Method for preparing dihydroindenamide compounds, pharmaceutical compositions containing these compounds and using them as protein kinase inhibitor

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydroindenamide specified in compounds described by general formula II, or their pharmaceutically acceptable salts. In general formula II, R1 represents piperazinyl which can be optionally substituted by one R1a; R1a represents H, CH3, C(O)Rd or C(O)ORa; Y represents pyrimidyl; Z represents pyridyl or pyrimidyl; Ra represents tert-butyl and Rd represents CH3. The above compounds represent tert-butyl-4-{5-[({(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl)-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate; N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide; 1-[4-acetylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide and (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide sulphate.

EFFECT: compounds inhibit activity of protein kinases specified in Abl, c-Kit and PDGFR, and can find application for treating diseases related to disturbed activity of the above protein kinases, eg leukaemia and other cancers.

4 cl, 4 tbl, 16 ex

 

The technical field

The present invention relates to a new type of connection dihydroindeno amide or pharmaceutically acceptable salts, their reception, pharmaceutical compositions containing these compounds, methods of use thereof for preventing or treating diseases associated with abnormal activity of protein kinases, especially in the case of diseases associated with abnormal activity of Abl, Bcr-Abl, c-Kit and DERIVED, and their use for producing medicaments for the prevention or treatment of such diseases.

Prior art

Protein kinases are enzymes, involved the transfer of a phosphate group from a nucleoside triphosphate to a specific serine, threonine or the tyrosine residue. Fosforilirovanii protein leads to activation of signal transduction pathways that play a crucial role in various biological processes, including cell growth, metabolism, differentiation and death. It is known that disturbance signals due to improper or abnormal activity of protein kinases, associated with a large number of diseases, including cancer, inflammation, autoimmune diseases, metabolic disorders, infections, disorders of the Central nervous system, cardiovascular diseases and So on protein kinases are attractive about the project in the development of drugs (Kogen (Cohen, Nat Rev. Drug Discovery 2002, 1, 309)).

Genes abl and bcr are normal genes located on chromosomes 9 and 22, respectively. Two hybrid gene formed by the segment of data exchange between two genes: bcr-abl gene, located on chromosome 22q-n abl-bcr gene, located on chromosome 9q+. Protein 210kD (s BCr-Abl) is encoded by bcr-abl gene of the Philadelphia chromosome. Fragment Abl protein Bcr-Abl includes the Abl tyrosinekinase, precisely regulated in the prototype C-Abl, but constantly activated fusion protein Bcr-Abl, leading to disruption of cell growth. Protein Bcr-Abl was detected in 95% of patients with chronic granulocytes leukemia ("HHL"), and 10-25% of patients with acute lymphoblastic leukemia (ALL). Imatinib, known under the trade name Gleevec is a tyrosine kinase inhibitor of Bcr-Abl and has been clinically proven as an effective compound for the treatment of " HHL " (Drucker and other Druker et al. N. Engl. J. Med. 2006, 355, 2408)). However, despite continuous treatment with Imatinib, some patients with " HHL " there are relapses in the final phase or stage of blast crisis due to immunity to the medication. The rationale for the immunity to the drug at the molecular level is the emergence of mutants resistant to imatinib in the kinase domain of Bcr-Abl protein. To date, we know more than 22 mutants, among which the most the more common are M244V, G250E, Q252H, Y253H, EC, E255V, F311L, T351I, F317L, F359V, V379I, L387M, NR, H396R, etc. (Nardi and others (Nardi, et al. Curr. Opin. Hematol. 2004, 11, 35)).

c-Kit (CD117, the receptor of stem cell factor), encoded by c-kit-protooncogene, is a growth factor receptor with tyrosinekinase activity. It can be activated by binding of stem cell factor (SCF). Mutations in c-kit leads to continuous activation function of c-Kit tyrosine kinase, which then leads to tyrosine kinase activity regardless of the ligands, the autophosphorylation of c-Kit and disturbance of cell proliferation. Overexpression and mutations of c-Kit revealed in the majority of gastrointestinal stromal tumors (GISO). Gastrointestinal stromal tumors are a series of mesenchymal tumors that can arise from precursor cells of the tissues of the gastrointestinal tract. Mostly, they occur in the population of middle and older age. Approximately 70% of tumors arise in the stomach, 20-30% of tumors in the small intestine and less than 10% in the esophagus, colon and rectum. It is well known that gastrointestinal stromal tumors are resistant to the effects of classical chemotherapy, however, is relatively effective in the inhibition of c-Kit with Imatinib, since it is assumed that c-Kit play a crucial role in the pathogenesis of these diseases (who joins and other Joensuu et al. N. Engl. J. Med. 2001, 344, 1052). c-Kit sverkhekspressiya and mutates, and other various cancers including mastocyte, neuroblastoma, germinoma, melanoma multi-cell lung cancer, breast cancer, oophoroma and acute myeloid leukemia (see Edling and other Edling et al. Int. J. Biochem. Cell Biol. 2007, 39, 1995; Lennartsson et al. Curr. Cancer Drug Targets, 2006, 6, 65).

In addition to participating in the development of cancers, SCF/c-Kit are also associated with autoimmune or inflammatory diseases. SCF is expressed in various structural and inflammatory cells of the respiratory tract. A large number of paths activated by the combination of SCF and c-Kit, including the path, using Phosphoinositide-3-kinase (PI3), phospholipase C (PLC)-gamma, the Src protein kinase, Janus kinase (JAK)/vector signal and activators of transcription (STAT)and mitogen-activated the protein kinase (MAP). Supprise SCF/c-Kit pathway might significantly reduce the level of histamine, reducing penetratio mast cells and eosinophils, to reduce the release of interleukin (IL)-4 and increased biological activity of the respiratory tract. Therefore, SCF/c-Kit is a potential target, controlling the fat cells and eosinophils, as well as controlling the activation of autoimmune or inflammatory diseases, including dermatitis, rheumatoid arthritis, allergic rhinitis, asthma, ankylosing spondylitis, psoriasis and diseases is ü Krona (see Ribs and other Reber et al. Eur. J. Pharmacol. 2006, 533, 327; Paniagua et al. Nat. Clin. Prac. Rheum. 2007, 3, 190).

Receptors of platelet growth factor (DERIVED), such as DERIVED-α and-DERIVED-β, are transmembrane tyrosinekinase receptors whose ligands are formed by two chains (PDGF-A), or two chains (PDGF-B), or heterodimers one chain and one chain (PDGF-AB). The receptors of growth factors, platelets undergo dimerization upon ligand binding, with subsequent activation of tyrosine kinase and signal transmission in descending order. Studies on animals in-vivo on PDGFs and PDGFRs showed that the DERIVED-α signaling plays a role in the development of gastrulation, brain and cardiac ganglion plates, gonads, lungs, gastrointestinal tract, skin, Central nervous system and bones. Also known role of signaling DERIVED-β in angiogenesis and early haematopoiesis. Signaling receptors of platelet growth factor is also associated with various other diseases. Autocrine activation of signaling pathways of growth factors associated with certain types of gliomatosis small blood vessels, myeloproliferative syndromes, tumors, multiple myeloma, and sarcoma, including wybuchowa dermatofibrosarcoma. The paracrine signaling of growth factors is usually found in epithelial cancer. He initiates inhalation matrix and may be involved in epithelial-mesenchimal the m transition and therefore will have an impact on the development of tumors, angiogenesis, invasion and metastasis. Growth factors, platelet organic cause pathological changes in vascular diseases, such as atheromatous, artery stenosis, pulmonary hypertension, retinal diseases, as well as hepatovirus, including pulmonary putting fibrosis, liver cirrhosis, scleroderma, glomerular sclerosis and fibrosis of the myocardium (see Andrea and others (Andrae et al. Gene Dev. 2008, 22, 1276)). So overexpressed DERIVED can help to prevent and treat the above mentioned diseases. In addition, overexpression of DERIVED can also help in the treatment of various autoimmune and inflammatory diseases, including diabetes, in particular diabetes type I, rheumatoid Artic, psoriasis, Crohn's disease, and others (Paniagua and others (Paniagua et al. Nat. Clin. Prac. Rheum. 2007, 3, 190; Louvet et al. Proc. Natl. Acad. Sci. USA, 2008, 105, 18895)).

The invention also relates to a new type of derivative dihydroindole, which can inhibit the activity of protein kinases, particularly of one or more kinases described above. These compounds, therefore, are useful in the prevention or treatment of diseases associated with disorder or disorder of the activity of protein kinases, especially in the case of diseases associated with impaired activity of Abl, Bcr-Abl, c-Kit and DERIVED protein kinases.

Brief description of the invention

The invention is a compound of Formula I

or their pharmaceutically acceptable salts, or prodrugs, where

R1is a saturated cyclic amino group which may optionally be substituted by 1, 2, 3 or 4 R1a;

R1arepresents H, halogen, cyano, C1-6alkyl, C1-6-hydroxyalkyl,1-6-haloalkyl, C1-6-cianelli, ORa, SRa, NRbRc, NRbC(O)Rd, NRbS(O)2RdC(O)NRbRcC(O)RdC(O)ORa, S(O)2RdC2-6alkenyl, C2-6quinil, aryl, heteroaryl, cycloalkyl or heteroseksualci where the specified C1-6alkyl, C2-6alkenyl,2-6quinil, aryl, heteroaryl, cycloalkyl and heteroseksualci may be optionally substituted by 1, 2 or 3 groups independently selected from ceanography, halogen, ORa, SRa, NRbRc, NRb(CO)Rd, NRbS(O)2RdC(O)NRbRc, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2Rd, haloalkyl, C1-6hydroxyalkyl,1-6zainoulline, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. Otherwise, the two groups R1atogether with the attached atoms may form cycloalkyl or heteroseksualci 3, 4, 5, 6 or 7-membered ring and may optionally be substituted by 1, 2 or 3 groups selected independently researched the mo from ceanography, halogen, ORa, SRa, NRbRc, NRb(CO)Rd, NRbS(O)2RdC(O)NRbRc, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2RdC1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline, C2.6alkenyl, C2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie;

R2represents H, halogen, cyano, ORa, SRa, NRbRcC1-6alkyl, C1-6hydroxyalkyl, C1-6halogenated, C1-6cianelli,2-6alkenyl,2-6quinil; Otherwise, two R2group together with the attached atoms may form cycloalkyl and heteroseksualci represents 3, 4, 5, 6 or 7-membered ring, and may be optionally substituted by 1, 2 or 3 groups independently selected from ceanography, halogen, ORa, SRa, NRbRc, NRb(CO)Rd, NRbS(O)2RdC(O)NRbRc, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2RdC1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline,2-6alkenyl and C2-6the quinil;

R3is H, halogen, cyano, ORa, SRa, NRbRcWith1-6the alkyl, C1-6hydroxyalkyl,1-6halogenation, C1-6zianout the scrap, With2-6alkenyl,2-6the quinil, cycloalkyl or heterocyclization. Otherwise, two R3group together with the attached atoms may form cycloalkyl and heteroseksualci 3, 4, 5, 6 or 7-membered ring and may be optionally substituted by 1, 2 or 3 groups independently selected from ceanography, halogen, ORa, SRa, NRbRcC1-6of alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline, C2-6alkenyl and C2-6the quinil;

W-X is an amide linkage;

Y is heteroaryl, which may be optionally substituted by 1, 2 or 3 R4;

Z is heterocyclization or heteroaryl, which may be optionally substituted by 1, 2 or 3 R5;

R4and R5independently from each other selected from halogen, ceanography, ORa, SRa, NRbRcWith1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane, C1-6zainoulline,2-6alkenyl,2-6the quinil, NRb(CO)RdC(O)NRbRc, NRbS(O)2Rd, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2Rd, cycloalkyl, geterotsiklicheskie, aryl and heteroaryl. Alternatively, two R4or two R5group together with the attached atoms may form cycloalkyl lieterally, represents a 5, 6 or 7-membered ring, and may optionally be substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, ORa, SRa, NRbRcWith1-6of alkyl, C1-6halogenoalkane, hydroxyalkyl, C1-6zainoulline,2-6alkenyl and C2-6the quinil;

Ra, Rb, Rcand Rdindependently from each other selected from H, C1-6of alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl,1-6zainoulline,2-6alkenyl,2-6the quinil, cycloalkyl, geterotsiklicheskie, aryl and heteroaryl; Alternatively, Rband Rcgroup together with the attached nitrogen atoms can form heteroseksualci, representing a 4, 5, 6 or 7-membered ring, and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, C1-6of alkyl, C1-6halogenoalkane,1-6hydroxyalkyl,1-6zainoulline,2-6alkenyl,2-6the quinil, cycloalkyl, geterotsiklicheskie, aryl and heteroaryl;

n is an integer from zero to four; m is an integer from zero to two.

