Some chemical structures, compositions and methods

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

 

In this application the benefit of the priority claimed in respect of provisional applications U.S. serial No. 61/009971, filed January 4, 2008; 61/194294, filed September 26, 2008, and 61/201146, filed December 5, 2008, and at the same time pending application number 35280-714.602 in the register of patent attorneys, filed herewith, each of which is hereby incorporated in its entirety by reference.

PRIOR to the INVENTION of the LEVEL of TECHNOLOGY

The activity of the cells can be regulated by external signals that stimulate or inhibit intracellular events. The process by which a stimulating or inhibiting signals are transmitted into the cell and inside the cell to cause an intracellular response, called signal transduction. In recent decades have been identified cascades of events in signal transduction, and found that they play a Central role in many biological responses. Found that violations of the various components of signal transduction pathways cause a large number of diseases, including many forms of cancer, inflammatory disorders, metabolic disorders, vascular and nervous diseases (Gaestel et al. Current Medicinal Chemistry(2007) 14: 2214-2234).

Kinases are an important class of signaling molecules. Kinases in General, you can divide the on protein kinases and lietkynes, and some kinases exhibit dual specificity. Protein kinases are enzymes that phosphorylate other proteins and/or themselves (i.e., autophosphorylation). Protein kinases in General can be divided into three main groups based on their substrate: tyrosine kinase that is predominantly phosphorylate substrates on tyrosine residues (for example, erb2, PDGF receptor (growth factor from platelets), the receptor for EGF (epidermal growth factor), VEGF receptor (growth factor vascular endothelial), src, abl), serine/trionychinae, which preferentially phosphorylate substrates on residues of serine and/or threonine (for example, mTorC1 (complex 1 target of rapamycin in mammals), mTorC2, ATM (mutated gene for ataxia-telangiectasia), ATR (modified ataxia-telangiectasia and Rad3 related), and DNA-PK (activated DNA protein kinase), Akt (protein kinase B)) and kinases with dual specificity, which phosphorylate substrates on tyrosine residues, serine and/or threonine.

Lietkynes are enzymes that catalyze the phosphorylation of lipids. These enzymes and the resulting phosphorylated lipids and originating from lipids of biologically active organic molecules play a role in many different physiological processes, including cell proliferation, migration,adhesion and differentiation. Some lietkynes are associated with the membrane and catalyze the phosphorylation of lipids contained in cell membranes or associated with cellular membranes. Examples of such enzymes include phosphoinositide-kinases such as PI3 (phosphatidylinositol-3)-kinase, R-kinase), diacylglycerols and sphingosines.

Signaling pathway involving phosphoinositide-3-kinase (PI3K) is one of the systems that are most susceptible to mutations in various cancers in humans. Also the transmission of the signal through PI3K is a key factor in many other diseases in humans. The process of transmission of the signal through PI3K is involved in many painful conditions, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive lung disorder, psoriasis, multiple sclerosis, asthma, disorders associated with complications of diabetes and inflammatory complications of the cardiovascular system, such as acute coronary syndrome.

PI3K are members of a unique and conservative family of intracellular lietkynes, which phosphorylate group 3'-Oh of phosphatidylinositol or phosphoinositides. RK-family contains 15 kinases with different substrate specificnosti, paintings of expression and sposobamiraboty (Katso et al., 2001). PI3K class I (p110α, p110β, p110δ and 110γ) are normally activated by tyrosine kinases or G-protein-coupled receptors with getting RR (phosphatidylinositol-triphosphate), which involves downstream "downstream effectors, such as effectors in the way Akt/PDK1 (Akt/phosphoinositide-dependent kinase-1), mTOR, a kinase of the TEC family and Rho GTPase family. P13-kinase class II and III play a key role in intracellular signal through the synthesis of PI(3)P (phosphatidylinositol-3-phosphate) and PI(3, 4)P2 (phosphatidylinositol-3,4-phosphate). PIKK (phosphatidylinositides) are protein kinases that regulate cell growth (mTORd) or monitor the integrity of the genome (ATM, ATR, DNA-PK, and hSmg-1).

Isoform Delta (δ) PI3K class I is involved, in particular, in a number of diseases and biological processes. PI3Kδ is expressed mainly in hematopoietic cells, including leukocytes such as T cells, dendritic cells, neutrophils, mast cells, b cells and macrophages. PI3Kδ involved as an integral part of such functions of the immune system of mammals, as function of T cells, activation of b-cells, activation of mast cells, the function of dendritic cells and the activity of neutrophils. Due to its integral role in the functioning of the immune system, PI3Kδ also involved in a number of diseases associated with unwanted immune response, so the x as allergic reactions, inflammatory diseases mediated inflammation, angiogenesis, rheumatoid arthritis, autoimmune diseases, such as ordinary erythematosus, asthma, emphysema and other respiratory diseases. Other PI3K class I, involved in the functioning of the immune system, includes I3γ, which plays a role in the signal transmission of leukocytes and are involved in inflammation, rheumatoid arthritis and autoimmune diseases, such as ordinary lupus.

Picks below the "downstream" in RC-path signal transduction include Akt and target of rapamycin in mammals (mTOR). Akt contains pleckstrin-homology (PH) domain that binds to PIP3, which causes activation of Akt kinase. Akt phosphorylates many substrates and is a Central downstream "downstream" effector of PI3K to obtain a variety of cellular responses. One of the important functions of Akt is to increase the activity of mTOR through phosphorylation TS(complex tuberose sclerosis) 2 and other mechanisms. mTOR is a serine-trionychinae related libidinal RC family. mTOR is involved in a wide range of biological processes, including cell growth, cell proliferation, motility and survival of cells. It was reported dysregulation of mTOR-pathway in various types of cancer. mTOR is a multifunctional Keene is, which integrates signals from growth factors and nutrients for regulation of translation protein, nutrient consumption, autophagy and mitochondrial function.

Essentially, kinases, in particular RK, are the most important targets for drug development. There remains a need for inhibitors RC suitable for drug development. The present invention is directed to satisfying this need and provides appropriate benefits, including by offering new classes of inhibitors of kinases.

The INVENTION

In the first aspect of the proposed invention the compounds of formula 1 or their pharmaceutically acceptable salts, where

Wa1represents CR3or N; Wa2represents CR5or N; Wa3represents CR6or N; Wa4represents N or CR7; Wb5represents CR8, CHR8or N, where not more than two adjacent atoms in the ring selected from Wa1, Wa2, Wa3, Wa4and Wb5represent heteroatoms. Wd is heteroseksualci, aryl or heteroaryl. In represents alkyl, amino, heteroalkyl, cycloalkyl is, heteroseksualci or a group of formula II,

,

where Wcrepresents aryl, heteroaryl, heteroseksualci or cycloalkyl, and q is an integer 0, 1, 2, 3 or 4. X is absent or represents -(CH(R9))z- and in each case z independently is an integer 1, 2, 3 or 4. Y is absent, represents-O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(=O)-(CHR9)z-, -C(=O)-, -N(R9)-C(=O) -, or-N(R9)-C(=O)NH-, -N(R9)C(R9)2- or-C(=O)-(CHR9)z-; where, when Wb5represents N, not more than one of X or Y is missing. R1represents hydrogen, alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate. R2represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate. R3represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, alkoxy, amido, amino, acyl, acyloxy, sulfonamide, halogen, cyano, is hydroxy or nitro. R5, R6, R7and R8independently represent hydrogen, C1-C4alkyl, C2-C5alkenyl,2-C5quinil,2-C5cycloalkyl, heteroseksualci,1-C4heteroalkyl,1-C4alkoxy, C1-C4amido, amino, acyl, C1-C4acyloxy,1-C4sulfonamide, halogen, cyano, hydroxy or nitro. In each case, R9independently represents hydrogen, C1-C10alkyl, C3-C7cycloalkyl or2-C10heteroalkyl.

In another aspect of the invention proposed the compounds of formula IX, or their pharmaceutically acceptable salts, where

Wa1and Wa2independently represent CR5, S, N or NR4and Wa4independently represents CR7, S, N or NR4where not more than two adjacent atoms in the ring are nitrogen or sulfur, and where Wa1is a S, one of Wa2and Wa4represents N or NR4. Wb5represents CR8, N or NR8. In represents alkyl, amino, heteroalkyl, cycloalkyl, heteroseksualci or a group of formula II:

,

where Wcrepresents Ari is, heteroaryl, heteroseksualci or cycloalkyl, and q is an integer 0, 1, 2, 3 or 4. Wdabsent or represents geterotsyklicescoe, aryl or heteroaryl group. X is absent or represents -(CH(R9))z- and in each case z independently is an integer 1, 2, 3 or 4. Y is absent, represents-O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(=O)-(CHR9)z, -C(=O)-, -N(R9)-C(=O) -, or-N(R9)-C(=O)NH-, --N(R9)C(R9)2- or-C(=O)-(CHR9)z-. R1represents hydrogen, alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate. R2represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate. R3represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, alkoxy, amido, amino, acyl, acyloxy, sulfonamide, halogen, cyano, hydroxy or nitro. R4represents hydrogen, acyl, C1-C4alkyl, C2-C5 alkenyl,2-C5quinil,3-C5cycloalkyl or1-C4heteroalkyl; R5, R7and R8independently represent hydrogen, C1-C4alkyl, C2-C5alkenyl,2-C5quinil,3-C5cycloalkyl,1-C4heteroalkyl, acyl, C1-C4alkoxy, C1-C4amido, amino, C1-C4acyloxy,1-C4sulfonamide, halogen, cyano, hydroxy or nitro. In each case, R9independently represents hydrogen, C1-C10alkyl, C3-C7cycloalkyl or2-C10heteroalkyl.

In some embodiments, the compound of formula I has the structure of formula IV:

.

In some embodiments, the compound of formula IV is a compound of formula V or VI:

or.

In some embodiments, the compound of formula VI has the structure of formula VI-A:

In some embodiments of compounds of formula VI-A R11represents amino. In some embodiments of compounds of formula VI-A R12represents alkyl, alkenyl, quinil, heteroaryl, aryl, heteroseksualci, cyano, amino, carboxylic acid or amido. In some embodiments of compounds of formula I-A R 12represents a monocyclic heteroaryl or bicyclic heteroaryl.

In some embodiments of compounds of formula VI is a compound has the structure of formula VI-C:

In some embodiments of formula VI compound has the structure of formula VI-D:

In another aspect of the invention proposed compound or its pharmaceutically acceptable salt having the structure of formula VI, where: represents alkyl, amino, heteroalkyl or a group of formula II, where We represents aryl, heteroaryl, heteroseksualci or cycloalkyl, and q is an integer 0, 1, 2, 3, or 4; X is absent or represents -(CH(R9))z-, and z independently is an integer 1, 2, 3 or 4; Y is absent, represents-N(R9)- or-N(R9)-CH(R9)-; Wdrepresents:

or;

R1represents hydrogen, alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate; R2represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroa the sludge, heteroallyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, or phosphate;

R3represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, aryl or heteroaryl; in each case, R9independently represents hydrogen, C1-C10alkyl, C3-C7cycloalkyl, heteroseksualci or2-C10heteroalkyl; and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl or amido.

In some embodiments, the compound of formula VI has the structure of formula 6-a:

In some embodiments, the compound of formula VI has the structure of formula 6-S1:

In some embodiments, the compound of formula VI has the structure of formula 6-C2:

In some embodiments, the compound of formula VI has the structure of formula 6-D:

In some embodiments, the compound of formula I has the structure of formula VII:

.

In some embodiments, the compound of formula 1 has the structure the PN formula VIII:

,

where X is absent, a Y represents-O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(=O)-(CHR9)z-, -C(=O)-, -N(R9)(C=O) -, or-N(R9)(C=O)NH-; or X represents -(CH(R9))z-, a Y is absent; or X represents -(CH(R9))z-, and Y represents-O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(=O)-(CHR9)z, -C(=O)-, -N(R9)-C(=O)-, or-N(R9)-C(=O)NH-, -N(R9)C(R9)2-, or-C(=O)-(CHR9)z. In each case z independently is an integer 1, 2, 3 or 4. Wdis a bicyclic aryl or bicyclic heteroaryl.

In some embodiments of compounds of formula IX this compound has a structure which is a member of the group consisting of: (1) Wa1represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents CR8; (2) Wa1represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents CHR8; (3) Wa1represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents N; (4) Wa1 represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents NR8; (5) Wa1represents NR4, Wa2represents N, Wa4represents CR7and Wb5represents CR8; (6) Wa1represents NR4, Wa2represents N, Wa4represents CR7and Wb5represents CHR8; (7) Wa1represents NR4, Wa2represents N, Wa4represents CR7and Wb5represents N; (8) Wa1represents NR4, Wa2represents N, Wa4represents CR7and Wb5represents NR8; (9) Wa1represents NR4, Wa2represents CR5, Wa4represents N, and Wb5represents CR8; (10) Wa1represents NR4, Wa2represents CR5, Wa4represents N, and Wb5represents CHR8; (11) Wa1represents the t a NR 4, Wa2represents CR5, Wa4represents N, and Wb5represents N; (12) Wa1represents NR4, Wa2represents CR5, Wa4represents N, and Wb5represents NR8; (13) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5represents CR8; (14) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5represents CHR8; (15) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5represents N; (16) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5represents NR8; (17) Wa1represents N, Wa2represents CR5, Wa4represents S, and Wb5represents CR8; (18) Wa1represents N, Wa2represents CR5, Wa4before the hat is S, and Wb5represents CHR8; (19) Wa1represents N, Wa2represents CR5, Wa4represents S, and Wb5represents N; (20) Wa1represents N, Wa2represents CR5, Wa4represents S, and Wb5represents NR8; (21) Wa1represents CR5, Wa2represents N, Wa4represents S, and Wb5represents CR8; (22) Wa1represents CR5, Wa2represents N, Wa4represents S, and Wb5represents CHR8; (23) Wa1represents CR5, Wa2represents N, Wa4represents S, and Wb5represents N; (24) Wa1represents CR5, Wa2represents N, Wa4represents S, and Wb5represents NR8; (25) Wa1is a S, Wa2represents N, Wa4represents CR7and Wb5represents CR8; (26) Wa1isone S, Wa2represents N, Wa4represents CR7and Wb5represents CHR8; (27) Wa1is a S, Wa2represents N, Wa4represents CR7and Wb5represents N; (28) Wa1is a S, Wa2represents N, Wa4represents CR7and Wb5represents NR8; (29) Wa1represents CR5, Wa2represents N, Wa4represents NR4and Wb5represents CR8; (30) Wa1represents CR5, Wa2represents N, Wa4represents NR4and Wb5represents CHR8; (31) Wa1represents CR5, Wa2represents N, Wa4represents NR4and Wb5represents N; (32) Wa1represents CR5, Wa2represents N, Wa4represents NR4and Wb5represents NR8; (33) Wa1represents CR5, Wa2represents CR , Wa4represents S, and Wb5represents CHR8; (34) Wa1represents CR5, Wa2represents CR5, Wa4represents S, and Wb5represents CR8; (35) Wa1represents CR5, Wa2represents CR5, Wa4represents S, and Wb5represents N; and (36) Wa1represents CR5, Wa2represents CR5, Wa4represents S, and Wb5represents NR8.

In some embodiments of the invention the compound of formula IX is a compound of the formula X:

.

In some embodiments of the invention the compound of formula IX is a compound where R4represents a C1-C4alkyl or C3-C5cycloalkyl. In some embodiments of the invention the compound of formula IX is a compound where R4represents methyl or ethyl.

In some embodiments of the invention the compound of formula IX

is a compound of formula XI:

.

In some embodiments of the invention the compound of formula IX to provide which enables a compound of formula XII:

.

In some embodiments of the invention the compound of formula VIII is a compound of formula XIII or XIV:

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-D, 6-a, 6-C1, 6-C2, 6-D, VII, VIII, IX, X, XI, XII, XIII or XIV is a connection that is a member of the group consisting of groups of formula II, where Wcrepresents aryl, including, but not limited to, substituted phenyl, heteroaryl, including, but not limited to, monocyclic heteroaryl, heteroseksualci or cycloalkyl, heteroseksualci, alkyl, including but not limited to, a group having the formula -(CH2)2-NRaRawhere each Raindependently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic, or-NRaRajoined together with formation of cyclic groups.

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-D, 6-a, 6-C1, 6-C2, 6-D, VII, VIII, IX, X, XI, XII, XIII or XIV is the compound where R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate.

In some embodiments invented the I compound of the formula I, IV, V, VI, VI-A, VI-C, VI-D, 6-a, 6-C1, 6-C2, 6-D, VII, VIII, IX, X, XI, XII, XIII or XIV is the compound where R2represents alkyl, halogeno, hydroxy, cyano, nitro, or phosphate, and q is 1 or 2.

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-D, 6-a, 6-C1, 6-C2, 6-D, VII or VIII is a compound where R3represents-H, halogeno, including, but not limited to, -CI or-F, alkyl, including but not limited to, -CH3or-CH2CH3, alkoxy, cycloalkyl or-CF3.

In some embodiments of the invention the compound of formula IX or X is a compound where R4selected from-H, methyl, ethyl, n-propyl,isopropyl,cyclopropyl,cyclobutyl and cyclopentyl.

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-d, VII, VIII, IX, XI, XII, XIII or XIV is the compound where R5represents H, -CN, -NH2With1-C4alkyl, C1-C4alkoxy, -CF3, NO2, -CH3, -CH2CH3, -Och3, -Och2CH3or halogeno, which includes, but is not limited to, -Cl or-F.

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-D, VII or VIII is a compound where R6represents H, -CN, -NH2With1-C4alkyl, C1-C4and is coxi, -CF3, NO2, -CH3or halogeno.

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-D, VII, VIII, IX or X is a compound where R7represents H, -CN, -NH2With1-C4alkyl, C1-C4alkoxy, -CF3, NO2, -CH3, -CH2CH3, -Och3, -Och2CH3or halogeno.

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-D, VII, IX, or XII is a compound where R8represents H, -CN, -NH2With1-C4alkyl, C1-C4alkoxy, -CF3, NO2, -CH3, -CH2CH3, -Och3, -Och2CH3or halogeno.

In some embodiments of compounds of formula I, IV, VI or VII R5, R6, R7and R8represent hydrogen.

In some embodiments of the invention the compound of formula I, IV, V, VI, VI-A, VI-C, VI-D, VII, VIII, IX, X, XI, XII, XIII or XIV is a compound where X represents-CH2-, -CH(CH2CH3)- or-CH(CH3)- including, but not limited to the case where CH(CH2CH3)- or-CH(CH3)-is (S)- or (R)-stereochemical configuration. In some embodiments of the invention the compound of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV is a compound where Y is absent, n is ecstasy a-O-, -NH(R9)- or-S(=O)2-. In some embodiments of the invention the compound of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV is the compound where R9represents methyl or hydrogen. In some embodiments of the invention the compound of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV is a compound where X-Y is-CH2N(CH3), -CH2-N(CH2CH3), -CH(CH3)NH-, -CH(CH2CH3)-NH-, -N(H)CH2-, -N(CH2CH3)CH2- or-N(CH3)CH2- including, but not limited to, -CH(CH3)NH - or-CH(CH2CH3)-NH, with (S)- or (R)-stereochemical configuration.

In some embodiments of the invention the compound of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV is a connection, where Wdis pyrazolopyrimidine, including, but not limited to, 4-amino-1H-pyrazolo[3,4-d]pyrimidine-1-yl or 7-amino-2-methyl-2H-pyrazolo[4,3-d]pyrimidine-3-yl, purine including, but not limited to, 6-amino-N-purine-9-yl or 6-metylene-N-purine-6-yl. In some embodiments of the invention the compound of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV is a connection where pyrazolopyrimidine has the formula III:

where R11represents H, alkyl, halogeno, amino, amido, hydroxy or alkoxy, the R 12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, including, but not limited to, monocyclic or bicyclic heteroaryl, heteroseksualci, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl or amido.

In another aspect of the invention, a method for inhibiting phosphatidylinositol 3-kinase (R-kinase), comprising: bringing the PI3-kinase in contact with an effective amount of one or more compounds set forth in this application. For example, the stage of bringing into contact includes the use of one or more compounds of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII and/or XIV. In some embodiments the stage of bringing into contact comprises bringing into contact with the cell that contains the specified R-kinase. In some embodiments of this method the inhibition occurs in a subject suffering from a disorder involving malfunction R-kinase one or more types. Some typical diseases involving misuse R-kinases selected from the group consisting of autoimmune diseases, rheumatoid arthritis, respiratory diseases and various types of cancer. If desirable, the connection used in this way has the structure of formula 6-a, where R11represents amino, and R12is a substituted phenyl.

In kotoryj embodiments of this method the inhibition occurs at the subject, suffering from rheumatoid arthritis or respiratory disease, and where the compound has the structure of formula 6-a, where R11represents amino, and R12is a bicyclic heteroaryl.

In some embodiments the method includes administration to the subject a second therapeutic agent.

In still another aspect of the present invention, a method of treatment of the disease, which manifests unwanted immune response. The method involves the step of introducing to a subject in need this, one or more compounds set forth in this application, including the compounds of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII and/or XIV, in an amount which is effective to improve the specified unwanted immune response. In some embodiments, one or more compounds inhibit independent of T-cell activation In-Katok, as evidenced by the decrease in the production of anti-TSR(trinitrophenyl) lgG3 at least about five times with the introduction of the test animals in an amount less than about 30 mg/kg portions 2 times per day (BID).

In some embodiments, the disease treated is associated with joint swelling or pain in the joint of the subject. This method can be effective in improving one or more symptoms of rheumatoid arthritis, as evidenced by the decrease with the front diameter of the joint is at least about 10% after 17 days and/or reducing the diameter of the ankle joint by at least 5-10% or more after treatment in a period of from several days to several weeks, including, for example, reducing the diameter of the ankle joint by at least 5% after 7 days of treatment. In another embodiment of the unwanted immune response is confirmed by enhanced production of antibodies against collagen type II, and the use of one or more compounds according to the invention reduces the level of antibodies against collagen type II in the serum with ED50 of less than about 10 mg/kg

In another aspect of the invention proposed a composition comprising a pharmaceutically acceptable excipient and one or more compounds of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII and/or XIV. In some embodiments of the invention the composition is in a liquid, solid, semi-solid form, gel form or aerosol form.

The INCORPORATION BY REFERENCE

All publications, patents and patent applications mentioned in this application are included in this application by reference to the same extent as if it were specifically and individually indicated that each individual publication, patent or patent application is incorporated by reference.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

In the accompanying claims set forth in detail the new features of the invention. A more complete understanding of the characteristics and advantages of the present invention will be achieved by reference to the following detailed description, in which alauda illustrative embodiment, using the principles of the invention and in the accompanying graphic materials which:

in FIG.1 shows a typical measurement Protocol-independent T-cell production of TNP-specific antibodies in vivo (BDA1 - brachydactyly type A1; ELISA - enzyme-linked immunosorbent assay);

in FIG.2 depicts fold decrease in TNP-specific lgGS response to antigens (Ad), due to the connections 7 and 53 of the formula IV, in comparison with the solvent in the quality control with the introduction of oral (p/o);

in FIG.3 shows the dose-dependent effect of oral administration twice a day connection 53 of the formula IV by reduction of the increase of diameter of the ankle (Ank) in time in the model of the developing collagen-induced arthritis in rats. Also presents the results for the control rats without arthritis, control rats with arthritis, which was introduced solvent as a negative control, and control rats with arthritis, which twice a day was administered methotrexate (MTX) (1K-1 - induced collagen 1);

in FIG.4 depicts the dose-dependent effect of compounds 7 and 53 of the formula IV to improve histopathological picture of the ankle joint with the introduction in the model of the developing collagen-induced arthritis in rats. Also presents the results for the control of rats with arthritis, it is which is injected with a solvent as a negative control or methotrexate;

in FIG.5 shows dose-dependent effect of compounds 7 and 53 of the formula IV to improve histopathological picture of the knee joint with the introduction in the model of the developing collagen-induced arthritis in rats. Also presents the results for the control of rats with arthritis, which was introduced solvent as a negative control or methotrexate as a positive control;

in FIG.6 depicts the dose-dependent effect of compounds 7 and 53 of the formula IV to reduce the level of antibodies against collagen type II in vivo when introduced into the model of the developing collagen-induced arthritis in rats. Also presents the results for rats with arthritis, which was introduced solvent as a negative control or methotrexate (MTX);

in FIG.7 shows dose-dependent effect of compound 7 formula IV to improve histopathological picture of the ankle joint with the introduction in the model of the developing collagen-induced arthritis in rats. Also presents the results for the control of rats with arthritis, which was introduced solvent, and rats with arthritis, which was administered methotrexate;

in FIG.8 shows dose-dependent effect of compound 53 of the formula IV, administered once a day, on the histopathology of the ankle joint in a model of collagen-induced installed arthritis in rats. So the e presents the results for the control of rats with arthritis, which was injected solvent, and rats with arthritis, which was administered Enbrel;

in FIG.9 shows the dose-dependent effect of compound 53 of the formula IV, administered twice a day, on the histopathology of the ankle joint in a model of collagen-induced installed arthritis in rats. Also presents the results for the control of rats with arthritis, which was introduced solvent, and rats with arthritis, which was administered Enbrel;

in FIG.10 depicts the dose-dependent effect of compound 53 of formula IV to the increase in the average volume of the paws in the model of adjuvant-induced arthritis;

in FIG.11 shows the effect over time of connection 53 of the formula IV on the average weight of the rats in the model of adjuvant-induced arthritis in rats.

DETAILED description of the INVENTION

Although in this application is shown and described a preferred embodiment of the present invention, specialists in the art it will be obvious that such embodiments are given only as an example. Specialists in the art will immediately appear ideas numerous variations, changes and substitutions without deviating from the invention. It should be understood that in the practical application of the present invention may be used various alternatives to the embodiments of the invention described in this application. Assumes that the supplied four the ula defines the scope of the invention and thereby covered by the ways and patterns, fall within the scope of this formula, and cash equivalents.

If not stated otherwise, all technical and scientific terms used in this application have the same values, as they are usually understood to be a specialist in the field of technology, belongs to this invention. All patents and publications cited in this application are incorporated by reference.

As used in the description and the claims, the singular includes reference to the plural, unless the context clearly stipulates otherwise.

As it is used in this application, the "agent" or "bioactive agent" refers to the biological, pharmaceutical or chemical compound or other grouping. Non-limiting examples include simple or complex organic or inorganic molecule, peptide, protein, oligonucleotide, antibody-derived antibody, an antibody fragment, a derivative of a vitamin, a carbohydrate, a toxin or a chemotherapeutic compound. Can be synthesized various compounds, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides) and synthetic organic compounds based on various core structures. Additionally, the compounds for screening can be obtained from various natural sources, such as extracts from plants is s or animals and the like. Specialist in the art can easily recognize that there are no restrictions on the structural nature of the agents according to the present invention.

The term "agonist", as used in this application refers to a compound which has the ability to initiate or enhance the biological function of the protein target, whether by inhibiting the activity or expression of the protein target. Accordingly, the term "agonist" is defined in the context of the biological role of polypeptide-target. Although the preferred agonists described in this application, specific interact with (e.g. bind to) the target compounds that initiate or enhance the biological activity of the polypeptide target through interaction with other members of the pathway of signal transduction, one member of which is the polypeptide-target, are also specifically included in the scope of this definition.

The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to compounds having the ability to inhibit a biological function of the protein target, whether by inhibiting the activity or expression of the protein target. Accordingly, the terms "antagonist" and "inhibitor" is defined in the context of the biological role of the protein target. Although the preferred ant who honesty, shown in this application, specific interact with (e.g. bind to) the target compounds that inhibit the biological activity of the protein target through interaction with other members of the pathway of signal transduction, one of whose members is given protein target, are also specifically included in the scope of this definition. Preferred biological activity, inhibiting the antagonist, is associated with the development, growth or spread of tumors or unwanted immune response, which is manifested in the form of autoimmune disease.

"Anticancer agent", "antineoplastic agent" or "chemotherapeutic agent" refers to any agent that is useful in the treatment of a neoplastic condition. One of the classes of anticancer agents contains chemotherapeutic agents. "Chemotherapy" means the addition of one or more chemotherapeutic drugs and/or other agents to a patient suffering from cancer, in a variety of ways, including intravenous, oral, intramuscular, intraperitoneal (/b), intravesical, subcutaneous (s/C), transdermal, transbukkalno or inhalation or in the form of a suppository.

The term "cell proliferation" refers to the phenomenon whereby the number of cells changes as a result of the division. This term also is hativat cell growth, as a result of which the morphology of the cells changes (for example, they increase in size), which is consistent with a proliferative signal.

The term "co-administration", "introduced in combination with" and their grammatical equivalents, as used in this application, cover the introduction of two or more agents to an animal so that both the agent and/or their metabolites were present in the animal at the same time. Co-administration includes simultaneous introduction in separate compositions, the introduction at different times in separate compositions or introduction to composition, in which there are both agent.

The term "effective amount" or "therapeutically effective amount" refers to that amount of the compound described in this application, which is sufficient to obtain the effect of the proposed use, including, but not limited to, treatment of diseases, which are described below. therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or entity and painful condition, which are treated, for example, mass and age of the subject, the severity of the disease condition, the route of administration and the like, which can be easily determined by the expert of ordinary skill in the art. The term is also applied to the dose, the which will induce a specific response in the target cells, for example, a decrease in the adhesion of platelets and/or migration of cells. The specific dose will vary depending on the specific compound, the mode of administration, which should be followed, enter whether in combination with other compounds, timing of introduction, the tissue into which it is injected, and the physical delivery system in which it is made.

As used in this application, the terms "treating" or "treatment" or "alleviation" or "reduced intensity" are used in this application interchangeably. These terms relate to an approach for obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and/or prophylactic benefit. Under therapeutic benefit understand the elimination or reduction of the intensity of the main disorders that are treated. Also therapeutic benefits reach by eliminating or reducing the intensity of one or more of the physiological symptoms associated with the primary disorder, so that patients see improvement, although the patient may still be affected by the main disorder. For prophylactic benefit, the compositions can be administered to the patient having a risk of developing a particular disease, or the patient with a confirmed one or more than one physical and the logical symptom, it is possible, even if the diagnosis of the disease might not supplied.

"Therapeutic effect" as that term is used in this application encompasses therapeutic benefit and/or prophylactic benefit, as described above. Preventive effect includes the delay or eliminate the onset of the disease or condition, delay or eliminate attack the symptoms of the disease or condition, slowing, stopping or reversing the development of the disease or condition or any combination of them.

The term "pharmaceutically acceptable salt" refers to salts derived from a number of organic and inorganic counterions, are well known in the art. Pharmaceutically acceptable salt accession acid can be formed with inorganic acids and organic acids. Inorganic acids, which can occur salts include, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids, which may occur salt include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid is, cinnamic acid, almond acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid and the like. Pharmaceutically acceptable salts of attaching the base can be formed with inorganic and organic bases. Inorganic bases which may occur salt include, for example, the base of the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Organic bases from which may occur salt include, for example, primary, secondary and tertiary amines, substituted amines, including those existing in nature substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine and ethanolamine. In some embodiments pharmaceutically acceptable salt attaching a base selected from the salts of ammonium, potassium, sodium, calcium and magnesium.

"Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion medium, substances for coatings, antibacterial and antifungal agents, isotonic and slowing down the absorption of the agents and the like. The use of such media and agents for pharmaceutics and active substances is well known in the art. Except when any conventional medium or agent will be incompatible with the active ingredient, its use in therapeutic compositions according to the invention, it is assumed. Supplementary active ingredients can also be included in the composition.

"Signal transduction" is a process in which stimulating or inhibiting signals are transmitted into the cell and inside the cell to cause an intracellular response. The modulator path signal transduction refers to a compound that modulates the activity of one or more cellular proteins, mapped in the same specific way of signal transduction. The modulator can enhance (agonist) or inhibit (antagonist) activity of the signaling molecule.

The term "selective inhibition" or "selectively inhibits" as applied to the biologically active agent refers to the ability of the agent to selectively reduce the activity of the target transmission signal is compared with the activity of the target on the signal transmission by direct or indirect interaction with the target.

The term "B-ALL", which in this application is used, apply to b-cell acute lymphoblastic leukemia.

"Subject" refers to an animal such as a mammal, such as man. The methods described in this application, m which may be useful for human therapy and for applications in veterinary medicine. In some embodiments the patient is a mammal, and in some embodiments the patient is a man.

"Radiation therapy" means the impact on the patient using conventional methods and compositions known to the practitioner, radioactive emitters, such as emitting alpha particles radionuclides (e.g., radionuclides sea anemone and thorium), radioactive emitters with low linear energy transfer (LET) (i.e., beta-emitters, emitters conversion electrons (e.g., strontium-89 and samarium-153-EDTMP (samarium-153-ethylenediaminetetramethylene)), or high energy radiation, including, without limitation, x-rays, gamma rays and neutrons.

"Prodrug" is intended to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described in this application. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when introducing his subject, but can be transformed in vivo into the active compound, for example, by hydrolysis. The connection, which is a prodrug, often offers advantages of solubility, the Kanev compatibility or delayed release in the body of a mammal (see, for example, Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems", A. C. S. Symposium Series, Vol.14 and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; and then, and more fully incorporated into this application by reference. It is also assumed that the term "prodrug" includes any covalently associated media, which released the active compound in vivo when such prodrug is administered to a subject is a mammal. Prodrugs of the active compounds, as described in this application can be obtained by modifying functional groups present in the active compound, so that these modified compounds were split or due to routine manipulation or in vivo with the receipt of the original active compounds. Prodrugs include compounds where the group hydroxy, amino or mercapto associated with any group that, when the prodrug of the active compound is administered to the subject is a mammal, cleaved with the formation of a free hydroxy group, the free amino group or a free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formiate and benzoate derivatives of alcohol or ndimethylacetamide, formamide and benzamidine derivative of the amine functional group in the active connection and the like.

