Triazoles used as protein kinase inhibitors

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

 

The technical FIELD

The present invention relates to inhibitors of protein kinases. This invention also provides pharmaceutical compositions containing the compounds of this invention, and methods of using the compositions to treat various diseases.

The LEVEL of TECHNOLOGY

Reached recently a deep understanding of the structure of enzymes and other biological molecules associated with different diseases, greatly facilitates the search for new therapeutic agents. One of the important classes of enzymes, subjected to extensive research, are protein kinases.

Protein kinases constitute a large family of structurally related enzymes that regulate various processes of signal transmission in the cell. (See, Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995.) Because protein kinases have a certain conservatism structures and catalytic functions, it is believed that they are descended from a common gene. Almost all kinases contain the same catalytic domain size of 250-300 amino acids. Kinases can be divided into families depending on the substrates they phosphorylate (e.g., protein-the tyrosine, protein-serine/threonine, lipid and other kinases). Identified motifs sequences, which generally correspond to each of the decrees of the data collection kinases (see, for example, Hanks, S.K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et al., Science 1991, 253, 407-414; Hiles et al., Cell 1992, 70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al., EMBO J. 1994, 13, 2352-2361).

Typically, protein kinases mediate intracellular signal transmission, ensuring the transfer of phosphoryla from nucleosidase to a protein acceptor, which is involved in signaling pathways. These phosphorylation events act as molecular mechanisms on/off, which can modulate or regulate the target biological function of the protein. These phosphorylation events ultimately run in response to a number of extracellular and other incentives. Examples of such stimuli include environmental signals and chemical stress (e.g., signals osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g. interleukin-1 (IL-I) and tumor necrosis factor α (TNF-α), growth factors (e.g., colony-forming granulocyte-macrophage factor (GM-CSF), and fibroblast growth factor (FGF)). Extracellular stimulus can affect one or more cellular responses associated with cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, the reduction of the muscles, glucose metabolism, regulation of protein synthesis and regulation glue the full cycle.

Many diseases are associated with abnormal cellular responses triggered by events, mediated by protein kinases, as described above. These diseases include, without limitation, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormonal disorders. Accordingly, in medicinal chemistry is an intensive search for inhibitors of protein kinases, which are effective therapeutic agents.

Family receptors tyrosinekinase type III, including Flt3, c-Kit, PDGF-receptor and c-Fms, plays an important role in the maintenance, growth and development of hematopoietic and nonhematopoietic cells. [Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333 and Reilly, JT, British Journal of Haematology, 2002, 116, 744-757.] FLT-3 and c-Kit regulate the maintenance of stem cell pools early predecessors, and the development of Mature lymphoid and myeloid cells [Lyman, S, Jacobsen S, Blood, 1998, 91, 1101-1134]. Both receptors contain characteristic kinase domain that is activated by ligand-mediated receptor dimerization. After activation of the kinase domain induces autophosphorylation of the receptor and phosphorylation of various cytoplasmic proteins, otrebusy spreading activation signal, which provides growth, differentiation and survival. Some of the step-down regulators of signaling pathways involving receptor FLT-3 and c-Kit, include PLCγ, PI3-kinase, Grb-2, SHIP - and Src-related kinases [Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333]. It is shown that both receptor tyrosine kinase plays an important role in the development of a number of hematopoietic and nonhematopoietic malignant diseases. Mutations leading to ligand-independent activation of FLT-3 and c-Kit, participate in the development of acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis and stromal tumors of the gastrointestinal tract (GIST). These mutations include single amino acid substitution in the kinase domain or internal tandem duplications, point mutations or deletions in the frame read kolomanbrunnen site receptors. In addition to activating mutations, ligand-dependent autocrine or paracrine hormone) stimulation overexpression FLT-3 or c-Kit wild type can participate in the formation of the malignant phenotype [Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333].

c-fms encodes the receptor for macrophage colony-stimulating factor (M-CSF-1R), which is expressed mainly in the lines of monocytes/macrophages [Dai, XM, et al., Blood, 2002, 99, 111-120]. MCSF-1R and its ligands regulate growth and differentiation of macrophages. Like other members of the family, MCSF-1R content is it characteristic of kinase domain, which is activated by ligand-induced dimerization of the receptor. MCSF-1R is also expressed in nonhematopoietic cells, including epithelial breast cells and neurons. Mutations of this receptor potentially associated with myeloid leukemias, and its expression correlates with metastatic carcinoma of the breast, ovary and endometrium ['reilly, JT, British Journal of Haematology, 2002, 116, 744-757 and Kacinski, BM, Mol. Reprod and Devel., 1997, 46, 71-74]. Another possible indication for use of antagonists MCSF-1R is osteoporosis [Teitelbaum, S, Science 2000, 289, 1504-1508].

The PDGF receptor (DERIVED) contains two subunit - DERIVED-α and-DERIVED-β, which can form Homo - or heterodimer upon binding with the ligand. There are several ligands PDGF: AB, BB, CC and DD. DERIVED is expressed early stem cells, mastocytoma, myeloid cells, mesenchymal cells and smooth muscle cells [Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333]. Only DERIVED-β is involved in the development of myeloid leukemia, usually as a partner Tel, Huntingtin-binding protein (HIP1) or Rabaptin5 for translocation. Recently it was shown that activating mutations in the kinase domain DERIVED-α are associated with stromal tumours of the gastrointestinal tract (GIST) [Heinrich MC et al., Sciencexpress, 2003].

Cyclin-dependent kinases (cdks) are serine/threonine protein kinases, consisting sabahudin β-pleated structure of aminobenzoic lobe and a larger carboxy-terminal lobe, which is mainly in the conformation of the α-helix. CDK contain 11 subdomains that are common to all protein kinases and having a molecular weight of from 33 to 44 kDa. For the full activation of kinases of this family, which includes CDK1, CKD2, CDK4 and CDK6, requires phosphorylation of the residue corresponding to CDK2 Thr160 [Meijer, L., Drug Resistance Updates 2000, 3, 83-88].

Each CDK complex is formed from a regulatory subunit cyclina (for example, cyclina A, B1, B2, D1, D2, D3 and E) and a catalytic kinase subunit (e.g., CDK1, CDK2, CDK4, CDK5 and CDK6). Each of the different pairs kinase/cyclin regulates different and specific phase of the cell cycle, known as phases G1, S, G2 and M [Nigg, E., 2001 Nature Reviews, 2, 21-32; Flatt, P., Pietenpol, J., Drug Metabolism Reviews 2000, 32, 283-305].

CDK involved in the development of disorders associated with cell proliferation, in particular cancer. The cause of cell proliferation is a direct or indirect violation of the regulation of the cell division cycle, cdks play a key role in the regulation of the different phases of this cycle. For example, overexpression of cycline D1 is typically associated with a number of human cancers, including carcinomas of the breast, colon and liver cells, and glioma [Flatt, P., Pietenpol, J., Drug Metabolism Reviews 2000, 32, 283-305]. The complex CDK2/cyclin E plays an important role in the development of the cell cycle from early phase G1 to phase S, and overexpression of the loop is and E is associated with various solid tumors. Therefore, inhibitors of tsiklonov D1, E, or associated CDK can be used as targets in anticancer therapy [Kaubisch, A., Schwartz, G., The Cancer Journal 2000, 6, 192-212].

CDK, especially CDK2, are also involved in apoptosis and the development of T-cells. CDK2 was identified as a key regulator of apoptosis of thymocytes [Williams, O., et al., European Journal of Immunology 2000, 709-713]. Stimulation of the kinase activity of CDK2 in response to specific stimuli associated with the development of apoptosis in thymocytes. Inhibition of kinase activity of CDK2 blocks the apoptosis and protects thymocytes.

In addition to cell cycle regulation and apoptosis CDK directly involved in the transcription process. For replication of many viruses require the presence of CDK. The CDK inhibitors inhibit the replication of the virus such as human cytomegalovirus, herpes simplex virus and varicella zoster virus [Meijer, L., Drug Resistance Updates 2000, 3, 83-88].

The CDK inhibitors can also be used to treat neurodegenerative diseases such as Alzheimer's disease. Hyperphosphorylated Tau protein under the action of CDK5/p25 leads to the appearance of paired helical filaments (PHF), associated with Alzheimer's disease [Meijer, L., Drug Resistance Updates, 2000 3, 83-88].

Another family of kinases, the calling of special interest are kinase Src. These kinases are involved in the development of cancers, disorders of the immune system is s and diseases associated with the restructuring of the bones. A General overview on this family can be found in Thomas and Brugge, Annu. Rev. Cell Dev. Biol. 1997, 13, 513; Lawrence and Niu, Pharmacol. Ther. 1998, 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow), 2000, 65, 49; Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).

Members of the Src family include the following eight kinases mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck and Blk. These kinases belong to preceptory kinases, molecular weight which varies from 52 to 62 kDa. They all have a common structural organization and contain six different functional domains: domain 4 Src-homology (SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain (SH1) and C-terminal regulatory domain. Tatosyan et al. Biochemistry (Moscow), 2000, 65, 49-58.

The published data allow us to examine the Src kinase as a potential therapeutic target for various human diseases. In mice with deficiency of Src developing osteoporosis, or bone formation, due to the suppression of bone resorption under the action of osteoclasts. This suggests that osteoporosis resulting from abnormally high bone resorption, can be treated by inhibition of Src. Soriano et al., Cell 1992, 69, 551 and Soriano et al., Cell 1991, 64, 693.

Overexpression of CSK in rheumatoid synoviocytes and osteoclasts leads to the suppression of arthritic bone destruction. Takayanagi et al., J. Clin. Invest. 1999, 104, 137. CSK, or C-terminal Src kinase, FOSFA iliret Src and therefore inhibits its catalytic activity. In turn, inhibition of Src can prevent joint destruction observed in patients suffering from rheumatoid arthritis. Boschelli et al., Drugs of the Future 2000, 25(7), 717.

Src is also involved in the replication of hepatitis B. Transcription of the encoded virus factor HBx activates the Src on stage, necessary for reproduction of the virus. Klein et al., EMBO J. 1999, 18, 5019, and Klein et al., Mol. Cell. Biol. 1997, 17, 6421.

Several studies have found an Association of the expression of Src with cancer, such as colon cancer, breast cancer, liver and pancreas, certain B-cell leukemias and lymphomas. Talamonti et al., J. Clin. Invest. 1993, 91, 53; Lutz et al., Biochem. Biophys. Res. 1998 243, 503; Rosen et al., J. Biol. Chem. 1986, 261, 13754; Bolen et al., Proc. Natl. Acad. Sci USA 1987, 84, 2251; Masaki et al., Hepatology 1998, 27, 1257; Biscardi et al., Adv. Cancer Res. 1999, 76, 61; Lynch et al., Leukemia, 1993, 7, 1416. In addition, it was shown that the expression of antisense sequences Src in cell tumors of the ovary and colon leads to the suppression of tumor growth. Wiener et al., Clin. Cancer Res., 1999, 5, 2164; Staley et al., Cell Growth Diff., 1997, 8, 269.

Other kinases of the Src family are also potential therapeutic targets. Lck is involved in T-cell signaling. Mice that lost Lck gene, there is a violation of the development of thymocytes. The ability of Lck activation of T-cell signaling pathway suggests that inhibitors of Lck can be used for the treatment of autoimmune diseases, such as rheumatoid arthritis. Molina et al., Nature, 1992, 357, 161. Hck, Fgr and Lyn were identified as important mediators integranova signaling pathways in myeloid leukocytes. Lowell et al., J. Leukoc. Biol., 1999, 65, 313. Therefore, the inhibition data kinase mediators can be used to treat inflammation. Boschelli et al., Drugs of the Future 2000, 25(7), 717.

Tyrosinekinase Syk plays a key role in FcεRI-mediated degranulation of mast cells and activation of eosinophils. Accordingly, the kinase Syk is involved in the development of various allergic diseases, particularly asthma. It is shown that Syk binds to phosphorylated gamma chain receptor FcεRI through the N-terminal SH2 domains and plays an important role in downstream signaling pathways [Taylor et al., Mol. Cell. Biol. 1995, 75, 4149].

Suppose that the inhibition of apoptosis of eosinophils is a key mechanism for the development of eosinophilia in the blood and tissues in asthma. In asthma there is increasing regulation of IL-5 and GM-CSF, which seems to cause eosinophilia in the blood and tissues by inhibiting the apoptosis of eosinophils. Suppose that the inhibition of apoptosis of eosinophils is a key mechanism for the development of eosinophilia in the blood and tissues in asthma. There are data (obtained using the antisense sequence)that the kinase Syk is necessary to prevent apoptosis of eosinophils under the action of the CIT is kinow [Yousefi et al., J Exp Med 1996, 183, 1407].

The role of Syk in FcγR-dependent and FcγR-independent response of macrophages bone marrow origin determined using irradiated chimeric mice, converted the fetal liver cells derived from embryos Syk -/-. In Syk-deficient macrophages do not undergo phagocytosis in response to FcγR, but is induced by normal phagocytosis in response to the complement [Kiefer et al., MoI Cell Biol 1998, 18, 4209]. It was also described that the introduction of an aerosol containing the antisense sequence of Syk suppresses the expression of Syk and the release of mediators from macrophages [Stenton et al., J Immunology 2000, 164, 3790].

The Janus kinase (JAK) are a family of tyrosinekinase, including JAK1, JAK2, JAK3 and TYK2. JAK play a key role in the signal transduction of cytokines. Downstream substrates collection tyrosinekinase JAK include proteins involved in signaling and activation of transcription (STAT). Signaling pathway JAK/STAT mediates many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid malignant diseases and malignant diseases of the blood, such as leukaemia and lymphoma. In the literature there is a review on pharmaceutical intervention in the path of the JAK/STAT [Frank Mol Med. 5, 432-46 (1999) & Seidel, et al., Oncogene 19, 2645-2656 (2000)].

JAK1, JAK2 and TYK2 are expressed ubiquitously, whereas JAK3 is expressed predominantly in hematopoietic cells. JAK3 is associated solely with the universal gamma-chain receptor cytokines (γc) and is activated by IL-2, IL-4, IL-7, IL-9 and IL-15. It is shown that in fact the proliferation and survival of murine mast cells induced by IL-4 and IL-9, associated with signalling pathways JAK3 and γc[Suzuki et al., Blood 96, 2172-2180 (2000)].

Cross-linking of high-affinity receptors of the immunoglobulin (Ig)E in sensitized mast cells leads to the release of proinflammatory mediators, including a number of vasoactive cytokines, which cause acute allergic response or reaction of immediate type hypersensitivity (type I) [Gordon et al., Nature 346, 274-276 (1990) & Galli, N. Engl. J. Med., 328, 257-265 (1993)]. It is established that JAK3 plays a key role in the response of fat cells, mediated by IgE receptor, in vitro and in vivo [Malaviya, et al., Biochem. Biophys. Res. Commun. 257, 807-813 (1999)]. Also described that inhibition of JAK3 prevents hypersensitivity reactions type I, including anaphylaxis mediated activation of mast cells [Malaviya et al., J. Biol. Chem. 274, 27028-27038 (1999)]. Targeting JAK3 inhibitors to the fat cells causes a modulation of degranulation of mast cells in vitro and prevent anaphylactic reactions, operado is by the receptor of IgE/antigen, in vivo.

In one recent study described the successful targeting JAK3, providing immunosuppression and donor allograft. This study demonstrates a dose-dependent survival of allograft heart of Buffalo recipients Wistar Furth after the introduction of JAK3 inhibitors, suggesting possible regulation of unwanted immune responses observed in graft-versus-host [Kirken, Transpl. Proc. 33, 3268-3270 (2001)].

IL-4-mediated STAT-phosphorylation is a mechanism involved in the development of the early and late stages of rheumatoid arthritis (RA). Elevated levels of proinflammatory cytokines in the synovial membrane and the synovial fluid is characteristic of rheumatoid arthritis. It was shown that IL-4-mediated activation pathway of IL-4/STAT participate Janus kinase (JAK 1 and 3) and that IL-4-associated JAK kinase is expressed in rheumatoid synovial membrane [Muller-Ladner, et al., J. Immunol. 164, 3894-3901 (2000)].

Family amyotrophic lateral sclerosis (FALS) is an incurable neurodegenerative disease that affects approximately 10% of patients suffering from ALS. The frequency of survival of mice with FALS increases after the introduction of a specific inhibitor of JAK3. This suggests that JAK3 is involved in the development of FALS [Trieu, et al., Biochem. Biophys. Res. Sarnico. 267, 22-25 (2000)].

Proteins involved in signaling and activation of transcription (STAT)are activated, among other kinases of the JAK family. The results of recent studies indicate the possibility of intervention in the signaling pathway JAK/STAT by targeting specific inhibitors for kinases of the JAK family and use this mechanism for the treatment of leukemia [Sudbeck, et al., Clin. Cancer Res. 5, 1569-1582 (1999)]. It is shown that specific inhibitors inhibit JAK3 count of clonogenic growth JAK3-expressing cell lines DAUDI, RAMOS, LC1;19, NALM-6, MOLT-3 and HL-60.

Hybrid proteins TEL/JAK2 induce myeloproliferative disease in animal models, and the introduction TEL/JAK2 in hematopoietic cell lines leads to activation of STAT1, STAT3, STAT5 and cytokine-independent growth [Schwaller, et al., EMBO J. 17, 5321-5333 (1998)].

