6-phenyl-1h-imidazo[4,5-c]pyridine-4-carbonitrile derivatives as catepsin k and s inhibitors

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

 

The present invention relates to derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile, to pharmaceutical compositions containing these derivatives, and to the use of such derivatives to obtain drugs for treatment associated with cathepsin S and/or cathepsin For diseases such as osteoporosis, atherosclerosis, inflammation, and immune disorders such as rheumatoid arthritis, 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 degradation and protein processing. Many pathological disorders or diseases are the result of abnormal activity of cysteinate, such as overexpression or increased activation. Cysteineless, such as cathepsins B, K, L, S, V, F, are a class of liposomal enzymes, which are involved in various disorders, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors, coronary disease, atherosclerosis, autoimmune diseases and infectious diseases.

Cathepsin S is expressed mainly in antigen presenting cells and plays a major role in the presentation of antigens due to the degradation of the invariant of the second circuit, which is associated with major histocompatibility complex class II. Mice with deficiency of cathepsin S was found significant resistance to the development of collagen-induced arthritis and autoimmune myasthenia gravis ((Nakagawa et al., Immunity, 10, 207, 1999; Yang et al., 174, 1729, 2005). Found that cathepsin S breaks down all the major components of the extracellular matrix and is involved in the pathogenic response, which leads to atherosclerosis, emphysema and chronic obstructive lung disease ((Shi et al., Immunity, 10, 197, 1999; Zheng et al., J Clin. Invest., 106, 1081, 2000). Cathepsin S also serves as a sign of pain (WO 2003020278).

Cathepsin It has a strong collagenolytic, elastase and gelatinase activities (Bromme et al., J. Biol. Chem, 271, 2126-2132, 1996) and is predominantly expressed in osteoclasts (Bromme and 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 as such participates in the metabolism of extracellular matrix, necessary for normal growth and remodeling of bone tissue (Bossard et al., J. Biol. Chem. 271, 12517-12524, 1996). Inhibition of cathepsin K should lead to a reduction mediated by osteoclasts of bone resorption. Inhibitors of cathepsin K may therefore represent a new therapeutic agents for the treatment of the individual is ka pathological conditions, such as osteoporosis.

Sukhova et al. (J. Clin. Invest. 102, 576-583, 1998) showed that cells (macrophages)that migrate into the developing atherosclerotic plaques of human rights and accumulate in them, also synthesize active elastase cathepsins K and S. the destruction of the matrix, especially in the fibrous coating of such plaques is a critical process in the destabilization of atherosclerotic damage. Therefore, the metabolism of extracellular matrix components, collagen and elastin, which give structural integrity of the fibrous cover if damaged, can critically affect the clinical manifestations of atherosclerosis, such as thrombosis of the coronary artery due to the rupture of atherosclerotic plaques. Inhibition of cathepsins K and/or S in the vicinity of plaques prone to rupture, can therefore be an effective way to prevent such incidents. Derivatives of 4-aminopyrimidine-2-carbonitrile have been described as inhibitors of cathepsin K and/or S in the international patent application WO 03/020278 (Novartis Pharma GMBH), while structurally related derivatives of 4-aminopyrimidine-2-carbonitrile recently described in WO 04/000819 (ASTRAZENECA AB) as inhibitors of cathepsin S. in the same way pyrrolopyrimidine have been described as inhibitors of cathepsin K and/or S in WO 03/020721 (Novartis Pharma GMBH) and WO 04/000843 (ASTRAZENECA AB). Recently carbonitridation the s bicyclic nitrogen-containing aromatic system is described in international patent application WO 05/085210 (Ono Pharmaceutical Co.) as inhibitors cysteinate, useful in the treatment of osteoporosis.

In this area, there remains a need for additional inhibitors of cathepsin, especially the need for compounds with preferred inhibitory activity against cathepsin S in comparison with cathepsin K.

To this end the present invention provides derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile having the formula I

where R is an optional ortho - or meta-Deputy selected from halogen and (C1-4)alkyloxy;

R1is a (C1-4)alkyl, (C1-4)alkyloxy, halogen or CF3;

R2represents H, (C1-4)alkyl, (C1-4)alkyloxy or halogen;

R3represents H or (CH2)n-NR5R6;

R4represents H or (C1-6)alkyl, optionally substituted COOR7or NR8R9;

R5and R6independently represent H, (C3-8)cycloalkyl, Hinkley-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted with halogen, CF3, (C3-8)cycloalkyl, (C6-10)aryl, 5 - or 6-membered heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, COOR10, CONR11R12, NR13R14or NR13SO2(C1-4)alkyl; or

p> R5and R6together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing 1 or more heteroatoms selected from O, S, SO2and NR15and the ring optionally substituted by oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17or CONR18R19;

R7represents H or (C1-4)alkyl;

R8and R9are independently H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or

R8and R9together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

R10represents H or (C1-4)alkyl;

R11and R12are independently H or (C1-4)alkyl; or

R11and R12together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

R13and R14are independently H or (C1-4)alkyl; or

R13and R14together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, not battelino optionally containing a heteroatom, selected from O and S;

R15represents H, (C1-4)alkyl (optionally substituted by OH, (C1-4)alkyloxy, di(C1-4)alkylamino or CONR21R22), phenyl, pyridyl, COR20or CONR21R22;

R16and R17are independently H or (C1-4)alkyl; or

R16and R17together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

R18and R19are independently H or (C1-4)alkyl;

R20represents H, (C1-4)alkyl, (C3-8)cycloalkyl, (C1-4)alkyloxy or furyl;

R21and R22are independently H or (C1-4)alkyl; or

R21and R22together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

n is 0 or 1;

or their pharmaceutically acceptable salts.

The compounds are inhibitors of cathepsin S and cathepsin K and therefore they can be used for getting medicines for treatment of osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, and chronic pain, such as neuropathic pain.

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

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

The term "(C1-6)alkyloxy" "(C1-6)alkyl" has the previously specified values.

The term "(C2-6)alkenyl"used in the definition of formula I means a branched or unbranched alkenylphenol group having 1-6 carbon atoms, such as 2-hexenyl, 2-pentenyl, 3-methyl-2-butenyl, 2-propenyl (allyl), 1-methylethenyl (β-allyl) or ethynyl.

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

The term "Hinkley-3-yl" means 1-azabicyclo[2,2,2]Oct-3-yl.

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

The term "5 - or 6-membered heteroaryl group"used in the definition of R5and R6means an aromatic 5 - and 6-membered ring, having 1-3 heteroatoms selected from nitrogen atoms, oxygen and sulfur. Examples of such heteroaryl groups are pyridyl, imidazolyl, pyrazolyl, pyrimidinyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, thienyl, oxadiazolyl and the like. Preferred heteroaryl groups are 2-pyridyl, 3-pyridyl, 1,3-thiazol-2-yl, 1,2-oxazol-3-yl and 5-methylisoxazol-3-yl.

In the definition of formula I R5and R6together with the nitrogen atom to which they are bound, may form a 4-8-membered saturated heterocyclic ring, such as ring of azetidine, pyrrolidine, piperidine or 1H-azepine. Such rings may contain 1 or more additional heteroatoms selected from O, S, SO2or NR15with the formation of such rings as the ring of the research, thiomorpholine, 4-dioxo-4-thiomorpholine, hexahydro-1,4-oxazepine, piperazine, homopiperazine, imidazolidine or tetrahydrothieno.

In the definition of formula I R8and R9together with the nitrogen atom to which they are bound, may form a 4-8-membered saturated heterocyclic ring, such as ring of azetidine, pyrrolidine, piperidine or 1H-azepine. Such rings can optionally contain heteroatom selected from O and S, with the formation of such rings as the ring of the research, thiomorpholine, hexahydro-1,4-oxazepine or tetrahydrothieno.

the definition of formula I R 11and R12together with the nitrogen atom to which they are bound, may form a 4-8-membered saturated heterocyclic ring, such as ring of azetidine, pyrrolidine, piperidine or 1H-azepine. Such rings can optionally contain heteroatom selected from O and S, with the formation of such rings as the ring of the research, thiomorpholine, hexahydro-1,4-oxazepine or tetrahydrothieno.

In the definition of formula I R13and R14together with the nitrogen atom to which they are bound, may form a 4-8-membered saturated heterocyclic ring, such as ring of azetidine, pyrrolidine, piperidine or 1H-azepine. Such rings can optionally contain heteroatom selected from O and S, with the formation of such rings as the ring of the research, thiomorpholine, hexahydro-1,4-oxazepine or tetrahydrothieno.

In the definition of formula I R16and R17together with the nitrogen atom to which they are bound, may form a 4-8-membered saturated heterocyclic ring, such as ring of azetidine, pyrrolidine, piperidine or 1H-azepine. Such rings can optionally contain heteroatom selected from O and S, with the formation of such rings as the ring of the research, thiomorpholine, hexahydro-1,4-oxazepine or tetrahydrothieno.

In the definition of formula I R21and R22together with the nitrogen atom to which they relate, can in order to form a 4-8-membered saturated heterocyclic ring, such as the ring of azetidine, pyrrolidine, piperidine or 1H-azepine. Such rings can optionally contain heteroatom selected from O and S, with the formation of such rings as the ring of the research, thiomorpholine, hexahydro-1,4-oxazepine or tetrahydrothieno.

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

In one embodiment, the invention provides compounds according to formula I

where R is absent;

R1is a (C1-4)alkyl, (C1-4)alkyloxy or CF3;

R2represents H, (C1-4)alkyl, (C1-4)alkyloxy;

R3represents H or (CH2)n-NR5R6;

R4represents H or (C1-6)alkyl, optionally substituted COOR7or NR8R9;

R5and R6independently represent H, (C3-8)cycloalkyl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted with halogen, CF3, (C3-8)cycloalkyl, (C6-10)aryl, 5 - or 6-membered heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, COOR10, CONR11R12or NR13R14; or

R5and R6together with atomo is nitrogen, to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing 1 or more heteroatoms selected from O, S, SO2and NR15and the ring optionally substituted by oxo, (C1-4)alkyl, NR16R17or CONR18R19;

R7represents H or (C1-4)alkyl;

R8and R9are independently H, (C1-4)alkyl or (C3-8)cycloalkyl; or

R8and R9together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

R10represents H or (C1-4)alkyl;

R11and R12are independently H or (C1-4)alkyl; or

R11and R12together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

R13and R14are independently H or (C1-4)alkyl; or

R13and R14together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

R15represents H, phenyl, pyridi is, COR20or CONR21R22;

R16and R17are independently H or (C1-4)alkyl; or

R16and R17together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S;

R18and R19are independently H or (C1-4)alkyl;

R20represents H, (C1-4)alkyl or furyl;

R21and R22are independently H or (C1-4)alkyl; or

R21and R22together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing a heteroatom selected from O and S, and

n is 0 or 1;

with the proviso that one of R3and R4represents H;

or their pharmaceutically acceptable salts.

Preferred in the invention are those compounds according to formula I, in which R1is a CF3. Then, preferred are the compounds of formula I, in which R2is a (C1-4)alkyloxy. Especially preferred are compounds according to the invention, in which R1is a CF3and R2represents ethoxy.

Especially preferred derivatives of 6-FeNi what-1H-imidazo[4,5-c]pyridine-4-carbonitrile according to the invention are

- 6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- [4-cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-c]pyridin-1-yl]acetic acid;

- [4-cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-c]pyridin-1-yl]butyric acid;

- 6-(4-ethoxy-3-triptoreline)-2-(3-oxopiperidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 2-(1,1-dioxothiazolidine-3-ylmethyl)methyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-(4-ethoxy-3-triptoreline)-1-(2-morpholine-4-retil)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-(4-ethoxy-3-triptoreline)-1-(2-piperidine-1-retil)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-(2-dimethylaminoethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-(4-ethoxy-3-triptoreline)-1-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-(3-dimethylaminopropyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-(4-ethoxy-3-triptoreline)-2-(4-methylpiperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile and

- 6-(4-ethoxy-3-triptoreline)-2-[(2-hydroxyethylamino)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-ethyl-2-(pyridine-4-illuminometer)-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-(4-ethoxy-3-triptoreline)-2-[4-(2-hydroxyethyl)-3-oxopiperidin-1-ylmethyl]-1H-imidazo[4,5-c]p is ridin-4-carbonitrile;

- 6-(4-ethoxy-3-triptoreline)-2-(4-Oxymetazoline-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile or its pharmaceutically acceptable salt.

The following aspect of the invention relates to pharmaceutical compositions containing the derivative of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile having the General formula I, or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable auxiliary means.

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I can be obtained as shown in scheme 1, a selective cyanide 4-amino-2,6-dichloro-3-nitropyridine (II) copper cyanide to obtain 4-amino-6-chloro-2-cyano-3-nitropyridine (III). Catalyzed by palladium combination of intermediate compound (III) with arylboronic acids or compounds alloleva, where the aryl group is substituted by R, R1and R2and everyone has the previously specified values, gives as a product of derivatives of 4-amino-2-cyano-3-nitro-6-phenylpyridine formula (IV). The restoration of the nitro group of the intermediate compound (IV) with Fe powder or SnCl2in acidic conditions or catalyzed by the palladium hydrogenation gives the derivative of 2-cyano-3,4-diamino-6-phenylpyridine formula (V) as a product. Treatment of compound (V) triethylorthoformate in the presence as catalyst of the Lewis acid, n is an example of the triflate (triftoratsetata)ytterbium, gives the derivative of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile formula (VI). Further transformation of N1-position of compounds of formula (VI) can be done by direct alkylation in the basic conditions a compound of formula R4X, where R4has the values given above, and where X represents a leaving group such as Br, Cl, OMs, or OTf, or by alkylation under conditions of Mitsunobu compound of formula R4X, where X is a HE.

Scheme 1

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, where R4is a (C1-6)alkyl group, substituted NR8R9can mostly be obtained from the corresponding bromides derivative of the formula VIII (scheme 2), where R, R1and R2have the meanings given above, and where m is 1-5. Direct substitution of the bromide compound (VIII) or a primary or secondary amine in a suitable solvent, such as dimethylsulfoxide, dimethylformamide, methanol or tetrahydrofuran, at a suitable temperature gives compound of General formula (IX) as a product.

