Pyrazolopyridine derivatives as nadph-oxidase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrazolopyridine derivatives of formula (I) , a based pharmaceutical composition, and using them for treating and/or preventing disorders or conditions related to nictonamide adenine dinucleotide phosphatoxidase (NADPH-oxidase), as well as to a method for preparing them and an intermediate of formula (VIII) . In general formula (I), G1 is specified in H; and optionally substituted heteroaryl-C1-C6-alkyl; G2 is specified in H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-heterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G3 is specified in H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy, optionally substituted alkoxy-C1-C6-alkyl; optionally substituted carbonyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted C1-C6-alkylaryl: optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-hterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G4 is specified in -NR2-C(O)-R1 and -(CHR3)m-(CH2)n-R4, G5 represents H.

EFFECT: preparing the pharmaceutical composition for treating and/or preventing the disorders and conditions related to nictonamide adenine dinucleotide phosphatoxidase.

16 cl, 3 tbl, 87 ex

 

The technical field to which the invention relates.

The present invention relates to pyrazolopyrimidinone derivatives of the formula (I), their pharmaceutical compositions and their use for the preparation of medicaments for treatment and/or prevention of cardiovascular diseases, respiratory diseases, diseases of violating metabolism, diseases of the skin and/or bone, neurodegenerative diseases, kidney diseases, disorders of the reproductive system, inflammatory diseases and various types of cancer. In particular the present invention relates to pyrazolopyrimidinone derivatives suitable for the preparation of pharmaceutical compositions for the modulation, notably the inhibition of the activity or functioning of nikotinamidadenindinukleotida (NADPH-oxidase).

The level of technology

NADPH-oxidase (NOX) are proteins that transfer electrons across biological membranes. Typically, the electron acceptor is oxygen, and the reaction product of electron transfer is superoxide. Thus, the biological function of NOX enzymes is the production of oxygen reactive oxygen species (ROS or ROS). Reactive oxygen species (ROS) are generated from oxygen small molecules, including oxygen radicals (superoxide anion [O2] hydroc the Il radical [BUT] peroxyl (peroxy) radical [ROO] alkoxy-radical [RO] and hydroperoxyl (hydropeaking) radical [IEO]), and certain non-radical molecules that are either oxidizing agents and/or are easily converted into radicals. The nitrogen-containing oxidizing agents such as nitric oxide, also known as the active forms of nitrogen (AFA or RNS). Generation of ROS is usually a cascade of reactions that start with superoxide production. Superoxide rapidly dismutase in hydrogen peroxide or spontaneously, especially at low pH values, or with the participation of the enzyme superoxide dismutase. Other events in the cascade of reactions is the generation of ROS include the reaction of superoxide with nitric oxide to form peroxynitrite, catalyzed by peroxidase formation of hypochlorous acid from hydrogen peroxide, catalyzed by iron in the Fenton reaction, leading to the generation of hydroxyl radical.

AFC avidly interact with a large number of molecules, including other small inorganic molecules as well as DNA, proteins, lipids, carbohydrates and nucleic acids. This initial reaction may generate a secondary radical, multiplying, thus, potential damage. ROS are involved not only in cell damage and destruction of pathogens, but also in a large number of reversible reg is atornic processes in virtually all cells and tissues. However, despite the important role of ROS in the regulation of fundamental physiological processes, production of ROS may also irreversibly damage or alter the function of a target molecule. As a consequence, ROS increasingly identified as key contributors to damage to biological organisms, the so-called "oxidative stress".

Inflammation of NADPH oxidase is one of the most important sources of ROS production in cells of blood vessels in inflammatory conditions (Thabut et al., 2002, J. Biol. Chem., 277:22814-22821).

In lung tissue continuously exposed to oxidants, which are formed either in endogenous metabolic reactions (for example, when breathing in mitochondria or upon activation of recruited inflammatory cells), or exogenous in the air (e.g., cigarette smoke or air pollutants). In addition, the lungs are constantly exposed to high partial pressures of oxygen compared with other tissues, have a large surface area and is actively supplied with blood, and are particularly sensitive to damage mediated by ROS (Brigham, 1986, Chest, 89(6): 859-863). Dependent on NADPH oxidase generation of ROS has been described in cells of the lung endothelium and smooth muscle cells. It is assumed that the activation of NADPH oxidase in response to stimuli involved in the development of lung for which olivani, such as pulmonary hypertension and vasoconstriction (narrowing of blood vessels in the lungs (Djordjevic et al., 2005, Arterioscler. Thromb. Vase. Biol., 25, 519-525; Liua et al 2004, Am. J. Physiol. Lung Cell. Mol. Physiol., 287: L111-118). In addition, the pulmonary fibrosis is characterized by pulmonary inflammation and excessive generation of ROS.

Osteoclasts, which are cells like macrophages and play a key role in the rebuilding of bone tissue (e.g., resorbtive bones), generate ROS through-dependent NADPH oxidase mechanisms (Yang et al., 2002, J. Cell. Chem. 84, 645-654).

It is known that diabetes oxidative stress is increased (for example, increased ROS generation due to the oxidation of glucose) as humans and animals, and it is known that increased oxidative stress plays an important role in the development of complications associated with diabetes. It was shown that the increased accumulation of peroxide and dysfunction of the Central zone of the retina in diabetic rats coincide with the areas of activity of NADPH oxidase in endothelial cells of the retina (Ellis et al., 2000, Free Rad Biol. Med., 28:91-101). In addition, it has been suggested that the control of oxidative stress (ROS) in the mitochondria and/or in the area of inflammation can be a useful approach for the treatment of diabetes (Pillarisetti et al., 2004, Expert Opin. Ther. Targets, 8(5}: 401-408).

AFC is also actively involved in the pathogenesis of atherosclerosis, cell proliferation, is hypertonia and overall cardiovascular disease, associated with damage during reperfusion (Cai et al., 2003, Trends Pharmacol. Sci., 24:471-478). When all the risk factors of atherosclerosis not only increases the production of superoxide, for example, in the wall of the arteries, but ROS also induce many "proatherogenic cell responses in vitro. An important consequence of ROS formation in cells of blood vessels is the consumption of nitric oxide (NO). NO inhibits the development of vascular diseases and the loss of NO is an important factor in the pathogenesis of cardiovascular diseases. It was reported about the increased activity of NADPH-oxidase in the vessel wall after injury balloon catheter (Shi et al., 2001, Throw. Vase. Biol., 2001, 21, 739-745).

It is believed that oxidative stress caused by free radical damage is also a major factor in neurodegenerative diseases. Such damage may include mitochondrial abnormalities, the demyelination of neurons, apoptosis, neuronal loss and reduced cognitive abilities, potentially leading to the development of progressive neurodegenerative diseases (Nunomura et al., 2001, J. Neuropathol. Exp.Neurol., 60:759-767; Girouard, 2006, J. Appl. Physiol. 100:328-335).

In addition, we demonstrated the generation of ROS by the sperm of a large number of species, and it has been suggested that this is due to the NADPH-oxidase present in the sperm (Vernet et al., Biol. Reprod., 2001, 65:1102-1113). Assumes the I, the increased generation of ROS is involved in the pathology of the sperm, including male infertility, as well as some diseases of the penis and prostate cancer.

NADPH-oxidase are multiobjective enzymes, consisting of associated with the membrane domain of cytochrome b558 and three cytoplasmic protein subunits, p47phox, p67phox and the small GTPase Rac. Identified seven isoforms of NOX enzymes, including NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 (Leto et al., 2006, Antioxid Redox Signal, 8(9-10): 1549-61; Cheng et al., 2001, Gene, 16;269(1-2):131-40).

Thus, generated from NADPH ROS contribute to the pathogenesis of many diseases, especially cardiovascular diseases or disorders, respiratory disorders or diseases, or disorders affecting the metabolism, bone disease, neurodegenerative diseases, inflammatory diseases, reproductive disorders or diseases, pain, cancers, and diseases or disorders of the gastrointestinal tract. Thus, it would be very desirable to create a new active agents aimed at ROS-signaling cascade, especially on NADPH-oxidase (NOX).

Disclosure of inventions

The present invention is directed to new molecules that are suitable for the treatment and/or prevention of diseases associated with nikotinamidadenindinukleotida (NADPH-oxidase), such casetechnology disease, respiratory diseases, diseases of violating metabolism, diseases of the skin and/or bone, neurodegenerative diseases, kidney disease, reproductive disorders, inflammatory diseases, different types of cancer, allergic diseases, injuries, septic, hemorrhagic and anaphylactic shock, diseases and disorders of the gastrointestinal tract, angiogenesis and angiogenesis-dependent condition. In particular the present invention relates to new molecules suitable for inhibiting or reducing the production of ROS in the cells.

The first aspect of the present invention provides pyrazolopyrimidinone derivative of the formula (I), where G1, G2, G3, G4and G5are as defined below, as well as its pharmaceutically acceptable salts and pharmaceutically active derivative.

The second aspect of the present invention relates to pyrazolopyrimidinone derivative of the formula (I), where G1, G2, G3, G4and G5are as defined below, as well as its pharmaceutically acceptable salts and pharmaceutically active derivative for use as a medicine.

The third aspect of the present invention relates to pharmaceutical compositions containing at least one pyrazolopyrimidine derivative according to the present image the structure, and its pharmaceutically acceptable salts and pharmaceutically active derivative, and a pharmaceutically acceptable carrier, solvent or excipient.

A fourth aspect of the present invention concerns the application pyrazolopyrimidine derivative according to the present invention and its pharmaceutically acceptable salts and pharmaceutically active derivative to obtain a pharmaceutical composition for the treatment or prevention of a disease or condition selected from cardiovascular diseases, respiratory diseases, diseases that violates the metabolism, skin diseases, bone disease, neuropeptidergic and/or neurodegenerative disorders, kidney diseases, reproductive system diseases, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic diseases, injuries, septic diseases, hemorrhagic and anaphylactic shock, diseases or disorders of the gastro-intestinal system disorders of angiogenesis-dependent angiogenesis diseases and/or other diseases and disorders associated with nikotinamidadenindinukleotida (NADPH-oxidase).

The fifth aspect of the present invented the I relates to a method of treatment of a patient, suffering from a disease or condition selected from cardiovascular diseases, respiratory diseases, diseases that violates the metabolism, skin diseases, bone disease, neuropeptidergic and/or neurodegenerative disorders, kidney diseases, reproductive system diseases, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic diseases, injuries, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal tract, angiogenesis-dependent angiogenesis diseases and/or other diseases and disorders associated with nikotinamidadenindinukleotida (NADPH-oxidase). This method includes the introduction of pyrazolopyrimidinone derivative of the formula (I), where G1, G2, G3, G4and G5are as defined below, as well as its pharmaceutically acceptable salts and pharmaceutically active derivative to a patient in need of such treatment.

The sixth aspect of the present invention relates to pyrazolopyrimidinone derivative of the formula (I), where G1, G2, G3, G4and G5are as defined below, and be supplied with the ski acceptable salts and pharmaceutically active derivative, for the treatment of a disease or condition selected from cardiovascular diseases, respiratory diseases, diseases that violates the metabolism, skin diseases, bone disease, neuropeptidergic and/or neurodegenerative disorders, kidney diseases, reproductive system diseases, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic diseases, injuries, septic disease/hemorrhagic and anaphylactic shock, diseases or disorders of the gastro-intestinal system, violations of angiogenesis-dependent angiogenesis diseases and other diseases and/or disorders associated with nikotinamidadenindinukleotida (NADPH-oxidase).

The seventh aspect of the present invention relates to an intermediate of formula (VIII), in which G2, G3, G5and R8are as defined below.

The eighth aspect of the present invention relates to an intermediate of formula (X), where G2, G5and R8are as defined below.

The ninth aspect of the present invention relates to methods of obtaining these intermediates of formula (VIII) or (X) according to the present invention.

The tenth aspect according to the present is th invention relates to methods for obtaining the compounds of formula (I) according to the present invention.

Other features and advantages of the present invention will be seen from the following embodiment of the invention.

The implementation of the invention

The following paragraphs provide definitions for the various chemical components that are part of the compounds according to the present invention, and are intended for uniform application hereinafter in the description and in the claims, except in those cases where the differently formulated definition provides a broader definition.

The term "alkyl", when used by itself or in combination with other terms includes non-branched chain or branched C1-C20-alkyl, which refers to monovalent alkyl groups having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl, ISO-butyl, tert-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-etylhexyl, 3-etylhexyl, 4-etylhexyl, 5-methylhexan, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydropyranyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-octadecyl, n-Needell, and n-eicosanol and the like. Preferably, they include C1-C9/sub> alkyl, more preferably C1-C6-alkyl, particularly preferably C1-C4-alkyl, which, by analogy, denote, respectively, monovalent alkyl groups having 1 to 9 carbon atoms, monovalent alkyl groups having from 1 to 6 carbon atoms and monovalent alkyl groups having from 1 to 4 carbon atoms. In particular, they include C1-C6-alkyl.

The term "alkenyl", when used by itself or in combination with other terms includes non-branched chain or branched C2-C20alkenyl. He can have any possible number of double bonds in all possible positions and configuration of the double bond may be (E) or (Z) configuration. This term can be exemplified by groups such as vinyl, allyl, Isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, geraniol, 1-decenyl, 1-tetrad azenil, 1-octadecenyl, 9-octadecenyl, 1-eicosanol and 3, 7, 11, 15-tetramethyl-1-hexadecanol, and the like. Preferably they include C2-C8alkenyl, more preferably C2-C6alkenyl. Among the other most preferred are the Xia vinyl or ethynyl (-CH=CH 2), n-2-propenyl (allyl, -CH2CH=CH2), Isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and 3-methyl-2-butenyl and the like.

The term "quinil", when used by itself or in combination with other terms includes non-branched chain or branched C2-C20-quinil. It can have any number of triple bonds in any possible positions. This term can be exemplified by groups such as alkyline group, which can have 2-20 carbon atoms and, optionally, the double bond, such as ethinyl (-C=CH), 1-PROPYNYL, 2-PROPYNYL (propargyl: -CH2C≡CH), 2-butinyl, 2-penten-4-inyl, and the like. Preferably they include C2-C8-quinil, more preferably C2-C6quinil and the like. Preferably they include C2-C6-quinil, which refers to a group having from 2 to 6 carbon atoms and having at least 1 or 2 of section alkenylphenol unsaturation.

The term "heteroalkyl" represents C1-C12-alkyl, preferably C1-C6-alkyl in which at least one carbon atom is replaced by a heteroatom selected from O, N or S, including 2-methoxyethyl and the like.

The term "aryl" refers to an unsaturated aromatic carbocyclic group containing from 6 to 14 atmosukarto, and having a single ring (e.g. phenyl) or multiple condensed rings (e.g., indenyl, naphthyl). Aryl includes phenyl, naphthyl, antril, phenanthrene and the like.

The term "C1-C6-alkylaryl" refers to aryl groups having C1-C6-alkyl substituent, including were, ethylphenyl and the like.

The term "aryl-C1-C6-alkyl" denotes a C1-C6is an alkyl group having aryl Deputy, including 3-of phenylpropyl, benzyl and the like.

The term "heteroaryl" denotes a monocyclic heteroaromatic, or. bicyclic or tricyclic heteroaromatic group of condensed rings. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, trienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuran, [2,3-dihydro]benzofuran, isobenzofuran, benzothiazyl, benzotriazolyl, isobenzofuranyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, hemolysins, hintline, phthalazine, honokalani, cinnoline, naphthyridine, pyrido[3,4-b]pyridyl, pyrid about [3,2 b] pyridyl, pyrido[4,3-b]pyridyl, hinely, ethanolic, tetrazolyl, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, purinol, pteridinyl, carbazolyl, xantener or benzopinacol.

The term "C1-C6-alkylglycerol" denotes a heteroaryl group having C1-C6-alkyl substituent, including methylphenyl and the like.

The term "heteroaryl-C1-C6-alkyl" denotes a C1-C6is an alkyl group having a heteroaryl Deputy, including furylmethyl and the like.

The term "C2-C6-alkynylaryl" refers to aryl groups having C2-C6-alkanniny Deputy, including vinylphenol and the like.

The term "aryl-C2-C6alkenyl" represents C2-C6-alkeline group having aryl Deputy, including fineliner and the like.

The term "C2-C6-alkenylphenol" denotes a heteroaryl group having C2-C6-alkanniny Deputy, including vinylpyridine and the like.

The term "heteroaryl-C2-C6alkenyl" represents C1-C6-alkeline group having a heteroaryl Deputy, including pyridinoline and the like.

The term "C3-C8-cycloalkyl" denotes a saturated carbocyclic group of from 3 to 8 carbon atoms, imoudu is a single ring (e.g., cyclohexyl), or multiple condensed rings (e.g., norbornyl). C3-C8-cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.

The term "heteroseksualci" represents C3-C8-cycloalkyl group according to the definition given above, in which up to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR where R represents hydrogen or methyl. Heterocicluri include pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, tetrahydrofuranyl and the like.

The term "C1-C6-alkyl-C3-C8-cycloalkyl" means3-C8-cycloalkyl group having C1-C6-alkyl substituent, including Methylcyclopentane and the like.

The term "C3-C8-cycloalkyl-C1-C6-alkyl" denotes a C1-C6is an alkyl group having From3-C8-cycloalkenyl Deputy, including 3-cyclopentylpropionyl and the like.

The term "C1-C6-alkylchlorosilanes" means heterocytolysine group having C1-C6-alkyl substituent, including 4-methylpiperidine and the like.

The term "heteroseksualci-C1-C6-alkyl" denotes a C1-C6is an alkyl group having heterologously Deputy, VK is UCA (1 methylpiperidin-4-yl)methyl and the like.

The term "carboxy" refers to a group-C(O)HE,

The term "carboxy-C1-C6-alkyl" denotes a C1-C6is an alkyl group having a carboxy-Deputy, including 2-carboxyethyl and the like.

The term "acyl" denotes the group-C(O)R where R includes H, "alkyl", preferably "C1-C6-alkyl", "aryl", "heteroaryl", "C3-C8-cycloalkyl", "heteroseksualci", "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl", "C3-C8-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl, including acetyl and the like.

The term "acyl-C1-C6-alkyl" denotes a C1-C6is an alkyl group having acyl Deputy, including 2-acetylethyl and the like.

The term "arylaryl" refers to aryl groups having acyl Deputy, including 2-acetylphenyl and the like.

The term "acyloxy" refers to the group-OC(O)R where R includes H, "C1-C6-alkyl", "C2-C6alkenyl", "C2-C6-quinil", "C3-C8-cycloalkyl", "heteroseksualci", "aryl", "heteroaryl", "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl", "aryl-C2-C6alkenyl", "heteroaryl-C2-C6alkenyl", "aryl-C2-C6-quinil", "heteroaryl-C2- 6-quinil", "C2-C6-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl", including the atomic charges and the like.

The term "acyloxy-C1-C6-alkyl" denotes a C1-C6is an alkyl group having acyloxy Deputy, including 2-(ethylcarbonate)ethyl and the like.

The term "alkoxy" denotes the group-O-R where R includes "C1-C6-alkyl", "aryl", "heteroaryl", "aryl-C1-C6-alkyl" or "heteroaryl-C1-C6-alkyl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.

The term "alkoxy-C1-C6-alkyl" denotes a C1-C6is an alkyl group having alkoxy-Deputy, including methoxyethyl and the like.

The term "alkoxycarbonyl" denotes the group-C(O)OR where R includes "C1-C6-alkyl", "aryl", "heteroaryl", "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl" or "heteroalkyl".

The term "alkoxycarbonyl-C1-C6-alkyl" denotes a C1-C6is an alkyl group having alkoxycarbonyl Deputy, including 2-(benzyloxycarbonyl)ethyl and the like.

The term "aminocarbonyl" denotes the group-C(O)NRR', where R and R' represent independently from each other H, C1-C6is alkyl, aryl, heteroaryl "aryl-C 1-C6-alkyl" or "heteroaryl-C1-C6-alkyl, including N-phenylcarbamoyl and the like.

The term "aminocarbonyl-C1-C6-alkyl" refers to alkyl groups having aminocarbonyl Deputy, including 2-(dimethylaminoethyl)ethyl, N-ethylacetamide, N,N-diethylacetamide and the like.

The term "acylamino" refers to the group-NRC(O)R', where R and R' represent independently from each other H, "C1-C6-alkyl," "C2-C6alkenyl," "C2-C6-quinil," " C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6alkenyl," "heteroaryl-C2-C6alkenyl," "aryl-C2-C6-quinil," "heteroaryl-C2-C6quinil," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl, including acetylamino and the like.

The term "acylamino-C1-C6-alkyl" denotes a C1-C6alkyl group having acylamino Deputy, including 2-(propionamido)ethyl and the like.

The term "ureido" refers to the group-NRC(O)NR'r R", where R, R' and R" represent independently of each other H, "C1-C6-alkyl," "alkenyl," "quinil," "C3-C8-cycloalkyl," "heteroseksualci," "C1-C6-aryl," "heteroaryl," "aryl-Csub> 1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6alkenyl," "heteroaryl-C2-C6alkenyl," "aryl-C2-C6-quinil," "heteroaryl-C2-C6-quinil," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl, and where R' and R" together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered geteroseksualnoe ring.

