Tyrosine kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I), treating a disease related to proteinkinase activity inhibition, specifically cancer, particularly leukaemia, a method of treating such disease and a method of producing such compounds. In formula (I) R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl; R2 represents lower alkyl substituted by one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzcyclopentyl(indane), benzcyclohexyl, penta-, hexa- or heptamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen and oxygen which can be unsaturated or completely saturated, and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl which is unsubstituted or substituted by one or two substituted specified in a group consisting of lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl, lower alkylcarbamoyl, amino mono- or disubstituted lower alkyl, morpholino, lower alkylsulphonyl, halogen and benzoyl; and the value R3 is specified in the patent claim, or R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl; hexamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen which can be unsaturated or completely saturated, and is unsubstituted or substituted according to the patent claim, R4 represents hydrogen or lower alkyl.

EFFECT: preparing the composition for treating a disease related to proteinkinase activity inhibition.

5 cl, 99 ex

 

The invention relates to new substituted pyrimidinediamine, methods for their preparation, containing their pharmaceutical compositions, their use is optional in combination with one or more other pharmaceutically active compounds for the treatment of the disease, which is associated with inhibition of protein kinase activity, especially tumor diseases, in particular leukemia, and treatment of such diseases.

The level of technology

Protein kinase (PK) are enzymes that catalyze the phosphorylation of specific residues of serine, threonine or tyrosine into cellular proteins. These posttranslational modification of substrate proteins act as molecular switches that regulate cell proliferation, activation and/or differentiation. Rejected from the norm or excessive activity PK observed for many diseases, including benign and malignant proliferative diseases. In some cases, cure of diseases, such as proliferative diseases, possibly through the use of PK inhibitors in vitro and in vivo.

Due to the large number of inhibitors of protein kinase and a variety of proliferative and other related PK diseases there is still a need for new classes of compounds that will be useful in quality is TBE PK inhibitors and, therefore, to treat these related PTK diseases. It provides new classes of pharmaceutically useful inhibiting PK connections.

The Philadelphia chromosome is the hallmark of chronic myelogenous leukemia (CML) and is a hybrid gene, which contains the N-terminal exons of the bcr gene and the main C-terminal part (exons 2-11) C-abl gene. The gene product is a protein of 210 kDa (R Bcr-Abl). Abl-protein Bcr-Abl contains abl-tyrosinekinase, which is heavily regulated by C-abl wild-type, but initially activated in fused protein Bcr-Abl. This unregulated tyrosinekinase interacts with numerous cellular signals leading to transformation and disruption of the regulation of cell proliferation (Lugo and others, Science 247, 1079 [1990]).

General description of the invention

It was found that various compounds of the class pyrimidinylpiperazine show inhibition of protein kinase activity. The compounds of formula I, described below in more detail, particularly showing the inhibition of one or more tyrosinekinase, such as C-Abl, Bcr-Abl, receptor tyrosinekinase PDGF-RFlt3, VEGF-R, EGF-R and C-Kit, as well as combinations of two or more of them; in the case of new pyrimidinylpiperazine in accordance with the invention compounds are suitable for the inhibition of these and/or other protein kinases, particularly of protein kinases referred to is use, and/or for the inhibition of the mutants of these enzymes, especially Bcr-Abl, such as mutant Glu255 -> valine. Due to this activity of the compounds can be used for treatment of diseases associated especially with deviated from the norm or excessive activity of these types of kinases, particularly those mentioned above.

Detailed description of the invention

The invention relates to a compound of formula I

where

R1represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkyl;

R2represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3cycloalkyl, bascically, heterocyclyl, aryl group, or a mono - or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atom and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono - or polyamideimide;

and R3represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amino, mono - or disubstituted amino, cycloalkyl, heterocyclyl, aryl group or mono - and bicyclic heteroaryl group, including zero, one, two or three ring nitrogen atom and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono - or polyamideimide;

or where R1and R2together they are alkylene with four, five or six carbon atoms, optionally mono - or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono - or disubstituted amino, oxo, pyridium, pyrazinium or pyrimidinyl; benzaclin with four or five carbon atoms; oxyalkylene with one oxygen atom and three or four carbon atoms; or Isaakyan with one atom of nitrogen and three or four carbon atoms, where the nitrogen atom is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower by alkyl, carboxy-lower alkyl, carbarnoyl-lower alkyl, N-mono - or N,N-disubstituted carbarnoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinium;

R4represents hydrogen, lower alkyl or halogen;

and N-oxide or pharmaceutically acceptable salt of such compounds.

Used here and hereinafter : General terms in the context of this description are, preferably, following the e values, if not specified otherwise.

The term "lower" denotes a radical having up to and including 7, especially up to and including 4 carbon atoms, these radicals are linear or branched with single or multiple branching.

When using multiple forms of the compounds, salts, etc. it also means a singular compound, salt or the like.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. The connection can in this way be present in the form of mixtures of isomers or as pure isomers, preferably in the form of enantiomerically pure diastereomers.

The invention also relates to the possible tautomers of the compounds of formula I.

Lower alkyl preferably represents alkyl with 1 to 7 inclusive, preferably with 1 to 4 inclusive carbon atoms and is linear or branched; preferably, lower alkyl represents butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferably the lower alkyl is a methyl, propyl or tert-butyl.

The lower acyl preferably represents formyl or lower alkylsulphonyl, in particular acetyl.

The aryl group represents an aromatic shall adikal, which is attached to the molecule through a bond with the carbon atom of the aromatic ring of this radical. In a preferred embodiment, aryl is an aromatic radical having 6-14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrene, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono - or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower quinil, phenyl, hydroxy, esterified hydroxy, nitro, cyano, carboxy, esterified or esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono - or N,N-disubstituted of carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkalinity, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylresorcinol, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylphenolate, halogen-lower allylmercaptan, halogen-lower alkylsulfonyl, such as especially trifloromethyl, dihydroxybis (-B(OH)2), heterocyclyl and lower alkylen-dioxetanes on the adjacent C-atom of the x ring, such as methylenedioxy. Aryl most preferably represents phenyl, naphthyl or tetrahydronaphthyl, which in each case are unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine or bromine; hydroxy; hydroxy etherified by lower alkyl, such as stands, halogen-lower alkyl, such as trifluoromethyl, or phenyl; lower alkylene-DIOXOLANYL with two adjacent C-atoms, for example, methylenedioxy, lower alkyl, for example methyl or propyl; halogen-lower alkyl, for example trifluoromethyl; hydroxy-lower alkyl, for example hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy-lower alkyl; for example, methoxymethyl or 2-methoxyethyl; lower alkoxycarbonyl-lower alkyl, for example methoxycarbonylmethyl; lower quinil, such as 1-PROPYNYL; esterified carboxy, especially lower alkoxycarbonyl, such as methoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl; N-mono-substituted carbarnoyl, in particular carbarnoyl, monosubstituted by lower alkyl, for example methyl, n-propyl or isopropyl; amino; lower alkylamino, such as methylamino; Denizli alkylamino, for example dimethylamino or diethylamino; lower alkylene-amino, such as pyrrolidino or piperidino; lower oxyalkylene-amino, for example, morpholino,lower Isaakyan-amino, for example, piperazine derivatives, acylamino, for example acetylamino or benzoylamine; lower alkylsulfonyl, for example methylsulphonyl; sulfamoyl; or phenylsulfonyl.

Cycloalkyl group preferably represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl and may be unsubstituted or substituted by one or more, especially one or two substituents selected from defined above for the substituents of the aryl, most preferably lower alkyl, such as methyl, lower alkoxy such as methoxy or ethoxy, or hydroxy, and oxo, or condensed with a benzene ring, as in benzocyclobutene or benzocycloheptene.

Substituted alkyl is an alkyl, as defined above, especially lower alkyl, preferably methyl; where may be one or more, especially up to three, substituents from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N,N-Denissenko alkylamino, N-lower alkanolamine, hydroxy, cyano, carboxy, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl. Trifluoromethyl is particularly preferred.

Mono - or disubstituted amino is especially represents amino, substituted by one or two radicals independently selected from lower alkyl, such as methyl; hydroxy-lower alkyl, is such as 2-hydroxyethyl; phenyl-lower alkyl, such as benzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl where the phenyl radical is, in particular, substituted by one or more, preferably one or two substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-Denissenko alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl and carbamoyl; and phenyl-lower alkoxycarbonyl, where the phenyl radical is unsubstituted or especially substituted by one or more, preferably one or two substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-Denissenko alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl and carbamoyl; and, preferably, is a N-lower alkylamino, such as N-methylamino, hydroxy-lower alkylamino, such as 2-hydroxyethylamino, phenyl-lower alkylamino, such as benzylamino, N,N-Denizli alkylamino, N-phenyl-lower alkyl-N-lower alkylamino, N,N-Denizli alkylenediamine, lower alkanolamine, such as acetylamino, or Deputy, selected from the group consisting of benzoylamino and phenyl-lower alkoxycarbonyl, where the phenyl radical in each case is unsubstituted or especially substituted by nitro or amino, or also halogeno is, amino, N-lower alkylamino, N,N-dignissim alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonyl. Disubstituted amino is also a lower alkylene-amino, for example pyrrolidino, 2-oxopyrrolidin or piperidino; lower oxyalkylene, for example, morpholino, or lower analcreampie, for example, piperazine derivatives or N-substituted, piperazine derivatives, such as N-methylpiperazine or N-ethoxycarbonylpyrimidine.

A represents a halogen especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine or bromine.

Esterified hydroxy is a particularly C8-C20alkyloxy, such as n-decyloxy, lower alkoxy (preferably), such as methoxy, ethoxy, isopropoxy or tert-Butylochka, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, or halogen-lower alkoxy, such as triptoreline, 2,2,2-triptoreline or 1,1,2,2-tetrafluoroethoxy.

Esterified hydroxy is a particularly lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyl, such as tert-butoxycarbonylamino or phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyloxy.

Esterified carboxy is a particularly low alkoxycarbonyl, such as tert-butoxycarbonyl, isopropoxycarbonyl, meloxicam is of IMT or etoxycarbonyl, phenyl-lower alkoxycarbonyl or phenoxycarbonyl.

Alkanoyl is above all alkylsulphonyl, especially lower alkanoyl, for example acetyl.

N-Mono - or N,N-disubstituted carbarnoyl especially substituted by one or two substituents, independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or Aza-lower alkylene, optionally substituted on the target nitrogen atom.

Mono - or bicyclic heteroaryl group comprising zero, one, two or three nitrogen atom in the ring and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono - or polyamidine, denotes a heterocyclic group which is unsaturated in the ring, connecting the heteroaryl radical to the rest of the molecule of formula I, and preferably is a ring, connecting ring, but not necessarily in any nonlinear ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the bonding ring preferably has 5 to 12, most preferably 5 or 6 atoms in the ring; and which may be unsubstituted or substituted by one or more, especially one or two substituents selected from GRU the dust, defined above for the substituents of the aryl, most preferably lower alkyl, such as methyl, lower alkoxy such as methoxy or ethoxy, or hydroxy. Preferably mono - or bicyclic heteroaryl group selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazole, purine, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-chinoiserie, izochinolina, chinoline, phthalazine, naphthyridine, finokalia, heatline, cinnoline, pteridine, indolizine, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, tetrazolyl, furazane, benzo[d]pyrazolyl, tanila and furanyl. Most preferably mono - or bicyclic heteroaryl group selected from the group consisting of pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazole, especially 5-indazole, pyridyl, especially 2-, 3 - or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, izochinolina, especially 3-izochinolina, chinoline, especially 4 - or 8-chinoline, indolyl, especially 3-indolyl, thiazolyl, benzo[d]pyrazolyl, tanila and furanyl. In one preferred embodiment of the invention peredelnyj radical substituted by hydroxy in the ortho-position to the nitrogen atom and, therefore, it has the edge, at least partially, in the form of a corresponding tautomer, which represents a pyridine-(1H)2-he. In another preferred embodiment, pyrimidinyl radical substituted by hydroxy in positions 2 and 4 and, therefore, exist in several tautomeric forms, for example in the form of pyrimidine-(1H,3H)2,4-dione.

Heterocyclyl represents a particularly five-, six - or semicolony heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo or heteroaryl, such as 2-piperazinil; heterocyclyl is an especially 2 - or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, 4-piperidinyl, N-benzyl-4-piperidinyl, 2 - or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl or 2-methyl-1,3-dioxolane-2-yl.

Salts are especially the pharmaceutically acceptable salts of compounds of formula I.

Such salts get, for example, in the form of an acid additive salts, preferably with organic or inorganic acids, from compounds of the formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acid is Tami are for example, halogenated acids, such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphoric, or sulfonic sulfamate acid, for example acetic acid, propanoic acid, octanoic acid, cekanova acid, dodekanisa acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, Emelyanova acid, subernova acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, hydroxymaleimide acid, methylmaleimide acid, cyclohexanecarbonyl acid, adamantanecarbonyl acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, ftalievogo acid, phenylacetic acid, mandelic acid, cinnamic acid, methane - or econsultancy acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonate acid, benzolsulfonat acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3 - or 4-methylbenzenesulfonic acid, mmelserna acid, atisara acid, modellerna acid, N-cyclohexylsulfamic acid, N-methyl, N-ethyl - or N-propylsulfonyl acid or other organic about the traditional acid, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy or sulfo, salt can also be obtained with bases, for example salts with metal or ammonium, such as salts with alkali metal or alkaline earth metal, for example, salts with sodium, potassium, magnesium or calcium, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or three(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethylpiperidine or N,N'-dimethylpiperazine.

When one molecule is present and the basic group and an acid group, the compound of formula I may also form internal salts.

For isolation or purification is also possible to use pharmaceutically unacceptable salts, for example the picrate or perchlorates. For therapeutic applications, the use of only pharmaceutically acceptable salts or free compounds (where appropriate - in the form of pharmaceutical compositions), and they are, therefore, preferred.

Due to the proximity of the new compounds in free form and compounds in the form of their salts, including salts, which can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the connection in St. the free form here and below should be understood as referring also to the corresponding salts, where it is appropriate and expedient.

The compounds of formula I and their N-oxides have valuable pharmacological properties, as described hereafter.

The effectiveness of the compounds according to the invention as inhibitors of the activity of C-Abl, Bcr-Abl and VEGF-receptor tyrosine kinase can be defined as follows.

Test for activity against C-Abl proteinkinase. The test was performed as a test for linkage in the following way: the His-tagged kinase domain of C-Abl has cloned and expressed in the system the baculovirus/Sf9, as described in br and others, J Biol Chem. 272, 16170-5 (1997). Protein 37 kDa (C-Abl kinase) was purified in a two-stage method on the column with the chelate of cobalt and then to anion exchange column with a yield of 1-2 mg/l of Sf9 cells. The purity of the C-Abl kinase was >90%, which is defined SDS-PAGE after coloring red blue. The test contains: C-Abl kinase (50 ng), 20 mm Tris-HCl, pH 7.5, 10 mm MgCl210 µm Na3VO4, 1 mm DTT and 0.06 MK Ci/test [γ33P]-ATP (5 μm ATP) with 30 μg/ml poly-Ala,Glu,Lys,Tyr - 6:2:5:1 (Poly-AEKY, Sigma P1152) in the presence of 1% DMSO, total volume of 30 µl. The reaction was stopped by adding 10 μl of 250 mm EDTA and 30 μl of reaction mixture was transferred to the membrane Immobilon-PVDF (Millipore, Bedford, MA, USA)previously soaked for 5 min with methanol, rinsed with water, then soaked for 5 min with 0.5% H3PO4and installed on the vacuum Kollek, the ora with disconnected vacuum source. After defining all of the samples was plugged in the vacuum and each well was washed with 200 µl of 0.5% H3PO4. The membrane was removed and washed on a mixer with 0.5% H3PO4(4 times) and once with ethanol. Quantitative determination of the membranes was carried out after drying at ambient temperature, setting in Packard TopCount 96-cell frame and adding 10 ál of cell Microscint TM (Packard).

Test for activity against Bcr-Abl. Muscle myeloid grandparent cell line 32Dcl3, transfected with the expression vector R Bcr-Abl pGDp210Bcr/Abl (32D-bcr/abl), was obtained from J. Griffin (Dana Faber Cancer Institue, Bosten, MA, USA). Cells expressed protein Bcr-Abl with the initially active abl kinase and proliferated independently growth factor. Cells were expanded in RPMI 1640 (AMIMED), 10% fetal calf serum, 2 mm glutamine (Gibco) ("complete medium") and a working stock was prepared by freeze aliquot quantities of 2×106cells on the vessel in freezing medium (95% FCS, 5% DMSO (SIGMA)). After thawing the cells were used for a maximum of 10-12 times in experiments.

