Pyrazole derivatives applied as protein kinase inhibitors

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

 

This application claims the priority of provisional patent application U.S. 60/232795, filed September 15, 2000, provisional application for U.S. patent 60/257887, filed December 21, 2000, and provisional application for U.S. patent 60/286949 filed April 27, 2001, the contents of which are included in this description by reference.

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to the field of medicinal chemistry and relates to compounds that are inhibitors of protein kinases, compositions containing such compounds, and methods of their application. In particular the present invention relates to compounds that are inhibitors of protein kinases GSK-3 or Aurora-2. The invention also concerns methods of treatment associated with these protein kinases diseases such as diabetes, cancer and Alzheimer's disease.

BACKGROUND of INVENTION

The search for new therapeutics in recent times largely contributed to a better understanding of the structure of enzymes and other biomolecules associated with certain diseases. An important class of enzymes that are the subject of extensive research, are protein kinases.

Protein kinases mediate intracellular signal transformation. They do this through the implementation of the transfer of phosphoryla from Amu is setRepeat to acceptor proteins, included in the transmission signals. There are many kinases and pathways through which extracellular and other stimuli induce various cellular responses that occur in the cell. Examples of such stimuli include environmental signals and chemical stress (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, N2About2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)) and growth factors (e.g. granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblastic growth factor (FGF)). Extracellular stimuli can cause one or more cellular responses associated with growth, migration and differentiation of cells, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, protein synthesis and regulation of cell cycle.

Many diseases are associated with abnormal cellular responses triggered by events mediated by protein kinase. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, or hormonal disease is. Therefore, in medical chemistry, considerable efforts have been made to find inhibitors of protein kinases, effective as medicines.

Aurora-2 is a serine-trainingtraining involved in the emergence of human malignant owhali, such as colon cancer, breast cancer and other solid tumors. I believe that this kinase is involved in the acts of protein phosphorylation, regulation of the cell cycle. In particular Aurora-2 may play a role in controlling the correct splitting of the chromosomes during mitosis. Rosregulirovanie cell cycle can lead to cell proliferation and other violations. It is established that in the tissue of malignant tumors of the human colon overly expressed protein Aurora-2. See Bischoff et al., EMBO J. 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glikogensintetazy-kinase-3 (GSK-3) is a serine-trainingtraining consisting of α and β isoforms, each encoded distinct genes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508 to 514 (2000)]. GSK-3 is implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative disease, and hypertrophy of the heart muscle [WO 99/65897; WO 00/38675;and Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases can be caused by abnormal functioning of some cellular pathways signaling, which plays the role of GSK-3, or lead to it. As already established, GSK-3 phosphorylates a number of regulatory proteins and modulates their activity. These proteins include glikogensintetazy, which is limiting the speed of an enzyme necessary for glycogen synthesis, the associated microtubule protein Tau, factor gene transcription β-catenin, the factor initiating broadcast e1F2B, as well as ATP-citrate lyase, axin, factor 1 heat shock, c-Jun, c-Myc, c-Myb, CREB, and SERVα. Various specified the target proteins complicit with GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development of cells.

In mediated GSK-3 conducting paths, suitable for the treatment of type II diabetes caused by insulin signaling leads to cellular uptake of glucose and glycogen synthesis. Along this path GSK-3 is a negative regulator of insulininduced signal. Usually the presence of insulin causes inhibition mediated by GSK-3 phosphorylation and deactivation glikogensintetazy. Inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem. J. 299, 123-128 (1994)]. But the hurt is about diabetes with the weakening reactions to insulin, glycogen synthesis and uptake of glucose is not able to rise despite the relatively high level of insulin in the blood. This leads to abnormally high blood glucose with acute and long-term effects, which ultimately can lead to cardiovascular disease, kidney failure and blindness. In such patients is not normal inhibition of GSK-3 induced by insulin. Already it was reported that in patients with type II diabetes is excessive expression of GSK-3 [WO 00/38675]. Thus, therapeutic inhibitors of GSK-3 may be useful for treatment of diabetes patients with impaired response to insulin.

The activity of GSK-3 has also been associated with Alzheimer's disease. This disease is characterized by a well-known β-amyloid peptide and the formation of intracellular neurofibrillary plexus. Neurofibrillary plexus contain hyperphosphorilated protein Tau, where Tau is phosphorylated on not correspond to the normal areas. Already shown that GSK-3 phosphorylates these anomalous areas in cell and zhivotnyh models. In addition, it was shown that inhibition of GSK-3 prevents hyperphosphorylated Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Thus, apparently, the activity of GSK-3 may promote the formation of neurofibrillary plexus and the development of Alzheimer's disease.

Another substrate for GSK-3 is β-catenin, which razloga the SJ after phosphorylation by GSK-3. It was reported that patients with schizophrenia have a reduced level β-catenin, which are accompanied by other diseases associated with loss of neural cells [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

Due to the biological importance of GSK-3 currently, there is interest in therapeutically effective inhibitors of GSK-3. There are recent reports [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)] small molecules that inhibit GSK-3.

For many of the above diseases associated with pathological activity of GSK-3, for their treatment goal is and other protein kinases. However, various protein kinases often operate on different biological pathways. For example, as recently reported (WO 00/12497 (Scios)), some derivatives of hintline are inhibitors of kinase R. It was reported that these compounds can be used to treat conditions characterized by increased activity R-α and/or increased activity of TGF-β. Although the activity R accompanied by a wide variety of diseases, including diabetes, there is no message indicating that the kinase R is an integral part of the transmission path insulininduced signal that regulates glycogen synthesis or uptake of glucose. Therefore, it is not expected that inhibition R unlike the tons of GSK-3 will enhance glycogen synthesis and/or uptake of glucose.

The need of search for new drugs to treat human diseases remains. Protein kinase Aurora-2 or GSK-3 is particularly attractive for the discovery of new medicines due to their important role in the occurrence and development of cancer, diabetes, Alzheimer's and other diseases.

DETAILED description of the INVENTION

It was found that the compounds of the present invention and the pharmaceutical composition can be used as inhibitors of protein kinases, in particular as inhibitors of protein kinases Aurora-2 or GSK-3. Provides compounds having the General formula I:

or their pharmaceutically acceptable derivatives or prodrugs where:

Z1-Z4such as described below;

ring a is selected from the group including:

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1any delegate not ortho-position in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with them the tick atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring, having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, where heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or a group-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, each specified phenyl, heteroaryl and heterocyclyl ring optionally substituted groups in number to three, selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and adjacent for estatel, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Rxand Ryindependently selected from T-R3or Rxand Rytogether with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Ryreplaced by oxopropoxy or T-R3and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Rysubstituted by the radical R4;

T is a bond or C1-4alkylidene chain;

R2and R2'independently selected from-R, -T-W-R6or R2and R2'together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, NO2, -R7or V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R 2and R2'substituted by the radical R4;

R3selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2,

-SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R or

-OC(=O)N(R7)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6al the factual group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6), -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring;

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6; and

R9selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2,

-OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR,

-N(R4)CON(R4)2 , -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2.

In this description should be used, unless specified otherwise, the following definitions of the used terms. The phrase "optionally substituted" is used interchangeably with the expression "substituted or unsubstituted" or with the term "(UN)substituted". Unless otherwise specified, optionally substituted group may have a substituent at each substitutable position of the group and each substitution is not dependent on another.

The term "aliphatic" as used in this description means an unbranched, branched or cyclic With1-With12hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted unbranched, branched or cyclic alkylene, alkeline, alkyline group, or their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl and alkoxycarbonyl used as such or as part of a larger fragment, cover both unbranched and branched chains containing one to twelve carbon atoms. Those who mines "alkenyl" and "quinil", used as such or as part of a larger fragment, cover both unbranched and branched chains containing two to twelve carbon atoms. The term "cycloalkyl used as such or as part of a larger fragment, includes cyclic With3-C12hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic.

The terms "halogenated", "halogenoalkanes and halogenoalkane" mean respectively an alkyl, alkenyl or alkoxy, substituted by one or more halogen atoms. The term "halogen" means F, Cl, Br, or I. the Term "heteroatom" means nitrogen, oxygen or sulfur, and covers any oxidized form of nitrogen and sulfur and quaternion the form of any of the nitrogenous base. The term "nitrogen" also includes substituted nitrogen in the heterocyclic ring. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be in the form of N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl).

The terms "carbocycle", "carbocyclic", "carbocycle" or "carbocyclic" as used in this description to mean aliphatic ring system having from three datetime.date members. The terms "carbocycle", "carbocyclic", "carbocycle" or "carbocyclic", saturated or partially unsaturated, also refers to rings that are optionally substituted. The terms "carbocycle", "carbocyclic", "carbocycle" or "carbocyclic" also cover aliphatic rings, condensed with one or more aromatic or non-aromatic rings, such as in decahydronaphthalene or tetrahydronaphthyl, where the radical or point of connection is located in the aliphatic ring.

The term "aryl"used herein alone or as part of a larger fragment, as in "aralkyl", "arakaki" or "aryloxyalkyl", refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-antracol and 2-antracol. The term "aryl" also refers to rings that are optionally substituted. The term "aryl" can be used interchangeably with the term "aryl ring". "Aryl" also includes a condensed polycyclic aromatic ring systems in which an aromatic ring condensed with one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-antracol and 2-antracol. The term "aryl" when used in this description includes changegroup, in which the aromatic ring condensed with one or more non-aromatic rings, such as indanyl, phenanthridine or tetrahydronaphthyl, where the radical or point of connection is located in the aromatic ring.

The term "heterocycle", "heterocyclyl" or "heterocyclic" as used in this description includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbon atoms, preferably from one to four, replaced each by a heteroatom such as N, O or S. Examples of heterocyclic rings include 3-1H-benzimidazole-2-(1-substituted)-2-oxopentanoate-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3]-DIOXOLANYL, [1,3]-dithiolane, [1,3]-dioxane, 2-tetrahydrothiophene, 3-tetrahydrothiophene, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholine, 3-thiomorpholine, 4-thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinil, 2-piperazinil, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidine, diisononyl N-substituted of diisononyl, l-phtalimide, benzoxazol, benzopyranyl, benzoperylene, benzocaine, benzothiophenes and sensational. In the scope of the term "heterocyclyl the or "heterocyclic" as used in this description also includes the group, in which the non-aromatic ring containing a heteroatom, condensed with one or more aromatic or non-aromatic rings, such as indolinyl, bromanil, phenanthridine or tetrahydroquinoline, where the radical or point of connection is a non-aromatic containing heteroatom ring. The term "heterocycle", "heterocyclyl" or "heterocyclic", saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term "heteroaryl", used alone or as part of a larger fragment, as in "heteroalkyl" or "heteroaromatics", refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4 pirimidil, 5 pirimidil, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothiazyl, benzofuranyl, indolyl, chinoline, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, ethenolysis, indolyl, ISO is refilled, acridine or benzisoxazole. In the scope of the term "heteroaryl" when used in this specification also includes the group in which the heterocyclic ring condensed with one or more aromatic or nonaromatic rings, where the radical or point of connection is heteroaromatic ring. Examples include tetrahydroquinoline, tetrahydroisoquinoline and pyrido[3,4-d]pyrimidinyl. The term "heteroaryl" also refers to rings that are optionally substituted. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Aryl (including aralkyl, Alcoxy, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl, heteroaromatics and the like) group may contain one or more substituents. Examples of suitable substituents at the unsaturated carbon atom aryl, heteroaryl, aranceles or heteroalkyl groups include halogen, -Rabout, -ORabout, SRabout, 1,2-methylenedioxy, 1,2-Ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O(Ph), substituted

-O(Ph), -CH2(Ph), substituted-CH2(Ph), -CH2CH2(Ph), substituted

-CH2CH2(Ph), -NO2, -CN, -N(R°)2, -NR°C(O)R°, -NR°C(O)N(R°)2,/p>

-NRaboutCO2Rabout, -NR°NR°C(O)R°, -NR°NR°C(O)N(R°)2, -NR°NR°CO2Rabout,

-C(O)C(O)R°, -C(O)CH2C(O)R°, -CO2R°, -C(O)R°, -C(O)N(R°)2,

-OC(O)N(R°)2, -S(O)2Rabout, -SO2N R°)2, -S(O)R°, -NR°SO2N R°)2,

-NRaboutSO2Rabout, -C(=S)N(R°)2, -C(=NH)-N(R°)2, -(CH2)yNHC(O)R°,

-(CH2)yNHC(O)CH(V-Rabout)(R°), where R° represents hydrogen, substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -O(Ph), substituted-O(Ph), -CH2(Ph), or substituted-CH2(Ph), y is 0-6 and V represents a linking group. Examples of substituents in the aliphatic group or the phenyl ring of the radical Raboutinclude amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylsulphonyl, hydroxy, halogenoalkane or halogenated.

Aliphatic group or non-aromatic heterocyclic ring may contain one or more substituents. Examples of suitable substituents at saturated carbon atom aliphatic the banking group or non-aromatic heterocyclic ring include those listed above for the unsaturated carbon atom of the aryl or heteroaryl group and the following:=O,=S,=NNHR*,=NN(R*) 2,=N-,=NNHC(O)R*,=NNHCO2(alkyl),=NNHSO2(alkyl), or=NR*, where each R* is independently selected from hydrogen, unsubstituted aliphatic group or substituted aliphatic group. Examples of substituents in the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylsulphonyl, hydroxy, halogenoalkane or halogenated.

Suitable substituents at the nitrogen atom non-aromatic heterocyclic ring include-R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2and-NR+SO2R+where R+represents hydrogen, an aliphatic group, substituted aliphatic group, phenyl (Ph), substituted Ph, -O(Ph), substituted-O(Ph), -CH2(Ph), substituted-CH2(Ph) or unsubstituted heteroaryl or heterocyclic ring. Examples of substituents in the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxy, nitro, cyano, carb is XI, alkoxycarbonyl, alkylsulphonyl, hydroxy, halogenoalkane or halogenated.

The term "linking group" or "linker" means an organic fragment that connects two parts of the connection. Linkers typically comprise atom such as an oxygen atom or a sulfur atom, a link, such as-NH-, -CH2-, -C(O)-, -C(O)NH-, or chain of atoms, such as alkylidene chain. The molecular weight of the linker is in the range of usually about 14-200, preferably 14-96, at a length of approximately six atoms. Examples of linking groups include saturated or unsaturated With1-6alkylidene chain, which is optionally substituted and in which one or two saturated carbon optionally substituted by a group-C(O)-, -C(O)C(O)-, -CONH-, -CONHNH-, -CO2-, -OC(O)-, -NHCO2-, -O-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S-, -SO-, -SO2-, -NH-, -SO2NH or-NHSO2-.

The term "alkylidene chain" refers to optionally substituted unbranched or branched carbon chain, which may be fully saturated or may have one or more units of unsaturation. Optional substituents such as described above for the aliphatic group.

A valid combination of the substituents or variables, only if this combination produces a stable or chemically possible connection. Stable or chemically possible connection is the connection, the chemical structure of which essentially does not change during curing at a temperature of 40°or lower in the absence of moisture or other chemically active compounds for at least a week.

If not specified, it is assumed that shown in this description of the structure include them all stereochemical forms, i.e. R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric offer a mixture of the compounds are within the scope of the present invention. If not specified, it is assumed that shown in this description of the structure include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having the proposed structure, excluding the replacement of hydrogen by deuterium or tritium, or the replacement of carbon on13With or14C-enriched carbon are within the scope of the present invention.

Of the compounds of the formula I or their salts can be prepared composition. Preferred is a pharmaceutical composition. In one embodiment, the composition contains an amount of an inhibitor of protein kinase, effective for inhibiting protein kinases, including GSK-3 in a biological sample or in a patient. In another embodiment, with the organisations of the present invention and their pharmaceutical compositions which contain the amount of inhibitor of protein kinase, is effective for treatment or prevention of GSK-3-mediated condition and a pharmaceutically acceptable carrier, excipient or filler, can be manufactured in a form suitable for administration to a patient.

The term "GSK-3-mediated condition" or "disease" when used herein means any disease or other degraded state in which, as you know, plays the role of GSK-3. Such diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, due to AIDS dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, hypertrophy of the heart muscle, reperfusion ischemia and baldness.

One object of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof which comprises the administration to a patient a therapeutically effective amount of the compounds of formula I or pharmaceutical compositions. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production hyperphosphorylated protein Tau, which is useful to stop or slow the development of Alzheimer's disease. Another way belongs to and is generowania phosphorylation β -catenin, which is useful for the treatment of schizophrenia. Another object of the present invention is a method of inhibiting the activity of GSK-3 in a biological sample, which includes the implementation of contacting a biological sample with an inhibitor of GSK-3 formula I.

Another object of the present invention is a method of inhibiting the activity of Aurora-2 in a patient, which comprises administration to a patient compounds of the formula I or compositions containing the specified connection.

Another object of the present invention is a method of treatment or prevention of Aurora-2-mediated disease inhibitor of Aurora-2, which includes an introduction to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its containing composition.

The term "Aurora-2-mediated condition" or "disease" when used herein means any disease or other degraded state in which, as you know, plays the role of Aurora-2. The term "Aurora-2-mediated condition" or "disease" also means those diseases or conditions, which facilitates the treatment of inhibitor of Aurora-2. Such conditions include, without limitation, cancer. The term "cancer" includes, but is not limited to the following types of cancer: colon cancer and ovarian cancer.

Another object this is the future of the invention is a method of inhibiting the activity of Aurora-2 in the biological sample, which includes the implementation of contacting a biological sample with the Aurora inhibitor-2 of formula I or its containing composition. Another object of the present invention is a method of treatment or prevention of CDK-2-mediated disease inhibitor of CDK-2, which includes an introduction to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its containing composition.

The term "CDK-2-mediated condition" or "disease" when used herein means any disease or other degraded state in which, as you know, plays the role of CDK-2. The term "CDK-2-mediated condition" or "disease" also means those diseases or conditions, which facilitates the treatment of inhibitor of CDK-2. Such conditions include, without limitation, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M. and Lane, D.P., Current Medicinal Chemistry, 1, 1213-1245 (2000); Mani, S., Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Qpin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, M.D., Current Opinion in Qncologic, Endocrine &Metabolic Investi-gational Drugs, 2, 40-59 (2000).

Another object of the present invention is a method of inhibiting the activity of CDK-2 in a biological sample or patient, to the which includes the introduction of the patient, the compounds of formula I or compositions, containing the specified connection.

Another object of the present invention is a method of treatment or prevention of ERK-2-mediated diseases inhibitor of ERK-2, which includes an introduction to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its containing composition.

The term "ERK-2-mediated condition" when used herein means any disease state or other degraded state in which, as is well known, plays a role of ERK-2. The term "ERK-2-mediated condition" or "disease" also means those diseases or conditions that facilitates treatment with an inhibitor of ERK-2. Such conditions include, without limitation, cancer, shock, diabetes, gepatomegalia, cardiovascular disease, including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, including asthma, inflammation, neurological disorders and hormonal disorders. The term "cancer" includes, but is not limited to the following types of cancer: cancer of the breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoakantoma, lung cancer, epidermoid, karzi the WMD, both carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, cancer of the colon, adenoma, pancreas cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, cancer of the liver and bile ducts, kidney cancer, myeloid disorders, lymphoid disorders, hairy cells, Hodgkin's lymphoma, cancer of the vestibule of the mouth and throat (oral part), cancer of the lips, tongue, mouth, pharynx, small intestine, colon and rectum, colon, rectum, brain and Central nervous system, and leukemia. The protein kinase ERK-2 and its role in various diseases already described [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589].

Another object of the present invention is a method of inhibiting the activity of ERK-2 in a biological sample or in a patient, which comprises administration to a patient compounds of the formula I or compositions containing the specified connection.

Another object of the present invention is a JV is a method for treatment or prevention ACT-mediated diseases inhibitor of the ACT, which includes an introduction to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its containing composition.

The term "ACT-mediated condition" when used herein means any disease state or other degraded state in which, as you know, plays the role of the ACT. The term "ACT-mediated condition" or "disease" also means those diseases or conditions that facilitates treatment by an inhibitor of the ACT. ACT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer and neurodegenerative violations. The communications ACT, also known as protein kinase B, with various diseases already described [Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q.Y., et al, Oncogene, 19 2000; Kazuhiko, N., et al, The Journal of Neuroscience, 20 2000].

Another object of the present invention is a method of inhibiting AKT activity in a biological sample or in a patient, which comprises administration to a patient compounds of the formula I or compositions containing the specified connection.

Another object of the present invention is a method of treatment or prevention of Src-mediated disease inhibitor of Src, which includes an introduction to a patient in need of such treatment, a therapeutically effective amount of a compound of the formula Or its containing composition.

The term "Scr-mediated condition" when used herein means any disease state or other degraded state in which, as you know, plays the role of Src. The term "Src-mediated condition" or "disease" also means those diseases or conditions, which facilitates the treatment of inhibitor of Src. Such conditions include, but are not limited to, hypercalcemia, osteoporosis, osteoarthritis, symptomatic treatment of metastasis in bone and Paget's disease. The protein kinase Src and its role in various diseases already described [Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25(7), 717, (2000); Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys. Res. 243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); Staley, Cell Growth Diff., 8, 269 (1997)].

Another object of the present invention is a method of inhibiting Src activity in a biological sample or in a patient, which comprises administration to a patient compounds of the formula I or compositions containing the specified connection.

The term "pharmaceutically acceptable carrier, excipient or excipient" refers to non-toxic carrier, auxiliary substance or filler, which(OU), you can enter the patient instead of the e with a compound of the present invention and which(OE) does not violate the pharmacological activity of the compounds.

The term "patient" includes human and subjects of veterinary medicine.

The term "biological sample" as used in this description includes, without limitation, cell cultures or extracts, enzyme preparations suitable for in vitro studies, Bobcat taken from a mammal or extracts and blood, saliva, urine, feces, semen, tears and other body fluids or extracts.

The amount effective for inhibiting protein kinases, such as GSK-3 or Aurora-2, is a number, which significantly inhibits the kinase activity compared with the activity of the enzyme in the absence of inhibitor. To determine the inhibition can be used any way, such as, for example, in the following examples of biological tests.

Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions, include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as serum human albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glycerides, and mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, disodium hydrogen phosphate, potassium phosphate, sodium chloride, zinc salts, the colloid is first silicon dioxide, the magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

The compositions of the present invention can be administered orally, parenterally, by using an aerosol for inhalation, topical, rectal, nasal, transbukkalno, vaginally or via an implanted reservoir. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, vnutrigrudne, vnutriobolochechnoe, intrahepatic, intralesionally and intracranial ways injection or infusion. Preferably the composition is administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention can be an aqueous or oil suspension. These suspensions can be made known in this region methods using suitable dispersing or wetting means and suspendida funds. The sterile injectable preparation may also be a sterile solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the acceptable fillers and solvent is th, which can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment convenient to use sterile non-volatile oil. For this purpose you can use any mild non-volatile oils, including synthetic mono - or diglycerides. Suitable for the manufacture of injectable dosage forms fatty acids such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically-acceptable oils, such as olive or castor oil, in particular their polyoxyethylene version. These oil solutions or suspensions may also contain long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing means, which are usually used for the manufacture of pharmaceutically acceptable dosage forms including emulsions and suspensions. To obtain the dosage forms can also use other commonly used surfactants, such as Twins, Spiny and other emulsifying means or amplifiers bioavailability, which is usually used for the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms.

The pharmaceutical compositions according to the present izobreteniya to be administered orally in any acceptable form for oral administration of the dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration commonly used carriers include lactose and corn starch. Usually add lubricants such as magnesium stearate. For oral administration in capsule form suitable diluents include lactose and dried corn starch. When oral administration desired aqueous suspensions of the active ingredient is mixed with emulsifying and suspenders substances. If necessary, can also be added on any sweetening, corrective or coloring matter.

The pharmaceutical compositions of the present invention can be also introduced in the form of suppositories for rectal use. Suppositories can be manufactured by mixing the active ingredient with a suitable non-irritating by excipients, which is solid at room temperature, but liquid at a temperature in the rectum and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutical compositions of the present invention can also be introduced locally, in particular, when the goal of treatment areas or organs readily accessible by the e for local use, for example, in diseases of the eyes, skin, or the lower part of the gastrointestinal tract. Suitable dosage forms for topical application to easily get to each of these places or bodies.

Topical application for the lower intestinal tract can be achieved by rectal dosage forms in the form of a suppository (see above) or via a suitable composition for enemas. You can also use the patches for local percutaneous injection.

For topical applications, the pharmaceutical compositions can be manufactured in the form of a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. In accordance with another variant, the pharmaceutical composition can be manufactured in a suitable form of lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carrier materials include, but are not limited to, mineral oil, servicemonitor, Polysorbate 60, wax from complex atilovykh esters, CE is eerily alcohol, 2-octyldodecanol, benzyl Speer and water.

For ophthalmic use, the pharmaceutical compositions can be manufactured in the form of very thin suspensions in sterile isotonic saline with pH adjusted or, preferably, in the form of solutions in sterile isotonic saline with pH adjusted with preservative, such as benzalkonium chloride, or without it. In accordance with another variant of a pharmaceutical composition for ophthalmic use may be made in the form of ointment, such as vaseline.

The pharmaceutical compositions of the present invention can be also introduced by aerosol spray in the nose or by inhalation. Such compositions receive in accordance with technology well known in the manufacture of dosage forms, and they can be made in the form of solutions in saline solution using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other traditional solubilizing or dispersing agents.

In addition to the compounds of the present invention in compositions for the treatment and prevention of these diseases and disorders may also be used pharmaceutically acceptable derivative or Proletarsk is and compounds of the present invention.

"Pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable derivative in the form of a salt, complex, ester, salt of ester or other derivative compounds of the present invention that when administered to a recipient is able to give, directly or indirectly, a compound of the present invention or inhibitore active metabolite or residue. Particularly suitable derivatives or prodrugs are those that increase the bioavailability of the compounds of the present invention with the introduction of their patients (for example, providing oral introduced connection for easy absorption into the blood) or enhance delivery of the parent compound in biological items (e.g., the brain or lymphatic system) relative to the other source connection types.

Pharmaceutically acceptable prodrugs of compounds of the present invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfate esters.

Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycyrrhizinate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate. Other acids, for example oxalic, and are not pharmaceutically acceptable may be used to produce salts which are useful as intermediates for producing compounds of the present invention and their pharmaceutically acceptable acid additive salts.

Salts derived from appropriate bases include alkali metal salts (e.g. sodium and potassium), salts of alkaline earth metals (e.g. magnesium), ammonium salts and salts of N+(C1-4alkyl)4. The present invention also envisions the quaternization osnovnih nitrogen-containing groups of the compounds of the present invention. By such quaternization can be derived products, soluble in water or oil, or dispersible products.

If estvo inhibitor of protein kinase, which can be mixed with the media to produce a single dosage form may vary depending on subject to the treatment of the patient and the particular route of administration. Preferably the composition should be manufactured to a patient receiving these compositions, it was possible to get a dose of the inhibitor in the range of 0.01-100 mg/kg body weight/day.

It should also be understood that a specific dosage and treatment regimen for a particular patient will depend on many factors, including the specific activity of the applied compound, the age, body weight, General health, sex, diet, time of administration, rate of excretion, drug combination and the assessment of the treating physician and the severity of the particular disease to be treated. The amount of inhibitor will depend on the particular compound in the composition. Depending on the specific mediated by protein kinase condition that must be treated or prevented, together with the inhibitors of the present invention can be introduced additional drugs that are usually administered for the treatment or prevention of this condition. For example, in the treatment of diabetes with inhibitors of GSK-3 according to the present invention, intended for the treatment of diabetes, can be combined with other antidiabetic agents is. These tools include, but are not limited to, insulin or insulin analogs in the form of injection or inhalation, glitazones, alpha-glucosidase inhibitors, biguanides, insulin sensitizers and sulfonylureas.

Other examples of tools that can also be combined inhibitors of the present invention, include, but are not limited to, chemotherapeutic agents or other anti-proliferative agents such as adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, Taxol, interferons and platinum derivatives; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazin; immunomoduliruushimi and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazin; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, blockers of ion channels, riluzole, and anti-Parkinson's disease; a means for treating cardiovascular disease such as beta-blockers, ACE inhibitors (ACE), diuretics, nitrates, calcium channel blockers, and statins; means for treating liver disease such as corticosteroids,cholestyramine, interferons and antiviral agents; agent for treating blood disorders such as corticosteroids, anti-leukemia funds and growth factors, and means for treating immunodeficiency disorders such as gammaglobulin.

These additional funds can be entered separately from the composition containing an inhibitor of protein kinases, as part of the regimen of multiple drugs. In accordance with another variant, these funds can be part of a single dosage form, mixed with the inhibitor of the protein kinase of the present invention in a single composition.

Compounds of the present invention may exist in alternative tautomeric forms, as tautomers 1 and 2, shown below. Unless otherwise noted, the representation of a single tautomer implies the inclusion of the other.

Rxand Ry(the provisions of the Z3and Z4respectively) can be taken together with the formation of a condensed ring, which gives a bicyclic ring system containing ring A. the Preferred ring Rx-Ryinclude 5-, 6-, 7 - or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms and the specified ring Rx-Ryis optionally substituted. Below shows examples of the system is m with the ring in the compounds I-A - I-DD, where Z1represents nitrogen or C(R9and Z2represents nitrogen or C(H).

Preferred bicyclic system with ring And include I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-I, I-J, I-K, I-L and I-M, more preferably I-A, I-B, I-C, I-F and I-H, and most preferably I-A, I-B and I-H.

In a monocyclic system with ring And preferred groups Rxwhen they are present, include hydrogen, alkyl - or dialkylamino, acetamido or1-4aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred groups Rywhen they are present, include T-R3where T represents a bond or methylene, and R3is a-R, -N(R4)2or-OR. Examples of preferred groups Ryinclude 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl, and methoxymethyl.

In a bicyclic system with the ring And the ring formed together Rxand Rymay be substituted or unsubstituted. Suitable substituents include-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -S, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2where R and R4defined above. Preferred substituents in the ring Rx-Ryinclude halogen, -R, -OR, -COR, -CO2R, -CON(R4)2, -CN, or-N(R4)2where R represents hydrogen or optionally substituted C1-6aliphatic group.

R2and R2'can be taken together with the formation of a condensed ring, which gives a bicyclic ring system containing pyrazol ring. The preferred condensed rings include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclic ring, and specified the condensed ring is optionally substituted. Examples of these condensed rings represented by the following compounds of formula I, having pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'include one or more of the following substituents:halogen, -N(R4)2- 1-3alkyl, -C1-3halogenated, -NO2, -O(C1-3alkyl), -CO2(C1-3alkyl), -CN, -SO2(C1-3alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-3alkyl), -NHC(O)(C1-3alkyl), -C(O)NH2and-CO(C1-3alkyl), where (C1-3alkyl) is most preferably represents methyl.

When pyrazol ring system is monocyclic, group, R2include hydrogen, C1-4aliphatic group, alkoxycarbonyl, (UN)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono - or dialkylaminoalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, phenylenecarbonyl and (N-heterocyclyl)carbonyl. Examples of such preferred substituents R2include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-butyl, cyclopentyl, phenyl, CO2H, CO2CH3CH2OH, CH2OCH3CH2CH2CH2OH, CH2CH2CH2OCH3CH2CH2CH2OCH2Ph, CH2CH2CH2NH2CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CH=CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H 7)2, CO(3-methoxypiperidine-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholine-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2and CO(piperidine-l-yl). Preferred R2'is hydrogen.

An option that is particularly useful for the treatment of GSK-3-mediated disease, refers to compounds of the formula II:

or their pharmaceutically acceptable derivatives or prodrugs where:

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1any replaced nearto-position in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl the nogo rings or 1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl rings are optionally substituted by each of the groups in the number to three, selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Rxand Ryindependently selected from T-R3or Rxand Rytogether with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Ryreplaced by oxopropoxy or T-R3and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Rysubstituted by the radical R4;

T is a bond or C1-4alkylidene chain;

R2and R2'independently selected from-R, -T-W-R6or R2and R2'together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated ilization unsaturated ring, having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, NO2, -R7or V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2'substituted by the radical R4; R3selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2,

-SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R or

-OC(=O)N(R7)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4the same is the volume of nitrogen, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C( 6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring; and

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO 2R6.

When the group Rxand Ryin formula II, together with the formation of the condensed ring, the preferred ring Rx-Ryinclude 5-, 6-, 7 - or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, and the specified ring Rx-Ryis optionally substituted. This gives the bicyclic ring system, containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula II are mono - or bicyclic system, shown below.

More preferred pyrimidine ring systems of formula II include II-A, II-B, II-C, II-F and II-H, most preferably II-A, II-B and II-H.

In monocyclic pyrimidine ring system of formula II, the preferred groups Rxinclude hydrogen, alkyl - or dialkylamino, acetamido or1-4aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred groups Ryinclude T-R3where T represents a bond or methylene, and R3is a-R,

-N(R4)2or-OR. When R3is a-R or-OR, preferably R is an optionally substituted group selected from C1-6aliphati eskay group, phenyl or 5-6 membered heteroaryl or heterocyclyl rings. Examples of preferred groups Ryinclude 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl, and methoxymethyl.

In bicyclic pyrimidine ring system of formula II, the ring formed together Rxand Rymay be substituted or unsubstituted. Suitable substituents include-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R,

-SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR,

-N(R4)CO2(optionally substituted C1-6aliphatic group),

-N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2where R and R4such as defined above. Preferred substituents in the ring Rx-Ryinclude halogen, -R, -OR, -COR, -CO2R, -CON(R4)2, -CN, or-N(R4)2where R is an optionally substituted C1-6aliphatic group.

Group R2and R2'formula II can be taken together with the formation of the condensed ring is, that gives the bicyclic ring system containing pyrazol ring. The preferred condensed rings include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclic ring. Examples of these condensed rings represented by the following compounds of formula II having pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'formula II include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated,

-NO2, -O(C1-4alkyl), -CO2(C1-4alkyl), -CN, -SO2(C1-4alkyl),

-SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl),

-C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

When pyrazol ring system of formula II is monocyclic, preferred groups R2include hydrogen, substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group. Examples of such preferred groups R2includes the t methyl, tert-butyl, -CH2OCH3cyclopropyl, furanyl, thienyl and phenyl. A preferred group R2'is hydrogen.

Preferred ring systems of formula II are the following systems, which can be substituted as described above, where R2and R2'taken together with the pyrazol ring, form indazol ring, and Rxand Ryare each methyl, or Rxand Rytaken together with the pyrimidine ring form hintline or tetrahydroquinazoline ring:

Especially preferred are those compounds of formula II-Aa, II-Ba or II-Ha, in which the ring is a phenyl ring and R1represents halogen, methyl or trifluoromethyl.

Preferred groups for rings in formula II are phenyl and pyridinyl. When two neighboring substituent in the ring together With each other to form a condensed ring, the ring is a bicyclic ring system. The preferred condensed ring include a benzene or pyridine ring. Such rings are preferably condensed in ortho - and meta-positions of ring C. Examples of preferred bicyclic systems for rings include naphthyl, chinoline and ethenolysis.

It is important the feature of the compounds of the formula II is ortho-substituent R 1in ring C. ortho-position in the ring C or ring D is relative to the position where the attached ring A. Preferred groups include halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN,

-SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or

-NHSO2R6. When R1represents an optionally substituted

C1-6aliphatic group, preferred optional substituents are halogen-free. Examples of preferred groups R1include-CF3, -Cl, -F, -CN, COCH3, -OCH3, -OH, -CH2CH3, -OCH2CH3, -CH3, -CF2CH3, cyclohexyl, tert-butyl, isopropyl, cyclopropyl- ≡- ≡CH3, -SO2CH3, -SO2NH2, -N(CH3)2, -CO2CH3, -CONH2, -NHCOCH3, -OC(O)NH2, -NHSO2CH3and-OCF3.

In the C ring of the formula II, preferred substituents R5when they are present, include halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2and-N(R4)SO2R. More preferred substituents R5include-Cl, -F, -CN, -CF , -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group). Examples of such preferred substituents include-Cl, -F, -CN, -CF3, -NH2, -NHMe, -NMe2, -OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl and-CO2Et.

Preferred compounds of formula II have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring;

(b) Rxrepresents hydrogen or C1-4aliphatic group, and Ryis a T-R3or Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogen atom;

(C) R1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH , -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; and

(d) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula II have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring;

(b) Rxrepresents hydrogen or methyl and Ryis a-R, N(R4)2or-OR, or Rxand Rytaken together with the intermediate atoms with the formation of a 5-7 membered unsaturated or partially unsaturated carbocyclic ring, optionally substituted by a group-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, SO 2R, -SR, -N(R4)2,

-CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group),

-N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2;

(C) R1represents a halogen, With1-6halogenations group1-6aliphatic group, phenyl, or-CN;

(d) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(e) each R5independently selected from halogen, -CN, -NO2,

-N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R.

Even more preferred compounds of formula II have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring represent a phenyl ring, optionally substituted by a group-R5;

(b) Rxrepresents hydrogen or methyl, and Ryrepresents methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, or Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted benzene ring or a partially unsaturated 6-membered carbocyclic ring;

(C) R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or-CN;

(d) R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN,

-SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl),

-NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group; and

(e) each R5independently selected from-Cl, -F, -CN, -CF3, -NH 2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2,

-O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group).

Representative compounds of formula II are shown below in table 1.

Table 1

In another embodiment, the present invention is a composition comprising a compound of formula II and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting the activity of protein kinase GSK-3 in a patient, included is a first introduction to the patient a therapeutically effective amount of the composition, containing the compound of formula II.

Another object of the present invention is a method of treatment of the disease, which facilitates treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula II.

Another object of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula II. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula II. This method is especially useful for stopping or slowing the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula II. This with the persons particularly useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula II.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula II. This method is particularly useful for the treatment of cancer such as cancer of the colon, ovarian cancer and lung cancer.

One object of the present invention is a method of inhibiting the activity of protein kinase CDK-2 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula II.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase CDK-2, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula II. This method is particularly useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, ater the sclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3, Aurora or CDK-2 of the formula II or its containing pharmaceutical composition in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

Each of the above methods directed to the inhibition of GSK-3, Aurora or CDK-2, or treatment of the disease, making it easier for the specified inhibition, preferably carried out using the preferred compounds of formula II, such as described above for the connection.

Another variant of the present invention relates to compounds of the formula III:

or their pharmaceutically acceptable derivatives or prodrugs where:

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or group

-R5and l is the God substitutable ring nitrogen by a group-R 4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

Rxand Rytaken together with the intermediate atoms, form a condensed benzene ring or a 5-8-membered carbocyclic ring, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Ryreplaced by oxopropoxy or group T-R3;

T is a bond or C1-4alkylidene chain;

R2and R2'independently selected from-R, -T-W-R6or R2and R2'together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, -NO2,

-R7or-V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2'substituted by the radical R4;

R3selected from-R, halogen,=O, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R4 )2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO 2R or

-OC(=O)N(R4)2;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-, -C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two grams of uppi R 6at the same nitrogen atom together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring; and

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring.

Preferred monocyclic ring to D ring in formula III include substituted and unsubstituted phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, aspenlea and morpholinyl rings. When two neighboring substituent D ring together with each other to form a condensed ring, the ring system D is bicyclic. Preferred bicyclic ring for ring D in the formula III include 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, ethenolysis, chinoline and naphthyl. Examples of preferred bicyclic systems for D rings include naphthyl and ethenolysis.

Preferred substituents R5in ring D of formula III include halogen, oxo, CN, -NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2 R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. More preferred substituents R5include halogen, -CN,

-oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. Examples of substituents in ring D include-OH, phenyl, methyl, CH2OH, CH2CH2OH, pyrrolidinyl, OPh, CF3C≡, Cl, Br, F, I, NH2C(O)CH3, isopropyl, tert-butyl, SEt, OMe, N(Me)2methylendioxy, Ethylenedioxy.

Preferred rings formed when Rxand Rytaken together form a condensed ring include 5-, 6 - or 7-membered unsaturated or partially unsaturated carbocyclic ring, where any substitutable carbon atom in this condensed ring substituted by oxopropoxy or group T-R3. Examples of preferred bicyclic ring systems shown below:

Preferred substituents in the condensed ring Rx-Ryin formula III include-R, oxo, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R )2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2where R and R4such as defined above. More preferred substituents in the condensed ring Rx-Ryinclude halogen, -CN, oxo, C1-6alkyl, C1-6alkoxy, (C1-6alkyl)carbonyl, (C1-6alkyl)sulfonyl, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl or 5-6-membered heteroaryl. Examples of such preferred substituents include methoxy, methyl, isopropyl, methylsulphonyl, cyano, chlorine, pyrrolyl, methoxy, ethoxy, ethylamino, acetyl, acetamido.

Preferred substituents R2in formula III include hydrogen, C1-4aliphatic group, alkoxycarbonyl, (UN)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono - or dialkylaminoalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, phenylenecarbonyl and (N-heterocyclyl)carbonyl. Examples of such preferred substituents R2include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-butyl, cyclopentyl, phenyl, CO2H, CO2CH3CH2OH, CH2CH 3CH2CH2CH2OH, CH2CH2CH2OCH3CH2CH2CH2OCH2Ph, CH2CH2CH2NH2CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CH=CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2, CO(3-methoxypiperidine-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholine-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2and CO(piperidine-l-yl).

When the group R2and R2'in the formula III, taken together, form a ring, preferred ring system R2-R2'containing pyrazol ring, include benzo, pyrido, pyrimido, 3-oxo-2H-pyridazino and partially unsaturated 6-membered carbocyclic ring. Examples of these preferred ring systems R2-R2'containing pyrazol ring, include:

Preferred substituents in the condensed ring R2-R2'in formula III include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated,

-NO2, -O(C1-4alkyl), -CO2(C1-4alkyl),-CN, -SO2(C1-4alkyl),

-SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl),

-C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

Preferred compounds of formula III have one or more, and more preferably all of the characteristics selected from the group including:

(a) ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Rxand Rytaken together with the intermediate atoms, form an optionally substituted benzene ring or a 5-7 membered carbocyclic ring; and

(C) R2'represents hydrogen or methyl and R2is a T-W-R6or R, where W represents-C(R6)2O-, -C(R6)2N(R6)-, -CO-, -CO2-, -C(R6)OC(O)-, -C(R6)2N(R6)CO-, -C(R6)2N(R6)With(O)is - or-CON(R 6)- and R is an optionally substituted group selected from C1-6aliphatic group or phenyl, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula III have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Rxand Rytaken together with the intermediate atoms, form a benzene ring or a 5-7 membered carbocyclic ring, optionally substituted by a group R, oxo, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4 )2, -N(R4)SO2R or-OC(=O)N(R4)2; and

(C) each R5independently selected from halogen, oxo, CN, NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl,6-10aryl or1-6aliphatic group.

Even more preferred compounds of formula III have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or 6-membered partially unsaturated carbocyclic ring, optionally substituted with halogen, CN, oxo, C1-6the alkyl, C1-6alkoxy, (C1-6alkyl)carbonyl, (C1-6alkyl)sulfonyl, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl or 5-6-membered heteroaryl;

(b) each R5independently selected from halogen, -CN, oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl,6-10aryl or1-6aliphatic group; and

(C) R2'represents hydrogen or methyl and R2is a T-W-R6or R, where W is the Wallpaper-C(R 6)2O-, -C(R6)2N(R6)-, -CO-, -CO2-, -C(R6)OC(O)-, -C(R6)2N(R6)CO -, or-CON(R6)-, and R represents an optionally substituted group selected from C1-6aliphatic group or phenyl, or R2and R2'taken together with the intermediate atoms, form a benzene, pyridine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen,

-N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN, -SO2(C1-4by alkyl), -SO2NH2,

-OC(O)NH2, -NH2SO2(C1-4by alkyl), -NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group.

Representative compounds of formula III are shown below in table 2.

Table 2

In another embodiment, the present invention relates to compositions containing a compound of formula III and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting the activity of protein kinase GSK-3 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula III.

Another object of the present invention is a method of treatment of the disease, which facilitates treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula III.

Another object of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula III. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula III. This method is particularly Olesen to stop or slow the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising introducing the indicated patient a therapeutically effective amount of a composition containing the compound of formula III. This method is particularly useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula III.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula III. This method is particularly useful for the treatment of cancer such as cancer of the colon, and breast cancer.

One object of the present invention is a method of inhibiting the activity of protein kinase CDK-2 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula III.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of the prot is skenazy CDK-2, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula III. This method is particularly useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis.

One object of the present invention is a method of inhibiting Src activity in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula III.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Src, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula III. This method is particularly useful for the treatment of hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of metastasis in bone and Paget's disease.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora, CDK-2 or Src in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3, Aurora, CDK-2 or Src formula III or containing the its pharmaceutical composition in an amount, effective for inhibition of GSK-3, Aurora, CDK-2 or Src.

Each of the above methods directed to the inhibition of GSK-3, Aurora, CDK-2 or Src or treatment of the disease, making it easier for the specified inhibition, preferably carried out using the preferred compounds of formula III, such as described above for the connection.

The compounds of formula III, where R2'represents hydrogen and Rxand Rytaken together with the pyrimidine ring form an optionally substituted khinazolinov ring system, are also inhibitors of protein kinases ERK-2, and ACT.

Thus, another object of the present invention is a method of inhibiting the activity of protein kinase ERK-2, or ACT in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula III, where R2'represents hydrogen and Rxand Rytaken together with the pyrimidine ring form an optionally substituted khinazolinov ring system.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase ERK-2 or the ACT, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula III,where R 2'represents hydrogen and Rxand Rytaken together with the pyrimidine ring form an optionally substituted khinazolinov ring system. This method is particularly useful for the treatment of cancer, shock, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, restenosis, psoriasis, allergic disorders, including asthma, inflammation and neurological disorders.

Another variant of the present invention relates to compounds of the formula IV:

or their pharmaceutically acceptable derivatives or prodrugs where:

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or group

-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R xand Ryindependently selected from T-R3or Rxand Rytaken together with the intermediate atoms, comprise the condensed unsaturated or partially unsaturated 5-8-membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring is optionally and independently substituted by a group T-R3and any substitutable nitrogen atom in the specified ring substituted by the radical R4;

T is a bond or C1-4alkylidene chain;

R2and R2'independently selected from-R, -T-W-R6or R2and R2'taken together with the intermediate atoms, comprise the condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the aforementioned condensed ring is optionally substituted groups in number to three, independently selected from halogen, oxo, -CN, -NO2, -R7or-V-R6;

R3selected from-R, halogen,=O, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2C=NN(R 4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6/sup> )C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-, -C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring; and

each R7not avisio selected from hydrogen or optionally substituted C 1-6aliphatic group, or two R7at the same nitrogen atom together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring.

