbonitrile salt triperoxonane acid

To a solution of 4-(3-oxopropyl)-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile (50 mg) in MeOH (1.5 ml) under stirring was added 2-methoxyethylamine (26 μl). Added macroporous cyanoborohydride (110 mg, 2.57 mmol/g) and acetic acid (16 μl) and the resulting suspension was stirred at room temperature for 16 hours. The reaction mixture is filtered and purified preparative LCMS, getting 4-(3,4-dimetilfenil)-6-[3, (2 methoxyethylamine)-propyl]-pyrimidine-2-carbonitrile salt triperoxonane acid in a solid white color (8 mg).

1H NMR (MeOD) δ: 8,07 (s, 1H), 8,00 (s, 1H), 7,94 (d, 1H), 7,33 (d, 1H), to 3.64 (t, 2H), 3,42 (s, 3H), 3,24 (t, 2H), 3,13 (t, 3H), 3,01 (t, 2H), of 2.38 (s, 3H), of 2.36 (s, 3H), 2,16-of 2.26 (m, 2H). MS m/z 325,5 (M+1), 100%.

The procedure described above was then applied, using the appropriate amine derivative, to obtain the following compounds:

14c: 4-(3,4-dimetilfenil)-6-{3-[(pyridine-2-ylmethyl)-amino]-propyl}-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (CDCl3) δ: to 8.62 (d, 1H), 7,98 (t, 1H), of 7.90 (s, 1H), to 7.84 (d, 1H), of 7.75 (s, 1H), 7,60 (d, 1H), 7,52 (m, 1H), 7,27 (d, 1H), 4,48 (s, 2H), 3.33 and (t, 2H), of 3.07 (t, 2H), a 2.36 (s, 3H), of 2.35 (s, 3H), 2.23 to to 2.35 (m, 2H). MS m/z 358,0 (M+1), 100%.

14d: 4-(3,4-Dimetilfenil)-6-{3-[3-(1H-imidazol-4-yl)-propylamino]-propyl}-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,81 (s, 1H), 8,08 (s, 1H), 8,00 (s, 1H), to 7.93 (d, 1H), 7,45 (s, 1H), 7,30 (d, 1H), 3,39 (t, 2H), 3,18-up 3.22 (m, 4H), 3.04 from (t, 2H), of 2.38 (s, 3H), of 2.36 (s, 3H), 2,20-of 2.28 (m, 2H). MS m/z 361,0 (M+1), 100%.

14e: 4-[3-(bicyclo[2,2,1]hept-2-ylamino)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (CDCl3) δ: 7,87 (s, 1H), 7,82 (d, 1H), of 7.70 (s, 1H), 7,52 (m, 1H), 3,37-of 3.42 (m, 1H), 3,01-to 3.09 (m, 2H), 2,96 (t, 2H), 2,54 (s, 1H), 2,35 (s, 3H), of 2.33 (s, 3H), 2,22-of 2.30 (m, 3H), 1.93 and-2,04 (m, 1H), 1,68-of 1.78 (m, 1H), 1,53 is 1.60 (m, 2H), 1,38-of 1.45 (m, 3H), 1.26 in (d, 1H). MS m/z 361,0 (M+1), 100%.

14f: 4-(3,4-dimetilfenil)-6-{3-[3-(2-oxopyrrolidin-1-yl)-propylamino]-propyl}-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (CDCl3) δ: to $ 7.91 (s, 1H), to 7.84 (d, 1H), 7,81 (s, 1H), 7,27 (d, 1H), 3,47-to 3.50 (m, 4H), of 3.12 (m, 2H), 3,05 (t, 2H), 2,98 (m, 2H), 2.49 USD (t, 2H), a 2.36 (s, 3H), of 2.34 (s, 3H), to 2.29 (m, 2H), 2,08-of 2.16 (m, 4H). MS m/z 392,3 (M+1), 100%.

14g: 4-[3-(1,1-dimethyl-2-morpholine-4-yl-ethylamino)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (CDCl3) δ: to $ 7.91 (s, 1H), 7,86 (d, 1H), 7,78 (s, 1H), 7,27 (d, 1H), 3,92 (m, 4H), to 3.34 (s, 2H), 3,14-3,18 (m, 6H), 3,01 (t, 2H), is 2.37 (s, 3H), of 2.35 (s, 3H), of 2.30 to 2.35 (m, 2H), of 1.52 (s, 6H). MS m/z 408,1 (M+1), 100%.

14h: 4-(3,4-dimetilfenil)-6-{3-[2-(1H-indol-3-yl)-ethylamino]-propyl}-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,03 (s, 1H), to 7.99 (s, 1H), to 7.93 (d, 1H), 7,58 (d, 1H), 7,31-7,37 (m, 2H), 7,19 (s, 1H), 7,12 (t, 1H),? 7.04 baby mortality (t, 1H), 3.33 and-to 3.38 (m, 2H), 3,14-is 3.21 (m, 4H), to 2.99 (t, 2H), of 2.38 (s, 3H), 2,35 (, 3H), 2,14-of 2.21 (m, 2H). MS m/z 411,0 (M+1), 100%.

14i: 4-(3,4-dimetilfenil)-6-[3-(methylcarbamoylmethyl)-propyl]-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: (8,07 (s, 1H), 8,00 (s, 1H), 7,94 (d, 1H), 7,31 (d, 1H), of 3.73 (s, 1H), is 3.08 (t, 2H), 3,01 (t, 2H), and 2.79 (s, 3H), of 2.38 (s, 3H), of 2.36 (s, 3H), 2,19 (t, 2H). MS m/z 338,5 (M+1), 100%.

14j: 4-[3-(2-Acetylaminofluorene)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,08 (s, 1H), 8,00 (s, 1H), 7,94 (d, 1H), 7,31 (d, 1H), 3,50 (t, 2H), 3.15 in (m, 4H), 3,01 (t, 2H), 238 (C, 3H), of 2.35 (s, 3H), of 2.21 (m, 2H), 1,99 (s, 3H). MS m/z 352,4 (M+1), 100%.

14k: 4-(3,4-dimetilfenil)-6-{3-[2-(l-methylpyrrolidine-2-yl)-ethylamino]-propyl}-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,08 (s, 1H), 8,00 (s, 1H), 7,94 (d, 1H), 7,33 (d, 1H), 3,70-of 3.77 (m, 1H), 3.33 and-to 3.41 (m, 1H), 3,12-is 3.21 (m, 5H), 3.04 from (t, 2H), equal to 2.94 (s, 3H), 2,38 is 2.43 (m, 2H), of 2.38 (s, 3H), of 2.36 (s, 3H), 2,20-of 2.28 (m, 2H), 2,04-to 2.18 (m, 2H), 1.93 and-2,04 (m, 1H), 1,75 is 1.86 (m, 1H). MS m/z 378,5 (M+1), 100%.

14l: 4-[3-(Carbamoylmethyl)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,08 (s, 1H), 8,00 (s, 1H), 7,94 (d, 1H), 7,32 (d, 1H), 4.00 points (ush. s, 2H), 3,24-3,30 (m, 2H), 3,01 (t, 2H), 2,98 (t, 2H), of 2.38 (s, 3H), of 2.36 (s, 3H), 2.23 to-2,30 (m, 2H). MS m/z 338,4 (M+1), 100%.

14m: 4-[3-(Dimethylcarbamoyl)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (CDCl3) δ: 7,89 (s, 1H), 7,83 (d, 1H), 7,76 (s, 1H), 7,27 (d, 1H), 4.00 points (s, 2H), 3,24 (t, 2H), 3,03 (m, 2H), 3,01 (s, 6H), a 2.36 (s, 3H), of 2.34 (s, 3H), 2.23 to to 2.35 (m, 2H). MS m/z 352,3 (M+1), 100%.

14n: 4-(3,4-dimetilfenil)-6-{3-[2-(2-Oxymetazoline-1-yl)-ethylamino]-propyl}-pyrimidine-2-carbonitrile salt triperoxonane acid

1H NMR (MeOD) δ: 8,08 (s, 1H), 8,00 (s, 1H), 7,94 (d, 1H), 7,33 (d, 1H), 3,51-3,55 (m, 2H), 3.43 points-of 3.48 (m, 4H), 3,23 (t, 2H), 3,17 (t, 2H), to 3.02 (t, 2H), of 2.38 (s, 3H), of 2.36 (s, 3H), 2,17-of 2.27 (m, 2H). MS m/z 379,4 (M+1), 100%.

A: 4-[3-(3-Dimethylaminopropylamine)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile salt triperoxonane acid

1NAMR (MeOD) δ: 8,07 (s, 1H), to 7.99 (s, 1H), to 7.93 (d, 1H), 7,31 (d, 1H), 3,24 (t, 2H), 3,13-3,20 (m, 4H), 3,03 (t, 2H), 2,92 (s, 6H), is 2.37 (s, 3H), of 2.35 (s, 3H), 2,20-of 2.28 (m, 2H), 2,12-2,19 (m, 2H). MS m/z 352,4 (M+1), 100%.

