6-phenyl-1h-imidazo[4,5-c]pyridine-4-carbonitrile derivatives as cathepsin inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of formula I or pharmaceutically acceptable salts thereof, wherein R1 represents H; R2 represents (C1-3)alkyl; R3 represents (C1-4)alkyl optionally substituted by three halogen atoms; R4 represents H; X represents O; n is equal to 1 or 2 or 3; Y is specified in OH, NR5R6 and Z, wherein Z represents a saturated 5- or 6-member heterocyclic ring containing 1 heteroatom specified in NR7, wherein the ring can be substituted by oxo(C1-3)alkyl, hydroxy(C1-3)alkyl; or wherein Z represents an aromatic 5- or 6-member heterocyclic ring containing 1-2 heretoatoms specified in N wherein the ring can be substituted by (C1-3)alkyl; R5 and R6 optionally represent H, (C3-8)cycloalkyl or (C1-6)alkyl optionally substituted 1-2 times by halogen, OH, (C1-6)alkyloxy, CONR14R15, NR14R15 or a 6-member saturated heterocyclic group containing a heteroatom specified in NR8; or R5 and R6 together with a nitrogen atom whereto attached form a 5-10-member saturated heterocyclic ring optionally additionally containing 1, 3 heteroatoms specified in NR9, with the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, CONR10R11 or NR10R11; R7 represents H; R8 represents (C1-3)alkyl; R9 represents H, (C1-3)alkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alykl, (C1-6)alkylcarbonyl, (C1-6)alkyloxycarbonyl, CONR12R13 or a 6-member heteroaryl group containing 1-2 heteroatoms specified in N; R10 and R11 optionally represent H or (C1-3)alkyl; R12 and R13 optionally represent (C1-3)alkyl; or R14 and R15 optionally represent (C1-3)alkyl. Also, the invention refers to the use of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of formula I and a pharmaceutical composition thereof.

EFFECT: there are prepared new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives effective for treating osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis and chronic pain, such as neuropathic pain .

9 cl, 31 ex

 

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

Cathepsin S highly expressed in antigen-presenting cells of the lymphatic tissue, mainly in the lysosomes (Bromme et a., Science,5, 789, 1996; Riese, et al., Immunity,4, 357, 1996). In antigen-presenting cells cathepsin S plays a major role in the presentation of antigen degradation of the invariant chain, which is associated with major histocompatibility complex class II. Mice with deficiency of cathepsin S are healthy and normal in many respects, but show a deficiency in immune functions and provide significant resistance to the development of collagen-induced arthritis (Nakagawa et al., Immunity,10, 207, 1999; Shi et al., Immunity, 10, 197, 1999; Yang et al.,174, 1729, 2005). Inhibitors of cathepsin S are effective in models of asthma (Riese et al., J. Clin. Invest.101, 2351, 1998). Blocking the degradation of the invariant chain must specifically to reduce the presentation of antigen to CD4 cells and as such should reduce undesirable side effects of other immunosuppressive drugs, such as steroids. In the latter patent publication (Johnson & Johnson, US 2007/0117785) it was shown that inhibitors of cathepsin S block the presentation of several total allergenic extracts in the analysis of ex vivo human, thus confirming the use of inhibitors of cathepsin S for the treatment of certain allergic conditions, such as rheumatoid arthritis, psoriasis. Unlike most other lysosomal proteases that are active only at acidic conditions, the AK is Yunosti cathepsin S is manifested in a wide pH value, the optimal value is attained at an alkaline pH value. This feature allows the cathepsin S to function inside and outside the lysosomes (Broemme et al., Febs Lett.,286, 189, 1991). Feature a wide range of pH and high Anastasya activity of extracellular cathepsin S may also contribute to extensive restructuring of the architecture of the extracellular matrix. In the result, found that cathepsin S destroys all the main components of the extracellular matrix and is involved in the pathogenic response, which leads to atherosclerosis, obesity, emphysema and chronic obstructive pulmonary disease and cancer (Shi, et al., Atherosclerosis,186, 411, 2006; Clement et al., Clin Chem Lab Med.,45(3), 328, 2007; Chang et al., J Cancer Mol.,3(1), 5, 2007; Shi et al., Immunity,10, 197, 1999; Zheng et al., J Clin. Invest.,106, 1081, 2000; Libby et al., J Clin Invest102, 576, 1998; Sukhova et al., ibid,111, 897, 2003). It has been described that the level of cathepsin S serum (blood) is significantly increased in patients with atherosclerosis and diabetes, and modulating the activity of cathepsin S may have a therapeutic application in the treatment of patients with these common diseases (Shi, et al., Atherosclerosis,186, 411, 2006; Clement et al., Clin Chem Lab Med.,45(3), 328, 2007). Cathepsin S has been shown in pain (WO 2003020278; Clark et al., PNAS,104, 10655, 2007), the development of cancer, for example, angiogenesis, metastasis, growth, and cell proliferation (Jonston et al., Am J Path.,163, 175, 2003; Kos et al., Brit J Cancer,85, 1193, 2001).

Other cysteineless, such as cathepsin To, 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 is involved in the metabolism of extracellular matrix, necessary for normal growth and bone remodeling (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. Therefore, inhibitors of cathepsin K may represent a new therapeutic agents for the treatment of pathological conditions in humans, such as osteoporosis, cancer, osteoarthritis. 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 potent elastase cathepsin and S. Degradation of the matrix, especially in fibrous head of such plaques is a key process in the destabilization of atherosclerotic damage. Thus, the metabolism of components vnekletochnogo the matrix, collagen and elastin, which give structural integrity when damaged fibrous head, can critically affect the clinical manifestations of atherosclerosis, such as thrombosis of the coronary artery, resulting in the rupture of atherosclerotic plaques. Inhibition of cathepsins K and S in the vicinity of plaques prone to rupture, can thus be an effective way to prevent such cases.

Derivatives of 4-aminopyrimidine-2-carbonitrile described as inhibitors of cathepsins K and/or S in the international patent application WO 03/020278 (Novartis Pharma GMBH), whereas the structurally related derivatives of 4-aminopyrimidine-2-carbonitrile were recently described in WO04/000819 (ASTRAZENECA AB) as inhibitors of cathepsin S. Pyrrolopyrimidine also described as inhibitors of cathepsins K and/or S in WO 03/020721 (Novartis Pharma GMBH) and WO 04/000843 (ASTRAZENECA AB). Recently carbonitridation bicyclic nitrogen-containing aromatic systems have been described in International patent application WO 05/085210 (Ono Pharmaceutical Co.) as inhibitors cysteinate applicable in the treatment of osteoporosis.

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

With this aim, the present invention offers the has derivative 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile, having a General formula I

where

R1represents H or (C1-3)alkyl;

R2represents H or (C1-3)alkyl;

R3represents halogen or (C1-4)alkyl, optionally substituted by one or more halogen atoms;

R4represents H, halogen or CN;

X represents CH2, O or S;

n is 1-5;

Y is selected from OH, CN, (C1-3)alkylsulphonyl, NR5R6and Z, where

Z represents a saturated 5-or 6-membered heterocyclic ring containing 1-3 heteroatom selected from O, S and NR7where the ring may be substituted by OH, oxo, (C1-3)alkyl, hydroxy(C1-3)alkyl or (C1-3)alkyloxy(C1-3)alkyl; or where

Z represents an aromatic 5 - or 6-membered heterocyclic ring containing 1-3 heteroatom selected from O, S and N, where the ring may be substituted by OH, (C1-3)alkyl or hydroxy(C1-3)alkyl;

R5and R6independently represent H, (C3-8)cycloalkyl or (C1-6)alkyl, optionally substituted with halogen, OH, CF3, (C3-8)cycloalkyl, (C1-6)alkyloxy, CONR14R15, NR14R15, SO2R16A 5 - or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, S and N, or a 5 - or 6-membered ring on sennou heterocyclic group, containing a heteroatom selected from O, S or NR8; or

R5and R6together with the nitrogen atom to which they are attached, form a 4-10-membered saturated heterocyclic ring, optionally additionally containing 1-3 heteroatom selected from O, S and NR9and the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, (C3-8)cycloalkyl, CONR10R11or NR10R11;

R7represents H, (C1-3)alkyl or hydroxy(C1-3)alkyl;

R8represents H, (C1-3)alkyl or hydroxy(C1-3)alkyl;

R9represents H, (C1-3)alkyl, (C3-8)cycloalkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alkyl, (C1-6)alkylsulphonyl, (C1-6)allyloxycarbonyl, CONR12R13CH2CONR12R13or 5 - or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, S and N;

R10and R11independently represent H or (C1-3)alkyl;

R12and R13independently represent H or (C1-3)alkyl; or

R12and R13together 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;

R14and R15independent pre whom represent H or (C 1-3)alkyl; or

R14and R15together 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;

R16is a (C1-3)alkyl; or their pharmaceutically acceptable salts.

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile of the invention 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, psoriasis, asthma, and chronic pain such as neuropathic pain.

The term "(1-6)alkyl"used in the definition of formula I means a branched or unbranched alkyl group having 1-6 carbon atoms such as hexyl, pentile, 3-methylbutyl, butile, isobutyl, tertiary butila, propylene, isopropyl, ethyl and stands.

The term "(1-4)alkyl" means a branched or unbranched alkyl group having 1-4 carbon atoms, such butila, isobutyl, tertiary butila, propylene, isopropyl, ethyl and stands.

The term "(1-3)alkyl" means a branched or unbranched alkyl group having 1-3 carbon atoms such as propylene, isopropyl, ethyl and stands.

the terms "( 1-3)alkylaryl" and "(1-3)alkyloxy(C1-3)alkyl in each case, (C1-3)alkyl has the same meaning as defined earlier.

The term "hydroxy(C1-3)alkyl" means a (C1-3)alkyl group as defined earlier, substituted hydroxy-group. Preferred hydroxy(C1-3)alkyl group is hydroxymethyl.

In terms of "(1-6)alkyloxy", "(1-6)alkylaryl" and "(1-6)allyloxycarbonyl" (1-6)alkyl has the same meaning as defined earlier.

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

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

In the definition of formula I, Z may be a saturated 5 - or 6-membered heterocyclic ring containing 1-3 heteroatom selected from O, S and NR7. Examples of such heterocyclic rings, which are attached via a carbon atom, are morpholinyl, piperazinil, piperidinyl, pyrrolidinyl, thiomorpholine, 4-thiomorpholine, hexahydro-1,4-oxazepines, homopiperazine, imidazolidinyl, tetrahydrofuranyl and tetrahydrofuryl.

In the definition of formula I, Z may be the romantic 5 - or 6-membered heterocyclic ring, containing 1-3 heteroatom selected from O, S and N. Examples of such aromatic heterocyclic rings, which are attached via a carbon atom or nitrogen, are pyridyl, imidazolyl, pyrazolyl, pyrimidinyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, thienyl, oxadiazolyl and the like. Preferred rings are 2-pyridyl, 3-pyridyl, 1,3-thiazol-2-yl, 1,2-oxazol-3-yl, imidazol-1-yl, tetrahydroimidazo-1-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 4-10-membered saturated heterocyclic ring, such as ring of azetidine, pyrrolidine, piperidine or 1H-azepine. Such rings may contain 1-3 additional heteroatoms selected from O, S and NR9for 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 defining these rings are also included system spiracles, such as 1-oxo-2,8-diazaspiro[4,5]Dec-8-yl, 2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-yl, 2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-3-yl, 6,9-diazaspiro[4,5]Dec-9-yl, and the like, as well as systems of condensed rings, such as hexahydropyrazino[1,2-a]pyrazin-2-yl and the like.

The term "5 - or 6-membered heteroaryl group, while anaemia in the definition of R 5and R6and in the definition of R9means an aromatic 5 - or 6-membered ring having 1-3 heteroatoms selected from nitrogen, 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 R12and R13together 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, for the formation of such rings as the ring of the research, thiomorpholine, hexahydro-1,4-oxazepine or tetrahydrothieno.

In the definition of formula I R14and R15may form together with the nitrogen atom to which they relate, 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, to form rings such as the ring of the research, thiomorpholine, hexahydro-1,4-oxazepine or tetrahydrothieno.

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

Preferred in the invention are compounds according to formula I, in which R1represents N. The following are preferred compounds of formula I in which R3is a CF3and R4represents N. Preferred are also compounds of the invention in which X represents O and n is 1 or 2 or 3. Especially preferred are compounds of the invention in which Y represents NR5R6.

Particularly preferred derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile invention are

- 6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-methyl-6-[4-(3-pyrrolidin-1 ipropose)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-[4-(3-N,N-diethylaminopropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-methyl-6-[3-(trifluoromethyl)-4-(3-(3,3,4-trimethylpyrazine-1-yl)propoxy)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-{4-[3-(3,3-dimethylpiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-{4-[3-(CIS-3,5-dime reparacin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-{4-[3-(4-ethylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-methyl-6-(4-{3-[4-(N-methylaminomethyl)piperidine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-{4-[3-(2-ethylimidazole-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-{4-[2-(CIS-3,5-dimethylpiperazine-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-diazaspiro[4.5]Dec-3-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 1-methyl-6-[4-(pyridine-2-ylethoxy)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 6-{4-[3-(4-ethylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

hydrochloride of 1-methyl-6-{3-(trifluoromethyl)-4-[(3-(S)-isopropylpiperazine-1-yl)propoxy]phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

- 2,2,2-triptorelin 6-(4-(2-(1-ethylpiperazin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile and

- 1-methyl-6-[4-(6-methylpyridin-2-ylethoxy)-3-triptoreline]-1H-imidazo[4,5-c]pyridine-4-carbonitrile or their pharmaceutically acceptable salts.

The invention in the following aspect relates to pharmaceutical is m songs containing 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, where R2represents H, can be obtained by the methods depicted in schemes 1, 2 and 3. Selective cyanide 4-amino-2,6-dichloro-3-nitropyridine (II) (see scheme 1) copper cyanide gives 4-amino-6-chloro-2-cyano-3-nitropyridine (III), from which 6-chloro-3,4-diaminopyridine-2-carbonitrile (VI) obtained after nitrogroup reduction or hydrogenation using Pd/C-H2) or the use of SnCl2or reducing agents on the basis of Fe.

Scheme 1

Cyclization of a derivative of 3,4-diaminopyridine (IV) orthoevra catalyzed by a Lewis acid, such as triplet ytterbium, or a proton acid, such as acetic acid, gives the desired imidazopyridine intermediate product (V), where R1matter mentioned previously. NH imidazopyridine compounds (V) then protect tetrahydropyranyloxy (TNR) group, thus obtaining the compound (VI) in a mixture with N3-substituted product. This mixture of regioisomers can be used without separation, since the final destruction of the protective GRU is dust TNR both isomers will give the same connection.

Scheme 2

Structural unit for 6-phenyl substituent of the compounds of formula (I), i.e. derived Bronevoy acid of formula (XII), can be synthesized as shown in scheme 2. Bromination of 2-substituted phenol of the formula (VII), where R3matter mentioned previously, bromine or other agent of synthesized gives derivatives of 4-bromophenol (VIII) the quality of the product. Gidroksietilirovaniya (VIII) hydroxyalkylated and potassium carbonate as base gives compound of formula (IX), the hydroxy-group is then protected by a TNR group under standard conditions, thus obtaining the compound of formula (X). Litrovaya last butyllithium followed by reaction with triisopropylsilane and processing of dilute acetic acid in water gives the derivative Bronevoy acid of formula (XI) with high yield. The protective group TNR then removed by heating the compounds of formula (XI) in 1 M hydrochloric acid in methanol, thus obtaining a derived Bronevoy acid of formula (XII) with a high output.

Scheme 3

By applying catalyzed by palladium of combination reaction between Suzuki key intermediate products of the formula VI (scheme 1) and formula (XII; see scheme 2), as shown in figure 3, get the derivative of 6-phenyl-1 is-imidazo[4,5-c]pyridine-4-carbonitrile formula (XIII). The reaction of the alcohol functional groups in these compounds with methanesulfonamide in dichloromethane or tetrahydrofuran, or NMP with triisopropanolamine as the basis gives methanesulfonate derivative of the formula (XIV)by reaction with a secondary or primary amine or other nucleophiles get compound of formula (XV). Remove tetrahydropyranyl protective group gives compound of formula (XVI), which is a compound of the invention according to formula I in which Y represents NR5R6and X represents O.

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, where R2is a (C1-3)alkyl, can be obtained by synthesis is given in figure 4. N-Alkylation of 4-amino-6-chloro-2-cyano-3-nitropyridine (II) appropriate alkylhalogenide and a base such as potassium carbonate, in a suitable solvent, such as acetonitrile or dimethylformamide, gives compound of formula (XVII) as a product. The subsequent restoration of the nitro group by hydrogenation using palladium-on-coal or using SnCl2or Fe/H+gives compound of formula (XVIII) with a high yield. The compound (XIX) is then obtained from the compound (XVIII) by condensation with orthoevra catalyzed by acid, such as acetic acid, or ytterbium triflate, when heating the AI. The combination of Suzuki compounds of formula (XIX) with the derived Bronevoy acid of formula (XII) gives compound of formula (XX). From compound (XX) is then received methanesulfonate of formula (XXI), and the substitution of the amine sulfonate or other nitrogen nucleophiles gives compound of formula (XXII), which is a compound according to formula (I) of the invention in which Y represents NR5R6and X represents O.

Scheme 4

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, where X represents a methylene (CH2), can be obtained as shown in scheme 5.