The term "ureido-C1-C6-alkyl" denotes a C1-C6is an alkyl group having ureido Deputy, including 2-(N'-methylurea)ethyl and the like.

The term "carbamate" refers to the group-NRC(O)OR', where R and R' represent independently from each other, "C1-C6-alkyl," "C2-C6alkenyl," "C2-C6-quinil," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "C1-C6-alkylaryl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6alkenyl," "heteroaryl-C2-C6alkenyl," "aryl-C2-C6-quinil," "heteroaryl-C2-C6-quinil," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl" and not necessarily R may also represent hydrogen.

The term "amino" denotes the group-NRR' where R and R' represent independently from each other H, "C1-C6-alkyl", "aryl","heteroaryl", "C1-C6-alkylaryl", " C1-C6-alkylglycerol," "cycloalkyl," or "heteroseksualci, and where R and R', together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered geteroseksualnoe ring.

The term "aminoalkyl" refers to alkyl groups having amino Deputy, including 2-(1-pyrrolidinyl)ethyl and the like. '

The term "ammonium" refers to a positively charged group-N+RR'R", where R, R' and R" represent independently of each "C1-C6-alkyl, C1-C6-alkylaryl", "C1-C6-alkylglycerol," "cycloalkyl," or "heteroseksualci, and where R and R', together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered geteroseksualnoe ring.

The term "ammonium-alkyl" refers to alkyl groups having ammonium Deputy, including 1 ethylpyrrolidin and the like.

The term "halogen" denotes fluorine atoms, chlorine, bromine and iodine.

The term "sulfonyloxy" denotes the group-OSO2-R, where R is selected from C1-C6-alkyl," "C1-C6-alkyl" substituted with Halogens, e.g.,- OSO2-CF3group "C2-C6-alkenyl," "quinil," "C3-C8-cycloalkyl," "geterotsiklicheskie," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "hetero is the Rila-C 1-C6-alkyl," "aryl-C1-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-quinil," "heteroaryl-C2-C6-quinil," "cycloalkyl-C1-C6-alkyl" or "geterotsiklicheskikh".

The term "sulfonyloxy-C1-C6-alkyl" refers to alkyl groups having sulfonyloxy Deputy, including 2-(methylsulfonylamino)ethyl and the like.

The term "sulfonyl" refers to a group "-SO2-R" where R is selected from aryl," "heteroaryl," "C1-C6-alkyl," "C1-C6-alkyl" substituted with Halogens, e.g.,- SO2-CF3group "C1-C6-alkenyl," "C2-C6-quinil," "C3-C8-cycloalkyl," "geterotsiklicheskie," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C1-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-quinil," "heteroaryl-C2-C6-quinil," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl".

The term "sulfonyl-C1-C6-alkyl" refers to alkyl groups having sulfanilyl Deputy, including 2-(methylsulphonyl)ethyl, and the like.

The term "sulfinil" denotes the group-S(O)-R", where R is selected from alkyl," "alkyl" substituted halogen is mi, for example, -SO-CF3group "C2-C6-alkenyl," "C2-C6-quinil," "C3-C8-cycloalkyl," "geterotsiklicheskie," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-quinil," "heteroaryl-C2-C6-quinil," "C3-C8-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6of alkyl".

The term "sulfanilate" refers to alkyl groups having sulfanilyl Deputy, including 2-(methylsulfinyl)ethyl and the like.

The term "sulfanyl" denotes the group-S-R where R includes H, "C1-C6-alkyl," "C1-C6-alkyl" substituted with Halogens, e.g.,- S-CF3group "C1-C6alkenyl," " C2-C6-alkyne," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6alkenyl," "heteroaryl-C2-C6alkenyl," "aryl-C1-C6-quinil," "alkynylaryl," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl". Preferred sulfanilimide groups include methylsulfonyl, ethylsulfonyl, and the like.

The term "effect-free remedy C1-Csub> 6-alkyl" denotes a C1-C5is an alkyl group having sulfanilyl Deputy, including 2-(ethylsulfanyl)ethyl and the like.

The term "sulfonylamino" denotes the group-NRSO2-R', where R and R' represent independently from each other, "C1-C6-alkyl," "C2-C6alkenyl," "C2-C6-quinil," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6alkenyl," "heteroaryl-C2-C6alkenyl," "aryl-C2-C6-quinil," "heteroaryl-C2-C6-quinil," "C3-C8-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6alkyl".

The term "sulfonylamino-C1-C6-alkyl"" denotes alkyl groups having sulfonylamino Deputy, including 2-(ethylsulfonyl)ethyl and the like.

The term "aminosulfonyl" denotes the group-SO2-NRR', where R and R' represent independently from each other H, "C1-C6-alkyl," "C2-C6alkenyl," "C2-C6-quinil," " C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "arylalkyl," "heteroaryl-C2-C6alkenyl," "aryl-C2-C6-quinil," "hetero is the Rila-C 2-C6-quinil," "C3-C8-cycloalkyl-C1-C6-alkyl, or heteroseksualci-C1-C6-alkyl, and where R and R', together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered geteroseksualnoe ring. Aminosulfonyl groups include cyclohexanesulfonyl, piperidinylcarbonyl and the like.

The term "aminosulfonyl-C1-C6-alkyl" denotes a C1-C6alkyl group having aminosulphonylphenyl Deputy, including 2-(cyclohexanesulfonyl)ethyl and the like.

Unless otherwise specified in the definition of the individual substituent, these substituents should be understood as not necessarily replaced.

Unless otherwise specified in the definition of the individual substituent, the term "substituted" refers to groups substituted by 1 to 5 substituents selected from the group that includes "C1-C6-alkyl," "C2-C6alkenyl," "C2-C6-quinil," "C3-C8-cycloalkyl," "heteroseksualci," "C1-C6-alkylaryl," "C1-C6-alkylglycerol," "C1-C6-alkylsilanes," "C1-C6-alkylchlorosilanes," "amino," "aminosulfonyl," "ammonia," "acylamino," "aminocarbonyl," "aryl," "heteroaryl," "sulfinil," "sulfonyl," "alkoxy," "alkoxycarbonyl is, carbamate," "sulfonyl," "halogen," trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like.

The term "pharmaceutically acceptable salts or complexes" refers to salts or complexes of the below compounds of formula (I). Examples of such salts include, but are not limited to, primary additive salts formed by the reaction of compounds of formula (I) with organic or inorganic bases such as hydroxide, carbonate or bicarbonate of a metal cation, such as metals selected from the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metal (e.g. calcium or magnesium), or an organic primary, secondary or tertiary alkylamines. Amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, research, N-Me-D-glucamine, N,N'-bis(phenylmethyl)-1,2-academia, tromethamine, ethanolamine, diethanolamine, Ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like are considered as being within the scope of the present invention.

Also in the present invention include salts, which are obtained from the acid additive salts formed with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), and salts formed with organic acid is Tami, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic (dikalova) acid, pamula acid (palmoic acid), alginic acid, polyglutamine acid, naphthalenesulfonic acid, naphthalenedisulfonic acid and polygalacturonase acid.

The term "pharmaceutically active derivative" refers to any compound that when administered to the recipient is capable of, directly or indirectly, to ensure disclose the activity here. The term "not right" also includes prodrugs that can be transformed into an active form of the drug under the action of endogenous enzymes or in the process of metabolism. A prodrug is a derivative of the compounds according to the present invention, and provides inhibition of NADPH-oxidase activity, which contains a chemically or metabolically remove the group, and is a compound that can be converted into a pharmaceutically active compound in vivo by cleavage of the solvent (solvolysis) under physiological conditions. The present invention also includes all tautomers of the compounds according to the present invention.

The term "cardiovascular disorder or disease" includes atherosclero is, particularly diseases or disorders associated with endothelial dysfunction, including, but not limited to, hypertension, cardiovascular complications of diabetes Type I or Type II hyperplasia of the intima of coronary heart disease, spasm of cerebral vessels, coronary vessels or arteries, endothelial dysfunction, heart failure, including chronic heart failure, peripheral artery disease, restenosis, injury caused by the stent, heart attack, ischemic stroke, vascular complications, such as occur after organ transplantation, myocardial infarction, hypertension, atherosclerosis plaque formation, platelet aggregation, angina, aneurysm, dissecting aneurysm of the aorta, coronary heart disease, cardiac hypertrophy, pulmonary embolism, thrombosis, including deep vein thrombosis, damage that occurs after ischemia in the restoration of blood flow or oxygen supply, as in the case of organ transplants, open heart surgery, angioplasty, hemorrhagic shock, coronary angioplasty organs, including heart, brain, liver, kidney, retina and intestines.

The term "respiratory disorders or disease includes asthma, bronchitis, allergic rhinitis, respiratory syndrome adults, cystic fibrosis, viral INF is the Ktsia light (flu), pulmonary hypertension, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD).

The term "allergic disease" includes hay fever and asthma.

The term "injury" includes polychromatism.

The term "disease or disorder affecting the metabolism" includes obesity, metabolic syndrome and diabetes Type II.

The term "skin disease" or "violation" includes psoriasis, eczema, dermatitis, wound healing and scarring.

The term "violation of bones" includes osteoporosis, osteoporos, osteosclerosis, a parody of ontic and hyperparathyroidism.

The term "neurodegenerative disease or disorder" includes a disease or condition characterized by degeneration or changes in the Central nervous system (CNS), particularly at the level of neurons, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), epilepsy, and muscular dystrophy. It also includes neirolepticalkie and associated with a demyelination condition or disease, such as leukoencephalopathy and leukodystrophy.

The term "demyelination" refers to the condition or disease of the CNS, including the degradation of the myelin sheath of axons. In the context of the present invention, the term "associated with demyelination Zab is levana" is intended to denote States, which include the process that leads to demyelination of the cells, such as multiple sclerosis, progressive multifocal (multifocal) leucoencephalopathy (progressive multifocal leukoencephalopathy, PML), myelopathy, any neirolepticalkie condition involving self-reactive leukocytes within the Central nervous system, congenital metabolic disorder, a neuropathy with abnormal myelination, demyelination induced by drugs, demyelination induced by radiation, hereditary condition, demyelination, state demyelination induced by prions, demyelination induced encephalitis or damage to the spinal cord. Preferably, the condition represents multiple sclerosis.

The term "disease or disorder of the kidneys includes diabetic nephropathy, renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides and platinum compounds and overactive bladder. In a specific embodiment, the term in accordance with the present invention includes chronic diseases or disorders of the kidneys.

The term "disturbance or disease of the reproductive system includes erectile dysfunction, impairment of fertility, hypertrophy of the prostate and benign prostatic hypertrophy.

The term "violation or disease affecting the eye and/or the lens" on the em cataracts, including diabetic cataract, a second lens opacity after surgical treatment of cataract, diabetic and other retinopathy.

The term "a condition affecting the inner ear includes presbyacusis (senile deafness), tinnitus (ringing in the ears, Meniere's disease (hydrocele of the labyrinth of the inner ear) and other problems with balance, trichomoniasis, vestibular migraine, and induced noise hearing loss and induced by drugs hearing loss (ototoxicity).

The term "inflammatory disorder or disease" refers to inflammatory bowel disease, sepsis (blood poisoning), septic shock, acute respiratory distress syndrome in adults, pancreatitis, shock, induced by trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatoid arthritis, atherosclerosis, intracerebral hemorrhage, ischemic stroke (cerebral infarction), heart failure, myocardial infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, myelitis (inflammation of the spinal cord), ankylosing spondylitis (Bechterew's disease-Strumpell-Marie). Reiter syndrome, psoriatic arthritis, spondylitis (inflammation of the intervertebral joints), chronically the arthritis children (of still's disease) or ankylosing spondylitis children, return arthritis, infectious arthritis or arthritis after infection, gonococcal arthritis, syphilitic arthritis, Lyme disease, arthritis, induced "vasculitis syndrome", Nowotny (nodular) polyarteritis disease (Kussmaul), anaphylactic vasculitis, granulomatous Lagreca, the rheumatoid rheumatica, rheumatoid arthritis cells of the joints, arthritis associated with deposition of calcium crystals, pseudogout, not associated with arthritis, rheumatism, bursitis, tendosynovitis, inflammation of namesake (tennis elbow or tennis elbow), carpal tunnel syndrome, a disease with recurring actions (typing on a typewriter), a mixed form of arthritis, the neuropathic arthropathy, hemorrhagic arthritis, purple vessels, the hypertrophic osteoarthropathy, mnogotsentrovye reticulohistiocytosis, arthritis, induced specific diseases, pigmentation blood, sickle cell anemia and other abnormalities of hemoglobin, the hyperlipoproteinemy, dysgammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Bechet disease, systemic autoimmune disease erythematous (SLE), multiple sclerosis and Crohn's disease (gerolimatos) or diseases such as recidivisim polychondritis (syndrome of Meyenburg-Altherr-Olinger), chronic vospitatel the s bowel disease (inflammatory bowel diseases, IBD) or the related diseases which require the mammal a therapeutically effective dose of the compounds of formula (I) in an amount sufficient for inhibition of NADPH oxidase.

The term "disease or liver disorder" includes liver fibrosis, alcoholic liver fibrosis, fatty degeneration of the liver and nonalcoholic steatohepatitis.

The term "arthritis" refers to acute rheumatoid arthritis, chronic rheumatoid arthritis, chlamydial arthritis, chronic absorptive arthritis, heleny (lymph) arthritis, arthritis associated with bowel disease, filariasis arthritis, gonococcal arthritis, gouty arthritis, hemophilic arthritis, hypertrophic arthritis, chronic arthritis in children, arthritis Lyme arthritis newborn foals, Nowotny (nodular) arthritis, agronomically arthritis, psoriatic arthritis or septic arthritis or related diseases, which require the mammal a therapeutically effective dose of the compounds of formula (I) in an amount sufficient for inhibition of NADPH-oxidase.

The term "pain" includes hyperalgesia (increased pain sensitivity) associated with pain and inflammation.

The term "cancer" refers to a carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordomas, angiosarcoma, with Ramu endothelium, lymphangiosarcoma, lymphangiectasia, periosteum (osteofit), mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma colon cancer, pancreatic cancer, breast cancer, ovarian cancer, kidney cancer, carcinoma of prostate, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, carcinoma of the sebaceous glands, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, carcinoma of the kidney cells, hepatocellular carcinoma, cholangiocarcinoma, horiokartsinoma, seminoma, embryonal carcinoma, Wilms ' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, adenocarcinoma lung cancer, bladder cancer or epithelial) or the related diseases which require the mammal a therapeutically effective dose of the compounds of formula (I) in an amount sufficient for inhibition of NADPH oxidase.

The term "disease or disorders of the gastrointestinal tract" includes violations of the gastric mucosa, resulting in ischemic bowel disease, enteritis/colitis, cancer chemotherapy or neutropenia.

The term "angiogenesis" includes the formation of new vessels due to branching, insusceptible (intussusceptive) angiogenesis, vasculogenesis, arteriole the ez and lymphangiogenesis. Angiogenesis is the formation of new blood vessels from preexisting capillaries and post-capillary venules and occurs under pathological conditions, such as different types of cancer, arthritis and inflammation. A large number of tissues or organs, including developing tissue, can support angiogenesis in disease conditions, including skin, muscles, digestive tract, connective tissue, joints, bones, and similar tissue in which blood vessels can penetrate under the influence of angiogenic stimuli. Used here is the term "angiogenesis-dependent condition" is intended to indicate the conditions under which the process of angiogenesis or vasculogenesis supports or enhances a pathological condition. Vasculogenesis is the result of the formation of new blood vessels arising from angioblasts, which are precursors of endothelial cells. Both processes lead to the formation of new blood vessel and into the meaning of the term "angiogenesis-dependent conditions. Similarly, the term "angiogenesis" is used here, the value includes the formation of blood vessels de novo, as is the case with vasculogenesis, and the process of branching and expansion of existing vessels, capillaries and venules.

The term "inhibiting angiogenesis" means, what the connection is effective in reducing the extent the number or the rate of formation of new blood vessels. Reducing the extent, amount or rate of proliferation or migration of endothelial cells into the tissue is a specific example of inhibition of angiogenesis. Inhibiting angiogenesis activity is especially suitable for the treatment of any type of cancer, because it focuses on the process of tumor growth and the lack of formation of new blood vessels in tumor tissue, resulting in tumor tissue does not receive the required nutrients, slows its growth stops further growth regresses and eventually becomes necrotic, resulting in the death of the tumor. In addition, inhibiting angiogenesis activity is especially suitable for the treatment of any type of cancer, because it is particularly effective against the formation of metastases, since their formation also requires masculinely primary tumor to metastatic cancer cells could exist in the primary tumors and their distribution in the secondary plot requires the formation of new blood vessels to support the growth of metastases.

In the value used here, the terms "treating", "treat" and the like generally mean obtaining a desired pharmaceutical or physiological effect. The effect may be prophylactic in terminalprogramme or partial prevention of the disease, symptom and condition in this disease, and/or may be therapeutic in terms of a partial or complete cure of the disease, condition, symptom or undesirable effect associated with the disease.

The term "treatment" used here is the value includes any treatment of a disease in a mammal, particularly human, and includes: (a) preventing the disease in a subject which may be predisposed to this disease, but it had not yet diagnosed; (b) suppression of the disease, that is, stopping the development or relief of disease, i.e. ensuring regression of the disease, and/or its symptoms or conditions.

The term "subject" used here is the value indicates mammals. For example, mammals considered in this invention include humans, primates, domestic animals such as cattle, sheep, pigs, horses and the like.

The term "inhibitor" as used in the context of the present invention, is defined as any molecule that partially or completely inhibits the activity of NADPH-oxidase and/or inhibits or reduces the generation of reactive oxygen species (ROS). Compounds according to the present invention

In one embodiment of the present invention provides pyrazolopyrimidinone proizvoditeli (I):