Among the many compounds of Formula I and their salts or prodrugs preferred are compounds according to the present invention of Formula II

or f is matemticas acceptable salt or prodrug, where R1represents a saturated cyclic amino group, which can be chosen from piperidinyl, piperazinil, pyrrolidinyl, azetidine and morpholinyl, each of which optionally may be substituted by 1, 2, 3, or 4 R1a;

R1arepresents H, halogen, cyano, C1-6alkyl, C1_6hydroxyalkyl,1-6halogenated,1-6cianelli, ORa, SRa, NRbRc, NRbC(O)Rd, NRbS(O)2RdC(O)NRbRcC(O)RdC(O)ORa, S(O)2RdC2-6alkenyl, C2-6quinil, aryl, heteroaryl, cycloalkyl or heteroseksualci where specified C1-6alkyl, C2-6alkenyl,2-6quinil, aryl, heteroaryl, cycloalkyl and heteroseksualci may be optionally substituted by 1, 2 or 3 groups selected independently from each other from ceanography, halogen, ORa, SRa, NRbRc, NRb(CO)Rd, NRbS(O)2RdC(O)NRbRc, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2RdC1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie; Otherwise, two R1agroup together with the attached atoms may form cycloalkyl or heteroseksualci 3, 4, 5, 6 or 7-membered number is CA, and may be optionally substituted by 1, 2 or 3 groups selected independently from each other from ceanography, halogen, ORa, SRa, NRbRc, NRb(CO)Rd, NRbS(O)2RdC(O)NRbRc, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2RdC1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline,2-6alkenyl, C2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie;

Y is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, triazolyl, isothiazoline, imidazolyl, oxazolyl, isoxazolyl, triazolyl or pyrazolyl, and can also be optionally substituted by 1, 2, or 3 R4;

Z is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, isothiazoline, imidazolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, nitrogen oxazolyl, pyridinol, pyrrolo-pyrimidine, pyrazolo-pyridyl, pyrazolo-pyrimidine, quinoline, isoquinoline, chinadoll, piperazinil or morpholinyl, and may be optionally substituted by 1, 2 or 3 R5;

R4and R5chosen independently of one another from halogen, ceanography, ORa, SRa, NRbRcC1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane, C1-6zainoulline, C2-6Ala the Nile, With2-6the quinil, NRb(CO)RdC(O)NRbRc, NRbS(O)2Rd, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2Rd, cycloalkyl, geterotsiklicheskie, aryl and heteroaryl. Otherwise, two R4or R5group together with the attached atoms may form cycloalkyl or heteroseksualci, which represents a 5, 6 or 7-membered ring and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, ORa, SRa, NRbRcC1-6of alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline, C2-6alkenyl and C2-6the quinil;

Ra, Rb, Rcand Rdindependently from each other selected from H, C1-6of alkyl, C1-6halogenoalkane,1-6hydroxyalkyl, C1-6zainoulline,2-6alkenyl, C2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. Alternative, Rband Rctogether with the attached nitrogen atoms may form a 4, 5, 6 or 7-membered ring and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline,2-6alkenyl,2-6the quinil, aryl, heteroaryl, cycloalkyl and GE is erotically;

Among the numerous compounds of the Formula I and their salts and prodrugs of the most preferred compounds of the present invention are the compounds of Formula IIa

or their pharmaceutically acceptable salts or prodrugs, where R6and R7independently from each other selected from H, halogen, ceanography, C1-6of alkyl, C1-6hydroxyalkyl,1-6halogenoalkane, C1-6zainoulline,2-6alkenyl,2-6the quinil. Otherwise, R6and R7together with the attached atoms to form carbocycle or a heterocycle, a 5, 6 or 7-membered ring, and may be optionally substituted by 1, 2 or 3 groups selected independently of one another from halogen, ceanography, ORa, SRa, NRbRcWith1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane, C1-6zainoulline,2-6alkenyl and C2-6the quinil;

R8represents H, C1-6alkyl, C2-6hydroxyalkyl,2-6halogenated, halogenated, C(O)NRbRcC(O)RdC(O)ORa, S(O)2RdC3-6alkenyl,3-6quinil, aryl, heteroaryl, cycloalkyl and heteroseksualci. Moreover, these C1-6alkyl, C3-6alkenyl,3-6quinil, aryl, heteroaryl, cycloalkyl and heteroseksualci can be the ü optionally substituted 1, 2 or 3 groups selected independently of one another from halogen, ceanography, ORa, SRaand NRbRc;

Y is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, triazolyl, isothiazoline, imidazolyl, oxazolyl, isoxazolyl, triazolyl or pyrazolyl, and he may be optionally substituted by 1, 2, or 3 R4;

Z is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, isothiazoline, imidazolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, nitrogen oxazolyl, pirandola, pyrrolo-pyrimidine, pyrazolo-pyridyl, pyrazolo-pyrimidine, quinoline, isoquinoline, chinadoll, piperazinil or morpholinyl, and can also be optionally substituted by 1, 2 or 3 R5;

R4and R5chosen independently of one another from halogen, ceanography, ORa, SRa, NRbRcWith1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane, C1-6zainoulline,2-6alkenyl,2-6the quinil, NRb(CO)RdC(O)NRbRc, NRbS(O)2Rd, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2Rd, cycloalkyl, geterotsiklicheskie, aryl and heteroaryl. Otherwise, two R4or R5group together with the attached atoms may form cycloalkyl and heteroseksualci, before the bringing of a 5, 6 or 7-membered ring and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, ORa, SRa, NRbRcWith1-6of alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline, C2-6alkenyl and C2-6the quinil;

Ra, Rb, Rcand Rdindependently from each other selected from H, C1-6of alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline,2-6alkenyl,2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. Otherwise, Rband Rctogether with the attached nitrogen atoms can form heteroseksualci, representing a 4, 5, 6 or 7-membered ring, and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, C1-6of alkyl, C1-6halogenoalkane, hydroxyalkyl,1-6zainoulline,2-6alkenyl,2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie;

p is an integer from zero to two.

Among the many compounds of Formula I and their salts and prodrugs, and other most preferred compounds of the present invention are substances of the formula

or their pharmaceutically acceptable salts or prole is ARSTA, where R9and R10independently from each other selected from H, C1-6of alkyl, C2-6hydroxyalkyl,2-6halogenoalkane, C1-6halogenoalkane, C(O)NRbRcC(O)RdC(O)ORa, S(O)2RdC3-6alkenyl,3-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. Moreover, the specified C1-6alkyl, C3-6alkenyl,3-6quinil, aryl, heteroaryl, cycloalkyl and heteroseksualci independently from each other may be substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, ORa, SRaand NRbR°. Otherwise, R9and R10together with the attached atoms may form cycloalkyl or heteroseksualci, which represents a 5, 6 or 7-membered ring, and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, ORa, SRa, NRbRcWith1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane, C1-6zainoulline, C2-6alkenyl,2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie;

R11represents H, halogen, cyano, ORa, SRa, NRbRcC1-6alkyl, C1-6hydroxyalkyl, C1-6halogenated, C1-6cianelli,2-6alkenyl,2-6quinil;

Y is selected from pyridyl, Pirim the Dila, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, isothiazoline, imidazolyl, oxazolyl, isoxazolyl, triazolyl or pyrazolyl, and he may be optionally substituted by 1, 2 or 3 R4;

Z is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, isothiazoline, imidazolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, nitrogen oxazolyl, pyridinol, pyrrolo-pyrimidine, pyrazolo-pyridyl, pyrazolo-pyrimidine, quinoline, isoquinoline, chinadoll, piperazinil or morpholinyl, and he may be optionally substituted by 1, 2 or 3 R5;

R4and R5chosen independently of one another from halogen, ceanography, ORa, SRa, NRbRcC1-6of alkyl, hydroxyalkyl, C1-6halogenoalkane, C1-6zainoulline, C2-6alkenyl, C2-6the quinil, NRb(CO)RdC(0)NRbRc, NRbS(O)2Rd, S(O)2NRbRcC(O)RdC(O)ORa, S(O)2Rd, cycloalkyl, geterotsiklicheskie, aryl and heteroaryl. Otherwise, two R4or R5group together with the attached atoms may form cycloalkyl or heteroseksualci, which represents a 5, 6 or 7-membered ring and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, ORa, SR , NRbRcWith1-6of alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl, C1-6zainoulline,2-6alkenyl and C2-6the quinil;

Ra, Rb, Rcand Rdindependently from each other selected from H, C1-6of alkyl, C1-6halogenoalkane, C1-6hydroxyalkyl,1-6zainoulline,2-6alkenyl,2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. Otherwise, Rband Rctogether with the attached nitrogen atoms can form heteroseksualci, representing a 4, 5, 6 or 7-membered ring, and may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, ceanography, C1-6of alkyl, C1-6halogenoalkane,1-6hydroxyalkyl, C1-6zainoulline,2-6alkenyl,2-6the quinil, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie;

q is an integer from zero to three.

Another object of the present invention is a method of regulating the activity of protein kinases, and this method includes the impact on the protein kinase of the above compounds or pharmaceutically acceptable salts or prodrugs.

Preferably, the protein kinase is chosen from Alb, Bcr-Abl, c-Kit and DERIVED. Also these include protein kinase mutant kinase, select the installed mutant Abl kinase, Bcr-Abl kinase, c-Kit kinase and DERIVED kinase.

Another object of the invention is the use of the above compounds or their pharmaceutically acceptable drugs for the production of medicaments for the treatment of diseases or disorders associated with the activity of protein kinases or abnormal cell proliferation.

Another object of the invention is a method of treating diseases or disorders of the patients associated with the activity of kinases, including the introduction of effective doses of the above compounds or their pharmaceutically acceptable salts or prodrugs patients.

Detailed description of the invention

Below will be described illustrative examples. However, these embodiments are only the demo and do not limit the scope of the present invention.

Use the following used in this determination, unless specified otherwise.

"Halogen" includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

"Alkyl" refers to linear or branched saturated hydrocarbon groups. Examples of Akilov include1-20alkali, preferably1-6alkali, such as methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl and tert-butyl), amyl (such as n-amyl, isoamyl and nioami), n-hexyl, etc. In each substituted alkyl - or al the Il-substituted group, the above-mentioned "alkyl" has the same meaning as described above.

"Hydroxyalkyl" refers to alkyl substituted by hydroxyl.

"Halogenated" refers to alkyl substituted by one or more Halogens, such as CH2F, CHF2, CF3C2F5, CCl3etc.

"Cianelli" or "tiananamen alkyl" refers to alkyl, substituted cyano-group.

"Alkenyl" refers to alcelam containing one or more double bonds in the carbon-carbon bonds, such as vinyl, propenyl, 1,3-butadienyl, CIS-butenyl, TRANS-butenyl etc.

"Quinil" refers to alcelam containing one or more triple relations of carbon-carbon bonds, such as acetylenyl, PROPYNYL, etc.

"Cycloalkyl" refers to non-aromatic carbon ring, including cycloalkyl, cycloalkenyl and cycloalkyl. Cycloalkyl may contain minocycline or polycyclic ring system (such as 2, 3 or 4 fused rings), including spirally. Cycloalkyl may contain 3-20 carbon atoms, as well as 0, 1, 2 or 3 double bonds and/or 0, 1 or 2 triple bond. Cycloalkyl may also include a single ring or multiple condensed aromatic rings (i.e., total communication), for example pentane, Panten, hexane and the like substituted derivatives of benzene. Cycloalkyl containing one or more to denserank aromatic rings, can be attached to other groups through a group that is part of the aromatic ring, or a group, not a member of an aromatic ring. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene, substituted etc.

"Heteroseksualci" refers to non-aromatic ring, where one or more ring atoms are heteroatoms such as N, O or S. Heteroseksualci may include monocyclic or polycyclic ring system (e.g., containing 2, 3 or 4 condensed rings, including spirally. Preferred examples of heterocyclization include, but are not limited to, aziridine, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolin, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidine, etc. Heteroseksualci may also include one heterocyclic ring or multiple condensed aromatic rings (i.e., total communication), for example 2, 3-dihydrobenzofuran, 1,3-benzodioxole, benzo-1,4-dioxane, methylphthalimide and naphthalimide. Heteroseksualci containing one or more of kondensirovannye the aromatic rings, can be attached to other groups through the group, which is aromatic or non-aromatic ring.

"Aromatic ring" refers to a monocyclic or polycyclic (such as 2, 3 or 4 condensed rings) aromatic hydrocarbon, such as benzene, naphthalene, anthracene, phenanthrene, etc.

"Hetero-aromatic ring" refers to aromatic heterocycles comprising at least one or more heteroatoms in the ring, such as S, O or N. Heteroaromatic ring may contain a monocyclic or polycyclic ring system (e.g., containing 2, 3 or 4 condensed rings). Any nitrogen atom in the heteroaromatic ring may be oxidized with the formation of nitric oxide. Preferred heteroaromatic rings include, but are not limited to: pyridine, pyrimidine, pyrazin, paradisin, triazine, furan, thiofuran, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiazole, pyrrole, pyrazole, oxazole, isoxazol, oxadiazol, benzofuran, benzothiophene, benzothiazole, indole, indazole, quinoline, isoquinoline, Pirin, carbazole, benzimidazole, merindol, pyrrolo-pyrimidine, pyrazolo-pyridine, pyrazolo-pyrimidine etc.

"Optional" means that the event or situation described below, may be or may not be designated. The above definition is s includes examples of cases or situations, described in this document, when they occur or not occur.

"Effective therapeutic dose" refers to the introduction of effective amounts of compounds of the formula to a mammal in case of need of such treatment. The effective therapeutic dose may be changed, depending on the specific activity of the drug, as well as age, physiological status, presence of other diseases and the nutritional status of the patient. In addition, the definition used for an effective therapeutic dose depends on another possible therapy received by the patient at this time.

"Treatment" means any therapy for the treatment of diseases of mammals, including:

(i) preventing the disease, i.e. preventing the occurrence of clinical symptoms of the disease;

(ii) suppression of the disease, i.e. preventing the development of clinical symptoms, and/or

(iii) facilitation of the disease, i.e. achieving the elimination of clinical symptoms.

In many cases, the connection of the present invention may be in the form of acidic and/or basic salts due to the presence of amino and/or carboxyl group or the like.

"Connection" in this document relates to all stereoisomers, geometric isomers, dynamic isomers and isotopes.

Connection of the giving of the present invention may be asymmetric, for example, containing one or more stereoisomers. Unless otherwise specified, includes all stereoisomers, such as enantiomers and diastereomers. The compound containing asimmetricheskii substituted carbon atom, can be isolated in optically active pure or racemic form. Optically active form can be isolated from racemic mixtures or to synthesize, using chiral materials or chiral reagents.

Compounds of the present invention also include dynamic isomers. Dynamic isomers obtained by exchange between single and adjacent double bond, accompanied by the migration of a proton.

The compound of the present invention also includes the target compound or intermediate including the atoms of the isotopes. Atoms, isotopes have the same atomic number but different mass number. For example, isotopes of hydrogen include deuterium and tritium.