Preferred monocyclic ring to D ring in formula IV include substituted and unsubstituted phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, aspenlea and morpholinyl rings. Preferred bicyclic ring for ring D in the formula IV include 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, ethenolysis, chinoline and naphthyl. Examples of preferred bicyclic rings, D rings include naphthyl and ethenolysis.

Preferred substituents in ring D of formula IV include halogen, oxo, CN, -NO2, -N(R4)2, -CO2R, -CONH(R4),

-N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. More preferred substituents R5include halogen, -CN,

-oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic GRU is dust. Examples of substituents in ring D include-OH, phenyl, methyl, CH2OH, CH2CH2OH, pyrrolidinyl, OPh, CF3C≡, Cl, Br, F, I, NH2C(O)CH3, isopropyl, tert-butyl, SEt, OMe, N(Me)2methylendioxy, Ethylenedioxy.

When the group Rxand Ryin formula IV, taken together, form a condensed ring, the preferred ring Rx-Ryinclude 5-, 6-, 7 - or 8-membered unsaturated or partially unsaturated ring having 1-2 heteroatom. This gives the bicyclic ring system, containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IV are mono - or bicyclic system, shown below.

More preferred pyrimidine ring systems of formula IV include IV-E, IV-G, IV-H, IV-J IV-K IV-L, IV-M, IV-T and IV-U.

In monocyclic pyrimidine ring system of the formula IV preferred groups Rxinclude hydrogen, amino, nitro, alkyl - or dialkylamino, acetamido or1-4aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred groups Ryinclude T-R3where T represents a bond or methylene, and R3is a-R, -N(R4)2or-OR. When R3represents R or or, the preferred R is an optionally substituted group selected from C1-6aliphatic group, phenyl, or 5-6 membered heteroaryl or heterocyclyl rings. Examples of preferred groups Ryinclude 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl, methoxyphenyl, trimethoxyphenyl or halogen-substituted phenyl, and methoxymethyl.

In bicyclic pyrimidine ring system of the formula IV, the ring formed together Rxand Rymay be substituted or unsubstituted. Suitable substituents include-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R,

-SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR,

-N(R4)CO2(optionally substituted C1-6aliphatic group),

-N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2where R and R4such as defined above for compounds of formula IV. Preferred substituents in the ring Rx-Ryinclude halogen, -R, -OR, -COR, -CO2R, -CON(R4)2,

-CN, or-N(R4)2where R PR is dstanley a substituted or unsubstituted With 1-6aliphatic group.

Group R2and R2'formula IV can be taken together with the formation of a condensed ring, which gives a bicyclic ring system containing pyrazol ring. The preferred condensed rings include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclic ring. Examples of these condensed rings represented by the following compounds of the formula IV with pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'formula IV include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated,

-NO2, -O(C1-4alkyl), -CO2(C1-4alkyl), -CN, -SO2(C1-4alkyl),

-SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl),

-C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

When pyrazol ring system of formula IV is monocyclic, preferred groups R2include hydrogen, substituted or nezameshchennogo, selected from aryl, heteroaryl or C1-6aliphatic group. Examples of such preferred groups R2include methyl, tert-butyl, -CH2OCH3cyclopropyl, furanyl, thienyl and phenyl. A preferred group R2'is hydrogen.

Preferred compounds of formula IV have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Rxrepresents hydrogen or C1-4aliphatic group, and Ryis a T-R3or Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 heteroatoms; and

(C) R2'represents hydrogen or methyl, and R2is a T-W-R6or R, where W is a

-C(R6)2O-, -C(R6)2N(R6)-, -CO-, -CO2-, -(R 6)OC(O)-, -C(R6)2N(R6)CO-, -C(R6)2N(R6)C(O)O -, or-CON(R6)-, and R represents an optionally substituted group selected from C1-6aliphatic group or phenyl, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula IV have one or more, and more preferably all of the characteristics selected from the group consisting of: (a) ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Rxrepresents hydrogen or methyl and Ryis a-R, -N(R4)2or-or, or Rxand Rytaken together with the intermediate atoms with the formation of a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogen atom, and the specified ring is optionally substituted by a group-R, halogen, oxo, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)sub> 2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2; and

(C) each R5independently selected from halogen, oxo, CN, NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR,

-OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl,6-10aryl or1-6aliphatic group.

Even more preferred compounds of formula IV have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Rxand Rytaken together with the intermediate atoms with the formation of 6-membered unsaturated or partially unsaturated ring with 1-2 ring nitrogen atoms, optionally substituted with halogen, CN, oxo, C1-6the alkyl, C1-6alkoxy, (C1-6alkyl)carbonyl, (C1-6alkyl)sulfonyl, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl or 5-6-membered heteroaryl;

(b) each R5independently selected from halogen, -CN, oxo, -SR, -OR, -N( 4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl,6-10aryl or1-6aliphatic group; and

(C) R2'represents hydrogen and R2is a T-W-R6or R, where W represents-C(R6)2O-, -C(R6)2N(R6)-, -CO-, -CO2-, -C(R6)OC(O)-, -C(R6)2N(R6)CO -, or-CON(R6)-, and R represents an optionally substituted group selected from C1-6aliphatic group or phenyl, or R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen, oxo, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN, -SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl), -NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group.

Representative compounds of formula IV shown below in table 3.

Table 3

In another embodiment, the present invention is a composition comprising a compound of formula IV and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting the activity of protein kinase GSK-3 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula IV.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula IV.

Another object of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula IV. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula IV. This method was particularly useful is n to stop or slow the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula IV. This method is particularly useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula IV. Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula IV. This method is particularly useful for the treatment of cancer such as cancer of the colon, ovarian cancer and breast cancer.

One object of the present invention is a method of inhibiting the activity of protein kinase CDK-2 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula IV.

Another object of the present invention is a method of treatment of the disease, providing treatment inhibitor is proteinkinase CDK-2, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula IV. This method is particularly useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3, Aurora or CDK-2 formula IV or its containing pharmaceutical composition in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

Each of the above methods directed to the inhibition of GSK-3, Aurora or CDK-2, or treatment of the disease, making it easier for the specified inhibition, preferably carried out using the preferred compounds of formula IV, such as described above for the connection.

Another variant of the present invention relates to compounds of the formula V:

or their pharmaceutically acceptable derivatives or prodrugs where:

Z1represents N, CRandor CH, and Z2represents N or CH, provided that Thu is one of the Z 1and Z2represents nitrogen;

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1any delegate not ortho-position in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or a group-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D submitted is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl rings are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Rxand Ryindependently selected from T-R3or Rxand Rytogether with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Ryreplaced by oxopropoxy or T-R3and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Rysubstituted by the radical R4;

T is a bond or C alkylidene chain;

R2and R2'independently selected from-R, -T-W-R6or R2and R2'together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, NO2, -R7or V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2'substituted by the radical R4;

R3selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2,

-SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R or

-OC(=O)N(R7)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl to what ICA, having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6 )2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-, -C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl the ring;

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6; and

Randselected from halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2,

-CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2,

-N(R4)SO2N(R4)2, -N(R4)SO2R, -OC(=O)N(R4)2or an optionally substituted group selected from C1-6aliphatic group6-10aryl group, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms.

The compounds of formula V can be represented with a specific Z1and Z2as shown below:

When the group Rxand Ryin the formula V taken together with each other to form a condensed ring, the preferred ring Rx-Ryinclude 5-, 6-, 7 - or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatom is, moreover, the specified ring Rx-Ryis optionally substituted. This gives the bicyclic ring system, containing the pyridine ring. Examples of preferred bicyclic ring systems of formula V is shown below.

Preferred bicyclic ring system of formula V include Va-B, Vb-A, Vc-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D, Va-E, Vb-E, Vc-E, Va-J, Vb-J, Vc-J Va-K, Vb-K Vc-K, Va-L, Vb-L Vc-L, Va-M Vb-M and Vc-M, most preferably Va-B, Vb-A, Vc-A, Va-B, Vb-B and Vc-B.

In monocyclic pyridine ring system of the formula V are preferred groups Rxinclude hydrogen, alkyl - or dialkylamino, acetamido or1-4aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred groups Ryinclude T-R3where T represents a bond or methylene, and R3is a-R,

-N(R4)2or-OR. When R3is a-R or-OR, preferably R is an optionally substituted group selected from C1-6aliphatic group, phenyl, or 5-6 membered heteroaryl or heterocyclyl rings. Examples of preferred groups Ryinclude 2-pyridyl, 4-pyridyl, piperidinyl, ethyl, ethyl cyclopropyl, isopropyl, tert-butyl, alkyl - or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl, and methoxymethyl.

In bicyclic pyrimidine ring system of the formula V ring formed together Rxand Rymay be substituted or unsubstituted. Suitable substituents include-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R,

-SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR,

-N(R4)CO2(optionally substituted C1-6aliphatic group),

-N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2where R and R4such as defined above. Preferred substituents in the ring Rx-Ryinclude halogen, -R, -OR, -COR, -CO2R, -CON(R4)2, -CN, or-N(R4)2where R is an optionally substituted C1-6aliphatic group.

Group R2and R2'formula V may be taken together with each other to form a condensed ring, which gives a bicyclic ring system containing pyrazol ring. The preferred condensed rings include benzo, pyrido, PI is imido and partially unsaturated 6-membered carbocyclic ring. Examples of these condensed rings represented by the following compounds of formula V having pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'formula V include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated,

-NO2, -O(C1-4alkyl), -CO2(C1-4alkyl), -CN, -SO2(C1-4alkyl),

-SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl),

-C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

When pyrazol ring system is monocyclic, preferred groups R2include hydrogen, C1-4aliphatic group, alkoxycarbonyl, (UN)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono - or dialkylaminoalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, phenylenecarbonyl and (N-heterocyclyl)carbonyl. Examples of such preferred substituents R2include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-butyl, cyclopentyl, phenyl, CO 2H, CO2CH3CH2OH, CH2OCH3CH2CH2CH2OH, CH2CH2CH2OCH3CH2CH2CH2OCH2Ph, CH2CH2CH2NH2CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CH=CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2, CO(3-methoxypiperidine-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholine-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2and CO(piperidine-l-yl). Preferred R2'is hydrogen.

Preferred ring systems of formula V are the following systems, which can be substituted as described above, where R2and R2'taken together with the PIR azole ring, form an optionally substituted indazol ring, and Rxand Ryare each methyl, or Rxand Rytaken together with the pyridine ring, form an optionally substituted quinoline, isoquinoline, tetrahydroquinoline or tetrahydroisoquinoline ring:

When G is a ring, the preferred groups for Kohl is as in formula V are phenyl and pyridinyl. When two neighboring substituent in the ring together With each other to form a condensed ring, the ring is a bicyclic ring system. The preferred condensed ring include a benzene or pyridine ring.

Such rings are preferably condensed in ortho - and meta-positions of ring C. Examples of preferred bicyclic systems for rings include naphthyl and ethenolysis. Preferred groups R1include halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN,

-SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or

-NHSO2R6.

When R1represents an optionally substituted

C1-6aliphatic group, preferred optional substituents are halogen-free. Examples of preferred groups R1include-CF3, -Cl, -F, -CN, COCH3, -OCH3, -OH, -CH2CH3, -OCH2CH3, -CH3, -CF2CH3, cyclohexyl, tert-butyl, isopropyl, cyclopropyl- ≡- ≡CH3, -SO2CH3, -SO2NH2, -N(CH3)2, -CO2CH3, -CONH2, -NHCOCH3, -OC(O)NH2, -NHSO2CH3and-OCF3.

In the ring C predpochtite the further substituents R 5when they are present, include halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2and-N(R4)SO2R. More preferred substituents R5include-Cl, -F, -CN, -CF3,

-NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group). Examples of such preferred substituents include-Cl, -F, -CN, -CF3, -NH2, -NHMe, -NMe2,

-OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl and-CO2Et.

When G is a ring D, the preferred monocyclic ring to D ring in the formula V include substituted and unsubstituted phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, aspenlea and morpholinyl rings. When two neighboring substituent D ring together with each other to form a condensed ring, the ring system D is bicyclic. Preferred bicyclic ring for ring D in the formula V include 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, ethenolysis, chinoline and naphthyl. Por the measures are more preferred bicyclic systems for D rings include naphthyl and ethenolysis.

Preferred substituents in ring D of formula V include one or more of the following substituents: halogen, oxo, CN, -NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. More preferred substituents for ring D include halogen, -CN, -oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. Examples of the substituents for ring D include-OH, phenyl, methyl, CH2OH, CH2CH2OH, pyrrolidinyl, OPh, CF3C≡, Cl, Br, F, I, NH2C(O)CH3, isopropyl, tert-butyl, SEt, OMe, N(Me)2methylendioxy, Ethylenedioxy.

Preferred compounds of formula V have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring, the R 1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; or ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Rxrepresents hydrogen or C1-4aliphatic group, and Ryis a T-R3or Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogen atom; and

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridinones is, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula V have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-6halogenations group1-6aliphatic group, phenyl, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahedrite-chinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-ISO-indolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Rxrepresents hydrogen or methyl and Ryis a-R, N(R4)2or-OR, or Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or a 5-7 membered partially unsaturated carbocyclic ring, optionally substituted by a group-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR,-N(R 4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2;

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) ring D is substituted by oxopropoxy or R5and each R5independently selected from halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R.

Even more preferred compounds of formula V have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5p is item when ring C and two adjacent substituent in it form a bicyclic ring system, bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or

-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahedrite-chinoline, 1,2,3,4-tetrahydroquinoline, izochinolina, chinoline or naphthyl;

(b) Rxrepresents hydrogen or methyl and Ryrepresents methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, or Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or 6-membered partially unsaturated carbocyclic ring, optionally substituted with halogen, CN, oxo, C1-6the alkyl, C1-6alkoxy, (C1-6alkyl)carbonyl, (C1-6alkyl)sulfonyl, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl or 5-6-membered heteroaryl;

(C) R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic to what ICA, optionally substituted with halogen, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN, -SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl), -NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group; and

(d) ring D is substituted by oxopropoxy or R5where each R5independently selected from-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group).

Representative compounds of formula V are shown below in table 4.

Table 4

In another embodiment, the present invention is a composition comprising a compound of formula V and pharmaceutically acceptable carrier.

One object of the present invention is a method Engibarov the ia activity of the protein kinase GSK-3 in a patient, includes introduction to the patient a therapeutically effective amount of a composition containing the compound of formula V.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula V.

Another object of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula V. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula V. This method is especially useful for stopping or slowing the progression of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the introduction of a given patient, therapist is Cesky effective amount of the composition, containing the compound of formula V. This method is particularly useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula V.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula V. This method is particularly useful for the treatment of cancer such as cancer of the colon, ovarian cancer and breast cancer. One object of the present invention is a method of inhibiting the activity of protein kinase CDK-2 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula V.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase CDK-2, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula V. This method is particularly useful for the treatment of cancer, diseases of Alzheime is a, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3, Aurora or CDK-2 formula V or its containing pharmaceutical composition in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

Each of the above methods directed to the inhibition of GSK-3, Aurora or CDK-2, or treatment of the disease, making it easier for the specified inhibition, preferably carried out using the preferred compounds of formula V, such as described above for the connection.

Another variant of the present invention relates to compounds of the formula VI:

or their pharmaceutically acceptable derivatives or prodrugs where:

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1any replaced nearto-position in the ring not avisio substituted by the radical R 5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or group

-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl the Noah rings are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Ryis a T-R3';

T is a bond or C1-4alkylidene chain;

R2and R2'independently selected from-R, -T-W-R6or R2and R2'together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, NO2, -R7or V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2'substituted by the radical R4; R3'is an optionally substituted group selected from C1-6aliphatic group3-10carbocycle,6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each is th R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R 6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6elevations the Oh group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring; and

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6.

Preferred groups Ryformula VI include T-R3'where T represents a bond or methylene and R3'is an optionally substituted group selected from C1-6aliphatic group3-10carbocycle,6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms. A preferred group R3'is optionally substituted group selected from C3-6carbocycle, phenyl or 5-6-membered heteroaryl or heterocyclyl rings. Examples of preferred Ryinclude 2-pyridyl, 4-pyridyl, piperidinyl, morpholinyl, cyclopropyl, cyclohexyl, and optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

Group R2and R2'formula VI can be taken together with each other to form a condensed ring, which gives bicyclic the massive ring system, containing pyrazol ring. The preferred condensed rings include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclic ring. Examples of these condensed rings represented by the following compounds of the formula VI with pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated, -NO2, -O(C1-4alkyl), -CO2(C1-4alkyl), -CN, -SO2(C1-4alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl), -C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

When pyrazol ring system is monocyclic, preferred groups R2in formula VI include hydrogen, C1-4aliphatic group, alkoxycarbonyl, (UN)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono - or dialkylaminoalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, phenylenecarbonyl and (N-hetero CLIL)carbonyl. Examples of such preferred substituents R2include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-butyl, cyclopentyl, phenyl, CO2H, CO2CH3CH2OH, CH2OCH3CH2CH2CH2OH, CH2CH2CH2OCH3CH2CH2CH2OCH2Ph, CH2CH2CH2NH2CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CH=CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2, CO(3-methoxypiperidine-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholine-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2and CO(piperidine-l-yl). Preferred R2'is hydrogen.

When G is a ring, the preferred groups for rings in formula VI are phenyl and pyridinyl. When two neighboring substituent in the ring together With each other to form a condensed ring, the ring is a bicyclic ring system. The preferred condensed ring include a benzene or pyridine ring. Such rings are preferably condensed in ortho - and meta-positions of ring C. Examples of PR is pactically bicyclic systems for rings include naphthyl and ethenolysis. Preferred groups R1include halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6. When R1represents an optionally substituted C1-6aliphatic group, preferred optional substituents are halogen-free. Examples of preferred groups R1include-CF3, -Cl, -F, -CN, COCH3, -OCH3, -OH, -CH2CH3, -OCH2CH3, -CH3, -CF2CH3, cyclohexyl, tert-butyl, isopropyl, cyclopropyl- ≡- ≡CH3, -SO2CH3, -SO2NH2, -N(CH3)2, -CO2CH3, -CONH2, -NHCOCH3, -OC(O)NH2, -NHSO2CH3and-OCF3.

In the ring C preferred substituents R5when they are present, include halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2and-N(R4)SO2R. More preferred substituents R5include-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4/sub> aliphatic group and-CO2(C1-4aliphatic group). Examples of such preferred substituents include-Cl, -F, -CN, -CF3, -NH2, -NHMe, -NMe2, -OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl and-CO2Et.

When G is a D, the preferred monocyclic ring to D ring in the formula VI include substituted and unsubstituted phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, aspenlea and morpholinyl rings. When two neighboring substituent D ring together with each other to form a condensed ring, the ring system D is bicyclic. Preferred bicyclic ring for ring D in the formula VI include 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, ethenolysis, chinoline and naphthyl. Examples of preferred bicyclic systems for D rings include naphthyl and ethenolysis.

Preferred substituents in ring D of formula VI include one or more of the following substituents: halogen, oxo, CN, -NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl and the and C 1-6aliphatic group. More preferred substituents for ring D include halogen, -CN, -oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. Examples of the substituents for ring D include-OH, phenyl, methyl, CH2OH, CH2CH2OH, pyrrolidinyl, OPh, CF3C≡, Cl, Br, F, I, NH2C(O)CH3, isopropyl, tert-butyl, SEt, OMe, N(Me)2methylendioxy, Ethylenedioxy.

Preferred compounds of formula VI have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) a ring selected from phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring, and R1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; or ring D is an optionally substituted ring selected from phenyl, pyridinyl the tion, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Ryis a T-R3'where T represents a bond or methylene; and

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VI have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-6halogenations group 1-6aliphatic group, phenyl, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Ryis a T-R3'where T represents a bond or methylene and R3'is an optionally substituted group selected from C1-6aliphatic group3-6carbocycle,6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) ring D is substituted by oxopropoxy or R5and each R5independently selected from halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR,-C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R.

Even more preferred compounds of formula VI have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Ryis a T-R3'where T represents a bond or methylene and R3'is an optionally substituted group selected from C1-4aliphatic group3-6carbocycle, phenyl or 5-6-membered heteroaryl or heterocyclyl ring;

(b) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, izochinolina, chinoline or naphthyl;

(C) R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine, PI is imaginova or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN, -SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl),

-NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group; and

(d) ring D is substituted by oxopropoxy or R5and each R5independently selected from-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group).

Another variant of the present invention relates to compounds of formula VIa:

or their pharmaceutically acceptable derivatives or prodrugs where:

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1any replaced nearto-position carbon in the ring is independently substituted by RA is calom-R 5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or a group-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl oliza are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

T is a bond or C1-4alkylidene chain;

R2and R2'taken together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, NO2, -R7or V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2'substituted by the radical R4;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic g is the SCP), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R66)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring; and

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6.

Preferred rings formed by groups of R2and R2'formula Via, include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclic ring. Examples of these rings are presented in the following compounds of the formula VIa with pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated, -NO2, -O(C1-4alkyl), -CO2(C1-4alkyl), -CN, -SO2(C1-4alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl), -C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

When G is a ring, the preferred groups for rings in the formula VIa are phenyl and pyridinyl. When two neighboring substituent in the ring together With each other to form a condensed ring, the ring represents iceslideshow ring system. The preferred condensed ring include a benzene or pyridine ring. Such rings are preferably condensed in ortho - and meta-positions of ring C. Examples of preferred bicyclic systems for rings include naphthyl and ethenolysis. Preferred groups R1include halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6. When R1represents an optionally substituted C1-6aliphatic group, preferred optional substituents are halogen-free. Examples of preferred groups R1include-CF3, -Cl, -F, -CN, COCH3, -OCH3, -OH, -CH2CH3, -OCH2CH3, -CH3, -CF2CH3, cyclohexyl, tert-butyl, isopropyl, cyclopropyl- ≡- ≡CH3, -SO2CH3, -SO2NH2, -N(CH3)2, -CO2CH3, -CONH2, -NHCOCH3, -OC(O)NH2, -NHSO2CH3and-OCF3.

In the ring C preferred substituents R5when they are present, include halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4), -NR 4)COR, -SO2N(R4)2and-N(R4)SO2R. More preferred substituents R5include-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group). Examples of such preferred substituents include-Cl, -F, -CN, -CF3, -NH2, -NHMe, -NMe2, -OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl and-CO2Et.

When G is a D, the preferred monocyclic ring to D ring in the formula VIa include substituted and unsubstituted phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, aspenlea and morpholinyl rings. When two neighboring substituent D ring together with each other to form a condensed ring, the ring system D is bicyclic. Preferred bicyclic ring for ring D in the formula VIa include 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, ethenolysis, chinoline and naphthyl. Examples of preferred bicyclic systems for D rings include naphthyl and ethenolysis.

Preferred substituents in ring D of formula Via can include one or more of the following is their substituents: halogen, oxo, CN, -NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. More preferred substituents for ring D include halogen, -CN, -oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. Examples of the substituents for ring D include-OH, phenyl, methyl, CH2OH, CH2CH2OH, pyrrolidinyl, OPh, CF3C≡, Cl, Br, F, I, NH2C(O)CH3, isopropyl, tert-butyl, SEt, OMe, N(Me)2methylendioxy, Ethylenedioxy.

Preferred compounds of formula VIa are one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring, and R1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -R 6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; or ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring; and

(b) R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VIa are one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-6halogenations group1-6aliphatic group, FeNi is or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN, -SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl), -NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group; and

(c) ring D is substituted by oxopropoxy or R5and each R5independently selected from halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R.

Even more preferred compounds of formula VIa are one or the few, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, izochinolina, chinoline or naphthyl;

(b) R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN, -SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl), -NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or qi is symbolic alkyl group; and

(d) ring D is substituted by oxopropoxy or R5and each R5independently selected from-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group). Representative compounds of formulas VI and VIa are shown below in table 5.

Table 5

In yet another embodiment, the present invention is a composition comprising a compound of the formula VI or VIa, and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting the activity of protein kinase GSK-3 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing a compound of the formula VI or VIa.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing a compound of the formula VI or VIa.

Another is bhakta of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient, in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing a compound of the formula VI or VIa. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing a compound of the formula VI or VIa. This method is especially useful for stopping or slowing the progression of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing a compound of the formula VI or VIa. This method is particularly useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing a compound of the formula VI or VIa.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the surrounding stage of introduction of the patient, in need of such treatment, a therapeutically effective amount of a composition containing a compound of the formula VI or VIa. This method is particularly useful for the treatment of cancer such as cancer of the colon, ovarian cancer and breast cancer.

One object of the present invention is a method of inhibiting the activity of protein kinase CDK-2 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing a compound of the formula VI or VIa.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase CDK-2, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing a compound of the formula VI or VIa. This method is particularly useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3, Aurora or CDK-2 of the formula VI or VIa, or containing pharmaceutical composition in Koli is este, effective for inhibition of GSK-3, Aurora or CDK-2.

Each of the above methods directed to the inhibition of GSK-3, Aurora or CDK-2, or treatment of the disease, making it easier for the specified inhibition, preferably carried out using the preferred compounds of formula VI or VIa, such as described above for the connection.

Another variant of the present invention relates to compounds of the formula VII:

or their pharmaceutically acceptable derivatives or prodrugs where:

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1any replaced nearto-position in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

ring D is a 5-7-member of the TES monocyclic ring or 8-10 membered bicyclic ring, selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or a group-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl rings are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Ryrepresents hydrogen or T-R3";

T is a bond or C1-4alkylidene chain;

R2 and R2'independently selected from-R, -T-W-R6or R2and R2'together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, NO2, -R7or V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2'substituted by the radical R4;

R3"is an optionally substituted group selected from C3-10carbocycle,6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4in one the e of the nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)or CR 6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring;

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2 R6; and

R9selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2,

-OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR,

-N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2.

Preferred groups Ryformula VII include T-R3"where T represents a bond or methylene. Preferred groups R3"include optionally substituted group selected from C3-6carbocycle, phenyl or 5-6-membered heteroaryl or heterocyclyl rings. Examples of preferred Ryinclude 2-pyridyl, 4-pyridyl, piperidinyl, cyclopropyl and optionally substituted phenyl, such as phenyl or halogen-substituted phenyl. Group R2and R2'formula VII can be taken together with each other to form a condensed ring, which gives a bicyclic ring system containing pyrazol ring. The preferred condensed rings include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclic ring. Examples of these condensed rings represented in follow what their compounds of formula VII, having pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated, -NO2, -O(C1-4alkyl), -CO2(C1-4alkyl), -CN, -SO2(C1-4alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl), -C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

When pyrazol ring system in formula VII is monocyclic, preferred groups R2include hydrogen, C1-4aliphatic group, alkoxycarbonyl, (UN)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono - or dialkylaminoalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, phenylenecarbonyl and (N-heterocyclyl)carbonyl. Examples of such preferred substituents R2include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-butyl, cyclopentyl, phenyl, CO2H, CO2CH3CH2OH, CH2OCH3CH2CH2CH2OH, CH2CH2 2OCH3CH2CH2CH2OCH2Ph, CH2CH2CH2NH2CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CH=CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2, CO(3-methoxypiperidine-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholine-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2and CO(piperidine-l-yl). Preferred R2'is hydrogen.

When G is a ring, the preferred groups for rings in the formula VII are phenyl and pyridinyl. When two neighboring substituent in the ring together With each other to form a condensed ring, the ring is a bicyclic ring system. The preferred condensed ring include a benzene or pyridine ring. Such rings are preferably condensed in ortho - and meta-positions of ring C. Examples of preferred bicyclic systems for rings include naphthyl and ethenolysis. Preferred groups R1include halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6. When R1represents an optionally substituted C1-6aliphatic group, preferred optional substituents are halogen-free. Examples of preferred groups R1include-CF3, -Cl, -F, -CN, COCH3, -OCH3, -OH, -CH2CH3, -OCH2CH3, -CH3, -CF2CH3, cyclohexyl, tert-butyl, isopropyl, cyclopropyl- ≡- ≡CH3, -SO2CH3, -SO2NH2, -N(CH3)2, -CO2CH3, -CONH2, -NHCOCH3, -OC(O)NH2, -NHSO2CH3and-OCF3.

In the ring C preferred substituents R5when they are present, include halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2and-N(R4)SO2R. More preferred substituents R5include-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group). Examples of such preferred substituents include-Cl, -F, -CN, -CF3, -NH2, -NHMe, -NMe2-OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl and-CO2Et.

When G is a D, the preferred monocyclic ring to D ring in the formula VII include substituted and unsubstituted phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, aspenlea and morpholinyl rings. When two neighboring substituent D ring together with each other to form a condensed ring, the ring system D is bicyclic. Preferred bicyclic ring for ring D in the formula VI include 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, ethenolysis, chinoline and naphthyl. Examples of preferred bicyclic systems for D rings include naphthyl and ethenolysis.

Preferred substituents in ring D include one or more of the following substituents: halogen, oxo, CN, -NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. More preferred substituents for ring D include halogen, -CN, -oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group is selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. Examples of the substituents for ring D include-OH, phenyl, methyl, CH2OH, CH2CH2OH, pyrrolidinyl, OPh, CF3C≡, Cl, Br, F, I, NH2C(O)CH3, isopropyl, tert-butyl, SEt, OMe, N(Me)2methylendioxy, Ethylenedioxy.

Preferred compounds of formula VII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring, and R1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; or ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-what ihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Ryis a T-R3"where T represents a bond or methylene; and

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-6halogenations group1-6aliphatic group, phenyl, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline the La, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Ryis a T-R3"where T represents a bond or methylene and R3"is an optionally substituted group selected from C3-6carbocycle, phenyl or heteroaryl heterocyclyl ring;

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) ring D is substituted by oxopropoxy or R5and each R5independently selected from halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R.

Even more preferred compounds of formula VII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Ryis a T-R3"where T represents the connection elimation and R 3"is an optionally substituted group selected from phenyl or 5-6-membered heteroaryl or heterocyclyl ring;

(b) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, izochinolina, chinoline or naphthyl;

(C) R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN,

-SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl),

-NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4 by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group; and

(d) ring D is substituted by oxopropoxy or R5and each R5independently selected from-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group).

Representative compounds of formula VII shown below in table 6.

Table 6

In yet another embodiment, the present invention is a composition comprising a compound of the formula VII and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting the activity of protein kinase GSK-3 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula VII.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula VII.

Another j the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient, in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula VII. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula VII. This method is especially useful for stopping or slowing the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula VII. This method is particularly useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula VII. Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the stage of introduction of the patient, n is gaudemus for such treatment, therapeutically effective amounts of compositions containing the compound of formula VII. This method is particularly useful for the treatment of cancer such as cancer of the colon, ovarian cancer and breast cancer.

One object of the present invention is a method of inhibiting the activity of protein kinase CDK-2 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula VII.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase CDK-2, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula VII. This method is particularly useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3, Aurora or CDK-2 formula VII or its containing pharmaceutical composition in an amount effective for inhibiting GSK-3, Aurora or CDK-.

Each of the above methods directed to the inhibition of GSK-3, Aurora or CDK-2, or treatment of the disease, making it easier for the specified inhibition, preferably carried out using the preferred compounds of formula VII, such as described above for the connection.

Another variant of the present invention relates to compounds of the formula VIII:

or their pharmaceutically acceptable derivatives or prodrugs where:

Z1represents N or CR9, Z2represents N or CH, and Z3represents N or CRxprovided that one of the Z1and Z3represents nitrogen;

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1any replaced nearto-position in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified to ndesirable ring is optionally substituted with halogen, oxopropoxy or the radical R8;

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by halogen, exography or a group-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl rings are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring, condensers the TES with the ring;

Rxis a T-R3;

T is a bond or C1-4alkylidene chain;

R2and R2'independently selected from-R, -T-W-R6or R2and R2'together with the intermediate atoms with the formation of condensed 5-8-membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, where any substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'substituted by halogen, exography, -CN, NO2, -R7or V-R6and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2'substituted by the radical R4;

R3selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2, -SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R or-OC(=O)N(R7)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, hetero is rolnego ring, having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6) SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom to obrazovanie-to 8-membered heterocyclyl or heteroaryl ring;

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6; and

R9selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2,

-OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR,

-N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2.

Thus, the present invention relates to compounds of formula VIIIa, VIIIb, VIIIc and VIIId shown below:

VIIIaVIIIbVIIIcVIIId

Preferred groups Rxin the formula VIII include T-R3where T represents a bond or methylene and R3represents CN, -R or-OR. When R3is a-R, preferred groups R3include optionally substituted group selected from C1-6ellipticheskoi group, phenyl, or 5-6-membered Goethe is Karelenergo or heterocyclyl rings. When R3represents-OR, preferred groups R include optionally substituted C1-6ellipticheskuyu group, such as alkyl - or dialkylaminoalkyl and aminoalkyl. Examples of preferred groups Rxinclude acetamido, CN, piperidinyl, piperazinil, phenyl, pyridinyl, imidazol-1-yl, imidazol-2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, NH2CH2CH2NH and NH2CH2CH2O.

Preferred groups R9in formula VIII, when they are present, include R, OR, and N(R4)2. Examples of preferred groups R9include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH, N(CH3)2CH2CH2Oh, (piperidine-1-yl)CH2CH2OH and NH2CH2CH2O.

Group R2and R2'formula VIII can be combined with each other to form a condensed ring, which gives a bicyclic ring system containing pyrazol ring. The preferred condensed rings include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclic ring. Examples of these condensed rings represented by the following compounds of the formula VIII with pirateradio bicyclic ring system:

Preferred substituents in the condensed ring R2-R2'in the formula VIII include one or more of the following substituents: halogen, -N(R4)2- 1-4alkyl, -C1-4halogenated,

-NO2, -O(C1-4alkyl), -CO2(C1-4alkyl), -CN, -SO2(C1-4alkyl),

-SO2NH2, -OC(O)NH2, -NH2SO2(C1-4alkyl), -NHC(O)(C1-4alkyl),

-C(O)NH2and-CO(C1-4alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably1-4the alkyl group is a methyl.

When pyrazol ring system in formula VIII is monocyclic, preferred groups R2include hydrogen, C1-4aliphatic group, alkoxycarbonyl, (UN)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono - or dialkylaminoalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, phenylenecarbonyl and (N-heterocyclyl)carbonyl. Examples of such preferred substituents R2include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-butyl, cyclopentyl, phenyl, CO2H, CO2CH3CH2OH, CH2OCH3CH2CH2CH2OH, CH2CH2CH2OCH3CH2CH2CH2OCH2Ph, CH2CH2/sub> CH2NH2CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CH=CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2, CO(3-methoxypiperidine-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholine-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2and CO(piperidine-l-yl). Preferred R2'is hydrogen.

When G is a ring, the preferred groups for rings in the formula VIII are phenyl and pyridinyl. When two neighboring substituent in the ring together With each other to form a condensed ring, the ring is a bicyclic ring system. The preferred condensed ring include a benzene or pyridine ring. Such rings are preferably condensed in ortho - and meta-positions of ring C. Examples of preferred bicyclic systems for rings include naphthyl and ethenolysis. Preferred groups R1include halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6/sup> , -OC(O)NH2or-NHSO2R6. When R1represents an optionally substituted C1-6aliphatic group, preferred optional substituents are halogen-free. Examples of preferred groups R1include-CF3, -Cl, -F, -CN, COCH3, -OCH3, -OH, -CH2CH3, -OCH2CH3, -CH3, -CF2CH3, cyclohexyl, tert-butyl, isopropyl, cyclopropyl- ≡- ≡CH3, -SO2CH3, -SO2NH2, -N(CH3)2, -CO2CH3, -CONH2, -NHCOCH3, -OC(O)NH2, -NHSO2CH3and-OCF3.

In the ring C preferred substituents R5when they are present, include halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2and-N(R4)SO2R. More preferred substituents R5include-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, -O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group). Examples of such preferred substituents include-Cl, -F, -CN, -CF3, -NH2, -NHMe, -NMe2, -OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl and-CO2Et.

It is when G is a D, preferred monocyclic ring to D ring in the formula VIII include substituted and unsubstituted phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, aspenlea and morpholinyl rings. When two neighboring substituent D ring together with each other to form a condensed ring, the ring system D is bicyclic. Preferred bicyclic ring for ring D in the formula VI include 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, ethenolysis, chinoline and naphthyl. Examples of preferred bicyclic systems for D rings include naphthyl and ethenolysis.

Preferred substituents R5in ring D of formula VIII include halogen, oxo, CN, -NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR, -OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. More preferred substituents R5include halogen, -CN, -oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl, C6-10aryl or C1-6aliphatic group. Examples of substituents glagolica D include-OH, phenyl, methyl, CH2OH, CH2CH2OH, pyrrolidinyl, OPh, CF3C≡, Cl, Br, F, I, NH2C(O)CH3, isopropyl, tert-butyl, SEt, OMe, N(Me)2methylendioxy, Ethylenedioxy.

Preferred compounds of formula VIII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring, and R1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; or ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Rxp is ecstasy a T-R 3where T represents a bond or methylene; and

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VIII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-6halogenations group1-6aliphatic group, phenyl, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinali the sludge or naphthyl;

(b) Rxis a T-R3where T represents a bond or methylene and R3represents CN, -R or-OR;

(C) R2'represents hydrogen and R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group, or R2and R2'taken together with the intermediate atoms with the formation of substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) each R5independently selected from halogen, -CN, -NO2, -N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R.

Even more preferred compounds of formula VIII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Rxis a T-R3where T represents a bond or methylene and R3is a-R or-OR, where R is an optionally substituted group selected from C1-6aliphatic group, phenyl, or 5-6-membered heteroaryl or heterocyclyl ring;

(b) the ring is a phenyl or pyridinoline ring, n is necessarily substituted by a group-R 5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, izochinolina, chinoline or naphthyl;

(C) R2and R2'taken together with the intermediate atoms with the formation of benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with halogen, -N(R4)2- 1-4by alkyl, -C1-4halogenation, -NO2, -O(C1-4by alkyl), -CO2(C1-4by alkyl), -CN, -SO2(C1-4by alkyl), -SO2NH2, -OC(O)NH2, -NH2SO2(C1-4by alkyl), -NHC(O)(C1-4by alkyl), -C(O)NH2or-CO(C1-4by alkyl), where (C1-4alkyl) represents an unbranched, branched or cyclic alkyl group;

(d) each group R5independently selected from-Cl, -F, -CN,

-CF3, -NH2, -NH(C1-4aliphatic group), -N(C1-4alipac the political group) -O(C1-4aliphatic group), With1-4aliphatic group and-CO2(C1-4aliphatic group); and

(e) R9represents R, or, or N(R4)2.

Representative compounds of formula VIII are shown below in table 7.

Table 7

In yet another embodiment, the present invention is a composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting the activity of protein kinase GSK-3 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula VIII.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula VIII. Another object of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof, comprising the introduction of a specified patient terapeutiche the key effective amount of the composition, containing the compound of formula VIII. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula VIII. This method is especially useful for stopping or slowing the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula VIII. This method is particularly useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula VIII.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound forms of the crystals VIII. This method is particularly useful for the treatment of cancer such as cancer of the colon, ovarian cancer and breast cancer.

One object of the present invention is a method of inhibiting the activity of protein kinase CDK-2 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula VIII.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase CDK-2, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula VIII. This method is particularly useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3, Aurora or CDK-2 formula VIII or its containing pharmaceutical composition in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

Each of the above methods directed to the inhibition of GSK-3, Aurora or CDK2 or treatment of disease, facilitate specified inhibition, preferably carried out using the preferred compounds of formula VIII, such as described above for the connection.

The above-described compounds of formula I contain pyrazol ring having the substituents R2and R2'. When searching for other inhibitors of protein kinases GSK-3 and Aurora applicants tried to replace pyrazol fragment of the formula I other heteroaromatic rings. It was found that one of the more effective replacement pyrazol ring is a triazole ring. Inhibitors that have a specified triazole ring, the other components of the structure are similar to the compounds of formula I. This variant of the present invention relates to the aforementioned inhibitors represented by the General formula IX:

or their pharmaceutically acceptable derivatives or prodrugs where:

Z1represents nitrogen or CR9and Z2represents nitrogen or CH, provided that one of the Z1and Z2represents nitrogen;

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, selected from R1 any replaced nearto-position carbon in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable carbon atom in the ring oxopropoxy or the radical R5provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these fenil the second, heteroaryl and heterocyclyl rings are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Rxand Ryindependently selected from T-R3or Rxand Rytogether with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Ryreplaced by oxopropoxy or T-R3and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Rysubstituted by the radical R4;

T is a bond or C1-4alkylidene chain;

R2is a-R or-T-W-R6;

R3selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2,

-SO2N(R7)2, -OC(=O)R, -N(R )COR, -N(R7)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R or

-OC(=O)N(R7)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6the independent is selected from hydrogen or optionally substituted C 1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring;

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6; and

R9selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2,

-OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR,

-N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2.

The compounds of formula IX may exist in alternative tautomeric forms, as tautomers 1-3, shown below. Unless otherwise noted, the representation of any of azannyh of tautomers implies the inclusion of the other two.

Group Rxand Ryin formula IX can be taken together with each other to form a condensed ring, which gives a bicyclic ring system containing ring A. the Preferred ring Rx-Ryinclude 5-, 6-, 7 - or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, and the specified ring Rx-Ryis optionally substituted. The following are examples of systems with ring a in compounds IX-A IX-DD, where Z1represents nitrogen or C(R9and Z2represents nitrogen or C(H).

Preferred bicyclic system with a ring As in formula IX include IX-A, IX-B, IX-C IX-D IX-E IX-F, IV-G, IV-H, IX-I IX-J, IX-K, IX-L IX-M, more preferably IX-A, IX-B, IX-C, IX-F IX-H and most preferably IX-A, IX-B and IX-H.

In a monocyclic system ring As in formula IX preferred groups Rxinclude hydrogen, alkyl - or dialkylamino, acetamido or1-4aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred groups Rywhen they are present, include T-R3where T represents a bond or methylene, and R3is a-R, -N(R4) 2or-OR. Examples of preferred groups Ryinclude 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl, and methoxymethyl. In a bicyclic system with a ring As in formula IX, the ring formed together Rxand Rymay be substituted or unsubstituted. Suitable substituents include-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2,

-CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2where R and R4such as defined above. Preferred substituents in the ring Rx-Ryinclude halogen, -R, -OR, -COR, -CO2R, -CON(R4)2, -CN, or-N(R4)2where R is an optionally substituted C1-6aliphatic group.

Preferred groups R2in formula IX include hydrogen, C1-4aliphatic group, alkoxycarbonyl, (UN)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, MES is - or dialkylaminoalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, phenylenecarbonyl and (N-heterocyclyl)carbonyl. Examples of such preferred substituents R2include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-butyl, cyclopentyl, phenyl, CO2H, CO2CH3CH2OH, CH2OCH3CH2CH2CH2OH, CH2CH2CH2OCH3CH2CH2CH2OCH2Ph, CH2CH2CH2NH2CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CH=CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2, CO(3-methoxypiperidine-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholine-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2and CO(piperidine-1-yl). A more preferred group R2for compounds of formula IX is hydrogen.

An option that is particularly useful for the treatment of GSK-3-mediated disease, refers to compounds of formula X, where ring a is a pyrimidine ring:

or their pharmaceutically acceptable derivatives or prodrugs where:

ring selected from phenyl, pyridinoline, pyrimidine inogo, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, independently selected from R1any replaced nearto-position carbon in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl rings are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Rxand Ry independently selected from T-R3or Rxand Rytogether with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Ryreplaced by oxopropoxy or T-R3and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Rysubstituted by the radical R4;

T is a bond or C1-4alkylidene chain;

R2is a-R or-T-W-R6;

R3selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2,

-SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R or

-OC(=O)N(R7)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 kalawy the atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6 2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered Goethe is olliloh or heteroaryl ring; and

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6, -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6.

The compounds of formula X are structurally similar to the compounds of formula II except for the replacement pyrazol ring fragment triazole ring fragment.

Preferred groups R2, Rx, Ryand rings of formula X are as described above for compounds of formula II.

Preferred compounds of formula X have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring;

(b) Rxrepresents hydrogen or C1-4aliphatic group, and Ryis a T-R3or Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted 5-7 membered unsaturated or partially unsaturated Kohl is a, having 0-2 ring nitrogen atom;

(C) R1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6,

-SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; and

(d) R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group.

More preferred compounds of formula X have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring;

(b) Rxrepresents hydrogen or methyl and Ryis a-R, N(R4)2or-OR, or Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or a 5-7 membered carbocyclic ring, and specified the ring formed by the groups Rxand Ryis optionally substituted by a group-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2-CN

-S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R,

-N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2,

-N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2;

(C) R1represents a halogen, With1-6halogenations group1-6aliphatic group, phenyl, or-CN;

(d) R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group; and

(e) each R5independently selected from halogen, -CN, -NO2,

-N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R.

Even more preferred compounds of formula X have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is n ptyline ring;

(b) Rxrepresents hydrogen or methyl and Ryrepresents methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, or Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted benzene ring or 6-membered carbocyclic ring;

(C) R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or-CN;

(d) R2represents hydrogen or C1-6aliphatic group; and

(e) each R5independently selected from-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2,

-O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group).

Another variant of the present invention relates to compounds of the formula XI:

or their pharmaceutically acceptable derivatives or prodrugs where:

ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocycle is inoe ring has 1-4 ring heteroatoms, selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or group

-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

Rxand Rytaken together with the intermediate atoms with the formation of a condensed benzene ring or a 5-8-membered carbocyclic ring, where any substitutable carbon atom in the specified condensed ring formed by the groups Rxand Ryreplaced by oxopropoxy or T-R3;

T is a bond or C1-4alkylidene chain;

R2is a-R or-T-W-R6;

R3selected from-R, halogen,=O, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2;

each R is independently selected from hydrogen or optional is entrusted substituted group, selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,/p>

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring; and

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl and the and heteroaryl rings.

