Replaced dihydropyrazolones as inhibitors of hif-prolyl-4-hydroxylase

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula ,

X means N or CH, R1 means hydrogen or cyano, R2 means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C3-C6-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

 

The present application relates to new substituted derivatives of dihydropyrazolo, methods for their preparation, their use for the treatment and/or prophylaxis of diseases and their use for producing drugs for the treatment and/or prophylaxis of diseases, in particular cardiovascular and hematological disease, kidney disease and to stimulate wound healing.

Insufficient oxygen supply to the human body or its organs, which because of the length and/or scale or interfere with the correct functioning of the organism or of its authorities, or completely paralyzes their functions, is called hypoxia. Hypoxia may be caused by the reduction of oxygen in the air we breathe (for example, when you stay high in the mountains), disorders of external respiration (for example, due to impaired lung function or blockage of the respiratory tract), decrease in cardiac output (for example, in heart failure, acute overload of the right ventricle, pulmonary embolism), low oxygen transport capacity of blood (for example, anemia (anemia) or intoxication, for example, carbon monoxide)may be localized by insufficient blood supply as a result of thrombosis (coronary heart condition, for example, heart, lower extremities alimosho, diabetic macro - or microangiopathy) or caused by increased oxygen demand of the tissue (for example, as a result of intensive muscular work or local inflammation) [Eder, Gedigk (Hrsg.), Allgemeine Pathologie und pathologische Anatomic, 33. Aufl., Springer Verlag, Berlin, 1990].

The human body is relatively able to adapt to situations of reduced supply of oxygen in acute and chronic cases. In addition to the immediate response, in which the vegetative nervous mechanisms include an increase in cardiac output and temporary displacement of breathing, as well as local dilation of blood vessels, hypoxia leads to changes in transcription of numerous genes. The function of the gene products compensates for lack of oxygen. Thus, strenuously released some enzymes of glycolysis and the vector of glycolysis 1, thereby increasing the isolation of anaerobic ATP and is overcoming a lack of oxygen [Schmidt, Thews (Hrsg.), Physiologic des Menschen, 27. Aufl., Springer Verlag, Berlin, 1997; Loffler, Petrides (Hrsg.), Biochemie und Pathobiochemie, 7. Aufl., Springer Verlag, Berlin, 2003].

Furthermore, hypoxia leads to enhanced expression of growth factor vascular endothelial cells, VEGF, resulting in suffering oxygen starvation of the tissues stimulates new blood vessel formation (angiogenesis). Thereby improving the long-term is the blood supply to the ischemic tissue. In various diseases associated with abnormal blood circulation, and diseases associated with thrombosis, such oppositely directed regulatory mechanism is insufficient [review: Simons und Ware, Therapeutic angio genesis in cardiovascular disease, Nat. Rev. Drug. Discov. 2 (11), 863-71 (2003)].

Further, in a systematic hypoxia strenuously released peptide hormone erythropoietin, produced mainly in the interstitial fibroblast kidney. This stimulates the formation of red blood cells in the bone marrow and together with the oxygen transport capacity of blood. This effect was used by athletes-Champions in the so-called high-altitude training. Reduced oxygen transport capacity of blood, for example, posthemorrhagic anemia, usually causes higher education eritropoetinov in the kidneys. In certain types of anemia, this regulatory mechanism may be either disrupted or products eritropoetinov does not reach the specified parameter. So, for example, suffering from renal failure patients, although erythropoetin and manufactured in the parenchyma of the kidney, but in much smaller quantities relative to the oxygen transport capacity of blood, resulting in a so-called renal anemia. In particular, the kidney is anemia, and anemia due to cancer and HIV infection, are treated usually by appointment for parenteral receiving recombinant human eritropoetinov (rhEPO). At the present time for such expensive treatment alternative treatment accept oral medication [reviews in the works: Eckardt, The potential of erythropoietin and related strategies to stimulate erythropoiesis, Curr. Opin. Investig. Drugs 2(8), 1081-5 (2001); Bems, Should the target hemoglobin for patients with chronic kidney disease treated with erythropoietic replacement therapy be changed?, Semin. Dial. 18 (1), 22-9 (2005)]. Recent studies confirm that erythropoietin in addition to enhancing erythropoiesis action also provides independent protective (anti-apoptotic) effect on affected due to hypoxia of the tissues, particularly the heart and brain. Further according to the latest research results treatment with erythropoietin in patients with renal insufficiency on average reduces the severity of the disease condition [reviews in the works:

Caiola und Cheng, Use of erythropoietin in heart failure management, Ann. Pharmacother. 38 (12), 2145-9 (2004); Katz, Mechanisms and treatment of anemia in chronic heart failure. Congest. Heart. Fail. 10 (5), 243-7 (2004)].

Together with induced hypoxia genes described above, is called increasing their expression during hypoxia by the so-called hypoxia-induced transcription factor (HIF). With regard to factor HIF, we are talking about the heterodimeric transcription factor that consists of the one alpha and one beta subunit. Describes the three alpha isoform factor HIF 1 alpha and HIF 2 alpha HIF represent homologous subunits, and are important for induced hypoxia gene expression. While beta-subunit (described in 2 isoforms), known as ARNT (aryl hydrocarbon receptor nuclear translocator: arylhydrocarbon receptor of translocator kernel)is the selected constitutive, expression of alpha-subunit depends on the oxygen content in the blood. When normoxia alpha protein factor HIF poly-ubiquitinated and then decomposed into a protease. During hypoxia, this decomposition is inhibited, so that HIF alpha forms a dimeric compound with ARNT and can activate their target genes. This dimer HIF is attached to the so-called active elements hypoxia (HRE) in regulatory sequences of their target genes. The HRE elements are defined semantic consistency. Functional HRE were found in the regulatory elements of many genes induced by hypoxia [reviews in the works: Semenza, Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol. Med. 7 (8), 345-50 (2001);

Wenger and Gassmann, Oxygen(es) and the hypoxia-inducible factor-1: Biol. Chem. 378 (7), 609-16 (1997)].

The molecular mechanism underlying the regulation of HIF-alpha, explained the work of several independent research groups. In General, this mechanism is represented as follows: HIF and is the hydroxylases referred to as PHD or EGLN subclass of prolyl-4-hydroxylase, dependent on oxygen, in two specific residue shed (R and R human subunit 1 alpha HIF). As for HIF prolyl - 4-hydroxylase, it is dependent on the iron dioxygenase that converts oxoglutarate [Epstein et al., .elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation, Cell 107 (1), 43-54 (2001); Bruick and McKnight, A conserved family of prolyl-4-hydroxylases that modify HIF, Science 294 (5545), 1337-40 (2001); Ivan et al., Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor, Proc. Natl. Acad. Sci. U.S.A. 99 (21), 13459-64 (2002)]. Enzymes were first opublikowany in 2001 as prolyl-hydroxylase [Aravind and Koonin, The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate-and iron-dependent dioxygenases, Genome Biol. 2 (3), research0007.1-0007.8, Epub Feb 2001 19].

To polyhydroxyalkanoic the alpha subunit of HIF is attached pVHL depressing tumor protein, which together with longina In and forms a so-called complex VBC, which adapts Adha subunit of HIF to EZ ubiquitin-ligase. Because prolyl-4-hydroxylation of the alpha subunit of HIF and its subsequent decay is dependent on the intracellular concentration of oxygen, HIF prolyl-4-hydroxylase are also called as a cellular oxygen sensor. Identified three isoforms of these enzymes: EGLN1/PHD2, EGLN2/PHD1 and EGLN3/PHD3. Of these two enzymes (EGLN2/PHD1 and EGLN3/PHD3) induced transcription even during hypoxia and may be responsible for Pade is their level of HIF alpha, seen in chronic hypoxia [see Schofield and Ratcliffe, Oxygen sensing by HIF hydroxylases, Nat. Rev. Mol. Cell. Biol. 5 (5), 343-54 (2004)].

Selective pharmacological inhibition of HIF prolyl-4-hydroxylase leads to an increase in the expression-dependent HIF target genes and is therefore used for treatment of many diseases. In particular, diseases of the cardiovascular system can be expected to improve disease by induction of new blood vessels, as well as when changing the metabolism of ischemic organs from aerobic to anaerobic ATP allocation. Improved vascularization of chronic wounds promotes healing process, in particular, it is difficult curable ulcers Ulcera cruris and other chronic skin wounds. In certain forms of the disease, particularly in patients with renal anemia, induction of autologous erythropoietin is also noteworthy therapeutic target.

Inhibitors of HIF prolyl-4-hydroxylase described to date in the scientific literature do not satisfy the requirements of a drug. It is either about the competitive analogues of oxoglutarate (as, for example, N-oxacillin), which have a very low efficiency, and therefore still not showed on the samples in vivo no action in the sense of induction of HIF target genes. Either we are talking about gelator is based complexes (chelating agents) as desferroxamine, which act as non-specific inhibitors containing iron dioxygenase, and which, while causing the induction of target genes, such as erythropoietin in vivo, but due to the complexation of available iron suppress erythropoiesis.

2-Heteroaryl-4-aryl-dihydropyrazolo with bactericidal and fungicidal action published applications EP 165 448 and EP 212281. Application 2-heteroaryl-4-aryl-dihydropyrazolo as lipoxygenase inhibitors for the treatment of respiratory diseases, diseases associated with abnormal blood circulation, and inflammatory diseases described in EP 183 159. 2,4-diphenyl-1,2-dihydropyrazolo with herbicide activity described in DE 2 651 008. On receipt of the pharmacological properties of some 2-pyridyl-dihydropyrazolo reported in the work Helv. Chim. Acta 49 (1), 272-280 (1966). In applications WO 96/12706, WO 00/51989 and WO 03/074550 described in connection with the partial structure of dihydropyrazolo for the treatment of various diseases, and in WO 2006/101903 published substituted hydroxy or alkoxygroup seperatly for the treatment of neuropsychiatric diseases. Further, in WO 03/051833 and WO 2004/089303 described substituted heteroaryl pyrazole derivatives for the treatment of pain and various diseases of the Central nervous system. In WO 2006/114213 were described 2,4-dipyridyl-1,2-dihydropyrazolo in the role of inhibitors of oil and gas fields-prolyl-4-hydroxylase.

Roentgenostructural analysis of crystals of compound 3-methyl-1-(pyridine-2-yl)-4-(1-pyridin-2-yl-3-methyl-1H-pyrazole-5-yl)-2H-3-pyrazolin-5(1H)-he (another name: 5,5'-dimethyl-2,2'-dipyridine-2-yl-1',2'-dihydro-2H,3'H-3,4'-beparasy-3'-Oh) are reported in working Acta Crystallogr., Section E: Structure Reports Online E57 (11), oll26-oll27 (2001) [Chem. Abstr. 2001:796190]. The synthesis of certain derivatives of 3',5-dimethyl-2-phenyl-1'-(1,3-thiazol-2-yl)-1H,2H-3,4'-beparasy-5'-tins described in Indian J. Heterocyclic Chem. 3. (1), 5-8 (1993) [Chem. Abstr. 1994:323362]. About obtaining and tautomerism separate derivatives of 4-(pyrazole-5-yl)-pyrazolin-5-ones reported in the work of J. Heterocyclic Chem. 27 (4), 865-870 (1990) [Chem. Abstr. 1991:428557]. Use for therapeutic purposes mentioned in these publications compounds hitherto not been described. In the application WO 2007/008541 is the compound 2-third-butyl-1'-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-3',5-dimethyl-1'H,2H-3,4'-beparasy-5'-ol as a test example.

The present invention is to provide new compounds that can be used for the treatment of diseases, in particular cardiovascular and hematological diseases.

In the framework of the present invention describes compounds that act as specific inhibitors of HIF-prolyl-4-hydroxylase, and which due to its specific mechanism of action in vivo after parenteral or oral administration results in induction of HIF target genes, such as erythropoietin, and the resulting biological processes, such as erythropoiesis.

The subject invention are the compounds of formula

,

in which

X represents N and the and CH,

R1means hydrogen or a piano,

R2means a saturated 4-7 membered residue heterocyclyl, linked through the nitrogen atom,

and heterocyclyl residue may be substituted by one Deputy, selected from the group consisting of hydroxy, hydroxycarbonyl, C1-C3-alkyl, C1-C3-alkylamino and C3-C6-jyyaskyla, or with heterophylly residue may be substituted by 1 to 4 fluorine substituents and their salts, solvate, and a solvate of their salts.

The compounds according to the invention are the compounds of formula (I) and their salts, solvate and solvate salts, and also covered by formula (I) compounds, subsequently named as an example (examples) performance, and their salts, solvate and solvate salts, if we are not talking about salt, solvate and solvate salts of both species covered by the formula (I), subsequently named connections.

Compounds according to the invention, depending on their structure may exist in stereoisomeric forms (enantiomers, diastereomers). Therefore, the invention encompasses enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers can be by known methods selected stereoisomeric homogeneous components.

If the compounds according to the invention can be represented in the tautomeric forms, the present invention encompasses all tautomeric forms.

As salts in the framework of the present invention is preferable not dangerous for physiology salts of the compounds according to the invention. Covered in salt, which are unsuitable for pharmaceutical uses but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Not dangerous for physiology salts of the compounds according to the invention include salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultancy, toluenesulfonic acid, benzosulfimide, naphthalenediol-acid, acetic acid, triperoxonane acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Not dangerous for physiology salts of the compounds according to the invention also include salts of conventional bases such as, for example, and preferably, alkali metal salts (sodium and potassium salts), salts of alkaline earth metals (e.g. calcium salts and magnesium), and ammonium salts, derived from ammonia or organic amines with 1 to 16 carbon atoms, as for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, ditano the amine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, Ethylenediamine and N-methylpiperidin.

As a solvate in the framework of the present invention are such types of compounds according to the invention, in which solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a special form of a solvate, which are coordinated with water. In the framework of the present invention as the solvate preferred hydrates.

In addition, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive but which in the body are converted into compounds according to the invention (e.g., metabolic or by hydrolytic).

In the framework of the present invention, the substituents have the following meaning, unless there are other definitions:

By itself, the alkyl or alkyl in the group alkylamino means linear or branched chain alkyl residue with 1 to 3 carbon atoms, for example, and preferably, methyl, ethyl, n-propyl, isopropyl.

Alkylamino means the rest of alkylamino with one or two (independently selected from one another) alkyl the substituents is, for example, and preferably, means methylamine, ethylamine, n-Propylamine, Isopropylamine, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino and N-isopropyl-N-n-propylamino. C1-C3-alkylamino means, for example, the balance monoalkylamines with 1-3 carbon atoms or the residue of dialkylamino respectively with 1-3 carbon atoms in each alkyl substituent.