For the cell test compounds were dissolved in DMSO and diluted in complete medium to obtain the initial concentration of 10 μm, followed by 3-fold serial dilutions in complete medium. 200'000 32D-Bcr/Abl cells in 50 μl of complete medium were planted in the cells in 96-round bottom cell padlock is for tissue culture. To the cells was added three times, 50 μl of the cell by 3-fold serial dilutions of the tested compounds. Untreated cells were used as control. Connection incubated with the cells for 90 min at 37°C, 5% CO2followed by centrifugation substrates tissue culture at 1300 rpm (Beckmann centrifuge GPR) and remove supernatant careful blowing, not to remove the damaged cells. The remains of the cells were subjected to lysis by addition of 150 μl lisanova buffer (50 mm Tris/HCl, pH 7,4, 150 mm sodium chloride, 5 mm EDTA, 1 mm EGTA, 1% NP-40, 2 mm ortho-sodium Vanadate, 1 mm PMSF, 50 μg/ml Aprotinin and 80 µg/ml leupeptin) and immediately used for ELISA or kept frozen in the substrate at -20°C until use. Black ELISA substrate (black matte Packard HTRF-96) pre-treated overnight at 4°C With 50 ng/cell polyclonal anti-abl-SH3 domain Ab 06-466 rabbit from Upstate in 50 μl PBS. After washing 3 times with 200 μl/cell PBS containing 0.05% Tween20 (PBST) and 0.5% TopBlock (Juro), the remaining protein binding sites were blocked with 200 μl/cell PBST, 3% TopBlock for 4 h at room temperature followed by incubation with 50 μl of the lysates of untreated or treated with connection of cells (20 µg total protein per cell) for 3-4 h at 4°C. After 3 washings were added 50 μl/cell anti-phosphotyrosine Ab PY20(AP)labeled with alkaline phosphate is zoé (Zymed), diluted to 0.2 μg/ml in blocking buffer, and incubated overnight (4°C). For all stages of the incubation of the substrate was covered with the caps (Costar). Finally, the substrate was washed three times with wash buffer and once with deionized water before adding 90 μl/cell AR-substrate CDPStar RTU with Emerald II. Substrate, closed-Packard TopSeal™ - lids for substrates, incubated for 45 min at room temperature in the dark and determined the amount of luminescence measurement per second (CPS) using a Packard Top Count Microplate Scintillation Counter (Top Count). Calculated the difference between ELISA-reading (CPS)obtained for the lysate from untreated 32D-Bcr/Abl cells, and reading testing-basics (all the components, but without cell lysate) and took over 100% reflection is initially phosphorylated protein Bcr-Abl present in these cells. The potency of the compound relative to the Bcr-Abl kinase were expressed as the percentage decrease in the phosphorylation of Bcr-Abl. The values of the IC50and IC90was determined from the curves of the dose graphical extrapolation.

Test for activity against VEGF receptor tyrosine kinase. The test was performed using Flt-1 VEGF receptor tyrosine kinase. The detailed methodology is as follows: 30 ál of kinase solution (10 ng of the kinase domain of Flt-1, Shibuya and others, Oncogene 5, 519-24 [1990]) in 20 mm Tris*HCl pH 7.5, 3 mm dichlo the IDA manganese (MnCl 2), 3 mm magnesium chloride (MgCl2), 10 μm sodium Vanadate, 0.25 mg/ml of polyethylene glycol (PEG) 20000, 1 mm dithiothreitol and 3 μg/ml poly(Glu,Tyr) 4:1 (Sigma, Buchs, Switzerland), 8 μm [33P]-ATP (0,2 MX), 1% DMSO and 0-100 μm of test compounds were incubated together for 10 minutes at room temperature. The reaction was then stopped by adding 10 ál of 0.25 M ethylenediaminetetraacetate (EDTA) pH 7. Using multi-channel distribution device (LAB SYSTEMS, USA) and an aliquot of 20 μl was applied to a PVDF membrane (= polyvinyldifluoride) Immobilon P (Millipore, Bedford, USA), through microtiter folded filter Gibco-BRL and is associated with a vacuum. After complete separation of the liquid membrane was washed 4 times in a bath containing 0.5% phosphoric acid (H3PO4), and once with ethanol, incubated for 10 minutes with shaking, and then installed on a Hewlett Packard TopCount Manifold and measured the radioactivity after addition of 10 μl of Microscint™ (liquid for scintillation counter). Determine the values of the IC50linear regression analysis of the percentage for the inhibition of each compound in at least four concentrations (typically of 0.01, 0.1, 1.0, and 10 Microm). The values of the IC50that can be found for compounds of formula I, are in the range from 1 to 10'000 nm, preferably in the range from 1 to 100 nm.

The inhibition caused by the CSOs VEGF autophosphorylation KDR-receptor can be also confirmed by the experiment in vitro on cells: transfetsirovannyh Cho cells they constantly Express the VEGF receptor human (KDR)were planted in a complete culture medium with 10% fetal calf serum (FCS) in 6-cell substrates for cell culture, and incubated at 37°C under 5% CO2up to 80% of confluence. Then the test compounds were diluted in culture medium (without FCS, 0.1% bovine serum albumin) was added to the cells. (The controls contained environment without test compounds.) After two hours of incubation at 37°C was added recombinant VEGF; the final concentration of VEGF was 20 ng/ml After five minutes incubation at 37°C. cells were washed two times with ice-cold PBS (phosphate-buffered saline solution) and immediately subjected to lysis in 100 μl lisinop buffer to the cell. The lysates are then centrifuged to remove cell nuclei and determine the protein concentration of supernatants using a commercial protein analysis (BIORAD). Then the lysates can be used immediately or, if necessary, stored at -20°C.

Sandwich ELISA was performed to measure the phosphorylation of the receptor KDR monoclonal antibody for KDR (for example, Mab 1495,12,14) immobilizerpower on ferrous substrates ELISA (OptiPlate™ HTRF-96 from Packard). The substrate is then washed and the remaining free protein binding sites were saturated with 1% BSA in PBS. The cell lysates (20 μg protein per cell) and then incubated on these substrates during the night at 4°C with antiphosphotyrosine antibody associated with alkaline phosphatase (PY20:AP from Transduction Laboratories). The substrate was rinsed again and then determined the binding antiphosphotyrosine antibodies from the captured phosphorylated receptor using fluorescent AR substrate (CDP-Star, ready-to-use, with Emerald II; TROPIX). The luminescence was measured using a Packard Top Count Microplate Scintillation Counter (Top Count). The difference between the signal of the positive control (stimulated VEGF) and the signal of the negative control (not stimulated VEGF) corresponds induced phosphorylation of VEGF receptor KDR (=100%). The activity of the test substances was calculated as % inhibition induced phosphorylation of VEGF receptor KDR, where the concentration of a substance that takes half the maximum inhibition was determined as ED50(effective dose for 50% inhibition). The compounds of formula I preferably show the values of the ED50in the area of from 0.25 nm to 1000 nm, preferably from 0.25 to 250 nm.

The compound of formula I or its N-oxide also inhibits in varying degrees, other tyrosine kinase involved in signaling, which mediasource trapnymi factors, such as Bcr-Abl and Abl kinase, Arg, kinases from the Src family, especially c-Src kinase, Lck, and Fyn; also kinases of the EGF family such as C-erbB2 kinase (HER-2), C-erbB3 kinase, C-erbB4 kinase; kinase receptor insulin-like factor Rho is the one (IGF-1 kinase), especially members of the family tyrosinekinase PDGF-receptor like kinase PDGF-receptor kinase CSF-1 receptor kinase Kit-receptor and kinase VEGF receptor; and serine/treoninovymi kinases, each of which plays a role in regulating the growth and transformation of mammalian cells, including human cells.

Inhibition of C-erbB2 tyrosine kinase (HER-2) can be measured, for example, similar to the inhibition of EGF-R protein kinase, using known methods.

Based on these studies, a compound of formula I in accordance with the invention shows therapeutic efficacy especially against diseases-dependent protein kinase, especially proliferative diseases.

On the basis of their efficacy as inhibitors of the tyrosine kinase activity of VEGF-receptor compounds of formula I primarily inhibit the growth of blood vessels and, thus, for example, effective against a variety of diseases associated with deregulated angiogenesis, especially diseases caused by ocular neovascularisation, especially retinopathy, such as diabetic retinopathy or age spots, psoriasis, haemangioblastoma, such as haemangioma, proliferative diseases mesangial cells, such as chronic or acute renal diseases, e.g. diabetic nephropathy, malignant nave is skleros, the syndrome of thrombotic microangiopathy or transplant rejection, or especially inflammatory kidney disease, such as glomerulonephritis, especially mesangiocapillary glomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma, and especially neoplastic diseases (solid tumors, but also leukemias and other "liquid tumors, especially tumors expressing c-kit, KDR, Flt-1 or Flt-3), such as especially breast cancer, colon cancer, lung cancer (especially cancer small cell the lung), cancer of the prostate or Kaposi's sarcoma. The compound of formula I (or its N-oxide) inhibits tumor growth and is particularly suitable for preventing the spread of metastatic tumors and growth micrometastases.

The compound of the formula I can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy is of the form of fixed combinations or the introduction of compounds according to the invention and one or more other therapeutic agents, injected or taken independently from each other, or combined introduction of fixed combinations and one or more other therapeutic agents. The connection f is rmula I can, additionally, be administered especially for tumor therapy, such as in the treatment of leukemia in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination. Equally possible as long therapy, and adjuvant therapy with other treatments as described above. Other possible treatment therapy is to maintain the condition of the patient after tumor regression or even chemotherapy, for example, in patients at risk.

Therapeutic agents for possible combination are especially one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or agents selected from the group comprising idarubicin, cytarabine, interferon, hydroxyurea, busulfan or biosynthesis inhibitor polyamine, an inhibitor of protein kinase, particularly serine/ser / thr protein kinase, such as protein kinase C, or tyrosinemia protein kinases, such as tyrosine kinase receptor, epidermal growth factor, a cytokine, a negative growth regulator, such as TGF-β or IFN-β, an aromatase inhibitor, classical cytotoxic agent and an inhibitor of the interaction of the SH2 domain with a phosphorylated protein.

Connection in accordance with the invention is useful not only for (preventive and preferably therapeutic is about) introduction to the people, but also for treatment of other warm-blooded animals, such as industrial useful animals, such as rodents, such as mice, rabbits or rats, or Guinea pigs. This connection can also be used as a reference standard in the above-described test systems for comparison with other compounds.

In General, the invention also relates to the use of compounds of formula I or its N-oxide for the inhibition of tyrosine kinase activity in vitro or in vivo.

In the groups mentioned further preferred compounds of formula I and their N-oxides of the definitions of substituents from the General previously mentioned definitions can be successfully used, for example, to replace more General definitions with more specific definitions or especially preferred definitions.

In particular, the invention relates to compounds of formula I, where

R1represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkyl;

R2represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R3cycloalkyl, bascically, heterocyclyl, aryl group, or a mono - or bicyclic heteroaryl group containing one, two Il the three nitrogen atom or one sulfur atom, where aryl and heteroaryl groups in each case are unsubstituted or mono - or polyamideimide;

and R3represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amino, mono - or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, furanol, toenail or mono - or bicyclic heteroaryl group containing one, two or three nitrogen atom in the ring, zero or one oxygen atom in the ring and zero or one sulfur atom in the ring, where aryl and heteroaryl groups in each case are unsubstituted or mono - or polyamideimide;

or where R1and R2together they are alkylene with four or five carbon atoms, optionally mono - or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono - or disubstituted amino, pyridium, pyrazinium or pyrimidinyl; benzaclin with four or five carbon atoms in alkalinous group; oxyalkylene with one Octomom oxygen and three or four carbon atoms, or Isaakyan with one atom of nitrogen and three or four carbon atoms, where the nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower Alky the Ohm, carbarnoyl-lower alkyl, N-mono - or N,N-disubstituted carbarnoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinium;

R4represents hydrogen, lower alkyl or halogen;

and N-oxide or pharmaceutically acceptable salt of such compounds.

More specifically, the invention relates to compounds of formula I, where

R1represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkyl;

R2represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R3cyclopentyl, benzocyclobutene, cyclohexyl, pyrrolidinyl, oxazolyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepine, oxazepine, oxazepines, phenyl, naphthalenyl, tetrahydronaphthalene or mono - or bicyclic heteroaryl group containing one or two nitrogen atom, where phenyl, naphthalenamine and heteroaryl groups in each case are unsubstituted or mono - or polyamidine, thienyl or lower alkoxycarbonyl lowest alkylthiol;

and R3represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbarnoyl, N-mono - or N,N-disubstituted carbama is l, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidin, piperidino, morpholino, imidazoline, Oxymetazoline, cycloalkyl, heterocyclyl, furyl, phenyl, naphthalenyl, tetrahydronaphthalene or mono - or bicyclic heteroaryl group containing one or two nitrogen atom, where phenyl, naphthalenamine and heteroaryl group is unsubstituted or mono - or polyamideimide;

or where R1and R2together they are alkylene with four or five carbon atoms, optionally mono - or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono - or disubstituted amino, pyridium, pyrazinium or pyrimidinyl; benzaclin with four or five carbon atoms in alkalinous group; oxyalkylene with one oxygen atom and four carbon atoms; or Isaakyan with one nitrogen atom and four carbon atoms, where the nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbarnoyl-lower alkyl, N-mono - or N,N-disubstituted carbarnoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinium;

R4to depict the place of a hydrogen, lower alkyl or halogen;

and N-oxide or pharmaceutically acceptable salt of such compounds.

More specifically, the invention relates to compounds of formula I, where

R1represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkyl;

R2represents hydrogen; lower alkyl, optionally substituted by one radical R3two phenyl groups, the two lower alkoxycarbonyl groups, phenyl and lower alkoxycarbonyl or hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzocyclobutene; cyclohexyl; pyrrolidinyl; oxazolyl; piperidinyl; N-lower alkylpiperidines; N-benzylpiperidine; N-pyrimidinylpiperazine; morpholinyl; azepine; oxazepine; oxazepine; phenyl, naphthalenyl, tetrahydronaphthalene or mono - or bicyclic heteroaryl group containing one or two nitrogen atom, where phenyl, naphthalenamine and heteroaryl groups in each case are unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl trifter-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, Denizli alkylamino-lower alkyl, N-cyclohexyl-N-lower alkilani is o-lower alkyl, lower alkoxycarbonyl-lower alkyl, N-lower alkylpiperazine-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifter-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, nissy alkyl-carbamoyl, amino, lower alkanolamine, benzoylamine, amino, mono - or disubstituted by lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazine derivatives, N-lower alkylpiperazine, morpholine, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylthio, phenylthio, phenyl, pyridyl, halogenide or benzoyl; tanila or lower alkoxycarbonyl lowest alkylthiol;

and R3represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbarnoyl, carbarnoyl, mono - or disubstituted by lower alkyl, phenyl or lower alkylene, amino, lower alkylamino, dignissim alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidin, piperidino, morpholino, imidazoline, Oxymetazoline, cycloalkyl, heterocyclyl, fullam; phenyl, naphthalenyl, tetrahydronaphthalene or mono - or bicyclic heteroaryl GRU is PU, comprising one or two nitrogen atom, where phenyl, naphthalenamine and heteroaryl group is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifter-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifter-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanolamine, benzoylamine, amino, mono - or disubstituted by lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazine derivatives, N-lower alkylpiperazine, N-lower alkoxycarbonylmethyl, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylthio, phenylthio, halogenide or benzoyl;

or where R1and R2together they are alkylene with four or five carbon atoms, optionally mono - or disubstituted by lower alkyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, amino, benzoylamine, piperidino, pyridium, pyrazinium or pyrimidinyl; benzaclin with four or five carbon atoms in alkalinous group; oxyalkylene with one oxygen atom and four carbon atoms; and the and Isaakyan with one nitrogen atom and four carbon atoms, where the nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbarnoyl-lower alkyl, carbarnoyl-lower alkyl, N-mono - or N,N-disubstituted by lower alkyl, phenyl, lower alkylene or oxa-lower alkylene, cycloalkyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, cryptomaterial, cryptomaterial, pyridinyl, pyrimidinyl or pyrazinium;

R4represents hydrogen or lower alkyl;

and N-oxide or pharmaceutically acceptable salt of such compounds.

In a preferred group of compounds of formula I

R1represents hydrogen, lower alkyl, lower alkoxy-lower alkyl or benzyl;

R2represents lower alkyl, optionally substituted by one radical R3two phenyl groups, the two lower alkoxycarbonyl groups, phenyl and lower alkoxycarbonyl or hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzocyclobutene; cyclohexyl; pyrrolidinyl; piperidinyl; N-lower alkylpiperidines; N-benzylpiperidine; N-pyrimidinylpiperazine; morpholinyl; azepine; oxazepine; phenyl; naphthalenyl; tetrahydronaphthalene; pyridyl; lower alkyl-pyridyl; chinoline; thienyl; lower alkoxycarbonylmethyl or phenyl, semese the hydrated one or two substituents, selected from the group consisting of lower alkyl, trifter-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, Denizli alkylamino-lower alkyl, N-cyclohexyl-N-lower alkylamino-lower alkyl, lower alkoxycarbonyl-lower alkyl, N-lower alkylpiperazine-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifter-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower allylcarbamate, amino, lower alkanolamine, benzoylamine, amino, mono - or disubstituted by lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazine derivatives, N-lower alkylpiperazine, morpholine, sulfamoyl, lower alkylsulfonyl, phenyl, pyridyl, halogenide or benzoyl;

and R3represents hydroxy, lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbarnoyl, amino, lower alkylamino, Denizli alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidin, piperidino, morpholino, imidazoline, Oxymetazoline, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, phenyl, naphthalenyl, Tetra createlines, furyl, mono - or bicyclic heteroaryl group containing one or two nitrogen atom, where the heteroaryl group is unsubstituted or mono - or disubstituted by lower alkyl, hydroxy and lower alkoxy, or phenyl, substituted by one or two substituents selected from the group consisting of lower alkyl, trifter-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifter-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanolamine, benzoylamine, amino, mono - or disubstituted by lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazine derivatives, N-lower alkylpiperazine, N-lower alkoxycarbonylmethyl, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, halogenide or benzoyl;

or where R1and R2together they are alkylene with four or five carbon atoms, optionally mono - or disubstituted by phenyl, hydroxy, amino, benzoylamine or piperidino; benzaclin with four or five carbon atoms in alkalinous group; oxyalkylene with one oxygen atom and four carbon atoms; or Isaakyan with one nitrogen atom and four carbon atoms, where the nitrogen which is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbarnoyl-lower alkyl, pyrrolidinecarbonyl-lower alkyl, morpholinomethyl-lower alkyl, cyclopentyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, cryptomaterial, pyridinyl, pyrimidinyl or pyrazinium;

R4represents hydrogen or methyl;

and N-oxide or pharmaceutically acceptable salt of such compounds.