The compounds of formula XI are structurally similar to the compounds of formula III except for the replacement pyrazol ring fragment triazole ring fragment. Preferred groups R2, Rx, Ryand ring D of formula XI are those as described above for compounds of formula III. Preferred compounds of formula XI are one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted benzene ring or a 5-7 membered carbocyclic ring; and

(C) R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group.

More preferred compounds of formula XI are one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or a 5-7 membered carbocyclic ring, and specified the ring formed by the groups Rxand Ryis optionally substituted by a group R, oxo, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R,

-SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR,

-N(R4)CO2(optionally substituted C1-6aliphatic group),

-N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2;

(c) R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group; and

(d) each R5independently selected from halogen, oxo, CN, NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR,

-OR, -C(or, or substituted or unsubstituted groups selected from 5-6-membered heterocyclyl,6-10aryl or1-6aliphatic group.

Even more preferred compounds of formula XI are one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or 6-membered carbocyclic ring, and these rings are formed by groups of Rxand Ryare optionally substituted with halogen, CN, oxo, C1-6the alkyl, C1-6alkoxy, (C1-6alkyl)carbonyl, (C1-6alkyl)sulfonyl, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl or 5-6-membered heteroaryl;

(b) each R5independently selected from halogen, -CN, oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl,6-10aryl or1-6aliphatic group; and

(C) R2represents hydrogen or C1-6aliphatic group.

Another variant of the present invention relates to compounds of the formula XII:

or their pharmaceutically acceptable derivatives or prodrugs where:

ring D is a 5-7 membered monocyclic ring or 8-10 and a member of the Noah bicyclic ring, selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or a group-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

Rxand Ryindependently selected from T-R3or Rxand Rytaken together with the intermediate atoms with the formation of a condensed benzene ring, unsaturated or partially unsaturated 5-8-membered ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon in the specified condensed ring is optionally and independently substituted by a group T-R3and any substitutable nitrogen in the specified ring substituted by a group R4;

T is a bond or C1-4alkylidene chain;

R2is a-R or-T-W-R6;

R3selected from-R, halogen,=O, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4 )2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group), -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(Rsup> 4)2;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at about the nogo and the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring; and

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring.

The compounds of formula XII are structurally similar to compounds of the formula IV with the exception of replacement of the pyrazol ring fragment triazole ring fragment. Preferred groups R2, Rx, Ryand ring D of formula XII are those as described above for compounds of formula IV. Preferred compounds of formula XII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Rxrepresents hydrogen or C1-4aliphatic group, and Ryis a T-R3or Rxand Rytaken together with the intermediate atoms with the formation of neobyazatel is substituted 5-7 membered unsaturated or partially unsaturated ring, having 1-2 heteroatoms; and

(C) R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group.

More preferred compounds of formula XII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Rxrepresents hydrogen or methyl and Ryis a-R, -N(R4)2or-OR, or Rxand Rytaken together with the intermediate atoms with the formation of a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogen atom, and the specified ring is optionally substituted by a group-R, halogen, oxo, -OR,

-C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2,

-CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4/sup> )2, -N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2;

(c) R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group; and

(d) each R5independently selected from halogen, oxo, CN, NO2, -N(R4)2, -CO2R, -CONH(R4), -N(R4)COR, -SO2N(R4)2, -N(R4)SO2R, -SR,

-OR, -C(O)R, or substituted or unsubstituted group selected from 5-6-membered heterocyclyl,6-10aryl or1-6aliphatic group.

Even more preferred compounds of formula XII have one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Rxand Rytaken together with the intermediate atoms with the formation of 6-membered unsaturated or partially unsaturated ring with 1-2 ring nitrogen atoms, optionally substituted with halogen, CN, oxo, C1-6the alkyl, C1-6alkoxy, (C1-6alkyl)carbonyl, (C1-6alkyl)sulfonyl, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl or 5-6-membered heteroaryl;

(b) each R5independently selected from halogen, -CN, oxo, -SR, -OR, -N(R4)2, -C(O)R, or substituted or unsubstituted groups selected the Oh from 5-6-membered heterocyclyl, With6-10aryl or1-6aliphatic group; and

(C) R2represents hydrogen or C1-6aliphatic group.

Another variant of the present invention relates to compounds of the formula XIII:

or their pharmaceutically acceptable derivatives or prodrugs where:

Z1represents nitrogen, CRandor CH, and Z2represents nitrogen or CH, provided that one of the Z1and Z2represents nitrogen;

G is a ring C or ring D;

ring selected from phenyl, pyridinoline, pyrimidinyl, pyridazinyl, piratininga or 1,2,4-trainlng rings, and the specified ring C has one or two substituent in the ortho-position, independently selected from R1any replaced nearto-position in the ring is independently substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, and specified the condensed ring is optionally substituted with halogen, exography or the radical R8;

ring D is a 5-7-membered monocyclic the mini-ring or 8-10 membered bicyclic ring, selected from aryl, heteroaryl, heterocyclyl or carbocycle rings, of which heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substitutable ring carbon by oxopropoxy or group

-R5and at any substitutable ring nitrogen by a group-R4provided that when ring D is a six-membered aryl or heteroaryl ring, -R5represents hydrogen at each ortho-position of ring D;

R1selected from halogen, -CN, -NO2T-V-R6, phenyl, 5-6-membered heteroaryl ring, 5-6 membered heterocyclyl rings or1-6aliphatic group, and these phenyl, heteroaryl and heterocyclyl rings are optionally substituted by each of the groups in the number to three, independently selected from halogen, oxo, or-R8specified With1-6the aliphatic group is optionally substituted with halogen, cyano, nitro, or oxygen, or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Rxand Ryindependently selected from T-R3or Rxand Rytogether with the intermediate atoms with the education of condensed unsaturated or partially unsaturated 5-8-membered ring, having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Ryreplaced by oxopropoxy or T-R3and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Rysubstituted by the radical R4;

T is a bond or C1-4alkylidene chain;

R2is a-R or-T-W-R6;

R3selected from-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR,

-COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2,

-SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R or

-OC(=O)N(R7)2;

each R is independently selected from hydrogen or optionally substituted group selected from C1-6aliphatic group6-10aryl, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms;

each R4independently selected from R7, -COR7, -CO2(optionally substituted C1-6aliphatic group, -CON(R7)2or-SO2R7or two radicals R4at the same nitrogen atom, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R5independently selected from-R, halogen, -OR, -C(=O)R,

-CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2,

-SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2,

-C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R or

-OC(=O)N(R4)2or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

V represents-O-, -S-, -SO-, -SO2-, -N(R6)SO2-,

-SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-,

-N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-,

-OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6 )=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)- or-C(R6)2N(R6)CON(R6)-;

W represents-C(R6)2O-, -C(R6)2S-, -C(R6)2SO-,

-C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-,

-C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-,

-C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, -C(R6)2N(R6)CON(R6)- or-CON(R6)-;

each R6independently selected from hydrogen or optionally substituted C1-4aliphatic group, or two groups R6at the same nitrogen atom are taken together with the nitrogen atom with the formation of 5-6-membered heterocyclyl or heteroaryl ring;

each R7independently selected from hydrogen or optionally substituted C1-6aliphatic group, or two R7at the same nitrogen atom are taken together with the nitrogen atom with the formation of a 5-8-membered heterocyclyl or heteroaryl ring;

each R8independently selected from optionally substituted C1-4aliphatic group, -OR6, -SR6, -COR6, -SO2R6 , -N(R6)2,

-N(R6)N(R6)2, -CN, -NO2, -CON(R6)2or-CO2R6; and

Randselected from halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2,

-N(R4)SO2N(R4)2, -N(R4)SO2R, -OC(=O)N(R4)2or an optionally substituted group selected from C1-6aliphatic group6-10aryl group, a heteroaryl ring having 5-10 ring atoms, or heterocyclyl ring having 5-10 ring atoms.

The compounds of formula XIII can be represented with a specific Z1and Z2as shown below:

The compounds of formula XIII is structurally similar to the compounds of the formula V with the exception of replacement of the pyrazol ring fragment triazole ring fragment. Preferred groups R2, Rx, Ry, Randand the ring G of the formula XIII are those as described above for compounds of formula V. Preferred compounds of formula XIII are one or more, and more preferably all of the sign is, selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova, rhinolining or ethanolamines ring, and R1represents halogen, optionally substituted C1-6aliphatic group, phenyl, -COR6, -OR6, -CN, -SO2R6, -SO2NH2, -N(R6)2, -CO2R6, -CONH2, -NHCOR6, -OC(O)NH2or-NHSO2R6; or ring D is an optionally substituted ring selected from phenyl, pyridinoline, piperidinyl, piperazinilnom, pyrrolidinyl, thienyl, sepanloo, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolering, ethanolamines, rhinolining or afternova ring;

(b) Rxrepresents hydrogen or C1-4aliphatic group, and Ryis a T-R3or Rxand Rytaken together with the intermediate atoms with formation of an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 to licevyh nitrogen atom; and

(C) R2represents hydrogen or substituted or unsubstituted group selected from aryl, heteroaryl or C1-6aliphatic group.

More preferred compounds of formula XIII are one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-6halogenations group1-6aliphatic group, phenyl, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, izochinolina, chinoline or naphthyl;

(b) Rxrepresents hydrogen or methyl and Ryis a-R, N(R4or-OR, or Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or a 5-7 membered carbocyclic ring, and specified the ring formed by the groups Rthe and Ryis optionally substituted by a group-R, halogen, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN,

-S(O)R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R,

-N(R4)COR, -N(R4)CO2(optionally substituted C1-6aliphatic group), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2,

-N(R4)SO2N(R4)2, -N(R4)SO2R or-OC(=O)N(R4)2;

(C) R2represents hydrogen or substituted or unsubstituted group selected from aryl or1-6aliphatic group; and

(d) each R5independently selected from halogen, -CN, -NO2,

-N(R4)2, optionally substituted C1-6aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R4)2, -N(R4)COR, -SO2N(R4)2or-N(R4)SO2R, and when ring G is a ring D, ring D is substituted by oxo group, or R5.

Even more preferred compounds of formula XIII are one or more, and more preferably all of the characteristics selected from the group consisting of:

(a) Rxrepresents hydrogen or methyl, and Ryrepresents methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl - or optionally substituted gr the PPU, selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, or Rxand Rytaken together with the intermediate atoms with the formation of a benzene ring or 6-membered carbocyclic ring, and specified the ring formed by the groups Rxand Ryis optionally substituted with halogen, CN, oxo, C1-6the alkyl, C1-6alkoxy, (C1-6alkyl)carbonyl, (C1-6alkyl)sulfonyl, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl or 5-6-membered heteroaryl;

(b) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is naphtalene ring, and R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen, or-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, izochinolina, chinoline or naphthyl;

(C) R2represents hydrogen or C1-6aliphatic group; and

(d) each R5Nezavisimoye from-Cl, -F, -CN, -CF3, -NH2, NH(C1-4aliphatic group), -N(C1-4aliphatic group)2,

-O(C1-4aliphatic group), C1-4aliphatic group and-CO2(C1-4aliphatic group), and when ring G is a ring D, ring D is substituted by oxo group, or R5.

Representative compounds of formula IX are shown below in table 8.

Table 8

In yet another embodiment, the present invention is a composition comprising a compound of formula IX and a pharmaceutically acceptable carrier. One object of the present invention is a method of inhibiting the activity of protein kinase GSK-3 in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing soy is inania formula IX.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula IX.

Another object of the present invention is a method of enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula IX. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula IX. This method is especially useful for stopping or slowing the progression of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of a composition containing the compound of formula IX. This method is particularly useful for Leche is of schizophrenia.

One object of the present invention is a method of inhibiting the activity of protein kinase Aurora in a patient, comprising the administration to a patient a therapeutically effective amount of a composition containing the compound of formula IX.

Another object of the present invention is a method of treatment of the disease, providing treatment by an inhibitor of protein kinase Aurora, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a composition containing the compound of formula IX. This method is particularly useful for the treatment of cancer such as cancer of the colon, ovarian cancer and breast cancer.

Another object of the present invention is a method of inhibiting the activity of GSK-3 or Aurora in a biological sample, comprising the implementation of contacting a biological sample with an inhibitor of GSK-3 or Aurora formula IX or its containing pharmaceutical composition in an amount effective for inhibiting GSK-3 or Aurora.

Each of the above methods directed to the inhibition of GSK-3 or Aurora or treatment of the disease, making it easier for the specified inhibition, preferably carried out using the preferred compounds of formula IX, such as described above for the connection.

Compounds of the present invention can be obtained is accordance with the methods of synthesis, described below are examples of the synthesis presented in this description, and the General methods known to experts in this field.

General methods of synthesis

The following common methods of synthesis are several common ways of reactions used to obtain the compounds of the present invention. Methods A-F is particularly useful for producing compounds of formula II. In most cases, the ring is presented as a phenyl ring containing substituent R1in the ortho-position. However, the person skilled in the art it is obvious that the same image can be obtained in connection with other groups, represented by the ring With. Ways similar to the ways A-F, are also useful to obtain other compounds of the present invention. The following methods F-I is particularly useful for preparing compounds of the formula III or IV.

Method And

Way a way to obtain compounds in which the ring is an aryl or heteroaryl ring. Source dichloropyrimidine 1 can be obtained by a method similar to that described in Chem. Pharm. Bull., 30, 9, 1982, 3121-3124. Chlorine in position 4 intermediate 1 can be replaced by aminopyrazole or aminoindazole with obtaining an intermediate compound 2 way similar to that described in J. Med. Chem., 38, 3547-3557 (1995). Then entering the ring, using sophisticated baranovy the ether under palladium catalysis (see Tetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by the following method.

A suspension of 1H-hinzelin-2,4-dione (10.0 g, of 61.7 mmol) in POCl3(60 ml, 644 mmol) and N,N-dimethylaniline (8 ml, 63.1 mmol) is refluxed for 2 hours. Excess POCl3evaporated in vacuo, the residue was poured on ice and the precipitate collected by filtration. The crude solid product 2,4-dechlorination can be used without further purification.

To a solution of 2,4-dichloroaniline (3.3 grams, of 16.6 mmol) in anhydrous ethanol (150 ml) is added 5-methyl-1H-pyrazole-3-yl-amine (3.2 g, from 32.9 mmol). The mixture is stirred at room temperature for 4 hours and the precipitate is collected by filtration, washed with ethanol and dried in vacuum to obtain (2-chlorination-4-yl)-(5-methyl-1H-pyrazole-3-yl)amine.

To a solution of (2-chlorination-4-yl)-(5-methyl-1H-pyrazole-3-yl)amine (50 mg, 0,19 mmol) in DMF (1.0 ml) is added to the desired arylboronic acid (0.38 mmol), 2M Na2CO3(0.96 mmol) and tri-tert-butylphosphine (0,19 mmol). In nitrogen atmosphere add one portion of PdCl2(dppf) (to 0.011 mmol). Then the reaction mixture is heated at 80°C for 5-10 hours, cooled to room temperature and poured into water (2 ml). The precipitate is collected by filtration, washed with water and purified by ASH.

Method In

Methods B-F represent the route of administration pyrazol ring system after building the ring and pyrimidine ring. Universal intermediate compound is 4-chloropyrimidine 4, which is easily obtained from pyrimidinone 3, as shown in method(i). This sequence of reactions is usually used for a variety of groups, rings, including aliphatic, aryl, heteroaryl or heterocyclyl group. See J. Med. Chem., 38,3547-3557 (1995).

For khinazolinov ring systems (where Rxand Rytaken together with the formation of the benzene ring) suitable intermediate compound 6 can be obtained by or Anthranilic acid or its derivative with benzamidine, as shown in method B(ii), or or of benzoyl chloride with anthranilamide, as shown in method B(iii). Many of the original materials, such as, for example, substituted Anthranilic acid, anthranilamide, benzamidine and benzoyl chloride can be obtained by known methods. See Aust. J. Chem., 38, 467-474 and J. Med. Chem., 38, 3547-3557 (1995). Method B(iii) are illustrated by the following procedure.

To a solution of anthranilamide (33 mmol) in THF and CH2Cl2(1:1, 70 ml) is added to the desired benzoyl chloride (33 mmol) and triethylamine (99 mmol) at room temperature. A mixture of p is remediat for about 14 hours. The precipitate is collected by filtration, washed with CH2Cl2and with water and dried in vacuum. The crude 2-benzylaminopurine can be used directly in the next stage without further purification.

To the solution obtained above product (13 mmol) in ethanol (50 ml) was added NaOEt (26 mmol) at room temperature. The mixture is refluxed for lasts for 48-96 hours. The solvent is evaporated and the residue is neutralized with concentrated HCl to pH 7. Then the product is collected by filtration and dried in vacuum to obtain 2-phenyl-3H-hinzelin-4-it, which can be used without further purification.

To the suspension obtained above product (12 mmol) in POCl3(120 mmol) is added tri-n-Propylamine (24 mmol). The mixture is refluxed for 1 hour. After removal of excess POCl3by evaporation the residue is dissolved in ethyl acetate and washed with 1 N. NaOH (twice) and water (twice). The organic layer is dried over MgSO4that is evaporated in vacuum, the solvent and the crude product purified flash chromatography (elution with 10% ethyl acetate in hexane) to obtain 4-chloro-2-originatin.

To a solution of 4-chloro-2-originatin (0.16 mmol) in DMF (or THF, ethanol) add required aminopyrazole or aminoindazole (0.32 mmol). The mixture is heated in DMF (or THF boiling with reverse, chilling the nickname) at 100-110° C for 16 hours (or in ethanol at 130-160°C for 16 hours and then poured into water (2 ml). The precipitate is collected by filtration and purified by HPLC.

Way

Method D(i)

In the above methods C and D(i) use β-ketoesters, respectively, 8 and 10 as precursors of pyrimidinone. The equivalent circuit for groups of Rxand Ryon pyrimidinone ring change on the return, if required benzamidine condense chlorocruorin 11 (Synth. Comm, (1986), 997-1002) instead of the β-keeeper 10. These methods are illustrated in the following General methods.

To a solution β-keeeper (5.2 mmol) and ahmedinijad (5.7 mmol) in ethanol (5 ml) add ethoxide sodium (7.8 mmol). The mixture is refluxed for 7-14 hours. After evaporation the resulting residue is dissolved in water, acidified with concentrated HCl to pH 6 and then filtered to obtain a solid product 2-aryl-3H-pyrimidine-4-it (exit 75-87%), which if necessary, can be cleaned by column flash chromatography. To the obtained pyrimidinone (3.7 mmol) is added POCl3(4 ml) and n-Pr3N (1.4 ml). The mixture is refluxed for 1 hour. After evaporation of excess POCl3the residue is dissolved in ethyl acetate, washed with nerastvorim NaOH (three times) and NaHCO 3(once) and dried over MgSO4. Removed in vacuum, the solvent and the residue is purified column flash chromatography, elwira 10% ethyl acetate in hexane, to obtain the 2-aryl-4-chloropyrimidine in the form of a pale yellow syrup. The crude product can be processed 3-aminopyrazole or 3-aminoindazole, as described above.

Method D(ii)

Method D(ii) shows a common way of obtaining the proposed connections, such as connection 40, where Ryrepresents N(R4)2. See Il Farmaco, 52(1) 61-65 (1997). For the substitution group 6-chloro here is an example using morpholine. This method is illustrated in the following method.

To a solution of complex diethyl ether 2-methylmalonic acid (5 mmol) and ethoxide sodium (15 mmol) is added a suitable amedieval salt (5 mmol) in ethanol (10 ml) and the reaction mixture is refluxed for 2-24 hours. The residue is dissolved in water and acidified by adding 2 N. HCl. The precipitate is filtered off and optionally purified flash chromatography (output 5-35%) with the receipt of pyrimidinedione 37. To pyrimidinedione 37 (1.6 mmol) is added POCl3(32 mmol) and tri-n-Propylamine (6.4 mmol) and the reaction mixture is refluxed for 1 hour. After evaporation of excess POCl3the residue is dissolved is in ethylacetate, alkalinized by addition of 1 N. NaOH, separated and the aqueous phase is twice extracted with ethyl acetate. The combined organic extracts are dried (sodium sulfate) and evaporated. Purification with flash chromatography gives dichloropyrimidine (38) in the form of a yellow oil with a yield of 23%.

A solution of the product 38 (0.33 mmol) in methanol (5 ml) is treated with an amine, in this case, for example, morpholine (0.64 mmol) and refluxed for 1 hour. After evaporation of the solvent the residue is purified flash chromatography with getting monochloramine 39 in the form of a colourless oil with a yield of 75%.

Monoglucuronide 39 (0,19 mmol) can be processed 3-aminopyrazole or 3-aminoindazole essentially as described above in methods a and B.

Method E

As shown in method E, arylisocyanate 12 may be condensed with an enamine with the receipt of pyrimidinone 9 (J. Org. Chem. (1993), 58, 414-418; J. Med. Chem., (1992), 35, 1515-1520; J. Org. Chem., (1967), 32, 213-214). This method is illustrated by the following General method.

The enamine get W. White, et al, J. Org. Chem. (1967), 32, 213-214. Arylisocyanate get G. Bradley, et al, J. Med. Chem. (1992), 35, 1515-1520. The reaction of the linking procedure was followed by S. Kawamura, et al, J. Org. Chem., (1993), 58, 414-418. The enamine (10 mmol) in tetrahydrofuran (30 ml) at 0°C in nitrogen atmosphere is added dropwise over 5 minutes a solution of arylisocyanate (10 IMO the ü) in tetrahydrofuran (5 ml). After stirring for 0.5 hours, add acetic acid (30 ml) and then ammonium acetate (50 mmol). The mixture is refluxed for 2 hours with continuous removal of tetrahydrofuran. The reaction mixture is cooled to room temperature and poured into water (100 ml). The precipitate is filtered off, washed with water and ether and dried to obtain 2-aryl-3H-pyrimidine-4-it.

Method F

Method F shows the General path of receipt of the proposed compounds in which Rxand Rytaken together with the formation of a 5-8-membered partially unsaturated or unsaturated ring having 1-3 heteroatoms. The condensation of 2-aminocarbonyl acid, such as 2-aminonicotinic acid 13, and the carboxylic acid 7 gives occasion 14. Treatment of compound 14 with ammonium hydroxide results in benzamid 15, may be subjected to cyclization with 2-(substituted)pyrido[2,3-d][1,3]pyrimidine-4-she's 16. This method is illustrated in the following method.

2-(Trifluoromethyl)benzoyl chloride (4,2 ml, 29.2 mmol) is added dropwise to a solution of 2-aminonicotinic acid (2,04 g of 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at 158°C for 30 minutes and then cooled to room temperature. The reaction mixture is poured into 200 ml of water, resulting in the oil, which is solidified under stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to obtain 2-(2-triptoreline)pyrido[2,3-d][1,3]oxazin-4-it (2,56 g, yield 60%), which can be used in the next stage without additional purification.

2-(2-Triptoreline)pyrido[2,3-d][1,3]oxazin-4-one (of 2.51 g) was stirred in 30% ammonium hydroxide (25 ml) at room temperature over night. The precipitate is filtered off and washed with water and diethyl ether. The precipitate is dried in vacuum at 50°during the night of obtaining 2-(2-triphtalocyaninine)nicotinamide (850 mg, yield 33%).

2-(2-Triphtalocyaninine)nicotinamide (800 mg, 2.6 mmol) dissolved in 10 ml of ethanol. To the solution add atoxic potassium (435 mg, 5.2 mmol) and the mixture refluxed for 16 hours. The reaction mixture is evaporated in vacuum to obtain a resinous residue which is dissolved in water and acidified with 10% sodium hydrosulphate to pH 7. The precipitate is filtered off and dried in vacuum at 50°obtaining 2-(2-triptoreline)-3H-pyrido[2,3-d]pyrimidine-4-it.

Method G

Method G similar to the above described method B(i). This method is illustrated by the following General method.

2-(3,4-Dichlorophenyl)-3H-hinzelin-4-one (1 g, 3.43 points mmol) suspended in phosphorus oxychloride (4 ml) and the reaction mixture was paramesh what happens when 110° C for 3 hours. Then the solvent is evaporated and the residue is carefully treated with an aqueous saturated solution of NaHCO3cooled with ice. The solid is collected by filtration and washed with ether to obtain 4-chloro-2-(3,5-dichlorophenyl)hintline in the form of a white solid (993 mg, 93%).

To 4-chloro-2-(3,5-dichlorophenyl)hintline (400 mg, 1,29 mmol) in THF (30 ml) is added 3-amino-5-methylpyrazole (396 mg, 2.58 mmol) and the reaction mixture is heated at 65°With during the night. Then evaporate the solvents and the residue triturated with ethyl acetate, filtered and washed with a minimum amount of ethanol to obtain [2-(3,4-dichlorophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine as a white solid (311 mg, 65%): TPL 274°;1H NMR (DMSO) δ of 2.34 (3H, s), 6,69 (1H, s), 7,60 (1H, m), to 7.84 (1H, d), of 7.96 (2H, d), 8,39 (1H, DD), at 8.60 (1H, d), 8,65 (1H, d), 10,51 (1H, s), 12,30,(1H, s); IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370,5 (M+N)+.

The THF solvent used at the previous stage may be replaced by other organic solvents, such as ethanol, N,N-dimethylformamide or dioxane.

Way N

In method H shows the path of transformation is represented by a D ring aryl group bearing a halogen (X represents Br or I)to other compounds of formula III. In method N(i) dormancy is the result of the binding of phenylboronic acid with a D ring with connection 18, and in the way N(ii) shows the binding of acetylene with a connection 19. Deputy X in connection 17 may be bromine or iodine. These methods are illustrated by the following methods.

Method N(i). To a mixture of [2-(4-bromophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, of 0.62 mmol) in a mixture of THF-water (1/1, 4 ml) was added Na2CO3(219 mg, of 2.06 mmol), triphenylphosphine (9 mg, 1/15 mol.%) and palladium acetate (1 mg, 1/135 mol.%). The mixture is heated at 80°during the night, the solvent is evaporated and the residue purified flash chromatography (gradient of CH2Cl2/Meon) to obtain (2-biphenyl-4-imaginaton-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine as a yellow solid (99 mg, 51%):1H NMR (DMSO) δ is 2.37 (3H, s), PC 6.82 (1H, s), 7,39-EUR 7.57 (4H, m), 7,73-7,87 (6H, m), to 8.57 (2H, d), 8,67 (1H, d), 10,42 (1H, s), 12,27 (1H, s); MS 378,2 (M+H)+.

Method H(ii). To a mixture of [2-(4-bromophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (114 mg, 0.3 mmol) and trimethylsilylacetamide (147 mg, 1.5 mmol) in DMF (2 ml) was added CuI (1.1 mg, 1/50 mol.%), Pd(PPh3)2Cl2(4.2 mg, 1/50 mol.%) and triethylamine (121 mg, 0.36 mmol). The mixture is heated at 120°during the night and the solvent is evaporated. The residue is triturated in ethyl acetate and the residue is collected by filtration.

To the precipitate obtained above, suspended in THF (3 ml), add tetrabutylammonium (1M in THF, 1.1 equiv.) The reaction mixture was stirred at room temperature for two hours and the solvent is evaporated. The residue is purified flash chromatography (gradient of CH2Cl2/Meon) to obtain [2-(4-ethynylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (68 mg, 70%):1H NMR (DMSO) δ of 2.34 (3H, s), 4,36 (1H, s), 6,74 (1H, s), 7,55 (1H, m), the 7.65 (2H, d), to 7.84 (2H, m), of 8.47 (2H, d), 8,65 (1H, d), 10,43 (1H, s), 12,24 (1H, s); MS to 326.1 (M+H)+.

The way I

This method is a common way to obtain a offer of compounds in which ring D is heteroaryl or heterocyclyl ring, directly attached to the pyrimidine at position 2 through the nitrogen atom. Substitution of 2-chloro using in this case, for example, piperidine can be carried out in a manner similar to that described in J. Med. Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method is illustrated in the following method.

To a solution of (2-chlorination-4-yl)-(1H-indazol-3-yl)amine (1 equivalent, 0.1 to 0.2 mmol) in N,N-dimethylacetamide (1 ml) is added to the desired amine (3 equivalents). The mixture was incubated at 100°C for 6 hours and then purified by HPLC with reversed phase.

Method J

Method J relates to the production of compounds of formula V by substitution of chlorine in the correspondingly substituted pyridinium ring. Method J(i) is a way of obtaining compounds of formula Va (see Indian J. Chem. Sect. B, 35, 8, 1996, 71-873). Method J(ii) is a way of obtaining compounds of formula Vb (see Bioorg. Med. Chem., 6, 12, 1998, 2449-2458). For convenience, chloropyridine 21 and 23 are presented with phenyl Deputy corresponding to the D ring in the formula V. the person skilled in the art it is obvious that the way J is also useful for preparing compounds of the formula V, in which ring D is heteroaryl, heterocyclyl, carbocyclic or other aryl rings. The way J is illustrated by the following methods.

Method J(i). (5-Methyl-2H-pyrazole-3-yl)-(2-phenylindolin-4-yl)amine. To 4-chloro-2-phenylindolin (J. Het. Chem., 20, 1983, 121-128) (0,53 g, 2.21 mmol) in diphenyl ether (5 ml) is added 3-amino-5-methylpyrazole (0,43 g, was 4.42 mmol) and the mixture is heated at 200°With over night with stirring. To the cooled mixture petroleum ether (20 ml) and the crude precipitate is filtered and optionally washed with petroleum ether. The crude solid is purified flash chromatography (SiO2, gradient DCM-Meon) obtaining specified in the title compounds as white solids: TPL 242-244°;1H NMR (DMSO) δ and 2.27 (3H, s), of 6.02(1H, s), 7,47 (2H, d), 7,53-7,40 (2H, osirm), to 7.67 (1H, m), 7,92 (1H, m), of 8.09 (2H, d), 8,48 (2H, m), 9,20 (1H, s), 12,17 (1H, users); IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301,2 (M+H)+.

Method J(ii). (5-Methyl-2H-pyrazole-3-yl)-(3-phenylethene-Lin-1-yl)amine. To 1-chloro-3-FeNi is the isoquinoline (J. Het. Chem., 20, 1983, 121-128) (0.33 g, 1.37 mmol) in dry DMF (5 ml) is added 3-amino-5-methylpyrazole (0.27 g, is 2.74 mmol) and potassium carbonate (0,57 g of 4.13 mmol) and the mixture refluxed for 6 hours. The mixture is cooled and most of the DMF is evaporated. The residue is extracted twice with ethyl acetate and the combined organic layers washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated. The crude residue purified flash chromatography (SiO2, gradient DCM-Meon) obtaining specified in the title compounds as a colorless oil:1H NMR (MeOD) δ of 2.23 (3H, s), 5,61 (1H, s), 7,41 (1H, m), 7,52(2H, m), a 7.62(1H, m), 7,81(1H, m), 8,07(1H, d), 8,19(2H, m), 8,29(1H, s), 8,54 (1H, d); MS 301,2 (M+H)+.

The way To

The way It is a way of preparing compounds of formula VI. Universal source material is 2,4,6-trichloro-[1,3,5]triazine 25, which represents chlorine substituents can be substituted. Substitution of one of the chlorine atoms of aryl Grignard reagent or arylboronic acid described in PCT application WO 01/25220 and Helv. Chim. Acta, 33, 1365 (1950). Substitution of one of the chlorine atoms heteroaryl ring is described in WO 01/25220; J. Het. Chem., 11 417 (1974); and Tetrahedron 31, 1879 (1975). These reactions give 2,4-dichloro-(6-substituted)[1,3,5]triazine 26, which is a useful intermediate compound to obtain with the dynany formula VI. In accordance with another variant of the intermediate connection 26 can be obtained by building a triazine ring by known methods. See U.S. patent No. 2832779 and U.S. patent No. 2691020 together with J. Am. Chem. Soc., 60, 1656 (1938). In turn, one of the chlorine atoms of the connection 26 may be substituted as described above, to obtain 2-chloro-(4,6-disubstituted)[1,3,5]-triazine 27. The process of joining the 27 appropriate aminopyrazole gives the desired compound of formula VI.

Method L

The way L is a way of preparing compounds of formula VII. For illustrative purposes as a source of material used cryptomaterial 28, but expert in this field, it is obvious that instead of triptoreline and phenyl rings connection 28 can be used other rings. Substituted chalcone can be obtained by known methods, for example as described in Indian J. Chemistry, 32V, 449 (1993). Condensation of chalcone with urea gives pyrimidine 29, which can be processed using POCl3obtaining chloropyrimidine 30. See J. Chem. Eng. Data, 30(4), 512 (1985) and Egypt. J. Chem., 37(3), 283 (1994). An alternative connection 30 one of the aryl rings attached to the pyrimidine, introduced by substitution group 4-chloro 2,4-dichloro-(6-aryl)pyrimidine arylboronic acid with the use of ballad is avago catalyst, such as (Ph3P)4Pd, in the presence of a base such as sodium carbonate, as described in Bioorg. Med. Lett., 9(7), 1057 (1999). The substitution of chlorine in connection 30 with a suitable aminopyrazole gives compounds of the present invention, such as compound 31. The last stage of this method is illustrated by the following method.

[4-(Methylpiperidin-1-yl)pyrimidine-2-yl]-(5-methyl-2H-pyrazole-3-yl)amine. To a solution of 2-chloro-4-(4-methylpiperidin-1-yl)pyrimidine (obtained by the procedure similar to that described in Eur. J. Med. Chem., 26(7), 729 (1991)) (222 mg, 1.05 mmol) in BuOH (5 ml) is added 3-amino-5-methyl-2H-pyrazole (305 mg, 3,15 mmol) and the reaction mixture is refluxed over night. The solvent is evaporated and the residue dissolved in a mixture of ethanol/water (1/3, 4 ml). Add potassium carbonate (57 mg, 0.41 mmol) and the mixture is stirred at room temperature for 2 hours. The resulting suspension is filtered, washed with water twice and with ether, twice with obtaining specified in the title compound as a white solid (143 mg, 50%): TPL 193-195°;1H NMR (DMSO) δ of 0.91 (3H, d), was 1.04 (2H, m)to 1.67 (3H, m)of 2.16 (3H, s), and 2.83 (2H, t), or 4.31 (2H, m), to 6.19 (2H, m), 7,87 (1H, d), 8,80 (1H, users), 11,71 (1H, s); IR(solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273,3(M+H)+.

Method M

Method M is a way of getting link the formula VIII. A General method of substitution of chlorine in the 4-chloro-6-substituted-pyridazine 32 appropriately substituted pyrazole obtaining compounds VIIIa described in J. Het. Chem., 20, 1473 (1983). Similar reactions can also be performed: (a) with 3-chloro-5-substituted-pyridazine 33 obtaining compound VIIIb, as described in J. Med. Chem., 41(3), 311 (1998); (b) 5-chloro-3-substituted-[1,2,4]triazine 34 obtaining compound VIIIc as described in Heterocycles, 26(12), 3259 (1987); and (C) with 3-chloro-5-substituted-[1,2,4]triazine 35 getting connection VIIId, as described in Pol. J. Chem., 57, 7 (1983); Indian J. Chem. Sect. B, 26, 496 (1987); and Agric. Biol. Chem., 54(12), 3367 (1990). An alternative method of preparing compounds of formula VIIIc described in Indian J. Chem. Sect. B, 29(5), 435 (1990).

The compounds of formula IX is obtained by methods substantially similar to those described above for personstaxi compounds of formula I. Methods A-J can be used to obtain triazolopyridine compounds of formula IX by substitution aminopyrazole aminotriazole. Specific examples of such methods are the following examples of synthesis 415-422. Intermediate derived aminotriazole can be obtained by methods described in J. Org. Chem., USSR, 27 952-957 (1991).

Some synthetic intermediate compounds useful for inhibiting protein kinases of the present invention, are new. Thus, another object of the present is subramania is a 3-aminoindazole formula:

where R10represents one to three substituent, each of which is independently selected from fluorine, bromine, C1-6halogenoalkane, nitro or 1-pyrrolyl. Examples of such compounds include the following compounds:

Another object of the present invention is 4-chloropyrimidine formula:

where Rxand Rysuch as defined above, R1selected from H, Cl, F, CF3, CN or NO2; and R5represents one to three substituent, each of which is independently selected from H, Cl, F, CF3, NO2or CN, provided that R1and R5not represent Cl at the same time. Examples of compounds of the formula shown below:

Another object of the present invention is a compound of the formula:

where Rx, Ry, R2and R2'defined above. Examples of compounds of the formula shown below:

Another object of the present invention is a compound of the formula D:

where R5, Rxand Rydefined above. Examples of compounds of the Fort is uly D and other useful intermediates derivatives of pyrimidinone shown below:

For a more complete understanding of the present invention the description of the following examples. Note that these examples are for illustrative purposes and should not be construed as in any way limiting the present invention.

EXAMPLES SYNTHESIS

For the analysis of specific compounds mentioned in the following examples of synthesis, the following methods were used HPLC. When used in this description, the term "Rt" refers to retention time for compounds analyzed using a specific HPLC method.

HPLC-method a:

Column: C18, 3 µm, 2.1 x 50 mm, "Lighting" F. Jones Chromatography.

Gradient: from 100% water (containing 1% acetonitrile, 0.1% of TFA) to 100% acetonitrile (containing 0.1% TFA) over 4.0 minutes, holding at 100% acetonitrile for 1.4 minutes and return to the original conditions. The total working time of 7.0 minutes. Flow rate: 0.8 ml/min

HPLC-method:

Column: C18, 5 µm, 4.6 x 150 mm, "Dynamax" F. Rainin.

Gradient: from 100% water (containing 1% acetonitrile, 0.1% of TFA) to 100% acetonitrile (containing 0.1% TFA) over 20 min, holding at 100% acetonitrile for 7.0 minutes and return to the original conditions. The total working time of 31.5 minutes. Flow rate: 1.0 ml/min

HPLC-method:

Column: Cyano, 5 µm, 4.6 x 150 mm, "Microsorb is F. Varian.

Gradient: 99% water with 0.1% TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water with 0.1% TFA), 50% acetonitrile (containing 0.1% TFA) over 20 minutes exposure for 8.0 minutes and return to the original conditions. Total working time is 30 minutes. Flow rate: 1.0 ml/min

HPLC-method D:

Column: Waters (YMC) ODS-AQ 2.0 x 50 mm, S5, 120A.

Gradient: from 90% water (0.2% of formic acid), 10% acetonitrile (containing 0.1% formic acid) to 10% water with 0.1% formic acid, 90% acetonitrile (containing 0.1% formic acid) over 5.0 min, exposure for 0.8 minutes and return to the original conditions. The total working time of 7.0 minutes. Flow rate: 1.0 ml/min

HPLC-method E:

Column: 50 x 2.0 mm, Hypersil BDS C18; 5 μm.

Gradient elution from 100% water with 0.1% TFA) to 5% water with 0.1% TFA), 95% acetonitrile (containing 0.1% TFA) for 2.1 minutes, return to the original conditions after 2,3 minutes. Flow rate: 1.0 ml/min

Example 1 [2-(2-Chlorophenyl)-5,6-dimethylpyrimidin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-1):1H NMR (500 MHz, DMSO-d6) δ 10,4 (with, of user., 1H), 7,74 (m, 2H), 7,68 (m, 1H), 7,60 (m, 1H), to 6.39 (s, 1H), 2,52 (s, 3H), of 2.30 (s, 3H), 2,22 (s, 3H); MS 314,1 (M+H).

Example 2 [2-(2-Chlorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl]-(1H-indazol-3-yl)amine (II-2): Compound obtained with 30%yield.1H NMR (500 MHz, DMSO-d6) δ 1,72 (m, 4H), 1.91 a (m, 2H), to 3.02 (m, 4H), 7,05 (t, 1H), 7,33 (t, 1H), 7,39 (m, 1H), 7,47 (d, 1H), 7,55 (m, 3H), to 7.59 (d, 1H), 10,4,(m, 1H), 13,11 (users, 1H); EI-MS,2 (M+H); HPLC-method A, Rt2,99 minutes

Example 3 (5-fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl]amine (II-3): Compound II-18 (90 mg, 0,17 mmol) was treated with an equal weight of Pd/C (10%) 4.4% formic acid in Meon at room temperature for 14 hours. The mixture was filtered through celite, the filtrate evaporated and the crude product was purified by HPLC to obtain 18 mg (24%) of the desired product as a pale yellow solid.1H NMR (500 MHz, DMSO-d6) δ 12,9 (s, 1H), 9,51 (s, 1H), 9,26 (s, 2H), 7,72 (d, 1H), 7,63 (t, 1H), 7,58 (t, 1H), 7,49 (m, 2H), 7,21 (TD, 1H), 7,15 (DD, 1H), 4,24 (s, 2H), of 3.56 (m, 2H), 2.95 and (m, 2H) ppm; MS (ES+): m/e=429,22 (M+H); HPLC-method A, Rt2,88 minutes

Example 4 [2-(2-Chlorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl]-(7-fluoro-1H-indazol-3-yl)amine (II-4): Connection obtained with the yield of 52% in the form of a white solid.1H NMR (500 MHz, DMSO-d6) δ 1,72 (m, 4H), of 1.92 (m, 2H), 3,00 (m, 4H), 7, 02 (TD, 1H), 7,20 (DD, 1H), 7,40 (m, 1H), 7,42 (d, 1H), 7,52 (m, 3H), 10,5 (m, 1H), 13,50 (users, 1H); EI-MS 408,2 (M+H); HPLC-method A, Rt3,00 minutes

Example 5 [2-(2-Chlorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-5): Obtained in 51%yield.1H NMR (500 MHz, DMSO-d6) δ 1,71 (m, 4H), 1.91 a (m, 2H), 3,01 (m, 4H),from 7.24 (TD, 1H), 7,41 (m, 2H), 7,54 (m, 4H), 10,5 (m, 1H), 13,1 (users, 1H); EI-MS 408,2 (M+H); HPLC-method A, Rt3,05 minutes

Example 6 [2-(2-Chlorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptatriene the-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-6): The way To exit 72%. 1H NMR (500 MHz, DMSO-d6) δ 1,72 (m, 4H), 1.91 a (m, 2H), 3,01 (m, 4H), 7,31 (m, 2H), 7,41 (m, 1H), 7,54 (m, 3H), 10,5 (m, 1H), 13,6 (users, 1H); EI-MS to 426.2 (M+H); HPLC-method A, Rt3,21 minutes

Example 7 (7-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)5,6,7,8-tetrahydroquinazolin-4-yl]amine (II-7): Obtained with a yield of 62%.1H NMR (500 MHz, DMSO-d6) δ 13,5 (with, of user., 1H), 10,1 (with, of user., 1H), to 7.75 (m, 4H), 7,33 (d, 1H), 7,17 (DD, 1H), 7,00 (TD, 1H), 2,80 (m, 2H), 2,71 (m, 2H), 1,89 (UserN) ppm; LC-MS (ES+) 428,44 (M+H). (ES-) 426,43 (M-H); HPLC-method A, Rt3,02 minutes

Example 8 (5-fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8-tetrahydroquinazolin-4-yl]amine (II-8): Obtained with a yield of 53%.1H NMR (500 MHz, DMSO-d6) δ 13,1 (s, 1H), 10,2 (with, of user., 1H), to 7.75 (m, 4H), to 7.50 (DD, 1H), 7,27 (DD, 1H), 7,21 (TD, 1H), 2,80 (m, 2H), 2,72 (m, 2H), of 1.88 (m, 4H) ppm; MS (ES+) 428,43 (M+H). (ES-) 426,43 (M-H); HPLC-method A, Rt3,01 minutes

Example 9 (5,7-Debtor-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8-tetrahydroquinazolin-4-yl]amine (II-9): Obtained with a yield of 37%.1H NMR (500 MHz, DMSO-d6) δ of 13.7 (s, 1H), 10,2 (with, of user., 1H), 7,80 (d, 1H), 7,76 (t, 1H), 7,69 (m, 2H), 7,31 (m, 1H), 7,18 (d, 1H), 2,81 (t, user., 2H), 2,72 (t, user., 2H), 1,90 (m, 4H) ppm; MS (ES+) 446,42 (M+H). (ES-) 444,37 (M-H); HPLC-method A, Rt3,09 minutes

Example 10 (5-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8-tetrahydroquinazolin-4-yl]amine (II-10): The way in ethanol with a yield of 35%.1H NMR (500 MHz, DMSO-d6) δ 13,2 (s, 1H), 10,1 (with, of user., 1H), 8,01 (s, 1H), 7,76 (d, 1H), 7,66 (m, 4H), EUR 7.57 (d, 1), and 2.79 (m, 2H), by 2.73 (m, 2H), 1,89 (m, 4H) ppm; MS (ES+) 478,45 (M+H). (ES-) 476,42 (M-H); HPLC-method A, Rt3,21 minutes

Example 11 (5,7-Debtor-1H-indazol-3-yl)-[2-(2-triptoreline)-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl]amine (II-11): Obtained with a yield of 60%. White solid.1H NMR (500 MHz, DMSO-d6) δ 1,72 (m, 4H), 1.91 a (m, 2H), 3,01 (m, 4H), to 7.15 (DD, 1H), 7,30 (TD, 1H), 7,66 (m, 2H), 7,72 (t, 1H), 7,78 (d, 1H), 10,2 (m, 1H), 13,5 (users, 1H); EI-MS 460,2 (M+H); HPLC-method A, Rt3,13 minutes

Example 12 (6-Benzyl-2-(2-triptoreline)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-yl)-(5-fluoro-1H-indazol-3-yl)amine (II-12): Obtained with a yield of 49%.1H NMR (500 MHz, DMSO-d6) δ to 12.8 (s, 1H), 9,11 (s, 1H), 7,68 (d, 1H), 7,58 (t, 1H), 7,53 (t, 1H), 7,44 (m, 4H), 7,37 (t, 2H), 7,29 (m, 1H), 7,19 (m, 2H), of 3.78 (s, 2H), 3,61 (s, 2H), 2,81 (s, UserN) ppm; LC-MS (ES+) 519,24 (M+H); HPLC-method A, Rt3,11 minutes

Example 13 (1H-Indazol-3-yl)-[2-(2-triptoreline)-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl]amine (II-13): Obtained with a yield of 40%.1H NMR (500 MHz, DMSO-d6) δ to 1.70 (m, 4H), 1,90 (m, 2H), 3,00 (m, 4H), 7,01 (t, 1H), 7,30 (TD, 1H), 7,44 (d, 1H), 7,49 (d, 1H), 7,68 (m, 3H), to 7.77 (d, 1H), 10,01 (m, 1H), 12,83 (s, 1H); EI-MS 424,2 (M+H); HPLC-method A, Rt3,17 minutes

Example 14 (7-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl]amine (II-14): Obtained with a yield of 78%.1H NMR (500 MHz, DMSO-d6) δ 1,71 (m, 4H), 1.91 a (m, 2H), 3,00 (m, 4H), 6,38 (TD, 1H), 7,16 (DD, 1H), 7,31 (d, 1H), 7,68 (m, 3H), to 7.77 (d, 1H), of 10.25 (m, 1H), 13,40 (users, 1H); EI-MS 442,2 (M+H); VE the X-method A, Rt3,12 minutes

Example 15 (5-fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl]amine (II-15): Obtained with a yield of 63%.1H NMR (500 MHz, DMSO-d6) δ 1,71 (m, 4H), 1.91 a (m, 2H), 3,00 (m, 4H), 7,20 (TD, 1H), 7,25 (DD, 1H), 7,49 (DD, 1H), 7,69 (ushort, 2H), 7,74 (m, 1H), 7,79 (d, 1H), 10,35 (m, 1H), 13,00 (users, 1H); EI-MS 442,2 (M+H); HPLC-method A, Rt3,21 minutes

Example 16 (7-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-yl]amine (II-16): a Solution of compound (II-12) (45 mg, 0,087 mmol) in methanol (4.4% HCOOH) was treated with an equal weight of Pd/C (10%) at room temperature for 14 hours. The mixture was filtered through celite, the filtrate evaporated and the crude product was purified preparative HPLC to obtain 15 mg (41%) of the desired product as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 12,9 (s, 1H), 9,52 (s, 1H), to 9.32 (s, 2H, TFA-OH), 7,72 (d, 1H), to 7.59 (m, 2H), 7,49 (m, 2H), 7,21 (m, 1H), 7,15 (m, 1H), or 4.31 (s, 2H), 3,55 (s, 2H), 3,00 (m, 2H) ppm; LC-MS (ES+) 429,20 (M+H); HPLC-method A, Rt2,79 minutes

Example 17 (1H-Indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8-tetrahydroquinazolin-4-yl]amine (II-17): Obtained with a yield of 58%.1H NMR (500 MHz, DMSO-d6) δ 13,0 (s, 1H), 10,3 (with, of user., 1H), 7,74 (m, 4H), 7,51 (d, 1H), 7,47 (d, 1H), 7,32 (m, 1H), 7,03 (t, 1H), 2,82 (m, 2H), by 2.73 (m, 2H), 1,90 (m, 4H) ppm, LC-MS (ES+) 410,21 (M+H); HPLC-method A, Rt2,99 minutes

Example 18 (7-Benzyl-2-(2-triptoreline)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-yl)-5-fluoro-1H-indazol-3-yl)amine (II-18): Obtained from compound B11 exit 92%. 1H NMR (500 MHz, DMSO-d6) δ 12,9 (s, 1H), 10,5 (with, of user., 1H), 9,58 (s, 1H, TFA-OH), 7,71 (d, 1H), 7,52 (m, 9H), 7,19 (m, 2H), 4,57 (s, 2H), 4,20 (m, 2H), 3,70 (m, 2H), 3,00 (m, 2H) ppm; LC-MS (ES+) 519,23 (M+H); HPLC-method A, Rt3,23 minutes

Example 19 (1H-Indazol-3-yl)-[6-methyl-2-(2-triptoreline)pyrimidine-4-yl]amine (II-19): Obtained with a yield of 42%. Melting point 235-237°C.1H NMR (500 MHz, DMSO) δ of 2.44 (3H, s), to 7.09 (1H, J=7.5 Hz, t), 7,40 (1H, J=7,1 Hz, t), 7,49 (1H, J=8,3 Hz, d), of 7.70 (3H, m), 7,79 (1H, J=7,3 Hz, t), 7,87 (1H, J=8,3 Hz, d), 8,03 (1H, J=7.7 Hz, d), 10,3 (1H, s), and 12.6 (1H, s) ppm; HPLC-method A, Rt2,958 min; MS (,FIA) 370,2 (M+H)+.