The compound of the present invention also include pharmaceutically acceptable salts, obtained by converting the primary group of the parent compound in the form of salt. Pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of basic groups, such as cyanamide. Pharmaceutically acceptable salts according to this document can be synthesized from ohodnocovanie, the main group of the parent compound interacts with 1-4 equivalents of acid in the solvent system. Suitable salts are listed in Remington''s Pharmaceutical Science, 17thed, Mark Publishing Company, Easton, Pa, 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

Pharmaceutically acceptable salt accession acid can be obtained from inorganic or organic salts. Salt obtained by adding acid, can be obtained from inorganic salts, including hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salt accession acid can be obtained from organic acids, including acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond acid, methanesulfonate acid, ethylsulfonyl acid, toluene-p-sulfonic acid, salicylic acid and etc

Used in the present invention, the term "pharmaceutically acceptable carriers" include any and all solvents, dispersion medium, coating, antibacterial or antifungal agents, isotonic agents or AIDS in slowing the absorption, and the like. Such environment and agents, COI is Lithuania in pharmaceutically active compounds, well known from the prior art. Their use in therapeutic compositions is predictable, except when any conventional medium or agent is incompatible with the active substances. Also in the composition may include additional active ingredients.

Described in this document composition is preferably prepared in the form of a single dosage form. The term "unit dosage form" refers to physically separate unit of a single dose that is suitable for administration to a human or other mammal. In order to achieve the required effective treatment, based on location, each unit contains a predetermined quantity of active substances and relevant suitable pharmaceutical excipients (such as tablets, capsules, ampoules). The compounds of Formula I are effective in a wide range of doses and is usually introduced in an effective amount. Preferably, in relation to oral administration, each unit dose may contain from 10 mg to 2 g of compound of Formula I, more preferably from 10 to 700 mg; while in relation to parenteral introduction of each unit dose can contain from 10 mg to 700 mg, more preferably from 50 mg to 200 mg However, it should be emphasized that the actual input to icesto compounds of the Formula I is determined by a physician, on the basis of certain conditions, including the type of curable diseases, the chosen route of administration, the particular compound and its relative activity, the age, body weight, response, and severity of illness of the patient, etc.

For solid compositions such as tablets, the principal active ingredients are mixed with pharmaceutical excipients (or carriers) with formation of a solid pre-composition containing a homogeneous mixture of compounds of the present invention. When this preliminary composition is called a homogeneous mixture, imply that the active components are evenly distributed throughout the composition that makes it easy to divide the composition into unit dosage forms with the same efficiency, such as tablets, pills or capsules.

The tablets or pills of the present invention can be coated or formed in other samples, with the aim of obtaining the medicinal form, with the privilege of renewal, efficiency, or protect the tablets or pills from the acidic environment of the stomach. For example, the tablet or pill can include the components of internal and external doses, where the latter exists in the form of a coating on top. These two types of components can be separated intersolubility layer, predotvraschayusch the disintegration in the stomach and allowing internal components to completely penetrate into the duodenum or slow to escape. As aerosolising layer or coating can be used with a variety of materials, these materials include polymeric acids and mixtures of polymeric acids and the following materials, such as shellac, hexadecanol and acetylcellulose.

Compositions used for inhalation and insufflate include pharmaceutically acceptable aqueous or organic solvents or solutions and suspensions are mixtures and powders. Liquid or solid compositions may contain suitable pharmaceutical excipients mentioned above. Preferably, these compositions are injected oral or nasal in order to achieve partial or systemic effects. Song data in the preferred pharmaceutically acceptable solvents can be sprayed using an inert gas sprayed solution can be placed directly in a device for spraying or atomizing device may be connected to a breathing mask or a pulse unit for creating a positive pressure. Composition of solutions, suspensions or powders can be entered using the device appropriately shipping dosage forms, preferably oral or nazalnam.

In the present invention compounds and their pharmaceutically acceptable salts also include the form of the solvate or hydrate. In General the, form of a solvate or hydrate equivalent forms of non-solvate and non-hydrate and included in the scope of the present invention. Some compounds of the present invention can probably exist in the form of polycrystals or be amorphous. In short, all guests can use the equivalent, and they are all included in the scope of the present invention.

The present invention also includes prodrugs of the compounds. A prodrug is a pharmaceutical substance, obtained from the original medication, and if it enters the body through metabolism goes into the original drug. The prodrug can be obtained by introducing one or more functional groups in the original remedy, which will be released in the decay of the substituting groups in vivo. The collection and use of prodrugs may be found in document Higuchi and Westella (.Higuchi and V.Stella), "Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutial Association and Pergmon Press, 1987.

The present invention also provides pharmaceutical compositions containing compounds of formula I or their pharmaceutically acceptable salts or prodrugs and at least one type of pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention can be administered orally, by injection, spray in the form of Inga is ACI, subcutaneous, rectal, nasal, vaginal, abdominal cavity, in the form of introduction or via transdermal patch, etc.

On the other hand, the present invention also provides a method of regulating the activity of protein kinase using compounds of Formula I. the Term "regulation of kinase activity" in the present description means a reduction in the activity of protein kinases to some extent under the influence of the kinase compounds Dictionnaire of the present invention, compared to the activity without the use of connections. Therefore, the present invention provides a method of regulation of protein kinase activity by affecting the protein kinase compounds of dihydroindole.

In particular, protein kinase described in the present invention are a protein-tyrosine kinase, including Abl, Bcr-Abl, c-Kit and DERIVED.

In addition, protein kinase in the present invention also includes a mutant kinases, such as Abl and Bcr-Abl kinase, mutant c-Kit kinase and mutant-DERIVED kinase. Mutant Abl and Bcr-Abl kinases include, for example, one or more of the following mutants: M244V, G250E, Q252H, Y253F, Y253H, EC, E255V, F311L, T351I, F317L, MT, F359V, V379I, L387M, NR, H396R, etc.

On the other hand, the present invention provides a method of treating diseases or disorders to regulate the activity of protein kinases. Disease or races is trojstva, associated with the activity of protein kinases include cancer, inflammation, autoimmune diseases, disorders of metabolism, infections, disorders of the Central nervous system, cardiovascular diseases, etc.

Another object of the present invention are compounds described herein that can be used for the treatment of diseases or disorders associated with abnormal cell proliferation, such as cancer, including leukemia, myeloproliferative syndrome, gelatos, gastrointestinal stromal tumor, colon cancer, breast cancer, stomach cancer, oophoroma, cervical cancer, lung cancer, kidney cancer, prostate cancer, bladder cancer, pancreas cancer, neuroblastoma, a tumor of fat cells, brain tumor, germinoma, melanoma, malignant tumors, sarcoma, such as wybuchowa of dermatofibrosarcoma, and so

Another object of the present invention is the possibility of using the described compounds for the treatment of diseases associated with autoimmune disorders or inflammatory diseases, including diabetes, dermatitis, rheumatoid arthritis, allergic rhinitis, asthma, ankylosing spondylitis, psoriasis, Crohn's disease, etc.

Another object of the present invention is the possibility of treating vascular diseases, such as teamates, stenosis of a blood vessel, pulmonary hypertension, retinal disease, and fibrosis such as pulmonary interstitial fibrosis, hepatovirus, liver cirrhosis, scleroderma, glomerular sclerosis, fibrosis of the myocardium, etc.

Another object of the present invention are methods of making compounds of Formula I. Compounds of the present invention can be obtained by using the following methods and procedures.

The intermediate compound of formula 1-5 can be obtained according to Scheme 1. 5-bromo-2,3-dihydroindol-1-he and CuCN boil in DMF with obtaining cyanide intermediate 1-1. Intermediate 1-1 can be restored to the intermediate connection 1-2, which is the alcohol, interaction with a reducing agent, such as borohydride sodium in a solvent such as methanol. The intermediate connection 1-2 may interact with thionyl chloride, which will lead to the formation of a chlorine group, you can replace the cyclic amino group in the presence of triethylamine or potassium carbonate to obtain the intermediate of 1-4. The cyano in the intermediate 1-4 can be subjected to hydrolysis with the formation of carbonic acid, which then is treated with methanol and thionyl chloride to obtain compounds 1-5. Two enantiomers of compounds 1-4 or compounds 1-5 can be divided chiral high-performance liquid chromatogr is FIA or crystallization using camphorsulfonic acid.

In another case, R1-substituted 2,3-dihydroindeno carboxylic acid (or its ester) can be obtained by the method depicted in Scheme 2. 5-bromo-2,3-dihydroindol-1-it can be restored to the intermediate alcohol compound 2-1 interaction with a reducing agent, such as borohydride sodium in the solvent-type methanol. After the hydroxy group of the intermediate compound 2-1 can be translated into a chloro group with thionyl chloride, chloride 2-2, you can substitute a cyclic amino group, using triethylamine or potassium carbonate as a base, to obtain the intermediate 2-3. Intermediate 2-3 interacts with CO in the presence of palladium, such as palladium diacetate/1,3-bis-(phenylphosphino) propane (dppp) or bis(triphenylphosphine) palladium dichloride (II) [(PPh3)2PdCl], as a catalyst with the formation of intermediate compounds of formula 2-4 in the form of a mixture of two enantiomers. When R in the compound is 2-4 H, the connection 2-4 can be obtained by the interaction of compounds 2-3 with butyllithium, followed by quenching with carbon dioxide. Connection 2-3 and two enantiomers of compounds 2-4 can be divided chiral high-performance liquid chromatography or methods using chiral acids, such as crystallization using camphorsulfonate.

The final compounds of formula 3-4 can be obtained as shown in Scheme 3. Carboxylic ester intermediate 3-1 can be subjected to alkaline hydrolysis, for example in the presence of sodium hydroxide, with the formation of carboxylic acids 3-2, which then condenses with aniline derivative, obtaining the target compound of formula 3-4 using a bonding agent, such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexaflurophosphate (BOP) or O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate (GATA). In addition, carboxylic acid, 3-2 can be treated with thionyl chloride, having acid chloride 3-3, which then interacts with a derivative of aniline, with the formation of the compounds of formula 3-4. The final compounds of formula 3-4 can also be obtained by reaction between the ether 3-1 and derivatives of aniline in the presence of trialkylamine type of trimethylaluminum or triethylaluminum as a bonding agent.

Example 1

Obtaining 1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide.

Stage A: 1-oxo-2,3-dihydro-1H-inden-5-carbonitril

5-bromo-2,3-dihydro-1H-inden-1-he (21.1 g, 100 mmol) and copper cyanide (17.9 g, 200 mmol) were mixed in 200 ml of dimethylformamide and stirred overnight at 140°C. After rest the R was cooled to room temperature, added 500 ml of ethyl acetate and the precipitate was filtered using diatomaceous earth. The precipitate was washed several times with ethyl acetate. The combined filtrate twice washed with 1 N. hydrochloric acid and then three times with saline, after dried over anhydrous magnesium sulfate, was filtered and was concentrated. The crude product was purified on silica gel, elwira a mixture of ethyl acetate/hexane (1:2), to obtain 7.9 g of the desired compound (50% yield). Data mass spectroscopy MS(M+1)=158,05.

Stage b: 1-hydroxy-2,3-dihydro-1H-inden-5-carbonitril

1-oxo-2,3-dihydro-1H-inden-5-carbonitril (a 7.85 g, 50 mmol) was dissolved in 50 ml of methanol. To the mixture was gradually added borohydride (2.3 g, 60 mmol) within 30 min After 2 hours of stirring the solution was concentrated. The residue was dissolved in ethyl acetate and the resulting solution was twice washed with sodium bicarbonate, then three times with saline and dried over magnesium sulfate, then filtered and concentrated, to obtain 8 g of the desired compound (100% yield). Data mass spectroscopy MS(M+1)=160,07.

Stage C: 1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carbonitril

1-hydroxy-2,3-dihydro-1H-inden-5-carbonitrile (4.77 g, 30 mmol) was dissolved in 10 ml of dichloromethane. Under ice cooling was added dropwise thionyl chloride (6.6 ml, 90 mmol) in quiescent is e 15 minutes. The solution after stirring for 3 hours and concentrated. The residue was dissolved in ethyl acetate and the resulting solution was washed three times with cooled saline solution, dried over anhydrous magnesium sulfate and concentrated to obtain 1-chloro-2,3-dihydro-1H-inden-5-carbonitrile.

The obtained 1-chloro-2,3-dihydro-1H-inden-5-carbonitrile was dissolved in 80 ml of acetonitrile and then added 1-methyl piperazine (6 g, 60 mmol) and potassium carbonate (to 4.14 g, 30 mmol). After the solution was stirred over night at 60°C. the acetonitrile was removed by concentration under reduced pressure. Next was added ethyl acetate. The resulting solution was washed three times with saline, dried over magnesium sulfate, concentrated and purified on silica gel, using as eluent 5% methanol/dichloromethane, having thus, 4.3 g of target compound (yield 60%). Data mass spectroscopy MS(M+1)=242,16.

Stage D: Methyl 1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate

1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carbonitrile (to 2.41 g, 10 mmol) was dissolved in 10 ml of 2 n sodium hydroxide solution. The solution was stirred over night at 100°C and then concentrated. Obtained after vacuum distillation, the residue was dissolved in 30 ml of methanol. Dropwise under stirring for 1 hour was added thionyl chloride (3.3 ml). The mixture to which was patili under reflux overnight and then concentrated. First added to water, then to translate the solution in the core was added potassium carbonate. The solution was extracted three times with ethyl acetate. The combined extracts were washed with saline, dried over magnesium sulfate, then concentrated. Next, perform the cleaning on silikagelevye column, using as eluent 5% methanol/dichloromethane, obtaining 2.1 g (yield 77%) of the target substance. Data mass spectroscopy MS(M+1)=275,17.