Especially preferred group of compounds includes compounds of formula I, where

R1represents hydrogen and

R2represents phenyl substituted by trifluoromethyl, especially 3-triptoreline, and do not necessarily also have a Deputy selected from the group consisting of hydroxy-lower alkyl, for example 1-hydroxy-1-methylethyl, lower alkylamino, for example methyl - or ethylamino, hydroxy-lower alkylamino, for example 2-hydroxy-1-propylamino or 2-hydroxy-2-propylamino, Denissenko alkylamino, for example, diethylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, for example 2 - or 4-methyl-1H-imidazolyl, carbamoyl, lower allylcarbamate, such as methylcarbamoyl, pyrrolidino, piperidino, piperazine derivatives, lower alkylpiperazine, for example 4-methylpiperazine, morpholine, lower alkoxy, for example methoxy, fluorine, lower alkoxy, for example, triptoreline or 2,2,2-triptoreline, Fe the sludge, pyridyl, for example 2-, 3 - or 4-pyridyl and halogenide, for example chlorine or fluorine;

R4represents methyl;

and N-oxide or pharmaceutically acceptable salt of such compounds.

Especially preferred are the compounds described in the examples.

Other compounds which are particularly preferred are:

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzanilide,

4-methyl-N-(3-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

N-(4-chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

2(R)- and 2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamine]propanoic acid,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(8-chinoline)benzamid,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-[triptoreline]phenyl)benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidinyl)benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-pyrrolidinyl)benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(1-[2-pyrimidinyl]-4-piperidinyl)benzamide,

N-(4-di-[2-methoxyethyl]amino-3-triptoreline)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

N-(4-[1H-imidazolyl]-3-triptoreline)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl-2-pyrimidinyl]amino]-N-(2-pyrrolidino-5-triptoreline)benzamid,

N-(3,4-differenl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifloromethyl)benzamid,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-triptoreline)benzamid,

N-(3-chloro-5-triptoreline)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

N-(4-dimethylaminomethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-N-[4-(4-methyl-1-piperazinil)-3-triptoreline]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,2,2-triptoreline)-3-triptoreline]benzamid,

4-methyl-N-[4-(2-methyl-1H-imidazolyl)-3-triptoreline]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-N-(4-phenyl-3-triptoreline)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-N-[4-(4-methyl-1H-imidazolyl)-3-triptoreline]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

methyl 2(R)- and 2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamine]-3-[4-hydroxyphenyl]propanoate,

N-[2-(N-cyclohexyl-N-methylaminomethyl)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

N-[3-[2-(1H-imidazolyl)ethoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-N-[3-morpholino-5-triptoreline]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]the Mino]-N-(4-pyrrolidino-3-triptoreline)benzamid,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-piperidino-3-triptoreline)benzamid,

4-methyl-N-[4-morpholino-3-triptoreline]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

N-(4-ethylamino-3-triptoreline)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifloromethyl)benzamid,

N-[4-(2-hydroxypropylamino)-3-triptoreline]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

N-(4-diethylamino-3-triptoreline)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(3-pyridinyl)-5-tryptophanyl]benzamid,

N-[3-[3-(1H-imidazolyl)propoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(3-pyridinyl)-3-tryptophanyl]benzamid,

4-methyl-N-[3-(4-methyl-1-piperazinil)-5-tryptophanyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-N-[3-methylcarbamoyl-5-tryptophanyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,

4-methyl-N-[3-methylcarbamoyl-5-morpholino]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide.

The following compounds which are particularly preferred are:

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]the Mino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(diethylamino)-3-(trifluoromethyl)phenyl]benzamide,

(±)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[(2-hydroxypropyl)amino]-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1-piperazinil)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-phenyl-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-PI is idini)-2-pyrimidinyl]amino]-N-[4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonyl]phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(3-pyridinyl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinil)-5-(trifluoromethyl)phenyl]benzamide and

4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide.

The invention also relates to 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid and 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid; intermediate compounds for obtaining the preferred amides according to the invention.

Particularly the invention relates to the use of compounds of formula I or its N-oxide or a possible tautomer or pharmaceutically acceptable salts of such compounds is Oia to obtain a pharmaceutical composition for the treatment of diseases, which is associated with inhibition of protein kinase activity, where the disease is a neoplastic disease.

More specifically, the invention relates to the use of compounds of formula I or its N-oxide or a possible tautomer or pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions for the treatment of leukemia, which is associated with inhibition of the activity of Abl tyrosine kinase.

In addition, the invention relates to a method of treatment of the disease, which is associated with inhibition of protein kinase activity, which includes the introduction of the compounds of formula I or its N-oxide or pharmaceutically acceptable salt, where the radicals and symbols have the meanings defined above, in a quantity effective against specified diseases of warm-blooded animal in need of such treatment.

The connection according to the invention can be obtained by processes that, though not applied hitherto for obtaining the novel compounds of this invention are known, especially by the way, characterized by the fact that for the synthesis of compounds of formula I, where the symbols R1, R2and R4are as defined for compounds of formula I, 4-R4-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid of formula II

where R4 is the same as defined for the compounds of formula I, or its derivative, where carboxypropyl-COOH is in the activated form, reacts with the amine of formula III

where R1and R2are as defined for compounds of formula I, optionally in the presence of a dehydrating agent and an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;

where the above starting compound II and III may also be present, if necessary, with functional groups in protected form or in the form of salts, provided that there is forming a salt of the group and the reaction in salt form is possible;

any protective group in the protected derivative of the compound of formula I is deleted;

and, if desired, the resulting compound of the formula I is converted into another compound of formula I or its N-oxide, a free compound of formula I is transformed into a salt obtained salt of a compound of the formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.

Detailed description of the method.

Derivative compounds of formula II, where carboxypropyl is in activated form, represents a particularly reactionary ether, the reaction of the anhydride or the reaction is first cyclic amide.

Reactive esters of the acids of formula II are especially esters unsaturated at the linked carbon atom of the ether radical, such as vinyl esters such as simply vinyl esters (obtained, for example, by transesterification of a corresponding ester with vinyl acetate; the method of activated vinyl ether), carbamoylphenoxy esters (obtained, for example, by treatment of the appropriate acid isoxazolines reagent; 1,2-oxasolinone method or method Woodward), or 1-lower alkoxyphenyl esters (obtained, for example, by treatment of the appropriate acid lowest alkoxyethanol; ethoxyacetylene method), or esters of aeginetia, such as N,N'-disubstituted amicinemici (obtained, for example, by treatment of the corresponding acid with a suitable N,N'-disubstituted by a carbodiimide, for example N,N-dicyclohexylcarbodiimide; carbodiimide method), or N,N-disubstituted amicinemici (obtained, for example, by treatment of the corresponding acid with N,N-disubstituted by cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters, respectively, substituted electron-acceptor substituents (obtained, for example, by treatment of the appropriate acid corresponding substituted phenol, for example 4-NITROPHENOL, 4-methylsulfinylphenyl, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or phenyldiazonium, in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide; method of activated aryl esters), cyanomethylene esters (obtained, for example, by treatment of the corresponding acid chloroacetonitrile in the presence of a base; method cyanomethylene esters, thioesters, especially unsubstituted or substituted, for example nitro-substituted, phenylthiourea (obtained, for example, by treatment of the corresponding acid with unsubstituted or substituted, for example nitro-substituted thiophenolate, inter alia anhydrite or carbodiimide method; method of activated thioesters), amino - or amidoamine (obtained, for example, by treatment of the appropriate acid N-hydroxyamino or N-gidrosiimidazolyatnye, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide or 1-hydroxybenzotriazole, for example, anhydrous or carbodiimide method; method of activated N-hydroxyamino) or silyl esters (obtained, for example, by treatment of the appropriate acid solaruim agent, such as hexamethyldisilazane, and reaction with hydroxy groups, but not with amino groups).

The anhydrides of the acids of formula II can be symmetric or preferably mixed anhydrides of this acid, for example anhydrides with inorganic acids, such as acid halide, especially the acid chloride is (get, for example, by treatment of the corresponding acid with thionyl chloride, pentachloride phosphorus or oxalylamino; method of acid chlorides), azides (obtained, for example, from a corresponding acid ester via the corresponding hydrazide and treatment by nitric acid; azide method), anhydrides with poluprovodnikov carboxylic acids, such as the corresponding esters, for example lower alkalemia palefire carboxylic acid (obtained, for example, by treatment of the appropriate acid lower alkylamino esters of halogenarenes, such as harmarville, acid or 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; method of mixed anhydrides O-alkalicarbonate acid, or anhydrides dihalogenoalkane, especially deklarirovannoe phosphoric acid (obtained, for example, by treatment of the corresponding acid with phosphorus oxychloride; method of phosphorus oxychloride), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtained, for example, by treatment of the corresponding acid with unsubstituted or substituted by a halide lower alkane - or phenylalaninol acids, such as chloride phenylacetic acid chloride pavlinovoi acid or chloride triperoxonane acid; method of mixed dioxide is the Idov carboxylic acid), with organic sulfonic acids (obtained, for example, by treatment of a salt, such as alkali metal salt, of the corresponding acid with a suitable halide of an organic sulfonic acid, such as chloride of lower alkane - or aryl-, for example methane - or p-toluensulfonate acid; method of mixed anhydrides of sulfonic acid), or organic phosphonic acids (obtained, for example, by treatment of the corresponding acid with a suitable organic phosphonic anhydride or phosphonic cyanide; method of mixed anhydrides of phosphonic acid) and symmetric anhydrides (obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropyl; method symmetrical anhydrides).

Suitable cyclic amides are especially amides with five-membered deathcycle aromatic nature, such as amides of imidazoles, for example imidazole (obtained, for example, by treatment of the corresponding acid with N,N'-carbonyl diimidazol; imidazolidinyl method), or pyrazoles such as 3,5-dimethylpyrazole (obtained, for example, from the acid hydrazide by treatment with acetylacetone; pyrazolidinone method).

Derivatives of acids of formula II, where carboxypropyl is in activated form, preferably obtain in situ. For example, N,N'-disubstituted amicinemici could the t to be obtained in situ by reaction of a mixture of acids of formula II and the amine of formula III in the presence of a suitable N,N-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide. Reaction mixed anhydrides of the acid of formula II with an organic phosphonic acid may be obtained in situ by reaction with, for example, propylphosphonic anhydride or diethylthiophosphate in the presence of a suitable base, preferably a tertiary amine, such as triethylamine or dimethylaminopyridine.

The reaction may be carried out in a known manner, and the reaction conditions will depend particularly on whether carboxypropyl carboxylic acid of formula II is activated, and if so, in what way, usually in the presence of a suitable solvent or diluent or a mixture thereof and optionally in the presence of a condensing agent, for example, when carboxypropyl is present in the reaction in the form of an anhydride, may also serve as acid binding agent, while cooling or heating, for example at temperatures from about -30°to about +150°C., especially from about 0°C. to +100°C, preferably from room temperature (approx. +20°C) to +70°C, in an open or closed reaction vessel and/or in the atmosphere of inert gas, for example nitrogen. The usual condensing agents are, for example, carbodiimide, for example N,N'-diethyl-, N,N'-dipropyl-, N,N'-DICYCLOHEXYL - or N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide suitable carbonyl connect the tion, for example carbonyldiimidazole, or 1,2-oxazoline compounds, such as 2-ethyl-5-phenyl-1,2-oxazoline 3'-sulfonate and 2-tert-butyl-5-methylisoxazole, or a suitable acylaminorhodanines, for example 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline. Normal linking acid condensing agents are, for example, carbonates of alkali metals or hydrogen carbonates, for example sodium carbonate or potassium or bicarbonate (usually together with a sulfate), or organic bases, such as, typically, pyridine or triethylamine, or steric employed trinessa the bonds alkylamines, for example N,N-aminobutiramida-N-ethylamine.

In a preferred embodiment, the carboxylic acid of the formula II is reacted with an amine of formula III in a suitable solvent, such as, for example, N,N-dimethylformamide, in the presence of propylphosphonic anhydride or diethylthiophosphate triethylamine, from 1 to 48 hours between 0°C and about 50°C., preferably at room temperature.

Protective groups

If one or more functional groups, for example carboxy, hydroxy, amino, or mercapto, are protected or must be protected in a compound of formula III, as they do not participate in the reaction, there are such groups, which are usually used in the synthesis of amides, in particular peptide compounds, and also cephalos is rinow and penicillins, and derivatives of nucleic acids and sugars.

The protective groups may already be present in the precursor and to protect the functional group from undesired side reactions, such as acylation, etherification, esterification, oxidation, solvolysis and similar reactions. Characteristic of the protective groups is that they are easily, i.e. without undesired side reactions are removed, usually by solvolysis, recovery, photolysis or also enzymatic activity, for example, in conditions similar to physiological conditions, and that they are not present in the final product. Specialist known or it can easily determine which protective groups are suitable for the reactions mentioned herein.

The protection of such functional groups such protective groups are themselves protective group and the reaction to their removal are described, for example, in the standard sources peptide synthesis, mentioned earlier, and special sources on protective groups, such as J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in "Methods der organischen Chemie" (Methods of organic chemistry), Houben-Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974 and .W.Greene, "Protective Groups in Organic Synthesis", Wiley, New York.

Additional stages of the process

In the advanced stages of the process carried out when necessary, functional groups of the parent compounds, which do not accept participants of the e in the reaction, may be present in unprotected form or may be protected, for example, one or more protective groups mentioned above as the "protective group". The protective groups are then completely or partially removed in accordance with one of methods described here.

Salts of the compounds of formula I with salt-forming group can be obtained in a known manner. Acid additive salts of compounds of formula I can be obtained by treatment with an acid or a suitable anion exchange reagent.

Salt can usually be converted into the free compounds, for example, treatment with a suitable basic agents, such as carbonates, alkali metal bicarbonates of alkali metals or hydroxides of alkali metals, typically potassium carbonate or sodium hydroxide.

Stoichiometric mixtures, for example mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by suitable methods of separation. Diastereomer mixture, for example, can be separated into their individual diastereoisomers by fractional crystallization, chromatography, choice of solvent and similar procedures. This separation may take place or for the parent compound, or compounds of formula I directly. Enantiomers can be separated by formation of diastereoisomeric salts, for example, the p-salt formation with enantiomerically pure chiral acid, or chromatography, such as HPLC, using chromatographic substrates with chiral ligands.

The compound of formula I, where R1represents hydrogen, can be converted into the corresponding compound where R1represents lower alkyl, by reaction with, for example, diakonissen alkyl compound, especially diazomethane, in an inert solvent, preferably in the presence of a catalyst of noble metals, especially in dispersed form, for example copper, or salt of a noble metal, such as copper chloride(I) or copper sulfate(II). It is also possible reaction with the lowest alkylhalogenide or other lower alkanes, bearing a leaving group, such as lower alkyl alcohols, esterified with a strong organic sulfonic acid, such as lower alkanesulphonic acid (optionally substituted with halogen, such as fluorine), an aromatic sulfonic acid, for example unsubstituted or substituted benzosulfimide acid, where the substituents are preferably selected from lower alkyl, such as methyl, halogen, such as bromine, and/or nitro, for example, esterified methanesulfonic acid, or p-toluensulfonate acid. The alkylation takes place under normal conditions of alkylation of amides, especially in aqueous solution and/or in the presence of polar the solvent, usually alcohols, such as methanol, ethanol, isopropanol or ethylene glycol, or dipolar aprotic solvents, such as tetrahydrofuran, dioxane or dimethylformamide, where possible, in the presence of acid or basic catalyst, usually at temperatures from about 0°C. to the boiling temperature of the corresponding reaction mixture, preferably between 20°C. and the boiling point of the solvent, optionally at elevated pressure, for example, in a sealed tube, and/or in the atmosphere of inert gas, usually nitrogen or argon.

It should be emphasized that for the corresponding intermediate compounds may also have a reaction similar to the transformations mentioned in this section.

General conditions of the process

All described here stage of the process can be carried out in a known reaction conditions, preferably specifically, the above-described conditions, in the absence of or usually in the presence of solvents or diluents, preferably those that are inert to the reagents and are able to dissolve them, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically kationoobmennikom, for example, N+form, depending on the type of reaction and/or reagent at low, normal, or is avicennae temperature, for example in the range from -100°C to about 190°C., preferably from about -80°to about 150°C., for example at from -80 to -60°C, at room temperature, at from -20 to 40°C. or at the boiling point solvent used, under atmospheric pressure or in a closed vessel, possibly under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.

Salt can be present in all source connections and intermediate substances, if they contain salt-forming groups. Salt may also be present in the reaction of such compounds, provided that they are not destroyed in the reaction.

In all reaction stages present isomeric mixtures can be separated into their individual isomers, for example diastereoisomers or enantiomers or any mixture of isomers, for example racemates or diastereomeric mixture.

The invention also relates to those forms of the process in which he starts from the compound obtained at any stage in the form of an intermediate substance, and performs the missing stages, or interrupt the process at any stage, or forms the starting material in the reaction conditions, or uses the specified source material in the form of a reactive derivative or salt, or does not receive the connection method in accordance with the invention and processes mentioned soy is inania. In the preferred embodiment, each stage begins from those starting materials which lead to the compounds described above as preferred, especially as particularly preferred, especially preferred and/or preferred above all.

In a preferred embodiment, the compound of formula I is produced by method or similar methods and stages of the process specified in the examples.

The compounds of formula I, including their salts, are also provided in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as MES).

Pharmaceutical compositions, methods and applications

The present invention also relates to a method of treatment of a tumor disease, which is associated with inhibition of protein kinase activity, which includes the introduction of the compounds of formula I or its N-oxide or pharmaceutically acceptable salt, where the radicals and symbols have the meanings as defined above for formula I, in an amount effective for the specified disease of warm-blooded animal in need of such treatment.

In particular, the invention relates to a method for the treatment of leukemia, which is associated with inhibition of the activity of the Abl tyrosine kinase, which includes the introduction of the compounds of formula I or N-oxide or pharmaceutically acceptable salt, where the radicals and symbols have the meanings as defined above for formula I, in an amount effective for the specified leukemia, a warm-blooded animal in need of such treatment.

The present invention also relates to pharmaceutical compositions which include a compound of formula I or its N-oxide as the active ingredient and which can be used especially for the treatment mentioned in the beginning of the disease. Compositions for enteral administration, such as nasal, buccal, rectal or, especially, oral introduction, and for parenteral administration, such as intravenous, intramuscular or subcutaneous injection, warm-blooded animal, especially humans, are especially preferred. The compositions comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the treated disease and on the type, age, weight and individual condition, individual pharmacokinetic data and method of administration.