Example 20 (1H-Indazol-3-yl)-[6-phenyl-(2-triptoreline)pyrimidine-4-yl]amine (II-20): Obtained with a yield of 32%.1H NMR (500 MHz, DMSO) δ 6,94 (1H, J=7,4 Hz, t), from 7.24 (1H, J=7,4 Hz, t), 7,33 (1H, J=8,4 Hz, d), 7,42 (3H, m), EUR 7.57 (1H, J=7,3 Hz, t), to 7.68 (2H, m), of 7.75 (1H, J=7.9 Hz, d), to 7.93 (3H, m), 8,18 (1H, users), 10,45 (1H, users), and 12.5 (1H, users) ppm; HPLC-method A, Rt4,0 min MS (FIA) 432,2 (M+H)+.

Example 21 (1H-Indazol-3-yl)-[6-(pyridin-4-yl)-2-(2-triptoreline)pyrimidine-4-yl]amine (II-21): Obtained with a yield of 12%.1H NMR (500 MHz, DMSO) δ 7,16 (1H, J=7,4 Hz, t), 7,46 (1H, J=7,6 Hz, t), 7,56 (1H, J=8,3 Hz, d), 7,80 (1H, J=7,2 Hz, t), of 7.90 (2H, m), of 7.97 (1H, J=7.8 Hz, d), of 8.09 (1H, usher.), by 8.22 (2H, J=4,9 Hz, d), to 8.45 (1H, users), 8,93 (2H, J=4,8 Hz, d), or 10.9 (1H, users), to 12.8 (1H, users) ppm; HPLC-method A, Rt3,307 min MS (FIA) 433,2 (M+H)+.

Example 22 (1H-Indazol-3-yl)-[6-(pyridin-2-yl)-2-(2-triptoreline)pyrimidine-4-yl]amine (II-22): Obtained vyhoda%. 1H NMR (500 MHz, DMSO) δ 7,07 (1H, J=7,4 Hz, t), of 7.36 (1H, J=7,4 Hz, t), 7,46 (1H, J=7,4 Hz, d), 7,53 (1H, J=5.0 Hz, t), of 7.70 (1H, J=7,4 Hz, t), 7,79 (1H, J=7,1 Hz, t), 7,83 (1H, J=7,4 Hz, d), 7,88 (1H, J=7,8 Hz, d), of 7.97 (1H, J=7.7 Hz, t), 8,02 (1H, J=5.5 Hz, userd), at 8.36 (1H, J=7.8 Hz, d), is 8.75 (2H, J=4,1 Hz, d), and 10.5 (1H, users), a 12.7 (1H, users) ppm; HPLC-method A, Rt3,677 min; MS (FIA) 433,2 (M+H)+.

Example 23 [6-(2-Chlorophenyl)-2-(2-triptoreline)pyrimidine-4-yl]-(1H-indazol-3-yl)amine (II-23): Obtained with a yield of 44%.1H NMR (500 MHz, DMSO) δ was 7.08 (1H, J=7.5 Hz, t), 7,37 (1H, J=7.5 Hz, t), was 7.45 (1H, J=8,4 Hz, d), 7,51 (2H, m), to 7.61 (1H, J=7,4, 1.9 Hz, DD), 7,69 (2H, m), 7,79 (2H, J=4.0 Hz, d), 7,86 (3H, J=7,8 Hz, d), of 8.04 (2H, J=6.2 Hz, userd)and 10.7 (1H, users), and 12.6 (1H, users) ppm; HPLC-method A, Rt3,552 min; MS (FIA), 466,2 (M+H)+.

Example 24 [5,6-Dimethyl-2-(2-triptoreline)pyrimidine-4-yl]-(1H-indazol-3-yl)amine (II-24): Obtained with a yield of 35%; TPL 183-186°C.1H NMR (500 MHz, DMSO) δ and 2.14 (3H, s), and 2.27 (3H, s), 6,85 (1H, J=7, 5 Hz, t), to 7.15 (1H, J=7,6 Hz, t), 7,32 (3H, m), 7,38 (1H, J=7.5 Hz, t), 7,42 (1H, J=7,4 Hz, t), 7,53 (1H, J=7,6 Hz, d), 8,88 (1H, ), and 12.5 (1H, s) ppm; HPLC-method A, Rt2,889 min; MS (FIA) 384,2 (M+H)'.

Example 25 [5,6-Dimethyl-2-(2-triptoreline)pyrimidine-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-25): Obtained with a yield of 44%. Melting point 160-163°C.1H NMR (500 MHz, DMSO) δ and 2.27 (3H, s), is 2.40 (3H, s), to 7.15 (2H, m), 7,44 (2H, m), 7,52 {1H, J=7,4 Hz, t), EUR 7.57 (1H, J=7,4 Hz, t), to 7.67 (1H, J=7.8 Hz, d), 9,03 (1H, s), was 12.75 (1H, s) ppm; HPLC-method A, Rt2,790 min; MS (FIA) 402,2 (M+H)+.

Example 26 [2-(2-Chlorophenyl)-5,6-di is ethylpyrimidine-4-yl]-(1H-indazol-3-yl)amine (II-26): Obtained with a yield of 30%. 1H NMR (500 MHz, DMSO) δ and 2.14 (3H, s), of 2.33 (3H, s), at 6.84 (1H, J=7,4 Hz, t), 7,13 (1H, J=7,4 Hz, t), 7,19 (1H, J=6,9 Hz, ushort), 7,27 (1H, J=7,4 Hz, d), 7,32 (3H, osirm), 7,37 (1H, J=7,1 Hz, d), and 10.0 (1H, user.), to 12.8 (1H, users) ppm; 8 2,919 min; MS (FIA) 350,1 (M+H)+.

Example 27 [5,6-Dimethyl-2-(2-triptoreline)pyrimidine-4-yl]-(7-fluoro-1H-indazol-3-yl)amine (II-27): Obtained with a yield of 92%.1H NMR (500 MHz, DMSO) δ of 2.33 (3H, s)of 2.50 (3H, s), 6,91 (1H, m), to 7.15 (1H, m), 7,30 (1H, J=8,1 Hz, d), the 7.65 (3H, m), 7,76 (1H, J=7, 5 Hz, d), and 10.0 (1H, s), and 13.4 (1H, s) ppm; HPLC-method A, Rt3,053 min; MS (FIA) 402,2 (M+H)+.

Example 28 (5,7-Debtor-1H-indazol-3-yl)-[5,6-dimethyl-2-(2-triptoreline)pyrimidine-4-yl]amine (II-28): Obtained with a yield of 50%.1H NMR (500 MHz, DMSO) δ to 2.42 (3H, s), 2.63 in (3H, s), 7,22 (1H, J=7,Hz, d), 7,38 (1H, J=9,3, 1.7 Hz, dt), 7,71 (1H, m), of 7.75 (1H, J=7,0 Hz, d), 7,79 (1H, J=6,7 Hz, d), 7,86 (1H, J=8.0 Hz, d), 10,0,(1H with), and 13.2 (1H, s) ppm; HPLC-method A, Rt3,111 min; MS (FIA) 420,2 (M+H)+.

Example 29 [2-(2-Chlorophenyl)-5,6-dimethylpyrimidin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-29): Obtained with a yield of 58%.1H NMR (500 MHz, DMSO) δ 2,47 (3H, s)to 2.66 (3H, s), 7,44 (2H, m), 7,53 (1H, m), of 7.64 (3H, m), 10,4 (1H, usher.), 13,8 (1H, users) ppm; HPLC - Method A, Rt2,921 min; MS (FIA) 386,1 (M+H)+.

Example 30 [2-(2-Chlorophenyl)-5,6-dimethylpyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)amine (II-30): Obtained with a yield of 70%.1H NMR (500 MHz, DMSO) δ to 2.35 (3H, s), of 2.51 (3H, s), 7,03 (1H, J=7,8, 4,4 Hz, dt), 1,22 (1H, m), 7,33 (1H, J=7,4 Hz, t), 7,42 (1H, m), 9,19 (1H, s), and 13.3 (1H, s) ppm; HPLC-method A, Rt2,859 min; MS (FIA) 38,2.

Example 31 [2-(2-Chlorophenyl)-5,6-dimethylpyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-31): Obtained with a yield of 86%.1H NMR (500 MHz, DMSO-d6) δ 2,49 (3H, s), 2,68 (3H, s), 7,38 (1H, J=9,0 Hz, t), 7,54 (2H, m), to 7.67 (4H, m), and 10.5 (1H, usher.), 13,2 (1H, users) ppm; HPLC-method A, Rt2,850 min; MS (FIA) 368,1 (M+H)+.

Example 32 [2-(2,4-Dichlorophenyl)-5,6-dimethylpyrimidin-4-yl]-(1H-indazol-3-yl)amine (II-32): Obtained with a yield of 52%.1H NMR (500 MHz, DMSO-d6) δ the 2.46 (3H, s)of 2.64 (3H, s), 7,16 (1H, J=7.5 Hz, t), 7,46 (1H, J=7,6 Hz, t), to 7.61 (2H, m), 7,68 (2H, J=8,2 Hz, d), 7,82 (1H, m), 10,2 (1H, usher.), 13,0 (1H, users) ppm; HPLC-method A, Rt2,983, min; MS (FIA) 384,1 (M+H).

Example 33 (5-Methyl-2H-pyrazole-3-yl)-[2-(2-were-hinzelin-4-yl]amine (II-33):1H NMR (DMSO) δ to 1.21 (3H,in), 2.25 (3H, s), 6,53 (1H, s), 7,38 (4H, m), a 7.62 (1H, d), 7,73 (1H, d), 7,81 (1H, d), 7,89 (1H, t), to 8.70 (1H, s), 12,20 (1H, s); MS 316,3 (M+H)+.

Example 34 [2-(2,4-Differenl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-34):1H NMR (500 MHz, DMSO-d6) δ 12,4 (users, 1H), 10,8 (users, 1H), 8,58 (d, 1H), 7,97 (m, 1H), at 8.36 (m, 1H), a 7.85 (m, 1H), 7,60 (m, 1H), 6,62 (s, 1H), 2,30 (s, 3H); MS 338,07 (M+H).

Example 35 [2-(2,5-Acid)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-35):1H NMR (500 MHz, DMSO-d6) δ 12,5 (users, 1H), 8,68 (user., 1H), 7,92 (t, J=7.5 Hz, 1H), 7,86 (d, J=8,2 Hz, 1H), 7,65 (t, J=7,5 Hz, 1H), 7,45 (s, 1H), 7,14 (m, 2H), 6,51 (s, 1H), 3,79 (s, 3H), to 3.67 (s, 3H), and 2.14 (s, 3H); MS 362,2 (M+H).

Example 36 [2-(2-Chlorophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-36):1H NMR (500 MHz, LCA is-d 6) δ 11,8 (user., 1H), 8,80 (d, J=8,3 Hz, 1H), 8,00 (t, J=7,6 Hz, 1H), 7,82 (d, J=8,3 Hz, 1H), 7,78 (m, 2H), to 7.67 (d, J=7.8 Hz, 1H), to 7.61 (t, J=7,0 Hz, 1H), 7,55 (t, J=7,4 Hz, 1H), 6,56 (s, 1H), 2,18 (s, 3H); MS 336,1 (M+H).

Example 37 [2-(2-Methoxyphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-37):1H NMR (500 MHz, DMSO-d6) δ 8,78 (with, of user., 1H), 8,00 (t, J=7,4 Hz, 1H), of 7.90 (m, 2H), 7,74 (t, J=7.5 Hz, 1H), 7,63 (t, J=7,3 Hz, 1H), 7,30 (d, J=8,4 Hz, 1H), 7,18 (t, J=7.5 Hz, 1H), 6,58 (with, of user., 1H), 3,90 (s, 3H), of 2.21 (s, 3H); MS 332,1 (M+H).

Example 38 [2-(2,6-Dimetilfenil)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-38):1H NMR (500 MHz, DMSO-d6) δ 12,2 (s, UserN), 8,88 (d, J=7.7 Hz, 1H), 8,05 (t, J=7.7 Hz, 1H), 7,80 (m, 2H), 7,37 (t, J=7,6 Hz, 1H), 7,21 (d, J=7.7 Hz, 2H), 6,36 (s, 1H), 2,16 (s, 3H), of 2.15 (s, 6H); MS 330,1 (M+H).

Example 39 [2-(2-Acetylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-39):1H NMR (500 MHz, DMSO-d6) δ 12,35 (with, of user., 1H), 8,93 (d, J=8,4 Hz, 1H), of 8.37 (d, J=8.6 Hz, 1H), to 8.20 (d, J=7,6 Hz, 1H), 8,11 (t, J=8.0 Hz, 2H), 7,89 (m, 2H), to 7.77 (m, 2H), 6,93 (s, 1H), 2,33 (s, 3H), 2,04 (s, 3H), MS 344,1 (M+H).

Example 40 [2-(2,3-Dimetilfenil)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-40):1H NMR (500 MHz, DMSO-d6) δ 12,6 (with, of user., 1H), 12,1 (with, of user., 1H), 8,91 (d, J=7.7 Hz, 1H), 8,14 (t, J=7.2 Hz, 1H), 7,95 (d, J=8,4 Hz, 1H), 7,89 (t, J=7,7 Hz, 1H), 7,58 (d, J=7,6 Hz, 1H), 7,53 (d, J=7,0 Hz, 1H), 7,42 (t, J=7,6 Hz, 1H), 6,60 (s, 1H), 2,43 (s, 3H), to 2.35 (s, 3H), 2,32 (s, 3H); MS 330,1 (M+H).

Example 41 (5-Methyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-41):1H NMR (500 MHz, DMSO-d6) δ to 12.3 (s, 1H), and 10.5 (s, 1H), 8,77 (d, J=8,2 Hz, 1), a 7.92 (m, 2H), a 7.85 (m, 3H), 7,56 (t, J=8,1 Hz, 1H), to 7.67 (t, J=7,4 Hz, 1H), 6,63 (s, 1H), and 2.27 (s, 3H); MS 370,1 (M+H).

Example 42 [2-(2-Ethylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-42):1H NMR (500 MHz, DMSO-d6) δ 8,80 (m, 1H), 8,02 (with, of user., 1H), 7,82 (d, J=8,4 Hz, 1H), to 7.77 (m, 1H), 7.62mm (d, J=7,6 Hz, 1H), 7,54 (m, 1H), 7,41 (m, 2H), 6,40 (s, 1H), 2,75 (kV, J=7,1 Hz, 2H), 2,17 (s, 3H), 0,99 (t, J=7.5 Hz, 3H); MS 330,1 (M+H).

Example 43 (2-Biphenyl-2-imaginaton-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (II-43):1H NMR (500 MHz, DMSO-d6) δ 8,76 (d, J=7,6 Hz, 1H), 8,04 (m, 1H), to 7.75 (m, 6H), 7,30 (m, 5H), of 5.34 (s, 1H), and 2.14 (s, 3H); MS 378,2 (M+H).

Example 44 [2-(2-Hydroxyphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-44):1H NMR (500 MHz, DMSO-d6) δ 10,9 (with, of user., 1H), to 8.62 (d, J=8,2 Hz, 1H), 8,28 (d, J=7.9 Hz, 1H), 7,87 (m, 2H), 7,60 (t, J=7.9 Hz, 1H), 7,37 (t, J=7.8 Hz, 1H), 6,92 (m, 2H), 6,45 (s, 1H), and 2.27 (s, 3H); MS 318,1 (M+H).

Example 45 [2-(2-Ethoxyphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-45):1H NMR (500 MHz, DMSO-d6) δ 12,1 (with, of user., 1H), up 8.75 (d, J=8,3 Hz, 1H), 7,97 (t, J=7.8 Hz, 1H), 7,82 (d, J=8,3 Hz, 1H), 7,78 (d, J=7.5 Hz, 1H), of 7.70 (t, J=7.8 Hz, 1H), 7,56 (t, J=7.8 Hz, 1H), 7,22 (d, J=8,4 Hz, 1H), 7,12 (t, J=7,6 Hz, 1H), 6,55 (s, 1H), 4,11 (kV, J=6,9 Hz, 2H), 2,16 (s, 3H), 1,22 (t, J=6.9 Hz, 3H); MS 346,1 (M+H).

Example 46 [5-(Thiophene-2-yl)-2H-pyrazole-3-yl]-[2-(2-Cryptor-were)hinzelin-4-yl]amine (II-46):1H NMR (500 MHz, DMSO-d6) δ of 8.04 (d, J=8,3 Hz, 1H), with 8.05 (DD, J=7,3, 8,2 Hz, 1H), to 7.93 (d, J=6,5 Hz, 1H), 7,81 (m, 5H), 7,34 (d, J=5.0 Hz, 1H), 7,25 (m, 1H), 7,00 (m, 1H), 6.87 in (s, 1H); MS 438,1 (M+H).

Example 47 [4-(Thiophene-2-yl)-2H-pyrazole-3-yl]-[2-(2-t is iformatter)hinzelin-4-yl]amine (II-47): Obtained by method C. 1H NMR (500 MHz, DMSO-d6) δ 6,97 (m, 1H), was 7.08 (m, 1H), 7,27 (m, 1H), was 7.36 (m, 1H), 7,66 (m, 2H), to 7.77 (m, 3H), 7,83 (m, 1H), 8,00 (m, 1H), 8,18 (s, 1H), to 8.62 (d, J=8,2 Hz, 1H), 10,7 (users, 1H); El-MS 438,1 (M+H); HPLC-method A, Rt2,97 minutes

Example 48 (4-Phenyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-48): Obtained by method C.1H NMR (500 MHz, DMSO-d6) δ 7,05 (users, 1H), 7,14 (t, J=7.8 Hz, 1H), 7,25 (m, 3H), 7,43 (m, 2H), 7,60 (m, 2H), 7,73 (m, 2H), 7,80 (d, 1H), 7,95 (m, 1H), 8,12 (users, 1H), at 8.60 (m, 1H), 10,6 (users, 1H); El-MS 432,2 (M+H); HPLC-method A, Rt3.04 from minutes

Example 49 (5-tert-Butyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-49):1H NMR (500 MHz, DMSO-d6) δ 8,76 (d, J=8,3 Hz, 1H), 7,94 (m, 2H), 7,79 (m, 4H), of 7.70 (t, J=7,6 Hz, 1H), 6,51 (s, 1H), 1,16 (s, 9H); MS 412,2 (M+H).

Example 50 (5-Phenyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-50):1H NMR (500 MHz, DMSO-d6) δ to 7.09 (s, 1H), was 7.36 (TD, J=7,8, 1.1 Hz, 1H), 7,46 (t, J=7.8 Hz, 2H), 7,65 (userd, J=8,1 Hz, 2H), 7,78 (m, 2H), of 7.90 (m, 4H), 7,95 (d, J=7.7 Hz, 1H), 8,00 (t, J=7.8 Hz, 1H), 8,81 (d, J=8.6 Hz, 1H), 11,29 (users, 1H); EI-MS 432,1 (M+H); HPLC-method A, Rt3.24 in minutes

Example 51 (4,5-Diphenyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-51):1H NMR (500 MHz, DMSO-d6) δ 7,13 (m, 1H), 7,18 (m, 5H), of 7.36 10 (m, 5H), a 7.62 (m, 3H), 7,73 (m, 2H), a 7.85 (m, 1H), 8,48 (d, J=8.7 Hz, 1H), 10,02 (s, 1H), 13,19 (s, 1H); EI-MS 508,2 (M+H); HPLC-method A, Rt3,39 minutes

Example 52 (4-Carbarnoyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-52): Received what hodom 40%. 1H NMR (500 MHz, DMSO-d6) δ is 12.85 (s, 1H), 12,77 (s, 1H), RS 11.80 (s, 1H), 10,80 (s, 1H), 8,35-7,42 (m, 9H); MS 399,13 (M+H) HPLC-method A, Rt2,782 minutes

Example 53 (2H-Pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-53): Obtained with a yield of 38%.1H NMR (500 MHz, DMSO-d6) δ to 12.52 (s, 1H), 10,65 (s, 1H), up 8.75 (d, 1H), to $ 7.91-to 7.68 (m, 8H), 6.87 in (s, 1H), MS: (M+H) 356,17, HPLC-method A, Rt2,798 minutes

Example 54 (5-Hydroxy-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-54): Obtained with a yield of 36%.1H NMR (500 MHz, DMSO-d6) δ 10,61 (s, 1H), up 8.75 (s, 1H), 8,03 to 7.75 (m, 9H), 5,97 (s, 1H); MS 372,18 (M+H); HPLC-method A, Rt2,766 minutes

Example 55 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-55): Obtained with a yield of 30%.1H NMR (500 MHz, DMSO-d6) δ 12,21 (s, 1H), 10,45 (s, 1H), 8,68 (s, 1H), 7,89 was 7.45 (m, 8H), 5 6,48 (s, 1H), 0,89 (m, 2H), and 0.62 (s, 2H), MS 396,18 (M+H); HPLC-method A, Rt3,069 minutes

Example 56 (5-Methoxymethyl-2H-pyrazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-56): Obtained with a yield of 33%.1H NMR (500 MHz, DMSO-d6) δ 12,51 (s, 1H), 10,48 (s, 1H), at 8.60 (s, 1H), 7,81-of 7.55 (m, 7H), of 6.71 (s, 1H), 4,28 (s, 2H), 3,18 (s, 3H), MS 400,19 (M+H): HPLC-method A, Rt2,881 minutes

Example 57 (1H-Indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-57): Obtained 51 mg (yield 78%) as a pale yellow solid.1H NMR (500 MHz, DMSO-d6) δ a 12.7 (s, 1H), 10,4 (s, 1H), 8,55 (d, 1H), 7,81 {t, 1H), 7,71 (d, 1H), to 7.61 (d, 1H), 7,58 (t, 1H),7,46 (m, 4H), 7,3-6(d, 1H), 7,22 (m, 1H), 6,91 (t, 1H) ppm; LC-MS (ES+) 406,16 (M+H). (ES-) 404,19 (M-H); HPLC-method A, Rt 3,00 minutes

Example 58 (4-Chloro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-58): Obtained in DMF (yield 70%) as a pale yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,3 (with, of user., 1H), 10,9 (with, of user., 1H), at 8.60 (d, 1H), 7,97 (t, 1H), 7,81 (d, 1H), of 7.75 (t, 1H), to 7.67 (d, 1H), 7,63 (DD, 1H), EUR 7.57 (m, 2H), 7,43 (d, 1H), 7,28 (DD, 1H), was 7.08 (d, 1H) ppm; LC-MS (ES+) 440,10 (M+H). (ES-) 438,12 (M-H); HPLC-method A, Rtis 3.08 min

Example 59 (5-fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-59): Obtained in DMF (yield 34%) as a pale yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,0 (s, 1H), 10,6 (s, 1H), 8,72 (d, 1H), 7,99 (t, 1H), 7,89 (d, 1H), 7,79 (d, 1H), of 7.75 (t, 1H), 7,68 (m, 3H), 7,56 (DD, 1H), 7,39 (d, 1H), 7,28 (m, 1H) ppm; LC-MS (ES+) 424,12 (M+H). (ES-) m/e=422,13 (M-H); HPLC-method A, Rt3,05 minutes

Example 60 (7-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-60): Obtained in DMF (yield 51%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ and 13.4 (s, 1H), 10,6 (s, 1H), 8,68 (d, 1H), 7,95 (t, 1H), a 7.85 (d, lH), 7,72 (m, 2H), 7,63 (m, 2H), 7,58 (m, 1H), 7,43 (d, 1H), 7,18 (DD, 1H), 7,00 (m, 1H) ppm; LC-MS (ES+) 424,11 (M+H). (ES-) 422,15 (M-H); HPLC-method A, Rt3,06 minutes

Example 61 (5-Methyl-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-61): Obtained in DMF (yield 81%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,0 (with, of user., 1H), 8,79 {user., 1H), 8,11 (user, 1H), of 7.96 (d, 1H), 7,82 (m, 5H), 7,46 (s, 1H), 7,41 (d, 1H), 7,20 (m, 1H), 2,33 (s, 3H) ppm; MS (ES+) 420,15 (M+H). (ES-) 418,17 (M-H); HPLC-method A, Rt3,07 minutes

Example 62 [2-(2,6-Dichlorophenyl)hinzelin-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-62): Obtained in DMF (yield 37%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,0 (s, 1H), and 10.8 (s, 1H), 8,72 (d, 1H), 7,97 (t, 1H), of 7.90 (d, 1H), of 7.75 (t, 1H), 7,53 (m, 3H), 7,43 (t, 1H), 7,35 (d, 1H), 7.23 percent (t, 1H) ppm; LC-MS (ES+) 424,08 (M+H). (ES-) 422,10 (M-H); HPLC-method A, Rt3,06 minutes

Example 63 [2-(2-Chlorophenyl)hinzelin-4-yl]-(1H-indazol-3-yl)amine (II-63): Obtained with a yield of 91%.1H NMR (500 MHz, DMSO-d6) δ 7,06 (t, 1H), was 7.36 (t, 1H), 7,39 (t, 1H), 7,52 (m, 3H), a 7.62 (d, 1H), 7,72 (d, 1H), 7,82 (m, 1H), of 7.90 (d, 1H), 8:05 (m, 1H), 8,76 (d, 1H), 11,5 (m, 1H), 13,02 (s, 1H); EI-MS 372,1 (M+l); HPLC-method A, Rt2,93 minutes

Example 64 (5-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-64): Obtained in DMF (yield 57%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,4 (, user., 1H), 11,4 (user., 1H), 8,72 (d, 1H), 8,12 (s, 1H), 7,98 (t, 1H), 7,83 (d, 1H), 7,76 (d, 1H), 7,73 (DD, 1H), 7,60 (m, 4H), 7,52 (d, 1H) ppm; LC-MS (ES+) 474,12 (M+H). (ES-) 472,17 (M-H); HPLC-method A, Rtof 3.25 minutes

Example 65 (4-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-65): Obtained in DMF (yield 8%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,7 (with, of user., 1H), and 11.2 (user., 1H), to 8.70 (d, 1H), with 8.05 (s, 1H), a 7.85 (m, 3H), of 7.65 (m, 4H), 7,51 (m, 2H) ppm; LC-MS (ES+) 474,13 (M+H). ES-) 472,17 (M-H); HPLC-method A, Rt3,15 minutes

Example 66 [2-(2,6-Dichlorophenyl)hinzelin-4-yl]-(1H-indazol-3-yl)amine (II-66): Obtained in DMF (30%yield) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 12,9 (s; 1H)and 11.1 (s, 1H), 8,69 (d, 1H), 7,95 (t, 1H), 7,82 (d, 1H)', 7,73 (t, 1H), 7,56 (d, 1H), 7,47 (s, 1H), 7,45 (s, 1H), 7,39 (m, 2H), 7,26 (t, 1H), 6,92 (t, 1H) ppm; LC-MS (ES+) 406,11 (M+N). (ES-) 404,12 (M-H); HPLC-method A, Rt3,00 minutes

Example 67 (1H-Indazol-3-yl)-[2-(2-were)hinzelin-4-yl]amine (II-67): Obtained with a yield of 55%.1H NMR (500 MHz, DMSO-d6) δ 2,15,(s, 3H), to 7.09 (t, 1H), 7,26 (d, 1H), 7,31 (m, 1H), 7,39 (t, 1H), 7,42 (m,1H), 7,55 (d, 1H), to 7.64 (d, 1H), 7,74 (d, 1H), 7,89 (m, 1H), of 7.96 (d, 1H), 8,10 (m, 1H), 8,81 (d, 1H), 12,0 (m, 1H), of 13.18 (s, 1H); EI-MS 352,2 (M+l); HPLC-method A, Rt2,93 minutes

Example 68 (7-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-68): Obtained in DMF (75%yield) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,5 (with, of user., 1H), and 11.2 (C, user., 1H), 8,68 (d, 1H), 7,97 {t, 1H),7,92 (d, 1H), 7,82 (d, 1H), 7,74 (t, 1H), of 7.70 (d, 1H), 7,68 (d, 1H), to 7.64 (m, 2H), EUR 7.57 (m, 1H), 7,14 (t, 1H) ppm; LC-MS (ES+) 474,11 (M+H). (ES-) 472,14 (M-H); HPLC-method A, Rt3.24 in minutes

Example 69 (6-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-69): Obtained by the method in DMF (yield 78%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,4 (, user., 1H), 11,1 (with, of user., 1H), 8,67 (d, 1H), 7,95 (t, 1H), 7,82 (m, 3H), 7,72 (m, 2H), 7,63 (m, 2H), EUR 7.57 (t, 1H), 7.23 percent (d, 1H) ppm; LC-MS (ES+) 474,12 (m+H).

p> (ES-) 472,15 (M-H); HPLC-method A, Rt3,28 minutes

Example 70 (5-Nitro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-70): Obtained in DMF (yield 72%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,6 (with, of user., 1H), 11,4 (with, of user., 1H), up 8.75 (s, 1H), 8,72 (d, 1H), 8,09 (DD, 1H), 7,98 (t, 1H), 7,83 (d, 1H), of 7.75 (t, 1H), of 7.70 (m, 2H), to 7.61 (m, 3H) ppm; LC-MS (ES+) 451,14 (M+H). (ES-) 449,12 (M-H); HPLC-method A, Rt3,02 minutes

Example 71 (5,7-Debtor-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-71): Obtained in DMF (yield 60%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,7 (with, of user. 1H), and 11.2 (C, user., 1H), 8,73 (d, 1H), 8,03 (t, 1H), 7,88 (d, 1H), 7,80 (m, 2H), of 7.70 (m, 3H), 7,32 (m, 2H) ppm; LC-MS (ES+) 442,14 (M+H). (ES-) 440,14 (M-H); HPLC-method A, Rt3,11,minutes

Example 72 (4-Pyrrol-1-yl-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-72): Obtained in DMF (yield 33%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,4 (, user., 1H), 11,0 (with, of user., 1H), 8,53 (d, 1H), 7,98 (t, 1H), to 7.75 (m, 4H), 7.62mm (m, 2H), 7,52 (d, 1H), 7,43 (t, 1H), 7,05 (d, 1H), 6,80 (s, 2H), 5,61 (s, 2H) ppm; LC-MS (ES+) 471,18 (M+H). (ES-) 469,18 (M-H); HPLC-method A, Rt3,12 minutes

Example 73 (5-Amino-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-73): a Solution of compound II-70 (70 mg, 0.16 mmol) in Meon (2 ml) was treated with Raney Ni as long until the solution became colorless (added about 1.5 g Raney Ni). After stirring at room is the temperature for 40 minutes, the mixture was filtered through celite, received celite was washed Meon (5 times) and evaporated in vacuo of the solvent to obtain the crude product which was then purified by HPLC, with a specified title compound as yellow solid (10 mg, 15%). TPL 221-223°;1H NMR (500 MHz, DMSO-d6) δ 13,2 (with, of user., 1H), 10,7 (with, of user., 1H), 9,80 (UserN), 8,68 (d, 1H), 7,97 (t, 1H), 7,87 (d, 1H), to 7.75 (m, 2H), 7,65 (m, 5H), 7,30 (d, 1H) ppm; MS (ES+) 421,16 (M+H). (ES-) 419,17 (M-H); HPLC-method A, Rt2,41 minutes

Example 74 [2-(2-Chlorophenyl)hinzelin-4-yl]-(7-fluoro-1H-indazol-3-yl)amine (II-74): Received in DMF (yield 35%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ of 13.7 (s, 1H), 11,7 (with, of user., 1H), 8,80 (d, 1H), 8,15 (t, 1H), to 7.99 (d, 1H), 7,88 (t, 1H), 7,68 (d, 1H), 7,60 (m, 2H), 7,53 (t, 1H), 7,46 (t, 1H), 7,25 (DD, 1H),? 7.04 baby mortality (m, 1H) ppm; LC-MS (ES+) 390,16 (M+H); HPLC-method A, Rt3,00 minutes

Example 75 [2-(2-Chlorophenyl)hinzelin-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-75): Obtained in DMF.1H NMR (500 MHz, DMSO-d6) δ 13,2 (s, 1H), 11,7 (with, of user., 1H), 8,80 (d,1H), 8,10 (t, 1H), to $ 7.91 (m, 2H), of 7.70 (d, 1H), 7,58 (m, 4H), to 7.50 (t, 1H), 7,29 (m, 1H) ppm; LC-MS (ES+) 390,17 (M+H); HPLC-method A, Rt3,00 minutes

Example 76 [2-(2-Chlorophenyl)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-76): Obtained in DMF (yield 55%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,8 (s, 1H), 11,5 (with, of user., 1H), 8,76 (d, 1H), 8,08 (t, 1H), to 7.93 (d, 1H), to 7.84 (t, 1H), to 7.64 (d, 1H), 7,55 (d, 1H), 7,50 (t, 1H), 7,44 (m, 2H), was 7.36 (t, 1H) ppm; LC-MS (ES+) 408,15 (MN). (ES-) 406,17 (M-H); HPLC-method A, Rtis 3.08 min

Example 77 [2-(2-Chlorophenyl)hinzelin-4-yl]-(5-trifluoromethyl-1H-indazol-3-yl)amine (II-77): Obtained in DMF (yield 66%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ and 13.5 (s, 1H), 11,4 (with, of user., 1H), 8,79 (d, 1H), 8,29 (s, 1H), 8,07 (t, 1H), to 7.93 (d, 1H), to 7.84 (t, 1H), 7,72 (d, 1H), 7,63 (d, 2H), 7,53 (d, 1H), of 7.48 (t, 1H), was 7.36 (t, 1H) ppm; LC-MS (ES+): m/e=440,16 (M+H); (ES-): m/e=438,18 (M-H); HPLC-method A, Rt3,22 minutes

Example 78 [2-(2-Tianfeng)hinzelin-4-yl]-(1H-indazol-3-yl)amine (II-78): Obtained with a yield of 13%.1H NMR (500 MHz, DMSO-d6) δ 12,9 (user., 1H), 10,8 (user., 1H), 8,73 (users, 1H), 7,97 (m, 4H), 7,74 (m, 1H), 7.5 (m, 4H), 7,42 (m, 1H), was 7.08 (m, 1H) ppm; MS (FIA) 363,2 (M+H); HPLC-method A, Rt2,971 minutes

Example 79 (5-Bromo-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-79): Obtained in DMF (yield 64%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ and 13.4 (s, 1H), 11,6 (with, of user., 1H), 8,93 (d, 1H), 8,21 (t, 1H), 8,14 (s, 1H), with 8.05 (d, 1H), 7,95 (m, 4H), 7,86 (t, 1H), 7,65 (d, 1H), to 7.59 (d, 1H) ppm; MS (ES+) 486,10 (M+H). (ES-) 484,09 (M-H); HPLC-method A, Rt3,22 minutes

Example 80 (6-Chloro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-80): Obtained in DMF (yield 94%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,1 (s, 1H), and 11.2 (C, user., 1H), 8,73 (d, 1H), 8,03 (t, 1H), 7,87 (d, 1H), 7,79 (m, 2H), 7,73 (m, 2H), to 7.67 (m, 2H), 7,58 (s, 1H),? 7.04 baby mortality (DD, 1H) ppm, LC-MS (ES+) 440,14 (M+H). (ES-) 438,16 (M-H); HPLC-method A, Rtof 3.25 minutes

Example 81 (7-Fluoro-6-reformer-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-81): Received in DMF (30%yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13,9 (s, 1H), 11,0 (with, of user., 1H), 8,64 (d, 1H), 7,94 (t, 1H), 7,81 (d, 1H), 7,71 (m, 2H), 7,60 (m, 4H), 7,20 (DD, 1H) ppm, LC-MS (ES+) 492,18 (M+H). (ES-) 490,18 (M-H); HPLC-method A, Rt3,44 minutes

Example 82 (6-Bromo-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-82): Obtained in DMF (yield 40%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,1 (s, 1H), and 11.2 (C, user., 1H), 8,73 (d, 1H), 8,03 (t, 1H), 7,87 (d, 1H), 7,80 (m, 2H), 7,73 (m, 3H), to 7.67 (m, 1H), to 7.61 (d, 1H), 7,15 (DD, 1H) ppm; MS (ES+) 486,07 (M+H); HPLC-method A, Rt3,28 minutes

Example 83 [2-(2,4-Bistrifluormethylbenzene)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-83): Received in DMF to yield 28%.1H NMR (500 MHz, MeOH-d4) δ 8,81 (d, J=8,4 Hz, 1H), 8,35-to 8.20 (m, 3H), 8,19-of 7.96 (m, 3H), 7,40-7,34 (m, 1H), 7,29-7,14 (m, 1H); LC-MS (ES+) 510,14 (M+H); HPLC-method C, Rt8,29 minutes

Example 84 (5,7-Debtor-1H-indazol-3-yl)-[2-(4-fluoro-2-triptoreline)hinzelin-4-yl]amine (II-84): Obtained with a yield of 48%.1H NMR (500 MHz, MeOH-d4) δ a total of 8.74-8,63 (m, 1H), 8,23-8,10 (m, 1H), 7,99-of 7.90 (m, 2H), 7,89-7,80 (m, 1H), 7,71-to 7.61 (m, 1H), to 7.61-to 7.50 (m, 1H), 7.24 to to 7.15 (m, 1H), 7,14-7,02 (m, 1H); LC-MS (ES+) 460,14 (M+H); HPLC-method C, Rtto 7.59 minutes

Example 85 [2-(2-Bromophenyl)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-85): Obtained in THF (yield 21%).1H NMR (500 MHz, MeOH-d4) δ 8,81 (d, J=8,4 Hz, 1H), 8,35-to 8.20 (m, 3H), 8,19-of 7.96 (m, 3H), 7,40-7,34 (m, 1H), 7,29-7,14 (m, 1H); LC-MS (ES+) 510,14 (M+H); HPLC-method C, Rt8,29 minutes

Example 86 (5,7-Debtor-1H-indazol-3-yl)-[2-(5-fluoro-2-thrift methylphenyl)hinzelin-4-yl]amine (II-86): Obtained in THF (yield 26%). 1H NMR (500 MHz, MeOH-d4) δ to 8.62 (d, J=8,4 Hz, 1H), 8,16-8,02 (m, 1H), of 7.96-7,73 (m, 3H), to 7.59-of 7.48 (m, 1H), of 7.48-7,35 (m, 1H), 7,21-to 7.09 (m, 1H), 7,09-6,89 (m, 1H); LC-MS (ES+) 460,16 (M+H); HPLC-method C, Rt7,28 minutes

Example 87 [2-(2,4-Dichlorophenyl)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-87): Obtained in THF (yield 16%).1H NMR (500 MHz, MeOH-d4) δ 8,81 (d, J=8,4 Hz, 1H), 8,35-to 8.20 (m, 3H), 8,19-of 7.96 (m, 3H), 7,40-7,34 (m, 1H), 7,29-7,14 (m, 1H); LC-MS (ES+) 510,14 (M+H); HPLC-method C, Rt8,29 minutes

Example 88 [2-(2-Chloro-5-triptoreline)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-88): Obtained in THF (yield 33%).1H NMR (500 MHz, DMSO-d6) δ of 10.76 (s, 1H), 8,66 (d, J=8,3 Hz, 1H), 8,06-to 7.84 (m, 3H), 7,81-7,63 (m, 3H), of 7.48-7,16 (m, 2H); LC-MS (ES+) 476,16 (M+H); HPLC-method C, Rt19,28 minutes

Example 89 (4-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-89): Obtained in NMP (yield 79%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,2 (s, 1H), 10,8 (with, of user., 1H), 8,63 (d, 1H), 7,97 (t, 1H), a 7.85 (d, 1H), 7,74 (m, 2H), to 7.64 (t, 1H), EUR 7.57 (m, 2H), 7,32 (m, 2H), PC 6.82 (m, 1H) ppm; LC-MS (ES+) 424,17 (M+H); HPLC-method A, Rt3,14 minutes

Example 90 (1H-Indazol-3-yl)-[8-methoxy-2-(2-triptoreline)hinzelin-4-yl]amine (II-90): the solvent used THF with obtaining specified in the title compounds as TFA salt (yield 23%). HPLC-method A, Rt2,97 minutes (95%)1H NMR (500 MHz, DMSO-d6) δ 12,9 (1H, users), and 11.0 and 10.7(1H, users), to 8.25 (1H, m), 7,75 is 7.50 (8H, s), 7,30 (1H, m), 6.90 to (1H, m), 4,0 (3H, s); M is (m/z) 436,2 (M+H).

Example 91 (5-fluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-triptoreline)hinzelin-4-yl]amine (II-91): the solvent used TFA obtaining specified in the title compounds as TFA salt (yield 23%). HPLC-method A, Rt3,10 minutes (99%);1H NMR (DMSO-d6, 500 MHz): 13,0 (1H, users), and 11.0 and 10.7(1H, users), to 8.25 (1H, m), 7,75 is 7.50 (7H, m), 7,35 (1H, m), 7,25 (1H, m), 4,0 (3H, s); MS (m/z) 454,2 (M+H).

Example 92 (7-Fluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-triptoreline)hinzelin-4-yl]amine (II-92): the solvent used THF with obtaining specified in the title compounds as TFA salt (98 mg, yield 58%). HPLC-method A, Rt3,20 minutes (92%);1H NMR (DMSO-d6, 500 MHz) δ 13,45 (1H, users), and 11.0 and 10.7(1H, users), to 8.25 (1H, m), 7,75-of 7.60 (5H, m)to 7.50 (1H,m), 7,40 (1H, m), to 7.15 (1H, m), to 6.95 (1H, m) 4,0 (3H, s); MS (m/z) 454,2 (M+H).

Example 93 (5,7-Debtor-1H-indazol-3-yl)-[8-methoxy-2-(2-triptoreline)hinzelin-4-yl]amine (II-93): the solvent used THF with obtaining specified in the title compounds as TFA salt (yield 36%). HPLC-method A, Rtwith 3.27 min (95%);1H NMR (DMSO-d6, 500 MHz): 13,65 (1H, users), and 11.0 and 10.7(1H, users), by 8.22 (1H, m), 7,75-of 7.60 (5H, m), 7,40 (1H, m), 7,35 (1H, m), 7,19 (1H, m), 4,0 (3H, s); MS (m/z) 472,2 (M+H).