Scheme 5

The reaction Hake 4-chloro-2-cryptomaterial with methyl acrylate using palladium catalyst gives substituted methylcinnamic formula (XXIV), which upon hydrogenation with palladium-on-coal as a catalyst to give methyl-3-(4-chloro-2-triptoreline)propionate (XXV) with high output, which is then restored using diisobutylaluminium, while receiving the corresponding alcohol of formula (XXVI), which is then converted into the corresponding derived ether Bronevoy acid of the formula (XXVII). The combination between Suzuki (XXVII) and the compound of the formula (XIX) gives compound of formula (XXVIII), which can be turned into meanswhen the t formula (XXIX) and then the compound of the invention according to the formula (XXX) with the use of methods, described previously.

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I of the invention can also be obtained by means of an intermediate phenol derivative of the formula (XXXIV), as shown in scheme 6. This intermediate product is obtained, on the basis of 4-bromo-2-triptoreline (VIII): after protection of the phenolic hydroxy-group in the form of a simple ester group, methoxyethoxyethoxy (MEMO) (XXXI) the connection is in turn derived Bronevoy acid (formula XXXII) in the manner described above (scheme 2). The subsequent combination of Suzuki with the compound of the formula (XIX) gives compound of formula (XXXIII), which group MEMO then removed using dilute aqueous hydrochloric acid. The resulting intermediate compound of formula (XXXIV) can be transformed into a derivative or alkylation, reaction of Mitsunobu, or using additional methods known in this field for more compounds of the formula (XXXV)in which R represents a Y-(CH2]nor its predecessor.

Scheme 6

For the compounds of formula (XXXV)in which R contains a primary or secondary amine, alcohol or carboxylic acid, these functional groups may be temporarily protected. Suitable protective groups are known in the field, in the example, from the publication Wuts, P.G.M. and Greene, T.W.: Protective Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

The resulting primary or secondary amine, alcohol or carboxylic acid can then be used for transformation into the following derivative as shown in scheme 7, for example by alkylation or reductive alkylation.

Scheme 7

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, in which R4is not a proton, can be obtained by means of an intermediate product of the formula (XXXIV), as shown in scheme 8. The halogenation and cyanidation of the compounds of formula (XXXIV) in position R4appropriate reagents can be achieved using standard conditions from the literature to obtain the compounds of formula (XXXIX). Further conversion of compound (HHHH), as shown in figure 8 and as described above, leads to the desired end product of formula (XXXXII) via intermediates of formula (XXXX) and (HHHHI).

Scheme 8

When obtaining the derivative of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile General formula I, in which R1or R2or R4or R5or R6contains basic nitrogen atom of the amino group, the nitrogen atom must be temporarily protected, such as, for example, Labi the other to the action of acid tert-butyloxycarbonyl (BOC) protective group. Other suitable protective groups for functional groups that must be temporarily protected during synthesis are 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 of 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, methanesulfonate 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 contains 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 trim the ylamine, the triethylamine and the like.

Compounds of the invention may exist in solvated, and resolutiony forms, including hydrated forms. Usually 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 may also be the possibility of multiple crystal forms. In General, all physical forms are equivalent for the uses proposed by the present invention, and it is assumed that these forms are within the scope of this invention.

Derivatives of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile of the invention and their salts may contain a center of chirality in one or more side chains and therefore you can get them in the form of a pure enantiomer or as a mixture of enantiomers or as a mixture containing diastereomers. Methods of asymmetric synthesis, through which pure stereoisomers are well known in this field, for example, synthesis of chiral induction or synthesis coming from chiral intermediates, enantioselective enzymatic transformation, separation of stereoisomers or enantiomers using chromatography on chiral environments. That is their ways 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 of the invention are inhibitors of cathepsin S and cathepsin K man, and therefore in the following aspect of the invention can be applied in therapy, and particularly for obtaining a medicinal product for the treatment of autoimmune diseases, chronic obstructive pulmonary disease, pain, cancer, obesity, osteoporosis, atherosclerosis and related dependent cathepsin S and K, disorders, such as rheumatoid arthritis, psoriasis, asthma and IBD.

Compounds of the invention can enter interline or parenterally to humans, preferably at a daily dose of 0.001-100 mg / kg body weight, preferably 0.01 to 10 mg per kg of body weight. In a mixture with a 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 be pressed to obtain a solid of uniform doses, such as pills, tablets, or be processed to obtain capsules or suppositories. Using a pharmaceutically suitable liquids the compounds can also be applied in the form of solution, suspension, emulsion, for example, for use as a drug for injection or in the form of a spray, for example, for the use as a nasal spray. For the manufacture of dosage units such as tablets, it is assumed the use of conventional additives such as fillers, colorants, polymeric binders, and the like. In General, you can apply any pharmaceutically acceptable additive, which does not inhibit the function of active connections.

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 were either purchased from standard commercial sources or were synthesized according to literature methods using commercial sources. Proton NMR (1H NMR) were obtained on a spectrometer Bruker DPX 400 referenced to the internal standard tetramethylsilane was (TMS). Mass spectra were recorded on a Shimadzu LC-8A (HPLC) PE Sciex API 150EX LC/MS. Analytical analysis of LC/MS reversed-phase was performed on a column LUNA C18 (5 μm; 30 × 4.6 mm) in 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), t is trihydrogen (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), methoxyethoxyethoxy (MEMO), tetrahydropyran (TNR), N-chlorosuccinimide (NCS), a strong cation exchange resin (SCX)and strong anion-exchange resin (SAX), deuterated DMSO (DMSO), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), methyl (Me), ethyl (Et), isopropyl (iPr).

EXAMPLE1

6-[4-(3-Hydroxypropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

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

Stir a suspension of 4-amino-2,6-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 was placed in an oil bath, preheated to 180°C, and stirring was continued for 12 minutes. The mixture was allowed to cool and was diluted with ethyl acetate (700 ml) and water (700 ml) and the resulting suspension was filtered. The organic layer was separated and further washed with water (500 ml) and 0.1 n HCl (500 ml). The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure, olucha this 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).

B:6-Chloro-4-methylamino-3-nitropyridine-2-carbonitrile

Stir a mixture of 4-amino-6-chloro-3-nitropyridine-2-carbonitrile (12.5 g), potassium carbonate (17,4 g) and iodomethane (22,5 g) in acetonitrile (150 ml) was heated at 80°C for 3 hours. At this point, add another portion of iodomethane (22,5 g); the mixture was heated with stirring for another 2 hours. The mixture then was diluted with ethyl acetate (500 ml) and washed with water (150 ml). The organic layer was then dried over sodium sulfate, the solvent was removed under reduced pressure, thus obtaining the intended product, 4-methylamino-6-chloro-3-nitropyridine-2-carbonitrile (13 g).

1H NMR (CD3OD) δ: 7.2V (s, 1H), to 3.02 (s, 3H). MS m/z 213 (M+H).

C:3-Amino-6-chloro-4-methylaminomethyl-2-carbonitril

The chloride dihydrate tin(II) (21 g) was added to a suspension of 6-chloro-4-methylamino-3-nitropyridine-2-carbonitrile (6.6 g) in ethanol (150 ml). The mixture was stirred at room temperature for 3 hours. By the above, painted in red-brown solution was then added ethyl acetate (1000 ml) followed by addition of 10% aqueous ammonium hydroxide (200 ml). The organic layer was separated, sticky solid cushion washed atilas what tatom (5 × 200 ml). The combined organic layer was then washed with a saturated aqueous solution of sodium chloride (2 × 200 ml), dried over sodium sulfate, the solvent was removed, thus obtaining a brown solid as the intended product (5.7 g).

1H NMR (CD3OD) δ: 6,45 (s, 1H), 2,89 (s, 3H).

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

A suspension of 3-amino-6-chloro-4-methylaminomethyl-2-carbonitrile (1.8 g) in DCM (5 ml), acetic acid (1.5 ml) and triethylorthoformate (10 ml) was heated in a microwave conditions at 150°C for 30 minutes. The mixture then was diluted with ethyl acetate (200 ml), washed with 10% sodium carbonate (100 ml), dried over sodium sulfate, the solvent was removed under reduced pressure, to the residue were then added DCM (5 ml), a certain amount of the product was broken into pieces and collected by filtration (0.5 g), the rest is then passed through a column of silica gel using a mixture of ethyl acetate-heptane (55:45) as the eluent, thus obtaining another 0.8 g of the intended product (1.3 g).

1H NMR (CDCl3) δ: 8,1 (s, 1H), and 7.6 (s, 1H), 3,93 (s, 3H). MS m/z 193 (M+H).

E:3-(4-Bromo-2-(trifluoromethyl)phenoxy)propan-1-ol

3-Improper (11,23 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)phenol (15 g) and potassium carbonate (17,2 g) in acetonitrile (150 ml). The above mixture was heated with reverse holodilniki is within 4 hours, then was diluted with ethyl acetate (500 ml) and water (300 ml). The organic layer was separated, dried over magnesium sulfate, the solvent was removed under reduced pressure, thus obtaining the intended product, sufficiently pure for use in the next stage (18.6 g).

1H NMR (CDCl3) δ: to 7.67 (d, 1H), 7,58 (DD, 1H), 6.90 to (DD, 1H), 4,18 (t, 2H), a 3.87 (square, 2H), 2,07 (TT, 2H).

F:2-[3-(4-Bromo-2-(trifluoromethyl)phenoxy)propoxy]tetrahydro-2H-Piran

A mixture of 3-(4-bromo-2-(trifluoromethyl)phenoxy)propan-1-ol (12 g), 3,4-dihydro-2H-Piran (6.75 g) and hydrate p-toluensulfonate acid (0,76 g) in THF (100 ml) was stirred at room temperature for 1 hour, then diluted with 10% sodium carbonate (50 ml) and was extracted with ethyl acetate (2 × 150 ml). The organic layer was then dried over sodium sulfate, the solvent was removed under reduced pressure, thus obtaining the intended product (15 g).

1H NMR (CDCl3) δ: to 7.67 (d, 1H), 7,56 (DD, 1H), 6.90 to (DD, 1H), 4,56 (DD, 1H), 4,15 (t, 2H), 3.75 to 4.0 a (m, 2H), 3,4-of 3.65 (m, 2H), 2,10 (m, 2H), 1,4-2,0 (m, 6H).

G:4-(3-(Tetrahydro-2H-Piran-2-yloxy)propoxy)-3-(trifluoromethyl)phenylboronic acid

BuLi (2.5 M, 19.1 ml) was added dropwise to a solution of 2-(3-(4-bromo-2-(trifluoromethyl)phenoxy)propoxy)tetrahydro-2H-Piran (16.6 g) in THF at -78°C in an atmosphere of N2within 3 minutes. After stirring at -78°C for another 10 minutes then added dropwise within 3 minutes at -78°C. obavljale triisopropylsilyl (11 ml). The mixture was stirred at -78°C for an additional 20 minutes, then slowly warmed up to room temperature and was stirred at room temperature for 30 minutes. The mixture was then extinguished acetic acid (10% in water, 20 ml), was extracted with EtOAc (200 ml), washed with saturated salt solution (100 ml × 5), dried over sodium sulfate, the solvent was removed under reduced pressure, the residue was dissolved in toluene and then the solvent was removed in vacuum for gripping them traces of acetic acid (repeated 3 times, to no smell of acetic acid). The product according to the NMR contains 3 sets of peaks of the product, which are supposed to belong to the monomer, dimer and trimer product.

1H NMR (CDCl3) δ: 7,8-8,4 (3×and 3×d, 2H), 6,9-7,2 (3×d, 1H), 4,6 (m, 1H), 3,4-4,3 (m, 6H), to 2.1-2.3 (m, 2H), 1,4-1,9 (m, 6H).

H:4-(3-Hydroxypropoxy)-3-(trifluoromethyl)phenylboronic acid

4-(3-(Tetrahydro-2H-Piran-2-yloxy)propoxy)-3-(trifluoromethyl)phenylboronic acid (30,6 g) was added to hydrochloric acid (1 M in Meon) and the mixture was heated at 50°C for 40 minutes. The solvent and HCl was then removed under reduced pressure and the residue (20,3 g) was used in the next stage without additional purification. Proton NMR showed 2 sets of peaks of the product, which are supposed to belong to the monomer and the dimer or trimer product.1H NMR (CDCl3 (0.7 ml) + CD 3D (0.2 ml)) δ: 7,7-8,0 (2×d 2×s, 2H), 7,0 (2×d, 1H), 4,22 (t, 2H), 3,86 (t, 2H), 3,48 (TT, 2H).

I:6-[4-(3-Hydroxypropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (6 g), 4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenylboronic acid (12.3 g), Tris(dibenzylideneacetone)diplegia (1.42 g), tricyclohexylphosphine (1,05 g) and tribalista (13,2 g) in dioxane (60 ml) and water (24 ml) was heated at 100°C in an atmosphere of N2within 4 hours. The mixture then was diluted with ethyl acetate (400 ml), the organic layer was separated and the solvent was removed under reduced pressure, to the residue was then added methanol (50 ml), the product has led and collected by filtration (7.7 g).

1H NMR (DMSO) δ: 8,67 (s, 1H), at 8.60 (s, 1H), 8,43 (d, 1H), of 8.37 (s, 1H), 7,41 (d, 1H), 4,55 (t, 1H), 4,25 (t, 2H), 3,99 (s, 3H), to 3.58 (square, 2H), 1,92 (TT, 2H). MS m/z 377 (M+H).

EXAMPLE2a

The HCl salt of 6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A:3-[4-(4-Cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy]propylaminosulfonyl

Methanesulfonanilide (2.65 g) was added dropwise to a solution of 6-[4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (6.7 g) and diisopropylethylamine (9.7 ml) in NMP (40 ml). The mixture was stirred at whom atoi temperature for 3 hours. After adding ice (100 g) of solid product was collected by filtration, washed with cold ethanol (20 ml), thus obtaining 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy]propylaminosulfonyl (7,4 g).

1H NMR (DMSO) δ: 8,69 (s, 1H), to 8.62 (s, 1H), 8,45 (d, 1H), to 8.41 (s, 1H), 7,47 (d, 1H), and 4.40 (t, 1H), 4,32 (t, 2H), 3,99 (s, 3H), 3,18 (s, 3H), 2,21 (TT, 2H).

B:The HCl salt of 6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy]propylenecarbonate (300 mg) and dimethylamine (2 M solution in THF, 1.65 ml) in NMP (3 ml) was heated at 100°C in a microwave conditions for 20 minutes. The product is then purified HPLC, while receiving 6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as TFA salt. The above TFA salt was then dissolved in Meon (3 ml) and passed through a column of strong cation-exchanger (SCX). After washing with methanol to remove the rest TFA, the product was washed with 2 M ammonia in methanol. Then after removal of the solvent was obtained the free base of 6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile. This free base was then dissolved in a mixture of THF-MeOH (5:1, 4 ml) was added 2 M HCl in diethyl ether (1 ml). After removal of all solvent, propanganda the pressure of the HCl salt of 6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (110 mg) was obtained as a white solid.

1H NMR (CD3OD) δ: charged 8.52 (s, 1H), to 8.62 (s, 1H), 8,35-to 8.45 (m, 3H), of 7.36 (d, 1H), 4,35 (t, 2H), Android 4.04 (s, 3H), 3,39 (t, 2H), 2,97 (s, 6H), 2,33 (TT, 2H). MS m/z 404 (M+H).

The procedure described in example2A, was then applied using suitable derivatives of secondary amines to obtain the following compounds as either TFA salt, free base or HCl salt.

2b:The TFA salt of 1-methyl-6-[4-(3-morpholine-4-ylpropionic)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,28 an 8.4 (m, 3H), 7,31 (d, 1H), 4,33 (t, 2H), 4,1 (user., 2H), as 4.02 (s, 3H), 3,8 (user., 2H), 3,55 (user., 2H), 3,42 (t, 2H), 3,22 (user., 2H), 2,35 (TT, 2H). MS m/z 446 (M+1).

2c:The TFA salt of 1-methyl-6-[4-(3-pyrrolidin-1 ipropose)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,32 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), 3,7 (user., 2H), 3.45 points (t, 2H), 3,15 (user., 2H), 2,32 (TT, 2H), 2,2 (user., 2H), 2,1 (user., 2H). MS m/z 430 (M+H).

2d:The TFA salt of 6-{4-[3-((S)-2-hydroxyethylpyrrolidine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,30 (d, 1H), 4,30 (m, 2H), was 4.02 (s, 3H), 3,91 (DD, 1H), 3,6-3,8 (m, 4H), 3,3 (m, 2H), 2,35 (m, 2H, in), 2.25 (m, 1H), 2,17 (m, 1H), 2.06 to (m, 1H), 1,95 (m, 1H). MS m/z 460 (M+H).

2e:The TFA salt of 6-{4-[3-((R)-2-hydroxyethylpyrrolidine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,30 (d, 1H), 4,30 (m, 2H), was 4.02 (s, 3H), 3,91 (DD, 1H), 3,6-3,8 (m, 4H), 3,3 (m, 2H), 2,35 (m, 2H, in), 2.25 (m, 1H), 2,17 (m, 1H), 2.06 to (m, 1H), 1,95 (m, 1H). MS m/z 460 (M+H).

2f:The TFA salt of 1-methyl-6-{4-[3-(4-methylpiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,30 (d, 1H), or 4.31 (t, 2H), was 4.02 (s, 3H), 3,61 (user. d, 2H), 3,32 (t, 2H), 3,02 (t OSiR., 2H), 2,3 (TT, 2H), 1,95 (t OSiR., 2H), 1,74 (m, 1H), 1,47 (m, 2H), and 1.0 (d, 3H). MS m/z 458 (M+H).