Stage E: Obtain 1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamidine

Methyl 1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate (of 1.37 g, 5 mmol) and 4-methyl-N(3)-(4-pyridine-3-Yeremey-2-yl)phenyl-1,3-diamine (Szakacs and others (Szakacs et al). J. Med. Chem. 2005, 48:249) (1.66 g, 6 mmol) was dissolved in 30 ml of toluene. Next was added a 2 M solution of trimethylaluminum in toluene (5 ml, 10 mmol) and the mixture was stirred over night at 50°C. the Reaction was incomplete. Next was added another portion of 2 M trimethylaluminum in toluene (3 ml, 6 mmol). The mixture was cooled in ice and stirred over night at 60°C. Under stirring was added aqueous saturated solution of tartrate of potassium and sodium (50 ml). The solution was extracted with dichloromethane (3×100 ml). The combined extracts were washed with sodium bicarbonate (100 ml) and then brine (2×100 ml), dried the hell magnesium sulfate, then concentrated. Purification was performed on silikagelevye column, using as eluent 50% ethyl acetate/dichlormethane/5-10% of triethylamine, to obtain 1.5 g of target compound (yield 58%). Data mass spectroscopy MS(M+1)=520,27.1H NMR (DMSO (dimethyl sulfoxide)-d6, ppm): δ 10,10 (s, 1H); 9,20 (s, 1H); of 8.95 (s, 1H); to 8.62 (d, J=4,8 Hz, 1H); 8,42 (d, J=4,8 Hz, 1H); to 8.40 (d, J=9.0 Hz, 1H); 8,00 (s, 1H); of 7.75 (s, 1H); 7,72 (d, J=9.0 Hz, 1H); was 7.45 (dd, J=8,2 Hz, 4.8 Hz, 1H); 7,40 (d, J=8.0 Hz, 1H); 7,38 (d, J=4,8 Hz, 1H); 7,28 (d, J=9.0 Hz, 1H); to 7.15 (d, J=9.0 Hz, 1H); 4.26 deaths (t, J=9.0 Hz, 1H); 2,2-2,9 (m, 1H); of 2.15 (s, 3H); of 2.08 (s, 3H); 2,0 (m, 2H).

Example 2

Obtain tert-butyl 4-{5-[({4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl}amino)carbonyl)-2,3-dihydro-1-H-inden-1-yl}piperazine-1-carboxylate

Stage A: 5-bromo-2,3-dihydro-1H-inden-1-ol

5-bromo-2,3-dihydro-1H-inden-1-he (210 g, 1000 mmol) suspended in 1 l of methanol, then gradually in the course of 1 hour was added sodium borohydride (41,6 g, 1100 mmol) under stirring. The solvent was evaporated at 50°C and reduced pressure, after the stirring was continued for 1 hour. Next was added ethyl acetate (1 l), then was added a saturated solution of sodium bicarbonate (500 ml). Stirring is continued for some time, then the solution was transferred into a separating funnel, the aqueous phase was removed. The organic phase is twice washed with saturated RA is tworoom sodium bicarbonate and twice with saline, then was dried (magnesium sulfate) and then concentrated, to obtain 198 g (93%) of the target substance.

Stage b: 5-bromo-1-chloro-2,3-dihydro-1H-inden

5-bromo-2,3-dihydro-1H-inden-1-ol (198 g, 934 mmol) was dissolved in 500 ml of dichloromethane. Under ice cooling is added dropwise within 2 hours to a solution in dichloromethane) was added thionyl chloride (275 ml, 3770 mmol). The solution was concentrated at 30°C and reduced pressure and then was stirred for 2 hours at room temperature. The residue was dissolved in ethyl acetate (1 l)and the resulting solution was washed with ice water (3×500 ml), then brine (2×300 ml), dried over magnesium sulfate, and then concentrated to obtain 5-bromo-1-chloro-2,3-dihydro-1H-indene.

Stage C: tert-butyl 4-(5-bromo-2,3-dihydro-1H-inden-1-yl) piperazine-1-carboxylate

5-bromo-1-chloro-2,3-dihydro-1H-inden (10 g, 43 mmol) was dissolved in 80 ml of acetonitrile, was then added tert-butyl piperazine-1-carboxylate (9.7 g, 52 mmol) and then sodium carbonate (4.8 g, 45 mmol). The mixture was stirred over night at 60°C. the Insoluble residue was separated by filtration, then the filtrate was concentrated. The residue was separated on silikagelevye column, using as eluent ethyl acetate/hexane (1:2 to 1:1), to obtain 12 g (yield 72%) of target compound. Data mass spectroscopy MS(M+1)=381,11, 383,11.

p> Stage D: tert-butyl 4-[5-(etoxycarbonyl)-2,3-dihydro-1H-inden-1-yl) piperazine-1-carboxylate

tert-butyl 4-(5-bromo-2,3-dihydro-1H-inden-1-yl) piperazine-1-carboxylate (11 g, 28,87 mmol) was dissolved in ethanol (50 ml), then was added dimethyl sulfoxide (5 ml) and triethylamine (5 ml). The system was evacuated and filled the N2. Added palladium acetate (2 g) and 1,3-bis(diphenylphosphino)propane (3 g). The system was evacuated and filled the N2. The system was again evacuated and stirred at 100°C for 24 hours with the connected cylinders. After cooling to room temperature the mixture was filtered through diatomaceous earth, which is then thoroughly washed with ethanol. The filtrate was concentrated. The residue was dissolved in ethyl acetate (500 ml), the resulting solution was washed with brine (3×200 ml), dried over magnesium sulfate, concentrated and finally separated on silikagelevye column, using as eluent ethyl acetate/hexane (1:2 to 1:1), to obtain 8.5 g (yield 79%) of target compound. Data mass spectroscopy MS(M+1)=375,22.

Stage E: 1-[4-(BOC)piperazine-1-yl]-2,3-dihydro-1H-inden-5-carboxylic acid

Tert-butyl 4-[5-(etoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate (8 g, 21,36 mmol) was dissolved in 20 ml of methanol, was added 30 ml of sodium hydroxide (1 BC). The solution per massively over night at room temperature and two hours at 50°C, then concentrated. The residue was dissolved in water (50 ml) and the resulting solution was acidified to pH 5 with 1 n HCl, then was extracted with ethyl acetate (3×100 ml). The extracts were combined, dried over magnesium sulfate, then concentrated to obtain the target compounds. Data mass spectroscopy MS(M+1)=347,19.

Stage F: tert-butyl 4-{5-[({4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl}amino)carbonyl]-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate

1-[4-(BOC)piperazine-1-yl]-2,3-dihydro-1H-inden-5-carboxylic acid (7.4 g, 21,36 mmol) and 4-methyl-N(3)-[(4-pyridine-3-Yeremey-2-yl)phenyl-1,3-diamine (6,1 g, 22 mmol) was dissolved in 20 ml of N,N-dimethylformamide. Was added triethylamine (8,9 ml, 64 mmol) and O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate (9.5 g, 25 mmol). The solution was stirred over night at room temperature, then added salt solution (100 ml) and ethyl acetate (200 ml). The aqueous phase was removed, and the ethyl acetate layer was washed brine (3×100 ml). Then, the solution was dried over magnesium sulfate, concentrated and finally purified on silikagelevye column, using as eluent methanol/mechaniloid (1:2 to 1:1), to obtain 9.5 g (yield 73%) of the specified connection. Data mass spectroscopy MS(M+1)=606,31.1H NMR (DMSO-d6, ppm): δ 10,15 (s, 1H); a 9.25 (s, 1H); 8,99 (s, 1H); 8,67 (d, J=4,8 Hz, 1H); and 8.50 (d, J=5,2 Hz, 1); 8,46 (d, J=8,4 Hz, 1H); with 8.05 (s, 1H); for 7.78 (s, 1H); 7,76 (d, J=8.0 Hz, 1H); to 7.50 (dd, J=8.0 Hz, 4.8 Hz, 1H); 7,46 (d, J=8,4 Hz, 1H); 7,41 (d, J=5,2 Hz, 1H); 7,38 (d, J=7,6 Hz, 1H); to 7.18 (d, J=8,8 Hz, 1H); of 4.35 (t, J=7.2 Hz, 1H); 3,30 (m, 3H); 3,05 (m, 1H); 2,08 (s, 2H); to 2.42 (m, 2H); 2,30 (m, 2H); of 2.20 (s, 3H); 2,04 (m, 2H); of 1.36 (s, 9H).

Example 3

Obtaining N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-1-piperazine-1-yl-2,3-dihydro-1H-inden-5-carboxamide

tert-butyl 4-{5-[({4-methyl-3-[(4-pyridine-3-Yeremey-2 yl)amino]phenyl}amino)carbonyl]-2,3-dihydro-1H-inden-1-yl}piperazine-1 carboxylate (2 g, 3.3 mmol) was dissolved in 4 BC HCl solution in dioxane (10 ml). After stirring at room temperature for 3 hours the solution was concentrated to obtain a solid product. The product (100 mg) was purified by high-performance liquid chromatography at pH=10 to obtain the desired product. Data mass spectroscopy MS(M+1)=506,26.1H NMR (DMSO-d6, ppm): δ 10,08 (s, 1H); 9,20 (s, 1H); 8,93 (s, 1H); to 8.62 (d, J=4,8 Hz, 1H); 8,44 (d, J=5,2 Hz, 1H); to 8.40 (d, J=8.0 Hz, 1H); 8,00 (s, 1H); 7,72 (s, 1H); of 7.70 (d, J=8.0 Hz, 1H); was 7.45 (dd, J=8,2 Hz, 4.8 Hz, 1H); 7,41 (d, J=8,2 Hz, 1H); of 7.36 (d, J=5,2 Hz, 1H); 7,31 (d, J=8.0 Hz, 1H); for 7.12 (d, J=8,8 Hz, 1H); 4,22 (t, J=6,8 Hz, 1H); 2,80 (m, 2H); 2,60 (m, 4H); 2,35 (m, 2H); 2,22 (m, 2H); of 2.15 (s, 3H); 2.00 (evens m, 2H).

Example 4

Obtaining 1-(4-ethylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide

N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-1-piperazine-1-the l-2,3-dihydro-1H-inden-5-carboxamid tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 ml)was then added triethylamine (101 mg, 1 mmol), and then acetaldehyde (26 mg, 0.6 mmol). After the solution was stirred for 20 minutes, then added triacetoxyborohydride (128 mg, 0.6 mmol). The resulting solution was stirred overnight at room temperature, then purified by high-performance liquid chromatography at pH=10 to obtain 50 mg (yield 63%) of target compound. Data mass spectroscopy MS(M+1)=523,29.1H NMR (DMSO-d6, ppm): δ 10,14 (s, 1H); a 9.25 (s, 1H); 8,98 (s, 1H); 8,67 (d, J=4,8 Hz, 1H); 8,49 (d, J=5,2 Hz, 1H); 8,46 (d, J=8.6 Hz, 1H); with 8.05 (s, 1H); to 7.77 (s, 1H); of 7.75 (d, J=8,8 Hz, 1H); to 7.50 (dd, J=8.0 Hz, 4.8 Hz, 1H); 7,46 (d, J=8,2 Hz, 1H); 7,41 (d, J=5,2 Hz, 1H); to 7.35 (d, J=7,6 Hz, 1H); 7,17 (d, J=8,8 Hz, 1H); or 4.31 (t, J=6,8 Hz, 1H); 2,2-3,0 (m, N); of 2.20 (s, 3H); 2, 03 (m, 2H); of 0.95 (t, J=7.0 Hz, 3H).

Example 5

Obtaining 1-(4-isopropylpiperazine-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide

N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-1-piperazine-1-yl-2,3-dihydro-1H-inden-5-carboxamid tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 ml)was then added triethylamine (101 mg, 1 mmol), then acetone (35 mg, 0.6 mmol). After the solution was stirred for 20 min, then was added triacetoxyborohydride sodium (128 mg, 0.6 mmol). The resulting solution was stirred overnight at room temperature and then purified highly the positive liquid chromatography at pH=10 to obtain 58 mg (71%yield) of the specified connection. Data mass spectroscopy MS(M+1)=548.31.1H NMR (DMSO-d6, ppm): δ 10,14 (s, 1H); 9,26 (s, 1H); 8,98 (s, 1H); 8,67 (d, J=4,8 Hz, 1H); 8,49 (d, J=4,8 Hz, 1H); 8,46 (d, J=8,4 Hz); with 8.05 (s, 1H); to 7.77 (s, 1H); 7,74 (d, J=8.0 Hz, 1H); 7,51 (dd, J=8.0 a & 4,8 Hz, 4,8 Hz, 1H); 7,46 (d, J=8,2 Hz, 1H); 7,41 (d, J=5,2 Hz, 1H); to 7.35 (d, J=7,6 Hz, 1H); 7,17 (d, J=8,4 Hz, 1H); 4,30 (t, J=7,0 Hz, 1H); 2.91 in (m, N); of 2.81 (s, 3H); 2,3-2,6 (m, N); 2,02 (m, 2H); to 0.92 (t, J=6,4 Hz, 6N).

Example 6

Obtaining 1-[4-(2-hydroxyethylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide

N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-1-piperazine-1-yl-2,3-dihydro-1H-inden-5-carboxamid tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 ml)was then added triethylamine (101 mg, 1 mmol) and {[tert-butyl (dimethyl)silyl]oxo}acetaldehyde (100 mg, 0.6 mmol). After the solution was stirred for 20 minutes, then added triacetoxyborohydride sodium (128 mg, 0.6 mmol). The resulting solution was stirred overnight at room temperature, then purified by high-performance liquid chromatography. The dried product was dissolved in 2 ml dichloromethane/2 ml triperoxonane acid. The solution was concentrated after stirring overnight and was purified by high-performance liquid chromatography at pH=10 to obtain 38 mg (yield 46%) of target compound. Data mass spectroscopy MS(M+1)=550,29.1H NMR (DMSO-d6pm): δ 10,16 (s, 1H); 9,23 (s, 1H); 8,97 (s, 1H); 8,65 (d, J=4.4 Hz, 1H); 8,48 (d, J=6.0 Hz, 1H); 8,46 (d, J=4,8 Hz); 8,02 (s, 1H); of 7.82 (m, 2H); 7,51 (m, 1H); 7,40 (m, 2H); 7,14 (d, J=8,4 Hz, 1H); 2,6-3,7 (m, 17H); of 2.16 (s, 3H).