EXAMPLE 15

4-(3-hydroxy-3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

To a stirred solution of 4-(3-hydroxypropyl)-6-(3-triptoreline)pyrimidine-2-carbonitrile (1.54 g) in acetonitrile (15 ml) was added 0,2M buffer KH2PO4pH 6.5 (15 ml), then TEMRO (120 mg). The mixture was heated to 45°C was added sequentially a solution of NaClO2(1.26 g in 5 ml of H2O) and 5% NaOCl (0.25 ml in 5 ml of N2A) 1 hour (approximately 1.5 ml of each was added as the initial aliquot). After 5 h the mixture was cooled and podslushivaet to a pH of 9.0 by the addition of 4 N. NaOH, followed by the addition of a cold solution of sodium sulfite. The neutral fraction was removed by extraction with ethyl acetate. The aqueous phase was acidified to pH 3.5 by adding 5 N. HCl and was extracted with DCM twice (material, insoluble in biphasic mixture were removed by filtration through celite), the organic layer was washed with water, then brine. Removal of solvent followed by rubbing with ether there was obtained a white precipitate, containing the remains of TAMRA and some derivatives of 2-carboxamidine as a by-product. The resulting stock solutions contained the desired acid, 4-(3-hydroxy-3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile, 370 mg.

sup> 1H NMR (CDCl3) δ: 8,35 (s, 1H), 8,31 (d, 1H), 7,83 (s, 1H), 7,83 (d, 1H), 7,68 (t, 1H), up 3.22 (t, 2H), 3.00 for (t, 2H). MS m/z 322,1 (M+1).

EXAMPLE 16a

4-[3-(piperidine-1-yl)-3-oxopropyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

To a solution of 4-(3-hydroxy-3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (64 mg) in DCM (6 ml) was added 1-hydroxybenzotriazole (30 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (38 mg). The solution was stirred at room temperature for 15 minutes and was added piperidine (22 mg). After incubation for 18 h, the reaction mixture was washed with HCl (1 M, 2×5 ml), N2Oh, then brine, and dried with sodium sulfate. After removal of solvent, crystallization from a mixture of acetone/ether there was obtained 4-(3-piperidine-1-yl-3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile in a solid white color, 35 mg.

1H NMR (CDCl3) δ: of 8.37 (s, 1H), 8,31 (d, 1H), to $ 7.91 (s, 1H), 7,80 (d, 1H), 7,66 (t, 1H), 3,51 (t, 2H), 3.46 in (t, 2H), 3,23 (t, 2H), 2.95 and (t, 2H), 1.70 to was 1.58 (m, 4H), 1.56 to to 1.48 (m, 2H). MS m/z 389,1 (M+1).

The following compounds were obtained analogously by combining the acid with the appropriate amine in the presence of HOBt and EDCl.

16b: 4-[3-(homopiperazin-1-yl)-3-oxopropyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile hydrochloride

1H NMR (CD3OD) δ: 8,51 (s, 1H), 8,48 (d, 1H), 8,28 (s, 1H), of 7.90 (d, 1H), 7,78 (t, 1H), 3,98-3,92 and 3,84-of 3.78 (m, 2H) (rotamer), 3,81 is 3.76 and 3,71-3,66 (m, 2H) (the company is a career), 3,50-3,45 and 3.33-of 3.27 (m, 2H) (rotamer), 3,41-and 3.33 to 3.35-of 3.27 (m, 2H) (rotamer), 3,29 is 3.23 (m, 2H), of 3.07 (t, 2H), and 2.26-2.16 and 2,10-2,02 (m, 2H) (rotamer). MS m/z 404,4 (M+1).

16c: 4-(3,4-dimetilfenil)-6-[2-(2-pyridin-2-yl-ethylcarbamate)-ethyl]-pyrimidine-2-carbonitrile triftorbyenzola

1H NMR (CDCl3) δ: to 8.62 (d, 1H), 8,27 (t, 1H), 7,88 (s, 1H), 7,81 (d, 1H), 7,62 for 7.78 (m, 4H), 7,28 (s, 1H), 3,70-of 3.80 (m, 2H), 3.33 and (t, 2H), 3.04 from (t, 2H), 2,70 (t, 2H), 2,34 (d, 6H). MS m/z 386,0 (M+1), 95%.

16d: 4-(3,4-dimetilfenil)-6-[2-(2-piperidine-1-yl-ethylcarbamate)-ethyl]-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: of 7.90 (s, 1H), a 7.85 (d, 1H), 7,78 (s, 1H), 7,28 (s, 1H), 3,29 (t, 2H), 3,19 (t, 2H), 2,75 (t, 2H), 2,30-to 2.40 (m, N), 1,52 is 1.60 (m, 4H), of 1.41 to 1.47 (m, 2H). MS m/z 392,1 (M+1), 100%.

EXAMPLE 17

4-(3-tert.-butylphenyl)-6-(3-oxopropyl)-pyrimidine-2-carbonitrile

A: 1-(3-tert.-butylphenyl)-alanon

To a solution of 1-tert.-butyl-3-ethylbenzene (of 11.15) in acetonitrile (350 ml) and water (150 ml) under stirring at room temperature was added sulfate, cerium (III) (6,05 g) and bromate barium (13.5 g). The resulting suspension was heated under reflux for 16 hours After cooling to room temperature, the reaction mixture was filtered. A saturated aqueous solution servational sodium was added to the filtrate and the product was extracted into DCM (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4and concentrated in VA is uume, getting 1-(3-tert.-butylphenyl)-Etalon as crude product in the form of a yellow oil (13.5 g).1H NMR (CDCl3) δ: 8,00 (s, 1H), of 7.75 (d, 1H), to 7.61 (d, 1H), 7,39 (t, 1H), 2,61 (s, 3H), of 1.36 (s, 9H).

B: 1,3-Dioxo-6-hydroxy-1-(3'-tert.-butylphenyl)-hexane

To a suspension of NaH (60% in oil, 7,66 g) in a simple ether (480 ml) at 0°C was added under stirring ethanol (479 μl), then γ-butyrolactone (6,18 ml). After this was added dropwise 1-(3-tert.-butylphenyl)-Etalon (13.5 g) in a simple ether (80 ml). The resulting mixture was allowed to warm to room temperature and was stirred for 72 hours. After careful addition of ethanol (10.5 ml)was added a solution of ammonium chloride (10 g in 250 ml water), the ether layer was separated and washed with brine (300 ml), dried over MgSO4and concentrated in vacuum, obtaining 1,3-dioxo-6-hydroxy-1(3'-tert.-butylphenyl)-hexane as the crude product (18.5 g). He didn't require any cleaning and immediately used in the next reaction.

MS m/z 245,4 (M+1), 80%.

C: 2-Methylsulfanyl-4-(3-hydroxypropyl)-6-(3-tert.-butylmethylether)-pyrimidine

1,3-Dioxo-6-hydroxy-1(3'-tert.-butylphenyl)-hexane (crude product, 18,5 g), and g S-methylisothiourea (30,7 g) was heated at 110°C for 3 hours. The reaction mixture was allowed to cool to room temperature, was added methanol (30 ml) and triethylamine (26 ml) and the resulting mixture was heated at 85°C for 4 hours. The reaction mixture con who was interaval in vacuum and the product was taken into ethyl acetate (400 ml), washed with water (2 x 200 ml) and the organic layer was dried over MgSO4. After removal of the solvent under vacuum, the residue was passed through a column of silica gel using petroleum ether and ethyl acetate (1:1) as eluent, obtaining 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3-tert.-butylmethylether)-pyrimidine (5,2 g) in the form of oil.

1H NMR (CDCl3) δ: 8,12 (s, 1H), 7,86 (d, 1H), 7,52 (d, 1H), 7,40 (t, 1H), 7,25 (s, 1H), 3,75 (t, 2H), 2,88 (t, 2H), 2,64 (s, 3H), 1,99 e 2.06 (m, 2H), to 1.38 (s, 9H). MS m/z is 317.1 (M+1), 95%.

D: 2-Methylsulphonyl-4-(3-hydroxypropyl)-6-(3-triptoreline)-pyrimidine

To a solution of 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3-tert.-butylphenyl)-pyrimidine (5,2 g) in a mixed solvent of methanol and water (122 ml, 10:1) was added OXONE (23,2 g). The mixture was stirred at room temperature overnight. After dilution with water (200 ml) the product was extracted with ethyl acetate (3×200 ml). The combined organic fractions were washed with brine (200 ml), dried over MgSO4and concentrated in vacuum, obtaining 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3-tert.-butylmethylether)-pyrimidine (4.6 g) in the form of a solid light brown color. It was used as a raw material in the next stage without further purification.

1H NMR (CDCl3) δ: 8,12 (s, 1H), 7,92 (d, 1H), 7,73 (s, 1H), to 7.59 (d, 1H), 7,45 (t, 1H), 3,75 (t, 2H), 3.43 points (s, 3H), is 3.08 (t, 2H), 2,08-of 2.16 (m, 2H), 1,40 (s, 9H). MS m/z 349,4 (M+1), 95%.

E:4-(3-Tret.-butyltin�l)-6-(3-hydroxypropyl)-pyrimidin-2-carbonitril

To a solution of 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3-tert.-butylmethylether)-pyrimidine (4.6 g) in dimethyl sulfoxide (120 ml) under stirring at room temperature was added sodium cyanide (647 mg). The resulting suspension was stirred at room temperature for 3 hours. After adding ethyl acetate (200 ml) and the mixture was washed with water (100 ml×3). The organic layer was dried over MgSO4and concentrated in vacuo, the residue was passed through a column of silica gel using petroleum ether and EtOAc as eluent, obtaining 4-(3-tert.-butylphenyl)-6-(3-hydroxypropyl)-pyrimidine-2-carbonitrile (4.0 g) in the form of oil.