2g:The TFA salt of 6-{4-[3-(N-ethyl-N-methylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,32 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), 3,47 (m, 1H), 3,2-3,4 (m, 3H), equal to 2.94 (s, 3H), 2,33 (m, 2H), to 1.38 (t, 3H). MS m/z 418 (M+H).

2h:The TFA salt of 6-{4-[3-(N-isopropyl-N-methylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3 an 8.4 (m, 3H), 7,31 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), of 3.69 (m, 1H), 3,5 (m, 1H), 3,3 (m, 1H), 2,87 (s, 3H), 2,3 (m, 2H), 1,40 (d, 3H), of 1.38 (d, 3H). MS m/z 432 (M+H).

2iThe TFA salt of 6-{4-[3-(N-cyclohexyl-N-methylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3 an 8.4 (m, 3H), 7,31 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), 3,5 (m, 1H), 3,3 (m, 2H), 2,9 (s, 3H), 2,3 (m, 2H), 2,1 (m, 2H), 1,95 (m, 2H), of 1.75 (m, 1H), 1,2-1,65 (m, 5H). MS m/z 472 (M+H).

2j:The TFA salt of 6-{4-[3-(4-hydroxypiperidine-1-the l)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3 an 8.4 (m, 3H), 7,32 (d, 1H), 4,32 (t, 2H), 4,1 (t, 0,5H), was 4.02 (s, 3H), 3,85 (m, 0,5H), 3,66 (m, 1H), of 3.45 (m, 1H), 3,35 (m, 3H), 3,12 (t OSiR., 1H), 2,35 (m, 2H), 2,2 (m, 1H), 2.0 (m, 2H), of 1.75 (m, 1H). MS m/z 460 (M+H).

2k:The TFA salt of 6-{4-[3-(N-isopropyl-N-2-methoxyethylamine)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,35-to 8.45 (m, 3H), 7,34 (d, 1H), 4,33 (t, 2H), a 4.03 (s, 3H), 3,65 to-3.9 (m, 3H), 3.25 to 3,55 (m, 4H), 3.46 in (overlapping with m atoms H, C, 3H), 2,35 (m, 2H), 1,40 (d, 6H). MS m/z 476 (M+H).

2l:The TFA salt of 6-{4-[3-(N,N-bis-(2-methoxyethyl)amino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,31 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), of 3.77 (t, 4H), 3,5-of 3.65 (m, 6H), 3,42 (s, 6H), 2,33 (m, 2H). MS m/z 492 (M+H).

2m:The TFA salt of 6-{4-[3-(N-2-hydroxyethyl-N-isopropylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,35-to 8.45 (m, 3H), 7,33 (d, 1H), 4,33 (t, 2H), was 4.02 (s, 3H), 3.75 to 3,95 (m, 3H), 3,35-3,5 (m, 3H), of 3.25 (m, 1H), 2,35 (m, 2H), of 1.41 (d, 6H). MS m/z 462 (M+H).

2n:The TFA salt of 6-{4-[3-(CIS-2,6-dimethylmorpholine-4-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,28 an 8.4 (m, 3H), 7,31 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), at 3.9 (m, 2H), of 3.56 (d, 2H), 3,4 (t, 2H), 2,78 (t, 2H), a 2.36 (m, 2H), 1.27mm (d, 6H). MS m/z 474 (M+1).

2o:The TFA salt of 6-{4-[3-(4-accomidate the DIN-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,28 an 8.4 (m, 3H), 7,31 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), of 3.97 (s, 2H), 3,55 (t, 2H), 2,32 (m, 2H). MS m/z 445 (M+1).

2p:The TFA salt of 6-{4-[3-(1-oxo-2,8-diazaspiro[4,5]Dec-8-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3 an 8.4 (m, 3H), 7,33 (d, 1H), 4,33 (t, 2H), was 4.02 (s, 3H), and 3.7 (m, 2H), 3,55 (m, 1H), 3,4 (m, 3H), 3.15 in (m, 1H), 2,37 (m, 2H), 1.8 to 2.3 (m, 6H). MS m/z 513 (M+H).

2q.:The TFA salt of 6-{4-[3-(2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,46 (s, 1H), 8,35-to 8.45 (m, 3H), of 7.36 (d, 1H), 4,34 (t, 2H), a 4.03 (s, 3H), 3,6-of 3.85 (m, 2H), 3.45 points (m, 1H), 3,2 (m, 1H), 2,35 (m, 3H), 2,1 (m, 1H). MS m/z 528 (M+H).

2r:The TFA salt of 1-methyl-6-{4-[3-(5-oxo[1,4]diazepan-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: at 2.36 (m, 2H), 2,86 (m, 2H), 3,38-3,62 (user. m, 4H), 3,44 (t, 2H), to 3.58 (m, 2H), was 4.02 (s, 3H), 4,33 (t, 2H), 7,35 (d, 1H), 8,39 (m, 1H), 8,40 (s, 2H), to 8.45 (s, 1H). MS m/z 473 (M+1).

2s:The TFA salt of 1-methyl-6-{4-[3-(2-methyl-1-oxo-2,8-diazaspiro[4,5]Dec-8-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 1,74-2,22 (user. m, 6H), to 2.35 (m, 2H), 2,86 (s, 3H), 3.15 in (m, 1H), 3,34-3,56 (user. m, 5H), 3,62-3,78 (user. m, 2H), was 4.02 (s, 3H), 4,33 (t, 2H), 7,35 (d, 1H), of 8.37 (m, 1H), 8,40 (s, 2H) to 8.45 (s, 1H). MS m/z 527 (M+1).

2t:The TFA salt of 1-methyl-6-{4-[3-((R)-2-methylpiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,43 (s, 1H), 8.34 per (user. s, 3H), 7,30 (d, 1H), 4,32 (m, 2H), 4,01 (s, 3H), 3.75 to (m, 0,5H), of 3.60 (m, 2H), 3,35 (m, 1H), 3,30 (m, 0,5H), of 3.12 (m, 1H), 2,35 (m, 1H, in), 2.25 (m, 1H), 2,02 (m, 2H), 1,80 (m, 2H), 1,65 (m, 2H), the 1.44 (d, 2H), 1,40 (d, 1H). MS m/z 458 (M+1).

2u:The HCl salt of 6-[4-(3-N,N-diethylaminopropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,76 (s, 1H), 8,51 (s, 1H), 8,43 (s, 1H), to 8.41 (d, 1H), 7,37 (d, 1H), 4,34 (t, 2H), 4,08 (s, 3H), 3,41 (t, 2H), 3,31 (square, 4H), 2,30 (m, 2H), 1,38 (t, 6H). MS m/z 432 (M+1).

The procedure described in example2A, was then applied using suitable derivatives of primary amines to obtain the following compounds as either TFA salt, neutral compounds, or salts of HCl.

EXAMPLE3a

3A:The TFA salt of 6-[4-(3-N-methylaminopropane)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,28 an 8.4 (m, 3H), 7,31 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), of 3.25 (t, 2H), 2,78 (s, 3H), 2,28 (m, 2H). MS m/z 390 (M+1).

3b:The TFA salt of 6-[4-(3-N-cyclobutylamine)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,28 an 8.4 (m, 3H), 7,31 (d, 1H), 4,32(t, 2H), as 4.02 (s, 3H), 3,85 (m, 1H), 3,17 (t, 2H), 2,47 (m, 2H), 2,15-2,31 (m, 4H), of 1.95 (m, 2H). MS m/z 430 (M+1).

3c:The TFA salt of 6-{4-[3-(2,2-diferentiating)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 2,32 (m, 2H), 3,38 (m, 2H), 3,49 (square, 2H), to 3.64 (t, 2H), 4.00 points (s, 3H), of 4.38 (t, 2H), 6.30-in (m, 3H), 7,35 (d, 1H), 8,39 (DD, 1H), 8,40 (s, 2H), to 8.45 (s, 1H). MS m/z 440 (M+1).

3d:The TFA salt of 1-methyl-6-(4-{3-[(pyridine-2-ylmethyl)amino]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 2,35 (m, 2H), 3,38 (m, 2H), was 4.02 (s, 3H), 4,35 (t, 2H), of 4.45 (s, 2H), 7,34 (d, 1H), 7,42 (m, 1H), of 7.48 (d, 1H), 7,87 (m, 1H), of 8.37 (DD, 1H), scored 8.38 (s, 2H), 8,44 (s, 1H), to 8.62 (d, 1H). MS m/z 467 (M+1).

3e:The TFA salt of 6-{4-[3-((R)-sec-butylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 1,04 (t, 3H), of 1.35 (d, 3H), 1,60 (m, 1H), 1,70 (m, 1H), and 2.27 (m, 2H), 3,26 (m, 3H), was 4.02 (s, 3H), 4,34 (t, 2H), 7,34 (d, 1H), scored 8.38 (DD, 1H), 8,39 (s, 2H), to 8.45 (s, 1H). MS m/z 432 (M+1).

3f:The TFA salt of 6-{4-[3-((R)-2-hydroxypropylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: of 1.25 (d, 3H), 2,30 (m, 2H), 3,05 (DD, 2H), and 3.31 (m, 2H), was 4.02 (s, 3H), of 4.05 (m, 1H), 4,33 (t, 2H), 7,33 (d, 1H), of 8.37 (DD, 1H), scored 8.38 (s, 2H), to 8.45 (s, 1H). MS m/z 434,5 (M+1).

3g:The TFA salt of 6-{4-[3-((S)-2-methoxy-1-methylethylamine)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD)δ: 1,37 (d, 3H), 2,28 (m, 2H), and 3.31 (m, 2H), 3.43 points (s, 3H), 3.46 in of 3.56 (m, 2H), to 3.67 (DD, 1H), was 4.02 (s, 3H), 4,33 (t, 2H), 7,33 (d, 1H), of 8.37 (DD, 1H), scored 8.38 (s, 2H), to 8.45 (s, 1H). MS m/z 448 (M+1).

3h:The TFA salt of 1-methyl-6-{4-[3-(1-methylpiperidin-4-ylamino)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 2,00 (m, 2H), 2,30 (m, 2H), 2,41 (m, 2H), 2.91 in (s, 3H), 3,07-up 3.22 (m, 2H), 3,35 (m, 2H), 3,53 (m, 1H), 3,68 (m, 2H), was 4.02 (s, 3H), 4,34 (t, 2H), 7,33 (d, 1H), of 8.37 (DD, 1H), 8,39 (s, 2H), 8,45 (, 1H). MS m/z 473 (M+1).

3i:The TFA salt of 1-methyl-6-[4-(3-{[(S)-1-(tetrahydrofuran-2-yl)methyl]amino}propoxy)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 1,65 (m, 1H), up to 1.98 (m, 2H), 2,15 (m, 1H), to 2.29 (m, 2H), 3.00 and-3,26 (m, 2H), and 3.31 (m, 2H), 3,83 (m, 1H), 3,94 (m, 1H), was 4.02 (s, 3H), 4,17 (m, 1H), 4,33 (t, 2H), 7,33 (d, 1H), of 8.37 (DD, 1H), scored 8.38 (, 2H), 8,44 (s, 1H). MS m/z 460 (M+1).

3j:The TFA salt of 6-(4-{3-[(1-hydroxyisopropyl)amino]propoxy}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 0,74 (t, 1H), of 0.91 (t, 1H), 2,32 (m, 2H), 2,97 (s, 2H), 3,35 (m, 2H), was 4.02 (s, 3H), 4,34 (m, 2H), 7,35 (d, 1H), 8,39 (DD, 1H), 8,40 (s, 2H), to 8.45 (s, 1H). MS m/z 446 (M+1).

3k:The TFA salt of 6-{4-[3-(4-hydroxycyclohexanone)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 1,32-of 1.52 (m, 4H), 2,07 (m, 2H), 2,16 (m, 2H), and 2.26 (m, 2H), 3,13 (m, 1H), 3,30 (m, 2H), only 3.57 (m, 1H), was 4.02 (s, 3H), 4,36 (t, 2H), 7,35 (d, 1H), 8,39 (DD, 1H), to 8.41 (s, 2H), to 8.45 (s, 1H). MS m/z 474 (is+1).

EXAMPLE4a

Hydrochloride of 1-methyl-6-{3-(trifluoromethyl)-4-[3-(3,3,4-trimethylpyrazine-1-yl)propoxy]phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)propylenecarbonate (200 mg) and 1,2,2-trimethylpyrazine (226 mg) in TMR (2 ml) was heated at 120°C in a microwave conditions for 20 minutes. The product is then purified HPLC, while receiving 1-methyl-6-{3-(trifluoromethyl)-4-[3-(3,3,4-trimethylpyrazine-1-yl)propoxy]phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA. The above salt FA then was dissolved in Meon (3 ml) and passed through a column of strong effects for cation-exchanger. After washing with methanol to remove the rest TFA, the product was washed with 2 M ammonia in methanol. Then after removal of the solvent was obtained the free base of 1-methyl-6-{3-(trifluoromethyl)-4-[3-(3,3,4-trimethylpyrazine-1-yl)propoxy]phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile. This free base was then dissolved in a mixture of THF-Meon (5:1, 4 ml) was added 2 M HCl in diethyl ether (1 ml). After removal of all solvent under reduced pressure the hydrochloride of 1-methyl-6-{3-(trifluoromethyl)-4-[3-(3,3,4-trimethylpyrazine-1-yl)propoxy]phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (125 mg) was obtained as a white solid.

1H NMR (CD3OD) δ: 8,73 (s, 1H), and 8.50 (s, 1H), 8,42 (s,1H), to 8.40 (d, 1H), 7,38 (d, 1H), 4,35 (t, 2H), 4,08 (s, 3H), 3,2-4,0 (user., 4H, the atoms H of piperazine ring), 3,7 (user., 2H), 3.45 points (t, 2H), 2,93 (s, 3H), 2,4 (m, 2H), of 1.62 (s, 6H). MS m/z 487 (M+H).

The procedure described in example4A, was then applied using suitable derivatives of piperazine to obtain the following compounds as either TFA salt, free base or HCl salt.

4b:The hydrochloride of 6-{4-[3-(3,3-dimethylpiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

This reaction was carried out at room temperature for 72 hours.

1H NMR (CD3OD) δ: 8,64 (s, 1H), 8,46 (s, 1H), 8,42 (s, 1H), 8,40 (d, 1H), 7,38 (d, 1H), 4,36 (t, 2H), 4,06 (s, 3H), 3,66 (user., 2H), 3.45 points (t, 2H), 3,3-3,7 (user., 4H, the atoms H of piperazine ring), a 2.45 (m, 2H), of 1.62 (s, 6H). MS m/z 473 (M+H).

4c:The hydrochloride of 6-{4-[3-(CIS-3,5-dimethylpiperazine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

This reaction was carried out at room temperature for 72 hours.

1H NMR (CD3OD) δ: 8,64 (s, 1H), of 8.47 (s, 1H), 8,44 (s, 1H), 8,42 (d, 1H), 7,40 (d, 1H), and 4.40 (t, 2H), 4,08 (s, 3H), of 3.95 (d, 2H), 3,90 (m, 2H), of 3.56 (t, 2H), 3.27 to (m, 2H), 2,48 (m, 2H)and 1.51 (d, 6H). MS m/z 473 (M+H).

4d:Hydrochloride of 1-methyl-6-{4-[3-(piperazine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

This reaction was carried out at room temperature for 72 hours.

1H NMR (the D 3OD) δ: cent to 8.85 (s, 1H), 8,53 (s, 1H), 8,42 (s, 1H), 8,40 (d, 1H), 7,39 (d, 1H), to 4.38 (t, 2H), 4,10 (s, 3H), 3,7 (user., 2H), 3,55 (t, 2H), 3,2-4,0 (user., 8H, the atoms H piperazine), a 2.45 (m, 2H). MS m/z 445 (M+H).

4e:Hydrochloride of 1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,59 (s, 1H), 8,45 (s, 1H), 8,42 (s, 1H), 8,40 (d, 1H), 7,39 (d, 1H), 4,37 (t, 2H), of 4.05 (s, 3H), 3,2-4,1 (user., 8H, the atoms H piperazine), and 3.5 (m, 2H), 3,05 (s, 3H), of 2.45 (m, 2H). MS m/z 459 (M+H).

4f:The hydrochloride of 6-{4-[3-(4-ethylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,84 (s, 1H), charged 8.52 (s, 1H), to 8.41 (s, 1H), 8,40 (d, 1H), 7,39 (d, 1H), to 4.38 (t, 2H), 4,10 (s, 3H), 3,2-4,1 (user., 8H, the atoms H piperazine), 3,55 (t, 2H), 3,40 (square, 2H), 2,45 (m, 2H), of 1.44 (t, 3H). MS m/z 473 (M+H).

4g:The hydrochloride of 6-(4-{3-[4-(2-hydroxyethyl)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,71 (s, 1H), 8,49 (s, 1H), 8,42 (s, 1H), 8,40 (d, 1H), 7,39 (d, 1H), to 4.38 (t, 2H), 4,07 (s, 3H), of 3.96 (m, 2H), 3,2-4,1 (user., 8H, the atoms H piperazine), of 3.54 (t, 2H), 3,47 (m, 2H), 2,45 (m, 2H). MS m/z 489 (M+H).