Scheme 2

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, where R4is a (C1-6)alkyl group, a substituted functional group is carboxylic acid, can mostly be obtained from the corresponding ester derivative by hydrolysis promoted by lithium hydroxide or sodium hydroxide, as shown in figure 3.

Scheme 3

In an alternative method for introducing an amino group at the 2-position of the 1H-imidazo[4,5-c]pyridine part of the compound having the formula (XII), it is possible to synthesize the path indicated in figure 4. Recovery nitro 4-amino-6-chloro-2-cyano-3-nitropyridine (III) or Fe, or SnCl2in acidic conditions or catalyzed by palladium hydrogenation gives the quality of the product 6-chloro-2-cyano-3,4-diaminopyridine (X). Treatment of compound (X) chloride dihlormetilen-N,N'-R5R6-substituted ammonium, where R5and R6have the meanings given above, in a mixture of chloroform/acetonitrile at boiling point gives the derivative 2-amino-6-chloro-4-cyano-1H-imidazo[4,5-c]pyridine of the formula (XI). Catalyzed by palladium or other transition metal, the combination of the compounds of formula (XI) or with arylboronic acid or arrolovon, where the aryl group is substituted by R, R1and R2with the values stated previously, gives the derivative 2-amino-6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile formula (XII) as the desired product.

Scheme 4

In another method introduction the ia group, R 3in the 2-position of the 1H-imidazo[4,5-c]pyridine part of the compound having the formula (XIII)can be synthesized by condensation of a derivative of 2-cyano-3,4-diamino-6-phenylpyridine formula (V), where R, R1and R2have the meanings given above, with a suitable acid, acylchlorides, orthoformiate or aldehyde under various conditions as shown in scheme 5.

Scheme 5

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, where R3is a (C1-6)alkyl group, substituted NR5R6can mostly be obtained from the corresponding chlorine substituted alkyl derivatives of formula XIII, as shown in scheme 6. Substitution of chloride compounds (XIII) of various primary or secondary amines give the desired product (XIV).

Scheme 6

In another method, compounds of General structure XIV, where n is 3, can mainly be obtained from compound XIII, where n is 1, in the manner indicated in figure 7. The reaction of XIII with triphenylphosphine in a suitable solvent, for example acetonitrile, gives the Wittig reagent XV. The reaction of the Wittig reagent XV with chloroacetaldehyde in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base gives substituted allylchloride XVI in the quality of the product. Substitution of chloride gives is connected to the I XVII and hydrogenation XVII using palladium on coal as a catalyst to give compound XIV, in which n is equal to 3.

Scheme 7

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, where both of R3and R4are not hydrogen, can be obtained according to scheme 8. Alkylation of compound III using alkylated or bromide and potassium carbonate as a base in a suitable solvent, such as acetonitrile or DMF, gives compound XIX in the quality of the product. The combination of the Suzuki reaction of XIX with arylboronic acid with the use of derivatives of palladium as catalyst gives compound XX in the quality of the product. Recovery nitro in NH2connection of the twentieth, using the method described in scheme 1, gives compound XXI. Cyclization using the method described in scheme 5, gives the product XXII and the substitution of the chloride with the amine by the method shown in scheme 6, gives the desired compound XXIII.

Scheme 8

Another way to connect with different values of R, R1and R2General formula I can be obtained synthetically, given in figure 9. Reconnection XIX using the method described in scheme 1, gives compound XXIV. The formation of the imidazole ring by the method of scheme 5 gives compound XXV. The combination according to the method of Suzuki XXV with different arylboronic acids network requirements the product has been created, the described General formula I.

Scheme 9

When obtaining the derivative of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, in which R3or R4contains the nitrogen atom of the primary amino group (either in the form NR5R6or NR7R8), the nitrogen atom must be temporarily protected, for example, labile under the action of acid tert-butyloxycarbonyl (BOC) protecting group. Other suitable protective groups for functional groups that must be temporarily protected during synthesis known in this field, for example, from the publication Wuts, P.G.M. and Greene, T.W.: Protective Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile according to the invention, which may be in free base form, can be isolated from the reaction mixture in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts such as acid additive salts can then be obtained by treatment of 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, meth is Sultonova acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.

Suitable salts of derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile formula I, which contain a carboxylate group may be salts of alkali metals such as sodium, potassium or lithium, or may be a salt derived from a combination with an organic base such as trimethylamine, triethylamine and the like.

Compounds according to the invention may exist in solvated, and resolutiony forms, including hydrated forms. In General, the solvated forms are equivalent nonsolvated forms and it is assumed that they are included in the scope of the present invention. Compounds of the present invention can exist in an amorphous form, but can also be numerous possible crystalline forms. In General, all of the crystalline forms are equivalent for the uses discussed by the present invention, and, as expected, are in the scope of this invention.

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile according to the invention and their salts may contain a center of chirality in one or more side chains of R1, R2, R4-R14, R20-R22and, therefore, can receive the diamonds in the form of a pure enantiomer or as a mixture of enantiomers or as a mixture, containing diastereomers. Methods of asymmetric synthesis, in which the pure stereoisomers are well known in this field, for example the synthesis of chiral induction or synthesis of chiral intermediates, enantioselective enzymatic transformation, separation of stereoisomers or enantiomers using chromatography on chiral environments. Such methods are described, for example, in Chirality in Industry (edited by A.N.Collins, G.N.Sheldrake and J. Crosby, 1992; John Wiley).

Found that the compounds according to the invention are inhibitors of cathepsin S and cathepsin To person and can therefore, in the following aspect of the invention be used in therapy, and particularly for obtaining a medicinal product for the treatment of autoimmune diseases, chronic obstructive lung diseases, pain, osteoporosis, atherosclerosis and related dependent cathepsin S and cathepsin K disorders, such as asthma and IBD.

Compounds according to the invention it is possible to enter interline or parenteral and for people preferably with a daily dose of 0.001-100 mg per 1 kg of body weight, preferably 0.01 to 10 mg per 1 kg of body weight. Mixed with pharmaceutically acceptable auxiliary means, for example, as described in the standard reference, Gennaro et al., Remington''s Pharmaceutical Sciences, (20th ed., Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing), compounds can press the ü in solid dosage forms, such as pills, tablets, or be made into capsules or suppositories. With the help of pharmaceutically acceptable liquids compounds can also be applied 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 in a nasal spray.

To get dosed medicinal forms, such as tablets, it is assumed the use of conventional additives such as fillers, coloring tools, polymer binder, and the like. In General, you can apply any pharmaceutically acceptable additive, which does not impede the functioning of the active compounds.

Suitable carrier materials with which you can enter the composition, include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in the right quantities.

The invention is further illustrated by the following examples.

Ways

General chemical methods

All reagents purchased from standard commercial sources or synthesized according to literature methods using commercial sources. Spectra proton NMR (1H NMR) were obtained on a spectrometer Bruker DPX 400 and counts conducted from the internal standard TMS. Mass spectra were recorded on a Shimadzu LC-8A (HPLC) PE Sciex API 150EX LCMS. Analysentechnik LC-MS reversed-phase was performed on a column LUNA C18 (5 μm; 30×4.6 mm) with a gradient conditions (from a mixture of 90% water/0.1% of formic acid to a mixture of 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 (tea), broadened (OSiR.), the singlet (s), doublet (d), triplet (t), triperoxonane acid (TFA), tert-butyloxycarbonyl (Vos), methanesulfonate (MsO), triftorbyenzola (TfO).

Example 1

6-(4-Ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 4-Bromo-1-ethoxy-3-cryptomaterial

Stir a suspension of 4-bromo-3-triptoreline (117,6 g, 0.49 mol), iodata (77,6 g, 0.49 mol) and potassium carbonate (101,2 g, 0.73 mol) in acetonitrile (600 ml) is refluxed for 2.5 hours. The mixture is concentrated under reduced pressure before distribution between dichloromethane (1 liter) and water (1 liter). The organic phase is collected and dried over magnesium sulfate before concentrating under reduced pressure, thus obtaining 4-bromo-1-ethoxy-3-triptoreline (126,97 g).1H NMR (CDCl3): δ 7,66 (s, 1H), 7,56 (d, 1H), 6,86 (s, 1H), 4.09 to (q, 2H), of 1.44 (t, 3H).

In: 4-Ethoxy-triftormetilfullerenov acid

A solution of 4-bromo-1-ethoxy-3-triptoreline (each holding 21.25 g, the 90.8 mmol) in dry tetrahydrofuran (120 ml) and purge with nitrogen, cooled to -78°C and added dropwise BuLi (2.5 M solution in hexano, 39,96 ml of 99.9 mmol), keeping the temperature below -70°C. the Mixture is stirred for 5 minutes before adding triisopropylsilane (17.9 g, 95,36 mmol) in one portion. Stirring is continued at -78°C for 30 min before providing a mixture of opportunities to warm to room temperature. The reaction mixture was quenched by adding 10 ml of acetic acid, dissolved in 150 ml of water, before concentrating under reduced pressure to remove tetrahydrofuran. The precipitate is collected by filtration, dissolved in ethyl acetate and dried over sodium sulfate. Cleaning reach by recrystallization from mixtures of ethyl acetate/hexane, thus obtaining 4-ethoxy-3-triftormetilfullerenov acid (10 g).1H NMR (DMSO-d6): δ 8,08 (s, 1H), 8,01 (d, 1H), 7,2 (d, 1H), 4,18 (kV, 2H), of 1.34 (t, 3H).

C: 4-Amino-6-chloro-3-nitropyridine-2-carbonitrile

Stir a suspension of 4-amino-1,6-dichloro-3-nitropyridine (17.5 g, 84,1 mmol) and copper cyanide(I) (15,1 g, 168,3 mmol) in 170 ml of 1-methyl-2-pyrrolidinone immersed in an oil bath, preheated to 180°C, and stirring is continued for 30 minutes the Mixture allow to cool and diluted with ethyl acetate (700 ml) and water (700 ml) and education is suusa the suspension is filtered. The organic layer was separated and further washed with water (500 ml) and 0.1 G. of HCl (500 ml). The organic layer is then dried over sodium sulfate, filtered and concentrated under reduced pressure, thus obtaining a brown solid, which was washed with diethyl ether and dichloromethane, while receiving 4-amino-6-chloro-3-nitropyridine-2-carbonitrile (8 g).1H NMR (DMSO): δ 8,8-7,7 (users, 2H), 7,18 (s, 1H).

D: 4-Amino-6-(4-ethoxy-3-triptoreline)-3-nitropyridine-2-carbonitrile

Stir a mixture of 4-amino-6-chloro-3-nitropyridine-2-carbonitrile (1 g, 5,04 mmol), 4-ethoxy-3-triftormetilfullerenov acid (1,33 g, 6,04 mmol), tetrakis(triphenylphosphine)palladium(0) (~500 mg, 10 mol.%), potassium carbonate (2,09 g, 15,12 mmol) and THF (10 ml) Tegaserod (free air) in a stream of nitrogen prior to heating in a microwave device Smith at 150°C for 10 min Crude mixture was concentrated under reduced pressure to remove THF before distribution between ethyl acetate and water. The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining a dark brown oil. Rubbing it with diethyl ether to give a light brown solid, which was filtered and dried in the air stream, while receiving 4-amino-6-(4-ethoxy-3-triptoreline)-3-nitropyridine-2-carbonitrile (900 mg).1H NMR (DMSO): δ 8,25 to 8.1 (m,3H), 7,63 (s, 1H), 7,44 (d, 2H), 4,27 (kV, 2H), to 1.38 (t, 3H).

E: 3,4-Diamino-6-(4-ethoxy-3-triptoreline)pyridine-2-carbonitrile

Into a flask containing 4-amino-6-(4-ethoxy-3-triptoreline)-3-nitropyridine-2-carbonitrile (5 g, of 14.2 mmol) and 10% Pd-C (wet) (5 g), under nitrogen atmosphere add ethyl acetate (500 ml). The vessel is rinsed with hydrogen and its contents stirred at room temperature for 1.5 h before being filtered through a layer of celite, followed by concentration under reduced pressure, thus obtaining 3,4-diamino-6-(4-ethoxy-3-triptoreline)pyridine-2-carbonitrile (2.5 g).1H NMR (DMSO): δ 8,02 (m, 2H), 7,31 (d, 1H), 7,14 (s, 1H), 6,1 (users, 2H), 5,69 (users, 2H), 4,25 (kV, 2H), of 1.35 (t, 3H). MS m/z 323,3 (M+1).

F: 6-(4-Ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Stir a suspension of 3,4-diamino-6-(4-ethoxy-3-triptoreline)pyridine-2-carbonitrile (4.4 g, 13.7 mmol)and ytterbium triflate (173 mg, 2 mol.%), triethylorthoformate (between 6.08 g, 41,1 mmol) and acetonitrile (50 ml) is refluxed for 30 minutes the Solid precipitate is collected by filtration and washed with a small amount of acetonitrile, thus obtaining 6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (2.6 g).1H NMR (DMSO): δ 8,67 (s, 1H), of 8.47 (s, 1H), at 8.36 (m, 2H), 7,49 (d, 1H), 4.26 deaths (kV, 2H), to 1.38 (t, 3H). MS m/z to 333.3 (M+1).

Example 2

Methyl ester [4-cyano-6-(4-ethoxy-3-triptoreline)is dazo[4,5-c]pyridin-1-yl]acetic acid

To a solution of 6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (example 1; 200 mg, 0.6 mmol) and methylpropanoate (276,2 mg, is 1.81 mmol) in dimethylformamide (4 ml) is added cesium carbonate (325,5 mg, is 1.81 mmol) and the mixture is stirred at room temperature for 30 minutes. The mixture is concentrated under reduced pressure to remove dimethylformamide before distribution between ethyl acetate (200 ml) and water (200 ml). The organic layer is collected and dried over sodium sulfate before purification on a column of 10 g of silica and elution with diethyl ether. The product is then washed with a small amount of diethyl ether and dried in the air stream, while receiving methyl ester [4-cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-c]pyridin-1-yl]acetic acid (110 mg).1H NMR (DMSO): δ 8,76 (s, 1H), 8,64 (s, 1H), 8,39 (d, 1H), at 8.36 (s, 1H), 7,44 (s, 1H), 5,44 (s, 2H), 4,27 (kV, 2H, in), 3.75 (s, 3H), of 1.38 (t, 3H). MS m/z 405,7 (M+1).