1H NMR (CDCl3) δ: 8,14 (s, 1H), 7,89 (d, 1H), 7,74 (s, 1H), 7,60 (d, 1H), 7,46 (t, 1H), 3,76 (t, 2H), 3.00 for (t, 2H), is 2.05 and 2.13 (m, 2H), 1,40 (s, 9H). MS m/z 296,0 (M+1), 95%.

F: 4-(3-tert.-butylphenyl)-6-(3-oxopropyl)-pyrimidine-2-carbonitrile

Periodical dessa-Martin (679 mg) was added to a solution of 4-(3-tert.-butylphenyl)-6-(3-hydroxypropyl)-pyrimidine of carbonitrile (394 mg) in DCM (5 ml) and the resulting suspension was stirred at room temperature for 45 minutes the Reaction mixture was diluted with EtOAc (100 ml), washed with water (2×100 ml). The organic layer was dried over MgSO4and concentrated in vacuum. The residue was passed through a column of silica gel using petroleum ether and ethyl acetate (1:1) as eluent to obtain 4-(3-tert.-butylphenyl)-6-(3-oxopropyl)-pyrimi the Jn-2-carbonitrile in the form of a solid light-yellow color (266 mg).

1H NMR (CDCl3) δ: 8,13 (s, 1H), 7,88 (d, 1H), 7,79 (s, 1H), 7,60 (d, 1H), 7,46 (t, 1H), 3,18 (m, 2H), 3,11 (m, 2H), 1,40 (s, 9H). MS m/z 294,0 (M+1), 95%.

EXAMPLE 18a

4-(3-Benzyloxyphenyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

A: ethyl ester of 6-benzyloxy-3-oxohexanoate acid

4-Benzyloxyethanol acid (6,38 ml), the acid Melodrama (5,76 g) and dimethylaminopyridine (9,77 g) was dissolved in DCM (200 ml) and cooled to 0°C. a Solution of Isopropenyl of chloroformate in dichloromethane (100 ml) was added dropwise and stirred at 0°C for another 2 hours. Was added potassium hydrosulfate (200 ml 10%aqueous solution), the organic phase was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethanol (200 ml) and was heated under reflux overnight. After cooling, the solvent is evaporated under reduced pressure and the resulting oil was purified flash chromatography on a column of silica gel. Allocated ethyl ester of 6-benzyloxy-3-oxohexanoate acid in the form of an orange oil (8.53 g).

1H NMR (CDCl3) δ: 7,26-to 7.35 (m, 5H), 4,48 (s, 2H), 4,18 (kV, 2H), 3,49 (t, 2H), 3,44 (s, 2H), to 2.67 (t, 2H), 1,90-of 1.97 (m, 2H), 1.27mm (t, 3H). MS m/z 287,0 (M+1), 100%.

B: 6-(3-Benzyloxyphenyl)-2-mercaptopyrimidine-4-ol

To a stirred suspension of sodium methylate (3,48 g) in methanol (40 ml), cooled to 0°C, was added tibmachuni is (of 3.56 g). The mixture was stirred to dissolve, then slowly added ethyl ester of 6-benzyloxy-3-oxohexanoate acid (charged 8.52 g in 20 ml of methanol). The solution was heated under reflux overnight, cooled to room temperature and concentrated under vacuum. The residue was dissolved in water (50 ml), acidified to pH 6 with acetic acid and was stirred for 1 hour. The precipitate was filtered, washed successively with water (2×20 ml) and isopropanol (2×20 ml), then dried, obtaining 6-(3-benzyloxyphenyl)-2-mercaptopyrimidine-4-ol in the form of a white powder (7,94 g). MS m/z 277,1 (M+1), 100%.

C: 6-(3-Benzyloxyphenyl)-2-methylsulfonylamino-4-ol

A mixture of 6-(3-benzyloxyphenyl)-2-mercaptopyrimidine-4-ol (7,94 g), potassium hydroxide (32 ml of a 1 n solution in methanol) and methyliodide (1.97 ml) was stirred at room temperature overnight. The precipitate was filtered, washed successively with methanol (2×20 ml), isopropanol (2×20 ml) and water (2×20 ml), then dried, obtaining 6-(3-benzyloxyphenyl)-2-methylsulfonylamino-4-ol in the form of a white powder (7.0 g). MS m/z 291,0 (M+1), 100%.

D: 6-(3-benzyloxyphenyl)-2-methylsulfonylamino-4-silt ether triperoxonane acid

A solution of 6-(3-benzyloxyphenyl)-2-methylsulfonylamino-4-ol (200 mg) and triethylamine (0.2 ml) in dichloromethane (5 ml) was cooled to 0°C, then added anhydride triperoxonane is islote (0,14 ml) and the resulting mixture was heated to room temperature. After 2 hours the reaction mixture was washed with water (2×20 ml), dried over sodium sulfate and evaporated under reduced pressure. Flash chromatography on a column of silica gel was obtained 6-(3-benzyloxyphenyl)-2-methylsulfonylamino-4-silt ether triperoxonane acid (160 mg) in the form of a yellow oil.

1H NMR (CDCl3) δ: 7,30-7,40 (m, 5H), to 6.58 (m, 1H), 4,49 (s, 2H), 3,51 (t, 2H), 2,88 (t, 2H), 2,54 (s, 3H), 2,04 is 2.10 (m, 2H).

E: 6-(3-benzyloxyphenyl)-2-methanesulfonamido-4-silt ether triperoxonane acid

A suspension of 6-(3-benzyloxyphenyl)-2-methylsulfonylamino-4-silt ether triperoxonane acid (494 mg) and Oxone (419 mg) in methanol/water (8/2 ml) was stirred at room temperature overnight. The methanol is evaporated under reduced pressure, and the resulting suspension was extracted with ethyl acetate (2 x 20 ml). The organic fraction was dried over sodium sulfate and evaporated under reduced pressure, obtaining 6-(3-benzyloxyphenyl)-2-methanesulfonamido-4-silt ether triperoxonane acid (135 mg).

1H NMR (CDCl3) δ: 7,28-7,40 (m, 5H), to 7.15 (m, 1H), 4,47 (s, 2H), 3,54 (t, 2H), 3.33 and (s, 3H), 3,11 (t, 2H), 2,10-to 2.18 (m, 2H). MS m/z 477,0 (M+1), 100%.

F: 4-(3-Benzyloxyphenyl)-2-methanesulfonyl-6-trimethylsilylacetamide

A mixture of 6-(3-benzyloxyphenyl)-2-methanesulfonamido-4-silt ether triperoxonane acid (13.5 g), hexamethylditin (11.8 g), Tetra is IP(triphenylphosphine)-palladium (0) (1.4 g), lithium chloride (1.4 g) and 2-6-di-tert.-butylphenol (150 mg) in dioxane (100 ml) was heated under reflux under N2within 3 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness under reduced pressure. Flash chromatography on silica gel was obtained 4-(3-benzyloxyphenyl)-2-methanesulfonyl-6-trimethylsilylacetamide (8.0 g) in the form of a light yellow oil.

1H NMR (CDCl3) δ: 7,47 (s, 1H), 7,25 to 7.4 (m, 5H), and 4.5 (s, 2H), 3,55 (t, 2H), 3,35 (s, 3H), 2,90 (t, 2H), 2.06 to (m, 2H), and 0.40 (s, 9H).

G: 4-(3-Benzyloxyphenyl)-6-trimethylsilylacetamide-2-carbonitril

A solution of 4-(3-benzyloxyphenyl)-2-methanesulfonyl-6-trimethylethylenediamine (200 mg) and sodium cyanide (42 mg) in dimethyl sulfoxide (1 ml) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (10 ml), washed with water (2×10 ml), dried over sodium sulfate and evaporated under reduced pressure. Flash chromatography on silica gel was obtained 4-(3-benzyloxyphenyl)-6-trimethylsilylacetamide-2-carbonitrile in the form of a yellow oil (111 mg).

1H NMR (CDCl3) δ: 7,45 (s, 1H), 7,28-7,37 (m, 5H), 4,50 (s, 2H), 3,54 (t, 2H), 2,84 (t, 2H), 2,02 is 2.10 (m, 2H), 0,39 (s, 9H).

H: 4-(3-Benzyloxyphenyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

A solution of 4-(3-benzyloxyphenyl)-6-trimethylsilylacetamide-2-carbonitrile (100 mg), cryptomaterial (36 m is) and 1,1'-(bescription)periodically (II) (16 mg) in dimethylformamide (5 ml) was heated in a microwave oven at 150°C for 5 minutes The resulting suspension was diluted with ethyl acetate and water (20 ml), the organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. Flash chromatography on silica gel was obtained 4-(3-benzyloxyphenyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile in the form of a yellow resin (47 mg).

1H NMR (CDCl3) δ: 8,31 (s, 1H), of 8.25 (d, 1H), 7,82 (d, 1H), 7,72 (s, 1H), to 7.67 (t, 1H), 7.24 to to 7.32 (m, 5H), of 4.49 (s, 2H), only 3.57 (t, 2H), to 3.02 (t, 2H), 2,10-to 2.18 (m, 2H). MS m/z 398,1 (M+1), 100%.