Example 94 [2-(2-Chloropyridin-3-yl)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-94): Obtained in DMF.1H NMR (500 MHz, DMSO-d6) δ 13,62 (users, 1H, 11,06-10,71 (m, 1H), 8,16-of 7.70 (m, 4H), 7,60-to 7.09 (m, 3H); LC-MS (ES+) 409,14 (M+H); HPLC-method Rt2,89 minutes

Example 95 [2-(2-Chloro-4-nitrophenyl)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-95): Obtained in THF.1H NMR (500 MHz, DMSO-d6) δ 13,35 (s, 1H), a 10.74 (s, 1H), 8,67 (d, J=8,4 Hz, 1H), 8,29 (d, J=2,05 Hz, 1H), 8,18-8,08 (m, 1H), 8.07-a of 7.60 (m, 4H-), 7,53-7,10 (m, 2H), LC-MS (ES+) 453,15 (M+H); HPLC-method e, Rt3,63 minutes

Example 96 [2-(4-Amino-2-chlorophenyl)hinzelin-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-96): a Solution of compound II-95 (8 mg, 0.018 mmol) chloride dihydrate tin (22 mg, 0.1 mmol) in ethanol (2 ml) was heated at 100°C for 24 hours. The reaction mixture was diluted with EtOAc (10 ml), washed with 1 N. NaOH solution (2 x 10 ml), saturated salt solution and dried over anhydrous sodium sulfate to obtain the crude product. Spent cleaning product flash chromatography on silica gel (elution 1-3% Meon in CH2Cl2). Allocated is specified in the title compound as a pale yellow solid (1.2 mg, yield 16%). LC-MS (ES+) 423,12 (M+H). HPLC method C, Rt13,78 minutes

Example 97 (4,5,6,7-Tetrahydro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-97): Obtained with a yield of 34%.1H NMR (500 MHz, DMSO-d6) δ was 1.58 (m, 2H), of 1.66 (m, 2H), 2,24 (m, 2H), 2,54 (m, 2H), 7,63 (m, 3H), 7,71 (t, 1H), of 7.75 (d, 1H), 7,78 (d, 1H), a 7.85 (t, 1H), 8,53 (d, 1H), 9,99 (s, 1H), 12,09 (s, 1H); EI-MS 410,2 (M+l); HPLC method A, Rt3,05 minutes

Example 98 (1H-pyrazolo[4,3-b]pyridine-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-98): Obtained in the MF (yield 37%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13,1,(with, of user., 1H), and 11.2 (C, user., 1H), 8,73 (d, 1H), 8,54 (DD, 1H), 8,12 (d, 1H), of 8.06 (t, 1H), of 7.90 (d, 1H), to 7.84 (t, 1H), of 7.75 (d, 1H), 7,69 (m, 2H), 7,65 (t, 1H), 7,47 (DD, 1H) ppm; LC-MS (ES+) 407,18 (M+H); HPLC-method A, Rt2,77 minutes

Example 99 (1H-pyrazolo[3,4-b]pyridine-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-99): Obtained in DMF (yield 45%).1H NMR (500 MHz, DMSO-d6) δ 13,5 (with, of user., 1H), 11,3 (with, of user., 1H), 8,78 (d, 1H), 8,49 (d, 1H), 8,17 (d, 1H), 8,03 (t, 1H), 7,89 (d, 1H), 7,80 (m, 2H), 7,74 (m, 2H), 7,68 (m, 1H), was 7.08 (DD, lH), ppm; MS (ES+) 407,16 (M+H). (ES-) 405,16 (M-H); HPLC-method A, Rt2,80 minutes

Example 100 (6-Methyl-1H-pyrazolo[3,4-b]pyridine-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-100): Obtained in DMF (yield 11%).1H NMR (500 MHz, DMSO-d6) δ 13,2 (with, of user., 1H), 10,8 (with, of user., 1H), to 8.57 (d, 1H), 7,95 (t, 1H), 7,82 (d, 1H), 7,72 (t, 1H), 7,65 (m, 2H), 7,58 (m, 2H), 2,44 (s, 3H, hidden DMCO), of 2.20 (s, 3H) ppm, LC-MS (ES+) 435,22 (M+H). (ES-) 433,25 (M-H); HPLC-method A, Rt2,94 minutes

Example 101 (6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo[4,3-C]-pyridazin-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-101): Obtained in DMF (yield 6%).1H NMR (500 MHz, DMSO-d6) δ of 12.6 (s, 1H), 11,0 (with, of user., 1H), at 8.60 (d, 1H), 7,95 (t, 1H), 7,88 (d, 1H), 7,80 (d, 1H), 7,68 (m, 4H), 7,40 (s, 3H), 7,22 (s, 2H), is 6.61 (s, 1H) ppm, LC-MS (ES+) 500,21 (M+H). (ES-) 498,16 (M-H); HPLC-method A, Rt3,00 minutes

Example 103 [6-Methyl-2-(2-trifloromethyl)pyrimidine-4-yl]-(5-phenyl-2H-pyrazole-3-yl)amine (II-103): MS 412,13 (M+H); HPLC-method E, Rt1,248 minutes

Example 104 (furan-2-yl-2H-pyrazole-3-yl)-[6-methyl-2-(2-trifloromethyl)pyrimidine-4-yl]amine (II-104): MS 402,12 (M+H); HPLC-method E, Rt1,188 minutes

Example 105 [6-Ethyl-2-(2-trifloromethyl)pyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-105): MS 364,14 (M+H); HPLC-method E, Rt1,112 minutes

Example 106 [2-(2-Chlorophenyl)pyrido[2,3-d]pyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (II-106):1H NMR (500 MHz, DMSO-d6) δ 12,23 (s, 1H), 10,78 (s, 1H), 7,73-7,47 (m, 7H), 6,72 (s, 1H), of 2.21 (s, 3H), MS: (M+H) 337,02, HPLC-method A, Rt2,783 minutes

Example 107 (5-fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-6,7-dihydro-5H-cyclopentadienide-4-yl]amine (II-107): Obtained with a yield of 68%.1H NMR (500 MHz, DMSO-d6) δ of 2.16 (t, 2H), 2,88 (m,2H), 2,98 (t, 2H), 7,21 (TD, 1H), 7,29 (DD, 1H), 7,50 (DD, 1H), 7,65 (t, 1H), to 7.67 (t, 1H), 7,73 (t, 1H), 7,79 (d, 1H), 10,22 (users, 1H), 12,99 (users, 1H); EI-MS level of 414.2 (M+H); HPLC method A, Rt2,92 minutes

Example 108 (1H-Indazol-3-yl)-[2-(2-triptoreline)pyrido-[2,3-d]pyrimidine-4-yl]amine (II-108): HPLC-method A, Rt2,78 minutes (95%);1H NMR (DMSO-d6, 500 MHz): 12,95 (1H, users), of 11.45 δ of 11.15(1H, users), 9,20 (2H, m), a 7.85-of 7.70 (2H, m), 7,70-of 7.55 (4H, m)to 7.50 (1H, m), 7,35 (1H, m), 7,05 (1H, m); MS (m/z) 407,03 (M+H).

Example 109 (5,7-Debtor-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)pyrido[2,3-d]pyrimidine-4-yl]amine (II-109): Yellow salt di-TFA (yield 25%). HPLC (Method A) 3,10 minutes (95%);1H NMR (DMSO-d6, 500 MHz): 13,8 of 13.6 (1H, users), and 11.4 to 11.2(1H, users), to 9.15 (2H, m), 7,85 to 7.75 (2H, m), of 7.75 to 7.62 (3H, m), 7,32 (2H, m); MS (m/z) 442,98 (M+H).

Example 110 [2-(2-Chlorophenyl)pyrido[2,3-d]pyrimidine-4-yl]-(1H-indazol-3-yl)amine (II-110): From 2-aminonicotinate is islote and 2-chlorobenzylchloride received specified in the title compound in the form of salts of di-TFA (yield 28%). HPLC-method A, Rt2,85 minutes (95%);1H NMR (DMSO-d6, 500 MHz): 12,90 (1H, s), 11,10 - 10,90 (1H, users), 9,05 (2H, m), 7,75-of 7.60 (2H, m), 7,51 (1H, m), 7,45-of 7.25 (5H, m), to 6.95 (1H, m); MS (m/z) 372,99 (M+H).

Example 111 (5-fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8,9,10-hexahydropirimidine-4-yl]amine (II-111): Obtained with a yield of 43%.1H NMR (500 MHz, DMSO-d6) δ of 1.46 (m, 2H), 1,53 (m, 2H), 1.77 in (m, 4H), 2.95 and (m, 2H), 3.04 from (m, 2H), 7,22 (m, 2H), 7,50 (DD, 1H), 7,72 (m, 3H), 7,80 (d, 1H), 10,5 (m, 1H), of 13.05 (users, 1H); EI-MS 456,2 (M+H); HPLC-method C, Rt11,93 minutes

Example 112 [2-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopentadienide-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-112): Obtained with a yield of 67%.1H NMR (500 MHz, DMSO-d6) δ to 2.18 (m, 2H), 2,89 (m, 2H), to 3.02 (t, 2H), 7,24 (TD, 1H), 7,42 (m, 2H), 7,49 (TD, 1H), 7,52 (DD, 1H), 7,54 (d, 1H), EUR 7.57 (DD, 1H), 10,50 (users, 1H), 13,06 (users, 1H); EI-MS 380,1 (M+l); HPLC-method C, Rt9,68 minutes

Example 113 (1H-Indazol-3-yl)-[2-(2-triptoreline)-6,7-dihydro-5H-cyclopentadienide-4-yl]amine (II-113): Obtained with a yield of 37%.1H NMR (500 MHz, DMSO-d6) δ to 2.65 (m, 2H), 2,85 (m, 2H), 2,99 (t, 2H), 7,02 (t, 1H), 7,32 (m, 1H), 7,47 (d, 1H), 7,55 (d, 1H), 7,68 (t, 1H), 7,74 (t, 1H), 7,80 (d, 1H), 10,37 (users, 1H), 12,91 (users, 1H); EI-MS 396,1 (M+H); HPLC-method B, Rt9,88 minutes

Example 114 (7-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-6,7-dihydro-5H-cyclopentadienide-4-yl]amine (II-114): Obtained with a yield of 40%.1H NMR (500 MHz, DMSO-d6) δ of 2.15 (m, 2H), 2,87 (m, 2H), 2,97 (t, 2H), 6,99 (TD, 1H), 7,17 (DD, 1H), 7,38 (d, 1H), 7,65 (m, 2H), 7,71 (t, 1H), and 78 (d, 1H), of 10.21 (users, 1H), 13,40 (users, 1H); EI-MS 414,1 (M+H); HPLC-method C, Rt9,99 minutes

Example 115 (5,7-Debtor-1H-indazol-3-yl)-[2-(2-triptoreline)-6,7-dihydro-5H-cyclopentadienide-4-yl]amine (II-115): Received way with the release of 52%.1H NMR (500 MHz, DMSO-d6) δ of 2.16 (m, 2H), 2,89 (m, 2H), 2,97 (t, 2H), 7,19 (DD, 1H), 7,29 (TD, 1H), 7,63 (t, 1H), 7,66 (d, 1H), 7,71 (t, 1H), 7,78 (d, 1H), 10,16 (users, 1H), 13,55 (users, 1H); El-MS 432,1 (M+H); HPLC-method C, Rtto 10.09 minutes

Example 116 [2-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopentadienide-4-yl]-(1H-indazol-3-yl)amine (II-116): Obtained with a yield of 56%.1H NMR (500 MHz, DMSO-d6) δ of 2.16 (m, 2H), 2,85 (m, 2H), 3,01 (t, 2H), 7,06 (t, 1H), 7,34 (t, 1H), 7,40 (t, 1H), of 7.48 (m, 2H), 7,53 (d, 1H), 7,56 (d, 1H), 7,63 (d, 1H), accounted for 10.39 (users, 1H), 12,91 (C, 10 1H); EI-MS 362,1 (M+H); HPLC-method A, Rt3,09 minutes

Example 117 [2-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopentadienide-4-yl]-(7-fluoro-1H-indazol-3-yl)amine (II-117): Obtained with a yield of 63%.1H NMR (500 MHz, DMSO-d6) δ of 2.15 (m, 2H), 2,87 (m, 2H), 3.00 for (t, 2H), 7,01 (TD, 1H), 7,19 (DD, 1H), 7,39 (t, 1H), 7,45 (m, 2H), 7,51 (d, 1H), 7,55 (d, 1H), 10,35 (users, 1H), 13,45 (users, 1H); EI-MS 380,1 (M+H); HPLC-method A, RtRt3,15 minutes

Example 118 [2-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopentadienide-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-118): Obtained with a yield of 60%.1H NMR (500 MHz, DMSO-d6) δ to 2.18 (m, 2H), 2.91 in (m, 2H), 3,01 (t, 2H), 7,32 (m, 1H), 7,33 (TD, 1H), 7,41 (t, 1H), of 7.48 (t, 1H), 7,53 (d, 1H), 7,55 (DD, 1H), 10,35 (users, 1H), 13,45 (users, 1H); EI-MS 398,1 (M+H); HPLC-method A, RtRt3,4 minutes

Example 119 (1H-Indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8,9,10-hexahydropirimidine-4-yl]amine (II-119): Obtained with a yield of 36%.1H NMR (500 MHz, DMSO-d6) δ to 1.47 (m, 2H), 1,53 (m, 2H), 1,78 (m, 4H), 2,96 (m, 2H), 3,06 (t, 2H), 7,03 (t, 1H), 7,47 (t, 1H), 7,72 (d, 1H), 7,73 (d, 1H), 7,72 (m, 3H), 7,81 (d, 1H), 10,52 (m, 1H), 12,97 (users, 1H); EI-MS 438,2 (M+1); HPLC-method A, Rt3,37 minutes

Example 120 (7-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8,9,10-hexahydropirimidine-4-yl]amine (II-120): Obtained with a yield of 40%.1H NMR (500 MHz, DMSO-d6) δ of 1.46 (m, 2H), of 1.52 (m, 2H), 1.77 in (m, 4H), to 2.94 (m, 2H), 3.04 from (m, 2H), 7,00 (TD, 1H), 7,17 (DD, 1H), 7,30 (d, 1H), of 7.70 (m, 3H), 7,79 (d, 1H), 10,5 (m, 1H), 13,49 (users, 1H); EI-MS 456,1 (M+H); HPLC method A, Rt3,43 minutes

Example 121 (5,7-Debtor-1H-indazol-3-yl)-[2-(2-triptoreline)-5,6,7,8,9,10-hexahydropirimidine-4-yl]amine (II-121): Obtained with a yield of 48%.1H NMR (500 MHz, DMSO-d6) δ of 1.46 (m, 2H), of 1.52 (m, 2H), 1.77 in (m, 4H), 2.95 and (m, 2H), 3,03 (m, 2H), 7,14 (d, 1H), 7,30 (m, 1H), 7,73 (m, 3H), 7,80 (d, 1H), 10,5 (m, 1H), 13,62 (users, 1H); EI-MS 475,1 (M+1); HPLC-method A, Rt3,52 minutes

Example 122 [6-Cyclohexyl-2-(2-triptoreline)pyrimidine-4-yl]-(1H-indazol-3-yl)amine (II-122): Obtained with a yield of 45%.1H NMR (500 MHz, DMSO-d6) δ of 1.30 (2H, m)of 1.46 (2H, m), of 1.65 (2H, m)of 1.76 (2H, m), at 1.91 (2H, m), 2,61 (1H, osirm), was 7.08 (1H, t, J=7,4 Hz), 7,27 (1H, d, J=8.0 Hz), 7,35 (1H, t, J=7,1 Hz)to 7.50 (1H, t, J=7.0 Hz), 7,58 (1H, t, J=7.4 Hz), 7,66 (3H, m), 7,72 (1H, d, J=7.8 Hz), and 8.0 (1H, usher.), 9,87 (1H, user.) ppm; HPLC-method D, Rtof 3.57 min; LC-MS 438,17 (MH) +.

Example 123 [6-(2-Forfinal)-2-(2-triptoreline)pyrimidine-4-yl]-(1H-indazol-3-yl)amine (II-123): Obtained with a yield of 8%.1H NMR (500 MHz, DMSO-d6) δ to 7.18 (3H, m), 7,37 (1H, m), the 7.43 (1H, t, J=7.9 Hz), 7,51 (1H, d, J=7.9 Hz), 7,55 (1H, t, J=7,6 Hz), the 7.65 (1H, t, J=7.4 Hz), 7,79 (1H, d, J=7.9 Hz), the 7.85 (1H, d, J=7,6 Hz), 8,19 (2H, m), 8,70 (1H, d, J=8.5 Hz) ppm; HPLC-method D, Rt4,93,min; LC-MS 450,13 (M+H)+.

Example 124 (6-Fluoro-1H-indazol-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (II-124): Obtained in DMF (yield 87%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,0 {s, 1H), 11,1 (with, of user., 1H), 8,66 (d, 1H), 7,95 (t, 1H), 7,80 (d, 1H), 7,72 (m, 2H), 7.62mm (m, 4H), 7,21 (DD, 1H), at 6.84 (TD, 1H) ppm, LC-MS (ES+) 424,15 (M+H); HPLC-method A, Rt3,05 minutes

Example 125 3-[2-(2-Triptoreline)hinzelin-4-ylamino]-1H-indazol-5-carboxylic acid methyl ester (II-125): To a solution of compound II-79 (100 mg, 0.21 mmol) in DMF (2 ml) was added Meon (1 ml), DIEA (54 μl, 0.31 mmol) and PdCl2(dppf) (4 mg, of 0.005 mmol). The flask was purged WITH three times and then were sent a bottle with WITH. The reaction mixture was heated at 80°C for 14 hours, then poured into water. The precipitate was collected and washed with water. Then the crude product was purified first by flash column (silica gel, 50% ethyl acetate in hexane) and then preparative HPLC and the result obtained compound II-125 (32%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13,3 (who, 1H), 11,3 (with, of user., 1H), to 8.70 (d, 1H), at 8.36 (s, 1H), 7,97 (t, 1H), 7,82 (m, 2H), 7,71 (m, 3H), 7,58 (m, 2H), 7,51 (d, 1H, in), 3.75 (s, 3H) ppm; LC-MS (ES+) 464,13 (M+H); HPLC-method A, Rt3,12 minutes

Example 208 (5-Methyl-2H-pyrazole-3-yl)-[2-(2-naphthyl-1-yl)-hinzelin-4-yl]amine (II-208):1H NMR (500 MHz, DMSO-d6) δ of 8.92 (s, 1H), 8,73 (m, 1H), 8,39 (m, 1H), 8,09 (m, 2H), 7,95 (m, 3H), a 7.62 (m, 3H), 6,78 (s, 1H), 2,32 (s, 3H); MS 352,2 (M+H).

Example 209 [2-(2-Chlorophenyl)pyrido[2,3-d]pyrimidine-4-yl]-(7-fluoro-1H-indazol-3-yl)amine (II-214): was Obtained from 4-chloro-2-(2-chlorophenyl)pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 7-fluoro-1H-indazol-3-ylamine (108 mg, to 0.72 mmol). Purification preparative HPLC gave specified in the title compound as a yellow salt di-TFA (93 mg, yield 46%). HPLC-method A, Rt3.04 from min1H NMR (500 MHz, DMSO-d6) δ 13,67 (1H, s), 11,40 of $ 11.25 (1H, users), 9,35-a 9.25 (2H, m), 7,95 (1H, m), 7,80-7,47 (5H, m), 7,35(1H, m), to 7.15 (1H, m); MS (m/z), MH+to € 391.1.

Example 210 [2-(2-Chlorophenyl)pyrido[2,3-d]pyrimidine-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-215): was Obtained from 4-chloro-2-(2-chlorophenyl)pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 5-fluoro-1H-indazol-3-ylamine (108 mg, to 0.72 mmol). Purification preparative HPLC gave specified in the title compound as a yellow salt di-TFA (45 mg, yield 22%). HPLC-method A, Rt3,00 min;1H NMR (500 MHz, DMSO-d6) δ 13,0 (1H, s)10,90(1H, users), 9,15-9,05 (2H, m), of 7.70 (1H, m), 7,60-7,30 (6H, m), 7,20 (1H, m); MS (m/z), MH+to € 391.1.

Example 211 [2-(2-Chlorophenyl)pyrido[2,3-d]pyrimidine-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-26): was Obtained from 4-chloro-2-(2-chlorophenyl)pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 7-debtor-1H-indazol-3-ylamine (112 mg, 0.66 mmol). Purification preparative HPLC gave specified in the title compound as a yellow salt di-TFA (130 mg, yield 62%). HPLC-method A, Rt3,12 min;1H NMR (DMSO, 500 MHz): 13,80-13,60 (1H, users), 11,30-11,10 (1H, users), 9,20-9,10 (2H, m), 7,80 (1H, m), 7,60-7,30 (6H, m); MS (m/z), MH+409,1.

Example 212 [2-(2-Chlorophenyl)pyrido[3,4-d]pyrimidine-4-yl]-(1H-indazol-3-yl)amine (II-217): was Obtained from 4-chloro-2-(2-chlorophenyl)pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 1H-indazol-3-ylamine (88 mg, 0.66 mmol). Purification preparative HPLC gave specified in the title compound as a yellow salt di-TFA (72 mg, yield 33%). HPLC-method A, Rtis 3.21 min;1H NMR (DMSO, 500 MHz): 12,95 (1H, s)10,90 (1H, users), a 9.25 (1H, s), is 8.75 (1H, 15 m), 8,55 (1H, m), the 7.65 (1H, m), 7,55 (1H, m), 7,50-7,30 (5H, m), 7,00(1H, m); MS (m/z), MH+373,1.

Example 213 [2-(2-Chlorophenyl)pyrido[3,4-d]pyrimidine-4-yl]-(7-fluoro-1H-indazol-3-yl)amine (II-218): was Obtained from 4-chloro-2-(2-chlorophenyl)pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 7-fluoro-1H-indazol-3-ylamine (108 mg, to 0.72 mmol). Purification preparative HPLC gave specified in the title compound as a yellow salt di-TFA (of 48.7 mg, yield 22%). HPLC-method A, Rtat 3.35 min;1H NMR (DMSO, 500 MHz): 12,95 (1H, s)10,90 (1H, users), a 9.25 (1H, s), is 8.75 (1H, m), 8,55 (1H, m), 7,70-to 7.35 (5H, m), 7,25(1H, m), to 6.95 (1H, m); MS (m/z, MH+ 391,08.

Example 214 [2-(2-Chlorophenyl)pyrido[3,4-d]pyrimidine-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (II-219): was Obtained from 4-chloro-2-(2-chloro-5-fluoro-1H-shall indazol-3-ylamine (108 mg, to 0.72 mmol). Purification preparative HPLC gave specified in the title compound as a yellow salt di-TFA (57,2 mg, yield 26%). HPLC-method A, Rtwith 3.27 min;1H NMR (DMSO, 500 MHz): δ of 13.05 (1H, s), 10,95 (1H, s), a 9.25 (1H, s), is 8.75 (1H, m), 8,55 (1H, m), 7,60 (1H, m), 7,55,(1H, m), 7,50-7,30 (5H, m), 7,25(1H, m); MS (m/z, MH+ to € 391.1.

Example 215 [2-(2-Chlorophenyl)pyrido[3,4-d]pyrimidine-4-yl]-(5,7-debtor-1H-indazol-3-yl)amine (II-220): was Obtained from 4-chloro-2-(2-chloro-7-debtor-1H-indazol-3-ylamine (112 mg, 0.66 mmol). Purification preparative HPLC gave specified in the title compound as a yellow salt di-TFA (57,2 mg, yield 26%). HPLC-method A, Rtof 3.45 min1H NMR (DMSO, 500 MHz): δ 13,65 (1H, s), and 11.0 (1H, s), a 9.25 (1H, s), 8,80 (1H, m), and 8.50 (1H, m), 7,60 (1H, m), 7,55 (1H, m), 7,50-7,30 (5H, m); MS (m/z), MH+409,1.

Example 216 6-Fluoro-1H-indazol-3-ylamine (A1):1H NMR (DMSO, 500 MHz): δ 11,4 (s, 1H), 7,68 (DD, 1H), 6,95 (DD, 1H), 6.75 in (TD, 1H), the 5.45 (s, 2H) ppm; LC-MS (ES+) 152,03 (M+H); HPLC-method A, Rt2,00 minutes

Example 217 5-fluoro-1H-indazol-3-ylamine (A2):1H NMR (DMSO, 500 MHz): δ and 11.3 (s, 1H), 7,43 (d, 1H), 7,22 (m, 1H), was 7.08 (m, 1H), from 5.29 (s, 2H) ppm; LC-MS (ES+) 152,01 (M+H); HPLC-method A, Rt1,93 minutes

Example 218 5,7-Debtor-1H-indazol-3-ylamine (A3):1H NMR (500 MHz, CD3OD): δ 7,22 (DD, J=2.0 A, 8,45HZ, 1H),? 7.04 baby mortality-6,87 (m, 1H); LC-MS (ES+) 169,95 (M+H); HPLC-method C, Rt2,94 minutes

Example 219 7-Fluoro-1H-indazol-3-ylamine (A4):1H NMR (500 MHz, DMSO): δ and 11.8 (s, 1H), 7,42 (d, 1H), 6,97 (m, 1H), 6,78 (m, 1H), of 5.40 (s, 2H) ppm; LCMC (KS+) 152,01 (M+H); HPLC-IU is od A, Rt2,00 minutes

Example 220 7-Fluoro-6-trifluoromethyl-1H-indazol-3-ylamine (A5):1H NMR (500 MHz, DMSO): δ 12,5 (s, 1H), of 7.75 (d, 1H), 7,25 (m, 1H), to 5.85 (m, 1H) ppm; MS (FIA) 220,0 (M+H); HPLC-method A, Rt2,899 minutes

Example 221 6-Bromo-1H-indazol-3-ylamine (A6):1H NMR (500 MHz, DMSO): δ 11,5 (s, 1H), 7,65 (d, 1H), 7,40 (s, 1H), 7,00 (d, 1H), 5,45 (users, 1H) ppm; MS (FIA) 213,8 (M+H); HPLC-method A, Rt2,441 minutes

Example 222 4-Fluoro-1H-indazol-3-ylamine (A7):1H NMR (500 MHz, DMSO): δ an 11.7 (s, 1H), 7,17 (m, 1H), 7,05 (d, 1H), 6,7 (UserN), 6,60 (DD, 1H), 5,20 (users, 2H) ppm; MS (FIA) to 152.0 (M+H); Method A, Rt2,256 minutes

Example 223 5-Bromo-1H-indazol-3-ylamine (A8):1H NMR (500 MHz, DMSO): δ 11,55 (users, 1H), 7,95 (s, 1H), 7,30 (d, 1H), 7,20 (m, 1H), 5,45 (users, 2H) ppm; MS (FIA) 213,8 (M+H); Method A, Rt2,451 minutes

Example 224 5-Nitro-1H-indazol-3-ylamine (A9):1H NMR (500 MHz, DMSO): δ 9,00 (s, 1H), to 8.20 (d, 1H), 7,45 (d, 1H), 6,15 (users, 1H) ppm; Method A, Rt2,184 minutes

Example 225 4-Pyrrol-1-yl-1H-indazol-3-ylamine (a10):1H NMR (500 MHz, DMSO): δ 7,20 (s, 2H), 7,00 (s, 2H), 6.75 in (m, 1H), and 6.25 (s, 2H), 4,30 (d, 1H) ppm; Method A, Rt2,625 minutes

Example 226 4-Chloro-5,6-dimethyl-2-(2-triptoreline)pyrimidine (B1): Obtained as a colourless oil with a yield of 75%.1H NMR (500 MHz, CDCl3): δ of 7.70 (d, J=7.8 Hz, 1H), to 7.64 (d, J=7,6 Hz, 1H), 7,55 (t, J=7,6 Hz, 1H), of 7.48 (t, J=7.5 Hz, 1H), 2,54 (s, 3H), of 2.36 (s, 3H) ppm; MS (FIA) 287,0 (M+H); HPLC-method A, Rt3,891 minutes

Example 227 4-Chloro-2-(2-chlorophenyl)-5,6-dimethylpyrimidin (B2): is Holocene in the form of an orange-yellow oil with a yield of 71%. 1H NMR (500 MHz, CDCl3): δ 7,73 (m, 1H), 7,52 (m, 1H), 7,39 (m, 2H), 2,66 (s, 3H), of 2.45 (s, 3H) ppm; MS (FIA) 253,0 (M+H); HPLC-method A, RtRt4,156 minutes

Example 228 4-Chloro-6-methyl-2-(2-triptoreline)pyrimidine (B3): Obtained as a pale yellow oil with a yield of 68%.1H NMR (500 MHz, CDCl3): δ 7,72 (d, J=7.8 Hz, 1H), 7,65 (d, J=7.9 Hz, 1H), EUR 7.57 (t, J=7.5 Hz, 1H), 7,52 (t, J=7.8 Hz, 1H), 7,16 (s, 1H), 2,54 (c, 3H) ppm; MS (FIA) 273,0 (M+H); HPLC-method A, Rt3,746 minutes

Example 229 4-Chloro-6-cyclohexyl-2-(2-triptoreline)pyrimidine (B4): Obtained as a yellow oil with a yield of 22%.1H NMR (500 MHz, CDCl3): δ of 7.70 (m, 2H), EUR 7.57 (t, J=7.5 Hz, 1H), 7,50 (t, J=7.5 Hz, 1H), 7,19 (s, 1H), 2,65 (m, 1H), and 1.9 (m, 2H), 1.8 m (m, 2H), 1,5 (m, 2H), 1,3 (m, 2H), 1,2 (m, 2H) ppm; MS (FIA) 341,0 (M+H).

Example 230 4-Chloro-6-phenyl-2-(2-triptoreline)pyrimidine (B5): Obtained as a yellow oil with a yield of 53%.1H NMR (500 MHz, CDCl3): δ 8,08 (DD, J=7,9, and 1.6 Hz, 2H), 7,80 (d, J=7,6 Hz, 1H), to 7.77 (d, J=7.8 Hz, 1H), to 7.67 (s, 1H), to 7.61 (t, J=7.5 Hz, 1H), 7,54 (t, J=7,6 Hz, 1H), 7,47 (m, 3H) ppm; MS (FIA) 335,0 (M+H); HPLC-method A, Rt4,393 minutes

Example 231 4-Chloro-2-(2,4-dichlorophenyl)-5,6-dimethylpyrimidin (B6): Obtained as a white solid with a yield of 91%.1H NMR (500 MHz, CDCl3): δ a 7.62 (d, J=8,3 Hz, 1H), 7,43 (d, J=7,0 Hz, 1H), 7,27 (DD, J=8,3, 2.0 Hz, 1H), to 2.55 (s, 3H), of 2.35 (s, 3H) ppm; MS (FIA) 287, 289 (M+H); HPLC-method A, Rt4,140 minutes

Example 232 4-Chloro-6-(2-chlorophenyl)-2-(2-triptoreline)-pyrimidine (V7): Obtained as a yellow oil with a yield of 52% 1H NMR (500 MHz, CDCl3): δ to 7.75 (m, 3H), of 7.65 (m, 2H), 7,53 (m, 1H), 7,44 (m, 1H), was 7.36 (m, 2H) ppm; MS (FIA) 369,1 (M+H); HPLC-method A, Rt4,426,minutes

Example 233 4-Chloro-6-(2-forfinal)-2-(2-triptoreline)-pyrimidine (B8): Obtained as a yellow oil with a yield of 95%.1H NMR (500 MHz, CDCl3): δ 8,24 (t, J=7.9 Hz, 1H), to 7.84 (s, 1H), 7,78 (d, J=7.7 Hz, 1H), 7,76 (d, J=8.0 Hz, 1H), 7,60 (t, J=7.5 Hz, 1H), 7,53 (t, J=7,6 Hz, 1H), 7,43 (m, 1H), 7.23 percent (t, J=7,6 Hz, 1H), 7,13 (m, 1H) ppm; MS (FIA) 353,0 (M+H).

Example 234 4-Chloro-6-pyridin-2-yl-2-(2-triptoreline)pyrimidine (B9): Obtained as a pale yellow oil with a yield of 50%.1H NMR (500 MHz, CDCl3): δ 8,68 (m, 1H), 8,48 (DD, J=7,9, 0.8 Hz, 1H), scored 8.38 (d, J=2.3 Hz, 1H), to 7.84 (m, 3H), 7.62mm (t, J=7,Hz, 1H), 7,55 (t, J=7,6 Hz, 1H), 7,38 (m, 1H) ppm; MS (FIA) 336,0 (M+H); HPLC-method A, Rt4,575 minutes

Example 235 6-Benzyl-4-chloro-2-(2-triptoreline)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (10):1H NMR (500 MHz, CDCl3): δ of 7.70 (d, 1H), 7.62mm (d, 1H), 7,55 (t, 1H), of 7.48 (t, 1H), 7,32 (m, 4H), 7,25 (m, 1H), 3,74 (s, 2H), 3,66 (s, 2H), 2,99 (t, 2H), 2,80 (t, 2H) ppm; LCMC (ES+) 404,17 (M+H); HPLC-method A, Rt3,18 minutes

Example 236 7-Benzyl-4-chloro-2-(2-triptoreline)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (B11):1H NMR (500 MHz, CDCl3): δ of 7.69 (d, 1H), 7,60 (d, 1H), 7,54 (t, 1H), 7,47 (t, 1H), 7,28 (m, 4H), 7,20 (m, 1H), 3,68 (s, 2H), to 3.67 (s, 2H), 2,86 (t, 2H), and 2.79 (t, 2H) ppm; MS (ES+) 404,18 (M+H); HPLC-method A, Rt3,12 minutes

Example 237 4-Chloro-2-(4-fluoro-2-triptoreline)hinzelin (B12):1H NMR (500 MHz, CD3OD): δ 8,43 (d, J=8,1 Hz, 1H), 8,20-805 (m, 2H), 8,05-of 7.82 (m, 2H), 7,71-7,51 (m, 2H), LC-MS (ES+) 327,09 (M+H). HPLC-method e, Rt4,56 minutes

Example 238 4-Chloro-2-(2-chloro-5-triptoreline)hinzelin (B13): LC-MS (ES+) 342,97 (M+H). HPLC-method e, Rt4,91 minutes

Example 239 4-Chloro-2-(2-chloro-4-nitrophenyl)hinzelin (B14): LC-MS (ES+) 319,98 (M+H). HPLC-method e, Rt4,45 minutes

Example 240 4-Chloro-2-(2-triptoreline)hinzelin (B15): Obtained with a yield of 57%. White solid.1H NMR (500 MHz, DMSO-d6) δ 7,79 (t, 1H), 7,86 (t, 1H), 7,94 (m, 3H), 8,15 (DD, 1H), to 8.20 (dt, 1H), of 8.37 (m, 1H); EI-MS 308,9 (M).

Example 241 4-Chloro-2-(2-triptoreline)-6,7-dihydro-5H-cyclopentadienide (B16): Obtained with a yield of 22%.1H NMR (500 MHz, DMSO-d6) δ 2,19 (m, H), a 3.01 (t, 2H), is 3.08 (t, 2H), 7,49 (t, 1H), 7,55 (t, 1H), 7.62mm (d, 1H), 7,71 (d, 1H), EI-MS 299,0 (M+H).

Example 242 4-Chloro-2-(2-chlorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptatrien (B17): The way To exit 82% in the form of a white solid.1H NMR (500 MHz, CDCl3) δ to 1.67 (m, 4H), to 1.87 (m, 2H), to 3.02 (m, 4H), 7,28 (m, 2H), 7,40 (m, 1H), 7,65 (m, 1H); EI-MS 293,0 (M+1).

Example 243 4-Chloro-2-(2-triptoreline)-5,6,7,8,9,10-hexahydropirimidine (B18): Obtained with a yield of 38% in the form of a brown oil.1H NMR (500 MHz, CDCl3) δ of 1.35 (m, 2H), 1,41 (m, 2H), 1,76 (m, 4H), 2,96 (m, 4H), of 7.48 (t, 1H), 7,56 (t, 1H), 7,66 (d, 1H), of 7.70 (d, 1H); EI-MS 341,0 (M+1).

Example 244 4-Chloro-8-methoxy-2-(2-triptoreline)hinzelin (B19): Obtained from 8-methoxy-2-(2-triptoreline)-3H-hin-azolin-4-it (1.0 g, 3.1 mmol), trietilenglikole (472 mg, of 3.43 mmol) and POCl3. Purification with flash chromatography gave a white solid (yield 89%). HPLC-method A, Rt4,10 minutes (98%), MS (m/z) 258,08 (M+H).

Example 245 2-(4-Chlorination-2-yl)benzonitrile (B20): Obtained as a yellow solid with a yield of 1.5%.1H NMR (500 MHz, CDCl3) δ of 8.47 (d, 1H), 8,24 (d, 1H), 8,16 (d, 1H), 8,07 (impurity), 7,94 (t, 1H), 7,92 (impurity), 7,86 (d, 1H), 7,68 (m, 2H), 7,65 (impurity), 7,54 (admixture), 7,49 (t, 1H), 4.2V (impurity), 1,05 (impurity) ppm; MS (LC/MS) 266,05 (M+H); HPLC-method A, Rt3,88 minutes

Example 246 6-Methyl-2-(2-triptoreline)-3H-pyrimidine-4-one (D3): Obtained as a yellow solid with a yield of 50%.1H NMR (500 MHz, DMCO-d6) δ 12,7 (users, 1H), 7,9 (m, 1H), 7,8 (m, 2H), and 7.7 (m, 1H), and 6.3 (s, 1H), of 2.21 (s, 3H) ppm; MS (FIA) 255,0 (M+H); HPLC-method A, Rt2,578 minutes

Example 247 6-Cyclohexyl-2-(2-triptoreline)-3H-pyrimidine-4-one (D4): Obtained in the form of not-quite-white solid with a yield of 54%.1H NMR (500 MHz, DMCO-d6) δ 12,9 (users, 1H), 7,9 (m, 4H), 5,3 (s, 1H), 2,5 (m, 1H), and 1.9 (m, 5H), 1,4 (m, 5H) ppm; MS (FIA) 323,1 (M+H); HPLC-method A, Rt3,842 minutes

Example 248 2-(2-Chloro-5-triptoreline)-3H-hinzelin-4-one (D10):1H NMR (500 MHz, CD3OD) δ 8,32 is 8.25 (m, 1H), 8,01 (s, 1H), to $ 7.91-7,72 (m, 1H), 7,66-of 7.55 (m, 1H), LC-MS (ES+) 325,01 (M+H). HPLC-method D, Rt3,29 minutes

Example 249 2-(4-fluoro-2-triptoreline)-3H-hinzelin-4-one (D14):1H NMR (500 MHz, CD3OD) δ of 8.28 (d, 8,OHZ, 1H), 7,94 to 7.4 (m, 1H), 7,84-to 7.77 (m, 1H), 7,76-to 7.67 (m, 2H), 7,65-7,53 (m, 2H), LC-MS (ES+) 309,06 (M+H). HPLC-method D, Rt2,88 minutes

Example 250 2-(4-Nitro-2-chlorophenyl)-3H-hinzelin-4-one (D15): LC-MS (ES+) 302,03 (M+H). HPLC-method D, Rt2,81 minutes

Example 251 2-(5-fluoro-2-triptoreline)-3H-hinzelin-4-one (D17):1H NMR (500 MHz, CD3OD) δ 8,28 (l, RtJ=8,Hz, 1H), of 7.96 (DD, J=OF 5.05, 8,55HZ, 1H), 7,89 (t, J=7,Hz, 1H), 7,78-of 7.69 (m,1H), 7,66-7,46 (m, 3H), LC-MS (ES+) 309,14 (M+H). HPLC-method e, Rt2,90 minutes

Example 252 (1H-Indazol-3-yl)-(2-phenylpyrazole-4-yl)amine (III-1): The way in DMF in the amount of 70 mg (yield 50%) as a pale yellow solid.1H NMR (500 MHz, DMCO-d6) δ 13,1 (with, of user., 1H), 8,48 (d, 1H), to $ 7.91 (d, 2H), 7,76 (UserN), was 7.45 (m, 2H), was 7.36 (d, 1H), 7,20 (m, 4H), 6,86 (t, 1H) ppm; MS (ES+) 338,07 (M+H); (ES-) 336,11 (M-H); HPLC-method A, Rt2,88 minutes

Example 253 (5-Methyl-2H-pyrazole-3-yl)-(2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)amine (III-7): Obtained by method A.1H NMR (500 MHz, DMCO-d6) δ 12,1 (with, of user., 1H), 8,70 (with, of user., 1H), of 8.37 (d, J=6,7 Hz, 2H), 7,54 (m, 3H), to 6.67 (s, 1H), 2,82 (m, 2H), 2,68 (m, 2H), is 2.37 (s, 3H), 1,90 (s, UserN); MS 306,1 (M+H).

Example 254 (5-Methyl-2H-pyrazole-3-yl)-(2-phenyl-6,7,8,9-tetrahydro-5H-cycloheptatrien-4-yl)amine (III-8): HPLC-method E, Rt1,124 minutes

Example 255 (5-Methyl-2H-pyrazole-3-yl)-(2-pyridin-4-yl-hinzelin-4-yl)amine (III-9): Yellow solid, TPL 286-289°,1H NMR (500 MHz, DMCO-d6) δ to 2.35 (3H, s)6,76 (1H, s), to 7.61 30 (1H, m), 7,89 (2H, m), 8,32 (2H, d), to 8.70 (1H, d), 8,78 (2H, d), and 1.56 (1H, users), 12,30 (1H, users); IR (solid) 1620, 1598, 1571, 1554, 1483, 1413, 1370, 1328; MS 303,2 (M+H)+

Example 256 (7-Chloro-2-pyridine-4-imaginaton-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (III-28):1H NMR (500 MHz, DMCO-d6) δ to 2.35 (3H, s), of 6.75 (1H, s), the 7.65 (1H, d), to 7.93 (1H, s), 8,30 (2H, d), 8,73 (1H, d), 8,79 (2H, d), 10,69 (1H, s), of 12.33 (1H, s); MS m/z 337,2 (M+H)+.

Example 257 (6-Chloro-2-pyridine-4-imaginaton-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (III-29):1H NMR (500 MHz, DMCO-d6) δ 2,31 (3H, S); 6,74 (lH,s), 7,89 (1H, s), 8,30 (2H, d), 8,80 (2H, d), 8,91 (1H, s), as 10.63 (1H, s), 12,29 (1H, s); MS 337,2 (M+H)+.

Example 258 (2-Cyclohexylphenol-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (III-30):1H NMR (DMCO) δ to 2.35 (3H, s)to 1.70 (3H, m)to 1.87 (2H, d), 1,99 (2H, d), 2,95 (1H, t), 6,72 (1H, s), of 7.75 (1H, d), 7,88 (1H, s), of 7.96 (1H, s), 8,83 (1H, s), 11,95 (1H, s)12,70 (1H, s); MS 308,4 (M+H)+.

Example 259 (5-Methyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-31): TPL 246about;1H NMR (400 MHz) δ to 2.35 (3H, s)6,70 (1H, users), 7,51-EUR 7.57 (4H, m), 7,83-to 7.84 (2H, d), of 8.47-of 8.50 (2H, d), 8,65 (1H, d), of 10.4 (1H, s), and 12.2 (1H, users); IR (solid) 3696, 3680, 2972, 2922, 2865; MS 302,1 (M+H)+.

Example 260 [2-(4-Itfeel)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-32):1H NMR (DMCO-d6) δ of 2.34 (3H, s), 6,72 (1H, s), 7,56 (1H, d), to 7.84 (2H, d), 7, 93 (2H, d), 8,23 (2H, d), 8,65 (1H, s), 10,44 (1H, s), 12,24 (1H, s); MS 428,5 (M+H)+.

Example 261 [2-(3,4-Dichlorophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-33): a Suspension of 2-(3,4-dichlorophenyl)-3H-hinzelin-4-it (1 g, 3.43 points mmol) oxychloride phosphor is a (4 ml) was stirred at 110° C for 3 hours. Was removed by evaporating the solvent and the residue was carefully treated with cold aqueous saturated solution of NaHCO3. The obtained solid substance was collected by filtration and washed with ether to obtain 4-chloro-2-(3,5-dichlorophenyl)hintline in the form of a white solid (993 mg, 93%). To the above compound (400 mg, 1,29 mmol) in THF (30 ml) was added 3-amino-5-methylpyrazole (396 mg, 2.58 mmol) and the resulting mixture was heated at 65°With during the night. Evaporated the solvent and the residue triturated with ethyl acetate, filtered and washed with a minimum amount of ethanol to obtain compound III-33 as a white solid (311 mg, 65%): TPL 274about;1H NMR (DMCO) δ of 2.34 (3H, s), 6,69 (1H, s), 7,60 (1H, m), to 7.84 (1H, d), of 7.96 (2H, d), 8,39 (1H, DD), at 8.60 (1H, d),' 8,65 (1H, d), 10,51 (1H, s), 12,30 (1H, s); IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370,5 (M+H)+.

Example 262 [2-(4-Bromophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-34): TPL 262-265about;1H NMR (DMCO) δ 2,34 (3S, s), 6.73 x,(1H, s), 7,55 (1H, m), 7,74 (2H, d), 7,83 (2H, m), 8,40 (2H, d), 8,65 (1H, d), 10,44 (1H, s), 12,25 (1H, s,); IR (solid) 1603, 1579, 1546, 1484, 1408, 1365; MS 380,1/382,1 (M+H)+.

Example 263 [2-(4-Chlorophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-35): TPL >300about;1H NMR (DMCO) δ of 2.34 (3H, s), 6,74 (1H, s), 7,53 to 7.62 (3H, m), to 7.84 (2H, d), of 8.47 (2H, d), 8,65 (1H, d), 10,44 (1H, s), of 12.26 (1H, s); IR (solid) 1628, 1608, 154, 1546, 1489, 1408, 1369, 1169; MS 336,2 (M+H)+.

Example 264 [2-(3,5-Dichlorophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-36):1H NMR (DMCO) δ of 2.34 (3H, s), 6,69 (1H, s), of 7.96 (1H, d), 8,21 (3H, m), 8,56 (1H, d), at 8.60 (2H, d), 10,51 (1H, s), 12,30 (1H, s); IR (solid) 1546, 1331, 802, 763, 729, 658, 652; MS 370,5 (M+H)+.

Example 265 [2-(4-Cyanophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-37): TPL 263about;1H NMR (DMCO) δ of 2.34 (3H, s), 6,72 (1H, s), to 7.61 (1H, d), 7,88 (2H, s), of 8.04 (2H, d), 8,63 (2H, d), 8,67 (1H, s)10,52 (1H, s), 12,27 (1H, s); IR (solid) 1739, 1436, 1366, 1229, 1217; MS 327,2 (M+H)+.