The term "in vivo" refers to an event that occurs in the body of the subject.

The term "in vitro" refers to an event that occurs outside the body of the subject. For example, analysis of in vitro covers any analysis outside of the subject. The in vitro covers the analysis using cells in which use live or dead cells. The in vitro also include cell-free analysis, in which no intact cells are not used.

Also, unless otherwise stated, it is understood that the structure described in this application include compounds that differ only in the presence of one or more than one enriched isotope of the atom. For example, compounds having presented the structure, except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon on13With or14C-enriched carbon are included in the scope of this invention.

Compounds of the present invention can also contain isotopes of atoms for one or more of the atoms forming the composition of such compounds in unnatural proportions. For example, compounds may be radioactively labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, both radioactive and non-radioactive fall the scope of the present invention.

In the case when the application uses ranges to describe physical properties such as molecular weight, or chemical properties, such as chemical formula, it is understood that included all combinations and podnominatsii ranges and specific corresponding embodiment. The term "about" when it refers to the amount or range of numeric values, means that the referenced number or range of numeric values represent an approximation within the scatter of the experimental data (or within statistical error of the experiment), and therefore, the number or range of numeric values may vary, for example, 1%-15% of the established amount or range of numeric values. The term "containing" (and related terms such as "include" or "includes" or "having" or "including") includes these embodiments, for example, any embodiment of the composition of the object, the composition, method or process, or the like, which comprise or essentially consist of the described features.

The following abbreviations and terms have the indicated meanings throughout this application:

R-TO - phosphoinositide-3-kinase; PI - phosphatidylinositol; PDK-phosphoinositide-dependent kinase; DNA-PK - dependent deoxyribonucleic acid protein kinase; PTEN - deletion fosfatazy homolog of Tenzin on chromosome ten; RCC - kinase, such phosphoinositides; AIDS - acquired immune deficiency syndrome; HIV - human immunodeficiency virus; Me - methyliodide; l3- oxychloride phosphorus; KCNS - isothiocyanate potassium; TLC is thin layer chromatography; Meon - methanol; and l3- chloroform.

Abbreviations used in this application, have their traditional importance in chemistry and biology.

"Alkyl" refers to a radical with a straight or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, containing no ninasimone having from one to ten carbon atoms (for example, C1-C10alkyl). In all cases, when it appears in this application, the range of numeric values, such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 10 carbon atoms, although the present definition also encompasses a variant of the term "alkyl", when there is no range of numeric values not marked. In some embodiments it is With1-C4an alkyl group. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Isobe is Il, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septal, octyl, nonyl, decyl and the like. Alkyl is attached to the remainder of the molecule through a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-etylhexyl, 2-etylhexyl and the like. If this description does not specifically specified otherwise, an alkyl group possibly substituted by one or more than one Deputy, which independently are: alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2where each Raindependently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Alkylaryl" refers to -(alkyl)aryl Radik the Lu, where aryl and alkyl such as they are disclosed in this application, and which may be substituted by one or more than one of the substituents described as suitable substituents for aryl and alkyl, respectively.

"Ancillary" refers to -(alkyl)retailnow the radical, where the hetaryl and alkyl such as they are described in this invention and may be substituted by one or more than one of the substituents described as suitable substituents for aryl and alkyl, respectively.

"Alkylchlorosilanes" refers to -(alkyl)heterocyclyl the radical, where the alkyl and heteroseksualci such as they have in this application described, and which may be substituted by one or more than one of the substituents described as suitable substituents for geterotsiklicheskie and alkyl, respectively.

"Allenova" group refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and "alkyne" group refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkyl group, regardless of whether it is saturated or unsaturated, may be a branched, straight chain or be circular.

"Alkenyl" refers to the radical-gruppes straight or branched hydrocarbon chain, consisting solely of carbon atoms and hydrogen, containing at least one double bond and having from two to ten carbon atoms (i.e.2-C10alkenyl). In all cases, when it appears in this application, the range of numeric values, such as "2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms" means that Alchemilla group may consist of 2 carbon atoms, 3 carbon atoms, etc. up to and including 10 carbon atoms. In some embodiments of alkenyl contains from two to eight carbon atoms. In other embodiments of alkenyl contains from two to five carbon atoms (for example, C2-C5alkenyl). Alkenyl attached to the remainder of the molecule through a single bond, for example, ethynyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, Penta-1-enyl, Penta-1,4-dienyl and the like. If this description does not specifically stated otherwise, Alchemilla group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)NR a)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Alkenyl-cycloalkyl" refers to -(alkenyl)cycloalkene the radical, where alkenyl and cycloalkyl such as they are described in this invention and may be substituted by one or more than one of the substituents described as suitable substituents for alkenyl and cycloalkyl, respectively.

"Quinil" refers to a radical group with a straight or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, containing at least one triple bond, having from two to ten carbon atoms (i.e.2-C10quinil). In all cases, when it appears in this application, the range of numeric values, such as "2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms" means that Alchemilla group can be composed and the 2 carbon atoms, 3 carbon atoms, etc. up to and including 10 carbon atoms. In some embodiments quinil contains from two to eight carbon atoms. In other embodiments quinil has from two to five carbon atoms (for example, C2-C5quinil). Quinil attached to the remainder of the molecule through a single bond, for example, ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl and the like. If this description does not specifically stated otherwise, Alchemilla group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3where each Raindependently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or CGU is arearelated.

"Quinil-cycloalkyl" refers to -(quinil)cycloalkene the radical, where quinil and cycloalkyl such as they are described in this application, and which may be substituted by one or more than one of the substituents described as suitable substituents for quinil and cycloalkyl, respectively.

"Carboxaldehyde" refers to the radical -(C=O)N.

"Carboxyl" refers to the radical -(C=O)HE.

"Cyano" refers to the radical-CN.

"Cycloalkyl" refers to monocyclic or polycyclic, the radicals, which contain only carbon and hydrogen and may be saturated or partially unsaturated. Cycloalkyl groups include groups having 3-10 ring atoms (i.e. With3-C10cycloalkyl). In all cases, when it appears in this application, the range of numeric values, such as "3 to 10" refers to each integer in the given range; e.g., "3-10 carbon atoms" means that cycloalkyl group may consist of 3 carbon atoms, etc. up to and including 10 carbon atoms. In some embodiments it is With3-C8cycloalkenyl radical. In some embodiments it is With3-C6cycloalkenyl radical. Illustrative examples cycloalkyl groups include, but are not limited to, the following groups: cyclopropyl, cyclobutyl, cyclopentyl, the cycle is pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, norbornyl and the like. If this description does not specifically stated otherwise, cycloalkyl group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3,where each Raindependently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Cycloalkyl-alkenyl" refers to -(cycloalkyl)Alchemilla the radical, where cycloalkyl and heteroseksualci such as they are described in this application, and which may be substituted by one or more than one of the substituents described as the suitable substituents for geterotsiklicheskie and cycloalkyl, respectively.

"Cycloalkyl-heteroseksualci" refers to -(cycloalkyl)-heterocycle safe radical, where cycloalkyl and heteroseksualci such as they are described in this application, and which may be substituted by one or more than one of the substituents described as suitable substituents for geterotsiklicheskie and cycloalkyl, respectively.

"Cycloalkyl-heteroaryl" refers to -(cycloalkyl)the heteroaryl radical, where cycloalkyl and heteroseksualci such as they are described in this application, and which may be substituted by one or more than one of the substituents described as suitable substituents for geterotsiklicheskie and cycloalkyl, respectively.

The term "alkoxy" refers to the group-O-alkyl comprising 1 to 8 carbon atoms in the straight, branched, cyclic configuration and combinations thereof attached to the original structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, cyclohexyloxy and the like. "Lower alkoxy" refers to alkoxygroup containing from one to six carbon atoms. In some embodiments With1-C4alkyl represents an alkyl group, which covers alkali as straight and branched chain of 1 to 4 carbon atoms.

The term "substituted alkoxy" refers to a group ALK is XI, where the alkyl constituent is substituted (i.e.,- O-(substituted alkyl)). If this description does not specifically specified otherwise, an alkyl group alkoxygroup possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

The term "alkoxycarbonyl" refers to a group of the formula (alkoxy)(C=O)-, attached through a carbonyl carbon, and the alkoxy group has the indicated number of carbon atoms. So, With1-C6alkoxycarbonyl the group is alkoxygroup, is within 1-6 carbon atoms, attached via its carbonyl oxygen to the linker. "Lower alkoxycarbonyl" refers to alkoxycarbonyl group, where alkoxygroup represents a lower alkoxygroup. In some embodiments With1-C4alkoxy represents alkoxygroup that covers alkoxygroup as straight and branched chain of 1 to 4 carbon atoms.

The term "substituted alkoxycarbonyl" refers to the group (substituted alkyl)-O-C(O)-, where the group attached to the original structure through the carbonyl functional group. If this description does not specifically specified otherwise, an alkyl group alkoxycarbonyl group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)sub> 2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Acyl" refers to groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)- and (heteroseksualci)-C(O)-, where the group attached to the original structure through the carbonyl functional group. In some embodiments, it is C1-C10acyl radical, which represents the total number of atoms in the chain, or ring alkyl, aryl, heteroaryl or geteroseksualnoe part of alloctype plus carbonyl carbon of acyl, there are three other atoms in the ring or chain plus the carbonyl. If the radical R represents heteroaryl or heteroseksualci, the heteroatoms in the ring or atoms in the chain contribute to the total number of atoms in the chain or in the ring. If this description does not specifically indicated otherwise, "R" alloctype possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl-ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Acyloxy" refers to the radical R(C=O)O-, where "R" represents alkyl, aryl, heteroaryl, heteroalkyl or heteroseksualci, such as they are described in this application. In some embodiments it is a radical C1-C4acyloxy that represents the total number of atoms in the chain, or ring alkyl, aryl, heteroaryl or geteroseksualnoe part of alloctype plus the carbonyl carbon of the acyl group, there are three other atoms in the ring or chain plus the carbonyl. If the radical R represents heteroaryl or heteroseksualci, the heteroatoms in the ring or atoms in the chain contribute to the total number of atoms in the chain or in the ring. If this description does not specifically indicated otherwise, "R" alloctype possibly substituted by one or more Deputy is a Fort worth, independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Amino" or "amine" refers to a radical of the group-N(Ra)2where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic if this description does not specifically specified otherwise. If the group-N(Ra)2has two R3that are not hydrogen, they can be combined with the nitrogen atom with the formation of 4-, 5-, 6 - or 7-membered number is CA. For example, assume that-N(Ra)2includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. If this description does not specifically stated otherwise, the amino group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic, and each of these groups can be substituted, as defined in this application.

The term "substituted amino" also refers to the N-oxides of each group-otherdand NRdRdthat described above. N-oxides can be obtained is by treating the appropriate amino, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The specialist in this area known reaction conditions for carrying out N-oxidation.

"Amide" or "amido" refers to a chemical group having the formula-C(O)N(R)2or-NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (linked via a ring carbon) and heteroalicyclic radical (linked via a ring carbon), and each group itself may possibly be substituted. In some embodiments it is a radical With1-C4amido or amide radical, and the total number of carbon atoms in this radical included the carbon atom of the carbonyl amide. R2in-N(R)2amide can be taken together with the nitrogen to which it is attached, with the formation of 4-, 5-, 6 - or 7-membered ring. If this description does not specifically stated otherwise, the amido group may independently substituted by one or more than one of the substituents listed in this application for alkyl, cycloalkyl, aryl, heteroaryl or geterotsiklicheskie. Amide can be a molecule of the amino acid or peptide attached to the compound of formula (I), resulting in the formation of a prodrug. Any amine-, hydroxy - or carboxyl-containing side chain in compounds contained in the data is th application can be liderovna. Methods and specific groups to receive such amides known to experts in the art and can readily be found in reference materials such as the book by Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, N. Y., 1999, which is incorporated in this application in its entirety by reference.

The term "aromatic" or "aryl" refers to aromatic radical containing from six to ten ring atoms (for example, C6-C10aromatic radical, or a C6-C10aryl), which has at least one ring containing a conjugated system of PI electionof, which is carbocyclic (e.g., phenyl, fluorenyl and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valence on the ring atoms are called substituted phenylanaline radicals. Bivalent radicals formed from the monovalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence, are named by adding "Eden" to the name of the corresponding univalent radical, for example, naftalina group with two connection points is called naphthylidine. In all cases, when he will find is in this application the range of numeric values, such as "6-10" refers to each integer in the given range; e.g., "6-10 ring atoms" means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc. up to and including 10 ring atoms. The term includes monocyclic or polycyclic, formed from condensed rings (i.e. rings that share adjacent pairs of ring atoms), group. If this description is not explicitly specified, the aryl group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, Aral is Il, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Aralkyl" or "arylalkyl" refers to (aryl)alkyl, the radical, where the aryl and alkyl such as they are described in this application, and which may be substituted by one or more than one of the substituents described as suitable substituents for aryl and alkyl, respectively.

"Ester" refers to a chemical moiety of the formula-COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked via a ring carbon) and heteroalicyclic radical (linked via a ring carbon). Any amine-, hydroxy - or carboxyl-containing side chain in compounds described in this application can be etherification. Methods and specific groups to receive such esters known to experts in the art and can readily be found in reference materials such as the book by Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, N. Y., 1999, which is incorporated in this description in its entirety by reference. If this description is not explicitly specified, the ester group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, Goethe is arylalkyl, hydroxy, halogeno, cyano, trifluoromethyl, triptoreline, nitro, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Foralkyl" refers to the alkyl radical, as defined above, which is substituted by one or more radicals, fluorescent, as defined above, for example, trifluoromethyl, deformatio, 2,2,2-triptoreline, 1-vermeil-2-veratile and the like. The alkyl part of the alkyl fluoride radical can be substituted as described above for alkyl groups.

"Halogeno", "halide" or alternatively, "halogen" means fluorescent, chloro, bromo or iodo. The terms "halogenated", "halogenoalkanes", "halogenoalkanes and halogenoalkane" include patterns of alkyl, alkenyl, quinil, alkoxy, substituted one or more than one group is Oh halogeno or their combinations. For example, the terms "foralkyl and feralcode" include group halogenoalkane, halogenoalkane, respectively, in which halogeno represents fluorine.

"Heteroalkyl", "heteroalkyl and heteroalkyl include a possibly substituted alkyl, alkeline and alkyline radicals which have one or more skeletal atoms in the chain, selected from an atom that is not carbon, such as oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Can be given a range of numeric values, for example With1-C4heteroalkyl related to the length of the chain in General, the length of which in this example is 4 atoms. For example, the radical-CH2Och2CH3denoted as "C4"heteroalkyl, which contains the direct center poutana the description of the chain length. Join the remainder of the molecule can be carried out either through a heteroatom or a carbon heteroalkyl chain. Heteroalkyl group may be substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, nitro, oxo, thioxo, trimethylsilanol, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra )C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

"Heteroalkyl" refers to -(heteroalkyl)the aryl radical, where heteroalkyl and aryl such as they are described in this application, and which may be substituted by one or more than one of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

Tetraalkylammonium" refers to -(heteroalkyl)the heteroaryl radical, where heteroalkyl and heteroaryl such as they are described in this application, and which may be substituted by one or more than one of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

Tetraalkylammonium" refers to -(heteroalkyl)heterocycle is the alkyl radical, where heteroalkyl and heteroaryl such as they are described in this application, and which may be substituted by one or more than one replaces the lei, described as suitable substituents for heteroalkyl and geterotsiklicheskie, respectively.

Heteroalicyclic" refers to -(heteroalkyl)cycloalkyl the radical, where heteroalkyl and cycloalkyl such as they are described in this invention and may be substituted by one or more than one of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

"Heteroaryl" or alternatively, "heteroaromatic" refers to a 5-18 membered aromatic radical (for example, C5-C13heteroaryl), which includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be monocyclic, bicyclic, tricyclic or tetracyclic ring system. In all cases, when it appears in this application, the range of numeric values, such as "5-18", refers to each integer in the given range; e.g., "5-18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms and so on, up to and including 18 ring atoms. Bivalent radicals formed from the monovalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence, name, EXT is vlaa "Eden" to the name of the corresponding univalent radical, for example, Peregrina group with two connection points is peridinian. N-containing heteroaromatic" or "heteroaryl" group refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroaryl group may be condensed or unfused. Heteroatom(s) in the heteroaryl radical is possibly oxidized(s). One or more nitrogen atoms, when present, may stereoselectivity. Heteroaryl attached to the remainder of the molecule through any atom of the ring(EC). Examples of heteroaryl include, but are not limited to, azepine, acridines, benzimidazolyl, bunzendahl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiazolyl, benzo[b][1,4]doxepin, benzo[b][1,4]oxazinyl, 1,4-benzodioxane, benzenepropanal, benzoxazolyl, benzodioxolyl, benzodioxolyl, benzoxazolyl, benzopyranyl, benzopyranones, benzofuranyl, benzofurazanyl, benzofurazanyl, benzothiazolyl, benzothiazyl (benzothiophenes), benzothieno[3,2-d]pyrimidinyl, benzothiazolyl, benzo[4,6]imidazo[1,2-d]pyridinyl, carbazolyl, cinnoline, cyclopent[d]pyrimidinyl, 6,7-dihydro-5H-cyclopent[4,5]thieno[2,3-d]pyrimidine, 5,6-dihydrobenzo[h]hintline, 5,6-dihydrobenzo[h]cinnolin, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]feast dainel, dibenzofurans, dibenzothiophenes, furanyl, furutani, furanones, furo[3,2-d]pyridinyl, 5,6,7,8,9,10-hexahydrite-Oct[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooct[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooct[d]pyridinyl, isothiazolin, imidazolyl, indazoles, indolyl, indazoles, isoindolyl, indolinyl, isoindolyl, ethanolic, indolizinyl, isoxazolyl, 5,8-methane-5,6,7,8-tetrahydroquinazoline, naphthyridine, 1,6-naphthyridine, oxadiazole, 2-oxoazetidin, oxazolyl, oxiranyl, 5,6,6 and,7,8,9,10,10 and octahedrons[b]hintline, 1-phenyl-1H-pyrrolyl, phenazines, phenothiazines, phenoxazines, phthalazine, pteridine, purinol, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, hintline, honokalani, chinoline, ethenolysis, tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-d]pyridazinyl, thiazolyl, thiadiazolyl, tierany, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-C]pyridinyl and thiophenyl (i.e. thienyl). If this description does not specifically stated otherwise, the heteroaryl group possibly substituted by one or more substituents, independently representing the mi a: alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, nitro, oxo, thioxo, trimethylsilanol, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic.

Substituted heteroaryl also includes ring systems substituted with one or more substituents oxide (-O-), as for example, pyridinyl-N-oxide.

"Heteroaromatic" refers to a group having the aryl group, as described in this invention, connected to alkalinous group, as described in this invention is joining the rest of the molecule through alkylenes group.

"Heteroseksualci" refers to a stable 3-18-membered non-aromatic ring is adekale, containing from two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. In all cases, when it appears in this application, the range of numeric values, such as "3-18" refers to each integer in the given range; e.g., "3-18 ring atoms" means that heterocytolysine group may consist of 3 ring atoms, 4 ring atoms and so on, up to and including 18 ring atoms. In some embodiments it is With5-C10heteroseksualci. In some embodiments it is With4-C10heteroseksualci. In some embodiments it is With3-C10heteroseksualci. If this description does not specifically stated otherwise, heterologously radical is a monocyclic, bicyclic, three cyclic or tetracyclic ring system, which may include condensed or United bridge connection ring system. Heteroatoms in heterocyclicamines radical may be oxidized. One or more nitrogen atoms, when present, may stereoselectivity. Heterologously moiety is partially or fully saturated. Heteroseksualci can be attached to the remainder of the molecule through any atom of the ring(EC). Examples of such geterotsiklicheskikh is dikalov include, but not limited to, DIOXOLANYL, thienyl[1,3]ditional, decahydroquinoline, imidazolines, imidazolidinyl, isothiazolinones, isoxazolidine, morpholine, octahedrally, activitiesunder, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, oxazolidinyl, piperidinyl, piperazinil, 4-piperidinyl, pyrrolidinyl, pyrazolidine, hinokitiol, diazolidinyl, tetrahydrofuryl, tritional, tetrahydropyranyl, thiomorpholine, thiomorpholine, 1-oxo-thiomorpholine and 1,1-dioxo-thiomorpholine. If this description does not specifically stated otherwise, heterocytolysine group possibly substituted by one or more substituents independently represents: an alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, hydroxy, halogeno, cyano, nitro, oxo, thioxo, trimethylsilanol, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -O(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2N(Ra)C(NRa)N(Ra)2, -N(Ra)S(OtRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2) or PO3(Ra)2, -OR3, -SR3where each R3independently represents bodoro is, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, heteroaryl or heteroaromatic.

"Heteroseksualci" also includes bicyclic ring system, where one non-aromatic ring, usually consisting of 3-7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and combinations containing at least one of the above heteroatoms; and the other ring, usually consisting of 3-7 ring atoms, may contain 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and is not aromatic.

"Isomers are different compounds with the same molecular formula. "Stereoisomers are isomers that differ only in the arrangement of these atoms in space. "Enantiomers" are a pair of stereoisomers that are analagies mirror images of each other. A mixture of 1:1 pair of enantiomers represents a "racemic" mixture. To denote a racemic mixture, where appropriate, uses the term "(±)". "Diastereoisomers" called stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. The absolute stereochemistry of opredelaetsa is on R-S-system Kan-Ingold-Prelog. In the case where the compound is a pure enantiomer the stereochemistry for each chiral carbon atom can be defined as R, or S. the Split connection, the absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right or levogyrate), in which they rotate plane-polarized light at the wavelength of D-line of sodium. Some of the compounds described in this application contain one or more asymmetric centers and therefore can be a source of enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)-or (S)-. Assumes that the proposed invention the chemical structure, pharmaceutical compositions and methods include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be obtained using chiral synthons or chiral reagents, or separated using traditional techniques. If the compounds described in this application contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is assumed that the compounds include both E and Z geometric isomers.

"Gruppirovki the" applies to a specific segment or functional group of the molecule. Under chemical groups often understand the chemical structure built into the molecule or is attached to it.

"Nitro" refers to the radical-NO2.

"Oxa" refers to the radical-O-.

"Oxo" refers to the radical =O.

"Tautomers" are distinguished by the structure of the isomers, which vzaimoprevrascheny in the tautomerizations. "Tautomerization represents the isomerization and includes prototroph tautomerization or tautomerization with proton transfer, which is considered a subgroup of chemistry acid-base interactions. It is understood that "phototropy tautomerization" or "tautomerization with proton transfer" includes the migration of a proton, which is accompanied by changes in the ratio of communication, often with vzaimoprevrascheny single bond and adjacent double bond. If there is a possibility tautomerizations (e.g., in solution), can be achieved chemical equilibrium of tautomers. Example tautomerizations is keto-enol tautomerization. A specific example of keto-enol tautomerizations is vzaimoprevrascheny of tautomers pentane-2,4-dione and 4-hydroxyben-3-EN-2-it. Another example tautomerizations is phenol-keto-tautomerization. Specific examples of phenol-keto-tautomerizations is vzaimoprevrascheny of tautomers pyridine-4-ol is pyridin-4(1H)-it.

Compounds of the present invention can also contain isotopes of atoms for one or more of the atoms forming part of such connections, unnatural proportions. For example, compounds may be radioactively labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, regardless of whether they are radioactive or not, are in the scope of the present invention.

"Leaving(s) group or atom" represents any group or any atom, which under the reaction conditions will be chipped off from the original substance, thereby undergo reaction at a specific site. Suitable examples of such groups are, unless otherwise stated, are halogen atoms, groups of mesilate, p-nitrobenzenesulfonate, tosyloxy.

The term "protective group" has the meaning with which it is traditionally associated in organic synthesis, that is, a group which selectively blocks one or more reactive site in a multifunctional compound such that a chemical reaction can take place selectively at another unprotected reactive site, and so that this group can be easily removed after completion of sberatel the Noah's reaction. Describes the number of protective groups, for example, So-called. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, third edition, John Wiley & Sons, New York (1999). For example, protected by a hydroxy-group form is one where at least one of the hydroxy groups present in the compound, protected hydroxy-protecting group. This way can be protected amines and other reactive group.

"MES" refers to the connection (for example, the compound selected from the compounds of formula I or its pharmaceutically acceptable salt) in physical Association with one or more molecules pharmaceutically acceptable solvent. It is obvious that the compound of formula I comprises a compound of formula I or solvate of this compound, and mixtures thereof.

"Substituted" means that the referenced group may be substituted by one or more than one additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, geterotsiklicheskie, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, cyano, halogen, carbonyl, ether complex, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhalogenated, perfluoroalkyl phosphate, Silla, sulfinil, sulfonyl, sulfonamide, sulfoxide, sulfonate, urea and amino, including mono - and di-C is displaced amino groups and their protected derivatives. Di-substituted amino group include the groups which form a ring together with the nitrogen of the amino group, such as, for example, morpholino. Themselves substituents can be substituted, for example, cycloalkenyl Deputy may be halide, substituted by one or more than one carbon atom in the ring, and the like. The protective group that can form a protected derivatives of the above substituents are known to experts in the art and can be found in such references as Greene and Wuts, above.

"Sulfanyl" refers to groups-S-(possibly substituted alkyl), S(possibly substituted aryl), S-(possibly substituted heteroaryl) and S-(possibly substituted heteroseksualci).

"Sulfinil" refers to the groups: -S(O)-H, -S(O)-(possibly substituted alkyl), -S(O)-(possibly substituted amino), -S(O)-(possibly substituted aryl), -S(O)-(possibly substituted heteroaryl) and-S(O)-(possibly substituted heteroseksualci).

"Sulfonyl" refers to the groups: -S(O2)-H, -S(O2)-(possibly substituted alkyl), -S(O2)-(possibly substituted amino), -S(O2)-(possibly substituted aryl), -S(O2)-(possibly substituted heteroaryl) and-S(O2)-(possibly substituted heteroseksualci).

"Sulfonamide" or "sulfonamide" refers to the radical-S(=O)2-NRR where each R is independently selected from the group Castiadas hydrogen, of alkyl, cycloalkyl, aryl, heteroaryl (linked via a ring carbon) and heteroalicyclic radical (linked via a ring carbon). Group R-NRR radical-S(=O)2-NRR can be taken together with the nitrogen to which they are attached, with the formation of 4-, 5-, 6 - or 7-membered ring. In some embodiments, it is C1-C10sulfonamide, where each R in sulfonamide contains a total of 1 carbon 2 carbon 3 or 4 carbon carbon. Group sulfonamide possibly substituted by one or more than one of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

"Sulfoxy" refers to the radical-S(=O)2HE.

"Sulfonate" refers to the radical-S(=O)2-OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked via a ring carbon) and heteroalicyclic radical (linked via a ring carbon). Sulphonate group possibly substituted by R is one or more than one of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

If the substitute groups defined by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would be in the writing patterns right to left, such as the er, -CH2O - is the equivalent-core2-.

Compounds of the present invention also include crystalline and amorphous forms of such compounds, including, for example, polymorphs, pseudopolymorphs, solvate, hydrate, nonsolvated polymorphs (including anhydrate), conformational polymorphs, and amorphous forms of the compounds, and their mixtures. "Crystalline form", "polymorph" and "new form" can be used in this application interchangeably, implying that they include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvate, hydrate, nonsolvated polymorphs (including anhydrate), conformational polymorphs, and amorphous forms, as well as their mixtures, if not referred to a particular crystalline or amorphous form.

Chemical structures include, but are not limited to, compounds of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII and XIV and their pharmaceutically acceptable forms. Pharmaceutically acceptable forms of the compounds described in this application include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. In some embodiments of the compounds described in this application are in the form of pharmaceutically acceptable salts. Thus, the terms "chemical structure" and "chemical structure" also HC is primarily pharmaceutically acceptable salt, chelates, non-covalent complexes, prodrugs, and mixtures.

In addition, if the compound of formula I, IV, V. VI, VII, VIII, IX, X, XI, XII, XIII or XIV receive in the form of salt accession acid, free base can be obtained by alkalizing the solution of salt of the acid. Conversely, if the product is a free base, salt accession, in particular pharmaceutically acceptable salt accession can be obtained by dissolving the free base in a suitable organic solvent and process this acid solution in accordance with the traditional methods of obtaining salt accession acid of the basic compounds. Specialists in the art will recognize various methodologies of synthesis that can be used to produce non-toxic pharmaceutically acceptable salts of the merger.

In one aspect of the present invention proposed a compound of formula 1 or its pharmaceutically acceptable salt:

,

where Wa1represents CR3or N; Wa2represents CR5or N; Wa3represents CR6or N; Wa4represents N or CR7; Wb5represents CR8, CHR8or N,

where not more than two adjacent atoma ring, selected from Wa1, Wa2, Wa3, Wa4and Wb5represent heteroatoms;

Wdis heteroseksualci, aryl or heteroaryl;

In represents alkyl, amino, heteroalkyl, cycloalkyl, heteroseksualci or a group of formula II:

,

where We represents aryl, heteroaryl, heteroseksualci or cycloalkyl, and q is an integer 0, 1, 2, 3 or 4;

X is absent or represents -(CH(R9z, in each case z independently is an integer 1, 2, 3 or 4;

Y is absent, represents-O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(O)-(CHR9)z-, -C(=O)- N(R9)-C(=O) or-N(R9)-C(=O)NH, -N(R9)C(R9)2- or-C(=O)-(CHR9)z-;

R1represents hydrogen, alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate;

R2represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, FOS is at, urea or carbonate;

R3represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, aryl or heteroaryl;

R5, R6, R7and R8independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamide, halogen, cyano, hydroxy or nitro; and

in each case, R9independently represents hydrogen, C1-C10alkyl, C3-C7cycloalkyl, heteroseksualci or2-C10heteroalkyl,

In some embodiments Wa1represents CR3. In some embodiments Wa1represents N. In some embodiments Wa2represents CR5. In some embodiments Wa2represents N. In some embodiments Wa3represents CR6. In some embodiments Wa3represents N. In some embodiments Wa4represents CR7. In some embodiments Wa4represents N. In some embodiments Wb5represents CR8. In some embodiments Wb5is CHR 8. In some embodiments Wb5represents N. In some embodiments Wa2represents CR5, Wa3represents CR6and Wa4represents CR7. In some embodiments Wa2represents N, Wa3represents CR6and Wa4represents CR7. In some embodiments Wa2represents CR5, Wa3represents N, and Wa4represents CR7. In some embodiments Wa2represents CR5, Wa3represents CR6and Wa4represents N. In some embodiments Wa2and Wa3represent N, and Wa4represents CR7. In some embodiments Wa2represents CR5and Wa3and Wa4are N. In some embodiments Wb5represents CR8. In some embodiments Wb5represents CHR8. In some embodiments Wb5represents N. In some embodiments Wa2represents CR5, Wa3represents CR6, a4represents CR7and Wb5represents CR8. In some embodiments Wa2represents CR5, Wa3represents CR6, Wa4represents CR7and Wb5represents CHR8. In some embodiments Wa2represents CR5, Wa3represents CR6, Wa4represents CR7and Wb5represents N. In some embodiments Wa2represents N, Wa3represents CR6, Wa4represents CR7and Wb5represents CR8. In some embodiments Wa2represents N, Wa3represents CR6, Wa4represents CR7and Wb5represents CHR8. In some embodiments Wa2represents N, Wa3represents CR6, Wa4represents CR7and Wb5represents N. In some embodiments Wa2represents CR5, Wa3represents N, Wa4represents CR7and Wb5presented yet a CR 8. In some embodiments Wa2represents CR5, Wa3represents N, Wa4represents CR7and Wb5represents CHR8. In some embodiments Wa2represents CR5, Wa3represents N, Wa4represents CR7and Wb5represents N. In some embodiments Wa2represents CR5, Wa3represents CR6, Wa4represents N, and Wb5represents CR8. In some embodiments Wa2represents CR5, Wa3represents CR6, Wa4represents N, and Wb5represents CHR8. In some embodiments Wa2represents CR5, Wa3represents CR6, Wa4represents N, and Wb5represents N. In some embodiments Wa2and Wa3represent N, Wa4represents CR7and Wb5represents CR8. In some embodiments Wa2and Wa3represent N, Wa4p is ecstasy a CR 7and Wb5represents CHR8. In some embodiments Wa2and Wa3represent N, Wa4represents CR7and Wb5represents N. In some embodiments Wa2represents CR5, Wa3and Wa4represent N, and Wb5represents CR8. In some embodiments Wa2represents CR5, Wa3and Wa4represent N, and Wb5represents CHR8. In some embodiments Wa2represents CR5, Wa3and Wa4represent N, and Wb5represents N.

In some embodiments represents a unsubstituted or substituted alkyl, including but not limited to, -(CH2)2-NRaRawhere each Raindependently represents hydrogen, alkyl, foralkyl, carbocyclic, carbocyclic, aryl, aralkyl, heteroseksualci, geterotsiklicheskikh, heteroaryl or heteroaromatic, or NRaR3joined together with formation of cyclic groups, which includes, but is not limited to this, piperidinyl, piperazinil and morpholinyl. In some embodiments In performance, which provides an unsubstituted or substituted amino. In some embodiments represents a unsubstituted or substituted heteroalkyl.

.