Cycloalkyl means monocyclic group cycloalkyl, usually with 3-6 carbon atoms, for example, and preferably, means cycloalkyl called cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Saturated 4-7 membered heterocycly residue linked through a nitrogen atom, means a monocyclic, saturated, heterocyclic residue with 4-7 ring atoms containing a nitrogen atom through which it is connected, and no more than 2, mostly not more than one additional heteroatom and/or heterogroup from the series N, O, S, SO, SO2and the nitrogen atom can form nitric oxide. Preferred 4-7-membered, monocyclic saturated heterocyclyl residues with a maximum of one additional heteroatom from the series O, N and S, for example, and preferably, azetidin-1-yl, pyrrolin-1-yl, piperidine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, piperazine-1-yl, 1,2-oxazine-2-yl, 1,4-oxazepan-4-yl, 1,4-thiazepan-4-yl.

Predpochtitel what s the compounds of formula (I), in which

X is N or CH,

R1means hydrogen or cyano,

R2means a saturated 4-7 membered heterocyclyl residue linked through a nitrogen atom,

and heterocyclyl residue substituted by 1 to 4 fluorine substituents, or R2means piperazine-1-yl,

moreover piperazine-1-yl substituted by one Deputy, selected from the group consisting of C3-C6-cycloalkyl, or R2means azetidin-1-yl,

azetidin-1-yl substituted by one Deputy, selected from the group consisting of hydroxycarbonyl, C1-C3-alkyl, C1-C3-alkylamino and C3-C6-cycloalkyl, or

R2means 1,2-oxazine-2-yl or 1,4-oxazepan-4-yl,

and their salts, solvate, and a solvate of their salts.

Preferred compounds of formula (I), in which

X represents N or CH,

R1means hydrogen or a piano,

R2means azetidin-1-yl, pyrrolin-1-yl or piperidine-1-yl,

azetidin-1-yl, pyrrolin-1-yl and piperidine-1-yl substituted

1-4 substituents fluorine,

or

R2means piperazine-1-yl,

moreover piperazine-1-yl, 4-th position substituted by one Deputy, selected from the group consisting of C3-C6-cycloalkyl,

or

R2means azetidin-1-yl,

azetidin-1-yl, 3-position is substituted by one Deputy,

selected the C group, consisting of hydroxycarbonyl, bromide and

dimethylamino,

or

R2means 1,2-oxazine-2-yl or 1,4-oxazepan-4-yl,

and their salts, solvate, and a solvate of their salts.

Preferred are also the compounds of formula (I), in which

X represents N or CH,

R1means hydrogen or cyano,

R2means a saturated 4-7 membered heterocyclyl the rest,

linked through the nitrogen atom,

and heterocyclyl residue substituted by 1 to 4 fluorine substituents and their salts, solvate, and a solvate of their salts.

Preferred are also the compounds of formula (I), in which

X represents N or CH,

R1means hydrogen or cyano,

R2means azetidin-1-yl, pyrrolin-1-yl or piperidine-1-yl,

azetidin-1-yl, pyrrolin-1-yl and piperidine-1-yl substituted

1-4 substituents fluorine,

and their salts, solvate, and a solvate of their salts.

Preferred are also the compounds of formula (I), in which

X is N or CH,

R1means hydrogen or cyano,

R2means azetidin-1-yl, pyrrolin-1-yl or piperidine-1-yl,

azetidin-1-yl, pyrrolin-1-yl and piperidine-1-yl substituted 2 fluorine substituents, and these substituents bound to the same carbon atom,

and their salts, solvate, and a solvate of their salts. Preferred are also the compounds of formula (I), in which

X represents N or CH,

R1OZNA the AET hydrogen or a piano,

R2means piperazine-1-yl,

moreover piperazine-1-yl substituted by one Deputy, selected from

group consisting of C3-C6-cycloalkyl, and their salts, solvate, and a solvate of their salts.

Preferred are also the compounds of formula (I), in which

X is N or CH,

R1means hydrogen or cyano,

R2means piperazine-1-yl,

moreover piperazine-1-yl, 4-th position substituted by one Deputy,

selected from the group consisting of C3-C6-cycloalkyl, and their salts, solvate, and a solvate of their salts. Preferred are also the compounds of formula (I), in which

X represents N or CH,

R1means hydrogen or a piano,

R2means azetidin-1-yl,

azetidin-1-yl substituted by one Deputy, selected from the group consisting of hydroxycarbonyl, C1-C3-alkyl, C1-C3-alkylamino and C3-C6-cycloalkyl,

and their salts, solvate, and a solvate of their salts.

Preferred are also the compounds of formula (I), in which

X represents N or CH,

R1means hydrogen or cyano,

R2means azetidin-1-yl,

azetidin-1-yl substituted in one Deputy selected from the group consisting of hydroxycarbonyl, methyl and dimethylamino,

and their salts, solvate, and a solvate of their salts.

Preferred are also compounds of the Fort the uly (I), in which

X represents N or CH,

R1means hydrogen or a piano,

R2means apicidin-1-yl,

apicidin-1-yl, 3-position is substituted by one Deputy, selected from the group consisting of hydroxycarbonyl, methyl and dimethylamino,

and their salts, solvate, and a solvate of their salts.

Preferred are also the compounds of formula (I), in which

X represents N or CH,

R1means hydrogen or a piano,

R2means 1,2-oxazine-2-ilili 1,4-oxazepan-4-yl.

Preferred are also the compounds of formula (I)in which X is N.

Preferred are also the compounds of formula (I)in which R1means hydrogen.

Preferred are also the compounds of formula (I)in which R1means the piano.

Preferred are also the compounds of formula (I)in which R2means 4-cyclobutyl-piperazine-1-yl.

Preferred are also the compounds of formula (I), in which

X represents N or CH,

R1means piano,

R2means a saturated 4-7 membered heterocyclyl residue linked through a nitrogen atom,

and heterocyclyl residue substituted with one Deputy, selected from the group consisting of hydroxy, hydroxycarbonyl, C1-C3-alkyl, C1-C3-alkylamino and C3-C6-cycloalkyl, or

and heterocyclyl residue substituted 1-4 cover the firs fluorine,

and their salts, solvate, and a solvate of their salts.

These in particular determination of residues in appropriate and preferred combinations of residues are replaced by arbitrary well as definitions of residues other combinations regardless of the respective combinations specified residues.

The most preferred combination of two or more of the above areas of preference.

According to the invention derivatives of 1,2-dihydropyrazol-3-one of formula (I) can be also represented in the tautomerism form 1H-pyrazole-5-ol (I') (see below figure 1); both tautomeric forms are encompassed by the present invention.

Scheme 1

Further, the subject invention is a method of obtaining compounds of formula (I)or their salts, solvate or solvate of salt, and according to the method

[A] compounds of the formula

,

in which R1has the above value, and

Z1means methyl or ethyl,

in an inert solvent, optionally in the presence of one of the acid with the compound of the formula

,

in which R2has the above value,

turn in the compounds of formula

in which Z1, R1and R2have the above values,

already the ri these reaction conditions or in a subsequent reaction under the influence of the base is converted into the cyclic compounds of formula (I),

and the compounds of formula (I), if necessary, using the appropriate (i) solvents and/or (ii) bases or acids may be converted into their salts, solvate or solvate salt,

or

[In] the compounds of formula

in which Z1and R1have the above values,

with the compound of the formula

in which

Z2means methyl or ethyl,

condense in the compounds of formula

in which Z1and R1have the above values,

and then in the presence of one of the acid with the compound of the formula (III) is transformed into the compounds of formula (IV), already under these reaction conditions or in a subsequent reaction under the action of the base is converted into the cyclic compounds of formula (I),

and the compounds of formula (I), if necessary, using the appropriate (i) solvents and/or (ii) bases or acids may be converted into their salts, solvate or solvate salt,

or

[With] the compound of the formula

in water as a solvent by the method of eintopf ("single tube"), subject to the first reaction with compounds of the formula

which R2has the above value,

and then with compounds of the formula (VII) with transformation to connect the Oia formula (I),

and the compounds of formula (I), if necessary, using the appropriate (i) solvents and/or (ii) bases or acids may be converted into their salts, solvate or solvate of their salts.

Free base salts can be obtained by an exchange reaction of salts of the compounds or solvate salts of the compounds with the base.

As a reason suitable the hydroxides of alkali metals, such as sodium hydroxide or potassium hydroxide, carbonates of alkaline or alkaline earth metals, such as sodium carbonate, potassium, calcium or cesium, or

an aqueous solution of ammonia.

In an alternative method the free base salts can be obtained, for example, using column chromatography with reversed phase with a gradient of acetonitrile-water with the addition of a base, in particular, using column RP18 Phenomenex Luna 18 (2) and diethylamine as a base.

The next subject of invention is a method of obtaining compounds of formula (I) and their solvate according to which salts of the compounds or solvate salts of the compounds of the exchange reaction with a base or by using chromatography adding base is converted into the compound.

Further, the compounds according to the invention can be obtained, under certain conditions, by transformation of functional groups of individual substituents, in particular, indicated by the symbols R1and R2and the walking of the compounds of formula (I), obtained in the ways described. These transformations provide standard, well-known specialists of ways and include, for example, such reactions as nucleophilic or electrophilic substitution, oxidation, reduction, hydrogenation, catalyzed by transition metals of combination reaction, alkylation, acylation, amination, the formation of ester, cleavage of ester, formation of simple ether, a simple splitting of the ether, the formation of carbonamides, sulfonamides, carbamates and urea, as well as the introduction and removal of temporary end groups.

As inert solvents for the stages of method (II)+(III)→(IV), (VII)+(III)→(IV) and (IV)→(I) are suitable, in particular, ethers like diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, or alcohols as methanol, ethanol, n-propanol, ISO-propanol, n-butanol and tert-butanol, or water, or a mixture of solvents, or a mixture of the solvent with water. It is preferable to use methanol, ethanol, tetrahydrofuran or water.

Stage method (V)+(VI)→(VII) is preferably carried out in dimethylformamide as solvent, or in the presence of an excess of compound (VI) without additional solvent. In some cases, the reaction can also be carried out mainly under microwave irradiation. The reaction is of BMENA carried out in General at temperatures from +20°C to +150°C, preferably at a temperature of from+80°C to 120°C [see also J.P. Bazureau et aL, Synthesis 1998, 967; ibid. 2001 (4), 581].

In some cases, the stage of the method (II)+(III)→(IV) and (VII)+(III)→(IV) can be carried out mainly with the addition of acid. For this purpose suitable conventional inorganic or organic acids, such as hydrogen chloride, acetic acid, triperoxonane acid, methanesulfonate, p toluensulfonate or camper-10-acid. Preferably acetic acid, in particular, triperoxonane acid or p-toluenesulfonic acid.

The exchange reaction (II)+(III)→(IV) in General perform at temperatures from 0°C to +100°C, preferably from+10°C to+50°C. the Reaction (VII)+(III)→(IV) carry out in General at temperatures from +20°C to +120°C, preferably from +50°C up to +100°C.

The sequence of method (II)+(III)→(IV)→(I) and (VIII)+(III)→(IV)→(I) can be performed in two stages or also as a reaction "eintopf" without isolating the intermediate of step (IV). For the last option, in particular, suitable transformation of the components of the microwave irradiation; the reaction is performed in General at temperatures from +50°C up to +200°C, preferably at temperatures from +100°C up to +180°C.

Part of the circuit loop, closer to the compound (I), begins upon receipt of the compound (IV); cyclization can be accomplished by treatment in situ reaction mixture to the Kim-or base.

As grounds for this highlighted the cyclization stage (IV)→(I) suitable conventional inorganic or organic bases. These include, in particular, hydroxides of alkali metals, such as sodium hydroxide or potassium hydroxide, carbonates of alkaline or alkaline earth metals, such as sodium carbonate, potassium, calcium or cesium, alkali metal alcoholate as methanolic sodium or potassium, ethanolic sodium or potassium, or tert-butyl sodium or potassium, or hydrides of alkali metals as sodium hydride. Preferably use methanolate or ethanolate sodium.

Induced by base exchange reaction (IV)→(I) carry out in General at temperatures from 0°C to +60°C, preferably from 0°C to +30°C.

The exchange reaction (VIII)+(IX)+(VII)→(I) carry out when using 1.1 to 2.0 equivalents of the compounds of formula (IX) with respect to 1 equivalent of the compound of formula (VIII), optionally in the presence of from 1.1 to 2.0 equivalents of a base. Preferred exchange reaction with 1.1 to 1.5 equivalents of the compounds of formula (IX).

As grounds for the exchange reaction (VIII)+(IX)(+(VIII)→(I) suitable conventional inorganic or organic bases. These include, in particular, hydroxides of alkali metals, such as sodium hydroxide or potassium, or amine bases, such as N-ethyl-N-(propan-2-yl)propane-2-amine. Preferred N-e is Il-N-(propan-2-yl)propane-2-amine.

The exchange reaction (VIII)+(IX)+(VII)→(I) is carried out in General at temperatures from +20°C to +100°C, preferably at a temperature of from +70°C up to +100°C.

All stages of the method can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Typically, work is carried out under normal pressure.

The compounds of formula (II) can be polucheny described in the literature methods for the C-acylation of esters of sulfonic acids of the compounds of the formula (V). Compounds of formula (III), (V), (VI), (VIII) and (IX) are commercially available, known from the literature or can be obtained by analogy with the methods described in the literature.

Obtaining the compounds according to the invention is illustrated in the following reaction scheme 2:

Scheme 2

[:dimethylformamide, 16 hours,+100°C; b): ethanol, triperoxonane acid, +78°C; (C): NaOEt, ethanol, 1 hour, room temperature].

Compounds according to the invention show unexpectedly full of pharmacological action spectrum.

They are therefore suitable for use as pharmaceuticals for the treatment and/or prevention of diseases in humans and animals.

Compounds according to the invention are distinguished as specific inhibitors NR-prolyl-4-hydroxylase.

Compounds according to the invention, thanks to their farmacologiche is Kim properties, can be used for the treatment and/or prevention of diseases of the cardiovascular system, in particular, heart failure, coronary heart disease, angina, myocardial infarction, stroke, arteriosclerosis, essential, and malignant pulmonary hypertension, and peripheral occlusive disease

Compounds according to the invention are suitable, furthermore, for the treatment and/or prevention of blood disorders, such as idiopathic anemia, renal anemia and anemia, followed by cancer (in particular, anemia caused by chemotherapy), infections (particularly HIV) infection, or other inflammatory diseases, such as rheumatoid arthritis. In addition, the compounds according to the invention is suitable for maintenance treatment of anemia due to blood loss, iron deficiency anemia, avitaminoses anemia (for example, due to lack of vitamin b-12 or lack of folic acid), gipoplasticheskaya and aplastic anemia, hemolytic anemia, or for the maintenance treatment of anemia in breach absorption of iron (ultratracker anemia or anemia due to other endocrine disorders (eg, hypothyroidism).