4h:The TFA salt of 1-methyl-6-(4-{3-[4-(2-methoxyethyl)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,32 (d, 1H), 4,30 (t, 2H), was 4.02 (s, 3H), 3,71 (t, 2H), of 3.45 (m, 2H), 3,40 (s, 3H), 3,2-3,5 (user., 8H), 3,17 (t, 2H, in), 2.25 (m, 2H). MS m/z 53 (M+H).

4i:The TFA salt of 6-{4-[3-(4-isopropylpiperazine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,30 (d, 1H), or 4.31 (t, 2H), was 4.02 (s, 3H), 3,3-3,7 (user., 9H, the atoms of the piperazine N + i-PrCH), 3,23 (t, 2H), 2,30 (m, 2H), 1,40 (d, 6H). MS m/z 487 (M+H).

4j:The TFA salt of 1-methyl-6-(4-{3-[4-(2-methoxyethyl)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,32 (d, 1H), 4,30 (t, 2H), was 4.02 (s, 3H), 3,71 (t, 2H), of 3.45 (m, 2H), 3,40 (s, 3H), 3,2-3,5 (user., 8H), 3,17 (t, 2H, in), 2.25 (m, 2H). MS m/z 503 (M+H).

4k:The TFA salt of 1-methyl-6-(4-{3-[4-(2-oxo-2-pyrrolidin-1-retil)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3 an 8.4 (m, 3H), 7,30 (d, 1H), 4,32 (m, 2H), was 4.02 (s, 3H), 3,76 (s, 2H), 3.45 points (square, 4H), 3,40 (m, 5H), and 3.31 (m, 5H), 2,3 (m, 2H), 2.0 (m, 2H), and 1.9 (m, 2H). MS m/z 556 (M+H).

4l:The TFA salt of 1-methyl-6-{4-[3-(4-(pyrimidine-2-reparation-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,42 (d, 2H), 8,3 an 8.4 (m, 3H), 7,33 (d, 1H), 6,74 (t, 1H), 4,34 (t, 2H), was 4.02 (s, 3H), 3,0-3,7 (user., 8H, the atoms H piperazine), of 3.45 (t, 2H), is 2.37 (m, 2H). MS m/z 523 (M+H).

4m:The TFA salt of 1-methyl-6-{4-[3-(4-pyridine-2-reparation-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,46 (s, 1H), 835-8,45 (m, 3H), 8,17 (DD, 1H), 7,80 (t, 1H), 7,37 (d, 1H), 7,10 (d, 1H), 6,91 (t, 1H), 4,36 (t, 2H), a 4.03 (s, 3H), 3.7 to 4.1 (user., 8H, the atoms H piperazine), of 3.45 (t, 2H), 2.40 a (m, 2H). MS m/z 522 (M+H).

4n:1-Methyl-6-{4-[3-(3-oxopiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,46 (s, 1H), 8,69 (s, 1H), to 8.62 (s, 1H), 8,35 to 8.5 (m, 2H), 7,52 (d, 1H), 4,25 (t, 2H), 3,99 (s, 3H), 3,2 (user., 2H), 2,98 (user., 2H), 2,6 (user., 4H), 2,0 (user., 2H). MS m/z 459 (M+H).

4o:The TFA salt of 6-{4-[3-(4-acetylpiperidine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,43 (s, 1H), 8,3 an 8.4 (m, 3H), 7,28 (d, 1H), 4,32 (t, 2H), 4,01 (s, 3H), 3,1-3,7 (user., 8H, the atoms H piperazine), of 3.45 (t, 2H), of 2.38 (m, 2H), 2,17 (s, 3H). MS m/z 487 (M+H).

4p:The TFA salt of 6-(4-{3-[4-(etoxycarbonyl)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,3 an 8.4 (m, 3H), 7,30 (d, 1H), 4,32 (t, 2H), 4,19 (square, 2H), was 4.02 (s, 3H), 3,1-3,7 (user., 8H, the atoms H piperazine), of 3.43 (t, 2H), of 2.38 (m, 2H), of 1.29 (t, 3H). MS m/z 517 (M+H).

4q.:The TFA salt of 6-(4-{3-[4-(dimethylaminoethyl)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: at 2.36 (m, 2H), 2.91 in (s, 6H), 3,29-of 3.32 (m, 7H), of 3.43 (m, 3H), was 4.02 (s, 3H), 4,33 (t, 2H), 7,33 (d, 1H), of 8.37 (m, 1H), scored 8.38 (s, 2H), to 8.45 (s, 1H). MS m/z 516 (M+1).

4r:The TFA salt of 1-methyl-6-{4-[3-(4-pyridin-4-reparation-1-yl)propoxy]-3-(cryptomite is)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 2,39 (m, 2H), 3,44 (m, 2H), 3,54 (user. s, 4H), was 4.02 (s, 3H), 4,07 (user. s, 4H), 4,36 (t, 2H), 7,31 (d, 2H), 7,35 (d, 1H), 8,27 (d, 2H), 8,39 (DD, 1H), to 8.41 (s, 2H), to 8.45 (s, 1H). MS m/z 522 (M+1).

4s:The TFA salt of 1-methyl-6-{4-[3-(6-methyl-6,9-diazaspiro[4,5]Dec-9-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 1,62-1,84 (user. m, 4H), 1,84-2,02 (user. m, 4H), of 2.08 (m, 2H), 2,58-3,00 (user. m, 6H), by 2.73 (t, 2H), 2,82 (s, 3H), was 4.02 (s, 3H), 4,28 (t, 2H), 7,33 (d, 1H), at 8.36 (DD, 1H), 8,39 (s, 2H), to 8.45 (s, 1H). MS m/z 513 (M+1).

4t:The TFA salt of 6-{4-[(R)-3-(hexahydropyrazino[1,2-a]pyrazin-2-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: of 1.88 (m, 1H), 2,08-2,30 (user. m, 5H), 2,80 (t, 1H), 2.95 and (t, 1H), 3,06 (m, 2H), 3,18 (m, 1H), 3,30 (m, 2H), 3,40-3,65 (user. m, 4H), was 4.02 (s, 3H), 4,30 (t, 2H), 7,32 (d, 1H), 8,35 (m, 1H), scored 8.38 (s, 2H), to 8.45 (s, 1H).

MS m/z 485 (M+1).

EXAMPLE5a

Hydrochloride of 1-methyl-6-(4-{3-[4-(N-methylaminomethyl)piperidine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl]-2-(trifluoromethyl)phenoxy)propylenecarbonate (83 mg) and N-methylpiperidin-4-carboxamide (78 mg) in TMR (1 ml) was heated at 120°C in a microwave conditions for 20 minutes. The product is then purified HPLC, while receiving the expected p is oduct, 1-methyl-6-(4-{3-[4-(N-methylaminomethyl)piperidine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile, as TFA salt. The above salt FA then was dissolved in Meon (3 ml) and passed through a column of strong effects for cation-exchanger. After washing with methanol to remove the rest FA product was washed with 2 M ammonia in methanol. Then after removal of the solvent was obtained the free base of 1-methyl-6-(4-{3-[4-(N-methylaminomethyl)piperidine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. This free base was dissolved in a mixture of THF-Meon (5:1, 4 ml) and then was added 2 M HCl in diethyl ether (1 ml). After removal of all solvent under reduced pressure the hydrochloride of 1-methyl-6-(4-{3-[4-(N-methylaminomethyl)piperidine-1-yl]propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (64 mg) was obtained as a white solid.1H NMR (CD3OD) δ: 8,66 (s, 1H), 8,48 (s, 1H), 8,42 (s, 1H), 8,40 (d, 1H), 7,33 (d, 1H), 4,33 (t, 2H), 4,06 (s, 3H), 3,70 (t OSiR., 2H), 3,49 (user., 1H), 3,37 (t, 2H), is 3.08 (t, 2H), 2,74 (s, 3H), by 2.55 (m, 1H), 2,35 (m, 2H), 2,1 (m, 2H), 2.0 (m, 2H). MS m/z 501 (M+H).

The procedure described in example5Athat was further applied, using the appropriate amine derivative to obtain the following compounds as either TFA salt, free base or HCl salt.

5b:The TFA salt of 6-(4-{3-[(R)-2-(aminocarbonyl)pyrrolidin-1-yl]propoxy}--(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,71 (s, 1H), 8,64 (s, 1H), 8,48 (d, 1H), 8,42 (s, 1H), 8,12 (s, 1H), 7,88 (s, 1H), 7,42 (d, 1H), 4,35 (m, 2H), 4,12 (m, 1H), 3,99 (s, 3H), 3,69 (user. m, 1H), 3,38 (user. m, 2H), 3,25 (user. m, 1H), 2.49 USD (m, 1H), 2,18 (m, 2H), 2,08 (m, 1H), of 1.88 (m, 2H). MS m/z 473 (M+1).

EXAMPLE6a

The TFA salt of 6-(4-{3-[N-(2-dimethylaminoethyl)-N-methylamino]propoxy}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)propylenecarbonate (20 mg) and N,N',N'- trimethylethylenediamine (22 mg) in TMR (1 ml) was heated at 100°C in a microwave conditions for 20 minutes. The product is then purified HPLC, while receiving 6-(4-{3-[N-(2-dimethylaminoethyl)-N-methylamino]propoxy}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA.

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,28 is 8.38 (m, 3H), 7,30 (d, 1H), 4,32 (t, 2H), was 4.02 (s, 3H), 3,70 (m, 4H), of 3.48 (t, 2H), 3,03 (s, 3H), 2,98 (s, 6H), 2,39 (m, 2H). MS m/z 461 (M+H).

The procedure described in example6A, was then applied using suitable derivatives bisamine to obtain the following compounds as either TFA salt, free base or HCl salt.

6b:The TFA salt of 1-methyl-6-(4-{3-[N-(2-morpholine-4-retil)amino]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,44 (s, 1H), 8,25 is 8.38 (who, 3H), 7,29 (d, 1H), 4,33 (t, 2H), 4,01 (s, 3H), of 3.94 (t, 4H), to 3.58 (t, 2H), 3,51 (t, 2H), 3,3-of 3.45 (m, 6H), 2,32 (m, 2H). MS m/z 489 (M+H).

6c:The TFA salt of 1-methyl-6-(4-{3-[4-(pyrrolidin-1-yl)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,35-8,43 (m, 3H), 7,32 (d, 1H), 4,33 (t, 2H), a 4.03 (s, 3H), and 3.7 (m, 2H), 3,48 (m, 1H), 3,38 (t, 2H), 3,7 (user., 2H), 3,15 (user., 4H), 2,5 (m, 2H), 2,35 (m, 2H), 2,0-2,3 (m, 6H). MS m/z 513 (M+H).

6d:The TFA salt of 6-[4-(3-[1,4]diazepan-1 ipropose)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,33-to 8.45 (m, 4H), 7,32 (d, 1H), 4,34 (t, 2H), was 4.02 (s, 3H), 3,76 (m, 2H), 3,68 (m, 2H), only 3.57 (m, 2H), 3,47 (4H), to 2.35 (m, 4H). MS m/z 459 (M+H).

6e:The TFA salt of 1-methyl-6-{4-[3-(4-methyl[1,4]diazepan-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 2,33 (m, 4H), to 2.99 (s, 3H), 3,40 (t, 2H), 3,51 (user. s, 4H), of 3.75 (s, 4H), was 4.02 (s, 3H), 4,33 (t, 2H), 7,34 (d, 1H), of 8.37 (DD, 1H), 8,39 (s, 2H), to 8.45 (s, 1H). MS m/z 473 (M+1).

6f:The TFA salt of 6-{4-[(1R,5S)-3-(3,8-diazabicyclo[3.2.1]Oct-3-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: a 2.01 (m, 4H), 2,10 (m, 2H), 2,48 (d, 2H), 2,68 (t, 2H), 2,93 (d, 2H), 3,99 (user. s, 2H), a 4.03 (s, 3H), 4,28 (t, 2H), 7,34 (d, 1H), of 8.37 (m, 1H), 8,39 (s, 2H), 8,44 (s, 1H). MS m/z 471 (M+1).

6g:The TFA salt of 6-{4-[3-((S)-3-dimethylaminopropan-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-it is dazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 2,35 (m, 3H), of 2.66 (m, 1H), 2,98 (s, 6H), 3,30 (m, 2H), 3,50 (m, 2H), 3,70-4,00 (user. m, 2H), was 4.02 (s, 3H), 4,18 (m, 1H), 4,33 (t, 2H), 7,33 (d, 1H), at 8.36 (m, 1H), scored 8.38 (s, 2H), to 8.45 (s, 1H). MS m/z 473 (M+1).

6h:The TFA salt of 6-{4-[3-((R)-3-dimethylaminopropan-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 2,35 (m, 3H), of 2.66 (m, 1H), 2,96 (s, 6H), 3,30 (m, 2H), 3,50 (m, 2H), 3,70-4,00 (user. m, 2H), was 4.02 (s, 3H), 4,18 (m, 1H), 4,33 (t, 2H), 7,33 (d, 1H), at 8.36 (DD, 1H), scored 8.38 (s, 2H), to 8.45 (s, 1H). MS m/z 473 (M+1).

EXAMPLE7a

The TFA salt of 1-methyl-6-{4-[3-(2-Mei-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)propylenecarbonate (20 mg) and 2-methylimidazole (22 mg) in TMR (1 ml) was heated at 120°C. in microwave for 50 minutes. The product is then purified HPLC, while receiving the expected product, 1-methyl-6-{4-[3-(2-Mei-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA.

1H NMR (CD3OD) δ: 8,48 (s, 1H), 8,35-to 8.45 (m, 3H), 7,54 (d, 1H), of 7.48 (d, 1H), 7,35 (d, 1H), 4,43 (t, 2H), or 4.31 (t, 2H), 4,06 (s, 3H), 2,68 (s, 3H), 2,48 (m, 2H). MS m/z 441 (M+H).

The procedure described in example7a, was then applied using suitable starting compounds to obtain the following compounds as TFA salt.

7b The TFA salt of 6-{4-[3-(2-ethylimidazole-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,35-8,44 (m, 3H), 7,54 (d, 1H), of 7.48 (d, 1H), 7,35 (d, 1H), 4,42 (t, 2H), 4,29 (t, 2H), a 4.03 (s, 3H), 3.04 from (square, 2H), 2,68 (s, 3H), 2,43 (m, 2H), 1.39 in (t, 3H). MS m/z 455 (M+H).

7c:The TFA salt of 1-methyl-6-{4-[3-(4,5,6,7-tetrahydroimidazo-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,56 (s, 1H), 8,45 (s, 1H), 8,35-8,43 (m, 3H), 7,32 (d, 1H), 4,35 (t, 2H), 4,28 (t, 2H), a 4.03 (s, 3H), 2,65 (m, 4H), is 2.37 (m, 2H), 1,90 (m, 4H). MS m/z 481 (M+H).

EXAMPLE8

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

A:2-(4-Bromo-2-(trifluoromethyl)phenoxy)ethanol

2-Bromoethanol (23.3 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)phenol (30 g) and potassium carbonate (34.4 g) in acetonitrile (200 ml). The above mixture was boiled under reflux for 8 hours, then added another portion of 2-bromoethanol (8 g) and kept boiling under reflux for a further 6 hours. After dilution with ethyl acetate (500 ml) and the mixture was washed with water (300 ml), then 0.1 M sodium hydroxide (200 ml). The organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure, the residue was dissolved in heptane by heating, 2-(4-bromo-2-(trifluoromethyl)phenoxy)ethane what l was led and collected by filtration (17 g).

1H NMR (DCl3) δ: of 7.69 (d, 1H), to 7.59 (DD, 1H), 6.90 to (d, 1H), 4,15 (t, 2H), of 3.97 (t, 2H).

B:2-(2-(4-Bromo-2-(trifluoromethyl)phenoxy)ethoxy)tetrahydro-2H-Piran

A mixture of 2-(4-bromo-2-(trifluoromethyl)phenoxy)ethanol (16 g), 3,4-dihydro-2H-Piran (9.5 g) and the hydrate p-toluensulfonate acid (0.5 g) in THF (100 ml) was stirred at room temperature for 1 hour, then diluted with 5% sodium bicarbonate (300 ml) and was extracted with ethyl acetate (500 ml). The organic layer was then dried over sodium sulfate, the solvent was removed under vacuum, thus obtaining the intended product (21 g).

1H NMR (DCl3) δ: to 7.67 (d, 1H), 7,58 (DD, 1H), 6,93 (d, 1H), 4,71 (m, 1H), 4,23 (t, 2H), 4,08 (m, 1H), 3.75 to 3,95 (m, 2H), 3,53 (m, 1H), of 1.5-1.9 (m, 6H).

C:4-(2-(Tetrahydro-2H-Piran-2-yloxy)ethoxy)-3-(trifluoromethyl)phenylboronic acid

BuLi (2.5 M, 6 ml) was added dropwise to a solution of 2-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethoxy)tetrahydro-2H-Piran (5 g) in THF (50 ml) at -78°C in an atmosphere of N2within 3 minutes. After stirring at -78°C for another 10 minutes and then for 2 minutes at -78°C was added dropwise triisopropylsilyl (3.8 ml). The mixture was stirred at -78°C for another 30 minutes, then slowly warmed up to room temperature and was stirred at room temperature for 30 minutes. The mixture was then extinguished acetic acid (10% in water, 20 ml), was extracted with EtOAc (300 ml), washed with water (200 ml× 3), was dried over sodium sulfate, the solvent was removed under reduced pressure, the residue was dissolved in toluene and then the solvent was removed under reduced pressure for removal of traces of acetic acid (repeated 3 times, until, until there was no odor of acetic acid (4.5 g).