Inhibition of JAK3 and TYK2 inhibits the phosphorylation of tyrosine STAT3 and cell growth of mycosis fungoides, a type T-cell lymphoma of the skin. These results suggest that kinases of the JAK family are involved in the pathway JAK/STAT, constitutively activated in mushroom avium [Nielsen et al., Proc. Nat. Acad. Sci U.S.A. 94, 6764-6769 (1997)]. Similarly it is shown that in mice with T-cell lymphoma, initially characterized by the overexpression of LCK, STAT3, STAT5, JAK1 and JAK2 are constitutively activated state, that is additionally the evidence about the participation of the way JAK/STAT in abnormal cell growth [Yu, et al., J. Immunol. 159, 5206-5210 (1997)]. In addition, the JAK inhibitor blocking IL-6-mediated STAT3 activation, which leads to the initiation of apoptosis of myeloma cells [Catlett-Falcone, et al., Immunity 10, 105-115 (1999)].

One of the important families of kinases includes Rho-associated sverhoperativnoe serine/threonine the protein kinase (ROCK), which is believed to be an effector of Ras-related small GTP-ases Rho. The ROCK collection includes p160ROCK (ROCK I) (Ishizaki et al., EMBO J. 1996, 15, 1885-1893) and ROKα/Rho-kinase/ROCK-II (Leung et al., J. Biol. Chem. 1995, 270, 29051-29054; Matsui et al., EMBO J. 1996, 15, 2208-2216; Nakagawa et al., FEBS Lett. 1996, 392, 189-193), protein kinase PKN (Amano et al., Science 1996, 271, 648-650; Watanabe et al., Science 1996, 271, 645-648) and citron-kinase (Madaule et al., Nature, 1998, 394, 491-494; Madaule et al., FEBS Lett. 1995, 377, 243-248). It is shown that the kinase family of ROCK involved in the implementation of a number of functions, including Rho-induced formation of actin stress fibers and adhesion foci (Leung et al., Mol Cell Biol. 1996, 16, 5313-5327; Amano et al., Science, 1997, 275, 1308-1311; Ishizaki et al., FEBS Lett. 1997, 404, 118-124), as well as in processes such as decreasing regulation of myosin-phosphatase (Kimura et al., Science, 1996, 273, 245-248), platelet activation (Klages et al., J. Cell. Biol., 1999, 144, 745-754), smooth muscle contraction of the aorta under the action of different stimuli (Fu et al., FEBS Lett, 1998, 440, 183-187), thrombin-induced responses of smooth muscle cells of the aorta (Seasholtz et al., Cir. Res., 1999, 84, 1186-1193), hypertrophy of cardiomyocytes (Kuwahara et al., FEBS Lett., 1999, 452, 314-318), the reduction is of smooth muscles of the bronchi (Yoshii et al., Am. J. Respir. Cell. Mol. Biol., 1999, 20, 1190-1200), smooth muscle contraction and reorganization of the cytoskeleton second cells (Fukata et al., Trends in Pharm. Sci. 2001, 22, 32-39), activation of reguliruemykh volume of anion channels (Nilius et al., J. Physiol, 1999, 516, 67-74), retraction of neurites (Hirose et al., J. Cell. Biol., 1998, 141, 1625-1636), chemotaxis of neutrophils (Niggli et al, FEBS Lett., 1999, 445, 69-72), wound healing (Nobes and Hall, J. Cell. Biol., 1999, 144, 1235-1244), tumor invasion (Itoh et al., Nat. Med., 1999, 5, 221-225) and transformation of cells (Sahai trust et al., Curr. Biol., 1999, 9, 136-145). More specifically, ROCK participates in the development of such diseases and disorders as hypertension (Satoh et al., J. Clin. Invest. 1994, 94, 1397-1403; Mukai et al., FASEB j 2001, 15, 1062-1064; Uehata et al., Nature 1997, 389, 990-994; Masumoto et al., Hypertension, 2001, 38, 1307-1310), spasm of cerebral vessels (Sato et al., Circ. Res. 2000, 87, 195-200; Miyagi et al., J. Neurosurg. 2000, 93, 471-476; Tachibana et al., Acta Neurochir (Wien) 1999, 141, 13-19), koronarospazm (Shimokawa et al., Jpn. Cir. J. 2000, 64, 1-12; Kandabashi et al., Circulation 2000, 101, 1319-1323; Katsumata et al., Circulation 1997, 96, 4357-4363; Shimokawa et al., Cardiovasc. Res. 2001, 51, 169-177; Utsunomiya et al., J. Pharmacol. 2001, 134, 1724-1730; Masumoto et al., Circulation 2002, 105, 1545-1547), bronchial asthma (Chiba et al., Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol. 1995, 11, 351-357; Chiba et al., Br. J. Pharmacol. 1999, 127, 597-600; Chiba et al., Br. J. Pharmacol. 2001, 133, 886-890; Iizuka et al., Eur. J. Pharmacol. 2000, 406, 273-279), premature birth (Niro et al., Biochem. Biophys. Res. Commun. 1997, 230, 356-359; Tahara et al., Endocrinology 2002, 143, 920-929; Kupittayanant et al., Pflugers Arch. 2001, 443, 112-114), erectile dysfunction (Chitaley et al., Nat. Med. 2001, 7, 119-122; Mills et al., J. Appl. Physiol. 2001, 91, 1269-1273), glaucoma (Honjo et al., Arch. Ophthalmo. 2001, 1171-1178; Rao et al., Invest. Ophthalmol. Vis. Sci. 2001, 42, 1029-1037), cell proliferation, vascular smooth muscle (Shimokawa et al., Cardiovasc. Res. 2001, 51, 169-177; Morishige et al., Arterioscler. Thromb. Vasc. Biol. 2001, 21, 548-554; Eto et al., Am. J. Physiol. Heart Circ. Physiol. 2000, 278, H1744-H1750; Sawada et al., Circulation 2000, 101, 2030-2023; Shibata et al., Circulation 2001, 103, 284-289), myocardial hypertrophy (Hoshijima et al., J. Biol. Chem. 1998, 273, 7725-77230; Sah et al., J. Biol. Chem. 1996, 271, 31185-31190; Kuwahara et al., FEBS Lett. 1999, 452, 314-318; Yanazume et al., J. Biol. Chem. 2002, 277, 8618 - 8625), malignoma (Itoh et al., Nat. Med. 1999, 5, 221-225; Genda et al., Hepatology 1999, 30, 1027-1036; Somlyo et al., Biochem. Biophys. Res. Commun. 2000, 269, 652-659), damage caused by ischemia/reperfusion (Ikeda et al., J. of Surgical Res. 2003, 109, 155-160; Miznuma et al., Transplantation 2003, 75, 579-586), endothelial dysfunction (Hernandez-Perera et al., Circ. Res. 2000, 87, 616-622; Laufs et al., J. Biol. Chem. 1998, 273, 24266 - 24271; Eto et al., Circ. Res. 2001, 89, 583-590), Crohn's disease and colitis (Segain et al., Gastroenterology 2003, 124(5), 1180-1187), the growth of neurites (Fournier et al., J. Neurosci. 2003, 23, 1416-1423), Raynaud's disease (Shimokawa et al., J. Cardiovasc. Pharmacol. 2002, 39, 319-327) and atherosclerosis (Retzer et al., FEBS Lett. 2000, 466, 70-74; Ishibashi et al., Biochim. Biophys. Acta 2002, 1590, 123-130). Accordingly, inhibitors of kinases ROCK can be used as therapeutic agents for the treatment of diseases associated with the path kinase ROCK.

ERK2 (kinase regulated by extracellular signals) is a member of the family kinases mitogen-activated protein (MAP)1 mammals. Kinase (MAP)1 are serine/threonine kinases, which mediate the transfer path Nutrilite the data signals (Cobb and Goldsmith, J Biol Chem., 1995, 270, 14843; Davis, Mol. Reprod. Dev. 1995, 42, 459) and are activated by mitogens and growth factors (Bokemeyer et al., Kidney Int. 1996, 49, 1187). Members of the kinase family of MAP have similar sequences and conserved structural domains and, in addition ERK2 include kinase JNK (N-terminal Jun kinase) and p38. Kinases JNK and p38 are activated in response to proinflammatory cytokines TNF-alpha and interleukin-1, and also on the factors of cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., Cell 1994, 76, 1025; Han et al., Science 1994, 265, 808; Raingeaud et al., J Biol Chem. 1995, 270, 7420; Shapiro and Dinarello, Proc. Natl. Acad. Sci. USA 1995, 92, 12230). ERK, on the contrary, are activated under the action of mitogens and growth factors (Bokemeyer et al., Kidney Int. 1996, 49, 1187).

ERK2 is a widespread protein kinase that exhibits maximum activity upon phosphorylation of both Thr183 and Tyr185 higher kinase MAP kinase, MEK1 (Anderson et al., Nature 1990, 343, 651; Crews et al., Science 1992, 258, 478). After activation of ERK2 phosphorylates many regulatory proteins, including protein kinases Rsk90 (Bjorbaek et al., J. Biol. Chem. 1995, 270, 18848) and MAPKAP2 (Rouse et al., Cell 1994, 78, 1027) and the factors transcriptio, such as ATF2 (Raingeaud et al., Mol. Cell Biol. 1996, 16, 1247), Elk-1 (Raingeaud et al., Mol Cell Biol 1996, 16, 1247), c-Fos (Chen et al., Proc. Natl. Acad. Sci. USA 1993, 90, 10952) and c-Myc (Oliver et al., Proc. Soc. Exp. Biol. Med. 1995, 210, 162). ERK2 is also lower target for Ras/Raf-dependence is imich ways (Moodie et al., Science 1993, 260, 1658), and can facilitate the transmission of signals from these potentially oncogenic proteins. It is shown that ERK2 plays a role in the negative growth control of breast cancer cells (Frey and Mulder, Cancer Res. 1993, 57, 628), and that in breast cancer cells human observed overexpression of ERK2 (Sivaraman et al., J Clin. Invest. 1997, 99, 1478). Activated ERK2 is also involved in proliferation endothelin-stimulated cells of smooth muscles of the respiratory tract, suggesting that this kinase plays an important role in the development of asthma (Whelchel et al., Am. J. Respir. Cell Mol Biol. 1997, 16, 589).

Kinase-3 glycogen synthase (GSK-3) is a serine/threonine a protein kinase, comprising α - and β-isoforms encoded by different genes [Coghlan et al., Chemistry & Biology 2000, 7, 793-803; and Kim and Kimmel, Curr. Opinion Genetics Dev., 2000 10, 508 to 514]. GSK-3 is involved in the development of various diseases including diabetes, Alzheimer's disease, CNS diseases, such as manic-depressive disorder and neurodegenerative diseases, and hypertrophy of cardiomyocytes [PCT application nos: WO 99/65897 and WO 00/38675; and Haq et al., J. Cell Biol. 2000, 151, 117-130]. These diseases are associated with abnormal functioning of certain cell signaling pathways, mediated by GSK-3. Found that GSK-3 phosphorylates a number of regulatory proteins and modulates their activity. Data proteins include glycogen synthase, the cat heaven is a enzyme, necessary for glycogen synthesis and limiting the rate of synthesis, Tau protein associated with microtubules, a transcription factor genes of β-catenin, the translation initiation factor e1F2B, as well as ATP-citrate-liasu, axin, factor heat shock-1, c-Jun, c-myc, c-myb, CREB, and CEPBα. These protein targets involve GSK-3 in different aspects of cellular metabolism, proliferation, differentiation and development.

GSK-3-mediated pathway, which is related to the treatment of type II diabetes, insulin-induced signaling leads to the absorption of glucose by cells and the synthesis of glycogen. Along with participation in this way, GSK-3 is a negative regulator of insulin-induced signal. Typically, insulin inhibits GSK-3-mediated phosphorylation and causes deactivation of glycogen synthase. Inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS 1996, 93, 8455-8459; Cross et al., Biochem. J. 1994, 303, 21-26); Cohen, Biochem. Soc. Trans. 1993, 21, 555-567; and Massillon et al., Biochem J. 1994, 299, 123-128]. However, in diabetic patients with the disorder insulin response, glycogen synthesis and glucose uptake did not increase in the presence of relatively high levels of glucose. This leads to abnormally high levels of glucose in the blood with acute and long attacks and, ultimately, can lead to cardiovascular sableman the Yu, kidney failure and blindness. In these patients there is no normal insulin-induced inhibition of GSK-3. Also described that patients with diabetes type II is observed overexpression of GSK-3 [see PCT application: WO 00/38675]. Therefore, therapeutic inhibitors of GSK-3 can be used for the treatment of diabetic patients with impaired response to insulin.

The activity of GSK-3 is also associated with Alzheimer's disease. The disease is characterized by the presence of widely known β-amyloid peptide and the formation of intracellular neurofibrillary tangles. The Aβ peptides are formed from the amyloid protein precursor (APP) by sequential proteolysis catalyzed by aspartyl-protease BACE2, with subsequent cleavage of presenilin-dependent γ-secretases. It was shown that antibodies against β-amyloid plaques can slow the deterioration of cognitive abilities in patients with Alzheimer's disease (Hock et al., Neuron, 2003, 38, 547-554), therefore, for the treatment of Alzheimer's disease and other psychotic and neurodegenerative diseases it is possible to use other strategies for reducing β-amyloid level (for example, using means that are able to inhibit β-amyloid peptide). In addition, neurofibrillary tangles contain hyperphosphorilated protein Tau, phosphorylation of which is carried out in the wrong areas, therefore, tools that are able to inhibit hyperphosphorylated protein Tau, can be used for the treatment of Alzheimer's disease and other psychotic and neurodegenerative diseases.

It is known that GSK-3 phosphorylates incorrect data plots from cellular and animal models. In addition, it was shown that inhibition of GSK-3 prevents hyperphosphorylated Tau in cells [Lovestone et al., Current Biology 1994, 4, 1077-86; and Brownlees et al., Neuroreport 1997, 8, 3251-55]. Thus, the activity of GSK-3 initiates the formation of neurofibrillary tangles and the development of Alzheimer's disease. Also it is shown that GSK-3 promotes the processing of APP and the inhibitor of GSK-3 (lithium) inhibits formation of Aβ peptides by inhibiting GSK-3 (Phiel et al. Nature 2003, 423, 435-439). Therefore, inhibitors of GSK-3 can be used to reduce the number of amyloid plaques and neurofibrillary tangles, the pathological hallmarks of Alzheimer's disease, and for treatment of other disorders and neurodegenerative diseases.

Another substrate of GSK-3 is a β-catenin, which is destroyed after phosphorylation under the action of GSK-3. Decreased levels of β-catenin observed in patients suffering from schizophrenia and other diseases associated with increased death of neural cells [Zhong et al., Nature 1998, 395, 698-702; Takashima et al., PNAS 1993, 90, 7789-93; and Pei et al., J. Neuropathol. Exp 1997, 56, 70-78].

Act what you want to make GSK-3 is also associated with stroke [Wang et al., Brain Res 2000, 859, 381-5; Sasaki et al., Neurol Res 2001, 23, 588-92; Hashimoto et al., J. Biol. Chem 2002, 277, 32985-32991].

Subfamily of AGC kinases phosphorylate substrates on serine and treningowy balances and participates in a number of well-known signaling processes, including, without limitation, the signaling pathway of cyclic AMP, the response to insulin, protection from apoptosis signaling pathway diacylglycerol and controlling broadcast proteins (Peterson et al., Curr. Biol 1999, 9, R521). This subfamily includes PKA, PKB (c-Akt), PKC, PRK1, 2, P70S6Kand PDK.

It is shown that in some types of cancer observed overexpression of AKT (also known as PKB or Rac-PK-beta), serine/ser / thr protein kinase, which mediates normal cellular functions [(Khwaja, A., Nature 1999, 401, 33-34); (Yuan, Z.Q., et al., Oncogene 2000, 19, 2324-2330); (Namikawa, K., et al., J Neurosci. 2000, 20, 2875-2886)]. AKT contains N-terminal domain plastikovoi homology (PH), kinase domain and C-terminal "tail" section. Until now describe the three isoforms of the human kinase AKT (AKT-1, -2 and -3) [(Cheng, J.Q., Proc. Natl. Acad. Sci. USA 1992, 89, 9267-9271); (Brodbeck, D. et at, J. Biol. Chem. 1999, 274, 9133-9136)]. Domain PH binds 3-phosphoinositides, which are synthesized via phosphatidylinositol-3-kinase (PI3K) after stimulation by growth factors such as platelet-derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor (IGF-1) [(Kulik et al., Mol. Cell. Biol., 1997, 17, 1595-1606); (Hemmings, B.A., Sciece, 1997, 275, 628-630)]. The binding of lipids to the domain PH triggers the translocation of AKT to the plasma membrane and facilitates phosphorylation under the action of other protein kinases containing PH domain, PDK1 - Thr308, Thr309 and Thr305 for AKT isoforms 1, 2 and 3, respectively. Second, still unknown, the kinase is required for the phosphorylation of Ser473, Ser474 or Ser472 in the C-terminal tail sections of AKT-1, -2 and -3 respectively with getting fully activated AKT enzyme.

After localization at the membrane, AKT mediates several cellular functions, including metabolic effects of insulin (Calera, M.R. et at, J. Biol. Chem. 1998, 273, 7201-7204), induction of differentiation and/or proliferation, protein synthesis and stress responses (Alessi, D.R. et at, Curr. Opin. Genet. Dev. 1998, 8, 55-62).

The change in the regulation of AKT occurs when injuries and diseases, the most important role it plays in cancer. The first mention of AKT is associated with carcinomas of the ovary, where the increased expression of AKT was observed in 15% of cases (Cheng, J.Q. et at, Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9267-9271). It was also found that overexpression of AKT was observed in 12% of cases of pancreatic cancer (Cheng, J. Q. et at, Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 3636-3641). It is shown that overexpression of AKT occurs in 12% of cases of ovarian carcinoma and that the high frequency amplification of AKT was observed in 50% of cases of undifferentiated tumors, this pozvoljaetrealizovat, that AKT may also be associated with aggressiveness of the tumor (Bellacosa et al., Int. J. Cancer 1995, 64, 280-285).