Further, the compound suitable for increasing hematocrit order to obtain blood for vospol the value of his own blood before the operation.

In addition, the compounds according to the invention can be used for the treatment and/or prevention caused by operations ischemic conditions and their consequences after surgery, especially after heart surgery with the use of artificial hearts and lungs (e.g., bypass surgery, implantation of heart valves), operations on the carotid artery operations on the aorta and operations with an instrumental opening or penetration of the roof of the skull. Further, the compound suitable for General treatment and/or prophylaxis in surgical interventions to accelerate wound healing and reduce the time of recovery.

In addition, the compound suitable for the treatment and prevention of the consequences of acute and prolonged ischemic brain States (e.g., stroke, birth asphyxia).

Further, the compounds can be used for the treatment and/or prevention of cancer and for the treatment and/or prevention of advancing the treatment of cancer of ill health, in particular, after therapy and cytotoxic drugs, antibiotics and radiation.

Compounds suitable for the treatment and/or prophylaxis of rheumatic diseases and other forms of diseases related to autoimmune diseases and, in particular, for the treatment and/or prevention of ill health occurring in the course of medication is about the treatment of such diseases.

In addition, the compounds according to the invention can be used for the treatment and/or prevention of diseases of the eye (e.g. glaucoma), brain (for example, Parkinson's disease, Alzheimer's disease, dementia, chronic pain), chronic kidney disease, renal failure and acute renal failure, but also to stimulate wound healing.

Further, the compounds according to the invention is suitable for treatment and/or prevention of General physical weakness often encountered in deep old age until exhaustion.

Further, the compound suitable for the treatment and/or prevention of sexual dysfunction.

In addition, the compound suitable for the treatment and/or prevention of diabetes and its complications, such as diabetic macro - and microangiopathy, diabetic nephropathy, and neuropathy.

Further, the compounds according to the invention is suitable for treatment and/or prevention of fibrotic diseases, such as heart, lungs and liver.

In particular, the compounds according to the invention is also suitable for the prevention and treatment of retinopathy of premature children (Retinopathia praematurorum).

The next subject of the present invention is the use of compounds according to the invention for the treatment and/or prevention of diseases, in particular, the above-mentioned diseases.

The following predmeta the present invention is the use of compounds according to the invention for the manufacture of medicinal products for the treatment and/or prevention of diseases, in particular, the above-mentioned diseases.

The next subject of the present invention is a method of treatment and/or prevention of diseases, in particular the aforementioned diseases, using the current number of at least one of the compounds according to the invention.

Compounds according to the invention can be used alone or, if necessary, in combination with other biologically active substances. The next subject of the present invention are drugs, containing at least one of the compounds according to the invention and one or more active substances, in particular for the treatment and/or prevention of the above diseases. As suitable for combinations of active substances, for example, and preferably, may be named the following: ACE inhibitors, receptor antagonists, angiotensin II antagonists beta-receptors, calcium antagonists, inhibitors of phosphodiesterase (PDE), antagonists mineralocorticoid receptors, diuretics, aspirin, iron supplements, supplements of vitamin b 12 and folic acid, statins, derivatives of digitalis (digoxin), cancer chemotherapeutic agents and antibiotics.

In a preferred form of execution of the invention compounds according to the invention are produced in kombinats and with any ACE inhibitor, as, for example, and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril, perindopril or trancopal.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any antagonist of angiotensin II, such as, for example, and preferably, losartan, candesartan, valsartan, telmisartan or embusartan.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any blocker beta-receptors, such as, for example, and preferably, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, daprela, landiolol, nebivolol, epanolol or bucindolol.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any calcium antagonist, such as, for example, and preferably, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any inhibitor of phosphodiesterase (PDE), such as, for example, and preferably, milrinone, amrinone, who imoinda, Cilostazol, sildenafil, vardenafil or tadalafil.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any antagonist mineralocorticoid receptors, such as, for example, and preferably, spironolactone, eplerenone, canrenone or canrenoate potassium.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any diuretic, as, for example, and preferably, furosemid, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, poetized, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerin, isosorbide, mannitol, amiloride or triamterene.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any inhibitor of HMG-CoA reductase inhibitor from the class of statins, such as, for example, and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, tseriwastatina or pitavastatin.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any cancer chemotherapeutic agent, for example, and preferably, from GRU the dust of the platinum complexes, as, for example, cisplatin and carboplatin, from a group of alkylenes, such as cyclophosphamide and chlorambucil, from the group of antimetabolites, such as 5-fluorouracil and methotrexate, group topoisomerase inhibitors, such as etoposide and camptothecin, from the group of antibiotics, such as doxorubicin and daunorubicin, or from groupy kinase inhibitors, such as sorafenib and sunitinib.

In a preferred form of execution of the invention compounds according to the invention are produced in combination with any antibiotic, for example, and preferably, from the group of penicillins, cephalosporins or quinolones, such as ciprofloxacin and moxifloxacin.

The next subject of the present invention are drugs, containing at least one compound according to the invention, usually together with one or more inert, non-toxic, adopted in pharmaceutical auxiliary substances, and their use for these purposes.

Compounds according to the invention can act systemically or locally. For this purpose, they can be taken in a proper way, as, for example, orally, parenterally, pulmonale, nasal, under the language in the language transbukkalno, rectal, dermal, transdermal, conjunctival, through the ears or in the form of a graft and stent.

the La these ways of reception of the connection according to the invention can be prepared in the relevant application forms.

For oral administration suitable operating on the state of the art applications, quickly and/or in a modified form giving compounds according to the invention, which contain compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (tablets, coated or uncoated, for example, are resistant to gastric juice membranes, soluble with the delay or insoluble membranes that control the release of the compounds according to the invention), quickly disintegrating in the oral cavity of the tablet or plate/wafer, plate/lyophilizate, capsules (for example, capsules hard or soft gelatin), pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral reception can be carried out in the crawl stage suction (for example, intravenously, intraarterially, intracardially, intraspinally or intralumbalno) or with inclusion of absorption (for example, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral receive suitable, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, liofilizatow or sterile powders.

For other ways of receiving suitable, for example, pharmaceutical forms for inhalation (inter alia powder is inhalers, sprayers), drops, solutions or sprays for the nose, tablets, taken on the tongue, under the tongue or cheek plates/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, mash), fat-soluble suspensions, ointments, creams, acting through the skin of the systems (for example patches), milk, pastes, foams, powders, implicate and stents.

Preferred oral or parenteral intake, particularly oral and intravenous administration.

Compounds according to the invention can be converted to these forms of application. This can be done in a known manner using an inert, non-toxic, adopted in pharmaceutical excipients. These excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polietilenglikol) emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polychiorinated), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants, such as ascorbic acid), colorants (for example inorganic pigments, such as iron oxides) and substances that improve the taste and/or smell.

To achieve the schutimye of the parenteral intake should be prescribed number, in General, from 0.001 to 1 mg/kg, mainly from 0.01 to 0.5 mg/kg of body weight. In oral administration the dosage is 0.01-100 mg/kg, mainly of 0.01-20 mg/kg and particularly preferably 0.1 to 1 mg/kg body weight.

However, in some cases it is necessary to deviate from these quantities, namely depending on the body weight, route of administration, individual tolerance of the active substance, the type of preparation and time or interval of administration. So, in some cases, the dosage may be sufficient in smaller quantities than the minimum specified dose, while in other cases must be exceeded the upper bound. If the higher dose is recommended to divide it into several doses per day.

The following application examples explain the invention. The invention is not limited to the given examples.

The data specified in percent in the following tests and examples, if no other instructions are vescovini percent; shares are weight parts. The ratio of solvents, diluents and the concentration of liquid/liquid solutions are relative to the corresponding volumes.

A. Examples

Abbreviations:

aq.An aqueous solution
cat.To calificaci
dDay(days)
DCIDirect chemical ionization (in MS)
DMFDimethylformamide
DMSODimethylsulfoxid
theory. prob.Relative to theoretically possible (output)
EIIonization by electron impact (MS)
ESIElectrospray-ionization (in MS)
EtEthyl
GC-MSGas chromatography in combination with mass spectroscopy
hHour (time)
HPLCLiquid chromatography high pressure liquid chromatography high-resolution
conc.Concentrated
LC-MSLiquid chromatography combined with mass spectroscopy
met.Method
minutesMinute (min)
MSMass spectroscopy
NMRThe nuclear resonance spectroscopy (NMR)
RtThe retention time (in HPLC)
KTRoom temperature
TFATriperoxonane acid
THFTetrahydrofuran

Methods LC-MS. GC-MS and HPLC:

Method 1 (LC-MS): instrument: Micromass Platfonn LCZ with HPLC Agilent Serie 1100; column: Thermo Hypersil GOLD 3µ, 20 mm × 4 mm; eluent A: 1 l water+0.5 ml of 50%acetic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50%acetic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9 min 30% A→3.1 min 10% A→5.5 min 10% A; oven: 50°C; flow: 0.8 ml/min; UV detection: 210 nm.

Method 2 (LC-MS): instrument type MS: Micromass ZQ; instrument type HPLC:

Waters Alliance 2795; column: Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm × 4 mm; eluent A: 1 l water+0.5 ml of 50%acetic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50%acetic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flow: 0.0 min 1 ml/min→2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50°C; UV detection: 210 nm.

Method 3 (LC-MS): instrument type MS: Micromass ZQ; instrument type HPLC:

Waters Alliance 275; column: Phenomenex Synergi 2.5µ. MAX-RP 100A Mercury 20 mm × 4 mm; eluent A: 1 l water+0.5 ml of 50%acetic acid, eluent B: 1 l of acetonitrile +0.5 ml of 50%acetic acid; gradient: 0.0 min 90% A→0.1 min 90% A→3.0 min 5% A→4.0 min 5% A→4.01 min 90% A; flow: 2 ml/min; oven: 50°C; UV detection: 210 nm.

Method 4 (LC-MS): Instrument: Micromass Quattro Micro MS c HPLC Agilent Serie 1100; column: Thermo Hypersil GOLD 3µ 20 mm × 4 mm; eluent A: 1 l water+0.5 ml of 50%acetic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50%acetic acid; gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% a (flow 2.5 ml/min)→5.00 min 100% A; oven: 50°C; flow: 2 ml/min; UV detection: 210 nm.

Method 5 (LC-MS): Instrument: Micromass QuattroPremier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9µ 50 mm × 1 mm; eluent A: 1 l water +0.5 ml of 50%acetic acid, eluent B: 1 l of acetonitrile +0.5 ml of 50%acetic acid; gradient: 0.0 min 90% A→0.1 min 90% A→1.5 min 10% A→2.2 min 10% A; flow: 0.33 ml/min; oven: 50°C; UV detection: 210 nm.

Method 6 (HPLC): Instrument: HP 1100 with DAD-detection; column: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; eluent A: 5 ml perchloro acid (70%) / l of water, eluent b: acetonitrile; gradient: 0 min 2% B→0.5 min 2% B→4.5 min 90% B→6.5 min 90% B→6.7 min 2% B→7.5 min 2% B; flow: 0.75 ml/min; temperature column: 30°C; UV detection: 210 nm.

Method 7 (GC-MS): Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; constant flow with helium: 0.88 ml/min; oven: 70°C; temperature of the inlet: 250°C; gradient: 70°C, 30°C/min→310°C (3 minutes is kept).

Method 8 (preparative HPLC): column: Kromasil 100 C 18, 5 μm, 250 mm × 20 mm; eluent A: water Milli-Q, eluent A: water 0.1%triperoxonane acid, eluent: acetonitrile; gradient: 0.0 min 76%, 5%, 19%→15 min 4%, 95%, 1%→15.1 76%, 5%, 19%→20 min 76% And 5% In, 19%; oven: 40°C; flow: 25 ml/min; UV detection: 210 nm.

Method 9 (preparative HPLC): column: Sunfire 18 5 μm, 19 mm × 150 mm; eluent A: water 0.2%triperoxonane acid, eluent b: acetonitrile; gradient: 0.0 min 95% A→8 min 50% A→8.01 min 95% A→12 min 95% A; CT;

flow: 25 ml/min; UV detection: 210 nm.

Method 10 (preparative HPLC): column: Sunfire 18 5 μm, 19 mm × 150 mm; eluent A: water 0.2%triperoxonane acid, eluent b: acetonitrile; 0 min 90% A→13 min 90% A; oven: 40°C; flow: 25 ml/min; UV detection: 210 nm.

Method 11 (preparative HPLC): column: XBridge 18 5 μm, 19 mm × 150 mm; eluent A: water 0.2%formic acid, eluent b: acetonitrile; 0 min 75% A→6 min 75% A; CT; flow: 25 ml/min; UV detection: 210 nm.

Method 12 (preparative HPLC): column: XBridge 18 5 μm, 19 mm × 150 mm; eluent A: water 0.2%formic acid, eluent b: acetonitrile; 0 min 93%→4 min 93% A; CT; flow: 25 ml/min; UV detection: 210 nm.

Method 13 (preparative HPLC): column: XBridge 18 5 μm, 19 mm × 150 mm; eluent A: water 0.2%triperoxonane acid, eluent b: acetonitrile;0 min 90% And the 12 min 90% A; oven: 40°C; flow: 25 ml/min; UV detection: 210 nm.

The source connections

Example 1A

(4-Cyano-1H-imidazol-1-yl)acetate

3.3 grams (35,3 mmol) of 1H-imidazole-4-carbonitrile [Matthews et al., J. Org. Chem. 1986, 51, 3228-3231] enter in 13.2 ml (11.5 g, 35.3 mmol) of 21%aqueous solution ethylate sodium in ethanol, and add 4.3 ml (6.5 g, for 38.9 mmol) Bromeliaceae. The reaction mixture is stirred 16 hours at room temperature. For processing filtered precipitated solid filter cake washed with ethanol, and the filtrate concentrated in vacuum. The residue is diluted diisopropyl ether, again filtered, the filtrate is again concentrated in a rotary evaporator apparatus, and the residue dried in vacuum. Yield: 3.8 g (60% of theory. prob.).

LC-MS (method I): Rt=1.17 min; MS (ESIpos): m/z=180 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.12 (s, 1H), 7.88 (s, 1H), 5.06 (s, 2H), 4.18(q,2H),1.22(t,3H).