In some embodiments represents a grouping of formula II, where We represents a member selected from the group consisting of unsubstituted or substituted aryl, substituted phenyl, unsubstituted or substituted heteroaryl, including, but not limited to, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidine-4-yl, pyrimidine-2-yl, pyrimidine-5-yl or pyrazin-2-yl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, heteroaryl, containing two heteroatoms as ring atoms, unsubstituted or substituted heteroaryl containing a ring nitrogen atom, heteroaryl containing two ring nitrogen atom, heteroaryl containing nitrogen and sulfur as ring atoms, unsubstituted or substituted geterotsiklicheskie, including, but not limited to, morpholinyl, tetrahydropyranyl, piperazinil and piperidinyl, unsubstituted or substituted cycloalkyl, including, but not limited to, cyclopentyl and cyclohexyl.

In some embodiments In represents one of the following groups:

-CH3-CH2CH3-CH(CH3)2

.

In some embodiments substituted In one or more of alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy or sulfonamide itself can be replaced.

In some embodiments, R1represents a member selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted quinil, unsubstituted or substituted cycloalkyl or unsubstituted or substituted geterotsiklicheskie. In some embodiments, R1represents an unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heteroaromatic. In some embodiments, R1represents an unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino. In some embodiments, R1represents an unsubstituted or substituted acyl, unsubstituted or substituted the th acyloxy, unsubstituted or substituted alkoxycarbonyl or unsubstituted or substituted, sulphonamido. In some embodiments, R1represents halogeno, which includes-Cl, -F, -I and-Br. In some embodiments, R1selected from the group consisting of cyano, hydroxy, nitro, unsubstituted or substituted phosphate, unsubstituted or substituted urea and carbonate.

In some embodiments, when R1represents alkyl, R1represents methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, emop-butyl, pentyl, hexyl or heptyl.

In some embodiments, when R1represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulphonamido or hydroxy, R1substituted phosphate or unsubstituted urea or substituted urea, or carboxylic acid or carbonate.

In some embodiments, when R1represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulphonamido, R1substituted by one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, harilal the La, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments, R2represents a member selected from the group consisting of unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted quinil, unsubstituted or substituted cycloalkyl and unsubstituted or substituted geterotsiklicheskie. In some embodiments, R2represents an unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heteroaromatic. In some embodiments, R2represents an unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino. In some embodiments, R2represents an unsubstituted or substituted acyl, unsubstituted or substituted, acyloxy, unsubstituted or substituted alkoxycarbonyl or unsubstituted or substituted Sul is enamide. In some embodiments, R2represents halogeno, which is the-I, -F, -CL or-Br. In some embodiments, R2selected from the group consisting of cyano, hydroxy, nitro, carboxylic acid and carbonate. In some embodiments, R2represents an unsubstituted or substituted phosphate. In some embodiments, R2represents an unsubstituted or substituted urea. In some embodiments, when R2represents alkyl, R2represents methyl, ethyl, propyl, isopropyl, W-butyl, tert-butyl, sec-butyl, pentyl, hexyl or heptyl.

In some embodiments, when R2represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulphonamido or hydroxy, he substituted phosphate, substituted urea or substituted carbonate.

In some embodiments, when R2represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulphonamido, he substituted one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amine is, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments q is an integer 0. In some embodiments q is an integer 1. In some embodiments q is an integer 2. In some embodiments q is an integer 3. In some embodiments q is an integer 4.

In some embodiments, R3represents a member selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl and unsubstituted or substituted quinil. In some embodiments, R3represents an unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted heteroseksualci. In some embodiments, R3represents an unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino. In some embodiments, R3represents an unsubstituted or substituted acyl, unsubstituted or substituted, acyloxy, unsubstituted or substituted alkoxycarbonyl or nezame the military or substituted, sulphonamido. In some embodiments, R3represents halogeno, which is the-I, -F, -Cl or-Br.

In some embodiments, R3selected from the group consisting of cyano, hydroxy and nitro. In some embodiments, when R3represents alkyl, R3represents methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, emop-butyl, pentyl, hexyl or heptyl. In some embodiments, R3represents-CF3.

In some embodiments, when R3represents alkyl, alkenyl, quinil, aryl, heteroaryl, cycloalkyl, heteroseksualci, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulphonamido, he substituted one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments, R5represents hydrogen, unsubstituted or substituted alkyl (including, but not limited to, unsubstituted or substituted C1-C4alkyl). In some embodiments, R5depict is to place an unsubstituted or substituted alkenyl, including, but not limited to, unsubstituted or substituted C2-C5alkenyl. In some embodiments, R5represents an unsubstituted or substituted quinil, including, but not limited to, unsubstituted or substituted C2-C5quinil. In some embodiments, R5represents an unsubstituted or substituted cycloalkyl, including, but not limited to, unsubstituted or substituted C3-C5cycloalkyl. In some embodiments, R5represents an unsubstituted or substituted heteroseksualci. In some embodiments, R5represents an unsubstituted or substituted heteroalkyl, including, but not limited to, unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R5represents an unsubstituted or substituted alkoxy, including but not limited to, unsubstituted or substituted C1-C4alkoxy. In some embodiments, R5represents an unsubstituted or substituted amido, including, but not limited to, unsubstituted or substituted C1-C4amido. In some embodiments, R5represents an unsubstituted or substituted amino. In some embodiments, R5represents an unsubstituted or substituted acyl, unsubstituted or substituted and is iloxi, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted, sulphonamido or unsubstituted or substituted C1-C4sulfonamide. In some embodiments, R5represents halogeno, which is the-I, -F, -Cl or-Br. In some embodiments, R5selected from the group consisting of cyano, hydroxy and nitro. In some other embodiments, R5represents-CH3, -CH2CH3, n-propyl, isopropyl, -och3, -Och2CH3or-CF3.

In some embodiments, when R5represents alkyl, alkenyl, quinil, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl or sulphonamido, R5possibly substituted by one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments, R6represents hydrogen, unsubstituted or substituted alkyl (including, n is not limited to, unsubstituted or substituted C1-C4alkyl). In some embodiments, R6represents an unsubstituted or substituted alkenyl, including, but not limited to, unsubstituted or substituted C2-C5alkenyl. In some embodiments, R6represents an unsubstituted or substituted quinil, including, but not limited to, unsubstituted or substituted C2-C5quinil. In some embodiments, R6represents an unsubstituted or substituted cycloalkyl, including, but not limited to, unsubstituted or substituted C2-C5cycloalkyl. In some embodiments, R6represents an unsubstituted or substituted heteroseksualci. In some embodiments, R6represents an unsubstituted or substituted heteroalkyl, including, but not limited to, unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R6represents an unsubstituted or substituted alkoxy, including but not limited to, unsubstituted or substituted C1-C4alkoxy. In some embodiments, R6represents an unsubstituted or substituted amido, including, but not limited to, unsubstituted or substituted C1-C4amido. In some embodiments, R6represents resumes the config or substituted amino. In some embodiments, R6represents an unsubstituted or substituted acyl, unsubstituted or substituted, acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted, sulphonamido or unsubstituted or substituted C1-C4sulfonamide. In some embodiments, R6represents halogeno, which is the-I, -F, -Cl or-Br. In some embodiments, R6selected from the group consisting of cyano, hydroxy and nitro. In some other embodiments, R6represents-CH3, -CH2CH3, n-propyl, isopropyl, -och3, -Och2CH3or-CF3.

In some embodiments, when R6represents alkyl, alkenyl, quinil, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl or sulphonamido, R6possibly substituted by one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments, R7represents hydrogen, unsubstituted or substituted alkyl (including, but not limited to, unsubstituted or substituted C1-C4alkyl). In some embodiments, R7represents an unsubstituted or substituted alkenyl, including, but not limited to, unsubstituted or substituted C2-C5alkenyl. In some embodiments, R7represents an unsubstituted or substituted quinil, including, but not limited to, unsubstituted or substituted C2-C5quinil. In some embodiments, R7represents an unsubstituted or substituted cycloalkyl, including, but not limited to, unsubstituted or substituted C2-C5cycloalkyl. In some embodiments, R7represents an unsubstituted or substituted heteroseksualci. In some embodiments, R7represents an unsubstituted or substituted heteroalkyl, including, but not limited to, unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R7represents an unsubstituted or substituted alkoxy, including but not limited to, unsubstituted or substituted C1-C4alkoxy. In some embodiments, R7represents an unsubstituted or substituted amido, including, but not what graniteware this, unsubstituted or substituted C1-C4amido. In some embodiments, R7represents an unsubstituted or substituted amino. In some embodiments, R7represents an unsubstituted or substituted acyl, unsubstituted or substituted, acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted, sulphonamido or unsubstituted or substituted C1-C4Sulfonamide. In some embodiments, R7represents halogeno, which is the-I, -F, -Cl or-Br. In some embodiments, R7selected from the group consisting of cyano, hydroxy and nitro. In some other embodiments, R7represents-CH3, -CH2CH3, n-propyl, isopropyl, -och3, -Och2CH3or-CF3.

In some embodiments, when R7represents alkyl, alkenyl, quinil, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl or sulphonamido, R7possibly substituted by one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, Elke the sludge, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments, R8represents hydrogen, unsubstituted or substituted alkyl (including, but not limited to, unsubstituted or substituted C1-C4alkyl). In some embodiments, R8represents an unsubstituted or substituted alkenyl, including, but not limited to, unsubstituted or substituted C2-C6alkenyl. In some embodiments, R8represents an unsubstituted or substituted quinil, including, but not limited to, unsubstituted or substituted C2-C5quinil. In some embodiments, R8represents an unsubstituted or substituted cycloalkyl, including, but not limited to, unsubstituted or substituted C2-C5cycloalkyl. In some embodiments, R8represents an unsubstituted or substituted heteroseksualci. In some embodiments, R8represents an unsubstituted or substituted heteroalkyl, including, but not limited to, unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R8represents an unsubstituted or substituted alkoxy, including but not limited to, nezam is placed or replaced With 1-C4alkoxy. In some embodiments, R8represents an unsubstituted or substituted amido, including, but not limited to, unsubstituted or substituted C1-C4amido. In some embodiments, R8represents an unsubstituted or substituted amino. In some embodiments, R8represents an unsubstituted or substituted acyl, unsubstituted or substituted, acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted, sulphonamido or unsubstituted or substituted C1-C4sulfonamide. In some embodiments, R8represents halogeno, which is the-I, -F, -Cl or-Br. In some embodiments, R8selected from the group consisting of cyano, hydroxy and nitro. In some other embodiments, R8represents-CH3, -CH2CH3, n-propyl, isopropyl, -och3, -Och2CH3or-CF3.

In some embodiments, when R8represents alkyl, alkenyl, quinil, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl or sulphonamido, R8possibly substituted by one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, is laksi, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments, R5, R6, R7and R8represent N.

In some embodiments X is absent. In some embodiments X is a -(CH(R9))zand z independently is an integer 1, 2, 3, or 4.

In some embodiments, R9represents an unsubstituted or substituted alkyl, including but not limited to, unsubstituted or substituted C1-C10alkyl. In some embodiments, R9represents an unsubstituted or substituted cycloalkyl, including, but not limited to, unsubstituted or substituted C3-C7cycloalkyl. In some embodiments, R9represents methyl or hydrogen. In some embodiments, R9represents an unsubstituted or substituted heteroseksualci, including, but not limited to, unsubstituted or substituted C2-C10heteroalkyl. In some embodiments, R9represents an unsubstituted or substituted heteroalkyl, including, but not limited to, nezamedin the th or substituted C 2-C10heteroalkyl.

When R9represents any of the above, in some embodiments X is a-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-or-CH(CH2CH3)-. In some embodiments, when X represents-CH(CH3)-, -CH(CH3)- is (S)- or (R)-stereochemical configuration.

In some embodiments of compounds of formula I Y is absent. In some embodiments Y is-O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -N(R9)(C=O)-, -N(R9)(C=O)NH-, -N(R9)C(R9)2- (such as-N(R9)CH2- specifically-N(CH3)CH2-, N(CH(CH3)2)CH2or N(CH2CH3)CH2-), -N(R9)-, -N(CH3)-, -N(CH2CH3)- or-N(CH(CH3)2)-. In some embodiments Y is-C(=O)-(CHR9)z-, and z independently is an integer 1, 2, 3, or 4.

In some embodiments, X-Y is-CH2-, -CH2-N(CH3), -CH(CH3)-NH-, (S) -CH(CH3)-NH - or (R) -CH(CH3)-NH-. In some embodiments, X-Y is-N(CH3)-CH2-, N(CH2CH3)CH2-, -N(CH(CH3)2)CH2- or-NHCH2-.

In some embodiments Wdrepresents a member selected from the group consisting of nezam the seal or substituted geterotsiklicheskie, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl. In some embodiments Wdrepresents an unsubstituted or substituted monocyclic heteroaryl or unsubstituted or substituted bicyclic heteroaryl. In some embodiments Wdis a bicyclic heteroaryl having at least one heteroatom, for example, bicyclic heteroaryl having at least one ring nitrogen atom. In some embodiments Wdis a bicyclic heteroaryl having at least two heteroatoms, for example, bicyclic heteroaryl having at least two ring nitrogen atom. In some embodiments Wdis a bicyclic heteroaryl having two heteroatoms in the ring which is attached to XY. In some embodiments Wdis a bicyclic heteroaryl having two ring nitrogen atom in the ring is attached to XY. In some embodiments Wdis a bicyclic heteroaryl having four heteroatoms, for example, bicyclic heteroaryl with four ring nitrogen atom. In some embodiments Wdrepresents an unsubstituted or substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidine-1-yl, unsubstituted or substituted 7-amino-2-methyl-2H-piraso what about[4,3-d]pyrimidine-3-yl, unsubstituted or substituted 6-metylene-N-purine-6-yl, or unsubstituted or substituted 6-amino-N-purine-9-yl.

In some embodiments Wdis one of the following:

,

where R3represents hydrogen, halogen, phosphate, urea, carbonate, alkyl, alkenyl, quinil, cycloalkyl, heteroalkyl or heteroseksualci;

R11represents H, alkyl, halogeno, amino, amido, hydroxy or alkoxy, and

R12represents H, alkyl, cyano, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci, cycloalkyl, amino, carboxylic acid, alkoxycarbonyl or amido.

In some embodiments Wdrepresents:

.

In some embodiments Wdrepresents:

.

In some embodiments Wdrepresents:

.

In some embodiments Wdrepresents:

.

In some embodiments WdR3represents a member selected from the group consisting of hydrogen, halogen, phosphate, urea, carbonate, unsubstituted or substituted alkyl, unsubstituted or substituted, alkene is a, unsubstituted or substituted quinil, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted geterotsiklicheskie.

In some embodiments Wdwhen R3represents alkyl, quinil, cycloalkyl, heteroalkyl or heteroseksualci, he substituted phosphate, urea, or carbonate.

In some embodiments, R11is a member of the group consisting of hydrogen, unsubstituted or substituted alkyl, halogeno, which includes the-I, -F, -Cl or-Br. In some embodiments, R11represents an unsubstituted or substituted amino, unsubstituted or substituted amido, hydroxy or unsubstituted or substituted alkoxy. In some embodiments, R11represents a phosphate, unsubstituted or substituted urea or carbonate.

In some embodiments, when R11represents alkyl, amino, amido, hydroxy or alkoxy, he substituted phosphate, urea, or carbonate.

In some embodiments-X-Y-Wdrepresents one of the following groups:

In some oploceni the x R 12is a member of the group consisting of hydrogen, cyano, halogen, unsubstituted or substituted alkyl, and unsubstituted or substituted quinil, unsubstituted or substituted alkenyl. In some embodiments, R12represents an unsubstituted or substituted aryl. In some embodiments, R12represents an unsubstituted or substituted heteroaryl, which includes, but is not limited to this, heteroaryl having a 5-membered ring, heteroaryl having the six-membered ring, heteroaryl at least one ring nitrogen atom, heteroaryl with two ring nitrogen atoms, monocyclic heteroaryl and bicyclic heteroaryl. In some embodiments, R12represents an unsubstituted or substituted heteroseksualci, which includes, but is not limited to this, heteroseksualci with one ring nitrogen atom, heteroseksualci with one ring oxygen atom, R12is heteroseksualci with one ring sulfur atom, 5-membered heteroseksualci, 6-membered heteroseksualci, rich heteroseksualci, unsaturated heteroseksualci, heteroseksualci having unsaturated group attached to geteroseksualnoe ring, heteroseksualci, substituted by oxo, and heteroseksualci, substituted with two oxo. In some embodiments, R represents an unsubstituted or substituted cycloalkyl, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl substituted by one oxo, cycloalkyl having unsaturated group attached to cycloalkyl ring. In some embodiments, R12represents an unsubstituted or substituted amido, carboxylic acid, unsubstituted or substituted, acyloxy or unsubstituted or substituted alkoxycarbonyl.

In some embodiments, when R12represents alkyl, quinil, alkenyl, aryl, heteroaryl, heteroseksualci or cycloalkyl, he substituted phosphate. In some embodiments, when R12represents alkyl, quinil, alkenyl, aryl, heteroaryl, heteroseksualci or cycloalkyl, he substituted urea. In some embodiments, when R12represents alkyl, quinil, alkenyl, aryl, heteroaryl, heteroseksualci or cycloalkyl, it is replaced by carbonate.

In some embodiments, when R12represents alkyl, quinil, alkenyl, aryl, heteroaryl, heteroseksualci, cycloalkyl, alkoxycarbonyl, amido or acyloxy, he substituted one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, su is ifosamide, halogeno, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl or sulfonamide itself can be replaced.

In some embodiments, R12Wdrepresents one of the following groups:

-CN, -Br, -Cl, -I, -H, -Me, -Et, -ISO-Pr,

In some embodiments Wdis pyrazolopyrimidine formula is III:

,

where R11represents H, alkyl, halogeno, amino, amido, hydroxy or alkoxy, and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci or cycloalkyl. In some embodiments, R11represents amino, and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci or cycloalkyl. In some embodiments, R11represents amino, and R12represents alkyl, halogeno, aryl, heteroaryl, heteroseksualci or cycloalkyl. In some embodiments, R11represents amino, and R12represents a monocyclic heteroaryl. In some embodiments, R11represents amino, and R12is a bicyclic heteroaryl. In some embodiments, R11represents amino, and R12represents cyano, amino, carboxylic acid, acyloxy, alkoxycarbonyl or amido.

In some embodiments, the compound of formula I is a compound that has a structure selected from the group consisting of compounds of the formula 1-a, 1-B, 2-a, 2-B, IV, V, V-A, VI, VI-A, VI-B, VI-C, 6-C1, 6 C2, VI-D and 6-D:

In another embodiment the compound of formula I is a compound that has a structure selected from the group consisting of compounds of the formula VII, 7-a, VIII, VIII-A and 8-a:

Any of the described elements and their substituents for compounds of formula 1 can be used in any combination.

In one aspect, relate to compounds of formula I, IV, V, VI, VII or VIII, R3represents H, CH3, CF3, Cl, F, aryl or heteroaryl; In represents an alkyl or a group of formula II

,

where Wcrepresents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is an integer 0, 1, 2, 3 or 4; R5, R6, R7The R 8are H; X is absent or represents (CH2)z; z is 1; Y is absent, represents-N(R9)- or-N(R9)CH(R9)-; R9represents hydrogen, C1-C10alkyl, C3-C7cycloalkyl or2-C10heteroalkyl; and Wdis pyrazolopyrimidine or purine.

In another aspect, related to the compounds of formula I, IV, V, VI, VII or VIII, R3represents H, CH3, CF3, Cl or F; b is an alkyl or a group of formula II, which represents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R5, R6, R7and R8are H; X is absent or represents (CH2)z; z is 1; Y is absent, represents-N(R9)- or-N(R9)CH(R9)-; R9represents hydrogen, methyl or ethyl; Wdrepresents:

or; R11represents amino; and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci, cycloalkyl, cyano, amino, carbon is th acid, alkoxycarbonyl or amido.

In another aspect, related to the compounds of formula I, IV, V, VI, VII or VIII, R3represents N, CH3, CF3, Cl or F; b is an alkyl or a group of formula II, which represents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R5, R6, R7and R8represents H; X represents (CH2)z; z is 1; Y is absent, and Wdis:; R11represents amino; and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl or amido.

In another aspect, related to the compounds of formula I, IV, V, VI, VII or VIII, R3represents N, CH3, CF3, Cl or F; b is an alkyl or a group of formula II, which represents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate;q is 0, 1 or 2; R5, R6, R7and R8represents H; X represents (CH2)z; z is 1; Y is-N(R9)-; R9represents hydrogen, methyl or ethyl; and Wdrepresents.

In another aspect, related to the compounds of formula I, IV, V, VI, VII or VIII, R3represents N, CH3, CF3, CL or F; b is an alkyl or a group of formula II, which represents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R5, R6, R7and R8are H; X is absent; Y is-N(R9)CH(R9)-; R9represents hydrogen, methyl or ethyl; and Wdrepresents.

In addition, according to the invention proposed compound of formula IX or its pharmaceutically acceptable salt,

,

where Wa1and Wa2independently represent CR5, S, N or NR4and Wa4independently represents CR7, S, N or NR4where not more than two adjacent atoms in the ring PR is astavliaut a nitrogen or sulfur, and where Wa1is a S, one of Wa2and Wa4represents N or NR4;

Wb5represents CR8, N or NR8;

In represents alkyl, amino, heteroalkyl, cycloalkyl, heteroseksualci or a group of formula II:

,

where Wcrepresents aryl, heteroaryl, heteroseksualci or cycloalkyl, and

q is an integer 0, 1, 2, 3 or 4;

Wdabsent or represents geterotsyklicescoe, aryl or heteroaryl group;

X is absent or represents -(CH(R9))z- and in each case z independently is an integer 1, 2, 3 or 4;

Y is absent, represents-O-, -S-, -S(=O)-, -S(=O)2-, -N(R9)-, -C(=O)-(CHR9)z-C(=O)-, -N(R9)- or-N(R9)-C(=O)NH-, -N(R9)C(R9)2 - or-C(=O)-(CHR9)z-;

R1represents hydrogen, alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate;

R2represents alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl, heteroaromatic, is laksi, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy, nitro, phosphate, urea, or carbonate;

R4represents hydrogen, acyl, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci or1-C4heteroalkyl;

R5, R7and R8independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halogen, cyano, hydroxy or nitro;

in each case, R9independently represents hydrogen, C1-C10alkyl, C3-C7cycloalkyl, heteroseksualci or3-C10heteroalkyl.

The substituents described for the compounds of formula I, applies equally to compounds of the formula IX, with the exception of Wa1, Wa2, Wa4and Wb5, which further defined as follows.

In some embodiments Wa1represents CR5, S, N or NR4.

In some embodiments Wa2represents CR5, S, N or NR4.

In some embodiments Wa4represents CR7, S, N or NR4.

In some embodiments Wb5represents CR8, N or NR8.

In some embodiments, the connection f is rmula IX has the structure which is a member of the group consisting of: (1) Wa1represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents CR8; (2) Wa1represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents CHR8; (3) Wa1represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents N; (4) Wa1represents NR4, Wa2represents CR5, Wa4represents CR7and Wb5represents NR8; (5) Wa1represents NR4, Wa2represents N, Wa4represents CR7and Wb5represents CR8; (6) Wa1represents NR4, Wa2represents N, Wa4represents CR7and Wb5represents CHR8; (7) Wa1represents NR4, Wa2represents N, Wa4represents a C 7and Wb5represents N; (8) Wa1represents NR4, Wa2represents N, Wa4represents CR7and Wb5represents NR8; (9) Wa1represents NR4, Wa2represents CR5, Wa4represents N, and Wb5represents CR8; (10) Wa1represents NR4, Wa2represents CR5, Wa4represents N, and Wb5represents CHR8; (11) Wa1represents NR4, Wa2represents CR5, Wa4represents N, and Wb5represents N; (12) Wa1represents NR4, Wa2represents CR5, Wa4represents N, and Wb5represents NR8; (13) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5represents CR8; (14) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5is Soboh the CHR 8; (15) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5represents N; (16) Wa1is a S, Wa2represents CR5, Wa4represents N, and Wb5represents NR8; (17) Wa1represents N, Wa2represents CR5, Wa4represents S, and Wb5represents CR8; (18) Wa1represents N, Wa2represents CR5, Wa4represents S, and Wb5represents CHR8; (19) Wa1represents N, Wa2represents CR5, Wa4represents S, and Wb5represents N; (20) Wa1represents N, Wa2represents CR5, Wa4represents S, and Wb5represents NR8; (21) Wa1represents CR5, Wa2represents N, Wa4represents S, and Wb5represents CR8; (22) Wa1represents CR5, Wa2not only is em a N, Wa4represents S, and Wb5represents CHR8; (23) Wa1represents CR5, Wa2represents N, Wa4represents S, and Wb5represents N; (24) Wa1represents CR5, Wa2represents N, Wa4represents S, and Wb5represents NR8; (25) Wa1is a S, Wa2represents N, Wa4represents CR7and Wb5represents CR8; (26) Wa1is a S, Wa2represents N, Wa4represents CR7and Wb5represents CHR8; (27) Wa1is a S, Wa2represents N, Wa4represents CR7and Wb5represents N; (28) Wa1is a S, Wa2represents N, Wa4represents CR7and Wb5represents NR8; (29) Wa1represents CR5That Wa2represents N, Wa4represents NR4and Wb5represents CR8; (30) Wa1is Soboh the CR 5, Wa2represents N, Wa4represents NR4and Wb5represents CHR8; (31) Wa1represents CR5, Wa2represents N, Wa4represents the NR4and Wb5represents N; (32) Wa1represents CR5, Wa2represents N, Wa4represents NR4and Wb5represents NR8; (33) Wa1represents CR5, Wa2represents CR5, Wa4represents S, and Wb5represents CHR8; (34) Wa1represents CR5, Wa2represents CR5, Wa4represents S, and Wb5represents CR8; (35) Wa1represents CR5, Wa2represents CR5, Wa4represents S, and Wb5represents N; and (36) Wa1represents CR5, Wa2represents CR5, Wa4represents S, and Wb5represents NR8.

In some embodiments, R4is a member of the group is, consisting of hydrogen, unsubstituted or substituted acyl, unsubstituted or substituted alkyl, which includes, but is not limited to, unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted alkenyl, which includes, but is not limited to this, With2-C5alkenyl, unsubstituted or substituted quinil, which includes, but is not limited to this, With2-C5quinil, unsubstituted or substituted cycloalkyl, which includes, but is not limited to this, With3-C5cycloalkyl, unsubstituted or substituted geterotsiklicheskie and unsubstituted or substituted heteroalkyl, which includes, but is not limited to, unsubstituted or substituted C1-C4heteroalkyl.

In some embodiments, when R4represents acyl, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci or heteroalkyl, he substituted one or more than one alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, sulfonamide, halogen, cyano, hydroxy or nitro, each alkyl, heteroalkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy or sulfonamide itself can be replaced.

In some embodiments the compound of formula IX represents a connection, which has a structure selected from the group consisting of compounds of formulas X, XI, XII, XIII and XIV:

Any of the described elements and their substituents for compounds of formula IX can be used in any combination.

In one aspect, related to the compounds of formulas IX, X, XI, XII, XIII or XIV, In represents an alkyl or a group of formula II:

,

where Wcrepresents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is an integer 0, 1, 2, 3 or 4; R4, R5, R7and R8represent H or methyl; X is absent or represents (CH2)z;

z is 1; Y is absent, represents-N(R9)- or-N(R9)CH(R9)-; R9represents hydrogen, C1-C10alkyl, C3-C7cycloalkyl or3-C10heteroalkyl; and Wdis pyrazolopyrimidine or purine.

In another aspect, related to the compounds of formulas IX, X, XI, XII, XIII or XIV, is alkiline grouping of the formula II, where Wwithrepresents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is an integer 0, 1, 2, 3 or 4; R4, R5and R7represent H or methyl; R8represents H; X is absent or represents (CH2)z;

z is 1; Y is absent or represents-N(R9)-; R9represents hydrogen, methyl or ethyl; Wdis:or; R11represents amino; and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl or amido.

In another aspect, related to the compounds of formulas IX, X, XI, XII, XIII or XIV, In represents a grouping of formula II, where We represents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3or nitro; R2represents halogeno, hydroxy, cyano or nitro; q is 0, 1 or 2; R4, R5and R7represent H or methyl; R8represents H; X p is ecstasy a (CH 2)z; z is 1; Y is absent, and Wdis:;

R11represents amino; and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci or cycloalkyl.

In another aspect, related to the compounds of formulas IX, X, XI, XII, XIII or XIV, In represents an alkyl or a group of formula II, where Wcrepresents aryl, heteroaryl, heteroseksualci or cycloalkyl, R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R4, R5and R7represent H or methyl; R8represents H; X represents (CH2)z; z is 1; Y is absent, and Wdis:; R11represents amino; and R12represents H, alkyl, quinil, alkenyl, halogeno, aryl, heteroaryl, heteroseksualci, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl or amido.

In another aspect, related to the compounds of formulas IX, X, XI, XII, XIII or XIV, In represents an alkyl or a group of formula II, where We represents aryl, heteroaryl, heteroseksualci or cycloalkyl; R1represents H, -, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R4, R5and R7represent H or methyl; R8represents H; X represents (CH2)z; z is 1; X represents (CH2)z; z is 1; Y is-N(R9)-; R9represents hydrogen, methyl or ethyl; and Wdrepresents.

In another aspect, related to the compounds of formulas IX, X, XI, XII, XIII or XIV, In represents an alkyl or a group of formula II, where We represents aryl, heteroaryl, heteroseksualci or cycloalkyl, R1represents H, -F, -Cl, -CN, -CH3, isopropyl, -CF3, -Och3, nitro, or phosphate; R2represents halogeno, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R4, R5and R7represent H or methyl; R8represents H; X is absent; Y is-N(R9)CH(R9)-; R9represents hydrogen, methyl or ethyl; Wdis:.

Illustrative embodiments of compounds of formula 1 and formula 1, where R3selected from any of H, Cl,F or methyl; any Wa2selected from CH, N, C-CN, or-och3; any Wa3selected from CH, N, CF3or-CH3; any Wa4selected from CH, N or C-CF3; R8selected from H, Me, or Cl; In any described as in Table 1; and R12described as in Table 2. The compounds of formula 1 and formula 1 can contain any substituents defined for R3, Wa2, Wa3, Wa4, R8, And R12. Described specific embodiments in no way limit the invention, and are descriptive examples of compounds according to the invention. Some additional typical compounds of formula 1-a and 1-b are illustrated in Table 5.

Table 1.
Illustrative examples In connection with
the structure of formulas IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV.
No. subclassInNo. subclassInNo. subclassIn
In-1In-2 B-3-CH(CH3)2
B-4B-5B-6
In-7In-8In-9
-10B-11B-12
B-13B-14B-15
B-16B-17 B-18
B-19B-20B-21
B-22B-23In-24
B-25In-26In-27
B-28B-29B-30

B-31In-32 B-33
B-34B-35B-36
B-37In-38B-39
In-40B-41In-42
B-43In-44B-45
In-46-47 B-48
In-49-50In-51
B-52In-53In-54
B-55In-56B-57
In-58In-59In-60
B-61In-62In-63

In-6465B-66
B-67In-68In-69
In-70B-71In-72
In-73In-74-75
-76In-77 In-78
In-79In-80In-81
In-82In-83In-84
In-85In-86In-87-CH3
In-88-CH2CH3In-89In-90
In-91To-92B-93

B-94B-95In-96
In-97In-98In-99
In-100In-101In-1022

Table 2.
Illustrative examples of R12in the compound having the structure of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV.
No. subclassR12No. subclassR12No. subclass R12
12-1-CN12-2-Br12-3-Cl
12-4-CH2CH312-5-CH312-6-CH(CH3)2
12-712-812-9
12-1012-1112-12
12-1312-1412-15
12-1612-7 12-18
12-1912-2012-21

12-2212-2312-24
12-2512-2612-27
12-2812-2912-30
12-31 12-3212-33
12-3412-34-H12-36
12-3712-3812-39
12-4012-4112-42
12-4312-4412-45
12-4612-47 12-48
12-4912-5012-51

12-5212-5312-54
12-5512-5612-57
12-5812-5912-60
12-61-I12-62 12-63
12-6412-6512-66
12-6712-6812-69
12-7012-7112-72
12-7312-7412-75
12-7612-77 12-78
12-7912-8012-81

12-8212-8312-84
12-8512-8612-87
12-8812-8912-90
12-9112-92 12-93
12-9412-9512-96

Illustrative embodiments of compounds of formula 2 and formula 2, where R3selected from any of H, Cl, F or methyl; any Wa2selected from CH, N, C-CN, or-och3; any Wa3selected from CH, N, CF3or-CH3; any Wa4selected from CH, N or C-CF3; R8selected from H, Me, or Cl; In any described as in Table 1; R12defined as in Table 2, and any X-Y-Wddescribed as in Table 3. The compounds of formula 2 and formula 2-In can contain any substituents defined for R3, Wa2, Wa3, Wa4, R8,, R12and X-Y-Wd. Described specific embodiments in no way limit the invention, and are descriptive examples of compounds according to the invention. Some additional typical compounds of formula 2-a and 2-In illustrated in Table 5.

Table 3.
Typical examples of X-Y-Wdto connect with
the structure of formula 1, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV.
No. subclassX-Y-WdNo. subclassX-Y-WdNo. subclassX-Y-Wd
123
456
789
10 1112
131415

161718
192021
222324
25 2627
282930
313233
343536

373839
40 4142
434445
464748
495051
525354
55

Illustrative embodiments of compounds of formula 6-a, where R3selected from any of H, Cl, F or methyl; In any described as in Table 1; and R12described as in Table 2. The compounds of formula 6-a can contain any substituents defined for R3, And R12. Described specific embodiments in no way limit the invention, and are descriptive examples of compounds according to the invention. Some additional typical compounds of formula 6-a is illustrated in Table 5.