The procedure described above was then applied, using the appropriate derivatives of arilbred, to obtain the following compounds:

18b: 4-(3-amino-5-triptoreline)-6-(3-benzyloxyphenyl)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: to 7.67 (s, 1H), to 7.59 (s, 1H), 7,56 (s; 1H), 7.24 to 7,35 (m, 5H), 7,05 (s, 1H), 4,49 (s, 2H), 4,08 (ush. s, 2H), of 3.56 (t, 2H), 3.00 for (t, 2H), 2,10-to 2.18 (m, 2H). MS m/z 413,3 (M+1), 100%.

18c: 4-(3-Benzyloxyphenyl)-6-(3-carboxy-5-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,86 (s, 1H), 8,55 (s, 1H), of 8.47 (s, 1H), 7,76 (s, 1H), 7.24 to 7,35 (m, 5H), 4,43 (s, 2H), 3,53 (t, 2H), 3.00 for (t, 2H), 2,09-of 2.15 (m, 2H). MS m/z 440,3 (M-H), 100%.

EXAMPLE 19

4-(3-Benzyloxyphenyl)-6-(3-methanesulfonamido-5-triptoreline)-pyrimidine-2-carbonitrile

A: N-(3-bromo-5-triptoreline)-methanesulfonamide

To a solution of 3-Amino-5-bromobenzonitrile (200 mg) in pyridine (2 ml) was added methanesulfonamide (115 mg) and a single crystal is 4-(ethanamine)pyridine. The mixture was stirred at room temperature for four hours, then was diluted with ethyl acetate (50 ml) and washed with HCl (2M, 50 ml) and a saturated solution (50 ml) of sodium chloride. The organic fraction was separated, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure, obtaining N-(3-bromo-5-triptoreline)-methanesulfonamide (264 mg).

1H NMR (MeOD) δ: to 7.59 (s, 1H), 7,58 (s, 1H), 7,40 (s, 1H), 7,00 (s, 1H), 3,11 (s, 3H). MS m/z 318,9 (M+1).

B: 4-(3-Benzyloxyphenyl)-6-(3-methanesulfonamido-5-triptoreline)-pyrimidine-2-carbonitrile

N-(3-bromo-5-triptoreline)-methanesulfonamide (37 mg), 4-(3-benzyloxyphenyl)-6-trimethylsilylacetamide-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium (II) (7 mg) in DMF (1 ml) was heated in a microwave oven at 180°C for five minutes. The mixture was diluted with ethyl acetate (10 ml) and filtered through celite. The filtrate was washed with water (10 ml) and a saturated solution (10 ml) of sodium chloride. The organic fraction was separated, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give crude product. The HPLC purification was obtained 4-(3-benzyloxyphenyl)-6-(3-methanesulfonamido-5-triptoreline)-pyrimidine-2-carbonitrile.

1H NMR (MeOD) δ: 8,10 (s, 1H), of 8.09 (s, 1H), 7,74 (s, 1H), of 7.70 (s, 1H), 7,29 (m, 5H), of 4.49 (s, 2H), to 3.58 (t, 2H), 3,12 (s, 3H), 3,06 (t, 2H), 2,17 (m, 2H). MS m/z 491,1 (M+1), 100%.

<> EXAMPLE 20

4-(3-Benzyloxyphenyl)-6-(3-methylsulfanyl-5-triptoreline)-pyrimidine-2-carbonitrile

A: 3-bromo-N-methyl-5-triftoratsetilatsetonom

To a solution of 3-bromo-5-(trifluoromethyl)-benzosulfimide (200 mg) in 1,4-dioxane (1 ml) was added methylamine (40%aqueous solution of 96 mg). The mixture was stirred at room temperature for three hours, then was diluted with ethyl acetate (20 ml) and washed with HCl (1 M, 2×20 ml). The organic fraction was separated, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure, obtaining 3-bromo-N-methyl-5-triftoratsetilatsetonom (181 mg) as a solid yellow color.1H NMR (MeOD) δ: 8,19 (s, 1H), with 8.05 (s, 1H), 7,98 (s, 1H), 4,58 (m, 1H), 2,74 (d, 3H). MS m/z 319,8 (M+1).

B: 4-(3-Benzyloxyphenyl)-6-(3-methylsulfanyl-5-triptoreline)-pyrimidine-2-carbonitrile

3-bromo-N-methyl-5-triftoratsetilatsetonom (37 mg), 4-(3-benzyloxyphenyl)-6-trimethylsilylacetamide-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium (II) (7 mg) in DMF (1 ml) was heated in a microwave oven at 180°C for five minutes. The mixture was diluted with ethyl acetate (20 ml) and washed with water (3×20 ml). The organic fraction was separated, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give crude product. Purification preparative HPLC on what Uchali 4-(3-benzyloxyphenyl)-6-(3-methylsulfanyl-5-triptoreline)-pyrimidine-2-carbonitrile (16.5 mg).

1H NMR (MeOD) δ: an 8.70 (s, 1H), 8,54 (s, 1H), of 8.27 (s, 1H), 7,82 (s, 1H), 7,27 (m, 5H), 4,78 (m, 1H), 4,48 (s, 2H)and 3.59 (t, 2H), 3,6 (t, 2H), 2,75 (d, 3H), of 2.16 (m, 2H). MS m/z 491,1 (M+1), 100%.

EXAMPLE 21

4-(3-hydroxypropyl)-6-(3-methylsulfanyl-5-triptoreline)-pyrimidine-2-carbonitrile

To a solution of 4-(3-benzyloxyphenyl)-6-(3-methylsulfanyl-5-triptoreline)-pyrimidine-2-carbonitrile (14.4 mg) in acetonitrile (700 ml) and water (300 ml) was added cerium sulfate (3 mg) and bromate barium (6 mg). The mixture was heated under reflux overnight, then filtered through a glass filter, the residue washed with DCM (10 ml). The filtrate was washed with saturated sodium thiosulfate (10 ml), the organic fraction was separated, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give crude product. Purification preparative HPLC was obtained 4-(3-hydroxypropyl)-6-(3-methylsulfanyl-5-triptoreline)-pyrimidine-2-carbonitrile (3.2 mg).

1H NMR (MeOD) δ: 8,89 (s, 1H), 8,78 (s, 1H), 8,31 (s, 1H), 8,28 (s, 1H), 3,66 (t, 2H), 3,05 (t, 2H), 2,61 (s, 3H), of 2.08 (m, 2H). MS m/z 401,1 (M+1), 100%.

EXAMPLE 22

4-(3-Dimethylsulphamoyl-5-triptoreline)-6-(3-piperidine-1-yl-propyl)-pyrimidine-2-carbonitrile

A: 4-(3-Methylsulfanyl-5-triptoreline)-6-(3-oxopropyl)-pyrimidine-2-carbonitrile

A suspension of 4-(3-hydroxypropyl)-6-(3-methylsulfanyl-5-triptime ylphenyl)-pyrimidine-2-carbonitrile (235 mg) and the reagent Tessa Martin (299 mg) in dichloromethane (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was purified flash chromatography on silica gel, receiving 4-(3-methylsulfanyl-5-triptoreline)-6-(3-oxopropyl)-pyrimidine-2-carbonitrile in the form of rose oil (300 mg).

MS m/z 399,0 (M+1), 100%.

This aldehyde was synthesized following connection with the recovery amination described above in EXAMPLE 7a:

B: 4-(3-Dimethylsulphamoyl-5-triptoreline)-6-(3-piperidine-1-yl-propyl)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: rate of 8.75 (s, 1H), at 8.60 (s, 1H), 8,28 (s, 1H), 7,88 (s, 1H), 2,98 (t, 2H), 2,77 (s, 3H), 2,35-2,50 (ush. m, 6H), 2,02-of 2.08 (m, 2H), 1,42-1,66 (ush. m, 6H). MS m/z 468,0 (M+1), 100%.

EXAMPLE 23

4-(4-methoxy-3-triptoreline)-6-propylpyrimidine-2-carbonitril

Bis(triphenylphosphine)palladium dichloride (34 mg, 0.05 mmol) was added under nitrogen atmosphere to a mixture of 4-propyl-6-trimethylsilylacetamide-2-carbonitrile (150 mg, 0.48 mmol) and 4-methoxy-3-triftormetilfullerenov (148 mg, of 0.58 mmol) in dimethylformamide (3 ml). The mixture was heated for 5 hours at 80°C, then concentrated under reduced pressure. The residue was separated between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: cyclohexane/DCM 7/3)to give a solid, which is triturated in pentane. After fil the radio received 4-(4-methoxy-3-triptoreline)-6-propylpyrimidine-2-carbonitrile (18 mg, 11%) in the form of a solid off-white color.

1H NMR (CDCl3) δ: a 8.34 (d, J=8 Hz, 1H); 8.30 to (s, 1H); the 7.65 (s, 1H); to 7.15 (s, 1H); 4,01 (s, 3H); 2,92 (t, J=8 Hz, 2H); 1,95-of 1.85 (m, 2H); of 1.05 (t, J=7 Hz, 3H). MS m/z: 322,1 (M+1).

EXAMPLE 24

4-(5-tert.-butyl-2-methoxyphenyl)-6-propylpyrimidine-2-carbonitril

A: 1-tert.-butyl-4-methoxy-3-iodobenzoyl

1H NMR (CDCl3) δ: 7,76 (d, J=2 Hz, 1H); 7,30 (DD, J=8 Hz, J'=2 Hz, 1H); 6,74 (d, J=8 Hz, 1H); a 3.83 (s, 3H); of 1.28 (s, 9H).

13C NMR (CDCl3) δ: 155,8 145,5, 136,3, 126,3, 110,4, 85,9, 56,3, 34,0, 31,4.