Example 7

Obtaining 1-[4-acetylpiperidine-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide

N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-1-piperazine-1-yl-2,3-dihydro-1H-inden-5-carboxamid tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 ml), then was added triethylamine (101 mg, 1 mmol) and acetylchloride (16 mg, 0.2 mmol) under cooling in an ice bath. After stirring for 20 minutes the resulting solution was purified by high-performance liquid chromatography at pH=10 with 45 mg (yield 55%) of target compound. Data mass spectroscopy MS(+1)=548,27.1H NMR (DMSO-d6, ppm): δ 10,15 (s, 1H); 9,26 (s, 1H); 8,99 (s, 1H); 8,66 (d, J=4,8 Hz, 1H); 8,49 (d, J=5,2 Hz, 1H); to 8.45 (d, J=8,4 Hz); with 8.05 (s, 1H); 7,79 (s, 1H); 7,76 (d, J=8.0 Hz, 1H); to 7.50 (dd, J=8.0 a & 4,8 Hz, 1H); 4,37 (t, J=7,0 Hz, 1H); 3.42 points (m, 1H); 3.40 in (m, 3H); 2.91 in (m, 1H); and 2.83 (m, 1H); 2,2-2,5 (m, 4H); of 2.20 (s, 3H); to 2.06 (m, 2H); 1,95 (s, 3H).

Example 8

Obtaining N-[3-(4,5'-bipyrimidin-2-ylamino)-4-were]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamid

Stage A: 5-acetylpyridine

5-bromopyrimidine (3,18 g, 20 mmol) was dissolved in 50 ml of tetrahydrofuran. When cooled to -78°C. dropwise with paramesh what the training was added 15 ml of a 1.6 M solution of n-utility in hexane. After stirring the solution for 30 minutes was slowly added a solution of N-methoxy-N-methylacetamide (2.58 g, 25 mmol) in a solution of tetrahydrofuran (10 ml). The mixture was stirred at -78°C for 1 hour, then left to slowly heat up. When the temperature of the mixture reached 0°C, was added an aqueous solution of ammonium chloride. The resulting solution was extracted three times with ethyl acetate. The combined extracts were washed with saline, dried over magnesium sulfate, concentrated under reduced pressure, then was purified on silikagelevye column, using as eluent 5% methanol/dichloromethane, to obtain 1 g of the target substance (yield 45%). Data mass spectroscopy MS(M+1)=123,05.

Stage b: (2E)-3-(Dimethylamino)-1-pyrimidine-5-rprop-2-EN-1-he

5-Acetylpyridine (1 g, 8.2 mmol) and N,N-dimethylformamide, dimethylacetal (1.3 g, 11 mmol) was dissolved in 20 ml of isopropanol. The solution was stirred at 100°C for 24 hours, cooled to room temperature and concentrated under reduced pressure. Further to the residue was added ethyl ether. After cooling in an ice bath for two hours the precipitate was filtered off, washed with cold ethyl ether, dried in vacuum to obtain 1 g (yield 59%) of target compound. Data mass spectroscopy MS(M+1)=178,0.

Stage C: N-(2-methyl-5-nitrophenyl)-4,5'-bipyrimidin the-2-amine

(2E)-3-(dimethylamino)-1-pyrimidine-5-rprop-2-EN-1-he (1 g, 5.6 mmol) and M-(2-methyl-5-nitrophenyl)guanidine nitrate (1.44 g, 5.6 mmol) (z-Szakacs et al. (Szakacs and others), J. Med. Chem. 2005, 48, 249) suspended in 20 ml of isopropanol. Next was added sodium hydroxide (0.28 g, 7 mmol). The mixture was stirred overnight and cooled to room temperature. The precipitate was filtered, washed with isopropanol and diethyl ether. The filtrate was concentrated under reduced pressure, the residue was dissolved in 15 ml of isopropanol. The resulting solution was boiled under reflux overnight and cooled to room temperature. The solid residue was filtered, washed with isopropanol and diethyl ether. The combined precipitate was washed with water and diethyl ether, then dried in vacuum to obtain 1.2 g (yield 70%) of target compound. Data mass spectroscopy MS(M+1)=309,10.

Stage D: N(3)-4,5'-bipyrimidin-2-yl-4-methylbenzo-1,3-diamine

The chloride dihydrate tin (3.6 g, 16 mmol) was dissolved in 10 ml of concentrated hydrochloric acid. To the solution was added N-(2-methyl-5-nitrophenyl)-4,5'-bipyrimidin 2-amine under vigorous stirring. The mixture was poured into ice water, then was stirred for 2 hours. Further neutralized to pH>8 with sodium carbonate and was extracted 4 times with ethyl acetate. Obyedinennaya washed with saline, was dried over magnesium sulfate and finally concentrated under reduced pressure to obtain 0.7 g of the desired compound. Data mass spectroscopy MS(M+1)=279,13.

Stage E: N-[3-(4,5'-bipyrimidin-2-ylamino)-4-were]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamid

Methyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate (823 g, 3 mmol) and N(3)-4,5'-bipyrimidin-2-yl-4-methylbenzo-1,3-diamine (973 g, 3.5 mmol) suspended in 15 ml of toluene, then added a 2 M solution of trimethylaluminum (3 ml, 6 mmol). The mixture was stirred over night at 50°C and again added 2 M solution of trimethylaluminum (2 ml, 4 mmol). The solution was stirred over night at 60°C and then left to cool in an ice bath. With stirring was added a saturated aqueous solution of tartrate of potassium and sodium. The resulting solution was extracted with dichloromethane (3×100 ml). The combined extracts were washed with sodium bicarbonate (100 ml) and brine (2×100 ml), dried over magnesium sulfate, concentrated and purified by chromatography on silikagelevye column, using as eluent 50% ethyl acetate/dichloromethane/5-10% triethylamine, to obtain the 702 mg of target compound (yield 45%). Data mass spectroscopy MS(M+1)=527,27,1H NMR (DMSO-d6, ppm): δ 10,10 (s, 1H); 9,46 (s, 2H); 9.28 are (s, 1H); remaining 9.08 (s, 1H); and 8.50 (d, J=5.7 Hz, 1H); 8,04 (s, 1H); 7,74 (s, 1H);of 7.70 (d, J=9.0 Hz, 1H); 7,46 (, J=5.7 Hz, 1H); 7,42 (d, J=9.0 Hz, 1H); to 7.32 (d, J=9.0 Hz, 1H); to 7.15 (d, J=9.0 Hz, 1H); 4.25 in (t, J=5.7 Hz, 1H); 2,2-2,9 (m, J); of 2.15 (s, 3H); 2,07 (s, 3H); 2,0 (m, 2H).

Example 9

Obtaining 1-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-N-{4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-yl)amino]phenyl}-2,3-dihydro-1H-inden-5-carboxamide

Stage A: (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-N,N-dimethylpyridin-3-amine

5-bromo-1-chloro-2,3-dihydro-1H-inden (2,03 g, 8,76 mmol) and (3S)-N,N-2,5-dimethylpyridin-3-amine (1 g, 8,76 mmol) was dissolved in 30 ml of acetonitrile, was then added potassium carbonate (1,81 g, 13,14 mmol). The mixture was stirred over night at 60°C, then concentrated. The residue was dissolved in ethyl acetate. The solution was washed three times with saline, dried over magnesium sulfate, then concentrated. Next conducted clearing column chromatography on silica gel, as the eluent used ethyl acetate/dichloromethane/triethylamine/methanol(10:10:1:1), obtaining 1.3 g of the target compound. Data mass spectroscopy MS(M+1)=309,0, 311,0.

Stage b: Methyl 1-[(35)-3-(N,N-dimethylamino)pyrrolidin-1-yl]-2,3-dihydro-1H-inden-5-carboxylate

(3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-N,N-2,5-dimethylpyridin-3-amine (1.3 g, 4.2 mmol) was dissolved in 30 ml of methanol, 5 ml of dimethyl sulfoxide and 7 ml of triethylamine. The reaction flask was evacuated and filled the N2 . Next was added palladium acetate (0.24 g, 1 mmol) and 1,3-bis(biphenylphosphine)propane (0.5 g, 1.5 mmol). The mixture was stirred at 80°C for two days in the presence of CO. After cooling to room temperature the mixture was filtered and concentrated. The residue was dissolved in ethyl acetate. The resulting solution was washed three times with saline, dried over magnesium sulfate, then concentrated. Next, perform the purification column chromatography on silica gel, using as eluent ethyl acetate/dichloromethane/triethylamine (10:10:1), to obtain 0.7 g of target compound (yield 58%). Data mass spectroscopy MS(M+1)=289,1.

Stage C: 1-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-N-{4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-yl)amino]phenyl}-2,3-dihydroindol-5-carboxamid

Methyl 1-[(35)-3-(N,N-dimethylamino)pyrrolidin-1-yl]-2,3-dihydroindol-5-carboxylate (0.2 g, 0.69 mmol) and 4-methyl-M(3)-(4-pyridine-3-Yeremey-2-yl)phenyl-1,3-diamine (0,22 g, 0.8 mmol) was dissolved in 5 ml of toluene. Next was added a 2 M solution of trimethylaluminum in toluene (1.3 ml, 2.6 mmol). The mixture was stirred at 60°C for 2 days and then cooled in an ice bath. Then add the tartrate of potassium and sodium in aqueous solution (15 ml) and dichloromethane (50 ml). The organic phase was separated and the aqueous was extracted twice with dichloromethane. The combined organic phase was washed salt rastv the rum, was dried over magnesium sulfate, then concentrated. It was further purified by high-performance liquid chromatography with getting 0,22 g (60% yield) of the target substance. Data mass spectroscopy MS(M+1)=534,29.1H NMR (CD3OD, ppm): δ 9,19 (s, 1H); 8,54 (d, J=5,2 Hz, 1H); and 8.50 (d, J=8,4 Hz, 1H); at 8.36 (d, J=5,2 Hz, 1H); 8,10 (s, 1H); 7,72 (s, 1H); to 7.67 (d, J=8,4 Hz, 1H); 7,44 (d, J=5,2 Hz, 1H); 7,41 (d, J=8,4 Hz, 1H); 7,32 (d, J=8,4 Hz, 1H); 7,28 (d, J=5,2 Hz, 1H); to 7.15 (d, J=8,4 Hz, 1H); 4,18 (m, 2H); 3,01 (m, 1H); 2,90 (m, 1H); 2,80 (m, 2H); 2,72 (m, 2H); 2,60 (m, 1H); is 2.37 (m, 1H); 2,22 (s, 3H); of 2.16 (m, 1H); 2,14 (s, 6H); 1,95 (m, 1H); of 1.62 (m, 1H).

Example 10

Obtaining 1-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-N-methyl-3-[(4-pyridin-3-yl pyrimidine-2-yl)amino]phenyl}-2,3-dihydro-1H-inden-5-carboxamide

The specified connection was obtained by the method described in Example 9. Data mass spectroscopy MS(M+1)=524,29,1H NMR (CD3OD, ppm): δ 9,19 (s, 1H); 8,54 (d, J=5,2 Hz, 1H); and 8.50 (d, J=8,8 Hz, 1H); at 8.36 (d, J=5,2 Hz, 1H); 8,10 (s, 1H); 7,72 (s, 1H); 7,6,7 (d, J=7.2 Hz, 1H); 7,44 (d, J=7.2 Hz, 1H); 7,41 (d, J=8,8 Hz, 1H); 7,32 (d, J=7.2 Hz, 1H); 7,28 (d, J=5,2 Hz, 1H); to 7.15 (d, J=7.2 Hz, 1H); 4,18 (m, 1H); to 3.02 (m, 1H); 2.95 and (m, 1H); to 2.85 (m, 2H); to 2.75 (m, 2H); to 2.65 (m, 1H), 2,39 (m, 1H); 2,24 (s, 3H); of 2.20 (m, 1H); 2,15 (s, 3H); to 1.98 (m, 1H); of 1.65 (m, 1H).

Example 11

Obtain (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl) amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide

Stage A: 1-((15)-5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazin

5-bromo-1-chloro-2,3-d the hydro-1H-inden (220 g 950 mmol) was dissolved in acetonitrile (1 l) was added 1-methylpiperazine (150 g, 1500 mmol) and potassium carbonate (131 g, 950 mmol). The mixture was stirred over night at 60°C. the Solid precipitate was filtered, the filtrate was concentrated. The residue was dissolved in ethyl acetate (1 l) and the resulting solution was washed twice with sodium hydroxide (2×300 ml), then brine three times (3×300 ml), dried over magnesium sulfate, concentrated and purified by chromatography on silikagelevye column, using as eluent 5% methanol/dichloromethane to obtain 202 g of product (yield 72%). Data mass spectroscopy MS(M+1)=295,07, 297,07.

The resulting product (202 g, 684,6 mmol) was dissolved in 2000 ml of methanol and then was added (1S)-(+)-10-camphorsulfonic acid (318 g, 1369 mmol), then 4000 ml of isopropanol. The solution was boiled under reflux by heating for 10 minutes, then stirred overnight at room temperature. The precipitate was filtered. When the liquid has ceased to drip, the precipitate was washed with isopropanol and then dissolved in 600 ml of methanol. Next was added isopropanol (1500 ml), the solution was heated to boiling for 15 minutes, and further stirred overnight at room temperature. The precipitate was filtered. When the liquid has ceased to drip, the precipitate was washed with isopropanol and then dissolved in 1 N. the sodium hydroxide (600 ml). The solution was stirred during the course the e 30 minutes and then was extracted three times with ethyl acetate (3×300 ml). The combined extract was washed 1 N. sodium hydroxide (300 ml) and brine (2×300 ml), dried over magnesium sulfate, and then concentrated to obtain 50 g of the target compound. Chiral purity was 99.7%, some chiral high-performance chromatography. X-ray single crystal structural analysis of the target compounds showed that the chiral center in the 1st position of the 2,3-dihydro-1H-indene is in the S configuration. Data mass spectroscopy MS(M+1)=295,07, 297,07.