Example 2A

2-(1 H-1,2,3-triazole-1-yl)acetate

129.2 g (5.6 mol) of sodium is added slowly to about 4.0 liters of ethanol. Then add 400,0 g (5.6 mol) of 1,2,3-1ST-triazole and pin 623 ml (938,2 g, 5.6 mol) of Bromeliaceae when the internal temperature of 20-25°Ssmes stirred for 48 hours at room temperature. Precipitated solid is filtered off, the ethanol is removed in vacuo and again filtered. The residue is diluted with ethyl acetate, filtered the, once again concentrated in vacuo and purified by distillation at 30-cm column. The product is obtained at a bath temperature of 140°C, the temperature of the top of 60-115°C and a pressure of 1 mbar. Output:: 440,0 g (50% of theory. prob.).

HPLC (method b): Rt=1.58 min;

LC-MS (method I): Rt=0.71 min; MS (ESIpos): m/z=156 [M+H]+.

Example 3A

1H-Imidazol-1-elatinaceae

118,2 g (5.1 mol) of sodium is added slowly to 2.5 liters of ethanol. Then add 350,0 g (5.1 mol) of imidazole and pin 570 ml (858,6 g, 5.1 mol) of Bromeliaceae when the internal temperature of 20-25°C. the Mixture is stirred for 24 hours at room temperature. Precipitated solid is filtered off, the ethanol is removed in vacuo and again filtered. The residue is purified in a chromatography column on silica gel (solvent: ethyl acetate). Output: 639,0 g (81% of theory. prob.).

GC-MS (method 7): Rt=4.55 min; MS (ESIpos): m/z=155 [M+H]+

Example 4A

(4-Cyano-1H-1,2,3-triazole-1-yl)acetate

4.1 g (31.9 per mmol) acetoacetate and 2.8 g (31.9 per mmol) of the nitrile 2-chloroacrylate acid are mixed in 32 ml of water for 16 hours at a bath temperature of 80°C. After cooling to room temperature, the solution is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuum. The residue is diluted with 50 ml of ethanol and 10 drops of concentrated sulfuric acid, and the mixture is stirred for 16 hours at reflux. For processing the reaction mixture was concentrated in vacuo, the residue diluted with ethyl acetate, the suspension was washed with policecontributing a solution of sodium bicarbonate, the organic phase is dried over sodium sulfate. The solvent is completely removed in a rotary evaporator apparatus, and the residue dried in vacuum. Yield: 1.5 g (25% of theory. prob.).

LC-MS (method 3): Rt=0.96 min; MS (ESIpos): m/z=181 [M+H]+;

1H-NMR (400 MHz, DMSOO: 5 - 9.06 (s, 1H), 5.57 (s, 2H), 4.19 (q, 2H), 1.22(t,3H).

Example 5A

3-(N,N-Dimethylamino)-2-(1H-imidazol-1-yl)acrylic acid ethyl ester

38.0 g (244,9 mmol) of the compound from example stirred FOR 126 ml (108,1 g, 734,7 mmol) of N,N-dimethylformamide-diethylacetal 16 hours at a bath temperature of 90°C. After cooling, the mixture is concentrated in vacuo, stirred with diisopropyl ether, the solid is filtered off, then washed with diisopropyl ether. Output: 49,0 g (95% of theory. prob.).

LC-MS (method 2): Rt=2.42 min; MS (ESIpos): m/z=211 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=7.52 (s, 1H), 7.49 (s, 1H), 7.05 (s, 1H), 6.91 (s, 1H), 4.02 (q, 2H), 2.63 (br. s, 6H), 1.12 (t, 3H).

Example 6A

3-(N-dimethylamino)-2-(4-cyano-1-imidazol-1-yl)acrylic acid ethyl ester

3.8 g (21,4 mmol) of the compound from example 1A and 7.4 ml (6.3 g, 42.8 mmol) of N,N-dimethylformamide di is tilateral stirred for 16 hours at a bath temperature of 100°C. For processing the cooled reaction solution was concentrated in a rotary evaporator apparatus, and the residue dried in vacuum. Yield: 5.0 g (73% purity, 73% of theory. prob.).

LC-MS (method I): Rt=2.69 min; MS (ESIpos): m/z=235 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.13 (s. 1H), 7.85 (s, 1H), 7.58 (s, 1H), 4.03 (q, 2H), 2.69 (br. s, 6H), 1.12 (t, 3H).

Example 7A

3-(Dimethylamino)-2-(4-cyano - 1-1,2,3-triazole-1-yl)acrylic acid ethyl ester

1.3 g (7.5 mmol) of the compound from example 4A and 1.4 ml (1.2 g, 8.2 mmol) of N,N-dimethylformamide-diethylacetal stirred for 16 hours at a bath temperature of 100°Sdla recycling the cooled reaction solution was concentrated in a rotary evaporator apparatus, and the residue dried in vacuum. Yield: 1.5 g (86% of theory. prob.).

LC-MS (method 4): Rt=1.55 min; MS (ESIpos): m/z=236 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=9.14 (s, 1H), 7.75 (s, 1H), 4.04 (q, 2H), 3.15 (br. s, 3H), 2.18 (br. s, 3H), 1.13 (t, 3h).

Example 8A

3-(Dimethylamino)-2-(1H-1,2,3-triazole-1-yl)acrylic acid ethyl ester

20,0 g (128,9 mmol) of the compound from example 2A are mixed with a 44.2 ml (38.0 g, 257,8 mmol) N,n dimethylformamide-diethylacetal, and the mixture is stirred for 16 hours at 100°Spoke cooling to room temperature the reaction mixture was concentrated in vacuum. The residue is stirred in diethyl ether, filtered and washed ditylum ether. Yield: 18.0 g (67% of theory. the Aur.). LC-MS (method 4): Rt=1.20 min; MS (ESIpos): m/z=211 [M+H]+.

1H-NMR (400 MHz. DMSO-d6): δ=8.10 (d, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 4.03 (q, 2H), 3.06 (br. s, 3H), 2.10 (br. s, 3H), 1.12 (t, 3H).

Example 9A

4-(4-Cyclobutylmethyl-1-yl)-6-hydrazinopyridazine

Stage a): 4-Chloro-6-(4-cyclobutylmethyl-1-yl)pyrimidine

1.8 g (8.4 mmol) of 1-cyclobutanecarbonitrile (Zaragoza et al., J. Med. Chem. 2004, 47, 2833) is injected into 18 ml of water and dilute to 2.9 ml (2.1 g, to 16.9 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine. The mixture is stirred for 30 minutes at room temperature and to it was added 1.3 g (8.4 mmol) of 4,6-dichloropyrimidine. The reaction mixture is stirred for 1 hour at 115°C, cooled to room temperature, diluted with 25 ml ethyl acetate and extracted with saturated aqueous sodium hydrogen carbonate solution. The organic phase is separated, dried over sodium sulfate, filtered and concentrated in vacuum. The original product was then purified by chromatography on a column of silica gel (solvent: diclomelan/methanol 100/3). Output: 1.9 grams (89% of theory. prob.)

HPLC (method 6): Rt=2.79 min; MS (DCI): m/z=254 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.32 (s, 1H), 6.95 (s, 1H), 3.65-3.58 (m, 4H), 2.70 (quintet, 1H), 2.27 (t, 4H), 2.00-1.93 (m, 2H), 1.87-1.75 (m, 2H), 1.67-1.55 (m,2H).

Stage b): 4-(4-Cyclobutylmethyl-1-yl)-6-hydrazinopyridazine

Into a solution of 1.9 g (7 mmol) 4-6-(4-cyclobutylmethyl-1-yl)pyrimidine in 28 ml of ethanol under stirring drops at room temperature, added to 4.4 ml (4.5 g, of 89.7 mmol) of hydrazine hydrate is added. The reaction solution is stirred for 16 hours at 80°SDS processing solution is concentrated under vacuum, the residue is repeatedly stirred in diethyl ether, the precipitated solid is filtered off and dried in vacuum. Then the resulting residue is purified by chromatography on a column of silica gel (solvent: diclomelan/methanol 10/2). Yield: 1.5 g (80% of theory. prob.).

LC-MS (method 6): Rt=1.36 min; MS (ESIpos): m/z=249 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=7.92 (s, 1H), 7.63 (s, 1H), 5.90 (NH), 4.09 (s, NH2), 3.45 (t, 4H), 2.69 (quintet, 1H), 2.26 (t, 4H), 2.00-1.93 (m. 2H), 1.82-1.75 (m, 2H), 1.67-1.60 (m,2H).

Example 10A

1-(6-Hydrazinopyridazine-4-yl)azetidin-3-ol

Stage a): 1-(6-chloropyrimidine-4-yl)azetidin-3-ol

of 7.3 g (of 48.7 mmol) of 4,6-dichloropyrimidine in 140 ml transform into a slurry and mixed with 47 ml of 1 N sodium hydroxide. Add 5.3g (48,7 mmol) 3-hydroxyazetidine, and the reaction mixture stirred for 3 days at 90°Spoke cooling to room temperature the reaction mixture was concentrated in vacuo and used without further purification.

LC-MS (method 5): Rt=0.36 min; MS (ESIpos): m/z=1.87 [M+H]+.

Stage b): 1-(6-Hydrazinopyridazine-4-yl)azetidin-3-ol

In a solution of 10.4 g (55,8 mmol) 1-(6-chloropyrimidine-4-yl)azetidin-3-ol in 100 ml of ethanol under stirring add drops of 27.2 ml (27.9 g, 279,1 mmol) g is of grasinger at room temperature. The reaction solution is stirred for 16 hours at 80°C. For processing concentrated in vacuo, the precipitate is filtered off and washed twice with ethanol (10 ml). Yield: 2.0 g (19% of theory. prob.).

LC-MS (method I): Rt=2.06 min; MS (ESIpos): m/z=194 [M+H]+.

Example 11A

4-Chloro-6-hydrazinopyridazine

In a solution of 20.0 g (134,3 mmol) of 4,6-dichloropyrimidine in 300 ml of ethanol under stirring add drops to 11.8 ml (12.1 g, 241,6 mmol) of hydrazine hydrate is added at room temperature. While adding hydrazine hydrate is added is the clouding of the solution, to it add more ethanol (400 ml). The reaction solution was stirred for 12 hours at room temperature. For processing precipitated solid is filtered off, the filter cake washed twice with water to 150 ml and twice with diethyl ether 100 ml, and the product is dried in vacuum. From the evaporated mother liquor get crystal product fraction. Output: 16,8 g (87% of theory. prob.).

LC-MS (method 1): Rt=1.17 min; MS (ESIpos): m/z=145 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.81 (s, 1H), 8.17 (br. s, 1H), 6.75 (s, 1H), 4.48 (br. s, 2H).

Example 12A

2-(6-Chloropyrimidine-4-yl)-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one hydrochloride

10.0 g (47,7 mmol) of the compound from example 8A and 8.3 g (to 57.1 mmol) of the compound from example PA is introduced into 100 ml of ethanol and diluted with 5 ml (2.2 g, 19.0 mmol) triperoxonane acid. The solution was stirred for 12 hours at reflux. Then to the cooled reaction mixture into excess added 4M solution of hydrogen chloride in dioxane, the mixture mix for about 1 hour, the precipitated crystals are filtered, and the filtration residue is washed with dioxane and ethanol. The obtained intermediate product is dissolved in 150 ml of ethanol, diluted with 50 ml of 25%methanol solution of sodium methylate and the mixture is stirred for 2 hours at room temperature. Then the reaction mixture was acidified with 1 N hydrochloric acid to pH=5, mix another 2 hours at room temperature, the residue is filtered, the filtration residue is washed with ethanol, and the product is dried in vacuum. Yield: 7.0 g (49% of theory. prob.).

LC-MS (method 5): Rt=1.20 min; MS (ESIpos): m/z=264 [M+H]+

Example 13A

2-(6-Chloropyrimidine-4-yl)-4-(1H-imidazol-1-yl)-1,2-dihydro-3H-pyrazole-3-one hydrochloride

10.0 g (of 47.8 mmol) of the compound from example 5A and 8.3 g (57,3 mmol) of the compound from example introduced in 100 ml of ethanol and diluted with 1.5 ml (2.2 g, 19.0 mmol) triperoxonane acid. The solution was stirred for 12 hours at reflux. The precipitated crystals are filtered, the filtration residue is washed with ethanol, and the intermediate product is dried overnight in vacuum. Then this product is transformed into a suspension of 20 ml, diluted with 10 ml of 4 M solution of hydrogen chloride in dioxane, and the mixture is stirred for 1 hour at room temperature. The solid is filtered, the filtration residue is washed with dioxane, ethyl acetate and diisopropyl ether, and the product is dried in vacuum. Yield: 4.6 g (32% of theory. prob.).

HPLC (method 6): Rt=2.81 min; MS (ESIpos): m/z=263 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=9.46 (s, 1H), 8.96 (s, 1H), 8.56 (s, 1H), 8.51 (d, 1H), 8.07-8.04 (m, 1H), 7.85-7.82 (m, 1H).

Example 14A

4-(6-Hydrazinopyridazine-4-yl)-1,4-oxazepan

Stage a): 4-(6-Chloropyrimidine-4-yl)-1,4-oxazepan

A mixture of 3.0 g (20,1 mmol) of 4,6-dichloropyrimidine, 2.8 g (20,1 mmol) of 1,4-oxazepan-hydrochloride and 6.4 g (60,4 mmol) of sodium carbonate in 45 ml of water is stirred for 16 hours at reflux. After cooling to room temperature the reaction mixture was extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and FilterOutputStream concentrated in a vacuum until dry. The product is obtained in the form of oil. Yield: 3.9 g (86% of theory. prob.).

LC-MS (method 4): Rt=1.32 min; MS (ESIpos): m/z=214 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.33 (s, 1H), 6.86 (s, 1H), 3.99-3.52 (m, 8H),1.84(m,2H).

Stage b): 4-(6-Hydrazinopyridazine-4-yl)-1,4-oxazepan

In a solution of 3.9 g (18.0 mmol) of 4-(6-chloropyrimidine-4-yl)-1,4-oxazepan in 25 ml of ethanol is at stirring add drops of 8.8 ml (9.0 g, 180,2 mmol) of hydrazine hydrate is added at room temperature. After 16 hours stirring at 80°C the reaction solution is concentrated in vacuum. The residue is stirred in the cold ethanol, and the precipitated solid is filtered off and the filter cake washed with 25 ml diethyl ether. The product is dried in vacuum. Yield: 1.4 g (36% of theory. prob.).

HPLC (method 11): Rt=2.48 min; MS (ESIpos): m/z=210 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): 5=7.91 (s, 1H), 7.56 (br. s, 1H), 5.81 (s, 1H), 4.12 (br. s, 2H), 3.75-3.55 (m, 8H), 1.85 (quintet, 2H).