Illustrative embodiments of compounds of formula 6-C1, where R3selected from any of H, Cl, F or methyl; In any described as in Table 1; R9selected from-H, -CH3or-CH2CH3; and any R12described as in Table 2. The compounds of formula 6-C1 can contain any substituents defined for R3,, R9and R12. Described specific embodiments in no way limit the invention, and are descriptive examples of compounds according to the invention. Some additional typical compounds of formula 6-C1 illustrated in Table 5.

Illustrative embodiments of compounds of formula 6-C2, where R3you are the wounds from any of H, Cl, F or methyl; In any described as in Table 1; and R9selected from-H, -CH3or-CH2CH3. The compounds of formula 6-C2 can contain any substituents defined for R3, And R9. Described specific embodiments in no way limit the invention, and are descriptive examples of compounds according to the invention. Some additional typical compounds of formula 6-C2 illustrated in Table 5.

Illustrative embodiments of compounds of formula 6-D, where R3selected from any of H, Cl, F or methyl; In any described as in Table 1; and R9selected from-H, -CH3or HE2CH3. The compounds of formula 6-D can contain any substituents defined for R3, And R9. Described specific embodiments in no way limit the invention, and are descriptive examples of compounds according to the invention. Some additional typical compounds of formula 6-D are illustrated in Table 5.

Illustrative embodiments of formula VIII, where R3selected from any of H, Cl, F or methyl; any Wa2selected from CH, N, C-CN, or-och3; any Wa3selected from CH, N, CF3or-CH3; any Wa4selected from CH, N or C-CF 3; In any described as in Table 1; R12described as in Table 2, and any X-Y-Wddescribed as in Table 3. The compounds of formula VIII can contain any substituents defined for R3, Wa2, Wa3, Wa4,, R12and X-Y-Wd. Described specific embodiments in no way limit the invention, and are descriptive examples of compounds according to the invention. Some additional typical compounds of formula VIII are illustrated in Table 5.

.

In addition, the proposed branch connection formulas 9A-9BD, owned by the General structural formula IX, where R4selected from-H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl; R5selected from H, Cl, F, methyl or trifloromethyl; R7selected from H, Cl, F, methyl, trifloromethyl, cyano, hydroxyl, ethyl, isopropyl and cyclopropyl; R8selected from H, methyl, or isopropyl; In any described as in Table 1; any X-Y-Wddescribed as in Table 3, and R12described as in Table 2. Compounds of formula 9A-9BD can contain any substituents defined for R4, R5, R7R8In X-Y-Wdand R12. Described specific embodiments in no way limit the invention, and are opiates the different examples of compounds according to the invention. Some additional typical compounds of formulas from 9-a to 9-BD is illustrated in Table 5.

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Other illustrative examples of the compounds include, but are not limited to, the following:

The chemical structure described in this application may be synthesized in accordance with one or more illustrative diagrams in this application and/or methods that are well known in the art.

Unless otherwise stated, the reactions set forth in this application are at atmospheric pressure, generally in the temperature range from -10°C up to 200°C. moreover, except where otherwise indicated, it is assumed that the duration of the reactions and conditions are approximate, for example, they run at about atmospheric pressure in the temperature range from prima is but -10°C to about 110°C for a period of time from about 1 to about 24 hours; the duration of the reaction left overnight, the average period of time of about 16 hours.

The terms "solvent", "organic solvent" or "inert solvent" each mean a solvent inert under the conditions described in this reaction, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane (DCM)), diethyl ether, methanol, N-organic ("NMP"), pyridine, and the like. Unless otherwise noted, solvents used in the reactions described in this application are inert organic solvents. If not indicated otherwise, for each g of the limiting reagent, an equivalent amount is one cm3(cc) (or ml) of solvent.

If desired, isolation and purification of chemical structures and intermediates described in this application can be implemented using any suitable methods of separation or purification, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick-layer chromatography, or a combination of these methods. Specific illustrations of suitable separation techniques, and selection can be obtained by reference to the following examples. However, can also be used which are in turn supported by other equivalent methods of separation or selection.

If desired, (R)- and (S)-isomers of the compounds of the present invention, if present, can be separated by methods known to experts in the art, for example, through education diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation diastereoisomeric derivatives that can be separated, for example, by crystallization, gas-liquid or liquid chromatography; through selective engagement of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or recovery, followed by separation of the modified and unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral environment, for example on a chiral substrate, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized in the asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by conversion of one enantiomer to the other by asymmetric transformation.

Compounds described in this application may be brought into contact with farmacevtichesky acceptable acid with formation of the corresponding salts accession acid.

Most possibly substituted parent compounds and other reagents are commercially available, for example from Aldrich Chemical Company (Milwaukee, WI), or can be easily obtained by specialists in the art using commonly used methodology of synthesis.

In General, compounds according to the invention can be synthesized using an appropriate combination of generally well known methods of synthesis. Methods useful for the synthesis of these chemical structures, as is easily understandable, and accessible to specialists in the relevant field of engineering with regard to the present description.

Compounds according to the invention can be synthesized using the appropriate combinations known in the art methods of synthesis. The following discussion is given to illustrate some of the diverse methods available for use in obtaining the compounds according to the invention and is not intended to limit the scope of reactions or sequences of reactions that can be used in obtaining the compounds of the present invention.

Reaction scheme 1:

According to Scheme 1, stage 1, ketone 101 is transformed into the corresponding alkene, using, for example, malononitrile and piperidine acetic acid. The product, a compound of formula 102, emit. According to the about Scheme 1, stage 2, the compound of formula 102 is subjected to cyclization to pyridine, using, for example, ammonia in methanol. The product, a compound of formula 103, emit. According to Scheme 1, stage 3, the compound of formula 103 is subjected to hydrolysis to obtain the corresponding carboxylic acid. The product, a compound of formula 104, emit. According to Scheme 1, stage 4, the compound of formula 104 is transformed into amide, using, for example, the standard amide reagent combinations, such as EDCI (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide). The product, a compound of formula 105, emit. According to Scheme 1, stage 5, the compound of formula 105 is transformed into the corresponding amide using, for example, chlorocatechol. The product, compound of formula 106, emit. According to Scheme 1, stage 6, the compound of formula 106 is converted into a compound of formula 107 using, for example, acetic acid. The product, a compound of formula 107, emit. According to Scheme 1, stage 7, the compound of formula 107 is subjected to substitution of the chlorine atom in the interaction with the nucleophile and the substrate, such as pyrazolopyrimidine 108 and potassium carbonate. The product, a compound of formula 109, emit. According to Scheme 1, stage 8, the compound of formula 109 is subjected to reaction combination with aryl - or heteroaryl-Bronevoy acid or derivative Bronevoy acid, such as, for example, brolan using, for example, conditions catalyzed p is lladies of combination reaction. The product, compound of formula 110, allocate.

Reaction scheme 2:

According to Scheme 2, stage 1, the compound of formula 108 is converted into a compound of formula 202, for example, by alkylation of compounds of formula 201. The product, compound of formula 202, emit. According to Scheme 2, step 2, compound of formula 202 is converted into a compound of formula 203, for example, by saponification. The product, a compound of formula 203, emit. According to Scheme 2, stage 3, the compound of formula 203 is subjected to cyclization to hintline formula 205, for example, by reaction in a sealed tube with compound of formula 204 and a dehydrating agent such as PCI5. The product, a compound of formula 205, allocate.

Reaction scheme 3:

According to Scheme 3, the compound of formula 109 is converted into a compound of formula 302, for example, by reaction of a combination of Sonogashira with a compound of formula 301. The product, compound of formula 302, allocate.

Reaction scheme 4:

According to Scheme 4, stage 1, the compound of formula 401 is converted into a compound of formula 403, for example, through a two-stage process combining Hake with a compound of formula 402 with subsequent acid catalyzed the cyclization in methanol. The product, a compound of formula 403, emit. what according to Scheme 4, stage 2, the compound of formula 403 is converted into a compound of formula 404, for example, by reaction with appropriately substituted aniline. The product, compound of formula 404, emit. According to Scheme 4, stage 3, the compound of formula 404 is converted into a compound of formula 405, for example, by reduction using lithium aluminum hydride. The product, compound of formula 405, emit. According to Scheme 4, stage 4, the compound of formula 405 is converted into a compound of formula 406, for example, by reacting with thionyl chloride. The product, compound of formula 406, emit. According to Scheme 4, stage 5, the compound of formula 406 is converted into a compound of formula 407, for example, by alkylation with pyrazolopyrimidines, using a base such as potassium carbonate. The product, compound of formula 407, emit. According to Scheme 4, stage 6, the compound of formula 407 is converted into a compound of formula 408, for example, via the Suzuki reaction. The product, compound of formula 408, allocate.

Reaction scheme 5:

According to Scheme 5, stage 1, the compound of formula 501 is converted into a compound of formula 502, for example, using a reagent suitable for introducing the carboxylic acid, for example, oxalicacid. The product, compound of formula 502 may emit. According to scheme 5, the stud and 2, the compound of formula 502 is converted into a compound of formula 503, for example, by reacting, for example, arylamines. The product, a compound of formula 503, emit. According to Scheme 5, stage 3, the compound of formula 503 is converted into a compound of formula 504, for example, through a combination of style, using the appropriate vinyl-stannane. The product, compound of formula 504, out. According to Scheme 5, stage 4, the compound of formula 504 turned into tertiary amide, the compound of formula 505, through interaction with charaterization and the base sodium hydride. The compound of formula 505 emit. According to Scheme 5, stage 5, the compound of formula 505 oxidized to the aldehyde using, for example, osmium tetroxide and peridinin sodium. The product, compound of formula 506, emit. According to Scheme 5, stage 6, the compound of formula 506 is converted into a compound of formula 404, for example, by aldol reaction in ethanol in the presence of a base such as cesium carbonate. The product, compound of formula 404, emit. According to Scheme 5, stage 7, the compound of formula 404 reduced to the primary alcohol by restoring using, for example, lithium aluminum hydride, to obtain the compounds of formula 405, which secrete. According to Scheme 5, stage 8, the compound of formula 405 is converted into a compound of formula 507 by interacting with cetarehhloristam carbon and trif what nilpotent. The compound of formula 507 may emit. This connection may be a Central intermediate compound in the synthesis of compounds according to the invention.

Reaction scheme 6:

According to Scheme 6, stage 1, the compound of formula 507, synthesized as described in Reaction scheme 5, is converted into a compound of formula 407 through a combination with the compound of the formula 108 in the presence of a base, for example, of potassium tert-butylate. The compound of formula 407 emit. According to Scheme 6, step 2, compound of formula 407 is converted into a compound of formula 408 through a combination of, for example, with arylboronic acid in the presence of catalysts reaction combinations and bases, for example, palladium acetate, triphenylphosphine and sodium carbonate, for example. The compound of formula 408 allocate.

Reaction scheme 7:

According to Scheme 7, stage 1, the compound of formula 701 lead in the interaction with the compound of the formula 702. The product, compound of formula 703, emit. According to Scheme 7, step 2, compound of formula 703 lead in the interaction with possibly substituted purine, such as the compound of formula 704. The product, compound of formula 705, allocate.

Reaction scheme 8:

According to Scheme 8, stage 1, the compound of formula 801 is treated with a reagent such as thionyl chloride,to obtain the compounds of formula 802, which secrete. According to Scheme 8, step 2, compound of formula 802 and the compound of formula 803 combine in the presence of a base. The product, compound of formula 804, emit. According to Scheme 8, stage 3, the compound of formula 804 is converted into a compound of formula 805, which allocate.

Reaction scheme 9:

According to Scheme 9, stage 1, the compound of formula 104 lead in the interaction, for example, sodium nitrite and potassium iodide in acidic conditions to obtain the compounds of formula 901, which can be selected. According to Scheme 9, step 2, compound of formula 901 converted into its acid chloride acid by reacting, for example, oxalicacid, obtaining the compounds of formula 902, which may be selected. According to Scheme 9, stage 3, the acid chloride of the acid of formula 902 lead in the interaction with possibly substituted amino aryl or amino-hetaryl, connection 903, receiving the connection formulas 904, which secrete. According to Scheme 9, stage 4, the compound of formula 904 is subjected to the reaction mixture, for example, aristandros, obtaining the compounds of formula 905, which secrete. According to Scheme 9, the stage 5, the compound of formula 905 is turned into its epoxide by treatment with, for example, meta-chloroperbenzoic acid, receiving the connection formulas 906, which may be selected. According to Scheme 9,stage 6, the compound of formula 906 is subjected to cyclization by treatment, for example with sodium hydride in dimethylformamide, to obtain the compounds of formula 907, which secrete. According to Scheme 9, stage 7, the primary hydroxyl of compounds of formula 907 converted into the bromide by treatment, for example cetarehhloristam carbon and triphenylphosphine, to obtain the compounds of formula 908, which secrete. According to Scheme 9, stage 8, the compound of formula 908 subjected to reaction combination with pyrazolopyrimidines formula 108A by processing, for example, potassium carbonate in dimethylformamide, receiving the connection formulas 909, which secrete. According to Scheme 9, stage 9, dihydroisoquinolin formula 909 subjected to reaction in combination with a possibly substituted aryl - or hetaryl-Bronevoy acid of the formula 910 obtaining the compounds of formula 911, which allocate.

Reaction scheme 10:

According to Scheme 10, stage 1, the compound of formula 1001 is treated with sodium acetate and acetone. The product, compound of formula 1002, allocate.

According to Scheme 10, step 2, compound of formula 1002 is subjected to cyclization to the corresponding pyrazole, for example, with the use of hydrazine in acetic acid and water. The product, compound of formula 1003, emit. According to Scheme 10, stage 3, the compound of formula 1003, for example, alkylate, using dimetilan the veils. The product, compound of formula 1004, emit. According to Scheme 10, stage 4, the compound of formula 1004 is subjected to nitration using, for example, a solution of nitric acid and sulfuric acid. The product, a compound of the formula 1005, emit. According to Scheme 10, the stage 5, the compound of the formula 1005 subjected to saponification using a base such as sodium hydroxide. The product, compound of formula 1006, emit. According to Scheme 10, stage 6, the compound of formula 1006 first converted into the acid chloride acid using thionyl chloride, and then lead into interaction with appropriately substituted aniline with formation of the corresponding amide. The product, compound of formula 1007, emit. According to Scheme 10, a stage 7, a compound of formula 1007 reduced to the corresponding amino-pyrazole, using the conditions of hydrogenation sheet Pd/C (palladium-carbon as catalyst. The product, compound of formula 1008, emit. According to Scheme 10, stage 8, the compound of formula 1008 is subjected to cyclization to the corresponding hintlian, using terms such as chloracetamide and acetic acid. The product, compound of formula 1009, emit. According to Scheme 10, stage 9, the compound of formula 1009 subjected to reaction combination with pyrazolopyrimidines formula 108, for example, using terms such as mpem-butyl potassium in DMF at room temperature (RT). Product is t, the compound of formula 1010, emit. According to Scheme 10, stage 9, the compound of formula 1010 subject of combination reaction with aryl-Bronevoy acid of the formula 910, for example, using catalysis with the use of palladium acetate, in the presence of triphenylphosphine and sodium carbonate in DMF to obtain the compounds of formula 1011. The product, compound of formula 1011, allocate.

Reaction scheme 11:

According to Scheme 11, stage 1, the compound of formula 1101 lead in interaction with titianium potassium in acetonitrile to obtain the compounds of formula 1102, which may be selected. According to Scheme 11, step 2, compound of formula 1102 lead in the interaction with the conjugated complex ester of the formula 1103 obtaining the compounds of formula 1104, which secrete. According to Scheme 11, stage 3, the compound of formula 1104 is subjected to cyclization, for example, by treatment with bromine in ethanol, receiving a thiazole of the formula 1105, which is marked. According to Scheme 11, stage 4, with the compounds of formula 1105 remove protection using, for example, potassium carbonate in aqueous dimethylformamide and receiving the connection formulas 1106, which secrete. According to Scheme 11, stage 5, ester compounds of the formula 1106 subjected to saponification using, for example, sodium hydroxide in water, to obtain the compounds of formula 1107, which secrete. According to Scheme 11, stage 6, St. the free acid of compounds of formula 1107 converted into the acid chloride acid using methods of processing, for example, thionyl chloride, receiving the connection formulas 1108, which may be selected. According to Scheme 11, stage 7, the acid chloride of the acid compounds of formula 1108 lead in the interaction with possibly substituted amino-aryl - or amino-heteroaryl-containing compound of the formula 1109, receiving the connection formula 1110, which secrete. According to Scheme 11, stage 8, primary amine compounds of formula 1110 lead in the interaction with halogenated-chloride, for example, chloroacetylation in pyridine and methylene chloride to obtain the compounds of formula 1111, which secrete. According to Scheme 11, the stage 9, the compound of formula 1111 subjected to cyclization, for example, by heating in a sealed tube in the presence of phosphorylchloride, receiving the connection formulas 1112, which secrete. According to Scheme 11, the stage 10, the connection of triazolopyrimidine formula 1112 lead in the interaction with an pyrazolopyrimidines formula 1113 in the presence of a base, for example /let-butyl potassium in dimethylformamide, to obtain the compounds of formula 1114, which allocate.

Reaction scheme 12:

According to Scheme 12, stage 1, the compound of formula 709 alkylate using possibly substituted purine of the formula 1210. The product, compound of formula 1211, allocate.

Reaction scheme 13:

With the according to Scheme 13, stage 1, the compound of formula 1301 first converted into the acid chloride acid using thionyl chloride, and then lead into engagement with the correspondingly substituted aniline. The product, compound of formula 1302, emit. According to Scheme 13, step 2, compound of formula 1302 is subjected to cyclization to the corresponding thieno-pyrimidinone, for example, using chlorocatechol in acetic acid. The product, compound of formula 1303, emit. According to Scheme 13, stage 3, the compound of formula 1303, such as alkylate, using correspondingly substituted pyrazolo-pyrimidine. The product, compound of formula 1304, emit. According to Scheme 13, stage 4, the compound of formula 1304, for example arriraw using correspondingly substituted Bronevoy acid. The product, compound of formula 1305, allocate.

Reaction scheme 14:

According to Reaction scheme 14, stage 1, iodine-containing ester 1401 result in interaction with Alcina 1402 in the presence of a palladium catalyst, copper iodide and triethylamine (TEA) to connect the alkyne to the aryl nucleus connection 1401 obtaining the compounds of formula 1403. The compound of formula 1403 emit. According to Reaction scheme 14, step 2, compound of formula 1403 is treated with a base potassium hydroxide to obtain carboxylic acid, with the organisations of the formula 1404, if the reaction product is acidified, or a salt thereof. The compound of formula 1404 emit. According to Reaction scheme 14, stage 3, the compound of formula 1404 treated with bis(acetonitrile)dichloro-palladium(II) and TEA for the implementation of the intramolecular ring closure to obtain the compounds of formula 1405. The compound of formula 1405 emit. According to Reaction scheme 14, stage 4, the compound of formula 1405 result in interaction with the primary amine to obtain the compounds of formula 1406. The compound of formula 1406 emit. According to Reaction scheme 14, the stage 5, the compound of formula 1406 treated with hydrochloric acid, removing the protective group on the nitrogen, and receiving the connection formulas 1407. The compound of formula 1407 may be selected. According to Reaction scheme 14, stage 6, the compound of formula 1407 lead in the interaction with the compound of the formula 1408 obtaining the compounds of formula 1409. The compound of formula 1409 allocate.

The reaction scheme 15:

According to Reaction scheme 15, stage 1, iodine-containing ester 1401 result in interaction with Alcina 1501 in the presence of palladium catalyst reaction combinations of copper iodide and TEA with obtaining the compounds of formula 1502. The compound of formula 1502 emit. According to Reaction scheme 15, step 2, compound of formula 1502 is treated with a base potassium hydroxide, receiving ka is boxylic or free acid of compounds of formula 1503. According to Reaction scheme 15, stage 3, the compound of formula 1503 treated with bis(acetonitrile)-dichloropalladium(II) and TEA for the implementation of the intramolecular ring closure to obtain the compounds of formula 1504. The compound of formula 1504 emit. According to Reaction scheme 15, stage 4, the compound of formula 1504 treated with a primary amine to obtain the compounds of formula 1505. The compound of formula 1505 allocate.

Reaction scheme 16:

According to Reaction scheme 16, stage 1, iodine-containing ester 1401 result in interaction with Alcina 1601 in the presence of palladium catalyst reaction combinations of copper iodide and TEA with obtaining the compounds of formula 1602. The compound of formula 1602 emit. According to Reaction scheme 16, step 2, compound of formula 1602 is treated with a base potassium hydroxide, getting carboxylate or free acid of compounds of formula 1603. According to Reaction scheme 16, stage 3, the compound of formula 1603 treated with bis(acetonitrile)-dichloropalladium(II) and TEA for the implementation of the intramolecular ring closure to obtain the compounds of formula 1604. The compound of formula 1604 emit. According to Reaction scheme 16, stage 4, the compound of formula 1604 treated with a primary amine to obtain the compounds of formula 1605. The compound of formula 1605 emit. According to the Reaction the scheme 16, stage 5, the compound of formula 1605 treated with acid to remove the protective groups TNR, receiving the connection formulas 1606, the Compound of formula 1606 allocate.

The reaction scheme 17:

According to Reaction scheme 17, phase 1, the compound of formula 1701 synthesize different ways of synthesis, including Schemes 1 or 2, where, for example, use benzylamine under transformation of compounds of formula 403 in the compound of formula 404. Benzyl protective group of the amine may be removed in accordance with standard chemical reactions removal of protection in obtaining compounds of formula 1701. The compound of formula 1701 is converted into a compound of formula 1702 by alkylation of the amide nitrogen, using a series of 2-carbon-containing synthons that can be subjected to the procedure for removal of protection, oxidation and re-introduction of protection in the form of the corresponding Catala on the connection formulas 1702, which may be selected. According to Reaction scheme 17, stage 2-1, compound of formula 1702 transform, for example, by reductive amination ester groups with the aim of introducing parinello group of compounds of formula 1703 or, alternatively, alkylate with the purpose of this introduction parinello group and obtain the compounds of formula 1703. According to Reaction scheme 17, stage 3-1, with the unity formula 1703 treated with acid to remove Catalinas protective group to obtain the compounds of formula 1704. The compound of formula 1704 emit. According to Reaction scheme 17, the stage 4-1, compound of formula 1704 is subjected to reductive aminating using amine, receiving the connection formulas 1705. The compound of formula 1705 emit. According to Reaction scheme 17, stage 2-2, compound of formula 1702 transform in accordance with the stages 7 and 8 of figure 5 and the stage 1 Scheme 6 with the aim of introducing pyrazolopyrimidinones group of compounds of formula 1706. The compound of formula 1706 emit. According to Reaction scheme 17, stage 3-2, compound of formula 1706 treated with acid to remove Catalinas protective group to obtain the compounds of formula 1707. The compound of formula 1707 can be selected. According to Reaction scheme 17, stage 4-2, the compound of formula 1707 subjected to reductive aminating using amine, to obtain the compounds of formula 1708. The compound of formula 1708 allocate.

The reaction scheme 18:

According to Reaction scheme 18, phase 1, the compound of formula 1701 synthesized as described in Scheme 17, or by any other well-known chemical reactions. The compound of formula 1701 transform by alkylation of the amide nitrogen, using a series of 2-carbon-containing synthons that can be subjected to removal of protection, and in turn alkoxy-protected variety, as long as the ANO for the compounds of formula 1801, which can be selected. According to Reaction scheme 18, step 2, compound of formula 1801 transform using chemical reactions described in stage 2-1 Circuit 17, with the purpose of introducing parinello groups and so convert the compound obtained by removing protection, activation and amination using an amine, receiving the connection formulas 1802, which allocate.

According to Reaction scheme 18, stage 3, the compound of formula 1801 transform using chemical reactions described in stage 2-2 Circuit 17, with the purpose of introducing pyrazolopyrimidinones groups and so convert the compound obtained by removing protection, activation and amination using an amine, receiving the connection formulas 1803, which allocate.

The reaction scheme 19:

According to Reaction scheme 19, phase 1, the compound of formula 1901 treated with amine to obtain the compounds of formula 1902. The compound of formula 1902 emit. According to Reaction scheme 19, step 2, compound of formula 1902 treated with phosphorus oxychloride to form compounds of formula 1903. The compound of formula 1903 emit. According to Reaction scheme 19, stage 3, the compound of formula 1903 lead in interaction with aminopurine formula 1904 obtaining the compounds of formula 1905. The compound of formula 1905 emit. The agreement is but the Reaction scheme 19, stage 4, the compound of formula 1905 treated with hydrochloric acid to remove the protective group on the nitrogen of the purine group to obtain the compounds of formula 1906. The compound of formula 1906 allocate.

The reaction scheme 20:

According to Reaction scheme 20, stage 1, the compound of formula 1401 handle complex air minilogues series 2001, using, for example, the reaction of Hake with subsequent cyclization, to obtain the compounds of formula 2002. The connection formulas allocate 2002. According to Reaction scheme 20, stage 2, the compound of formula 2002 lead in the interaction with 4-amino-N-BOC-piperidine with obtaining the compounds of formula 2002. The compound of formula 2003 emit. The compound of formula 2003 can be used as intermediate compounds in the synthesis of compounds according to the invention. The reaction scheme 21:

According to Reaction scheme 21, the stage 1, the compound of formula 1401 handle alkinilovymi alcohol, for example, formula 2101, in the presence of copper iodide and a catalyst of palladium on coal with obtaining the compounds of formula 2102. The compound of formula 2102 may provide and may cleanse. According to Reaction scheme 21, the stage 1, the compound of formula 2102 lead in the interaction with 4-amino-N-BOC-piperidine with obtaining the compounds of formula 2103. The compound of formula 2103 you elaut. The compound of formula 2103 can be used as intermediate compounds in the synthesis of compounds according to the invention.

Any of the compounds of formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV can be synthesized using the reaction schemes outlined in this application, or variants of these methods that are well known in the art.

These chemical structures can be synthesized using an appropriate combination of generally well known methods of synthesis.

In some embodiments, one or more compounds, which is the object of the invention, specific contact R kinase or a protein kinase selected from the group consisting of mTor, DNA-dependent protein kinase (inventory number of the protein in the database Pubmed (PPAN) AAA79184), tyrosine kinase Abl (CAA52387), Bcr-Abl, kinase hematopoietic cells (PPAN SAN 9695), Src (PPAN CAA24495), receptor-2 growth factor vascular endothelial (PPAN ABB82619), receptor-2 growth factor vascular endothelial (PPAN ABB82619), the receptor for epidermal growth factor (PPAN AG43241), NRN-receptor B4 (iminovogo receptor B4) (PPAN EAL23820), receptor of stem cell factor (PPAN AAF22141), receptor tyrosine-protein kinase TIE-2 (PPAN Q02858), frns-like tyrosine kinase 3 (PPAN NP_004110), receptor-alpha growth factor from platelets (PPAN NP_990080), RET (PPAN CAA73131) and any other protein kinases, are shown in the attached tablecache graphic materials as well as any of their functionally active mutants. In some embodiments IC50 for compounds, which is the object of the invention, in relation to 110α, 110β, 110γ or 110δ is less than about 1 μm, less than about 100 nm, less than about 50 nm, less than about 10 nm, less than 1 nm or even less than about 0.5 nm. In some embodiments IC50 for compounds, which is the object of the invention, in relation to mTor is less than about 1 μm, less than about 100 nm, less than about 50 nm, less than about 10 nm, less than 1 nm or even less than about 0.5 nm. In some other embodiments, one or more compounds which are the object of the invention exhibits a dual binding specificity and is able to inhibit R-kinase (for example, R-kinase class I), as well as a protein kinase (e.g., mTor) with IC50 value of less than about 1 μm, less than about 100 nm, less than about 50 nm, less than about 10 nm, less than 1 nm or even less than about 0.5 nm. One or more compounds which are the object of the invention possess the ability to inhibit tyrosine kinase including, for example, DNA-dependent protein kinase (inventory number of the protein in the database Pubmed (PPAN) AAA79184), tyrosinekinase Abl (CAA52387), Bcr-Abl, kinase hematopoietic cells (PPAN SAN 9695), Src (PPAN CAA24495), receptor-2 growth factor vascular endothelial (PPAN ABB82619), cocktail recipes. is -2 growth factor vascular endothelial (PPAN ABB82619), the receptor for epidermal growth factor (PPAN AG43241), NRN-receptor B4 (PPAN EAL23820), the receptor of stem cell factor (PPAN AAF22141), receptor tyrosine-protein kinase TIE-2 (PPAN Q02858), fms-like tyrosinekinase 3 (PPAN NP_004110), receptor-alpha growth factor from platelets (PPAN NP_990080), RET (PPAN CAA73131) and their functional mutants. In some embodiments of tyrosinekinase represents the Abl, Bcr-Abl, EGFR, or Flt-3 and any other kinase contained in this application Tables.

In some embodiments of the compounds of the present invention exhibit one or more functional characteristic features disclosed in this application. For example, one or more compounds, which is the object of the invention, specific contact R-kinase. In some embodiments S to connect, which is the object of the invention, in relation to 110α, 110β, 110γ or 110δ is less than about 1 μm, less than about 100 nm, less than about 50 nm, less than about 10 nm, less than about 1 nm, less than about 0.5 nm, less than about 100 PM, or less than about 50 PM.

In some embodiments, one or more than one connection, which is the object of the invention may selectively inhibit one or more members of the phosphatidylinositol-3-kinase (R-kinase) type I or class I with IC50 value of about 100 nm, 50 nm, 10 nm, 5 nm, 100 PM, 10 PM or 1 PM or less, kakskerta kinase in the in vitro assays.

In some embodiments, one or more than one of the compounds which are the object of the present invention may selectively inhibit one or two kinase of the phosphatidylinositol-3-kinase (R-kinase type 1 or class 1, consisting of R-kinase α, R-kinase β, R-kinase γ, and R-kinase δ. In some aspects, some of the compounds which are the object of the invention selectively inhibit R-kinase δ compared with all other R-kinase type 1. In other aspects of some of the compounds which are the object of the invention selectively inhibit R-kinase δ and R-kinase γ in comparison with the rest of R-kinase type 1. In still some other aspects of some of the compounds which are the object of the invention selectively inhibit R-kinase α and R-kinase β as compared with the rest of R-kinase type 1. In still some other aspects of some of the compounds which are the object of the invention selectively inhibit R-kinase δ and R-kinase α in comparison with the rest of R-kinase type 1. In still some other aspects of some of the compounds which are the object of the invention selectively inhibit R-kinase δ and R-kinase β as compared with the rest of R-kinase type 1, or selectively inhibit R-kinase δ and R-kinase α in comparison with the rest of R-kinase type I, or selectively inhibit R-kinase α and R-kinase γ is about comparison with other R-kinase type I, or selectively inhibit R-kinase γ, and R-kinase β as compared with the rest of R-kinase type I.

In still another aspect, the inhibitor that selectively inhibits one or more kinases of R-kinase type I, or an inhibitor that selectively inhibits one or more than one R-kinase type I, mediating transmission signal, an alternative may be understood as referring to the connection that demonstrates causing 50% inhibition concentration (S) in relation to a given R-kinase type I, which is below at least 10 times, at least 20 times, at least 50 times, at least 100 times, at least 1000-fold, at least 10100 times or below the IC50 for this inhibitor in the remaining other P13-kinase type 1.

The pharmaceutical composition

According to this invention proposed pharmaceutical compositions containing one or more compounds of the present invention.

In some embodiments according to this invention proposed pharmaceutical composition for treating diseases or conditions associated with undesirable, overactive, harmful or damaging immune response in a mammal. Such undesirable immune response may be associated with or may cause, for example, asthma, emphysema, bronchitis, psoriasis, Allergy, anaphylaxis, and communie disease, rheumatoid arthritis, graft-versus-host and lupus erythematosus. The pharmaceutical compositions of the present invention can be used to treat other respiratory diseases, including, but not limited to, diseases affecting the lobe of the lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract or the nerves and is involved in the act of breathing muscles.

In some embodiments according to this invention proposed pharmaceutical composition for the treatment of disorders such as hyperproliferative disorder, including, but not limited to, cancers such as acute myeloid leukemia, a cancer of the thymus gland, brain, lung, squamous cell carcinoma, skin cancer, eye, retinoblastoma, intraocular melanoma, cancer of oral cavity and oropharyngeal, bladder, gastrointestinal tract, stomach, pancreas, bladder, breast, cervix, head, neck, renal sphere, kidney, liver, ovarian, prostate, colon, esophageal, testicular, gynecological, thyroid, CNS (Central nervous system), PNS (peripheral nervous system), AIDS-associated (e.g., lymphoma and sarcoma Galoshes) or induced by cancer viruses. In some embodiments mentioned pharmaceutical composition is intended the La treatment of benign hyperproliferative disorders, such as benign hyperplasia of the skin (e.g. psoriasis), restenosis, or benign hyperproliferative disorder of the prostate (e.g., benign prostatic hypertrophy (national Department of standardization)).

Also, according to the invention proposed composition for the treatment of liver diseases (including diabetes), pancreatitis or kidney disease (including proliferative glomerulonephritis and induced diabetes renal disease) or pain in a mammal.

Moreover, according to the invention proposed composition for the prevention of implantation of blastocytes the mammal.

The invention also relates to compositions for treating diseases related to vasculogenesis or angiogenesis in a mammal, which may manifest itself in the form of tumor angiogenesis, chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, sarcoma Galoshes and cancer of the ovaries, breast, lung, pancreas, prostate, colon and epidermoid cancer.