Stage b: Ethyl (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate

1-((1S)-5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazine (29.6 g, 100 mmol) was dissolved in 300 ml of ethanol, 30 ml of DMSO and 42 ml of triethylamine. The system was evacuated and filled the N2. After added palladium acetate (2.4 g, 10 mmol) and 1,3-bis(diphenylphosphino)propane (3.3 g, 10 mmol), the system was evacuated and filled the N2. After degassing the mixture was stirred at 90°C for 2 days in an atmosphere WITH. Next was cooled to room temperature, the solution was filtered through diatomaceous earth and then concentrated. The residue was dissolved in ethyl acetate (500 ml) and the resulting solution was washed with brine (3×200 ml), dried over magnesium sulfate, concentrated and then separated by chromatography on silikagelevye column, using kachestvenna 50% ethyl acetate/45% dichloromethane/5% triethylamine to obtain 17.3 g of target compound (yield 60%). Data mass spectroscopy MS(M+1)=289,18.

Stage C: (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamid

Ethyl (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate (7.2 g, 25 mmol) and 4-methyl-N(3)-(4-pyridine-3-Yeremey-2-yl)phenyl-1,3-diamine (8,3 g, 30 mmol) was dissolved in 150 ml of toluene, then added a 2 M solution of trimethylaluminum in toluene (20 ml, 40 mmol). The resulting solution was stirred overnight at 50°C, then added to 20 ml of 2 M solution of trimethylaluminum in toluene. After stirring at 60°C for 24 hours the solution was cooled in an ice bath and then added an aqueous solution of sodium tartrate and potassium (200 ml)and then dichloromethane (300 ml). The organic phase was twice extracted with dichloromethane. The combined extracts were washed twice with saline, dried over magnesium sulfate and then concentrated. Next was purified column chromatography on silica gel, using as eluent 50% ethyl acetate/dichloromethane/5-10% triethylamine to obtain 7.5 g (yield 58%) of the specified connection. MS(M+1)=520,27,1H NMR (DMSc-d6, ppm): δ 10,10 (s, 1H); 9,20 (s, 1H); of 8.95 (s, 1H); 8,66 (d, J=6.0 Hz, 1H); 8,48 (d, J=6,0 10 Hz, 1H); 8,43 (d, J=8,4 Hz, 1H); 8,02 (s, 1H); to 7.77 (s, 1H); 7,74 (d, J=8,4 Hz, 1H); of 7.48 (dd, 1H); 7,42 (dd, 1H);7,40 (d, J=6.0 Hz, 1H); to 7.32 (d, J=8,4 Hz, 1H); to 7.18 (d, J=8,4 Hz, 1H); 4.26 deaths (t, J=8,4 Hz, 1H); 2,2-3,0 (t, J); of 2.20 (s, 3H); 2,12 (, 3H); 2,02 (m, 2H).

Example 12

Obtaining (1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide

Stage A: 1-((1S)-5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazin

In stage a of example 11, the filtrate methanol/isopropanol 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methyl-and (1S)-(+)-10-camphorsulfonic acid was concentrated under reduced pressure. The residue was dissolved in 1 l of sodium hydroxide (1 BC). After stirring for 30 minutes the solution was extracted with ethyl acetate (3×300 ml). The combined extracts washed with 1 N. sodium hydroxide (300 ml) and brine (3×300 ml), dried over magnesium sulfate and then concentrated to obtain 140 g (474 mmol) 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazin, where the dominant was the R-enantiomer. The residue was dissolved in 1.4 l of methanol, and then added (1R)-(-)-10-camphorsulfonic acid (220 g, 948 mmol) and 2.8 l of isopropanol. The resulting solution was heated to boiling for 15 minutes and further stirred overnight at room temperature. The precipitate was filtered. When the liquid has ceased to drip, the precipitate was washed with isopropanol and dissolved in 600 ml of methanol. After added isopropanol (1500 ml), the solution was heated to boiling for 15 minutes and then stirred overnight Ave is room temperature. The precipitate was filtered. After cleavage of the liquid residue was washed with isopropanol and then dissolved in 800 ml of sodium hydroxide (1 BC). The mixture was stirred for 30 minutes, then was extracted three times with ethyl acetate (3×300 ml). The combined extracts washed with 1 N. a solution of sodium hydroxide (500 ml) and brine (2×400 ml), dried over magnesium sulfate and then concentrated to obtain 60 g of the desired compound. Chiral purity was 99.8% according to chiral high-performance liquid chromatography. Data mass spectroscopy MS(M+1)=295,07, 297,07.

Stage b: Ethyl (1R)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate

On the basis of 1-((1R)-5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazine, the target compound was obtained according to the method described in stage b of example 11. Data mass spectroscopy MS(M+1)=289,18.

Stage C: (1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino] phenyl)-2,3-dihydro-1H-inden-5-carboxamid

The target compound was obtained by condensation of ethyl (1R)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate and 4-methyl-N(3)-(4-pyridine-3-Yeremey-2-yl) phenyl-1,3-diamine according to the method described at the stage of example 11. Data mass spectroscopy MS(M+1)=520.27.1H NMR (DMSO-d6, ppm): δ 10,15 (s, 1H); which 9.22 (s, 1H); 8,98 (s, 1H); 8,64 (d,J=6.0 Hz, 1H); 8,46 (d, J=6.0 Hz, 1H); 8,42 (d, J=8,4 Hz, 1H); 8,02 (s, 1H); of 7.75 (s, 1H); 7,72 (d, J=9.0 Hz, 1H); to 7.50 (dd, 1H); was 7.45 (dd, 1H);7,40 (d, J=5.4 Hz, 1H); to 7.35 (d, J=8,4 Hz, 1H); to 7.18 (d, J=9.0 Hz, 1H); 4.26 deaths (t, J=6.0 Hz, 1H); 2,2-3,0 (m, 10H); of 2.20 (s, 3H); 2,12 (s, 3H); 2,3 (m, 2H).

Example 13

Obtain (1S)-N-[3-(4,5'-bipyrimidin-2-yl amino)-4-were]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide

The target compound was obtained by condensation of ethyl (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate and N-(3)-4,5'-bipyrimidin-2-yl-4-were-1,3-diamine by the method described in the stage of example 11. Data mass spectroscopy MS(M+1)=521,27,1H NMR (DMSO-d6, ppm): δ 10,10 (s, 1H); 9,40 (s, 2H); 9.28 are (s, 1H); remaining 9.08 (s, 1H); and 8.50 (d, J=4,8 Hz, 1H); 8,04 (s, 1H); 7,74 (s, 1H); of 7.70 (d, J=9.0 Hz, 1H); 7,46 (d, J=4,8 Hz, 1H); 7,42 (d, J=7.8 Hz, 1H); to 7.32 (d, J=7.8 Hz, 1H); to 7.15 (d, J=9.0 Hz, 1H); 4.25 in (t, J=7.8 Hz, 1H); 2,2-2,9 (m, 10H); of 2.15 (s, 3H); 2,07 (s, 3H); 2,0 (m, 2H).

Example 14

Obtaining (1R)-N-[3-(4,5'-bipyrimidin-2-ylamino)-4-were]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide

The specified connection was obtained by condensation of (1R)-1-(4-methylpiperazin-1-yl)-2,3-dihydroindol-5-carboxylate and N-(3)-4,5'-bipyrimidin-2-yl-4-were-1,3-diamine, according to the method described at the stage of example 11. Data mass spectroscopy MS(M+1)=521,27,1H NMR (DMSO-d6, ppm): δ 10,10 (s, 1H); 9,40 (s, 2H); 9.28 are (s, 1H); remaining 9.08 (s, 1H); and 8.50 (d, J=5.7 Hz, 1H); 8,04 (s, 1H); 7,74 (s, 1H); of 7.70 (d, J=8,4 Hz, 1H); 7,46 (d, J=5.7 Hz, 1H); 7,42 d, J=8,4 Hz, 1H); to 7.32 (d, J=8,40 Hz, 1H); to 7.15 (d, J=8,4 Hz, 1H); 4.25 in (t, J=7.5 Hz, 1H); 2,2-2,9 (m, 10H); of 2.15 (s, 3H); 2,07 (s, 3H); 2.0 (t, 2H).

Example 15

Obtain (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-Yeremey-2-yl) amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamid

Stage A: N-(2-Methyl-5-nitrophenyl)-4-pyridin-4-Yeremey-2-amine

The target compound was obtained by condensation reaction between (2E)-3-(dimethylamino)-1-pyridin-4-rprop-2-EN-1-one and N-(2-methyl-5-nitrophenyl)guanidine nitrate, according to the method described in Stage With example 8. Data mass spectroscopy MS(M+1)=308,11.

Stage b: 4-methyl-N(3)-(4-pyridin-4-Yeremey-2-yl)benzene-1,3-diamine

The specified connection has been recovering N-(2-methyl-5-nitrophenyl)-4-pyridin-4-Yeremey-2-amine according to the method described in Stage D of example 8. Data mass spectroscopy MS(M+1)=278,13.

Stage C: (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamid

The target compound was obtained by reaction of condensation between ethyl (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylate and 4-methyl-N(3)-(4-pyridin-4-Yeremey-2-yl)benzene-1,3-diamine according to the method described at the stage of example 11. Data mass spectroscopy MS(M+1)=520,27,1NAMR (DMSO-d 6, ppm): δ 10,14 (s, 1H); 9,04 (s, 1H); 8,07 (d, J=4.4 Hz, 2H); 8,55 (d,=4.8 Hz, 1H); of 8.06 (s, 1H); 8,04 (d, J=4.4 Hz, 2H); for 7.78 (s, 1H); of 7.75 (d, J=8,8H4, 1H); was 7.45 (d, J=7,6 Hz, 1H); 7,44 (d, J=4,8 Hz, 1H); to 7.35 (d, J=7,6 Hz, 1H); to 7.18 (d, J=8,8 Hz, 1H); or 4.31 (t, J=7.2 Hz, 1H); 2.0 to 3.0 (m, 10H); 2,19 (s, 3H); 2,12 (s, 3H); 2,04 (m, 2H).

Example 16

Obtain (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide sulfate

Stage A: (18)-1-(4-methylpiperazin-1-yl)-2,3-dihydroindol-5-carboxylic acid

In a protective atmosphere N2, 1-((1S)-5-bromo-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazine (660 g, 2,235 mol) and THF (3.3 l) was added to a 10 l three-neck flask, and then the solution was stirred until complete dissolution. The temperature of the mixture was lowered to -78°C in a liquid nitrogen-acetone bath. n-Utility (n-BuLi) (2.5 M in hexane solution) (1072 ml, 2,682 mol, 1.2-fold) was added dropwise to the solution at a temperature of -78°C ~ -82°C. After stirred for 10 minutes, when the analysis of LC-MS (Liquid chromatography-mass spectrometry) showed complete reaction of the starting compounds, caution was added dry ice (170 g, 3,86 mol, 1,73-excess). The solution was further stirred for 10 minutes at a temperature of -60° ~ -75°C. After completion of the reaction the cold bath was removed and added to an aqueous solution of 2 N. HCl to adjust the pH to pH=2. Most of the water was evaporated naretara evaporator. Next, the mixture was dried overnight at 50°C ~ 60°C in a vacuum drying oven to obtain the target compound (1289 g, a valid product 583 g provides 100% output). This crude product is directly used in the next stage.

Stage b: (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-inden-5-carbonyl chloride hydrochloride

SOCl2(2.5 l) was added to a 5 l three-neck flask. (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxylic acid (1289 g, the actual content 583 g, equivalent 2,235 mol) was added in batches for 1 hour. The solution was heated at boiling for the night, then cooled to room temperature. A large part of SOCl2was removed with a rotary evaporator. After adding ethyl acetate (1.5 l) the solution was cooled to 0°C, filtered with suction to obtain a white precipitate, which was then dried in vacuum to obtain the target compound (about 1325 g, yield 100%).

Stage C: (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamid

N-(5-amino-2-were)-4-(3-pyridyl)-2-aminopyrimidine (681 g, 2,46 mol, 1,1-fold) was dissolved in pyridine (3 l). (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carbonyl chloride hydrochloride (1325 g, the actual maximum content 626 g, equivalent is into 2,235 mol, 1-fold) was slowly added over 300 minutes under stirring. The solution was very hot, since the reaction proceeded very rapidly, however, the cooling was not required. After the solution was stirred over night at room temperature, the solution is further under stirring was added to aqueous solution of 2 n sodium hydroxide (2 l)was immediately added dichloromethane (2 l). After stirring for some time, the solution was transferred into a 5 liter separating funnel and separated dichloromethane layer. The aqueous phase was extracted with dichloromethane (2×500 ml). The extracts were combined, dried over anhydrous magnesium sulfate, then concentrated. The residue was dissolved in dichloromethane and then purified column chromatography on silica gel, using as eluent dichloromethane/5% methanol/1% triethylamine. The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in 1 l of warm ethyl acetate, and after stirring began to fall crystals. The precipitate was filtered and dried in vacuum at 50°C to obtain the target product (617 g, 53% of the total output of the three stages). Data mass spectroscopy MS(M+1)=520,27.