where G1is selected from H; optionally substituted acyl; optionally substituted acyl-C1-C6-alkyl; optionally substituted alkyl, such as aminocarbonylmethyl (for example, phenylacetamide), optionally substituted C3-C8-cycloalkenyl, optionally substituted geterotsiklicheskikh, optionally substituted arylalkyl, such as optionally substituted phenylalkyl, such as optionally substituted phenylmethyl (for example, phenylmethyl, or 3-methylphenylethyl, or 4-tormentil, or 2-Chlorobenzyl, or 4-Chlorobenzyl, or 4-methylbenzyl, or 4-bromobenzyl); and optionally substituted heteroaromatic, such as optionally substituted pyridinyl, such as pyridine-2-ylmethyl; G2is selected from H; optionally substituted C1-C6-alkyl, such as optionally substituted methyl (e.g., methyl); optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl, or 4-forfinal, or 4-methoxyphenyl, or 4-nitrophenyl, or 2-chlorophenyl, 3-chlorophenyl, or 2-were, or 4-(trifluoromethyl)phenyl, or 4-(triptoreline)phenyl, or 2,5-differenl, or 2,5-dichlorophenyl, or 2-methoxyphenyl, or 4-(Ben is yloxy)phenyl, or 3-benzonitrile, or 3-phenylacetamide, or 2-chloro-4-forfinal, or 3-chloro-4-forfinal, or 3,4-dichlorophenyl, or 2,3-dichlorophenyl, or 2-(benzyloxy)phenyl); optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl, such as optionally substituted benzyl (e.g., benzyl); optionally substituted heteroaryl, such as optionally substituted benzothiazolyl (for example, 1,3-benzothiazol-2-yl), or optionally substituted pyridinyl (e.g. pyridin-2-yl, or 4-methylpiperazin-1-yl)-sulfanilamide-2-yl), or optionally substituted thiazolyl (for example, 4-phenyl-1,3-thiazol-2-yl), or optionally substituted (1,2,4)-triazole(4,3-b)pyridazin-6-yl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl, such as optionally substituted cyclohexyl (e.g., cyclohexyl); optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylchlorosilanes and optionally substituted heteroseksualci-C1-C6-alkyl; G3is selected from H; optionally substituted amino; optionally substituted aminoalkyl, such as benzyl(methyl)aminomethyl; optionally substituted aminocarbonyl; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6-alkyl, such as optionally substituted methoxy-C1-C6-alkyl, such as optionally substituted methoxymethyl (for example, 4-methoxymethyl), optionally substituted, phenoxy-C1-C6-alkyl, such as optionally substituted phenoxyethyl (for example, 3,4-divergence)ethyl) or such as optionally substituted benzoyloxymethyl (for example, 3-methoxybenzyl); optionally substituted acyl; optionally substituted C1-C6-alkyl, such as methyl, ethyl, butyl; optionally substituted C2-C6-alkenyl; optionally substituted C1-C6-quinil; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl, or 3-chlorophenyl, or 4-chlorophenyl, or 2-chlorophenyl, or 3-dimethylaminophenyl, or 3-morpholine-4-ylphenyl, or 2-forfinal); NeoMaster is but substituted C 1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl, such as optionally substituted phenyl-C1-C6-alkyl, such as optionally substituted benzyl (e.g., 3-methoxybenzyl); optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted geterotsiklicheskie, such as optionally substituted piperidine derivatives (for example, methylpiperidin-1-carboxylate); optionally substituted C1-C6-alkyl - C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylchlorosilanes and optionally substituted heteroseksualci - C1-C6-alkyl, such as optionally substituted morpholinyl - C1-C6-alkyl (for example, morpholine-4-ylmethyl); G4is selected from-NR2-C(O)-R1and -(CHR3)m-(CHsub> 2)n-R4; R1is selected from H; optionally substituted amino; -NR5R6; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6-alkyl, such as optionally substituted methoxy (for example, 4-forfinancial); optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6of alkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkylchlorosilanes; and optionally substituted heteroseksualci-C1-C6-alkyl; R2is selected from H; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6 -alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl - C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkylchlorosilanes; optionally substituted heteroseksualci - C1-C6-alkyl; R3is selected from H; halogen; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkylchlorosilanes;. and optionally substituted Goethe is cycloalkyl-C 1-C6-alkyl; R4is selected from H; -C(O)R7;- - ;- CHR8R9and -(CH2)q-E; R5and R6independently from each other selected from H; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl, such as optionally substituted pyridine-C1-C6-alkyl (for example, pyridine-2-ylmethyl); optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8cycloalkyl-C1-C6-alkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkylchlorosilanes; and optionally substituted heteroseksualci-C1-C6-alkyl or-NR5R together form an optionally substituted ring selected from optionally substituted heteroaryl and optionally substituted geterotsiklicheskie, such as optionally substituted morpholinyl (for example, 2-morpholine-4-yl) or the optional somesensitivefile (for example, 4-methylpiperazin-1-yl or 4-benzylpiperazine-1-yl); R7is selected from optionally substituted amino; optionally substituted alkoxy, such as methoxy; optionally substituted aminoalkyl; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted C1-C6-alkenyl; optionally substituted C1-C6-quinil; -NR5R6; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl - C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted geterotsiklicheskie, such as optionally substituted piperazine (e.g., 4-methylpiperazin-1-yl); optionally substituted C1-C6-alkylchlorosilanes; and optionally substituted heteroseksualci-C1-C6-alkyl; R8and R9independently from each other selected from neoba is consequently substituted aryl, such as optionally substituted phenyl (e.g. phenyl); optionally substituted heteroaryl; optionally substituted C3-C8-cycloalkyl, such as optionally substituted cyclohexyl (e.g., cyclohexyl), and optionally substituted geterotsiklicheskie, such as optionally substituted morpholinyl (for example, 2-morpholine-4-yl); R10is selected from H; hydroxyl; optionally substituted amino-C1-C6-alkyl; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl); optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkylchlorosilanes; and optionally substituted heteroseksualci-C1-C6-alkyl; R11and 12independently from each other selected from H; optionally substituted acyl, such as optionally substituted acetyl (e.g., acetyl); optionally substituted C1-C6-alkyl, such as optionally substituted methyl (e.g., methyl or optionally substituted ethyl (e.g., ethyl); and optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkylchlorosilanes; and optionally substituted heteroseksualci-C1-C6-alkyl or-NR11R12together form an optionally substituted ring selected from optionally substituted heteroaryl and optionally substituted, heterotic is valkila, such as optionally substituted morpholinyl (for example, 2-morpholine-4-yl), optionally substituted pyrrolidinyl (for example, 6-pyrrolidin-1-yl), optionally substituted piperazinil (for example, 4-methylpiperazin-1-yl); R13is selected from optionally substituted aryl, such as optionally substituted phenyl (e.g. phenyl); optionally substituted heteroaryl; optionally substituted C3-C8-cycloalkyl and optionally substituted geterotsiklicheskie, such as optionally substituted piperazine (e.g., 4-methylpiperazin) or optionally substituted morpholinyl (for example, 6-morpholine-4-yl); R14, R15and R16independently from each other selected from H and optionally substituted C1-C6-alkyl, such as optionally substituted methyl (e.g., methyl or optionally substituted ethyl (e.g., ethyl); R17is selected from optionally substituted C1-C6-alkyl, such as optionally substituted methyl (e.g., methyl); optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl such as optionally substituted phenyl (for example, 4-forfinal); optionally substituted C1-C6-alkylaryl; optionally substituted aryl - C1-C6-al the sludge; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkylchlorosilanes; and optionally substituted heteroseksualci - C1-C6-alkyl; a is selected from optionally substituted aryl, such as optionally substituted phenyl (e.g. phenyl, methoxyphenyl), and optionally substituted heteroaryl, such as optionally substituted pyridine (e.g. pyridin-2-yl); C is selected from-OR10, -NR11R12and -(CH2)p-R13; E is selected from optionally substituted C3-C8-cycloalkyl, such as optionally substituted cyclohexyl (e.g., cyclohexyl); optionally substituted C2-C6-quinil, such as optionally substituted PROPYNYL (for example, 3-phenylprop-2-in-1-yl); -NR14R15; -(CH2)r-OR15and-NR16C(O)-R17; m, n, p and q are integers selected from 0 to 5; g is an integer number is ω, choose from 3 to 5; G5is selected from H; optionally substituted C1-C6-alkyl; optionally substituted C1-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl - C1-C6-alkyl; optionally substituted C2-C6-alkynylaryl; optionally substituted aryl - C1-C6-alkenyl; optionally substituted C2-C6-alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylchlorosilanes and optionally substituted heteroseksualci - C1-C6-alkyl; as well as its pharmaceutically acceptable salts and pharmaceutically active derivative.

In another embodiment of the feast is iloperidone derivative of the formula (I) is not a

1H-Pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione, 5-(3,3-diphenylpropyl)-4-methyl-2-phenyl-(RN 1010935-27-9).

In another embodiment pyrazolopyrimidinone derivative of the formula (I) is not a

1H-Pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione, 5-(3,3-diphenylpropyl)-4-methyl-2-phenyl-(RN 1010935-27-9) or 1H-Pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione, 5-cyclopropyl-4-methyl-2-(4-nitrophenyl)- (RN 1010882-92-4).

Composition

The present invention provides pharmaceutical and therapeutic agents in the compositions and methods of treatment of the patient, preferably the patient is a mammal, and most preferably the patient is a person who suffers from a medical condition, and in particular, from a disease mediated by NADPH-oxidase, such as a cardiovascular disorder or disease, respiratory disorders or disease, the disease or disorder affecting the metabolism, disorder of the skin, impaired bone, neirolepticalkie violation, neurodegenerative violation, kidney disease, reproductive system disease or disorder affecting the eye and/or the lens, condition, affecting the inner ear, inflammatory disorders or disease, liver disease, pain, cancer, angiogenesis, angiogenesis-dependent condition and/or disease or disorders of the gastrointestinal tract.

Headlight is asepticheskie compositions of the present invention can contain one or more pyrazolopyrimidinone derivative described here in any form. Compositions of the present invention may also include one or more additional pharmaceutically acceptable ingredient(s), such as alum, stabilizers, antimicrobial agents, buffers, colorants, flavorings, excipients and the like.

Compounds of the present invention together with a commonly used adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and dosage forms, and in this form can be used in solid form, such as tablets or filled capsules, or in liquid forms such as solutions, suspensions, emulsions, elixirs, or filled their capsules for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and dosage forms may include ingredients in conventional proportions, with or without adding additional active compounds or components, such dosage forms may contain any suitable effective amount of the active ingredient corresponding to the range used daily dosages. Compositions according to the present invention are preferably compositions for injecti is.

Compositions of the present invention may also be a liquid dosage form, including but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous media, buffers, suspendresume and dispersing agents, colorants, flavorings and the like. The composition can also be prepared in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid dosage forms may contain additives including, but not limited to, suspendresume agents, emulsifying agents, non-aqueous carriers and preservatives. Suspendresume agents include, but are not limited to, orbitology syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel of aluminum stearate and hydrogenomonas dietary fats. Emulsifying agents include, but are not limited to, lecithin, servicemanuals and gum Arabic. Non-aqueous carriers include, but are not limited to, edible oil, almond oil, fractionated coconut oil, oily esters, propylene glycol and ethyl alcohol. Preservatives include, but are not limited to, methyl - or propyl-n-hydroxy who Insaat and sorbic acid. Additional materials, as well as the production methods and the like described in Chapter 5 of the publication Remington's Pharmaceutical Sciences, 21stEdition, 2005, University of the Sciences in Philadelphia, Lippincott Williams & Wilkins, which is included in the present invention by reference.

Solid compositions of the present invention can be in the form of tablets or pellets, prepared in the usual way. For example, tablets and capsules for oral administration may contain conventional excipients, including, but not limited to, binders, fillers, lubricants, dezintegriruetsja and moisturizing agents. Binding agents include, but are not limited to, syrup, gum Arabic, gelatin, sorbitol, tragakant, vegetable starch glue and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar(RAM), microcrystalline cellulose, corn starch, calcium phosphate and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol and silica. Dezintegriruetsja agents include, but are not limited to, potato starch glycolate, sodium starch. Moisturizing agents include, but are not limited to, sodium dodecyl sulfate. The pill can have coatings that are well known in the art.

Compositions for injection are usually prepared nestabilnom solution for injection or phosphate buffer solution, or other injection solutions, which are known in the art.

Compositions of the present invention can also be prepared in the form of suppositories which may contain bases for suppositories, including, but not limited to, cocoa butter or glycerides. Compositions of the present invention can also be prepared for inhalation and to be in shape, including, but not limited to, solution, suspension or emulsion that may be administered in the form of a dry powder or in the form of an aerosol using a compressed fluid, such as DICHLORODIFLUOROMETHANE or Trichlorofluoromethane. Compositions of the present invention can also be prepared in the form of compositions for transdermal administration, including aqueous or nonaqueous carriers, including, but not limited to, creams, ointments, lotions, pastes, medical patch, sticker or membrane.

Compositions of the present invention can also be prepared for parenteral administration, including, but not limited to, by injection or continuous infusion. Compositions for injection may be in the form of suspensions, solutions or emulsions in oily or aqueous carriers can contain additional agents, including, but not limited to, suspendida, stabilizing and dispersing agents. The composition can also p is dostavlyaetsya in powder form to be dissolved in a suitable carrier, including, but not limited to, sterile, free of pyrogens water.

Compositions of the present invention can also be prepared in the form of preparations for deposition (slow release), which can be administered by implantation or by intramuscular injection. Compositions can be prepared with suitable polymeric or hydrophobic materials (in the form of an emulsion in a suitable oil, for example), ion exchange resins, or in the form of poorly soluble derivatives (in the form of a poorly soluble salt, for example).

Compositions of the present invention can also be prepared in the form of liposomal drugs. Compositions in the form of liposomal preparations may include liposomes, which penetrate into cells of interest or through the Horny layer of the skin (stratum corneum) and merge with the cell membrane, ensuring the delivery of the contents of the liposome into the cell. Other suitable compositions may apply neosome. Nozomi are lipid vesicles such as liposomes, membranes, consisting largely of non-ionic lipids, some forms of which are effective for the transport of compounds through the stratum corneum of the skin.

Compounds of the present invention can also be entered in the form for extended release or systems for long-term DOS is where it is refuelled drugs. Description of representative materials for long-term delivery can also be found in the incorporated by reference the source - Remington''s Pharmaceutical Sciences.

Route of administration

Compositions of the present invention can be administered by any method, including, but not limited to, oral, parenteral introduction under the tongue, transdermal, rectal, transmucosal (through the mucous membranes), topical, by inhalation, buccal or intranasal introduction or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, vnutriarterialno, subcutaneous, intramuscular, vnutriobolochechnoe introduction and introduction to the joint. Compositions of the present invention can also be administered in the form of the implant, which allows slow release compositions, as well as in the form of slow, controlled intravenous infusion. In the preferred embodiment pyrazolopyrimidinone derivatives according to the present invention are administered intravenously or subcutaneously.

The present invention is further illustrated by the following Examples, which in no way limit the scope of the present invention.

Injected dose in the form of single or multiple dosages of the individual will vary depending on many factors, including farmacocinetica is the cue properties the condition and patient characteristics (gender, age, body weight, health, size), the severity of symptoms, while the ongoing treatment, frequency of administration and the desired effect.

Combination

According to one embodiment of the present invention the compounds according to the present invention and their pharmaceutical compositions can be administered, either by itself or in combination with additional agent suitable for the treatment of cancer, such as substances used in conventional chemotherapy directed against solid tumors and for monitoring the formation of metastases, or substances used in hormonal therapy, or any other molecule that acts by triggering programmed cell death, for example, the additional agent selected from the category of drugs that stop the synthesis of the building blocks of molecules pre-DNA, such as methotrexate (Abitrexate®), fluorouracil (Adrucil®), hydroxyurea (Hydrea®), and mercaptopurine (Purinethol®), for example, the additional agent selected from the category of drugs that directly destroy the DNA in the cell nucleus, such as cisplatin (Platinol®) and antibiotics daunorubicin (Cerubidine®), doxorubicin (Adriamycin®) and etoposide (VePesid®), for example, the additional agent selected from the category of drugs known to affect the synthesis or decomposition of the mitotic spindle, such as Vinblastine (Velba®), Vincristine (Oncovin®) and Paclitaxel (Taxol®).

According to another embodiment of the present invention, the compounds according to the present invention and their pharmaceutical compositions can be administered in combination with agents that target proteins on the cell surface, such as a gene transport chain cytokine receptor, and can be entered with cytotoxin aimed at the receptor.

According to another embodiment of the present invention, the compounds according to the present invention and their pharmaceutical compositions can be administered in combination with radiation therapy.

The present invention includes the introduction of compounds according to the present invention or its pharmaceutical composition where the compound according to the present invention or pharmaceutical composition is administered to the individual prior to, simultaneously or sequentially in relation to other therapeutic procedures or joint agents suitable for treating various types of cancer (for example, when multiple schemas medication), in therapeutically effective amounts. Compounds according to the present invention or pharmaceutical compositions that are injected simultaneously with the specified joint agents can be administered in the same composition or different compositions, and the same put the m or different routes of administration.

In another specific embodiment, the compounds and methods of the present invention are intended for use in the treatment of various types of cancer, where the introduction of compounds according to the present invention, as a rule, is carried out during or after chemotherapy, hormonal therapy or radiotherapy.

In another specific embodiment, the compounds and methods of the present invention are intended for use in the treatment of various types of cancer, where the introduction of compounds according to the present invention, usually done after a course of chemotherapy, hormonal therapy or radiotherapy in those moments of time when the tumor will respond to toxic attack by inducing angiogenesis to restore supply to tumor tissue with blood and nutrients.

In another embodiment, introduction of the compounds according to the present invention is performed after surgery, during which were removed solid tumors, and is a good prevention against metastasis

Patients

In one embodiment, patients according to the present invention are patients suffering from cardiovascular disorders or diseases.

In another embodiment, patients according to the present invention are patients suffering from respiratory disorders or diseases the project.

In another embodiment, patients according to the present invention are patients suffering from diseases or disorders affecting the metabolism.

In another embodiment, patients according to the present invention are patients suffering from disorders of the skin.

In another embodiment, patients according to the present invention are patients suffering from disorders of the bones.

In another embodiment, patients according to the present invention are patients suffering from neuropsychologia disorders and/or neurodegenerative disorders.

In another embodiment, patients according to the present invention are patients suffering from kidney disease.

In another embodiment, patients according to the present invention are patients suffering from reproductive dysfunction.

In another embodiment, patients according to the present invention are patients suffering from diseases or disorders, striking eyes and/or lens and/or from the state, damaging the inner ear.

In another embodiment, patients according to the present invention are patients suffering from inflammatory disorders or diseases.

In another embodiment, patients according to the present invention are patients suffering from the disease is echani.

In another embodiment, patients according to the present invention are patients suffering from pain, such as pain and inflammation.

In another embodiment, patients according to the present invention are patients suffering from cancer.

In another embodiment, patients according to the present invention are patients suffering from angiogenesis or an angiogenesis-dependent condition.

In another embodiment, patients according to the present invention are patients suffering from allergic disorders.

In another embodiment, patients according to the present invention are patients suffering from injuries.

In another embodiment, patients according to the present invention are patients suffering from septic, hemorrhagic or anaphylactic shock.

In another embodiment, patients according to the present invention are patients suffering from diseases or disorders of the gastrointestinal tract.

The use according to the present invention

In another embodiment of the present invention provides pyrazolopyrimidinone derivative of the formula (I); and its pharmaceutically acceptable salts and pharmaceutically active derivative for use as a medicine.

In an additional embodiment of the present invention p is dostavljaet pyrazolopyrimidine derivative according to the present invention, in which G1represents N.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G1is selected from optionally substituted aryl-C1-C6-alkyl and optionally substituted heteroaryl-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G1represents an optionally substituted C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G1represents an optionally substituted acyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G1represents an optionally substituted acyl-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G2is selected from optionally substituted aryl and optionally substituted heteroaryl.

In another complement enom embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G2represents an optionally substituted C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G2is selected from optionally substituted aryl-C1-C6-alkyl and optionally substituted heteroaryl-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents an optionally substituted C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents optionally substituted amino.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents an optionally substituted aminoalkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents an optionally substituted aminocarbonyl.

In another further the second embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents an optionally substituted acyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents an optionally substituted alkoxy.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents an optionally substituted alkoxy-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents optionally substituted aryl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3represents an optionally substituted heteroaryl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G3is selected from optionally substituted geterotsiklicheskie and C2-C6cycloalkyl.

In another additional embodiment of the present invention provides pyrazole the pyridine derivative according to the present invention, in which G4represents-NR2-C(O)-R1; R1and R2are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G4represents-NR2-C(O)-R1; R1represents an optionally substituted alkoxy-C1-C6-alkyl; R2is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G4represents -(CHR3)m-(CH2)n-R4; R3, R4type are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G4represents -(CHR3)m-(CH2)n-R4; m is 0; n, R3and R4are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G4present is employed, a (CHR 3)m-(CH2)n-R4; n is 1; m, R3and R4are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G4 is a (CHR3)m-(CH2)n-R4; n is 2; m, R3and R4are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G4 is a -(CHR3)m-(CH2)n-R4; n is 3; m, R3and R4are as defined in carrying out the invention.

In an additional embodiment the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G4 is a -(CHR3)m-(CH2)n-R4; R4represents N; m, n and R3are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-C(O)R7; R7is like the Oprah is Elena in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-C(O)R7; R7represents an optionally substituted heteroseksualci.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-C(O)R7; R7represents-NR5R6; R6and R7are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-C(O)R7; R7represents-NR5R6; R5represents H; R6is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-C(O)R7; R7represents-NR5R6; R6is selected from optionally substituted heteroaryl-C1-C6-alkyl and aryl-C1-C6-alkyl; R5is the fast way as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-C(O)R7; R7represents-NR5R6; R5represents H; R6is selected from optionally substituted heteroaryl-C1-C6-alkyl and aryl-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; a and b are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; a represents an optionally substituted aryl; b is as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; a represents an optionally substituted phenyl; b is as defined in carrying out the invention.

In other the Ohm additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R represents-a-b; a represents an optionally substituted heteroaryl;

In is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; a represents an optionally substituted pyridine; is as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; represents-NR11R12; R12and a are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; represents-NR11R12; R" represents H; R12and a are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; represents-NR 11R12; R12represents an optionally substituted acyl; R11and a are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; represents-NR11R12; -NR11R12together form an optionally substituted heteroseksualci; And is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; represents -(CH)p-R13; R13represents an optionally substituted heteroseksualci; a and p are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b; represents -(CH2)p-R13; p is 1; and R13are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidinone PROIZVODSTVENNO the present invention, in which R4represents-a-b; represents -(CH2)p-R13; p is 0; and R13are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R represents-a-b, where a is a-OR10where R10is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b, where a is a-OR10where R10represents a hydroxyl; a is as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-a-b, where a is a-OR10where R10is selected from optionally substituted aryl and optionally substituted heteroaryl; And is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidinone derived according to nastasemarian, in which R4represents-CHR8R9where R8and R9are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-CHR8R9where R8represents optionally substituted aryl; R9is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-CHR R, where R represents optionally substituted phenyl; R9is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents-CHR8R9where R9represents an optionally substituted heteroseksualci; R8is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4pre is is-CHR 8R9where R8represents optionally substituted phenyl; R9represents an optionally substituted heteroseksualci.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E and q are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH1)q-E, where q is 1; E is as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E is an optionally substituted C3-C8-cycloalkyl; q is as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E is an optionally substituted C1-C6-quinil; q t is aetsa such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E represents-NR14R15where R14, R15and q are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E represents-NR14R15where R14and R15represent an optionally substituted C1-C6-alkyl; q is as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E represents -(CH2)r-OR15where R15and r are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E is provided which allows a -(CH 2)r-OR15where R15represents an optionally substituted C1-C6-alkyl; r is as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R represents -(CH2)q-E, where E represents -(CH2)r-OR15where r is 3; R15is the same as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E represents-NR16C(O)-R17where q, R16and R17are as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention, in which R4represents -(CH2)q-E, where E represents-NR16C(O)-R17where R17represents an optionally substituted alkoxy-C1-C6-alkyl; q and R16are as defined in carrying out the invention.