Examples of execution

Example 1

2-[6-(4-Cyclobutylmethyl-1-yl)pyrimidine-4-yl]-4-(1H-imidazol-1-yl)-1,2-dihydro-3H-pyrazole-3-one

A mixture of 211 mg (1.0 mmol) of the compound from example 5A and 250 mg (1.0 mmol) of the compound from example 9A in 4 ml of ethyl acetate diluted with 16 ml (23 mg, 0.2 mmol) triperoxonane acid and stirred for 20 hours at 100°C. the Reaction mixture was concentrated in vacuo, re-diluted with an equal amount of ethyl acetate and triperoxonane acid and stirred for further 20 hours at 100°C. the Reaction mixture is cooled to room temperature, the precipitated solid is filtered off and washed with diethyl ether. The residue is purified first by chromatography on a column over silica gel (solvent: diclomelan/methanol/ammonia 10/2/0,2), and then using preparative HPLC (RPlS-column; solvent: gradient and ethical/water). Yield: 137 mg (36% of theory. prob.).

HPLC (method 6): Rt=2.73 min; MS (ESIpos): m/z=367 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.40 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.50 (s, 1H), 7.07 (s, 1H), 3.65-3.58 (m, 4H), 2.77 (quintet, 1H), 2.38-2.35 (m, 4H), 2.01-1.96 (m, 2H), 1.89-1.79 (m, 2H). 1.67-1.62 (m, 2H).

Example 2

2-[6-(4-Cyclobutylmethyl-1-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one

A mixture of 211 mg (1.0 mmol) of the compound from example 8A and 250 mg (1.0 mmol) of the compound from example 9A in 4 ml of ethyl acetate diluted with 16 ml (23 mg, 0.2 mmol) triperoxonane acid and stirred for 20 hours at 100°Sreaction the mixture is concentrated in vacuo, re-diluted with an equal amount of ethyl acetate and triperoxonane acid and stirred for 3 days at 100°C. the Reaction mixture is cooled to room temperature, the precipitated solid is filtered off and washed with diethyl ether. The residue is converted into a suspension in 2 ml of water, dissolve by adding aqueous 1 N sodium hydroxide (pH=9-10) and purified using preparative HPLC (RP18-column; solvent: gradient acetonitrile/water). Yield: 195 mg (51% of theory. prob.).

HPLC (method 6): Rt=2.90 min; MS (ESIpos): m/z=368 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.41 (s, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 3.70-3.65 (m, 4H), 3.03-2.97 (m, 1H), 2.60-2.57 (m, 4H), 2.06-2.02 (m, 2H), 1.98-1.90 (m, 2H), 1.70-1.64 (m, 2H).

Example 3

1-{2-[6-(4-Cyclobutylmethyl-1-yl)Piri is one-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitril

A mixture of 236 mg (1.0 mmol) of the compound from example 6A and 250 mg (1.0 mmol) of the compound from example 9A in 4 ml of ethyl acetate diluted with 16 ml (23 mg, 0.2 mmol) triperoxonane acid and stirred for 20 hours at 100°C. the Reaction mixture was concentrated in vacuo, re-diluted with an equal amount of ethyl acetate and triperoxonane acid and stirred for 3 days at 100°Sreaction the mixture is cooled to room temperature, the precipitated solid is filtered off and washed with diethyl ether. The residue is converted into a suspension in 2 ml of water, dissolve by adding aqueous 1 N sodium hydroxide (pH=9-10) and purified using preparative HPLC (RP18-column; solvent: gradient acetonitrile/water). Output: 219 mg (56% of theory. prob.).

HPLC (method 6): Rt=3.10 min; MS (ESIpos): m/z=392 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.38 (d, 1H), 8.37 (d, 1H), 8.17 (d, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 3.68-3.62 (m, 4H), 3.38-3.30 (m, 4H), 2.96-2.91 (m, 1H), 2.06-2.00 (m, 2H), 1.95-1.85 (m, 2H), 1.70-1.63 (m, 2H).

Example 4

1-{2-[6-(3-Hydroxyazetidine-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitril

A mixture of 700 mg (3.0 mmol) of the compound from example 6A and 541 mg (3.0 mmol) of the compound from example 10A in 10 ml of ethyl acetate diluted with 46 ml (68 mg, 0.6 mmol) triperoxonane acid and stirred for 10 hours at 100°C. the Reaction mixture is concentrated under vacuum, the solution is ut 5 ml of ethanol, and sediment othertransaction substance is transformed into a suspension in 10 ml of water and dilute to dissolution with 1 N sodium hydroxide (pH=9). Then 1 N hydrochloric acid is set pH=7, the solution is concentrated to a volume of about 5 ml, and the precipitate othertransaction washed with water and diisopropyl ether and chromatographies using preparative HPLC (method 8). Then the solid is converted into a suspension in 10 ml of water and dilute to dissolution of 1 N sodium hydroxide (pH=9). Then with 1 N hydrochloric acid is set pH=7, the solution is concentrated to a volume of about 2.5 ml, and the precipitate othertreatment concentrated to a volume of about 2 ml and again filtrauto balance unite, washed with water and ethyl acetate and dried in vacuum. Yield: 78 mg (8% of theory. prob.).

HPLC (method 6): Rt=2.90 min; MS (ESIpos): m/z=325 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=8.35 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.66 (s, 1H), 7.34 (s, 1H), 5.80-5.75 (m, 1H), 4.63-4.58 (m, 1H), 4.24-4.20 (m, 2H), 3.75-3.73 (m, 2H).

Example 5

1-{6-[4-(1H-Imidazol-1-yl)-5-oxo-2,5-dihydro-1H-pyrazole-1-yl]pyrimidine-4-yl}azetidin-3-carboxylic acid

46 mg (0.3 mmol) of the hydrochloride azetidin-3-carboxylic acid is introduced into a mixture of 1 ml of water and 0.3 ml of ethanol. Add 100 mg (0.3 mmol) of the compound from example 13A, and the mixture is stirred for 1 hour at 100°C. Then the reaction mixture divorce is t aqueous 1 N sodium hydroxide to pH=7 and stirred for 16 hours at 100°C. Again diluted 1 N sodium hydroxide to pH=7 and subjected to the exchange reaction for 1 hour at 150°C in a single-mode microwave oven {single mode-Mikrowelle (Emrys Optimizer)). The reaction mixture was concentrated in vacuo and purified by preparative HPLC (RPlS-column; solvent: gradient acetonitrile/water). Yield: 23 mg (21% of theory. prob.).

LC-MS (method 8): Rt=0.86 min; MS (ESIpos): m/z=328 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.41 (s, 1H), 7.79 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 6.89 (s, 1H), 4.09 (t, 2H), 3.99 (t, 2H).

Example 6

1-{6-[5-oxo-4-(177-1,2,3-triazole-1-yl)-2,5-dihydro-1H-pyrazole-1-yl]pyrimidine-4-yl} azetidin-3-carboxylic acid

55 mg (0.4 mmol) of the hydrochloride azetidin-3-carboxylic acid is introduced into 2 ml of water. Add 100 mg (0.3 mmol) of the compound from example 12A, and the mixture was diluted aqueous 1 N sodium hydroxide to pH=7. The solution for 1 hour at 150°C is subjected to the exchange reaction in a single-mode microwave (Emrys Optimizer). The reaction mixture was concentrated in vacuo and purified by preparative HPLC (CR-column; solvent: gradient acetonitrile/water). Yield: 15 mg (13% of theory. prob.).

HPLC (method 6): Rt=2.81 min; MS (ESIpos): m/z=329 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.42 (s, 1H), 8.26 (s, 1H), of 7.70 (s, 1H), 7.67 (s, 1H), 7.34 (s, 1H), 4.05-3.96 (m, 2H und 2H), 3.13-3.07 (m, 1H).

Example 7

4-(1H-Imidazol-1-yl)-2-[6-(3-methylaziridine-1-yl)pyrimidine-4-yl]-1,2-dihydro-3H-pyrazole-3-one

43 mg (0.4 mmol) of 3-methylacetanilide, 100 mg (0.3 mmol) of the compound from example 13A and 174 μl (130 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine turn in suspension in 2 ml of tetrahydrofuran, and the mixture is subjected to reaction in exchange for 4.5 hours at 120°C in a single-mode microwave (Emrys Optimizer). The reaction mixture was concentrated in vacuum, diluted with water, adding aqueous 1 N sodium hydroxide (to pH=9-10) and purified by preparative HPLC (CR-column; solvent: gradient acetonitrile/water). Yield: 30 mg (30% of theory. prob.).

HPLC (method b): Rt=3.07 min; MS (ESIpos): m/z=298 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.25 (s, 1H), 7.81 (s, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 6.88 (s, 1H), 4.10 (t, 2H), 3.54 (dd, 2H), 2.86-2.75 (m, 1H), 1.25(d, 3H).

Example 8

2-[6-(3-Methylaziridine-1-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one

43 mg (0.4 mmol) of 3-methylacetanilide, 100 mg (0.3 mmol) of the compound from example 12A and 174 μl (130 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine turn in suspension in 2 ml of tetrahydrofuran, and the mixture is subjected to the exchange reaction for 1.5 hours at 120°C in a single-mode microwave (Emrys Optimizer). The reaction mixture was concentrated in vacuum, diluted with water, adding aqueous 1 N sodium hydroxide (pH=9-10), and purified by preparative HPLC (CP-column; solvent: gradient acetonitrile/water). Output: 2 mg (25% of theory. prob.).

HPLC (method 6): Rt=3.00 min; MS (ESIpos): m/z=299 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.41 (s, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.41 (s, 1H), 4.11 (t, 2H), 3.56 (dd, 2H), 2.86-2.78 (m, 1H), 1.25 (d, 3H).

Example 9

2-{6-[3-(dimethylamino)azetidin-1-yl]pyrimidine-4-yl}-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-C-it dihydrochloride

271 mg (1.5 mmol) of N,N-dimethylacetal-3-unindividualized, 400 mg (1.5 mmol) of the compound from example 12A and 847 mg (6.1 mmol) of potassium carbonate is transformed into a suspension in 8 ml of N,N-dimethylformamide, and the mixture is stirred for 16 hours at 100°C. the Reaction mixture was concentrated in vacuo and purified by preparative HPLC (CR-column; solvent: gradient acetonitrile/water with addition of 0.1%triperoxonane acid). Sledujushjuju cleaning is realized by means of preparative HPLC (RP18-column; solvent: gradient acetonitrile/water with addition of 0.1%formic acid). Containing the product fraction was diluted with 2 ml of 1 N hydrochloric acid and stirred for 1 hour at room temperature. The solid is filtered off and dried in vacuum. Yield: 62 mg (17% of theory. prob.).

LC-MS (method 5): Rt=0.19 min; MS (ESIpos): m/z=328 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.42 (s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 4.02 (t, 2H), 3.76 (dd, 2H), 3.24-3.18 (m, 1H), 2.12 (s, 6H).

Example 10

2-[6-(4,4-deformability-1-yl)pyrimidine-4-yl]-4-(1H-they are the azole-1-yl)-1,2-dihydro-3H-pyrazole-3-one

100 mg (0.3 mmol) of the compound from example 13A, 63 mg (0.4 mmol) of 4,4-deformability-hydrochloride and 116 μl (86 mg, 0.7 mmol) N-ethyl-N-(propan-2-yl)propan-amine are introduced into 2 ml of tetrahydrofuran, and the mixture is subjected to the exchange reaction for 2.5 hours at 120°C in a single-mode microwave (Emrys Optimizer). When the mixture in vacuo, the residue is dissolved in acetonitrile and water and purified by preparative HPLC (RP18-column; solvent: gradient acetonitrile/water). Yield: 82 mg (71% of theory. prob.).

HPLC (method 6): Rt=3.37 min; MS (ESIpos): m/z=348 [M+H]+;

1H-NMR (400 MHz, DMSO-dg): §=8.49 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.22 (s, 1H), 3.80 (t, 4H), 2.06 (septet, 4H).

Example 11

2-[6-(4,4-deformability-1-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one

250 mg (0.8 mmol) of the compound from example 12A, 158 mg (1.0 mmol) of 4,4-deformability-hydrochloride and 435 μl (323 mg, 2.5 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine is introduced into 5 ml of tetrahydrofuran, and the mixture is subjected to the exchange reaction for 30 minutes at 120°C in a single-mode microwave (Emrys Optimizer). After preliminary purification of the mixture by preparative HPLC (CR-column; solvent: gradient acetonitrile/water) the product is optionally purified by chromatography on a column over silica gel (solvent: diclomelan/methanol, 10/1) Yield: 29 mg (10% of theory. prob.). HPLC (method 6): Rt=3.49 min; MS (ESIpos): m/z=349 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.56 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 3.91-3.81 (m. 4H), 2.09 (septet, 4H).

Example 12

1-{2-[6-(4,4-deformability-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitril

A mixture of 200 mg (1.4 mmol) of the compound from example, 262 mg (1.7 mmol) of 4,4-diversityminority and 289 μl (215 mg, 1.7 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine was stirred in 3 ml of water for 16 hours at 100°C. After adding 53 μl (79 mg, 0.7 mmol) triperoxonane acid and 324 mg (1.4 mmol) of the compound from example 6A the resulting reaction mixture is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then diethyl ether. The product is dried in vacuum. Yield: 111 mg (21% of theory. prob.).

LC-MS (method 4): Rt=1.69 min; MS (ESIpos): m/z=373 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.55 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.22 (d, 1H), 7.60 (br. s, 1H), 3.84 (br. s, 4H), 2.09 (septet, 4H).

Example 13

1-{2-[6-(4,4-deformability-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-1,2,3-triazole-4-carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound from example, 262 mg (1.7 mmol) of 4,4-deferreddelete and 289 μl (215 mg, 1.7 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine was stirred in 3 ml of water for 16 hours n and 100°C. After adding 53 μl (79 mg, 0.7 mmol) triperoxonane acid and 325 mg (1.4 mmol) of the compound from example 7A the resulting reaction mixture is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then diethyl ether. The product is dried in vacuum. Yield: 34 mg (7% of theory. prob.).

LC-MS (method 4): Rt=1.77 min; MS (ESIpos): m/z=374 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=9.24 (s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 7.54 (s, 1H), 3.90 (br. s, 4H), 2.12 (septet, 4H).

Example 14

2-[6-(3,3-debtorprovidian-1-yl)pyrimidine-4-yl]-4-(1H-imidazol-1-yl)-1,2-dihydro-3H-pyrazole-3-one

100 mg (0.3 mmol) of the compound from example 13A, 58 mg (0.4 mmol) of 3,3-debtorprovidian-hydrochloride and 175 μl (130 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine injected into 2 ml of tetrahydrofuran, and the mixture is subjected to the exchange reaction for 1 hour at 120°C in a single-mode microwave (Emrys Optimizer). After condensation in vacuum, the residue is diluted with acetonitrile and water and purified by preparative HPLC (CR-column; solvent: gradient acetonitrile/water). Yield: 111 mg (99% of theory. prob.).