Example 266 [2-(3-Itfeel)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-38): TPL 234-235about;1H NMR (DMCO) δ to 2.35 (3H, s), of 6.73 (1H, s), 7,35 (1H, m), 7,56 (1H, m), a 7.85 (3H, m), of 8.47 (1H, m), 8,65 (1H, m), 8,86 (1H, s), 10,49 (1H, s)to 12.28 (1H, users); IR (solid) 1560, 1541, 1469, 1360; MS 428,1 (M+H)+.

Example 267 [2-(4-Ethylsulfanyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-39): TPL 229-231about;1H NMR (DMCO) δ of 1.29 (3H, t)to 2.35 (3H, s), of 3.07 (2H, HF), 6,76 (1H, s), the 7.43 (2H, d), 7,51 (1H, m), 7,81 (2H, m), to 8.41 (2H, d), 8,64 (1H, d), 10,38 (1H, s), 12,24 (1H, user. C); IR (solid) 1587, 1574, 1555, 1531, 1484, 1412, 1369; MS 362,1 (M+H)+.

Example 268 (5-Cyclopropyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-40): TPL 218-219about;1H NMR (DMCO-d6) δ 0,70-0,80(2H, m), 0,90-1,00 (2H, m), 6,70 (1H, s), 7,45-of 7.55 (4H, m), 7,80-a 7.85 (2H, m), 8,45-8,55 (2H, m), 8,65 (1H, d), the 10.40 (1H, s), 12,27 (1H, s); IR (solid) 1624, 1605, 1591, 1572, 1561, 1533, 1479, 1439, 1419, 1361, 1327, 97, 828, 803, 780, 762, 710; MS 328,2 (M+H)+.

Example 269 [2-(4-tert-Butylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-41): MP >300°C;1H NMR (DMCO-d6) δ to 1.35 (9H, s), of 2.34 (3H, s), 6,79 (1H, s), 7,55 (3H, d), a 7.85 (2H, d), 8,39 (2H, d), to 8.62 (1H, d), 10,35 (1H, s), 12,22 (1H, s); IR (solid) 1603, 1599, 1577, 1561, 1535, 1481, 1409, 1371, 1359, 998, 841, 825, 766, 757; MS 358,3 (M+H)+.

Example 270 [2-(4-Chlorophenyl)hinzelin-4-yl]-(5-cyclopropyl-2H-pyrazole-3-yl)amine (III-42):1H NMR (DMCO-d6) δ 0,77 (4H, osirm),was 2.05 (1H, m), 6,59 (1H, s), 7,60 (1H, d), a 7.85 (2H, d), to $ 7.91 (2H, d), by 8.22 (2H, d), 8,65 (1H, s), 10,51 (lH,s), of 12.33 (1H,s); MS 362,1 (M+H)+.

Example 271 (2-Benzo[1,3]dioxol-5-imaginaton-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-43):1H NMR (DMCO) δ of 2.33 (3H, s), 6,13 (2H, s), is 6.78 (1H, s), 7,11 (1H, d), 7,80 (1H, t), 7,94 (1H, s), of 8.09 (3H, m), of 8.25 (1H, d), 10,34 (1H, s), 12,21 (1H, S); MS 346,5 (M+H)+.

Example 272 [2-(4-Dimethylaminophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-44):1H NMR (DMCO-d6) δ 2,02 (6H, S), 2,39 (3H, s), 6,83 (1H, s), 7,71 (1H, d), 7,98 (2H, s), of 8.04 (2H, d), with 8.33 (2H, d), 8,67 (1H, s), 11,82 (1H, s), 12,72 (1H, s); MS 345,3 (M+H)+.

Example 273 [2-(3-Methoxyphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-45): TPL 226about;1H NMR (DMCO-d6) δ of 2.34 (3H,s)to 3.92 (3H, s), 6,72 (1H, s), 7,21 (1H, d), EUR 7.57 (1H, t), 7,79 (1H, t), 8,02 (3H, m)to 8.14 (1H, s), 8,79 (1H, d), accounted for 10.39 (1H, s), 12,22 (1H, s); IR (solid) 1599, 1572, 1538, 1478, 1427, 1359, 833, 761, 661; MS 332,2 (M+H)+.

Example 275 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(3,4-dichlorophenyl)hinzelin-4-yl]amine (III-6): 1H NMR (DMCO-d6) δ 0,86 (2H, d), of 1.02 (2H, d), was 1.69 (1H, m), 6,56 (1H, s), EUR 7.57 (1H, d), to 7.84 (4H, m), 8,40 (1H, d), 8,58 (1H, s)8,64 (1H, s), 10,53 (1H, s), 12,36 (1H, s); MS 396,0 (M+H)+.

Example 276 (2-Biphenyl-4-imaginaton-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (III-47): To a mixture of [2-(4-bromophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-34) (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, of 0.62 mmol) in a mixture of THF-water (1:1, 4 ml) was added Na2CO3(219 mg, of 2.06 mmol), triphenylphosphine (9 mg, 1/15 mol.%) and palladium acetate (1 mg, 1:135 mol.%). The resulting mixture was heated at 80°during the night, evaporated the solvent and the residue was purified flash chromatography (gradient mixture of dichloromethane-Meon) to obtain compound III-21 in the form of a yellow solid (99 mg, 51%):1H NMR (DMCO) δ is 2.37 (3H, s), PC 6.82 (1H, s), 7,39-EUR 7.57 (4H, m), 7,73-7,87 (6H, m), to 8.57 (2H, d), 8,67 (1H, d), 10,42 (1H, S), 12,27 (1H, s); MS 378,2 (M+H)+.

Example 277 [2-(4-Ethylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-48): To a mixture of [2-(4-bromophenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-34) (114 mg, 0.3 mmol) and trimethylsilylacetamide (147 mg, 1.5 mmol) in DMF (2 ml) was added CuI (1.1 mg, 1:50 mol.%), Pd(PPh3)2Cl2(4.2 mg, 1:50 mol.%) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120°during the night and the solvent evaporated. The residue is triturated in ethyl acetate and the precipitate was collected by filtration. Collected solid is suspended the THF (3 ml) was added TBAF (1 M in THF, 1.1 EQ.). The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified flash chromatography (silica gel, gradient of a mixture of DCM-Meon) to obtain compound III-48 as a white solid (68 mg, 70%):1H NMR (DMCO) δ of 2.34 (3H, s), 4,36 (1H, s), 6,74 (1H, s), 7,55 (1H, m), the 7.65 (2H, d), to 7.84 (2H, m), of 8.47 (2H, d), 8,65 (1H, d), 10,43 (1H, s), 12,24 (1H, s); MS to 326.1 (M+H)+.

Example 278 [2-(3-Ethynylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-49): TPL 204-207about;1H NMR (DMCO) δ of 2.34 (3H, s), 4,28 (1H, s), 6,74 (1H, s), 7,55-7,63 (3H, m), 7,83-7,87 (2H, m), 8,49 (1H, d), to 8.57 (1H, s), 8,65 (1H, d), 10,46 (1H, s), 12,27 (1H, s); IR (solid) 1598, 1574, 1541, 1489, 1474, 1422, 1365; MS to 326.1 (M+N)+.

Example 279 [2-(3-Were)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-50): a Suspension of 1H-hinzelin-2,4-dione (10.0 g, of 61.7 mmol) in POCl3(60 ml, 644 mmol) and N,N-dimethylaniline (8 ml, 63.1 mmol) was boiled under reflux for 2 hours. Excess POCl3was removed in vacuo, the residue was poured on ice and the precipitate was collected by filtration. The crude solid product 2,4-dechlorination (6.5 g, yield 53%) was washed with water and dried in vacuum for use in the next stage without additional purification. To a solution of 2,4-dichloroaniline (3.3 grams, of 16.6 mmol) in anhydrous ethanol (150 ml) was added 5-methyl-1H-pyrazole-3-ylamine (3.2 g, from 32.9 mmol) and the resulting mixture was stirred at room is based temperature for 4 hours. The precipitate was collected by filtration, washed with ethanol and dried in vacuum to obtain 4.0 g (yield 93%) (2-chlorination-4-yl)-(5-methyl-1H-pyrazole-3-yl)amine, which was used in the next stage without additional purification. To a solution of (2-chlorination-4-yl)-(5-methyl-1H-pyrazole-3-yl)amine (50 mg, 0,19 mmol) in DMF (1.0 ml) was added m-tolylboronic acid (0.38 mmol), 2M Na2CO3(0.96 mmol) and tri-tert-butylphosphine (0,19 mmol). The flask was purged with nitrogen, and was added to the catalyst PdCl2(dppf) in one portion. Then the reaction mixture was heated at 80°C for 10 hours, cooled to room temperature and poured into water (2 ml). The precipitate was collected by filtration, washed with water and purified by HPLC to obtain compound III-50 in the form of a pale yellow solid (61 mg, 75%):1H NMR (500 MHz, DMSO-d6) δ 12,3 (users, 1H), 10,4 (users, 1H), up 8.75 (d, 1H), 8.30 to (s, 1H), of 8.25 (d, 1H), 7,78 (s, 2H), 7,55 (m, 1H), 7,45 (m, 1H), 7,35 (m, 1H), 6,80 (s, 1H), 2,47 (s, 3H), of 2.30 (s, 3H); MS 316,1 (M+H).

Example 280 [2-(3,5-Differenl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-51):1H NMR (500 MHz, DMSO-d6) δ 12,3 (users, 1H), 10,8, (users, 1H), 8,63 (d, 1H), 7,95 (d, 2H), a 7.85 (m, 2H), 7,58 (t, 1H), 7,41 (t, 1H), 6,59 (s, 1H), and 2.27 (s, 3H); MS 338,1 (M+H).

Example 281 [2-(3-Chloro-4-forfinal)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-52):1H NMR (500 MHz, DMSO-d6) δ 12,4 (users, 1H), 10,8 (users, 1H), 8,65 (d, 1H), and 8.50 (d, 1H), 8,6,(m, 1H), a 7.85 (m, 1H), 7,60 (m, 1H), 6,62 (s, 1H), 2,30 (s, 3H); MS 354,1 (M+H).

Example 282 (5-Methyl-2H-pyrazole-3-yl)-[2-(3-triptoreline)hinzelin-4-yl]amine (III-53):1H NMR (500 MHz, DMSO-d6) δ 12,2 (user., 1H), 10,45 (user., 1H), 7,53 (s, 1H), 7,43 (d, J=7.2 Hz, 1H), 7,06 (d, J=8,2 Hz, 1H), 6,65 (d, J=8,3 Hz, 1H), to 6.57 (t, J=7,6 Hz, 1H), 6,51 (d, J=7.8 Hz, 1H), gold 6.43 (t, J=7.8 Hz, 1H), 6,32 (t, J=7,6 Hz, 1H), 5,51 (s, 1H), 2,03 (s, 3H); MS 370,2 (M+H).

Example 283 [2-(3-Tianfeng)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-54):1H NMR (500 MHz, DMSO-d6) δ 9,01 (s, 1H), 8,96 (m, 2H), 8,28 (d, J=7,3 Hz, 1H), 8,16 (with, of user., 2H), of 8.06 (t, J=7.8 Hz, 1H), 7,88 (m, 1H), of 6.96 (s, 1H), 2,58 (s, 3H); MS 327,1 (M+H).

Example 284 [2-(3-Isopropylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-55):1H NMR (500 MHz, DMSO-d6) δ 8,89 (d, J=7.5 Hz, 1H), of 8.37 (s, 1H), compared to 8.26 (s, 1H), 8,08 (m, 2H), 7,81 (t, user., 1H), to 7.67 (m, 2H), to 6.88 (s, 1H), 3,12 (m, 1H), 2.40 a (s, 3H), 1,38 (d, J=6.9 Hz, 6H); MS 344,2 (M+H).

Example 285 (5-Methyl-2H-pyrazole-3-yl)-(2-pyridin-3-yl-hinzelin-4-yl)amine (III-56):1H NMR (500 MHz, DMSO-d6) δ 9,50 (s, 1H), 8,84 (d, J=7,3 Hz, 1H), 8,80 (d, J=4.4 Hz, 1H), 8,66 (d, J=8,2 Hz, 1H), 7,87 (m, 2H), to 7.77 (m, 1H), 7,60 (t, J=7.2 Hz, 1H), to 6.67 (s, 1H), 2,28 (s, 3H); MS 303,1 (M+H).

Example 286 [2-(3-Acetylphenyl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-57):1H NMR (500 MHz, DMSO-d6) δ 8,80 (s, 1H), 8,55 (d, J=7.7 Hz, 1H), 8,42 (d, J=7,6 Hz, 1H), 8,00 (d, J=7,0 Hz, 1H), 7,76 (m, 2H), 7,58 (t, J=7.7 Hz, 1H), of 7.48 (s, user., 1H), 6,60 (s, 1H), 2.49 USD (s, 3H), 2,03 {s, 3H); MS 344,1 (M+H).

Example 287 [2-(3,5-Dateformatter)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)and the in (III-58): 1H NMR (500 MHz, DMSO-d6) δ 10,7 (with, of user., 1H), 8,95 (s, 2H), 8,63 (d, J=8,2 Hz, 1H), of 8.25 (s, 1H), 7,86 (m, 2H), 7,58 (t, J=6,9 Hz, 1H), 6,62 (s, 1H), and 2.26 (s, 3H); MS 438,1 (M+H).

Example 288 [2-(3-Hydroxymethylene)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-59):1H NMR (500 MHz, DMSO-d6) δ a total of 8.74 (d, J=7.9 Hz, 1H), with 8.33 (s, 1H), 8,17 (with, of user., 1H), 7,95 (with, of user., 1H), 7,89 (with, of user., 1H), a 7.62 (m, 3H), 6,72 (s, 1H), of 5.53 (s, 1H), 4,60 (s, 2H), 2,28 (s, 3H); MS 332,1 (M+H).

Example 289 (5-Methyl-2H-pyrazole-3-yl)-[2-(3-phenoxyphenyl)-hinzelin-4-yl]amine (III-60): TP-232°C;1H NMR (DMSO-d6) δ of 2.21 (3H, s), 6,59 (1H, s), 7,10-7,22 (4H, m), 7,41 was 7.45 (2H, m), 7,54-to 7.59 (2H, m), 7,81 (2H, s), of 8.09 (1H, s), of 8.27 (1H, m)8,64 (1H, m), the 10.40 (1H, s), 12,20 (1H, s); IR (solid) 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394,7 (M+H)+.

Example 290 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(3-phenoxyphenyl)hinzelin-4-yl]amine (III-61): TPL 193-195°C;1H NMR (DMSO-d6) δ to 0.67 (2H, m)of 0.93 (2H, m), 1,87 (lH, m), 6,56 (1H, s), 7,06-7,20 (4H, m), 7,40-the 7.43 (2H, m), 7,55-to 7.59 (2H, m), 7,81 (2H, s), 8,11 (1H, s), of 8.27 (1H, m), 8,63 (1H, m), 10,43 (1H, s), of 12.26 (1H, ); IR (solid) 1589, 1574, 1527, 1483, 1369, 1226; MS 420,7 (M+H)+.

Example 291 (5-Methyl-2H-pyrazole-3-yl)-(2-thiophene-3-yl-hinzelin-4-yl)amine (III-62):1H NMR (500 MHz, DMSO-d6) δ 11,78 (with, of user., 1H), up 8.75 (d, J=8,1 Hz, 1H), 8,68 (s, 1H), 7,98 (DD, J=7,9, 7.5 Hz, 1H), 7,89 (m, 2H), 7,81 (m, 1H), 7,68 (t, J=7.5 Hz, 1H), 6,69 (s, 1H), 2,30 (s, 3H); MS 308,1 (M+H).

Example 292 (2-Phenylpyrazole-4-yl)-(2H-pyrazole-3-yl)amine (III-63): TPL 247-249°C;1H NMR (DMSO) δ 6,99 (1H, users), 7,49-7,58 5H, m), 7,81 (1H, users), 7,83 (2H, m), of 8.47-8,49 (2H, m), 8,66 (1H, d), 10,54 (1H, s), 12,59 (1H, s); IR (solid) 3145, 2922, 1622, 1597; MS 288,2 (M+H)+.

Example 293 (2H-Pyrazole-3-yl)-(2-pyridin-4-yl-hinzelin-4-yl)amine (III-64): TPL 285-286°C;1H NMR (DMSO) δ 6,99 (1H, users), the 7.65 (1H, m), 7,81-7,94 (3H, m), 8,3-8,35 (2H, m), 8,73 (1H, d), 8,84-of 8.90 (2H, m), of 10.76 (1H, s), and 12.6 (1H, s); IR (solid) 3180, 2972, 1600, 1574; MS 289,2 (M+H)+.

Example 294 (5-Ethyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-65): TPL 221-222about;1H NMR (DMSO) δ to 1.31 (3H, t), 2,68 (2H, d), to 6.80 (1H, s), 7,50-of 7.60 (4H, m), 8,45-8,55 (2H, m), 8,65 is 8.75 (1H, m), 10,44 (1H, s), 12,27 (1H,s); IR (solid) 3190, 1622, 1595, 1575, 1533, 1482, 1441, 1420, 1403, 1361, 758, 711; MS 316,2 (M+H)+.

Example 295 (2-Phenylpyrazole-4-yl)-(5-propyl-2H-pyrazole-3-yl)amine (III-66): TPL 204-205°C;1H NMR (DMSO-d6) δ of 1.02 (3H, t), of 1.66 and 1.75 (2H, m), 2,69 (2H, t), to 6.80 (1H, s), 7,45-7,60,(4H,m), 7,80-7,88 (2H, m), 8,45-of 8.50 (2H, m), 8,65 (1H, d), accounted for 10.39 (1H, s), 12,25 (1H, s); IR (solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827, 808, 763, 709, 697; MS 330,2 (M+H)+.

Example 296 (5-Isopropyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-67): TPL 218-219°C;1H NMR (DMSO-d6) δ of 1.36 (6H, d), 3,05 (1H, m)6,86 (1H, s)of 7.48-to 7.59 (4H, m), 7,80-7,88 (2H, m), 8,49-8,58 (2H, m), 8,66 (1H, d), of 10.47 (1H, s), 12,30 (1H, s); IR (solid) 3173, 2968, 1619, 1593, 1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798, 761, 707, 666, 659; MS 330,2 (M+H)+.

Example 297 (5-tert-Butyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-68): TPL 136-137about;1H NMR (who MCO-d 6) δ to 1.38 (9H, s), 6.87 in (1H, users), 7,51-EUR 7.57 (4H, m), 7,84-a 7.85 (2H, m), 8,49-8,51 (2H, m), 8,65 (1H, d), 10,43 (1H, s), 12,21 (1H, users); IR (solid) 3162, 2963, 1621, 1590, 1572; MS 344,2 (M+H)+.

Example 298 (5-tert-Butyl-2H-pyrazole-3-yl)-(2-pyridin-4-yl-hinzelin-4-yl)amine (III-69): TPL >300about;1H NMR (DMSO) δ to 1.38 (9H, s), PC 6.82 (1H, users), 7,63 (1H, m), 7,86-to $ 7.91 (2H, m), 8,32-of 8.33 (2H, d), 8,69 (1H, d), 8,75-8,76 (2H, d), or 10.60 (1H, s), 12,31 (1H, users); IR (solid) 3683, 3149, 2963, 1621; MS 345,2 (M+H)+.

Example 299 (5-Cyclopentyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-70): TPL 240-241about;1H NMR (DMSO-d6) δ 1,68-1,89 (6H, m), 2,03-2,17 (2H, m), 3,14-up 3.22 (1H, m), to 6.80 (1H, s), 7,50-of 7.60 (4H, m), 7,80-7,89 (2H, m), 8,45-charged 8.52 (2H, m), 8,67 (1H, d), 10,52 (1H, s), of 12.26 (1H, s); IR (solid) 2957, 1621, 1591, 1571, 1531, 1476, 1438, 1405, 1370, 1325, 999, 951, 801, 775, 761, 747, 710695, 668, 654; MS 356,2(M+H)+.

Example 300 (5-Phenyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-71): TPL 207-209about;1H NMR (DMSO) δ 7,38-7,40 (1H, m), 7,50-7,58 (6H, m), 7,82-7,88 (4H, m), 8,51 (2H, m), 8,67 (1H, s), of 10.58 (1H, s), 13,11 (1H, users); IR (solid) 3345, 3108, 1627, 1612; MS 364,2 (M+H)+.

Example 301 (5-Carboxy-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-72): (5-Methoxycarbonyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-73) (345 mg, 1 mmol) in THF (6 ml) was treated with NaOH (1 M, 4.0 ml), was stirred at 50°C for 5 hours, cooled to room temperature and neutralized by adding 1 M HCl. The mixture was concentrated in vacuum Claudine THF, then was diluted with water and the resulting precipitate was filtered. The obtained solid substance was dried at 80°in vacuum to obtain compound III-72 in the form of not-quite-white solid (312 mg, 94%): TPL 289-291about;1H NMR (DMSO) δ was 7.45 (1H, users), 7,50-of 7.60 (5H, m), 7,80-7,88 (2H, m), 7,40-to 7.50 (2H, m), 8,60-to 8.70 (1H, d), 10,70 (1H, s), 13,00-13,80 (2H, users); IR (solid) 1699, 1624, 1607, 1570,1539, 1506, I486, 1398, 1333, 1256, 1177, 1004, 827, 764, 705; MS 332,3 (M+H)+.

Example 302 (5-Methoxycarbonyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-73): TPL 271-273about;1H NMR (DMSO) δ of 3.95 (3H, s), 7,50-the 7.65 (5H, m), 7,80-7,98 (2H, m), 8,40-of 8.50 (2H, m), 8,65-8,73 (1H, m), 10,80 (1H, S), 13,80 (1H, s); IR (solid) 3359, 1720, 1624, 1597, 1561, 1538, 1500, 1475, 1435, 1410, 1358, 1329, 1283, 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763, 703, 690, 670; MS 346,3 (M+H)+.

Example 303 (5-Hydroxymethyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-74): a Solution of (5-methoxycarbonyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-73) (345 mg, 1 mmol) in anhydrous THF (10 ml) was treated with lithium borohydride (125 mg, of 5.75 mmol) at 65°C for 5 hours. The mixture was cooled to room temperature and then combined with 2 M HCl and ethyl acetate. Added solid sodium bicarbonate to obtain pH 8 and the mixture was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated. Purification with flash chromatography (SiO2gradient of methanol dichlo is methane) gave compound III-74 (95 mg, 30%) in the form of not quite white solids:1H NMR (DMSO) δ 4,58 (2H, d, CH2), to 5.35 (1H, s, OH), 6,94 (1H, s), 7,50-of 7.60 (4H, m), a 7.85-of 7.90 (2H, m), 8,48-8,54 (2H, m), 8,69 (1H, 1H), the 10.40 (1H, s), 12,48 (1H, s); IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532, 1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793, 780, 7124; MS 318,2(M+H)+.

Example 304 (5-Methoxymethyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-75): TPL 190-191about;1H NMR (DMSO) δ 3,34-(3H, s), of 4.45 (2H, s), 7,00 (1H, s), 7,50-of 1.62 (4H, m), 7,82-of 7.90 (2H, m), 8,45-charged 8.52 (2H, m), 8,65 (1H, users), 10,50 (1H, s), 12,30 (1H, s); IR (solid) 3177, 1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, 1329, 1152, 1099, 999, 954, 834, 813, 766, 707, 691; MS 332,3(M+H)+.

Example 305 [5-(3-Hydroxyprop-1-yl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-76): a Solution of (5-benzyloxyphenyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-78) (200 mg, 0.46 mmol) in toluene (4 ml) and acetonitrile (8 ml) was stirred with trimethylsilylimidazole (of 0.64 ml, 4.6 mmol) in 55°C for 3 hours to obtain a solution of an amber color. The resulting mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate solution. The resulting layers were separated, the organic layer was dried over magnesium sulfate and concentrated in vacuum. Purification with flash chromatography (SiO2the gradient mixture of methanol-dichloromethane) gave a yellow oil (115 mg). Rubbing with dichloromethane gave compound III-76 in the form of not quite white solids, dried at 75°With vacuum (83 mg,52%): TPL 164-165°C;1H NMR (DMSO) δ 1,80-1,90 (2H, m), 2.70 height is 2.80 (2H, m), 3,50-3,60 (2H, m), 4,59 (1H, s), to 6.80 (1H, s), 7,50-of 7.60 (4H, m), 7,82-of 7.90 (2H, m), 8,48 are 8.53 (2H, m), 8,63 (1H, s), the 10.40 (1H, s), 12,25-(1H, s); IR (solid) 1622, 1587, 1574, 1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952, 833, 762, 734, 706, 690, 671, 665; MS 346,0 (M+H)+.

Example 306 [5-(3-Methoxypropyl-1-yl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-77): TPL 169-170about;1H NMR (DMSO-d6) δ 1,86-of 1.97 (2H, m)of 2.75 (2H, t), 3,30 (3H, s), of 3.45 (2H, t), to 6.80 (1H, s), 7,50-of 7.60 (4H, m), 7,80-of 7.90 (2H, m), 8,45-8,55 (2H, m), 8,67 (1H, d), 10,30 (1H, S), 12,25 (1H, S); IR (solid) 1620, 1591, 1572, 1532, 1476, 1425, 1408, 1373, 1326, 1117, 1003, 831, 764, 714, 695; MS 360,3(M+H)+.

Example 307 [5-(3-Benzyloxy-1-yl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-78): TPL 177-178about;1H NMR (DMSO) δ 1,92-2,03 (2H, m), 3,76-of 3.85 (2H, m), 3,52-3,62, (2H, m), 4,51 (2H, s), PC 6.82 (1H, s), 7,28-7,40 (5H, m), 7,46-7,58 (4H, m), 7,80-a 7.85 (2H, m), of 8.47-charged 8.52 (2H, m), 8,66 (1H, d), 10,45 (1H, s); IR (solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426, 1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436,3(M+H)+.

Example 308 [5-(3-Aminopropan-1-yl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-79): a Solution of [5-(3-tert-butoxy-carbonylation-1-yl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)-amine (III-80) (250 mg, of 0.56 mmol) in dichloromethane (3 ml) at 0°was treated with TFA (2 ml) and the Mixture was heated to room temperature and then concentrated in vacuum. The residue was washed and concentrated from dichloromethane (3 x 5 ml) and ether and then triturated with dichloro is an obtaining crystalline TFA salt. The obtained solid substance was collected by filtration and was dissolved in ethanol (3 ml) and water (3 ml). Was added potassium carbonate portions to obtain a pH of 8, after which the mixture was allowed to crystallize. The product was collected by filtration and dried at 80°in vacuum to obtain compound III-79 in the form of not quite white powder (122 mg, 63%): TPL 205-207aboutWith; (DMCO) 61,68 of-1.83 (2H, m), 2,65 is 2.80( 4H, m), to 6.80 (1H, s), 7,50-of 7.60 (4H, m), 7,80-of 7.90 (2H, m), 8,45 are 8.53 (2H, m), 8,65 (1H, d), 10,45 (1H, users); IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705, 677; MS 345,3(M+H)+.

Example 309 [5-(3-tert-Butoxycarbonylamino-1-yl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-80): TPL 199-200°C;1H NMR (DMSO) δ to 1.37 (9H, s), 1,71-to 1.82 (2H,m)to 2.67 (2H, t), 3.00 and-3,11 (2H, m), 7,81 (1H, s), 7-99 (1H, s), 7,50-of 7.60 (4H, m), 7,80-a 7.85 (2H, m), 8,48-charged 8.52 (2H, m), 8,63 (1H, d), the 10.40 (1H, s), of 12.26 (1H, m); IR (solid) 2953, 1687, 1622, 1594, 1573, 1535, 1481, 1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848, 807, 768, 740, 728, 710,693; MS 445,3 (M+H)+.

Example 310 (5-Isopropylcarbamate-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-81):1H NMR (DMSO-d6) δ of 1.20 (d, J=6.6 Hz, 6H), of 4.13 (m, 1H), 7,42 (users, 1H), to 7.61 (DD, J=7,0, 7.7 Hz, 2H), 7,66 (t, J=7,1 Hz, 1H), 7,71 (m, 1H), 7,99 (m, 2H), 8,39 (m, 1H), 8,42 (d, J=7,1 Hz, 2H), total of 8.74 (d, J=8,2 Hz, 1H), 11,41 (users, 1H); EI-MS 373,2 (M+H); HPLC-method C, Rt14,09 minutes

Example 311 (5-Arylcarbamoyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-82):1H NMR (500 MHz, DMSO-d6) δ was 4.02 (m, 2H), 5,15 (m, 1H), 5,23 (who, 1H), 5,94 (m, 1H), 7,45 (users, 1H), 7,60 (t, J=6.9 Hz, 2H), to 7.64 (m, 1H), 7,72 (m, 1H), 7,98 (m, 2H), 8,43 (m, 2H), 8,72 (d, J=8,2 Hz, 1H), 8,84 (users, 1H), 11,34 (users, 1H); EI-MS 371,2 (M+H); HPLC-method C, Rt13,67 minutes

Example 312 [5-(2-Methoxyethanol)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-83):1H NMR (500 MHz, DMSO-d6) δ of 3.32 (s, 3H), of 3.48 (m, 4H), of 7.36 (users, 1H), 7.62mm (m, 2H), 7,63 (m, 1H), 7,71 (m, 1H), 7,98 (m, 2H), to 8.41 (DD, J=1,4, 7,0, 2H), 8,70 (m, 2H), 11,30 (users, 1H); EI-MS 389,2,(M+H); HPLC-method C, Rt12,37 minutes

Example 313 (5-Benzylcarbamoyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-84):1H NMR (DMSO-d6) δ to 4.52 (d, J=6.0 Hz, 2H), 7,29 (m, 1H), 7,38 (d, J=4,2 Hz, 4H), 7,58 (t, J=7.5 Hz, 2H), 7,63 (m, 1H), 7,72 (m, 1H), 7,98 (m, 2H), 8,43 (d, J=7.7 Hz, 2H), 8,72 (d, J=7.5 Hz, 1H), 9,23 (users, 2H), 11,34 (users, 1H); EI-MS UAH 421,2 (M+H); HPLC-method C, Rt16,76 minutes

Example 314 (5-Cyclohexylcarbonyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-85):1H NMR (500 MHz, DMSO-d6) δ to 1.16 (m, 1H), of 1.34 (m, 4H), of 1.62 (d, J=2.6 Hz, 1H), 1,76 (m, 2H), of 1.85 (m, 2H), 3,79 (m, 1H), 7,43 (m, 1H), 7,60 (t, J=7.2 Hz, 2H), 7,65 (t, J=7,1 Hz, 1H), 7,71 (DDD, J=2,2, 5,4, 8,2 Hz, 1H), 7,98 (m, 2H), 8,35 (m, 1H), 8,43 (DD, J=1,4, 7.2 Hz, 2H), 8,72 (d, J=8,2 Hz, 1H), 11,34 (users, 1H); EI-MS 413,5 (M+H); HPLC-method C, Rt17,18 minutes

Example 315 (5-Diethylcarbamoyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-86):1H NMR (500 MHz, DMSO-d6) δ 1,18 (users, 3H), 1,25 (users, 3H), 3,49 (users, 2H), 3,69 (users, 2H), 7,21 (s, 1H), to 7.59 (t, J=6.9 Hz, 2H), 7.62mm (m, 1H), of 7.70 (m, 1H), of 7.96 (m, 2H), 8,39 (d, J=7,1 Hz, 2H), total of 8.74 (d, J=8,4 Hz, 1H), 11,37 (users, 1H); EI-MS,2 (M+H); HPLC method C, Rt14,50 minutes

Example 316 [5-(2-Benzylaminocarbonyl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-87):1H NMR (500 MHz, DMSO-d6) δ to 3.33 (s, 3H), and 4.75 (s, 2H), 7,26 (m, 1H), 7,31 (m, 1H), 7,38 (m, 4H), 7,58 (m, 2H), of 7.70 (m, 1H), 7,95 (m, 3H), compared to 8.26 (m, 1H), 8L40 (d, J=7.8 Hz, 2H), up 8.75 (m, 1H), and 11.2 (users, 1H); EI-MS 435,2,(M+H); HPLC-method C, Rt16,77 minutes

Example 317 (2-Phenylpyrazole-4-yl)-(5-propellerblades-2H-pyrazole-3-yl)amine (III-88):1H NMR (500 MHz, DMSO-d6) δ to 0.94 (t, J=7,3 Hz, 3H), of 1.57 (m, 2H), 3,24 (sq, J=6,5 Hz, 2H), 7,39 (users, 1H), 7,60 (t, J=7,3 Hz, 2H), to 7.64 (m, 1H), 7,71 (ushort, J=6,5 Hz, 1H), 7,98 (m, 2H), 8,42 (d, J=7.2 Hz, 2H), 8,61 (users, 1H), 8,72 (d, J=8.5 Hz, 1H), 11,34 (users, 1H); EI-MS 373,3 (M+H); HPLC-method C, Rt13,51 minutes

Example 318 [5-(2-Ethylisopropylamine)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-89):1H NMR (500 MHz, DMSO-d6) δ to 0.92 (t, J=7.4 Hz, 6H), of 1.52 (m, 2H), 1,59 (m, 1H), 3,79 (m, 2H), 7,53 (users, 1H), EUR 7.57 (t, J=7.5 Hz, 2H), 7,65 (t, J=7.2 Hz, 1H), 7,71 (m, 1H), 7,99 (m, 2H), 8,23 (userd, J=8,8 Hz, 1H), 8,46 (d, J=7.5 Hz, 2H), total of 8.74 (d, J=8,4 Hz, 1H), 11,34 (users, 1H); EI-MS 4,01,2 (M+H); HPLC-method C, Rt15,51 minutes

Example 319 (5-Cyclopropanecarbonyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-90):1H NMR (500 MHz, DMSO-d6) δ of 0.60 (m, 2H), 0.74 and (m, 2H), 2,86 (m, 1H), 7,34 (users, 1H), 7.62mm (m, 3H), of 7.70 (m, 1H), 7,97 (m, 2H), to 8.41 (d, J=7.9 Hz, 2H), 8,63 (users, 1H), 8,72 (d, J=7.8 Hz, 1H), 11,35 (users, 1H); El-MS 371,2 (M+H); HPLC-method C, Rt12,64 minutes

Example 320 (5-Isobutylbarbituric-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III91): 1H NMR (500 MHz, DMSO-d6) δ to 0.94 (d, J=6,7 Hz, 6H), of 1.88 (m, 1H), 3,12 (t, J=6.4 Hz, 2H), 7,45 (users, 1H), 7,58 (t, J=7.2 Hz, 3H), of 7.64 (t, J=7,1 Hz, 1H), 7,71 (m, 1H), 7,98 (m, 2H), 8,44 (DD, J=1,3, 7.9 Hz, 2H), 8,62 (users, 1H), 8,72 (d, J=8,3 Hz, 1H), 11,33 (users, 1H); EI-MS 387,2 (M+H); HPLC-method C, Rt14,70 minutes

Example 321 {5-[(3S)-3-Methoxypiperidine-1-carbonyl]-2H-pyrazole-3-yl}-(2-phenylpyrazole-4-yl)amine (III-93):1H NMR (500 MHz, DMSO-d6) δ 2,00 (m, 2H), 2,12 (m, 1H), 3,29 (s, 3H), of 3.45 (t, J=8.7 Hz, 1H), only 3.57 (DD, J=3.2, and to 9.3 Hz, 1H), 3,86 (m, 1H), 3,92 (m, 1H), 4,36 (m, 2H), 7,45 (users, 1H), to 7.59 (t, J=7.2 Hz, 2H), 7,63 (m, 1H), 7,69 (m, 1H),7,97 (m, 2H), 8,40 (d, J=7.5 Hz, 2H), total of 8.74 (d, J=7,6 Hz, 1H), 11,38 (users, 1H); EI-MS 429,2 (M+H); HPLC-method C, Rtat 13.84 minutes

Example 322 (2-Phenylpyrazole-4-yl)-(5-m-trikarbonil-2H-pyrazole-3-yl)amine (III-94):1H NMR (500 MHz, DMSO-d6) δ of 2.33 (s, 3H), 6,97 (d, J=7.5 Hz, 1H), 7,27 (t, J=7.8 Hz, 1H), 7.62mm (m, 7H), 7,72 (m, 1H), 7,98 (m, 2H), 8,46 (DD, J=2,0, 7.9 Hz, 2H), 8,71 (m, 1H), 10,29 (s, 1H), 11,31 (users, 1H); EI-MS UAH 421,2 (M+H); HPLC-method C, Rt17.11 per bbl minutes

Example 323 (2-Phenylpyrazole-4-yl)-(5-p-trikarbonil-2H-pyrazole-3-yl)amine (III-95):1H NMR (500 MHz, DMSO-d6) δ of 2.30 (s, 3H),7,20 (d, J=8,3 Hz, 2H), 7.62mm (m, 5H), to 7.68 (d, J=8,3 Hz, 2H), 7,72 (m, 1H), 7,98 (m, 2H), 8,46 (DD, J=1,8, 7,0 Hz, 2H), 8,72 (m, 1H), 10,31 (s, 1H), 11,36 (users, 1H); El-MS UAH 421,2 (M+H); HPLC-method C, Rt16,95 minutes

Example 324 (5-Methylcarbamoyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-96):1H NMR (500 MHz, DMSO-d6) δ 2,82 (d, J=4,6 Hz, 3H), 7,31 (users, 1H), 7.62mm (m, 3H), of 7.69 (m, 1H), 7,97 (m, 2H), 8,42 (d, J=7,1 Hz,2H), 8,59 (users, 1H), 8,71- (d, J=8.0 Hz, 1H), 11,30 (users, 1H); EI-MS 345,1 (M+H); HPLC-method C, Rt11,02 minutes

Example 325 [5-(Morpholine-4-carbonyl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-97):1H NMR (500 MHz, DMSO-d6) δ to 3.33 (m, 4H), 3,83 (m, 4H), 7,34 (users, 1H), 7,53 (m, 4H), 7,86 (m, 2H), 8,43 (m, 2H), 8,67 (d, J=8.6 Hz, 1H), 10,70 (s, 1H), 13.56MHz (s, 1H); EI-MS 401,2 (M+H); HPLC-method A, Rt2,68 minutes

Example 326 [5-(1-Methylpiperazin-4-carbonyl)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-98):1H NMR (500 MHz, DMSO-d6) δ of 2.25 (s, 3H), 2,43 (m, 4H), a 3.87 (m, 4H), 7,33 (users, 1H), 7,53 (m, 4H), 7,87 (m, 2H), 8,45 (m, 2H), 8,67 (d, J=7,6 Hz, 1H), 10,70 (s, 1H), 13,30 (s, 1H); EI-MS level of 414.2 (M+H); HPLC-method A, Rt2,38 minutes

Example 327 [5-(2-Hydrooximethylcarbamil)-2H-pyrazole-3-yl]-(2-phenylpyrazole-4-yl)amine (III-99):1H NMR (500 MHz, DMSO-d6) δ to 3.36 (m, 2H), 3,52 (m, 2H), 4,79 (m, 1H), 7,50 (m, 5H), 7,83 (m, 2H), and 8.50 (m, 4H), 10,52 (users, 1H), 13,25 (s, 1H); EI-MS 375,1 (M+H); HPLC-method A, Rtof 2.51 minutes

Example 328 (5-Carbarnoyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-100): To a solution of 2,5-dioxopiperidin-1 silt ester 5-(2-phenylpyrazole-4-ylamino)-1H-pyrazole-3-carboxylic acid (270 mg, to 0.63 mmol) in DMF (20 ml) was added a solution of ammonia in 1,4-dioxane (0.5 M, 10 ml). The resulting mixture was stirred at room temperature for 24 hours. After concentration of the solvents the residue was introduced into water (20 ml). The precipitate was collected to obtain compound III-100 (168 mg, 80%) as a yellow t Agogo substances: 1H NMR (500 MHz, DMSO-d6) δ to 7.77-7,51 (m, 6H), 7,86 (users, 2H), 8,11 (m, 1H), and 8.50 (m, 2H), 8,63 (m, 1H), 10,52 (s, 1H), 11,25 (s, 1H); EI-MS 331,1 (M+H); HPLC-method A, Rt2,52 minutes

Example 329 (4-Bromo-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-101): Obtained by the method And in the form of a yellow solid: MP 189°;1H NMR (DMSO-d6) δ 7,44-7,46 (3H, m), 7,58 (1H, m), 7,87 (2H, d), of 8.15 (1H, s), 8,31-to 8.34 (2H, m), 8,49 (1H, d), 10,08 (1H, s), 13,13 (1H, s); IR (solid) 3286, 2969, 1738, 1632; MS 366,2/368,2(M+H)+.

Example 330 (4-Bromo-5-methyl-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-102): MP 183-185°;1H NMR (DMSO) δ of 2.33 (3H, users), 7,44-7,46 (3H, m), EUR 7.57 (1H, m), 7,84-7,87 (2H, m), 8,31-to 8.34 (2H, m), 8,48 (1H, d), of 10.05 (1H, s), 12,91 (1H, users); IR (solid) 3362, 3065, 2831, 1619, 1578; MS 380,2/382,2(M+H)+.

Example 331 (4-Cyano-2H-pyrazole-3-yl)-(2-phenylpyrazole-4-yl)amine (III-103): TPL >250°C;1H NMR (DMSO) δ 7,47-7,49 (3H, m), of 7.64 (1H, m), to $ 7.91 (2H, m), 8,40-8,43 (2H, m), 8,53 (1H, d), 8,71 (1H, d), 10,61 (1H, s), 13,60 (1H, s); IR (solid) 3277, 3069, 2855, 2231, 1625; MS 313,2 (M+H)+.

Example 332 (5-Methyl-2H-pyrazole-3-yl)-(2-morpholine-4-yl-hinzelin-4-yl)amine (III-104): TPL p.223-224°C;1H NMR (DMSO) δ and 2.26(3H, s), 3,-65 (4H, m), of 3.75(4H, m), 6,44(1H, s), 7,12(1H, d), 7,33(1H, d), 7,56(1H, t), of 8.37(1H, d), of 10.01(1H, s), 12,13(1H, users); IR (solid) 1621, 1578, 1537, 1475, 1434, 1385; MS 311,0 (M+H)+.

Example 333 (5-Methyl-2H-pyrazole-3-yl)-(2-piperazine-4-yl-hinzelin-4-yl)amine (III-105): TPL 179-181°C;1H NMR (DMSO) δ and 2.26(3H, s), 2,74 4H, users), 3,71(4H, users), to 6.43(1H, s), was 7.08(1H, t), 7,30(1H, d), 7,53(1H, t), to 8.34(1H, d), 9,50(1H, s), 12,08(1H, users); IR (solid) 2853, 1619, 1603, 1566, 1549, 1539; MS 310,0 (M+H)+.

Example 334 [2-(4-Methylpiperidin-1-yl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-106): TPL 148-150°C;1H NMR (DMSO) δ of 1.06(3H, d), of 1.03(2H, m)and 1.51 is 1.70 (3H, m), and 2.26(3H, s), of 2.86(2H, m), to 4.73(2H, d), 6,44(1H, s), 7,06(1H, d), 7,29(1H, d), 7,52(1H, t), 8,32(1H, d), 9,92(1H, s), 12,09{1H, users); IR (solid) 2917, 2840, 1629, 1593, 1562, 1546, 1486; MS 323,0 (M+H)+.

Example 335 [2-(4-Methylpiperazin-1-yl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-107): TPL 105-107°C;1H NMR (DMSO) δ of 2.21(3H, s), and 2.26 (3H, s), 2,34 (4H, m), of 3.75 (4H, m), of 6.45 (1H, s), to 7.09 (1H, t), 7,31 (1H, d), 7,54 (1H, t), to 8.34 (1H, d), 9,96 (1H, s), 12,12 (1H, users); IR (solid) 2934, 2844, 2804, 1620, 1593, 1572, 1536, 1476; MS 324,0 ((M+H)+.

Example 336 (5-Methyl-2H-pyrazole-3-yl)-(2-piperidine-1-yl-hinzelin-4-yl)amine (III-108): TPL 294°C;1H NMR (DMSO) δ 1,45 is 1.58 (4H, m), and 1.63 (2H, m), and 2.26 (3H, s), with 3.79 (4H, m), 6,45 (1H, users), 7,06 (1H, t), 7,29 (1H, d), 7,52 (1H, t), with 8.33 (1H, d), 9,92 (1H, s), 12,11 {1H, users); IR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, 1382; MS 309,3 ((M+H)+.

Example 337 (2-Azepin-1-yl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-109): TPL 269°C;1H NMR (DMSO) δ a 1.50 (4H, users), to 1.76 (4H, ushers in), 2.25 (3H, s), of 3.78 (4H, t), 6,55 (1H, users), 7,03 (1H, t), 7,28 (1H, d), to 7.50 (1H, t), with 8.33 (1H, d), 9,92 (1H, s), 12,09 (1H, users); IR (solid) 3427, 2963, 2927, 2909, 2872, 2850, 1623, 1595, 1586, 1568, 1504, 1486, 1468, 1386, 1427; MS 323,3 (M+H)+.

Example 338 [2-(4-(2-Hydroxyethylpiperazine-1-yl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-110): TPL 175°C;1H NMR (DMSO) δ a 1.08 (2H, m)to 1.38 (2H, m), 1,57 of-1.83 (3H, m), and 2.26 (3H, s), 2,85 (2H, t), 3,47 (2H, m), to 4.38 (1H, t), and 4.75 (2H, d), of 6.45 (1H, users), 7,06 (1H, t), 7,29 (1H, d), 7,52 (1H, t), 8,32 (1H, d), to 9.93 (1H, s), 12,12 (1H, users); IR (solid) 3365, 3073, 2972, 2868, 1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353,2 ((M+H)+.

Example 339 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(4-methylpiperidin-1-yl)hinzelin-4-yl]amine (III-111): To a solution of (5-cyclopropyl-1H-pyrazole-3-yl)-(2-chlorination-4-yl)amine (118 mg, 0.41 mmol) in tert-butanol (3.0 ml) was added 4-methylpiperidine (0,49 ml, 4.1 mmol) and the resulting mixture was boiled under reflux throughout the night. The reaction mixture was concentrated in vacuo and the residue was dissolved in a mixture of EtOH-water (1:3, 4 ml). Was added potassium carbonate (57 mg, 0.41 mmol) and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (2 times) and Et2O (2 times) to obtain compound III-111 as a white solid (123 mg, 85%): TPL 190°C;1H NMR (DMSO) δ 0,66 (2H, s), 0,93,(5H, users), of 1.07 (2H, d), of 1.66 (3H, S), at 1.91 (1H, s), 2,85 (2H, t), 4,72 (2H, d), 6,33 (1H, s), 7,06 (1H, t), 7,29 (1H, d), 7,52 (1H, t), 8,31 (1H, d), for 9.95 (1H, ), 12,18 (1H, users); IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, 1394; MS 349,2 ((M+H)+.