The present invention relates especially to pharmaceutical compositions which include a compound of formula I, its tautomer, N-oxide or pharmaceutically acceptable salt, or hydrate, or MES, and at least one pharmaceutically acceptable carrier.

The invention that the same applies to pharmaceutical compositions for use in the method of prevention or especially therapeutic treatment of the human or animal, the method of obtaining them (especially in the form of compositions for the treatment of tumors and for the treatment of neoplastic diseases, especially those mentioned above.

The invention also relates to methods for use of the compounds of the formula I or their N-oxides to obtain pharmaceutical compositions that include the compounds of formula I or their N-oxides as active component (active ingredient).

In a preferred embodiment, the pharmaceutical composition is suitable for the introduction of a warm-blooded animal, especially a human or industrial useful mammals suffering from a disease associated with inhibition of Abl tyrosine kinase, such as chronic myelogenous leukemia (CML), and includes an effective amount of the compounds of formula I or N-oxides for the inhibition of the fused protein Bcr-Abl, or its pharmaceutically acceptable salt, if salt-forming groups, together with at least one pharmaceutically acceptable carrier.

Pharmaceutical composition for prophylactic or especially therapeutic treatment of cancer and other proliferative diseases in a warm-blooded animal, especially humans or industrial useful mammal in need of such treatment, especially suffering from such disease, comprising as an active ingredient in a quantity that is prophylactically or especially therapeutically active against these diseases, a new compound of formula I or its N-oxide is particularly preferred.

Pharmaceutical compositions include from about 1% to about 95% active ingredient, form the introduction of a single dose include in the preferred embodiment, from about 20% to about 90% of the active ingredient and form are not separate doses include in the preferred embodiment, from about 5% to about 20% of the active ingredient. Unit dosage forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules. Other dosage forms are, for example, ointments, creams, pastes, foams, tinctures, sprays, etc. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.

The pharmaceutical compositions of the present invention receive a known manner, for example, conventional methods of mixing, granulating, coating, dissolving or lyophilization.

Preference is given to using solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example, in the case liofilizovannyh compositions comprising the active ingredient alone or together with a carrier, can be obtained before use. The pharmaceutical compositions can be sterile and/or may switch the th excipients, for example preservatives, stabilizers, moisturizing agents and/or amplificatory, soljubilizatory, salts for regulating osmotic pressure and/or buffers, and are obtained in a known manner, for example, conventional methods of dissolution and lyophilization. These solutions or suspensions can include increasing the viscosity agents or solubilization.

Suspensions in oil include as the oil component of the vegetable, synthetic or semi-synthetic oils, customary for injection purposes. In this respect, can be applied liquid fatty acid esters that contain as the acid component of the fatty acid with a long chain having from 8 to 22 carbon atoms. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and a is a monovalent or polyvalent, for example mono-, di - or trivalent alcohol, especially glycol and glycerin.

Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, optionally grinding the resulting mixture and processing the mixture or granules, if desired or necessary, with the inclusion of additional excipients, to form tablets or tablet core.

Suitable carriers are especially fillers, such as sugar, with the rods of cellulose and/or calcium phosphates, and also binders, such as starch and/or polyvinylpyrrolidone, and/or, if desired, disintegrators. Additional excipients are especially fluid conditioners and lubricants.

Core tablets may be formulated with suitable, optionally enteric coatings through the use of concentrated solutions of sugars, which may comprise gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solution in suitable organic solvents or solvent mixtures, or to obtain enteric coatings are suitable solutions of cellulose compositions.

Pharmaceutical compositions for oral administration also include hard gelatin capsules, and also soft sealed capsules consisting of gelatin and a plasticizer. Hard capsules can contain the active ingredient in the form of granules, for example, in a mixture with fillers, binders and/or galantai and optional stabilizers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquid excipients, which can also be added stabilizers and detergents.

Pharmaceutical compositions suitable for rectal administration, are, for example, suppositories, which consist of the combination is the active ingredient and base for the candle.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, for example water-soluble salt, or aqueous injection suspensions which contain substances which increase the viscosity, for example, carboxymethylcellulose sodium, sorbitol and/or dextran, and, if desired, stabilizers, are particularly suitable. The active ingredient, optionally together with excipients, can also be in the form of a lyophilisate and can be dissolved before parenteral introduction the addition of suitable solvents.

Solutions, which are used, for example, for parenteral administration, can also be used as infusion solutions.

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.

The invention likewise relates to a process or method of treating one of the above mentioned pathological conditions, especially of the disease, which is associated with inhibition of tyrosine kinase, especially of the corresponding tumors. The compounds of formula I or their N-oxides can be also or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in a quantity effective against the mentioned the of deseases, warm-blooded animal, such as man, in need of such treatment. When the patient has a body weight of approximately 70 kg, a daily injected dose is from about 0.05 g to about 5 g, preferably from about 0.25 g to about 1.5 g of compound of the present invention.

The present invention applies particularly well to the use of compounds of formula I or N-oxides or pharmaceutically acceptable salts, especially the compounds of formula I, which is preferred, or its pharmaceutically acceptable salts, as such or in the form of a pharmaceutical composition with at least one pharmaceutically acceptable carrier for therapeutic and also prophylactic injection for one or more of the above-mentioned diseases, preferably of the disease, which is associated with inhibition of protein kinase, especially tumor diseases, more specifically leukemia, which is associated with inhibition of Abl tyrosine kinase.

The preferred dose quantity, composition and obtaining pharmaceutical compositions (drug)that should be used in each case described above.

Raw materials

New raw materials and/or intermediate compounds and methods for their production, are also an object of the invention. In a preferred embodiment, the wasp is estline using such starting materials and reaction conditions, to get the preferred connection.

Substituted aminobenzoic acid of the formula II, for example, can be obtained by the reaction of ester 3-amino-4-R4benzoic acid, for example 3-amino-4-methylbenzoic acid, cyanamide and obtained by condensation of guanidine with 3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one and, finally, hydrolysis of the ether group.

Starting materials of formula III are known, industrially available or can be obtained analogously or in accordance with methods known from the prior art.

The following examples serve to illustrate the invention without limiting the scope of the invention.

Reduction

DMSOthe sulfoxide
HPLC/MS-MShigh-performance liquid
chromatography/tandem mass spectrometry
minminutes
tPLmelting point
NMPN-organic
NMRnuclear magnetic resonance
PEGthe polyethylene glycol
THFtetrahydrofuran

Examples

Example 1: N-(2-Furylmethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide

A solution containing ~50% propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μl, ~1 mmol)was added during 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (214,4 mg, 0.7 mmol), furfurylamine (Aldrich, Buchs, Switzerland; 61,8 μl, 0.7 mmol) and triethylamine (776 μl, 5.6 mmol) in 2 ml of N,N-dimethylformamide. After stirring for 24 hours at room temperature the mixture was treated polysystem aqueous solution of sodium bicarbonate and was extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuum. The crude product was recrystallized from dichloromethane to obtain specified in the connection header in the form of a crystalline solid.

1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); 4,43 (d, 2H); 6,23 (m, 1H); 6,33-6,37 (m, 1H); 7,30 (d, 1H); 7,42 (d, 1H); 7,49 (ddd, 1H); 7,53 (m, 1H); to 7.59 (dd, 1H); 8,11 (d, 1H); scored 8.38 (m, 1H); 8,49 (d, 1H); 8,66 (dd, 1H); 8,87 (t, 1H); 9,05 (s, 1H); which 9.22 (m, 1H).

The original material was prepared as follows.

Example 1A: Mononitrate ethyl ester 3-[(aminoiminomethyl)amino]-4-methylbenzoic acid

The Cyanamide (Flua, Buchs, Switzerland; 77,4 g 1,842 mol) was added to a solution of ethyl ester of 3-amino-4-methylbenzoic acid (J. Med. Chem. 16, 118-122, 1973; 150 g, 0,837 mol) in 850 ml of ethanol. Then was added dropwise hydrochloric acid (Fluka, Buchs, Switzerland; 108 ml of 12M, of 1.27 mol) over 15 min and the reaction mixture was then stirred at 90°C. (bath temperature) for 15 hours. The solvent was evaporated under reduced pressure to obtain residue, which was treated with water (1000 ml), and stirred while cooling to 5-10°C. was added dropwise a solution of ammonium nitrate (Merck, Darmstadt, Germany; 134,8 g, 1,68 mol) in water (400 ml) for 30 min, then ice water (1200 ml). After stirring for an additional 30 min, the product was filtered, washed with ice water (3×1000 ml), and dried in air. The residue was washed with diethyl ether (2×2000 ml), and dried in vacuum at 50° with obtaining specified in the connection header in the form of a crystalline solid, tPL195-197°C.

Example 1b: Ethyl ester of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinamine]benzoic acid

Stir a mixture of the intermediate from example 1A (164 g, 0,577 mol), 3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-it (113,8 g, 0,646 mol) and powdered NaOH (99%; Merck, Darmstadt, Germany; 26,6 g, 0,658 mol) in ethanol (2200 ml) was heated at the boil under reflux for 68 hours, the reaction Solvent was evaporated under reduced pressure, the NII and the residue was separated between ethyl acetate and water. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with water and with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to obtain residue, which was recrystallized from diethyl ether to obtain specified in the connection header in the form of a crystalline solid, tPL95-96°C.

Example 1C: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid

Aqueous sodium hydroxide (500 ml, 2M) was added dropwise to a stirred suspension of intermediate compound of example 1b (132,8 g, 0,397 mol) in ethanol (1200 ml) and water (1200 ml). The reaction mixture was stirred at 45°C for 2.5 h and then was treated dropwise aqueous HCl (1000 ml 1M) for 1.5 hours. After adding water (1000 ml) the precipitate was filtered, washed with water (4×500 ml) and dried at room temperature. The remaining water present in the air-dried product was removed by azeotropic distillation with toluene under reduced pressure. Dried toluene suspension was diluted with diethyl ether and was filtered. The remaining solid was washed with diethyl ether, and dried in vacuum at 80°C To produce specified in the connection header, tPL277-278°C.

Example 2: N-[4-Methyl-3-[[4-(3-pyridinyl)-pyrimidinyl]amino]benzoyl]-4-[(4-methyl-1-piperazinil)methyl]benzolamide

A solution containing ~50% propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 875 ál, ~1.5 mmol) was added during 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (306 mg, 1.0 mmol), 4-[(4-methyl-1-piperazinil)methyl]benzenamine (Chem. Abstr. Reg. Number: 70261-82-4; 205 mg, 1.0 mmol) and triethylamine (830 μl, 6.0 mmol) in 8 ml of N,N-dimethylformamide. After stirring for 24 hours at room temperature the mixture was treated with saturated aqueous ammonium chloride and was extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuum. The crude product is recrystallized from a mixture of ethanol-ethyl acetate to obtain specified in the connection header in the form of a crystalline solid, tPL153 to 155°C.

Example 3: 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(2-pyridinyl)piperazine

A solution containing ~50% propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μl, ~1 mmol)was added during 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (214,4 mg, 0.7 mmol), 1-(2-pyridyl)piperazine (Aldrich, Buchs, Switzerland; 114,3 mg, 0.7 mmol) and triethylamine (776 μl, 5.6 mmol) in 2 ml of N-dimethylformamide. After stirring for 24 hours at room temperature the mixture was treated according to analysandum aqueous solution of sodium bicarbonate and was extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuum. The crude product was purified column chromatography on silica gel, eluent 5-10% methanol in dichloromethane, to obtain specified in the connection header in the form of a solid substance.1H-NMR (400 MHz, DMSO-d6, δ): 2,31 (s, 3H); 3,35-3,74 (m, 8H); of 6.65 (ddd, 1H); 6,79 (d, 1H); 7,13 (dd, 1H); to 7.32 (d, 1H); 7,44 (d, 1H); 7,49-7,56 (m, 2H); of 7.69 (m, 1H); 8,11 (m, 1H); to 8.40 (m, 1H); charged 8.52 (d, 1H); 8,66 (dd, 1H); 9,06 (s, 1H); 9,24 (m, 1H).

The following compounds were obtained analogously using the corresponding amine (given in parentheses).

Example 4: 4-Methyl-N-[2-(2-pyridinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 2-(2-amino-ethyl)pyridine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): of 2.27 (s, 3H); of 2.97 (t, 2H); to 3.58 (m, 2H); 7.18 in (ddd, 1H); 7,25 (m, 1H); 7,29 (d, 1H); 7,42 (d, 1H); 7,47-7,56 (m, 2H); the 7.65 (m, 1H); of 8.06 (d, 1H); 8,39 (m, 1H); 8,44-8,51 (m, 3H); 8,66 (dd, 1H); 9,04 (s, 1H); which 9.22 (m, 1H).

Example 5: 4-Methyl-N-[1-(phenylmethyl)-4-piperidinyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 4-amino-1-benzylpiperidine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,47-to 1.63 (m, 2H); was 1.69 and 1.80 (m, 2H); 1,92-2,05 (m, 2H); and 2.27 (s, 3H); 2,73-and 2.83 (m, 2H); 3.43 points (s, 2H); 3,68-a 3.83 (m, 1H); 7.18 in-7,33 (m, 6H); 7,42 (d, 1H); 7,49 (ddd, 1H); at 7.55 (dd, 1H); 8,10 (m, 1H); to 8.14 (d, 1H); of 8.37 (m, 1H); 8,49 (d, 1H); 8,65 (dd, 1H); 9,04 (s, 1H); of 9.21 (m, 1H).

Example 6: 4-Methyl-N-(4-pyridinylmethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 4-(aminomethyl)pyridine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d , δ): 2,30 (s, 3H); to 4.46 (d, 2H); 7,26 (m, 2H); 7,33 (d, 1H); the 7.43 (d, 1H); 7,47 (ddd, 1H); a 7.62 (dd, 1H); is 8.16 (d, 1H); scored 8.38 (m, 1H); to 8.45 (m, 2H); and 8.50 (d, 1H); 8,66 (dd, 1H); 9,03 (t, 1H); remaining 9.08 (s, 1H); 9,23 (m, 1H).

Example 7: 4-Methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 2-(2-amino-ethyl)-1-methylpyrrole [Chem. Abstr. Reg. Number: 83732-75-6].1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); to 2.75 (t, 2H); 3.42 points (m, 2H); 3,51 (s, 3H); 5,76-to 5.85 (m, 2H); to 6.57 (m, 1H); 7,30 (d, 1H); the 7.43 (d, 1H); 7,46-7,58 (m, 2H); 8,10 (br, 1H); to 8.40 (m, 1H); 8,48-8,55 (m, 2H); 8,64-8,69 (m, 1H); 9,05 (s, 1H); 9,23 (m, 1H).

Example 8: N-[(4-Methoxyphenyl)methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 4-methoxybenzylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); of 3.69 (s, 3H); 4,37 (d, 2H); to 6.80-6.87 in (m, 2H); 7,17-of 7.23 (m, 2H); 7,31 (d, 1H); 7,42 (d, 1H); 7,47 (ddd, 1H); to 7.59 (dd, 1H); 8,11 (d, 1H); scored 8.38 (m, 1H); 8,49 (d, 1H); 8,66 (dd, 1H); 8,87 (t, 1H); 9,05 (s, 1H); 9,23 (m, 1H).

Example 9: 4-Methyl-N-(2-methylpropyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using isobutylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 0,85 (d, 6H); is 1.81 (m, 1H); and 2.27 (s, 3H); 3.04 from (m, 2H); 7,29 (d, 1H); 7,42 (d, 1H); of 7.48 (dd, 1H); at 7.55 (dd, 1H); 8,07 (d, 1H); 8,31-to 8.41 (m, 2H); 8,49 (d, 1H); 8,65 (dd, 1H); 9,05 (s, 1H); which 9.22 (m, 1H).

Example 10: 4-Methyl-N-(2-morpholinoethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 4-(2-amino-ethyl)morpholine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); 2,33 is 2.46 (m, 6H); 3.30 is is 3.40 (m, 2H); of 3.53 (m, 4H); 7,30 (d, 1H); 7,42 (d, 1H); 7,46-EUR 7.57 (m, 2H); of 8.06 (d, 1H); 8.30 to (m, 1H); scored 8.38 (m, 1H); 8,49 (d, 1H); 8,66 (dd, 1H); 9,05 (s, 1H); which 9.22 (m, 1H).

Example 11:4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(tetrahydro-2-furanyl)methyl]benzamide, using tetrahydrofurfurylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,49-to 1.63 (m, 1H); 1.70 to of 1.93 (m, 3H); and 2.27 (s, 3H); with 3.27 (m, 2H); to 3.58 (m, 1H); and 3.72 (m, 1H); of 3.94 (m, 1H); 7,29 (d, 1H); 7,42 (d, 1H); 7,49 (ddd, 1H); 7,56 (dd, 1H); 8,08 (d, 1H); 8,35-to 8.45 (m, 2H); 8,49 (d, 1H); 8,66 (dd, 1H); 9,04 (s, 1H); of 9.21 (m, 1H).

Example 12: N-[2-(2,4-Dihydroxy-5-pyrimidinyl)ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 5-(2-amino-ethyl)-2,4(1H,3H)-pyrimidinedione [Chem. Abstr. Reg. Number: 221170-25-8].1H-NMR (400 MHz, DMSO-d6, δ): of 2.27 (s, 3H); 2.40 a (t, 2H); to 3.34 (m, 2H); to 7.15 (m, 1H); 7,29 (d, 1H); 7,42 (d, 1H); 7,47-of 7.55 (m, 2H); 8,07 (d, 1H); 8,35-8,42 (m, 2H); 8,49 (d, 1H); 8,66 (dd, 1H); 9,04 (s, 1H); which 9.22 (m, 1H); 10,59 (s, 1H); br11.01 (s, 1H).

Example 13: N-Cyclohexyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using cyclohexylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,00-of 1.16 (m, 1H); 1.18 to about 1.36 (m, 4H); 1,52-of 1.85 (m, 5H); and 2.27 (s, 3H); 3,66-3,82 (m, 1H); 7,28 (d, 1H); 7,41 (d, 1H); of 7.48 (m, 1H); at 7.55 (dd, 1H); 8,06-to 8.12 (m, 2H); of 8.37 (m, 1H); 8,49 (d, 1H); 8,66 (dd, 1H); 9,04 (s, 1H); of 9.21 (m, 1H).