It is shown that PKA (also known as camp-dependent protein kinase) regulates many vital functions, including energy metabolism, gene transcription, proliferation, differentiation, reproductive function, secretion, neuronal activity, memory, contractility and locomotor activity (Beebe, S.J., Semin. Cancer Biol. 1994, 5, 285-294). PKA is a tetramer of Holofernes, which contains two catalytic subunits, associated with homodimeric regulatory subunit (the function of which is the inhibition of the catalytic subunits). After binding of camp (activating enzyme) catalytic subunit are separated from the regulatory subunits with the formation of the active serine/ser / thr kinase (McKnight, G.S. et al., Recent Prog. Horm. Res. 1988, 44, pp. 307). Today describes the three isoforms of the catalytic subunit (C-α, C-β and C-γ) (Beebe, S.J. et al., J. Biol. Chem. 1992, 267, 25505-25512), the most widely studied subunit C-α, mainly due to the fact that it is expressed at high levels in cells of primary and metastatic melanomas (Becker, D. et al., Oncogene 1990, 5, 1133). Currently, methods of modulating the activity of subunit C-α include the use of antibodies, molecules that block the activity Repute impact on regulatory dimers, and the expression of antisense oligonucleotides.

Ribosomal protein kinase p70S6K-1 and -2 are also members of the subfamily of protein kinases AGC and catalyze the phosphorylation and subsequent activation of ribosomal protein S6, which is involved in increasing regulation of mRNAs encoding components of the protein synthesis apparatus. These mRNAs contain oligopyrimidine fragment at the 5'-site of transcription initiation, called the 5'TOP, which, as shown, is required for regulation at the level of translation (Volarevic, S. et al., Prog. Nucleic Acid Res. Mol. Biol., 2001, 65, 101-186). p70S6K-dependent phosphorylation of S6 is initiated in response to a number of hormones and growth factors, mainly through the PI3K path (Coffer, P.J. et al., Biochem. Biophys. Res. Commun, 1994 198, 780-786)that may be regulated by mTOR, since rapamycin inhibits the activity of p70S6Kand blocks protein synthesis, especially through down-regulation of mRNAs encoding ribosomal proteins (Kuo, C.J. et al., Nature 1992, 358, 70-73).

In vitro PDK1 catalyzes the phosphorylation Thr252 in the activation loop of the catalytic domain p70, which is necessary for the exercise of the activity of p70 (Alessi, D.R., Curr. Biol., 1998, 8, 69-81). Research dp70S6K Drosophila and mouse p70S6K-1 using rapamycin and deletions of genes showed that p70 plays a key role in signal transduction associated with cell growth and Strait is ferocia.

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a key role in regulating the activity of several kinases belonging to the subfamily of AGC protein kinases (Alessi, D. et al., Biochem. Soc. Trans 2001, 29, 1). These kinases include isoforms of protein kinase B (PKB, also known as AKT), protein kinase p70 ribosomal S6 (S6K) (Avruch, J. et al., Prog. Mol. Subcell. Biol. 2001, 26, 115) and kinase p90 ribosomal S6 (Frödin, M. et al., EMBO J. 2000, 19, 2924-2934). Mediated by PDK1 signaling is activated in response to insulin and growth factors, as well as to attach cells to the extracellular matrix (integrity signaling pathway). After activation, these enzymes mediate a variety of cellular events through phosphorylation of key regulatory proteins that play an important role in controlling processes such as survival, growth and cell proliferation and glucose metabolism [(Lawlor, M.A. et al., J. Cell Sci. 2001, 114, 2903-2910), (Lawlor, M.A. et al., EMBO J. 2002, 21, 3728-3738)]. PDK1 is a protein of 556 amino acids containing an N-terminal catalytic domain and C-terminal domain plastikovoi homology (PH), which activates its substrates by phosphorylation of these kinases in the activation loop (Belham, C. et al., Curr. Biol. 1999, 9, R93-R96). In many cancer diseases, including prostate cancer and NSCL, increasing the functioning of PDK1 signalling pathway in the genetic event is th, such as PTEN mutations or overexpression of certain key regulatory proteins [(Graff, J.R., Expert Opin. Ther. Targets 2002, 6, 103-113), (Brognard, J., et al., Cancer Res. 2001, 61, 3986-3997)]. The possibility of using inhibition of PDK1 as a potential mechanism for cancer treatment was demonstrated by transfection of PTEN-negative cancer cell line person (U87MG) antimyeloma the oligonucleotides directed against PDK1. In the reach of decrease protein PDK1, which leads to reduced proliferation and survival of cells (Flynn, P., et al., Curr. Biol. 2000, 10, 1439-1442). Therefore, the creation of inhibitors of ATP-binding site of PDK1, among other treatments, is an important task for chemotherapy of cancer.

Differences in the genotypes of cancer cells lead to the manifestation of six essential alterations in cell physiology: self-sufficiency signaling pathways associated with growth, evasion of apoptosis, insensitivity to signals, inhibiting growth, unlimited replicative potential, continuous angiogenesis and invasion of tissue, leading to metastasis (Hanahan, D. et al., Cell 2000, 100, 57-70). PDK1 is a key mediator of signaling pathways PI3K, which regulates a number of cellular functions, including growth, proliferation and survival. Therefore, inhibition of this pathway may affect h is four or more of the six signs, necessary for the development of cancer. It can be expected that the PDK1 inhibitor will affect the growth of a very wide range of cancer man.

Namely, increasing the activity level of the path PBK directly associated with the development of a number of human cancers, their progression to aggressive refractory state (acquired resistance to chemotherapy and poor prognosis. This increased activity is due to a number of key events, including a decrease in the activity of negative regulators of the pathway, such as the phosphatase PTEN, activating mutations in positive regulators of the pathway, such as Ras, and overexpression of path components, such as PKB, examples include cancers of the brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian cancer, pancreatic, prostate, sarcoma, cancer of the thyroid gland [(Teng, D.H. et al., Cancer Res., 1997 57, 5221-5225), (Brognard, J. et al., Cancer Res., 2001, 61, 3986-3997), (Cheng, J.Q. et al., Proc. Natl. Acad. Sci. 1996, 93, 3636-3641), (Int. J. Cancer 1995, 64, 280), (Graff, J.R., Expert Opin. Ther. Targets 2002, 6, 103-113), (Am. J. Pathol. 2001, 159, 431)].

In addition, it is shown that the decrease in activity path as the result of a gene knockout, knockdown of the gene, a dominant negative studies and the use of low molecular weight inhibitors path leads to the reduction of many signs Raco the th phenotype in vitro (some studies show a similar effect in vivo), for example, to block proliferation, decreased viability and sensitivity to known chemotherapeutic tools in a number of cell lines representing cancers of the pancreas [(Cheng, J.Q. et al., Proc. Natl. Acad. Sci. 1996, 93, 3636-3641), (Neoplasia 2001, 3, 278)], lung [(Brognard, J. et al., Cancer Res. 2001, 61, 3986-3997), (Neoplasia 2001, 3, 278)], ovarian [(Hayakawa, J. et al., Cancer Res. 2000, 60, 5988-5994), (Neoplasia 2001, 3, 278)], breast cancer (Mol. Cancer Ther. 2002, 1, 707), colon [(Neoplasia 2001, 3, 278), (Arico, S. et al., J. Biol. Chem. 2002, 277, 27613-27621)], cervical cancer (Neoplasia 2001, 3, 278), prostate [(Endocrinology 2001, 142, 4795), (Thakkar, H. et al. J. Biol. Chem. 2001, 276, 38361-38369), (Chen, X. et al., Oncogene 2001, 20, 6073-6083)] and brain (glioblastomas) [(Flynn, P. et al., Curr. Biol., 2000, 10, 1439 - 1442)].

Accordingly, there is an urgent need to develop inhibitors of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), protein kinases CDK, GSK, SRC, ROCK, and/or SYK, which can be used to treat various diseases or conditions associated with activation of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), protein kinases CDK, GSK, SRC, ROCK, and/or SYK, especially considering the fact that at the present time there is no satisfactory treatment for most of these diseases.

The INVENTION

It was shown that the compounds of this invention and their pharmaceutically acceptable compositionallegra effective inhibitors of kinases. In some embodiments, these compounds are effective inhibitors of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), protein kinases CDK, GSK, SRC, ROCK, and/or SYK. In other embodiments, these compounds are effective inhibitors of protein kinases FLT-3 and/or c-KIT. These compounds have the General formula A:

where R1, R3, R4, R5, R6and R7described below.

These compounds and their pharmaceutical compositions can be used to treat or prevent a number of diseases, including, without limitation, heart disease, diabetes, Alzheimer's disease, immunodeficiency, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone diseases such as osteoporosis, proliferative disorders, infectious diseases, diseases mediated by the immune system and viral diseases. The composition can also be used to prevent cell death and hyperplasia and, consequently, for the treatment or prevention of reperfusion/ischemia in stroke, heart attacks and hypoxia bodies. The composition can also be used to prevent thrombin-induced platelet aggregation. Compositions especially under the W ill result for the treatment of such diseases, as chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, without limitation, ovarian cancer, breast cancer and uterine cancer), liver disease, including ischemia of the liver, heart disease, such as myocardial infarction and acute heart failure, pathologic immune conditions, including T-cell activation, and neurodegenerative diseases.

DETAILED description of the INVENTION

The compounds of this invention include compounds broadly described above and further illustrated with the help disclosed in this description of classes, subclasses and types. Unless otherwise stated in this description uses the following definitions. For purposes of this invention, the elements identified in accordance with the periodic system of the elements, CAS version, Handbook of Chemistry and Physics, 75thEd. In addition, in this description uses the General principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the full contents of which are incorporated in this description by reference.

As described herein, the compounds of this invention can be optional is tion substituted by one or more substituents, as broadly described above, or they can be represented by certain classes, subclasses and types of the present invention. It should be understood that the phrase "optionally substituted" and "substituted or unsubstituted" are used interchangeably. As a rule, the term "substituted", which may be preceded by the term "optional"refers to the replacement of radical hydrogen in a certain structure on the specific radical substituent. Unless otherwise specified, optionally substituted group may contain a Deputy for each position, which could be a substitution, and if given the structure of the substitution can be carried out in more than one location and more than one Deputy, selected from the specific groups, the substituents may be the same or different in each position. This invention allowed such combinations of substituents, which lead to the formation of a stable or chemically possible connections. The term "stable" in this description refers to compounds, which practically do not change when exposed to conditions used in the preparation, detection, and also, preferably, the extraction and purification of these compounds, and have one or more target destinations described in this document. In some embodiments stable or chemically in which you connection it is the connection that practically does not change during storage at 40°C, or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

The term "aliphatic" or "aliphatic group" in this description refers to the line (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more elements of unsaturation, or monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more elements of unsaturation, but which is not aromatic (in this description, it is also called "carbocycle" "cycloaliphatic group" or "cycloalkyl"), and the aliphatic group has one attachment point to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments of the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments aliphatic groups contain 1-8 aliphatic carbon atoms. In another embodiments of the aliphatic groups contain 1-6 aliphatic carbon atoms, and in the following embodiments of the aliphatic groups contain 1-4 aliphatic carbon atoms. In some of the which the embodiments, the term "cycloaliphatic group" (or "carbocycle", or cycloalkyl") refers to a monocyclic C3-C8the hydrocarbon or bicyclic C8-C12the hydrocarbon that is completely saturated or that contains one or more elements of unsaturation, but is not aromatic, and cycloaliphatic group has one attachment point to the rest of the molecule, and any single cycle specified in the bicyclic system has 3-7 members. Suitable aliphatic groups include, without limitation, linear or branched, substituted or unsubstituted alkyl, alkeline, alkyline groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term "heteroaromatics" in this description refers to aliphatic groups in which one or two carbon atoms are independently replaced by one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycles", "heterocyclizations" or "heterocyclic" group.

The term "heterocycle", "geterotsiklicheskikh" or "heterocyclic" in this description refers to non-aromatic, monocyclic, bicyclic or three is ilicheskom systems in which one or more members of the cycle are independently selected heteroatoms. In some embodiments, the "heterocycle", "heterocyclizations" or "heterocyclic" group contains from three to fourteen cyclic atoms in which one or more members of the cycle are heteroatoms independently selected from oxygen, sulfur, nitrogen or phosphorus, each cycle in the system contains 3 to 7 members of the loop.

The term "heteroatom" refers to one or more elements from oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the Quaternary form of any basic nitrogen or a substituted nitrogen atom of the heterocyclic fragment, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

The term "unsaturated" in this description refers to a fragment containing one or more elements of unsaturation.

The term "alkoxy" or "thioalkyl" in this description refers to a higher alkyl group that is attached to the main carbon chain through an oxygen atom ("alkoxy") or sulfur ("thioalkyl").

The terms "halogenated", "halogenoalkanes and halogenoalkane" refer to alkyl, alkenyl or alkoxy, substituted by one or more, dependent on the particular circumstances, atoms of halogen. The term "halogen" means F, Cl, Br or I.

The term "aryl"used alone or as part of a larger fragment, as, for example, in "aralkyl", "arakaki", or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic systems containing only five to fourteen members of the cycle, where at least one cycle in the system is aromatic and wherein each loop in the system contains 3 to 7 members of the cycle. The terms "aryl" and "aryl cycle" can be used interchangeably. The term "aryl" also refers to heteroaryl cyclic systems defined below.

The term "heteroaryl", used alone or as part of a larger fragment, as, for example, in "heteroalkyl" or "heteroaromatics", refers to monocyclic, bicyclic and tricyclic systems containing only five to fourteen members of the cycle, where at least one cycle in the system is aromatic and wherein each loop in the system contains 3 to 7 members of the cycle. The terms "heteroaryl", "heteroaryl cycle" and "heteroaromatic" can be used interchangeably.

Aryl (including kalkilya, alcoxylate, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl, heterokedasticity and the like) group may contain one or a few is to deputies and, therefore, it may be "optionally substituted". If not stated otherwise, suitable substituents at the unsaturated carbon atoms of aryl or heteroaryl groups are usually chosen from the group comprising halogen; R0; -OR0; -SR0; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -NO2; -CN; -N(R0)2; -NR0C(O)R0; -NR0C(S)R0; -NR0C(O)N(R0)2; -NR0C(S)N(R0)2; -NR0CO2R0; -NR0NR0C(O)R0; -NR0NR0C(O)N(R0)2; -NR0NR0CO2R0; -C(O)C(O)R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(S)R0; -C(O)N(R0)2; -C(S)N(R0)2; -OC(O)N(R0)2; -OC(O)R0; -C(O)N(OR0R0; -C(NOR0R0; -S(O)2R0; -S(O)3R0; -SO2N(R0)2; -S(O)R0; -NR0SO2N(R0)2; -NR0SO2R0; -N(OR0R0; -C(=NH)-N(R0)2; -P(O)2R0; -PO(R0)2; -OPO(R0)2; -(CH2)0-2NHC(O)R0; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), it is certainly substituted R 0; or-CH=CH(Ph), optionally substituted R0; where each R0independently selected from the group comprising hydrogen, optionally substituted C1-6aliphatic group, an unsubstituted 5-6 membered heteroaryl or heterocyclic fragment, phenyl, -O(Ph), or-CH2(Ph), or, regardless of the above definitions, two independently selected R0present in a substituent or different substituents, together with the atom (atoms)is attached to the group R0, form an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic fragment containing 0 to 4 heteroatoms, independently selected from nitrogen, oxygen or sulfur.

Optional substituents of aliphatic groups of R0can be selected from NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(Halogens1-4aliphatic group) or Halogens1-4aliphatic group, where all of these C1-4aliphatic group, R0are unsubstituted.

Aliphatic, or heteroaromatics group or non-aromatic heterocyclic the Kai group may contain one or more substituents, and therefore, it may be "optionally substituted". If not stated otherwise, suitable substituents at the saturated carbon atom aliphatic or heteroaromatics group or non-aromatic heterocyclic group selected from the substituents listed above for the unsaturated carbon atoms of aryl or heteroaryl group and additionally include =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R* is independently selected from hydrogen or optionally substituted C1-6aliphatic group.

If not stated otherwise, the optional substituents at nitrogen non-aromatic heterocyclic group, usually selected from R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+1)2, -C(=NH)-N(R+)2or-NR+SO2R+; where R+denotes hydrogen, optionally substituted C1-6aliphatic group, optionally substituted phenyl, optionally substituted-O(Ph), optionally substituted-CH2(Ph), optionally substituted -(CH2)1-2(Ph); optionally substituted-CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic group containing from one to h is four heteroatoms, independently selected from oxygen, nitrogen or sulfur, or, regardless of the above definitions, two independently selected R+present in a substituent or different substituents, together with the atom (atoms)is attached to the group R+, form an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic fragment containing 0 to 4 heteroatoms, independently selected from nitrogen, oxygen or sulfur.

Optional substituents of the aliphatic group or the phenyl cycle R+selected from-NH2, -NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, -OH, -O(C1-4aliphatic group), -NO2, -CN, -CO2H, -CO2(C1-4aliphatic group), -O(Halogens1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above C1-4aliphatic groups of R+is unsubstituted.

If heterocyclyl is substituted, the substituents can be attached on the substituted provisions as to the atom of carbon and heteroatom. For example, if replaced described structure is a pieperazinove cycle, and Deputy represents CH3described the e compound may have the structure or.