1H NMR (DCl3) δ: scored 8.38 (m, 1H), 8,33 (m, 1H), 7,16 (m, 1H), 4,74 (m, 1H), 4,22 (m, 2H), 4,08 (m, 1H), 3,92-of 3.80 (m, 2H), 3,56-to 3.50 (m, 1H), 1,90 by 1.68 (m, 2H), 1,65 is 1.48 (m, 4H).

D:4-(2-Hydroxyethoxy)-3-(trifluoromethyl)phenylboronic acid

4-(2-(Tetrahydro-2H-Piran-2-yloxy)ethoxy)-3-(trifluoromethyl)phenylboronic acid (8 g) was added to hydrochloric acid (1 M in Meon) and the mixture was heated at 60°C for 60 minutes. The solvent and HCl was then removed under reduced pressure and the residue (5,52 g) was used for the next stage without additional purification.

1H NMR (CDCl3(0.7 ml) + CD3OD (0.2 ml)) δ: of 7.97 (s, 1H), 7,88 (d, 1H), 7,0 (d, 1H), 4,19 (t, 2H), 3,98 (t, 2H).

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

A mixture of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.75 g), 4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenylboronic acid (1,46 g), Tris(dibenzylideneacetone)diplegia (0.18 g), tricyclohexylphosphine (0,13 g) and tribalista (1.65 g) in dioxane (7.5 ml) and water (3 ml) was heated at 100°C in an atmosphere of N2within 3 hours. The mixture is then razbavitelyami (100 ml), the organic layer was separated and the solvent was removed under reduced pressure, the residue is then passed through a column of silica gel using a mixture of DC-Meon (3%) as eluent, thus obtaining 6-[4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.07 g).

1H NMR (DMSO) δ: 8,65 (s, 1H), at 8.60 (s, 1H), 8,40 (d, 1H), 8,39 (s, 1H), 7,43 (d, 1H), 4,9 (t, 1H), 4,25 (t, 1H), of 3.97 (s, 3H), 3,30 (m, 1H). MS m/z 363 (M+H).

EXAMPLE9a

The TFA salt of 6-{4-[2-(6,9-diazaspiro[4,5]Dec-9-yl)ethoxy]-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A:2-(4-(4-Cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate

Methanesulfonanilide (0,23 ml) was added dropwise to a solution of 6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0,77 g) and diisopropylethylamine (1.2 ml) in TMR (6 ml). The mixture was stirred at room temperature for 3 hours. After adding cold water (20 ml), the solid product was collected by filtration, washed with cold ethanol (20 ml), thus obtaining 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate (0,89 g).1H NMR (DMSO) δ: 8,72 (s, 1H), 8,64 (s, 1H), of 8.47 (d, 1H), 8,43 (s, 1H), of 7.48 (d, 1H), 4,58 (t, 2H), 4,51 (t, 2H), 3,99 (s, 3H), 3,23 (s, 3H). MS m/z 441 (M+1).

B:The TFA salt of 6-{4-[2-(6,9-diazaspiro[4,5]Dec-9-yl)ethoxy]3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate (20 mg) and 6.9-diazaspiro[4,5]decane (33 mg) in TMR (1 ml) was stirred at room temperature for 72 hours. The product was then HPLC purified, thus obtaining the intended product, 6-{4-[2-(6,9-diazaspiro[4,5]Dec-9-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile, in the form of a salt FA.1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3-8,43 (m, 3H), 7,34 (d, 1H), 4,36 (t, 2H), was 4.02 (s, 3H), 3,26 (t, 2H), to 3.02 (t, 2H), 2,90 (user., 2H), 2,77 (s, 2H), 2.05 is (m, 2H), 1,6-1,9 (m, 6H). MS m/z 485 (M+H).

The procedure described in example9athat was further applied, using the appropriate amine derivative to obtain the following compounds as either TFA salt, free base or HCl salt.

9b:The TFA salt of 6-{4-[2-(3,3-dimethylpiperidin-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3-8,43 (m, 3H), 7,34 (d, 1H), 4,36 (t, 2H), was 4.02 (s, 3H), of 3.28 (t, 2H), to 3.02 (t, 2H), 2,92 (user., 2H), a 2.75 (s, 2H), of 1.42 (s, 6H). MS m/z 459 (M+H).

9c:The TFA salt of 1-methyl-6-{4-[2-(piperazine-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3CN) δ: at 8.60 (s, 1H), 8,56 (d, 1H), 8,48 (s, 1H), 8,45 (s, 1H), 7,51 (d, 1H), 4.72 in (t, 2H), 4,14 (s, 3H), to 3.58-to 3.73 (m, 10H). MS m/z 431 (M+H).

9d:6-{4-[2-(CIS-3,5-Dimethylpiperazine-1-yl)ethoxy]-3-(t is iformity)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ: 8,28 (d, 1H), they were 8.22 (s, 1H), 8,08 (s, 1H), 7,87 (s, 1H), 7,12 (d, 1H), 4,28 (t, 2H), 3,99 (s, 3H), 3,49 (s, 1H), 2,85 was 3.05 (m, 6H), of 1.88 (t, 2H), of 1.09 (d, 6H). MS m/z 459 (M+H).

9e:6-{4-[2-(4-Isopropylpiperazine-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDl3) δ: of 8.27 (d, 1H), they were 8.22 (s, 1H), 8,08 (s, 1H), 7,87 (s, 1H), 7,11 (d, 1H), 4,28 (t, 2H), 3,99 (s, 3H), of 2.92 (t, 2H), 2,5-2,8 (user., 9H, the H atoms of the piperazine + CH of isopropyl), a 1.08 (d, 6H). MS m/z 473 (M+H).

EXAMPLE10a

The TFA salt of 1-methyl-6-{4-[2-(2-Mei-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate (20 mg) and 2-methylimidazole (20 mg) in TMR (1 ml) was heated using microwave conditions at 120°C for 40 minutes. The product was then HPLC purified, thus obtaining the intended product, 1-methyl-6-{4-[2-(2-Mei-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile, in the form of a salt FA.

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,3-8,43 (m, 3H), to 7.61 (d, 1H), 7,50 (d, 1H), 7,37 (d, 1H), 4,69 (t, 2H), 4,59 (t, 2H), was 4.02 (s, 3H), of 2.75 (s, 3H). MS m/z 427 (M+H).

The procedure described in example10Athat was further applied, using the appropriate amine derivatives/imidazole to obtain the following compounds or salts TFA, HCl salt or a neutral soy is inane.

10b:The TFA salt of 1-methyl-6-{4-[2-(4,5,6,7-tetrahydroimidazo-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,76 (s, 1H), 8,46 (s, 1H), 8,3-8,43 (m, 3H), of 7.36 (d, 1H), 4,66 (t, 2H), 4,55 (t, 2H), was 4.02 (s, 3H), was 2.76 (m, 2H), 2,68 (m, 2H), 1.85 to 2.05 is (m, 4H). MS m/z 467 (M+H).

10c:1-Methyl-6-{4-[2-(4-(2-methoxyethyl)piperazine-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDl3) δ: of 8.27 (d, 1H), they were 8.22 (s, 1H), 8,08 (s, 1H), 7,87 (s, 1H), 7,11 (d, 1H), 4,28 (t, 2H), 3,99 (s, 3H), 3,53 (t, 2H), on 3.36 (s, 3H), of 2.92 (t, 2H), 2,5-2,8 (user., 10H). MS m/z 489 (M+H).

10d:6-(4-{2-[4-(2-Hydroxyethyl)piperazine-1-yl]ethoxy}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-Spiridon-4-carbonitril

1H NMR (CDl3) δ: of 8.27 (d, 1H), they were 8.22 (s, 1H), 8,08 (s, 1H), 7,87 (s, 1H), 7,12 (d, 1H), 4,28 (t, 2H), 3,99 (s, 3H), of 3.65 (t, 2H), 2,92 (t, 2H), 2,5-2,8 (user., 10H). MS m/z 475 (M+H).

10e:1-Methyl-6-(4-{2-[4-(pyridin-4-yl)piperazine-1-yl]ethoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,72 (s, 1H), 8,64 (s, 1H), 8,44 (m, 1H), 8,42 (s, 1H), 8,15 (d, 2H), 7,49 (m, 1H), 6,83 (d, 2H), 4,37 (m, 2H), 3,99 (s, 3H), 3,30 (m, 4H), 2,84 (m, 2H), 2,66 (m, 4H). MS m/z 508 (M+1).

EXAMPLE11

1-Methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-diazaspiro[4.5]Dec-3-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of 8-methyl-1,3,8-diazaspiro[4.5]decane-2,dione (40 mg) in DMF (0.6 ml) was added to a solution of 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate (50 mg) in DMF (0.4 ml), K2CO3(41 mg) and tetrabutylammonium iodide (TV, 26 mg). The mixture was stirred at 90°C for 14 hours. The crude mixture was directly purified preparative HPLC (HPLC: column, XBridge MS C18 30×100 mm, 5 μm, eluent: A: NH4HCO3, 10 mmol, pH=9.5/B: acetonitrile, focused gradient/8 minutes/50 ml/min), while receiving 1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-diazaspiro[4.5]Dec-3-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg).

1H NMR (DMSO) δ: 8,77 (user. s, 1H), 8,72 (s, 1H), 8,64 (s, 1H), 8,43 (m, 1H), 8,39 (s, 1H), 8,16 (user. s, 1H), 7,47 (m, 1H), to 4.41 (m, 2H), 3,99 (s, 3H), 3,81 (m, 2H), by 2.73 (m, 2H), 2,33 (m, 2H), of 2.23 (s, 3H), of 1.86 (m, 2H)and 1.51 (m, 2H). MS m/z 528 (M+1).

EXAMPLE12

6-{4-[2-(2,4-Dioxo-1,3,8-diazaspiro[4.5]Dec-3-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A solution of 8-tert-butoxycarbonyl-1,3,8-diazaspiro[4.5]decane-2,4-dione (75 mg) in DMF (1 ml) was added to a solution of 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate (90 mg) in DMF (1 ml), K2CO3(83 mg) and TWA (48 mg). The mixture was stirred overnight at 90°C. the Solvent was removed under reduced pressure. The residue was distributed between ethyl acetate (50 ml) and a saturated solution of Na2CO3(20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure, p is the best at this, tert-butyl ester 3-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-triptoreline)ethyl)-2,4-dioxo-1,3,8-diazaspiro[4.5]decane-8-carboxylic acid (70 mg). The crude product was dissolved in Meon (2 ml) was added 5 n HCl in iPrOH (0.05 ml). The mixture was stirred 2 hours at 60°C. the solvent is then evaporated under reduced pressure. The crude product was purified preparative HPLC (HPLC: column, XBridge MS C18 30×100 mm, 5 μm, eluent: A: NH4HCO3, 10 mmol, pH=9.5/B: acetonitrile, focused gradient/8 minutes/50 ml/min), while receiving 6-{4-[2-(2,4-dioxo-1,3,8-diazaspiro[4.5]Dec-3-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (23 mg).

1H NMR (DMSO) δ: 8,82 (user. s, 1H), 8,71 (s, 1H), 8,64 (s, 1H), 8,43 (m, 1H), scored 8.38 (s, 1H), 7,47 (m, 1H), to 4.41 (m, 2H), with 3.89 (s, 3H), 3,80 (m, 2H), 2,87 (m, 2H), 2,71 (m, 2H), 1,73 (m, 2H), 1,38 (m, 2H). MS m/z 514 (M+1).

EXAMPLE13a

Hydrochloride of 1-methyl-6-{4-[2-(6-methylpyridin-2-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A:4-Bromo-1-(2-methoxyethoxyethoxy)-2-cryptomaterial

Sodium hydride (60% wt./mass. the dispersion in mineral oil, 0.96 g) was added to a solution of 4-bromo-2-triptoreline (5.0 g) in dry THF (200 ml) and the mixture was stirred for 30 minutes. Then added 1 chloromethoxy-2-methoxyethane (2,85 ml) and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and tert-butyllithium simple ether, the organic layer was washed saturated with the second salt solution, was dried over sodium sulfate and concentrated under reduced pressure, thus obtaining 4-bromo-1-(2-methoxyethoxyethoxy)-2-triptoreline (6.4 g) in the form of oil.

1H NMR (CDCl3) δ: of 7.69 (m, 1H), 7,53 (m, 1H), 7,19 (m, 1H), 5,33 (s, 2H), 3,83 (m, 2H), 3,55 (m, 2H), 3,37 (s, 3H).

B:4-(2-Methoxyethoxyethoxy)-3-triftormetilfullerenov acid

n-Utility (2.5 M solution in hexane, to 91.2 ml) was added dropwise to a solution of 4-bromo-1-(2-methoxyethoxyethoxy)-2-triptoreline (30 g) in dry THF (335 ml) at -78°C under nitrogen atmosphere. The mixture was then stirred at -78°C for another 30 minutes. Then at -78°C under nitrogen atmosphere was slowly added triisopropylsilyl (101 ml), the mixture was then allowed to slowly warm to room temperature and stirred at this temperature over night. After adding water (300 ml) the mixture was extracted with ethyl acetate (300 ml × 3). The combined organic layers were dried over sodium sulfate. After removal of the solvent under reduced pressure the residue was passed through a column of silica gel using DC-Meon as the eluent, thus obtaining 4-(2-methoxyethoxyethoxy)-3-triftormetilfullerenov acid (14.4 g).

1H NMR (CDCl3) δ: scored 8.38 (m, 1H), 8,33 (m, 1H), 7,42 (m, 1H), 5,46 (s, 2H), 3,86 (m, 2H), of 3.56 (m, 2H), 3,38 (s, 3H).

C:6-(4-(2-Methoxyethoxyethoxy)-3-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbon is home to the thrill

A mixture of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (5.9 g), 4-(2-methoxyethoxyethoxy)-3-triftormetilfullerenov acid (9,92 g), potassium phosphate (11.1 g), Tris(dibenzylideneacetone)diplegia (1.4 g) and tricyclohexylphosphine (1,03 g) in dioxane (190 ml) and water (60 ml) was heated at 100°C in nitrogen atmosphere for 2 hours. After cooling to room temperature the mixture was then extracted with ethyl acetate (500 ml × 2), the combined organic layers were dried over sodium sulfate and the solvent was then removed under reduced pressure. To the residue was then added methanol (20 ml) and the solid product, 6-(4-(2-methoxyethoxyethoxy)-3-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile, collected by filtration (of 8.95 g).

1H NMR (CDCl3) δ: of 8.27 (m, 1H), 8,19 (m, 1H), 8,10 (s, 1H), 7,88 (s, 1H), 7,42 (m, 1H), 5,44 (s, 2H), 3,99 (s, 3H), 3,88 (m, 2H), to 3.58 (m, 2H), 3,38 (s, 3H). MS m/z 407 (M+1).

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

6-(4-(2-Methoxyethoxyethoxy)-3-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (7.5 g) was added to a mixed solvent of THF (300 ml) and 1 M HCl (aqueous). The mixture was heated to 65°C. until complete disappearance of all starting compound. After adding a saturated solution of sodium chloride (200 ml) the mixture was extracted with ethyl acetate (300 ml × 3) and the combined organic layers were then dried over with what LifeCam sodium, the solvent was removed under reduced pressure and the residue triturated in a simple ether. The product, 6-(4-hydroxy-3-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (5.9 g)was collected by filtration.

1H NMR (CD3OD) δ: to 8.45 (s, 1H); 8.34 per (s, 1H); 8,29 (s, 1H); to 8.20 (m, 1H); to 7.09 (m, 1H); Android 4.04 (s, 3H). MS m/z 319 (M+1).

E:Hydrochloride of 1-methyl-6-{4-[2-(6-methylpyridin-2-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Diisopropylethylamine (80 mg) was added under stirring at room temperature in a nitrogen atmosphere to a mixture of 6-(4-hydroxy-3-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (42 mg)associated with the resin triphenylphosphine (3 mmol/g, 130 mg) and 2-(6-methylpyridin-2-yl)ethanol (54 mg) in DC (2 ml). The mixture was then shaken for 8 hours. After separation of the resin by filtration, the filtrate was concentrated under reduced pressure and the residue was purified HPLC, while receiving 1-methyl-6-{4-[2-(6-methylpyridin-2-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA. This salt was then converted into the free base and the HCl salt using the method described in example 2.

1H NMR (CD3OD) δ: charged 8.52 (s, 1H), 8,35 to 8.5 (m, 4H), 7,92 (d, 1H), 7,82 (d, 1H), 7,39 (d, 1H), 4,63 (t, 2H), a 4.03 (s, 3H), 3,61 (t, 2H), and 2.83 (s, 3H). MS m/z 438 (M+1).

The procedure described in example13A, was then applied using suitable p is ossadnik alcohols to obtain the following compounds as either TFA salt, the neutral compound or salt of HCl.

13b:Hydrochloride of 1-methyl-6-{4-[2-(5-methylpyridin-2-yl)ethoxy]-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,68 (s, 1H), 8,59 (s, 1H), 8,35 to 8.5 (m, 4H), 8,03 (d, 1H), 7,38 (d, 1H), with 4.64 (t, 2H), Android 4.04 (s, 3H), of 3.60 (t, 2H), 2.57 m (s, 3H). MS m/z 438 (M+1).