Example 14: N-[(3S)-Hexahydro-2-oxo-1H-azepin-3-yl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using L(-)-alpha-amino-Epsilon-caprolactam [Chem. Abstr. Reg. Number: 21568-87-6].1H-NMR (400 MHz, DMSO-d6, δ): to 1.11 to 1.31 (m, 1H); 1,37-to 1.82 (m, 3H); 1,83 is 1.96 (m, 2H); of 2.28 (s, 3H); 3,00-3,13 (m, 1H); 3,15-3,30 (m, 1H); 4,58 (m, 1H); to 7.32 (d, 1H); the 7.43 (d, 1H); 7,51 (ddd, 1H); at 7.55 (dd, 1H); to 7.84 (m, 1H); 8,08 (d, 1H); 8,13 (d, 1H); to 8.40 (m, 1H); and 8.50 (d, 1H); 8,66 (dd, 1H); 9,06 (s, 1H); which 9.22 (m, 1H).

Example 15: N-[2-(3,4-Acid)ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, COI is lsua 2-(3,4-acid)ethylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): of 2.27 (s, 3H); to 2.75 (t, 2H); 3.43 points (m, 2H); to 3.67 (s, 6H); 6,70 (dd, 1H); 6,77-6,83 (m, 2H); 7,30 (d, 1H); 7,42 (d, 1H); 7,46-EUR 7.57 (m, 2H); 8,07 (d, 1H); at 8.36-8,46 (m, 2H); 8,49 (d, 1H); 8,66 (dd, 1H); 9,05 (s, 1H); which 9.22 (m, 1H).

Example 16: Ethyl ester of 2-[[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]-4-titlecase acid using ethyl 2-amino-4-thiazoleacetate (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 1.16 (t, 3H); 2,32 (s, 3H); 3,70 (s, 2H); 4,06 (q, 2H); 7,01 (s, 1H); of 7.36 (d, 1H); 7,42-rate of 7.54 (m, 2H); of 7.82 (d, 1H); 8.34 per-of 8.47 (m, 2H); charged 8.52 (d, 1H); 8,66 (m, 1H); remaining 9.08 (s, 1H); 9,24 (m, 1H); 12,57 (br., 1H).

Example 17: N-[3-(1H-Imidazol-1-yl)propyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 1-(3-aminopropyl)imidazole (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,96 (qui, 2H); 2,30 (s, 3H); 3.24 in (m, 2H); 4,01 (t, 2H); 6,91 (s, 1H); 7,22 (m, 1H); 7,34 (d, 1H); was 7.45 (d, 1H); 7,51 (ddd, 1H); to 7.59 (dd, 1H); of 7.70 (s, 1H); to 8.14 (d, 1H); 8,42 (m, 1H); of 8.47 (t, 1H); charged 8.52 (d, 1H); 8,68 (dd, 1H); 9,10 (s, 1H); 9,25 (m, 1H).

Example 18: N-(Cyclopropylmethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using cyclothiomethylation (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 0,17-0,22 (m, 2H); 0,36 at 0.42 (m, 2H); 0,96 was 1.06 (m, 1H); of 2.28 (s, 3H); 3,11 (m, 2H); 7,31 (d, 1H); the 7.43 (d, 1H); to 7.50 (ddd, 1H); 7,58 (dd, 1H); 8,10 (d, 1H); to 8.40 (m, 1H); of 8.47 (t, 1H); and 8.50 (d, 1H); 8,67 (dd, 1H); 9,07 (s, 1H); 9,23 (m, 1H).

Example 19: N-(2-methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 2-methoxyethylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); 3,23 (s, 3H); 3,36-of 3.46 (m, 4H); 7,31 (d.l); the 7.43 (d, 1H); 7,51 (ddd, 1H); EUR 7.57 (dd, 1H); 8,10 (d, 1H); scored 8.38-of 8.47 (m, 2H); and 8.50 (d, 1H); 8,68 (dd, 1H); 9,07 (s, 1H); 9,23 (m, 1H).

Example 20: 4-Methyl-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 1-(3-aminopropyl)-2-pyrrolidinone (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,67 (m, 2H); 1,89 (m, 2H); to 2.18 (t, 2H); of 2.28 (s, 3H); 3,19 (m, 4H); of 3.32 (m, 2H); 7,30 (d, 1H); 7,42 (d, 1H); 7,49 (ddd, 1H); rate of 7.54 (dd, 1H); of 8.09 (d, 1H); 8,31-8,42 (m, 2H); 8,49 (d, 1H); 8,66 (dd, 1H); 9,04 (s, 1H); which 9.22 (m, 1H).

Example 21: N,4-Dimethyl-N-(phenylmethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using N-benzylmethylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); of 2.86 (s, 3H); 4,51-and 4.68 (m, 2H); 7,08-7,35 (m,7H); the 7.43 (d, 1H); of 7.48 (m, 1H); 7,71 (s, 1H); 8,35-8,54 (m, 2H); 8,67 (m, 1H); 8,97-of 9.09 (m, 1H); 9,24 (m, 1H).

Example 22: N-[4-(Acetylamino)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 4-aminoacetanilide (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): a 2.01 (s, 3H); 2,32 (s, 3H); 7,38 (d, 1H); was 7.45 (d, 1H); 7,47-rate of 7.54 (m, 3H); 7,63-7,71 (m, 3H); by 8.22 (m, 1H); 8,43 (m, 1H); charged 8.52 (d, 1H); 8,67 (dd, 1H); 9,13 (s, 1H); 9,25 (m, 1H); for 9.90 (s, 1H); 10,11 (s, 1H).

Example 23: N-(4-Methoxy-2-were)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 4-methoxy-2-methylaniline (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): of 2.16 (s, 3H); 2,32 (s, 3H); to 3.73 (s, 3H); 6.75 in (dd, 1H); PC 6.82 (m, 1H); 7,16 (d, 1H); 7,37 (d, 1H); was 7.45 (d, 1H); 7,49 (ddd, 1H); of 7.69 (dd, 1H); of 8.25 (d, 1H); to 8.41 (m, 1H); charged 8.52 (d, 1H); 8,67 (dd, 1H); 9,12 (s, 1H); 9,25 (m, 1H); RS 9.69 (s, 1H).

Example 24: 4-Methyl-N-[4-(methylsulphonyl)benzyl]-3-[[4-(3-perilin the l)-2-pyrimidinyl]amino]benzamide, using the hydrochloride of 4-methylsulfonylbenzoyl (Acros, Morris Plains, NJ).1H-NMR (400 MHz, DMSO-d6, δ): 2,30 (s, 3H); and 3.16 (s, 3H); of 4.54 (d, 2H); 7,34 (d, 1H); 7,44 (d, 1H); 7,49 (ddd, 1H); at 7.55 (m, 2H); 7,63 (dd, 1H); 7,86 (m, 2H); is 8.16 (d, 1H); to 8.40 (m, 1H); 8,51 (d, 1H); 8,67 (dd, 1H); 9,10 (m, 2H,); 9,24 (m, 1H).

Example 25: N-[[4-(Dimethylamino)phenyl]methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using dihydrochloride of 4-(dimethylamino)benzylamine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); 2.82 from (s, 6H); 4,32 (d, 2H); only 6.64 (m, 2H); 7,11 (m, 2H); 7,31 (d, 1H); the 7.43 (d, 1H); of 7.48 (ddd, 1H); to 7.59 (dd, 1H); to 8.12 (d, 1H); 8,39 (m, 1H); and 8.50 (d, 1H); 8,68 (dd, 1H); 8,81 (t, 1H); 9,07 (s, 1H); 9,24 (m, 1H).

Example 26: N-(2-Amino-2-oxoethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using hydrochloride glycinamide (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 2.29 (s, 3H); of 3.78 (d, 2H); 7,02 (s, 1H); 7,30 and 7.36 (m, 2H); 7,44 (d, 1H); 7,53 (ddd, 1H); to 7.61 (dd, 1H); 8,11 (m, 1H); to 8.41 (m, 1H); and 8.50 (d, 1H); to 8.57 (t, 1H); 8,67 (dd, 1H); remaining 9.08 (s, 1H); 9,24 (m, 1H).

Example 27: Methyl ester of N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]glycine, hydrochloride using licensedialog ether (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 2.29 (s, 3H); 3,63 (s, 3H); 3,98 (d, 2H); 7,34 (d, 1H); 7,44 (d, 1H); 7,52 (ddd, 1H); to 7.59 (dd, 1H); 8,11 (d, 1H); to 8.41 (m, 1H); and 8.50 (d, 1H); 8,67 (dd, 1H); 8,87 (t, 1H); which is 9.09 (s, 1H); 9,23 (m, 1H).

Example 28: Methyl ester of N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]beta-alanine, hydrochloride using methyl ester of beta-alanine (Fluka, Buchs, Switzerland).1Mr. YAM is (400 MHz, DMSO-d6, δ): of 2.27 (s, 3H); 2.57 m (t, 2H); 3.46 in (m, 2H); of 3.57 (s, 3H); 7,31 (d, 1H); the 7.43 (d, 1H); 7,50-of 7.55 (m, 2H); 8,07 (d, 1H); to 8.40 (m, 1H); of 8.47 (t, 1H); and 8.50 (d, 1H); 8,67 (dd, 1H); 9,07 (s, 1H); 9,23 (m, 1H).

Example 29: N-[[4-(Aminosulfonyl)phenyl]methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using hydrochloride n-(aminomethyl)benzosulfimide (Sigma, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 2.29 (s, 3H); 4,51 (d, 2H); 7,30 (s, 2H); 7,34 (d, 1H); 7,43 is 7.50 (m, 4H); a 7.62 (dd, 1H); to 7.75 (m, 2H); is 8.16 (d, 1H); to 8.40 (m, 1H); 8,51 (d, 1H); 8,68 (dd, 1H); 9,06 (t, 1H); which is 9.09 (s, 1H); 9,24 (m, 1H).

Example 30: N-(3-Hydroxypropyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 3-amino-1-propanol (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,65 (qui, 2H); of 2.28 (s, 3H); 3,29 (m, 2H); 3.42 points (m, 2H); 4,50 (m, 1H); 7,30 (d, 1H); the 7.43 (d, 1H); 7,51 (ddd, 1H); 7,56 (dd, 1H); of 8.09 (d, 1H); at 8.36-8,43 (m, 2H); and 8.50 (d, 1H); 8,67 (dd, 1H); 9,07 (s, 1H); 9,23 (m, 1H).

Example 31: N,N-Diethyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using diethylamine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,04 (m, 6N); of 2.28 (s, 3H); and 3.31 (m, 4H); 7,02 (dd, 1H); 7,27 (d, 1H); 7,44 (d, 1H); 7,51 (ddd, 1H); to 7.61 (m, 1H); 8,39 (m, 1H); 8,51 (d, 1H); 8,68 (dd, 1H); 9,01 (s, 1H); 9,23 (m, 1H).

Example 32: 1,1-Dimethylethylene ester of N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-(L)-phenylalanine using hydrochloride tert-butyl ester of L-phenylalanine (Novabiochem (Juro), Lucerne, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 1.32 (s, 9H); of 2.28 (s, 3H); of 3.07 (m, 2H); 4.53-in (m, 1H); 7,13-7,29 (m, 5H); to 7.32 (d, 1H); 7,44 (d, 1H); to 7.50 (ddd, 1H); at 7.55 (dd, 1H); with 8.05 (m, 1H); 8,39 (m, 1H); 8,49 (d, 1H); 863 (d, 1H); 8,67 (dd, 1H); remaining 9.08 (s, 1H); 9,23 (m, 1H).

Example 33: 1,1-Dimethylethylene ester of N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-(D)-alanine, hydrochloride using tert-butyl ester of D-alanine (Novabiochem (Juro), Lucerne, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): of 1.34 (d, 3H); to 1.38 (s, 9H); of 2.28 (s, 3H); 4,32 (m, 1H); 7,33 (d, 1H); the 7.43 (d, 1H); 7,51 (ddd, 1H); to 7.61 (dd, 1H); to 8.14 (m, 1H); to 8.40 (m, 1H); and 8.50 (m, 1H); 8,58 (d, 1H); 8,67 (dd, 1H); remaining 9.08 (s, 1H); 9,23 (m, 1H).

Example 34: N-[1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-piperidinyl]benzamide using N-4-piperidinylmethyl (Maybridge Chemical Co. Ltd).1H-NMR (400 MHz, DMSO-d6, δ): 1,49 (m, 2H); 1,68-of 1.94 (m, 2H); 2,30 (s, 3H); 2,92 (m, 1H); and 3.16 (m, 1H); with 3.79 (m, 1H); of 4.05 (m, 1H); was 4.42 (m, 1H); was 7.08 (dd, 1H); 7,31 (d, 1H); 7,41-rate of 7.54 (m, 5H); 7,63 (m, 1H); 7,79-to 7.84 (m, 2H); of 8.28 (d, 1H); to 8.40 (m, 1H); 8,51 (d, 1H); 8,66 (dd, 1H); 9,06 (s, 1H); 9,24 (m, 1H).

Example 35: 4-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]morpholine, using morpholine (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 2.29 (s, 3H); 3,47 (m, 8H); 7,10 (dd, 1H); 7,30 (d, 1H); 7,44 (m, 1H); 7,52 (ddd, 1H); the 7.65 (m, 1H); to 8.40 (m, 1H); 8,51 (d, 1H); 8,69 (dd, 1H); 9,05 (s, 1H); 9,23 (m, 1H).

Example 36: 1-(4-Methoxyphenyl)-4-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]piperazine using 1-(4-methoxyphenyl)piperazine (Emka Chemie, Neufahrn, Germany).1H-NMR (400 MHz, DMSO-d6, δ): 2,30 (s, 3H); 2,87-is 3.08 (m, 4H); 3,50-3,75 (m, 4H); to 3.67 (s, 3H); 6,78-to 6.88 (m, 4H); for 7.12 (dd, 1H); 7,31 (d, 1H); 7,44 (m, 1H); 7,51 (ddd, 1H); to 7.67 (m, 1H); scored 8.38 (m, 1H); charged 8.52 (m, 1H); 8,67 (dd, 1H); 9,06 (s, 1H); 9,23 (m, 1H).

Example 37: 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzo is l]-4-(4-pyridinyl)piperazine, using 1-(4-pyridyl)piperazine (Emka Chemie, Neufahrn, Germany). H-NMR (400 MHz, DMSO-d6, δ): 2,31 (s, 3H); 3,30 (m, 4H); 3,59 (m, 4H); 6,77 (m, 2H); 7,14 (dd, 1H); to 7.32 (d, 1H); was 7.45 (d, 1H); 7,52 (ddd, 1H); of 7.70 (m, 1H); 8,16 (m, 2H); to 8.41 (m, 1H); 8,53 (d, 1H); 8,67 (dd, 1H); 9,07 (s, 1H); 9,24 (m, 1H).

Example 38: 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(pyrazinyl)piperazine, using 1-(2-pyrazinyl)piperazine (Emka Chemie, Neufahrn, Germany). H-NMR (400 MHz, DMSO-d6, δ): 2,31 (s, 3H); 3,57 (m, 8H); 7,14 (dd, 1H); to 7.32 (d, 1H); was 7.45 (d, 1H); 7,51 (ddd, 1H); 7,72 (m, 1H); a 7.85 (d, 1H); 8,08 (d, 1H); 8,29 (d, 1H); to 8.40 (m, 1H); 8,53 (d, 1H); 8,65 (dd, 1H); 9,06 (s, 1H); 9,24 (m, 1H).

Example 39: 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(phenylmethyl)piperazine using 1-benzylpiperazine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2.21 are to 2.42 (m, 4H); of 2.28 (s, 3H); 3,34-3,63 (m, 6H); 7,07 (dd, 1H); 7,21-7,34 (m, 6H); 7,43 is 7.50 (m, 2H); 7,63 (m, 1H); scored 8.38 (m, 1H); and 8.50 (d, 1H); 8,65 (dd, 1H); 9,03 (s, 1H); which 9.22 (m, 1H).

Example 40: 1-Cyclopentyl-4-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]piperazine using 1-cyclopentylpropionate (Emka Chemie, Neufahrn, Germany).1H-NMR (400 MHz, DMSO-d6, δ): of 1.20 to 1.31 (m, 2H); 1,39-of 1.62 (m, 4H); of 1.65 and 1.75 (m, 2H); 2,18-2,47 (m, 8H); 3.27 to 3,62 (m, 4H); was 7.08 (dd, 1H); 7,29 (d, 1H); 7,44 (d, 1H); 7,51 (ddd, 1H); a 7.62 (m, 1H); scored 8.38 (m, 1H); 8,51 (d, 1H); 8,68 (dd, 1H); 9,04 (s, 1H); which 9.22 (m, 1H).

Example 41: 4-{{4-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1-piperazinil}acetyl}morpholine, using 4-[2-(piperazine-1-yl)acetyl]morpholine (Emka Chemie, Neufahrn, Germany).1H-NMR (400 MHz, DMSO-d6, δ): to 2.29 (s, 3H); 2,31-2,49 (m, 4H); and 3.16 (s, 2H); 3,37-of 3.60 (m, 12H); 7,07(dd, 1H); 7,29 (d,lH); was 7.45 (d, 1H); 7,52 (ddd, 1H); the 7.65 (m, 1H); 8,39 (m, 1H); 8,51 (d, 1H); 8,68 (dd, 1H); 9,04 (s, 1H); 9,23 (m, 1H).