HPLC (method 6): Rt=3.18 min; MS (ESIpos): m/z=334 [M+H]+;

1H-NMR (400 MHz, methanol-d4): δ=8.41 (s, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.56 (s, 1H). 7.29 (s, 1H), 7.03 (s, 1H), 3.91 (t, 2H), 3.76 (t, 2H), 2.55 (septet, 2H).

Example 15

2-[6-(3,3-debtorprovidian-1-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazo the-1-yl)-1,2-dihydro-3H-pyrazole-3-one

100 mg (0.8 mmol) of the compound from example 12A, 57 mg (0.4 mmol) of 3,3-debtorprovidian-hydrochloride and 174 μl (129 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine injected into 2 ml of tetrahydrofuran, and the mixture is subjected to the exchange reaction for 30 minutes at 120°C in a single-mode microwave (Emrys Optimizer). After condensation in vacuum, the residue is diluted with acetonitrile and water and purified by preparative HPLC (RCR-column; solvent: gradient acetonitrile/water). Yield: 13 mg (12% of theory. prob.).

HPLC (method 6): Rt=3.33 min; MS (ESIpos): m/z 335 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.42 (s, 1H), 8.35 (s, 1H), 7.72-7.66 (m, 3H), 3.87 (t, 2H), 3.65 (t, 2H), 2.64-2.50 (m, partly under the signal from DMSO, 2H).

Example 16

1-{2-[6-(3,3-debtorprovidian-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitril

A mixture of 200 mg (1.4 mmol) of the compound from example 11A, 238 mg (1.7 mmol) of 3,3-differentcolored and 289 μl (215 mg, 1.7 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred for 16 hours at 100°C. After adding 53 μl (79 mg, 0.7 mmol) triperoxonane acid and 324 mg (1.4 mmol) of the compound from example 6A the resulting reaction mixture is stirred for 16 hours at 100°Sreaction the mixture is mixed with 1 ml 1 N hydrochloric acid. Dropped when this hydrochloride is the original product is filtered off, promycelium ether and dried. The intermediate product still contains unreacted source connection (connection example). Therefore, the intermediate product is subjected to exchange reactions with 108 μl (80 mg, 0.6 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine, 10 mg (0.1 mmol) of 3,3-differentcolored and 2 ml of water for 15 minutes at 170°C in a single-mode microwave (Emrys Optimizer). The reaction solution is purified by preparative HPLC (CR-column; solvent: gradient acetonitrile/water). Yield: 30 mg (6% of theory. prob.).

LC-MS (method 4): Rt=1.58 min; MS (ESIpos): m/z=359 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): 8=8.55 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.21 (d, 1H), 7.26 (br. s, 1H), 3.99 (t, 2H), 3.75 (br. s, 2H), 2.66-2.54 (m, partly under the signal from DMSO, 2H).

Example 17

1-{2-[6-(3,3-debtorprovidian-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-1,2,3-triazole-4-carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound from example 11A, 238 mg (1.7 mmol) of 3,3-differentcolored and 289 μl (215 mg, 1.7 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine in 33 ml of water is stirred for 16 hours at 100°C. After adding 53 μl (79 mg, 0.7 mmol) triperoxonane acid and 325 mg (1.4 mmol) of the compound from example 7A the resulting reaction mixture is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then diethyl ether. The product is dried in vacuum. In the move: 137 mg (27% of theory. prob.).

LC-MS (method 4): Rt=1.66 min; MS (ESIpos): m/z=360 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=9.25 (s, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 7.21 (br. s, 1H), 4.06 (t, 2H), 3.82 (br. s, 2H), 2.69-2.55 (m, partly under the signal from DMSO, 2H).

Example 18

2-[6-(3,3-defloration-1-yl)pyrimidine-4-yl]-4-(1H-imidazol-1-yl)-1,2-dihydro-3H-pyrazole-3-one

100 mg (0.3 mmol) of the compound from example 13A, 52 mg (0.4 mmol) of 3,3-defloration-hydrochloride and 175 μl (130 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine injected into 2 ml of tetrahydrofuran, and the mixture is subjected to the exchange reaction for 3 hours at 120°C in a single-mode microwave (Emrys Optimizer). Precipitated solid is filtered off and the filtrate concentrated in vacuum. The residue is diluted with acetonitrile and water and purified by preparative HPLC (RP18-column; solvent: gradient acetonitrile/water). Yield: 36 mg (32% of theory. prob.).

HPLC (method 6): Rt=3.00 min; MS (ESIpos): m/z=320 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.42 (s, 1H), 8.16 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.07 (s, 1H), 4.49 (t, 4H).

Example 19

2-[6-(3,3-defloration-1-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one

100 mg (0.3 mmol) of the compound from example 12A, 52 mg (0.4 mmol) of 3,3-defloration-hydrochloride and 174 μl (130 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine injected into 2 ml of tetrahydrofuran, and the mixture is subjected to the reaction is the AI of the exchange within 30 minutes at 120°C in a single-mode microwave (Emrys Optimizer). After condensation in vacuum, the residue is diluted with acetonitrile and water and purified by preparative HPLC (RP18-column; solvent: gradient acetonitrile/water). Yield: 36 mg (34% of theory. prob.).

HPLC (method 6): Rt=3.20 min; MS (ESIpos): m/z=321 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.42 (s, 1H), 8.39 (s, 1H), 7.71 (s, 2H), 7.62 (s, 1H), 4.46 (t, 4H).

Example 20

1-{2-[6-(3,3-defloration-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitril

A mixture of 120 mg (0.8 mmol) of the compound from example 11A, 129 mg (1.0 mmol) of 3,3-differencematerialised and 174 μl (129 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine was stirred in 3 ml of water for 16 hours at 100°C.

After adding 32 μl (47 mg, 0.4 mmol) triperoxonane acid and 194 mg (0.8 mmol) of the compound from example 6A the resulting reaction mixture is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then ditylum ether. The product is dried in vacuum. Yield: 32 mg (11% of theory. prob.).

LC-MS (method 4): Rt=1.48 min; MS (ESIpos): m/z=345 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.80-8.08 (m, 4H), 7.25 (s, 1H), 4.61 (br. s, 4H).

Example 21

1-{2-[6-(3,3-defloration-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-1,2,3-triazole-4-carbonitrile

A mixture of 120 mg (0.8 mmol) of the compound from example 11A, 129 mg (1.0 mmol)of 3,3-differencematerialised and 174 μl (129 mg, 1.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred for 16 hours at 100°C. After adding 32 μl (47 mg, 0.4 mmol) triperoxonane acid and 194 mg (0.8 mmol) of the compound from example 7A the resulting reaction mixture is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then ditylum ether. The product is dried in vacuum. Yield: 51 mg (18% of theory. prob.).

LC-MS (method 4): Rt=1.56 min; MS (ESIpos): m/z=346 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=9.26 (s, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 7.18(s,1H), 4.69 (t,4H).

Example 22

4-(1H-Imidazol-1-yl)-2-[6-(1,4-oxazepan-4-yl)pyrimidine-4-yl]-1,2-dihydro-3H-pyrazole-3-one hydrochloride

A mixture of 200 mg (1.0 mmol) of the compound from example 5A, 200 mg (1.0 mmol) of the compound from example 14A and 37 μl (54 mg, 0.5 mmol) triperoxonane acid in 3 ml of water is stirred for 16 hours at 100°C. After preliminary purification by preparative HPLC (IR-column; solvent: gradient acetonitrile/water) intermediate product is stirred with 1 ml of 1 N hydrochloric acid, filtered and washed with diethyl ether. The product is dried in vacuum. Yield: 21 mg (6%Theor. prob.)

LC-MS (method 4): Rt=0.95 min; MS (ESIpos): m/z=364 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): 5=9.46 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.06 (t, 1H), 7.83 (t, 1H), 7.50-7.33 (m, 1H), 4.05 (br. s, 2H), 3.91-3.70 (m, 4H), 3.68 (t, 2H), 2.04-1.73 (m,2H).

Note the R 23

2-[6-(1,4-Oxazepan-4-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one hydrochloride

A mixture of 400 mg (1.3 mmol) of the compound from example 12A and 220 mg (1.6 mmol) of 1,4-oxazaborolidine subjected exchange reaction in 4 ml of propan-2-ol for 30 minutes at 115°C in a single-mode microwave (Emrys Optimizer). Add 232 μl (172 mg, 1.3 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine, and the reaction mixture is subjected to the exchange reaction for 20 minutes at 115°C in a single-mode microwave (Emrys Optimizer). After condensation in vacuum, the residue diluted with acetonitrile/water/triperoxonane acid and treated with preparative HPLC (method 9). Obtained by separation by chromatography HPLC, lyophilized salt trifenatate using 2 ml of 1 N hydrochloric acid was transferred into the hydrochloride. Yield: 7 mg (1% theory. prob.).

LC-MS (method 4): Rt=1.20 min; MS (ESIpos): m/z=329 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.86 (d, 1H), 7.35 (br. s, 1H), 4.14-3.69 (m, 6H), 3.67 (t, 2H), 2.03-1.77 (m, 2H).

Example 24

2-[6-(1,4-Oxazepan-4-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one

A mixture of 500 mg (1.7 mmol) of the compound from example 12A, 688 mg (5.0 mmol) of 1,4-oxazaborolidine and 1.4 ml (1077 mg, 8.3 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine is subjected to the exchange reaction in 10 ml of tetrahydrofuran and ethane is La (1/1) for 30 minutes at 140°C in a single-mode microwave (Emrys Optimizer). After preliminary purification by preparative HPLC (CR-column; solvent: gradient acetonitrile/water) intermediate product is diluted with acetonitrile and triperoxonane acid and treated with preparative HPLC (method 10). In obtained by separation by chromatography HPLC, lyophilized salt trifenatate with 1 N caustic soda set pH=7-8. The product distinguish by preparative HPLC (CP-column; solvent: gradient acetonitrile/water). Yield: 176 mg (31% of theory. prob.).

LC-MS (method 4): Rt=1.19 min; MS (ESIpos): m/z=329 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): 6=8.41 (d, 1H), 8.33 (d, 1H), 7.78 (br. s, 1H), 7.72-7.70 (m, 2H), 3.91-3.65 (m, 6H), 3.62 (t, 2H), 1.95-1.83 (m, 2H).

Example 25

1-{2-[6-(1,4-Oxazepan-4-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitril

A mixture of 200 mg (0.9 mmol) of the compound from example 6A, 178 mg (0.9 mmol) of the compound from example 14A and 33 μl (49 mg, 0.4 mmol) triperoxonane acid in 3 ml of water is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then diethyl ether. The product is dried in vacuum. Yield: 120 mg (40% of theory. prob.).

HPLC (method 6): Rt=3.27 min; MS (ESIpos): m/z=353 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.52 (s, 1H), 8.42 (d, 1H), 8.25 (s, 1H), 8.19 (d, 1H). 7.39 (br. s, 1H), 4.14-3.70 (m, 6H), 3.66 (t, 2H), 2.05-1.68 (m, 2H).

Example 26

1-{2-[6-1,4-Oxazepan-4-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-1,2,3-triazole-4-carbonitrile

A mixture of 200 mg (0.9 mmol) of the compound from example 7A, 178 mg (0.9 mmol) of the compound from example 14A and 33 μl (49 mg, 0.4 mmol) triperoxonane acid in 3 ml of water is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then diethyl ether. The product is dried in vacuum. Yield: 80 mg (27% of theory. prob.).

LC-MS (method 4): Rt=1.40 min; MS (ESIpos): m/z=354 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=9.22 (s, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.45-7.26 (m, 1H), 4.06 (br. s, 2H), 3.92-3.71 (m, 4H), 3.68 (t, 2H), 2.06-1.74 (m, 2H).

Example 27

2-[6-(1,2-Oxazine-2-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one

A mixture of 200 mg (0.7 mmol) of the compound from example 12A, 99 mg (0.8 mmol) of 1,2-occasionalheadline [br et al., J. Chem. Soc. Perkin Trans. 2 2000, 7, 1435-1446] and 348 μl (258 mg, 2.0 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine is subjected to the exchange reaction in 4 ml of tetrahydrofuran for 30 minutes at 140°C in a single-mode microwave oven (single mode-Mikrowelle (Emrys Optimizer)). After preliminary purification by preparative HPLC (CR-column; solvent: gradient acetonitrile/water) intermediate product diluted with acetonitrile/water/methanol and treated with preparative HPLC (method 11). In obtained by separation by chromatography HPLC, freeze-dried formate salt with 1 N sodium hydroxide base is t pH=7-8. The product distinguish by preparative HPLC (CR-column; solvent: gradient acetonitrile/water). Yield: 23 mg (11% of theory. prob.).

LC-MS (method 4): Rt=1.38 min; MS (ESIpos): m/z=315 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.58 (d, 1H), 8.42 (d, 1H), 8.40 (br. s, 1H), 7.88 (d, 1H), 7.66 (br. s, 1H), 4.09 (t, 2H), 3.98 (t, 2H), 1.86-1.68 (m, 4H).

Example 28

1-{2-[6-(1,2-Oxazine-2-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitril

A mixture of 200 mg (1.4 mmol) of the compound from example 11A, 205 mg (1.7 mmol) of 1,2-occasionalheadline [br et al., J. Chem. Soc. Perkin Trans. 2 2000, 7, 1435-1446] and 289 μl (215 mg, 1.7 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred for 1.5 hours at 100°Spoke add 59 μl (49 mg, 0.4 mmol) triperoxonane acid and 324 mg (1.4 mmol) of the compound from example 6A the resulting reaction mixture is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then diethyl ether. The product is dried in vacuum. Output: 199 mg (39% of theory. prob.) LC-MS (method 5): Rt=0.87 min; MS (ESIpos): m/z=339 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): 8=8.57 (d, 1H), 8.45 (d, 1H), 8.40 (br. s, 1H), 8.23 (d, 1H), 7.70 (br. s, 1H), 4.07 (t, 2H), 3.96 (t, 2H), 1.85-1.65 (m, 4H).

Example 29

1-{2-[6-(1,2-Oxazine-2-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro - 1H-pyrazole-4-yl}-1H-1,2,3-triazole-4-carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound and the sample, 205 mg (1.7 mmol) of 1,2-occasionalheadline [br et al., J. Chem. Soc. Perkin Trans. 2 2000, 7, 1435-1446] and 289 μl (215 mg, 1.7 mmol) N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred for 1.5 hours at 100°C. After adding 59 μl (49 mg, 0.4 mmol) triperoxonane acid and 325 mg (1.4 mmol) of the compound from example 7A the resulting reaction mixture is stirred for 16 hours at 100°C. the Precipitated solid is filtered off and washed first with water and then diethyl ether. The product is dried in vacuum. Yield: 122 mg (24% of theory. prob.).