B: 4-(5-tert.-butyl-2-methoxyphenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: with 8.05 (s, 1H); to 7.99 (s, 1H); 7,51 (d, J=8 Hz, 1H); 6,97 (d, J=8 Hz, 1H); 3,90 (s, 3H); of 2.81 (t, J=8 Hz, 2H); 1.85 to about 1.75 (m, 2H); of 1.36 (s, 9H); a 1.01 (t, J=8 Hz, 3H). MS m/z: 310 (M+1).

EXAMPLE 25

4-(3-cyclopropylmethyl)-6-propyl-pyrimidine-2-carbonitrile

A: 3-bromo-1-cyclopropylmethyl

Iodine (0,335 g of 1.32 mmol), diiodomethane (4.3 ml, to 53.0 mmol) and 3-Postira (5 g of 26.4 mmol) were added sequentially to a suspension of copper (7.5 g, of 118.8 mmol) in toluene (50 ml). The mixture was heated under reflux for 140 h, then filtered and concentrated in vacuum. The rest drove away under reduced pressure, obtaining 3-bromo-1-cyclopropylbenzene (0.55 g, 10%) in the form of a colorless oil.

1H NMR (CDCl3) δ: 7,35-7,25 (m, 1H); 7,25-7,20 (m, 1H); 7,15-7,05 (m, 1H); 7,05-to 6.95 (m, 1H); 1,95-of 1.85 (m, 1H); of 1.05 to 0.95 (m, 2H); 0,75-of 0.65 (m, 2H).

B: 4-(3-Cyclopropylmethyl)-6-p is epidermidis-2-carbonitril

1H NMR (CDCl3) δ: a 7.85-7,80 (m, 2H); 7,68 (s, 1H); 7,41 (t, J=8 Hz, 1H); 7,30-7,20 (m, 1H); 2,84 (t, J=8 Hz, 2H); 2,05-2,95 (m, 1H); 1,90 and 1.80 (m, 2H); 1,10-of 0.95 (m, 5H); to 0.80 to 0.75 (m, 2H). MS m/z: 264 (M+1).

HPLC (200-400 nm): 92,2%.

EXAMPLE 26a

4-(3,4-acid)-6-propylpyrimidine-2-carbonitril

A: 4-iodine-6-propylpyrimidine-2-carbonitril

Iodine (1.64 g, 6.5 mmol) was added at room temperature to a solution of 4-propyl-6-trimethylsilylacetamide-2-carbonitrile (2.0 g, 6.5 mmol) in THF (100 ml). The mixture was stirred at room temperature for 2 hours, then was diluted with saturated sodium thiosulfate solution and the THF was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 5/5)to give 4-iodine-6-propylpyrimidine-2-carbonitrile (1.28 g, 72%) in the form of a colorless oil.

1H NMR (CDCl3) δ: 7,81 (s, 1H); a 2.71 (t, J=8 Hz, 2H); to 1.8-1.7 (m, 2H); 0,99 (t, J=8 Hz, 3H).

13C NMR (CDCl3) δ: 172,0, 143,7, 134,2, 129,2, 114,7, 38,8, 21,8, 13,7. MS m/z: 274 (M+1).

B: 4-(3,4-acid)-6-propylpyrimidine-2-carbonitril

In nitrogen atmosphere, the solution (C=0,18M) 4-iodine-6-propylpyrimidine-2-carbonitrile (1 ml, 0.18 mmol) in degassed toluene, an aqueous solution (C=2M) carbonate is Aliya (0,225 ml, 0.45 mmol) and tetrakis-(triphenylphosphine)palladium (10 mg, 0.09 mmol), was added to solution (C=0,216 M) of 3,4-dimethoxyphenylacetic acid (1 ml, 0,216 mmol) in degassed toluene. The mixture was heated at 105°C for 4 h, then left to cool to room temperature and was mixed with water (4 ml). The organic layer was evaporated under reduced pressure. The residue was chromatographically in preparative HPLC (N2O+0.05% of TFA / CH3CN+0,05% TFA)to give 4-(3,4-acid)-6-propylpyrimidine-2-carbonitrile (28 mg).

1H NMR (CDCl3) δ: of 7.75 (s, 1H); 7,66 (d, J=8 Hz, 1H); 7,63 (s, 1H); 6,97 (d, J=8 Hz, 1H); was 4.02 (s, 3H); of 3.97 (s, 3H); 2.82 from (t, J=8 Hz, 2H); 1.85 to about 1.75 (m, 2H); of 1.02 (t, J=7 Hz, 3H). MS m/z: 284 (M+1).

The above procedure was applied, using appropriate derivative Bronevoy acid in the synthesis of the following derivatives:

26b: 4-(2,3-dihydrobenzofuran-5-yl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,1-8,0 (m, 1H); 7,9-7,8 (m, 1H); 7,58 (s, 1H); from 6.9 to 6.8 (m, 1H); 4,7-4,6 (m, 2H); 3,35-of 3.25 (m, 2H); 2,85-2,70 (m, 2H); 1.9 to 1.8 m (m, 2H); and 1.00 (t, J=8 Hz, 3H). MS m/z: 266 (M+1).

-26 C: 4-(3-cyanophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: an 8.4 to 8.3 (m, 2H); 7,86 (d, J=8 Hz, 1H); 7,73 (s, 1H); of 7.69 (t, J=8 Hz, 1H); 2,89 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); was 1.04 (t, J=8 Hz, 3H). MS m/z: 249 (M+1).

26d: 4-(3-chlorophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,10 (s, 1H); to 7.99 (d, J=8 Hz, 1H); to 7.67 (s, 1H); 7,55 was 7.45 (m, 2H);2,86 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=8 Hz, 3H). MS m/z: 258/260 (M+1).

26e: 4-(4-Dimethylaminophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,03 (d, J=8 Hz, 2H); 7,53 (s, 1H); 6.75 in (d, J=8 Hz, 2H); is 3.08 (s, 6H); was 2.76 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); and 1.00 (t, J=8 Hz, 3H). MS m/z: 267 (M+1).

26f: 4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: of 7.7 and 7.6 (m, 2H); 7,58 (s, 1H); 6,98 (d, J=8 Hz, 1H); 4,35-of 4.25 (m, 4H); 2,80 (t, J=8 Hz, 2H); 1.85 to about 1.75 (m, 2H); of 1.01 (t, J=8 Hz, 3H). MS m/z: 282 (M+1).

25g: 4-Propyl-6-(4-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 8,23 (d, J=8 Hz, 2H); 7,80 (d, J=8 Hz, 2H); of 7.75 (s, 1H); is 2.88 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); was 1.04 (t, J=8 Hz, 3H). MS m/z: 292 (M+1).

26h: 4-(2-methoxyphenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,07 (d, J=8 Hz, 1H); 8,02 (s, 1H); 7,50 was 7.45 (m, 1H); 7,15-7,10 (m, 1H);? 7.04 baby mortality (d, J=8 Hz, 1H); 3,93 (s, 3H); 2.82 from (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.02 (t, J=8 Hz, 3H). MS m/z: 254 (M+1).

26i: 4-Propyl-6-(2-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (CDCl3) δ: 7,83 (d, J=8 Hz, 1H); 7,75 is 7.50 (m, 2H); rate of 7.54 (d, J=8 Hz, 1H); 7,49 (s, 1H); 2,87 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.01 (t, J=8 Hz, 3H). MS m/z: 292 (M+1).

26j: 4-(3-acetylphenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,67 (s, 1H); of 8.37 (d, J=8 Hz, 1H); to 8.14 (d, J=8 Hz, 1H); 7,80 (s, 1H); to 7.67 (t, J=8 Hz, 1H); is 2.88 (t, J=8 Hz, 2H); of 2.72 (s, 3H); 1.9 to 1.8 m (m, 2H); of 1.03 (t, J=8 Hz, 3H). MS m/z: 266 (M+1).

26k: 4-(4-isopropylphenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDC 3) δ: 8,04 (d, J=8 Hz, 2H); to 7.67 (s, 1H); 7,39 (d, J=8 Hz, 2H); 3,05-2,95 (m, 1H); and 2.83 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.30 (s, 3H); of 1.29 (s, 3H); of 1.02 (t, J=8 Hz, 3H). MS m/z: 266 (M+1).

26l: 4-(Benzo[1.3]dioxol-5-yl)-6 propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: to 7.68 (d, J=8 Hz, 1H); a 7.62 (s, 1H); 7,58 (s, 1H); 6,94 (d, J=8 Hz, 1H); between 6.08 (s, 2H); of 2.81 (t, J=8 Hz, 2H); 1.85 to about 1.75 (m, 2H); of 1.01 (t, J=8 Hz, 3H). MS m/z: 268 (M+1).

26m: 4-(3-nitrophenyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: of 8.92 (s, 1H); 8,53 (d, J=8 Hz, 1H); 8,43 (d, J=8 Hz, 1H); 7,81 (s, 1H); to 7.77 (t, J=8 Hz, 1H); 2.91 in (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); of 1.05 (t, J=8 Hz, 3H). MS m/z: 269 (M+1).

26n: 4-(3-chloro-4-forfinal)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,21 (d, J=8 Hz, 1H); for 8.1 to 8.0 (m, 1H); 7,66 (s, 1H); 7,35-7,20 (m, 1H); 2,9-2,8 (m, 2H); 1,90 is 1.75 (m, 2H); of 1.03 (t, J=7 Hz, 3H). MS m/z: 266 (M+1).