Pharmaceutical compositions reveal what iesa object of the invention, usually made containing a therapeutically effective amount of the compounds of the present invention as the active ingredient or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative. Where desirable, the pharmaceutical compositions contain a pharmaceutically acceptable salt and/or coordination complex and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, substances that increase the permeability of solubilization and adjuvants.

The pharmaceutical compositions of the subject invention can be introduced alone or in combination with one or more than one other agent, which is usually administered in the form of pharmaceutical compositions. Where desirable, the compounds according to the invention and the other(s) agent(s) can be mixed in one product or both components can be prepared as separate preparations for use in combination separately or at the same time.

In some embodiments, the concentration of one or more compounds proposed in the pharmaceutical compositions of the present invention, is less than 100%, 90%, 0%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0,5%, 0,4%, 0,3%, 0,2%, 0,1%, 0,09%, 0,08%, 0,07%, 0,06%, 0,05%, 0,04%, 0,03%, 0,02%, 0,01%, 0,009%, 0,008%, 0,007%, 0,006%, 0,005%, 0,004%, 0,003%, 0,002%, 0,001%, 0,0009%, 0,0008%, 0,0007%, 0,0006%, 0,0005%, 0,0004%, 0,0003%, 0,0002% or is 0.0001% wt./mass., mass./about. or about./about.

In some embodiments, the concentration of one or more compounds of the present invention is more 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19,75%, 19,50%, 19,25% 19%, 18,75%, 18,50%, 18,25% 18%, 17,75%, 17,50%, 17,25% 17%, 16,75%, 16,50%, 16,25% 16%, 15,75%, 15,50%, 15,25% 15%, 14,75%, 14,50%, 14,25% 14%, 13,75%, 13,50%, 13,25% 13%, 12,75%, 12,50%, 12,25% 12%, 11,75%, 11,50%, 11,25% 11%, 10,75%, 10,50%, 10,25% 10%, 9,75%, 9,50%, 9,25% 9%, 8,75%, 8,50%, 8,25% 8%, 7,75%, 7,50%, 7,25% 7%, 6,75%, 6,50%, 6,25% 6%, 5,75%, 5,50%, 5,25% 5%, 4,75%, 4,50%, 4,25%, 4%, 3,75%, 3,50%, 3,25%, 3%, 2,75%, 2,50%, 2,25%, 2%, 1,75%, 1,50%, 125%, 1%, 0,5%, 0,4%, 0,3%, 0,2%, 0,1%, 0,09%, 0,08%, 0,07%, 0,06%, 0,05%, 0,04%, 0,03%, 0,02%, 0,01%, 0,009%, 0,008%, 0,007%, 0,006%, 0,005%, 0,004%, 0,003%, 0,002%, 0,001%, 0,0009%, 0,0008%, 0,0007%, 0,0006%, 0,0005%, 0,0004%, 0,0003%, 0,0002% or is 0.0001% wt./mass., mass./about. or about./about.

In some embodiments, the concentration of one or more compounds of the present invention is in the range from about 0,0001% to about 50%, from about 0,001% to about 40%, from approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, from approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, from about 0.07 per cent to bring the LNA 24%, from approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, from approximately 0.1% to approximately 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from approximately 0.5% to approximately 17%, from approximately 0.6% to approximately 16%, from approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, from about 1% to about 10% wt./mass., mass./about. or about./about. about./about.

In some embodiments, the concentration of one or more compounds of the present invention is in the range of from about 0,001% to about 10%, from about 0.01% to about 5%, from approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from approximately 0,07% to about 2%, from about 0.08% to about 1.5%, from about 0,09% to about 1%, from about 0.1% to about 0.9% wt./mass., mass./about. or about./about.

In some embodiments, the one or more compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 grams, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0,009 g, 0.008 g, 0,007 g 0,006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0,0009 g, 0.0008 g, 0,0007 g 0,0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 G.

In some embodiments, the one or more compounds of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0,0006 g 0,0007 g, 0.0008 g, 0,0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0,0035 g, 0.004 g, 0,0045 g, 0.005 g, 0,0055 g 0,006 g, 0,0065 g 0,007 g, 0.0075 g, 0.008 g, 0,0085 g 0,009 g, 0,0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0,045 g, 0.05 g, by 0.055 g, 0.06 g, 0,065 g, 0.07 g, 0.075 g, 0.08 g of 0.085 g, 0.09 g, 0,095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 grams, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5 a, 3, y, 3,5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g

In some embodiments, the one or more compounds of the present invention is in the range of 0.0001-10 g, of 0.0005-9 g, 0.001 to 8 g of 0.005-7 g, 0.01 to 6 g, 0.05 to 5 g, about 0.1-4 g, 0.5 to 4 g, or 1-3,

Compounds according to the invention is effective in a wide range of doses. For example, in the treatment of adult examples of dosages which can be used are the dosage of 0.01-1000 mg; 0.5-100 mg; 1-50 mg per day and 5-40 mg per day. Typical dosage is 10-30 mg / day. The exact dosage will depend on the method of administration, f is RMI, in which injected the connection of the subject being treated, the body weight of the subject being treated, and the preference and experience of the treating physician.

The following describes non-limiting typical pharmaceutical compositions and methods for their manufacture.

Pharmaceutical compositions for oral administration. In some embodiments according to this invention proposed pharmaceutical composition for oral administration containing a compound of the present invention and pharmaceutical excipient, suitable for oral administration.

In some embodiments according to this invention proposed a solid pharmaceutical composition for oral administration containing: (1) an effective amount of the compounds of the present invention; possibly (2) an effective amount of a second agent; and (3) pharmaceutical excipient, suitable for oral administration. In some embodiments, the composition further comprises: (4) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral administration. The pharmaceutical compositions according to the invention suitable for oral administration may be presented as discrete dosage forms, such as capsules fruit is s, sachets or tablets, or liquid or aerosol sprays, each containing a predetermined amount of the active ingredient in the form of powder or granules, a solution or suspension in an aqueous or anhydrous liquid emulsion of the type oil-in-water or a liquid emulsion of the type water-in-oil. Such dosage forms can be manufactured by any method known in the pharmaceutical industry, however, all methods include the stage of bringing the active ingredient into Association with a carrier which constitutes one or more than one necessary ingredient. In General the compositions are produced by continuous and uniformly mixing the active ingredient with liquid carriers or finely ground solid carriers or both and then, if necessary, provide the product form desired. For example, a tablet may be made by extrusion or molding, possibly with one or more than one auxiliary ingredient. Molded tablets may be made by molding in a suitable machine the active ingredient in free-flowing form such as powder or granules, possibly mixed with such excipients, as a binder, a lubricating substance, inert diluent and/or surface-active agent or dispersing agent, but does not exhaust anievas it. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened inert liquid diluent.

Furthermore, this invention encompasses anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, since water can facilitate the destruction of some compounds. For example, in pharmaceuticals, water can be added (for example, 5%) as a tool for modeling long-term storage in order to determine characteristics such as shelf-life or stability of the compositions over time. Anhydrous pharmaceutical compositions and dosage forms according to the invention can be manufactured using anhydrous ingredients or ingredients with low moisture content and low moisture or low humidity. Pharmaceutical compositions and dosage forms according to the invention, which contain lactose, can be made anhydrous, if in the process of manufacturing, packaging and/or storage is expected substantial contact with moisture and/or moisture. Anhydrous pharmaceutical composition can be produced and stored in such a way as to preserve its anhydrous state. Accordingly, anhydrous compositions can be packaged using materials known to those they protect against penetration of water, such that can be incorporated into suitable sets defined in pharmacological reference. Examples of suitable packaging include, but are not limited to, foil, plastic or the like for hermetic sealing, disposable containers, blister packaging and blister tape type.

The active ingredient may be combined in a homogeneous mixture with a pharmaceutical carrier according to conventional methods of preparing pharmaceutical mixtures. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. In the manufacture of the compositions, dosage forms for oral administration as carriers may be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols, corrigentov, preservatives, colorants and the like in the case of oral liquid preparations such as suspensions, solutions and elixirs) or aerosols; or carriers as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without the use of lactose. For example, the right media include powders, capsules and tablets containing solid oral drugs. If necessary, the tablets may be coated using standard aqueous or anhydrous methods.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic resins, such as the Arabian gum, sodium alginate, alginic acid, other alginates, powdered tragakant, guar gum, cellulose and its derivatives (for example, ethylcellulose, acetate cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone (PVP), methylcellulose, pregelatinized starch, hydroxypropylmethyl-cellulose, microcrystalline cellulose and mixtures thereof.

Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms described in this application include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrans, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

In the compositions according to the invention can be is used leavening agents, to prepare tablets, which disintegrate when placed in an aqueous environment. If baking powder is too much, the manufacture can be obtained in tablets, which can break down in the bottle. Too small amount may be insufficient to have been destroyed, and thus may alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, for the formation of dosage forms of the compounds described in this application can be used enough baking powder, i.e. not too small and not too big not to have a detrimental effect on the release of the active ingredient(s). The amount of baking powder can vary depending on the type of composition and the method of administration and can be readily assessed by a specialist of ordinary skill in the art. In the pharmaceutical compositions can be used from about 0.5 to about 15 weight percent of the powder or from about 1 to about 5 weight percent of the powder. Leavening agents that can be used for education of pharmaceutical compositions and dosage forms according to the invention, include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microci the metallic cellulose, sodium salt croscarmellose, crosspovidone, polacrilin potassium, sodium starch glycolate, starch from potato or tapioca, other starches, pregelatinized starch, other starches, clays, other algini, other cellulose resin, or a mixture thereof.

Lubricants that can be used to form pharmaceutical compositions and dosage forms according to the invention, include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol (PEG), other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, etiloleat, tillaart, agar, or a mixture thereof. Additional lubricants include, for example, silica gel syloid, a coagulated aerosol of synthetic silica or mixtures thereof. The lubricating substance can be added in amounts less than about 1 mass percent of the pharmaceutical composition.

If desired the aqueous suspensions and/or elixirs for oral administration, the active ingredient may be combined with various sweetening or what Orientali, coloring matter or dyes and, if so, it will be necessary, emulsifying and/or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

Tablets may be uncoated or coated inflicted on them by known techniques to delay raspadaemosti and absorption in the gastrointestinal tract and thereby to ensure continuous operation over a prolonged period of time. For example, you can use this provides a time delay substance, as glyceryl-monostearate or glyceryl-distearate. Compositions for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin oil or olive oil.

Surfactants that may be used to form pharmaceutical compositions and dosage forms according to the invention, include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and the x of the mixture. That is, there may be used a mixture of hydrophilic surfactants may be used a mixture of lipophilic surfactants or can be used a mixture of at least one hydrophilic surfactant and at least one lipophilic surface-active substances.

Suitable hydrophilic surfactant can usually have a HLB value of at least 10, while suitable lipophilic surfactants can usually have an HLB value equal to or less than about 10. Empirical parameter used for this relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds, is hydrophilic-lipophilic balance (value "HLB"). Surfactants with lower HLB values are more lipophilic or hydrophobic and have a higher solubility in oils, whereas surfactants with higher HLB values are more hydrophilic and have a higher solubility in aqueous solutions. In General it is believed that the hydrophilic surface-active substances are compounds which have an HLB value above about 10, and anionic, cationic or zwitterionic connection for which the HLB scale is usual is not applied. Similarly, lipophilic (i.e., hydrophobic) surface-active substances are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only approximate landmark commonly used in the manufacture of pharmaceutical and cosmetic emulsions in the industry.

Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, salts of alkylamine; the salt fuseboy acid; derivatives of fatty acids and amino acids, oligopeptides and polypeptides, derivatives of glycerides and amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipid and their derivatives; salts esters of fatty acids and carnitine; salts of alkyl sulphates, salts of fatty acids; sodium docusinate; allactivity; mono - and diacetylpyridine esters of tartaric acid and mono - and diglycerides; succinylcholine mono - and diglycerides; esters of citric acid and mono - and diglycerides; and mixtures thereof.

Among the above-mentioned groups of ionic surfactants include as an example: lecithins, linoleic is h, phospholipids, lysophospholipids and their derivatives; salts esters of fatty acids and carnitine; salts of alkyl sulphates, salts of fatty acids; sodium docusinate; allactivity; mono - and diacetylpyridine esters of tartaric acid and mono - and diglycerides; succinylcholine mono - and diglycerides; esters of citric acid and mono - and diglycerides; and mixtures thereof.

Ionic surfactants can be an ionized form of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, effective absorption with added, lysophosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidyl acid, lysophosphatidyl-serine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylate esters of fatty acids, stearoyl-2-lactylate, stearylamine, succinylcholine monoglycerides, mono/diacetylpyridine esters of tartaric acid and mono/diglycerides, esters of citric acid and mono/diglycerides, cholylsarcosine, caproate, kaprilat, capret, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl, teracecyi sulfate, docusinate, lauroyl-carnitine, Palmitoyl-carnitine, myristoyl-carnitine and their salts and mixtures.

Hydrophilic non-ionic surfactants may include, but are not Ogre is nicolalde this, Alkylglucoside; alkylsulfonate; alkylthiophene; lauryl-macrogolglycerol; alkalemia ethers of polyoxyalkylene, such as alkalemia ethers of polyethylene glycols; alkyl phenols of polyoxyalkylene, such as ALKYLPHENOLS polyethylene glycols; esters of fatty acids and alkyl phenols of polyoxyalkylene, such as monetary fatty acids and of polyethylene glycol and diesters of fatty acids and polyethylene glycol; esters of fatty acids and polyethylene glycol and glycerin; esters of fatty acids and polyglycerol; esters of fatty acids and polyoxyalkylene-sorbitan, such as esters of fatty acids and polyethylene glycol-sorbitan; hydrophilic products of the transesterification of a polyol with at least one member of the group, consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene-sterols, their derivatives and analogues; polyoxyethylene vitamins and derivatives thereof; copolymers of polyoxyethylene and polyoxypropylene and mixtures thereof; esters of fatty acids and polyethylene glycol-sorbitan and hydrophilic products of the transesterification of a polyol with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be a glycerol, a glycol,polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryltrinitrate, PEG-32 dioleate, PEG-20 literallayout, PEG-30 literallayout, PEG-20 literallayout, PEG-20 picarella, PEG-30 picarella, PEG-30 literallayout, PEG-40 literallayout, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 capret/kaprilat-glycerides, PEG-8 capret/kaprilat-glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy Sterol, PEG-20 trioleate, PEG-40 sorbitan the oleate, PEG-80 sorbitan laurate, Polysorbate 20, Polysorbate 80, POE-9 simple lauric ether, POE-23 simple lauric ether, POE-10 simple alerby ether, POE-20 simple alerby ether, POE-20 simple stearyl ether, Tocopheryl-PEG-100-succinate, PEG-24-cholesterol, polyglyceryl-10 oleate, tween 40, tween 60, sucrose monostearate, monlaur the t sucrose, monopalmitate sucrose, a series of PEG-10-100 nonylphenols, a series of PEG-15-100 of ops and poloxamer.

Suitable lipophilic surfactants include, only as an example: fatty alcohols; esters of fatty acids and glycerol; acetylated esters of fatty acids and glycerol; esters of fatty acids and lower alcohols; esters of fatty acids and propylene glycol; esters of fatty acids and sorbitan; esters of fatty acids and polyethylene glycol-sorbitan; sterols and derivatives of sterols; polyoxyethylene sterols and derivatives of sterols; alkalemia ethers of glycols; esters of Sugars; ethers, Sugars, derivatives of lactic acid and mono - and diglycerides; hydrophobic products of the transesterification of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; soluble in oil vitamins/vitamin derivative; and mixtures thereof. Among this group preferred lipophilic surfactants include esters of fatty acids and of glycerol, esters of fatty acids and propylene glycol and mixtures thereof, or they are hydrophobic products of the transesterification of a polyol with at least one member of the group consisting of rastitel the x oils, hydrogenated vegetable oils and triglycerides.

In one embodiment the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compounds of the present invention and to minimize deposition of the compounds of the present invention. This may be especially important for compositions intended for refererlog applications, for example, compositions for injection. The solubilizer can also be added to increase the solubility of hydrophilic drugs and/or other components such as surfactants, or to maintain the composition in the form of a stable and homogeneous solution or dispersion.

Examples of suitable solubilization include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butandiol and their isomers, glycerin, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl-isosorbide, polyethylene glycol, polypropyleneglycol, polyvinyl alcohol, hypromellose and other cellulose derivatives, cyclodextrins cyclodextrins and derivatives; ethers of polyethylene glycols having an average molecular weight of from about 200 to about 6000, such as a simple ester of PEG and tetrahydrofuro the silt alcohol (glucotrol) or methoxy-PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, Epsilon-caprolactam, N-alkylpyridine, N-hydroxyethylpyrrolidine, N-alkylpiperazine, N-alkaliproof, dimethylacetamide, and polyvinylpyrrolidone; esters, such as ethylpropane, tributyltin, acetyltributyl, acetyltributyl, triethylcitrate, etiloleat, eticaret, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and their isomers, δ-valerolactone and their isomers, β-butyrolactone and isomers; and other solubilization, known in the art, such as dimethylacetamide, dimetridazole, M-methylpyrrolidone, monooctyltin, monotropy simple ether of diethylene glycol and water.

Additionally, there may be used a mixture of solubilization. Examples include, but are not limited to, triacetin, triethylcitrate, etiloleat, eticaret, dimethylacetamide, N-organic N-hydroxyethyl-pyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, hydroxypropyl-cyclodextrins, ethanol, polyethylene glycol 200-100, glycoluril, transcutol, propylene glycol and dimetridazole. Especially preferred solubilization include sorbitol, glycerin, triacetin, ethyl alcohol, PEG-400, glycoluril and propylene glycol.

The amount of solubilizer that can be VK is uchino, particularly not limited. The specified number of solubilizer may be limited biologically acceptable quantity that can be easily determined by a person skilled in the art. In some cases, the advantage may be the inclusion of a number of solubilization much larger than the biologically acceptable amount, for example to maximize the concentration of the medicinal product, with an excess of a solubilizer removed before the introduction of the composition to the patient, using traditional techniques, such as distillation or evaporation. So, if it is present, the solubilizer may be in the mass ratio, comprising 10%, 25%, 50%, 100% or up to about 200% by weight inclusive based on the combined weight of drug and other excipients. If you want, you can also use a very small amount of a solubilizer, such as 5%, 2%, 1% or even less. Usually, the solubilizer may be present in amount from about 1% to about 100%, more typically from about 5% to about 25% by weight.

In addition, the composition may include one or more than one pharmaceutically acceptable auxiliary substances and excipients. Such auxiliary substances and excipients include, without limitation, substances, menshawi the stickiness, protivovspenivayushchie substances, buffer agents, polymers, antioxidants, preservatives, chelating agents, substances that modify the viscosity of a substance that alters toychest, corrigentov, dyes, fragrances, masking agents, suspendresume agents, binders, fillers, softeners, lubricants, and mixtures thereof.

In addition, the composition can be included acid or base to facilitate manufacturing techniques, to enhance stability or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, esters of amino acids, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminosilicate, synthetic aluminum silicate, synthetic hydrotalcite, aluminum hydroxide, magnesium, diisopropylethylamine, ethanolamine, Ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, Tris(hydroxymethyl)aminomethan (TRIS) and the like. Also suitable bases, which are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulphonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydrokinesitherapy acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylacetate acid, propionic acid, p-toluensulfonate acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolate acid, toluensulfonate acid, uric acid, and the like. Salt polyprotein acids, such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrophosphate, can also be used. If the base is a salt, the cation may be any pharmaceutically acceptable cation such as ammonium, cations of alkali metals, alkaline earth metals and the like. An example may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acid. Examples of suitable inorganic acids include hydrochloric acid, Hydrobromic acid, idiscovered acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, algino the Yu acid, alkanesulphonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydrokinesitherapy acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonate acid, oxalic acid, para-brompheniramine acid, propionic acid, p-toluensulfonate acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluensulfonate acid, uric acid, and the like.

Pharmaceutical compositions for injection. In some embodiments according to this invention proposed pharmaceutical composition for injection containing the compound of the present invention and pharmaceutical excipient, suitable for injection. Components and the number of agents in such compositions such as described in this application.

Forms, which can be included new compositions of the present invention for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution and the such pharmaceutical diluents.

Aqueous solutions of physiological solution is also traditionally used for injection. Can also be used ethanol, glycerin, propylene glycol, liquid polyethylene glycol and the like, and suitable mixtures), derivatives of cyclodextrins and vegetable oil. The proper fluidity can be maintained, for example, through the use of substances for the coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be done in various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by adding the compounds of the present invention in the required amount in the appropriate solvent with various other ingredients enumerated above, as will be required, followed by sterilization by filtration. Typically, the dispersion is prepared by introduction of various sterile active ingredients into a sterile diluent, which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile the x injectable certain desired ways of making methods are vacuum drying and lyophilization drying, which allow to obtain a powder of the active ingredient plus any additional desired ingredient from a solution, subjected to preliminary sterilization by filtration.

Pharmaceutical compositions for local (e.g. transdermal) delivery. In some embodiments according to this invention proposed pharmaceutical composition for transdermal delivery, containing the compound of the present invention and pharmaceutical excipient, suitable for transdermal delivery.

The compositions of the present invention can be made in the form of preparations in solid, semi-solid or liquid forms suitable for local or topical administration, such as gels, water-soluble jelly, creams, lotions, suspensions, foams, powders, suspensions, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, salt solutions, solutions based on dimethyl sulfoxide (DMSO). As a rule, the use of media with a higher density values, allows to obtain an area with prolonged action of the active ingredients. On the contrary, the composition in solution can provide a more rapid action of the active ingredient on the selected area.

Pharmaceutical compositions may also contain suitable carriers or excipients in a solid or gel phase, PR is dostavlyaya a connection, which allow to increase the penetration or contribute to the delivery of therapeutic molecules funds through defined Horny layer of the skin permeability barrier. There are many such enhances the penetration of molecules known to specialists in the field of compositions for local application. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g. propylene glycol), alcohols (e.g. ethanol), fatty acids (e.g. oleic acid), surfactants (for example, isopropylmyristate and sodium lauryl sulphate), pyrrolidone, glycerylmonostearate, sulfoxidov, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

In another typical compositions intended for use in the methods of the present invention, devices are used for transdermal delivery ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, either in the presence or in the absence of another agent.

Construction and use of transdermal patches for shortcuts is Cai pharmaceutical agents is well known in the art. See, for example, U.S. patent No. 5023252, 4992445 and 5001139. Such patches can be designed for continuous, pulsating delivery or delivery on the need for pharmaceutical agents.

Pharmaceutical compositions for inhalation. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or their mixtures and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered orally or nazalnam way through the respiratory tract to provide local or systemic effect. The compositions are preferably in pharmaceutically acceptable solvents can be sprayed using inert gases. Sprayable solutions can be inhaled directly from the spraying device or spray device may be attached to the respirator, or using respiratory installation, operating under intermittent positive pressure. Compositions in the form of a solution, suspension or powder can be introduced, preferably oral or nasal, device, through which the composition is delivered in a proper way.

Other pharmaceutical compositions. Pharmaceutical compositions can also be made and the songs, set forth in this application and one or more than one pharmaceutically acceptable excipient suitable for sublingual, transbukkalno, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal introduction. The manufacture of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, tenth edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, third edition, Churchill Livingston, New York, 1990; Katzung, ed., Bas/c and Clinical Pharmacology, ninth edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, tenth edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20-e edition, Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, thirty-second edition (The Pharmaceutical Press, London, 1999); they are all included in this description in its entirety by reference.

The introduction of the compounds or pharmaceutical compositions of the present invention can be carried out by any method that enables delivery of the compounds to the site of action. These methods include oral methods, intraduodenal ways, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), local (e.g., transdermal application, rectal administration, through the om local delivery using a catheter or stent, or by inhalation. Connections can also be entered inside the adipose tissue or intrathecal.

The number of input connections will depend on being treated mammal, the severity of the disorder or condition, rate of administration, pharmacokinetics connection and choice of physician. However, an effective dosage is in the range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day in single or divided doses. For a person weighing 70 kg, this amount will be from about 0.05 to 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, more may be adequate levels of dosages lower than the lower limit of the above range, whereas in other cases, there may be used a significantly higher dose that will not cause any dangerous side effect, for example, by dividing such large doses into several small doses for administration throughout the day.

In some embodiments of the compound according to the invention is administered in a single dose. Usually, this introduction will be carried out by injection, for example, intravenous injection, for the rapid introduction of the agent. However, there can be used other ways that would be appropriate. A single dose of the compounds according to the invention also which you can use for the treatment of an acute condition.

In some embodiments of the compound according to the invention is administered in multiple doses. The introduction can be performed about once, twice, three times, four times, five times, six times or more than six times per day. The introduction can be performed approximately once a month, once every two weeks, once a week or once in every subsequent day. In another embodiment of the connection according to the invention and the other agent are administered together from about once per day to about 6 times per day. In another embodiment, the introduction of the compounds according to the invention and the agent continues to perform within less than about 7 days. In one another embodiment of introduction continue to run for more than about 6, 10, 14, 28 days, two months, six months or one year. In some cases, ongoing introduction and support him as long as is necessary.

Introduction agents according to the invention can continue as long as necessary. In some embodiments, the agent according to the invention is administered for more 1, 2, 3, 4, 5, 6, 7, 14 or 28 days. In some embodiments, the agent according to the invention is administered for less 28, 14, 7, 6, 5, 4, 3, 2 or 1 day. In some embodiments, the agent according to the invention is administered continuously, for example, for the treatment of chronic effects.

An effective amount of the compounds according to the invention can b shall be entered or a single dose, or multiple doses by any of the acceptable ways of administration of agents having similar application, including rectal, transbukkalno, intranasal and transdermal methods, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as tools for inhalation.

The composition of the invention can also be delivered using the device impregnated with or coated, such as a stent, for example, or injected into an artery of a polymeric material in a cylindrical shape. This method of introduction can help, for example, in preventing or reducing restenosis after such procedures as balloon angioplasty. Without communication with theory believe that the compounds according to the invention can slow down or inhibit the migration and proliferation of smooth muscle cells in the artery wall, which can contribute to restenosis. The connection according to the invention can be introduced, for example, by local delivery of the strata of the stent, stent graft, grafts or from the cover or sheath of the stent. In some embodiments of the compound according to the invention is mixed with the matrix. Such a matrix can be a polymer matrix and can be used to associate a connection with a stent. Polymer matrix suitable for such use, including the indicate, for example, polyesters or copolymers of polyesters on the basis of a lactone, such as polylactide, polycaprolactone, complex poliorcetes, polyanhydride, polyaminoamide, polysaccharides, polyphosphazenes, copolymers of poly-[(simple ether)-(ester)] (e.g. PEO-PLLA (copolymer based on polyethylene oxide and polylactic acid)); polydimethylsiloxane, poly(ethylene-vinyl acetate), polymers or copolymers based on acrylate (for example, polyhydroxyethyl-methyl methacrylate, polyvinyl-pyrrolidine), fluorinated polymers such as polytetrafluoroethylene and esters of cellulose. Suitable matrix can be non-biodegradable or may decompose, releasing the connection or connections. Compounds according to the invention can be applied to the surface of the stent in a variety of ways, such as coating, dipping/centrifugation, the coating method of spraying, coating, immersion, and/or coating using a brush device (brush-coating). The connection can be applied in the solvent, and the solvent can be left to evaporate, resulting in a layer connections on the stent. Alternatively, the connection can be localized in the body of the stent or graft, for example in micro-channels or micro pores. After the implant is the compound diffuses from the body of the stent to contact with the artery wall. Such stents can be produced by immersing the stent, manufactured, so that it contained such micropores or microchannels, in a solution of the compounds according to the invention in a suitable solvent, followed by evaporation of the solvent. The excess of the medicinal product on the surface of the stent can be removed by additional short washing solvent. In the following other embodiments of the compounds according to the invention can be linked covalent bond with a stent or graft. You can use covalent linker, which is destroyed in vivo, leading to the release of the compounds according to the invention. For such purpose can be used any biologically labile linkage, as for example, ester, amide or anhydrite communication. Compounds according to the invention can be additionally introduced intravascular from a container used in the process of angioplasty. To reduce restenosis may also be performed extravascular introduction connections by making compositions according to the invention through the pericardium or adventitious shell.

A variety stendovye devices that can be used as described, disclosed, for example, in the following references, all of them are thereby incorporated herein by reference: U.S. patent No. 5451233; U.S. patent No. 5040548; U.S. patent No. 5061273; Pat the NT U.S. No. 5496346; U.S. patent No. 5292331; U.S. patent No. 5674278; U.S. patent No. 3657744; U.S. patent No. 4739762; U.S. patent No. 5195984; U.S. patent No. 5292331; U.S. patent No. 5674278; U.S. patent No. 5879382; U.S. patent No. 6344053.

Compounds according to the invention can be introduced gradually. In the art it is known that due to interpersonal variability in the pharmacokinetics of compounds, the individualization of the injection mode is a necessary feature for optimal therapy. The dosage regimen for the compounds according to the invention can be determined on the basis of the ordinary experimentation in the present description.

In the case where the connection according to the invention is administered in a composition that contains one or more agents and the agent has a shorter half-life compared with the connection according to the invention, a standard dosage form of the agent and the compounds according to the invention can be appropriately adjusted.

The pharmaceutical composition which is the object of the invention may be, for example, in a form suitable for oral administration in the form of tablets, capsules, pills, powder, compositions with the continuous release, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration in the form of ointment or cream or for rectal administration in the form of suppositor who I am. Such pharmaceutical composition may be in a standard dosage forms, suitable for a single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the connection according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

Typical forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, for example solutions, aqueous propylene glycol or dextrose. Such dosage forms can be suitably buffered, if necessary.

The activity of the compounds of the present invention can be determined according to the following method, and the method described below in the Examples section below. The kinase activity assessed by measuring, in the presence of a kinase, the inclusion γ33P-phosphate from γ-33P-ATP containing N-terminal His-tag substrate, which is expressed in E. Li, and which is purified by traditional methods. This analysis is performed in 96-well polypropylene plate. Encubierta mixture (100 μl) contains 25 mm Hepes (N-2-hydroxyethyl-piperazine-N-2-econsultancy acid), pH 7.4, 10 mm MgCl2, 5 mm β-glycerol, 100 μm Na-ortolan the date 5 mm DTT (dithiothreitol), 5 nm kinase and 1 μm substrate. Inhibitors suspended in DMSO and all reactions, including controls, perform at the final concentration of DMSO is 1%. The reaction initiated by addition of 10 μm ATP (at a dose of 0.5 µci γ-33P-ATP/well) and incubated at ambient temperature for 45 minutes. Add an equal volume of 25% TCA (trichloroacetic acid) to stop the reaction and precipitate proteins. Precipitated proteins captured on the filter tablets with a glass fiber filter In and excess labeled ATP washed using harvester Tomtec MACH III. Tablets leave to air dry, after which each well was added 30 μl of Packard Microscint 20 and tablets calculate using a Packard TopCount.

According to the invention also suggested sets. Sets include a compound or compounds of the present invention, as set forth in this application, in suitable packaging, and written document, which may include instructions for use, discussion of clinical issledovania, the list of side effects and the like. Such kits can also include information such as references from the scientific literature, materials related to the instructions for use of the drug, the results of clinical trials and/or short report on them and the like, which indicate or set activity and/and and advantages of this composition and/or in which the described dosage, the routes of administration, side effects, drug interactions, or other information useful to the agencies and professionals providing medical care. Such information may be based on the results of various studies, for example, studies using experimental animals involved in the models in vivo, and studies based on clinical trials in humans. This kit may further comprise another agent. In some embodiments, the compound of the present invention and the agent provided in the kit in separate compositions in separate containers. In some embodiments, the compound of the present invention and the agent provided in the kit in the form of a single composition in the container. Suitable packaging and additional products for use (for example, a measuring Cup for liquid medications, wrap in foil for information in the minimum exposure to air and the like) known in the art and can be included in the set. The sets described in this application may be offered for sale and/or advertised institutions and professionals, providing medical services, including doctors, nurses, pharmacists, officials responsible for compiling forms of medicines, and the like. In addition, the sets, in some embodiments, can be sold directly to the consumer.

WAYS

In addition, according to the invention methods of using compounds or pharmaceutical compositions of the present invention for the treatment of painful conditions, including, but not limited to, diseases associated with incorrect work R-kinase one or more types. Detailed description of conditions and disorders mediated 110δ kinase activity described in the application Sadu and others, WO 01/81346, which is included in this description in its entirety by reference for all purposes.

The treatments proposed in this application include introduction to the subject therapeutically effective amounts of compounds according to the invention. In one embodiment of the present invention, a method for treatment of inflammatory disorders, including autoimmune disease, in a mammal. The method includes the introduction of the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative. Examples of autoimmune diseases include, but are not limited to, acute dissimilitude encephalomyelitis (ADEM), Addison disease, the antiphospholipid syndrome is (APS), gipoplasticheskaya anemia, autoimmune hepatitis, gluten enteropathy, Crohn's disease, diabetes (type 1), syndrome?, graves ' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, severe pseudoparalysis myasthenia, needs to be myoclonus syndrome (OMS), retro-bulbar neuritis, thyroiditis Horde, hand, foot, arthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter syndrome, Takayasu's arteritis, temporal arteritis diagnostics (also known as "giant cell arteritis diagnostics"), autoimmune hemolytic anemia syndrome heat agglutinins, Wegener's granulomatosis, universal alopecia, Chagas disease, chronic fatigue syndrome, vegetative dystonia, endometriosis, suppurative hydradenitis, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo and vulvodynia. Other disorders include disorders of bone resorption and thrombosis.