In another additional embodiment of the present invention give the em pyrazolopyrimidine derivative according to the present invention, in which G5represents N.

In another embodiment of the present invention provides the use of pyrazolopyrimidinone derivative of the formula (I), where G1, G2, G3, G4and G5are as defined in carrying out the invention and its pharmaceutically acceptable salts and pharmaceutically active derivative for the manufacture of pharmaceutical compositions for the treatment or prevention of diseases or disorders selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuropeptidergic and/or neurodegenerative disorders, kidney diseases, disorders of the reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic disorders, injuries, septic, hemorrhagic and anaphylactic shock, disorders of the gastrointestinal tract, angiogenesis, angiogenesis-dependent conditions and other diseases and disorders associated with nikotinamidadenindinukleotida (NADPH-oxidase).

In another embodiment of the present invention provides pyrazolopyrimidinone derivative of the formula (I), where G1, G2, G3, G4 and G5are as defined in carrying out the invention and its pharmaceutically acceptable salts and pharmaceutically active derivative, for the treatment or prevention of a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuropeptidergic and/or neurodegenerative disorders, kidney diseases, disorders of the reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, disorders of the gastrointestinal tract, angiogenesis, angiogenesis-dependent conditions and other diseases and disorders associated with nikotinamidadenindinukleotida (NADPH-oxidase).

Compounds of the present invention include in particular those selected from the following groups:

2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-ylbenzyl)-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-{4-[(4-methylpiperazin-1-yl)methyl]benzyl}-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)5-[2-(3-methoxyphenyl)ethyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-[2-(4-hydroxyphenyl)ethyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dione;

5-(3-ethoxypropan)-4-methyl-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-forfinal)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-methyl-5-(3-phenoxybenzyl)-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4,5-dimethyl-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

R-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-2-(4-pertenece)ndimethylacetamide;

2-(2-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-(4-methoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6 (2H,5H)-dione;

5-(3-ethoxypropan)-2-(2-forfinal)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-forfinal)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

3-(4,5-dimethyl-3,6-dioxo-1,3,5,b-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl)benzonitrile;

2-(2-forfinal)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione

2-(3-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[2-(2-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-(2-chlorophenyl)-4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-methyl-5-(3-phenoxybenzyl)-2-[1,2,4]triazole[4,3-B]pyridazin-6-yl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

3-[5-(3-ethoxypropan)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]benzonitrile;

2-[4-(benzyloxy)phenyl]-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4-methyl-5-(3-phenoxybenzyl)-1H-feast of the olo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

3-{4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-3,b-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl}benzonitrile;

2-(2-chlorophenyl)-5-(3-hydroxypropyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-[2-(3-cyanophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-[2-(3-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C] pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-(2-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1-(pyridine-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2,4-dimethyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-[3-(diethylamino)propyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-(cyclohexylmethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-5-(3-hydroxypropyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione

2-(3-chlorophenyl)-4-methyl-5-(3-morpholine-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-(3-fenil the op-2-in-1-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4,5-dimethyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dione;

2-(2-forfinal)-4-methyl-5-(3-morpholine-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-forfinal)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorophenyl)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[2-(benzyloxy)phenyl]-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione;

N-{2-[2-(2,5-dichlorophenyl)-4-methyl-3,b-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}ndimethylacetamide;

2-(2-chloro-4-forfinal)-4-(methoxymethyl)-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3,4-Dichlor the Nile)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2,5-dichlorophenyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-(3-phenylprop-2-in-1-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-{3-[5-(3-ethoxypropan)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]phenyl}ndimethylacetamide;

2-benzyl-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3,4-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-forfinal)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

3-[5-(3,5-dimethoxybenzyl)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C] pyridine-2-yl]benzonitrile;

2-[4-(benzyloxy)phenyl]-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3,4-dichlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

methyl [2-(2,5-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]acetate;

N-{3-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]phenyl}ndimethylacetamide;

2-(2,3-dichlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-{3-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl] phenyl} ndimethylacetamide;

5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(3,4-dichlorophenyl)-4-methyl-1H-pyrazolo [4,3-C]pyridine-3,(2H,5H)-dione;

2,4-dimethyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2,4-dimethyl-5-(3-morpholine-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione; and

N-{3-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo [4,3-C]pyridine-5-yl]phenyl}ndimethylacetamide.

Compounds of the present invention further include, in particular, those which are selected from the following groups:

2-(3-chlorophenyl)-5-(3-ethoxypropan)-4-(3-methoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,4-dimethyl-3,6-dioxo-1,2,3,b-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl)-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-(3-chloro-4-forfinal)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(3-chloro-4-forfinal)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-forfinal)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-chloro-4-forfinal)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,3-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-forfinal)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-(3-{[2-(3-chloro-4-forfinal)-4-methyl-3,6 dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;

5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(3-chloro-4-forfinal)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-(3-{[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;

2-(2-chloro-4-forfinal)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

3-{4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl} benzonitrile;

N-{2-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}-4-perbenzoic;

N-{2-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-l,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}-4-perbenzoic;

2-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

N-(2-{2-[4-(benzyloxy)phenyl]-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl}ethyl)-4-perbenzoic;

2-(3-chloro-4-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-(3-{4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl}phenyl)ndimethylacetamide;

2-(4-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-[4-butyl-2-(3-chloro-4-forfinal)-3,6-dioxo-12,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

2-[2,4-bis(3-chlorophenyl)-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

4-(3-chlorophenyl)-5-(3-ethoxypropan)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C] pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

N-(3-{[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;

2,4-bis(3-chlorophenyl)-5-(3-hydroxypropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-{3-[4-(3-chlorophenyl)-5-(3-hydroxypropyl)-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl] phenyl} ndimethylacetamide;

4-(3-chlorophenyl)-2-methyl-5-[3-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione;

-2-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;

4-(3-chlorophenyl)-2-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-what irazola[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(3-ethoxypropan)-2-methyl-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione;

N-(3-{[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;

4-(4-chlorophenyl)-2-methyl-5-[3-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-{2-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl]ethyl}ndimethylacetamide;

4-(4-chlorophenyl)-5-[3-(dimethylamino)benzyl]-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[(6-pyrrolidin-1-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-(3-ethoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-(2-forfinal)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-[3-(dimethylamino)propyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-PI is azolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-methyl-4-(3-morpholine-4-ylphenyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-[1-(3,4-divergence)ethyl]-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[1-(benzyloxy)ethyl]-2-(2-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione; and

4-[3-(dimethylamino)phenyl]-2-(2-methoxyphenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione.

In another embodiment of the present invention provides an intermediate of formula (VIII):

in which G1, G3, G4and G5are as defined in carrying out the invention; R18represents a C1-C6-alkyl, such as methyl, ethyl, propyl, isopropyl or butyl.

In an additional embodiment the present invention provides an intermediate of formula (VIII), which is selected from the group consisting of:

methyl [(4E)-1-(2-chlorophenyl)-4-(1-{[2-(morpholine-4-ylmethyl)benzyl]amino}ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]acetate; methyl [(4E)-1-(2-chloro-4-forfinal)-4-(2-methoxy-1-{[2-(morpholine-4-ylmethyl)benzyl]amino}ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]acetate.

In another embodiment of the present invention provides an intermediate of formula (X):

in which G2, G3and G5are as defined in carrying out the invention; R18is a Csub> 1-C6-alkyl, such as methyl, ethyl, propyl, isopropyl or butyl.

In an additional embodiment the present invention provides an intermediate of formula (X), which represents methyl [1-(2-chloro-4-forfinal)-5-hydroxy-4-(methoxyacetyl)-1H-pyrazole-3-yl]acetate.

In another embodiment of the present invention provides a method of obtaining the intermediate of formula (VIII), including the stage of reacting the compounds of formula (VII)] with an amine of the formula (II):

where G2, G3, G4, G5are as defined in carrying out the invention. R18and R19represents a C1-C6-alkyl, such as methyl, ethyl, propyl, isopropyl or butyl.

In another embodiment of the present invention provides a method of obtaining the intermediate of formula (X), including the stage of reacting the compounds of formula (IV) with acylchlorides formula (IX):

where G2, G3, G5are as defined in carrying out the invention. R18represents a C1-C6-alkyl, such as methyl, ethyl, propyl, isopropyl or butyl.

In another embodiment of the present invention provides a method for obtaining compounds of formula (I), including phase cyclization of compounds of formula (VIII) in the presence of a base:

where G1represents H; G2, G3, G4and G5are as defined in carrying out the invention; R18represents a C1-C6alkyl, such as methyl, ethyl, propyl, isopropyl or butyl.

In another embodiment of the present invention provides a method of treatment of a patient suffering from a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuropeptidergic and/or neurodegenerative disorders, kidney diseases, disorders of the reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, disorders of the gastrointestinal tract, angiogenesis, angiogenesis-dependent conditions and other diseases and disorders associated with nikotinamidadenindinukleotida (NADPH-oxidase). The method includes the introduction of the compounds of formula (I) to a patient in need.

In another embodiment of the present invention provides a method of inhibiting angiogenesis in a patient who needs it, which includes the introduction is their inhibiting angiogenesis dose of the compounds of formula (I) to a patient, who needs this.

In another embodiment of the present invention provides a method of inhibiting neovascularization of the tumor by inhibiting tumor angiogenesis according to the present methods. Similarly, the present invention provides a method of inhibiting tumor growth by applying the angiogenesis-inhibiting methods.

In a particular embodiment of the compounds and methods of the present invention are intended for use in the treatment of tumor tissue in a patient with a tumor, solid tumor metastasis, cancer, melanoma, skin cancer, breast cancer, a hemangioma or angiofibroma and the like cancer, and inhibition of angiogenesis in tumor tissue, where there is neovascularization of the tumor tissue. Typical fabric with solid tumors that are susceptible to treatment by the compounds and methods of the present invention include, but are not limited to, skin tumors, melanoma, tumors of the lung, pancreas, breast, colon, larynx, ovary, prostate, colorectal tumors, tumors of the head, neck, testicles, lymphoid tissue, bone marrow, bone, sarcoma, tumors of the kidney, sweat glands and other tissues. Other examples of cancers that are subject to treatment are glioblastomas.

In another specific embodiment of the compounds and methods of nastoyascheevremya are intended for use in the treatment of inflamed tissue and angiogenesis for the inhibition of angiogenesis in inflamed tissue, where there is neovascularization of inflamed tissue. In this case, the connection method according to the present invention are intended for inhibiting angiogenesis in an arthritic tissue, such as in a patient with chronic rheumatoid arthritis, inflammatory tissue with immune or non-immune inflammation, tissue, psoriasis, and the like.

In its embodiments the present invention is intended for inhibiting angiogenesis in the tissue. The degree of angiogenesis in the tissue and, thus, the degree of inhibition achieved by the methods of the present invention, can be measured by many methods, such as described here.

In another embodiment of the present invention provides a pharmaceutical composition comprising at least one pyrazolopyrimidinone derivative of the formula (I) and its pharmaceutically acceptable carrier, solvent or excipient.

Compounds of the present invention were named according to IUPAC standards used in the program ACD/Name (product version 10.01).

Compounds according to the present invention include a compound of formula (I), its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as their pharmaceutically acceptable salts. In the present invented and as examples of derivatives can be obtained from readily available starting materials using the following standard methods and procedures. Be aware that where there are common or preferred experimental conditions (i.e., temperature, reaction time, moles of reagents, solvents, and so on) may also be used and other experimental conditions, unless expressly agreed. Optimum reaction conditions may vary in the case of the use of specific reagents or solvents, but such conditions can be determined by a specialist in the art using routine optimization techniques.

In the present invention, references are incorporated by reference in its entirety. The present invention is not limited to the specific embodiments that are described here because they are intended only to illustrate individual aspects of the present invention, therefore, is functionally equivalent methods and components are within the scope of the present invention. Indeed, various modifications of the present invention in addition to those here shown and described will be obvious to those skilled in the art from the following description and the accompanying Figures and Diagrams. Such modifications are within the scope of the attached claims.

The present invention already described, the following Examples are intended to 1 is illustratie and do not limit the scope of the present invention.

The synthesis of compounds of the present invention:

New derivatives of formula (I) can be obtained from readily available {similar materials using conventional techniques and procedures. You must understand that where there are common or preferred experimental conditions (i.e., temperature, reaction time, moles of reagents, solvents, and so on) may also be used and other experimental conditions, unless expressly agreed. Optimum reaction conditions may vary in the case of use of specific reagents or solvents, but such conditions can be determined by a specialist in the art using routine optimization techniques.

The General approach to the synthesis for the preparation of compounds of formula (I) shown in the Diagram below, 1.

Pyrazolopyrimidinone derivatives of the formula (I) in which the substituents G1, G2, G3, G4and G5are as defined above, can be obtained for four or five chemical stages of custom-made or commercially available substituted hydrazine derivatives of the formula (VI), derivatives of aceondeckmusic formula (V), the derivative of a primary amine of the formula (II) and derivatives trialkylamine formula (III) according to the Protocol of the synthesis, as shown in PR is transcribed Scheme 1. In a more specific method hydrazine derivative of the formula (VI), in which G2is the same as defined above, is reacted with a derivative of aceondeckmusic formula (V), where G5and R18are as defined above, in a neutral environment and under reflux in a suitable solvent, such as benzene, toluene or other inert solvents in the course of time, which depends on its own reactivity of compounds of the formula (VI) to obtain the corresponding 4-substituted derivatives of 2-hydroxypyrazolo formula (IV). Intermediate compounds of formula (IV) further react with derivatives trialkylamine formula (III), in which G3and R19are as defined above, in the presence of acetic acid and reflux condenser with the formation of the intermediate of formula (VII). Intermediate compounds of formula (VII) is further processed derivative of a primary amine of the formula (II) where G4 is the same as defined above, in a solvent such as toluene or benzene, and under reflux, to obtain the intermediate compounds of formula (VIII). Derivatives of pyrazole of the formula (Ia), i.e. of formula (I) in which G1represents H, are allocated after cyclization of the intermediate compounds of formula (VIII), preferably in proton solvents in the presence of a base, such ka is methanolate sodium, isopropanolate sodium or the like, using standard conditions with a reflux condenser, a well-known specialists in the art, as shown in figure 1.

This reaction can be carried out in solvents, such as methanol, ethanol, isopropanol, or other inert solvents at room temperature over a period of time, which depends on its own reactivity of compounds of the formula (VIII), but the reaction usually requires heating in a bath or in a microwave oven using standard conditions well known to the person skilled in the technical field, as shown above in Scheme 1. At the next stage pyrazolopyrimidinone derivatives of the formula (Ia) were treated with an alkylating agent such as alkylchloride, bromides, iodides or mesylates, where G1is the same as defined above, in the presence of a suitable base, such as triethylamine, sodium hydride or potassium carbonate as a base in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, using conventional heating or microwave technology. An alternative to this, pyrazolopyrimidinone derivatives of the formula (1A) were treated anhydrides, acylchlorides or carboxylic acids in the presence of binders, where G1is this how op is Adelino above, in the presence of a suitable base, such as triethylamine, sodium acetate in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, dichloromethane using conventional heating or microwave technology. After that pyrazolopyrimidinone derivatives of the formula (Ib) are allocated using standard conditions well known to the person skilled in the technical field, as shown above in Scheme 1.

Pyrazolopyrimidinone derivatives of the formula (I) in which the substituents G1, G2, G3, G4and G5are as defined above, can be obtained for four or five chemical stages of custom-made or commercially available substituted hydrazine derivatives of the formula (VI), derivatives of aceondeckmusic formula (V), the derivative of a primary amine of the formula (II) and derivatives acylchlorides formula (IX) according to the Protocol of the synthesis, as shown in the above Scheme 2. In a more specific method hydrazine derivative of the formula (VI), in which G2is the same as defined above, is reacted with a derivative of aceondeckmusic formula (V), where G5and R18are as defined above, in a neutral environment and under reflux in a suitable solvent, such as benzene, toluene is whether other inert solvents, in the course of time, which depends on its own reactivity of compounds of the formula (VI) to obtain the corresponding 4-substituted derivatives of 2-hydroxypyrazolo formula (IV). Intermediate compounds of formula (IV) further react with derivatives acylchlorides formula (IX), in which G3is the same as defined above, with the formation of the intermediate of formula (X) in the presence of calcium hydroxide and under reflux. Intermediate compounds of formula (X) is processed further derived primary amine of the formula (II), of which €4 is the same as defined above, in a solvent such as toluene or benzene, and under reflux, to obtain the intermediate compounds of formula (VIII). Derivatives of pyrazole of the formula (Ia), i.e. of formula (I) in which G1represents H, are allocated after cyclization of the intermediate compounds of formula (VIII), preferably in proton solvents in the presence of a base, such as methanolate sodium, isopropanolate sodium or the like, using standard conditions and with a reflux condenser, a well-known specialists in the art as shown in Scheme 2.

This reaction can be carried out in solvents, such as methanol, ethanol, isopropanol, or other inert solvents, at room temperature in the course of time, which depends on the own reactivity of compounds of the formula (VIII), but the reaction usually requires traditional methods of heating or using microwave technology, using standard conditions well known to the person skilled in the technical field, as shown above in Scheme 2. At the next stage pyrazolopyrimidinone derivatives of the formula (Ia) were treated with an alkylating agent such as alkylchloride, bromides, iodides or mesylates, where G1is the same as defined above, in the presence of a suitable base, such as triethylamine, sodium hydride or potassium carbonate as a base in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, using conventional heating or microwave technology. An alternative to this, pyrazolopyrimidinone derivatives of the formula (Ia) were treated anhydrides, acylchlorides or carboxylic acids in the presence of binders, where G1is the same as defined above, in the presence of a suitable base, such as triethylamine, sodium acetate in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, dichloromethane using conventional heating or microwave technology. After that pyrazolopyrimidinone derivatives of the formula (Ib) are allocated using standard conditions well known JV is the expert in this field of technology as shown above in Scheme 2.

Pyrazolopyrimidinone derivatives of the formula (I) in which the substituents G1, G2, G3, G4and G5are as defined above, may be obtained for five or six chemical stages of custom-made or commercially available substituted hydrazine derivatives of the formula (VI), derivatives of aceondeckmusic formula (V), the derivative of a primary amine of the formula (II), derived trialkylamine formula (XI) and derived secondary amine of the formula (XV) according to the Protocol of the synthesis, as shown in the above Scheme 3. In a more specific method hydrazine derivative of the formula (VI) where Gz is the same as defined above, is reacted with a derivative of aceondeckmusic formula (V), where G5 and R18are as defined above, in a neutral environment and under reflux in a suitable solvent, such as benzene, toluene or other inert solvents, in the course of time, which depends on its own reactivity of compounds of the formula (VI) to obtain the corresponding 4-substituted derivatives of 2-hydroxypyrazolo formula (IV). Intermediate compounds of formula (IV) further react with a derivative of trialkylamine formula (XI) in which R9is the same as defined above, in the presence of the tvii acetic acid and reflux condenser with obtaining the intermediate of formula (XII). Intermediate compounds of formula (XII) is further processed derivative of a primary amine of the formula (II), in which G4is the same as defined above, in a solvent such as toluene or benzene at room temperature to obtain the intermediate compounds of formula (XIII). Intermediate compounds of formula (XIII) is processed further derived a secondary amine of the formula (XV) in which G3is the same as defined above, in a solvent such as toluene or benzene at room temperature to obtain the intermediate compounds of formula (XIV). Derivatives of pyrazole of the formula (Ia), i.e. of formula (I) in which G1represents H, are allocated after cyclization of the intermediate compounds of formula (XIV), preferably in proton solvents in the presence of a base, such as methanolate sodium, isopropanolate sodium or the like, using standard conditions with reverse outflow, well known to experts in the art, as shown in figure 3.

This reaction can be carried out in solvents, such as methanol, ethanol, isopropanol, or other inert solvents, at room temperature over a period of time, which depends on its own reactivity of compounds of the formula (XIV), but the reaction usually requires traditional methods of heating or IP is the use of microwave equipment, using standard conditions well known to the person skilled in the technical field, as shown above in Scheme 3. At the next stage pyrazolopyrimidinone derivatives of the formula (Ia) were treated with an alkylating agent such as alkylchloride, bromides, iodides or mesylates, where G1is the same as defined above, in the presence of a suitable base, such as triethylamine, sodium hydride or potassium carbonate as a base in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, using conventional heating or microwave technology. An alternative to this, pyrazolopyrimidinone derivatives of the formula (Ia) were treated anhydrides, acylchlorides or carboxylic acids in the presence of binders, where G1is the same as defined above, in the presence of a suitable base, such as triethylamine, sodium acetate in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, dichloromethane using conventional heating or microwave technology.