Example 3

[4-Cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-c]pyridin-1-yl]acetic acid

To a solution of methyl ester [4-cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-c]pyridin-1-yl]acetic acid (110 mg, 0.27 mmol) in a mixture of 1:1 dimethylformamide (2 ml) and water (2 ml) is added lithium hydroxide (19 mg, 0.81 mmol), dissolved in 200 μl of water. To improve the dissolution add an additional 2 ml dimethylformamid is Yes. The mixture is stirred at room temperature for 30 min before acidification to pH 12 N. HCl solution and filtered. The obtained solid is washed with ether before dissolving in acetone and concentrated under reduced pressure to remove residual organic solvents and obtain [4-cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-c]pyridin-1-yl]acetic acid (100 mg).1H NMR (DMSO): δ 8,76 (s, 1H), 8,64 (s, 1H), of 8.37 (m, 3H), 7,43 (d, 1H), 5,31 (s, 2H), 4,27 (kV, 2H), to 1.38 (t, 3H); MS m/z 391,7 (M+1).

Example 4

[4-Cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-c]pyridin-1-yl]butyric acid

This compound is obtained from 6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (example 1) using methyl-4-bromobutyrate instead of methylpropanoate and using the methods described in examples 2 and 3.1H NMR (DMSO): δ 8,69 (m, 2H), 8,43 is 8.38 (m, 2H), 7,42 (d, 1H), of 4.44 (t, 2H), 4,27 (kV, 2H), to 2.29 (t, 2H), 2,11 (m, 2H), to 1.38 (t, 3H). MS m/z 419,5 (M+1).

Example 5A

6-(4-Ethoxy-3-triptoreline)-2-(isobutylamino)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 2-Chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

To a solution of 3,4-diamino-6-(4-ethoxy-3-triptoreline)pyridine-2-carbonitrile (1.86 g, 5,78 mmol) and 2-chloro-1,1,1-triethoxysilane (3,41 g, 17.3 mmol) in acetonitrile (40 ml) add triplet is terbia (180 mg, 5 mol.%) and the mixture is refluxed over night. The mixture is concentrated under reduced pressure before distribution between ethyl acetate and water. The organic layer is dried over sodium sulfate and concentrated before adding diethyl ether. The precipitate is filtered and dried in the air stream, while receiving 6-(4-ethoxy-3-triptoreline)-2-(chloromethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.2 g).1H NMR (DMSO): δ 8,42 (s, 1H), scored 8.38 (d, 1H), 8.34 per (s, 1H), 7,40 (d, 1H), of 5.05 (s, 2H), 4.26 deaths (kV, 2H), to 1.38 (t, 3H). MS m/z 381,1 (M+1).

B: 6-(4-Ethoxy-3-triptoreline)-2-(isobutylamino)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of 2-chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0.06 mmol) and isobutylamine (21 mg, 0.3 mmol) in dimethylsulfoxide (500 ml) is heated in a microwave device Creator at 120°C for 5 minutes the Mixture is filtered and purified preparative HPLC, while receiving 6-(4-ethoxy-3-triptoreline)-2-(isobutylamino)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (11.6 mg).1H NMR (MeOD) δ 8,31 (s, 1H), 8,28 compared to 8.26 (m, 2H), 7,28 (d, 1H), of 4.45 (s, 2H), 4,23 (kV, 2H), 3,13 (d, 2H), 2,16 (m, 1H), 1,45 (t, 3H), of 1.11 (d, 6H). MS m/z 418,6 (M+1).

To obtain the following compounds further apply the method described in example 5B, using suitable derivatives of amines.

5b: 6-(4-Ethoxy-3-triptoreline)-2-[(2-phenoxyethylamine)-1H-imidazo[4,5-Spiridon-4-carbonitril

1H NMR (MeOD) δ 8,3-of 8.25 (m, 3H), 7,32-7,26 (m, 3H), 7.03 is-of 6.96 (m, 3H), 4,78 (s, 2H), 4,39 (t, 2H), 4,23 (kV, 2H), 3,76 (t, 2H), 1,45 (t, 3H). MS m/z 482,4 (M+1).

5c: 2-(3-Acetamidobenzoic-1-ylmethyl)-6-(4-ethoxy-3-triptoreline))-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,29-8,24 (m, 3H), 7,27 (d, 2H), 4.92 in (s, 2H), 4,51 (m, 1H), 4,23 (kV, 2H), 3.96 points-of 3.85 (m, 2H), 3.75 to 3,61 (m, 2H), 2,54 (m, 1H), 2,19 (m, 1H), 1,99 (s, 3H), of 1.46 (t, 3H). MS m/z 473,3 (M+1).

5d: 6-(4-Ethoxy-3-triptoreline)-2-(3-oxopiperidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ at 8.36-8,31 (m, 3H), 7,81 (s, NH), 7,39 (d, 1H), 4.26 deaths (kV, 2H), 3,98 (s, 2H), 3,21 is 3.15 (m, 4H), by 2.73 (m, 2H), to 1.38 (t, 3H). MS m/z 445,5 (M+1).

5e: 6-(4-Ethoxy-3-triptoreline)-2-{[2-(2-Oxymetazoline-1-yl)ethylamino]methyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,29-8,24 (m, 3H), 7,27 (d, 1 H), to 4.73 (s, 2H), 4,22 (kV, 2H), 3,64-3,47 (m, 8H), of 1.45 (t, 3H). MS m/z 474,3 (M+1).

5f: 6-(4-Ethoxy-3-triptoreline)-2-[(N,N-dimethylcarbamoyl)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 compared to 8.26 (m, 3H), 7,28 (d, 1H), 4.72 in (s, 2H), 4,35 (s, 2H), 4.26 deaths (kV, 2H), 3,05 (s, 3H), 3,03 (s, 3H), of 1.46 (t, 3H). MS m/z 447,3 (M+1).

5g: 2-(1,1-Dioxothiazolidine-3-ylmethyl)methyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,30 is 8.22 (m, 3H), 7,28 (d, 1H), of 4.54 (s, 2H), 4,23 (kV, 2H), 4,22 (m, 1H), 4,13 (m, 1H), of 3.56 (m, 1H), 3,40 (m, 1H), 3,24 (m, 2H), 2,17 (m, 1H), 2,33 (m, 1H), 1,45 (t, 3H). MS m/z 480,0 (M+1).

5h: 6-(4-Ethoxy-3-triptoreline)-2-[(4-N,N-dimethylcarbamoyl-1-yl)methyl]-N-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,29 compared to 8.26 (m, 3H), 7,26 (d, 1H), 4.72 in (s, 2H), 4,23 (kV, 2H), 3,56-of 3.48 (m, 8H), 2,90 (s, 6H), of 1.46 (t, 3H). MS m/z 502,3.

5i: 2-(3-Dimethylimidazolidin-1-ylmethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ scored 8.38-8.34 per (m, 3H), 7,331 (d, 1H), 5,16 (m, 1H), 5,08 (s, 1H), to 4.81 (s, 2H), 4,77 (m, 1H), 4,49 (m, 1H), 4,25 (kV, 2H), 3,47 (s, 3H), 3,42 (s, 1H), and 3.31 (s, 3H), 1,46 (kV, 3H). MS m/z 445,5 (M+1).

5j: 6-(4-Ethoxy-3-triptoreline)-2-{[(5-methylisoxazol-3-ylmethyl)amino]methyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8.30 to-8,24 (m, 3H), 7,25 (d, 1H), 6,33 (s, 1H), 4,74 (s, 2H), 4,56 (s, 2H), 4,22 (kV, 2H), 2,46 (s, 3H), of 1.45 (t, 3H). MS m/z 457,8 (M+1).

5k: 2-Aminomethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5,c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 compared to 8.26 (m, 3H), 7,29 (d, 1H), of 4.54 (s, 2H), 4,23 (kV, 2H), 1,45 (t, 3H). MS m/z 362,6 (M+1).

5l: 6-(4-Ethoxy-3-triptoreline)-2-methylaminomethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 compared to 8.26 (m, 3H), 7,26 (d, 1H), with 4.64 (s, 2H), 4,23 (kV, 2H), 2.95 and (s, 3H), of 1.45 (t, 3H). MS m/z USD 376.6 (M+1).

5m: 2-Dimethylaminomethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 is 8.25 (m, 3H), 7,28 (d, 2H), 4,23 (kV, 2H), 3,14 (s, 6H), of 1.46 (t, 3H). MS m/z 390,6 (M+1).

5n: (4 Ethoxy-3-triptoreline)-2-[(4-carbamoylbiphenyl-1-yl)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,29-8,24 (m, 3H), 7,25 (d, 1H), amounts to 4.76 (s, 2H), 4,22 (kV, 2H), 3,84-3,81 (m, 2H), 3,35-3,30 (m, 2H), 2,64 (m, 1H), 2,16-2,07 (m, 4H), of 1.45 (t, 3H). MS m/z 473,3 (M+1).

5o: 2-[(N-is Lil-N-methylamino)methyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,30 is 8.25 (m, 3H), 7,27 (d, 2H), between 6.08 (m, 1H), 5,69 (m, 2H), 4,79 (s, 2H), 4,23 (kV, 2H), of 4.05 (d, 2H), to 3.09 (s, 3H), 1,46 (kV, 3H). MS m/z 416,8 (M+1).

5p: 2-(4-Acetylpiperidine-1-ylmethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,28-8,23 (m, 3H), 7,26 (s, 1H)and 4.65 (s, 2H), 4,23 (kV, 2H), 3,88 (m, 4H), 3,44-3,30 (m, 4H), of 2.16 (s, 3H), of 1.46 (t, 3H). MS m/z 473,3 (M+1).

5q: 6-(4-Ethoxy-3-trifluoromethyl)phenyl)-2-[(4-ethoxycarbonylmethyl-1-yl)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ compared to 8.26-to 8.20 (m, 3H), 7,25 (d, 1H), to 4.52 (s, 2H), 4,24-4,13 (m, 4H), of 3.75 (m, 4H), 3,23 (m, 4H), of 1.45 (t, 3H), of 1.26 (t, 3H). MS m/z 503,0 (M+1).

5r: 6-(4-Ethoxy-3-triptoreline)-2-{[3-(2-oxopyrrolidin-1-yl)propylamino]methyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 is 8.25 (m, 3H), 7,27 (d, 1H), 4,67 (s, 2H), 4,23 (kV, 2H), 3,53 (t, 2H), 3.46 in (t, 2H), 3,29 (m, 2H), 2,42 (t, 2H), 2,13-2,03 (m, 4H), of 1.45 (t, 3H). MS m/z 487,5 (M+1).

5s: 6-(4-Ethoxy-3-triptoreline)-2-(4-pyrrolidin-1-reparacin-1-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31-8,23 (m, 3H), 7,29 (d, 1H), 4,35 (s, 2H), 4,24 (kV, 2H), 3,68 is-3.45 (m, 6H), 3,21-3,10 (m, 2H), 2,86-of 2.81 (m, 2H), 2,39-1,90 (m, 7H), of 1.45 (t, 3H). MS m/z 499,4 (M+1).

5t: 6-(4-Ethoxy-3-triptoreline)-2-[4-(furan-2-ylcarbonyl)piperazine-1-ylmethyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ compared to 8.26 (s, 1H), 8,23 (d, 1H), 8,18 (s, 1H), 7,68 (s, 1H), 7,24 (d, 1H), to 7.09 (m, 1H), 6,59 (m, 1H), 4,4 (s, 2H), is 4.21 (q, 2H), Android 4.04 (m, 4H), 3,18 (m, 4H), of 1.45 (t, 3H). MS m/z 525,7 (M+1).

5u: 6-(4-Ethoxy-3-triptoreline)-2-[(2-methoxyethylamine is)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,32 compared to 8.26 (m, 3H), 7,29 (d, 1H), 4,69 (s, 2H), 4,24 (kV, 2H), of 3.77 (m, 2H), 3,53 (m, 2H), 3.46 in (s, 3H), of 1.46 (t, 3H). MS m/z 420,3 (M+1).

5v: 2-(2,6-Dimethylpiperidin-1-ylmethyl)-6-(4-ethoxy-3-triptoreline)]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 compared to 8.26 (m, 3H), 7,28 (d, 1H), 4,9-4,6 (m, 2H), 4,23 (kV, 2H), 3,89-3,71 (m, 2H), 2,07-to 1.63 (m, 6H), 1,61-of 1.32 (m, 9H). MS m/z 459,0 (M+1,5).

5w: 6-(4-Ethoxy-3-triptoreline)-2-{[(furan-2-ylmethyl)amino]methyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,30 is 8.25 (m, 3H), 7,66 (s, 1H), 7,27 (d, 1H), 6,7 (m, 1H), of 6.52 (m, 1H), to 4.62 (s, 2H), 4,56 (s, 2H), 4,23 (kV, 2H), 1,45 (t, 3H). MS m/z 442,5 (M+1).

5x: 2-[(Cyclopropylamino)methyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 compared to 8.26 (m, 3H), 7,28 (d, 1H), and 4.68 (s, 2H), 3,17 (d, 2H), 1,45 (t, 3H), 1,21 (m, 1H), 0,77 (m, 2H), 0,48 (m, 2H). MS m/z 416,5 (M+1).

Example 6A

2-[(1-Azabicyclo[2.2.2]Oct-3-ylamino)methyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of 2-chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0.06 mmol), dihydrochloride 3-aminoquinuclidine (22.9 mg, 0.12 mmol) and triethylamine (18.2 mg, 0.18 mmol) in dimethylsulfoxide (500 ml) is heated in a microwave device Creator at 120°C for 5 minutes the Mixture is filtered and purified preparative HPLC, thus obtaining 2-[(1-azabicyclo[2.2.2]Oct-3-ylamino)methyl]-6-(4-ethoxy-3-triptoreline)-1 is imidazo[4,5-c]pyridine-4-carbonitrile (14,8 mg). 1H NMR (MeOD) δ 8.34 per-of 8.27 (m, 3H), 7,29 (d, 2H), 4.95 points (s, 2H), 4,29-is 4.21 (m, 3H), 4.00 points (m, 1H), 3,86 at 3.69 (m, 5H), 2,46 (m, 1H), 2,27 is 2.10 (m, 4H), of 1.45 (t, 3H). MS m/z and 471.8 (M+1).