Example 42: 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-[2-oxo-2-(1-pyrrolidinyl)ethyl]piperazine using 1-[2-(piperazine-1-yl)-acetylpyrrolidine (Emka Chemie, Neufahrn, Germany).1H-NMR (400 MHz, DMSO-d6, δ): at 1.73 (m, 2H); to 1.83 (m, 2H); to 2.29 (s, 3H); 2,43 (m, 4H); to 3.09 (s, 2H); of 3.25 (m, 2H); 3,34-3,63 (m, 6H); 7,07 (dd, 1H); 7,29 (d, 1H); was 7.45 (d, 1H); 7,52 (ddd, 1H); to 7.64 (m, 1H); 8,39 (m, 1H); 8,51 (d, 1H); 8,68 (dd, 1H); 9,04 (s, 1H); which 9.22 (m, 1H).

Example 43: Ethyl ester of 4-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1-piperazinecarboxamide acid using ethyl 1-piperidinecarboxylate (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 1.16 (t, 3H); to 2.29 (s, 3H); 3,19-3,63 (m, 8H); was 4.02 (q, 2H); 7,10 (dd, 1H); 7,30 (d, 1H); was 7.45 (d, 1H); 7,52 (ddd, 1H); 7,66 (m, 1H); to 8.40 (m, 1H); 8,51 (d, 1H); 8,68 (dd, 1H); 9,06 (s, 1H); 9,23 (m, 1H).

Example 44: 2-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1,2,3,4-tetrahydroisoquinoline using 1,2,3,4-tetrahydroisoquinoline (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,31 (s, 3H); and 2.79 (m, 2H); 3,57-3,90 (m, 2H); 4,58-rate 4.79 (m, 2H); 7,08-of 7.23 (m, 5H); to 7.32 (d, 1H); 7,42-to 7.50 (m, 2H); of 7.70 (m, 1H); 8,39 (m, 1H); 8,51 (d, 1H); 8,67 (dd, 1H); 9,05 (s, 1H); 9,24 (m, 1H).

Example 45: N,N-bis(2-Methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using bis(2-methoxyethyl)amine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,28 (s, 3H); 3,09 (br.s, 3H); 3,23 (br.s, 3H); 3,47 (m, 8H);? 7.04 baby mortality (dd, 1H); 7,27 (d, 1H); 7,44 (d, 1H); 7,51 (ddd, 1H); a 7.62 (m, 1H); 8,39 (m, 1H); 8,51 (d, 1H); 8,68 (dd, 1H); 9,01 (s, 1H); 9,23 (m, 1H).

Example 46: 1'-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1,4'-bipiperidine using 4-piperidinophenyl (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,21 of 1.50 (m, 8H); 1,51 of-1.83 (m, 2H); to 2.29 (s, 3H); 2,39 (m, 4H); in 2.68 (m, 1H); 2.95 and (m, 1H); 3,71 (m, 1H); was 4.42 (m, 1H); 7,07 (dd, 1H); 7,28 (d, 1H); was 7.45 (d, 1H); 7,52 (ddd, 1H); 7,63 (m, 1H); 8,40 (m, 1H); 8,51 (d, 1H); 8,67 (dd, 1H); 9,03 (s, 1H); 9,23 (m, 1H).

Example 47: Ethyl ester of N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-N-(phenylmethyl)glycine, using the ethyl ester of N-benzylglycine (Fluka, Buchs, Switzerland).1H-NMR (300 MHz, DMSO-d6, δ): 0,97-l,20 (m, 3H); and 2.27 (s, 3H); 3,90-4,12 (m, 4H); 4,58-and 4.68 (m, 2H); 7,07 (m, 1H); 7,15-7,34 (m, 6H); 7,38-7,53 (m, 2H); 7,65-7,74 (m, 1H); 8,35-8,51 (m, 2H); 8,66 (dd, 1H); 8,96-9,04 (m, 1H); which 9.22 (m, 1H).

Example 48: N-(3-Chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 3-Chloroaniline (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): of 2.33 (s, 3H); 7,14 (m, 1H); of 7.36 (m, 1H); 7,41 (d, 1H); 7,46 (d, 1H); 7,49 (ddd, 1H); 7.68 per-7,73 (m, 2H); to 7.95 (m, 1H); of 8.25 (m, 1H); 8,43 (m, 1H); 8,53 (d, 1H); 8,66 (dd, 1H); to 9.15 (s, 1H); 9,26 (m, 1H); 10,33 (s, 1H).

Example 49: N-(2,2-Diphenylether)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, 2,2-diphenylethylamine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,24 (s, 3H); a 3.87 (m, 2H); to 4.41 (m, 1H); 7,12-7,17 (m, 2H); 7.23 percent-7,31 (m, 9H); 7,41-7,44 (m, 2H); 7,51 (ddd, 1H); 7,97 (m, 1H); of 8.37-8,44 (m, 2H); 8,48 (d, 1H); 8,68 (dd, 1H); 9,05 (s, 1H); 9,23 (m, 1H).

Example 50: N-(2,3-Dihydro-1H-inden-1-yl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 1-aminoindan (Fluka, Buchs, Switzerland). H-NMR (400 MHz, DMSO-d6, δ): 1,90 for 2.01 (m, 1H); to 2.29 (s, 3H); 2,43 (m, 1H); 2.77-to of 2.86 (m, 1H); 2.91 in are 2.98 (m, 1H); to 5.56 (m, 1H); 7,08-7,25 (m, 4H); 7,31 (d, 1H); the 7.43 (d, 1H); to 7.50 (ddd, 1H); to 7.64 (dd, 1H); to 8.20 (m, 1H); to 8.40 (m, 1H); and 8.50 (d, 1H); 8,68-8,72 (m, 2H); remaining 9.08 (s, 1H); 9,24 (m, 1H).

Example 51: N-(Diphenylmethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using alpha aminodiphenylamine (Fluka, Buchs, Switzerland)1H-NMR (400 MHz, DMSO-d6, δ): to 2.29 (s, 3H); 6,41 (d, 1H); 7,20 was 7.36 (m, 11H); the 7.43 (d, 1H); 7,46 (ddd, 1H); to 7.67 (dd, 1H); 8,18 (m, 1H); scored 8.38 (m, 1H); and 8.50 (d, 1H); 8,68 (dd, 1H); 9,10 (s, 1H); 9,20 (d, 1H); 9,24 (m, 1H).

Example 52: 4-Methyl-N-[2-(1-piperidinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 1-(2-amino-ethyl)piperidine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1.30 and to 1.38 (m, 2H); of 1.41 to 1.48 (m, 4H); of 2.28 (s, 3H); 2,31-to 2.41 (m, 6H); to 3.33 (m, 2H); 7,31 (d, 1H); 7,44 (d, 1H); 7,51 (ddd, 1H); at 7.55 (dd, 1H); 8,08 (m, 1H); 8,28 (t, 1H); to 8.40 (m, 1H); 8,51 (d, 1H); 8,67 (dd, 1H); 9,07 (s, 1H); 9,24 (m, 1H).

Example 53: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(5,6,7,8-tetrahydro-1-naphthalenyl)benzamide using 5,6,7,8-tetrahydro-1-naphtylamine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,63-1,71 (m, 4H); 2,32 (s, 3H); 2,60 (m, 2H); to 2.74 (m, 2H); of 6.96 dd, 1H); 7,07-7,14 (m, 2H); 7,37 (d, 1H); was 7.45 (d, 1H); 7,49 (ddd, 1H); of 7.69 (dd, 1H); of 8.25 (m, 1H); to 8.41 (m, 1H); charged 8.52 (d, 1H); 8,67 (dd, 1H); 9,12 (s, 1H); 9,25 (m, 1H); 9,65 (br.s).

Example 54: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide, using 4-(trifluoromethyl)benzylamine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,30 (s, 3H); 4.53-in (d, 2H); 7,34 (d, 1H); 7,44 (d, 1H); 7,46-7,53 (m, 3); a 7.62 (dd, 1H); 7,66 (m, 2H); 8,16 (m, 1H); to 8.40 (m, 1H); 8,51 (d, 1H); 8,67 (dd, 1H); remaining 9.08 (t, 1H); 9,10 (s, 1H); 9,24 (m, 1H).

Example 55: 4-Methyl-N-[(5-methylpyridyl)methyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 2-(aminomethyl)-5-methylpyrazine (TCI-JP, Distrib. Zürich, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): to 2.29 (s, 3H); of 2.45 (s, 3H); of 4.54 (d, 2H); 7,33 (d, 1H); 7,44 (d, 1H); 7,49 (ddd, 1H); a 7.62 (dd, 1H); to 8.14 (m, 1H); to 8.40 (m, 1H); to 8.45 (m, 2H); and 8.50 (d, 1H); 8,66 (dd, 1H); 9,07 (t, 1H); which is 9.09 (s, 1H); 9,23 (m, 1H).

Example 56: N-(2-Ethoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 2-amoxicillin (TCI-JP, Distrib. Zurich, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ)with 1.07 (t, 3H); of 2.28 (s, 3H); 3,30-to 3.49 (m, 6H); 7,31 (d, 1H); the 7.43 (d, 1H); 7,51 (ddd, 1H); EUR 7.57 (dd, 1H); of 8.09 (m, 1H); scored 8.38-to 8.45 (m, 2H); and 8.50 (d, 1H); 8,67 (dd, 1H); 9,07 (s, 1H); 9,24 (m, 1H).

Example 57: 4-Methyl-N-[2-(2-oxo-l-imidazolidinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 1-(2-amino-ethyl)imidazolidin-2-[Chem. Abstr. Reg. Number: 6281-42-1].1H-NMR (400 MHz, DMSO-d6, δ): of 2.27 (s, 3H); 3,13-up 3.22 (m, 4H); 3.30 is is 3.40 (m. 4H); 6,27 (br.s, 1H); 7,30 (d, 1H); the 7.43 (d, 1H); 7,49-7,56 (m, 2H); 8,08 (d, 1H); to 8.40 (m, 1H); to 8.45 (t, 1H); and 8.50 (d, 1H); 8,67 (dd, 1H); 9,06 (s, 1H); 9,23 (m, 1H).

Example 58: 4-Methyl-N-(5-methyl-2-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, using 2-amino-5-picoline (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): and 2.26 (s, 3H); 2,32 (s, 3H); 7,35 (d. 1H); was 7.45 (d, 1H); 7,49 (ddd, 1H); to 7.64 (dd, 1H); to 7.77 (dd, 1H); 8,07 (d, 1H); 8,18 (m, 1H); 8,31 (d, 1H); 8,43 (m, 1H); charged 8.52 (d, 1H); 8,66 (dd, 1H); remaining 9.08 (s, 1H); 9,25 (m, 1H); of 10.58 (s, 1H).

Example 59: 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]am is but]benzoyl]-4-phenyl-4-piperidinol, using 4-hydroxy-4-phenylpiperidine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,45-of 1.73 (m, 2H); of 1.88 (m, 2H); of 2.28 (s, 3H); 3.15 in (m, 1H); 3,47 (m, 1H); to 3.64 (m, 1H); 4,39 (m, 1H); 5,14 (s, 1H); 7,14 (dd, 1H); 7,19 (m, 1H); 7,26-7,31 (m, 3H); the 7.43 (d, 1H); 7,45-7,51 (m, 3H); of 7.69 (d, 1H); to 8.40 (m, 1H); 8,48 (d, 1H); 8,67 (dd, 1H); 9,03 (s, 1H); 9,24 (m, 1H).

Example 60: N-(3-Benzoylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 3-aminobenzophenone (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 2,32 (s, 3H); 7,39 (d, 1H); 7,43-7,58 (m, 6H); to 7.67 (m, 1H); 7,70-to 7.77 (m, 3H); 8,13 (m, 1H); to 8.20 (m, 1H); of 8.27 (m, 1H); 8,42 (m, 1H); charged 8.52 (d, 1H); 8,66 (dd, 1H); 9,14 (s, 1H); 9,25 (m, 1H); 10,41 (s, 1H).

Example 61: 1,1-Dimethylethylene ester of N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]glycine, hydrochloride using tert-butyl ester of glycine (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): of 1.40 (s, 9H); to 2.29 (s, 3H); 3,86 (d, 2H); 7,33 (d, 1H); the 7.43 (d, 1H); 7,51 (ddd, 1H); 7,58 (dd, 1H); 8,10 (d, 1H); to 8.40 (m, 1H); and 8.50 (d, 1H); 8,67 (dd, 1H); is 8.75 (t, 1H); remaining 9.08 (s, 1H); 9,23 (m, 1H).

Example 62: Ethyl ester of 4-[[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]benzooxazol acid using ethyl 4-aminophenylacetate (Maybridge Chemical Co. Ltd.).1H-NMR (400 MHz, DMSO-d6, δ): to 1.16 (t, 3H); 2,32 (s, 3H); of 3.60 (s, 2H); 4,06 (q, 2H); 7,21 (m, 2H); 7,38 (d, 1H); was 7.45 (d, 1H); of 7.48 (ddd, 1H); of 7.70 (m, 3H); 8,23 (m, 1H); to 8.41 (m, 1H); charged 8.52 (d, 1H); 8,66 (dd, 1H); 9,13 (s, 1H); the 9.25 (m, 1H); to 10.16 (s, 1H).

Example 63: 4-Methyl-N-[3-(methylpentylamino)propyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using N-(3-aminopropyl)-N-methylaniline (TCI-JP, Distrib. Zürich Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1,73 (qui, 2H); of 2.28 (s, 3H); 2,84 (s, 3H); 3.24 in-3,37 (m, 4H); 6,55 (m, 1H); of 6.65 (m, 2H); 7,10 (m, 2H); 7,31 (d, 1H); the 7.43 (d, 1H); 7,47 (ddd, 1H); at 7.55 (dd, 1H); 8,10 (d, 1H); of 8.37-8,44 (m, 2H); 8,50 (d, 1H); 8,65 (dd, 1H); 9,06 (s, 1H); 9,23 (m, 1H).

Example 64: Ethyl ester of 1-[[3-[[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]phenyl]methyl]-4-piperidinecarboxylic acid using ethyl 1-(3-aminobenzyl)piperidine-4-carboxylate (Maybridge Chemical Co. Ltd.).1H-NMR (400 MHz, DMSO-d6, δ): 1.14 in (t, 3H); 1,49-to 1.61 (m, 2H); 1,72 and 1.80 (m, 2H); 1,92-2,02 (m, 2H); and 2.27 (m, 1H); 2,32 (s, 3H); to 2.74 (m, 2H); 3.40 in (s, 2H); is 4.03 (q, 2H); 6,98 (d, 1H); 7,25 (m, 1H); 7,38 (d, 1H); 7,43-7,51 (m, 2H); 7,66-7,73 (m, 3H); of 8.25 (s, 1H); 8,42 (m, 1H); charged 8.52 (d, 1H); 8,65 (dd, 1H); 9,12 (s, 1H); 9,25 (m, 1H); 10,14 (s, 1H).

Example 65: Diethyl ether [[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]papandonatos acid using hydrochloride diethylaminoacetate (Aldrich, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): 1,19 (t, 6H); 2,30 (s, 3H); 4,10-4,22 (m, 4H); at 5.27 (d, 1H); to 7.35 (d, 1H); 7,44 (d, 1H); 7,51 (ddd, 1H); 7,63 (dd, 1H); 8,15 (m, 1H); to 8.40 (m, 1H); and 8.50 (d, 1H); 8,67 (dd, 1H); 9,11 (s, 1H); of 9.21-9,25 (m, 2H).

Example 66 N-[2-[bis(1-Methylethyl)amino]ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide using 2-diisopropylaminoethyl (Fluka, Buchs, Switzerland).1H-NMR (400 MHz, DMSO-d6, δ): of 0.95 (m, 12H); of 2.28 (s, 3H); 2.49 (m, 2H); to 2.94 (m, 2H); 3,17 (m, 2H); 7,30 (d, 1H); the 7.43 (d, 1H); to 7.50 (ddd, 1H); rate of 7.54 (dd, 1H); 8,09 (br.s, 1H); of 8.27 (m, 1H); to 8.40 (m, 1H); and 8.50 (d, 1H); 8,67 (dd, 1H); 9,06 (s, 1H); 9,23 (m, 1H).

Example 67 N-[3-(Diethylamino)phenyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzo the MFA

A solution containing ~50% propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μl, ~1.05 mmol)was added during 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (214,4 mg, 0.7 mmol), N,N-diethyl-1,3-benzydamine (115 mg, 0.7 mmol) and triethylamine (776 μl, 5.6 mmol) in 2 ml of N-dimethylformamide. After stirring for 24 hours at room temperature the mixture was treated polysystem aqueous solution of sodium bicarbonate and was extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuum. The crude product was purified by chromatography on silica gel, eluent 2% methanol in dichloromethane and recrystallized from acetone to obtain specified in the connection header in the form of a crystalline solid.1H-NMR (400 MHz, DMSO-d6, δ)with 1.07 (t, 6H); 2,31 (s, 3H); 3,29 (m, 4H); 6,38 (m, 1H); 7,06 (m, 2H); 7,11 (m, 1H); of 7.36 (d, 1H); 7,43 is 7.50 (m, 2H); to 7.67 (m, 1H); 8,21 (m, 1H); 8,43 (m, 1H); 8,51 (d, 1H); 8,66 (dd, 1H); 9,12 (s, 1H); 9,24 (m, 1H); for 9.90 (s, 1H).

Example 68: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[[3-[(1-hydroxy-1-methylethyl)1-5-(1,1,1-trifluoromethyl)phenyl]methyl]benzamide

Diethylthiophosphate (Aldrich, Buchs, Switzerland; 0.33 ml, 2.0 mmol) was added to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (306 mg, 1.0 mmol), 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)Ben is alumina (220 mg, 1.0 mmol) and triethylamine (560 μl, 4.0 mmol) in 5 ml of N,N-dimethylformamide at 10°C. After stirring for 3 hours at 60°C. the mixture was treated with saturated aqueous sodium bicarbonate and was extracted three times with ethyl acetate. The combined extracts were dried (MgSO4), was filtered and the solvent was evaporated under reduced pressure to get crude product, which was recrystallized from ethyl acetate to obtain specified in the connection header in the form of a crystalline solid, tPL253-258°C.