After that pyrazolopyrimidinone derivatives of the formula (Ib) are allocated using standard conditions well known to the person skilled in the technical field, as shown above in Scheme 3. For the following definitions shall yli used the following abbreviations:

Å (angstroms), Ac2O (Acetic anhydride), EQ. (equivalent), min (minute), h (hour), g (grams), MHz (Megahertz), ml (milliliter), mm (millimeter), mmol (millimoles), mm (millimolar), ng (nanogram), nm (nanometer), rt (room temperature), BLM (Bleomycin), BSA (Bovine serum albumin), DCF (2.7-DICHLORODIFLUOROMETHANE), DCM (dichloromethane), DIPEA (di-isopropylaniline), DMSO (Dimethylsulfoxide), DMF (N,N-Dimethylformamide), DAPI (4,6-Diamidino-2-phenylindol), DPI (Diphenyliodonium), snekh (Cyclohexane), EDTA (ethylenediaminetetraacetic acid), EGF (Epidermal growth factor), EtOAc (ethyl Acetate), FC (Flash chromatography on silica gel), HBSS (Buffer saline Hanks), HPLC (high performance liquid chromatography), H2DCF-DA (2',7'-DICHLORODIFLUOROMETHANE), MEM (2-methoxyethoxymethyl), MS (Macc spectrometry), NADPH (Nicotinamide-dinucleotide, reduced form), NBT (Nicrosini tetrazole), NMR (Nuclear magnetic resonance), PBS (Phosphate buffer solution), PetEther (Petroleum ether), TEA (Triethylamine), TFA (Triperoxonane acid), TGF-β (growth Factor tumors beta), THF (Tetrahydrofuran), tBuOK (Treat-piperonyl potassium), ROS (reactive oxygen species), SOD (superoxide Dismutase), SPA (Scintillation analysis of convergence). TLC (Thin layer chromatography), UV (Ultraviolet light).

If the above set of General methods for the synthesis does not fit the La obtain compounds of formula (I) and/or the necessary intermediates for the synthesis of compounds of formula (I), can be used appropriate methods for their preparation, are known to the person skilled in the art. As a rule, the way of synthesis of any of the individual compounds of formula (I) will depend on the specific substituents in each molecule, and the availability of the necessary intermediates, again, these are well understood by a person skilled average level of skill in the art. To explore all the ways you can protect and unprotect see Philip J. Kocienski, in the book "Protecting Groups", Georg Thieme Verlag Stuttgart, 2005 and Theodora W. Greene and Peter G. M. Wuts in the book "Protective Groups in Organic Synthesis ", Wiley Interscience, 4thEdition, 2006.

Compounds of the present invention can be selected as associates with the molecules of the solvent by crystallization by evaporation of a suitable solvent. Pharmaceutically acceptable acid additive salts of compounds of formula (I) which contain a basic centre can be obtained in the usual way. For example, a solution of the free base may be treated with an appropriate acid, either in pure form or in a suitable solution, and the resulting salt can be isolated either by filtration or by evaporation of the reaction solvent under vacuum. Pharmaceutically acceptable basic additive salts can be obtained in a similar way by treating a solution of the compound forms of the crystals (I) with a suitable base. Both types of salts can be obtained, or converted into each other using the techniques of ion exchange resins.

Hereinafter the present invention will be illustrated with some examples, which should not be construed as limiting the scope of the present invention.

Data HPLC, NMR and MS, are presented in the following Examples were obtained as follows: HPLC: column Waters Symmetry C8 50×4.6 mm, Conditions: MeCN/H2O, from 5 to 100% (8 min) absorption in the region of 230-400 mesh nm; Mass spectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD (ES);1H-NMR: BrukerDPX-300 MHz.

Purification using preparative HPLC was carried out using a HPLC Waters Prep LC 4000 System equipped with columns Prep Nova-Pak®HR 186 μm 60A, 40×30 mm (up to 100 mg) or XTerra®Prep MS C8, 10 μm, 50×300 mm (up to 1 g). All cleaning was carried out with a gradient elution of MeCN/H2O 0,09% TFA; UV registration at 254 nm and 220 nm; flow rate 20 ml/min (up to 50 mg). TLC analysis was performed on plates Merck Precoated 60 F254. Cleaning method flash chromatography was carried out on the substrate SiO2using as eluents mixture cyclohexane/EtOAc or DCM/MeOH.

Example 1: Obtaining 2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-ylbenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (1) (Compound 1A, Scheme 1)

a) methyl [1-(2-chlorophenyl)-5-hydroxy-1H-pyrazole-3-yl] acetate (Compound of formula (IV) Schemes is 1).

To a suspension of 2-chlorophenylhydrazone (1,82 g, 10,16 mmol, 1 equivalent) in anhydrous toluene (50 ml) were added sequentially diisopropylethylamine (2.1 ml, 12,19 mmol, 1.2 equivalent) and dimethyl-3-oxopentanoate (1.77 g, 10,16 mmol, 1 equivalent). The resulting mixture was heated at 130-140°C with use of the Dean-stark (some number of wet toluene was allowed to evaporate). After 2 hours was fully formed gerasoulis intermediate. After this was further added diisopropylethylamine (2.1 ml, 12,19 mmol, 1.2 equivalent) and the resulting mixture was heated at 140°C for 46 hours with use of the Dean-stark. Much of the remainder of the hydrazone can be removed through leaching crude mixture of toluene. The obtained brown oil was purified by flash chromatography on SiO2. Received of 1.65 g of pure methyl[1-(2-chlorophenyl)-5-hydroxy-1H-pyrazole-3-yl] acetate in the form of a solid yellow color. The yield was 61%. MS(ESI+): of 267.8; MS(ESI-): 265,6.

b) methyl[(4E)-1-(2-chlorophenyl)-4-(1-amoxicilian)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl] acetate (Compound of formula (VII), Scheme 1).

The mixture obtained above methyl[1-(2-chlorophenyl)-5-hydroxy-1H-pyrazole-3-yl]acetate (Compound of formula (IV), and 1.00 g), glacial acetic acid (21 μl, 0.1 equivalent), and 1,1,1-triethoxysilane (2.00 ml) was heated at 60°C for the of 1 hour 15 minutes. The obtained red solution was concentrated under vacuum to obtain a red syrup which was washed with cyclohexane and then dried under vacuum. Due to its relative instability, further purification of methyl[(4E)-1-(2-chlorophenyl)-4-(1-amoxicilian)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl] acetate did not (1.26 g, quantitative yield). MS(ESI+): 336,8; MS(ESI+): 334,6.

C) methyl[(4E)-1-(2-chlorophenyl)-4-(1-{[2-(morpholine-4-ylmethyl)benzyl]amino}ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]acetate (Compound of formula (VIII), Scheme 1).

The mixture obtained above methyl[(4E)-1-(2-chlorophenyl)-4-(1-amoxicilian)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]acetate (Compound of formula (VII), 1.26 g) and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine (0,344 mg) were mixed at room temperature in toluene (25 ml) for 0.5 hours. The solvent was removed under vacuum. The precipitate was dissolved in a minimum volume of CH2Cl2and added dropwise to a mixed solution of 200 ml of cyclohexane, resulting in a brown precipitate, which was filtered. It was found that this residue is a pure methyl[(4E)-1-(2-chlorophenyl)-4-(1-{[2-(morpholine-4-ylmethyl)benzyl] amino}-ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl] acetate (1,59 g). The yield was 88%. MS(ESI+): 497,9; MS(ESI-): 495,7.

g) 2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-and is benzyl)-1H-pyrazolo[4,3-C]pyridine -3,6(2H,5H)-dione (Compound of formula (Ia), Scheme 1)

Solution i-PrONa in isopropanol obtained by dissolving sodium (0,082 g of 3.57 mmol, 1 equivalent) in i-D (75 ml) was treated with methyl [(4E)-1-(2-chlorophenyl)-4-(1-{[2-(morpholine-4-ylmethyl)benzyl]amino}ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]-acetate (Compound of formula (VIII) (1,59 g, 3.2 mmol, 1 equivalent). The reaction mixture was maintained under reflux for 1 hour, then cooled and have kind of balanced out to pH 7 by the addition of 0.56 ml of 20% aqueous HCl solution. Under vacuum was removed and 50 ml of i-D and added 25 ml of H2O, after which the flask was placed overnight in a refrigerator. The resulting white precipitate was filtered, washed with water (2×5 ml), then with cyclohexane and dried under vacuum. It was received with 0.93 g of the pure product 2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-ylbenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione. The yield was 80%.1H NMR (500 MHz, CDCl3) to 2.67 (s, 3H), 3.00 for (t, J4,l Hz, 4H), 3,91 (t, J 4,1 Hz, 4H), to 5.56 (s, 2H), 6,24 (s, 1H), 6.89 in (dd, J of 7.6, 0.9 Hz, 1H), 7,06 (td, J of 7.6, 0.9 Hz, 1H), 7,17 (dd, J of 7.6, 0.9 Hz, 1H), 7,29 (td, J of 7.6, 0.9 Hz, 1H), 7,37-7,35 (m, 2H), 7,55 is 7.50 (m, 2H). MS(ESI+): 452,3; MS(ESI-): 450,4.

Example 2: Obtaining 2-(2-chlorophenyl)-4-methyl-5-{4-[(4-methylpiperazin-1-yl)metres}-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (2) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-t is ethoxyethane and 1-{4-[(4-methylpiperazin-1-yl)methyl] phenyl }methanamine, the title compound (2). was allocated in the form of a solid yellow color with 30% yield (purity 97% according to HPLC). MS(ESI-): 479,1; MS(ESI+): 477,2.

Example 3: Obtaining 2-(2-chlorophenyl)-4-methyl-5-(2-Mor(Holin-4-yl-2-phenyl ethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (3) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-morpholine-4-yl-2-fenilalanina, the title compound (3) was isolated in a solid yellow color with a yield of 37% (98% purity according to HPLC). MS(ESI+): 466,5; MS(ESI"): 464,2.

Example 4: Obtaining 2-(2-chlorophenyl)-5-[2-(3-methoxyphenyl)etil-4-methyl-1H-pyrazolo[4,3-Spiridon-3,6(2H,5H)-dione (4) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-(3-methoxyphenyl)ethanamine, the title compound (4) was isolated in a solid yellow color with 38% (98% purity according to HPLC). MS(ESI+): 410,9; MS(ESI-): 408,8.

Example 5: Obtaining 2-(2-chlorophenyl)-5-[2-(4-hydroxyphenyl)ethyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (5) (Compound Ia. Scheme 1)

According to the General methods of synthesis, as is shown in Example 1, based on 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 4-(2-amino-ethyl)phenol, the title compound (5) was isolated in a solid yellow color with a yield of 39% (98% purity according to HPLC). MS(ESI+): 396,5; MS(ESI-):

394,8. Example 6: Obtaining 2-(2-chlorophenyl)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (6) (Compound Ia. Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3,5-acid)methanamine, the title compound (6) was isolated in a solid yellow color with a yield of 34% (purity 97% according to HPLC). MS(ESI+): 426,9; MS(ESI-): 424,8.

Example 7: Obtain 5-(3-ethoxypropan)-4-methyl-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (7) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-hydrazine-4-phenyl-1,3-thiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (7) was isolated in a solid yellow color with a yield of 37% (purity 99% according to HPLC). MS(ESI+): 411,5; MS(ESI-): 409,2.

Example 8: Obtaining 2-(2-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (8) (Compound Ia Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (8) was isolated in a solid white color with a yield of 34% (purity 96% according to HPLC). MS(ESI+): 290,5; MS(ESI-): 288,2.

Example 9: Obtaining 2-(2-forfinal)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (9) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (9) was isolated in a solid yellow color with a yield of 41% (purity 99% according to HPLC). MS(ESI+): 274,8; MS(ESI-): 272,6.

Example 10: Obtain 4-methyl-5-(3-phenoxybenzyl)-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (10) (Compound Ia. Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-hydrazine-4-phenyl-1,3-thiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3-phenoxyphenyl)methanamine, the title compound (10) was isolated in a solid yellow color with a yield of 49% (98% purity according to HPLC). MS(ESI+): 507,7; MS(ESI-): 505,6.

Example 11: Obtain 4,5-dimethyl-2-(4-phenyl-1,3-ti is evil-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (11) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-hydrazine-4-phenyl-1,3-thiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (11) was isolated in a solid yellow color with 38% (purity 97% according to HPLC). MS(ESI+): 339,4; MS(ESI-): 337,8.

Example 12: Obtain 2-(3-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (12) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (12) was isolated in a solid white color with 30% yield (98% purity according to HPLC). MS(ESI+): 290,8; MS(ESI-): 288,7.

Example 13: Obtaining N-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-2-(4-pertenece)ndimethylacetamide (13) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-(4-pertenece)acetohydrazide, the title compound (13) was isolated in a solid yellow color with a yield of 32% (purity 99% according to HPLC). MS(ESI+): 443,8; MS(ESI-):441,7.

Example 14: N the torching of 2-(2-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (14) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3-phenoxyphenyl)methanamine, the title compound (14) was isolated in a solid yellow color with 30% yield (purity 99% according to HPLC). MS(ESI+): are 460.9; MS(ESI-): 458,8.

Example 15: Obtaining 2-(2-chlorophenyl)-5-(4-methoxybenzyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (15) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(4-methoxyphenyl)methanamine, the title compound (15) was isolated in a solid yellow color with 30% yield (purity 99% according to HPLC). MS(ESI+): 396,8; MS(ESI-): 394,7.

Example 16: Obtain 5-(3-ethoxypropan)-2-(2-forfinal)-4-methyl-1H-pyrazolo,3-Spiridon-3,6(2H,5H)-dione (16) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (16) was isolated in a solid white color with a yield of 47% (purity 99% according to HPLC). MS(ESI+): 346,5; MS(ESI-): 344,3.

Note the p 17: Getting 2-(3-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (17) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (17) was isolated in a solid yellow color with a yield of 39% (purity 97% according to HPLC). MS(ESI+): 362,8; MS(ESI-): 360,9.

Example 18; Obtaining 2-(3-chlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo,3-Spiridon-3,6(2H,5H)-dione (18) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (18) was isolated in a solid yellow color with a yield of 33% (purity 97% according to HPLC). MS(ESI+): 466,6; MS(ESI-): 464,6.

Example 19: Obtaining 2-(2-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (19) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (19) was isolated in a solid yellow color with a yield of 33% (purity 97% according to ASH). MS(ESI+): 449,5; MS(ESI-): 447,7.

Example 20: Obtaining 2-(2-forfinal)-4-methyl-5-1(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (20) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(6-morpholine-4-espiridion-2-yl)methanamine, the title compound (20) was isolated in a solid yellow color with a yield of 37% (purity 95% according to HPLC). MS(ESI+): 436,5; MS(ESI-): 434,6.

Example 21: Getting 2-(2-4)terphenyl)-4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (21) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[4-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (21) was isolated in a solid yellow color with a yield of 28% (purity 97% according to HPLC), MS(ESI+): 449.6 M.; MS(ESI-): 447,5.

Example 22: Obtain 2-(3-chlorophenyl)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (22) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-ox is pentanoate, 1,1,1-triethoxysilane, and 1-(6-morpholine-4-espiridion-2-yl)methanamine, the title compound (22) was isolated in a solid yellow color with a yield of 47% (98% purity according to HPLC). MS(ESI+): 452,9; MS(ESI-): 450,8.

Example 23: Obtain 3-(4,5-dimethyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl)benzonitrile (23) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-hydrazinobenzothiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (23) was isolated in a solid yellow color with a yield of 54% (purity 99% according to HPLC). MS(ESI+): 281,4; MS(ESI-): 279,2.

Example 24: Obtaining 2-(2-forfinal)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (24) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3-phenoxyphenyl)methanamine, the title compound (24) was isolated in a solid yellow color with a yield of 59% (purity 99% according to HPLC). MS(ESI+): 442,5; MS(ESI-): 440,2.

Example 25: Obtain 2-(3-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (25) (Compound Ia. Scheme 1)

With the according to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3-phenoxyphenyl)methanamine, the title compound (25) was isolated in a solid yellow color with a yield of 52% (purity 97% according to HPLC). MS(ESI+): 458,7; MS(ESI-): 456,5.

Example 26; Obtaining 2-(2-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (26) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (26) was isolated in a solid yellow color with a yield of 45% (purity 96% according to HPLC). MS(ESI+): 362,4; MS(ESI-): 360,4.

Example 27: Obtaining 2-(2-chlorophenyl)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (27) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(6-morpholine-4-espiridion-2-yl)methanamine, the title compound (27) was isolated in a solid yellow color with a yield of 40% (purity 96% according to HPLC). MS(ESI+): 452,3; MS(ESI-): 451,4.

Example 28: Obtaining 2-(3-chlorophenyl)-4-methyl-5-[4-(4-metile the Razin-1-yl)-4-oxobutyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (28) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 4-(4-methylpiperazin-1-yl)-4-oxobutyl-1-amine, the title compound (28) was isolated in a solid yellow color with a yield of 50% (purity 95% according to HPLC). MS(ESI+): 444,8; MS(ESI-): 441,7.

Example 29: Obtain 2-(3-chlorophenyl)-4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (29) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[4-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (29) was isolated in a solid yellow color with a yield of 56% (purity 99% according to HPLC). MS(ESI+): 466,8; MS(ESI-): 464,6.

Example 30: Obtain 2-[2-(2-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl-1H-(pyridine-2-ylmethyl)ndimethylacetamide (30) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(pyridine-2-ylmethyl)glycinamide, the title compound (30) was isolated in a solid yellow color with what hodom 43% (purity 97% according to HPLC). MS(ESI+): 408,4; MS(ESI-): is 406.5.

Example 31: Obtaining 2-(2-chlorophenyl)-4-methyl-5-[4-(morpholine-4-ylmethyl) benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (31) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[4-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (31) was isolated in a solid yellow color with a yield of 23% (purity 97% according to HPLC). MS(ESI+): 466,0; MS(ESI-): 464,1.

Example 32: Obtaining 2-(2-chlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (32) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (32) was isolated in a solid yellow color with a yield of 56% (98% purity according to HPLC). MS(ESI+): 465,2; MS(ESI-): 463.0.

Example 33: Obtain 4-methyl-5-(3-phenoxybenzyl)-2-[1,2,4]triazole[4,3-c]pyridazin-6-yl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (4) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 6-hydrazine[1,2,4]triazole[4,3-b]pyridazine, imethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3-phenoxyphenyl)methanamine, the title compound (33) was isolated in a solid yellow color with a yield of 45% (98% purity according to HPLC). MS(ESI+): 466,4; MS(ESI-): rub464.3.

Example 34: 3-[5-(3-ethoxypropan)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-ilmenorutile (34) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-hydrazinobenzothiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (34) was isolated in a solid yellow color with a yield of 37% (purity 97% according to HPLC). MS(ESI+): 353,4; MS(ESI-): 351,2.

Example 35: Obtain 2-[4-(benzyloxy)phenyl-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (35) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from [4-(benzyloxy)phenyl]hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (35) was isolated in a solid yellow color with a yield of 32% (purity 99% according to HPLC). MS(ESI+): 362,4; MS(ESI-): 360,3. Example 36: Obtain 2-[4-(benzyloxy)phenyl-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (36) (Compound la, Scheme 1)

the according to the General methods of synthesis, as shown in Example 1, from [4-(benzyloxy)phenyl]hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3-phenoxyphenyl)methanamine, the title compound (36) was isolated in a solid yellow color with a yield of 40% (purity 97% according to HPLC). MS(ESI+): 530,6; MS(ESP-): consists 528.3.

Example 37: Obtain 2-[4-(benzyloxy)phenyl]-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (37) (Compound Ia. Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from [4-(benzyloxy)phenyl]hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (37) was isolated in a solid yellow color with a yield of 34% (purity 95% according to HPLC). MS(ESI+): 434,5; MS(ESI-): 432,6.

Example 38: Obtain 3-{4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-yl}benzonitrile (38) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-hydrazinobenzothiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[4-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (38) was isolated in a solid yellow color with a yield of 36% (purity 96% according to HPLC). MS(ESF+): 456,3; MS(ESI-): 454,8.

Example 39: the Floor is an increase of 2-(2-chlorophenyl)-5-(3-hydroxypropyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (39) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-aminopropan-1-ol, the title compound (39) was allocated in the form of a solid yellow color with 30% yield (purity 97% according to HPLC). MS(ESI+): 334,3; MS(ESI-): 332,3.

Example 40: Obtain 2-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide (40) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(pyridine-2-ylmethyl)glycinamide, the title compound (40) was isolated in a solid yellow color with a yield of 27% (98% purity according to HPLC). MS(ESI+): 424,7; MS(ESI-): 422,5.

Example 41: Obtain 2-[2-(3-cyanophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide (41) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-hydrazinobenzothiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(pyridine-2-ylmethyl)glycinamide, the title compound (41) was isolated in a solid yellow color with exit 37% purity 99% according to HPLC). MS(ESI+): 415,8; MS(ESI-): 413,7.

Example 42: Obtain 2-[2-(3-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide (42) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(pyridine-2-ylmethyl)glycinamide, the title compound (42) was isolated in a solid yellow color with a yield of 42% (purity 99% according to HPLC). MS(ESI+): 424,7; MS(ESI-): to 422.8.

Example 43: Obtaining 2-(2-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1-(pyridine-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (43) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, by alkylation with 2-(chloromethyl)pyridine (1 equivalent) of the corresponding intermediate compounds of formula (Ia) (1 equivalent) in the presence of triethylamine (1.5 equivalents) in tetrahydrofuran under reflux, the title compound (43) was isolated in a solid yellow color with a yield of 45% (purity 97% according to HPLC). MS(ESI+):.453,8; MS(ESI-): 451,8.