LC-MS (method 4): Rt=1.66 min; MS (ESIpos): m/z=340 [M+H:G;

1H-NMR (400 MHz, DMSO-d6) δ=9.28 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.60 (br. s, 1H), 4.12 (t, 2H), 4.03 (t, 2H), 1.88-1.70 (m, 4H).

C. Evaluation of pharmacological efficacy

Pharmacological properties of the compounds according to the invention can be illustrated in the following tests:

Abbreviations:

DMEM, the Dulbecco's Modified Eagle

FCS Rest calf serum

TMB 3,3',5,5'-tetramethylbenzidine

Iris Tris(hydroxymethyl)-aminomethan

1. Tested in vitro to determine the activity and selectivity of inhibitors NR-prolyl-4-hydroxide basics

1.a) inhibition of the activity of HIF-prolylhydroxylase:

Gidroksilirovanii HIF specifically bound to the complex protein Hippel-Lindau - alongin In - Longin (VBC complex). This interaction occurs only if HIF gidroksilirovanii in canned OST the ke shed. This is the basis for the biochemical determination of activity of HIF-prolylhydroxylase. The test is carried out according to the method described in the paper [F. Oehme, Jonghaus W., Narouz-L. Ott, J. Huetter, Flamme I., Anal. Biochem. 330(1), 74-80 (2004)]:

Transparent coated with NeutrAvidin HBC 96-well microtiter tablet (firm Pierce) for 30 minutes, incubated blocker-casein. The tablet then washed three times with 200 μl washing buffer (50 mm Tris, pH 7.5, 100 mm Nad, 10% (V/V) blocker-casein, 0.05% (V/V) Tween 20) per well. Add the peptide Biotin-DLDLEMLAPYIPMDDDFQL (company Eurogentec, 4102 Seraing, Belgium) at a concentration of 400 nm in 100 μl of washing buffer solution. This peptide serves as a nutrient medium for prolylhydroxylase and bound to the microtiter plate. After 60 minutes incubation tablet three times washed with washing buffer solution, 30 minutes incubare Biotin in the blocker-casein, and then again washed three times with washing buffer.

To perform the reaction prolylhydroxylase attached to the tablet peptide growth medium is incubated for 1 to 60 minutes, the cell lysate containing prolylhydroxylase. The reaction is carried out in 100 μl reaction buffer (20 mm Tris, pH 7.5, 5 mm KCl,1.5 mm MgCl2, 1 μm-1 mm 2-oxoglutarate, 10 μm FeSO4, 2 mm ascorbate) at room temperature. Reacciona mixture in addition to intended for test ing is the inhibitor contains prolylhydroxylase in various concentrations. The test substance is preferred, but only at concentrations between 1 nm and 100 μm. By triple rinsing tablet washing buffer solution to the reaction stopped.

For the quantitative determination of prolylhydroxylase add compound protein that contains both thioredoxin from E. coli (Escherichia coli microflora)and VBC complex, 80 μl of binding buffer (50 mm Tris, pH 7.5, 120 mm NaCl). After 15 minutes, add 10 ál of a solution of polyclonal anti-thioredoxin antibodies from rabbit in binding buffer solution. After 30 minutes incubation at room temperature the tablet thrice washed with washing buffer to remove unbound antibody and VBC complex. To determine the number associated VBC complex are incubated for 15 minutes with TMB. Painted the reaction is stopped by adding 100 μl of 1M sulfuric acid. The amount of bound VBC complex is determined by measuring the optical density at 450 nm wave. It is proportional to the number gidrauxilirovannogo prolyl peptide in a nutrient medium.

To indicate prolylhydroxylase alternative can be used VBC complex associated with europium (firm Perkin Elmer). In this case, the amount of bound VBC complex is determined by the time of fluorescence. In addition, you can use VB complex, the labeled radioactive [35S]methionine. For this VBC complex with a radioactive label can be produced in the laboratory by transcription-translation in the lysate of reticulocyte.

Examples of execution inhibit the activity of HIF-prolylhydroxylase in this test with the index IC50order <30 μm. The following table 1 shows the characteristic indicators so for examples of execution.

Table 1
Example No.IC50[nm]Example No.IC50[nm]
28802170
554025180
976026380
1713029170
20 90

1.b) Cellular, functional test in vitro:

The effectiveness of the compounds according to the invention quantitatively evaluated by using recombinant cell lines. Cells originally derived from human cancer cell lines of the lung (A, ATS: American Type Culture Collection, Manassas, VA 20108, USA). The tested cell line stably transmitted by a vector, which contains the reporter gene luciferase Photinus pyralis (hereinafter luciferase) under the control of artificial Minpromtorg. Minpromtorg consists of two sensitive to hypoxia elements against the TATA sequence-block [F. Oehme, P. Ellinghaus, Kolkhof P., Smith T.J., S. Ramakrishnan, Htitter J., Schramm M., Flamme I., Biochem. Biophys. Res. Commun. 296 (2), 343-9 (2002)]. When exposed to hypoxia (e.g., culturing in the presence of 1% oxygen for 24 hours) or the impact of non-selective inhibitors dioxygenase (for example, desferrioxamine at a concentration of 100 μm, cobalt chloride at a concentration of 100 μm or diethyl ether iV-oxacillin concentration of 1 mm) of the tested cell line produces a luciferase, which can be detected and quantified using the appropriate reagents of bioluminescence (for example, Steady-Glo® Luciferase Assay System, Promega Corporation, Madison, Wisconsin 53711, USA) and a suitable luminometer.

The progress test is: the Cells the day before the test is administered in the exact nutrient medium (DMEM, 10% FCS, 2 TM glutamine) in the microtiter plate with 384 or 1536 wells and placed in a cell incubator (96% humidity, 5% V/V CO2, 37°C). On the day of the test to the nutrient medium was added subjects substances in graded concentrations. In consoles, serving as a negative control, cells test substance is added. As a positive control to determine the sensitivity of cells to inhibitors add, for example, desferrioxamine at a final concentration of 100 μm. After 6-24 hours after application of test substances in the wells of microtiter plasma measure the resulting signal light in a luminometer. On the measured values establish the dose of action, which serves as a basis for determining premaxillae concentration steps (denoted as EC50).

1.) Cellular, functional test in vitro for the changes of gene expression:

To investigate changes in the expression of specific mRNA in human cell lines after treatment subjects substances cultivate these cell lines on tablets 6 or 24 holes:

human hepatoma cells (HUH, JCRB Cell Bank, Japan), human embryonic kidney fibroblast (SOME/293, ATSS, Manassas, Virginia 20108, USA), human cervical cancer cells (HeLa, ATSS, Manassas, the tat Virginia 20108, USA), human venous endothelial cells of the umbilical cord (HUVEC, Cambrex, East Rutherford, new Jersey 07073, USA). 24 hours after addition of the test substances, the cells are washed with saline phosphate, and from them to the appropriate method of get total RNA (e.g., Trizol®-Reagenz, Invitrogen GmbH, 76131 Karlsruhe, Germany).

For routine analytical experiment each 1 µg thus obtained total RNA DNase has absorbed 1, and a suitable reaction reverse transcriptase (ImProm-II Reverse reduced System, Promega Corporation, Madison, WI 53711, USA) is converted into complementary DNA (cDNA). 2.5% of the thus obtained composition of cDNA used for the polymerase chain reaction. The level of expression of the studied genes mRNA installed using a quantitative analysis of the polymerase chain reaction in real time [TaqMan-PCR; Heid C.A, Stevens j, Livak K.J, Williams P.M., Genome Res. 6 (10), 986-94 (1996)] using the device serial readout ABI Prism 7700, Applied Biosystems, Inc.). The combination of the seed-probe produced by the program Primer Express 1.5 (company Applied Biosystems, hie.). In particular, investigate mRNA erythropoietin, carbonic anhydrase IX, lactate dehydrogenase and growth factor vascular endothelial cells.

The substances according to the present invention resulted in significant, dose-dependent increase in mRNA induced by hypoxia genes in the cells of h is of human origin.

2. The in vivo tests to prove action in the cardiovascular system

2.a) Test t vivo to modify gene expression:

Mice or rats administered compound, dissolved in appropriate solvents, orally or via gastric tube, intraperitoneally or intravenously. Typical doses are 0,1, 0,5, 1,5, 10, 20, 50, 100 and 300 mg of substance per kg of body weight and reception. Control animals received only the solvent. After 4, 8 or 24 hours after administration of the test substance, animals were omertvlenie cordozo izoflurana with subsequent fracture of the cervical spine, and get intended for research bodies. Fragments of bodies immediately frozen in liquid nitrogen. From the fragments of the bodies of the obtained total RNA, as described in paragraph B.I. (a), converted to cDNA. The level of expression of the studied genes mRNA installed using a quantitative analysis of the polymerase chain reaction in real time [TaqMan-PCR; Heid CA, Stevens j, Livak K.J., Williams P.M., Genome Res. 6 (10), 986-94 (1996)] using the device serial readout ABI Prism 7700, Applied Biosystems, Inc.).

The substances according to the present invention after oral or parenteral intake resulted in significant, dose-dependent increase in mRNA of erythropoietin in the kidneys compared to control samples that received a placebo.

2.b) determining the level of Erie is repeating serum:

Mice or rats administered the test substance in an appropriate solvent or intraperitoneally or orally once or twice daily. Typical doses are 0,1, 0,5, 1, 5, 10, 20, 50, 100 and 300 mg of substance per kg of body weight and reception. Control animals received only the solvent. Before taking over four hours after the last drug administration in animals under anesthesia, a brief take 50 ál of blood from retroorbital venous plexus or from the tail vein. Clotting prevents the addition of lithium heparin. By centrifugation get the blood plasma. In plasma determine the content of erythropoietin using a device Erythropoetin-ELISA (Quantikine® mouse Epo Immunoassay, R&D Systems, Inc., Minneapolis, USA) according to the manufacturer's instructions. The measured values are converted to PG/ml based on a key measurement of erythropoietin in mouse.

The substances according to the present invention after oral or parenteral intake resulted in significant, dose-dependent increase erythroprotein compared to the original indicator and control samples that received a placebo.

2) Determining the cellular composition of peripheral blood:

Mice or rats administered the test substance in an appropriate solvent or intraperitoneally, or orally once or twice during a number of the x days. Typical doses are, for example, 0,1, 0,5, 1,5, 10, 20, 50, 100 and 300 mg of substance per kg of body weight and reception. Control animals received only the solvent. At the end of the test animals under anesthesia, a brief take blood from the venous plexus of the angle of the palpebral fissure or from the tail vein, and blood clotting prevents the addition of sodium citrate. In a suitable electronic measuring device detect in the blood sample to the concentration of erythrocytes, leukocytes and platelets. The concentration of reticulocytes determined by the strokes of blood that stained the appropriate staining solution (firm KAV Labortechnik, Numbrecht) by viewing through the microscope every 1000 erythrocytes. To determine the hematocrit of the blood of retroorbital plexus of veins take with hematocrite capillary, and hematocrit read manually after processing of the capillary in a suitable centrifuge.

The substances according to the present invention after oral or parenteral intake resulted in significant, dose-dependent increase in hematocrit, number of erythrocytes and leukocytes in comparison with the original indicator and control samples that received a placebo.

3. Determination of solubility

Manufacture of the starting solution ('primary solution):

At least 1.5 mg of the test substance exactly resp who're asked in Wide Mouth 10 mm Screw V-Vial (firm Glastechnik world Cup GmbH, Art.-Nr. 8004-WM-H/V15 MK) with a suitable screw cap and septum, the substance is diluted compound DMSO to a concentration of 50 mg/ml and within 30 minutes shaken using a vortex mixer.

Manufacturer calibration solutions:

Necessary steps of dispensing osushestvliayut tablet Deep Well Plate (DWP) with 96 wells 1.2 ml robotically manipulating liquids. As solvent a mixture of acetonitrile and water 8:2.

Making an initial solution for the calibration solutions (concentrated solution): 10 ál of diluted primary 833 μl of the mixture solution (concentration=600 µg/ml) and the mixture is homogenized. Each test substance was diluted to a concentration of 1:100 in separate tablets DWP and again homogenized.

Calibration solution 5 (600 ng/ml): 30 μl of concentrated solution was diluted with 270 μl of the mixture solution and homogenized.

The calibration solution 4 (60 ng/ml): 30 μl of calibration solution 5 was diluted with 270 μl of the mixture solution and homogenized.

The calibration solution of 3 (12 ng/ml): 100 μl of calibration solution 4 was diluted with 400 μl of the mixture solution and homogenized.

Calibration solution 2 (1.2 ng/ml): 30 μl of calibration solution 3 was diluted with 270 μl of the mixture solution and homogenized.

Calibration solution 1 (0.6 ng/ml): 150 μl of calibration solution 2 times ablaut 150 μl of the mixture solution and homogenized.

Manufacturing test solutions:

Necessary steps of dispensing is carried out in the tablet DWP with 96 holes 1.2 ml robotically manipulating liquids. 10,1 µl of the concentrated solution is diluted to 1000 μl of PBS buffer solution pH 6.5. (PBS buffer solution pH 6.5: 61,86 g of sodium chloride, 39,54 g of sodium dihydrophosphate and 83,35 g of 1 N sodium hydroxide was weighed in a volumetric flask of 1 liter, complementary water, and the mixture is stirred for about 1 hour. 500 ml of this solution is poured into a volumetric flask of 5 liters, and add water. Using 1 N sodium hydroxide establish a pH of 6.5.)

Execution:

Necessary steps of dispensing is carried out in the tablet DWP with 96 holes 1.2 ml robotically manipulating liquids. Thus prepared test solutions shaken 24 hours at 1400 rpm using a temperature-controlled vortex mixer at 20°SIZ these solutions take the sample to 180 μl and placed in polyallomer contribuye tubes Beckman. These solutions are centrifuged for 1 hour with the power 223.000 × , From each of the test solution are selected based on 100 µl of the liquid fraction, which is diluted PBS buffer solution of 6.5 at a concentration of 1:10 and 1:1000.

The analysis method is:

Analysis of samples is carried out using HPLC/MS-MS. Quantification receive five-point calibration curve of the test compound. The solubility is expressed in mg/L. Consequently the efficiency of the analysis: 1) control sample (a mixture of solvents); 2) calibration solution of 0.6 ng/ml; 3) calibration solution of 1.2 ng/ml; 4) calibration solution 12 ng/ml; 5) calibration solution 60 ng/ml; 6) calibration solution 600 ng/ml; 7) control sample (a mixture of solutions); 8) a trial solution 1:1000; 7) a trial solution of 1:10.