In one embodiment of the present invention relates to a compound of the formula I:

where

X denotes CH or N;

Y denotes CH2, NH, NR, O or S;

R1denotes hydrogen or C1-6alkyl;

R2denotes hydrogen;

R3denotes optionally substituted aryl group selected from 5-6-membered monocyclic or 8-12 membered bicyclic group; mentioned aryl group contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R5denotes hydrogen, -C1-6aliphatic group, -CN, -OH, -O(C1-6aliphatic group), -CO2H, -CO2(C1-6aliphatic group), -CON(R)2, -O(Halogens1-4aliphatic group), -Halogens1-4aliphatic group, -NO2, -halogen, -NR02or-C1-6aliphatic group, optionally substituted NH2;

R4denotes hydrogen, halogen; R0; -OR0; -SR0; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -NO2; -CN; -N(R0)2; -NR0C(O)R0; -NR0C(S)R0; -NR0C(O)N(R0)2; -NR0C(S)N(R0)2; -NR0CO2R0; -NR0NR0C(O)R0; -NR0NR0C(O)N(R0)2; -NR0NR0CO2R0; -C(O)C(O)R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(S)R0; -C(O)N(R0)2; -C(S)N(R0)2; -C(=NH)-N(R0)2, -OC(O)N(R0)2; -OC(O)R0; -C(O)N(OR0R0; -C(NOR0R0; -S(O)2R0; -S(O)3R0; -SO2N(R0)2; -S(O)R0; -NR0SO2N(R0)2; -NR0SO2R0; -N(OR0R0; -C(=NH)-N(R0)2; -(CH2)0-2NHC(O)R0, =0, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R0independently selected from hydrogen, optionally substituted C1-6aliphatic group, an unsubstituted 5-6 membered heteroaryl or heterocyclic group, phenyl, -O(Ph), or-CH2(Ph), or, regardless of the above definitions, two independently selected R0present in a substituent or different substituents, together with the atom (atoms)is attached to the group R0form a 5-8-membered heterocyclic, aryl or heteroaryl group, or a 3-8-membered cycloalkyl group containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ali is eticeskaja group R 0optionally substituted NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(Halogens1-4aliphatic group), or halogen(C1-4aliphatic group), where each of the above C1-4aliphatic group is unsubstituted;

each R* is independently selected from hydrogen or C1-6aliphatic group, optionally substituted NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(Halogens1-4aliphatic group), or halogen(C1-4aliphatic group), where each of the above C1-4aliphatic group is unsubstituted; and R represents hydrogen or C1-6aliphatic group, optionally substituted by =O, =S, -NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(Halogens1-4aliphatic group) or galag is n(C 1-4aliphatic group), where each of the above C1-4aliphatic group is unsubstituted.

Another embodiment of the present invention relates to the compound of formula II:

where

X denotes CH or N;

Y denotes CH2, NH, NR, O or S;

n is 0-4;

m is 0-4;

R1denotes hydrogen or-N(H)R2;

R2denotes hydrogen or C1-6aliphatic group;

R3denotes aryl group selected from 5-6-membered monocyclic or 8-12 membered bicyclic group; mentioned aryl group contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where each substitutable position R3optionally and independently replaced by R7;

R5denotes hydrogen, -C1-6aliphatic group, -CN, -OH, -O(C1-6aliphatic group), -CO2H, -CO2(C1-6aliphatic group), -SOP(R0)2, -NO2, -halogen, -NR02where the aliphatic carbon atoms in each substitutable position optionally and independently substituted with halogen or NH2;

R7denotes halogen; R0; -OR0; -SR0; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), long is Ino substituted R 0; -CH=CH(Ph), optionally substituted R0; -NO2; -CN; -N(R0)2; -NR0C(O)R0; -NR0C(S)R0; -NR0C(O)N(R0)2; -NR0C(S)N(R0)2; -NR0CO2R0; -NR0NR0C(O)R0; -NR0NR0C(O)N(R0)2; -NR0NR0CO2R0; -C(O)C(O)R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(S)R0; -C(O)N(R0)2; -C(S)N(R0)2; -OC(O)N(R0)2; -OC(O)R0; -C(O)N(OR0R0; -C(NOR0R0; -S(O)2R0; -S(O)3R0; -SO2N(R0)2; -S(O)R0; -NR0SO2N(R0)2; -NR0SO2R0; -N(OR0R0; -C(=NH)-N(R0)2; or -(CH2)0-2NHC(O)R0;

each of R4and R6denotes hydrogen; halogen; -R0; -OR0; -SR0; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -NO2; -CN; -N(R0)2; -NR0C(O)R0; -NR0C(S)R0; -NR0C(O)N(R0)2; -NR0C(S)N(R0)2; -NR0CO2R0; -NR0NR0C(O)R0; -NR0NR0C(O)N(R0)2; -NR0NR0CO2R00; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(S)R0; -C(O)N(R0)2; -C(S)N(R0)2; -C(=NH)-N(R0)2, -OC(O)N(R0)2; -OC(O)R0; -C(O)N(OR0R0; -C(NOR0R0; -S(O)2R0; -S(O)3R0; -SO2N(R0)2; -S(O)R0; -NR0SO2N(R0)2; -NR0SO2R0; -N(OR0R0; -C(=NH)-N(R0)2; -(CH2)0-2NHC(O)R0, =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*.

X and Y together with the atoms to which they are attached, form a six-membered cycle, preferably containing 2 heteroatoms, more preferably 1 heteroatom.

R4, R6and R7can join on any substitutable with the provisions of cycles, as shown in formula II. In the case of substituted heterocyclyl R4, R6and R7can join on the substituted provisions as to the atom of carbon and heteroatom. For example, if X and Y denote N, and R6denotes CH3third monocycle in the formula II can be eitheror

In another embodiment of the present invention features a compound of formula (II), where

X denotes CH or N;

Y denotes CH2, NH, NR0, O or S;

n is 0-4;

m equally is 0-4;

R1denotes hydrogen or-N(H)R2;

R2denotes hydrogen or C1-6alkyl;

R3denotes aryl group selected from 5-6-membered monocyclic or 8-12 membered bicyclic group; and specified aryl group contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where each substitutable position R3optionally and independently replaced by R7;

R5denotes hydrogen, -C1-6aliphatic group, -CN, -OH, -O(C1-6aliphatic group), -CO2H, -CO2(C1-6aliphatic group), -CON(R0)2, -halogen, or-NR02where each substitutable position of aliphatic carbon atom optionally and independently substituted with halogen;

R7denotes halogen; R0; -OR0; -SR0; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -NO2; -CN; -N(R0)2; -NR0C(O)R0; -NR0C(S)R0; -NR0C(O)N(R0)2; -NR0C(S)N(R0)2; -NR0CO2R0; -NR0NR0C(O)R0; -NR0NR0C(O)N(R0)2; -NR0NR0CO2R0; -C(O)C(O)R0; -C(OCH 2C(O)R0; -CO2R0; -C(O)R0; -C(S)R0; -C(O)N(R0)2; -C(S)N(R0)2; -OC(O)N(R0)2; -OC(O)R0; -C(O)N(OR0R0; -C(NOR0R0; -S(O)2R0; -S(O)3R0; -SO2N(R0)2; -S(O)R0; -NR0SO2N(R0)2; -NR0SO2R0; -N(OR0R0; -C(=NH)-N(R0)2; or -(CH2)0-2NHC(O)R0; where each R0independently selected from hydrogen, optionally substituted C1-6aliphatic group, an unsubstituted 5-6-membered heteroaryl or heterocyclic group (provided that the nitrogen atom in the heterocyclic group is optionally replaced by-R+or-C(O)R+where R+means (C1-6alkyl), preferably (C1-4alkyl), phenyl, -O(Ph), or-CH2(Ph), or, regardless of the above definitions, two independently selected R0present in a substituent or different substituents, together with the atom (atoms)is attached to the group R0form a 5-8-membered heterocyclic, aryl or heteroaryl group, or a 3-8-membered cycloalkyl group containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Each R4and R6independently represents halogen; R0; -OR0; -SR0; 1,2-Matelandia the si; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -CN; -N(R0)2; -NR0C(O)R0; -NR0CO2R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(O)N(R0)2; -OC(O)N(R0)2; -OC(O)R0; -S(O)2R0; -SO2N(R0)2; -S(O)R0; -NR0SO2R0; or =On;

aliphatic group, R0optionally substituted NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), where each of the above C1-4aliphatic groups optionally substituted with halogen;

R denotes hydrogen or C1-6aliphatic group, optionally substituted by =O, =S, -NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), where each of the above C1-4aliphatic groups optionally substituted with halogen.

In accordance with one wapl is the incarnation of formula I R 1denotes hydrogen.

In accordance with one embodiment of formula II, R1denotes hydrogen. In another embodiment of formula II, R1denotes N(H)R2.

In accordance with another embodiment of formula I or II, R2denotes hydrogen.

In accordance with another embodiment of formula I or II, if X is CH, Y is CH2.

In accordance with another embodiment of formula I or II, X is N.

In accordance with another embodiment of formula I or II Y represents O.

In accordance with another embodiment of formula I or II Y represents NR.

In some embodiments of formula II, m, n and p independently represent 1 or 2. In another embodiment m is 0. in another embodiment m is 1. In one embodiment n is 0. in another embodiment n is 1. In another embodiment p is 0; in another embodiment p is 1. In the following embodiment, each of m, n and p are equal to 0.

In some embodiments of formula II, each R4, R6and R7independently denotes a halogen; C1-4aliphatic group; OR0; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -CN; -N(R0)2; -NR0C(O)R0; -NR0CO2R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0 ; -C(O)N(R0)2; -OC(O)N(R0)2; -OC(O)R0; -S(O)2R0; -SO2N(R0)2; -S(O)R0; -NR0SO2R0; or two hydrogen atoms associated with one carbon atom replaced by =O.

In other embodiments each of R4, R6and R7independently denotes a halogen; C1-4aliphatic group, optionally substituted with halogen; OR0; -CN; -N(R0)2; -NR0C(O)R0; -NR0CO2R0; or two hydrogen atoms associated with one carbon atom replaced by =O.

In other embodiments, R4and R6denote C1-6alkyl or halogen, preferably C1-3alkyl, F, or Cl.

In another embodiment R7denotes halogen, -CN, C1-6alkyl, C1-6alkoxy, -N(R)2or C1-4halogenated.

In some embodiments of formulas I and II, R3denotes aryl group selected from 6-membered monocyclic group containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where each substitutable position R3optionally replaced by R7.

In accordance with one embodiment R3denotes aryl group selected from 6-membered monocyclic group containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, where each substitutable position R3obazatelno replaced by R 7.

In accordance with another embodiment R3denotes a 6-membered heteroaryl containing 1 or 2 nitrogen heteroatom, preferably 1 atom of nitrogen. In accordance with the following embodiment R3represents 2-pyridyl.

In one embodiment of formula I or II, R5denotes hydrogen, halogen, OH, NR0, CN, O-(C1-6aliphatic group), or C1-6alkyl, optionally substituted by-NR2.

In another embodiment R5represents C1-6alkyl, optionally substituted-N(R)2.

In another embodiment R5refers to-CN. In the following embodiment R5denotes hydrogen.

One embodiment is represented by formula I-a.

Another embodiment is represented by formula I-b:

Another embodiment is represented by formula I:

Another embodiment is represented by compounds I-1 and I-2:

Another embodiment is represented by compounds I-3 and I-4:

The compounds of this invention also include compounds which include a cycle containing X and Y, is attached to the rest of the molecule through any atom, not only through the atom X.

In another embodiment, the invention provides a compound of formula (III)

where

ring a is a 3-8-membered saturated carbocyclic group;

ring B is a 3-8-membered saturated or partially saturated cycle which contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

X denotes CH or N;

Y denotes CH2, NR, O or S;

n is 0-4;

m is 0-4;

p is 0-4;

R1denotes hydrogen;

R2denotes hydrogen or C1-6aliphatic group;

R3denotes aryl group selected from 5-6-membered monocyclic group or a 8-12 membered bicyclic group; mentioned aryl group contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where each substitutable position R3optionally and independently replaced by R7;

R5denotes hydrogen, -C1-6aliphatic group, -CN, -OH, -O(C1-6aliphatic group), -CO2H, -CO2(C1-6aliphatic group), -CON(R0)2, -NO2, -halogen, -NR02where each substitutable position of aliphatic carbon atom optionally and independently replaced by halogen or NH2;

R7denotes halogen; R0; -OR0; -SR0; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0 ; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -NO2; -CN; -N(R0)2; -NR0C(O)R0; -NR0C(S)R0; -NR0C(O)N(R0)2; -NR0C(S)N(R0)2; -NR0CO2R0; -NR0NR0C(O)R0; -NR0NR0C(O)N(R0)2; -NR0NR0CO2R0; -C(O)C(O)R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(S)R0; -C(O)N(R0)2; -C(S)N(R0)2; -OC(O)N(R0)2; -OC(O)R0; -C(O)N(OR0R0; -C(NOR0R0; -S(O)2R0; -S(O)3R0; -SO2N(R0)2; -S(O)R0; -NR0SO2N(R0)2; -NR0SO2R0; -N(OR0R0; -C(=NH)-N(R0)2or -(CH2)0-2NHC(O)R0;

where each R0independently selected from hydrogen, optionally substituted C1-6aliphatic group, an unsubstituted 5-6-membered heteroaryl or heterocyclic group (provided that the nitrogen atom in the heterocyclic group is optionally replaced by-R+or-C(O)R+where R+means (C1-6alkyl), preferably (C1-4alkyl), phenyl, -O(Ph), or-CH2(Ph), or, regardless of the above definitions, two independently selected R0makeups one Deputy or asnyk substituents, together with the atom (atoms)is attached to the group R0form a 5-8-membered heterocyclic, aryl or heteroaryl group, or a 3-8-membered cycloalkyl group containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of R4and R6independently represents hydrogen; halogen; -R0; -OR0; -SR0; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -NO2; -CN; -N(R0)2; -NR0C(O)R0; -NR0C(S)R0; -NR0C(O)N(R0)2; -NR0C(S)N(R0)2; -NR0CO2R0; -NR0NR0C(O)R0; -NR0NR0C(O)N(R0)2; -NR0NR0CO2R0; -C(O)C(O)R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(S)R0; -C(O)N(R0)2; -C(S)N(R0)2; -C(=NH)-N(R0)2, -OC(O)N(R0)2; -OC(O)R0; -C(O)N(OR0R0; -C(NOR0R0; -S(O)2R0; -S(O)3R0; -SO2N(R0)2; -S(O)R0; -NR0SO2N(R0)2; -NR0SO2R0; -N(OR0R0; -C(=NH)-N(R0)2; -(CH2)0-2NHC(O)R0, =O, =S, =NNHR*, =NN(R*)2/sub> , =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where

each R0independently selected from hydrogen, optionally substituted C1-6aliphatic group, an unsubstituted 5-6 membered heteroaryl or heterocyclic group, phenyl, -O(Ph), or-CH2(Ph), or, regardless of the above definitions, two independently selected R0present in a substituent or different substituents, together with the atom (atoms)is attached to the group R0form a 5-8-membered heterocyclic, aryl or heteroaryl group, or a 3-8-membered cycloalkyl group containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

aliphatic group, R0optionally substituted NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), (Halogens1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above C1-4aliphatic group is unsubstituted;

each R* is independently selected from hydrogen or C1-6aliphatic group, optionally substituted NH2, NH(C1-4aliphatic group), N(C1-4Lam is practical group) 2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(Halogens1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above C1-4aliphatic group is unsubstituted; and

R denotes hydrogen or C1-6aliphatic group, optionally substituted by =O, =S, -NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(Halogens1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above C1-4aliphatic group is unsubstituted.

In another embodiment, the invention provides a compound of formula III, where

R2denotes hydrogen or C1-6alkyl;

R5denotes hydrogen, -C1-6aliphatic group, -CN, -OH, -O(C1-6aliphatic group), -CO2H, -CO2(C1-6aliphatic group), -CON(R0)2, -halogen, or-NR02where each substitutable position of aliphatic carbon atom optionally and independently replaced by halogen;

each of R4, R6and R7 independently represents halogen; R0; -OR0; -SR0; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted R0; -O(Ph), optionally substituted R0; -(CH2)1-2(Ph), optionally substituted R0; -CH=CH(Ph), optionally substituted R0; -CN; -N(R0)2; -NR0C(O)R0; -NR0CO2R0; -C(O)CH2C(O)R0; -CO2R0; -C(O)R0; -C(O)N(R0)2; -OC(O)N(R0)2; -OC(O)R0; -S(O)2R0; -SO2N(R0)2; -S(O)R0; -NR0SO2R0; or two hydrogen atoms associated with one carbon atom replaced by =On;

where each R0independently selected from hydrogen, optionally substituted C1-6aliphatic group, an unsubstituted 5-6 membered heteroaryl or heterocyclic group, phenyl, -O(Ph), or-CH2(Ph), or, regardless of the above definitions, two independently selected R0present in a substituent or different substituents, together with the atom (atoms)is attached to the group R0form a 5-8-membered heterocyclic, aryl or heteroaryl group, or a 3-8-membered cycloalkyl group containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

aliphatic group, R0optionally substituted NH , NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), where each of the above C1-4aliphatic groups optionally substituted with halogen;

R denotes hydrogen or C1-6aliphatic group, optionally substituted by =O, =S, -NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), where each of the above C1-4aliphatic groups optionally substituted with halogen.

In accordance with another embodiment of formula III, R2denotes hydrogen.

In accordance with another embodiment of formula III or any multiple of m, n and p are 0. In accordance with another embodiment of each of R4, R6and R7independently denotes a halogen; C1-4aliphatic group, optionally substituted with halogen; OR0; -CN; -N(R0)2; -NR0C(O)R0; -NR0CO2R0; or two hydrogen atoms associated with one carbon atom replaced by =O. In the following embodiment R4and R6denote C1-6alkyl or halogen another embodiment R 7denotes halogen, -CN, C1-6alkyl, C1-6alkoxy, -N(R)2or C1-4halogenated.