Example 44: Obtaining 2,4-dimethyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]feast the Dean-3,6(2H,5H)-dione (44) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3-phenoxyphenyl)methanamine, the title compound (44) was isolated in a solid yellow color with a yield of 45% (purity 97% according to HPLC). MS(ESI+): 362,8; MS(ESI-): 360,6.

Example 45: Obtaining 2-(2-chlorophenyl)-5-[3-(diethylamino)propyl]-4-methyl-1H-pyrazolo[4.3-C]pyridine-3,6(2H,5H)-dione (45) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N,N-diethylpropane-1,3-diamine, the title compound (45) was isolated in a solid yellow color with a yield of 50% (98% purity according to HPLC). MS(ESI+): 389,8; MS(ESI-): 387,7.

Example 46: Obtaining 2-(2-chlorophenyl)-5-(cyclohexylmethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (46) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1 cyclohexylethylamine, the title compound (46) was isolated in a solid yellow color in 51% yield (purity 99% according to HPLC). MS(ESI+): 372,8; MS(ESI-): 370,9.

the example 47: Obtain 2-(3-chlorophenyl)-5-(3-hydroxypropyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (47) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-aminopropan-1-ol, the title compound (47) was isolated in a solid yellow color with a yield of 28% (98% purity according to HPLC). MS(ESI+): 334,9; MS(ESI-): to 332.8.

Example 48: Obtaining 2-(2-chlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (48) (Compound Ia. Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 4-(4-methylpiperazin-1-yl)-4-oxobutyl-1-amine, the title compound (48) was allocated in the form of a solid yellow color with 30% yield (98% purity according to HPLC). MS(ESI+): 444,8; MS(ESF-): 442,7.

Example 49: Obtaining 2-(2-chlorophenyl)-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (49) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxypropane and 1-(3-phenoxyphenyl)methanamine, the title compound (49) was allocated in the form of a solid yellow color with a yield of 33% (98% purity according to HPLC). MS(ESI+): 444,6; S(ESI -): TP 442.6.

Example 50; Obtaining 2-(3-chlorophenyl)-4-methyl-5-(3-morpholine-4-yl-3-phenyl propyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (50) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-morpholine-4-yl-3-phenylpropane-1-amine, the title compound (50) was isolated in a solid yellow color with a yield of 57% (purity 97% according to HPLC). MS(ESI+): 480,8; MS(ESF-): 478,6.

Example 51: Obtain 2-(3-chlorophenyl)-4-methyl-5-(3-phenylprop-2-in-1-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (51) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-phenylprop-2-in-1-amine, the title compound (51) was isolated in a solid yellow color with a yield of 24% (purity 96% according to HPLC). MS(ESI+): 390,8; MS(ESI-): 388,6.

Example 52: Obtaining 2-(2-chloro-4-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (52) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from (2-chloro-4-forfinal)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(Moholy the-4-ylmethyl)phenyl]methanamine, the title compound (52) was allocated in the form of a solid yellow color with a yield of 23% (98% purity according to HPLC). MS(ESI+): 483,8; MS(ESI-): 481,9.

Example 53: Obtain 2-(3-chlorophenyl)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (53) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3,5-acid)methanamine, the title compound (53) was isolated in a solid yellow color with a yield of 41% (purity 97% according to HPLC). MS(ESI+): 426,7; MS(ESI-): 424,9.

Example 54: Obtaining 4,5-dimethyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl}-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (54) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 1-[(6-hydrazinopyridazine-3-yl)sulfonyl]-4-methylpiperazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (54) was allocated in the form of a solid yellow color with a yield of 43% (purity 97% according to HPLC). MS(ESI+): 419,7; MS(ESI-): 417,8.

Example 55: Obtaining 2-(2-forfinal)-4-methyl-5-(3-morpholine-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (55) (Compound Ia, Scheme 1)

p> According to the General methods of synthesis, as shown in Example 1 from 2-forfamilies, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-morpholine-4-yl-3-phenylpropane-1-amine, the title compound (55) was allocated in the form of a solid yellow color with a yield of 34% (purity 99% according to HPLC). MS(ESF+): 463,6; MS(ESI-): 461,5.

Example 56: Obtaining 2-(2-chloro-4-forfinal)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (56)(Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from (2-chloro-4-forfinal)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3,5-acid)methanamine, the title compound (56)was allocated in the form of a solid yellow color with 30% yield (purity 97% according to HPLC). MS(ESI+): 444,8; MS(ESI-): byr442.9.

Example 57: Obtain 2-(2,5-dichlorophenyl)-5-(3,5-dimethoxybenzyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (57) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,5-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3,5-acid)methanamine, the title compound (57) was allocated in the form of a solid yellow color with a yield of 50% (purity 97% according to HPLC). MS(ESI+): 461,3; MS(ESF-): 459,2.

P the emer 58: Obtain 2-(2,5-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (58) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,5-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (58) was allocated in the form of a solid yellow color with a yield of 33% (purity 99% according to HPLC). MS(ESI+): 500,1; MS(ESI-): 498,4.

Example 59: Obtain 2-[2-(benzyloxy)phenyl-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (59) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-morpholine-4-yl-2-oxetanone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (59) was allocated in the form of a solid yellow color with a yield of 45% (purity 99% according to HPLC). MS(ESI+): 434,5; MS(ESI-): 432,4.

Example 60: Obtain 2-(2,5-dichlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (60) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,5-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-morpholine-4-yl-2-oxetanone, the title compound (60) was allocated in the form of a solid yellow color with a yield of 36% (purity 98% according to the on HPLC). MS(ESI+): 438,2; MS(ESI-): km 436.0.

Example 61: Obtaining N-{2-[2-(2,5-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl} ndimethylacetamide (61) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,5-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(2-amino-ethyl)ndimethylacetamide, the title compound (61) was isolated in a solid yellow color with a yield of 39% (98% purity according to HPLC). MS(ESI+): 396,2; MS(ESI-): 394,4.

Example 62: Obtaining 2-(2-chloro-4-forfinal)-4-(methoxymethyl)-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (62) (Compound Ia, Scheme 2)

a) methyl [1-(2-chloro-4-forfinal)-5-hydroxy-1H-pyrazole-3-yl]acetate (Compound of formula (IV), Scheme 2)

To a suspension of (2-chloro-4-forfinal)hydrazine (1,82 g, 1 equivalent) in anhydrous toluene (50 ml) were added sequentially diisopropylethylamine (1.2 equivalent) and dimethyl-3-oxopentanoate (1 equivalent). The resulting mixture was heated at 130-140°C with use of the Dean-stark (some number of wet toluene was allowed to evaporate). After 2 hours was fully formed gerasoulis intermediate. After this was further added diisopropylethylamine (1,2 ek is ivalent) and the resulting mixture was heated at 140°C for 46 hours with use of the Dean-stark. Much of the remainder of the hydrazone can be removed by washing the crude mixture of toluene. The obtained brown oil was purified by flash chromatography on SiO2. Was obtained 1.85 g of pure methyl[1-(2-chloro-4-forfinal)-5-hydroxy-1H-pyrazole-3-yl]acetate in the form of a solid yellow color. The yield was 62%. MS(ESI+): 285,7; MS(ESI-): 283,6. b) methyl[1-(2-chloro-4-forfinal)-5-hydroxy-4-(methoxyacetyl)-1H-pyrazole-3-yl]acetate (Compound of formula (X), Scheme 2)

The mixture obtained above methyl[1-(2-chloro-4-forfinal)-5-hydroxy-1H-pyrazole-3-yl]acetate (Compound of formula (IV), 0,600 g, 2,11 mmol, 1 equivalent) was suspended in dioxane (10 ml) and CA(Oh)2(0,313 g, 4,22 mmol, 2 equivalent) and methoxyacetanilide (0,229 g, 2,11 mmol, Equivalent) under nitrogen atmosphere and was heated at 70°C for 45-60 minutes. The resulting solution was concentrated under vacuum and the residue was distributed between dichloromethane (50 ml) and a mixture of brine (10 ml) and 2N hydrochloric acid (1 ml, 2.00 mmol). Was collected phase dichloromethane. The aqueous phase was Proektirovanie additional dichloromethane (50 ml) and then ethyl acetate (50 ml). The combined organic phase was dried over Na2SO4and the solvent evaporated to obtain methyl[1-(2-chloro-4-forfinal)-5-hydroxy-4-(methoxyacetyl is)-1H-pyrazole-3-yl]acetate in the form of a solid beige color (550 mg, 1.55 mmol, yield 74%, purity 92% according to HPLC), which can be used in the next stage without further purification. MS(ESI+): 357,7; MS(ESI-): 355,8.

C) methyl [(4E)-1-(2-chloro-4-forfinal)-4-(2-methoxy-1-{[2-(morpholine-4-ylmethyl)benzyl]amino}ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]acetate

(Compound of formula (VIII), Scheme 2)

The mixture obtained above methyl[1-(2-chloro-4-forfinal)-5-hydroxy-4-(methoxyacetyl)-1H-pyrazole-3-yl] acetate (Compound of formula (X), 400 mg, 1.12 mmol, 1 equivalent) and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine (347 mg, 1,68 mmol, 1.5 equivalents) in acetonitrile and acetic acid (101 mg, 1,68 mmol, *1.5 equivalent) stirred at room temperature in a nitrogen atmosphere in a mixture of toluene/DFID(10/1) or acetonitrile (3 ml). The reaction mixture was heated to 70°C. and the reaction course was monitored by HPLC. After 1 hour the reaction mixture was attended by mostly original material, so it added more acetic acid (0.5 equivalent), and then 30 minutes later was even added acetic acid (0.5 equivalent). After another 30 minutes was added to 0.5 equivalent of 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine. The reaction mixture is stirred for an additional 30 minutes, after which the reaction was stopped, despite the fact that not all starting material was consumed. Solvent is was evaporated and the residue was dissolved in ethyl acetate (containing 0.1% of triethylamine) and passed through compacted silica gel (diameter 6 cm, thickness 2 cm) by elution with 250 ml of the same solvent. Evaporation of the solvent there was obtained pure methyl[(4E)-1-(2-chloro-4-forfinal)-4-(2-methoxy-1-{[2-(morpholine-4-ylmethyl) benzyl]amino}ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]acetate (149 mg, quantitative yield) that was used in the next stage without additional purification. MS(ESI+): 546,3; MS(ESI-): 544,5.

g) 2-(2-chloro-4-forfinal)-4-(methoxymethyl)-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (Compound of formula (Ia), Scheme 2)

To methyl [(4E)-1-(2-chloro-4-forfinal)-4-(2-methoxy-1-{[2-(morpholine-4-ylmethyl)-benzyl]amino}ethylidene)-5-oxo-4,5-dihydro-1H-pyrazole-3-yl]acetate (Compound of formula (VIII) (215 mg, 0.40 mmol, 1 equivalent) dissolved in Meon (2 ml), was added a solution of sodium methoxide (0,29 N, of 1.36 ml, 0.40 mmol, 1 equivalent) [obtained by dissolving sodium (100 mg) in Meon (15 ml)]. The solution was mixed at room temperature until almost complete disappearance of the original enamine (t=20 min). The reaction was stopped by adding 0.1 M HCl to pH 6, and then the mixture was concentrated under vacuum. The compound was purified by chromatography on silica gel (diameter 2.2 cm, height 10 cm) with elution by ethyl acetate (containing 0.1% triethylamine) to give the pure product 5-benzyl-2-(2-chlorophenyl)-4-(3-methoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione in the form of solid substances is yellow (56 mg, the purity of 92% according to HPLC, the output of the two stage amounted to 10%).

1NAMR (500 MHz, DMSO-d6): 2,33-2,39 (m, 4H); up 3.22 (s, 3H); 3,53-3,62 (m, 6H); 4,88 (bs, 1H); of 4.77 (bs, 1H); 6,41 (s, 1H);? 7.04 baby mortality-was 7.08 (m. 1H); to 7.15 (t, 1H, 1=7.5 Hz); 7.18 in-7,34 (m, 5H); 7,41 (bs, 1H). MS(ESr+): 514,5; MS(ESF-): 512,4.

Example 63: Obtaining 2-(2-chlorophenyl)-5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (63) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N,N-dimethylated-1,2-diamine, the title compound (63) was allocated in the form of a solid yellow color with a yield of 20% (purity 99% according to HPLC). MS(ESI+): 347,8; MS(ESI-): 345,6.

Example 64: Obtain 2-[4-(benzyloxy)phenyl]-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (64) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from [4-(benzyloxy)phenyl]hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (64) was allocated in the form of a solid yellow color with a yield of 41% (purity 99% according to HPLC). MS(ESI+): 537,6; MS(ESI-): 535,6.

Example 65: Obtain 2-(3-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,(2H,5H)-dione (65) (Compound Ia. Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 3-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(4-methylpiperazin-1-yl)phenyl]methanamine, the title compound (65) was allocated in the form of a solid white color with a yield of 46% (purity 97% according to HPLC). MS(ESI+): 465,2; MS(ESI-): 463,4.

Example 66: Obtain 2-(3,4-dichlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (66) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (3,4 - dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 4-(4-methylpiperazin-1-yl)-4-oxobutyl-1-amine, the title compound (66) was allocated in the form of a solid yellow color with a yield of 40% (98% purity according to HPLC). MS(ESI+): 479,4; MS(ESI-).477,6.

Example 67: Obtain 5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2,5-dichlorophenyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (67) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,5-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-(4-benzylpiperazine-1-yl)-2-oxetanone, the title compound (67) was allocated in the form of solid substances is TBA yellow with 29% (purity 99% according to HPLC). MS(ESI+): 527,8; MS(ESI-): 525,6.

Example 68: Obtaining 2-(2-chlorophenyl)-4-methyl-5-(3-phenylprop-2-in-1-yl)-1H-pyrazolo,3-Spiridon-3,6(2H,5H)-dione (68) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from 2-chlorophenylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-phenylprop-2-in-1-amine, the title compound (68) was allocated in the form of a solid yellow color with a yield of 50% (purity 97% according to HPLC). MS(ESI+): 390,8; MS(ESI-): 389,7.

Example 69: Obtaining N-{3-[5-(3-ethoxypropan)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]phenyl}ndimethylacetamide (69) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from N-(3-hydrazinophenyl)ndimethylacetamide, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-ethoxypropan-1-amine, the title compound (69) was allocated in the form of a solid yellow color with a yield of 39% (purity 99% according to HPLC). MS(ESI+): 385,7; MS(ESI-): 383,6.

Example 70: Getting 2-benzyl-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-Spiridon-3,6(2H,5H)-dione (70) (Compound Ia. Scheme 1)

According to the General methods of synthesis, as shown in Example 1, based on benzoylhydrazone, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpho is in 4-ylmethyl)phenyl]methanamine, the title compound (70) was allocated in the form of a solid yellow color with a yield of 45% (purity 99% according to HPLC). MS(ESI+): 445,3; MS(ESI-): 443,2.

Example 71: Obtain 2-(3,4-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (71) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (3,4-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (71) was allocated in the form of a solid yellow color with a yield of 39% (purity 97% according to HPLC). MS(ESI+): 500,4; MS(ESI-): 498,2.

Example 72: Obtaining 2-(2-chloro-4-fluoro(Genil)-4,5-dimethyl-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (72) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from (2-chloro-4-forfinal)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (72) was allocated in the form of a solid yellow color with 38% (purity 97% according to HPLC). MS(ESI+): 308,7; MS(ESI-): 306,6.

Example 73: Obtain 3-[5-(3,5-dimethoxybenzyl)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]benzonitrile (73) (Compound Ia, Scheme 1)

According to General m the methods of synthesis, as shown in Example 1 from 3-hydrazinobenzothiazole, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-(3,5-acid)methanamine, the title compound (73) was allocated in the form of a solid yellow color with a yield of 26% (98% purity according to HPLC). MS(ESI+): 417,4; MS(ESI-): 415,0.

Example 74: Obtain 2-[4-(benzyloxy)phenyl]-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (74) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from [4-(benzyloxy)phenyl]hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-morpholine-4-yl-2-oxetanone, the title compound (74) was allocated in the form of a solid yellow color with a yield of 33% (purity 97% according to HPLC). MS(ESI+): 475,5; MS(ESI-): to 473.6.

Example 75: Obtain 2-(3,4-dichlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (75) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (3,4-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-morpholine-4-yl-2-oxetanone, the title compound (75) was allocated in the form of a solid yellow color with a yield of 34% (purity 97% according to HPLC). M8(ESI+): 438,3; MS(ESI-): 436,3.

Example 76: Receiving m is Teal [2-(2,5-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo [4,3-C]pyridine-5-yl]acetate (76) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,5-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylglycine, the title compound (76) was allocated in the form of a solid yellow color with 30% yield (purity 99% according to HPLC). MS(ESI+): 383,4; MS(ESI-): 381,3.

Example 77: Obtaining N-{3-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl]phenyl}ndimethylacetamide (77) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,3-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(3-AMINOPHENYL)ndimethylacetamide, the title compound (77) was allocated in the form of a solid yellow color with a yield of 24% (purity 97% according to HPLC). MS(ESI+): 444,3; MS(ESI-): 442,3.

Example 78: Obtain 2-(2,3-dichlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (78) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (2,3-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 4-(4-methylpiperazin-1-yl)-4-oxobutyl-1-amine, the title compound (78) was allocated in the form of a solid yellow color with a yield of 41% (pure the and 97% according to HPLC). MS(ESI+): 479,5; MS(ESI-): 477,4.

Example 79: Obtaining N - {3-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]phenyl}ndimethylacetamide (79) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (3-chloro-4-forfinal)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(3-AMINOPHENYL)ndimethylacetamide, the title compound (79) was allocated in the form of a solid white color with a yield of 34% (98% purity according to HPLC). MS(ESI+): 427,8; MS(ESI-): 425,6.

Example 80: Obtain 5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(3,4-dichlorophenyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (80) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, from (3,4-dichlorophenyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-(4-benzylpiperazine-1-yl)-2-oxetanone, the title compound (80) was allocated in the form of a solid yellow color with a yield of 35% (purity 99% according to HPLC). MS(ESI+): 527,6; MS(ESI-): 525,5.

Example 81: Obtaining 2,4-dimethyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (81) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, based on methylhydrazine, dimethyl-3-oxopent is indioate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (81) was allocated in the form of a solid yellow color with a yield of 39% (98% purity according to HPLC). MS(ESI+): 369,7; MS(ESI-): 367,5.

Example 82: Obtaining 2,4-dimethyl-5-(3-morpholine-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (82) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-morpholine-4-yl-3-phenylpropane-1-amine, the title compound (82) was allocated in the form of a solid yellow color with a yield of 45% (purity 99% according to HPLC). MS(ESI+): 383,5; MS(ESI-): 381,4.

Example 83: Obtaining N-{3-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazole[4,3-c]pyridine-5-yl]phenyl}ndimethylacetamide (83) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1 from (2-chloro-4-forfinal)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and N-(3-AMINOPHENYL)ndimethylacetamide, the title compound (83) was allocated in the form of a solid white color with 38% (purity 96% according to HPLC). MS(ESI+): 427,9; MS(ESI-): 425,8.