Example 69: 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-N-[(4-methyl-1-piperazinil)methyl]benzamide

Diethylthiophosphate (Aldrich, Buchs, Switzerland; and 0.50 ml, 3.0 mmol) was added to a stirred mixture of 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (438 mg, 1.5 mmol), 4-[(4-methyl-1-piperazinil)methyl]benzenamine (308 mg, 1.5 mmol) and triethylamine (840 μl, 3.0 mmol) in 10 ml of N-dimethylformamide at 10°C. After stirring for 12 hours at 60°C. the mixture was treated with water a solution of sodium bicarbonate and was extracted three times with ethyl acetate. The combined extracts were washed with water and the solvent was evaporated under reduced pressure to obtain a residue. The residue is suspended in water and was filtered to obtain crude product, which was recrystallized from a mixture of tetrahydrofuran-ethyl acetate to p is by receiving N-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(4-methyl-1-piperazinil)methyl]benzamide in the form of a crystalline solid, tPL220-224°C.

Example 69A: Mononitrate methyl ester 3-[(aminoiminomethyl)amino]-4-methylbenzoic acid

Using the procedure described in example 1A, but with the methyl ester of 3-aminobenzoic acid (Fluka, Buchs, Switzerland) instead of ethyl ester of 3-amino-4-methylbenzoic acid, has been specified in the title compound in the form of crystalline solids, tPL170-172°C.

Example 69b: Methyl ester of 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid

Using the procedure described in example 1b, but with an intermediate compound of example 69A instead of Mononitrate ethyl ester 4-methyl-3-[(aminoiminomethyl)amino]-4-methylbenzoic acid, has been specified in the title compound in the form of crystalline solids, tPL195-200°C.

Example C: 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid

Using the procedure described in example 1C, but with an intermediate compound of example 69b instead of the ethyl ester of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid, has been specified in the title compound in the form of crystalline solids, tPL285-293°C.

Example 70: 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-N-[(3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but with 3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)b is Salamina instead of 4-[(4-methyl-1-piperazinil)methyl]benzoylamino, received 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)phenyl]benzamide in the form of a crystalline solid, tPL213-215°C.

Example 71: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]phenyl] benzamide

Using the procedure described in example 3, but using 3-[3-(1H-imidazol-1-yl)propoxy]benzolamide (Takao Nishi, etc., JP 10182459) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound as a solid substance.1H-NMR (400 MHz, DMSO-d6, δ): 2,12-of 2.21 (m, 2H); of 2.33 (s, 3H); a 3.87 (t, 2H); of 4.13 (t, 2H); 6,66 (dd, 1H); 6.87 in (s, 1H); 7,15-7,26 (m, 2H); 7,32-7,42 (m, 2H); 7,44-7,52 (m, 3H); to 7.61 (s, 1H); of 7.70 (d, 1H); 8,24 (s, 1H); 8,43 (d, 1H); 8,53 (d, 1H); 8,67 (d, 1H); 9,13 (s, 1H); 9,26 (br. s, 1H); 10,13 (s, 1H).

Example 72: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide

Using the procedure described in example 3, but using 3-[2-(1H-imidazol-1-yl)ethoxy]benzolamide (Rolf Paul, and others, Journal of Medicinal Chemistry (1993), 36 (19), 2716-25) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound as crystalline solid.1H-NMR (400 MHz, DMSO-d6, δ): was 2.34 (s, 3H); 4,22 (t, 2H); 4,37 (t, 2H); of 6.68 (dd, 1H); 6.90 to (s, 1H); 7,21-7,27 (m, 2H); of 7.36-the 7.43 (m, 2H); 7,46-7,53 (m, 3H); to 7.67-7,74 (m, 2H); of 8.25 (br. s, 1H); 8,44 (dt, 1H); 8,54 (d, 1H); 8,68 (dd, 1H); to 9.15 (s, 1H); 9,27 (br. d, 1H); 10,15 (s, 1H).

Example 73: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethyl)phenyl]benzamide

PL178-180°C.

Aniline was prepared as follows.

Example 73a: N-ethyl-2-(trifluoromethyl)-1,4-benzydamine

A mixture of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis GmbH; of 5.4 g, 20 mmol) and a solution of ethylamine in ethanol (50 ml 2M, 100 mmol) was heated at 80°C for 18 hours in a steel pressure vessel. The mixture was then cooled and the solvent was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent 20% ethyl acetate in hexane) to give N-ethyl-4-nitro-6-(trifluoromethyl)benzenamine in the form of a yellow oil. This product was dissolved in ethanol (180 ml) and was first made at atmospheric pressure over Raney Nickel (0.5 g) at 45°C. the calculated amount of hydrogen was applied for 50 hours. The mixture then was filtered and the solvent was evaporated under reduced pressure to get crude product, which was purified by chromatography (silica gel; eluent 50% ethyl acetate in hexane) and recrystallized from a mixture of ether-hexane to obtain specified in the title compound as a beige crystalline solid.1H-NMR (400 MHz, DMSO-d ): a 1.11 (t, 3H), 3,05 (m, 2H), 4,18 (br t, 1H), 4,66 (br.s, 2H), 6,58-only 6.64 (m, 1H) and 6.68-6.75 in (m, 2H).

Example 74: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(diethylamino)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using N,N-diethyl-2-(trifluoromethyl)-1,4-benzydamine (Toshio Niwa, DE 3524519) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL128-131°C.

Example 75: (±)-4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[(2-hydroxypropyl)amino]-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using (±)-1-[[4-amino-2-(trifluoromethyl)phenyl]amino]-2-propanol (Tsutomu Mano, EP 299497) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL184-186°C.

Example 76: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using N,N-bis(2-methoxyethyl)-2-(trifluoromethyl)-1,4-benzydamine (Toshio Niwa, DE 3524519) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL156-157°C.

Example 77: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1-piperazinil)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in the example 3, but using 4-(4-methyl-1-piperazinil)-3-(trifluoromethyl)benzolamide (Anthony David Baxter, WO 0119800) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL214-217°C.

Example 78: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using 4-(1-piperidinyl)-3-(trifluoromethyl)benzolamide (Leping Li, WO 0151456) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL201-202°C.

Example 79: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using 4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzolamide (Steven Lee Bender WO 0153274) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL129-130°C.

Example 80: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 4-(4-morpholinyl)-3-(trifluoromethyl)benzolamide (Steven Lee Bender WO 0153274) instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL 216-218°C.

Example 81: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-phenyl-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using 4-(phenyl)-3-(trifluoromethyl)benzolamide instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL172-174°C.

Aniline was prepared as follows.

Example a: 4-(Phenyl)-3-(trifluoromethyl)benzolamide

Phenylboric acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), palladium acetate (II (0,225 g, 1 mmol), tri-o-tolylphosphino (0,608 g, 2 mmol) and aqueous potassium carbonate solution (50 ml of 1 M) was added to a stirred solution of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis GmbH; of 5.4 g, 20 mmol) in dimethylformamide (200 ml) and was heated at 120°C under argon atmosphere for 1 h the Mixture was then evaporated to dryness under reduced pressure and the residue was treated with water (100 ml) and was extracted with ethyl acetate (3×80 ml). The combined extracts were washed (brine solution), dried (MgSO4), was filtered and the solvent was evaporated under reduced pressure to obtain 4'-nitro-2'-(trifluoromethyl)-[1,11-biphenyl]. Biphenyl was dissolved in ethanol (200 ml) and was first made at atmospheric pressure over Raney Nickel (2 g) at 22°C. the calculated amount of hydrogen was applied for 11 hours. The mixture then was filtered and the solvent was evaporated the ri reduced pressure to obtain crude product, which was purified by chromatography (silica gel; eluent ethyl acetate) to obtain the specified title compound as a brown oil.1H-NMR (400 MHz, DMSO-d6): 5,62 (br.s, 2H), 6,80 (dd, 1H), of 6.96 (d, 1H), 6,99 (d, 1H), 7,19-of 7.23 (m, 2H), 7,29-7,39 (m, 3H).

Example 82: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide

Using the procedure described in example 69, but using 4-(3-pyridinyl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL276-280°C.

Aniline was prepared as follows.

Example a: 4-(3-Pyridinyl)-3-(trifluoromethyl)benzolamide

Mix a solution of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis GmbH; 3,37 g, 12.5 mmol) and 3-(tri-n-butylstannyl)pyridine (Maybridge Chemical Co. Ltd., England; 5.0 g, 13.5 mmol) in xylene (75 ml) was saturated with argon for 10 minutes at 20°C. Then was added tetrakis(triphenylphosphine)palladium (0) (1.4 g, 1.25 mmol) and the resulting mixture was heated at 130°C for 24 hours under argon atmosphere. The mixture was then cooled, treated with an aqueous solution of sodium hydroxide (150 ml 0.1 M) and saturated air for 2 hours. Poluchennuyu mixture then was diluted with ethyl acetate (200 ml) and was filtered. The organic phase is then washed with water is th (2×80 ml) and saturated aqueous sodium chloride (1×80 ml), dried (MgSO4), was filtered and the solvent was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent 50% ethyl acetate in hexane) to give 3-[(4-nitro-3-(trifluoromethyl)phenyl]pyridine. This product was dissolved in ethanol (200 ml) and was first made at atmospheric pressure over Raney Nickel (0,23 g) at 22°C. the calculated amount of hydrogen was applied within 24 hours. The mixture then was filtered and the solvent was evaporated under reduced pressure to get crude product, which was purified by chromatography (silica gel; eluent 50% ethyl acetate in hexane) and recrystallized from a mixture of ether-hexane to obtain specified in the title compound as a colourless crystalline solid, tPL92-93°C.

Example 83: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using 4-(1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide (Steven Lee Bender WO 0153274) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL226-229°C.

Example 84: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69,but using 4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine, got mentioned in the title compound as amorphous solid.

Aniline was prepared as follows.

Example a: 4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide

A mixture of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis GmbH; 6.0 g, 22 mmol) and 2,4-dimethylimidazole (10.6 g, 110 mmol) was heated at 120°C for 36 hours under argon atmosphere. The mixture was then cooled and the residue was treated with water (150 ml) and was extracted with ethyl acetate (3×80 ml). The combined extracts were washed (brine solution), dried (MgSO4), was filtered and the solvent was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent ethyl acetate), obtaining 1-[4-nitro-2-(trifluoromethyl)phenyl]-1H-imidazole as a yellow crystalline solid. This product was dissolved in ethanol (290 ml) and was first made at atmospheric pressure over Raney Nickel (1,15 g) at 25°C. the calculated amount of hydrogen was filed within 14 hours. The mixture then was filtered and the solvent was evaporated under reduced pressure to get crude product, which was purified by recrystallization from a mixture of ether-hexane to obtain specified in the connection header in the form of a crystalline solid, tPL163-164°C.

Example 85: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]Amin is]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL154-163°C.

Aniline was prepared as follows.

Example 85a: 4-(4-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzolamide

Using the procedure described in example a, but using 4(5)-methyl-1H-imidazole instead of 2,4-dimethylimidazole got mentioned in the title compound as a beige crystalline solid, tPL141-143°C.

Example 86: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL154-163°C.

Aniline was prepared as follows.

Example 86a: 4-(2-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide

Using the procedure described in example a, but using 2-methyl-1H-imidazole instead of 2,4-dimethylimidazole got mentioned in the title compound as a colourless crystalline solid substances is a, tPL117-119°C.

Example 87: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonylmethyl]benzamid

Using the procedure described in example 69, but using 3-amino-5-(4-morpholinyl)-N-(methyl)benzamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL153-156°C.

Aniline was prepared as follows.

Example 87a: 3-Bromo-5-nitrobenzoic acid, 1,1-dimethylethylene ether

A solution of p-utility in hexane (12,8 ml of 2.5 M, 32 mmol) was added under stirring to tert-butanol (46 ml) at 25°C under argon atmosphere. After 30 min the mixture was treated dropwise with a solution of 3-bromo-5-nitrobenzotrifluoride (J. Mindl, Collect. Czech. Chem. Commun. (1973), 38, 3496-505; 32 mmol) in dry THF (40 ml) and was stirred for 17 h the Mixture was then treated with ether (250 ml) and washed with brine. The ether solution was dried (MgSO4) and the solvent was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent 20% ethyl acetate in hexane) and recrystallized from a mixture of ether-hexane to obtain specified in the title compound as a colourless crystalline solid, tPL77-78°C.

Example 87b: 3-(4-Morpholinyl)-5-nitrobenzoic acid, 1,1-d is metaliteracy ether

Stir a mixture of 3-bromo-5-nitrobenzoic acid, 1,1-dimethylethylene ester (example 86a; to 3.02 g, 10 mmol) and research (1,22 ml, 14 mmol) in toluene (50 ml) was treated with tert-butyl sodium (1,34 g, 14 mmol), tri-tert-butylphosphine (3 ml, 1.5 mmol) and Tris(dibenzylideneacetone)dipalladium[0] (0.45 g, 0.5 mmol) under argon atmosphere and then heated at 60°C for 18 hours the Mixture was diluted with ethyl acetate (150 ml), was filtered, washed with brine (2×50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent : 15% ethyl acetate in hexane) and recrystallized from a mixture of ethyl acetate-hexane to obtain specified in the title compound as a colourless crystalline solid, tPL116-118°C.

Example C: 3-(4-Morpholinyl)-5-nitrobenzoic acid, methyl ester

A mixture of 3-(4-morpholinyl)-5-nitrobenzoic acid, 1,1-dimethylethylene ester (example 87b; of 0.77 g, 2.5 mmol), 1,8-diazabicyclo[5,4,0]undec-7-ene (of 0.56 ml, 3.75 ml) and potassium bromide (1,09 g, 12.5 mmol) in methanol (25 ml) was stirred at 90°C for 250 minutes Then add the cooled mixture to hydrochloric acid (50 ml, 0.1 M) and was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (2×25 ml), water (2×25 ml) and lanim solution (2×50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to get crude product, which was purified by recrystallization from a mixture of ethyl acetate-hexane to obtain specified in the title compound as a yellow crystalline solid.

Example 87d: 3-(4-Morpholinyl)-5-nitro-N-(methyl)benzamide

Stir a solution of 3-(4-morpholinyl)-5-nitrobenzoic acid, methyl ester (example s; of 0.53 g, 2 mmol) in toluene (5 ml) under argon atmosphere was treated with a mixture of methylamine hydrochloride (0.27 g, 4 mmol), trimethylaluminum (2 ml, 2 M solution in toluene, 4 mmol) in toluene (5 ml) and heated at 60°C for 18 hours, the Cooled mixture was then treated with hydrochloric acid (10 ml, 2 M)was stirred for 5 min and then was treated with aqueous hydroxide sodium (5 ml, 4 M). The mixture then was treated with water (100 ml) and was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (2×50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to get crude product, which was purified by recrystallization from ethyl acetate to obtain specified in the title compound as a yellow crystalline solid, tPL204-207°C.

Example a: 3-Amino-5-(4-morpholinyl)-N-(methyl)benzamide

A solution of 3-(4-morpholinyl)-5-nitro-N-(methyl)benzamide (example 86d; 300 mg, 112 mmol) in ethanol (20 ml) was first made at atmospheric pressure over Raney Nickel (0.2 g) at 25°C. The calculated amount of hydrogen was applied for 19 hours. The mixture then was filtered and the solvent was evaporated under reduced pressure to get crude product, which was purified by recrystallization from ethyl acetate, to obtain specified in the title compound as a beige crystalline solid, tPL201-204°C.

Example 88: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 3-amino-5-(trifluoromethyl)-N-(methyl)benzamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL245-249°C.

Example a: 3-Amino-5-(trifluoromethyl)-N-(methyl)benzamide

Using the procedure described in example 86 serial, but using α,α,α,-Cryptor-N-methyl-5-nitro-m-toluamide (Dean E. Welch, J. Med. Chem. (1969), 12, 299-303) instead of 3-(4-morpholinyl)-5-nitro-N-(methyl)benzamide was obtained is listed in the title compound as a beige crystalline solid, tPL113-115°C.

Example 89: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(3-pyridinyl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 5-(3-pyridinyl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-crypto is methyl)benzoylamino, got mentioned in the title compound in the form of a crystalline solid, tPL275-279°C.

Aniline was prepared as follows.

Example 89a: 5-(3-Pyridinyl)-3-(trifluoromethyl)benzolamide

Stir a solution of 3-amino-5-bromobenzonitrile (Apollo, England; 1.12 g, 5 mmol) and 3-(tri-n-butylstannyl)pyridine (Maybridge Chemical Co. Ltd., England; 2.0 g, 5.4 mmol) in xylene (30 ml) was saturated with argon for 10 minutes at 20°C. Then was added tetrakis(triphenylphosphine)palladium(0) (1,16 g, 1.0 mmol) and the resulting mixture was heated at 140°C for 36 hours under argon atmosphere. The mixture was then cooled, treated with an aqueous solution of sodium hydroxide (100 ml, 0.1 M) and saturated air for 2 hours. The resulting mixture then was diluted with ethyl acetate (200 ml) and was filtered. The organic phase is then washed with water (2×80 ml) and saturated aqueous sodium chloride (1×80 ml), dried (MgSO4), was filtered and the solvent was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent ethyl acetate) to obtain the specified title compound as a brown oil.1H-NMR (400 MHz, DMSO-d6, δ): 5,73 (br s, 2H), 6,83 (dd, 1H), 6,99 (d, 1H),? 7.04 baby mortality (d, 1H), 7,39 (dd, 1H), to 7.64 (d, 1H), 8,42 (m, 1H) and 8,53 (dd, 1H).

Example 90: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-morpholinyl)-3-(triptime the l)phenyl]benzamide

Using the procedure described in example 69, but using 5-(4-morpholinyl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL208-211°C.

Aniline was prepared as follows.

Example 90A: [3-Bromo-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether

A mixture of 3-amino-5-bromobenzonitrile (Apollo, England; 12 g, 50 mmol), di-tert-BUTYLCARBAMATE (12 g, 55 mmol) and 4-dimethylaminopyridine (and 0.61 g, 5 mmol) in acetonitrile (100 ml) was stirred at 60°C for 8 h, the Solvent then was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent 10% ethyl acetate in hexane) and recrystallized from hexane to obtain specified in the title compound as a colourless crystalline solid, tPL113-115°C.