In some embodiments a method of treating inflammatory or autoimmune diseases includes an introduction to the subject (e.g. a mammal) a therapeutically effective amount of one or more compounds of the present invention that selectively inhibit PI3K-δ and/or PI3K-γ in comparison with all other PIS-kinase type I. Such selective inhibition of PI3K-δ is/or PI3K-γ may have an advantage when treating any of the diseases or conditions, outlined in this application. For example, selective inhibition of PI3K-δ can inhibit inflammatory responses associated with inflammatory diseases, autoimmune disease or diseases associated with unwanted immune response, including, but not limited to, asthma, emphysema, allergies, dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus, or graft-versus-host. In addition, selective inhibition of PI3K-δ can provide a reduction of inflammatory or unwanted immune response without concomitant reduction of the ability to weaken bacterial, viral and/or fungal infection. Selective inhibition RK-δ and PI3K-γ may have the advantage of a greater degree of inhibition of the inflammatory response in the subject than could be obtained by using inhibitors that selectively inhibit only RK-δ or PI3K-γ. In one aspect of one or more of the methods, which is the object of the invention is effective in reducing the production of antigen specific antibodies in vivo about 2 times, 3 times, 4 times, 5 times 7.5 times, 10 times, 25 times, 50 times, 100-fold, 250-fold, 500-fold, 750 times or about 1000 times or more. In another aspect, one or more of the methods, which is the object of the invention is effective in reducing the production of antigen specific lgG3 and/or gGM in vivo about 2 times, 3 times, 4 times, 5 times 7.5 times, 10 times, 25 times, 50 times, 100-fold, 250-fold, 500-fold, 750 times or about 1000 times or more.

In one aspect of one or more of the methods, which is the object of the invention is effective in reducing the intensity of symptoms associated with rheumatoid arthritis, including, but not limited to, reducing swelling of the joints, reducing the levels of antibodies against collagen in the serum and/or reduction of joint pathology such as bone resorption, loss of cartilage, pannus and/or inflammation. In another aspect of the methods, which is the object of the invention is effective in reducing inflammation of the ankle joint at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60% approximately 75%-90%. In another aspect of the methods, which is the object of the invention is effective in reducing inflammation of the knee joint at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60% approximately 75%-90% or more. In yet one other aspect of the methods, which is the object of the invention is effective in reducing the levels of antibodies against collagen type II in the serum of at least about 10%, 12%, 15%, 20%, 24%, 25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87% or about 90% or more. In another aspect of the methods, which is the object of the invention is effective in reducing the indicators on histopathological scale for ankle joint about 5%, 10%, 15%, 0%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more. In yet one other aspect of the methods, which is the object of the invention is effective in reducing the indicators on histopathological scale for knee joint about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In other embodiments of the present invention methods of using compounds or pharmaceutical compositions for the treatment of respiratory diseases, including, but not limited to, diseases affecting the lobe of the lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract or the nerves and is involved in the act of breathing muscles. For example, methods for the treatment of obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is an umbrella term for a group of respiratory tract diseases that are characterized by obstruction or restriction of the Airways. States included in this umbrella term are: chronic bronchitis, emphysema and bronchiectasis.

In another embodiment of the compounds set forth in this application, is used to treat asthma. In addition, the compounds or pharmaceutical compositions described in this application can be applied for the treatment of endotoxemia and sepsis. In one embodiment of the compounds or pharmaceutical compositions described in this is avce, used for the treatment of rheumatoid arthritis (RA). In one another embodiment of the compounds or pharmaceutical compositions described in this application, is used to treat contact or atopic dermatitis. Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact dermatitis type and the like. Irritant dermatitis may occur when applied to the skin too much substance or when the skin has sensitivity to a particular substance. Atopic dermatitis, sometimes called eczema, is a type of dermatitis - atopic skin disease.

The invention also relates to a method of treatment of hyperproliferative disorders in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative. In some embodiments of this method relates to the treatment of cancer such as acute myeloid leukemia, a cancer of the thymus gland, brain, lung, squamous cell carcinoma, skin cancer, eye, retinoblastoma, intraocular melanoma, cancer of the oral cavity and oropharynx, machevo what about the bubble, gastro-intestinal tract, stomach, pancreas, bladder, breast, cervix, head, neck, renal sphere, kidney, liver, ovarian, prostate, colorectal cancer, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-associated (e.g., lymphoma and sarcoma Galoshes) or induced by cancer viruses. In some embodiments of this method relates to the treatment of benign hyperproliferative disorder such as benign hyperplasia of the skin (e.g. psoriasis), restenosis, or benign hyperproliferative disorder of the prostate (e.g., benign prostatic hypertrophy (national Department of standardization)).

The invention also relates to a method of treatment of a disease associated with vasculogenesis or angiogenesis in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative. In some embodiments of this method relates to the treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases, such as rheumatoid arthritis, atherosclerosis, Vespa is sustained fashion bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer, lung, pancreas, prostate, colon and epidermoid cancer.

Patients who can be treated by the compounds of the present invention or a pharmaceutically acceptable salt, complex, ester, prodrug, MES, hydrate or derivative of these compounds in accordance with the methods according to this invention include, for example, patients who have been diagnosed with psoriasis; restenosis; atherosclerosis; national Department of standardization; breast cancer such as Doctrina carcinoma in tissue ducts of the breast, species of medullary cancer, types of colloidal cancer, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma, which migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the epithelium of the cervix, including squamous cell(s) cancer and adenocarcinomas; prostate cancer, for example prostate cancer, selected from the following next: adenocarcinoma or adenocarcinoma, the cat heaven migrate into the bone; cancer of the pancreas, such as epithelioma carcinoma in tissue of pancreatic duct and an adenocarcinoma in a pancreatic duct cancer; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothelial carcinomas (transitional cell carcinomas), tumors in urothelial cells that line the bladder, squamous cell carcinoma, adenocarcinoma and small cell lung cancer; leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and myelodysplastic syndrome (MDS); bone cancer; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinoma, adenocarcinoma and both dedifferentiate carcinoma, and small cell lung cancer; skin cancer such as basal cell cancer, melanoma, squamous cell carcinoma and actinic keratosis, which represents a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular melanoma (melanoma of the eye); primary liver cancer (cancer which is begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-associated lymphoma, such as diffuse In both lymphoma, b-cell immunoblastic lymphoma and small cell lymphoma of the unsplit cells; sarcoma Galoshes; cancers induced by viruses, including cancer induced by hepatitis b virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; cancer induced T-lymphotropic virus human type 1 (HTLV-1), and T-cell leukemia/lymphoma adult; and cancer induced papilloma virus human (HPV) and cervical cancer; cancers of the Central nervous system (CNS) such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), oligodendroglioma, ependymoma, meningioma, lymphoma, sandamu and medulloblastoma; cancers of the peripheral nervous system (PNS), such as acoustic neuromas and malignant tumor of the meninges, peripheral nerves (MPNST) including neurofibromas and swannery, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed tumor Mueller; cancer of the oral cavity and oropharynx, such as cancer porotocol part of the pharynx, larynx cancer, hoco the tray cancer and cancer of the oropharynx; stomach cancer such as lymphomas, stromal tumors, and carcinoid tumors of the gastrointestinal tract; testicular cancers such as embryonal cell tumors (GCT), which include seminoma and desaminase tumors, and gonadal stromal tumors, which include tumors of the Leydig cells and tumors from Sertoli cells; cancer of the thymus gland, such as thymoma, carcinoma of the thymus, Hodgkin's disease, non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; and colon cancer.

The invention also relates to a method of treating diabetes in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative.

In addition, the compounds described in this application can be applied for the treatment of acne.

In addition, the compounds described in this application can be applied for the treatment of arteriosclerosis, including atherosclerosis. Arteriosclerosis is a General term describing any hardening of medium or large arteries. Atherosclerosis is a hardening of the arteries mainly due to atherosclerotic plaques.

Other compounds described in this application can be p imieniny for the treatment of glomerulonephritis. Glomerulonephritis is a primary or secondary autoimmune renal disease characterized by inflammation of the glomeruli. It may be asymptomatic or be together with hematuria and/or proteinuria. There are many recognized types, which are divided into acute, subacute or chronic glomerulonephritis. The causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.

In addition, the compounds described in this application can be used to treat bursitis, lupus, acute disseminules encephalomyelitis (ADEM), Addison's disease, antiphospholipid syndrome (APS), gipoplasticheskaya anemia, autoimmune hepatitis, gluten enteropathy, Crohn's disease, diabetes (type 1), syndrome?, graves disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, inflammatory bowel disease, lupus erythematosus, severe pseudoparallelism infants, needs to be myoclonus syndrome (OMS), retro-bulbar neuritis, thyroiditis Horde, osteoarthritis, uveoretinitis, bladderworts, arthritis, primary biliarnogo cirrhosis, Reiter syndrome, Takayasu's arteritis, temporal arteritis diagnostics, autoimmune hemolytic anemia syndrome heat agglutinins, Wegener's granulomatosis, universal alope the AI, Chagas disease, chronic fatigue syndrome, vegetative dystonia, endometriosis, purulent hidradenitis, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, appendicitis, Takayasu, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, Ostia, otitis media, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis or velvita.

The invention also relates to a method of treating cardiovascular disease in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative. Examples of cardiovascular conditions include,but are not limited to, atherosclerosis, restenosis, vascular occlusion and obstructive disease of the carotid artery.

In another aspect of the present invention proposed a way of breaking the function of leukocytes or impairment of the function of osteoclasts. The method includes the conversion of cells or osteoclasts in contact with disrupt the function of a number of compounds according to the invention.

In another aspect of the present invention methods of treatment of eye diseases by introducing one or more than one connection or one or more than one pharmaceutical composition, which is the object of the invention, in the eyes of the subject.

In addition, the proposed methods of administration of the compounds of the present invention, by eye drops, intraocular injection, intravitreal injection, topically, or through the use of devices, drug eluting, microcapsules, implants or microfluidic device. In some cases, compounds of the present invention are administered together with a carrier or excipient, which improves the penetration of the compounds into the eye, such as oil and water emulsion with colloidal particles having an oil core surrounded by a film on the phase boundary.

In some cases, colloidal particles include at least one cationic agent and at least the bottom nonionic surface-active substance, such as poloxamer, tyloxapol, Polysorbate, polyoxyethylene derivative and castor oil, ester sorbitan or polyoxyl-stearate. In some cases, the cationic agent is alkylamino, tertiary alkylamine, the connection Quaternary ammonium compounds, cationic lipid, amerosport, salt biguanide, cationic compound or their mixture. In some cases, the cationic agent is a salt of biguanide, such as chlorhexidine, polyaminopropyl-biguanide, phenformin, alkylsilane or their mixture. In some cases, the connection of the Quaternary ammonium is a benzalconi-halide, lauralkonium-halide, cetrimide, hexadecyltrimethylammonium-halide, tetradecyltrimethyl ammonium halide, dodecyltrimethylammonium-halide, ceremony-halide, benzethonium-halide, behealthy-halide (behenalkonium halide), Catalani-halide, settingkey-halide (cetethyldirnonium halide), pyridinium-halide, benzododecinium-halide, chlorallyl-methenamine-halide, monistically-halide, stearalkonium-halide or a mixture of two or more than two of them. In some cases, the cationic agent is a benzalconi-chloride, lauralkonium-chloride, benzododecinium-bromide, benzethonium chloride, hexadecyltrimethylammonium-bromide, tetradecyltrimethylammonium-bromide, dodecyltrimethylammonium-bromide or a mixture of the Vuh or more than two of them. In some cases, the oil phase is a mineral oil and light mineral oil, triglycerides with a chain of medium length (MCT), coconut oil; hydrogenated oils, including hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated castor oil or hydrogenated soybean oil; derivatives and polyoxyethylene hydrogenated castor oils, including polyoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

In addition, according to the invention methods of modulating kinase activity by bringing kinase in contact with a number of compounds according to the invention sufficient to modulate the activity of kinases.

Modulation may be an activation or inhibition of kinase activity, In some embodiments according to the invention methods of inhibiting kinase activity by bringing kinase in contact with a number of compounds according to the invention, sufficient for inhibiting the activity of the kinase. In some embodiments according to the invention methods of inhibiting kinase activity in solution by bringing the specified solution in contact with the number of connections and the finding, sufficient for inhibiting the activity of the kinase in the specified solution. In some embodiments according to the invention methods of inhibiting kinase activity in a cell by bringing the specified cell in contact with a number of compounds according to the invention, sufficient for inhibiting kinase activity in a specified cell. In some embodiments according to the invention methods of inhibiting kinase activity in the tissue by bringing the specified fabric in contact with a number of compounds according to the invention, sufficient for inhibiting the activity of the kinase in the specified fabric. In some embodiments according to the invention methods of inhibiting kinase activity in the body by bringing the specified organism in contact with a number of compounds according to the invention, sufficient for inhibiting the activity of the kinase in the specified organism. In some embodiments according to the invention methods of inhibiting kinase activity in an animal by bringing the specified animal in contact with a number of compounds according to the invention, sufficient for inhibiting the activity of the kinase in the specified animal. In some embodiments according to the invention methods of inhibiting kinase activity in a mammal by bringing this melicope the surrounding in contact with a number of compounds according to the invention, sufficient for inhibiting the activity of the kinase in the specified mammal. In some embodiments according to the invention methods of inhibiting kinase activity in humans by bringing this person in contact with a number of compounds according to the invention, sufficient for inhibiting the activity of the kinase in the specified person. In some embodiments % of kinase activity after bringing kinase in contact with the connection according to the invention is less than 1,5, 10, 20, 30, 40, 50, 60, 70, 80 90, 95 or 99% of the kinase activity measured in the absence of a specified stage of bringing into contact.

In some embodiments, the kinase is lietkynes or protein kinase. In some embodiments, the kinase is selected from the group consisting of R-kinase, including different isoforms, such as R-kinase α, R-kinase β, R-kinase γ, R-kinase δ; DNA-PK; mTor; Abl, VEGFR, iminovogo receptor B4 (h4); receptor tyrosine kinase TECH (CHE); Fms-like tyrosine kinase 3 (FLT-3); growth factor receptor of platelets (DERIVED); RET; ATM; ATR; hSmg-1; Hck; Src; the receptor for epidermal growth factor (EGFR); KIT (the receptor for the growth factor, stem cells); insulin receptor (IR) and IGFR (the receptor for insulin-like growth factor).

In addition, according to the invention proposed modulation methods PI3-kinase activity by bringing R-kinase in the control of the CT with a number of compounds according to the invention, sufficient to modulate the activity R-kinase. Modulation may be an activation or inhibition R kinase activity. In some embodiments according to the invention methods of inhibiting R kinase activity by bringing R-kinase in contact with a number of compounds according to the invention, sufficient for inhibiting the activity R-kinase. In some embodiments according to the invention methods of inhibiting R kinase activity. Such inhibition can occur in solution, in a cell expressing one or more than one R-kinase, in the tissue containing the cell expressing one or more than one R-kinase, or organism expressing one or more than one R-kinase. In some embodiments according to the invention methods of inhibiting R kinase activity in animal (including mammals, e.g. humans) by bringing the specified animal in contact with a number of compounds according to the invention, sufficient for inhibiting the activity R-kinase in the specified animal.

COMBINED TREATMENT

Also, according to the present invention methods of combination therapy, in which an agent known to modulate other ways or other components of the same path or even overlapping sets of EN zymes the s-targets use in combination with the compound of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrug, MES, hydrate or derivative. In one aspect of this therapy includes, but is not limited to, a combination of compounds, which is the object of the invention with chemotherapeutic agents, therapeutic antibodies and radiation therapy to provide a synergistic or additive therapeutic effect.

In one aspect, the compounds or pharmaceutical compositions of the present invention can be synergistic or additive efficacy when introduced in combination with agents that inhibit the production or activity of IgE. This combination can reduce the adverse effect of high levels of IgE associated with the use of one or more inhibitors I3δ, if such an effect takes place. This can be particularly useful in the treatment of autoimmune and inflammatory disorders (AIID), such as rheumatoid arthritis. In addition, the introduction of inhibitors I3δ or PI3Kδ/γ according to the present invention in combination with mTOR inhibitors can also lead to synergistic action through increased inhibition RC-path.

In a separate but related aspect of the present invention proposed combined treatment of diseases, ACC is chiromassage with I3δ, including the introduction of inhibitor I3δ and an agent that inhibits the production or activity of IgE. For this combination is applicable to other typical inhibitors I3δ, and they are described, for example, in U.S. patent No. 6800620. This combined treatment is particularly useful for the treatment of autoimmune and inflammatory disorders (AIID), including rheumatoid arthritis, but is not limited to them.

Agents that inhibit the production of IgE, known in the art and include, but are not limited to, one or more agents from THE-9874, 2-(4-(6-cyclohexyloxy-2-naphthyloxy)phenylacetamide)benzoic acid, rapamycin analogues of rapamycin (i.e. replagal), inhibitors of TORC1, TORC2 inhibitors or any other compounds that inhibit mTORd and mTORC2. Agents that inhibit the activity of IgE, include, for example, anti-IgE antibodies such as, for example, omalizumab and TNX-901.

For the treatment of autoimmune diseases of the compounds or pharmaceutical compositions of the subject invention can be used in combination with commonly prescribed drugs, including, but not limited to, Enbrel®, Remicade®, Humira®, Avonex®and Rebif®. For the treatment of respiratory diseases, the compounds or pharmaceutical compositions of the subject invention can be introduced in combination with usually the prescription drugs, including, but not limited to, Xolair®, Advair®, Singulair®and Spiriva®.

Compounds according to the invention can be made or put together with other agents that act by eliminating the symptoms of inflammatory conditions such as encephalomyelitis, asthma, and other conditions set forth in this application. These agents include non-steroidal anti-inflammatory drug (NSAID), for example, acetylsalicylic acid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; and so on, Corticosteroids are used to reduce inflammation and suppress immune system activity. The most commonly prescribed drug of this type is prednisone. Chloroquin (aralen) or hydroxychloroquine (plaquenil) can also be very useful for some individuals with a diagnosis of lupus. They are most often prescribed for skin and joint symptoms of lupus. Azathioprine (imuran) and cyclophosphamide (cytoxan inhibit inflammation and tend to suppress the immune system. Other agents, such as methotrexate and cyclosporine, are used to regulate the symptoms of lupus. Anticoagulants are used to prevent rapid blood clotting. Diapason anticoagulants varies from aspirin in a very low dose that prevents the adhesion of platelets to heparincoated.

In one of the other aspects, the invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal, which contains a number of compounds of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative in combination with an amount of an anticancer agent (e.g., chemotherapeutic agent). Many chemotherapeutic agents currently known in the art and can be used in combination with the compounds according to the invention.

In some embodiments of the chemotherapeutic agent selected from the group consisting of inhibitors of mitosis, alkylating agents, antimetabolites, intercalating antibiotics, inhibitors of growth factors, inhibitors of the cell cycle, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors and anti-androgens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents and small ones molecule, such as Gleevec (imatinib mesilate), Velcade (bortezomib), casodex (bikalutamid), iressa (gefitinib) and adriamycin, as well as many chemotherapeutic agents. Non-limiting examples of chemotherapeutic is hentov include alkylating agents, such as thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulphonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimines and methylmelamine, including altretamin, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and triethylenemelamine; nitrogen mustard analogues, such as chlorambucil, chlornaphazine, halophosphate, estramustine, ifosfamide, mechlorethamine, hydrochloride oxide mechlorethamine, melphalan, novemberin, finestein, prednimustine, trofosfamide, oralloy mustard; nitrosoanatabine, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine, ranimustine; antibiotics, such as aclacinomycin, actinomycin, autralian, azaserine, bleomycin, actinomycin, calicheamicin, carubicin, karminomitsin, casinopolis, Casodex™, chromomycin, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, zorubicin, idarubitsin, marsellaise, mitomycin, mycofenolate acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, colomycin, radiobeacon, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); analogs of folic acid, such as deeperin, methotrexate, peripherin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, timipre, tioguanin; pyrimidine analogs, such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergic tools such as aminoglutetimid, mitotane, trilostane; DOPOLNITEL folic acid, such as folinovaya acid; Eagleton; glycoside aldophosphamide; aminolevulinic acid; amsacrine; astroball; bisantrene; edatrexate; defaming; demecolcine; diazinon; alphabetin; slipline acetate; etoposide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitrogen; pentostatin; penomet; pirarubicin; podophyllin acid; 2-acylhydrazides; procarbazine; PSK.R™; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trihlortrietilamin; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; Galitsin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N. J.) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; espiramicina; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also as substances that are suitable for str is Ksenia state of cells during chemotherapy, included antihormonal agents, which act by regulating or inhibiting hormonal activity of tumors, such as antiestrogens, including, for example, tamoxifen (Nolvadex™), raloxifene, inhibiting aromatase 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and toremifene (fareston); and antiandrogens, such as flutamide, nilutamide, bikalutamid, leuprolide and gecelerin; chlorambucil; gemcitabine; 6-tioguanin; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; Novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; deformational (DMFO). Where desirable, the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®and Velcade®.

This invention also relates to a method of using compounds or pharmaceutical compositions in combination with radiation therapy for inhibiting abnormal cell growth or treatment of hyperproliferate the aqueous disorders in a mammal. Techniques of radiation therapy known in the art, and these techniques can be used in combination therapy described in this application. Introduction compounds according to the invention in such combination therapy can be determined, as set forth in this application.

Radiation therapy can be performed by using one of several methods or combinations of methods, including, without limitation, external remote radiation therapy, internal radiation therapy, radiation therapy using implants, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and long-term or short-term interstitial brachytherapy. The term "implant" as used in this application refers to radiation therapy through spatially limited radioactive substance injected into the site of the tumor or near it, or in another place proliferative disease tissue. It is implied that the term includes, without limitation, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and radioactive isotopes of Lu). Suitable radiation sources for use as improving the condition of the cells of the substances of the present invention include both solids and liquids. As Neagra Iceweasel example, the radiation source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source or other radionuclides that emit photons, beta particles, gamma rays or other types of radiation used in therapy. In addition, the radioactive substance can be a liquid made from any solution of the radionuclide(s), for example, a solution of I-125 or I-131, or radioactive liquid can be prepared using suitable liquid suspension containing small particles of solid radionuclides, such as Au-198, Y-90. In addition, the radionuclide(s) may be included in the gel or to be part of the radioactive microspheres.

Not limiting myself to any theory, it is possible to say that the compounds of the present invention can make abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention also relates to a method of sensitizing abnormal cells in a mammal to treatment with radiation, comprising administration to the mammal of an amount of the compound of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative, which is effective for sensitizing abnormal cells to treatment is July irradiation. The number of compounds, salts or MES in this way can be determined in accordance with the methods for determining effective amounts of such compounds described in this application.

The compounds or pharmaceutical compositions of the present invention can be used in combination with one or more substances selected from antiangiogenetic agents, inhibitors of signal transduction and antiproliferative agents.

Antiangiogenesis agents, such as inhibitors of MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors SOH-11 (cyclooxygenase 11), can be used together with the compound of the present invention and pharmaceutical compositions described in this application. Examples of useful inhibitors of COX-II include CELEBREX™ (elecoxib), valdecoxib and rofecoksib. Examples of useful inhibitors of matrix metalloproteinases described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), the application for the European patent No. 97304971.1 (filed July 8, 1997), the application for the European patent No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published 26 February 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), the publication of the European patent 606046 (published 13 July 1994), the publication of the European patent 931788 (published on July 28, 1999), WO 90/05719 (published may 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published 17 June 1999), international PCT application number PCT/V/01113 (filed July 21, 1998), the application for the European patent No. 99302232.1 (filed March 25, 1999), the application for a patent of great Britain No. 9912961.1 (filed June 3, 1999), the provisional application U.S. No. 60/148464 (filed August 12, 1999), U.S. patent 5863949 (published January 26, 1999), U.S. patent 5861510 (published 19 January 1999) and the publication of the European patent 780386 (published June 25, 1997), all of them are included in this description in its entirety by reference. Preferred inhibitors of MMP-2 and MMP-9 are such that they have a low activity or no activity against inhibition of MMP-1. More preferred are those that selectively inhibit MMP-2 and/or AMR-9 compared to the other matrix-metalloproteinases (i.e. MAR 1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830.

Izobreteniya relates to a method of treatment and pharmaceutical compositions for treating cardiovascular disease in a mammal, contains a number of compounds of the present invention or its pharmaceutically acceptable salt, complex, ester, prodrugs, MES, hydrate or derivative or isotope-labeled derivative and one or more therapeutic agents used for the treatment of cardiovascular diseases.

Examples for use in relation to cardiovascular disease are antithrombotic agents, for example, prostacyclin and salicylates, thrombolytic agents, such as streptokinase, urokinase, tissue plasminogen activator (TPA) and Antilibanus activator complex of plasminogen and streptokinase (APSAC), antiplatelet agents, for example, acetyl-salicylic acid (ASA) and clopidrogel, vasodilators, such as nitrates, drugs that block calcium channels, antiproliferative agents, such as colchicine and alkylating agents, intercalating agents, modulating growth factors such as interleukins, transforming growth factor-beta and connections related to the growth factor from platelets, monoclonal antibodies directed against growth factors, anti-inflammatory agents, both steroidal and non-steroidal drugs, and other agents that can modulate vascular tone, function, arteriosclerosis, and the reactions the healing of damage to the vessels or organs after exposure. According to the invention in the composition or combinations of substances for coating may also be included antibiotics. Moreover, the substance for coating can be used to implement therapeutic delivery to the lesion in the vessel wall. By incorporating the active agent in nabuhay polymer active agent will be released when the swelling of the polymer.

Compounds described in this application can be made and put together with substances representing a liquid or solid tissue barriers, also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, politicians, seprafilm, Intersil and hyaluronic acid.

Medicines that can be put together with the compounds described in this application include any suitable medicines usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; anti-allergic drugs, e.g., cromoglycate, ketotifen or nedocromil; anti-infective agents, such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines or pentamidine; antihistamines, for example, methapyrilene; anti-inflammatory agents, for example, beclomet the zones, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives,. for example, noscapine; bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol, izoprenalin, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, ortsiprenalin or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzoimidazol; diuretics, such as amiloride; anticholinergic agents, for example, ipratropium, atropine or oxitropium; hormones such as cortisone, hydrocortisone or prednisolone; xantina, for example, aminophylline, choline theophyllinate, the lysine theophyllinate or theophylline; therapeutic proteins and peptides, such as insulin or glucagon. Specialist in the art it will be obvious that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal salts or amines or salts accession acid) or as esters (e.g. lower alilovic esters) or in the form of a solvate (e.g., hydrates) to optimise the activity and/or stability of the drug.

Other typical therapeutic agents useful for combination therapy include, but are not limited to, those described what use agents, radiation therapy, hormone antagonists, hormones and hormone-releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocorticosteroid and their synthetic analogs; inhibitors of the synthesis and actions of adrenal cortex hormones, insulin, oral hypoglycemic agents and the pharmacology of the endocrine division of the pancreas; agents affecting calcification and bone remodeling: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins, such as water-soluble vitamins, vitamin b complex, ascorbic acid, fat-soluble vitamins, vitamins a, K and E, growth factors, cytokines, chemokines, agonists and antagonists of muscarinic receptors; anticholinesterase agents; agents acting at the neuromuscular synapse and/or autonomic ganglion; catecholamines, sympathomimetic drugs, and agonists or antagonists adrenergic receptor; and agonists and antagonists of the receptor 5-hydroxytryptamine (5-HT, serotonin).

Therapeutic agents can also include agents against pain and inflammation, such as histamine and antagonists of histamine, bradykinin and antagonists of bradykinin, 5-hydroxytryptamine (serotonin), a lipid substance that is created by biotransformation p is the FL selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretics, agents that inhibit the synthesis of prostaglandins and thromboxanes, are selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids is characterized, hormones paracrine actions, somatostatin, gastrin, cytokines mediating interactions involved in humoral and cellular immune responses, autacoids is characterized lipids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methyl xantina, blockers of sodium channels, opioid agonists, calcium channel blockers, stabilizers of membranes and leukotriene inhibitors.

Additional therapeutic agents discussed in this application include diuretics, vasopressin, agents affecting water retention by the kidneys, renin, angiotensin, agents, useful in the treatment of myocardial ischemia, antihypertensive agents, inhibitors of angiotensin-converting enzyme antagonists of β-adrenergic receptor agents for the treatment of hypercholesterolemia and agents for the treatment of dyslipidemia.

Further therapeutic agents include medicines used to regulate the acidity of the gastrointestinal tract, with whom estva for the treatment of peptic ulcers, tools for the treatment of gastroesophageal reflux disease, prokinetics agents, antiemetics, and agents used in irritable bowel syndrome, drugs used in diarrhea, drugs used in constipation, drugs used in inflammatory bowel disease, drugs used for diseases of the biliary tract, drugs used in diseases of the pancreas. Therapeutic agents used to treat protozoal infections, medicines used to treat malaria, amebiasis, giardiasis, trichomoniasis, trypanosomiasis and/or leishmaniasis, and/or drugs used in the chemotherapy of helminthiasis. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins and other β-lactam antibiotics, the agent containing an aminoglycoside, inhibitors of protein synthesis, medicines used in chemotherapy of tuberculosis, complex disease, caused by Mycobacterium avium, leprosy, antifungal agents, antiviral agents, including nairoviruses agents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with the compound, t is aushima object of the invention, include, but are not limited to, antibodies against the receptor tyrosinekinase (cetuximab, panitumumab, trastuzumab), antibodies against CD20 (cluster of differentiation 20) (rituximab, tositumomab) and other antibodies, such as alemtuzumab, bevacizumab and gemtuzumab.

In addition, the methods described in this application provides therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogenic and Immunostimulants. In addition, therapeutic agents affecting blood and blood-forming organs, hematopoietic agents, growth factors, vitamins and minerals, anticoagulant, thrombolytic and antiplatelet drugs.

Additional therapeutic agents that can be combined with the connection, which is the object of the invention, can be found in the book by Goodman and Oilman's "The Pharmacological Basis of Therapeutics, tenth edition, edited by Hardman, Limbird and Gilman, or in the Desktop directory of the doctor (Physician''s Desk Reference); both are included in this description in its entirety by reference.

Compounds described in this application can be used in combination with the agents described in this application or other appropriate agents, depending on the subject to the treatment condition. In other words, some is, some embodiments of the compounds according to the invention will be introduced together with other agents, as explained above. When used in combination therapy, the compounds described in this application can be put together with a second agent simultaneously or separately. This introduction in combination may include the simultaneous introduction of two agents in the same pharmaceutical form, the simultaneous introduction in separate dosage forms and separate introduction. That is, the compound described in this application and any of the agents described above, can be produced together in the same dosage form and entered at the same time. Alternatively, the compound of the present invention and any of the agents described above can be introduced simultaneously, both agents are present in separate compositions. In another alternative embodiment, in the compound of the present invention can be immediately entered and any of the agents described above, or Vice versa. According to the Protocol of separate introduction of the compound of the present invention and any of the agents described above can be introduced every few minutes or every few hours or every few days.

Examples and preparation examples presented below, further illustrate the compounds of the present invention and methods for producing such compounds and are given as PR is a measure. It should be understood that the scope of the present invention is in no way limited to the scope of the following examples and preparation examples. In the following examples of molecules with a single chiral center unless specified otherwise, exist as racemic mixtures. Such molecules with two or more chiral centers, unless otherwise noted, are in the form of a racemic mixture of diastereomers. Single enantiomers/diastereomers can be obtained by methods known to experts in this field of technology.

EXAMPLES

Example 1. Synthesis of 2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-tailpiece[2,3-d]pyrimidine-4(3H)-she (Connection 1406).

Scheme 14. Describes the synthesis of 2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-tailpiece[2,3-d]pyrimidine-4(3H)-she (Connection 1406).

To a stirred solution of 4,4-dimethoxy-2-butanone (101) (61 g; 85%; 0,393 mol), acetic acid (2.2 ml; of 0.038 mmol) and piperidine (3.8 ml; of 0.038 mol) in toluene (150 ml), in portions over 20 min was added malononitrile (25 g; 0,394 mmol). The reaction mixture was stirred over night at room temperature. The obtained dark red solution was washed H2O (50 ml), dried over MgSO4and concentrated in vacuum, which allowed to obtain the desired product 2-(4,4-dimetho sebutan-2-ilidene)malononitrile (102) (70 g; 99%) which was used directly in the next stage.

Gaseous ammonia was barbotirovany through a solution of 102 (32 g; 0,178 mmol) in Meon (500 ml) for 3 h, the obtained dark red solution was stirred overnight at room temperature. The mixture was concentrated and the residue was distributed between aqueous HCl (2 N.; 600 ml) and EtOAc (600 ml). The aqueous layer was separated and was podslushivaet chilled on ice concentrated solution of NaHCO3(600 ml). The solid precipitated from solution and was collected by filtration, which allowed to obtain the desired product 2-amino-4-methylnicotinamide (103) (3.0 g; 33%).

Compound 103 (5.32 g; 40 mmol) suspended in a solution of potassium hydroxide (26,88 g, 480 mmol) in water (26,85 ml) and isopropanol (9.6 ml). The reaction mixture was heated to the temperature of reflux distilled for 50 h, then cooled to room temperature, the mixture was diluted with ice-water (100 ml) and neutralized with concentrated HCl solution to pH 6-7. The mixture was concentrated in vacuo and the resulting residue was purified flash chromatography, elwira ethanol, which allowed to obtain the desired product 2-amino-4-methylnicotinic acid (104) (3,284 g; 54,7%).