The structure of the other synthesized in the present invention compounds are presented below in Table 1:

Table 1
ConnectionStructureNameDataMethod
842-(3-chlorophenyl)-5-(3-ethoxypropan)-4-(3-methoxy benzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):469,1Example 62, Scheme 2
852-(2,4-dimethyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl)-N-(pyridine-2-ylmethyl)ndimethylacetamideMS(ESI+):328,5Example 1, Scheme 1

ConnectionStructureNameDataMethod
862-(3-chloro-4-forfinal)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):421,8 Example 1, Scheme 1
872-(3-chloro-4-forfinal)-4-methyl-5-[4-(4-methyl-piperazine-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):462,9Example 1, Scheme 1
882-(2-chloro-4-forfinal)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):421,9Example 1, Scheme 1
895-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-chloro-4-forfinal)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):511,0Primer, Scheme 1
902-[4-(benzyloxy)phenyl]-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):byr516.7Example 1, Scheme 1
912-(2,3-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+):501,6Example 1, Scheme 1
922-(2-chloro-4-forfinal)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):483,2Example 1, Scheme 1
93N-(3-{[2-(3-chloro-4-fluoro phenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo [4,3-C]pyridine-5-yl]methyl}phenyl)-ndimethylacetamideMS(ESI+):441,9Example 1, Scheme 1

ConnectionStructureNameDataMethod
945-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(3-chloro-4-forfinal)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):511,2Example 1, Scheme 1
95 N-(3-{[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)-ndimethylacetamideMS(ESI+):442,0Example 1, Scheme 1
962-(2-chloro-4-forfinal)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 462,9Primer, Scheme 1
973-{4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl}benzonitrileMS(ESI+):456,5Example 1, Scheme 1
98N-{2-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}-4-perbenzoicMS(ESI+):459,9Example 1, Scheme 1
99N-{2-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}-4-perbenzoic MS(ESI+): 459,9Primer, Scheme 1
1002-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamideMS(ESI+):442,7Example 1, Scheme 1

ConnectionStructureNameDataMethod
101N-(2-{2-[4-(benzyloxy) phenyl]-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl}ethyl)-4-perbenzoicMS(ESI+):513,5Example 1, Scheme 1
1022-(3-chloro-4-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):483,9Example 1, Scheme 1
103N-(3-{4-methyl-5-[2-(morpholine-4-ylmethyl) benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl}phenyl)ndimethylacetamide MS(ESI+):488,7Example 1, Scheme 1
1042-(4-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):458,9Example 1, Scheme 1
1052-[2-(3-chloro-4-fluoro phenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamideMS(ESI+):442,7Example 1, Scheme 1
1062-[4-butyl-2-(3-chloro-4-forfinal)-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamideMS(ESI+):484,9Example 1, Scheme 1
1072-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamideMS(ESI+):459,2Example 1, Scheme 1
2-[2,4-bis(3-chlorophenyl)-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamideMS(ESI+):521,3Example 62, Scheme 2

ConnectionStructureNameDataMethod
1094-(3-chlorophenyl)-5-(3-ethoxypropan)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):362,8Example 62, Scheme 2
1102-[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-helmeted)ndimethylacetamideMS(ESI+):424,9Example 62, Scheme 2
111N-(3-{[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide MS(ESI+):423,9Example 62, Scheme 2
1122,4-bis(3-chlorophenyl)-5-(3-hydroxypropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):431,4Example 62, Scheme 2
1132-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):403,8Example 1, Scheme 1
1144-(3-chlorophenyl)-2-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+);403,8Example 62, Scheme 2
1154-(4-chlorophenyl)-2-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):466,2Example 62, Scheme 2
116N-{3-[4-(3-chlorophenyl-5-(3-hydroxypropyl)-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]phenyl}ndimethylacetamide MS(ESI+):453,9Example 62, Scheme 2
1174-(3-chlorophenyl)-2-methyl-5-[3-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):466,1Example 62, Schema

ConnectionStructureNameDataMethod
1182-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamideMS(ESI+): 424,9Example 62, Scheme 2
1194-(3-chlorophenyl)-2-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):466,1Example 62, Scheme 2
1204-(3-CHL is henyl)-2-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+):466,1Example 62, Scheme 2
1214-(3-chlorophenyl)-2-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):416,9Example 62, Scheme 2
1222-(2-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):416,8Example 1, Scheme 1
1234-(4-chlorophenyl)-5-(3-ethoxypropan)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):362,8Example 62, Scheme 2
1244-(4-chlorophenyl)-2-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):466,1Example 62, Scheme 2
125/td> N-(3-{[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamideMS(ESI+): 423,9Example 62, Scheme 2

ConnectionStructureNameDataMethod
1264-(4-chlorophenyl)-2-methyl-5-[3-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):466,1Example 62, Scheme 2
1274-(4-chlorophenyl)-2-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):452,9Example 62, Scheme 2
128N-{2-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}ndimethylacetamideMS(ESI+):361,7Example 62, Scheme 2
1294-(4-chlorophenyl)-5-[3-(dimethylamino)benzyl]-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):409,9Example 62, Scheme 2
1304-(4-chlorophenyl)-2-methyl-5-[(6-pyrrolidin-1-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):436,9Example 62, Scheme 2
1312-(2-chlorophenyl)-4-(4-chlorophenyl)-5-(3-ethoxy propyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):459,5Example 62, Scheme 2
1322-(2-chlorophenyl)-4-(4-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):387,4Example 62, Scheme 2
1332-(2-chlorophenyl)-4-(2-forfinal)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+):370,7Example 62, Scheme 2

ConnectionStructureNameDataMethod
1342-(2-chlorophenyl)-4-(4-chlorophenyl)-5-[3-(dimethylamino)propyl]-1 H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):458,5Example 62, Scheme 2
1352-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):395,9Example 62, Scheme 2
1362-(2-chlorophenyl)-5-methyl-4-(3-morpholine-4-ylphenyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):437,8Example 62, Scheme 2
1372-(2-chlorophenyl)-4-[1-(3,4-divergence)ethyl]-5-methyl-1H-pyrazole,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+):432,9Example 62, Scheme 2
1384-[1-(benzyloxy)ethyl] -2-(2-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):410,9Example 62, Scheme 2
1394-[3-(dimethylamino)phenyl]-2-(2-methoxyphenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):391,5Example 62, Scheme 2

Example 84: measurement of the levels of active forms of oxygen in different cell cultures

The active compounds according to the present invention can be tested for their activity in inhibiting or reducing the production of reactive oxygen species (ROS) of oxygen in the cells. The activity of the compounds was tested in the following cell cultures using different methods, such as using narasinga of tetrazole, Amplex Red, Chemiluminescence (Lyuminola) and 2',7'-DICHLORODIFLUOROMETHANE (H2DCF-DA) as described in the following detailed protocols.

The cell line of microglia person

The cell line of microglia person (NMS, microheli of man clone 3) (Janabi et al., 1995, Neurosci. Lett. 195:105) were cultured in MEM medium (minimum sufficient medium Needle) containing 10% FBS with 50 U/ml of sodium salt of penicillin G and 50 μg/ml streptomycin sulfate, and incubated at 37°C for 24 hours. In culture medium was added to IFN-γ (IFN-γ person, Roche. 11 040 596 001) to a final concentration of 10 ng/ml for 24 h before determination of education O2-. Endothelial cells of the umbilical vein of a person (HUVEC)

The HUVEC cells were cultured in minimal endothelial environment, which has been added hydrocortisone (1 μg/ml, CalbioChem), extract the brain of a bull (12 µg/ml), gentamicin (50 μg/ml, CalbioChem), amphotericin b (50 ng/ml, CalBioChem), EGF (10 ng/ml) and 10% FCS, until the fourth passage. Proceeding from the fifth passage cells were cultured at lower concentrations of FCS (2%) in the absence of EGF, unless otherwise noted. All experiments were performed with cells at the fifth passage. Cells were incubated with OxLDL (oxidized low-density lipoprotein) or in the corresponding buffer as control for 24 h before determination of education About2-.

Cells HL-60

Cell line acute myeloid leukemia human HL-60 were cultured in medium RPMI 1640 (Invitrogen), enriched with 10% thermoinactivation calf serum, 2 mm glutamine, 100 U/ml penicillin (Sigma), and 100 µg of streptomycin (Sigma) at 37°C in a humid atmosphere with 5% CO2. The WPPT is erentiable in HL60 phenotype of neutrophils was started by adding to the culture medium Me 2SO (the final concentration of 1.25% (by volume) for 6 days).

1. Nicrosini tetrazolium (NBT)

Intracellular and extracellular superoxide was measured using colorimetric methods using quantitative test using narasinga of tetrazole (NBT). Inhibiting SOD turning NBT in formazan, thin blue precipitate in the presence of superoxide anion was measured on the spectrometer Fluostar Optima spectrometer (BMG labtech). After incubation with the appropriate stimulus, the cells were treated with trypsin (IX Trypsin-EDTA), were collected by centrifugation and were washed PBS to remove culture medium. 48-hole tablets were placed on a 5×105cells and incubated them in a balanced salt Hanks solution containing 0.5 mg/ml NBT with or without adding 800 U/ml SOD in the presence or absence of the compounds according to the present invention. As a control were injected DPI at final concentration of 10 μm. After 2.5 h, the cells were fixed and washed with methanol to remove any remaining not restored NBT. The restored formazan was dissolved in 230 μl of 2 M potassium hydroxide in 280 μl of dimethylsulfoxide. The absorption was measured at 630 nm. For calculations of the absorption at 630 nm were normalized for each individual wells. The average value of the four empty holes subtracted from each skorrektiroval the th values for each time point. The activity of NADPH oxidase was expressed in % of the activity in the control cells. The residual activity of DPI-treated cells was usually <10%. 2. Amplex Red

Extracellular hydrogen peroxide was measured using Amplex UltraRed (Molecular Probes). Cells were treated with trypsin (IX Trypsin-EDTA), collected by centrifugation and resuspendable environment HBSS, enriched with 1% glucose. Cells were sown in black 96-well tablets with a density of 50,000 cells in 200 ál buffer (HBSS with 1% glucose containing 0.005 U/ml of horseradish peroxidase (Roche) and 50 µm Amplex Red in the presence or absence of the compounds according to the present invention. As a control were injected DPI at final concentration of 10 μm. The tablets were placed in a fluorescent Optima Fluorescent plate reader and kept at 37°C for 20 minutes Fluorescence was measured for 15 minutes (hours?) when the wavelength of the exciting and emitted light 544 nm and 590 nm, respectively. The activity of NADPH oxidase was expressed in % of the activity in the control cells. The residual activity of DPI-treated cells was usually <10%.

The following Table 2 shows the percentage inhibition activity of NADPH-oxidase, measured using Amplex Red using differentiated under the action of DMSO HL60 cells as described above:

The table is 2
Connection # Inhibition(%)
(1)53
(2)56
(3)48
(4)53
(7)68
(8)55

(10)43
(13)58
(20)60
(23)100
(28)79
(30)55
(39)81
(41)88
(45)80
(46)78
(48)80
(50)95
96
(54)76
(60)82
(61)82
(62)74
(67)87
(74)94
(76)80
(77)78
(80)90
(90)100
(96)90
(98)100
(100)78
(105)90
(108)89
(115)89
(116)88
(129)49
(130)88

(136)
83
(137)80

The following Table 3 shows the values of the IC50for the activity of NADPH-oxidase, measured using Amplex Red using differentiated under the action of DMSO HL60 cells as described above:

Table 3
Connection # IC50(ΜM)
(1)<5
(2)<5
(3)<5
(4)<5
(7)<5
(8)<5
(10)<5
(13)<5
(20)<5
(28)<5
(30)<5

3. Chemiluminescence (Luminal)

ROS was measured using chemiluminescent the th probe lyuminola. Cells were cultured and were placed into tablets as described for Amplex Red, except that the Amplex Red was replaced with 10 μg/ml lyuminola (Sigma 09235). The light emission was recorded continuously at 37°C for 60 min, using a mode of luminescence on the device FluoStar Optima fluorescent plate reader. The average value of the four empty holes subtracted from each of the adjusted values for each time point. The activity of NADPH oxidase was expressed in % of the activity in the control cells. The residual activity of DPI-treated cells was usually <10%.

4.2',7'-DICHLORODIFLUOROMETHANE diacetate (H2DCF-DA)

The HUVEC cells were placed on top of the glass and left alone overnight in 0.5% BSA prior to the stimulation of TGF-β. Cells were loaded for 10 min with 5 μm CM-H2DCFDA in free of phenol red medium in the dark, and then was treated with TGF-β (R&D Systems) in the presence or absence of the compounds according to the present invention. The cells are then visualized using immunofluorescence microscopy after fixation and staining of nuclei DAPI or assessment of living condition using confocal microscopy. The DCF fluorescence was visualized at a wavelength of excitation light of 488 nm and emission at 515-540 nm. To avoid photo-oxidation of the dye image was obtained with a quick scan using identical PA is ometry for all samples. For calculations of the absorption at 540 nm were normalized to the absorption at 540 nm for each individual holes (each individual sample?). The average value of the four empty holes subtracted from each of the adjusted values for each time point. The activity of NADPH oxidase was expressed in % of the activity in the control cells. The residual activity of DPI-treated cells was usually <10%.

Example 85: Measurement of blood pressure in Spontaneously Hypertensive Rats (SHR)

To assess the feasibility of using compounds according to the present invention for the treatment of hypertension was conducted the following experiment.

Were used rat lines SHR age 11 weeks with systolic blood pressure above 170 mm Hg. The connection according to the present invention was administered to rats orally at a dose of approximately 3, 10, 30 and 100 mg/kg in the period of time from about 10:00 to 12:00 PM Average systolic and diastolic blood pressure and heart rate were measured after 2, 4, 6, 8, and 24 after the first injection of the compounds according to the present invention for carrying out the kinetic analysis in a single day. After that, the pressure was measured every two days for two weeks in the morning at the point 24 hours after injection and the point corresponding to the half-life of the connection.

After the last injection control what was the point of the 24 hours. Animals were monitored for an additional week without treatment to assess the excretion of the compounds. Animals were treated once a day for two weeks using a probe with a special needle, adapted to the probe, at a dose of 5 ml/kg Before taking in the experiment animals acclimatized for two days, then coached for one week. Pressure was measured in awake rats using plethysmography combined with a tail cuff (Codas 6, Kent). Animals included in group after training for a few days and if the change in systolic pressure from them was ≤40 mm Hg, that is +/- 20 mm Hg. Measure baseline spend at least two days before the experiment. Before the experiment the animals randomized to obtain homogeneous groups.

Example 86: Induced by bleomycin lung damage in mice

To assess the feasibility of using compounds according to the present invention for the prevention or treatment of respiratory disorders or diseases was conducted the following experiment.

In order to get lung damage, which is comparable to those for respiratory disorder or disease, such as idiopathic pulmonary fibrosis, animals were injected into the trachea of a single sublethal dose of bleomycin (BLM) (2,5 U/kg body weight, dissolved in 0.25 ml of 0.9% NaCl). is completed, the animals were subjected to similar processing, but instead of bleomycin them in the trachea were administered the same volume of saline. Injection into the trachea was performed under anesthesia using ketamine (80 mg/kg body weight, intraperitoneally) and xylazine (20 mg/kg body weight, intraperitoneally).

2 weeks after introduction into the trachea BLM or saline, animals were killed with a lethal injection of sodium phenobarbital and then releasing blood from the abdominal aorta. Was held bronchoalveolar washing, light weighed and used separately for biochemical (right lung homogenate, n=10) and histological (left lung, n=10) studies, as described below. Animals were randomly divided into four groups: control saline (n=8) and control + BLM (n=10); and Compound Dose 1+BLM (n=10) and Compound Dose 2+BLM (N=10). Media or connection was administered within 2 weeks.

Mice in the treatment daily orally administered the compound according to the present invention or physiological/control solution based on day 0 within two weeks. Accumulation in whole lung acid-soluble collagen was analyzed using the method Sircol assay.

Example 87: Animal models of cancer

To assess the feasibility of using compounds according to the present invention for the treatment of cancer, in particular, to slow tumor growth and/or EN is iogenes, conducted the following experiments. The study of angiogenesis In vivo

Females of mice C57BL6/J age from 7 to 10 weeks were injected subcutaneously with 400 ál filled with growth factor gel Matrigel (Matrigel) with the addition of 500 ng/ml angiogenic factor (b-FGF or VEGF). One week after injection, mice were scanned using MicroCT (CT skyscan). Mice retro-orbital by injection was injected indicator (400 μl of labeled iodine liposomes) to visualize the density of blood vessels. Image scans then reconstructed using Recon, and the density of the shading in the area injected Matrigel was counted on each side of the seal. Compounds of the present invention is administered orally in appropriate doses 1 and 2 once a day for 10 days. The results are expressed in density dimming, which correlates with the density of blood vessels. The matrix of the Matrigel was also frozen and progressively for CD31 to visualize vessels. Measurement of tumor growth

Cell carcinoma of the lung Lewis (LLC1) in an amount of 5×105was administered by subcutaneous injection into the back of mice. Mice were daily injected compound according to the present invention is administered orally in a dose of 40 mg/kg When control tumors reached approximately 1 cm in length, mice were killed, and tumors were excised, weighed and frozen. For analysis of therapeutic action, the mice by injecti is introduced LLC1 cells, after tumors had reached a size of approximately 0.5 cm, mice were treated daily controlled the size of the tumor. After killing the mice tumors and frozen sections of the tumors were progressively antibodies against CD31, and analyzed the level of ROS.

1. Pyrazolopyrimidinone derivative of the formula (I):

where G1selected from H; optionally substituted heteroaryl-C1-C6-alkyl; G2selected from H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-geterotsiklicheskie;optionally substituted C 1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl; G3selected from H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted carbonyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted C1-C6-alkylaryl: optional substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylphenol; optionally substituted heteroaryl-C2-C 6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl; G4selected from-NR2-C(O)-R1and -(CHR3)m-(CH2)n-R4where R1selected from H; amino; -NR5R6; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C3-C8-geterotsiklicheskie; not battelino substituted C 1-C6-alkyl-C3-C8-geterotsiklicheskie; and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl; R2selected from H; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C3-C8-geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie; optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl; R3selected from H; halogen; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6-alkylaryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; substituted heteroaryl; long is correctly substituted C 1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C3-C8-geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie; and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl; R4selected from H; -C(O)R7; -A-B; CHR8R9and -(CH2)q-E; R5and R6independently from each other selected from H; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; neo is Astelin substituted C 3-C8-geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie; and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl or-NR5R6together form a ring selected from optionally substituted heteroaryl and optionally substituted C3-C8-geterotsiklicheskie; R7is selected from optionally substituted amino; optionally substituted alkoxy; optionally substituted aminoalkyl; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; -NR5R6; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; neoba is consequently replaced With 3-C8-geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie; and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl; R8and R9independently from each other selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C3-C8-cycloalkyl and optionally substituted C3-C8-geterotsiklicheskie; R10selected from optionally substituted by hydroxy; optionally substituted amino-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted alkoxy-C1-C6-alkyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C3-C8-heterocyclic is a; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie; and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl; R11and R12independently from each other selected from H; optionally substituted acyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C3-C8-geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie; and optionally substituted C3-C8-heteroseksualci-C1-C6-alkyl or-NR11R12together form a ring selected from optionally replaced the military heteroaryl and optionally substituted C 3-C8-geterotsiklicheskie; R13selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C3-C8-cycloalkyl and optionally substituted C3-C8-geterotsiklicheskie; R14, R15and R16independently from each other selected from H and optionally substituted C1-C6-alkyl; R17selected from optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-quinil; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C3-C8-geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-geterotsiklicheskie; and optionally substituted C3-C8-heteroseksualci-C 1-C6-alkyl; And a is chosen from optionally substituted aryl and optionally substituted heteroaryl; choose from OR10, -NR11R12and -(CH2)p-R13; E is chosen from optionally substituted C3-C8-cycloalkyl; optionally substituted C2-C6-quinil; -NR14R15; -(CH2)r-OR15and-NR16C(O)-R17; m, n, p and q are integers selected from 0 to 5; r is an integer selected from 3 to 5; G5represents H; and its pharmaceutically acceptable salts,
where the term "substituted" refers to groups substituted by 1 to 5 substituents selected from the group that includes "C1-C6-alkyl", "C2-C6alkenyl", "C2-C6-quinil", "C3-C8-cycloalkyl", "C3-C8-heteroseksualci", "C1-C6-alkylaryl", "C1-C6-alkylglycerol", "C1-C6-alkylsilanes", "C1-C6-alkyl-C3-C8-heteroseksualci", "amino", "aminosulfonyl," "ammonia," "acylamino," "aminocarbonyl," "aryl," "heteroaryl", "sulfinil", "sulfonyl", "alkoxy", "alkoxycarbonyl", "carbamate", "sulfanyl", "halogen", trihalomethyl, cyano, hydroxy, mercapto, and nitro;
the term "aryl" refers to an unsaturated aromatic carbocyclic group containing from 6 to 14 atoms ug is erode, and having a single ring or multiple condensed rings;
the term "heteroaryl" denotes a monocyclic heteroaromatic, or a bicyclic or tricyclic heteroaromatic group of condensed rings.

2. Derived under item 1, in which G1represents N.

3. Derived under item 1, in which G3represents a C1-C6-alkyl.

4. Derived under item 1, in which G3represents amino.

5. Derived under item 1, in which G4represents-NR2-C(O)-R1; R1and R2are as defined in any of the preceding paragraphs.

6. Derived under item 1, in which G4represents -(CHR3)m-(CH2)n-R4; R3, R4, m, and n are as defined in any of the preceding paragraphs.