In another embodiment of formula III, R3denotes aryl group selected from 6-membered monocyclic group containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where each substitutable position R3optionally replaced by R7. In the following embodiment R3denotes a 6-membered heteroaryl group containing 1 or 2 nitrogen heteroatom. In another embodiment R3represents 2-pyridyl.

In accordance with another embodiment of formula III, R5denotes hydrogen, halogen, OH, NR0, CN, O-(C1-6aliphatic group), or C1-6alkyl, optionally substituted by-NR2. In the following embodiment R5represents C1-6alkyl, optionally substituted-N(R)2. In the following embodiment R5represents-CN or hydrogen.

In another embodiment of formula III, ring a is a 5-7-membered carbocyclic group.

In another embodiment of formula III, the ring B is a 5-7-membered saturated or partially saturated cycle. In the following embodiment ring B is a 5-7-membered saturated or partially saturated heterocyclic group.

Other embodiments of formulas I, II, and III represented by the following compounds:

img src="https://img.russianpatents.com/1055/10553227-s.jpg" height="67" width="122" />

As described above, the present invention provides compounds that are inhibitors of protein kinases and therefore can be used for the treatment of diseases, disorders and conditions, including without limitation, proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, a disorder mediated by the immune system, viral disease or bone disease. In preferred embodiments of the compounds can be used to treat allergies, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, disease, Lou Gehrig (Lou Gehrig''s disease)), multiple sclerosis (MS), schizophrenia, hypertrophy of cardiomyocytes, reperfusion/ischemia (e.g. stroke), alopecia, cancer, hepatomegaly, cardiovascular disease, comprising cardiomegaly, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, inflamed the I, hypertension, angina, narrowing of cerebral vessels, impaired peripheral circulation, premature birth, atherosclerosis, vasospasm (spasm of cerebral vessels, koronarospazma), retinopathy, erectile dysfunction (ED), AIDS, osteoporosis, Crohn's disease and colitis, the growth of neurites and disease Raynaud's syndrome. In preferred embodiments, the disease, condition or disorder are atherosclerosis, hypertension, erectile dysfunction (ED), reperfusion/ischemia (e.g. stroke) or vasospasm (spasm of cerebral vessels and koronarospazm).

Accordingly, in another aspect of the present invention offers a pharmaceutically acceptable compositions that contain one described in this document connections and, optionally, a pharmaceutically acceptable carrier, adjuvant or excipient. In some embodiments these compositions can optionally contain one or more other therapeutic agents.

It should be understood that certain compounds of the present invention can be used for treatment in free form or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In accordance with the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prolec stennie form, salts, esters, salts of such esters, or any other adducts or derivatives, which when administered to a patient in need this, is able to provide, directly or indirectly, a compound described herein, or a metabolite or residue. In this description, the term "pharmaceutically acceptable salt" refers to salts that are within the submitted medical reports suitable for use in contact with the tissues of humans and lower animals without causing excessive toxic or irritant, allergic response and the like, in addition, they meet an acceptable ratio of benefit/risk. The term "pharmaceutically acceptable salt" refers to any non-toxic salt or salt of ester compounds of the present invention that when administered to the recipient is capable of providing, directly or indirectly, a compound of this invention or its metabolite or residue possessing inhibitory activity. In this description, the term "metabolite or residue having inhibitory activity" means that a metabolite or residue also is an inhibitor of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK.

Pharmaceutically acceptable salts are well known in this field. For example, S.M. Berge et al. describe pharmaceutically PR is acceptable salt J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated in this description by reference. Pharmaceutically acceptable salts of the compounds of this invention include salts of suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid additive salts are salts of an amino group, obtained using inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, Perlina acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods known in this field, such as the exchange of ions. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, Persol the dude 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate, and the like, Salts of suitable bases include alkali metal salts, alkaline earth metal, ammonium and N+(C1-4alkyl)4. This invention also considers the quaternization of any basic nitrogen-containing groups of the compounds disclosed in this description. As a result of such quaternization can get products that are soluble or dispersible in water or oil. Typical salts of alkaline or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium salts, Quaternary ammonium and aminoketones obtained using such protivoionov as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As stated above, the pharmaceutically acceptable compositions of the present invention optionally contain pharmaceutically acceptable carriers, auxiliary AIDS or environment for drugs that, in accordance with this description, include any and all solvents, diluents, or other liquid medium, means facilitating the dispersion or suspen the licensing, surface-active products, isotonic means, thickening or emulsifying means, preservatives, solid binders, lubricants and the like, depending on the target dosage forms. In Remington''s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used to obtain pharmaceutically acceptable compositions, as well as known methods for producing such compositions. The use of any traditional media vehicles is included in the scope of this invention except in those cases where the media is incompatible with the compounds of this invention and, for example, causing undesirable biological effect or shall have harmful consequences of interaction with any other component (components) pharmaceutically acceptable composition. Examples of substances that can be used as pharmaceutically acceptable carriers include, without limitation, ion exchange substance, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, disodium hydrogen phosphate, potassium phosphate, chlorine is the ID of sodium, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, block copolymers of polyethylene and polyoxypropylene, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethylcellulose sodium, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients, such as coconut oil and candle waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as etiloleat and tillaart; agar; sautereau tools, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic; ringer's solution; ethyl alcohol and phosphate buffer solutions; in addition, at the discretion of the pharmacist, the compositions may include other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as dyes, tools, helps to release covering means, sweeteners, flavors and fragrances, preservatives and antioxidants.

In the following aspect features a method of treating or decrease the Oia severity of a proliferative disorder, cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, a disorder mediated by the immune system, viral infections, or bone diseases, the method includes introducing an effective amount of a compound or pharmaceutically acceptable composition comprising the compound, to a subject in need of such introduction. In some embodiments of the present invention an "effective amount" of a compound or pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, a disorder mediated by the immune system, viral disease or bone disease. In accordance with the method of the present invention the compounds and compositions can be entered in any amount and any route of administration that can effectively treat or reduce the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative what about the disorder, autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, a disorder mediated by the immune system, viral disease or bone disease. The amount used varies from subject to subject, depending on the species, age and General condition of the subject, the severity of infection, the means used, method of its introduction, etc. For ease of administration and uniformity of dosage of the compounds of the present invention is preferably introduced in the form of a standard dosage forms. The expression "standard dosage form" in this description refers to a physically discrete unit of funds, appropriate for the patient to be treated. However, it should be understood that the total daily dose of the compounds and compositions of the present invention is prescribed by the attending physician depending on the medical report. The specific effective dose for any particular patient or organism will depend on several factors, including the subject of the treatment of the disorder and the severity of the disorder; activity of the specific compound; the specific composition; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration and the degree of removal of the concrete used with the organisations; the duration of the treatment; drugs used in combination or in conjunction with the specific connection; and other factors well known in medicine. The term "patient" in this description refers to an animal, preferably a mammal, most preferably to humans.

Pharmaceutically acceptable compositions of this invention can enter humans and other animals orally, rectally, parenterally, intracisternally, vnutrivaginalno, intraperitoneally, locally (powders, ointments or drops), buccal, in the form of oral or nasal spray, etc, depending on the severity of the treatment to be infection. In some embodiments of the compounds of this invention can be administered orally or parenterally at a dose level which is from about 0.01 mg/kg to 50 mg/kg, preferably from about 1 mg/kg to 25 mg/kg of body weight of the subject per day, once or several times a day to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, without limitation, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents conventionally used is this area, such as, for example, water or other solvents, solubilizing means and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also contain auxiliary agents such as humectants, emulsifying and suspendresume tools, sweeteners, flavors and fragrances.

Injectable preparations, for example, sterile aqueous or oily suspension for injection, can be obtained by means known in the field of methods using suitable dispersing or moisturizer and suspendresume funds. Sterile injectable preparations can also be a sterile solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. It is suitable for use acceptable mediums and solvents include water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, ka is este solvent or suspendida environment typically use sterile fatty oil. For this purpose you can use any soft fatty oils, including mono - or diglycerides. To obtain drugs for injection also use fatty acids such as oleic acid.

Compositions for injection can be sterilized, for example, by filtration through a filter traps bacteria, or by incorporating sterilizing means in the composition of sterile solid compositions, which before use can be dissolving or dispersing in sterile water or other sterile environment for injection.

To prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of compounds by subcutaneous or intramuscular injection. This can be achieved by applying a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the degree of absorption of the connection depends on the degree of dissolution, which in turn may depend on the size and shape of the crystals. Alternative a slower absorption of parenteral input forms of connection can be achieved by dissolution or suspension of the compound in oily environments. Drugs depot for injection is obtained by microencapsulation bases containing compound, in biorazlagaemykh polymers, such as polylactide-polyglycolide. The degree of release of connection m which should be adjusted by changing the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biorazlagaemykh polymers include complex poly(orthoevra) and poly(anhydrides). Composition depot injection also produced by the conclusion of the compounds in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal injection preferably represent candles, which can be obtained by mixing the compounds of this invention with suitable non-irritating fillers or carriers, such as coconut oil, polyethylene glycol or candle wax, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity, releasing the active connection.

Solid dosage forms for oral administration include capsules, tablets, pillule, powders and granules. To obtain such solid dosage forms the active compound is mixed, with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and/or a) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum Arabic, c)with moisturizing means, such as glycerol, d) with dezinfeciruyuhimi means, such as agar-agar, calcium carbonate, potato or manioc starch, alginic acid, certain silicates and sodium carbonate, e) retarding solution, such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds, g) with the moistening means, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) with lubricating means, such as talc, calcium stearate, stearate magnesium, solid polyethylene glycols, sodium lauryl sulfate, as well as mixtures thereof. In the case of capsules, tablets and pillule dosage form may also contain tabularasa tools.

Solid compositions of a similar type can also be used as fillers to obtain soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight glycols and other Such solid dosage forms such as tablets, pills, capsules, pillule and granules, may have coatings and shells, such as intersolubility and other coatings well known in the pharmaceutical field. They may not necessarily contain opalescent components and can also represent HDMI is tion, which releases only the active ingredient (the active ingredients), or, preferably, releases the active ingredients in a certain part of the intestinal tract, optionally in slow mode. Examples of coating compositions include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers to obtain soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight glycols, etc.

As mentioned above, the active compound together with one or more fillers can also be enclosed in microcapsules. Solid dosage forms such as tablets, pills, capsules, pills and granules can have coatings and shells, such as intersolubility cover, cover, control release, and other coatings well known in this field. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Typically, such dosage forms can also contain additional substances other than inert diluents, for example, lubricants used in the pelletizing and other tools that facilitate tableting, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain tabularasa funds. They may not necessarily contain opalescent components and can also be a composition that releases only the active ingredient (the active ingredients), or, preferably, releases the active ingredients in a certain part of the intestinal tract, optionally in slow mode. Examples of coating compositions include polymeric substances and waxes.

Dosage forms for local or percutaneous introduction of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, pharmaceutical forms for inhalation or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, optionally, any suitable preservatives or buffers. In the scope of the present invention also includes ophthalmic composition, ear drops and eye drops. In addition, the present invention encompasses the use of transdermal patches, which have the additional advantage of providing controlled delivery of compounds into the body. Such dosage forms can be obtained by dissolving or dissolved, is adelene compound in a suitable medium. You can also use amplifiers absorption to increase the penetration of compounds through the skin. Speed can be controlled either through a membrane that regulates the speed, or by dispersing the compound in a polymer-based or gel.

As broadly described above, the compounds of this invention can be used as inhibitors of protein kinases. In one embodiment of the compounds and compositions of this invention are inhibitors of one or more of the subfamilies of protein kinases FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK, and, therefore, without regard to any theory, the compounds and compositions are particularly suitable for the treatment or reduction of the severity of the disease, condition or disorder associated with the activation of one or more of the subfamilies of protein kinases FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK. If the activation of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK is involved in the development of a particular disease, condition or disorder, the disease, condition or disorder also called FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK-mediated disease or symptom of the disease. Accordingly, in another TSA is regarding subsection the present invention provides a method of treating or reducing the severity of the disease, condition or disorder associated with the activation of one or more of the subfamilies of protein kinases FLT-3, FMS, c - KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK.

The potency of the compound used in this invention as an inhibitor of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK, can be analyzed in vitro, in vivo or in cell lines. The in vitro tests include assays that determine inhibition of either fosforiliruyusciye activity or ATP-aznoe activity of activated protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK. Alternative in vitro tests allow us to quantitatively determine the ability of the inhibitor to bind protein kinase subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK. The binding of the inhibitor can be measured by tagging inhibitor radioactive isotope before binding, separation of the complex inhibitor/protein kinase subfamily FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, or SYK and determine the amount of bound radioactive label. Alternatively, the binding of the inhibitor can be determined using competitive analysis, where new inhibitors are incubated with Proteus is a kinase subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK associated with known ligands, labeled with radioactive isotopes.

In one embodiment, the invention provides a compound of formula I, II or III, which selectively inhibits FLT-3 and/or c-KIT. In another embodiment, the invention provides a compound of formula I, which selectively inhibits FLT-3 and/or c-KIT. In this description, the term "selectively inhibits" means that Kior IC50for inhibition of FLT-3 and/or c-KIT under the action of the connection, at least two times lower than for one or more other kinases such as protein kinase subfamilies Aurora-2, FMS-DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK-3, JNK, KDR, MET, SRC, ROCK, and/or SYK. In the following embodiment, the compound that selectively inhibits FLT-3 and/or c-KIT, is a compound that inhibits FLT-3 and/or c-KIT with Kior IC50that, at least five times lower, or at least ten times lower than in the case of inhibiting one or more other kinases such as protein kinase subfamilies Aurora-2, FMS-DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK-3, JNK, KDR, MET, SRC, ROCK, and/or SYK.

The term "inhibits on detektiruya level" in this description means detective changes in the activity of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (on the example, PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK in the sample containing the specified composition and protein kinase subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK, compared with a similar sample containing a protein kinase subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK in the absence of a specified composition.

The term "FLT-3-mediated disease" in this description refers to any disease or unhealthy condition in the development of which involved the kinase family of FLT-3. Such conditions include, without limitation, hematopoietic disorders, particularly acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) and acute lymphocytic leukemia (ALL).

In accordance with another embodiment of the invention provides a method of treating or reducing the severity of FMS-mediated disease or condition in a patient, comprising the stage of introduction of the indicated patient a composition of the present invention.

The term "FMS-mediated disease" in this description refers to any disease or unhealthy condition in the development of which involved the kinase family of FMS. Such conditions include, without limitation, cancer (including, without limitation, ovarian cancer, uterine and breast cancer), inflammatory the e disorders and hypertension.

In accordance with another embodiment of the invention provides a method of treating or reducing the severity of c-KIT-mediated disease or condition in a patient, comprising the stage of introduction of the indicated patient a composition of the present invention.

The term "c-KIT-mediated disease" in this description refers to any disease or unhealthy condition in the development of which involved the kinase family of c-KIT. Such conditions include, without limitation, AML, chronic myelogenous leukemia (CML), mastocytosis, both anaplastic lymphoma, ALL, and stromal tumor of the gastrointestinal tract (GIST), T-cell lymphoma, adenomatosnuu carcinoma, angiosarcoma, carcinoma of the uterus, small cell lung carcinoma, prostate cancer, ovarian cancer, carcinoma of the breast, thyroid carcinoma, malignant carcinoma, carcinoma of the rectum and glioblastoma.

In accordance with another embodiment of the invention provides a method of treating or reducing the severity of CDK-2-mediated disease or condition in a patient, comprising the stage of introduction of the indicated patient a composition of the present invention.

The term "CDK-2-mediated disease" in this description refers to any disease or another painful condition, which participates to the unique family of CDK-2. Accordingly, these compounds can be used to treat diseases or conditions, which are affected by the kinase activity of CDK-2. Such diseases or conditions include cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis, viral infections, neurodegenerative disorders, disorders associated with apoptosis of thymocytes, or proliferative disorder resulting from a disorder of cell cycle regulation, especially in the development cycle from phase G1 to phase s

In accordance with another embodiment of the invention provides a method of treating or reducing the severity of GSK-3-mediated disease or condition in a patient, comprising the stage of introduction of the indicated patient a composition of the present invention.

In accordance with another embodiment of the invention provides a method of treating or reducing the severity of Src-mediated disease or condition in a patient, comprising the stage of introduction of the indicated patient a composition of the present invention.

The term "Src-mediated disease" in this description refers to any disease or unhealthy condition in the development of which part is there is a kinase of the Src family. Such diseases or conditions include, without limitation, cancers, such as colon cancer, breast cancer, liver and pancreatic cancer, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, leukemia, diseases associated with the restructuring of the bones, such as osteoporosis, and viral diseases such as hepatitis B.

In accordance with another embodiment of the invention provides a method of treating or reducing the severity of Syk-mediated disease or condition in a patient, comprising the stage of introduction of the indicated patient a composition of the present invention.

The term "Syk-mediated disease" or "Syk-mediated condition" in this description refers to any disease or unhealthy condition in the development of which involved the protein kinase Syk. Such conditions include, without limitation, allergic disorders, especially asthma.

The term "JAK-mediated disease" in this description refers to any disease or unhealthy condition in the development of which involved the kinase of the JAK family. Such conditions include, without limitation, immune responses, such as allergic reactions or hypersensitivity reactions type I, asthma, autoimmune diseases such as rejection is transplantat, graft-versus-host, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, neurodegenerative disorders, such as familial amyotrophic lateral sclerosis (FALS), as well as solid and hematological malignant diseases such as leukemia and lymphoma.