To obtain the following compounds further apply the method described in example 6, using suitable derivatives of amines:

6b: 6-(4-Ethoxy-3-triptoreline)-2-{[(thiazole-2-ylmethyl)amino]methyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31-of 8.27 (m, 3H), 7,92 (d, 1H), of 7.75 (d, 1H), 7,28 (d, 1H), 4,89 (s, 2H), 4,23 (kV, 2H), 1,46 (t, 3H). MS m/z 459,6 (M+1).

6c: 6-(4-Ethoxy-3-triptoreline)-2-(carbamoylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,31 is 8.25 (m, 3H), 7,28 (d, 1H), 4,18 (users, 2H), 4,23 (kV, 2H), 4,07 (users, 2H), 1,45 (t, 3H). MS m/z 419,4 (M+1).

6d: 6-(4-Ethoxy-3-triptoreline)-2-(pyridine-4-illuminometer)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ 8,28 is 8.22 (m, 5H), 7,27 (d, 1H), 6,93 (m, 2H), of 5.75 (s, 2H), 4,23 (kV, 2H), 1,45 (t, 3H). MS m/z 439,5 (M+1).

Example 7

A: 6-Chloro-2-dimethylamino-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Iron powder (8.5 g) is added in small portions to a solution of 4-amino-6-chloro-2-cyano-3-nitropyridine in the Meon (90 ml) and concentrated hydrochloric acid (30 ml) for 20 minutes the Mixture is refluxed for a further 30 minutes After cooling the reaction mixture are mainly concentrated aqueous ammonia to pH 10. The mixture extragere is by ethyl acetate (200 ml × 5), the combined organic layer was washed with saturated salt solution, dried over sodium sulfate, the solvent is removed under vacuum, thus obtaining the crude product (4 g), which is used for the next stage without additional purification. The above crude product (0.33 g) is added to the chloroform (5 ml) and acetonitrile (20 ml) followed by the addition of chloride of dichlorodimethylsilane (0.33 g). The mixture is refluxed for 4 hours. After cooling, the solid product 6-chloro-2-dimethylamino-1H-imidazo[4,5-c]pyridine-4-carbonitrile, is collected by filtration.1H NMR (MeOD) δ to 7.61 (s, 1H), 3,37 (s, 3H), 3,30 (s, 3H).

In: 2-Dimethylamino-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A suspension of 6-chloro-2-dimethylamino-1H-imidazo[4,5-c]pyridine-4-carbonitrile (100 mg, 0.45 mmol), 4-ethoxy-3-triftormetilfullerenov acid (198 mg, 0.88 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, ~10 mol.%) and potassium carbonate (193,0 mg of 1.39 mmol) in THF (3 ml) is heated to 130°C for 6 min in a microwave device Smith. The crude mixture was concentrated under reduced pressure to remove THF before distribution between ethyl acetate and water. The organic layer is separated, dried over sodium sulfate and concentrate under reduced pressure. The substance is then dissolved in DMSO and purified in the form of an aliquot of preparative HPLC. Need is racchi collect and concentrate, while receiving white solid, which was washed with simple ether, thus obtaining 2-dimethylamino-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (5.0 mg).1H NMR (DMSO) δ 8,24 (m, 2H), to 7.84 (s, 1H), 7,35 (d, 1H), 4,24 (kV, 2H), 3,19 (s, 6H), to 1.37 (t, 3H). MS m/z 376,7 (M+1).

Example 8

A: 4-Amino-6-(4-methoxy-3-triptoreline)-3-nitropyridine-2-carbonitrile

Stir a mixture of 4-amino-6-chloro-3-nitropyridine-2-carbonitrile (152 mg, from 0.76 mmol), 4-methoxy-3-triftormetilfullerenov acid (332 mg and 1.51 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 10 mol.%), potassium carbonate (418 mg, 3.03 mmol) and THF (5 ml) Tegaserod in a stream of nitrogen prior to heating in a microwave device, Smith Creator at 150°C for 10 min Crude mixture was concentrated under reduced pressure to remove THF before distribution between ethyl acetate (20 ml) and water (20 ml). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining a dark brown oil. The mixture is flash chromatographic on the silicon dioxide (cartridge Combiflash 10 g of a mixture of 7:3 heptane/ethyl acetate to a mixture of 1:1 heptane/ethyl acetate)to give 68 mg of 4-amino-6-(4-methoxy-3-triptoreline)-3-nitropyridine-2-carbonitrile as an orange solid.1H NMR (DMSO) δ of 8.25 (d, 1H), 8,18 (m, 2H), 7.62mm (s, 2H), 7,46 (d, 1H), 3,99 (s, H). MS m/z 339,3 (M+1).

In: 3,4-Diamino-6-(4-methoxy-3-triptoreline)pyridine-2-carbonitrile

4-Amino-6-(4-methoxy-3-triptoreline)-3-nitropyridine-2-carbonitrile (65 mg, 0,19 mmol) suspended in methanol (1.5 ml) and added dropwise concentrated HCl (0.5 ml) (exothermic effect). The suspension is stirred while adding portions of iron powder (37 mg, 0.67 mmol) (exothermic effect) and the mixture refluxed for 1 hour. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). The organic layers are dried and evaporated, then flash chromatographic on the silicon dioxide (cartridge Combiflash 4 g, a mixture of 7:3 heptane/ethyl acetate), to thereby obtain 29 mg of 3,4-diamino-6-(4-methoxy-3-triptoreline)pyridine-2-carbonitrile in the form of a pale brown solid.1H NMR (DMSO) δ 8,08 shed 8.01 (m, 2H), 7,05-7,00 (m, 2H), of 3.94 (s, 3H). MS m/z 309,7 (M+1).

From: 6-(4-Methoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

3,4-Diamino-6-(4-methoxy-3-triptoreline)pyridine-2-carbonitrile (20 mg, 0,065 mmol) suspended in toluene (1 ml)in one portion add triethylorthoformate (12 mg, 0,078 mmol) and the mixture is refluxed over night. The mixture was purified preparative LC-MS, while receiving 7 mg of 6-(4-methoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a white solid.1H NMR (DMSO) is 8,68 (s, 1H), 8,45-8,35 (m, 2H), 8,31 (s, 1H), 7,40 (d, 1H), 3,98 (s, 3H). MS m/z 319,1 (M+1).

Example 9a

6-(4-Ethoxy-3-triptoreline)-1-(2-morpholine-4-retil)-1H-imidazo[4,5-C]pyridine-4-carbonitrile

A: 1-(2-Bromacil)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-(4-Ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (300 mg, 0.90 mmol) dissolved in THF (10 ml), add 2-bromoethanol (225 mg, of 1.80 mmol) followed by the addition of betaine (738 mg, of 1.80 mmol) and the mixture is stirred at room temperature for 3 hours. Add additional 0.5 equivalent of betaine (0.45 mmol, 162 mg) and the mixture is stirred at room temperature for an additional hour. The mixture is distributed between ethyl acetate (20 ml) and water (20 ml). The organic layer is dried and evaporated, then flash chromatographic on the silicon dioxide (cartridge Combiflash 10 g, DCM to 1% methanol in DCM), while receiving white solid which is a mixture of N-1 and N-3-alkyl products. The mixture is flash chromatographic on the silicon dioxide (cartridge Flashmaster 10 g of toluene to 20% ethyl acetate in toluene), while receiving 130 mg of 1-(2-bromacil)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a white solid.1H NMR (DMSO) δ 8,80 (s, 1H), total of 8.74 (s, 1H), 8,48-8,39 (m, 2H), 7,44 (d, 1H), 4,88 (t, 2H), 4,29 (kV, 2H), of 4.05 (t, 2H), 1,40 (t, 3H).

In: 6-(ethoxy-3-triptoreline)-1-(2-morpholine-4-retil)-1H-imidazo[4,5-C]pyridine-4-carbonitrile

1-(2-Bromacil)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (92 mg, 0.21 mmol) dissolved in DMF (2 ml) and added morpholine (91 mg, 1.05 mmol). The mixture is heated to 120°C for 5 min in a microwave device Smith. The mixture is diluted with methanol (5 ml) and passed through a SCX cartridge 5 g, then elute with 2 M ammonia in ethanol, while receiving 62 mg 6-(4-ethoxy-3-triptoreline)-1-(2-morpholine-4-retil)-1H-imidazo[4,5-C]pyridine-4-carbonitrile in the form of a clear oil.1H NMR (CDCl3) δ compared to 8.26-of 8.15 (m, 3H), 7,87 (s, 1H), was 7.08 (d, 1H), 4,35 (t, 2H), 4,20 (kV, 2H), 3,69 (m, 4H), 2,82 (t, 2H), 2,52 (m, 4H), to 1.48 (t, 3H). MS m/z KZT 446.4 (M+1).

To obtain the following compounds were then applied the methodology described in example 9, using suitable derivatives of amines.

9b: 1-[2-(Cyclopropylamino)ethyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ 8,23 (m, 2H), 8,18 (s, 1H), 7,92 (s, 1H), 7,11 (d, 1H), 4,35 (t, 2H), 4,20 (kV, 2H), 3,14 (t, 2H), 2,50 (d, 2H), 1,48 (t, 3H), 0.88 to (m, 1H), 0,48 (m, 2H), and 0.08 (m, 2H). MS m/z 430,5 (M+1).

9c: 6-(4-Ethoxy-3-triptoreline)-1-(2-ethylaminomethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ 8,29-8,18 (m, 3H), 7,92 (s, 1H), 7,12 (d, 1H), 4,35 (t, 2H), 4,20 (kV, 2H), 3,12 (t, 2H), to 2.67 (q, 2H), 1,49 (t, 3H), of 1.08 (t, 3H). MS m/z 404,7 (M+1).

9d: 6-(4-Ethoxy-3-triptoreline)-1-(2-piperidine-1-retil)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ 8,28 is 8.22(m, 2H), 8,19 (s, 1H), 7,92 (s, 1H), 7,12 (d, 1H), 4,32 (t, 2H), 4,22 (kV, 2H), 2,74 (t, 2H), 2,45 (m, 4H), 1,59 was 1.43 (m, 9H). MS m/z 444,5 (M+1).

9e: Salt triperoxonane acid 6-(4-ethoxy-3-triptoreline)-1-(2-pyrrolidin-1-retil)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ to 8.57 (s, 1H), 8,51 (s, 1H), 8,39 (m, 2H), 7,30 (d, 1H), 4,88 (m, 2H), 4,24 (kV, 2H), 3,86 (t, 2H), 3,79-to 3.58 (m, 2H), 3,24 (m, 2H), 2,35-of 1.95 (m, 4H), of 1.46 (t, 3H). MS m/z 430,5 (M+1).

9f: 1-(2-Dimethylaminoethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ compared to 8.26-8,23 (m, 2H), 8,18 (s, 1H), 7,88 (s, 1H), 7,11 (d, 1H), or 4.31 (t, 2H), is 4.21 (q, 2H), 2,75 (t, 2H), 2,31 (s, 6H), for 1.49 (t, 3H). MS m/z 404,7 (M+1).

9g: 1-[2-(2-Diethylaminoethylamine)ethyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,97 (m, 1H), 8,78 (m, 1H), 8,43 (m, 2H), 7,29 (d, 1H), 4,99 (m, 2H), 4,23 (kV, 2H), 3,79 (m, 2H), 3,60 (m, 4H), 2,96 (s, 6H), of 1.45 (t, 3H). MS m/z 447,4 (M+1).

Example 10A

6-(4-Ethoxy-3-triptoreline)-1-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 1-(3-Bromopropyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-(4-Ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (500 mg and 1.51 mmol) dissolved in THF (20 ml), add 3-bromopropane (396 mg, 3.0 mmol) followed by the addition of betaine (1,23 g, 2.0 mmol) and the mixture is stirred at room temperature for 2 hours. Add an additional 0.5 equivale is the betaine (0.45 mmol, 162 mg) and the mixture is stirred at room temperature for an additional 16 hours. The mixture is distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer is dried and evaporated, then flash chromatographic on the silicon dioxide (cartridge Combiflash 40 g of toluene to 40% ethyl acetate in toluene), while receiving 520 mg of a white solid. The mixture is triturated with ether, then the resulting solid is washed with ether (20 ml), while receiving 310 mg of 1-(3-bromopropyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a white solid.1H NMR (DMSO) δ 8,30 is 8.22 (m, 2H), 8,18 (s, 1H), 7,98 (s, 1H), 7,13 (d, 1H), 4,56 (t, 2H), 4,23 (kV, 2H), 3,48 (t, 2H), 2,48 (m, 2H), 1,50 (t, 3H).

In: 6-(4-Ethoxy-3-triptoreline)-1-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1-(3-Bromopropyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile dissolved in DMF (0.5 ml) and added morpholine (19 mg, 0.22 mmol). The mixture is heated to 120°C. in a microwave device, Smith Creator. The mixture is diluted with methanol and passed through a SCX cartridge, then elute with 2 M ammonia in methanol. The mixture is then purified preparative HPLC and the acetonitrile removed under reduced pressure. The resulting aqueous solution do the main sodium bicarbonate, extracted with DCM (5 ml), then the organic layers are dried and evaporated, thus obtaining 6-(4-ethoxy-3-three is timeteller)-1-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a white solid (8 mg). 1H NMR (CDCl3) δ of 8.25 (d, 1H), 8,18 (s, 1H), 8,14 (s, 1H), 7,89 (s, 1H), 7,11 (d, 1H), 4,42 (t, 2H), is 4.21 (q, 2H), 3,71 (m, 4H), is 2.37 (m, 4H), and 2.26 (t, 2H), 2,08 (m, 2H), 1,49 (t, 3H). MS m/z 460,6 (M+1).

To obtain the following compounds were then applied the methodology described in example 10, using suitable derivatives of amines.

10b: 6-(4-Ethoxy-3-triptoreline)-1-(3-ethylaminomethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ of 8.27 (d, 1H), to 8.20 (s, 1H), 8,14 (s, 1H), of 7.97 (s, 1H), 7,12 (d, 1H), 4,45 (t, 2H), is 4.21 (q, 2H), 2,61 (m, 4H), to 2.06 (m, 2H), 1,50 (t, 3H), 1,10 (t, 3H). MS m/z 404,7 (M+1).