Stage D: (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide sulfate

(1S)-1-(4-methylpiperazin--yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamid (248 g, 0,477 mol) was dissolved in ethanol (4,76 l). After stirring for 20 minutes the solution was filtered on a filter with suction. The filtrate was added to 20 l three-neck flask. Slowly through the funnel was added a solution of sulfuric acid (46,74 g, 0,477 mol, 1-fold), diluted with ethanol (532 ml) under stirring to obtain yellow suspension. Then added ethanol (9.5 litres). The mixture was boiled under reflux for 2 hours until, until the suspension has acquired a milky white color. The suspension was cooled to room temperature, filtered on a filter with suction, and then dried to obtain the target product (183 g, 57.5 per cent). the pH of the filtrate were transferred to basic (pH≈11) aqueous solution of NaOH and then was extracted with dichloromethane (4×200 ml). The extract was dried and concentrated to obtain (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide (98 g, 39.5 per cent). The melting point of the specified product: 187~189°C. Elementary analysis for C31H36N7O7S1.5computed value: 55,84; N 5,44; N 14,71; experimental value: 55,72; N 5,70; N 14,40.

Regulation of protein kinase activity and inhibition of cell proliferation by compounds according to the invention can be identified using the methods described below.

Example: the Study of the enzymatic activity of Abl, c-Kit and DERIVED Keene is s

The activity of the compounds of the present invention Abl, c-Kit and DERIVED kinases investigated Test shift mobility (TSP, mobility shift assay). ATP concentration was measured for each kinase in Km, i.e. Abl Km ATP=12 µm, C-Kit Km ATP=87 µm, Km DERIVED ATP=38 mm.

Materials: Abl (purchased from the company Carna, Lot No. 06CBS-2988C); C-Kit (purchased from BPS, Cat. No. 40250, Lot No. 1003); - DERIVED (purchased from BPS, Cat. No. 40263, Lot No. 1001); DMSO (purchased from Sigma, Cat. No. D2650, Lot No. 474382); 96-well culture tablet (purchased from Corning, Cat. No. 3365, Lot No. 22008026); 384 - well culture tablet (purchased from Corning, Cat. No. 3573, Lot No. 12608008); Staurosporine (purchased from Sigma, Cat. No. S4400-1MG, Lot No. 046K4080).

Ways:

1. Getting kinase buffer and stopping buffer;

(1) Kinase buffer: 62.5 mm HEPES, pH 7.5; 0,001875% Brij-35; 12.5 mm MgCl2; 2.5 mm DTT (dithiothreitol);

(2) Stop buffer: 100 mm HEPES, pH 7.5; of 0.015% Brij-35; 0.2% of the coating substance No. 3; 50 mm EDTA;

(3) Obtaining kinase solution: kinase solution was obtained by dissolving kinase in kinase buffer as described above. In relation to c-Kit the kinase preliminary activation treatment should be performed as follows: 700 nm c-Kit, 2 vM ATP, 4 mm DTT, and 10 mm MgCl2was dissolved in kinase buffer. After incubation at 28°C for 15 minutes the solution was added to the kinase buffer;

(4) obtaining the polypeptide solution: Poly is eptid FAM and ATP was dissolved in kinase buffer;

(5) the Kinase solution was transferred into a culture plate. Concentrations of ATP in the Abl, c-Kit and DERIVED was of 0.45 nm, 12 nm, 8 nm, respectively;

(6) Polypeptide solution was transferred into the culture planstate concentration of ATP in the Abl, c-Kit and DERIVED environment was 12 μm, 87 μm and 38 μm, respectively. Obtained concentrations of MgCl2in all cases was 10 mm;

(7) the Mixture in each well of the tablet were incubated at 28°C for one hour for Abl, 40 minutes for c-Kit and 5 hours for PDGFE. Then to terminate the reaction was added to stop the buffer;

(8) Data collected using equipment Caliper? further processed using software XLift to calculate IC50 values.

The required concentration (IC50, nm) of each of the compounds of the present invention, resulting in 50% inhibition, are shown in Table 1. For comparison, the IC50 values, leading to inhibition of these kinases in similar experimental conditions in the case of Imatinib. As a positive control in this study used staurosporin.

Table 1
ConnectionIC50 (nm)
Al c-KitDERIVED
EXAMPLE 15,82217
EXAMPLE 220441186233
EXAMPLE 36,21612
EXAMPLE 46,32615
EXAMPLE 5of 5.42318
EXAMPLE 6123220
EXAMPLE 741152941
EXAMPLE 85,33222
EXAMPLE 912151 15
EXAMPLE 10703221
EXAMPLE 112,28,59,6
EXAMPLE 12256225153
EXAMPLE 132,41513
EXAMPLE 14266226065
EXAMPLE 152352624
Imatinib20770339
Staurosporin1622,00,50

As shown in table 1, the compounds according to the invention have a very high inhibitory activity against Abl, c-Kit and DERIVED: IC50 values in the range from 2.2 NMDA 2044 nm when the inhibition of Abl, IC50 values in the range from 8.5 nm to 2260 nm in the inhibition of c-Kit and IC50 values in the range from 9.6 nm to 233 nm in the case of inhibition DERIVED. Except for examples 2, 7, 12 and 14, the compounds according to the invention have greater activity than Imatinib in inhibiting the three kinases of the given type.

Example: the Study of kinase activity of mutant Abl and c-Kit

Inhibitory activity of compounds of the present invention mutants of Abl, c-Kit and DERIVED kinases were identified in the study labeled isotope of phosphorus of ATP (33P-ATP).

1. Using freshly prepared reaction buffer, the received substrate solution: 20 mM HEPES, pH 7.5, 10 mm MgCl2, 1 mm of FRM, to 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mm Na3VO4, 2 mm DTT, 1% DMSO. For c-Kit and c-Kit (V654A)optionally, a buffer was added to 2 mm MnCl2;

2. To the above substrate solution was added the required coenzyme;

3. Added kinase and gently stirred;

4. The compounds were dissolved in DMSO, was then added above the kinase rastvor using acoustic method (h550, range nanolitre) and incubated for 20 minutes;

5. To initiate the reaction by the above reaction solution was added33P-ATP;

6. The mixture is incubated for 2 hours at room temperature;

7. The kinase activity was determined by filtering the hand;

. The data were processed in Excel and read control data. To obtain the values of IC50 curve built using the software GraphPad Prism.

Values S connection example 11, which may inhibit Abl and 7 mutants, as well as c-Kit and 5 mutants are listed in Table 2. Also, for comparison, Table 2 also lists the IC50 values for Nilotinib, inhibition of the same mutants in similar experimental conditions. As a positive control in this study used staurosporin.

Table 2
KinaseATP concentration (µm)EXAMPLE 11 IC50 (nm)Nilotinib IC50 (nm)Staurosporine IC50 (nm)
Alb100,211,1914,5
Alb (T)1014090>200003,38
Alb (EK)103,7236,327,0
Alb (G250E)102,9424,8of 5.68
Alb (NR)100,382,999,02
Alb (MT)100,291,89was 9.33
Alb (Q252H)100,42of 4.664,47
Alb (Y253F)100,715,1315,4
c-Kit30132302to 8.41
c-Kit (D816H)3083,6574<1,0
c-Kit (D816V)301738>20000<1,0
c-Kit T670I)30 2057>20000to 2.67
c-Kit301,7716,5<1,0
(V560G)
c-Kit (V654A)30969139401,16

As shown in Table 2, the compounds according to example 11 have greater inhibitory capacity for inhibition of mutant Abl and c-Kit compared to Nilotinib. Nilotinib (trade name Tasigna) has a good effect in the treatment of patients suffering from leukemia with resistance to Imatinib (trade name Gleevec). Because the connection in example 11 has a large effect in the inhibition of mutants of Imatinib in the test compared Nilotinib, the compounds according to the invention allows to achieve the best results in the treatment of patients suffering from leukemia with resistance to Imatinib. Mutants of c-Kit are widely distributed in the gastrointestinal stromal tumors, when mastocyte and acute myeloid leukemia. As shown in Table 2, the connection by the use of the 11 has a good effect in the inhibition of all types of c-Kit mutants. Therefore, the connection according to the invention can be used for the treatment of gastrointestinal stromal tumors, when mastocyte and acute myeloid leukemia.

Example: Study C cells

The inhibitory activity of the compounds according to the invention in relation to cell growth of chronic myeloid leukemia K studied luminescent method CellTiter-Glo.

Materials: C cell strain (obtained from ATS, Cat. No. CCL-243, Lot No. 50644810); IMDM (obtained from Invitrogen, Cat. No. 12440-053); fetal bovine serum (obtained from Invitrogen, Cat. No. 10099141, Lot No. 613866);

DMSO (obtained from Sigma, Cat. No. D2650, Lot No. 077k2357); 96-well culture the tablet received from Coming, Cat. No. 3903); 15 ml centrifuge tubes (obtained from Greiner, Cat. No. 0703115, Lot No. 2012-01);

set analysis cell viability (CellTiter-Glo) (ordered from Promega, Cat. No. G7571, Lot No. 256984); staurosporin (ordered from Sigma, Cat. No. S4400-1MG, Lot No. 046K4080).

Methods:

1. Inoculation of cell cultures

(1) the Receipt of complete medium: Complete medium consisted of a thoroughly stirred mixture of 90% IMDM and 10% fetal serum;

(2) Selected cell strain with good character growth;

(3) the Cell suspension was transferred into centrifuge tubes using a pipette and then centrifuged at a speed of 800-1000 rpm for 3-5 minutes.

(4) the Supernatant liquid in the test tube was removed by pipette;

(5) In a test tube was added tonigobe environment and the cells resuspendable, caution when the solution in the pipette and releasing back;

(6) the Cells were counted using the camera for counting blood cells;

(7) Adjusted concentration of cell suspension to 4x104cells/ml;

(8) the Cell suspension was added to 96-well culture tablet, 100 μl into the hole, i.e. 4000 cells per well. Tablet incubated overnight in an atmosphere of CO2in the incubator.

2. Receiving and adding the connection

(1) Compounds were dissolved in DMSO and then diluted with 10 different concentrations;

(2) with 0.5 μl of a solution of the compound was transferred into the culture tablet;

(3) Cultural tablet incubated at 37°C in an incubator for 72 hours.

3. Test and analysis

(1) Inverted microscope studied cell morphology;

(2) In each well was added 100 μl of reagent analysis of cell viability;

(3) Plate was shaken for 2 minutes in a shaker, achieving cell lysis;

(4) To stabilize the luminescence signal the tablet is kept at room temperature for 10 minutes.

(5) To the bottom of the tablet was attached a white membrane, the tablet was measured using equipment Flexstation 3 (luminescence, the integration time of 500 MS);

(6) the Results were recorded and analyzed.

The required concentration (IC50, nm) of the compounds according to examples 3, 11, 12, 13 and 1 of the present invention, leading to 50% inhibition are shown in Table 3. In addition, for comparison, Table 3 shows the IC50 values for Imatinib, inhibiting the growth of cells C in similar experimental conditions. As a positive control in this study used staurosporin.

Table 3
Example311121315ImatinibStaurosporin
IC50 (nm)123,22082.235206139

As can be seen from Table 3, the compounds according to examples 3,11,12,I have a very high inhibitory activity against the growth of cells of chronic myeloid leukemia K562. With the exception of example 12, the concentration (IC50, nm) of the compounds according to example 3, 11, 13 and 15, resulting in 50% inhibition of the growth rate of cells C significantly lower concentrations of Imatinib (p≤0,05). Connection example 12 was optical enantiomer compounds the Oia example 11. Although its inhibitory activity on cell growth C was 65 times lower connection example 11, it was more effective than Imatinib. It can be assumed that the compounds of the present invention can be used for the effective treatment of chronic myeloid leukemia.

Example D: the Study of cellular strains C, KU812, MEG-01, Kasumi-1 and Sup-B15

The present invention also tested the inhibitory activity of the compounds of the present invention in the growth of cells of chronic myeloid leukemia K, KU812, MEG-01 cells acute myeloide leukemia Kasumi-1 cells and acute lymphatic leukemia Sup-B15.

Materials: Spectrophotometer SpectraMAX Plus for measurement of the microplate, the model 3011 (supplied Molecular Devices Corp, California, USA); incubator CO2with the water jacket (comes Therma, USA); inverted microscope Chongguang XDS-1B (Chongqing Optical &Electrical Instrument Co.,Ltd., Chongqing, China); powder water reagent CellTiter 96® MTS (comes Promega, Cat. No. G1112); fenesin methosulfate (FMS) (available as Sigma Product No. P9625); RPMI1640 (comes GIBCO, USA, Cat. No. 31800-022); IMDM (comes GIBCO, USA, Cat. No. 12200-036); fetal calf serum (FBS) (comes GIBCO, USA, Cat. No.FCS100).

Ways:

1. Obtaining researched solution

(1) preparation of a solution of the FMS: FMS was dissolved in phosphate-saline buffer Dulbecco (DPBS), having a concentration of 0.92 g/ml Then RA the solution was filtered and placed in a sterile and light-tight container;

(2) acquisition of MTS solution: a) 21 ml of DPBS was added in a light-tight container; b) 42 mg powder MTS weighed and then added to DPBS; C) the above components were mixed by means of a magnetic stirrer until complete dissolution of the powder; d) measured pH. Preferably the pH should be in the range from 6.0 to 6.5. If the pH is higher than 6.5, it should be brought to 6.5 with 1 N. HCl; d) the solution was filtered and placed in a sterile covered container;

(3) Obtaining a mixture of MTS/FMS: a) 2 ml of solution was transferred into a test tube; b) 100 μl of a solution of the FMS was added into a test tube; the tube was gently shaken to mix the solution.

2. Inoculation of cell cultures

(1) the Counting of cells was performed using a camera counting of blood cells after cell growth to a certain size;

(2) the Concentration of cells ostanavlivali equal to 2,78×104cells/ml in RPMI1640 medium containing 10% FBS (K562, KU812, MEG-01 or Kasumi-1 cells) or IMDM medium containing 0.05 mm 2-mercaptoethanol and 20% FBS (Sup-B15 cells);

(3) 180 ál of cell suspension was added into each well of 96-well culture plate with a final density of cells 5×103on the hole.