7. Derived under item 6, in which R4represents-C(O)R7; R7is as defined in any of the preceding paragraphs.

8. Derived under item 6, in which R4represents-a-b; a and b are as defined in any of the preceding paragraphs.

9. Derived under item 6, in which R4represents-CHR8R9; R8and R9are as defined in any of the preceding paragraphs.

10. Derived by p. 6, inwhich R 4represents -(CH2)q-E; E and q are as defined in any of the preceding paragraphs.

11. Derived under item 1, selected from the following groups:
2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-ylbenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-{4-[(4-methylpiperazin-1-yl)methyl]benzyl}-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-5-[2-(4-hydroxyphenyl)ethyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(3-ethoxypropan)-4-methyl-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-forfinal)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-methyl-5-(3-phenoxybenzyl)-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4,5-dimethyl-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-2-(4-pertenece)ndimethylacetamide;
2-(2-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(3-ethoxypropan)-2-(2-forfinal)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-[2-(m is Holin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-forfinal)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo-[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-forfinal)-4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
3-(4,5-dimethyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl)benzonitrile;
2-(2-forfinal)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[2-(2-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-(2-chlorophenyl)-4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-methyl-5-(3-phenoxybenzyl)-2-[1,2,4]triazole[4,3-b]pyridazin-6-yl-1H-piraso what about[4,3-C]pyridine-3,6(2H,5H)-dione;
3-[5-(3-ethoxypropan)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]benzonitrile;
2-[4-(benzyloxy)phenyl]-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[4-(benzyloxy)phenyl]-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[4-(benzyloxy)phenyl]-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
3-{4-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-3,b-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl}benzonitrile;
2-(2-chlorophenyl)-5-(3-hydroxypropyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-[2-(3-cyanophenyl)-4-methyl-3,b-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-[2-(3-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-(2-chlorophenyl)-5-(3-ethoxypropan)-4-methyl-1-(pyridine-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2,4-dimethyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-5-[3-(diethylamino)propyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-5-(cyclohexylmethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-5-(3-hydroxypropyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-p is razole[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-(3-morpholine-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-(3-phenylprop-2-in-1-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chloro-4-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4,5-dimethyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl} -1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-forfinal)-4-methyl-5-(3-morpholine-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,5-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[2-(benzyloxy)phenyl]-5-(3-ethoxypropan)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,5-dichlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-{2-[2-(2,5-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}ndimethylacetamide;
2-(2-chloro-4-forfinal)-4-(methoxymethyl)-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[4-(benzyloxy)phenyl]-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3,4-dichlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)4-oxobutyl]-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dione;
5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2,5-dichlorophenyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-(3-phenylprop-2-in-1-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-{3-[5-(3-ethoxypropan)-4-methyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]phenyl}ndimethylacetamide;
2-benzyl-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3,4-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chloro-4-forfinal)-4,5-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[4-(benzyloxy)phenyl]-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3,4-dichlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
methyl [2-(2,5-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]acetate;
N-{3-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]phenyl}ndimethylacetamide;
2-(2,3-dichlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-{3-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]phenyl}ndimethylacetamide;
5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(3,4-dichlorophenyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2,4-dimethyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2,4-dimethyl-5-(3-morpholine-4-yl-3-Hairdryer shall propyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-{3-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]phenyl}ndimethylacetamide;
2-(3-chlorophenyl)-5-(3-ethoxypropan)-4-(3-methoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,4-dimethyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl)-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-(3-chloro-4-forfinal)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(3-chloro-4-forfinal)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chloro-4-forfinal)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-chloro-4-forfinal)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[4-(benzyloxy)phenyl]-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,3-dichlorophenyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chloro-4-forfinal)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-(3-{[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;
5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(3-chloro-4-forfinal)-4-methyl-1H-
pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione
N-(3-{[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;
2-(2-chloro-4-forfinal)-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
3-{4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl}benzonitrile;
N-{2-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}-4-perbenzoic;
N-{2-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}-4-perbenzoic;
2-[2-(2-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
N-(2-{2-[4-(benzyloxy)phenyl]-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl}ethyl)-4-perbenzoic;
2-(3-chloro-4-forfinal)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-(3-{4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl}phenyl)ndimethylacetamide;
2-(4-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[2-(3-chloro-4-forfinal)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-[4-butyl-2-(3-chloro-4-forfinal)-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
2-[2,4-bis(3-chlorophenyl)-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
4-(3-chlorophenyl)-5-(3-ethoxypropan)-2-methyl-1H-feast of the ash[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
N-(3-{[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;
2,4-bis(3-chlorophenyl)-5-(3-hydroxypropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3-chlorophenyl)-2-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-{3-[4-(3-chlorophenyl)-5-(3-hydroxypropyl)-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-C]pyridine-2-yl]phenyl}ndimethylacetamide;
4-(3-chlorophenyl)-2-methyl-5-[3-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]-N-(pyridine-2-ylmethyl)ndimethylacetamide;
4-(3-chlorophenyl)-2-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3-chlorophenyl)-2-methyl-5-[4-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3-chlorophenyl)-2-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(3-ethoxypropan)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)--methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-(3-{[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]methyl}phenyl)ndimethylacetamide;
4-(4-chlorophenyl)-2-methyl-5-[3-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-methyl-5-[(6-morpholine-4-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-{2-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-yl]ethyl}ndimethylacetamide;
4-(4-chlorophenyl)-5-[3-(dimethylamino)benzyl]-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-methyl-5-[(6-pyrrolidin-1-espiridion-2-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-(3-ethoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-(2-forfinal)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-[3-(dimethylamino)propyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-5-methyl-4-(3-morpholine-4-ylphenyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-[1-(3,4-divergence)ethyl]-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[1-(benzyloxy)ethyl]-2-(2-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione; and
4-[3-(dimethylamino)phenyl]-2-(2-methoxyphenyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione.

12. Farmace the political composition, having the ability to inhibit NADPH oxidase, containing at least one derivative according to any one of paragraphs.1-11 and a pharmaceutically acceptable carrier, solvent or excipient.

13. Derivative according to any one of paragraphs.1-11 for use as a medicinal product having the properties of an inhibitor of NADPH oxidase.

14. Pyrazolopyrimidine derivative according to any one of paragraphs.1-11 for the treatment of a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuropeptidergic and/or neurodegenerative disorders, kidney diseases, reproduction disorders, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal tract, angiogenesis, angiogenesis-dependent conditions and other diseases and/or disorders associated with nikotinamidadenindinukleotida (NADPH-oxidase).

15. The intermediate of formula (VIII):

in which R18represents a C1-C6-alkyl, such as methyl, ethyl, propyl, isopropyl or Boo the sludge; G2, G3, G4and G5are as defined in any of the preceding paragraphs, except for the following connections:

16. The method of obtaining the compounds of formula (I), including phase cyclization of compounds of formula (VIII) in the presence of a base:

in which R18represents a C1-C6-alkyl, such as methyl, ethyl, propyl, isopropyl or butyl; G1represents H; G2, G3, G4and G5are as defined in any of the preceding paragraphs.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein A1 represents N or C (A2); A2 represents H, F, Cl or CN; B1 represents H, OR1, SO2R1, NHR1, NHC(O)R1, F or Cl; D1 and E1 represents H or Cl; Y1 represents H, CN, NO2, F, Cl, Br, CF3, R17, OR17, SO2R17 or C(O)NH2; or Y1 and B1 together with atoms to which they are attached, represent 5- or 6-merous heteroarene having 2-3 nitrogen atoms, wherein heteroarene rings are unsubstituted or substituted by (O); G1 represents H; Z1 represents uncondensed phenylene substituted by OR41; R41 represents 6-merous heteroaryl having 1 N atom, wherein heteroaryl is condensed with R43A, R43A represents 5-merous heteroarene having 1 N atom; Z2 represents monocyclic 6-merous heterocycloalkylene having 1-2 N atoms and 0 double bonds; Z1A and Z2A are both absent; L1 represents -CH2-; Z3 represents R38 or R40; R38 represents uncondensed phenyl; R40 represents cycloalkyl, wherein cycloalkyl represents a monocyclic ring system having 3 to10 C atoms and 0 double bonds, cycloalkenyl, wherein cycloalkenyl represents monocyclic 6-merous ring having 1 heteroatom specified in a group consisting of O and N, and 1 double bond, wherein cycloalkenyl is uncondensed or condensed with R40A; R40A represents cycloalkane, wherein cycloalkane represents a monocyclic ring having 3-10 C atoms and 0 double bonds, or heterocycloalkane, wherein heterocycloalkane represents monocyclic 6-merous ring having 1 N atom and 0 double bonds (the rest substitutes are those as specified in cl. 1 of the patent claim). The invention also refers to compounds of formula

and a pharmaceutical composition containing an effective amount of the compound of formula (I) or (II) or its pharmaceutically acceptable salt.

EFFECT: compounds of formula (I) or (II) inhibiting the activity of anti-apoptotic Bcl-2 proteins.

6 cl, 5 tbl, 378 ex

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new phenylamide or pyridylamide derivatives of formula

or their acceptable salts, wherein A1 is CR12 or N; A2 is CR13 or N; R1 and R2 are independently specified in hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup; R12 and R13 are independently specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino group and C1-7-alkylsulphanyl; R3 is specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, cyano group, C3-7-cycloalkyl, five-merous heteroaryl and phenyl; R4 is specified in methyl and ethyl; or R3 and R4 together represent -X-(CR14R15)n- and form a part of the ring, wherein X is specified in -CR16R17-, O, S, C=O; R14 and R15 are independently specified in hydrogen or C1-7-alkyl; R16 and R17 are independently specified in hydrogen, C1-7-alkoxycarbonyl, heterocyclyl substituted by two groups specified in a halogen, or R16 and R17 together with an atom C, which they are attached to, form =CH2 group; or X is specified in a group NR18; R14 and R15 are hydrogen; R18 is specified in hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarbonyloxy-C1-7-alkyl, phenyl, wherein phenyl is unsubstituted, phenylcarbonyl, wherein phenyl is substituted by C1-7-alkoxycarbonyl, and phenylsulphonyl, wherein phenyl is substituted by carboxyl-C1-7-alkyl, or R18 and R14 together represent -(CH2)3- and form a part of the ring, or R18 together with R14 and R15 represent -CH=CH-CH= and form a part of the ring; and n has the value of 1, 2 or 3; B1 represents N or CR19 and B2 represents N or CR20, provided no more than one of B1 and B2 represents N; and R19 and R20 are independently specified in a group consisting of hydrogen and halogen-C1-7-alkyl; R5 and R6 are independently specified in a group consisting of hydrogen, halogen and cyano group; and one-three, provided R4 represents methyl or ethyl, two of the residues R7, R8, R9, R10 and R11 are specified in C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxygroup, cyano group, C1-7-alkoxycarbonyl, hydroxy-C3-7-alkynyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkynyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl-carbonyl, wherein phenyl is unsubstituted, phenyl-C1-7-alkyl, wherein phenyl is substituted by 1-2 groups specified in a halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-alkynyl, wherein phenyl is substituted by 2 groups specified in halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidine carbonyl-C1-7-alkyl, wherein pyrrolidinyl is substituted by carboxyl, and the other R7, R8, R9, R10 and R11 represent hydrogen; the term 'heteroaryl' means an aromatic 5-merous ring containing one or two atoms specified in nitrogen or oxygen; the term 'heterocyclyl' means a saturated 4-merous ring, which can contain one atom specified in nitrogen or oxygen. Besides, the invention refers to a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new compounds possessing the GPBAR1 agonist activity.

21 cl, 1 tbl, 190 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazolopyridine derivatives of formula (I), a pharmaceutical composition based thereon, use for treating and/or preventing disorders or conditions associated with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and an intermediate of formula (VIII). In general formula (I) G1 denotes H; G2 is selected from H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted phenyl; optionally substituted C1-C6-alkylaryl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted-C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G3 is selected from -(CH2)n-R1 and -(CH2)p-R5; G4 is selected from H; optionally substituted acyl; optionally substituted acylamino; optionally substituted acyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G5 dentes H.

EFFECT: high effectiveness of compounds.

15 cl, 2 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention refers to new phenoxymethyl compounds of formula (I) or its pharmaceutically acceptable salts, wherein: HET represents a heterocyclic ring having formula A29 or A31, wherein the far left part is connected to the group X of formula (I); X represents substituted phenyl or optionally substituted pyridinyl, wherein the substitutes are specified in C1-C4alkoxy and cyano; Z represents imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[1,2-b]pyridazin-6-yl each of which can be substituted, wherein the substitutes are specified in C1-C4alkyl and a halogen atom; and each R2 are independently specified in C1-C4 alkyl inhibiting at least one phosphodiesterase 10, as well as to pharmaceutical compositions containing these compounds, and methods of treating various CNS disorders.

EFFECT: preparing the new compounds.

23 cl, 2 tbl, 732 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,2,3,4-tetrahydropyrido[4,3-b]indole-containing phenothiazines of general formula 1 as inhibitors of cholinestrerases and blockers of serotonin receptors 5-HT6, a pharmaceutical preparation on their base, in particular for treatment of neurodegenerative diseases. In general formula 1, in which R1=H, (C1-C6) alkyl; R2, R3, R4, R5=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, R6, R7=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, NH2, NHAlkyl, NAlkyl2; A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2; CH2CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2, CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: increased efficiency of the application of compounds.

6 cl, 1 dwg, 1 tbl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (I)

,

in which R1 stands for a phenyl group, optionally substituted with one or several halogen atoms; R2 stands for hydrogen or a halogen atom or a cyanogroup; group -C(=O)Y, in which Y stands for a hydrogen atom or the group -NH2 or -OR3; group -C(=S)NH2; group -C(=NH)NH-OH; group -CH2OH or -CH2F; group -CH=N-OH; group -CH=CH2 or -C≡C-Ra; group (II) or (III); and Ra stands for the hydrogen atom or the (C1-C4)alkyl group; R3 stands for thehydrogen atom or the (C1-C4)alkyl group; and R4 stands for -NH2, (C1-C4)alkyl, (C1-C4)fluoroalkyl or (C3-C7)cycloalkyl group. The invention also relates to methods of obtaining compounds of formula (I), a medical preparation, a pharmaceutical composition, intermediate compounds for obtaining the formula (I) compound and the application of the formula (I) compound and intermediate compounds.

EFFECT: claimed compounds have anti-cancer activity.

21 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phenothiazine-containing 1,2,3,4-tetrahydropyrido[4,3-b]indole derivatives of general formula 1 and hydrochlorides thereof as an agent for reducing uncontrolled protein aggregation in the nervous system, methods for production thereof, a pharmacological agent based thereon and a method of reducing uncontrolled protein aggregation in the nervous system. In general formula 1: R1=H, (C1-C6)alkyl; R2, R3, R4, R5=H, F, O, Br, (C1-C6)alkyl, (C1-C6)alkoxy, R6, R7= H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2, A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2); CH2CH[((C1-C6)alkyl]C(O)N[(C1-C6))alkyl]CH2CH2), CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: improved properties of derivatives.

9 cl, 2 tbl, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to endocrinology, and can be used for treating non-alcoholic liver disease accompanying type 2 diabetes mellitus. The declared preparation Mexicor provides reducing manifestations of cytolysis and cholestasis, decreasing the steatosis index, enables improving metabolic lipid and glycaemic values and reducing insulin resistance. Mexicor is applied in a daily therapeutically effective dose of 100 mg 4 times a day for at least 16 weeks.

EFFECT: high pharmacological activity of Mexicor has been shown by achieving the pronounced and stable elimination of fatty liver disease that enables reducing the length of treatment with no side effects.

2 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition contains aleglitezar or its sodium salt in a dose of 0.01 to 0.9 mg.

EFFECT: pharmaceutical composition of aleglitezar is used for treating or preventing type II diabetes mellitus or cardiovascular diseases.

32 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biotechnology. Characterised is application of therapeutically efficient quantity of peptide GGF2, which contains domain, similar to epidermal growth factor (EGF-like), in treatment or prevention of heart failure in mammal by injection of said peptide every 48 hours in dose, which constitutes from approximately 0.001 mg/kg to approximately 10 mg/kg.

EFFECT: invention improves therapeutic effect with introduction of neuroregulin with minimisation of any potential side effects.

14 cl, 15 dwg, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to compositions containing vasoactive intestinal peptide (VIP) or its fragments, and to application of such compositions in treatment of aorta fibrosis.

EFFECT: group of inventions is effective in treatment and prophylaxis of aorta fibrosis.

10 cl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics and represents a pharmaceutical composition for parenteral administration containing sub-micron particles of dosocahexaenoic acid ester dispersed in a water phase with the use of mixture of at least two surfactants specified in a) at least one fatty acid polyoxyethylene ester and b) at least one phospholipide derivative, as well as a method for preparing the above pharmaceutical composition.

EFFECT: invention provides higher pharmacological activity.

14 cl, 3 dwg, 3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: what is presented is a fused protein that is a Notch1 antagonist, which consists of a human Fc region fused with the EGF-like repeat 1-13 of Notch1 or the EGF-like repeat 1-24 of Notch1. Fc-portion is localised on a carboxy-terminal portion of the EGF-repeat. There are described a pharmaceutical composition for the protein-based Notch signal transmission inhibition and using it for preparing the pharmaceutical composition for treating an individual suffering from: tumour; ovarian cancer; metabolic disorder; vascular proliferative retinopathy. What is presented is using the fused protein for producing the pharmaceutical composition for inhibition: angiogenesis in the individual; physiological lymphangiogenesis or pathological lymphangiogenesis in the individual; tumour deposits in the individual.

EFFECT: using the invention provides the proteins expressed in a supernatant at a level by several times more than the fused protein containing the EGF-like repeats 1-36 of Notch1; they penetrate into the tumour better, maintain a ligand-binding ability with the fused protein containing the repeats 1-24, binds to DLL4 and JAG1, whereas the fused protein containing the repeats 1-13 only binds to DLL4, but not to JAG1 that can find application in therapy of various diseases related to the Notch1 activity.

18 cl, 124 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1), which possess an affinity to the µ-opiod receptor and the ORL1-receptor. The invention also relates to the application of the said compounds for obtaining medications, which can be used in treatment of fear, stress and associated with stress syndromes, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as nootropic), withdrawal syndromes, alcohol and/or drug abuse and/or abuse of medications and/or alcohol, narcotic and medication addiction, etc. In general formula (1) (1) Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' in each case stand for -H; Q stands for -R0, -C(=O)-R0, -C(=O)OR0, -C(=O)NHR0, -C(=O)N(R0)2 or-C(=NH)-R0; R0 in each case stands for -C1-8-aliphate, -C3-12-cycloaliphate, -aryl, -heteroaryl, -C1-8-aliphate-C3-12-cycloaliphate, -C1-8-aliphate-aryl, -C1-8-aliphate-heteroaryl, -C3-8-cycloaliphate-C1-8-aliphate, -C3-8-cycloaliphate-aryl or -C3-8-cycloaliphate-heteroaryl; R1 and R2 independently on each other stand for -C-1-8-aliphate; R3 stands for -C1-8-aliphate, -aryl, -heteroaryl or -C1-8-aliphate-C3-12-cycloaliphate; n stands for 0; X stands for -NRA-;RA stands for -C1-8-aliphate; RB stands for -C1-8-aliphate; on condition that R1, R2, RA and RB simultaneously do not stand for the non-substituted-C1-8-aliphate.

EFFECT: increased efficiency of the application of the compounds.

9 cl, 11 tbl, 164 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bi- and polycyclic substituted isoquinoline and isoquinolinones of formula (I), or to its stereoisomeric and/or tautomeric forms and/or to its pharmaceutically acceptable salts, where R1 represents OH; R3, R4, R5 and R8 represents H; R7 represents halogen or (C1-C6) alkyl; R6 represents one (C1-C4)alkylene, bound to a cycloalkyl ring, in which (C1-C4)alkylene forms the second bond with the other carbon atom of the cycloalkyl ring with the formation of a bicyclic ring system, where in the bicyclic ring system one carbon atom is substituted with a group, independently selected from O, S or SO2; and if m and s equal 2 or m equals 3 and s equals 1, R6 represents a group CH2-CH-(CH2)2, which via one group CH2 is bound to the cycloalkyl ring, and two other CH2 groups are bound to different carbon atoms of the cycloalkyl ring, and if m equals 3 and s equals 3, R6 represents two methylene groups, bound to different carbon atoms of the cycloalkyl ring, where the methylene groups or group CH2-CH-(CH2)2 are bound to the carbon atoms of the cycloalkyl ring and form an adamantane system of formula (XX) , where L can be bound to any secondary or tertiary carbon atom, or R6 together with R11 and an N atom form (C5) heterocycloalkyl, bound with the cycloalkyl residue in the form of a spirocyclic ring system, where the bicyclic ring system, or the adamantane system, or a ring system, containing (C5) heterocycloalkyl, represent non-substituted or optionally substituted with substituent R9; R9 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C6)aryl or cyclopropyl R11 and R12 independently on each other represent H or (C1-C6)alkylene-(C6)aryl; n equals 0 or 1; m equals 2 or 3; s equals 1, 2 or 3; L represents O; its stereoisomeric and/or tautomeric forms and/or its pharmaceutically acceptable salts. The invention also relates to the application of a formula (I) compound.

EFFECT: novel bi- and polycyclic isoquinoline and isoquinolinone derivatives, useful as inhibitors of Rho-kinase, are obtained.

22 cl, 22 ex

FIELD: biotechnologies.

SUBSTANCE: peptide is characterised with sequence Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ ID NO: 16). The invention also relates to peptide/lipid complex based on the above peptide, in which phospholipid represents one or more of sphingomyelin, DPPC and DPPG, a pharmaceutical composition that contains it, and treatment methods of dyslipidemia, cardiovascular disease, endothelial malfunction, macrovascular illnesses and microvascular illnesses using it.

EFFECT: invention allows obtaining ApoA-I mimetic that is more stable in comparison to ApoA-I and that is easy to obtain.

14 cl, 21 dwg, 14 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical industry, particularly to compositions for treating and/or preventing obesity. The composition contains the peptide compound Pro-Val-Asn-Phe-Lys-Phe-Leu-Ser-His in water containing a salt solution in the physiologically acceptable concentration. A therapeutic agent containing the above composition can be presented in the form of spray/drops applicable for nasal, subglossal or oral administration. A dosage form of the nasal or subglossal spray/drops, as well as oral film provides ease of administration and makes it applicable by the patient in need of treating and/or preventing obesity.

EFFECT: compositions and agents are effective for treating obesity.

45 cl, 4 tbl, 2 ex

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