To a stirred solution of compound 104 (3.2 g; of 21.2 mmol) in DMF (40 ml) and DCM (80 ml) was added EDCI (8,12 g; 42,4 mmol), HOBt (1-hydroxybenzotriazole) (2.86 g; 21,4 mmol) and o-Toluidine (4,53 ml; 42,4 mmol). The reaction is mesh was stirred over night at room temperature and then poured into water (120 ml). The aqueous phase was extracted with DCM (60 ml × 2). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The solid precipitated from solution. The solid is collected by filtration and dried, which allowed to obtain the desired product 2-amino-4-methyl-N-o-callincoming (1401) (3.6 g; 70,4%).

To a suspension of compound 1401 (1.2 g; 4,96 mmol) in anhydrous THF (60 ml) dropwise in an argon atmosphere was added utility (2.5 M; 2.38 ml; 5,96 mmol) at -40°C and stirred at this temperature for 1 h Then the reaction mixture was cooled to -78°C and added chlorocatechol (0,432 ml; 5.4 mmol). After stirring for 2 h at -78°C. the reaction mixture was poured into a mixture of ice-water (100 ml). After extracting most of the THF in vacuo, the solid precipitated from solution. The solid is collected by filtration and washed with ether, which allowed to obtain the desired product 2-(2-chloroacetamido)-4-methyl-N-o-callincoming (1402) (890 mg, 56.4 per cent).

The mixture of compounds 1402 (320 mg; 1 mmol) and phosphorus oxychloride (20 ml, 214 mmol) was heated at 115°C overnight in a sealed tube. The reaction mixture was cooled to room temperature and concentrated in vacuum. The residue was poured into a mixture of ice-water and neutralized with saturated solution of NaHCO3to pH 8-9, the obtained precipitated in the sediment firmly the substance was collected by filtration and washed with ether, that allowed to obtain the desired product 2-(chloromethyl)-5-methyl-3-o-tailpiece[2,3-d]pyrimidine-4(3H)-he (1403) (200 mg; 66,8%).

To a solution of 3-iodine-4-Amin-1H-pyrazolo[3,4-d]pyrimidine (108A) (261 mg; 1.2 mmol) in anhydrous DMF (9 ml) under nitrogen atmosphere was added at 0°C. tert-butyl potassium (123 mg; 1.1 mmol). The resulting mixture was stirred at this temperature for 45 minutes was Added a solution of compound 1403 (300 mg; 1 mmol) in anhydrous DMF (5 ml). The reaction mixture was stirred for 1 h at 0°C and then further for 1 h at room temperature. The mixture was concentrated in vacuo and the resulting residue was purified flash chromatography, which allowed to obtain the desired product 2-((4-amino-3-iodine-1H-pyrazolo[3,4-C1]pyrimidine-1-yl)methyl)-5-methyl-3-o-tailpiece[2,3-d]pyrimidine-4(3H)-he (1404) (450 mg; 83,3%).

To a solution of compound 1404 (36 mg; 0,069 mmol) and 3-hydroxyphenyl-Bronevoy acid (1405) (12 mg; 0,083 mmol) in DMF (2 ml), EtOH (1 ml) and water (1 ml) was added in an atmosphere of argon, Pd(PPh3)4(7 mg; 0,006 mmol) and a solution of Na2CO3(1 M, 0.5 ml; 0.5 mmol). The resulting mixture was degirolami and again filled with argon three times, and then was heated over night at 80°C. the Reaction mixture was left to cool to room temperature, concentrated. The residue was diluted with water (20 ml), neutralized with HCl solution (1 M) to pH 6-7 and was extracted with DCM (10 ml × 3). The combined organic with the AOI were washed with brine, dried over Na2SO4and concentrated. The residue was purified flash chromatography, which allowed to obtain the desired product 2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-tailpiece[2,3-d]pyrimidine-4(3H)-he (1406) (8 mg; 23,7%).

Example 2. Synthesis of 5-((4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-1,3-dimethyl-6-o-tolyl-1H-pyrazolo[4,3-d]pyrimidine-7(6N)-she (Connection 1511).

Scheme 15. Describes the synthesis of 5-((4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-1,3-dimethyl-6-o-tolyl-1H-pyrazolo[4,3-d]pyrimidine-7(6N)-she (Connection 1512).

Sodium (5,2 g; 0,226 mol) was dissolved in anhydrous ethanol (120 ml). To the above solution was added a mixture of diethyloxalate (1501) (31.8 ml; 0,235 mol) and acetone (16.0 ml; 0,218 mol), keeping the temperature below 10°C. the Reaction mixture was stirred over night at KG. The precipitate was collected by filtration, washed with petroleum ether (PE) and dried, which allowed to obtain the desired product 1502 in the form of a yellow solid (30,4 g; 77,5%).

Hydrazine hydrate (9.7 ml; 85%; 0,200 mol) was added dropwise to acetic acid (34 ml). To this solution at 25°C. portions were added connection 1502 (30,4 g; 0,169 mol). The resulting mixture was stirred for 2 h at room temperature, then was podslushivaet a saturated solution of NaHCO3D. the pH 8 and extracted with DCM (200 ml × 3). The combined organic phases were washed with brine, dried and concentrated, allowing to obtain the desired product, compound 1503, in the form of a yellow solid (22 g; 84,6%).

Dimethylsulfate (3,2 ml, 33.8 mmol) was added dropwise to a solution of compound 1503 (4,2 g; and 29.9 mmol) in toluene (20 ml). The reaction mixture was stirred for 4 h at 80°C., then left to cool to room temperature and concentrated. Added to the balance of 40% NaOH solution (15 ml). The resulting mixture was stirred for 1 h at 80°C, then cooled to room temperature, diluted with H2O (30 ml) and acidified with concentrated HCl to pH 3-4. Precipitated precipitated solid substance was collected by filtration, washed with cold water and dried, which allowed to obtain the desired product, compound 1505, in the form of a whitish solid (3,54 g; 84,4%).

To a stirred mixture of concentrated H2SO4(3.6 ml) and fuming HNO3(3.1 ml; 73,9 mmol) was added acid 1505 (2,813 g; 20 mmol) at 70-80°C. the Reaction mixture was stirred for 6 h at 70°C, cooled to room temperature and then poured into a mixture of ice and water. Precipitated precipitated solid substance was collected by filtration, washed with water and dried, which allowed to obtain the desired product, compound 1506, in the form of a yellow solid (0,795 g; 21.5 per cent).

The mixture of compounds is of 1506 (1,508 g; 8,15 mmol) and SOCl2(6 ml) was boiled under reflux for 3 h, then concentrated to remove SOCl2. The residue was dissolved in CH2Cl2(8 ml). To this solution at 0°C was added Et3N (1.13 ml) and o-toluidine (1.12 g; 12,23 mmol). The resulting mixture was stirred for 2 h at 10°C, concentrated and diluted with water. The solid is collected by filtration, washed with water and petroleum ether, dried, allowing to obtain the desired product, compound 1507, in the form of a yellow solid (1,74 g; 77,6%).

To a stirred mixture of compound 1507 (1.73 g; of 6.31 mmol) in Meon (100 ml) and THF (10 ml) was added 5% Pd/C (0.2 g). The mixture was degirolami and again was filled with hydrogen three times. The reaction mixture was stirred over night at room temperature and then filtered. The filtrate was concentrated in vacuum. The solid is dried, which allowed to obtain the desired product, compound 1508, in the form of a solid pale color (1.47 g; 95,4%).

Chlorocatechol (1,44 ml; 1,99 mmol) was added to a solution of compound 1508 (1,46 g; 5,98 mmol) in acetic acid (20 ml) and the reaction mixture was heated to the temperature of reflux distilled for 4 hours the Reaction mixture was cooled to room temperature and concentrated in vacuum. The residue was diluted in DCM (100 ml), washed with saturated solution of NaHCO3and brine, dried and the concentration of Aravali. The residue was purified flash chromatography with elution with petroleum ether in ethyl acetate (EA) (10/1), which allowed to obtain the desired product, compound 1509, in the form of a whitish solid (0,48 g; 26.7 percent).

A solution of 3-iodine-1H-pyrazolo[3,4-d]pyrimidine-4-amine (108A) (311 mg; 1,19 mmol) and K2CO3(330 mg; 2,39 mmol) in DMF (10 ml) was stirred at room temperature for 15 min, was added dropwise a solution of compound (1509) (180 mg; 1.15 mmol; 1 EQ.) in DMF (5 ml) at room temperature. The resulting mixture was stirred for 2 h at 80°C. the Reaction mixture was concentrated in vacuo to remove organic solvent. The obtained residue was purified column chromatography on silica gel, which allowed to obtain the desired product, compound 1509, (142 mg; yield of 44.9%) as a pale yellow solid.

Connection 1510 (40 mg; 0,076 mmol), Na2CO3(40 mg; 0.38 mmol), Pd(PPh3)4(17.6 mg; 0.015 mmol) and 3-fluoro-4-hydroxyphenylarsonic acid (15.8 mg; 0,101 mmol) was dissolved in a solution of DMF, ethanol and water (4 ml/2 ml/2 ml). The resulting mixture was degirolami, again filled with argon three times and then heated up to 80°C for 4 h under stirring. The reaction mixture was cooled to room temperature, neutralized 1 N. HCl solution to pH 7, concentrated in vacuo and extracted with ethyl acetate. The combined organic f the s was dried over Na 2SO4, filtered and concentrated. The residue was purified column flash chromatography with elution with a mixture of DCM/MeOH (50/1), which allowed to obtain the desired product 1511 (32 mg; 82%).

Example 3. Synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1 (2H)-she (Connection 1610) (method A).

Scheme 16. Describes the synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-a]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (Connection 1610) method A.

A solution of 2-amino-6-methylbenzoic acid (104) (106,5 g; 705 mmol) in H2O (200 ml) was cooled to 0-5°C, was slowly added concentrated HCl (250 ml). The solution was stirred for 15 min at 0-5°C. is added dropwise at 0-5°C was added a solution of sodium nitrite (58,4 g; 6,85 mol) in N2O (120 ml) and the resulting mixture was stirred for 30 minutes Then the above solution was added to a solution of KI (351 g; 2,11 mol) in N2O (200 ml) and the resulting mixture was stirred at KG over 16 hours the Solution was poured into ice water (2000 ml) and was extracted with ethyl acetate (3×1000 ml). The combined organic layer washed with aqueous NaOH (15%, 3×200 ml). The aqueous layer was acidified to pH 1 and extracted with ethyl acetate (3×1000 ml). The combined organic layers were dried over Na2SO4and filtered. The filtrate is concentrated is in vacuum, that allowed to obtain the desired product 2-iodine-6-methylbenzoic acid (901) (145 g; yield 79%) as a yellow solid.

To a stirred mixture of 2-iodine-6-methylbenzoic acid (901) (105 g, 400 mmol), Pd(OAc)2(27 g; 120 mmol) and PPh3(63 g; 240 mol) in THF (1000 ml) when KG was added tributyl(vinyl)tin (152 g, 480 mmol). The resulting mixture was heated to the temperature of reflux distilled during the night. The mixture was left to cool to KG, filtered through silica gel (10 g) and then concentrated in vacuum. The residue was poured into ice water (1000 ml) and was extracted with ethyl acetate (3×1000 ml). The combined organic layer washed with aqueous NaOH (15%, 5×200 ml). The combined aqueous layer was acidified to pH 1, extracted with ethyl acetate (3×1000 ml). The combined organic layer was dried over Na2SO4and filtered. The filtrate was concentrated in vacuum, which allowed to obtain the desired product 2-methyl-6-vinylbenzoic acid (902) (61 g; yield 95%) as a yellow solid.

A mixture of 2-methyl-6-vinylbenzoic acid (902) (56 g, 350 mmol) and thionyl chloride (208 g; 1750 mmol) in toluene (400 ml) was stirred at the temperature of reflux distilled for 2 hours the Mixture was concentrated in vacuum, which allowed to obtain the desired product 2-methyl-6-vinylbenzoate (1601) (63 g; yield 95%) as a yellow oil. The obtained product is used directly in the following with the adiya's without purification.

A mixture of on-toluidine (45 g, 420 mmol) and triethylamine (71 g; 70 mmol) in CH2Cl2(300 ml) was stirred for 10 min at RT. To this mixture was added 2-methyl-6-vinylbenzoate (1601) (63 g; 35 mmol) and the resulting mixture was stirred at RT for 30 min the Solution was poured into water (300 ml), was extracted with CH2CL g (3×200 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum, which allowed us to obtain the crude product. The crude product is suspended in IPE (isopropyl ether (300 ml), was stirred at the temperature of reflux distilled for 30 min and then was cooled to 0-5°C. the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product 2-methyl-N-o-tolyl-6-vinylbenzene (1602) (81 g; yield 80%) as a yellow solid.

To a solution of 2-methyl-N-o-tolyl-6-vinylbenzene (1602) (80 g, 320 mmol) in DMF (250 ml) when KG was slowly added NaH (60% in mineral oil; 25,6 g, 640 mmol) and the resulting mixture was stirred at RT for 30 minutes To this mixture was added ethylchloride (78 g, 640 mmol) and the resulting mixture was stirred at KG within 2 hours the Solution was poured into water (500 ml), extracted with ethyl acetate (3×200 ml), dried over Na3SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in the Meon (160 ml), was stirred at a temperature of delegats and for 10 min and then was cooled to 0-5°C. The precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product ethyl-2-(2-methyl-N-o-tolyl-6-vinylbenzene)acetate (1603) (67 g; yield 62%) as a white solid.

To a stirred mixture of ethyl-2-(2-methyl-N-o-tolyl-6-vinylbenzene)acetate (1603) (67 g; 200 mmol) in 1,4-dioxane (300 ml) and H2O (100 ml) at RT was added osmium tetroxide (20 mg) and stirred at RT for 30 minutes To this mixture was added periodate sodium (86 g, 400 mmol) and the resulting mixture was stirred at RT for 16 h the Reaction mixture was filtered through silica gel (10 g), the filtrate was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was then dried in a vacuum that has allowed to obtain the desired product ethyl-2-(2-formyl-6-methyl-N-o-toolbarname)acetate (1604) (38 g; yield 57%) as a yellow solid.

To a stirred solution of ethyl-2-(2-formyl-6-methyl-N-o-toolbarname)acetate (1604) (38 g, 112 mmol) in EtOH (200 ml) and ethyl acetate (100 ml) at RT was added cesium carbonate (22 g, 112 mmol). The resulting mixture was degirolami, again filled with argon three times and then stirred at 50°C for 5 hours the Mixture was left to cool to CT, filtered through silica gel (10 g) and the filtrate was concentrated in vacuum. The balance in lively in H 2O (200 ml), extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in IPE (120 ml), was heated to the temperature of reflux distilled for 10 min and then was cooled to 0-5°C. the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product ethyl-8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carboxylate (1605) (28 g; yield 77%) as a white solid.

To a stirred solution of lithium aluminum hydride (8,28 g; 218 mol) in anhydrous THF (500 ml) at -78°C. in a nitrogen atmosphere slowly over 10 min was added ethyl-8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carboxylate (1605) (28 g, 87 mmol). The resulting mixture was left to warm to -30°C., stirred for 30 min, and data TLC showed that the reaction is complete. Then the mixture was cooled to -78°C. and slowly added water (50 ml). The mixture was left to warm to CT, filtered through silica gel (10 g) and the filtrate was concentrated in vacuum. The crude product was poured into H2O (200 ml) and was extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in utilize the ATA (30 ml) and was stirred for 10 minutes The solid is collected by filtration and then dried in vacuum, which allowed to obtain the desired product 3-(hydroxymethyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1606) (22 g; yield 92%) as a white solid.

PBr3(25,6 g, 95 mmol) was slowly added to a stirred solution of DMF (11.5g; 158 mol) in acetonitrile (200 ml) at 0°C and the resulting mixture was stirred at 0°C for 30 minutes was Slowly added 3-(hydroxymethyl)-8-methyl-2-o-cholelithiasis-1-(2H)-he (1606) (22 g; of 78.8 mmol). Then the reaction mixture was left to warm to CT and was stirred for 30 minutes was Slowly added saturated aqueous solution of NaHCO3(50 ml) and was extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine, dried over MAG and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in IPE (50 ml) and then was stirred for 10 minutes the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product 3-(methyl bromide)-8-methyl-2-o-cholelithiasis-1(2H)-he (1607) (21 g; yield 80%) as a white solid.

3-Iodine-1H-pyrazolo[3,4-d]pyrimidine-4-amine (108A) (10.8 g; 41,4 mmol) and tert-butyl potassium (4.4 g; 40 mmol) was dissolved in anhydrous DMF (150 ml) and stirred at RT for 30 minutes was Added 3-(methyl bromide)-8-methyl-2-o-cholelithiasis-1(2H)-he (1607) (13,7 g; 40 mmol). The resulting mixture plumage is shivali when KG over 30 min, was poured into ice water (300 ml) and then extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated to about 100 ml in vacuo, the precipitate was collected by filtration, which allowed to obtain the first batch of the desired product 3-((4-amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (1608) (12 g, yield 60%) as a white solid. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (2-20% MeOH/DCM), which allowed to obtain a second batch of the desired product 3-((4-amino-3-iodine-1 H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (1608) (6 g, 30% yield) as a white solid.

3-((4-Amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1608) (13 g; 24,9 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1609) (6.6 g; 30 mmol) was dissolved in DMF-EtOH-H2O (120 ml; 40 ml; 40 ml). Consistently added Pd(OAc)2(1,684 g; 7.5 mmol), PPh3(3,935 g; 15 mmol) and Na2CO3(13,25 g; 125 mmol). The resulting mixture was degirolami, again filled with argon three times and then stirred at 100°C for 1 h the Mixture was left to cool to CT, filtered through silica gel (10 g) and concentrated in vacuum. The residue was purified colonoscopy because it allows the Noah flash chromatography on silica gel (2-20% MeOH/DCM), that allowed us to obtain the product (1610) (9 g; yield 76%) as a pale yellow solid. Then the above product is suspended in EtOH (100 ml) and was heated to the temperature of reflux distilled for 30 minutes and the Mixture was left to cool to CT and the solid substance was collected by filtration. The solid is then suspended in EA (ethyl acetate) (100 ml) and was stirred over night. The precipitate was collected by filtration then dried in a vacuum that has allowed to obtain the desired product 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1610) (8,4 g; yield 69%) as a white solid.

Example 4. Synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (Connection 1610) (method).

Scheme 17. Describes the synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (Connection 1610) method C.

3-(3-Methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (1701) (964 mg; 4 mmol) and tert-butyl potassium (0,44 g; 4 mmol) was dissolved in anhydrous DMF (150 ml) and stirred at RT for 30 minutes was Added 3-(methyl bromide)-8-methyl-2-o-cholelithiasis-1(2H)-he (1607) (1,37 g; 4.0 mmol). The resulting mixture was stirred at KG for 30 min, poured into ice-cold water (30 ml) and then extracted with ethyl acetate (3×5 ml). The combined organic layer was washed with brine (25 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (2-20% MeOH/DCM), which allowed to obtain the desired product 3-((4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1702) (1.4 g; yield 70%) as a white solid.

To a solution of 3-((4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (1702) (100 mg; 0.2 mmol) in CH2Cl2(20 ml) at -78°C under nitrogen atmosphere was added BBr3(1 ml) and the resulting mixture was stirred at -78°C for 3 hours the Mixture was left to warm to CT, was poured into a mixture of ice-water (200 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (20 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (10-50% MeOH/CH2Cl2), which allowed to obtain the desired product 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1610) (87 mg, yield 91%) as a white solid.

Example 5. Synthesis of (R)-3-((4-amino-3-(3-hydroxymet-1-inyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-it (Connect the tion 1802).

Scheme 18. Describes the synthesis of (R)-3-((4-amino-3-(3-hydroxymet-1-inyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (Connection 1802).

3-((4-Amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1608) (522 mg; 1 mmol) and (R)-but-3-in-2-ol(84 mg; 1.2 mmol) was dissolved in anhydrous THF (40 ml). The mixture was degirolami and again filled with nitrogen three times. Consistently added Pd(PPh3)2CL2(12 mg, 0.1 mmol), Cul (47 mg, 0.25 mmol) and (ISO-Pr)NH (505 mg, 5 mmol). The resulting mixture was degirolami, again filled with argon three times and then stirred at the temperature of reflux distilled for 4 hours the Mixture was left to cool to CT, filtered through silica gel (10 g) and concentrated in vacuum. The residue was purified column flash chromatography on silica gel (2-20% MeOH/DCM), which allowed to obtain the product of 3(R)-3-((4-amino-3-(3-hydroxymet-1-inyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1802) (324 mg, yield 70%) as a pale yellow solid.

Example 6. Synthesis of 3-((6-amino-N-purine-9-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (Connection 1902).

Scheme 19. Describes the synthesis of 3-((6-amino-N-purine-9-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (Connection 1902).

N-Purine-6-amine (1901) (540 mg; 4.0 mmol) was dissolved in anhydrous DMF (20 ml). Add the Yali NaH (60% in mineral oil; 160 mg; 4.0 mmol) and the resulting mixture was stirred at RT for 30 minutes was Added 3-(methyl bromide)-8-methyl-2-o-cholelithiasis-1(2H)-he (1607) (1,37 g; 4.0 mmol). The reaction mixture was stirred at RT for 30 min, then poured into a mixture of ice-water (30 ml) and then extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (25 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (2-20% MeOH/DCM), which allowed to obtain the desired product 3-((6-amino-N-purine-9-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he (1902) (1.1 g; yield 70%) as a white solid.

Example 7. Synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-2-isopropyl-8-methylisoquinoline-1(2H)-she (Connection 2009).

Scheme 20. Describes the synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-2-isopropyl-8-methylisoquinoline-1(2H)-she (Connection 2009).

To a stirred mixture of 2-iodine-6-methylbenzoic acid (901) (105 g, 400 mmol), Pd(OAc)2(27 g; 120 mmol) and PPh3(63 g; 240 mol) in THF (1000 ml) at RT was added tributyl(vinyl)tin (152 g, 480 mmol). The resulting mixture was heated to the temperature of reflux distilled during the night. The mixture was left to cool to CT, filtered through silica gel (10 g) and the ATEM concentrated in vacuum. The residue was poured into ice water (1000 ml) and was extracted with ethyl acetate (3×1000 ml). The combined organic layer washed with aqueous NaOH (15%; 5×200 ml). The combined aqueous layer was acidified to pH 1, extracted with ethyl acetate (3×1000 ml). The combined organic layer was dried over Na2SO4and filtered. The filtrate was concentrated in vacuum, which allowed to obtain the desired product 2-methyl-6-vinylbenzoic acid (902) (61 g; yield 95%) as a yellow solid.

A mixture of 2-methyl-6-vinylbenzoic acid (902) (56 g, 350 mmol) and thionyl chloride (208 g; 1750 mmol) in toluene (400 ml) was stirred at the temperature of reflux distilled for 2 hours the Mixture was concentrated in vacuum, which allowed to obtain the desired product 2-methyl-6-vinylbenzoate (1601) (63 g; yield 95%) as a yellow oil. The obtained product was used directly in the next stage without purification.

Propane-2-amine (2001) (59 g; 1.0 mol) and ethylchloride (122 g; 1.0 mol) was dissolved in toluene (200 ml) and the mixture was stirred at the temperature of reflux distilled for 2 hours the Reaction mixture was left to cool to CT, was poured into a mixture of ice-water (500 ml) and was extracted with ethyl acetate (3×250 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on si is imagele (10-50% EA/PE), that allowed us to get the product ethyl-2-(isopropylamino)acetate (2002) (70 g; 51% yield) as oil.

Ethyl-2-(isopropylamino)acetate (2002) (14.5 g; 100 mmol) and triethylamine (200 g; 200 mmol) was dissolved in CH2Cl2(300 ml) and the mixture was stirred for 10 min at RT. Was added 2-methyl-6-vinylbenzoate (1601) (18 g; 100 mmol) and the resulting mixture was stirred at KG over 30 minutes, the Reaction mixture was poured into water (300 ml) and was extracted with CH2Cl2(3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum, which allowed us to obtain the crude product. The crude product is suspended in IPE (isopropyl ether (300 ml), was stirred at the temperature of reflux distilled for 30 min and then was cooled to 0-5°C. the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product ethyl-2-(N-isopropyl-2-methyl-6-vinylbenzene)-acetate (2003) (14.5 g; yield 50%) as a yellow solid.

To a stirred solution of ethyl-2-(N-isopropyl-2-methyl-6-vinylbenzene)acetate (2003) (14.0 g; 48,0 mmol) in 1,4-dioxane (100 ml) and N2O (30 ml) was added osmium tetroxide (20 mg) and the resulting mixture was stirred at RT for 30 minutes To this mixture was added periodate sodium (22 g; 100 mmol) and then stirred at RT for 16 h the Reaction to the offer was filtered through silica gel (10 g), the filtrate was extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was then dried in a vacuum that has allowed to obtain the desired product ethyl-2-(2-formyl-N-isopropyl-6-methylbenzamide)acetate (2004) (8,33 g; yield 57%) as a yellow solid.

To a stirred solution of ethyl-2-(2-formyl-N-isopropyl-6-methylbenzamide)acetate (2004) (8,3 g; 28,0 mmol) in EtOH (100 ml) and ethyl acetate (50 ml) at RT was added cesium carbonate (5.9 g; 30 mmol). The resulting mixture was degirolami, again filled with argon three times and then stirred at 50°C for 5 hours the Mixture was left to cool to CT, filtered through silica gel (10 g) and the filtrate was concentrated in vacuum. The residue was poured into H2O (200 ml), extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in IPE (120 ml), was stirred at the temperature of reflux distilled for 10 min and then was cooled to 0-5°C. the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product ethyl-2-isopropyl-8-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (2005) (5.35 g; yield 70%) as a white solid.

the mixed solution of lithium aluminum hydride (2,88 g; 76 mol) in anhydrous THF (200 ml) at -78°C. slowly over 10 min under nitrogen atmosphere was added ethyl-2-isopropyl-8-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (2005) (5,2 g; 19 mmol). The resulting mixture was left to warm to -30°C., stirred for 30 min, and data TLC showed that the reaction is complete. Then the mixture was cooled to -78°C was slowly added water (50 ml). The mixture was left to warm to CT, filtered through silica gel (10 g) and the filtrate was concentrated in vacuum. The crude product was poured into H2O (200 ml) and was extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in ethyl acetate (30 ml) and was stirred for 10 minutes, the Solid was collected by filtration, then dried in vacuum, which allowed to obtain the desired product 3-(hydroxymethyl)-2-isopropyl-8-methylisoquinoline-1(2H)-he (2006) (3.51 g; yield 80%) as a white solid.

To a solution of 3-(hydroxymethyl)-2-isopropyl-8-methylisoquinoline-1 (2H)-it (2006) (1,61 g; 7.0 mmol) in CH2Cl2added PPh3(to 3.67 g, 14.0 mmol) and the mixture was stirred at RT for 30 min the Mixture was cooled to 0°C and portions were added CBr4(with 4.64 g; 14.0 mmol). The resulting mixture was stirred at a temperature from 0°C to KG within 30 m of the h and then concentrated in vacuum. The crude product was purified column flash chromatography on silica gel (30-50% EA/PE), which allowed to obtain the desired product 3-(methyl bromide)-2-isopropyl-8-methylisoquinoline-1(2H)-he (2007) (1.65 g; yield 80%) as a white solid.

A mixture of 3-iodine-1H-pyrazolo[3,4-a]pyrimidine-4-amine (108A) (1.3 g; 5 mmol) and of potassium tert-butylate (0.55 g; 5 mmol) in anhydrous DMF (20 ml) was stirred at RT for 30 min and then was added 3-(methyl bromide)-2-isopropyl-8-methylisoquinoline-1(2H)-he (2007) (1.47 g; 5 mmol). The resulting mixture was stirred at RT for 30 min, then poured into a mixture of ice-water (30 ml) and then extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (25 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (2-20% MeOH/DCM), which allowed to obtain the desired product 3-((4-amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-2-isopropyl-8-methylisoquinoline-1 (2H)-he (2008) (1.66 g; yield 70%) as a white solid.

To a stirred mixture of 3-((4-amino-3-iodine-1H-pyrazolo[3,4-a]pyrimidine-1-yl)methyl)-2-isopropyl-8-methylisoquinoline-1(2H)-she (2008) (95 mg; 0.2 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (66 mg; 0.3 mmol) in a mixture of DMF-EtOH-H2O (3:1:1; 20 ml), was added Pd(OAc)2(16 mg; of 0.075 mmol), PPh3(39,3 mg; 0.15 mmol) and Na2CO3

Example 8. Synthesis of 7-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-she (Connection 2115).

Scheme 21. Described the synthesis of 7-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-she (Connection 2115).

To a mixture of ethyl-2-cyanoacetate (2101) (45,2 g, 400 mmol) and acetone (46,4 g, 800 mmol) in glacial acetic acid (50 ml) was added piperidine (2 ml; 20 mmol) and the resulting mixture was stirred at the temperature of reflux distilled within 24 hours the Reaction mixture was left to cool to KG and then concentrated in vacuum. The residue was diluted with water (200 ml) and was extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (50 ml), dried over Mas and filtered. The filtrate was concentrated in vacuo and the residue was purified kolonen the th flash chromatography on silica gel (0-2% EA/PE), that allowed to obtain the desired product ethyl-2-cyano-3-methylbut-2-ENOAT (2102) (49,6 g; yield 81%) as a white solid.

To a solution of ethyl-2-cyano-3-methylbut-2-enoate (2102) (43,6 g; 285 mol) in absolute EtOH (300 ml) was added dropwise, dimethylacetal N,N-dimethylformamide (37,3 g, 313 mmol) and the resulting mixture was stirred at the temperature of reflux distilled for 6 hours the Mixture was left to cool to CT, concentrated in vacuum, which allowed us to obtain the crude desired product ethyl-2-cyano-5-(dimethylamino)-3-methylpentan-2,4-dienoate (2103) (39,8 g; yield 67%) as a yellow solid.

Ethyl-2-cyano-5-(dimethylamino)-3-methylpentan-2,4-dienoate (2103) (30,8 g, 148 mmol) was dissolved in Asón (120 ml) and the mixture was stirred at 40°C. was added dropwise a solution of 45% HBr-Asón (120 ml) and the mixture is then stirred at 55°C for 2 hours the Mixture was left to cool to CT, poured into ice, neutralized solid Na2CO3and were extracted with ethyl acetate (3×150 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (5-20% EA/PE), which allowed to obtain the desired product ethyl-2-bromo-4-methylnicotinate (2104) (17.6 g; yield 49%) as a yellow oil.

To a solution of ethyl-2-bromo-4-methylnicotinate (2104) (12.8 g; 52 mmol) in 1,4-dio the San (15 ml) was added a solution of NaOH (8.0 g; 200 mmol) in N2O (15 ml) and the resulting mixture was stirred at the temperature of reflux distilled for 12 hours the Mixture was left to cool to CT, diluted in N2O, washed with ethyl acetate (3×30 ml). The aqueous layer was acidified with concentrated hydrochloric acid to pH 1 and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (25 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum, which allowed to obtain the desired product 2-bromo-4-methylnicotinic acid (2105) (9.7 g; yield 85%) as a white solid.

To a solution of 2-bromo-4-methylnicotinic acid (2105) (13 g, 60 mmol) and DMF (3 drops) in CH2Cl2(150 ml) was added dropwise oxalicacid (11.4 g; 90 mmol) and the resulting mixture was stirred at RT for 2 h the Reaction mixture was concentrated in vacuum, which allowed to obtain the desired product 2-bromo-4-methylnicotinate (2106) (13,4 g; yield 95%) as a yellow oil. The obtained product was used directly in the next stage without further purification.

o-Toluidine (7,7 g; 72 mmol) and triethylamine (9.1 g; 90 mmol) was dissolved in CH2Cl2(100 ml) and was stirred for 10 min at KG. Was added 2-bromo-4-methylnicotinate (2106) (13,4 g; 57 mmol) and the resulting mixture was stirred at KG over 1 h the Mixture was poured into water (200 ml) and was extracted with CH2Cl (3×50 ml). The combined organic layer was washed with brine (20 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum, which allowed us to obtain the crude product. The crude product is suspended in IPE (isopropyl ether (50 ml). The mixture was stirred at the temperature of reflux distilled for 30 min and then was cooled to 0-5°C. the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product 2-bromo-4-methyl-N-o-callincoming (2107) (13 g; 75% yield) as a yellow solid.

To a solution of 2-bromo-4-methyl-N-o-telinekataja (2107) (13 g; 43 mmol) and tributyl(vinyl)tin (16.4 g; 52 mmol) in THF (200 ml) under nitrogen atmosphere was added Pd(OAc)2(2.9 g; 13 mmol) and PPh3(6.8 g; 26 mol). The resulting mixture was stirred at the temperature of reflux distilled for 16 hours Then the mixture was left to cool to CT, filtered through silica gel (10 g) and concentrated in vacuum. The residue was poured into water (200 ml), extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (30 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (20-50% EA/PE), which allowed to obtain the desired product 4-methyl-N-o-tolyl-2-wiselycautioned (2108) (8.7 g; yield 80%) as a yellow solid.

the mixed solution of 4-methyl-N-o-tolyl-2-wiselycautioned (2108) (8,1 g; 32 mmol) in DMF (50 ml) at RT was slowly added NaH (60% in mineral oil; 2.6 g; 65 mmol) and the resulting mixture was stirred at KG over 30 minutes To this mixture was added dropwise ethylchloride (78 g, 640 mmol) in KG and was stirred for 2 h the Solution was poured into water (300 ml) and was extracted with ethyl acetate (3×80 ml). The combined organic layer was washed with brine (25 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in the Meon (60 ml) and stirred at the temperature of reflux distilled within 10 minutes Then the mixture was cooled to 0-5°C. the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product ethyl-2-(4-methyl-N-o-tolyl-2-wiselycautioned)acetate (2109) (6.3 g; yield 58%) as a white solid.