The term "PDK1-mediated condition" or "disease" in this description refers to any disease or another painful condition in which PDK1 is involved. The term "PDK1-mediated condition" or "disease" also refers to diseases or conditions that can be treated with an inhibitor of PDK1. PDK1-mediated diseases or conditions include, without limitation, proliferative disorders and cancer. Preferably specified cancer is a pancreatic cancer, prostate or ovarian cancer.

The term "PKA-mediated condition" or "disease" in this description refers to any disease or another painful condition in the development of which involved PKA. The term "PKA-mediated condition" or "disease" also refers to diseases or conditions that can be treated with PKA inhibitor. PKA-mediated diseases or conditions include, without limitation, proliferative disorders and cancer.

The term "p70S6Koposredovany the condition" or "disease" in this description refers to any disease or another painful condition, in the development of which involved p70S6K. The term "p70S6K-mediated condition" or "disease" also refers to diseases or conditions that can be treated with an inhibitor of p70S6K. p70S6K-mediated diseases or conditions include, without limitation, proliferative disorders such as cancer and tuberose sclerosis.

The term "GSK-3-mediated disease" in this description refers to any disease or another painful condition in the development of which involved GSK-3. Such diseases or conditions include, without limitation, autoimmune diseases, inflammatory diseases, metabolic, neurological and neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, Parkinson's disease and movement disorders of the basal ganglia, horey, dystonia, Wilson's disease, a disease of the Peak, the degeneration of the frontal lobe, progressive supranuclear palsy (PSP), a disease of Creutzfeldt-Jakob, thaumatology and corticobasal degeneration (CBD)), psychotic disorders (e.g. schizophrenia, AIDS-associated dementia, depression, bipolar disorder, and fear), cardiovascular disease, allergies, asthma, diabetes, amyotrophic lateral sclerosis (AML, disease Louis Gehrig), multiple sclerosis (MS), hypertrophy of cardiome is Titov, the reperfusion/ischemia, stroke and baldness.

The term "ROCK-mediated condition" or "disease" in this description refers to any disease or another painful condition in the development of which involved ROCK. The term "ROCK-mediated condition" or "disease" also refers to diseases or conditions that can be treated with ROCK inhibitor. Such conditions include, without limitation, hypertension, angina, narrowing of cerebral vessels, asthma, peripheral circulatory disorder, premature birth, cancer, erectile dysfunction, atherosclerosis, spasm (spasm of cerebral vessels and koronarospazm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, damage caused by ischemia/reperfusion, and endothelial dysfunction.

In other embodiments, this invention relates to a method for enhancing glycogen synthesis and/or lowering blood glucose in a patient in need thereof, and the said method includes the introduction of the indicated patient a therapeutically effective amount of a composition containing a compound of formula I, II or III. This method is mainly intended for diabetic patients.

In the following embodiment, the invention relates to a method Inga is investing products hyperphosphorylated Tau protein in a patient, in need thereof, and the said method includes the introduction of the indicated patient a therapeutically effective amount of a composition containing a compound of formula I, II or III. This method is mainly intended to stop or slow the development of Alzheimer's disease.

In the following embodiments, the invention relates to a method of inhibiting the phosphorylation of β-catenin in a patient in need thereof, and the said method includes the introduction of the indicated patient a therapeutically effective amount of a composition containing a compound of formula I, II or III. This method is mainly intended for the treatment of schizophrenia.

It should also be understood that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e. the compounds and pharmaceutically acceptable compositions can be administered simultaneously with one or more other suitable medicines or medical procedures, before or after. When using the particular combination of therapies (drugs or procedures) should consider the use of drugs and/or procedures are desirable therapeutic effect. You should also understand that your therapy can be EmOC is aulani to achieve the desired effect for the same disorder (for example, the compound of this invention can be entered together with another agent used to treat the same disorder), or they can be designed to achieve different effects (e.g., to reduce side effects). In this description of additional therapeutic agents that are normally administered to treat or prevent a specific disease or condition referred to as "suitable for treating the disease or condition to be treated."

For example, chemotherapeutic agents or other anti-proliferative tools can be used in combination with the compounds of the present invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, without limitation, other anti-cancer therapies or means suitable for use in combination with anticancer means of the present invention, which include surgery, radiotherapy (as some examples of gamma-irradiation, nationalreview radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic injection of radioactive isotopes), endocrine therapy, the use of biological response modifiers (e.g. interferons, interleukins and tumor necrosis factor (TNF)), hyperthermia and cryo is arapey, means for reducing side effects (e.g., antiemetics), and other admitted to the use of chemotherapeutic agents, including, without limitation, alkylating agents (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine (6-mercaptopurine, 5-fluorouracil, cytarabin, gemcitabine), spun poisons (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoanatabine (carmustin, lomustin)inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide and megestrol), GleevecTM, adriamycin, dexamethasone, and cyclophosphamide. More extensive information on cancer therapies can be found in The Merck Manual., The Seventeenth Ed. 1999, the full contents of which are incorporated in this description by reference.

Other examples of tools that can also be used in combination with inhibitors of this invention include, without limitation: a treatment for Alzheimer's disease such as Aricept® and Excelon®; for the treatment of Parkinson's disease such as L-DOPA/carbidopa, entacapone, ropinirol, pramipexol, bromkriptin, pergolid, trihexyphenidyl and amantadine; means for treating asianova sclerosis (MS), such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; means for asthma such as albuterol and Singulair®; means for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotropic factors, such as inhibitors acetylcholinesterase, MAO inhibitors, interferons, anti-convulsants, blockers of ion channels, riluzole, and anti-Parkinson's disease; a means for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; means for treatment of liver disease such as corticosteroids, cholestyramine, interferons and antiviral agents; means for treating blood disorders such as corticosteroids, protivoanemicheskoe funds and growth factors; and means for treatment of immunodeficiency States, such as gamma globulin.

The amount of another therapeutic agent that is present in a composition of the present invention, not the debtor is about to exceed the number, which usually enter in the composition that contains therapeutic agent as the only active ingredient. Preferably the amount of another therapeutic agent in the compositions of the present invention varies from about 50% to 100% relative to the amount normally present in a composition containing the tool as the only therapeutically active component.

The compounds of this invention or their pharmaceutically acceptable compositions can also be included in compositions used for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, in another aspect of the present invention includes a composition for coating an implantable device containing the compound of the present invention, described herein above in General and in classes and subclasses, and a carrier suitable for coating of specified implanted device. The following aspect of the present invention includes an implantable device coated with a composition comprising a compound of the present invention, described herein above in General and in classes and subclasses, and a carrier suitable for coating specified and plateruena device.

Vascular stents, for example, used to overcome restenosis (re-narrowing of the vessel lumen after injury). However, in patients with stents or other implantable devices, there is a risk of blood clots or activated platelets. These adverse effects can be prevented or reduced by pre-coating device pharmaceutically acceptable composition comprising an inhibitor of the kinase. Suitable coatings and the General ways of obtaining a coated implantable devices are described in U.S. patents 6099562; 5886026; and 5304121. Coatings are typically biocompatible polymeric materials, such as polymer hydrogel, polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating can be further coated with a suitable surface coating of Versiliana, polysaccharides, polyethylene glycol, phospholipids or combinations thereof, giving the song features a controlled release.

Another aspect of this invention relates to a method for inhibiting the activity of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK in a biological sample or in a patient, the method includes the administration to a patient compounds forms the crystals I, II or III, or a composition containing the specified connection, or the bringing into contact of the mentioned biological sample with a specified compound or composition. The term "biological sample" in this description includes, without limitation, cell cultures or extracts; material obtained biopsy from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

The inhibition of the activity of protein kinases subfamilies FLT-3, FMS, c-KIT, DERIVED, JAK, AGC (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK in the biological sample used for different purposes, known to specialists in this field. Examples of such purposes include, without limitation, blood transfusion, organ transplantation, storage of biological samples and biological tests.

EXAMPLES

Compounds of General formula I are obtained by the General methods described in examples 1 and 2.

Example 1

N3-[4-(4-(Morpholine-4-illlogical)phenyl]-1-pyridin-2-yl-1H-[1,2,4]triazole-3,5-diamine

The HPLC method A:

Column: Lighting 3 μm, and 2.1×50 mm

Gradient: 100% B (0.1% OF TFU/1,0% MeCN/water) to 100% D (0,1% TFU/MeCN) within 4 minutes Support D @ 100% D to 5.6 min, then transferred to 100% B for 0.4 min, and maintain it within 1 min

Flow rate: 0.8 to the l/min

Synthesis of dimethyl 4-cyano-4-(4-nitrophenyl)heptanoate (2);

To a solution of 2-(4-nitrophenyl)acetonitrile (1) (50,12 g, 0.31 mol) in CH3CN (1 l) at RT in the atmosphere N2add the Triton-B/40% MeOH (14,5 ml, 0.03 mol)to give a dark purple solution. The mixture is heated under reflux, then add (~2.5 h) acrylate (160 ml, 1.78 mol) and continue to reflux for 4 hours the Reaction mixture is cooled and evaporated, then diluted with EtOAc and acidified with 2 N. HCl. The layers separated, the aqueous layer was again extracted with EtOAc, the combined organic layers washed with saturated NaCl solution, dried over Na2SO4, filtered and evaporated. Purified flash chromatography on silica gel (1 l), elwira a mixture of 1:2 EtOAc:hexane, and obtain compound 2 as a yellow oil (88,96 g, 86%).

1H-NMR (500 MHz, DMSO-d6) 8,31 (d, 2H), 7,78 (d, 2H), 3,52 (c, 6H), 2,4 (m, 6H), was 2.05 (m, 2H) ppm

MC-FIA: 333,1 (M-N).

HPLC (method A): 3,484 minutes

Synthesis of methyl 5-cyano-5-(4-nitrophenyl)-2-oxocyclohexanecarboxylate (3)

To a solution of compound 2 (88,96 g, 0.27 mol) in DME (1 l) at RT in the atmosphere N2add (carefully), NaH (60% in mineral oil, 31,92 g, 0.80 mol)to give a dark purple solution. The reaction mixture is heated under reflux for 4 h, cooled and carefully quenched with a 2O, acidified with 2 N. HCl and extracted 2×EtOAc. The combined organic layers washed with saturated NaCl solution, dried over a mixture of activated carbon and Na2SO4, filtered through celite and evaporated, obtaining the crude product 3 as a brown solid (83,42 g, 100%).

1H-NMR (500 MHz, DMSO-d6) 12,1 (c, 1H), 8,31 (d, 2H), 7,88 (d, 2H), 3.75 to (c, 3H), 2,86 (AB Quartet, 2H), 2,65 (m, 1H), and 2.6 (m, 1H), 2,4 (m, 1H), 2,35 (m, 1H) ppm

MC-FIA: 301,1 (M-N).

HPLC (method A): 3,729 minutes

Synthesis of 1-(4-nitrophenyl)-4-oxocyclohexanecarboxylate

The crude compound 3 (0.27 mol), NaCl (80 g, 1.37 mol) and water (80 ml) is heated in DMSO (1.2 l) at 150-160°C for 3 hours the Solvent is distilled off, the residue was diluted with H2O and extracted with 3×EtOAc. The combined organic layers washed with 2 N. HCl, 3×H2O, NaCl, dried over Na2SO4and evaporated. Clean flash chromatography (1 l SiO2), elwira a mixture of EtOAc:hexane 1:3 then 1:2, and get the pure product 4 as not quite white solid (36,47 g, yield 56%), and slightly contaminated product 4 in the form of a greenish solid (14,33 g, yield 22%).

1H-NMR (500 MHz, DMSO-d6) 8,31 (d, 2H), 7,92 (d, 2H), 2,74 (m, 2H), 2,5 (m, 6H) ppm

MC-FIA: 243,2 (M-N).

HPLC (Method A): cash consideration of USD 3,121 minutes

Synthesis of 4-morpholino-1-(4-nitrophenyl)cyclohexanecarbonitrile (5a)

2O (3×). The solid is dried in vacuum at 40°C for 18 h and get a mixture of isomers (5a and 5c, 54,9 g, yield 84%).

Cleaning isomer 5a (required for method of producing example 2; is not necessary for the method of producing example 1)

A mixture of 5a and 5b (79,4 g) dissolved in CH2Cl2(200 ml) and applied on SiO2(2 l), loaded into a funnel with a porous glass filter with a volume of 3 L. Elute 13 l of a mixture 1:1 ethyl acetate:hexane in flask 1 liter, receiving a mixture of 5a and 5b (19,77 g, yield 25%) as a pale yellow solid. Then elute 8 l mixtures 5:95 methanol:CH2Cl2and obtain 57 g of pure isomer 5a (yield 72%).

5a:1H-NMR (500 MHz, DMSO-d6) 8,28 (d, 2H), to 7.84 (d, 2H)and 3.59 (m, 4H), 2,52 (m, 4H), 2.40 a (TT, 1H), 2,18 (d, 2H), 2,02 (m, 4H), to 1.60 (m, 2H) ppm

MC-FIA 316,1 (M+H).

HPLC (method B) 2,537 minutes (100%).

5b:1H-NMR (500 MHz, DMSO-d6) 8,30 (d, 2H), 7,82 (d, 2H)and 3.59 (m, 4H), of 2.38 (m, 4H), 2,28 (d, 2H), and 2.26 (m, 1H), was 1.94 (m, 4H), 1,74 (who, 2H) ppm

MC-FIA 316,1 (M+H).

HPLC: 2,449 min (100%).

Synthesis of TRANS - and CIS-4-(4-(morpholine-4-illlogical)phenylamine (6A and 6b)

(Reference: S.B. Christensen et al., J. Med. Chem., 1998, 41, 821-835; and J.A. Marshall, et al., J. Org. Chem., 1977, 42, 3309-3311.)

3-Necked round bottom flask with a volume of 2 l, equipped with top mechanical stirrer, adapter Claisen with an additional funnel (1 l), and a fridge with dry ice, dry it on fire in a nitrogen atmosphere and allowed to cool. Refrigerator, charged with a mixture of dry ice/2-propanol and the flask was cooled to -78°C using a mixture of dry ice/2-propanol under positive nitrogen pressure. Gaseous ammonia (1 l) condense in the atmosphere of nitrogen. Then the solution load of 26.6 g (of 1.16 mol) of metallic sodium. After 30 min added dropwise a solution of 30 g (0,0951 mol) of 4-morpholino-1-(4-nitrophenyl)cyclohexanecarbonitrile in anhydrous THF (300 ml) via an additional funnel over 10 minutes. After completion of the addition funnel is washed with 50 ml of THF from residues 4 morpholino-1-(4-nitrophenyl)cyclohexanecarbonitrile, the reaction mixture is left to warm up to -33°C and stirred for 5 hours. The reaction mixture was quenched by adding dropwise a mixture of NH4Cl/NH4OH (9/1, 100 ml) under positive nitrogen pressure. Add water (200 ml), then EtOAc (350 ml) and left under stirring overnight to evaporate the ammonia. Received the second suspension is filtered through celite and the aqueous layer was extracted with EtOAc (3×200 ml). The combined organic layers dried over MgSO4, filtered, concentrated under reduced pressure (rotary evaporator) and after vacuum drying at RT receive a mixture of 6a:6b ~5:1 in the form of a pale yellow solid (23,87 g, yield 96,4%).

1H-NMR (500 MHz, DMSO-d6for 6a: at 6.84 (d, 2H), 6,46 (d, 2H), 3,55 (m, 4H), 2,48 (m, 4H), 2,25 (TT, 1H), 2,22 (TT, 1H), 1,88 (d, 2H), 1,78 (d, 2H), of 1.34 (m, 4H) ppm; distinguishable peaks for 6b: 6,86 (d, 2H), of 6.49 (d, 2H), 3,60 (m, 4H), is 2.37 (m, 4H) ppm

MC-FIA 261,2 (M+H),69%).

Synthesis of (Z)-3-(4-(4-morpholinoethoxy)phenyl)-2-phenylazomethine

The mixture of CIS - and TRANS-4-(4-(morpholine-4-illlogical)phenylamine 6b and 6a (to 20.28 g, up 77.9 mmol) and diphenylcarbonate (20,44 g, 85.6 mmol) in dioxane (350 ml) is stirred in an atmosphere of N2within 4 days. The reaction mixture was evaporated and then diluted with water and extracted with 5 portions (200 ml) CH2Cl2. The combined organic phase was washed with NaHCO3and evaporated to dryness, obtaining a dark brown viscous oil. After grinding with Et2O (300 ml) receive a yellowish-brown solid, which is then washed with 2 portions Et2O (150 ml), and receiving the product 7a in the form of a yellowish-brown solid (21,70 g, 69%).

1H-NMR (500 MHz, DMSO-d6) 10,7 (USS, 1H), 7,44 (t, 2H), 7,35 (d, 2H), 7,25 (m, 5H), of 3.57 (m, 4H), of 2.51 (m, 4H), 2,44 (TT, 1H), 2,30 (m, 1H), 1,92 (d, 2H), 1,85 (d, 2H), 1,45 (m, 2H), of 1.34 (m, 2H) ppm

LC/MC(5-45% CH 3CN) 405,1 (M+H), 403,2 (M-N).

tR=3,4 minutes

HPLC: 2,798 minutes

Synthesis of N3-[4-(4-(morpholine-4-illlogical)phenyl]-1-pyridin-2-yl-1H-[1,2,4]triazole-3,5-diamine

A solution of (Z)-3-(4-(4-morpholinoethoxy)phenyl)-2-phenylazomethine 7a (7,00 g, 17.3 mmol) and 2-pyridyldithio of 2.27 g of 20.8 mmol) is heated under reflux in isopropanol (100 ml) for 2 days. The reaction mixture is cooled, filtered and the obtained solid is washed with ethanol. The residue is recrystallized from dioxane, the crystals are filtered, suspended in methanol under stirring for 1 h, evaporated and dried at 60°C in high vacuum for 3 days. The result is a pure compound I-3 (4,88 g, yield 67%) as a white solid.