Example 90b: [3-(4-Morpholinyl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether

Using the procedure described in example 86b, but using [3-bromo-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ester (Example 90A) instead of 3-bromo-5-nitrobenzoic acid, 1,1-dimethylethylene ether, has been specified in the title compound in the form of a crystalline solid, PL146-148°C.

Example 90: 5-(4-Morpholinyl)-3-(trifluoromethyl)benzolamide

[3-(4-Morpholinyl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ester (Example 90b; 1.7 g, 5 mmol) was treated with a solution of hydrogen chloride in isopropanol (30 ml, 4 M) and heated at 60°C for 5 h the Solvent was evaporated under reduced pressure and the residue was treated with an aqueous solution of sodium bicarbonate (80 ml) and was extracted with ethyl acetate (3×80 ml). The combined extracts were washed with brine (2×50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to get crude product, which was purified by recrystallization from a mixture of ether-hexane to obtain specified in the title compound as a yellow crystalline solid, tPL96-97°C.

Example 91: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL242-247°C.

Aniline was prepared as follows.

Example a: 3-(2-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile

A mixture of 3-fluoro-5-(trifluoromethyl)benzonic the sludge (Lancaster Synthesis GmbH; 17 g, 89 mmol) and 2-methylimidazole (Fluka, Buchs, Switzerland; 22,2 g, 270 mmol) in N,N-dimethylacetamide (80 ml) was stirred at 145°C for 19 h, the Solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with brine (200 ml), dried (Na2SO4) and the solvent was evaporated under reduced pressure to get crude product, which was purified by recrystallization from a mixture of ether-hexane to obtain specified in the title compound as a yellow crystalline solid, tPL132-134°C.

Example 91b: 3-(2-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid

A solution of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile (example a; 16.7 g, 66 mmol) in dioxane (300 ml) was added to aqueous sodium hydroxide solution (275 ml of 1 M) and the mixture was heated at 95°C for 18 hours the Solvent was evaporated under reduced pressure and the residue was neutralized with hydrochloric acid (1 M) and was extracted with butanol (2×250 ml). The solvent was evaporated under reduced pressure to obtain specified in the connection header.1H-NMR (400 MHz, DMSO-d6, δ): 7,17 (s, 1H); 8,03 (s, 1H); to 8.12 (s, 1H); 8,35 (s, 1H); to 8.41 (s, 1H); 8,53 (s, 1H); 13,90 (br., 1H).

Example 91p: [3-(2-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether

The triethylamine (5,23 ml, 37.5 mmol) was added to stir susp is sii 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (example 91b; 6.8 g, 25 mmol) in tert-butanol (200 ml). To the resulting solution was added diphenylphosphoryl (7.6 g, 27.5 mmol) and the mixture was heated at 80°C for 16 hours the Solvent was evaporated under reduced pressure and the residue was treated with water (100 ml) and was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with brine (100 ml), dried (Na2SO4) and the solvent was evaporated under reduced pressure to get crude product, which was purified column chromatography (silica gel, eluent 2% ethanol in ethyl acetate) and recrystallized from a mixture of ether-hexane to obtain specified in the title compound as a colourless crystalline solid, tPL203-208°C.

Example 91d: 5-(2-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide

Using the procedure described in example 90, but using [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ester (example 91p) instead of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether, has been specified in the title compound as a yellow crystalline solid, tPL130-133°C.

Example 92: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 5-(4-methyl-1H and idazole-1-yl)-3-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine, got mentioned in the title compound in the form of a crystalline solid, tPL235-236°C.

Aniline was prepared as follows.

Example 92A: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile

Using the procedure described in example a, but using 4-methyl-1H-imidazole instead of 2-methylimidazole, got mentioned in the title compound in the form of a crystalline solid, tPL127-128°C.

Example 92b: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid

Using the procedure described in example 91b, but using 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile (example 92A) instead of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile got mentioned in the title compound in the form of a crystalline solid, tPL>300°C.

Example C: [3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether

Using the procedure described in example 91p, but using 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (example 92b) instead of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid, has been specified in the title compound in the form of crystalline solids, tPL186-188°C.

Example 92d: 5-(2-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide

Using the procedure described in example 91d, but used the [3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid 1,1-dimethylethylene ester (example C) instead of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether, has been specified in the title compound as a colourless crystalline solid, tPL127-131°C.

Example 93: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using 5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound in the form of a crystalline solid, tPL231-233°C.

Aniline was prepared as follows.

Example 93A: 3-(5-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile

Using the procedure described in example a, but using 4-methyl-1H-imidazole instead of 2-methylimidazole, got mentioned in the title compound in the form of a crystalline solid, tPL99-101°C.

Example 93b: 3-(5-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid

Using the procedure described in example 91b, but using 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile (example 93A) instead of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile got mentioned in the title compound as a colourless crystalline solid, tPL243-245°C.

Primers: [3-(5-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether

Using the procedure described in example 91p, but using 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (example 93b) instead of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid, has been specified in the title compound in the form of crystalline solids, tPL169-171°C.

Example 93d: 5-(5-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzolamide

Using the procedure described in example 91d, but using [3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ester (example 93s) instead of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether, has been specified in the title compound as a colourless crystalline solid, tPL131-133°C.

Example 94: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinil)-5-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 69, but using 3-(4-methyl-1-piperazinil)-5-(trifluoromethyl)benzolamide instead of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzenamine got mentioned in the title compound in the form of a crystalline solid, tPL192-194°C.

Aniline was prepared as follows.

Example a: [3-(4-Methyl-1-piperazinil)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether

IP is by using the procedure described in example 87b, but using 1-methyl-1-piperazine instead of the research that has been specified in the title compound in the form of crystalline solids, tPL225°C.

Example 94b: 3-(4-Methyl-1-piperazinil)-5-(trifluoromethyl)benzolamide

Using the procedure described in example 90, but using [3-(4-methyl-1-piperazinil)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ester (example a) instead of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]carboxylic acid, 1,1-dimethylethylene ether, has been specified in the title compound in the form of oil.1H-NMR (400 MHz, DMSO-d6): of 2.20 (s, 3H), 2,42 (m, 4H), of 3.07 (m, 4H), 3,32 (br s, 2H), of 5.34 (s, 1H) and of 6.31 (s, 2H).

Example 95: 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 3, but using 2-(1-pyrrolidinyl)-5-(trifluoromethyl)benzolamide (Lancaster Synthesis Ltd.; Yasuhiro Ohtake and other WO 9965874) instead of 1-(2-pyridyl)piperazine was obtained is listed in the title compound as crystalline solid.1H-NMR (400 MHz, DMSO-d6): 1,77-to 1.82 (m, 4H); of 2.34 (s, 3H); 3,31-3,37 (m, 4H); 6,86 (d, 1H); 7,34-7,44 (m, 2H); 7,47 (d, 1H); 7,49-7,53 (m, 1H); 7,73 (dd, 1H); of 8.27 (d, 1H); 8,43 (dt, 1H); 8,53 (d, 1H); 8,69 (dd, 1H); 9,13 (s, 1H); 9,27 (d, 1H); 9,96 (s, 1H).

Example 96: 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Using the procedure described in example 1, but PR is changing 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid instead of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid and 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzolamide instead of furfurylamine, got mentioned in the title compound as a pale yellow crystalline solid, tPL264-266°C.

Example 96A: Mononitrate ethyl ester 3-[(aminoiminomethyl)amino]benzoic acid

Using the procedure described in example 1, but using the ethyl ester of 3-aminobenzoic acid (Fluka, Buchs, Switzerland) instead of ethyl ester of 3-amino-4-methylbenzoic acid, has been specified in the title compound in the form of crystalline solids, tPL170-172°C.

Example 96b: Ethyl ester of 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid

Using the procedure described in example 1b, but using Mononitrate ethyl ester 3-[(aminoiminomethyl)amino]benzoic acid instead of Mononitrate ethyl ester 3-[(aminoiminomethyl)amino]-4-methylbenzoic acid, has been specified in the title compound in the form of crystalline solids, tPL197-199°C.

Example C: 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid

Using the procedure described in example 1C, but using the ethyl ester of 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid instead of the ethyl ester of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid, has been specified in the title compound in the form of crystalline solids, tPL291-295°C.

Example 97: Soft capsules

5000 m is gcih gelatin capsules, each of which comprises as active ingredient 0.05 g of one of the compounds of formula I mentioned in examples, was prepared as follows:

250 g of powdered active ingredient is suspended in 2 l of Lauroglykol® (propilenglikolstearat, Gattefbssé S.A., Saint Priest, France) and placed in a wet pulverizer to obtain a particle size of about 1 to 3 μm. 0,419 g of the mixture was then placed in a soft gelatin capsule with filling capsules.

Example 98: Pharmacokinetic data

The test compound of formula I is formulated for administration to a female OF1 mice from IFACREDO, France, first dissolving in N-organic (NMP) and then diluting PEG300 to a final concentration of 10% vol./about. NMP: 90% vol./about. PEG300, getting a clean solution for the connection. Concentration made for the introduction of a constant volume of 10 ml/kg body weight. The connection was received immediately before use. Formulated compound is administered orally by stomach probe to provide doses of 50 mg/kg At certain time points mice (4 in each time) was anestesiologi using 3% izoflurana medical oxygen and blood samples were collected by cardiac puncture in heparinized tubes (approximately 30 IU/ml). Animals were then slaughtered without recovery after anesthesia. Plasma was obtained from blood by centrifugation (10,000 g, 5 min) and the Academy of Sciences who was literally immediately or kept frozen at -70°C.

Plasma samples (10-250 µl), for example, was destroyed using 5 µl of the internal standard, mixed with 200 ál of 0.1 M NaOH and 500 μl of chloroform in a test tube Eppendorf 1.5 ml and were thoroughly shaken for 10 minutes in the Eppendorf mixer. The mixture is then centrifuged (3 min at 10'000×rpm), the organic phase is transferred into a second Eppendorf tube and evaporated to dryness in a vacuum centrifuge (Speedvac 5301). The dry residue, for example, was dissolved in 250 μl of 10% vol./about. acetonitrile in water containing 0.1% formic acid. Subsequent analysis was carried out, for example, high performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) using a HPLC system Agilent 1100 Series (Agilent, Palo Alto, CA, USA) with a vacuum degasser, a double pump and thermostatic column compartment, associated with the cooling system Avtobaza (HTS PAL, CTC Analytics, Zwingen, Switzerland). Sample (5-15 μl) was applied, for example, on a column Ultra Phenyl (particle size 3 μm, 50×1 mm; Restek, Bellefonte, USA) with a protective column (4×2 mm) of the same material (Phenomenex, Torrance, USA). After equilibration, for example, water and latent period of 1 min, the sample was suirable, for example, a linear gradient of 0-100% acetonitrile in water containing 0.2% vol./about. formic acid for 11 min at a flow rate of 60 µl/min the Column was received for the next sample, for example, by re-balancing within min 100% water to the source provisions. The separation was carried out, for example, when the column temperature 40°C. the Flow was injected on the column, for example, directly into the ion source of a triple stage quadropole mass spectrometer (Quattro Ultima™, Micromass, Manchester, UK), controlled by the software Masslynx™ To 3.5 (Micromass, Manchester, UK), using as a method of ionization electrospray ionizing positive device (ESI+). The compound was identified using MS/MS with subsequent fragmentation of the incoming ions. Limitation of santovenia determined, for example, 0.002 nmol/L. Kalibrovochnye curves built on the known quantities of connections, including a fixed amount of internal standard in plasma treated as described above. The concentration of unknown samples was calculated from the ratio of the area under the peak of the selected child ion analytical sample of the product for its internal standard (y-axis) from the nominal concentration (x-axis). Regression analysis was performed using the software Quanlynx™, Masslynx™ To 3.5 (Micromass, Manchester, UK).

Example 99: Data inhibition in vitro

Data enzymatic (C-Abl, KDR, Flt3) inhibition of in vitro expressed as % inhibition at 10 μm. The measurements were carried out as described above in the General description.

Example Abl % @ 10 micronKDR % @ 10 micronFlt 3% @ 10 micron
15157
29773
36671
47746
57160
65156
77245
87081
94439
10 5748
115341
122233
137848
144954
156023
164210
175462
185662
194133
205622
2130/td> 93
22597
239067
248070
254473
265556
275451
287361
2978
305737
316883
3290 37
339751
347389
352747
365777

45 98
ExampleAbl % @ 10 micronKDR % @ 10 micronFlt 3% @ 10 micron
411352
423256
433763
447597
3461
46143
473974
489050
497237
508783
519252
527837
538879
546974
554354
56 4044
57842
584026
597583
607936
619565
625944
637482
645659
659660
666723
678841
689996

1. The compound of the formula

where R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl;
R2 represents lower alkyl, substituted by one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzocyclobutene(indan), bassilekin, five-, six - or semicolony heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen and oxygen, which may be unsaturated or fully saturated and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl, which is unsubstituted or substituted by one or two substituents selected from the group comprising lower alkyl, lower alkoxycarbonyl-lower alkyl, N-lower alkylpiperazine-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl lowest allylcarbamate, amino, mono - or disubstituted by lower alkyl, morpholino, lower alkylsulfonyl, halogen and benzoyl; and
R3 represents hydroxy, lower alkoxy, carboxy, missiologically, N-monophonically, mono - or disubstituted by lower alkyl or lower alkoxy, amino, cyclopropyl, five - or six-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen and oxygen, which may be unsaturated or fully or partially saturated and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl, which is unsubstituted or substituted by one or two substituents selected from the group comprising lower alkoxy, sulfamoyl, lower alkylsulfonyl; monocyclic heteroaryl group containing two nitrogen atom in the ring and zero oxygen atoms selected from imidazolyl, pyrazinyl and furanyl where they are unsubstituted; or where
R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono - or disubstituted by lower alkyl; six-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, which may be unsaturated or fully saturated and is unsubstituted or substituted by lower alkyl, hydroxy, pyridium, pyrazinium or pyrimidinyl; oxyalkylene with one oxygen atom and three or four carbon atoms or Isaakyan with one atom of nitrogen and three or four atoms is of Pereda, where the nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, substituted lower alkoxy, a phenyl, pyridinyl or pyrazinium;
R4 represents hydrogen or lower alkyl;
and R2 does not mean 3-aminopropyl, if R1 and R4 represents hydrogen, and the prefix "lower" denotes a radical having up to and including 7 carbon atoms,
or pharmaceutically acceptable salt of such compounds.

2. The compound of formula I according to claim 1, where
R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl;
R2 represents lower alkyl, substituted by one or two identical or different radicals R3, benzocyclobutene(indan), bassilekin, cyclohexyl, pyrrolidinyl, oxazolyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepine, oxazepine, oxazepines, phenyl, which is unsubstituted or substituted by one or two substituents selected from the group comprising lower alkyl, lower alkoxycarbonyl-lower alkyl, N-lower alkylpiperazine-lower alkyl, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl lowest allylcarbamate, amino mono - or disubstituted by lower alkyl, morpholino, halogen and benzoyl; and
R3 represents hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbarnoyl, N-monophonically, five - or testicle is nnow heterocyclic system with one or two heteroatoms, selected from the group comprising nitrogen and oxygen, which may be unsaturated or fully or partially saturated and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo, phenyl, which is unsubstituted or substituted by one or two substituents selected from the group comprising lower alkoxy, sulfamoyl, lower alkylsulfonyl; phenyl, pyridium, halogenatom and benzoyl; monocyclic heteroaryl group containing one or two nitrogen atom, selected from imidazolyl, benzimidazolyl, pyrazinyl and furanyl, or where
R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono - or disubstituted by lower alkyl; six-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, which may be unsaturated or fully saturated and is unsubstituted or substituted by lower alkyl, hydroxy, pyridium, pyrazinium or pyrimidinyl; oxyalkylene with one oxygen atom and four carbon atoms or Isaakyan with one nitrogen atom and four carbon atoms, where the nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, pyridinyl or pyrazinium;
R4 represents hydrogen or lower alkyl;
and R2 does not mean 3-amine is propyl, if R1 and R4 are hydrogen, and the prefix "lower"denotes a radical having up to and including 7 carbon atoms, or a pharmaceutically acceptable salt of such compounds.

3. The method of obtaining the compounds of formula I according to claim 1

or pharmaceutically acceptable salts, where the symbols R1, R2 and R4 are as defined in claim 1, characterized in that the compound of formula II

where R4 is as defined for compounds of formula I, or its derivative, where carboxypropyl-COOH is in the activated form, is subjected to reaction with the amine of formula III

where R1 and R2 are as defined for compounds of formula I, optionally in the presence of a dehydrating agent and an inert base, and optionally in the presence of an inert solvent;
where the above starting compound II and III may also be present with protected functional groups, if necessary and/or in the form of salts provided that salebrosa group and the possibility of reaction in salt form;
any protective group in the protected derivative of the compound of formula I delete;
and, if necessary, a free compound of formula I is transformed into a pharmaceutically acceptable salt, obtained pharmaceutically acceptable salt link the formula I is converted into the free compound or another pharmaceutically acceptable salt.

4. The pharmaceutical composition inhibiting activity of a protein kinase, comprising as active ingredient a compound of the formula I according to any one of claims 1 and 2 or pharmaceutically acceptable salt in an effective amount together with a pharmaceutically acceptable carrier.

5. The method of treatment of the disease, which is associated with inhibition of protein kinase activity, which includes the introduction of the compounds of formula I according to any one of claims 1 or 2 or a pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (XVIII): which can be used for monitoring and studying the metabolism in clinical and preclinical examinations. The invention also concerns a method for preparing the specified compound.

EFFECT: development of the effective method for preparing the compound.

2 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

Mglur5 modulators // 2439068

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel compounds of general formula I:

(where values R1-R5, X and Z are defined in invention description), pharmaceutical composition, which contains them, and application of claimed compounds as MGLUR5 modulators for inhibition of transient relaxations of lower esophageal sphincter or for treatment or prevention of gastroesophageal reflux disease.

EFFECT: obtaining compounds for treatment or prevention of gastroesophageal reflux disease.

14 cl, 87 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

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