13c:Hydrochloride of 1-methyl-6-[4-(pyridine-2-ylethoxy)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,72 (s, 1H), 8,69 (d, 1H), 8,64 (s, 1H), 8,45 to 8.5 (m, 2H), 8,03 (t, 1H), 7,66 (d, 1H), 7,55 (d, 1H), 7,49 (t, 1H), 5,49 (s, 2H), 3,99 (s, 3H). MS m/z 410 (M+1).

13d:Hydrochloride of 1-methyl-6-{4-[2-(pyridin-2-yl)ethoxy]-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,80 (d, 1H), to 8.70 (s, 1H), 8,63 (s, 1H), 8,45 (DD, 1H), 8,3 an 8.4 (m, 2H), 7,9 (d, 1H), 7,76 (t, 1H), 7.5 (d, 1H), 4,67 (t, 2H), 3,99 (s, 3H), 3,51 (t, 2H). MS m/z 424 (M+1).

13e:1-Methyl-6-{4-[2-(4-methylthiazole-5-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,86 (s, 1H), 8,72 (s, 1H), 8,64 (s, 1H), 8,44 (d, 1H), 8,40 (s, 1H), 7,44 (d, 1H), to 4.38 (t, 2H), 3,99 (s, 3H), 3,29 (t, 2H), is 2.37 (s, 3H). MS m/z 444 (M+1).

13f:6-[4-(1,5-Dimethyl-1H-pyrazole-3-ylethoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,72 (s, 1H), 8,64 (s, 1H), 8,43 (d, 1H), 8,40 (s, 1H), to 7.59 (d, 1H), 6,11 (s, 1H), 5,19 (s, 2H), 3,99 (s, 3H), and 3.72 (s, 3H), 2,24 (s, 3H). MS m/z 427 (M+1).

13g:1-Methyl-6-{4-[(S)-5-oxo-2-pyrrolidin-2-elmet is XI]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,73 (s, 1H), 8,65 (s, 1H), 8,46 (d, 1H), 8,43 (s, 1H), 7,71 (s, 1H), 7,45 (d, 1H), 4.16 the (s, 2H), 3,99 (s, 3H), 3,95 (user., 1H), 1,9-2,4 (m, 4H). MS m/z 416 (M+1).

13h:1-Methyl-6-[4-(tetrahydrofuran-3-ylethoxy)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,72 (s, 1H), 8,65 (s, 1H), 8,44 (d, 1H), to 8.41 (s, 1H), 7,45 (d, 1H), 4,21 (DD, 1H), 4,18 (DD, 1H), 3,99 (s, 3H), 3,80 (m, 2H), 3,71 (DD, 1H), to 3.67 (DD, 1H), 2,70 (m, 1H), 2.06 to (m, 1H), 1,72 (m, 1H). MS m/z 403 (M+1).

13i:6-[4-(3-Cyanopropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,73 (s, 1H), 8,65 (s, 1H), 8,45 (d, 1H), 8,42 (s, 1H), 7,47 (d, 1H), 4,28 (t, 2H), 3,99 (s, 3H), to 2.67 (t, 2H), 2,11 (m, 2H). MS m/z 386 (M+1).

13j:1-Methyl-6-[4-(4-oxapentane)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,72 (s, 1H), 8,64 (s, 1H), 8,45 (d, 1H), to 8.41 (s, 1H), 7,42 (d, 1H), 4,18 (t, 2H), 3,99 (s, 3H), of 2.64 (t, 2H), 2,12 (s, 3H), of 1.95 (m, 2H). MS m/z 403 (M+1).

13k:6-[4-(4-Cyanobenzoyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,73 (s, 1H), 8,65 (s, 1H), 8,46 (d, 1H), 8,45 (s, 1H), 7,95 (d, 2H), to 7.67 (d, 2H), 7,52 (d, 1H), 5,50 (s, 2H), 3,99 (s, 3H). MS m/z 434 (M+1).

13l:1-Methyl-6-{4-[3-(2-oxopyrrolidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: of 8.47 (s, 1H), scored 8.38 (s, 1H+1H), 8,35 (d, 1H), 7,30 (d, 1H), 4,23 (t, 2H), of 4.05 (s, 3H), 3,5-3,6 (m, 4H), to 2.41 (t, 2H), 2.05 is-2,2 (m, 4H). MS m/z 444 (M+1).

13m:Methyl-6-{4-[2-(2-oxopyrrolidin-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ: 8,23-8,31 (m, 2H), 8,08 (s, 1H), 7,87 (s, 1H), 7,11 (d, 1H), 4,29 (t, 2H), 3,98 (s, 3H), of 3.75 (t, 2H), to 3.64 (t, 2H), 2.40 a (t, 2H), 2.06 to (m, 2H). MS m/z 430 (M+1).

EXAMPLE14a

Hydrochloride of 1-methyl-6-{4-[2-(piperidine-4-yl)ethoxy]-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

Diisopropylethylamine (380 mg) was added under stirring at room temperature in a nitrogen atmosphere to a mixture of 6-(4-hydroxy-3-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (300 mg)associated with the resin triphenylphosphine (3 mmol/g, 630 mg) and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (430 mg) in DC (2 ml). The mixture was then shaken for 8 hours. After separation of the resin by filtration, the filtrate was concentrated under reduced pressure, the residue was again dissolved in DCM (5 ml) and to this solution is then added triperoxonane acid (3 ml). After stirring at room temperature for 10 minutes all solvent and excess triperoxonane acid was removed under reduced pressure. The residue was dissolved in NMP (5 ml) and was purified HPLC, while receiving 1-methyl-6-{4-[2-(piperidine-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA. This salt was then converted to free base and HCl salt (230 mg) using the method described in example 2.

1H NMR (CD3

The procedure described in example14a, was then applied using suitable derivatives of alcohol to obtain the following compounds.

14b:1-Methyl-6-{4-[(piperidine-4-yl)methoxy)]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,71 (s, 1H), 8,64 (s, 1H), 8,44 (d, 1H), to 8.41 (s, 1H), 7,42 (d, 1H), was 4.02 (d, 2H), 3,98 (s, 3H), 3.00 and (d, 2H), by 2.55 (m, 2H), 1,90 (m, 1H), 1,75 (d, 2H), 1,25 (m, 2H). MS m/z 416 (M+1).

EXAMPLE15

6-[4-(3-Hydroxypropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A:(E)-Methyl 3-(4-chloro-2-(trifluoromethyl)phenyl)acrylate

A mixture of 4-chloro-1-iodine-2-(trifluoromethyl)benzene (15 g), methyl acrylate (6,74 g), tetrabutylammonium chloride (14 g), palladium acetate (0,22 g) and potassium carbonate (13,6 g) in DMF (150 ml) was stirred at room temperature for 4 days. After simple dilution with ether (1 l) and the mixture was washed with water (5 × 200 ml), then dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was passed through a column of silica gel using a mixture of 5:1 heptane:EtOAc as the eluent, thus obtaining (E)-methyl-3-(4-chloro-2-(trifluoromethyl)phenyl)acrylate (13 g).

1H NMR (CDCl3) δ: 7,99 (d, 1H), of 7.70 (s, 1H), 7,65 (who, 1H), 7,56 (d, 1H), 6,4 (d, 1H), 3,83 (s, 3H).

B:Methyl 3-(4-chloro-2-(trifluoromethyl)phenyl)propanoate

A mixture of (E)-methyl-3-(4-chloro-2-(trifluoromethyl)phenyl)acrylate (5 g) and palladium-on-coal (10%, dry, 2 g) in ethyl acetate (50 ml) was stirred under hydrogen pressure from a cylinder within 3 hours. After filtration, the filtrate was concentrated, thus obtaining methyl-3-(4-chloro-2-(trifluoromethyl)phenyl)propanoate (5 g).

1H NMR (CDCl3) δ: a 7.62 (s, 1H), 7,45 (d, 1H), 7,30 (d, 1H), 3,69 (s, 3H), 3,10 (t, 2H), 2,61 (t, 2H).

C:3-(4-Chloro-2-(trifluoromethyl)phenyl)propan-1-ol

Diisobutylaluminium (20% in toluene, 34 ml) was added dropwise to a solution of methyl-3-(4-chloro-2-(trifluoromethyl)phenyl)propanoate (5 g) in DCM (150 ml) at -78°C under nitrogen atmosphere for 10 minutes. The mixture was then stirred at -78°C for 1 hour before warming to room temperature. The mixture was then carefully poured onto crushed ice (500 g). After addition of 5 M HCl to pH 2, the mixture was extracted with DCM (200 ml × 3), the combined DCM layer was then dried over sodium sulfate, the solvent was then removed under reduced pressure. The residue was pure enough for the next stage (4.5 g).

1H NMR (CDCl3) δ: 7,60 (s, 1H), 7,44 (d, 1H), 7,30 (d, 1H), 3,71 (t, 2H), 2,85 (t, 2H), to 1.87 (m, 2H).

D:3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)propan-1-ol

A mixture of 3-(4-chloro-2-(trifluoromethyl)phenyl)propan-1-ol (1 g), Tris(dibenzyl inceton)diplegia (0,192 g), tricyclohexylphosphine (0,141 g), potassium acetate (0,62 g) and bis(pinacolato)Debora (1,17 g) in dry dioxane (15 ml) was heated at 80°C for 6 hours. After dilution with ethyl acetate (100 ml), washing with water (100 ml), saturated salt solution (100 ml), then drying over sodium sulfate the solvent was removed under reduced pressure and the residue was passed through a column of silica gel using a mixture of heptane:EtOAc (4:1) as eluent, thus obtaining 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)propan-1-ol (1 g).

1H NMR (CDCl3) δ: of 8.06 (s, 1H), 7,9 (d, 1H), 7,37 (d, 1H), and 3.72 (t, 2H), 2,9 (t, 2H), and 1.9 (m, 2H), of 1.35 (s, 12H).

E:6-[4-(3-Hydroxypropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-Chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.29 g), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)propan-1-ol (UAH 2.432 g), Tris(dibenzylideneacetone)dipalladium (0,307 g), tricyclohexylphosphine (0,225 g) and potassium phosphate (2,417 g) suspended in dioxane (20 ml) and water (8 ml). The reaction mixture was placed in a nitrogen atmosphere and was heated to boiling under reflux (110°C) for 1.5 hours. The mixture was allowed to cool to room temperature, then diluted with EtOAc (500 ml), filtered through celite and washed with water (200 ml). The organic layer was dried over sodium sulfate and the solvent evaporated PR is the reduced pressure. The solid residue was washed by a simple ether, thus obtaining 6-[4-(3-hydroxypropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.5 g).

1H NMR (CD3OD) δ: 8,46 (s, 1H), 8,45 (s, 1H), 8,44 (s, 1H), 8,31 (d, 1H), 7,60 (d, 1H), Android 4.04 (s, 3H), 3,66 (t, 2H), equal to 2.94 (t, 2H), 1,90 (m, 2H).

EXAMPLE16a

1-Methyl-6-{4-[3-(3-oxopiperidin-1-yl)propyl]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

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

6-[4-(3-Hydroxypropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.3 g) was carefully heated in THF (36 ml) to dissolve all connection and then the solution was cooled to 0°C in an ice bath. Added tetrabromide carbon (2.4 g) followed by addition of triphenylphosphine (1.9 g). The mixture was stirred at 0°C for 15 minutes and then at room temperature for 20 minutes before until the cloudy suspension became a clear liquid. The reaction mixture was diluted DSM (100 ml) and washed with water (100 ml × 2). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is then passed through a column (column of 100 g of SiO2, a gradient of a mixture of 1:1 EtOAc/heptane to EtOAc)to give 6-(4-(3-bromopropyl)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]feast the DIN-4-carbonitrile (1.2 g) as a white solid.

1H NMR (DMSO) δ: 8,77 (s, 1H), 8,66 (s, 1H), 8,46 (s, 1H), 8,40 (d, 1H), 7,69 (d, 1H), 4.00 points (s, 3H), of 3.65 (t, 2H), 2.95 and (t, 2H), 2,17 (m, 2H).

B:1-Methyl-6-{4-[3-(3-oxopiperidin-1-yl)propyl]-3-triptoreline}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-(4-(3-Bromopropyl)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (50 mg) and 2-oxopiperidin (103 mg) in DMF (750 ml) was heated at 100°C in a microwave for 25 minutes. Purification preparative LC-MS with the main phase gave 1-methyl-6-{4-[3-(3-oxopiperidin-1-yl)propyl]-3-triptoreline}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (15 mg).

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,43 (s, 1H), 8,42 (s, 1H), 8,29 (d, 1H), 7,60 (d, 1H), a 4.03 (s, 3H), 3,34 (t, 2H), 3,12 (s, 2H), 2.91 in (t, 2H), 2,70 (t, 2H), has 2.56 (t, 2H), 1,90 (m, 2H). MS m/z 443 (M+1).

The procedure described in example16Athat was further applied, using the appropriate amine derivative to obtain the following compounds as either TFA salt, free base or HCl salt using the method described in example 2.

16b:6-[4-(3-(Dimethylamino)propyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,45 (s, 2H), 8,43 (s, 1H), 8,29 (d, 1H), 7,60 (d, 1H), a 4.03 (s, 3H), 2,88 (t, 2H), 2.57 m (t, 2H), 2,35 (s, 6H), 1,90 (m, 2H). MS m/z 388 (M+1).

16c:1-Methyl-6-[4-(3-morpholine-4-ylpropyl)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 845 (, 1H), 8,44 (s, 1H), 8,42 (s, 1H), 8.30 to (d, 1H), 7,60 (d, 1H), a 4.03 (s, 3H), and 3.72 (t, 4H), 2,90 (t, 2H), 2,54 (m, 6H), of 1.92 (m, 2H). MS m/z 430,6 (M+1).

16d:1-Methyl-6-{4-[3-(4-methylpiperazin-1-yl)propyl]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,76 (s, 1H), 8,65 (s, 1H), 8,43 (s, 1H), 8,39 (d, 1H), 7,68 (d, 1H), 4.00 points (s, 3H), and 2.83 (t, 2H), 2,36 (m, 10H)of 2.16 (s, 3H), 1.77 in (m, 2H). MS m/z 443 (M+1).

16e:The TFA salt of 6-(4-{3-[4-(2-methoxyethyl)piperazine-1-yl]propyl}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,78 (s, 1H), 8,67 (s, 1H), 8,48 (s, 1H), 8,45 (d, 1H), 7,71 (d, 1H), 4,01 (s, 3H), 3,63 (t, 2H), 3,30 (s, 3H), 3,28 (user. m, 8H), 3,21 (user. m, 2H), 3,09 (user. m, 2H), 2,86 (t, 2H), 1,99 (m, 2H). MS m/z 487,5 (M+1).

16f:6-(4-{3-[N-(2-dimethylamino-2-oxoethyl)-N-methylamino]propyl}-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: rate of 8.75 (s, 1H), 8,65 (s, 1H), 8,43 (s, 1H), 8,39 (d, 1H), to 7.67 (d, 1H), 4.00 points (s, 3H), 3,23 (s, 2H), 3,03 (s, 3H), 2,82 (m, 5H), of 2.51 (user. m, 2H, in), 2.25 (s, 3H), of 1.78 (m, 2H). MS m/z 459 (M+1).

The following compound was purified using acid HPLC as TFA salt.

16g:The TFA salt of 1-methyl-6-[4-(3-piperazine-1-ylpropyl)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,79 (s, 1H), 8,67 (s, 1H), 8,48 (s, 1H), 8,44 (d, 1H), 7,71 (d, 1H), 4,01 (s, 3H), 3,35 (user. m, 8H), 3,19 (user. m, 2H), 2,87 (t, 2H), 2,01 (user. m, 2H). MS m/z 429,4 (M+1).

EXAMPLE17

1-Methyl-6-{4-[2-(2-oxoacridine-3-yl)ethoxy]-3-(reformer)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

To oxazolidin-2-ONU (29,7 mg) in TMR (1 ml) was added sodium hydride (60% in paraffin oil, to 13.6 mg). After stirring at room temperature for 10 minutes and then was added 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate (100 mg) and the mixture was stirred at room temperature for 14 hours. The mixture was immediately purified using HPLC, while receiving 1-methyl-6-{4-[2-(2-oxoacridine-3-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (10 mg).

1H NMR (DMSO) δ: an 8.70 (s, 1H), 8,63 (s, 1H), 8,45 (d, 1H), to 8.41 (s, 1H), 7,47 (d, 1H), 4,37 (t, 2H), 4,27 (t, 2H), 3,99 (s, 3H), to 3.67 (t, 2H), 3,61 (t, 2H). MS m/z 432 (M+1).

EXAMPLE18a

Hydrochloride of 1-methyl-6-{4-[3-(2-oxopiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

To tert-butyl 3-oxopiperidine-1-carboxylate (106 mg) in TMR (2 ml) was added sodium hydride (60% in paraffin oil, 22 mg). After stirring at room temperature for 10 minutes was added 3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)propylaminosulfonyl (200 mg) and the mixture was stirred at room temperature for 14 hours. After dilution with ethyl acetate (50 ml) and the mixture was washed with water (20 ml). The organic layer was then separated, the solvent was removed in vacuo, the residue was then added a mixture of 1:1 DC:FA (4 ml). After stirring at room temperature for 5 minutes, all solvent was removed under reduced pressure, the residue was dissolved in Meon (2 ml) and purified HPLC, while receiving 1-methyl-6-{4-[3-(2-oxopiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA. This salt FA was converted into HCl salt using the method described above (example 2).