1H-NMR (500 MHz, DMSO-d6) 8,92 (c, 1H), 8,40 (m, 1H), 7,97 (m, 1H), 7,68 (d, 1H), 7,63 (c, 2H), 7,51 (d, 2H), 7,20 (m, 1H), to 7.09 (d, 2H), only 3.57 (m, 4H), of 2.50 (m, 4H), 2,37 (TT, 1H), 2.26 and (TT, 2H), 1.91 a (d, 2H), 1,84 (d, 2H), 1,43 (m, 2H), 1,33 (m, 2H) ppm

LC/MC (5-95% CH3CN) 420,0 (M+H).

tR=3,1 minutes

HPLC: 2,602 minutes

Synthesis of nelfinavir N3-[4-(4-(morpholine-4-illlogical)phenyl]-1-pyridin-2-yl-1H-[1,2,4]triazole-3,5-diamine

The compound of example 1 (128.0 g, 0,305 mol) are suspended in dioxane (1.5 l) and heated at 60-70°C. for 10 minutes, added dropwise methanesulfonyl acid (to 19.8 ml, 0,305 mol). Stirring is continued for 1 h the ri 60-70°C and 3 h at room temperature. The solid is filtered and washed with Et2O, then 4 times suspended in methanol, evaporated and dried in high vacuum at 50-60°C for 20 h the Procedure for suspension/evaporation/drying again with methanol, and then once with ethanol in an unsuccessful attempt to remove traces of dioxane of salt. The solid is suspended in water (1 l) and heated under reflux for 15 min, then the solid is separated from the water by centrifugation. Centrifugation is repeated twice more. The wet solid is diluted with ethanol, evaporated and dried at 45-50°C in high vacuum, receiving compound I-3, mesilate (129,95 g), in the form of a white solid. The final product contains (according to NMR) 0.3% dioxane.

1H-NMR (500 MHz, DMSO-d6) 9,51 (USS, 1H), 8,98 (c, 1H), to 8.41 (m, 1H), 7,99 (m, 1H), 7,69 (d, 1H), to 7.64 (c, 2H), 7,54 (d, 2H), 7,21 (m, 1H), 7,11 (d, 2H), was 4.02 (d, 2H), and 3.72 (t, 2H), 3,44 (d, 2H), or 3.28 (m, 1H), 3,14 (m, 2H), 2,46 (m, 1H), 2,34 (c, 3H), 2,19 (m, 2H), 1,95 (m, 2H), 1,53 (m, 4H) ppm

LC/MC (5-95% CH3CN) 420,1 (M+H).

tR=3,2 minutes

HPLC: 2,593 minutes

Example 2

1-(4-(5-Amino-1-(pyridine-2-yl)-1H-1,2,4-triazole-3-ylamino)phenyl-4-morpholinosydnonimine

Synthesis of (Z)-1-cyano-3-(4-((1s,4s)-1-cyano-4-morpholinoethoxy)phenyl)-2-phenylazomethine (6)

Intermediate compound 5a receive according to the method of example 1. Tra is s-4-morpholino-1-(4-nitrophenyl)cyclohexanecarbonitrile (20 g, 63.5 mmol) and the catalyst 10% Pd-C (750 mg) in 250 ml of ethanol is kept in a hydrogen atmosphere (38 psi) in a Parr shaker for 2 hours. To dissolve the product, add dichloromethane, 200 ml, then the catalyst is filtered off. The solvent is evaporated, receiving TRANS-1-(4-AMINOPHENYL)-4-morpholine-4-enciclopedicanyfile (18,1 g, 63.5 mmol) in the form of pure yellowish-brown solid which is used without further purification.

1H NMR CDC13: 7,25 (m, 2H), 6,70 (m, 2H), and 3.7 (m, 6H), to 2.65 (m, 4H), to 2.35 (m, 1H, in), 2.25 (m, 2H), 2.05 is (m, 2H), of 1.85 (m, 4H).

FIA MC M+1, 286,0.

HPLC: method 10-90% CH3CN: 2,488 minutes 100%.

The solution obtained TRANS-1-(4-AMINOPHENYL)-4-morpholine-4-enciclopedicanyfile (18,1 g, 63.5 mmol) and diphenylcyanoarsine (18,1 g, 76,2 mmol) was stirred in 1,4-dioxane (140 ml) at RT for 24 hours Add distilled water (200 ml) and receive a white precipitate, which is filtered off and washed with water (100 ml), saturated sodium bicarbonate solution (150 ml) and water (200 ml). The solid is dried in a desiccator under vacuum over night, getting mentioned in the title compound 6 (21.1 g, yield 78%).

1H-NMR (DMSO, 500 MHz) of 7.55 (m, 4H), 7,45 (m, 2H), and 7.3 (m, 3H), 3,6 (m, 4H), of 2.45 (m, 4H), 2,37 (t, 1H), 2,15 (d, 2H), 2.0 (d, 2H), and 1.9 (t, 2H), 1,6 (m, 2H)

MC+ 430,18, MC - 428,13, HPLC Rt=4,652 min (10-90% acetonitrile for a period of 7.5 minutes

Synthesis of 1-(4-(5-amino-1-(pyridine-2-yl)-1H-1,2,4-triazole-ylamino)phenyl-4-morpholinosydnonimine

1-(4-(5-Amino-1-(pyridine-2-yl)-1H-1,2,4-triazole-3-ylamino)phenyl-4-morpholinosydnonimine (73 g, 0,164 mol) are added to a dioxane (1 l) and the mixture is heated to 60-70°C. for 10 minutes, added dropwise methanesulfonyl acid (15,8 g, 0,164 mol). The heating bath is removed and the slurry is mixed for 3 hours. Add isopropanol (200 ml) and the mixture filtered. Salt is washed with isopropanol (50 ml), then diethyl ether (200 ml). The solid is suspended in a mixture of 10% methanol-dichloromethane (500 ml) and stirred for 18 hours. Add isopropanol (100 ml), the solid is filtered, washed with ether, and get clean mesilate (I-4, in the form of nelfinavir) as a white solid (81 g, yield 91%).

1H NMR: DMCO-d6: 9,70 (USS, 1H), 9,25 (c, 1H), 8,40 (c, 1H), 7,95 (m, 1H), 7,65 (m, 3H), 7,40 (m, 2H), 7,20 (m, 1H), 4,06 (m, 2H, in), 3.75 (m, 2H), 3,55 (m, 2H), 3,50 (USS, 1H), 3,35 (m, 1H), 3.15 in (m, 2H), 2,32 (m, 7H), 1,90 (m, 2H), 1,80 (m, 2H).

FIA MC M+1 445,2

LC-MC M+1: 445,3 of 1.88 min method 10-90% CH3CN.

HPLC: method 10-90% CH3CN: 4,2 min 100%.

Compounds of formulas I, II and II specialist in this field can be obtained using methods similar to those described in this document.

Example 3

Analytical data

A number of other compounds of formula I are obtained by methods essentially similar to those described in this document. Typical characteristics is their data for these compounds are given in the table below and includes HPLC data, LC/MS (observed), retention time (vrad) and1H NMR. The numbers of the compounds correspond to the numbers of the compounds listed in this description.

Room connection.LC/MSVrod1H NMR
I-1420,103,10(500 MHz, DMSO-d6) 9,01 (c, 1H), to 8.41 (m, 1H), 7,97 (m, 1H), 7,68 (d, 1H), 7,65 (c, 2H), to 7.59 (d, 2H), 7.23 percent (d, 2H), 7,21 (m, 1H), 3,98 (d, 2H), 3,68 (t, 2H), 3,49 (d, 2H), 3,32 (m, 1H), 3.04 from (m, 2H), 2,85 (m, 1H), 2,11 (m, 2H), 1,89 (m, 2H), of 1.75 (m, 4H) ppm
I-2445,003,20(500 MHz, DMSO-d6) of 9.21 (c, 1H), to 8.41 (m, 1H), 7,98 (m, 1H), 7,73 (d, 1H), to 7.67 (m, 4H), 7,39 (d, 2H), 7,21 (m, 1H), to 3.58 (m, 4H), of 2.38 (m, 4H), of 2.25 (m, 3H), 1,89 (m, 4H), 1,72 (m, 2H) ppm
I-5484,003,20(DMSO-d6, 500 MHz) 9,24 (c, 1H), 8,42 (m, 1H), 7,98 (m, 1H), 7,71 (d, 1H), to 7.67 (m, 4H), 7,40 (d, 2H), 7,22 (m, 1H), 3,53 (m, 2H), or 3.28 (m, 1H), and 3.16 (m, 2H), 2,99 (m, 2H), 2,66 (d, 2H), 2,28 (m, 4H), 1.91 a (m, 3H), of 1.78 (m, 2H), 0,54 (m, 2H), 0,45 (m, 2H) ppm
I-6486,202,05DMSO-d6: 8,90 (c, 1H), 8,40 (m, 1H), 7,98 (who, 1H), to 7.75 (m, 1H), 7,65 (c, 2H), 7,50 (m, 2H), 7,20 (m, 1H), 7,10 (m, 2H), was 4.02 (c, 2H), 4,50 (m, 2H), and 4.40 (m, 2H), 2,60 (m, 1H), 2,45 (m, 4H), 2,22 (c, 1H), 2,1,85 (m, 4H), 1,50 (m, 4H)
I-7459,103,10(500 MHz, DMSO-d6) 9,00 (c, 1H), to 8.41 (m, 1H), 7,97 (m, 1H), 7,68 (d, 1H), 7,65 (c, 2H), 7,58 (d, 2H), 7,22 (m, 3H), 3,50 (m, 2H), 3,30 (m, 1H), is 3.08 (m, 2H), 2,98 (m, 2H), 2,85 (m, 1H), 2.63 in (m, 2H), 2,12 (m, 2H), 1,8 (m, 7H), and 0.50 (m, 2H), 0,39 (m, 2H) ppm
I-8419,201,54DMSO-d6: 8,95 (c, 1H), 8,40 (m, 1H), 7,95 (m, 1H), 7,68 (m, 1H), 7,60 (USS, 2H), 7,55 (m, 2H), 7,20 (m, 1H), 7,10 (m, 2H), 5,1 (ocess, 1H), 2,85 (m, 4H), 4,60 (m, 1H), 2,50 (m, 4H), of 2.20 (m, 1H), 1,90 (m, 2H), 1,80 (m, 2H), 1,45 (m, 4H)
I-9459,103,10(500 MHz, DMSO-d6) 8,98 (c, 1H), 8,40 (m, 1H), 7,97 (m, 1H), 7,68 (d, 1H), to 7.64 (c, 2H), 7,53 (d, 2H), 7,19 (m, 1H), to 7.09 (d, 2H), of 3.45 (m, 2H), 3,26 (m, 1H), 3,10 (m, 2H), 2,99 (m, 2H), 2.63 in (m, 3H), of 2.15 (m, 2H), 1.93 and (d, 2H), is 1.81 (m, 1H), 1,50 (m, 4H), and 0.50 (m, 2H), 0,39 (m, 2H) ppm
I-10447,201,74MeOH-d4: to 8.40 (m, 1H), of 7.90 (m, 1H), to 7.75 (m, 1H), 7,50 (m, 2H), to 7.15 (m, 3H), 3,5-2,5 (m, 10H), 2.0 (m, 4H), to 1.70 (m, 4H), of 1.30 (t, 3H)
I-11418,002,20(50 MHz, DMSO-d6) 8,98 (c, 1H), 8,42-8,39 (m, 1H), 8,00-to 7.93 (m, 1H), 7,73-to 7.59 (m, 3H), 7,56 (d, 2H), 7.24 to 7,16 (m, 1H), 7,11 (d, 2H), 3,40 (d, 2H), 3,29-3,17 (m, 1H), 3,05-only 2.91 (m, 2H), 2,45 (m, 1H), 2,11 (m, 2H), 1.93 and (d, 2H), 1,85 (d, 2H), 1,76 is 1.34 (m, 8H) ppm
I-12483,003,10(500 MHz, DMSO-d6) 8,93 (c, 1H), 7,94 (d, 2H), 7,79 (d, 2H), of 7.48 (d, 2H), was 7.08 (d, 2H), 6.73 x (c, 2H), 3,44 (m, 2H), 3,25 (m, 2H), 3,05 (m, 2H), 2,98 (m, 1H), 2,58 (m, 2H), 2,42 (m, 1H), 2,15 (m, 2H), 1,92 (m, 2H), 1,75 (m, 1H), 1,53 (m, 4H), of 0.47 (m, 2H), 0,35 (m, 2H) ppm
I-13561,102,00DMSO-d6: or 10.60 (USS, 1H); 9,10 (USS, 1H); scored 8.38 (d, 1H); 7,80-8,20 (USS, 2H); of 7.48 (d, 2H); 7,30 (m, 2H); 6,62 (m, 1H); 3,30-4,10 (m, 15H); 3,00 (m, 2H); 2,78 (m, 1H); of 2.20 (m, 2H); 1,62-to 1.98 (m, 11H)
I-14586,102,00DMSO-d6: 9,35 (c, 1H); 9,20 (USS, 1H); 8,35 (d, 1H); 7,78 (USS, 2H); of 7.70 (d, 2H); of 7.48 (d, 2H); 6,62 (d, 1H); 3,50-4,00 (m, 10H); 3,40-to 3.50 (m, 5H); 3,00 (m, 2H); 2,72 (m, 2H); 1,75-of 2.15 (m, 9H); of 1.52 (m, 2H)
I-15586,102,00DMSO-d6: 9,73 (USS, 1H); 9.28 are (c, 1H); 8,35 (d, 1H); 7,76 (USS, 2H); a 7.62 (d, 2H); to 7.35 (d, 2H); 6,62 (d, 1H); 3,55-4,08 (m, 10H); 3.25 to 3,55 (m, 5H); 3.15 in (m, 2H); 2,32 (m, 4H); 1,75-of 2.15 (m, 9H)
I-16561,10 DMSO-d6: 9,60 (USS, 1H); 9,05 (c, 1H); 8,35 (d, 1H); 7,78 (USS, 2H); 7,50 (d, 2H); was 7.08 (d, 2H); 6,60 (d, 1H); 3,50-4,10 (m, 11H); to 3.45 (m, 4H); of 3.25 (m, 1H); 3.15 in (m, 2H); 2,12 (m, 2H); 1.70 to 2,00 (m, 7H); 1,50 (m, 4H)

Example 4

Inhibition of FLT-3

Compounds are screened for the ability to inhibit the activity of FLT-3 using radiometric analysis of binding to the filter. This analysis allows to register the inclusion of33P in the substrate poly(Glu, Tyr) 4:1 (pE4Y). The analyses carried out in a solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mm DTT, 0.01% BSA and 2.5% DMSO. The final substrate concentration in the reaction mixture is 90 μm for ATP and 0.5 mg/ml for pE4Y (both receive from Sigma Chemicals, St Louis, MO). The final concentration of the compound is usually in the range from 0.01 to 5 μm. Normally have a 12-point titration by making serial dilutions from 10 mm initial solution of test compound in DMSO. The reaction was performed at room temperature.

Get two analytical solution. Solution 1 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mg/ml pE4Y and 180 μm ATP (containing 0.3 µci [γ-33P]ATP in each reaction mixture). Solution 2 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT, 0.02% BSA and 3 nm FLT-3. The analysis is performed in 96-well tablet by mixing 50 μl of solution 1 and 2.5 μl of the solution under test connection is possible. The reaction is initiated by adding a solution of 2. After incubation for 20 minutes at room temperature the reaction is stopped by adding 50 μl of 20% trichloroacetic acid containing 0.4 mm ATP. Then all of the reaction mixture is transferred on a filter pad and washed with 5% THU by using Harvester9600 from TOMTEC (Hamden, CT). The number of33P included in pE4y, measured with a scintillation counter for microplate Packard TopCount (Meriden, CT). The results processed using the software Prism, the receiving IC50or Ki.

The compounds of this invention effectively inhibit FLT-3.

Example 5

Inhibition of c-KIT

Compounds are screened for the ability to inhibit the activity of c-KIT using radiometric analysis of binding to the filter. This analysis allows to register the inclusion of33P in the substrate poly(Glu, Tyr) 4:1 (pE4Y). The analyses carried out in a solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mm DTT, 0.01% BSA and 2.5% DMSO. The final substrate concentration in the reaction mixture is 700 µm for ATP and 0.5 mg/ml for pE4Y (both receive from Sigma Chemicals, St Louis, MO). The final concentration of the compound is usually in the range from 0.01 to 5 μm. Normally have a 12-point titration by making serial dilutions from 10 mm initial solution of test compound in DMSO. Reaction p is avodat at room temperature.

Get two analytical solution. Solution 1 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mg/ml pE4Y and 1.4 mm ATP (containing 0.5 µci [γ-33P]ATP in each reaction mixture). Solution 2 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT, 0.02% BSA, and 25 nm c-KIT. The analysis is performed in 96-well tablet by mixing 33 μl of solution 1 and of 1.65 μl solution of the test compound. The reaction is initiated by addition of 33 μl of solution 2. After incubation for 20 minutes at room temperature the reaction is stopped by adding 50 μl of 10% trichloroacetic acid containing 0.2 mm ATP. Then all of the reaction mixture is transferred on a filter pad and washed with 5% THU by using Harvester9600 from TOMTEC (Hamden, CT). The number of33P included in pE4y, measured with a scintillation counter for microplate Packard TopCount (Meriden, CT). The results processed using the software Prism, the receiving IC50or Ki.