10c: 1-[3-(Cyclopropylamino)propyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ of 8.27 (d, 1H), to 8.20 (s, 1H), 8,15 (s, 1H), of 7.97 (s, 1H), 7,13 (d, 1H), 4,46 (t, 2H), is 4.21 (q, 2H), 2,61 (t, 2H), 2,42 (d, 2H), 2,07 (m, 2H), 1,49 (t, 3H), of 0.91 (m, 1H), 0,48 (m, 2H), 0,10 (m, 2H). MS m/z 444,8 (M+1).

10d: 6-(4-Ethoxy-3-triptoreline)-1-(3-piperidine-1-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ compared to 8.26 (d, 1H), to 8.20 (s, 1H), 8,15 (s, 1H), 7,92 (s, 1H), 7,12 (d, 1H), and 4.40 (t, 2H), is 4.21 (q, 2H), 2,37 was 2.25 (m, 4H), of 2.20 (t, 2H), 2.05 is (m, 2H), 1,67-of 1.40 (m, 9H). MS m/z 459,0 (M+1).

10e: 6-(4-Ethoxy-3-triptoreline)-1-(3-pyrrolidin-1-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ at 8.36 (d, 1H), to 8.20 (s, 1H), 8,13 (s, 1H), of 7.97 (s, 1H), 7,12 (d, 1H), 4,43 (t, 2H), is 4.21 (q, 2H), 2,45 (m, 4H), of 2.38 (t, 2H), 2,08 (m, 2H), 1,80 (m, 4H), for 1.49 (t, 3H). MS m/z 444,8 (M+1).

10f: 1-(3-Dimethylaminopropyl)-6-(4-ethoxy-3-triptoreline)-1H-what imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ 8,29 (d, 1H), 8,21 (s, 1H), 8,14 (s, 1H), of 7.97 (s, 1H), 7,12 (d, 1H), to 4.41 (t, 2H), 4,32 (kV, 2H), 2.26 and-of 2.16 (m, 8H), was 2.05 (m, 2H), 1,49 (t, 3H). MS m/z 418,6 (M+1).

10g: 1-(3-tert-Butylaminoethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile; connection in the form of a salt triperoxonane acid

1H NMR (MeOH) δ 8,53 (s, 1H), 8,43 (s, 1H), at 8.36 (m, 2H), 7,30 (d, 1H), 4,57 (t, 2H), 4.26 deaths (kV, 2H), 3,11 (m, 2H), 2,30 (m, 2H), 1,48 (t, 3H), of 1.37 (s, 9H). MS m/z KZT 446.4 (M+1).

Example 11a

6-(4-Ethoxy-3-triptoreline)-2-(4-methylpiperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 2-Chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

3,4-Diamino-6-(4-ethoxy-3-triptoreline)pyridine-2-carbonitrile (1 g, 3.1 mmol) dissolved in acetonitrile (20 ml) and add triplet ytterbium (38 mg, holding 0.062 mmol) and 2-chloro-1,1,1-triethoxide (1,83 g, 9.3 mmol). The mixture is refluxed over night. The mixture is evaporated under reduced pressure, distributed between ethyl acetate (100 ml) and water (100 ml) and the organic layer is dried, then evaporated under reduced pressure, thus obtaining a dark brown oil. Rubbing it with DCM (50 ml) to give 495 mg of 2-chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a light brown solid.1H NMR (DMSO) δ of 8.47-of 8.33 (m, 3H), 7,41 (d, 1H), of 5.05 (s, 2H), 4.26 deaths (kV, 2H), to 1.38 (t, 3H). The m/z 381,1 (M+1).

In: 6-(4-Ethoxy-3-triptoreline)-2-(4-methylpiperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

2-Chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0,053 mmol) is dissolved in DMF and added dropwise N-methylpiperazine (26 mg, 0.26 mmol). The mixture is heated to 120°C for five minutes in a microwave device, Smith Creator. The mixture is diluted with methanol (4 ml) and loaded onto an SCX cartridge. The cartridge is washed three times with methanol (5 ml), then elute with 2 M ammonia in methanol. Ammonia in methanol is removed by evaporation under reduced pressure, the mixture is then purified preparative HPLC, while receiving 8 mg of 6-(4-ethoxy-3-triptoreline)-2-(4-methylpiperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a white solid.1H NMR (MeOH) δ 8,28-to 8.20 (m, 2H), 8,13 (s, 1H), 7,26 (d, 1H), 4,22 (kV, 2H), 3,92 (s, 2H), to 2.67 (m, 8H), of 2.38 (s, 3H), of 1.45 (t, 3H). MS m/z 445,5 (M+1).

To obtain the following compounds were then applied the methodology described in example 11, using suitable derivatives of amines.

11b: 2-Cyclohexylamino-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,31 compared to 8.26 (m, 3H), 7,28 (d, 1H), of 4.66 (s, 2H), 4,23 (kV, 2H), 3,35 (m, 1H), 2,25-2,22 (m, 2H), 1,95-of 1.92 (m, 2H), of 1.75 (m, 1H), 1,53-of 1.26 (m, 8H). MS m/z 444,5 (M+1).

11c: 6-(4-Ethoxy-3-triptoreline)-2-[(2,2,2-triptoreline)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1NMR (MeOH) δ 8,27 is 8.22 (m, 2H), 8,15 (s, 1H), 7,26 (d, 1H), 4,30 (s, 2H), 4,22 (kV, 2H), 3,47 (kV, 2H), 1,45 (t, 3H). MS m/z 444,4 (M+1).

11d: 6-(4-Ethoxy-3-triptoreline)-2-[(3-phenylpropylamine)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,31 compared to 8.26 (m, 3H), 7,32-7,14 (m, 6H), with 4.64 (s, 2H), 4,23 (kV, 2H), 3,26 (m, 2H), 2,78 (t, 2H), and 2.14 (m, 2H), 1,45 (t, 3H). MS m/z 480,3 (M+1).

11e: 6-(4-Ethoxy-3-triptoreline)-2-[1,4]oxazepan-4-ylmethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,31-8,24 (m, 3H), 7,27 (d, 1H), 4,88 (s, 2H), 4,23 (kV, 2H), 3,99 (m, 2H), a 3.87 (m, 2H), of 3.77 at 3.69 (m, 4H), and 2.26 (m, 2H), 1,45 (t, 3H). MS m/z KZT 446.4 (M+1).

11f: 2-(Benzylamino)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,31 is 8.25 (m, 3H), to 7.59-7,49 (m, 5H), 7,28 (d, 1H), with 4.64 (s, 2H), 4,49 (s, 2H), 4,23 (kV, 2H), 1,45 (t, 3H). MS m/z 452,1 (M+1).

11g: 6-(4-Ethoxy-3-triptoreline)-2-(phenethylamines)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,33 is 8.25 (m, 3H), 7,40-7,26 (m, 6H), 4,69 (s, 2H), 4,23 (kV, 2H), 3,54 (t, 2H), 3,14 (t, 2H), 1,45 (t, 3H). MS m/z 466,3 (M+1).

11h: 6-(4-Ethoxy-3-triptoreline)-2-[(2-hydroxyethylamino)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,32-of 8.27 (m, 3H), 7,29 (d, 1H), 4,70 (s, 2H), 4,23 (kV, 2H), 3,92 (m, 2H), 3,41 (m, 2H), 1,45 (t, 3H). MS m/z is 406.5 (M+1).

11i: 6-(4-Ethoxy-3-triptoreline)-2-(2-amino-1,1-dimethyl-2-oxoethylidene)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,32-of 8.28 (m, 3H), 7,29 (d, 1H), 4,63 (s, 2H), 4,23 (kV, 2H), of 1.75 (s, 6H), of 1.45 (t, 3H). MS m/z 447,3 (M+1).

11j: 2-Cyclopropylmethyl-6-(4-this is C-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,30 is 8.25 (m, 3H), 7,27 (d, 1H), to 4.73 (s, 2H), 4,23 (kV, 2H), 3,00 (m, 1H), 1,45 (t, 3H), and 0.98 (m, 4H). MS m/z 402,4 (M+1).

11k: 2-(tert-Butylaminoethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,28-to 8.20 (m, 2H), 8,13 (s, 1H), 7,27 (d, 1H), 4,22 (m, 4H), of 1.45 (t, 3H), of 1.30 (s, 9H). MS m/z 418,4 (M+1).

11l: 6-(4-Ethoxy-3-triptoreline)-2-morpholine-4-ylmethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ to 8.20 (m, 2H), 8,00 (users, 1H), 7,10 (d, 1H), is 4.21 (q, 2H), 3,99 (s, 2H), 3,81 (m, 4H), 2,68 (m, 4H), to 1.48 (t, 3H). MS m/z 432,4 (M+1).

11m: 6-(4-Ethoxy-3-triptoreline)-2-(4-phenylpiperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,31-8,24 (m, 3H), 7,33-7,26 (m, 3H), was 7.08 (d, 2H), 6,97 (m, 1H), 4,80 (s, 2H), 4,23 (kV, 2H), to 3.67 (m, 4H), 3,55 (m, 4H), of 1.45 (t, 3H). MS m/z 507,3 (M+1).

11n: 6-(4-Ethoxy-3-triptoreline)-2-{[(pyridine-2-ylmethyl)amino]methyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,68 (d, 1H), 8,31-8,24 (m, 3H), 7,92 (t, 1H), 7,53 (DD, 1H), 7,46 (m, 1H), 7,28 (d, 1H), amounts to 4.76 (s, 2H)and 4.65 (s, 2H), 4,23 (m, 2H), 1,45 (t, 3H). MS m/z 453,3 (M+1).

11o: 2-[(2-Diethylaminoethylamine)methyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,33 is 8.25 (m, 2H), by 8.22 (s, 1H), 7,28 (d, 1H), to 4.38 (s, 2H), 4,23 (kV, 2H), 3,37 (m, 2H), and 3.31 (m, 2H), to 3.02 (s, 6H), of 1.45 (t, 3H). MS m/z 433,5 (M+1).

11p: 6-(4-Ethoxy-3-triptoreline)-2-(4-pyridin-4-reparation-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,32-8,24 (m, 2H), to 8.20 (s, 1H), 8,16 (d, 2H), 7,28 (d, H), then 7.20 (d, 2H), 4,27-4,20 (m, 4H), 3,92-3,86 (m, 4H), to 3.02 (m, 4H), of 1.45 (t, 3H). MS m/z 508,4 (M+1).

11q: 6-(4-Ethoxy-3-triptoreline)-2-[(2-pyridin-2-ylethylamine)methyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,84 (m, 2H), 8,31-of 8.25 (m, 3H), 8,12 (m, 2H), 7,28 (d, 1H), of 4.77 (s, 2H), 4,24 (kV, 2H), 3,80 (t, 2H), 3,50 (t, 2H), 1,45 (t, 3H). MS m/z 467,4 (M+1).

Example 12

A: 4-Amino-3-nitro-6-(3-(trifluoromethyl)phenyl)pyridine-2-carbonitrile

Stir a suspension of 4-amino-6-chloro-3-nitropyridine-2-carbonitrile (1.0 g, 5,04 mmol), 3-(trifluoromethyl)phenylboronic acid (1148 mg, 6,04 mmol) and potassium carbonate (2,08 g, 15.1 mmol) in THF (16 ml) Tegaserod nitrogen before adding paradimethylaminobenzaldehyde (582 mg, 0.50 mmol). The resulting suspension is heated to 150°C for 5 min using a microwave device Creator. The reaction mixture was filtered through celite and concentrated in vacuo. The residual brown oil chromatographic on a column of silica gel using dichloromethane as eluent, thus obtaining specified in the title compound as a yellow solid (300 mg).

1H NMR (MeOD): δ 8,32 (s, 1H), 8,27 (d, 1H), 7,81 (d, 1H), 7,72 (t, 1H), 7,63 (s, 1H).

In: 3,4-Diamino-6-(3-(trifluoromethyl)phenyl)pyridine-2-carbonitrile

To a stirred suspension of 4-amino-3-nitro-6-(3-triptoreline)pyridine-2-carbonitrile (300 mg, 0.97 mmol) in ethyl acetate (80 ml) is added is 10% palladium on coal (wet) (300 mg, 2.82 mmol). The contents of the vessel rinsed with hydrogen (balloon) and stirred at room temperature for 1.5 hour. The reaction mixture was filtered through celite and concentrated in vacuo, while receiving specified in the title compound as a dark orange solid (240 mg, 89%).1H NMR (MeOD): δ 8,15 (s, 1H), 8,04 (d, 1H), 7,58-the 7.65 (m, 2H), 7,18 (s, 1H). MS m/z 279,3 (M+1).

From: 6-(3-Triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

3,4-Diamino-6-(3-(trifluoromethyl)phenyl)pyridine-2-carbonitrile (120 mg, 0.43 mmol) suspended in acetonitrile (5 ml) and the vessel with the slurry rinsed with nitrogen. Add triplet ytterbium (5 mg, 0,009 mmol) and triethylorthoformate (214 μl, 1,29 mmol) and the resulting orange suspension is refluxed for 1 hour. The reaction mixture was concentrated in vacuo, while receiving specified in the title compound as a yellow solid (116 mg).1H NMR (MeOD): δ 8,55 (s, 1H), 8,35-to 8.41 (m, 3H), 7,71-7,76 (m, 2H). MS m/z 288,9 (M+1).

D: 1-Ethyl-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

To a stirred solution of 6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (50 mg, 0,17 mmol) in acetonitrile (1 ml) is added cesium carbonate (62 mg, 0,19 mmol) and Iodate (15 μl, 0,19 mmol). The resulting suspension is stirred at room temperature over night. The reaction mixture is diluted with dihl what Rotana (5 ml) and water (5 ml) and filtered through a hydrophobic Frit and concentrated in vacuo. The residual orange oil triturated with ether (5 ml) and the resulting precipitate is filtered and dried, thus obtaining specified in the title compound as a pale yellow solid (4 mg).1H NMR (MeOD): δ 8,56 (s, 1H), charged 8.52 (s, 1H), 8,46 (s, 1H), to 8.41 (d, 1H), 7,71-7,74 (m, 2H), 4,46-4,51 (kV, 2H), 1,57-to 1.61 (t, 3H). MS m/z 317,0 (M+1).