1H NMR (MeOD) δ: 8,53 (s, 1H), 8,42 (s, 1H), 8,40 (s, 1H), of 8.37 (d, 1H), 7,35 (d, 1H), 4.26 deaths (t, 2H), Android 4.04 (s, 3H), 3,83 (s, 2H), 3,65 to 3.8 (m, 4H), of 3.56 (t, 2H), 2,18 (m, 2H). MS m/z 459 (M+1).

The procedure described in example18ahereinafter was applied using 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)ethylmethanesulfonate to obtain the following compounds as TFA salt.

18b:The TFA salt of 1-methyl-6-{4-[2-(2-oxopiperidin-1-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,71 (s, 1H), 8,64 (s, 1H), 8,46 (d, 1H), 8,44 (s, 1H), 7,45 (d, 1H), 4,36 (t, 2H), 3,99 (s, 3H), 3,80 (t, 2H), of 3.77 (s, 1H), 3,70 (d, 2H), 3,41 (t, 2H). MS m/z 445 (M+1).

EXAMPLE19

The TFA salt of 6-{4-[3-(3,3-dimethyl-2-oxopiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A:tert-Butyl-2,2-dimethyl-3-oxopiperidine-1-carboxylate

Di-tert-BUTYLCARBAMATE (4 g) was added to a solution of hydrochloride 3,3-dimethylpiperazine-she (3 g) and DIPEA (3 ml) in a mixture DC-Meon (100 ml-30 ml). The mixture was stirred at room temperature for 2 days, then washed with water (100 ml × 2), the organic layer was dried over sodium sulfate, the solvent was removed and the residue is then passed through a column of silica gel using a mixture of 9:1 DCM:MeOH as the eluent, thus obtaining tert-butyl-2,2-dimethyl-3-oxopiperidine-1-carboxylate (3.6 g).

1H NMR (DCl3) δ: 3,2-3,35 (user., 2H), 3,35-3,4 (user., 2H), 1.50 in (C), 1,47 (C)of 1.44 (s).

B:The TFA salt of 6-{4-[3-(3,3-dimethyl-2-oxopiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

The procedure described in example18athen applied using tert-butyl-2,2-dimethyl-3-oxopiperidine-1-carboxylate to obtain 6-{4-[3-(3,3-dimethyl-2-oxopiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA.

1H NMR (CD3OD) δ: to 8.45 (s, 1H), 8,35-8,43 (m, 3H), 7,32 (d, 1H), 4.26 deaths (t, 2H), was 4.02 (s, 3H), 3,6-of 3.75 (m, 6H), 2,17 (m, 2H), of 1.62 (s, 6H). MS m/z 487 (M+1).

Example20a

6-[4-(3-Morpholine-4-ylpropionic)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

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

A mixture of 3,4-diamino-6-chloropicolinic (3.2 g), triethylorthoformate (16 ml) and AcOH (5,4 ml) was heated to 150°C in DC (16 ml) in a microwave for 15 minutes. The solvent issue is rivali, the residue was dissolved in EtOAc (250 ml) and washed with water (150 ml). The organic layer was dried over sodium sulfate. The solvent is evaporated under reduced pressure, thus obtaining 6-chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (2.2 g).

1H NMR (DMSO) δ: 8,72 (s, 1H), of 8.06 (s, 1H).

B:6-Chloro-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-Chloro-1H-imidazo[4,5-C]pyridine-4-carbonitrile (620 mg) and monohydrate p-toluensulfonate acid (10 mg) suspended in ethyl acetate (10 ml) and was heated to 60°C. was added dropwise 3,4-dihydro-2H-Piran (0,48 ml) and the reaction mixture was stirred at 60°C over night. The reaction was suppressed to 5 ml of ammonium hydroxide before addition of water (100 ml) and ethyl acetate (200 ml). The organic layer was separated, dried over sodium sulfate and the solvent evaporated under reduced pressure. The crude product was dissolved in minimum amount of EtOAc was added heptane. The resulting brown solid was collected by filtration, thus obtaining 6-chloro-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (630 mg).

1H NMR (DMSO) δ: of 8.92 (s, 1H), 8.30 to (s, 1H), 5,80 (d, 1H), of 4.05 (m, 1H, in), 3.75 (m, 1H), 2,19 (m, 1H), 2,11 (m, 1H), 1,62 (m, 4H).

C:6-[4-(3-Hydroxypropoxy)-3-(trifluoromethyl)phenyl]-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

6-Chloro-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1,4) - Rev.), 4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenylboronic acid (2.2 g), Tris(dibenzylideneacetone)dipalladium (0.25 g), tricyclohexylphosphine (0.18 g) and potassium phosphate (2 g) were added to dioxane (20 ml) and water (6 ml) and the mixture was heated to boiling under reflux in nitrogen atmosphere for two hours. The reaction mixture was diluted with EtOAc (200 ml), filtered through celite and washed with water (150 ml). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure. The crude product was purified flash chromatography using a mixture of EtOAc:heptane as the eluent, thus obtaining 6-[4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl]-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.5 g).

MS m/z 447 (M+1).

D:3-(4-(4-Cyano-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)propylaminosulfonyl

To a solution of 6-(4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (670 mg) and DIPEA (1.4 ml) in TMR (7.5 ml) at 0°C was added methanesulfonamide (0.2 ml). The mixture was stirred for 45 minutes at room temperature, then diluted with EtOAc (75 ml) and washed with saturated sodium bicarbonate (70 ml) followed by washing with water (2 × 40 ml). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure, thus obtaining 3-(4-(4-cyano-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)propylaminosulfonyl (720 mg).

MS m/z 525 (M+1).

E:The TFA salt of 6-{4-[3-(3,3-dimethyl-2-oxopiperidin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A mixture of 3-(4-(4-cyano-1-(tetrahydro-2H-Piran-2-yl)-1H-imidazo[4,5-c]pyridine-6-yl)-2-(trifluoromethyl)phenoxy)propylenecarbonate (23 mg) and research (20 μl) in TMR (500 μl) was heated at 120°C in a microwave conditions for 20 minutes. Then was added aqueous HCl (2M, 500 ml) and the mixture was stirred for 2 hours at 50°C. the Mixture was then purified using preparative HPLC, while receiving the product, 6-[4-(3-morpholine-4-ylpropionic)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile, in the form of a salt FA, which was then converted into the free base using the method described in example 2.

1H NMR (DMSO) δ: 8,66 (s, 1H), of 8.47 (s, 1H), scored 8.38 (d, 1H), 8.34 per (s, 1H), 7,40 (d, 1H), 4,24 (t, 2H), 3,57 (user. m, 4H), of 2.45 (t, 2H), 2,37 (user. m, 4H), of 1.92 (m, 2H). MS m/z 432 (M+1).

The procedure described in example20A, was then applied using suitable amines to obtain the following compounds as either TFA salt, free base or HCl salt.

20b:The TFA salt of 6-[4-(3-Ethylenedioxy)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,53 (s, 1H), at 8.36 (m, 2H), 8,30 (s, 1H), 7,35 (d, 1H), 4,33 (t, 2H), 3,26 (t, 2H), 3,12 (square, 2H), 2,28 (m, 2H), of 1.34 (t, 3H). MS m/z 390 (M+1).

20c:6-{4-[3-((R)-2-Hydroxymethyl who irreligion-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,66 (s, 1H), of 8.47 (s, 1H), scored 8.38 (d, 1H), 8.34 per (s, 1H), 7,41 (d, 1H), 4,25 (m, 2H), 3,40 (m, 1H), 3,25 (m, 1H), 3.15 in (m, 1H), 3,05 (m, 1H), 2,60 (m, 1H), 2.49 USD (m, 1H), 2,31 (m, 1H), 1,95 (m, 2H), of 1.85 (m, 1H), 1,70 (m, 1H), 1,60 (m, 2H). MS m/z 446 (M+1).

20d:The TFA salt of 6-[4-(3-perhydro-1,4-oxazepine-4-ylpropionic)-3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,53 (s, 1H), at 8.36 (s, 1H), with 8.33 (d, 1H), 8,31 (s, 1H), 7,35 (d, 1H), 4,33 (t, 2H), 3,94 (user. m, 4H), 3,63 (user. m, 2H), 3,48 (t, 2H), 3,36 (user. m, 2H), 2,35 (user. m, 2H), 2,19 (user. m, 2H). MS m/z 446 (M+1).

20e:The TFA salt of 6-{4-[3-(3,3-debtorprovidian-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: 8,53 (s, 1H), at 8.36 (s, 1H), 8.34 per (d, 1H), 8,31 (s, 1H), 7,35 (d, 1H), 4,33 (t, 2H), 3,95 (user. m, 2H), 3,75 (user. m, 2H), 3,49 (t, 2H), 2,69 (m, 2H), 2,32 (m, 2H). MS m/z 452,5 (M+1).

20f:6-{4-[3-(4-Ethylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,64 (s, 1H), 8,45 (s, 1H), scored 8.38 (d, 1H), 8.34 per (s, 1H), 7,39 (d, 1H), 4,22 (t, 2H), of 2.45 (t, 2H), 2,39 (user. m, 8H), 2,31 (m, 2H), 1.91 a (m, 2H), and 0.98 (t, 3H).

MS m/z 459 (M+1).

20g:6-(4-{3-[4-(2-Methoxyethyl)piperazine-1-yl]propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,66 (s, 1H), 8,46 (s, 1H), 8,35 (d, 1H), with 8.33 (s, 1H), 7,39 (d, 1H), 4,22 (t, 2H), 3,41 (t, 2H), up 3.22 (s, 3H), 2,46 (user. m, 12H), at 1.91 (m, 2H). MS m/z 489 (M+1).

20h:6-(4-{3-[4-(2-Oxo-2-pyrrolidin-1-retil)piperazine-1-yl]propoxy}-3-(Tr is permitil)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,66 (s, 1H), 8,46 (s, 1H), 8,35 (d, 1H), with 8.33 (s, 1H), 7,40 (d, 1H), 4,23 (t, 2H), 3.46 in (t, 2H), 3,25 (m, 2H), 3,06 (s, 2H), 2,47 (m, 2H), 2.40 a (user. m, 8H), 1.91 a (m, 2H), of 1.84 (m, 2H), 1,74 (m, 2H). MS m/z 542 (M+1).

20i:The TFA salt of 6-{4-[3-(4-hydroxypiperidine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CD3OD) δ: charged 8.52 (s, 1H), 8,31 (s, 1H), 8,28 (d, 1H), compared to 8.26 (s, 1H), 7,30 (d, 1H), or 4.31 (t, 2H), 4,12 (user. C, 0,5H), 3,88 (user. m, 0,5H), 3,62 (user. d, 1H), 3.45 points (user. d, 1H), 3,35 (user. m, 3H), 3,11 (user. t, 1H), 2,32 (user. m, 2H), 2,18 (user. d, 1H), 1,98 (user. m, 2H), 1,71 (user. m, 1H). MS m/z 446 (M+1).

20j:6-{4-[3-((S)-3-dimethylaminopropan-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,65 (s, 1H), 8,46 (s, 1H), scored 8.38 (d, 1H), 8.34 per (s, 1H), 7,39 (d, 1H), 4,23 (t, 2H), 2,80 (m, 1H), 2,70 (t, 1H), 2,61 (m, 3H), 2,47 (m, 1H), of 2.38 (m, 1H), 2,16 (s, 6H), of 1.92 (m, 3H), 1,60 (m, 1H). MS m/z 459 (M+1).

EXAMPLE 21

6-{3-Chloro-4-[3-(piperazine-1-yl)propoxy]-5-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

A:6-(3-Chloro-4-hydroxy-5-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

N-Chlorosuccinimide (84 mg) was added to a solution of 6-(4-hydroxy-3-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (200 mg) in DMF (4 ml). The mixture was stirred at room temperature for 24 hours, then was added ethyl acetate (50 ml) and water (20 ml) and organically the layer washed twice with water (2 × 20 ml) and saturated salt solution (20 ml), then was dried over sodium sulfate, filtered and concentrated under reduced pressure, thus obtaining the crude 6-(3-chloro-4-hydroxy-5-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (165 mg), which is contaminated source connection. The compound obtained was used for the next stage without additional purification.

MS m/z 353 (M+1).

B:tert-Butyl ester 4-(3-hydroxypropyl)piperazine-1-carboxylic acid

Di-tert-BUTYLCARBAMATE (1.50 g) was added to a solution of 3-(1-piperazine)propanol (1,00 g) in THF (50 ml) at 0°C. the Mixture was stirred over night at room temperature, then the solvent was removed under reduced pressure, thus obtaining tert-butyl ester 4-(3-hydroxypropyl)piperazine-1-carboxylic acid (1.66 g).

1H NMR (CD3CN) δ: 3,81 (m, 2H); 3.43 points (m, 4H); 2,62 (m, 2H); 2,47 (m, 4H); at 1.73 (m, 2H); 1,45 (s, 9H).

C:tert-Butyl ester 4-(3-bromopropyl)piperazine-1-carboxylic acid

Under nitrogen atmosphere a solution of triphenylphosphine (0,94 g) in THF (4 ml) was slowly added to a mixture of tert-butyl ester 4-(3-hydroxypropyl)piperazine-1-carboxylic acid (0,80 g) and tetrabromomethane (1.19 g) in THF (15 ml). The mixture was stirred at room temperature for 16 hours, then was added ethyl acetate (100 ml) and a saturated solution of sodium carbonate (30 ml) and the organic layer was washed with a saturated solution Sol is, then was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographically on silica gel (eluent: a mixture 8/2 cyclohexane/ethyl acetate), thus obtaining tert-butyl ester 4-(3-bromopropyl)piperazine-1-carboxylic acid (0.66 g).

1H NMR (CD3CN) δ: 3,47 (m, 2H); 3.42 points (m, 4H); 2,48 (m, 2H); of 2.38 (m, 4H); 2,02 (m, 2H); of 1.46 (s, 9H).

D:tert-Butyl ether 4-{3-[2-chloro-4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-6-triptoreline]propyl}piperazine-1-carboxylic acid

tert-Butyl ester 4-(3-bromopropyl)piperazine-1-carboxylic acid (172 mg) was added to a mixture of 6-(3-chloro-4-hydroxy-5-triptoreline)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (165 mg) and potassium carbonate (130 mg) in acetonitrile (15 ml). The mixture was boiled under reflux for 4 hours, then was added ethyl acetate (50 ml) and water (30 ml) and the organic layer was washed with saturated salt solution, then dried over sodium sulfate, filtered and concentrated under reduced pressure, thus obtaining the crude product, tert-butyl ester 4-{3-[2-chloro-4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-6-triptoreline]propyl}piperazine-1-carboxylic acid.

MS m/z 579 (M+1).

E:6-{3-Chloro-4-[3-(piperazine-1-yl)propoxy]-5-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

The crude product, tert-butyl ester 4-{3-[2-PI is R-4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridine-6-yl)-6-triptoreline]propyl}piperazine-1-carboxylic acid, was dissolved in Meon (7 ml) was added 5 n HCl in iPrOH (7,6 ml). The mixture was stirred 3 hours at room temperature, then the solvent is evaporated under reduced pressure. The crude product was purified preparative HPLC (HPLC: column, XBridge MS C18, 30×100 mm, 5 μm, eluent: A: NH4HCO3, 10 mmol, pH=9.5/B: acetonitrile, focused gradient/8 minutes/50 ml/min), while receiving 6-{3-chloro-4-[3-(piperazine-1-yl)propoxy]-5-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile.

1H NMR (CDCl3) δ: 8.34 per (s, 1H), 8,16 (s, 1H), 8,13 (s, 1H), to $ 7.91 (s, 1H), 4,20 (t, 2H), 4,01 (s, 3H), of 2.93 (t, 4H), 2,60 (t, 2H), 2.49 USD (user., 4H), of 2.09 (t, 2H). MS m/z 479 (M+H). MS m/z 479 (M+1).

The procedure described in example7a, was then applied using suitable starting compounds to obtain the following compounds.

EXAMPLE22

6-(4-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)propoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO-d6) δ: 8,72 (s, 1H), 8,64 (s, 1H), 8,44 (d, 1H), 8,43 (s, 1H), 7,41 (d, 1H), 5,79 (s, 1H), 4,17 (t, 2H), 4,10 (t, 2H), 3,99 (s, 3H), 2,19 (m, 2H), of 2.15 (s, 3H), of 2.09 (s, 3H). MS m/z to 455.2 (M+1).

The procedure described in example4A, was then applied using suitable derivatives of piperazine to obtain the following compounds as either TFA salt, free base or HCl salt.

EXAMPLE23

Hydro is lorid 1-methyl-6-{3-(trifluoromethyl)-4-[(3-(S)-isopropylpiperazine-1-yl)propoxy]phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (D) δ: 8,83 (s, 1H), charged 8.52 (s, 1H), to 8.41 (s, 1H), 8,40 (d, 1H), 7,40 (d, 1H), 4,37 (m, 2H), 4.09 to (s, 3H), 3,93 (m, 2H), 3,76 (m, 1H), to 3.67 (m, 2H), 3.45 points and 3.6 (m, 3H), 3,37 (t, 1H), 2,45 (m, 2H), of 2.10 (m, 1H), of 1.16 (d, 3H), 1.14 in (d, 3H). MS m/z 487 (M+1).

EXAMPLE24

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

Hydrochloride of 1-methyl-6-{4-[2-(piperidine-4-yl)ethoxy]-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg), ethyliodide (10 mg) and potassium carbonate (20 mg) in acetonitrile (1 ml) was stirred at room temperature for 20 hours. After removing solids by filtration, the filtrate was purified HPLC, while receiving 6-{4-[2-(1-ethylpiperazin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile in the form of a salt FA.