A: 4-(2,5-acid)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,07 (s, 1H); 7,66 (d, J=3 Hz, 1H); 7,05 (DD, J=8 Hz, J'=3 Hz, 1H); 6,97 (d, J=8 Hz, 1H); 3,88 (s, 3H); a 3.87 (s, 3H); 2.82 from (t, J=8 Hz, 2H); 1.85 to about 1.75 (m, 2H); of 1.02 (t, J=7 Hz, 3H). MS m/z: 284 (M+1).

EXAMPLE 27a

4-(2-chloro-5-triptoreline)-6-propylpyrimidine-2-carbonitril

In nitrogen atmosphere, the solution (C=0,18M) 4-iodine-6-propylpyrimidine-2-carbonitrile (1 ml, 0.18 mmol) in degassed toluene, an aqueous solution (C=2 M), potassium carbonate (0,225 ml, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (10 mg, 0.09 mmol) were sequentially added to the solution (C=0,216 M) of 2-chloro-5-(trifluoromethyl)phenylboron the howling acid (1 ml, 0,216 mmol) in degassed toluene. The mixture was heated at 105°C for 4 h, then left to cool to room temperature and was mixed with water (4 ml). The organic layer was evaporated under reduced pressure. The residue was chromatographically preparative HPLC (N2O+0.05% of TFA / CH3CN+0,05% TFA)to give 4-(2-chloro-5-triptoreline)-6-propylpyrimidine-2-carbonitrile (34 mg, 58%) in the form of solids.

1H NMR (CDCl3) δ: 7,99 (s, 1H); for 7.78 (s, 1H); and 7.7 and 7.6 (m, 2H); 2,89 (t, J=8 Hz, 2H); 1,90 and 1.80 (m, 2H); of 1.03 (t, J=8 Hz, 3H). MS m/z: 326/328 (M+1).

The described procedure was applied, using the appropriate derivative arylboronic acid in the synthesis of the following derivatives:

27b: 4-(3-Methanesulfonyl)-6-propylpyrimidine-2-carbonitril

1H NMR (CDCl3) δ: 8,63 (s, 1H); 8,48 (d, J=8 Hz, 1H); to 8.14 (d, J=8 Hz, 1H); 7,80 to 7.75 (m, 2H); 3.15 in (s, 3H); 2,89 (t, J=8 Hz, 2H); 1.9 to 1.8 m (m, 2H); was 1.04 (t, J=8 Hz, 3H). MS m/z: 308 / 310 (M+1).

EXAMPLE 28

4-(3-Cyclopentenyl)-6-propylpyrimidine-2-carbonitril

A: N,N-dibenzyl-3-cyclopentenyl

The solution bromocyclopentane (a 7.62 g of 51.1 mmol) in dry THF (25 ml) was added dropwise to a suspension of magnesium particles (1.24 g, 51 mmol) in a simple ether (3 ml) in a nitrogen atmosphere in such quantity to maintain the internal temperature of 45-50°C. (After adding a few drops of the solution and the mixture was heated to approximately 50°C to initiate f is armirovanie Grignard reagent). After 1.5 h the Grignard reagent was Coulibaly in an addition funnel, diluted with 25 ml of dry THF and added dropwise over 30 minutes to a cold (0°C) solution dried ZnBr2(11,5 g, 51 mmol) in dry THF (90 ml) under nitrogen atmosphere. After 15 minutes the reaction mixture was cooled to -60°C was added PdCl2(dppf)2(249 mg, 0.34 mmol) (the solution became red). A solution of 3-bromo-N,N-dibenzyl-aniline (6 g, 17 mmol) in dry THF (50 ml) was added to this solution in 35 minutes. Then deleted the tub with dry ice and the solution was allowed to warm to room temperature over night. After adding 3 N. HCl (70 ml), THF was removed under reduced pressure. The aqueous residue was extracted three times with AcOEt (3 x 70 ml). The combined organic layers were washed with brine (50 ml), then with saturated solution of NaHCO3(50 ml). Insoluble material was filtered and the solution was again washed with brine (50 ml). The organic layer was dried over MgSO4and concentrated under reduced pressure, obtaining the specified connection (5.8 g)which was used in the next stage without further purification.

1H NMR (CDCl3) δ: 7,28-to 7.32 (4H, m), 7,21-of 7.25 (6H, m), was 7.08 (1H, t, J=8 Hz), 6,60-only 6.64 (2H, m), 6,55 (1H, DD, J1=8 Hz, J2=2,4 Hz), to 4.62 (4H, s), 2,85 (1H, HF), 1,90-2,00 (2H, m)of 1.65 and 1.75 (2H, m), 1,5-of 1.65 (2H, m), 1,45-1,5 (2H, m).

B: 3-cyclopentadienylcobalt

N,N-dibenzyl-3-cyclopentylamine (6,07 g, 17,03 mmol) Geri is ovali on Pd(OH) 2(600 mg) under a pressure of 10 bar in a mixture of MeOH (80 ml), methoxyethanol (20 ml), CH2Cl2(20 ml) and concentrated HCl (1,63 ml) for 20 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The residue was divided between CH2Cl2and water. Installed approximately pH 10 by adding NaOH pellets. The organic layer was washed with brine, dried over MgSO4and concentrated under reduced pressure, obtaining 2.65 g of the expected aniline. The hydrochloride was obtained by treating the volatile HCl: 2.38 g, yield: 71%.

HPLC: 100%.

1H NMR (CCD3OD) δ: 7,44 (1H, t, J=8 Hz), 7,38 (H, d, J=8 Hz), 7,29 (1H, s), 7,21 (1H, m), is 3.08 (1H, HF), is 2.09 and 2.13 (2H, m), 1,83 is 1.86 (2H, m), of 1.73 to 1.76 (2H, m), 1.60-to and 1.63 (2H, m).

C: 1-cyclopentyl-3-iodobenzoyl

A solution of sodium nitrite (558 mg, 8.1 mmol) in water (10 ml) was added over 5 minutes to a chilled (5°C) solution of 3-cyclopentadienylcobalt (1 g, 5.1 mmol) in 6 BC HCl (25 ml). After 50 minutes was added over 5 minutes a solution of potassium iodide (2,02 g, 12.2 mmol) in water (10 ml). The mixture was heated for 1 hour at 70°C. After cooling to room temperature was set pH over 11 using 6 N. NaOH and the mixture was extracted three times with CH2Cl2(3 x 100 ml). The combined organic layers were washed with sodium thiosulfate (75 ml), then brine (75 ml) and dried over MgSO4. The solvent was removed under reduced pressure, the floor is th of 1.23 g of raw material (HPLC: 67%), which was purified by chromatography on silica gel (eluent: cyclohexane)to give the specified named connection in the form of oil: 825 mg, yield: 60%.

1H NMR (CDCl3) δ: 7,58 (1H, m)to 7.50 (1H, d, J=8 Hz), 7,19 (1H, ush. d)to 7.00 (1H, t, J=8 Hz), 2,92 (1H, quintet), 2,03-2,07 (2H, m), 1,76-to 1.82 (2H, m), 1,65-1,70 (2H, m), 1,54-of 1.57 (2H, m).

D: 4-(3-cyclopentenyl)-6-propylpyrimidine-2-carbonitril

A mixture of 1-cyclopentyl-3-iodobenzene (158 mg, of 0.58 mmol), 4-propyl-6-trimethylsilylacetamide-2-carbonitrile (150 mg, 0.48 mmol) and PdCl2(PPh3)2(34 mg, 0.05 mmol) in dry DMF (3 ml) was heated at 80°C for 6 hours in nitrogen atmosphere. Added additional catalyst (40 mg, 0.06 mmol) and the mixture was heated for 12 hours at 80°C. the Solvent was removed under reduced pressure and the residue was separated between water (5 ml) and AcOEt (5 ml). The aqueous layer was extracted with AcOEt twice (2 x 5 ml). The combined organic layers were washed with brine, dried over MgSO4and concentrated under reduced pressure, getting 272 mg of the crude product, which was purified by chromatography on silica gel (eluent: cyclohexane/AcOEt 95/5), receiving the connection specified: 51 mg, yield: 36%, HPLC: 98%.

1H NMR (CDCl3) δ: 7,99 (1H, s), 7,87 (1H, dt, J1=5 Hz, J2=2 Hz), 7,69 (1H, s), 7,44 (2H, d, J=5 Hz), 3,10 (1H, quintet), 2,84 (2H, t, J=7,6 Hz), 2,12-of 2.15 (2H, m), 1,81-of 1.88 (4H, m), 1,60 to 1.76 (4H, m)of 1.02 (3H, t, J=7.2 Hz). MS m/z: 292 (M+1).

EXAMPLE 29a

4-(3-Cycle is propylaminoethyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile

To a solution of 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (153 mg) in methanol (2 ml) was added cyclopropylamine (140 μl), acetic acid (0,12 ml) and then triacetoxyborohydride sodium (210 mg). The mixture was stirred at room temperature for 24 hours, then was purified preparative HPLC. 4-(3-cyclopropylamino)-6-(3-triptoreline)-pyrimidine-2-carbonitrile, TFA salt, was isolated in a solid white color (70 mg).