Method HPLC/MS-MS

HPLC: Agilent 1100, Quaternary pump (G1311A), an automatic sampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: Oasis HLB 20 mm × 2.1 mm, 25 MK; temperature: 40°C; solvent A: water+0.5 ml of formic acid/l; solvent b: acetonitrile+0.5 ml of formic acid/l; flow rate: 2.5 ml/min; stop time 1.5 min; gradient: 0 min 95% A, 5% B; change: 0-0,5 min 5% A, 95% B; 0.5 to 0,84 min 5% A, 95% B; change: 0,84-0,85 min 95% A, 5% B; 0,85-1,5 min 95% A, 5% C.

MS/MS: WATERS Quattro Micro Tandem MS/MS; Z-Spray API Interface; HPLC-MS-divider input 1:20; measurement mode ESI.

Sprimary performance for pharmaceutical compounds

Compounds according to the invention can be converted into pharmaceutical preparations in the following way:

Tablets:

Composition:

100 mg of the compounds according to the invention, 50 mg of lactose (monohydrate), 50 mg corn Coahuila (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Weight pills 212 mgtime 8 mm, the radius of convexity 12 mm

Manufacturer:

The mixture of compounds according to the invention, lactose and krahm the La with a 5%solution (weight/weight) PVP granularit in the water. After drying the granulated product 5 minutes, mixed with magnesium stearate. This mixture is pressed a standard tablet press (format tablet see above). The estimated value for pressing is the press force of 15 kN.

Suspension for oral administration:

Composition:

1000 mg of the compounds according to the invention, 1000 mg of ethanol (96%), 400 mg Rhodigel® (xanthan gum company FMC, Pennsylvania, USA) and 99 g of water.

Single dose of 100 mg of the compounds according to the invention corresponds to 10 ml of oral suspension.

Manufacturer:

Redigel turn in ethanol suspension, suspension type connection according to the invention. When the mixing water is added. Stirring continued for about 6 hours until the final swelling rodies.

Solution for oral administration:

Composition:

500 mg of the compounds according to the invention, 2.5 g of Polysorbate and 97 g of polyethylene glycol 400. Single dose of 100 mg of the compounds according to the invention corresponds to 20 g of oral solution.

Manufacturer:

The connection according to the invention with stirring in a mixture of polyethylene glycol and Polysorbate turn in suspension. The process of remesiana continued until complete dissolution of the compounds according to the invention.

Solution for intravenous infusion:

The connection according to the invention with a concentration below the saturated RA is torimoto, dissolved in a physiologically acceptable solvent (e.g. isotonic solution of sodium chloride, glucose solution 5% and/or a solution of PEG 400 30%). The solution is filtered under sterile conditions and poured into sterile and pyrogen-free containers for injection.

1. The compound of the formula

in which
X represents N or CH,
R1means hydrogen or cyano,
R2means a saturated 4-7 membered residue heterocyclyl, linked through the nitrogen atom, which contains 1 to 2 heteroatoms selected from N and O,
and heterocyclyl residue may be substituted by one Deputy, selected from the group consisting of C3-C6-cycloalkyl,
or
and heterocyclyl residue is substituted by 1-4 substituents fluorine, or one of its pharmaceutically acceptable salts.

2. The compound according to claim 1, characterized in that X represents N or CH,
R1means hydrogen or cyano,
R2means a saturated 4-7 membered residue heterocyclyl, linked through the nitrogen atom, which contains 1 to 2 heteroatoms selected from N or O, and heterocyclyl residue is substituted by 1-4 substituents fluorine,
or
R2means piperazine-1-Il,
moreover piperazine-1-yl substituted by one Deputy, selected from the group consisting of C3-C6-cycloalkyl,
moreover piperazine-1-yl substituted by one Deputy who, selected from the group consisting of C3-C6-cycloalkyl,
or
R2means azetidin-1-Il,
moreover, azetidin-1-yl substituted by one Deputy, selected from the group consisting of C3-C6-cycloalkyl,
or one of its pharmaceutically acceptable salts.

3. The compound according to claim 1, characterized in that
X represents N or CH,
R1means hydrogen or cyano,
R2means azetidin-1-yl, pyrrolin-1-yl or piperidine-1-Il,
moreover, azetidin-1-yl, pyrrolin-1-yl and piperidine-1-yl substituted by 1-4 substituents fluorine,
or
R2means piperazine-1-Il,
moreover piperazine-1-yl, 4-th position substituted by one Deputy, selected from the group consisting of C3-C6-cycloalkyl,
or one of its pharmaceutically acceptable salts.

4. The compound according to claim 1, characterized in that
X represents N or CH,
R1means hydrogen or cyano,
R2means piperazine-1-Il,
moreover piperazine-1-yl substituted by one Deputy, and the Deputy is chosen from the group consisting of C3-C6-cycloalkyl,
or one of its pharmaceutically acceptable salts.

5. The compound according to claim 4, characterized in that
X represents N or CH,
R1means hydrogen or cyano,
R2means piperazine-1-Il,
moreover piperazine-1-yl, 4-th position substituted by one Deputy, and the Deputy in baraut from the group consisting of C3-C6-cycloalkyl,
or one of its pharmaceutically acceptable salts.

6. The compound according to claim 1, characterized in that
X represents N or CH,
R1means hydrogen or cyano,
R2means azetidin-1-Il,
moreover, azetidin-1-yl substituted by one Deputy, selected from the group consisting of C3-C6-cycloalkyl,
or one of its pharmaceutically acceptable salts.

7. The compound according to claim 1, characterized in that
R2means 4-cyclobutyl-piperazine-1-yl.

8. 1-{2-[6-(4-Cyclobutylmethyl-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitrile according to claim 1, having the following formula

and its pharmaceutically acceptable salts.

9. 1-{2-[6-(4-Cyclobutylmethyl-1-yl)pyrimidine-4-yl]-3-oxo-2,3-dihydro-1H-pyrazole-4-yl}-1H-imidazol-4-carbonitrile according to claim 1, having the following formula

10. 2-[6-(4-Cyclobutylmethyl-1-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-1H-pyrazole-3-one according to claim 1 the following formula

or one of its pharmaceutically acceptable salts

11. 2-[6-(4-Cyclobutylmethyl-1-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-1H-pyrazole-3-one of claim 10 following formula:

12. The compound of formula (I)

in which the residues X, 1and R2have mentioned in one of claims 1 to 11 values, and which has the properties of selective inhibitors of HIF-prolyl-4-gidroksilazy for the treatment and/or prevention of diseases mediated by the activity of HIF-prolyl-4-gidroksilazy.

13. The compound of formula (I)

in which the residues X, R1and R2have mentioned in one of claims 1 to 11 values, to obtain the drug, suitable for use in the method of treatment and/or prevention of cardiovascular diseases, cardiac insufficiency, anemia, chronic kidney disease and renal failure.

14. The method of obtaining the compounds of formula (I) or one of its pharmaceutically acceptable salts according to claim 1, characterized in that the compound of the formula

in which X, Z1and R1have specified in claim 1, with a compound of the formula

in which
Z2means methyl or ethyl,
condense in connection formulas

in which X, Z1and R1have specified in claim 1 values
and then in the presence of one of the acids is subjected to interaction with the compound of the formula (III)

in which R2has specified in claim 1 is,
and the connection under these conditions is eacli interaction of the compounds of formula (VII) with the compound of the formula (III) or under the influence of the base is converted into the cyclic compound of the formula (I),
and the compound of formula (I), if necessary, using the appropriate (i) solvents and/or (ii) bases or acids is converted into one of its salts.

15. Drug, possessing properties of selective inhibitors of HIF-prolyl-4-gidroksilazy containing compound according to one of claims 1 to 11 in an effective amount in combination with an inert, non-toxic, pharmaceutically acceptable auxiliary substance.

16. The drug is indicated in paragraph 15 for the treatment and/or prevention of cardiovascular diseases, cardiac insufficiency, anemia, chronic kidney disease and kidney failure.



 

Same patents:

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a medicinal agent for antagonistic action on angiotensin II, which contains a compound of formula (I) , in which R1 is a group of formula or , in which R2, R3, R4, R5, R6, R7 and R8, each independently, denote a hydrogen atom or a C1-6alkyl or salt thereof, which is intended for preventing or treating blood circulation disorders such as diabetes and diseases caused by insulin resistance. The invention relates to a medicinal agent which further contains a calcium antagonist and diuretic. The invention relates to use of said medicinal agents to treat said diseases, as well as methods of treating and preventing said diseases and disorders.

EFFECT: high efficiency of using said compounds.

17 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 5-phenyl-1 H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one of general formulas I-III: , where: R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl, which stands for monocyclic radical, which contains 5-6 atoms in cycle and one or several heteroatoms N, optionally substituted by one or some lower alkyls; R2 represents -C(=O), -C(=O)NR2'; where R2' represents H or lower alkyl; R3 represents H or R4; where R4 represents lower alkyl or heterocycloalkyl, which stands for monovalent saturated cyclic radical, consisting of one ring, which contains one or two ring-shaped heteroatoms, selected from N and O; X represents CH or N; Y1 represents H, lower alkyl or lower halogenalkyl; each Y2 independently represents lower alkyl, which is optionally substituted by one or several substituents, selected from group, which consists of hydroxygroup, lower alkoxygroup; n has value 0, 1, 2 or 4; Y3 represents Y4a, Y4b, Y4c or Y4d; where Y4a represents H; Y4b represents lower alkyl, optionally substituted by one or sseveral substituents, selected from group, consisting of lower halogenalkyl, halogen; Yc represents lower cycloalkyl, optionally substituted by one or some substituents, selected from group, consisting of lower alkyl, lower halogenalkyl, halogen; and Y4d represents aminogroup, optionally substituted by one or some lower alkyls; or to its pharmaceutically acceptable salt. Also described are: pharmaceutical composition, based on upper said compounds, as well as application of compounds of I-III formulas for treatment of inflammatory or autoimmune condition.

EFFECT: described are novel compounds, which can be useful for modulating Btk activity and treatment of diseases, associated with excess Btk activity.

14 cl, 102 ex, 1 tbl

Jnk inhibitors // 2504545

FIELD: biotechnologies.

SUBSTANCE: in formula

each of R1 and R2 independently represents H or C1-6alkyl; or R1 and R2 together form C3-6cycloalkyl circle, which is optionally replaced with one or more R2'; R2' represents C1-6alkyl, hydroxy group, halogen, amino group, C1-6alkoxy group, C1-6hydroxyalkyl or C1-6haloalkyl; R3 represents H or N(R4)(R5); R4 represents H, C1-6alkyl or C(=O)OR4'; R4' and R5 represents H or C1-6alkyl; represents H or C1-6alkyl; or R2 and R3 together form 5-membered heterocycle containing 1 atom of N in the amount of heteroatom, which is optionally replaced with one or more R2'; Q represents CH or N; Z1 represents (CH2)u; u and v mean 1; Z2 represents (CH2)v; m, n, p, r, q mean 0; Y1 represents CH(Y1'); Y1' represents H or C1-6alkyl; Y2 represents H or represents C1-6alkyl. Invention also refers to compounds of structural formulae (II), (IV) and to pharmaceutical composition containing the above compounds.

EFFECT: improving inhibiting activity in relation to JNK kinase.

10 cl, 4 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphonamide derivatives of general formula:

where m equals 0, 1 or 2; n equals 1 or 2; o equals 0, 1 or 2; p equals 0, 1 or 2; q equals 0, 1, 2 or 3; r equals 0, 1 or 2, under the condition that q+r is not greater than 3; v equals 0 or 1; w equals 0 or 1; under the condition that if v equals 0, then w equals 0; An- denotes a halide anion; Q denotes a single bond, -O- or -CH2-; R1 denotes aryl; R2 and R3 have values given in (i) or (ii): (i) R2 denotes H, C1-6-alkyl, C3-8-cycloalkyl, a bicyclic 8-12-member carbocyclyl, CH(aryl)2 or aryl; or denotes a heteroaryl bonded through a C1-6-alkylene group, the heteroaryl being selected from pyridinyl; R3 denotes H, C1-6-alkyl or aryl; or (ii) R2 and R3, together with the -N-(CH-)- group bonding them, form a heterocycle which can be annelated with an aryl residue, where the heterocycle is 6-membered, saturated or at least monounsaturated but not aromatic, and together with the N heteroatom to which the residue R2 is bonded, can contain at least another O heteroatom; R4 denotes aryl or heteroaryl, selected from pyridinyl; R5 and R6 independently denote H or C1-6-alkyl, wherein R5 and R6 do not simultaneously denote H; or R5 and R6 together denote a substituted or unsubstituted 5- or 6-member heteroaryl which, together with an N atom to which R5 and R6 are bonded, can contain at least another N heteroatom; or R5 and R6 together denote a group selected from -(CH2)d- or -(CH2)e-X-(CH2)f, where d denotes 2, 3, 4, 5 or 6 and e and f are independently equal to 1, 2 or 3, under the condition that e+f is not greater than 5; and X denotes NR12, where R12 denotes H or C1-6-alkyl; R20 denotes C1-6-alkyl; and where said aryl and heteroaryl residues in case can be unsubstituted or monosubustituted or multi-substituted with the same or different residues selected from a group comprising F, Cl, Br, I, O-C1-6-alkyl, CF3 and C1-6-alkyl; and said C1-6-alkyl residues in each case can be branched or straight; in form of a separate enantiomer or separate diastereomer, racemate, enantiomers, diastereomers, mixtures of enantiomers and/or diastereomers, and in each case in form of bases and/or physiologically compatible salts thereof. The invention also relates to a method of producing the described compound, a drug having antagonistic action on B1R, based on compounds of formula I and use of said compound to produce a drug.

EFFECT: novel compounds which can be used in medicine are obtained and described.

15 cl, 131 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 5-fluorouracil derivatives of general formula (I) or pharmaceutically acceptable salts thereof. In general formula (I), R1 denotes a hydrogen atom or a protective hydroxy group which is selected from a C1-C6aliphatic acyl group; C5-C6 alicyclic acyl group; aromatic acyl group which is selected from a benzoyl group or a halogen-benzoyl group, R2 denotes a lower alkoxy-lower alkyl group; X denotes CH or a nitrogen atom and Y denotes a halogen atom.

EFFECT: compounds have anti-tumour activity, balanced with toxicity level, and can be used as an active ingredient for producing a drug for treating malignant diseases.

11 cl, 4 dwg, 4 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

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