Example 340 [2-(1,4-Dioxa-8 azaspiro[4,5]Dec-8-yl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-112): TPL 191°C;1H NMR (DMSO) δ of 1.65 (4H, s), and 2.26 (3H, s), 3,90 (4H, s), 3,93 (4H, s), to 6.43 (1H, users), 709 (1H, t), 7,32 (1H, d), 7,54 (1H, t), 8,35 (1H, d), 9,99 (1H, users), 12,13 (1H, users); IR (solid) 3069, 2964, 2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367,3 ((M+H)+.

Example 341 [2-(4-Cyclopentenopyridine-1-yl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-113): TPL 191°C;1H NMR (DMSO) δ of 1.33 (2H, d), of 1.65 (4H, s)to 1.87 (2H, d), 2,20 (1H, s), and 2.26 (3H, s), 2.49 USD (2H, s)of 3.00 (2H, t)to 3.36 (2H, s), br4.61 (2H, d), of 6.45 (1H, users), 7,07 (1H, s), 7,31 (1H, d), 7,52 (1H, s), with 8.33 (1H, d), 9,94 (1H, users), 12,12 (1H, users); IR (solid) 3371, 2943, 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378,2 ((M+H)+.

Example 342 [2-(4-Hydroxypiperidine-1-yl)hinzelin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (III-114): TPL 123°C;1H NMR (DMSO) δ of 1.34 (2H, d), of 1.80 (2H, d), and 2.26 (3H, s), 3,24 (2H, t), and 3.72 (1H, users), 4,39 (2H, d), 4,70 (1H, d), 6,44 (1H, users), 7,07 (1H, t), 7,30 (1H, d), 7,53 (1H, t), with 8.33 (1H, d), 9,94 (1H, users), 12,11 (1H, users); IR (solid) 3265, 3151, 2927, 2863, 1622, 1600, 1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325,3 ((M+H)+.

Example 343 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(4-hydroxy-4-phenylpiperidine-1-yl)hinzelin-4-yl]amine (III-115): TPL 131°C;1H NMR (DMSO) δ of 0.64 (2H, q), of 0.93 (2H, HF), 1,68 (2H, d), 1,83-of 1.97 (3H, m), 3,20-of 3.45 (2H, m), 4,69 (2H, d), 5,11 (1H, s), 6,37 (1H, users), was 7.08 (1H, t), 7,20 (1H, t), 7,31 (3H, t), 7,49 (2H, d), 7,53 (1H t), with 8.33 (1H, d), 9,98 (1H, users), 12,18 (1H, users); IR (solid) 3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559, 1536, 1481, 1459, 1431, 1372, 1336, 1213, 994; MS 427,6, ((M+H)+.

Example 344 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(1,3-dihydroindol-2-yl)hinzelin-4-yl]amine (II-116): Received by way of E-I as not quite white solids, TPL 237°S: TPL 237°C;1H NMR (DMSO-d6) δ of 0.79 (2H, s), and 1.00 (2H, d), of 1.99 (1H, m)to 4.92 (4H, d), 6,72 (1H, users), 7,13 (1H, t), 7,33 (2H, s), 7,30-of 7.48 (3H, m), 7,58 (1H, t), of 8.40 (1H, d), 10,12 (1H, s), 12,17 (1H, s); IR (solid) 3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 1482, 1432, 1391, 1359, 1141, 1027, 877, 814; MS 369,4 ((M+H)+.

Example 345 (2-Azepin-1-yl)hinzelin-4-yl]-(5-cyclopropyl-2H-pyrazole-3-yl)amine (III-117): TPL 199-200°C;1H NMR (DMSO-d6) δ 0,60-0,70 (2H, m), 0,90-1,00 (2H, m), 1,45-of 1.57 (4H, m), 1.70 to of 1.85 (4H, m), 1,88-of 1.97 (1H, m), 3.75 to a 3.87 (4H, m), 6.42 per (1H, s), 7,02 (1H, t), 7,27 (1H, d), 7,49 (1H, t), 8,29 (1H, d), to 9.91 (1H, s), 12,19 (1H, users); IR (solid) 2929, 1624, 1595, 1581, 1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, 1000, 825, 754; MS 349,2 ((M+H)+.

Example 346 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(3,4-dihydro-1H-isoquinoline-2-yl)hinzelin-4-yl]amine (III-118): TPL 182-184°C;1H NMR (DMSO) δ 0,75 (2H, d), of 1.02 (2H, d), a 1.96 (1H, m), 2,89 (2H, m), of 4.05 (2H, m), 4,94 (2H, s), 6,46 (1H, s), 7,10 (1H, t), 7,21 (4H, d), 7,37 (1H, d), 7,55 (1H, d), at 8.36 (1H, d), of 10.05 (1H, s), 12,23 (1H, users); IR (solid) 1621, 1581, 1560, 1537, 1479, 1456, 1426, 1396, 1374, 1341, 1222; MS 383,3 ((M+H)+.

Example 347 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(2,3-dihydroindol-1-yl)hinzelin-4-yl]amine (III-119): TPL 150-153°C;1H NMR (DMSO) δ 0,74 (2H, d), and 0.98 (2H, d), a 1.96 (1H, m)and 3.15 (2H, t), 4,25 (2H, t), of 6.45 (1H, users), to 6.88 (1H, t), to 7.09 (1H, t), 7,20 (2H, m), 7,53 (1H, d), the 7.65 (1H, t), 8,43 (2H, users), to 10.09 (1H, s), to 12.28 (1H, users); IR (solid) 1621, 1588, 1577, 1564, 1537, 1487, 1455, 1425, 1386, 1259; MS 369,3 ((M+H)+.

Example 348 (5-Cyclopropyl-2H-pyrazole-3-yl-[2-(4-hydroxyethylpiperazine-1-yl)hinzelin-4-yl]amine (III-120): TPL 142°C;1H NMR (DMSO) δ to 0.67 (2H, d), is 0.96 (2H, d), 1,10 (2H, HF), 1,55-1,70 (3H, m), at 1.91 (1H, m), 2,85 (2H, t), of 3.28 (2H, s), 4,48 (1H, s), was 4.76 (2H, d), 6,34 (1H, S), 7,06 (1H, t), 7,30 (1H, d), 7,52 (1H, t), 8,31 (1H, d), 9,96 (1H, s), 12,19 (1H, s); IR (solid) 3363, 3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314, 1241, 1186, 1091, 995, 941, 823; MS 365,8 ((M+H)+.

Example 349 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(3,4-dihydro-2H-quinoline-1-yl)hinzelin-4-yl]amine (III-121): TPL 137-145°C;1H NMR (DMSO-d6) δ 0,55 (2H, d), 0,88 (2H, d), of 1.78 (1H, m), with 1.92 (2H, t), of 2.75 (2H, t), Android 4.04 (2H, t), of 6.20 (1H, users), 6,97 (1H, t), 7,14 (1H, m), 7,19 (1H, t), 7,42 (1H, d), to 7.61 (1H, t), to 7.67 (1H, d), 8,43 (1H, d), 10,04 (1H, s), 12,21 (1H, users); IR (solid) 1622, 1572, 1539, 1493, 1454, 1420, 1373, 1249; MS 383,3 ((M+H)+.

Example 350 (5-Methoxycarbonyl-2H-pyrazole-3-yl)-[2-(piperidine-1-yl)hinzelin-4-yl]amine (III-122):1H NMR (500MHz, CDCl3) δ l,7-1,8(6H, m), 83,8 (4H, m), 83,9 (3H, s), 8 to 5.5 (1H, s), 8 to 7.15 (1H, t), 8 to 7.4 (1H, d), 8 to 7.6 (1H, t), δ 8,0 (1H, d); HPLC-method B, (starting with 95% H2O) Rtof 7.4 min; MS (ES+) 353,24 (M+H).

Example 351 [5-(piperidine-1-carbonyl)-2H-pyrazole-3-yl]-[2-(piperidine-1-yl)hinzelin-4-yl]amine (III-123): HPLC-method B, (starting with 95% H2A: 0,1% TFA) Rt8,0 min; MS (ES+) 406,30, (ES-) 404,30.

Example 352 (5-Hydroxymethyl-2H-pyrazole-3-yl)-[2-(piperidine-1-yl)hinzelin-4-yl]amine (III-124): To a solution of compound III-122 (10.0 mg, 0,028 mmol) in THF (6 ml) at ambient temperature was slowly added a 1 M solution of LiAlH4in THF (0.05 ml, 0.05 mmol). After 15-minutes the solution was suppressed by the addition of water and 1 N. HCl. From the aqueous layer, the product was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuum. The residue was purified preparative HPLC to obtain compound III-124 (4.0 mg, 44%). HPLC-method B, (starting with 95% H2A: 0,1% TFA) Rt6,1 min; MS (ES+) 325,13, (ES-) 323,13.

Example 353 (5-Carbarnoyl-2H-pyrazole-3-yl)-[2-(piperidine-1-yl)hinzelin-4-yl]amine (III-125): a Solution of compound III-122 (1.5 g, 4.3 mmol) in 2.0 M solution of NH3in the Meon (100 ml) was heated at 110°C for 2 days. The dark brown reaction mixture was concentrated in vacuum to obtain a viscous oil, which was purified column chromatography to obtain 0.7 g (50%) of compound III-125:1H NMR (500 MHz, CD3OD-d3) δ 1,6 (4H, m); 81,7 (2H, m), 8 and 3.3 (1H, s), 8 of 3.8 (4H, m), 8 to 5.5 (1H, S), 8 to 7.15 (1H, t), 8 was 7.45 (1H, d), 8 of 7.55 (1H, t), 8 8,0 (1H, d); HPLC-method B, (starting with 95% H2O:0,1% TFA) Rt5,9 min; MS (ES+) 338,13, (ES-) 336,15.

Example 354 (5-Carbarnoyl-2H-pyrazole-3-yl)-[2-(4-methylpiperidin-1-yl)hinzelin-4-yl]amine (III-126): HPLC-method B, (starting with 95% H2O:0,1% TFA) Rt6,4 min; MS (ES+) 352,19, (ES-) 350,20.

Example 355 (5,7-Debtor-1H-indazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)amine (III-127):1H NMR (500 MHz, DMSO-d6) δ of 13.7 (s, 1H), 10,3 (with, of user., 1H), of 7.90 (d, 2H), 7,52 (t, 1H), 7,45 (m, 3H),7,26 (d, 1H), 2,99 (m, 2H), 2,75 (m, 2H), 1,95 (UserN) ppm; MS (ES+) 378,24 (M+H), (ES-) 376,23 (M-H); HPLC-method A, Rt3.04 from minutes

Example 356 (2-Phenyl-5,6,7,8-tetrahydroquinazolin the-4-yl)-(5-trifluoromethyl-1H-indazol-3-yl)amine (III-128): 1H NMR (500 MHz, DMSO-d6) δ and 13.4 (s, 1H), 10,2 (with, of user., 1H), 8,13 (s, 1H), 7,86 (d, 2H), 7,78 (d, 1H), 7,69 (d, 1H), 7,50 (t, 1H), 7,35 (DD, 2H), 2,89 (m, 2H), 2,72 (m, 2H), 1,90 (s, UserN) ppm; MS (ES+) 410,24 (M+H); (ES-) 408,23 (M-H); HPLC-method A, Rt3,19 minutes

Example 357 (7-Fluoro-1H-indazol-3-yl)-(2-phenylpyrazole-4-yl)amine (III-129):1H NMR (500 MHz, DMSO-d6) δ to 13.6 (s, 1H), 11,1 (with, of user., 1H), 8,65 (d, 1H), 8,03 (d, 2H), 7,95 (s, 2H), to 7.67 (m, 1H), 7,45 (m, 2H), 7,33 (t, 2H), 7,22 (DD, 1H), 6,99 (TD, 1H) ppm; MS (ES+): m/e=356,20 (M+H); HPLC-method A, Rt3,00 minutes

Example 358 (5-fluoro-1H-indazol-3-yl)-(2-phenylpyrazole-4-yl)amine (III-130):1H NMR (500 MHz, DMSO-d6) δ 13,2 (s, 1H), 11,3 (with, of user., 1H), 8,67 (d, 1H), 8,04 (d, 2H), of 7.96 (s, 2H), of 7.70 (m, 1H), 7,58 (DD, 1H), 7,43 (m, 4H), 7,28 (TD, 1H) ppm; MS (ES+) 356,20 (M+H); HPLC-method A, Rt3,00 minutes

Example 359 (5,7-Debtor-1H-indazol-3-yl)-(2-phenylpyrazole-4-yl)amine (III-131):1H NMR (500 MHz, DMSO-d6) δ of 13.7 (s, 1H), 8,65 (d, 1H), 8,04 (d, 2H), 7,95 (s, 2H), 7,68 (m, 1H), 7,45 (m, 1H), 7,35 (m, 4H) ppm; MS (ES+): m/e=374,17 (M+H); HPLC-method A, Rt3,07 minutes

Example 360 (1H-Indazol-3-yl)-[2-(3-triptoreline)hinzelin-4-yl]amine (III-132):1H NMR (500 MHz, DMSO-d6) δ 7,06 (t, 1H), 7,42 (t, 1H), 1,59 (d, 1H), 7,63 (t, 1H), 7,66 (d, 1H), 7,71 (m, 1H), 7,80 (d, 1H), 7,98 (m, 2H), with 8.33 (s, 1H), 8,46 (d, 1H), 8,71 (d, 1H), 11,04 (users, 1H), 12,97 (s, 1H); EI-MS 406,1 (M+l); HPLC-method A, Rt3,15 minutes

Example 361 (2-Phenylpyrazole-4-yl)-(1H-pyrazolo[4,3-b]pyridine-3-yl)amine (III-133):1H NMR (500 MHz, DMSO-d6) δ 13,3 (with, of user., 1H), 11,4 (with, of user., 1H), 8,78 (d, 1H), ,58 (DD, 1H), 8,24 (d, 1H), 8,10 (m, 2H), 7,95 (d, 2H), 7,86 (t, 1H), 7,56 (m, 2H), 7,44 (t, 2H) ppm; MS (ES+) 339,11 (M+H); HPLC-method A, Rt2,63 minutes

Example 362 [5-(3-Methoxyphenyl)-6-oxo-5,6-dihydro-1H-pyrazolo-[4,3-C]pyridazin-3-yl]-(2-phenylpyrazole-4-yl)amine (III-134):1H NMR (500 MHz, MeOH-d4) δ 8,65 (d, 1H), 8,17 (m, 3H), 8,10 (d, 1H), of 7.90 (t, 1H), of 7.75 (t, 1H), 7,58 (m, 2H), 7,25 (m, 1H), 6,95 (m, 2H), 6,85 (d, 1H), 6,80 (s, 1H), to 3.64 (s, 3H) ppm; MS (ES+): m/e=462,2 (M+H).

Example 363 (6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo[4,3-C]-pyridazin-3-yl)-(2-phenylpyrazole-4-yl)amine (III-135):1H NMR (500 MHz, MeOH-d4) δ 8,61 (d, 1H), 8,13 (m, 3H), with 8.05 (d, 1H), a 7.85 (t, 1H), of 7.70 (t, 1H), 7,58 (m, 2H), 7,32 (m, 5H), 6,79 (s, 1H) ppm; MS (ES+): m/e=432,2 (M+H).

Example 364 [5-(4-Methoxyphenyl)-6-oxo-5,6-dihydro-1H-pyrazolo-[4,3-C]pyridazin-3-yl]-(2-phenylpyrazole-4-yl)amine (III-136): MS (ES+) 462,2 (M+H).

Example 365 [5-(2,4-Dichlorophenyl)-6-oxo-5,6-dihydro-1H-pyrazolo-[4,3-C]pyridazin-3-yl]-(2-phenylpyrazole-4-yl)amine (III-137):1H NMR (500 MHz, MeOH-d4) δ 8,63 (d,1H), 8,17 (m, 4H), 7,89 (t, 1H), 7,73 (t, 1H), to 7.61 (t, 2H), EUR 7.57 (d, 1H), 7,32 (m, 1H), 7,21 (d, 1H), 6,84 (s, 1H) ppm; MS (ES+): m/e=500,1(M+H).

Example 366 [6-Oxo-5-(triptoreline)-5,6-dihydro-1H-pyrazolo[4,3-C]pyridazin-3-yl]-(2-phenylpyrazole-4-yl)amine (III-138):1H NMR (500 MHz, MeOH-d4) δ 8,55 (d, 1H), 8,19 (d, 2H), 7,92 (m, 2H), 7,65 (m, 3H), 7,45 (t, 2H), 7,25 (m, 1H), 7,13 (t, 1H), 7,05 (t, 1H), 6.75 in (s, 1H) ppm; MS (ES+): m/e=500,2 (M+H).

Example 367 [6-Oxo-5-(4-phenoxyphenyl)-5,6-dihydro-1H-pyrazolo-[4,3-C]pyridazin-3-yl]-(2-phenylpyrazole-4-yl)amine (III-139): MS (ES+) 524,3 (M+H).

Example 368 [5-(4-Chlorophenyl)-6-oxo-5,6-dihydro-1H-pyrazolo-[4,3-C]pyridazin-3-yl]-(2-phenylpyrazole-4-yl)amine (III-140): MS (ES+) 466,2 (M+H).

Example 369 (2-Imidazol-1-imaginaton-4-yl)-(1H-indazol-3-yl)amine (III-141):1H NMR (500 MHz, DMSO-d6) δ 7,10 (t, 1H), 7,44 (t, 1H), 7,50 (users, 1H), 7,60 (d, 1H), 7,72 (m, 2H), to 7.77 (m, 1H,), 7,88 (d, 1H), 7,98 (t, 1H), 8,73 (d, 1H), 8,96 (s, 1H), 11,23 (s, 1H), 13,06 (s, 1H); EI-MS 328,1 (M+l); HPLC-method A, Rt2,93 minutes

Example 370 (1H-Indazol-3-yl)-[2-(2-Mei-1-yl-hinzelin-4-yl]amine (III-142):1H NMR (500 MHz, DMSO-d6) δ 2,48 (s, 3H), 7,10 (t, 1H), 7,43 (t, 1H), EUR 7.57 (d, 1H), 7,60 (d, 1H), to 7.67 (d, 1H), 7,76 (TD, 1H), 7,86 (d, 1H), to $ 7.91 (d, 1H), 8,01 (TD, 1H), 8,72 (d, 1H), of 11.15 (s, 1H), 13,10 (s, 1H); El-MS 342,1 (M+l); HPLC-method A, Rt3,06 minutes

Example 371 (1H-Indazol-3-yl)-(2-piperidine-1-imaginaton-4-yl)amine (III-143):1H NMR (500 MHz, DMSO-d6) δ to 1.48 (m, 6H), of 3.60 (m, 4H), 7,11 (t, 1H), 7,52 (t, 1H), 7,55 (d, 1H), to 7.64 (d, 1H), 7,69 (d, 1H), of 7.75 (d, 1H), of 7.90 (t, 1H), 8,58 (d, 1H), 11,82 (users, 1H), 13,25 (s, 1H); EI-MS 345,1 (M+l); HPLC method A, Rt3,03 minutes

Example 372 (1H-Indazol-3-yl)-[2-(octahedrally-1-yl)-hinzelin-4-yl]amine (III-144):1H NMR (500 MHz, DMSO-d6) δ 0,6-1,9 (m, 13 H)and 3.15 (m, 1H), 3,25 (m, 1H), 4,0 (m, 1H), 7,10 (t, 0,5H), 7,12 (t, 0,5H), 7,55 (m, 2H), 7,66 (d, 0.5 H), of 7.69 (d, 0.5 H), to 7.77 (d, 1H), to $ 7.91 (t, 1H), 8,55 (d, 0.5 H), 8,59 (d, 0.5 H), 11,46 (s, 0.5 H), 11,54 (s, 0.5 H), 11,78 (s, 0.5 H), 11,84 (s, 0.5 H), 13,10 (s, 0.5 H), 13,12 (s, 0.5 H); EI-MS 399,3 (M+l); HPLC-method A, Rt3,37 minutes

Example 373 (1H-Indazol-3-yl)-[2-(2,6-dimethylmorpholine-4-yl)-hinzelin-4-yl]amine (III-145):1 H NMR (500 MHz, DMSO-d6) δ 1,0 (m, 6H), 4,0 (m, 6H), 7,12 (t, 1H), 7,41, (TD, 1H), 7,56 (t, 1H), 7,58 (d, 1H), 7,68 (DD, 1H), to 7.77 (t, 1H), to 7.93 (t, 1H), at 8.60 (d, 1H), of 11.69 (s, 1H), 13,16 (s, 1H); EI-MS 375,3 (M+l); HPLC-method A, Rt2,93 minutes

Example 374 (5-Methyl-2H-pyrazole-3-yl)-(2-phenylpyrimidine-4-yl)amine (IV-1): TPL 245-246°C;1H NMR (DMSO) δ and 2.26 (3H, s), 6,32 (1H, users), 7,07 (1H, users), of 7.48-rate of 7.54 (3H, m), 8,33-8,39 (3H, m), 9,87 (1H, s), a 12.03 (1H, s); IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, 1336; MS 252,2 (M+H)+.

Example 375 [6-(4-Acetamidobenzenesulfonyl)-2-phenylpyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-3): a Suspension of Pinklolita (Fenclorim) (4,6-dichloro-2-phenylpyrimidine) (0.1 g, 0.44 mmol), 3-amino-5-methylpyrazole (0,045 g, 0.47 mmol), N,N-diiso-propylethylene (of 0.08 ml, 0.47 mmol) and sodium iodide (0,067 g, 0.44 mmol) in n-butanol (5 ml) was heated at 117°C for 18 hours. Was removed in vacuum, the solvent and the crude product was purified flash chromatography (silica gel, petrol:EtOAc=3:2) to give 0.037 g (yield 29%) of (6-chloro-2-phenylpyrimido-DIN-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine in the form of not-quite-white solid. The suspension obtained pyrimidine (0.037 g, 0.13 mmol) and thioacetamide (to 0.108 g, 0.64 mmol) in tert-butanol was heated at 80°C in nitrogen atmosphere for 2 days. The reaction mixture was cooled to room temperature and was removed in vacuum solvent. The concentrate was dissolved in EtOAc and washed with saturated aqueous NaHCO 3. The organic layer was concentrated in vacuum and the crude product was purified preparative HPLC. Residual disulfide, which may still be in the mix after HPLC, can be removed by precipitation from EtOAc and filtered. The mother liquor was concentrated to obtain compound IV-3 (7 mg, yield 13%) as not quite white solid: TPL 235-236°C;1H NMR (DMSO) δ 2,10 (3H, s), of 2.21 (3H, s), 6,33 (1H, users), to 7.50 (3H, m), 7,7-to 7.59 (2H, m), 7,76 for 7.78 (2H, m), of 8.25 (2H, m), 9,72, 10,26 and 11,93 (3 H, 3 x users); IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417,3 (M+H)+.

Example 376 [2-(4-Methylpiperidin-1-yl)pyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-4): TPL 215-216°C;1H NMR (CD3OD) δ to 0.96 (3H, d), of 1.16 (2H, m)of 1.66 (3H, m), and 2.27 (3H, s), of 2.86 (2H, t), 4,58 (2H, m), 4,78 (2H, exchange of protons), 6,13 (2H, m), 7,83 (1H, d); IR (solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273,1 (M+H)+.

Example 377 [2-(4-Methylpiperidin-1-yl)-5-nitropyrimidin-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-5): TPL 185-187°C;1H NMR (DMSO) δ of 0.93 (3H, d), 1,06-of 1.18 (2H, m), 1,68 and 1.80 (3H, m), and 2.26 (3H, s), 3,01-of 3.12 (2H, m), 4,63 (1H, d), 4,80 (1H, d), to 6.39 (1H, s), of 9.00 (1H, s), 10,41 (1H, s), 12,36 (1H, s); IR (solid) 1589, 1517, 1479, 1446, 1346, 1317, 1246, 1222, 1055; MS 318,2 (M+H)+.

Example 378 [5-Amino-2-(4-methylpiperidin-1-yl)pyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-6): To a solution of compound IV-5 (48 mg, 0,151 mmol) in ethanol (2.0 ml) was added dichloro dihydrate is Yes tin (171 mg, 0,756 mmol) and the resulting mixture was boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into a mixture of 1 M NaOH-dichloromethane-propanol (18:8:4 ml) and stirred 15 minutes. Separated the layers and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were concentrated in vacuo and the residue was purified flash chromatography (silica gel, gradient mixture of dichloromethane-Meon) to obtain compound IV-6 as a gray solid (27 mg, 63%):1H NMR (DMSO) δ 0.88 to 1.04 million (5H, m), 1,55-of 1.62 (3H, m), of 2.21 (3H, s), 2,70 (2H, m)to 3.36 (2H, m), and 4.40 (2H, m), 6,37 (1H, s), 7,49 (1H, s), 8,40 (1H, s), 11,92 (1H, users); MS 288,2 (M+H)+.

Example 379 [5-Amino-6-methyl-2-(4-methylpiperidin-1-yl)pyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-7): TPL 172-175°C;1H NMR (DMSO) δ of 0.90 (3H, d), of 1.03 (2H, m), 1,52-of 1.62 (3H, m)to 2.13 (3H, s), measuring 2.20 (3H, s), 2,69 (2H, m)to 3.92 (2H, users), of 4.44 (2H, d), 6.35mm (1H, s), to 8.41 (1H, s), 11,85 (1H, users); IR (solid) 1612, 1589, 1489, 1446, 1317; MS 302,5 (M+H)+.

Example 380 [6-Methyl-2-(4-were)pyrimidine-4-yl]-(5-phenyl-2H-pyrazole-3-yl)amine (IV-10): MS 342,34 (M+H); HPLC-method E, Rt1,334 minutes

Example 381 [2-(4-Chlorophenyl)-6-methylpyrimidin-4-yl]-(5-furan-2-yl-2H-pyrazole-3-yl)amine (IV-11): MS 352,11 (M+H); HPLC-method E, Rt1,194 minutes

Example 382 (5-Furan-2-yl-2H-pyrazole-3-yl)-(6-methyl-2-phenylpyrimidine-4-yl)amine (IV-12): MS 318,21 (M+H); HPLC-method E, Rt1,192 minutes

Example 383 [6-Methyl-2-(triptoreline)pyrimidine-4-yl]-(5-phenyl-2-yl-2H-pyrazole-3-yl)amine (IV-13): MS 396,24 (M+H); HPLC-method E, Rt1,419 minutes

Example 384 (5-Furan-2-yl-2H-pyrazole-3-yl)-[6-methyl-2-(4-triptoreline)pyrimidine-4-yl]amine (IV-14): MS 386,08 (M+H); HPLC-method E, Rt1,347 minutes

Example 385 [2-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)-6-methylpyrimidin-4-yl]-(5-furan-2-yl-2H-pyrazole-3-yl)amine (IV-15): MS 376,18 (M+H); HPLC-method E, Rt1,181 minutes

Example 386 [2-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)-6-ethylpyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-16): MS 338,17 (M+H); HPLC-method E, Rt1,082 minutes

Example 387 (6-Ethyl-2-phenylpyrimidine-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (IV-17): MS 280,18 (M+H); HPLC-method E, Rt1,024 minutes

Example 388 (6-Methyl-2-phenylpyrimidine-4-yl)-(5-phenyl-2H-pyrazole-3-yl)amine (IV-19): MS 328,51 (M+H); HPLC-method E, Rt1,192 minutes

Example 389 [6-Ethyl-2-(4-triptoreline)pyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-20): MS 348,5 (M+H); HPLC-method E, Rt1,224 minutes

Example 390 (5-Furan-2-yl-2H-pyrazole-3-yl)-[6-methyl-2-(4-were)pyrimidine-4-yl]amine (IV-21): MS 332,23 (M+H); HPLC-method E, Rt1,139 minutes

Example 391 (6-Methoxymethyl-2-phenylpyrimidine-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (IV-22): MS 296,31 (M+H); HPLC-method E, Rt0,971 minutes

Example 392 (5,6-Dimethyl-2-phenylpyrimidine-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (IV-23): MS 280,2 (M+H); HPLC-method E, Rt0,927 minutes

Example 393 (6-Methyl-2-phenylpyrimidine-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (IV-24): MS 266,18 (M+H); HPLC-method E, Rt0,925 minutes

Example 394 [6-Ethyl-2-(4-Mei is phenyl)pyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-25): MS 294,46 (M+H); HPLC-method E, Rt1,174 minutes

Example 395 [2-(4-Chlorophenyl)-6-ethylpyrimidine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-26): MS 314,42 (M+H); HPLC-method E, Rt1,213 min

Example 396 (5-Methyl-1H-pyrazole-3-yl)-(6-methyl-2-p-tolyl-pyrimidine-4-yl)amine (IV-27): MS 280,45 (M+H); HPLC-method E, Rt1,135 min

Example 397 (1H-Indazol-3-yl)-(6-methoxymethyl-2-phenylpyrimidine-4-yl)amine (IV-28):1H NMR (500 MHz, DMSO) δ of 3.57 (3H, s)and 4.65 (2H, s), 7.23 percent (1H, J=7.5 Hz, t), 7,52 (1H, J=7,6 Hz, t), 7,63 (4H, m), of 7.75 (1H, usher.), 8,13 (1H, J=5.5 Hz, userd), 8,44 (1H, J=5.7 Hz, userd), or 10.6 (1H, usher.), of 12.8 (1H, users) ppm; HPLC-method A, Rt2,944 min; MS (FIA) 332,1 (M+H).

Example 398 (5-Methyl-2H-pyrazole-3-yl)-(2-pyridin-4-illiano[3,2-d]pyrimidine-4-yl)amine (IV-29):1H NMR (DMSO) δ of 2.34 (3H, s), of 6.66 (1H, s), 7,53 (1H, d), 7,84,(1H, d), 8,32 (2H, d), to 8.70 (2H, d); MS 309,6 (M+H)+.

Example 399 (5-Methyl-2H-pyrazole-3-yl)-(2-phenylpyrimido[3,4-d]-pyrimidine-4-yl)amine (IV-30): TPL 225°C;1H NMR (DMSO) δ to 2.35 (3H, s), for 6.81 (1H, s), 7,50-7,63 (3H, m), 8,45-charged 8.52 (2H, m), 8,54 (1H, d), to 8.62 (1H, d), 9,20 (1H, s), 10,79 (1H, s), 12,38 (1H, users); IR (solid) 2958, 2917, 2852, 1593, 1565, 1524, 1467, 1450; MS 303,2 (M+H)+.

Example 400 (5-Methyl-2H-pyrazole-3-yl)-(2-phenylpyrimido[2,3-d]-pyrimidine-4-yl)amine (IV-31): To a solution of 4-chloro-2-phenylperhydro-[2,3-d]pyrimidine (J. Pharm. Belg., 29, 1974, 145-148) (109 mg, 0.45 mmol) in THF (15 ml) was added 3-amino-5-methylpyrazole (48 mg, 0.5 mmol) and the resulting mixture was heated at 65°With during the night. The mixture was cooled to room temperature and obtained the second suspension was filtered and washed with Et 2O. the Solid was dissolved in a mixture of EtOH-water and the pH was brought to pH 7. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuum. The residue was purified flash chromatography (SiO2the gradient mixture DHM(DCM)-Meon) to obtain compound IV-31 in the form of not-quite-white solid (69 mg, 50%): TPL 234°C;1H NMR (DMSO) δ and 2.14 (3H, s), of 5.99 (1H, s), 7,20-7,40 (3H, m), 7,40-to 7.50 (3H, m), 8, 60 (1H, d), 8,79 (1H, d), 12,82 (1H, users); IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303,2 (M+H)+.

Example 401 (5-Cyclopropyl-2H-pyrazole-3-yl)-(2-phenylpyrimido[3,4-d]pyrimidine-4-yl)amine (IV-32): Not quite white solid, TPL 232-233°;1H NMR (DMSO) δ 0,70-0,85 (2H, m), 0,90-of 1.05 (2H, m), 1,05-2,07 (1H, m), of 6.75 (1H, s), 7,50 to 7.75 (3H, m), 8,40-8,70 (4H, m), 9,20 (1H, s)10,80 (1H, s), 12,41 (1H); IR (solid) 3178, 1601, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781, 667; MS 329,2 (M+H)+.

Example 402 [2-(4-Methylpiperidin-1-yl)purine-4-yl]-(5-methyl-2H-pyrazole-3-yl)amine (IV-33): To a suspension of 2,4-dichloropurine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 ml) was added 5-methyl-1H-pyrazole-3-ylamine (2,05 g of 21.2 mmol). The resulting mixture was stirred at room temperature for 48 hours. The precipitate was collected by filtration, washed with ethanol and dried in vacuum to obtain 1,524 g (yield 58%) (2-globulin-4-yl)-(5-methyl-1H-pyrazole-3-yl)amine, which is used without the optional purification in the next stage. To a solution of (2-globulin-4-yl)-(5-methyl-1H-pyrazole-3-yl)amine (200 mg, 0.80 mmol) was added 4-methylpiperidine (4 ml, 8,01 mmol) and the reaction mixture is boiled under reflux during the night. The solvent evaporated and the residue was dissolved in a mixture of EtOH-water (1:3, 4 ml). Was added potassium carbonate (57 mg, 0.41 mmol) and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (2 times) and Et2O (2 times) to give compound IV-33 as a white solid (225 mg, 90%): TPL >300°C;1H NMR (DMSO) δ of 0.91 (3H, d), 1,10 (2H, m), of 1.65 (3H, m), 2,24, (3H, s)2,84 (2H, m), 4,60 (2H,m), 6,40 (1H, s), 7,87 (1H, m), 9,37-9,59 (1H, m), a 12.03-KZT 12.39, (2H, m); IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313,3 (M+H)+.

Example 403 (5-Cyclopropyl-2H-pyrazole-3-yl)-[2-(4-methylpiperidin-1-yl)pyrrolo[3,2-d]pyrimidine-4-yl]amine (IV-34): white solid;1H NMR (DMSO) δ of 0.65 (2H, m), 0,91-0,96 (5H, m)a 1.08 (2H, m), 1,58-of 1.64 (3H, m), 1,89 (1H, m), 2,77 (2H, t), of 4.57 (2H, d), 6,09 (1H, s)6,38 (1H, s), 7,33 (1H, s), 9,42 (1H, s), 10,65 (1H, s), 12,02 (1H, users); MS 338,3 (M+H)+.

Example 404 [6-Benzyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (IV-35):1H NMR (500 MHz, DMCO-d6): δ 13,0 (s, 1H), 10,4 (with, of user. 1H), 9,73(s, 1H, TFA-OH), of 8.00 (d, 2H), to 7.64 (m, 2H), to 7.59 (DD, 1H), 7,52 (m, 3H), 7,41 (t, 1H), 7,31 (m, 3H), 7,14 (DD, 1H), 4,58 (s, 2H), 4,35 (UserN), 3,74 (m, 2H), 3,17 (s, 2H) ppm; MS (ES+): m/e=451,30 (M+H); HPLC-method A, Tret2,96 minutes

When the EP 405 (5-fluoro-1H-indazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-yl)amine (IV-36): Obtained from compound IV-35 (0.13 mmol) by treatment with an equal weight of Pd/C (10%) 4.4% HCOOH in the Meon at room temperature for 12 hours. The mixture was filtered through celite, the filtrate evaporated and the crude product was purified by HPLC to obtain compound IV-36 in the form of a yellow solid with a yield of 35%.1H NMR (500 MHz, DMCO-d6): δ 12,9 (s, 1H), 9,06 (s, 1H), to 7.99 (d, 2H), EUR 7.57 (DD, 1H), 7,34 (m, 1H), 7,28 (m, 3H), 7,22 (d, 1H), 3,83 (s, 2H), 3,05 (m, 2H), 2,72 (m, 2H) ppm; MS (ES+): m/e=361,20 (M+H); HPLC-method A, Tret2,68 minutes

Example 406 (5-Methyl-2H-pyrazole-3-yl)-(3-phenylisoxazole-1-yl)amine (V-1): To a solution of 1-chloro-3-phenylethylamine (J. Het. Chem., 20, 1983, 121-128) (0.33 g, 1.37 mmol) in DMF (anhydrous, 5 ml) was added 3-amino-5-methylpyrazole (0.27 g, is 2.74 mmol) and potassium carbonate (0,57 g of 4.13 mmol) and the resulting mixture was boiled under reflux for 6 hours. Then the reaction mixture was cooled and was removed in vacuum solvent. The residue was extracted twice with ethyl acetate and the combined organic layers were washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified flash chromatography (SiO2the gradient mixture DHM-Meon) to give compound V-1 as a colorless oil:1H NMR (MeOD) δ of 2.23 (3H, s), 5,61 (1H, s), 7,41 (1H, m), 7,52(2H, m), a 7.62(1H, m), 7,81(1H, m), 8,07(1H, d), 8,19(2H, m), 8,29(1H, s), 8,54 (1H, d); MS 301,2 (M+H)+.

Example 407 (1H-Indazol-3-yl)-[3-(2-triptoreline)isoquinoline-1-yl]amine (V-2): a Solution of 1-chloro-3-(2-triptoreline)isoquinoline (100 mg, 0,326 mmol) and 1H-indazol-3-ylamine (mg, 0,651 mmol) in ethanol (3 ml) was heated at 160°and evaporated with a stream of nitrogen the solvent. The remaining oil was then heated at 160°C for 18 hours under nitrogen atmosphere. The resulting melt was dissolved in a mixture of 5% methanol-dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (1 x 25 ml) and then dried over magnesium sulfate. Purification by chromatography on silica gel (mixture of 25-50% hexanitrate) gave compound V-2 as a yellow solid (35 mg, 27%).1H NMR (500 MHz, DMCO-d6): δ 9,78 (users, 1H), to 8.62 (d, 1H), 7,9-a 7.85 (m, 1H), 7,78-7,72 (m, 1H), 7,70-to 7.68 (m, 1H), 7,65 to 7.62 (m, 1H), 7,60-of 7.55 (m, 1H), 7,52 was 7.45 (m, 3H), 7,41-7,38 (m, 1H), 7,28-7,25 (m, 1H), 7,18 (s, 1H), 6,95-6,92 (m, 1H), USD 5.76 (s, 1H); LC-MS (ES+) m/e=405,18 (M+H); HPLC-method D Rt2,74 minutes

Example 408 (5,7-Debtor-1H-indazol-3-yl)-[3-(2-triptoreline)isoquinoline-1-yl]amine (V-3): Compound V-3 obtained from 5,7-debtor-1H-indazol-3-ylamine as in the form of a yellow solid (90 mg, 63%).1H NMR (500 MHz, DMCO-d6): δ 13,25 (s, 1H), 9,92 (users, 1H), 8,61 (d, 1H), 7,9 (d, 1H), 7,81-7,49 (m, 6H), 7,26 to 7.2 (m, 2H), 7,12-7,10 (m, 1H); LC-MS (ES+) m/e=441,16 (M+H); HPLC-method e, Rtto 3.58 min

Example 409 (5-Methyl-2H-pyrazole-3-yl)-(2-phenylindolin-1-yl)amine (V-4): To a mixture of 4-chloro-2-phenylindolin (J. Het. Chem., 20, 1983, 121-128) (0,53 g, 2.21 mmol) in diphenyl ether (5 ml) was added 3-amino-5-methylpyrazole (0,43 g, was 4.42 mmol) and the resulting mixture was heated at 200°With over night with stirring. The reaction is ionic mixture was cooled to ambient temperature, then was added petroleum ether (20 ml) and the precipitate was removed by filtration. The crude solid was purified flash chromatography (SiO2the gradient mixture DHM-Meon) to give compound V-4 as a white solid: TPL 242-244°;1H NMR (DMCO): δ and 2.27(3H, s), of 6.02(1H, s), 7,47(2H, d), 7,53-7,40(2H, osirm), to 7.67(1H, m), 7,92(1H, m), of 8.09(2H, d), 8,48(2H, m), 9,20(1H, s), 12,17 (1H, users); IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301,2 (M+H)+.

Example 410 (1H-Indazol-3-yl)-(2-phenylindolin-4-yl)amine (V-5):1H NMR (500 MHz, DMCO-d6): δ 12,78 (s, 1H), 9,50 (s, 1H), 8,65 (d, 1H), 8,15 (s, 1H), 8,04-7,98 (m, 3H), 7,94 (s, 1H), 7,78 to 7.75 (m, 1H), 7,60-7,40 (m, 6H), 7,15-7,10 (m, 1H), LC-MS (ES+) m/e=337,11 (M+H); HPLC-method e, Rt2,10 minutes

Example 411 (2-Phenylindolin-4-yl)-(1H-pyrazolo[4,3-b]pyridine-3-yl)amine (V-6):1H NMR (500 MHz, DMCO-d6): δ to 13.6 (s, 1H), and 11.4 (s, 1H), to 8.94 (d, 1H), 8,61 (DD, 1H), 8,23 (d, 1H), 8,16 (DD, 1H), 8,12 (t, 1H), 7,89 (t, 1H), 7,86 (d, 1H), 7,65 (m, 4H), 7,54 (s, 1H), 7,52 (DD, 1H) ppm; MS (ES+): m/e=338,11 (M+H); HPLC-method A HPLC-method e, Rt2.91 in minutes

Example 412 (1H-Indazol-3-yl)-[2-(2-triptoreline)quinoline-4-yl]amine (V-7):1H NMR (500 MHz, DMCO-d6): δ 12,68 (s, 1H), 9,51 (s, 1H), 8, 7 (d, 1H), 7.95 is-7,89 (m, 2H), 7,83-of 7.70 (m, 3H), 7.68 per to 7.62 (m, 2H), 7,60 (s, 1H), 7,55-7,52 (m, 1H), 7,49 was 7.45 (m, 1H), 7,40-7,37 (m, 1H), 7,12-to 7.09 (m, 1H); LC-MS (ES+) m/e=405,15 (M+H); HPLC-method D Rtof 2.25 minutes

Example 413 (5,7-Daftar-1H-indazol-3-yl)-[2-(2-triptoreline)quinoline-4-yl]amine (V-8):1H NMR (500 MHz, DMCO-d6) δ 1331 (, 1H), 9,49 (s, 1H), 8,70-8,67 (m, 1H), of 7.96-7,92 (m; 1H), a 7.85-7,66 (m, 7H), 7,63-of 7.60 (m, 1H), 7,42-7,40 (m, 1H), LC-MS (ES+) m/e=441,18 (M+H); HPLC-method D Rt2,39 minutes

Example 414 [2-(2-Triptoreline)quinoline-4-yl]-(1H-pyrazolo-[4,3-b]pyridine-3-yl)amine (V-9):1H NMR (500 MHz, DMCO-d6) δ to 13.6 (s, 1H), 11,6 (with, of user., 1H), 8,98 (d, 1H), to 8.57 (DD, 1H), 8,12 (m, 3H), of 7.97 (m, 2H), 7,86 (m, 3H), 7,49 (DD, 1H), 7.23 percent (s, 1H) ppm; MS (ES+): m/e=406,20 (M+H); HPLC-method A, Rt2.91 in minutes

Example 415 (2-Phenylpyrazole-4-yl)-(2H-[1,2,4]triazole-3-yl)amine (IX-154): not quite white solid, TPL 266-267°With:1H NMR (DMCO) δ 7,50-of 7.70 (4H, m), a 7.85-of 8.00 (2H, m), 8,15-of 8.25 (2H, m), of 8.37-to 8.45 (2H, m), 8,58 (1H, d), 13,90 (1H, users); IR (solid) 3344, 3059, 1630, 1609, 1570, 1557, 1543, 1501, 1495, 1445, 1411, 1355, 1326, 1267, 1182, 1053, 1038, 760, 676, 667, 654; MS 289,2 (M+H)+.