1H NMR (CD3OD) δ: to 8.45 (s, 1H), scored 8.38 (s, 2H), of 8.37 (d, 1H), 7,33 (d, 1H), 4,28 (t, 2H), was 4.02 (s, 3H), 3,62 (m, 2H), 3,18 (square, 2H), 2.95 and (m, 2H), and 2.14 (m, 2H), 2.0 (m, 1H), and 1.9 (m, 2H), 1.55V (m, 2H), of 1.35 (t, 3H). MS m/z 458 (M+1).

The procedure described in example13A, was then applied using suitable derivatives of alcohols to obtain the following compounds as either TFA salt, neutral compounds, or salts of HCl.

EXAMPLE25a

1-Methyl-6-[4-(6-methylpyridin-2-ylethoxy)-3-triptoreline]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: a total of 8.74 (s, 1H), 8,65 (s, 1H), 8,44 (d, 2H), 7,78 (t, 1H), 7,52 (d, 1H), 7,31 (d, 1H), 7.23 percent (d, 1H), of 5.40 (s, 2H), 3,99 (s, 3H), of 2.50 (s, 3H). MS m/z 424,0 (M+1).

EXAMPLE25b

1-Methyl-6-[4-(pyrimidine-2-ylethoxy)-3-triptoreline]-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (DMSO) δ: 8,86 (d, 2H), to 8.70 (s, 1H), 8,64 (s, 1H), 8,42 (s, 1H), 8,35 (d, 1H), 7,49 (t, 1H), 7,38 (d, 1H), 5.56mm (s, 2H), 3,98 (s, 3H). MS m/z 411,0 (M+1).

EXAMPLE25c

6-(4-((5-Isopropylthiazole-3-yl)methoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ: 8,28 (1H, s); 8,23 (1H, d); 8,10 (1H, s); 7,88 (1H, s); from 7.24 (1H, d); 6,12 (1H, s); 5,31 (2H, s); 3,99 (3H, s); is 3.08 (1H, m); of 1.32 (6H, d). MS m/z 442 (M+1).

EXAMPLE25d

6-(4-((3-Isopropylthiazole-5-yl)methoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDCl3) δ: of 8.27 (1H, s); compared to 8.26 (1H, d); of 8.09 (1H, s); 7,89 (1H, s); to 7.18 (1H, d); 6,27 (1H, s); and 5.30 (2H, s); 4,00 (3H, s); is 3.08 (1H, m); of 1.30 (6H, d). MS m/z 442 (M+1).

EXAMPLE25th

6-(4-((3-Isopropyl-1,2,4-oxadiazol-5-yl)methoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile

1H NMR (CDl3) δ: 8,29 (1H, d); compared to 8.26 (1H, s); 8,10 (1H, d); 7,89 (1H, s); of 7.23 (1H, d); 5,44 (2H, s); 4,00 (3H, s); 3.15 in (1H, m); of 1.35 (6H, d). MS m/z 443 (M+1).

EXAMPLE26

The method of analysis of cathepsin S

Inhibitory activity of compounds of the invention was demonstrated in vitro by measuring the inhibition of recombinant human cathepsin S as follows. In 384-well titration 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 dithiothreitol) with 10% dimethyl sulfoxide (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 in the wells add 25 ál of 2 mg/l solution of activated recombinant human cathepsin S in the buffer for analysis, getting 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 at time 20 minutes. Percentage of enzyme activity was calculated by comparing this activity with the activity of a solution containing no inhibitor. Compounds are then subjected to analysis with the curve of dependence “dose-effect” to determine the values of the IC50for active compounds (where IC50is the concentration of test compound causing 50% inhibition of enzyme activity). Compounds of the invention typically have a pic50(negative logari the m concentration IC 50for inhibition of human cathepsin S is greater than 6. Most of the compounds of the invention have pic50more than 7, for example, are given as examples of the compounds of examples 1, 2a, 2c, 2u, 4a, 4b, 4c, 4e, 4f, 5a, 7b, 9d, 11, 12, 13c, 20f.

EXAMPLE 27

The method of analysis of cathepsin K

Inhibitory activity of compounds of the invention was demonstrated in vitro by measuring the inhibition of recombinant cathepsin-To person in the following way. In 384-well titration 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 dithiothreitol) 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 the wells, add 10 ál of 1 mg/l solution of activated recombinant cathepsin To the man in the buffer for analysis, getting 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 at time 10 minutes. Percentage of enzyme activity was calculated by comparing this activity with the activity of a solution containing no inhibitor. Compounds are then subjected to analysis using revuew dependence “dose-effect” to determine the values of the IC 50for active compounds (where IC50is the concentration of test compound causing 50% inhibition of enzyme activity). Compounds of the invention have pic50(the negative logarithm of the concentration IC50for inhibition of cathepsin K of less than 7.

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

where R1represents H;
R2is a (C1-3)alkyl;
R3is a (C1-4)alkyl, optionally substituted by three halogen atoms;
R4represents H;
X represents O;
n is 1 or 2 or 3;
Y is selected from OH, NR5R6and Z, where
Z represents a saturated 5 - or 6-membered heterocyclic ring containing 1 heteroatom selected from NR7where the ring may be substituted by oxo, (C1-3)alkyl, hydroxy(C1-3)alkyl; or where
Z represents an aromatic 5 - or 6-membered heterocyclic ring containing 1-2 heteroatoms selected from N, where the ring may be substituted (C1-3)alkyl;
R5and R6independently represent H, (C3-8)cycloalkyl or (C1-6)alkyl, optionally substituted 1-2 times by halogen, OH, (C1-6)alkyloxy, CONR14R15, NR14R15or 6-member of the th saturated heterocyclic group, containing a heteroatom selected from NR8; or
R5and R6together with the nitrogen atom to which they are bound, form a 5-to 10-membered saturated heterocyclic ring, optionally additionally containing 1 to 3 heteroatom selected from NR9and the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, CONR10R11or NR10R11;
R7represents H;
R8is a (C1-3)alkyl;
R9represents H, (C1-3)alkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alkyl, (C1-6)alkylsulphonyl, (C1-6)allyloxycarbonyl, CONR12R13or 6-membered heteroaryl group containing 1-2 heteroatoms selected from N;
R10and R11independently represent H or (C1-3)alkyl;
R12and R13independently represent a (C1-3)alkyl; or
R14and R15independently represent a (C1-3)alkyl; or
or their pharmaceutically acceptable salts.

2. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to claim 1, where R3is a CF3and R4represents H.

3. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to claim 1, where Y represents NR5R6.

4. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-Carbo is itril according to claim 1, where Y represents Z, where Z is a pyridyl.

5. The derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to claim 1, which is selected from
- 6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 1-methyl-6-[4-(3-pyrrolidin-1 ipropose)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 6-[4-(3-N,N-diethylaminopropyl)-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 1-methyl-6-[3-(trifluoromethyl)-4-(3-(3,3,4-trimethyl-piperazine-1-yl)propoxy)phenyl]-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 6-{4-[3-(3,3-dimethylpiperidin-1-yl)propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 6-{4-[3-(CIS-3,5-dimethylpiperazine-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 6-{4-[3-(4-ethylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 1-methyl-6-(4-{3-[4-(N-methylaminomethyl)piperidine-1-yl]-propoxy}-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 6-{4-[3-(2-ethylimidazole-1-yl)propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 6-{4-[2-(CIS-3,5-dimethylpiperazine-1-yl)ethoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-C]pyridine-4-to the of bontril;
- 1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-diazaspiro-[4.5]Dec-3-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 1-methyl-6-[4-(pyridine-2-ylethoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 6-{4-[3-(4-ethylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
the hydrochloride of 1-methyl-6-{3-(trifluoromethyl)-4-[(3-(S)-isopropyl-piperazine-1-yl)propoxy]phenyl}-1H-imidazo[4,5-C]pyridine-4-carbonitrile;
- 2,2,2-trifenatate 6-(4-(2-(1-ethylpiperazin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile and
- 1-methyl-6-[4-(6-methylpyridin-2-ylethoxy)-3-trifluoromethyl-phenyl]-1H-imidazo[4,5-C]pyridine-4-carbonitrile
or their pharmaceutically acceptable salts.

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

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

8. Pharmaceutical compositions the Oia for the treatment of osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis, and chronic pain, such as neuropathic pain, containing derivative of 6-phenyl-1H-imidazo[4,5-C]pyridine-4-carbonitrile according to any one of claims 1 to 5, or its pharmaceutically acceptable salt in a mixture with pharmaceutically acceptable excipients.

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



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula I, wherein W and Z represent CH; Y represents CH2; wherein R1 and R2 independently represent H, halogen, CH2F, CHF2, CF3, CF2CF3, or C1-C6alkyl; R' represents H; R3 and R4 independently represent H, or C1-C3alkyl, all mentioned C1-C3alkyl groups and mentioned C1-C6alkyl groups are independently substituted by one or two groups independently substituted by one or two groups independently specified in OH, halogen, C1-C3alkyl, OC1-C3alkyl or trifluoromethyl; q=1 or 0; R5 represents C1-C6alkyl; and to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a composition, a tablet and pharmaceutical syrup having potassium channel modulation activity and containing the compound of formula I, to a method of preventing and treating diseases that are affected by the activation of potentially opened potassium channels.

EFFECT: there are prepared and described the new biologically active compounds which may be effective in the prevention or treatment of diseases or disorders that are affected by potassium channel activity.

21 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline modification of para-methoxyanilide of 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid of formula: (I) , which is obtained by crystallisation from ethyl acetate, where values of interplanar distance (d) and relative reflection intensities (Irel) are given in claim 1.

EFFECT: novel crystalline modification exhibits a high diuretic effect.

2 dwg, 9 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to complexes of lanthanides and organic ligands which are luminescent in the visible spectrum and are used in electroluminescent devices, means of protecting security paper and documents from falsification etc. Disclosed are novel luminescent coordination compounds of lanthanides of formula: where Ln is Eu3+, Tb3+, Dy3+, Sm3+, Gd3+.

EFFECT: said compounds have high luminescence intensity and considerable thermal tolerance of up to 400°C, which enables use thereof in modern production of light-emitting diodes.

4 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) in free form or in form of a pharmaceutically acceptable salt or solvate, which are useful in treating inflammatory or obstructive airways, pulmonary hypertension, pulmonary fibrosis, liver fibrosis, muscle diseases and systemic skeletal disorders and other diseases which are mediated by activity of the ALK-5 receptor or ALK-4 receptor. The invention also relates to a method of producing compounds of formula (I) and pharmaceutical compositions. In formula , T is a pyridin-2-yl which is optionally substituted in one position with R1; T1 is a pyridinyl which is optionally substituted in one or two positions with R1, R2, R5, C1-C4-alkoxy group, C1-C4-alkoxycarbonyl or cyano group; and Ra and Rb are independently hydrogen; C1-C8-alkyl, optionally substituted in one, two or three positions with R4; C3-C10-cycloalkyl, which is optionally substituted in one or two positions with a hydroxy group, amino group, C1-C8-alkyl, C1-C8-alkoxy group, halogen, cyano group, oxo group, carboxy group or nitro group; or C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, amino group, cyano group, oxo group, carboxy group, nitro group or R5; R1 is C1-C8-alkyl; R2 is C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, R1, R5, C1-C8-alkylthio group, amino group, C1-C8-alkylamino group, etc. The rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of using said compounds.

20 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel biologically active substances of the class of 4-aryl-2,4-dioxobutanoic acids. Disclosed is 4-(4-bromophenyl)-4-oxo-2-{[3-ethoxycarbonyl)-4,5-dimethylthien-2-yl]amino}-2-butenoic acid, having anti-inflammatory and analgesic activity, of formula (1): .

EFFECT: obtaining a compound with high output, having marked anti-inflammatory and analgesic activity as well as low toxicity.

1 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely a new biologically active compound of indazole: 3-(3,4-dimethoxyphenyl)-4,5,6,7-tetahydroindazole hydrochloride (I) having formula presented above. The declared compound exhibit analgesic activity, twice less than Analgin and having higher action level. Furthermore, it exhibits high bacteriostatic activity on Staphylococcus aureus (3.8 mg/ml) and manifested bacteriostatic activity on Staphylococcus epidermidis (15.6-31.2 g/ml), Staphylococcus saprophyticus (250 mcg/ml) and the fungus Candida albicans (500-1000 mcg/ml) as well as bactericidal activity on these three species of staphylococci (62.5, 500 and 1000 mcg/ml respectively), having higher action level than phenyl salicylate. The compound (I) is referred to low-toxic (LD50=1500 mg/kg).

EFFECT: invention refers to analgesic and antimicrobial agents representing the compound (I).

3 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns an agent for prevention and treatment of cardiovascular diseases. The peptide 3-mercaptopropionyl-Phe-Ile-lle-Arg-Lys-Pro-Asp-Lys-NH2 is synthetised which has greater availability and lower price than known analogues; it possesses the antiplatelet, anti-inflammatory and cytoprotective properties.

EFFECT: invention provides reduced spontaneous thrombocyte aggregation, inflammation inhibition by reducing histamine secretion, cell protection against neurotoxic actions of thrombin.

1 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented 3-(2',2'-dimethylpropanoylamino)-tetrahydropyridin-2-one , (S)-3-(2',2'-dimethylpropanoylamino)-tetrahydropyridin-2-one and pharmaceutical compositions prepared with using said compound or its isomer, as well as the use thereof for preparing a therapeutic agent for preventing or treating inflammatory conditions, and a related method of treating. What is shown is the advantage of the compounds as related to the other broad spectrum chemokine inhibitors (BSCI) on anti-inflammatory activity; it possesses the pharmacokinetic, toxicological properties and the pharmaceutical safety parameters: (S)-3-(2',2'-dimethylpropanoylamino)-tetra-hydropyridin-2-one is 5-25 times more active than (R)-isomer.

EFFECT: higher anti-inflammatory activity.

13 cl, 10 dwg, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to combined antipyretic drug in form of rectal suppositories. Drug contains paracetamol, dimedrol and papaverine hydrochloride as active components, and lipophilic suppository base Suppocire (Suppocire NA-15) as auxiliary substance, with the following component ratio in g per 1 suppository with 2.0 g weight: paracetamol 0.3-0.5; dimedrol 0.03-0.05; papaverine hydrochloride 0.03-0.05; Suppocire (Suppocire NA-15) - the remaining part (to 2.0 g).

EFFECT: increased efficiency of paracetamol suppositories as antipyretic drugs, with absence of narcotic and psychostimulating substances in their composition.

4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as heparan sulphate-binding protein inhibitors. The invention also refers to a pharmaceutical or veterinary composition having heparan sulphate-binding protein inhibitory activity for preventing or treating a disorder in a mammal, and to the use of these compounds and compositions for antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and/or antithrombotic therapy in a mammal.

EFFECT: preparing the new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as the heparan sulphate binding protein inhibitors.

10 cl, 31 ex, 11 tbl, 40 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an aminopropylidene derivative presented by formula wherein R1 and R2, which may be identical or different, represent hydrogen or a substitute specified in the following (a)-(c), provided the case of both representing hydrogen is excluded: (a) carbonyl substituted with hydroxy, alkoxy or hydroxy alkylamino, (b) carbonylalkyl substituted by hydroxy or alkoxy, and (c) acrylic acid including its alkyl ester, R3 and R4, which may be identical or different, represent hydrogen, alkyl which may be substituted by phenyl or cycloalkyl, or R3 and R4, which together form a heterocyclic ring with a nitrogen atom bound thereto, represent pyrrolidino, piperidino, which may be substituted by oxo or piperidino, piperazinyl substituted by alkyl or penyl, morpholino or thiomorpholino; A means oxo or is absento, B represents canbon or oxygen; one of X and Y represents carbon, while the other one represents sulphur, a part represented by a dash line represents a single bond or a double bond, and a wavy line represents a cys-form and/or a transform. Also, the invention refers to a pharmaceutical composition exhibiting histamine receptor antagonist activity on the basis of said compounds.

EFFECT: there are produced new compounds and pharmaceutical compositions thereof, which can be used in medicine for treating asthma, allergic rhinitis, pollen allergy, hives and atopic dermatitis.

10 cl, 12 tbl, 58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a pharmaceutical composition for treating skin diseases. The composition contains a combination of methylprednisolone aceponate and glycoceramides and a glycoceramide complex containing cholesterol in the amount of 1-3%, and phospholipids in the amount of 25-34%, and excipients. A method for preparing the composition consists in the fact that methylprednisolone aceponate is introduced into an emulsion base containing the glycoceramide complex in the form of a solution to form a coagulation structure.

EFFECT: new pharmaceutical composition is characterised by a wide spectrum of pharmacological properties, stability, uniform distribution of the active ingredients.

9 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: claimed invention relates to granulated from liquid pharmaceutical compositions, which contain rhein or diacerein, or their salts, and pharmaceutically acceptable carrier. Compositions contain from 20 to 45 mg of rhein or diacerein. Invention also relates to methods of producing claimed compositions. Compositions by invention are bioequivalent to preparative form of diacerein in dosage 50 mg, sold under the trade name Art 50®. Compositions do not demonstrate variability in after meal condition and on an empty stomach.

EFFECT: considerable reduction of side effects, such as pulpy stool, in comparison with Art 50®.

13 cl, 37 tbl, 17 ex

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