Example 13A

6-(4-Ethoxy-3-triptoreline)-2-(pyridine-3-illuminometer)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of 2-chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0,052 mmol), diisopropylethylamine (28,4 μl, 0.16 mmol) and 3-aminopyridine (9.8 mg, 0.1 mmol) in dimethylsulfoxide (500 ml) is heated in a microwave device Creator at 120°C for 5 minutes the Mixture is filtered and purified preparative HPLC, while receiving specified in the header of the connection.1H NMR (MeOH) δ of 8.3 to 8.2 (m, 5H), 7,76-7,74 (m, 2H), 7,27 (d, 1H), 6,07 (s, 2H) to 4.23 (q, 2H), 1,45 (t, 3H). MS m/z 439,1 (M+1).

To obtain the following compounds were then applied the methodology described above, using suitable derivatives of amines.

13b: 6-(4-Ethoxy-3-triptoreline)-2-(pyridine-2-illuminometer)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,33-8,23 (m, 3H), 8,08 (d, 1H), 8,00 (t, 1H), 7,30 (d, 1H), 7,22 (d, 1H), 7,01 (t, 1H), of 5.83 (s, 2H), 4,24 (kV, 2H), 1,46 (t, 3H). MS m/z 439,1 (M+1).

13c: N-(2-{[4-Cyano-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-2-and the methyl]amino}ethyl)methanesulfonamide

1H NMR (MeOH) δ 8,32-of 8.28 (m, 3H), 7,30 (m, 2H), 4.72 in (s, 2H), 4,25 (kV, 2H), 3,56-2,96 (m, 4H), 3.04 from (s, 3H), 1,46 (kV, 3H). MS m/z 483,5 (M+1).

13d: 6-(4-Ethoxy-3-triptoreline)-2-(4-Oxymetazoline-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ of 8.37 compared to 8.26 (m, 3H), 8,21 (s, 1H), 7,40 (d, 1H), 4,27 (kV, 2H), 4,20 (s, 2H), 4,15 (s, 2H), to 1.38 (t, 3H). MS m/z 431,9 (M+1).

13e: 2-[4-(2-Dimethylaminoethyl)-3-oxopiperidin-1-ylmethyl]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,31 is 8.25 (m, 2H), to 8.20 (s, 1H), 7,28 (d, 1H), 4,23 (kV, 2H), 4,07 (s, 2H), of 3.78 (t, 2H), 3,52 (t, 2H), 3,42-to 3.35 (m, 4H), 2,98 (m, 8H), of 1.46 (t, 3H). MS m/z 516,3 (M+1).

13f: 6-(4-Ethoxy-3-triptoreline)-2-[4-(2-hydroxyethyl)-3-oxopiperidin-1-ylmethyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,31-8,24 (m, 2H), 8,18 (s, 1H), 7,28 (d, 1H), 4,23 (kV, 2H), 4.16 the (s, 2H), 3,74 (t, 2H), 3,61 (t, 2H), 3,54 (t, 2H), 3,47 (s, 2H), 3,06 (t, 2H), 1,46 (TM, 3H). MS m/z 489,4 (M+1).

13g: 6-(4-Ethoxy-3-triptoreline)-2-(3,3,4-trimethylpyrazine-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ of 8.27 (s, 1H), of 8.25 (d, 1H), 8,16 (s, 1H), 7,24 (d, 1H), 4,23 (kV, 2H), 3,99 (s, 2H), 3,41-3,35 (osirm, 2H), 3,19-3,10 (osirm, 1H), 2,98-2,0 (osirm, 1H), 2,82 (s, 3H), 2,69-2,59 (osirm, 1H), 2.57 m-2,48 (osirm, 1H), 1,50-of 1.40 (m, 9H). MS m/z 473,5 (M+1).

13h: 2-{[(5-Dimethylaminomethylene-2-ylmethyl)amino]methyl}-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ at 8.36-of 8.28 (m, 3H), 7,29 (d, 2H), 7,05 (d, 1H), 6.73 x (d, 1H), 5,00 (s, 2H), to 4.98 (s, 2H), 4,27-4,22 (m, 4H), 3,34-3,30 (m, 6H), of 1.46 (t, 3H). The m/z 499,6 (M+1).

13i: 6-(4-Ethoxy-3-triptoreline)-2-[4-(2-methoxyethyl)piperazine-1-ylmethyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ of 8.28 (s, 1H), of 8.25 (d, 1H), 8,16 (s, 1H), 7,27 (d, 1H), 4,24 (kV, 2H), Android 4.04 (s, 2H), 3,74 (t, 2H), 3,65 to 3.2 (osirm, 8H), 3,15-2,6 (osirm, 4H), of 1.46 (t, 3H). MS m/z 489,5 (M+1).

13j: 6-(4-Ethoxy-3-triptoreline)-2-[4-(3-hydroxypropyl)piperazine-1-ylmethyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ of 8.28 (s, 1H), of 8.25 (d, 1H), 8,16 (s, 1H), 7,27 (d, 1H), 4,24 (kV, 2H), of 4.05 (s, 2H), and 3.7 (t, 2H), 3,7-3,4 (osirm, 2H), 3,4-2,55 (osirm, 6H), to 1.96 (m, 2H), 1,46 (t, 3H). MS m/z 489,5 (M+1).

13k: 2-{4-[4-Cyano-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-2-ylmethyl]piperazine-1-yl}-N-isopropylacetate

1H NMR (MeOH) δ of 8.28 (s, 1H), 8,27 (d, 1H), 8,17 (s, 1H), 7,27 (d, 1H), 4,23 (kV, 2H), 4,08 (s, 2H), was 4.02 (m, 1H), with 3.89 (s, 2H), 3,44 (users, 4H), 3,29 (users, 4H), of 1.46 (t, 3H), of 1.18 (d, 6H). MS m/z us $ 530, 3 (M+1).

13l: 6-(4-Ethoxy-3-triptoreline)-2-[4-(2-hydroxyethyl)piperazine-1-ylmethyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ of 8.28 (s, 1H), compared to 8.26 (d, 1H), 8,16 (s, 1H), 7,24 (d, 1H), 4,23 (kV, 2H), of 4.05 (s, 2H), 3,90 (m, 2H), 3,65-2,65 (osirm, 10H)of 1.46 (t, 3H). MS m/z 475,5 (M+1).

13m: 2-{[(2-Dimethylaminoethyl)methylamino]-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8.30 to (s, 1H), of 8.25 (d, 1H), they were 8.22 (1, 1H), 7,29 (d, 1H), 4,24 (kV, 2H), 4,11 (s, 2H), 3,38 (t, 2H), 3,03 (m, 8H), of 2.50 (s, 3H), of 1.46 (t, 3H). MS m/z 447,5 (M+1).

13n: 6-(4-Ethoxy-3-triptoreline)-2-(4-isopropylpiperazine-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitril the

1H NMR (MeOH) δ compared to 8.26 (s, 1H), 8,21 (d, 1H), 8,14 (s, 1H), 7,25 (d, 1H), 4,22 (kV, 2H), Android 4.04 (s, 3H), 3,59-3,39 (m, 3H), 3,31-3,12 (osirm, 4H), 2,81-2,64 (osirm, 2H), 1,46 (t, 3H), of 1.39 (d, 6H). MS m/z 473,5 (M+1).

13o: 6-(4-Ethoxy-3-triptoreline)-2-(4-methyl[1,4]diazepan-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,29 (s, 1H), of 8.25 (d, 1H), 8,19 (s, 1H), 7,28 (d, 1H), 4.26 deaths-is 4.21 (m, 4H), of 3.53-3.46 in (osirm, 4H), 3,19 (t, 2H), 3.00 for (t, 2H), 2,97 (s, 3H), 2.13 in (m, 2H), 1,46 (t, 3H). MS m/z 459,6 (M+1).

13p: 6-(4-Ethoxy-3-triptoreline)-2-(1-oxo-1λ4-thiomorpholine-4-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOH) δ 8,28-8,24 (m, 2H), 8,17 (s, 1H), 7,28 (d, 2H), 4,23 (kV, 3H), 3,48-to 3.36 (m, 2H), 3,20-3,00 (m, 6H), of 1.46 (t, 3H). MS m/z rub464.3 (M+1).

13q: 2-(1,1-Dioxo-1λ6-thiomorpholine-4-ylmethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ 8,39 is 8.25 (m, 3H), 7,40 (d, 1H), 4.26 deaths (kV, 2H), 4,11 (s, 2H), 3,18 (m, 4H), is 3.08 (m, 4H), 1,36 (kV, 3H). MS m/z 480,3 (M+1).

Example 14

6-(4-Ethoxy-3-triptoreline)-2-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-C]pyridine-4-carbonitrile

A: [4-Cyano-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-2-ylmethyl]triphenylphosphonium

2-Chloromethyl-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (100 mg, 0.26 mmol) and triphenylphosphine in acetonitrile heated to 60°C. and stirred over night. The reaction mixture was concentrated and triturated with ether, thus obtaining velo-yellow solid. MS m/z 607,5 (M).

In: 2-(3-Chlorpropyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of [4-cyano-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-2-ylmethyl]triphenylmethylchloride of 167.2 mg, 0.26 mmol), chloroacetaldehyde (50% in water) (32,6 mg, 0.41 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (62,4 mg, 0.41 mmol) dissolved in a mixture of 1:1 THF:ethanol (4 ml) at room temperature over night. The mixture is concentrated and purified preparative HPLC, while receiving specified in the header connection. MS m/z of 407.5 (M+1).

From: 6-(4-Ethoxy-3-triptoreline)-2-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of 2-(3-chlorpropyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (23 mg, 0.05 mmol), research (16.1 mg, 0.15 mmol) in DMSO (500 μl) was heated to 120°C for 5 minutes the Mixture is purified using ion exchange chromatography, thus obtaining specified in the header of the connection.

MS m/z 458,9 (M+1).

D: 6-(4-Ethoxy-3-triptoreline)-2-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Into a flask containing a solution of 6-(4-ethoxy-3-triptoreline)-2-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (16 mg) in ethanol, add 5% Pd/C (5 mg) and the flask rinsed hydrogen. The mixture is stirred for 1 hour before being filtered and purified preparative HPLC, while e is ω specified in the header of the connection. 1H NMR (MeOH) δ 8,32 is 8.25 (m, 2H), 8,17 (s, 1H), 7,30 (d, 1H), 4,24 (kV, 2H), 4,20-3,84 (osirm, 4H), 3,65-3,60 (osirm, 2H), 3,40 (t, 2H), up 3.22 (m, 4H), 2.40 a (m, 2H), 1,45 (t, 3H). MS m/z 460.7 M. (M+1).

Example 15A

2,2,2-Triptorelin 2-((4-(pyridin-4-yl)piperazine-1-yl)methyl)-6-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 2-(Chloromethyl)-6-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

To a solution of 3,4-diamino-6-(3-triptoreline)pyridine-2-carbonitrile (1.6 g) and 2-chloro-1,1,1-triethoxysilane (3,41 g) in acetonitrile (40 ml) add triplet ytterbium (180 mg, 5 mol.%) and the mixture is refluxed over night. The mixture is concentrated under reduced pressure before distribution between ethyl acetate (100 ml) and water (100 ml). The organic layer is dried over sodium sulfate and concentrated before adding diethyl ether (20 ml). The precipitate was separated by filtration and dried in air stream, while receiving specified in the header of the connection.1H NMR (MeOD) δ of 8.40 (s, 1H), 8,32 is 8.38 (m, 2H), 8,13-of 8.15 (d, 2H), 7.68 per for 7.78 (m, 2H), 4,96 (s, 2H). MS m/z 337,5, 339,1 (M+1).

In: 2,2,2-Triptorelin 2-((4-(pyridin-4-yl)piperazine-1-yl)methyl)-6-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of 2-(chloromethyl)-6-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (15 mg, 0.045 mmol) and 1-(4-pyridyl)piperazine (36 mg, 0,223 mmol) in dimethylsulfoxide (500 ml) is heated in a microwave device Creator pri°C for 5 minutes The mixture is filtered and purified preparative HPLC, while receiving specified in the header of the connection.1H NMR (MeOD) δ of 8.40 (s, 1H), 8,32-to 8.34 (m, 2H), 8,13-of 8.15 (d, 2H), 7.68 per for 7.78 (m, 2H), 7,18 to 7.2 (d, 2H), 4,11 (s, 2H), 3,82-3,88 (m, 4H), 2,85-only 2.91 (m, 4H). MS m/z 464,1 (M+1).

To obtain the following compounds were then applied the methodology described above, using suitable derivatives of amines.

15b: 2,2,2-Triptorelin 2-((2-hydroxyethylamino)methyl)-6-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ to 8.41 (s, 2H), 8,35-of 8.37 (d, 1H), 7,70-to 7.77 (m, 2H), to 4.73 (s, 2H), 3,92-of 3.94 (t, 2H), 3,42 is-3.45 (t, 2H). MS m/z 362,8 (M+1).

15c: 2,2,2-Triptorelin 2-((pyridin-4-ylamino)methyl)-6-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD) δ of 8.40 (s, 1H), of 8.37 (s, 1H), 8.34 per-at 8.36 (d, 1H), they were 8.22-8,24 (m, 2H), 7,71-7,76 (m, 2H), 6,92-6,94 (m, 2H), 5,77 (s, 2H). MS m/z 395,1 (M+1).

Example 16A

Bestrefiratecom 1-ethyl-2-(4-methylpiperazin-1-ylmethyl)-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 6-Chloro-4-ethylamino-3-nitropyridine-2-carbonitrile

At room temperature, potassium carbonate (3,06 g) is added in several portions to a solution of 4-amino-6-chloro-3-nitropyridine-2-carbonitrile (4.0 g) in DMF (60 ml). To the mixture is added dropwise a solution of ethyliodide (of 3.46 g) in DMF (20 ml), the mixture is then stirred for 24 hours at room temperature and concentrate under reduced pressure. Estato is partitioned between water (50 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers washed with saturated salt solution (3×50 ml), then concentrated under reduced pressure. The remainder chromatographic on silica gel (eluent: dichloromethane), while receiving specified in the header connection (2,94 g) as yellow crystals (TPL = 120°C).1H NMR (DMSO-d6) δ: 8,67 (users, 1H); 7,46 (s, 1H); 3,51 (kV, J=8 Hz, 2H); to 1.21 (t, J=8 Hz, 3H). MS m/z: 227/229 (M+1).