Example 416 (5-Methyl-2H-[1,2,4]triazole-3-yl)-(2-phenylpyrazole-4-yl)amine (IX-155):1H NMR (500 MHz, DMCO-d6) δ 8,59 (s, 1H), 8,42 (d, J=6,7 Hz, 2H), 7,79 (m, 4H), 8,03 (m, 2H), 7,74 (m, 4H), of 2.51 (s, 3H) ppm; MS (ES+): m/e=303,08 (M+H); HPLC-method A, Rt2,64 minutes

Example 417 (2H-[1,2,4]-triazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (IX-47): pale yellow solid (yield 52%):1H NMR (500 MHz, DMCO-d6) δ 8,54 (s, 1H), 8,15 (with, of user., 1H), to $ 7.91 (t, 1H), a 7.85 (m, 2H), 7,76 (m, 3H), 7,66 (t, 1H) ppm; MS (ES+): m/e=357,13 (M+H); (ES-): m/e=355,15 (M-H); HPLC-method A, Rt2,81 minutes

Example 418 (5-Methyl-2H-[1,2,4]triazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (IX-38): pale yellow solid (yield 54%):1H NMR (500 MHz, DMCO-d6 ) δ 8,44 (with, of user., 1H), 7,92 (m, 3H), to 7.84 (m, 1H), to 7.77 (m, 2H), 7,68 (t, 1H), 2,28 (s, 3H) ppm; MS (ES+): m/e=371,14 (M+H); (ES-): m/e=369,18 (M-H); HPLC-method A, Rt2,89 minutes

Example 419 (5-Methylsulfanyl-2H-[1,2,4]triazole-3-yl)-[2-(2-triptoreline)hinzelin-4-yl]amine (IX-156): pale yellow solid (yield 65%):1H NMR (500 MHz, DMCO-d6) δ 8,56,(OSiR., 1H), of 7.90 (t, 1H),to 7.84 (m, 2H), 7,78 (m, 2H), to 7.67 (m, 2H), of 2.51 (s, 3H, hidden DMCO) ppm; MS (ES+): m/e=403,12 (M+H); (ES-): m/e=401,16 (M-H); HPLC-method A, Rt3,20 minutes

Example 420 (1H-[1,2,4]Triazole-3-yl)-[3-(2-triptoreline)isoquinoline-1-yl]amine (IX-175): a Solution of 1-chloro-3-(2-triptoreline)isoquinoline (0,326 mmol) and 1H-[1,2,4]triazole-3-ylamine (0,651 mmol) in ethanol (3 ml) was heated at 160°and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160°C for 18 hours under nitrogen atmosphere. The resulting melt was dissolved in a mixture of 5% methanol-dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (1 x 25 ml) and then dried over magnesium sulfate. Purification by chromatography on silica gel gave compound IX-175 in the form of a colorless oil (yield 4%).1H NMR (500 MHz, DMCO-d6) δ 9,18 (d, 1H), 8,82 (s, 1H), of 7.90 (d, 1H), 7,85 to 7.75 (m, 3H), 7,71-7,52 (m, 3H), 7,60-of 7.55 (m, 2H), 4,42 is 4.35 (m, 1H), LC-MS (ES+) 356,16 (M+H); HPLC-method e, Rt3,55 minutes

Example 421 (2-Phenylindolin-4-yl)-(1H-[1,2,4]triazole-3-yl)amine (IX-176): pale yellow solid (30%yield):1H NMR (500 MHz, DMCO-d6) B4; 13,82 (s, 1H), to 9.91 (s, 1H), 8,80 (s, 1H), 8,70-8,65 (m, 1H), 8,55 (s, 1H), 8,15-to 8.12 (m, 2H), 8,03-7,98 (m, 1H), 7,75-7,72 (m, 1H), EUR 7.57-7,49 (m, 3H), LC-MS (ES+) m/e=288,11 (M+H); HPLC-method e, Rt1,55 minutes

Example 422 (1H-[1,2,4]Triazole-3-yl)-[2-(2-triptoreline)quinoline-4-yl]amine (IX-177): pale yellow solid (yield 46%):1H NMR (500 MHz, DMCO-d6) δ 13,70 (s, 1H), 9,98 (s, 1H), to 8.70 (d, 1H), 8,49 (s, 1H), 8,30,(s, 1H), 7,94-7,88 (m, 2H), 7,80-to 7.68 (m, 3H), of 7.64-7,56 (m, 2H), LC-MS (ES+) m/e=356,18 (M+H); HPLC-method e, Rt1,68 minutes

Example 423 (1H-Indazol-3-yl)-[5-methyl-6-morpholine-4-yl-2-(2-triptoreline)pyrimidine-4-yl]amine (II-251): Colorless film, the yield of 2%:1H NMR (500 MHz, DMCO-d6) δ to 7.84 (m, 2H), 7,71 (m, 3H), 7,41 (t, 2H), 7,14 (m, 1H), 3,74 (m, 4H), of 3.69 (m, 4H), 1,24 (s, 3H) ppm; HPLC-method A, Rt3,26 min; MS (FIA) 455,1 (M+H).

BIOLOGICAL TESTS

The activity of compounds as inhibitors of protein kinases can be determined in vitro, in vivo and in cell lines. In vitro studies include methods for determining inhibition fosforiliruyusciye activity or ATPase activity of activated protein kinase. Alternate in vitro tests provide a quantitative determination of the ability of the inhibitor to contact the protein kinase. The binding of the inhibitor can be measured by tagging inhibitor radioactive labels before binding, separation of the complex of the inhibitor-protein kinase and determine the number of associated radioactive labels. In choosing the accordance with another variant of the binding of the inhibitor can be determined by comparative experiment where new inhibitors are incubated with a protein kinase that is associated with the famous radio.

EXAMPLE 1 BIOLOGICAL TESTS

DEFINITIONiFOR inhibition of GSK-3

Compounds were tested for their ability to inhibit the activity of GSK-3β (AA 1-420), using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). The reaction was performed in a solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 300 μm NADH, 1 mm DTT and 1.5% DMSO. The final substrate concentration in the sample was 20 μm ATP (Sigma Chemicals, St Louis, MO) and 300 μm peptide (HSSPHQS(PO3H2)EDEEE, American Peptide, Sunnyvale, CA). The reaction was carried out at 30°and 20 nm GSK-3β. The final concentrations of the components of the coupled enzyme system were 2.5 mm phosphoenolpyruvate, 300 μm NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

Prepare the source buffer solution for testing, containing all of the above reagents except for ATP and interest of the test compounds. The original buffer solution (175 μl) were incubated in 96-well-plate with 5 μl of the person of the test compounds at final concentrations in the range of 0.002 to 30 μm at 30°C for 10 minutes. Usually held a 12-point titration, preparing serial dilutions (from 10 mm solutions of the starting compounds) by DMSO subjects is of soedinenii in the child tablets. The reaction was initiated by adding 20 μl of ATP (final concentration 20 μm). Using reader for tablets Molecular Devices Spectramax (Sunnyvale, CA), received a response speed for 10 minutes at 30°C. According to the speed determined values of Kidepending on the concentration of the inhibitor.

The following connections mattered Toiless than 0.1 μm for GSK-3: compounds II-1, II-105, II-33, II-34, II-36, II-39, II-38, II-39, II-40, II-41, II-42, II-46, II-57, II-59, II-60, II-61, II-62, II-63, II-64, II-66, II-67, II-69, II-70, II-53, II-71, II-99, II-73 II-74 II-75 II-76 II-77, II-7, II-8, II-9, II-10, II-24, II-19, II-78, II-54, II-79, II-80, II-81, II-82, II-83, II-84, II-56, II-86, II-20, II-25, II-26, II-85, II-21, II-27, II-28, II-87, II-88, II-29, II-11, II-12, II-30, II-31, II-13, II-14, II-15, II-16, II-17, II-18, II-79, II-23, II-2, II-90, II-91, II-92, II-93, II-3, II-4, II-5, II-6, II-94 II-95 II-96, II-107 II-108 II-109 II-110, II-124 II-125, II-111 II-112 II-113 II-114 II-115 II-116 II-117, II-118 II-119 II-120 II-121; II-208, III-8, III-7, III-9, III-37, III-38, III-39, III-40, III-42, III-45, III-46, III-47, III-48, III-49 III-51 III-52 III-53 III-54 III-55 III-56 III-57 III-58 III-59 III-60 III-61, III-62, III-63, III-30, III-65 III-66 III-67 III-70 III-73, III-31, III-75 III-76 III-77 III-33, III-34, III-106 III-108 III-109, III-111 III-35, III-116 III-117 III-118 III-119 III-120 III-121, III-127 III-128 III-141, III-130 and III-131, IV-15, IV-16, IV-17, IV-20, IV-25, IV-26, IV-30, IV-34, V-3 and IX-47.

The following connections mattered Toibetween 0.1 and 1.0 μm for GSK-3: compounds II-103, II-104, II-35, II-44, II-45, II-49, II-50, II-97, II-101, II-22, II-32, III-41, III-43, III-44, III-28, III-50, III-29, III-64, III-71, III-74, III-78 III-82 III-88, III-90, III-102 III-105 III-107, III-110, III-112 III-114, III-115 III-122 III-124, III-124, IV-1, III-l, III-138, III-140 III-142 III-129 III-132, III-134 III-135, III-136, IV-1, IV-10, IV-11, IV-12, IV-13, IV-14, IV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV-6, IV-7, IV-8, IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V-7, IX-38, IX-154 and IX-177.

The following connections mattered Toibetween 1.0 and 20 μm for GSK-3: compounds II-43, II-65, II-48, II-47, II-51, II-68, II-52, II-72, II-100, II-98, II-89, III-68, III-81 III-83 III-91 III-94 III-95 III-96 III-97 III-98 III-99 III-100, III-101, III-103, III-123 III-137, III-139 III-143, III-145, III-146, V-4, V-8, IX-156 and IX-176.

EXAMPLE 2 BIOLOGICAL TESTS

DEFINITIONiFOR inhibition of AURORA-2

Compounds were tested following manner for their ability to inhibit the activity of AURORA-2, using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249).

To the original buffer solution for analysis, containing 0.1 M HEPES (pH 7.5), 10 mm MgCl2, 1 mm DTT, 25 mm NaCl, 2.5 mm of phosphoenolpyruvate, 300 μm NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mm ATP, and 800 μm peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added to a solution of the compound of the present invention in DMSO to a final concentration of 30 μm. The resulting mixture was incubated at 30°C for 10 minutes. The reaction was initiated by adding 10 ál of a solution of AURORA-2 to obtain a final concentration of 70 nm in the sample. Using reader for tablets BioRad Ultramark (Hercules, CA), received the reaction rate by monitoring the absorbance at 340 nm for 5 minutes read at 30°C. By Dan the output speed determined values of K idepending on the concentration of the inhibitor.

The following connections mattered Toiless than 0.1 μm for AURORA-2: compound II-33, II-34, II-36, II-37, II-40, II-41, II-55, III-7, III-9, III-37, III-38, III-39, III-40, III-41, III-42, III-44, III-45, III-46, III-47, III-48, III-49, III-50, III-51 III-52 III-53 III-54 III-55 III-56 III-57 III-59 III-60 III-61, III-63, III-30, III-65 III-66 III-67 III-70 III-31, III-76 III-77 III-78 III-80, III-32, III-33, III-34, III-106 III-108, III-109 III-110, III-111 III-112 III-114, III-35, III-115 III-116 III-117 III-118 III-119 III-120 III-121, IV-7, IV-30, IV-32 IV-34.

The following connections mattered Toibetween 0.1 and 1.0 μm for AURORA-2: compounds II-1, II-105, II-35, II-38, II-39, II-42, II-64, II-70, II-53, II-99, II-77, II-79, II-86, II-20, II-93, II-94, III-28, III-58, III-64, III-71, III-73 III-74, III-75, III-102 III-105 III-107, III-113 III-124, III-1, III-130, IV-1, IV-3, IV-4, IV-6, IV-29, IV-33 and V-4.

The following connections mattered Toibetween 1.0 and 20 μm for AURORA-2: compounds II-103, II-104, II-57, II-59, II-61, II-63, II-67, II-69, II-75, II-76, II-10, II-19, II-78, II-54, II-80, II-82, II-21, II-90, II-91, II-96, II-107, III-68, III-79, III-82 III-101, III-103, III-127 III-141, III-129 III-132, IV-31, V-2, IX-47, IX-154 and IX-177.

EXAMPLE 3 BIOLOGICAL TESTS

TEST FOR INHIBITION of CDK-2

Compounds were tested following manner for their ability to inhibit the activity of CDK-2, using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249).

To the original buffer solution for analysis, containing 0.1 M HEPES (pH 7.5), 10 mm MgCl2, 1 mm DTT, 25 mm NaCl, 2.5 mm of phosphoenolpyruvate, 300 μm NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lacquer is aldehydogenic, 100 mm ATP and 100 μm peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added to a solution of the compound of the present invention in DMSO to a final concentration of 30 μm. The resulting mixture was incubated at 30°C for 10 minutes.

The reaction was initiated by adding 10 μl of the original solution CDK-2/Cyclin a final concentration of 25 nm in the sample. Using reader for tablets BioRad Ultramark (Hercules, CA), received the reaction rate by monitoring the absorbance at 340 nm for 5 minutes read at 30°C. According to the speed determined values of Kidepending on the concentration of the inhibitor.

EXAMPLE 4 BIOLOGICAL TESTS

TEST FOR INHIBITION of ERK

Compounds were tested for inhibition of ERK2 by spectrophotometric analysis of the coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). When this analysis was incubated with a fixed concentration of activated ERK2 (10 nm) with different concentrations of compounds in DMSO (2.5%) for 10 minutes at 30°C in 0.1 M HEPES buffer (pH 7.5)containing 10 mm MgCl2, 2.5mm phosphoenolpyruvate, 200 μm NADH, 150 μg/ml pyruvate kinase, 50 μg/ml lactate dehydrogenase and 200 μm peptide Arctic. The reaction was initiated by addition of 65 μm ATP. Controlled the rate of decline in absorbance at 340 nm. According to the speed is estimated IC 50depending on the concentration of the inhibitor.

The following connections mattered Toi<1 μm for ERK-2: III-109, III-111 III-115 III-117 III-118 III-120, IV-4.

The following connections mattered Toibetween 1 μm and 12 μm for ERK-2: III-63, III-40, III-108.

EXAMPLE 5 BIOLOGICAL TESTS

TEST FOR INHIBITION of the ACT

Compounds were tested for their ability to inhibit the ACT of using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). The tests were carried out in a mixture of 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mm DTT and 1.5% DMSO. The final substrate concentration in the sample was 170 μm ATP (Sigma Chemicals) and 200 μm peptide (RPRAATF, American Peptide, Sunnyvale, CA). The test was carried out at 30°and 45 nm ACT. The final concentrations of the components of the coupled enzyme system were 2.5 mm phosphoenolpyruvate, 300 μm NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

Prepare the source buffer solution for testing, containing all of the above reagents except the ACT, DTT and interest of the test compounds. The original buffer solution (56 ml) was placed in a 384-well plate, and then added 1 μl of 2 mm initial solution in DMSO containing the test compound (final concentration 30 μm). The tablet was subjected to pre-incubation for about 10 minutes n and 30° And then initiated the reaction by adding 10 ál of enzyme (final concentration of 45 nm) and 1 mm DTT. Using reader for tablets BioRad Ultramark (Hercules, CA), received a response speed for 5 minutes read at 30°C. Compounds showed more than 50% inhibition in comparison with the standard wells containing the mixture for analysis and DMSO without test compounds were titrated to determine the values IC50.

EXAMPLE 6 BIOLOGICAL TESTS

TEST FOR INHIBITION of SRC

Compounds were evaluated as inhibitors of Src kinase person using radioactive method of analysis or spectrophotometric method.

Test And inhibition of Src: Radioactive method of analysis

Compounds were tested as inhibitors of recombinant human Src kinase full length (Upstate Biotechnology, cat. No. 14-117), expressed and purified from rod-shaped viral cells. The activity of Src kinase was examined after incorporation33P from ATP to tyrosine arbitrary poly Glu-Tyr polymer substrate composition, Glu:Tyr=4:1 (Sigma, cat. No. p-0275). The final concentration of the components for analysis were as follows: 0.05 M HEPES (pH 7,6), 10 mm MgCl2, 2 mm DTT, 0.25 mg/ml BSA (BSA), 10 μm ATP (1-2 µci33P-ATP per reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of recombinant human Src kinase. Under normal tested by the Institute of all components of the reaction mixture except for ATF pre-mixed and Liquefiable in wells for testing. To the wells were added inhibitors dissolved in DMSO to obtain final concentration of DMSO equal to 2.5%. Tablet incubated at 30°C for 10 minutes, after which initiated the reaction by adding33P-ATP. After 20 minutes the reaction was suppressed by the addition of 150 ál of 10% trichloroacetic acid (TCA)containing 20 mm Na3PO4. The quenched samples then were transferred to 96-well filter plate (Whatman, glass fiber filter UNI-Filter GF/F, cat. No. 7700-3310), mounted on a vacuum manifold to the filter plate. The filter plate was washed 4 times with 10% TCA containing 20 mm Na3PO4and then 4 times with methanol. Then to each well was added 200 μl of scintillation fluid. Plate hermetically closed and determined the amount of radioactivity associated with the filters on a TopCount scintillation counter. Incorporated radioactivity was depicted in the form of a graph depends on the concentration of the inhibitor. Data were agreed with the comparative model of the kinetics of inhibition of obtaining values Forifor the connection.

Test for inhibition of Src: spectrophotometric method

Determined the amount of ADP derived from ATP catalyzed by recombinant human Src kinase phosphorylation of poly Glu-Tyr substrate, using paired EN zymes the Noah system (Fox et al. (1998) Protein Sci. 7, 2249). In this method, one molecule of NADH oxidized to NAD for each molecule of ATP obtained in the kinase reaction. The disappearance of NADH can be conveniently traced at 340 nm.

The final concentration of the components for analysis were as follows: 0.025 M HEPES (pH 7,6), 10 mm MgCl2, 2 mm DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nm of recombinant human Src kinase. The final concentrations of the components of the coupled enzyme system were as follows: 2.5mm phosphoenolpyruvate, 200 μm NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

Under normal test all components of the reaction mixture except for ATF pre-mixed and Liquefiable in wells for testing. To the wells were added inhibitors dissolved in DMSO to obtain final concentration of DMSO equal to 2.5%. Tablet incubated at 30°C for 10 minutes, after which initiated the reaction by addition of 100 μm ATP. On the reader for tablets recorded the change in time absorbance at 340 nm, i.e. the reaction rate. The resulting data rate as a function of the concentration of the inhibitor was agreed with the comparative model of the kinetics of inhibition of obtaining values Forifor the connection.

The following connections mattered Toi<100 nm for Src: III-31 III-32 III-33 III-34 III-35, III-47, III-65 III-66 III-37, II-38, III-39, III-40, III-42, III-44, III-48, III-49, III-70, III-45, III-78 III-76 and IV-32.

The following connections mattered Toibetween 100 nm and 1 μm for Src: III-63, III-71, III-75 III-73, III-72, III-74, III-80, III-50, IV-30.

The following connections mattered Toibetween 1 μm and 6 μm for Src: III-79, IV-1 and IV-31.

The above was presented a number of embodiments of the present invention, but it is obvious that the basic structure can be modified for other options, using the compounds and methods of the present invention. Therefore, it is clear that the scope of the present invention is defined by the points of the attached claims rather than specific options, which are presented as an example.

1. Derivatives of pyrazole of the formula II

or its pharmaceutically acceptable salt, where

ring selected from phenyl or pyridinoline rings, where the specified ring C has one or two substituent in the ortho-position, independently selected from R1and any delegate of Porto-position in the ring is independently and optionally substituted by the radical R5and two neighboring substituent in the ring With optional together with the intermediate atoms with the formation of the phenyl ring;

R1selected from halogen; -CN; -HE; phenyl; C1-6aliphatic group of neobythites is but substituted with halogen; -O-C1-6the alkyl, optionally substituted with halogen; or C(=O)1-6of alkyl; or R1and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

Rxand Ryindependently selected from T-R3; or Rxand Rytogether with the intermediate atoms with the formation of condensed unsaturated or partially unsaturated 5-8-membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Rythat includes the nitrogen atom, optionally substituted by exography, -O(C1-6alkyl)om, -S(C1-6alkyl)om or NH2; and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Ry, optionally substituted benzyl group; and any substitutable carbon atom in the benzene ring formed by Rxand Ryoptionally substituted C1-6the alkyl, N(R7)2or-O(C1-6by alkyl), optionally substituted amino group;

T is a bond;

R2and R2'independently selected from hydrogen, HE, WITH1-6of alkyl, phenyl, cyclopropyl, teinila, Shrila or-T-W-R6or R2and R2' combined together with the intermediate atoms, form a condensed 6-membered unsaturated or partially unsaturated ring having 0-2 ring heteroatoms selected from nitrogen, where each substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'optionally substituted with halogen, exography, NO2, NH2, pirrallo, CO2(C1-6alkyl)om or1-6the alkyl, optionally substituted with halogen; and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2', optionally substituted by a radical of the phenyl;

R3selected from hydrogen; halogen; -CN; -N(R4)2; -SO2NH2; phenyl, optionally substituted with halogen; phenoxy; pyridyl; imidazolyl; C1-6the alkyl, optionally substituted N(R4)2or NHSO2(C1-6alkyl)om; cyclohexyl, optionally substituted by N(R4)2or NHSO2(C1-6alkyl)om; morpholinyl, piperidinyl, or piperidinyl or piperazinil, where the above-mentioned morpholinyl, piperidinyl, or piperazinil optionally substituted C1-6the alkyl, O-phenyl, -C(=O)C1-6by alkyl, -CO2(C1-6alkyl)-phenyl, or-SO2(C1-6alkyl)om;

each R4independently selected from C1-6of alkyl, -C(=O)1-6alkyl, -CO2(C1-6alkyl)-phenyl, or CH2phenyl;

each R5independently selected from-C1-6the alkyl, optionally substituted with halogen, halogen, -O-C1-6the alkyl-, NH2and-NO2; or R5and neighboring Deputy, together with the intermediate atoms, comprise the specified ring condensed with the ring;

W represents-C(R6)2O-, -CO2-, or-CON(R6)-;

each R6independently selected from hydrogen or C1-4of alkyl;

each R7independently selected from hydrogen or C1-4aliphatic group, optionally substituted NH2or NH(C1-6by alkyl); or two R7at the same nitrogen atom together with the nitrogen atom with the formation of morpholinyl or piperazine ring, optionally substituted C1-6the alkyl.

2. The compound according to claim 1, where the specified connection has one or more characteristics selected from a group including:

(a) the ring is a phenyl or pyridinoline ring, optionally substituted by a group-R5and when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is raftiline or hyalinella ring;

(b) Rxis Soboh is hydrogen or C 1-4alkyl group, and Ryis a T-R3or Rxand Rytaken together with the intermediate atoms, form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogen atom; and any substitutable carbon atom in the specified condensed ring Rxand Ryformed by the radicals Rxand Rythat includes the nitrogen atom, optionally substituted by exography, -O(C1-6alkyl)om, -S(C1-6alkyl)om or NH2; and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Ry, optionally substituted benzyl group; and any substitutable carbon atom in the benzene ring formed by Rxand Ryoptionally substituted C1-6the alkyl, N(R7)2or-O(C1-6by alkyl), optionally substituted amino group;

(c) R1is a halogen; C1-6aliphatic group, optionally substituted with halogen; phenyl; -C(=O)1-6alkyl; -O(C1-6alkyl; or-CN and

(d) R2'represents hydrogen and R2represents hydrogen, phenyl, thienyl, furyl, C1-6alkyl, or cyclopropyl; or R2and R2'taken together with the intermediate atoms, form a substituted or unsubstituted benzene, pyridine, PI is imaginova or partially unsaturated 6-membered carbocyclic ring, where each substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2'optionally substituted with halogen, exography, -NO2, -NH2, pirrallo, -CO2(C1-6alkyl)om or-C1-6the alkyl, optionally substituted with halogen; and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Ry, optionally substituted phenyl.

3. The compound according to claim 2, where

(a) the ring is a phenyl or pyridinoline ring, where the aforementioned ring is optionally substituted by a group-R5or ring C and two adjacent substituent in it form a bicyclic ring system selected from afternova or rhinolining rings;

(b) Rxrepresents hydrogen or C1-4alkyl, and Ryis a T-R3; or Rxand Rytaken together with the intermediate atoms, form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogen atom; and any substitutable carbon atom in the specified condensed ring formed by the radicals Rxand Rythat includes the nitrogen atom, optionally substituted by exography, -O(C1-6alkyl)om, -S(C1-6alkyl)om or NH2; and any substitutable nitrogen atom in kasanakalle, formed by the radicals Rxand Ry, optionally substituted benzyl group; and any substitutable carbon atom in the benzene ring formed by Rxand Ry, optionally substituted C1-6the alkyl, N(R7)2or-O(C1-6by alkyl), optionally substituted amino group;

(c) R1represents halogen, optionally substituted with halogen With1-6aliphatic group, phenyl, -C(=O)1-6alkyl, -OS1-6alkyl, -HE or-CNH and

(d) R2'represents hydrogen and R2represents hydrogen, phenyl, thienyl, furyl,1-6alkyl or cyclopropyl or R2and R2'taken together with the intermediate atoms, form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, where each substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2', optionally substituted with halogen, exography, -NO2, -NH2, pirrallo, -CO2(C1-6alkyl)om or1-6the alkyl, optionally substituted with halogen; and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Ry, optionally substituted phenyl.

4. The compound according to claim 2, where the specified connection has one or more which of Reznikov, selected from the group including

(a) the ring is a phenyl or pyridinoline ring, the said ring is optionally substituted by a group-R5or ring C and two adjacent substituent in it form a bicyclic ring system selected from afternova ring;

(b) Rxrepresents hydrogen or methyl, and Ryrepresents phenyl, optionally substituted with halogen; phenoxy; -N(R4)2; pyridyl; imidazolyl; C1-6alkyl, optionally substituted N(R4)2; cyclohexyl, optionally substituted-N(R4)2; morpholinyl; piperidinyl; or piperazinil, where the mentioned morpholinyl, piperidinyl or piperazinil optionally substituted C1-6by alkyl, -C(=O)(C1-6alkyl)om, -CO2(C1-6alkyl)-(phenyl)Ohm or-SO2With1-6by alkyl; or Rxand Rytaken together with the intermediate atoms, form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring, where any substitutable carbon atom in the benzene ring formed by the radicals Rxand Ry, optionally substituted C1-6the alkyl, N(R7)2or-O(C1-6by alkyl), optionally substituted amino group;

(c) R1represents halogen, C1-6aliphatic group, optionally substituted haloge the Ohm, phenyl, or-CN;

(d) R2'represents hydrogen, and R2represents hydrogen, phenyl, or C1-6alkyl, or R2and R2'taken together with the intermediate atoms, form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and where each substitutable carbon atom in the specified condensed ring formed by the radicals R2and R2', optionally substituted with halogen, exography, -NO2, -NH2, pirrallo, -CO2(C1-6alkyl)om or-C1-6the alkyl, optionally substituted with halogen; and any substitutable nitrogen atom in the specified ring formed by the radicals Rxand Ry, optionally substituted by phenyl; and

(e) each R5independently selected from halogen, -NO2, -NH2With1-6the alkyl, optionally substituted with halogen, or-O-C1-6the alkyl.

5. The compound according to claim 4, where

(a) the ring is a phenyl or pyridinoline ring, where the aforementioned ring is optionally substituted by a group-R5where, when ring C and two adjacent substituent in it form a bicyclic ring system, the bicyclic ring system is selected from afternova ring;

(b) Rxrepresents hydrogen or methyl, and Ryp is ecstasy phenyl, optionally substituted with halogen; phenoxy; -N(R4)2; pyridyl; imidazolyl; C1-6alkyl, optionally substituted N(R4)2; cyclohexyl, optionally substituted-N(R4)2; morpholinyl; piperidinyl; or piperazinil, where the mentioned morpholinyl, piperidinyl or piperazinil optionally substituted C1-6by alkyl, -C(=O)(C1-6alkyl)om, -CO2(C1-6alkyl)-(phenyl)Ohm or-SO2With1-6by alkyl; or Rxand Rytaken together with the intermediate atoms, form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring, where any substitutable carbon atom in the benzene ring formed by the radicals Rxand Ry, optionally substituted C1-6the alkyl, N(R7)2or-O(C1-6alkyl)om, optionally substituted amino group;

(c) R1is a halogen; C1-6aliphatic group, optionally substituted with halogen; phenyl; or-CN;

(d) R2'represents hydrogen and R2represents hydrogen, phenyl, or C1-6alkyl, or R2and R2'taken together with the intermediate atoms, form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and where each substitutable carbon atom indicated in the data condensed ring, formed by the radicals R2and R2', optionally substituted with halogen, exography, -NOz, -NH2, pirrallo, -CO2(C1-6alkyl)om or-C1-6the alkyl, optionally substituted with halogen; and any substitutable nitrogen atom in the specified ring formed by the radicals R2and R2', optionally substituted by phenyl; and

(e) each R5independently selected from halogen, -NO2, -NH2With1-6the alkyl, optionally substituted with halogen, or-OS1-6the alkyl.

6. The compound according to claim 4, where the specified connection has one or more characteristics selected from a group including:

(a) Rxrepresents hydrogen or methyl and Ryrepresents methyl, ethyl, isopropyl, tert-butyl, 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, optionally substituted with halogen; or Rxand Rytaken together with the intermediate atoms, form a 6-membered unsaturated or partially unsaturated carbocyclic ring, where any substitutable carbon atom in the benzene ring formed by the radicals Rxand Ry, optionally substituted C1-6the alkyl, N(R7)2or-O(C1-6alkyl)om, optionally substituted amino group;

(b) R1represents a halogen, With1-4aliphatic group, optionally substituted Gal the genome; or-CN;

(c) R2and R2'taken together with the intermediate atoms, form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, where each substitutable carbon atom in the above-mentioned condensed ring formed by R2and R2', optionally substituted with halogen, exography, -NO2, -NH2, CO2(-C1-4alkyl)om, or-C1-4the alkyl, optionally substituted with halogen, where (C1-4alkyl) represents an unbranched or branched alkyl group; and

(d) each R5independently selected from-Cl, -F, -CF3, -NH2or C1-4the alkyl.

7. The compound according to claim 2, where

(a) Rxrepresents hydrogen or methyl and Ryrepresents methyl, ethyl, isopropyl, tert-butyl, 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, optionally substituted with halogen; or Rxand Rytaken together with the intermediate atoms, form a benzene ring, peregrinae ring or 6-membered partially unsaturated carbocyclic ring;

(b) R1represents a halogen, With1-4aliphatic group, optionally substituted with halogen; or-CN;

(c) R2and R2'taken together with the intermediate atoms, form a benzene, pyridine, pyrimidine sludge is partially unsaturated 6-membered carbocyclic ring, where each substitutable carbon atom in the above-mentioned condensed ring formed by R2and R2'optionally substituted by exography, -NH2or1-4the alkyl, optionally substituted with halogen, where (C1-4alkyl) represents an unbranched or branched alkyl group; and

(d) each R5independently selected from-Cl, -F, -CF3, -NH2or C1-4the alkyl.

8. The connection according to claim 7, where each of Rxand Ryrepresents methyl or Rxand Rytaken together with the pyrimidine ring form an optionally substituted ring selected from hintline, and R2and R2'taken together with the pyrazol ring, form an optionally substituted indazol ring.

9. The compound according to claim 1, where the specified connection is selected from the following compounds:

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10. The pharmaceutical composition inhibiting GSK-3 or AURORA-2 activity containing a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, further containing a second therapeutic agent selected from agents for the treatment of diabetes, chemotherapeutic agent or anti-proliferative agent, an anti-inflammatory agent, immunomodulatory and immunosuppressive agents, neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent or an agent for treating blood disorders.

12. The pharmaceutical composition according to claim 11, where therapeutic agent is selected from insulin or insulin analogues, glitazones, alpha-glucosidase inhibitors, biguanides, insulin sensitizers and sulfonylurea, adriamycine, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, Taxol, interferons, platinum derivatives, corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, sulfasalazin; cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazin; inhibitors of acetylcholine is sterzi, MAO inhibitors, anticonvulsants, blockers of ion channels, riluzole, and anti-Parkinson's disease; beta-blockers, ACE inhibitors (ACE), diuretics, nitrates, calcium channel blockers, and statins; cholestyramine, antiviral agents; anti-leukemia funds, growth factors, and gammaglobulin.

13. A method of inhibiting the activity of GSK-3 or AURORA we need in this patient, including the stage of introduction of the indicated patient a therapeutically effective amount of a compound according to claims 1-9.

14. The method according to item 12, where the specified way inhibit the activity of GSK-3 in a patient.

15. A method of inhibiting the activity of GSK-3 or AURORA in a biological sample, comprising the implementation of contact specified biological sample with a compound according to claims 1-9.

16. The method of treatment of disease, facilitate inhibitor of GSK-3, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a compound according to claims 1-9.

17. The method according to item 16, further comprising a stage of introduction of the indicated patient a second drug selected from antidiabetic agents, chemotherapeutic agents or other anti-proliferative agents, anti-inflammatory agents, immunomodulatory and immunosuppressive agents, neurotrophic factor, the block is tori ion channels, of riluzole, and anti-Parkinson's disease; an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating blood diseases and agents for treating immunodeficiency disorders.

18. The method according to clause 16, in which the disease is diabetes.

19. The method according to clause 16, in which the disease is Alzheimer's disease.

20. The method according to clause 16, in which the disease is schizophrenia.

21. A method of enhancing glycogen synthesis in a patient in need thereof, comprising the stage of introduction of the indicated patient a therapeutically effective amount of a compound according to claims 1-9.

22. A method of reducing blood glucose in a patient in need thereof, comprising the stage of introduction of the indicated patient a therapeutically effective amount of a compound according to claims 1-9.

23. A method of inhibiting the production hyperphosphorylated Tau protein in a patient in need thereof, comprising the stage of introduction of the indicated patient a therapeutically effective amount of a compound according to claims 1-9.

24. Method of inhibiting the phosphorylation β-catenin in a patient in need thereof, comprising the stage of introduction of the indicated patient a therapeutically effective amount of a compound according to claims 1-9.

25. The method of treatment of the disease, providing treatment Inga is forom AURORA, including the stage of introduction to a patient in need of such treatment, a therapeutically effective amount of a compound according to claims 1-9.

26. The method according A.25 additionally includes the stage of introduction of the indicated patient a second drug from antidiabetic agents, chemotherapeutic agents or other anti-proliferative agents, anti-inflammatory agents, immunomodulatory and immunosuppressive agents, neurotrophic factor, blockers of ion channels, riluzole, and anti-Parkinson's disease; an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating blood diseases and agents for treating immunodeficiency disorders.

27. The method according A.25, in which the disease is cancer.

28. The pharmaceutical composition of claim 10 in combination with anti-proliferative agent or chemotherapeutic agent.

29. A method of treating cancer in a patient who needs it, including the stage of introduction of said patient therapeutically effective amounts of compounds according to claims 1 to 9, where the above-mentioned cancer is a melanoma or selected from cancer of the colon, lung, stomach, mammary glands.

30. The method according to clause 29, comprising the additional step of introducing the patient an anti-proliferative agent or chemotherapeutic who Ghent, moreover, the additional therapeutic agent is introduced together with said composition as a single dose or separately with the said composition as part of multiple forms.

31. A method of treating Alzheimer's disease in a patient who needs it, including the stage of introduction of said patient therapeutically effective amounts of compounds according to claims 1-9.

32. A method of treating schizophrenia in a patient who needs it, including the stage of introduction of said patient therapeutically effective amounts of compounds according to claims 1-9.

33. A method of treating diabetes in a patient who needs it, including the stage of introduction of said patient therapeutically effective amounts of compounds according to claims 1-9.

34. A method of treating cancer in a patient who needs it, including the stage of introduction of said patient therapeutically effective amounts of compounds according to claims 1-9.

35. The connection formulas And

selected from the group including

36. The compound of formula

where R1is a CF3;

R5represents one to three substituent, each of which is independently selected from Cl, F, CF3or NO2;

Rxand Ryindependently selected from T-R3or Rxand Rytaken together with the intermediate atoms, comprise the condensed unsaturated or partially unsaturated 5-8-membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the groups Rxand Rynot necessarily and independently substituted by oxo group, -O(C1-6by alkyl), -S(C1-6by alkyl) or NH2and any substitutable nitrogen atom in the specified ring formed by the groups Rxand Ry, optionally substituted benzyl group, and any substitutable carbon atom in the benzene ring formed by Rxand Ry, optionally substituted C1-6the alkyl, N(R7)2or-O(C1-6alkyl)om, optionally substituted amino group

T is a bond;

R3selected from hydrogen, halogen, -CN, - N(R4)2, -SO2NH2/sub> , phenyl, optionally substituted with halogen, phenoxy, pyridyl, imidazolyl; C1-6the alkyl, optionally substituted-N(R4)2or-NHSO2(C1-6by alkyl); cyclohexyl, optionally substituted-N(R4)2or-NHSO2(C1-6by alkyl); morpholinyl, piperidinyl or piperazinil where these morpholinyl, piperidinyl or piperazinil optionally substituted C1-6the alkyl, O-phenyl, C(=O)(C1-6by alkyl), -CO2-(C1-6alkyl)-(phenyl) or-SO2C1-6by alkyl;

each R4independently selected from C1-6of alkyl, -C(=O)(C1-6the alkyl), -CO2-(C1-6alkyl)-(phenyl), or CH2phenyl.

each R7independently selected from hydrogen or C1-4aliphatic group, optionally substituted NH2or NH(C1-6alkyl)om; or two R7at the same nitrogen atom, taken together with the nitrogen atom, form morpholinyl or piperazinilnom ring, optionally substituted C1-6the alkyl.

37. The compound of formula

where R2and R2'independently selected from hydrogen, HE, WITH1-6of alkyl, phenyl, cyclopropyl, teinila, Shrila or-T-W-R6or R2and R2'taken together with the intermediate atoms, form a condensed 6-membered unsaturated is whether partially unsaturated ring, having 0-2 ring heteroatoms nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the groups R2and R2'substituted by halogen, exography, NO2, NH2, pirrallo, CO2(C1-6alkyl)om, optionally substituted with halogen, and any substitutable nitrogen atom in the specified ring formed by the groups R2and R2', optionally substituted by phenyl group;

Rxand Ryindependently selected from T-R3or Rxand Rytaken together with the intermediate atoms, comprise the condensed unsaturated or partially unsaturated 5-8-membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the groups Rxand Ry, which contains a nitrogen atom optionally and independently replaced by-O(C1-6alkyl)om, -S(C1-6alkyl)om or NH2; and any substitutable nitrogen atom in the specified ring formed by the groups Rxand Ry, optionally substituted benzyl group; and any substitutable carbon atom in the benzene ring formed by Rxand Ry, optionally substituted C1-6the alkyl, N(R7)2, -O(C1-6by alkyl), optionally substituted amino group;

T represents the Wallpaper link;

W represents-C(R6)2O -, or-CON(R6)-;

R3selected from hydrogen, halogen, -CN, -N(R4)2, -SO2NH2, phenyl, optionally substituted with halogen, phenoxy, pyridyl, imidazolyl,1-6the alkyl, optionally substituted N(R4)2or NHSO2(C1-6the alkyl, cyclohexyl, optionally substituted by N(R4)2or NHSO2(C1-6by alkyl), morpholinyl, piperidinyl, or piperidinyl, or piperazinil, where the above-mentioned morpholinyl, piperidinyl, or piperazinil optionally substituted C1-6the alkyl, O-phenyl, -C(=O)C1-6by alkyl, -CO2(C1-6alkyl)-phenyl, or-SO2(C1-6alkyl)ω, for every R4independently selected from C1-6of alkyl, -C(=O)1-6of alkyl, -CO2(C1-6alkyl)-phenyl, or CH2phenyl;

each R6independently selected from hydrogen or C1-4of alkyl; and

each R7independently selected from hydrogen or C1-4aliphatic group, optionally substituted NH2or NH(C1-6)alkyl, or two R7at the same nitrogen atom together with the nitrogen atom with the formation of morpholinyl or piperazine ring, optionally substituted C1-6by alkyl;

provided that R2is not tert-bootrom, and R2 is not the stands, when Rxrepresents Br, Ryrepresents hydrogen, R2'represents hydrogen.

38. The connection clause 37, where each of Rxand Ryrepresents methyl or Rxand Rytaken together with the pyrimidine ring form hintline ring.

39. Connection § 38, where R2and R2'taken together with the pyrazol ring, form indazol ring.

40. The compound of formula D

where Rxand Ryindependently selected from T-R3or Rxand Rytaken together with the intermediate atoms, comprise the condensed unsaturated or partially unsaturated 5-8-membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in the specified condensed ring formed by the groups Rxand Ry, which contains a nitrogen atom, optionally and independently substituted by a group-O(C1-6the alkyl), -S(C1-6the alkyl) or NH2; and any substitutable nitrogen atom in the specified ring formed by the groups Rxand Ry, optionally substituted benzyl group; and any substitutable carbon atom in the benzene ring formed by Rxand Ry, optionally substituted C1-6the alkyl, N(R7)2, -O( 1-6alkyl)om, optionally substituted amino group;

T is a bond;

R3selected from halogen, -CN, -N(R4)2, -SO2NH2, phenyl, optionally substituted with halogen, phenoxy, pyridyl, imidazolyl, C1-6the alkyl, optionally substituted N(R4)2or NHSO2(C1-6alkyl)om, cyclohexyl, optionally substituted by N(R4)2or NHSO2(C1-6alkyl)om, morpholinyl, piperidinyl, or piperidinyl or piperazinil, where the above-mentioned morpholinyl, piperidinyl or piperazinil optionally substituted C1-6the alkyl, O-phenyl,-C(=O)1-6by alkyl, -CO2(C1-2alkyl)-phenyl, or-SO2(C1-6alkyl)om;

each R4independently selected from C1-6of alkyl, -C(=O)1-6of alkyl, -CO2(C1-6alkyl)-phenyl, or CH2phenyl;

each R5independently selected from-C1-6the alkyl, optionally substituted with halogen, halogen, -O-C1-6of alkyl, NH2and NO2;

each R7independently selected from hydrogen or C1-4aliphatic group, optionally substituted NH2or NH(C1-6)alkyl, or two R7at the same nitrogen atom together with the nitrogen atom with the formation of morpholinyl or piperazine rings, optional Zam is placed With 1-6the alkyl.

41. Connection p, where each of Rxand Ryrepresents methyl or Rxand Rytaken together with the pyrimidine ring form hintline ring.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

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6 cl, 4 tbl, 106 ex

FIELD: chemistry.

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EFFECT: increased efficiency of compounds.

6 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

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EFFECT: new derivatives of cyclic sulphonamide, activating gamma-secretase inhibition and suitable for treatment and prevention of Alzheimer's disease.

9 cl, 7 ex

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12 cl, 166 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

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10 cl, 4 tbl, 26 ex

FIELD: pharmaceutical industry.

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3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds of formula I , or stereoisomers, or pharmaceutically acceptable salts thereof, wherein Q is SO2; n = 2 or 3; each R1 and R2 is independently H, halogen, OR22 or C1-C6-alkyl; each R3 and R4 is H; each R5 and R6 is independently H or C1-C6-alkyl optionally substituted with phenyl or R5 and R6 together with together with atom to which they are attached may form 5-7-membered ring optionally containing N as the second heteroatom optionally substituted with COOH or C1-C6-alkyl; R7 is H; R7 is optionally substituted 8013-membered bicyclic or tricyclic ring system, containing N in bridge bond and optionally 1, 2 additional heteroatoms selected from N, S wherein substituent represent 1 or 2 halogen atoms; R22 is H or C1-C6-phenyl optionally substituted with C1-C6-alkyl. Compounds of present invention specifically bond to 5-HT6 receptor and are useful in pharmaceutical compositions.

EFFECT: compounds with specific bonding to 5-HT6 receptor.

10 cl, 3 tbl, 45 ex

FIELD: chemistry.

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EFFECT: production of the pharmaceutical compositions having anti-influenza virus activity.

12 cl, 2 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (1a) or its pharmaceutically acceptable salt, esters or imides where A is a thiophenyl group containing, probably, substitution, the thiophenyl group A containing, probably, substitution with one or several groups as follows: alkyl, halo or arylalkyl, Y is O, S or NR2 where R2 is hydrogen or alkyl group containing 1 to 6 carbon atoms, and R1 is an non-ramified alkyl group containing 6 to 25 carbon atoms, ramified alkyl group containing 6 to 25 carbon atoms, aryl alkyl group where the alkyl group contains 2 to 25 carbon atoms or phenyl group containing substitution with one or several groups as follows: phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR16- phenyl, NR16CO-phenyl or NR16 -phenyl containing, probably, substitution where R16 is hydrogen or alkyl group containing 1 to 4 carbon atoms, the groups phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR-phenyl or NR-phenyl containing, probably, substitution with one or several groups as follows: halo, alkyl, alkylhalo or phenyl group containing substitution with one or several groups or alkyl groups provided the above compound is not 5-methyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on, 6-amyl-2-(4-chlorophenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on or 6-amyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on Invention also relates to method of obtaining compounds of the formula (Ia) or (IIa), to pharmaceutical compound and application, as well as cosmetic technique.

EFFECT: obtaining of new biologically active compounds and pharmaceutical compounds based on them.

27 cl, 4 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein X represents heteroatom, such as oxygen (O) or sulfur (S) atoms; X and Z mean independently of one another one or some identical or different substitutes bound any available carbon atom and they can represent hydrogen atom or halogen atom; R1 represents a substitute of the formula (II): , wherein R2 and R3 can represent simultaneously or independently of one another hydrogen atom or (C1-C4)-alkyl, or R1 can represent hydrogen, halogen atom, (C1-C7)-alkyl, -CHO, -(CH2)2COOH, -(CH2)2CO2Et, (CH2)mL wherein L means -OH or bromine atom (Br); m represents a whole number from 1 to 3; n represents a whole number from 0 to 3; Q1 and Q2 represent independently of one another oxygen atom or group of the formula: wherein substitutes y1 and y2 represent hydrogen atom, and to their pharmacologically acceptable salts. Also, invention relates to use of these compounds as intermediate substances used in synthesis of novel compounds of dibenzoazulene class, and to their using for preparing drugs.

EFFECT: valuable medicinal properties of compounds.

9 cl, 4 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1,2,3,7-tetrahydropyrrolo[3,2-f][1,3]benzoxazin-5-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing the antiviral effect. In compounds of the general formula (1) each R1 and R4 represents independently of one another a substitutes of amino group chosen from hydrogen atom, optionally substituted linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides; R2 represents alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl or cycloalkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, optionally substituted linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and optionally an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides; R6 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and optionally annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention. Proposed compounds can be used as active components of drugs used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods of synthesis.

22 cl, 3 tbl, 6 dwg, 7 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula 1 (G1 is group of general formulae 2 G1 is group of general formulae ; meanings of the rest substituents are as described in specification) or pharmaceutically acceptable salts thereof and use thereof in srug production. Said compounds are useful in treatment of male and female sexual disorders.

EFFECT: new oxytocin antagonists.

30 cl, 177 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of E-2-aroylmethylene-1-phenyl-1,2,3,4-tetrahydroquinazolin-4-ones of general formula I wherein R represents H, methyl, Cl. Claimed method includes interaction of 5-aryl-2,3-dihydro-2,3-furandiones with N-phenylanthranyl acid amide in medium of inert aprotic solvent (preferably benzene) followed by isolation of target products. Process is carried out preferably at 79-80°C. Claimed compounds have fluorescent properties and are useful in labeling and copying agents, intermediates for synthesis of new heterocyclic compounds, etc.

EFFECT: new fluorescent compounds.

3 cl, 1 dwg, 3 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted of dihydropyranoindole-3,4-dione of formula I and formula II: where X stands for H, R1 stands for H, phenyl, benzyl, cycles of said phenyl and benzyl can be substituted with 1-3 substituents, selected independently on each other from group, which includes halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup; where R2 stands for H, -OH; R3 stands for H, phenyl, benzyl, benzyloxygroup, cycles of these groups can be optionally substituted with 1-3 substituents, selected independently on each other from group including phenyl, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup, pharmaceutically acceptable salts of said compounds. Compounds demonstrate activity of inhibiting plasminogene activator inhibitor (PAI-1), which allows using them for production of medication for treatment of pathological states resulting from fibrinolytic disorders.

EFFECT: obtaining compounds, demonstrating activity in inhibiting plasminogene activator inhibitor which allows using them in pharmacology.

23 cl, 1 dwg, 1 tbl, 13 ex

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