3. Receiving and adding connections

(1) the Investigated compounds were dissolved in DMSO and then diluted with 10 different concentrations;

(2) 20 m is l solution of each concentration was transferred into each well, already containing the cell suspension (3 wells for each concentration);

(3) the plates were incubated for 72 hours at 37°C, 5% CO2and 95% humidity.

4. Testing and analysis

(1) 40 μl of MTS solution/FMS transferred with a pipette into each well containing 200 μl of medium, to obtain the General solution of 240 μl of each cell;

(2) the Tablet were incubated for 1-4 hours at 37°C, 5% CO2and 95% humidity;

(3) Recorded the absorbance at a wavelength of 490 nm using a SpectraMax Plus;

(4) IC50 values were calculated using version 5 of the software GraphPad Prism.

Table 4 shows the concentration of the compound from EXAMPLE 16 (IC50, nm)required for 50% inhibition C, KU812, MEG-01, Kasumi-1 and Sup-815 cell strains. In addition, for comparison, also shown inhibitory activity of Imatinib and Nilotinib in similar experimental conditions. As a positive control used staurosporin.

Table 4
Cellular strainIC50 (nm)
example 16ImatinibNilotinibStaurosporin
C 0,251216,2671,5
KU8120,02451,42,10to 9.57
MEG-010,08519,31,658,97
Kasumi-111,229722,31,04
Sup-B1539,63821356,84

As can be seen from Table 4, the compound from example 16 shows a very high inhibitory activity against the growth of cell strains chronic myeloid leukemia K, KU812 and MEG-01 cell strains acute myeloid leukemia Kasumi-1, and cell strains acute lymphatic leukemia Sup-B15. The IC50 values for the compounds ranged from 0,024 nm to 39.6 nm. In addition, the potency of the compound from example 16 when the growth inhibition data cell strains was much higher than Imatinib or Nilotinib. These results suggest that the compounds according to the present izopet the tion can be used for the effective treatment of chronic myeloid leukemia, acute myeloid leukemia and acute lymphatic leukemia.

Although the invention is described with illustrative embodiments, the specialists in the art will be understood various modifications and variations do not result in a change of scope and the objectives of the present invention. It should be understood that the invention is not limited to the illustrative examples shown in this document.

1. The compound of Formula II

or its pharmaceutically acceptable salt, where
R1represents piperazinil, which may be optionally substituted with one R1a;
R1arepresents H, CH3C(O)Rdor C(O)ORa;
Y represents pyrimidyl;
Z represents a pyridyl or pyrimidyl;
Rarepresents tert-butyl and Rdrepresents CH3and
where the specified connection is selected:
tert-butyl 4-{5-[({(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl}amino)carbonyl)-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate;
N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-1-piperazine-1-yl-2,3-dihydro-1H-inden-5-carboxamide;
1-[4-acetylpiperidine-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide;
(1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-yerimede the-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide;
(1S)-N-[3-(4,5'-bipyrimidin-2-ylamino)-4-were]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide;
(1R)-N-[3-(4,5'-bipyrimidin-2-ylamino)-4-were]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide;
(1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide and
(1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridine-3-Yeremey-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamidine.

2. Pharmaceutical composition having the properties of an inhibitor of the activity of protein kinases selected from Abl, c-Kit and DERIVED where the specified pharmaceutical composition contains a therapeutically effective amount of the compound or its pharmaceutically acceptable salt according to claim 1 and at least one pharmaceutically acceptable carrier.

3. A method of inhibiting the activity of a protein kinase selected from Abl, c-Kit and DERIVED, where the method includes the impact of the compound or its pharmaceutically acceptable salt according to claim 1 to the indicated protein kinase.

4. The use of compound or its pharmaceutically acceptable salt according to claim 1 in the manufacture of medicinal preparations for the treatment of disorders or diseases where the specified disease or disorder associated with the activity of a protein kinase selected from Abl, c-Kit and DERIVED.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazole derivatives of general formula or its pharmaceutically acceptable salt, wherein R1 means halogen, C1-6-alkyl or C1-6-alkoxy; R2 means C1-6-alkyl; R3 means hydrogen, C1-6-alkyl; Q means -N= or -CH=; R4 represents a group of formula or , wherein X, Y and Z independently represent -CH= or -N=, and only one of X or Y can be a nitrogen atom; R5 and R6 independently represent a hydrogen atom, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, -(CH2)m-(CO)O-C1-6-alkyl, -(CH2)m-S(O)2-C1-6-alkyl, -(CH2)m-C(O)-NR'R" and wherein m=1 and R' and R" independently represent hydrogen or C1-6-alkyl. Also, the invention refers to a therapeutic agent based on the compound of formula (I) and using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective for treating and preventing mGluR5 receptor mediated disorders.

26 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel alkyl [2-(2-{5-[4-(4-{2-[1-(2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-buta-1,3-diinyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamates or their naphthalene-1,5-disulfonates, which possess properties of NS5A protein inhibitor and can be used for prevention and treatment of viral diseases, caused by viruses of hepatitis C (HCV) and hepatitis GBV-C. In claimed invention compounds, corresponding to general formula 1 R1, R2, R3 and R4 independently on each other stand for C1-C3 alkyl; R5 and R6 independently on each other stand for C1-C3alkyloxymethyl, or R3, and R5, and R4, and R6, together with carbon atoms, which they are bound with, independently on each other form tetrahydrofurane cycle.

EFFECT: improved propertied of compounds.

7 cl, 2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel indole and benzomorpholine derivatives of a formula (I) or its pharmaceutically acceptable salt, where R1 represents C1-6-alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 represents halogeno; R3 represents hydrogen; n equals 2, X represents -CH2CH2-O or -CH=CH-; Y represents -O- or -CR4(OH)-; R4 represents hydrogen or C1-3 alkyl. Invention also relates to a pharmaceutical composition based on formula (I) compound and a method of treatment or prevention of the said pathological states.

EFFECT: obtained are novel compounds, which are positive allosteric modulators of matabotropic subtype 2 receptors (mGluR2), which are useful for treatment or prevention of neurological and psychiatric disorders, associated with glutamate dysfunction, and diseases, involving metabotropic subtype 2 receptors GluR2.

22 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, where R1 is H or R1 and R2 together with a nitrogen group can form where A, B, C and D are independently selected from a group consisting of CR1a and N; where at least one of A, B, C and D is CR1a; where R1a is selected from a group consisting of H, -ORi, -SRii, -S(O)Riii, -C(O)NRvRvi and CF3, where Ri is selected from a group consisting of methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, 2-oxo-2-phenylethyl, butyl, acetonitrile and benzyl; Rii, Riii and Riv denote methyl; Rv and Rvi are independently selected from a group consisting of H, methyl, ethyl, hydroxyethyl, hydroxypropyl, diethyalminoethyl, phenyl, pyridinyl, methoxyethyl, hydroxyethoxyethyl, benzyl, phenylethyl, 2-hydroxy-1-hydroxymethyl-2-phenylethyl and carbomoylethyl, or Rv and RVi together form morpholine or ethyl ester of piperazine; R2 is selected from a group consisting of phenyl, naphthyl, pyrazolyl and C1-C8alkylene phenyl; R3 is C1-C8alkylene; R4 is selected from a group consisting of H, C1-C8alkyl and -C=NH(NH2). The invention also relates to compounds of formulae I-A

I-B I-C

I-D I-E

values of radicals of which are given in the claim; a method of treating said pathological conditions, a pharmaceutical composition based on said compounds, a method of identifying a Trp-p8 agonist and specific compounds.

EFFECT: obtaining compounds which are useful as Trp-p8 modulators.

25 cl, 19 dwg, 8 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel alkyl [(S)-1-((S)-2-{5-[4-(4-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-buta-1,3-diinyl)-phenyl]-1H-imidazol-2-yl}pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamate naphthalene-1,5-disulphonates of general formula 1, which are NS5A inhibitors and can be used as an active component for producing a pharmaceutical composition and an antiviral medicinal agent for treating and preventing viral diseases caused by hepatitis C virus (HCV) and hepatitis GBV-C virus. In general formula 1 R denotes C1-C3alkyl.

EFFECT: obtaining novel compounds.

6 cl, 2 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazole derivatives of general formula or its pharmaceutically acceptable salt, wherein R1 means halogen, C1-6-alkyl or C1-6-alkoxy; R2 means C1-6-alkyl; R3 means hydrogen, C1-6-alkyl; Q means -N= or -CH=; R4 represents a group of formula or , wherein X, Y and Z independently represent -CH= or -N=, and only one of X or Y can be a nitrogen atom; R5 and R6 independently represent a hydrogen atom, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, -(CH2)m-(CO)O-C1-6-alkyl, -(CH2)m-S(O)2-C1-6-alkyl, -(CH2)m-C(O)-NR'R" and wherein m=1 and R' and R" independently represent hydrogen or C1-6-alkyl. Also, the invention refers to a therapeutic agent based on the compound of formula (I) and using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective for treating and preventing mGluR5 receptor mediated disorders.

26 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula

,

wherein A1 means benzene or heterocycle specified in a group consisting of pyridine, pyrazine, imidazole, thiazole, pyrimidine, thiophen, pyridazine, benzoxazine and oxobenzoxazine; A2 means benzene, if needed substituted by fluorine, or thiophen; B1 means hydrogen, lower alkyl, if needed substituted by piperazinyl or morpholino, halogen-substituted lower alkyl, lower alkoxy substituted by carbamoyl, acylamino, carbamoyl or lower alkylcarbonyloxy (provided A1 means thiazole, B1 does not mean acylamino); B2 means hydrogen or a functional group containing at least one nitrogen atom specified in a group consisting of acylamino, pyrrolidinyl, morpholino, piperidinyl, if needed substituted by acyl, piperazinyl, if needed substituted by lower alkyl or acyl, pyrazolyl, diazabicyclo[2.2.1]heptyl, if needed substituted by acyl, and di-(lower alkyl)amino, if needed substituted by amino or acylamino (provided A1 means thiazole, B2 does not mean acylamino); Y means a group presented by formula

,

wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.

EFFECT: benzene or thiophen derivative as a VAP-1 inhibitor.

13 cl, 25 tbl, 125 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula (1), which possess affinity for µ-opioid receptor and ORL1-receptor, to medications, containing said compounds, and to application of said compounds for obtaining medications, suitable for treating pain, fear, stress and other diseases or conditions. In general formula (1) Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' stand for -H; R1 and R2 independently on each other stand for -H or -CH3; on condition that R1 and R2 both simultaneously do not stand for -H; Q stands for: -C6-16-aryl, non-substituted or mono- or poly-substituted with -F, -Cl, -Br or -I; or heteroaryl; R3 stands for: -C1-8-alkyl, non-substituted or mono- or poly-substituted -OR0, where R0 stands for non-substituted -C1-3-alkyl; non-substituted -C3-6-cycloalkyl-C1-4-alkyl; non-substituted -C1-4-alkyl-C3-6-cycloalkyl; -C6-16-aryl, non-substituted or mono- or poly-substituted with -F, -Cl, -Br, -I, -CN, -R0 or -OR0, where R0 stands for non-substituted -C1-8-alkyl; or heteroaryl; n stands for 0; X stands for -NRA-; RA stands for -H or -R0; where R0 stands for non-substituted -C1-4-alkyl; and RB stands for -C(=O)R0; where R0 stands for non-substituted -C2-8-alkenyl-C6-16-aryl or non-substituted -C1-8-alkyl-(C6-16-aryl)1-2.

EFFECT: obtaining compounds for obtaining medications, suitable for treatment of pain, fear, stress and other diseases or conditions.

10 cl, 14 tbl, 164 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound for formula (1) , antioxidant, containing formula (1) compound or its salt as active ingredient, and to application of formula (1) compound or its salt for oxidant manufacturing. Invention also relates to formula (2) compound, which is intermediate for obtaining formula (1) compound.

EFFECT: formula compound, demonstrating antioxidant properties.

4 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phenyl alkyl piperazines of formula (I) , in which: R1 represents independently on each other hydrogen atom, halogen atom, (C1-C5)alkyl group, (C1-C5)halogenalkyl group, (C1-C2)perfluoroalkyl group, (C1-C5)alkoxyl group or (C1-C2)perfluoroalkoxyl group; R2 stands for (C1-C5)alkyl group or (C1-C5)alkoxyl group, R3 represents (C1-C5)alkyl group; A represents =CH- and =N-; in form of base or additive salt with acid. Invention also relates to pharmaceutical composition for modulation of activity of TNF-alpha, which contains claimed compounds, and to method of their obtaining.

EFFECT: obtained are novel compounds which can be applied in medicine as medications for treating or preventing pain and/or diseases, associated with inflammatory of immune disorders.

24 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, particularly novel pyridinone derivatives of formula (I) or stereochemically isomeric forms thereof, where R1 is C1-6alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 is a halogen, trifluoromethyl, C1-3alkyl or cyclopropyl; X is a covalent bond, O or O-CH2; Ar is an unsubstituted phenyl or phenyl substituted with n radicals R4, where n equals 1, 2 or 3; where each R4 is a halogen; or pharmaceutically acceptable addition salts or solvates thereof. The invention also relates to a pharmaceutical composition, having the activity of positive allosteric modulators of the metabotropic glutamate receptor subtype 2, based on compounds of formula I and use of compounds of formula I to prepare a medicinal agent for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved.

EFFECT: novel compounds which can be useful in treating and preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved are obtained and described.

15 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics, namely to a pharmaceutical composition (a solid oral dosage form (a tablet or a capsule)) of tyrosine kinase Bcr-Abl inhibitor - imatinib(4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide). The pharmaceutical composition contains 25-45 wt % of imatinib, preferentially imatinib mesylate, more preferentially an α-crystalline form of imatinib mesylate, a binding agent representing povidone, and at least two desintegrant representing low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

EFFECT: invention provides the min 80% imatinib release from the tablet for 15 minutes after oral administration and enables extending the range of drugs used for leukaemia.

14 cl, 4 dwg, 3 tbl, 2 ex

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