In: 4-Ethylamino-3-nitro-6-(3-triptoreline)pyridine-2-carbonitrile

Tetrakis(triphenylphosphine)palladium (2,78 g) added under nitrogen atmosphere to a mixture of 6-chloro-4-ethylamino-3-nitropyridine-2-carbonitrile (10,9 g), 4-triftormetilfullerenov acid (10.0 g) in degassed dioxane (500 ml) and 2 M aqueous potassium carbonate solution (60 ml). The mixture is refluxed for 4 hours, then concentrated under reduced pressure. The residue is distributed between ethyl acetate (300 ml) and water (300 ml). The aqueous layer was extracted with ethyl acetate (2×300 ml). The combined organic layers washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The remainder chromatographic on silica gel (eluent: DCM then a mixture of DCM/acetone 95/5), while receiving specified in the title compound (10.4 g, 64%).1H NMR (DMSO-d6) δ: 8,59 (users, 1H); 8,50-to 8.40 (m, 2H); to $ 7.91 (d, J=8 Hz, 1H); 7,79 (t, J=7 is C, 1H); 7,74 (s, 1H); the 3.65 (q, J=7 Hz, 2H); to 1.24 (t, J=7 Hz, 3H). MS m/z: 337 (M+1).

With: 3-Amino-4-ethylamino-6-(3-triptoreline)pyridine-2-carbonitrile

At 0°With a solution of chloride dihydrate tin (30,2 g) in concentrated aqueous HCl (150 ml) is added dropwise over 2 h to a solution of 4-ethylamino-3-nitro-6-(3-triptoreline)pyridine-2-carbonitrile (5.0 g) in DMF (100 ml). The mixture is further stirred for 1 hour at 5°C, then poured to a mixture of ice (900 g) and potassium hydroxide (440 g), extracted with ethyl acetate (2×1.4 l). The combined organic layers washed with saturated salt solution (700 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, thus obtaining specified in the header connection (4,56 g) as a solid.1H NMR (DMSO-d6) δ: 8,30-to 8.20 (m, 2H); 7,75-of 7.60 (m, 2H); was 7.08 (s, 1H); 6,11 (t, J=6 Hz, 1H); 5,95 (users, 2H); 3,4-3,3 (m, 2H); of 1.27 (t, J=7 Hz, 3H).

D: 2-Chloromethyl-1-ethyl-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Triplet ytterbium (1,16 g, 1.8 mmol) and 2-chloro-1,1,1-trimethoxymethane (7,56 ml, 56.0 mmol) are added to a solution of 3-amino-4-ethylamino-6-(3-triptoreline)pyridine-2-carbonitrile (5.73 g of 18.7 mmol) in acetonitrile (150 ml). The mixture is refluxed for 48 h, then concentrated under reduced pressure. The residue is distributed between ethyl acetate and water. The organic layer is dried over sodium sulfate, filter is t, and concentrate under reduced pressure. The residue is triturated with diethyl ether, filtered, thus obtaining specified in the header of the connection (of 5.92 g, 87%) as a solid.1H NMR (DMSO-d6) δ: cent to 8.85 (s, 1H); 8,50-of 8.00 (m, 2H); of 7.90-of 7.70 (m, 2H); of 5.26 (s, 2H); 4,55 is 4.45 (m, 2H); to 1.48 (t, J=7 Hz, 3H). MS m/z: 365 (M+1).

E: Bestrefiratecom 1-ethyl-2-(4-methylpiperazin-1-ylmethyl)-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1-Methylpiperazine (30 mg) are added to a solution of triethylamine (76 μl) and 2-chloromethyl-1-ethyl-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0,100 g) in acetonitrile (4 ml). The mixture is stirred at room temperature for 16 h, then concentrated under reduced pressure. The remainder chromatographic preparative HPLC (eluent: N2O+0.05% of TFA/CH3CN + 0.05% of TFA), while receiving specified in the title compound (156 mg).1H NMR (MeOD4) δ: 8,53 (s, 1H); 8,48 (s, 1H); 8,42 (d, J=8 Hz, 1H); 7,80-of 7.70 (m, 2H); 4,58 (kV, J=7 Hz, 2H); 4,10 (s, 2H); 3,6-3,4 (m, 2H); 3,3-3,1 (m, 4H); to 2.94 (s, 3H); 2,8-2,6 (m, 2H); 1.57 in (t, J=7 Hz, 3H). MS m/z: 429 (M+1).

Using the same experimental techniques get the following connection.

16b: Bestrefiratecom 1-ethyl-2-(4-pyridin-4-reparation-1-ylmethyl)-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD4) δ: 8,58 (s, 1H); charged 8.52 (s, 1H); to 8.45 (d, J=8 Hz, 1H); 8,19 (d, J=8 Hz, 2H); 7,80-the 7.65 (m, 2H); 7.23 percent (d, J=8 Hz, 2H); with 4.64 (q, J=7 Hz, 2H); to 4.17 (s, 2H); 3.75 to the 3.65 (m, 4H); 2,80-to 2.65 (m, 4H); 1,61 (t, J=7 Hz, 3H).

<> 16c: Triptorelin 2-[(cyclopropylamino)methyl]-1-ethyl-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD4) δ: 8,63 (s, 1H); 8,53 (s, 1H); 8,48 (d, J=8 Hz, 1H); 7,70-of 7.60 (m, 2H); 4,84 (s, 2H); to 4.52 (q, J=7 Hz, 2H); 3.24 in (d, J=8 Hz, 2H); of 1.55 (t, J=7 Hz, 3H); 1,35-1,20 (m, 1H); of 0.85 to 0.75 (m, 2H); 0,55-0,50 (m, 2H). MS m/z: 400 (M+1).

16d: 1-Ethyl-2-(pyridine-4-illuminometer)-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

4-Aminopyridine (26 mg, 0.27 mmol) are added to a solution of diisopropylethylamine (of 0.24 ml, 1.37 mmol) and 2-chloromethyl-1-ethyl-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0,100 g, 0.27 mmol) in DMF (3 ml). The mixture is heated at 80°C for 2 h, then filtered. The precipitate is washed with water and then with isopropyl ether, and dried, thus obtaining specified in the title compound (55 mg, 47%) as a solid (TPL = 340°C).1H NMR (DMSO-d6) δ: 8,84 (s, 1H); 8.6 out of 8.5 (m, 2H); 8,31 (d, J=8 Hz, 2H); from 7.9 to 7.7 (m, 2H); 6,97 (d, J=8 Hz, 2H); 5,98 (s, 2H); 4,51 (kV, J=7 Hz, 2H); 1,45 (t, J=7 Hz, 3H). MC m/z: 423 (M+1).

16e: 2-(2(R,S)-Cyclohexylpiperidine-1-ylmethyl)-1-ethyl-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ: from 8.3 to 8.2 (m, 2H); 7,88 (s, 1H); of 7.69 (d, J=8 Hz, 1H); to 7.64 (t, J=8 Hz, 1H); 4,7-4,4 (m, 2H); 4,22 (d, J=14 Hz, 1H); 3,82 (d, J=14 Hz, 1H); 2,7-2,6 (m, 1H); 2,5-2,3 (m, 2H); 1,9-1,4 (m, 13H); 1,2-0,9 (m, 5H). MC m/z: 482 (M+1).

16f: 2-(4-Cyclopropanecarbonyl-[1,4]diazepan-1-ylmethyl)-1-ethyl-6-(3-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ: from 8.3 to 8.2 (m, 2H); 7,89 (s, 1H); of 7.69 (d, J=8 Hz, 1H); 7,63 (t, J=8 Hz, 1H); 4,55 is 4.45 (m, 2H); to 4.1 to 4.0 (m, 2H); 3,8-3,6 (m, 4H); 2.95 and is 2.75 (m, 4H); 1,95-of 1.85 (m, 2H); 1,75-of 1.65 (m, 1H); 1,54 (t, J=7 Hz, 3H); of 1.05 to 0.95 (m, 2H); 0,8-0,7 (m, 2H). MS m/z: 497 (M+1).

Example 17A

1-Ethyl-6-(3,4-dichlorophenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 3-Amino-6-chloro-4-ethylaminomethyl-2-carbonitril

At 0°With a solution of chloride dihydrate tin (25,9 g) in concentrated aqueous HCl (76 ml) is added dropwise over 40 min to a solution of 6-chloro-4-ethylamino-3-nitropyridine-2-carbonitrile (2.9 g) in DMF (70 ml). The mixture is stirred for 2.5 hours, then poured to a mixture of ice (400 g) and 50% sodium hydroxide (400 ml), extracted with ethyl acetate (3×100 ml). The combined organic layers washed with 2 N. sodium hydroxide (700 ml), then saturated salt solution (3×100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The remainder chromatographic on silica gel (eluent: dichloromethane/ethyl acetate, 9/1), while receiving specified in the title compound (2.0 g) as white crystals (TPL = 150°C).1H NMR (DMSO-d6) δ: 6,46 (s, 1H); 6.42 per (users, 1H); 6,02 (users, 2H); 3,20 (kV, J=8 Hz, 2H); of 1.26 (t, J=8 Hz, 3H). MS m/z: 197/199 (M+1).

B: 6-Chloro-1-ethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Triplet ytterbium (75 mg) are added to a solution of 3-amino-6-chloro-4-ethylaminomethyl-2-carbonitrile (1,41 g) triethylorthoformate (50 ml). The mixture heating is t at 120°C and under stirring for 2.5 hours, then concentrate under reduced pressure. The remainder chromatographic (eluent: dichloromethane/ethyl acetate, 9/1), while receiving solid, which is triturated with diethyl ether and filtered, thus obtaining specified in the header connection (0,973 g, 66%) as white crystals (TPL = 138°C).1H NMR (CDCl3) δ: 8,17 (s, 1H); a 7.62 (s, 1H); or 4.31 (q, J=8 Hz, 2H); of 1.62 (t, J=8 Hz, 3H).13C NMR (CDCl3) δ: 147,5, 143,8, 142,9, 141,7, 124,0, 114,1, 109,2, 40,9, 15,2.

With: 1-Ethyl-6-(3,4-dichlorophenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Tetrakis(triphenylphosphine)palladium (15 mg) is added under nitrogen atmosphere to a mixture of 6-chloro-1-ethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (42 mg), 3,4-dichlorophenylamino acid (152 mg) and cesium fluoride (100 mg) in DME (2 ml) and methanol (1 ml). The mixture is heated at 80°C for 24 h, then filtered. The filtrate is concentrated under reduced pressure. The residue is purified using the method of preparative LC-MS (eluent: A: NH4HCO3, 10 mm/In: CH3CN), while receiving specified in the title compound (30 mg) as a white solid.1H R (CDCl3) δ: 8,20-of 8.15 (m, 2H); 7,94 (d, J=8 Hz, 1H); to $ 7.91 (s, 1H); 7,58 (d, J=8 Hz, 1H); 4,37 (kV, J=7 Hz, 2H); 1,65 (t, J=7 Hz, 3H). MS m/z: 317/319 (M+1).

The above methodology is applied using suitable derivatives Baranovich acids for the synthesis of the following derivatives.

17b: 1-Ethyl-6-(4-chloro-3-triptoreline)-1H-imidazo,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ: at 8.36 (s, 1H); 8,23 (d, J=8 Hz, 1H); 8,19 (s, 1H); to 7.95 (s, 1H); the 7.65 (d, J=8 Hz, 1H); 4,39 (kV, J=7 Hz, 2H); of 1.66 (t, J=7 Hz, 3H). MS m/z: 351/353 (M+1).

17c: 1-Ethyl-6-(3,5-dichlorophenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (MeOD4) δ: 8,59 (s, 1H); 8,55 (s, 1H); 8.17 and (s, 2H); 7,52 (s, 1H); 4,47 (kV, J=7 Hz, 2H); 1,58 (t, J=7 Hz, 3H). MS m/z: 317/319 (M+1).

Example 18

6-(2-Ethoxy-5-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A: 6-Chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile

This compound is synthesized in the same manner as for compound 17A, stage, on the basis of 6-chloro-3,4-diaminopyridine-2-carbonitrile.1H NMR (DMSO) δ: 8,72 (s, 1H), of 8.06 (s, 1H).

B: 6-Chloro-2-tetrahydropyranyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-Chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1 g) dissolved in ethyl acetate (20 ml). To the above solution was added 3,4-dihydro-2H-Piran (1 ml) and hydrate toluensulfonate acid (50 mg). The mixture is heated at 60°C for 10 h, then washed with sodium bicarbonate (5%, 10 ml). The organic layer is dried over sodium sulfate, the solvent is removed, thus obtaining specified in the header of the connection.1H NMR (DMSO) of 8.92 (s, 1H), 8.30 to (s, 1H), of 5.81 (d, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), 2,18 (m, 1H), 2,07 (m, 1H), 1,67 (m, 4H).

From: 6-(2-Ethoxy-5-triptoreline)-1-(tetrahydropyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

The flask containing 6-chloro-1-(tetrahydro the Iran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (60 mg), (2 ethoxy-5-triptoreline)baronova acid (59,2 mg), Tris(dibenzylideneacetone)dipalladium(0) (10.5 mg), tricyclohexylphosphine (7.7 mg), seal and purge with nitrogen before the addition of dioxane (615 μl). The mixture Tegaserod by blowing nitrogen through the mixture before adding a solution of potassium phosphate (83,0 mg) in water (305 μl). The mixture is heated to 100°C and vigorously stirred over night. The crude mixture is filtered through a layer of silicon dioxide before adding ethyl acetate (30 ml) and water (50 ml). The ethyl acetate layer concentrated before purification on a column of 10 g of silica with elution with a mixture of 40% ethyl acetate/heptane, while receiving specified in the header connection. MS m/z 417,5 (M+1).

D: 6-(2-Ethoxy-5-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-(2-Ethoxy-5-triptoreline)-1-(tetrahydropyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (67 mg) and hydrate pair-toluensulfonate acid (10 mg) is added to methanol (5 ml) and DCM (5 ml). The mixture is stirred at room temperature overnight before being concentrated and purified preparative HPLC, while receiving 6-(2-ethoxy-5-triptoreline)-1H-imidazo[4,5-c]pyridine-4-carbonitrile.1H NMR (MeOH) δ 8,55 (s, 1H), 8,48 (s, 1H), 8,15 (s, 1H), of 7.70 (d, 1H), 7,29 (d, 1H), 4.26 deaths (kV, 2H), 1,46 (t, 3H). MS m/z 333,1 (M+1).