1H NMR (MeOD) δ: 8,50 (s, 1H), of 8.47 (d, 1H), of 8.25 (s, 1H), of 7.90 (d, 1H), 7,81 (t, 1H), or 3.28 (t, 2H), to 3.09 (t, 2H), 2,80 (m, 1H), 2,25 (m, 2H), 0,85-1,05 (m, 4H). MS m/z 347,4 (M+1), 30%.

29b: 4-[3-(1-(s)-Methyl-2-methoxyethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

To a solution of 4-(3-oxopropyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile (610 mg) in methanol (8 ml) was added 1-(s)-methyl-2-methoxyethylamine of 0.85 ml), acetic acid (0.5 ml) and then triacetoxyborohydride sodium (0,82 g). The mixture was stirred at room temperature for 4 hours, then was diluted aqueous solution of sodium bicarbonate (5%, 50 ml). The mixture was extracted with ethyl acetate (50 ml plus 3×20 ml). The combined organic layer was dried over sodium sulfate, filtered, the solvent was removed under vacuum. The residue was passed through a column of silica gel using DCM-MeOH (20:1) as eluent, obtaining 4-[3-(1-(s)-methyl-2-methoxyethylamine)-propyl]-6-(3-trifluoromethyl who enyl)-pyrimidine-2-carbonitrile (250 mg). Specified neutral product was dissolved in DCM and then added HCl (1M in simple ether, 1 ml), 4-[3-(1-(s)-methyl-2-methoxyethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile, HCl salt, was collected by filtration (180 mg).

1H NMR (MeOD) δ: 8,50 (s, 1H), 8,48 (d, 1H), of 8.27 (s, 1H), of 7.90 (d, 1H), 7,79 (t, 1H), 3,68 (m, 1H), 3,48 (m, 2H), 3.43 points (s, 3H), 3,17 (m, 2H), 3,10 (t, 2H, in), 2.25 (m, 2H), of 1.36 (d, 3H). MS m/z 379,5 (M+1), 80%.

The procedure described above was then applied, using the appropriate amine derivative, to obtain the following compounds:

29c: 4-[3-(1-(S)-Carbamoylethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (MeOD) δ: 8,51 (s, 1H), 8,48 (d, 1H), they were 8.22 (s, 1H), 7,88 (d, 1H), to 7.77 (t, 1H), 3,29 (m, 1H), 3,01 (t, 2H), 2,70 (t, 2H), 2.05 is (m, 2H), 1,32 (d, 3H). MS m/z 377,9 (M+1), 100%.

29d: 4-[3-(1-(R)-Carbamoylethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (MeOD) δ: 8,51 (s, 1H), 8,48 (d, 1H), they were 8.22 (s, 1H), 7,88 (d, 1H), to 7.77 (t, 1H), 3,23 (kV, 1H), 3.00 for (t, 2H), 2,65 (t, 2H), 2.05 is (m, 2H), 1.28 (in d, 3H). MS m/z 378,4 (M+1), 100%.

29e: 4-[3-(1-Ethyl-1-methylpropylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile, salt triperoxonane acid (1:1)

1H NMR (MeOD) δ: 8,54 (s, 1H), 8,48 (d, 1H), 8,24 (s, 1H), of 7.90 (d, 1H), 7,79 (t, 1H), 3,12 (m, 4H), and 2.27 (m, 2H), 1,76 (m, 4H), 1,32 (s, 3H), 0,99 (t, 6H). MS m/z 391,3 (M+1), 100%.

29f: 4-[3-(1-Methylcyclopropyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile, salt triperoxonane acid (1:1)

1H NMR (CDCl3) δ: 9,13 (Shir. the, 2H), at 8.36 (s, 1H), 8,31 (d, 1H), 7,83 (s, 1H), 7,82 (d, 1H), 7,68 (t, 1H), 3,24 (m, 2H), 3.04 from (t, 2H), 2,28 (m, 2H), 1,50 (s, 3H), 1,21 (t, 2H), 0.74 and (t, 2H). MS m/z: 361,1 (M+1), 27%.

29g: 4-[3-(2-hydroxyethylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile, salt triperoxonane acid (1:1)

1H NMR (CDCl3) δ: 9,04 (Shir. s, 2H), 8.34 per (s, 1H), 8,29 (d, 1H), to 7.84 (s, 1H), 7,81 (d, 1H), 7,66 (t, 1H), 4.00 points (m, 2H), up 3.22 (m, 4H), 3,05 (t, 2H), 2,34 (m, 2H). MS m/z: to 351.3 (M+1), 20%.

29h: 4-[3-(1-Carbarnoyl-1 methylethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile

1H NMR (MeOD) δ: 8,55 (s, 1H), 8,48 (d, 1H), they were 8.22 (s, 1H), of 7.90 (d, 1H), 7,79 (t, 1H), 3,03 (t, 2H), 2,74 (t, 2H), 2,02-2,12 (m, 2H), 1.39 in (s, 6H). MS m/z 392,0 (M+1), 100%.

29i: 4-[3-(2-oxopyrrolidin-3-(S)-ylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile, salt triperoxonane acid (1:1)

1H NMR (MeOD) δ: charged 8.52 (s, 1H), 8,48 (d, 1H), of 8.25 (s, 1H), to $ 7.91 (d, 1H), 7,80 (t, 1H), 4,12 (t, 1H), 3,38-3,47 (m, 3H), 3,20-of 3.27 (m, 1H), 3,10 (t, 2H), 2,60 of 2.68 (m, 1H), 2,11 to 2.35 (m, 3H). MS m/z 390,3 (M+1), 100%.

EXAMPLE 30

Procedure test

The activity of cathepsin K

Inhibitory activity of the compounds according to the invention showedin vitroby measuring the inhibition of recombinant human cathepsin K as follows.

384-well plate for micrometrology was added 5 μl of a 100 μm solution of test compound in the test buffer (100 mm sodium acetate pH 5.5, 5 mm EDTA, 5 mm dithiothreitol) with 10% dimethyl sulfoxide (DMSO), the Luce 10 μl of a 100 μm solution of the substrate Z-Phe-Arg-AMC (Bachem; 7-aminocoumarin derivative of the dipeptide N-benzyloxycarbonyl-Phe-Arg-OH) in the test buffer and 25 μl of test buffer. Then the wells were added 10 μl of a solution of 1 mg/l of activated recombinant human cathepsin K in the test buffer, receiving the final concentration of inhibitor 10 μm.

Enzymatic activity was determined by measuring the fluorescence of released aminoethylamino at 440 nm using excitation at 390 nm, at time 10 minutes. The enzyme activity in percent was calculated in comparison of this activity relative to the activity of a solution containing no inhibitor. Compounds were then subjected to analysis on the basis of the curve dose-response to determine the values of the IC50for active compounds (where IC50the concentration of test compound causing 50%inhibition of enzyme activity).

Compounds according to the invention typically have a pIC50(the negative logarithm of the concentration IC50in relation to the inhibition of human cathepsin K more than 6, preferably more than 7, as for the compounds of Examples 1, 2, 4h, and most preferably pIC50more than 8, as for the compounds of Examples 3, 4a, 4d, 4e, 4f, 4g, 4i, 4r, 4s, 4u, 4a', 8a, 8c, 14j, 14n.

The activity of cathepsin S.

Inhibitory activity of the compounds according to the invention showedin vitromeasuring ing the repression of recombinant human cathepsin S as follows.

384-well plate for micrometrology was added 10 μl of a 100 μm solution of test compound in the test buffer (100 mm sodium acetate pH 5.5, 5 mm EDTA, 5 mm dithiothreitol) with 10% dimethyl sulfoxide (DMSO), plus 20 μl of a 250 μm solution of the substrate Z-Val-Val-Arg-AMC (Bachem; 7-aminocoumarins derived Tripeptide N-benzyloxycarbonyl-Val-Val-Arg-OH) in the test buffer and 45 ál of buffer. Then the wells were added 25 μl of a solution of 2 mg/l of activated recombinant human cathepsin S in the test buffer, receiving the final concentration of inhibitor 10 μm.

Enzymatic activity was determined by measuring the fluorescence of released aminoethylamino at 440 nm using excitation at 390 nm, at time 20 minutes. The enzyme activity in percent was calculated in comparison of this activity relative to the activity of a solution containing no inhibitor. Compounds were then subjected to analysis on the basis of the curve dose-response to determine the values of the IC50for active compounds (where IC50the concentration of test compound causing 50%inhibition of enzyme activity).