The compounds of this invention effectively inhibit c-KIT.

Example 6

Inhibition of GSK-3

Compounds are screened for the ability to inhibit the activity of GSK-3β (AA 1-420)using standard solid-phase enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). The reaction is carried out in solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 300 μm NADH, 1 mm DTT and 1.5% DMSO. The final substrate concentration in the reaction, see the si is 20 µm for ATP (Sigma Chemicals, St Louis, MO) and 300 μm for peptide (American Peptide, Sunnyvale, CA). The reaction is carried out at 30°C and the concentration of GSK-3β 20 nm. The final concentration of the components of solid-phase enzyme system were 2.5 mm for phosphoenolpyruvate, 300 μm for NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

Get the source buffer solution for analysis, containing all of the above reagents except for ATP and test the connection. The original buffer solution for assay (175 μl) are incubated in 96-well-plate with 5 μl of the test compounds, the final concentration is in the range from 0.002 μm to 30 μm at 30°C for 10 minutes As a rule, 12-point titration is carried out by preparation of serial dilutions (starting at 10 mm initial solution of compound) of the test compounds in DMSO in the child tablets. The reaction is initiated by adding 20 μl of ATP (final concentration 20 μm). The reaction rate is determined using the tablet reader (Molecular Devices Spectramax (Sunnyvale, CA) for 10 min at 30°C. the Ki Values determined on the basis of the value of the velocity as a function of the concentration of the inhibitor.

The compounds of this invention effectively inhibit GSK-3.

Example 7

Inhibition of CDK-2

Compounds are screened for the ability to inhibit the activity of CDK-2/cyclin a using standard solid-phase farm is private analysis (Fox et al. (1998) Protein Sci. 7, 2249). The analyses carried out in a solution containing 100 mm HEPES pH 7.5, 10 mm MgCl2, 25 mm NaCl, 1 mm DTT and 1.5% DMSO. The final substrate concentration in the reaction mixture up to 100 µm for ATP (Sigma Chemicals) and 100 μm for peptide (American Peptide, Sunnyvale, CA). The reaction is carried out at 30°C and the concentration of CDK-2/cyclin a 25 nm. The final concentration of the components of solid-phase enzyme system were 2.5 mm for phosphoenolpyruvate, 350 μm for NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

Get the source buffer solution for analysis, containing all of the above reagents except CDK-2/cyclin a, DTT and test the connection. 56 μl of the test reaction mixture is placed in a 384-well plate, then add 1 ál of 2 mm initial solution of test compound in DMSO (final concentration 30 μm). The tablet is pre-incubated for ~10 minutes at 30°C and then the reaction is initiated by adding 10 μl of enzyme (final concentration 25 nm). The reaction rate is determined using the tablet reader (BioRad Ultramark (Hercules, CA) during a read time of 5 minutes at 30°C. values of Kidefine standard methods.

The compounds of this invention effectively inhibit CDK-2.

Example 8

Inhibition of SRC

Compounds examined for the ability to inhibit the activity of human is coy kinase Src, using either analysis, based on the measurement of radioactivity, or spectrophotometric analysis.

Analysis of A inhibition of Src: Analysis based on measurement of radioactivity

Compounds examined for the ability to inhibit full-size recombinant human Src kinase (Upstate Biotechnology, catalog No. 14-117), expressed in cells infected with baculovirus, and isolated from these cells. The activity of Src kinase is determined by measuring the incorporation33P from ATP to tyrosine statistical polymer substrate Glu-Tyr ratio Glu:Tyr = 4:1 (Sigma, catalog No. P-0275). The components of the analytical mixture have the following final concentrations: 0,05M HEPES, pH of 7.6, 10 mm MgCl2, 2 mm DTT, 0.25 mg/ml BSA, 10 μm ATP (1-2 µci33P-ATP in each reaction mixture), 5 mg/ml Glu-Tyr and 1-2 units of recombinant human Src kinase. In the standard analysis of all components of the reaction mixture except for ATF are pre-mixed and portions are inserted in holes analytical tablet. In wells add inhibitors dissolved in DMSO, getting the final concentration of DMSO of 2.5%. Analytical tablet incubated at 30°C for 10 min, then initiate the reaction by adding33P-ATP. After 20 min the reaction is quenched using 150 μl of 10% solution of trichloroacetic acid (THU)containing 20 mm Na3PO4Then the samples are transferred into a 96-well filter tablet (Whatman, UNI-Filter GF/F Glass Fiber Filter, catalog No. 7700-3310 inserted into the vacuum manifold to the filter plates. Filter plates are washed four times with 10% trichloroacetic acid containing 20 mm Na3PO4and then 4 times with methanol. Then to each well add 200 μl of scintillation fluid. Tablets are close and using a TopCount scintillation counter consider the amount of radioactivity associated with the filters. Build a dependency graph included radioactivity concentration of the inhibitor. The data fit to a kinetic model of competitive inhibition, receiving values of Kifor each connection.

Analysis B inhibition of Src: spectrophotometric analysis

The number of ATP derived from ATP in the phosphorylation of the substrate Glu-Tyr catalyzed by human recombinant Src kinase, is determined using solid-phase enzyme assay (Fox et al., (1998) Protein Sci. 7, 2249). In this analysis, one molecule of NADH is oxidized to NAD, each molecule of ADP formed in the kinase reaction. Reducing the number of NADH can be monitored at 340 nm.

The components of the analytical mixture have the following final concentrations: 0,025M HEPES, pH of 7.6, 10 mm MgCl2, 2 mm DTT, 0.25 mg/ml Glu-Tyr, and 25 nm of recombinant human Src kinase. The final concentration of the components of solid-phase enzyme is istemi be 2.5 mm for phosphoenolpyruvate, 200 μm for NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

In the standard analysis of all components of the reaction mixture except for ATF are pre-mixed and portions are inserted in holes analytical tablet. In wells add inhibitors dissolved in DMSO, getting the final concentration of DMSO of 2.5%. Analytical tablet incubated at 30°C for 10 min, then initiate the reaction by addition of 100 μm ATP. The change in absorption at 340 nm with time and the reaction rate is measured using a tablet reader (molecular devices. Velocity values as a function of the concentration of inhibitor fit to the kinetic model of competitive inhibition, receiving values of Kifor each connection.

The compounds of this invention effectively inhibit the SRC.

Example 9

Inhibition of SYK

Compounds are screened for the ability to inhibit the activity of SYK using standard solid-phase enzyme assay (Fox et al. (1998) Protein Sci. 7, 2249). The analyses carried out in a solution containing 100 mm HEPES, pH 7.5, 10 mm MgCl2, 25 mm NaCl, 1 mm DTT and 1.5% DMSO. The final substrate concentration in the reaction mixture is 200 µm for ATP (Sigma Chemicals, Co.) and 4 μm for peptide Gly-Tyr (Sigma Chemicals, Co.). Tests conducted at 30°C and the concentration of SYK 200 nm. The final concentration of the components of solid-phase enzyme the system is 2.5 mm for phosphoenolpyruvate, 300 μm for NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

Get the source buffer solution for analysis, containing all of the above reagents except SYK, DTT and test the connection. 56 μl of the test reaction mixture is placed in a 96-well plate, then add 1 ál of 2 mm initial solution of test compound in DMSO (final concentration 30 μm). The tablet is pre-incubated for ~10 minutes at 30°C and then the reaction is initiated by adding 10 μl of enzyme (final concentration 25 nm). The reaction rate is determined using the tablet reader (BioRad Ultramark (Hercules, CA) during a read time of 5 minutes at 30°C using standard methods to determine the values of Ki.

The compounds of this invention effectively inhibit SYK.

Example 10

Inhibition of FMS

Compounds are screened for the ability to inhibit the activity of FMS using radiometric analysis of binding to the filter. This analysis allows to register the inclusion of33P in the substrate poly(Glu, Tyr) 4:1 (pE4Y). The reaction is carried out in solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mm DTT, 0.01% BSA and 2.5% DMSO. The final substrate concentration in the reaction mixture is 90 μm for ATP and 0.5 mg/ml for pE4Y (both receive from Sigma Chemicals, St Louis, MO). The final concentration with the organisations is usually in the range from 0.01 to 5 μm. Normally have a 12-point titration by making serial dilutions from 10 mm initial solution of test compound in DMSO. The reaction was performed at room temperature.

Get two analytical solution. Solution 1 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mg/ml pE4Y and 180 μm ATP (containing 0.3 µci [γ-33P]ATP in each reaction mixture). Solution 2 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT, 0.02% BSA and 3 nm FMS. The analysis is performed in 96-well tablet by mixing 50 μl of solution 1 and 2.5 μl of a solution of test compounds. The reaction is initiated by adding a solution of 2. After incubation for 20 minutes at room temperature the reaction is stopped by adding 50 μl of 20% trichloroacetic acid containing 0.4 mm ATP. Then all of the reaction mixture is transferred on a filter pad and washed with 5% THU by using Harvester9600 from TOMTEC (Hamden, CT). The number of33P included in pE4y, measured with a scintillation counter for the microplate Packard TopCount (Meriden, CT). The results processed using the software Prism, the receiving IC50or Ki.

The compounds of this invention effectively inhibit FMS.

Example 11

Analysis of inhibition of Rock

Compounds are screened for the ability to inhibit the activity of ROCK I (AA 6-553)using standard cordobazo the enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). The reaction is carried out in solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT and 1.5% DMSO. The final substrate concentration in the reaction mixture is 45 µm for ATP (Sigma Chemicals, St Louis, MO) and 200 μm for peptide (American Peptide, Sunnyvale, CA). The reaction is carried out at 30°C and the concentration of ROCK I 45 nm. The final concentration of the components of solid-phase enzyme system were 2.5 mm for phosphoenolpyruvate, 350 μm for NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

I found that some of the compounds of this invention inhibit ROCK.

Example 12

Analysis of inhibition of JAK3

The ability of compounds to inhibit JAK analyzed according to the method described G.R. Brown, et al., Bioorg. Med. Chem. Lett. 2000, vol. 10, pp 575-579 as follows. In tablets Maxisorb, pre-coated at 4°C poly(Glu, Ala, Tyr) 6:3:1 and then washed with phosphate buffered saline solution of 0.05% tween (PBST), add 2 μm ATP, 5 mm MgCl2and the solution of the compound in DMSO. The reaction is initiated by adding enzyme JAK and tablets incubated for 60 minutes at 30°C. Then the tablets washed with PBST, add 100 ál of HRP-conjugated antibody 4G10 and incubated for 90 minutes at 30°C. the plate again washed with PBST, add 100 ál of TMB solution, and incubated another 30 minutes at 30°C. to stop the reaction, add sulfuric acid (100 μl of 1M solution), Lancet read at 450 nm and get the values of optical density, which are used to determine the values of Ki.

The compounds of this invention effectively inhibit JAK-3.

Example 13

Analysis of inhibition of PDK-1

Compounds are screened for the ability to inhibit the activity of PDK-1 by analyzing the inclusion of radioactive phosphate (Pitt and Lee, J. Biomol. Screen., (1996) 1, 47). The analyses carried out in a solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT. The final substrate concentration in the reaction mixture is 40 µm for ATP (Sigma Chemicals) and 65 μm for peptide (PDKtide, Upstate, Lake Placid, NY). The reaction is carried out at 30°C and the concentration of PDK-1 to 25 nm in the presence of ~27,5 NCI/ál [γ-32P]ATP (Amersham Pharmacia Biotech, Amersham, UK). Get the source buffer solution for analysis, containing all of the above reagents except for ATP and test the connection. 15 ál of solution placed in a 96-well plate, then add 1 ál of 0.5 mm initial solution of test compound in DMSO (final concentration 25 μm, final concentration of DMSO 5%). The tablet is pre-incubated for approximately 10 minutes at 30°C and then the reaction is initiated by adding 4 μl of ATP (final concentration of 40 nm).

The reaction is stopped after 10 minutes by adding 100 μl of 100 mm phosphoric acid, 0.01% tween-20. Phosphocellulose 96-well plate (Millipore, catalog No. MAPHNOB50) the seat reservation process 100 ál of 100 mm phosphoric acid, 0.01% tween-20, then add the reaction mixture (100 μl). Spots leave to soak for at least 5 minutes, then washed (4×200 μl of 100 mm phosphoric acid, 0.01% tween-20). After drying, the wells, add 20 μl of scintillation mixture Optiphase 'SuperMix' (Perkin Elmer), and consider the scintillation liquid scintillation counter 1450 Microbeta, Wallac).

Compounds showing greater than 50% inhibition versus standard wells containing the analytical mixture and DMSO without test compound, titrated to determine the values of the IC50.

The compounds of this invention effectively inhibit PDK-1.

The authors described a number of embodiments of the present invention, however, it is clear that the basic examples can be modified for other embodiments, which can be applied compounds and methods of the present invention. Thus, it should be understood that the scope of the present invention is largely determined by the attached claims than the specific embodiments above as an illustration.

1. The compound of formula (I):

X represents N;
Y denotes CH2, NH, NR or 0;
each of R1and R2denotes hydrogen;
R3denotes phenyl, substituted by-CN, 6-membered heteroaryl containing 1-2 nitrogen atom, not necessarily for ewenny 7-membered heterocyclyl, containing 2 nitrogen atom, which, in turn, substituted C1-6alkylcarboxylic;
R4denotes hydrogen;
R5denotes hydrogen or -- CN; and
R denotes a1-6alkyl group, a C1-6alkylcarboxylic group substituted by-CN, or C3-6cycloalkyl group.

2. The compound according to claim 1, where Y represents O.

3. The compound according to claim 1, where Y represents NR.

4. The compound according to claim 1, where R3denotes a 6-membered heteroaryl group containing 1 or 2 heteroatoms of nitrogen.

5. The compound according to claim 1, where R3represents 2-pyridyl.

6. The compound according to claim 1, having the formula (I-b) or (I-c):
.

7. The compound according to claim 1, where the specified connection selected from the group consisting of:

.

8. The compound according to claim 1, where the specified connection selected from the group consisting of



.

9. The compound according to claim 1, which is selected from the group consisting of

10. Method of inhibiting kinase activity of FLT-3 or c-KIT protein kinases in a biological sample, comprising a stage of bringing into contact of the specified biological sample with a compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt.

11. The use of compounds according to claims 1 to 9 to obtain drugs for treating or reducing the severity of acute myelogenous leukemia.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 4-substituted 3-(3-dialkylaminomethyl-indol-1-yl)maleimide derivatives of general formula

and ,

where: X1-X4 denote C; Z denotes H; R1 denotes alkyl, H, -(CH2)3-N-(C2H5)2; R2 and R3 denote alkyl, or together with the nitrogen atom to which they are bonded form a C4-7-monocyclic ring containing 1 or 2 heteroatoms, selected from O and N, possibly substituted with an alkyl; R4 denotes H; Y denotes S, -N-(C2H5); where in formula I compounds R5 and R6 together with the nitrogen atom to which they are bonded form a C9-10 a condensed bicyclic ring containing an N heteroatom, possibly substituted with R, where R denotes -N-(R2)-R3; in formula II compounds R5 denotes phenyl, optionally substituted with OCH3.

EFFECT: obtaining new compounds which can be used as protein kinase inhibiting agents.

2 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

Chemical method // 2386636

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.

EFFECT: design of an efficient method of obtaining the said compound.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3,3'-bis-(3,4-dihydro-3-phenyl-2H-1,3-benzoxazin-6-yl)-1(3H)-isobenzofuranone and analogues based on phenolphthalein, formaldehyde and a primary amine of formula 1: , in which R independently represents allyl or phenyl, and to a method of synthesising the said compounds. The invention also pertains to a method of making a refractory cast or layered material based on the said compounds and laminating compositions since through thermal hardening, these compounds form a net which does not catch fire easily and is resistant to high temperatures. The said compounds can be particularly useful in making printed circuit boards.

EFFECT: obtaining fire-resistant compounds.

5 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula , where X, R1, R2, R3, R4 and R5 assume values given in the description and paragraphs of the formula of invention, and their pharmaceutically acceptable salts.

EFFECT: compounds have antagonistic activity on histamine receptor 3 (H3).

25 cl, 3 tbl, 215 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-phenylpyrimidine-2-carbonitrile of formula

(values of R, R1, R2 are given in the formula of invention) or their pharmaceutically acceptable salts which have inhibition properties towards catepsin K and catepsin S. The invention also relates to use of derivatives of formula I for treating catepsin K and catepsin S related disorders, as well as to a pharmaceutical composition containing the said derivative.

EFFECT: improved properties of derivatives.

9 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a combined product containing compounds of formula (I): where: R1 and R2 represent CF3; R3 and R4 represent fluoro; R5 and R6 represent hydrogen; R7 presents Cl, X represents CR8, where R8 represents Cl; and R9 represents NH2; or its veterinary acceptable salt, and b) doramectin. The invention also relates to an antiparasitic veterinary composition based on the said combined product.

EFFECT: obtaining a combined product which can be used in veterinary for treating parasitic infections in mammals.

4 cl, 1 dwg, 1 tbl, 37 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: medicine.

SUBSTANCE: there is described new compound - choline salt 2-(3,4-dimethylphenyl)-4-{[2-hydroxy-3'-(1H-tetrazole-5-yl)biphenyl-3-yl]hydrazono}-5-methyl-2,4-dihydropyrazole-3-one, a pharmaceutical composition containing it, and method for making said composition.

EFFECT: new compound is an improved thrombopoietin mimetic and can be used as a TRO-receptor agonist.

3 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

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