Example 19

The method of analysis of cathepsin S

Inhibitory activity of compounds from which retenu was confirmed by measuring the in vitro inhibition of recombinant human cathepsin S as follows. For 384-well tetralonia the microplate, add 10 μl of a 100 μm solution of the test compound in the buffer for analysis (100 mm sodium acetate, pH 5.5, 5 mm EDTA, 5 mm dithiotreitol) with 10% dimethylsulfoxide (DMSO), plus 20 μl of a 250 μm solution of the substrate Z-Val-Val-Arg-AMC (7-aminocoumarins derived Tripeptide N-benzyloxycarbonyl-Val-Val-Arg-OH) in the buffer for analysis, and 45 μl of buffer for analysis. Then well add 25 ál of 2 mg/l solution of activated recombinant human cathepsin S in the buffer for analysis, while receiving the final concentration of inhibitor 10 μm.

The enzymatic activity is determined by measuring the fluorescence of the selected aminoethylamino at 440 nm using excitation at 390 nm within 20 minutes of Enzyme activity in percent is calculated by comparing this activity with the activity of a solution containing no inhibitor. Compounds are then subjected to analysis using curve dose-response to determine the values of the IC50for active compounds (where IC50is the 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 IC50for inhibition of human cathepsin S is greater than 6. The majority of the compounds according to the invention are set pIC5 more than 7, for example, are given as examples of the compounds of examples 1, 3, 4, 5d, 5g, 9a, 9d, 9f, 10a, 10f, 11a, 11h, 13d, 13l.

Example 20

The method of analysis of cathepsin K

Inhibitory activity of the compounds according to the invention was demonstrated in vitro by measuring the inhibition of recombinant cathepsin-To person in the following way. For 384-well tetralonia the microplate add 5 μl of a 100 μm solution of the test compound in the buffer for analysis (100 mm sodium acetate, pH 5.5, 5 mm EDTA, 5 mm dithiotreitol) with 10% dimethyl sulfoxide (DMSO), plus 10 μl of a 100 μm solution of the substrate Z-Phe-Arg-AMC (7-aminocoumarin derivative of the dipeptide N-benzyloxycarbonyl-Phe-Arg-OH) in the buffer for analysis, and 25 µl of buffer for analysis. Then well add 10 μl solution of 1 mg/l of activated recombinant cathepsin To the man in the buffer for analysis, while receiving the final concentration of inhibitor 10 μm.

The enzymatic activity is determined by measuring the fluorescence of the selected aminoethylamino at 440 nm using excitation at 390 nm within 10 min of Enzymatic activity in percent is calculated by comparing this activity with the activity of a solution containing no inhibitor. Compounds are then subjected to analysis using curve dose-response to determine the values of the IC50for active compounds (where IC50one is by the concentration of the test compound, causing 50% inhibition of enzyme activity). Compounds according to the invention typically have a pIC50(the negative logarithm of the concentration IC50for inhibition of cathepsin For people between 5 and 7.

1. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile having a General formula I

where R is an optional ortho - or meta-Deputy selected from halogen and (C1-4)alkyloxy;
R1represents a halogen or CF3;
R2represents H, (C1-4)alkyloxy or halogen;
R3represents H or (CH2)n-NR5R6;
R4represents H or (C1-6)alkyl, optionally substituted COOR7or NR8R9;
R5and R6independently represent H, (C3-8)cycloalkyl, Hinkley-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally mono-substituted CF3, (C3-8)cycloalkyl, (C6)aryl, 5 - or 6-membered heteroaryl group, HE, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14or NR13SO2(C1-4)alkyl; or
R5and R6together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing 1 heteroatom, is selected from Oh, SO2and NR15and the ring is optionally mono-substituted or di-substituted by oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17or CONR18R19;
R7represents H or (C1-4)alkyl;
R8and R9are independently H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or
R8and R9together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing one heteroatom, representing About;
R11and R12are independently H or (C1-4)alkyl;
R13and R14are independently H or (C1-4)alkyl;
R15represents H, (C1-4)alkyl (optionally mono-substituted, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20;
R16and R17are (C1-4)alkyl; or
R16and R17together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring;
R18and R19represent H;
R20is a (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and
n is 0 or 1;
or its pharmaceutically acceptable salt.

2. The derivative of 6-FeNi what-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to the formula I according to claim 1, where
R is absent;
R1is a CF3;
R2represents H or (C1-4)alkyloxy;
R3represents H or (CH2)n-NR5R6;
R4represents H or (C1-6)alkyl, optionally substituted COOR7or NR8R9;
R5and R6independently represent H, (C3-8)cycloalkyl, (C2-6)alkenyl or (C1-6)alkyl, optionally mono-substituted CF3, (C3-8)cycloalkyl, (C6)aryl, 5 - or 6-membered heteroaryl group, HE, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12or NR13R14; or
R5and R6together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing 1 heteroatom selected from O, SO2and NR15and the ring is optionally mono-substituted or di-substituted by oxo, (C1-4)alkyl, NR16R17or CONR18R19;
R7represents H or (C1-4)alkyl;
R8and R9are independently H or (C1-4)alkyl; or
R8and R9together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring, optionally additionally containing one heteroatom, representing the nd themselves;
R11and R12are independently H or (C1-4)alkyl;
R13and R14are independently H or (C1-4)alkyl;
R15represents H, phenyl, pyridyl, COR20;
R16and R17are (C1-4)alkyl; or
R16and R17together with the nitrogen atom to which they are bound, form a 4-8-membered saturated heterocyclic ring;
R18and R19represent H;
R20is a (C1-4)alkyl or furyl; and
n is 0 or 1;
provided that one of R3and R4represents H;
or its pharmaceutically acceptable salt.

3. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to claim 1 or 2, where R1is a CF3.

4. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to claim 2, where R2is a (C1-4)alkyloxy.

5. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to claim 2, where R2represents ethoxy.

6. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile formula I according to claim 1, which is selected from
6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
[4-cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-C]pyridin-1-yl]acetic acid;
[4-cyano-6-(4-ethoxy-3-triptoreline)imidazo[4,5-C]pyridin-1-yl]butyric to the slots;
6-(4-ethoxy-3-triptoreline)-2-(3-oxopiperidin-1-ylmethyl)-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
6-(4-ethoxy-3-triptoreline)-1-(2-morpholine-4-retil)-1H-imidazo [4,5-C]pyridine-4-carbonitrile;
6-(4-ethoxy-3-triptoreline)-1-(2-piperidine-1-retil)-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
1-(2-dimethylaminoethyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
6-(4-ethoxy-3-triptoreline)-1-(3-morpholine-4-ylpropyl)-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
1-(3-dimethylaminopropyl)-6-(4-ethoxy-3-triptoreline)-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
6-(4-ethoxy-3-triptoreline)-2-(4-methylpiperazin-1-ylmethyl)-1H-imidazo[4,5-C]pyridine-4-carbonitrile and
6-(4-ethoxy-3-triptoreline)-2-[(2-hydroxyethylamino)methyl]-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
1-ethyl-2-(pyridine-4-illuminometer)-6-(3-triptoreline)-1H-imidazo [4,5-C]pyridine-4-carbonitrile;
6-(4-ethoxy-3-triptoreline)-2-[4-(2-hydroxyethyl)-3-oxopiperidin-1-ylmethyl]-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
6-(4-ethoxy-3-triptoreline)-2-(4-Oxymetazoline-1-ylmethyl)-1H-imidazo[4,5-C]pyridine-4-carbonitrile
or their pharmaceutically acceptable salts.

7. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to claim 1 for use in the treatment of osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, and XP the technical pain, such as neuropathic pain.

8. The use of the derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to any one of claims 1 to 6 for the manufacture of a medicinal product for the treatment of osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, and chronic pain, such as neuropathic pain.

9. Pharmaceutical composition having inhibitory activity against cathepsin S and cathepsin K, containing derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to any one of claims 1 to 6, or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable auxiliary means.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of photoactivation of a photocatalyst by irradiating a composition containing the said catalyst. The method of using a photolatent catalyst (a) in which a composition containing said catalyst is irradiated before subsequent treatment is characterised by that, the photolatent catalyst is: (a1) a compound selected from a group consisting of a photolatent acid, an aromatic iodonium salt or oxime-based photolatent acid; (a2) a photolatent base compound. Also described is a substrate on which a coating made from the composition is deposited in accordance with the above described method. Also described is a method of using photolatent catalyst (a), in which a composition containing said catalyst is irradiated before subsequent treatment, characterised by that subsequent treatment is preparation of foam material and the composition contains polyol and isocyanate components and photolatent base (a2) as photolatent catalyst.

EFFECT: provision for solidification of the system.

13 cl, 10 tbl, 16 ex

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a dynamic nuclear polarisation method of a compound which contains one or more carboxyl groups, distinguished by that, the radical of formula (I) , where M is one equivalent cation of an alkali metal; and R1, which are identical or different, each represents a C1-C6-alkyl group with a straight or branched chain or a -(CH2)n-X-R2 group, where n equals 1, 2 or 3; X is O; and R2 is a C1-C4alkyl group with a straight or branched chain, which are used a paramagnetic agent in the said dynamic nuclear polarisation process. The invention also relates to new radicals, to their use as paramagnetic agents.

EFFECT: obtaining new radicals of formula (I), which are used as paramagnetic agents in dynamic nuclear polarisation processes.

17 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a liquid composition which contains hyperpolarised 13C-pyruvate, involving: a) formation of a liquid mixture containing a radical of formula (I) , where M is hydrogen or one equivalent cation; and R1, which are identical or different, each represents hydroxylated and/or alkoxolated C1-C4-hydrocarbon group with a straight or branched chain, 13C-pyroracemic acid and/or 13C-pyruvate, and freezing this mixture; b) increasing polarisation of 13C nuclei of pyroracemic acid and/or pyruvate in this mixture through dynamic nuclear polarisation c) addition of a physiologically transferable buffer, which provides for pH in the range from 7 to 8, and a base to the frozen mixture for its dissolution and for converting 13C-pyroracemic acid to 13C-pyruvate, obtaining a liquid composition or, when at stage (a) only 13C-pyruvate is used, addition of a buffer to the frozen mixture for its dissolution, obtaining a liquid composition; and d) possible removal of the radical and/or its reaction products from the liquid composition. The invention also relates to use of such a composition and to a radical of formula (I).

EFFECT: obtaining a composition for use as MP of a visualising agent.

22 cl, 2 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which exhibits inhibitory effect on the FAAH enzyme having formula I , where n denotes an integer from 1 to 6; A denotes a group X; where when n equals an integer from 2 to 6, groups A are identical or different; X denotes C1-2-alkylene; R1 denotes a hydrogen atom; R2 denotes a hydrogen atom or a group selected from the following groups: phenyl, phenyloxy; R3 denotes either 2,2,2-trifluoroethyl or phenyl, if necessary substituted with one or more halogen atoms or C1-3-alkyl, C1-3-alkoxy, trifluoromethyl; provided that: the formula 1 compound is not 2,2,2-trifluoroethyl benzylcarbamate, when R3 denotes 2,2,2-trifluoroethyl and group -[A]n- denotes a -CH2- group, when R3 denotes phenyl, if necessary substituted, and group -[A]n-denotes a -CH2-, -CH2CH2-,-CH2CH2CH2- group, then R2 is not a hydrogen atom and is in form of a base, an addition salt with a pharmaceutically acceptable acid, as well as to a method for synthesis of the formula I compound and a pharmaceutical composition having inhibitory effect on FAAH, containing at least one formula I compound.

EFFECT: improved method.

5 cl, 6 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to novel pyrrolo[3,2-b]pyridine derivatives of formula I , where values of radicals R1-R5 are given in the description. The invention also covers pharmaceutically acceptable salts of these compounds, methods of producing these compounds and pharmaceutical compositions containing these compounds. Pyrrolo[3,2-b]pyridine derivatives and their pharmaceutically acceptable salts can provide proton pump reversible inhibitory effect.

EFFECT: obtaining novel pharmaceutically acceptable salts which can provide proton pump reversible inhibitory effect.

5 cl, 2 tbl, 289 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds having anxiolytic and antidepressant activity, which are derivatives of the formula 1 (a-b), or formula 2 (a-b) at that compounds of formula 2 (a-b) are intermediate products in synthesis of compounds of the formula , where R-Cl is a compound 1a or R'=COOC2H5 - compound 1b, , where R=COOC2H5 and R'=C1 - compound 2a; R=R-COOC2H5 - compound 2b.

EFFECT: obtaining new biologically active compounds that differ from analogues as intended in low toxicity and lack of side effects.

5 cl, 3 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have CDK1 and/or CDK2 kinase inhibiting activity. In formula R1 is selected from hydrogen, hydroxy-lower alkyl, C3-C6 cycloalkyl and R2-(X)n; X is selected from lower alkylene, hydroxy-lower alkylene, lower cycloalkylene or lower alkanoyloxy-lower alkylene; R2 is and is selected from phenyl and a 5- or 6-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of sulphur and nitrogen; R5 and R6 are independently selected from a group consisting of hydrogen, lower alkyl, halogen and lower alkoxy; and n equals 0 or 1.

EFFECT: design of a pharmaceutical composition for treating and preventing diseases whose condition can be improved by inhibiting CDK1 and/or CDK2 kinase, containing an effective amount of formula I compounds.

47 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to orthopedics and can be used for complex therapy in children of early age with cytomegalovirus and locomotor system pathology in case of planned surgery. For this purpose 10 days before taking patient to hospital 1 capsule of eubiotic "Bifiform" is introduced three times a day. Since the day of hospitalisation introduction of the medicine is continued in dose 1 capsule two times a day during 7-10 days. Two days before the operation immunomodulator "Viferon" is introduced in dose 1 suppository a day rectally. 30 minutes before the operation antibiotic "Ceftriaxon" is introduced intravenously in dose 15-20 mg/kg. After operation introduction of "Ceftriaxon" is continued for 2 days. Day dose of "Viferon" is increased to three suppositories every 8 hours during three days. After that it is introduced in dose one suppository per day every second day during 10 days.

EFFECT: elaborated regimen of therapy ensures prevention of post-operation complications, favours faster normalisation of blood parametres and reduction of index of leukocyte intoxication in post-operation period.

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