1. Derivatives of 4-phenylpyrimidine-2-carbonitrile having a General formula I
,
in which R denotes 1-3 possible substituent, independently selected from (C1-6)alkyl (if necessary the cost is substituted by 1 to 3 Halogens), (C1-6)alkyloxy (if necessary substituted by 1 to 3 Halogens), cyano, halogen, nitro, (C3-6)cycloalkyl, (C1-6)alkyl, SO2(C1-6)alkyl, SO2NH(C1-6)alkyl and CO2N; or 2 substituent R in adjacent positions together represent och2Oh, och2CH2Oh or CH2CH2About;
R1represents H or (C1-6)alkyl;
R2means (C2-6)alkyl, if necessary, replaced IT, phenyl(C1-4)alkyloxy, 1-3 halogen atoms, NR3R4, CO2N or CONR6R7;
R3and R4independently represent H, (C1-8)alkyl [if necessary substituted by 1-3 halogen atoms, (C1-4)alkyloxy], (C3-8)cycloalkyl, (C1-4)alkyl, substituted 4-8 membered saturated heterocycle, including a heteroatom selected from NR5, 4-8-membered saturated a heterocycle, including a heteroatom selected from NR5, phenyl, heteroaryl [if necessary substituted by 1-3 substituents selected from halogen, CF3, (C1-4)alkyl and (C1-4)alkyloxy], phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl, where heteroaryl is a 5-6-membered heteroaromatic cycle-containing 1-2 heteroatoms selected from N, possibly condensed with a benzene ring; or
R3and R4together with azo is om, to which they are bound, form a 4-8-membered saturated the heterocycle and, if necessary substituted by 1-3 Halogens, or CONR8R9and which may optionally include a heteroatom selected from O or NR5; or
R3represents H or (C1-4)alkyl; and R4means (C1-4)alkyl, substituted
CONR8R9, COOR10, NR8R9or NR8COR9;
R5denotes H, (C1-4)alkyl [if necessary substituted by phenyl]phenyl or heteroaryl where heteroaryl is a 5-6-membered heteroaromatic cycle that includes a heteroatom selected from N;
R6and R7independently represent H, (C1-4)alkyl; or
R6and R7together with the nitrogen to which they are bound, form a 4-8-membered saturated a heterocycle, which may optionally include a heteroatom selected from NR5;
R8and R9independently represent H or (C1-4)alkyl; or
R8and R9together with the atoms to which they are linked, form a 4-8-membered saturated a heterocycle, which may optionally include a heteroatom selected from O or NR5;
R10represents H or (C1-4)alkyl;
or their pharmaceutically acceptable salt.

2. Derived 4-phenylpyrimidine-2-carbonitrile according to claim 1, in which
R denotes 1-3 possible Deputy, not avisio selected from (C 1-6)alkyl [if necessary substituted by 1-3 Halogens], (C1-6)alkyloxy [if necessary substituted by 1-3 Halogens], cyano and halogen;
R1represents H or (C1-6)alkyl;
R2means (C2-6)alkyl, if necessary, replaced IT, 1-3 halogen or NR3R4;
R3and R4independently represent H, (C1-8)alkyl [if necessary substituted by 1-3 Halogens], (C3-8) cycloalkyl, 4-8-membered saturated a heterocycle, including a heteroatom selected from NR5, phenyl, heteroaryl, phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl; or
R3and R4together with the nitrogen to which they are bound, form a 4-8-membered saturated the heterocycle and, if necessary substituted by 1-3 Halogens, and which may optionally include a heteroatom selected from O or NR5,
R5denotes H, (C1-4)alkyl [if necessary substituted by phenyl]phenyl or heteroaryl;
or its pharmaceutically acceptable salt.

3. Derived 4-phenylpyrimidine-2-carbonitrile according to claim 2, in which R2means (C2-6)alkyl, substituted HE, 1-3 halogen or NR3R4.

4. Derived 4-phenylpyrimidine-2-carbonitrile according to claim 3 in which R2denotes propyl, substituted in position 3 by a group NR3R4.

5. A derivative is 4-phenylpyrimidine-2-carbonitrile according to claim 4, in which 4-phenyl includes trifluoromethyl as a substituent in the meta position.

6. Derived 4-phenylpyrimidine-2-carbonitrile formula I, selected from:
-4-(3-hydroxy-1-propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
-4-(3-(piperidine-1-yl)propyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(1-ethylpropylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(4-methyl-[1,4]diazepan-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-(3-cyclohexylamino)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-{3-[methyl-(1-methylpiperidin-4-yl)-amino]-propyl}-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(4-methylpiperazin-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
-4-(3-isopropylaminomethyl)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
-4-[3-(4-pyridin-2-yl-piperazine-1-yl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(carbamoylmethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(carboxymethylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(2-diethylaminoethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(2-acetylaminofluorene)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
-4-{3-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-propyl}-6-(3-triptoreline)-pyrim the DIN-2-carbonitrile;
4-(3,4-dimetilfenil)-6-[3-(methylcarbamoylmethyl)-propyl]-pyrimidine-2-carbonitrile;
4-[3-(2-acetylaminofluorene)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile;
4-[3-(3-dimethylaminopropylamine)-propyl]-6-(3,4-dimetilfenil)-pyrimidine-2-carbonitrile;
4-(3,4-dimetilfenil)-6-{3-[2-(1-methylpyrrolidine-2-yl)-ethylamino]-propyl}-pyrimidine-2-carbonitrile;
4-(3-cyclopropylamino)-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(1-(s)-methyl-2-methoxyethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(1-(S)-carbamoylethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(1-(R)-carbamoylethyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
-4-[3-(1-ethyl-1-methylpropylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(1-methylcyclopropyl)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(2-hydroxyethylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
-4-[3-(1-carbarnoyl-1 methylethylamine)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile;
4-[3-(2-oxo-pyrrolidin-3-(S)-ylamino)-propyl]-6-(3-triptoreline)-pyrimidine-2-carbonitrile; or its pharmaceutically acceptable salt.

7. Derived 4-phenylpyrimidine-2-carbonitrile according to any one of claims 1 to 6 for use in therapy for the treatment of cathepsin To and cathepsin S-related violations is s.

8. The use of derivative 4-phenylpyrimidine-2-carbonitrile according to any one of claims 1 to 6 to obtain drugs for the treatment of cathepsin To and cathepsin S-related disorders.

9. Pharmaceutical composition having the property of an inhibitor of cathepsin K and cathepsin S, which contains a derivative of 4-phenylpyrimidine-2-carbonitrile according to any one of claims 1 to 6, or its pharmaceutically acceptable salt in an effective amount in a mixture with pharmaceutically acceptable excipients.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula compounds, as well as their pharmaceutically acceptable salts, a pharmaceutical composition based on them, with inhibitory activity towards phosphorylation of protein Tau, and to methods of producing said compounds. In formula (I), R5 is aryl, aryl(C1-C6)alkyl; R6 is halogen; R3 is (C1-C6)alkyl, possibly substituted with substitutes selected from halogen, OH, NH2, azetidine; or monocyclic aryl or heteroaryl, such as thiophene or pyridine, possibly substituted with substitutes selected from NO2, CN, (C1-C6)alkoxy, (C1-C6)alkyl; or CONR1R2, SO2Ra, C(=NH)R1b, COOR1c; R1, R2 independently represent a hydrogen atom, possibly substituted with one halogen atom, (C1-C6)alkyl, moncyclic aryl or monocyclic 5- or 6-member heteroaryl containing 1 or 2 heteroatoms, such as S, O, N, possibly substituted with one or more substitutes selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifluoromethyl, N(CH3)2; or R1 and R2 can form a 5- or 6-member ring which optionally contains a heteroatom such as N; R1a is aryl, possibly substituted with (C1-C6)alkoxy; R1b is (C1-C6)alkyl, possibly substituted aryl or 6-member heteroaryl, containing 1 or 2 N atoms, where the substitute is (C1-C6)alkoxyl; R1c is (C1-C6)alkyl, (C2-C6)alkenyl; and their pharmaceutically acceptable salts.

EFFECT: aminoindazole derivatives as kinase inhibitor.

8 cl, 44 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula ; or their pharmaceutically acceptable salts, where A is phenyl, X is CH2- or C=O; Y is O; k equals 1; m equals 0; R2 and R3 each independently represents hydrogen or alkyl, R4 is a group of formula or . Disclosed compounds have selective affinity to 5-HT6 and 5-HT2A receptors. Also described is a pharmaceutical composition containing said compounds and use of the said compounds in making a medicinal agent for treating diseased conditions of the central nervous system.

EFFECT: more effective treatment.

49 cl, 1 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to compound of formula I wherein X represents -S- or -NH-; R1 represents C1-12alkyl, C2-12alkenyl, phenyl C1-12alkel, phenyl C2-12alkenyl or phenyl-O-C1-12alkyl and wherein said phenyl groups are optionally substituted with one or two assistants chosen from the group consisting of lower C1-7alkyl, C C1-7alkoxy and halogen C1-7alkyl; R2 represents hydrogen, lower C1-7alkyl or C3-6cycloalkyl; R3/R4 together with N-atom whereto attached, form nonaromatic 5,6-members heterocyclic ring system which optionally contains in addition to N-atom one additional heteroatom chosen from the group, consisting of O or N and where the ring system is optionally substituted group lower C1-7alkyl, lower C1-7alkoxy, -NR2, -CONR2; or R3/R4 together with N-atom whereto attached, can form heterocyclic ring system which contains at least two rings and which optionally contains one or two additional heteroatoms chosen from group, consisting of N and O; R represents hydrogen or lower C1-7alkyl; R5 represents hydrogen or lower C1-7alkyl; or to pharmaceutically acceptable additive salts with acid of this compound. The invention also concerns a medical product.

EFFECT: improved clinical effectiveness.

16 cl, 4 dwg, 3 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: proposed invention relates to a method of producing symmetrical gem-diamines with general formula where , involving reacting secondary acyclic or cyclic amines R2NH with excess N,N,N1,N1-tetramethyl methanediamine in the presence of a copper chloride (CuCl) catalyst at temperature 80°C and atmospheric pressure for 2-4 hours. Output of symmetrical gem-diamines is 85-98%.

EFFECT: improved method.

2 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of pyridinecarboxamides with formula (I), where the descriptions of radicals are given in the formula of the invention and its salts.

EFFECT: compounds exhibit insecticide activity.

7 cl, 5 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

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