To a solution of ethyl-2-(4-methyl-N-o-tolyl-2-wiselycautioned)acetate (2109) (6,1 g; 18 mmol) in 1,4-dioxane (90 ml) and N2O (30 ml) at KG was added osmium tetroxide (5 mg) and the resulting mixture was stirred for 30 minutes was Added periodate sodium (7,7 g; 36 mmol) and the mixture was stirred at RT for 16 h the Mixture was filtered through silica gel (5 g) and the filtrate was extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (25 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue further what about dried under reduced pressure, that allowed to obtain the desired product ethyl-2-(2-formyl-4-methyl-N-o-telinekataja)acetate (2110) (4.4 g; yield 72%) as a yellow solid.

To a stirred solution of ethyl-2-(2-formyl-4-methyl-N-o-telinekataja)acetate (2110) (4.4 g; 13 mmol) in EtOH (30 ml) and ethyl acetate (10 ml) at RT was added cesium carbonate (4.3 g; 13 mmol). The resulting mixture was degirolami, again filled with argon three times and then stirred at 50°C for 5 hours the Mixture was left to cool to CT, filtered through silica gel (5 g) and the filtrate was concentrated in vacuum. The residue was poured into H2O (200 ml), extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in RE (30 ml), was stirred at the temperature of reflux distilled for 10 min and then was cooled to 0-5°C. the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product ethyl-4-methyl-5-oxo-6-o-tolyl-5,6-dihydro-1,6-naphthiridine-7-carboxylate (2111) (3.0 g; yield 72%) as a white solid.

To a stirred solution of lithium aluminum hydride (0,86 g; 23 mol) in anhydrous THF (100 ml) at -78°C under nitrogen atmosphere was added dropwise a solution of ethyl-4-methyl-5-oxo-6-o-tolyl-5,6-dihydro-1,6-naphthiridine-7-carboxylate (2111) (2.9 g; 9.0 mmol) in anhydrous THF (20 ml). Received the th and the mixture was left to warm to -10°C, was stirred for 30 min, and data TLC showed that the reaction is complete. Then the mixture was cooled to -78°C. and slowly added water (50 ml). The mixture was left to warm to CT, filtered through silica gel (5 g) and the filtrate was concentrated in vacuum. The crude product was poured into H2O (100 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (25 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum. The crude product is suspended in ethyl acetate (10 ml) and was stirred for 10 minutes, the Solid was collected by filtration and then dried in vacuum, which allowed to obtain the desired product 7-(hydroxymethyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-he (2112) (2.1 g; yield 83%) as a white solid.

To a solution of 7-(hydroxymethyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-she (2112) (1,96 g; 7.0 mmol) in CH2CL2added PPh3(to 3.67 g, 14.0 mmol) and stirred at RT for 30 minutes To a mixture of portions was added CBr4(with 4.64 g; 14.0 mmol) at 0°C. the resulting mixture was left to warm to CT, was stirred for 30 min and concentrated in vacuum. The residue was purified column flash chromatography on silica gel (30-50% EA/PE), which allowed to obtain the desired product 7-(methyl bromide)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-he (2113) (1.92 g; yield 80%) as a white firmly what about the substance.

A mixture of 3-iodine-1H-pyrazolo[3,4-d]pyrimidine-4-amine (108A) (1,08 g, 4.14 mmol) and of potassium tert-butylate (0,44 g; 4.0 mmol) in anhydrous DMF (50 ml) was stirred at RT for 30 min and then was added 7-(methyl bromide)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-he (2113) (1,37 g; 4.0 mmol). The resulting mixture was stirred at RT for 30 min, poured into ice water (300 ml) and then extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with brine (30 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (0-2% MeOH/DCM), which allowed to obtain the desired product 7-((4-amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-(2114) (1.07 g; yield 50%) as a white solid.

To a stirred mixture of 7-((4-amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-she (2114) (1,05 g; 2.0 mmol) and 3-hydroxyphenylpropionic acid (0.33 g; 2.4 mmol) in a mixture of DMF-EtOH-H2O (3:1:1, 50 ml), was added Pd(OAc)2(0.14 g; a 0.60 mmol), PPh3(0.31 g; 1.2 mmol) and Na2CO3(1.06 g; 10.0 mmol). The resulting mixture was degirolami, again filled with argon three times and then stirred at 80°C for 1 h the Mixture was left to cool to CT, filtered through silica gel (5 g) and concentrated in vacuum. The residue was purified count the night flash chromatography on silica gel (2-5% MeOH/DCM), that allowed to obtain the desired product 7-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-he (2115) (0.68 g; yield 69%) as a pale yellow solid. Then the product was dissolved in EtOH (5 ml) and stirred at the temperature of reflux distilled for 30 minutes the Solution was left to cool to CT and the solid substance was collected by filtration. The solid is then suspended in ethyl acetate (5 ml) and stirred at RT for 16 h the Precipitate was collected by filtration and then dried in vacuum, which allowed to obtain the desired product 7-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthiridine-5(6N)-he (2115) (0,59 g; yield 60%) in the form of a white solid.

Example 9. 3-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he (Connection 2208).

Scheme 22. Described 3-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-she (Connection 2208).

2-Iodine-6-methyl-N-o-toolbarname (2201) (1,5 r; 4,27 mmol), obtained in the result of the interaction of compounds 902 and 2-methyl-aniline and allyltrimethylsilane (2.10 g; 1.5 mmol), was dissolved in anhydrous DMF (12 ml). The solution was degirolami and again was filled with argon (three times). Was added Pd(PPh3) 4(148 mg; 0.13 mmol). The reaction mixture was degirolami, again filled with argon (three times) and then stirred at 90°C for 16 hours the Mixture was left to cool to CT, was distributed between ethyl acetate and N2O. the Organic layer was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column chromatography on silica gel, elwira EtOAc and hexane, which allowed to obtain the desired product 2-allyl-6-methyl-N-o-toolbarname (2202) (1.1 g; yield 95%).

2-Allyl-6-methyl-N-o-toolbarname (2202) (800 mg; a 3.01 mmol) was dissolved in anhydrous dichloromethane (20 ml). Added m-SRV (meta-chloroperoxybenzoic acid) (70%; 1,11 g; to 4.52 mmol) and the resulting mixture was stirred at RT for 24 h was Added Na2SO3(1.0 g) and was stirred for 1 h, the Mixture was distributed between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column chromatography on silica gel, elwira EtOAc and hexane, which allowed to obtain the desired product 2-methyl-6-(oxiran-2-ylmethyl)-N-o-toolbarname (2203) (660 mg, yield 83%).

2-Methyl-6-(oxiran-2-ylmethyl)-N-o-toolbarname (2203) (860 mg; a 3.06 mmol) was dissolved in anhydrous DMF (15 ml) and cooled to 0°C in an argon atmosphere. Portions was added NaH (60% in mineral the asle; 245 mg, 6.12 mmol) and the resulting mixture was stirred at 0°C for 3 hours was Slowly added N2O (30 ml) and the mixture was extracted with EtOAc (3×25 ml). The combined organic layers were washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column chromatography on silica gel, elwira EtOAc and hexane, which allowed to obtain the desired product 3-(hydroxymethyl)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he (2204) (435 mg, 51% yield).

3-(Hydroxymethyl)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he (2204) (430 mg; 1.53 mmol) was dissolved in anhydrous dichloromethane (25 ml) and cooled to 0°C in an argon atmosphere. Consistently added PPh3(600 mg; to 2.29 mmol) and CBr4(761 mg; to 2.29 mmol) and the resulting mixture was stirred at a temperature from 0°C to CT for 16 hours the Reaction mixture was distributed between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column chromatography on silica gel, elwira EtOAc and hexane, which allowed to obtain the desired product 3-(methyl bromide)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he 2205) (480 mg, yield 91%).

3-(methyl bromide)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he (2205) (387 mg; 1.12 mmol) and 3-iodine-1H-pyrazolo[3,4-d]pyrimidine-4-amine (108A) (440 mg; 1,69 mmol) was dissolved in izvozna DMF (20 ml). Added To2CO3(309 mg; 2,24 mmol) and the resulting mixture was stirred at 50°C for 3 hours the Reaction mixture was distributed between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column chromatography on silica gel, elwira methanol and dichloromethane, which allowed to obtain the desired product 3-((4-amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he (2206) (100 mg, yield 17%).

3-((4-Amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he (2206) (100 mg; 0.11 mmol) and 3-fluoro-5-hydroxyphenylarsonic acid (2207) (36 mg; 0.23 mmol) was dissolved in DME (4 ml). The solution was degirolami and again was filled with argon (three times). Consistently added Pd(PPh3)4(6.4 mg; 5.5 mmol) and an aqueous solution of Na2CO3(1.0 M; of 0.44 ml, 0.44 mmol). The reaction mixture was degirolami, again filled with argon (three times) and then stirred at 80°C for 24 h the Mixture was left to cool to CT, was distributed between ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira methanol and dichloromethane, which allowed to obtain the desired product 3-((4-am is but-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-C1]pyrimidine-1-yl)methyl)-8-methyl-2-o-tolyl-3,4-dihydroisoquinoline-1(2H)-he (2208) (12 mg; yield 22%).

Example 10. Synthesis of 6-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-3-methyl-5-o-cholelithiasis[5,4-d]pyrimidine-4(5H)-she (Connection 2313).

Scheme 23. Describes the synthesis of 6-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-3-methyl-5-o-cholelithiasis[5,4-d]pyrimidine-4(5H)-she (Connection 2313).

A solution of compound 2302 (24,9 g; to 0.19 mol) in CH3CN (50 ml) was added to a solution of compound 2301 (30 g; to 0.19 mol) at 0°C. the Mixture was stirred for 1 hour at room temperature and was poured into 500 ml of water. The reaction mixture was left to stand for 1 h, the Solid precipitated from solution, was collected by filtration, washed with water and dried, which allowed us to obtain the desired compound 2303 in the form of a red-orange solid (50 g; 85,5%).

To a solution of compound 2303 (54 g; 0,175 mol) in ethyl acetate (200 ml) dropwise at room temperature was added a solution of Br3(56 g; 0.35 mol) in ethyl acetate (50 ml). The resulting mixture was stirred for 3 h at room temperature. The solid is collected by filtration, washed with ethyl acetate, which allowed to obtain the desired product, compound 2304 (40 g; 74,6%).

The mixture of compounds 2304 (40 g; 0.13 mol) and saturated solution of Na2CO3(10 ml) in DMF (100 ml) was heated for 5 h at 80°C. the Reaction mixtures is ü cooled to room temperature and was added to 1 l of water. The solid is collected by filtration and dried, which allowed to obtain the desired product, compound 2305 (16 g; 66%).

The mixture of compounds 2305 (16 g; 0,086 mol) and NaOH (6,88 g; 0,172 mol) in water (50 ml) was heated for 4 hours at a temperature of reflux distilled. The reaction mixture was cooled to room temperature and acidified to 1 N. the solution of HCI to pH 3-4. The solid is collected by filtration and dried, which allowed to obtain the desired product, compound 2306 (12 g; 88%).

A mixture of compound 2306 (1 g; 0,0063 mol) in SOCl2(15 ml) was stirred for 5 hours at a temperature of reflux distilled, the reaction mixture was cooled to room temperature and concentrated to remove excess SOCl2. To the residue was added anhydrous toluene (30 ml) and concentrated. This process was repeated twice to remove the rest SOCl2.

The crude compound 2307 was dissolved in anhydrous toluene (5 ml). To the above solution was added 2-methyl-aniline (2 g; 0,0187 mol). The resulting mixture was heated for 1 h at the temperature of reflux distilled, cooled to room temperature and filtered. The filtrate was concentrated to dryness and distributed between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried using MgSO4and filtered. The residue was purified flash chromatography with elution is with a mixture of petroleum ether: ethyl acetate (from 50:1 to 5:1), that allowed to obtain the desired product, compound 2308 (600 mg; 38,55%).

A solution of compound 2308 (600 mg; 2,43 mmol) and pyridine (0,78 ml) in DCM (30 ml) was stirred for 10 min at 0°C. was Added chlorocatechol (423 mg; 3,74 mmol). The reaction mixture was stirred for 2 h and extinguished with water. The organic phase was separated and washed with water, brine, dried, filtered and concentrated, allowing to obtain the desired product, compound 2309 (700 mg; 89%).

The mixture of compounds 2309 (600 mg; of 1.85 mmol) and l3(10 ml) was heated overnight at 120-130°C (oil bath) in a sealed tube. The reaction mixture was cooled to room temperature and concentrated. The residue was distributed between ethyl acetate and water and then podslushivaet a saturated solution of Na2CO3to pH 7-8. The organic layer was separated, washed with brine, dried over MgSO4and concentrated. The residue was purified flash chromatography with elution with petroleum ether in ethyl acetate (PE/EA is 20/1), which allowed to obtain the desired product, compound 2310, in the form of a yellow powder (300 mg; 53,0%).

tert-BuOK (28,7 mg; 0,256 mmol) was added to a solution of compound 2311 (76 mg; 0,295 mmol) in anhydrous DMF (3 ml) at RT. The reaction mixture was stirred for 30 min and was added dropwise a solution of compound 2310 (60 mg; 0,196 mmol) in DMF (2 ml). The resulting mixture was stirred is for 2 h and concentrated. The residue was purified flash chromatography with elution with a mixture (DCM/MeOH is 50/1), which allowed to obtain the desired product 2312 in the form of a whitish solid (65 mg; 62,7%).

To a solution of compound 2312 (40 mg; 0,076 mmol) in anhydrous DCM (10 ml) dropwise at -78°C was added BBr3(190,4 mg; 0,76 mmol), then the reaction mixture was left to warm to room temperature and was stirred overnight. The reaction mixture was poured into a mixture of ice-water, was podslushivaet a saturated solution of NaHCO3to pH 8-9 and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified flash chromatography with elution with a mixture of DCM/MeOH (30/1), which allowed to obtain the desired product, compound 2313 (15 mg; 38,5%).

Example 11. Synthesis of 2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-trilliane[2,3-C1]pyrimidine-4(3H)-she (Connection 2407).

Scheme 24. Describes the synthesis of 2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-trilliane[2,3-d]pyrimidine-4(3H)-she (Connection 2407).

To a stirred solution of 2-amino-4-methylthiophene-3-carboxylic acid (2401) (2.4 g, and 15.2 mmol) in THF (50 ml) slowly over 20 min dropwise at 0°C was added a solution of triphosgene (9.0 g; 30 mmol; 2 EQ.) in THF (10 ml). The resulting mixture was stirred at 0°C for 2 hours is actionnow mixture extinguished with water (20 ml) at 0°C and then concentrated in vacuo to remove organic solvent. Brown solid precipitated from solution. The solid is collected by filtration, washed with water (5 ml × 2) and dried in vacuum, which allowed to obtain the desired product 5-methyl-1H-thieno[2,3-d][1,3]oxazin-2,4-dione (2402) (2.5 g; yield 89.3%) in the form of a brown solid.

To a stirred solution of o toluidine (1.4 g; 12.8 mmol; 1.2 EQ.) in anhydrous THF (20 ml) slowly over 30 min dropwise at -40°C in argon atmosphere was added n-BuLi (2.5m N., and 7.7 ml; or 19.3 mmol; 1.8 EQ.). The resulting mixture was stirred at -40°C over the next 30 minutes

Slowly over 20 min dropwise at -40°C was added a solution of 5-methyl-1H-thieno[2,3-d][1,3]oxazin-2,4-dione (2402) (1,95 g; of 10.7 mmol; 1 EQ.) in anhydrous THF (50 ml). The reaction mixture was stirred at -40°C for 1 h and then left to warm to room temperature over night. The reaction mixture was extinguished with water (20 ml) at 0°C and then neutralized with concentrated HCl solution to pH 8-9. The mixture was concentrated in vacuo to remove organic solvent. The residue was extracted with ethyl acetate (25 ml × 3). The combined organic phases were washed with brine (10 ml), dried over MgSO4and concentrated in vacuum. The obtained residue was purified column chromatography on silica gel using 5%-20% ethyl acetate in petroleum ether as eluent, which allowed to obtain the desire is the range of the product 2-amino-4-methyl-N-o-tolylthio-3-carboxamide (2403) (0.74 g; the output of 28.1%) as a yellow solid.

To a stirred solution of 2-amino-4-methyl-N-o-tolylthio-3-carboxamide (2403) (740 mg; 3 mmol) and pyridine (406,8 mg; 3.6 mmol; 1.2 EQ.) in anhydrous DCM (20 ml) slowly over 30 min dropwise at 0°C was added 2-chloroacetanilide (284,8 mg; 3.6 mmol; 1.2 EQ.). The resulting mixture was stirred at 0°C for 2 h, the Reaction mixture was extinguished with water (20 ml) at 0°C. and was extracted with DCM. The combined organic phases are washed with 1 N. HCl solution (10 ml), brine (10 ml), dried over MgSO4and concentrated in vacuum, which allowed to obtain the desired product 2-(2-chloroacetamido)-4-methyl-N-o-tolylthio-3-carboxamide (2404) (950 mg; output 98,1%) as a yellow solid.

A mixture of 2-(2-chloroacetamido)-4-methyl-N-o-tolylthio-3-carboxamide (2404) (1.07 g; of 3.32 mmol) and l3(25 ml) was stirred overnight in a sealed tube at 120°C. the Reaction mixture was concentrated in vacuum to remove excess l3. The residue was distributed between DCM (30 ml) and saturated solution of NaHCO3(10 ml). The organic layer was separated, washed with saturated NaHCO3(10 ml), brine (10 ml), dried over MgSO4and concentrated in vacuum. The obtained residue was purified column chromatography on silica gel, which allowed to obtain the desired product 2-(chloromethyl)-5-methyl-3-o-trilliane[2,3-d]pyrimidine-4(3H)-he (2405) (76 mg; the yield of 75.2%) as a yellow solid.

A solution of 3-iodine-1H-pyrazolo[3,4-d]pyrimidine-4-amine (108A) (314,3 mg; 1.2 mmol; 1.5 EQ.) and tert-BuOK (155 mg; 1.38 mmol; 1.2 EQ.) in DMF (10 ml) was stirred at room temperature for 15 minutes, dropwise at room temperature was added a solution of 2-(chloromethyl)-5-methyl-3-o-trilliane[2,3-d] pyrimidine-4(3H)-she (2405) (350 mg; 1.15 mmol; 1 EQ.) in DMF (5 ml). The resulting mixture was stirred at room temperature for 2 hours the Reaction mixture was concentrated in vacuo to remove organic solvent. The obtained residue was purified column chromatography on silica gel, which allowed to obtain the desired product 2-((4-amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-trilliane[2,3-d]pyrimidine-4(3H)-he (2406) (250 mg; output 41,1%) as a yellow solid.

2-((4-Amino-3-iodine-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-trilliane[2,3-d]pyrimidine-4(3H)-he (2406) (50 mg; 0,092 mmol), PPh3(14,5 mg; 0,056 mmol; 0.6 EQ.) and 3-fluoro-5-hydroxyphenylarsonic acid (2207) (17,2 mg; 0.11 mmol; 1.2 EQ.) was dissolved in a solution of DMF, ethanol and water (5 ml/2 ml/2 ml). To this mixture was sequentially added Pd(OAc)2(4,14 mg; 0.018 mmol; 0.2 EQ.) and sodium carbonate (48.7 per mg; 0.46 mmol; 5 EQ.). The resulting mixture was degirolami, again filled with argon three times and then heated up to 80°C for 0.5 h with stirring. The reaction mixture was concentrate which has demonstrated in vacuo to remove organic solvent. The obtained residue was purified column chromatography on silica gel, which allowed to obtain the desired product 2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-5-methyl-3-o-trilliane[2,3-d]pyrimidine-4(3H)-he (2407) (22,8 mg; output 48,2%) as a yellow solid.

Example 12. Synthesis of 8-methyl-3-((methyl(N-purine-6-yl)amino)methyl)-2-o-cholelithiasis-1 (2H)-it.

Scheme 25. Describes the synthesis of 8-methyl-3-((methyl(N-purine-6-yl)amino)methyl)-2-o-cholelithiasis-1(2H)-she (Connection 4004).

3-(methyl bromide)-8-methyl-2-o-cholelithiasis-1(2H)-he (342 mg; 1.0 mmol) (1607) was dissolved in a solution of methylamine (100 ml) and was stirred for 2 hours the Mixture was poured into a mixture of ice water (200 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (20 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuum, which allowed to obtain the desired product 8-methyl-3-((methylamino)methyl)-2-o-cholelithiasis-1(2H)-he (4001) (250 mg, yield 86%) as a yellow solid. The obtained product is used directly in the next stage without purification.

8-Methyl-3-((methylamino)methyl)-2-o-cholelithiasis-1 (2H)-he (233 mg; 0.8 mmol) (4001) and 6-chloro-9-(tetrahydro-2H-Piran-2-yl)-N-purine (4002) (238 mg; 1.0 mmol) was dissolved in EtOH (50 ml) and the resulting mixture was stirred at the temperature of reflux distilled is over 2 hours The mixture was left to cool to CT and concentrated in vacuum. The residue was purified column flash chromatography on silica gel (2-20% MeOH/DCM), which allowed to obtain the product 8-methyl-3-((methyl(9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-yl)amino)methyl)-2-o-cholelithiasis-1(2H)-he (4003) (200 mg, 51% yield) as a pale yellow solid.

8-Methyl-3-((methyl(9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-yl)amino)methyl)-2-o-cholelithiasis-1(2H)-he (4003) (180 mg; 0.36 mmol) was dissolved in Meon (Hcl) (50 ml) and the mixture was stirred at RT for 2 hours To the reaction mixture were added an aqueous solution of NaHCO3and the pH was brought to 9. The mixture was filtered and the filtrate was concentrated in vacuum, which allowed to obtain the desired product 8-methyl-3-((methyl(N-purine-6-yl)amino)methyl)-2-o-cholelithiasis-1(2H)-he (4004) (80 mg, yield 54%) as a yellow solid.

Example 13. Synthesis of 3-(1-(N-purine-6-ylamino)ethyl)-8-methyl-2-o-cholelithiasis-1(2H)-it.

Scheme 26. Describes the synthesis of 3-(1-(N-purine-6-ylamino)ethyl)-8-methyl-2-o-cholelithiasis-1(2H)-she (Connection 4106).

To a stirred solution of 3-(hydroxymethyl)-8-methyl-2-o-cholelithiasis-1(2H)-she 1606 (2,79 g; 10 mmol) in CH2Cl2(200 ml) was added to Mno2(5 g) and the resulting mixture was stirred at the temperature of reflux distilled for 3 hours the Mixture was left to cool to CT and concentrated in vacuum. Remainder the eyes of the Ali column flash chromatography on silica gel (10-50% EA/PE), that allowed us to get the product 8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carbaldehyde 4101 (2.5 g; yield 90%) as a white solid.

8-Methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carbaldehyde 4101 (2.4 g; 8.6 mmol) was dissolved in anhydrous THF (280 ml) and was cooled to -78°C. in a nitrogen atmosphere. Was slowly added methyl-MgBr (2 M, 5 ml, 10 mmol) and the resulting mixture was stirred at -78°C for 2 hours was Added N2O (5 ml) and then the solution was poured into a mixture of ice-water (200 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuum and the remaining product was purified column flash chromatography on silica gel (10-50% EA/PE), which allowed to obtain the product 3-(1-hydroxyethyl)-8-methyl-2-o-cholelithiasis-1(2H)-he 4102 (1.8 g; 71% yield) as a white solid.

To a solution of 3-(1-hydroxyethyl)-8-methyl-2-o-cholelithiasis-1 (2H)-she 4102 (1.6 g; 5.5 mmol) in CH2Cl2added PPh3(2,88 g; 11.0 mmol) and the resulting mixture was stirred at RT for 30 min Then to the mixture in portions at 0°C was added CBr4(of 3.64 g; 11.0 mmol). The resulting mixture was left to warm to CT, was stirred for 30 min and concentrated in vacuum. The crude product was purified column flash chromatography on silica gel (30-50% EA/PE), which allowed p in order to obtain the desired product 3-(1-bromacil)-8-methyl-2-o-cholelithiasis-1(2H)-he 4103 (1.8 g; yield 91%) as a white solid.

To a stirred solution of 9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine 4103 (436 mg; 2 mmol) in anhydrous DMF (10 ml) was added NaH (60% in mineral oil; 77 mg; 2 mmol) and the mixture was stirred for 30 minutes was Added 3-(1-bromacil)-8-methyl-2-o-cholelithiasis-1(2H)-he 4104 (700 mg; 2 mmol). The mixture was stirred for 2 h, then poured into a mixture of ice-water (200 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (20 ml), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified column flash chromatography on silica gel (10-50% MeOH/DCM), which allowed to obtain the product 8-methyl-3-(1-(9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-ylamino)ethyl)-2-o-cholelithiasis-1(2H)-he 4105 (500 mg, 51% yield) as a white solid.

8-Methyl-3-(1-(9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-ylamino)ethyl)-2-o-cholelithiasis-1(2H)-he 4105 (180 mg; 0.36 mmol) was dissolved in Meon (HCl) (50 ml) and was stirred for 2 hours To the reaction mixture were added an aqueous solution of NaHCO3and the pH was brought to 9. The mixture is then filtered and the filtrate was concentrated in vacuum, which allowed to obtain the desired product 3-(1-(N-purine-6-ylamino)ethyl)-8-methyl-2-o-cholelithiasis-1 (2H)-he 4106 (80 mg, yield 54%) as a yellow solid.

Example 14. Synthesis of 3-(4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-Digi raiskinen-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)-5-forfinal-dihydrophosphate.

Scheme 27. Describes the synthesis of 3-(4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)-5-forfinal-dihydrophosphate (Connection 4303).

3-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)-8-methyl-2-o-cholelithiasis-1(2H)-he 4301 (250 mg; 0.5 mmol) was dissolved in anhydrous THF (15 ml) in the dark in a round bottom flask covered with aluminum foil) and cooled to 0°C in an argon atmosphere. Added CBr4(498 mg; 1.5 mmol), then diethylphosphate (129 μl; 1.0 mmol) and triethylamine (417 μl; 1.5 mmol). The resulting mixture was stirred in the dark at a temperature from 0°C to KG over 16 hours Then the mixture was distributed between ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira methanol and dichloromethane, which allowed to obtain the desired product 3-(4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)-5-forfinal-diethylphosphate 4302 (200 mg; yield 62%) in the form of a whitish solid.

3-(4-Amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)-5-forfinal-diethylphosphate 4302 (170 mg; 0.26 mmol) was dissolved in anhydrous CH2CL2(5 ml) and cooled to 0°C in an atmosphere of ar is she. Slowly with a syringe was added TMSBr (trimethylsilyl-Br) (0,34 ml; of 2.64 mmol) and the resulting mixture was stirred at a temperature from 0°C to CT for 16 hours Data LC-MS (liquid chromatography/mass spectrometry) showed that consumed a small amount of the source material, so I added an additional amount of TMSBr (0.1 ml) and stirred at RT for 5 h Data LC-MS showed complete conversion of starting material. The mixture was concentrated in vacuo and the residue was dissolved in Et2O (10 ml) and H2O (0.5 ml) and was stirred for 30 minutes the Mixture was concentrated in vacuum, which allowed to obtain the desired product 3-(4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl)-5-forfinal-dihydrophosphate 4903 (140 mg, yield 91%).

Example 15. The value of the IC50for individual compounds table 4. Data in vitro no IC50for individual connections.

Table 5.
Patterns of connections, giving the IC50in Table 4.
Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Example 16. Analyses of the expression and inhibition 110α/85α, 110β/85α, 110δ/85α and 110γ.

PI3-K class I can be either acquired (110α/85α, 110β/85α, 110δ/85α from Upstate and 110γ from Sigma), or expressed as previously described (Knight and others, 2004). The IC50 values measured using either a standard TLC analysis for libidinosus activity (described below), or high-performance analysis with capture on the membrane. Kinase reactions are carried out, preparing a reaction mixture containing kinase, inhibitor (final concentration of DMSO 2%), buffer (25 mm HEPES; pH 7.4; 10 mm MgCl2) and freshly prepared, treated with ultrasound fosfatados the t (100 µg/ml). The reaction initiated by addition of ATP solution containing 10 µci γ-32P-ATP to a final concentration of 10 or 100 μm and left to proceed for 5 minutes at room temperature. Further, for carrying out the TLC analysis, the reaction is stopped by adding 105 μl of 1 N. HCl, then 160 μl of the mixture l3:Meon (1:1). A two-phase mixture is stirred on the vortex, quickly centrifuged and the organic phase transferred to a new tube using a pipette tip to be applied on the gel pre-coated l3. This extract is applied in the form of spots on the TLC plates and chromatographic for 3-4 hours in a solution of 65:35 n-propanol:1 M acetic acid. Then the TLC plate is dried, placed on a screen of phosphoimager (Storm, Amersham) and produce quantitative determination. Kinase activity for each compound measured for 10-12 concentrations of the inhibitor, which represents a two-fold dilutions of the highest tested concentration (typically 200 μm). For compounds showing significant activity, determination of IC50 repeat two to four times, and the presented values are the average of these independent measurements.

Available other commercially available kits or systems for the analysis of the activities of PI3-K. commercially Available kits or systems can be used for screening inhibitors and/and and agonists PI3-K, including, but not limited to, R-kinase α, β, and γ. A typical system is a system for analyzing R-kinase (human) HTRF™ from Upstate. This analysis can be carried out in accordance with the methods offered by the manufacturer. Briefly, this analysis is a study of resonance energy transfer fluorescence with time resolution (TR-FRET), which indirectly measure the product PIP3, formed by the action of PI3-K. the Kinase reaction is performed in a microtiter tablet (e.g., 384-well microtiter-plate). The total volume of the reaction mixture is approximately 20 ál per well. At the first stage in each well put 2 μl of a solution of test compound in 20% dimethyl sulfoxide, which results in obtaining a final DMSO concentration of 2%. Next to each well add approximately 14,5 µl mixture kinase/RR (phosphatidylinositol-diphosphate) (diluted in 1X reaction buffer) to obtain a final concentration of kinase 0.25 to 0.3 ág/ml and 10 μm PIP2. The tablet is sealed and incubated for 15 minutes at room temperature. To start the reaction in each well add 3.5 μl of ATP solution (diluted in 1X reaction buffer) to obtain a final concentration of 10 μm ATP. The tablet is sealed and incubated for 1 hour at room is temperature. The reaction is stopped by adding 5 µl of a solution to stop reaction on one hole and then 5 μl of detection mix per well. The tablet is sealed, incubated for 1 hour at room temperature and then read on an appropriate plate reader. The data is analyzed and IC50 values of gain, using GraphPad Prism 5.

Example 17. Analyses of the expression and inhibition of Abl

The cross-activity or lack thereof of one or more compounds of the present invention in respect of the Abl-kinase can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be analyzed in three repetitions against recombinant full-Abl or Abl (315l) (Upstate) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 200 μm ATP (2,5 µci γ-32P-ATP), and 0.5 mg/ml BSA (bovine serum albumin). Optimized peptide substrate for Abl EAIYAAPFAKKK used as photoacceptor (200 μm). The reaction is stopped, causing the reaction mixture in the form of spots on phosphocellulose plates are washed with 0.5% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and transported radioactive compound quantitatively measured by imaging is using radionuclide phosphorus (phosphorimaging).

Example 18. Analyses of the expression and inhibition of Hck

The cross-activity or lack thereof of one or more compounds of the present invention in respect of Hck kinase can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be analyzed in three repetitions against recombinant full-Hck in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 200 μm ATP (2,5 µci γ-32P-ATP), and 0.5 mg/ml BSA. Optimized peptide substrate for kinases Src family EIYGEFKKK used as photoacceptor (200 μm). The reaction is stopped, causing the reaction mixture in the form of spots on phosphocellulose plates are washed with 0.5% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 19. Analyses of the expression and inhibition of the insulin receptor (IR)

The cross-activity or lack thereof of one or more compounds of the present invention in relation to receptor IR kinase can be measured according to any method known in the art, or by methods described below. Connection, a presentation is given in this application can be analyzed in three repetitions against recombinant kinase domain of the insulin receptor (Upstate) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 10 mm nCl2; 200 μm ATP (2,5 µci γ-32P-ATP), and 0.5 mg/ml BSA. As the substrate using poly-E-Y (copolymer of glutamic acid and tyrosine) (Sigma; 2 mg/ml). The reaction is stopped, causing the reaction mixture in the form of spots on the nitrocellulose, which was washed with a mixture of 1 M NaCl/1% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 20. Analyses of the expression and inhibition of Src

The cross-activity or lack thereof of one or more compounds of the present invention in respect of Src-kinase can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be analyzed in three repetitions against recombinant full-Src or Src (T3381) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 200 μm ATP (2,5 µci γ-32P-ATP), and 0.5 mg/ml BSA. Optimized peptide substrate for kinases Src family EIYGEFKKK used as photoacceptor (200 μm). The reaction is stopped is, causing the reaction mixture in the form of spots on phosphocellulose plates are washed with 0.5% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 21. Analyses of the expression and inhibition of DNA-PK (DNAK) Cross-activity or lack thereof of one or more compounds of the present invention in relation kinase DNAK can be measured according to any method known in the art. DNA-PK can be purchased from Promega and analyzed using the system for the analysis of DNA-PK (Promega) according to manufacturer's instructions.

Example 22. Analyses of the expression and inhibition of mTOR Cross-activity or lack thereof of one or more compounds of the present invention in relation to mTOR can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be tested against recombinant mTOR (Invitrogen) in the analysis, containing 50 mm HEPES, pH 7.5; 1 mm EGTA (ethylene glycol-tetraoxane acid), 10 mm MgCl2; 2.5 mm, 0.01% Tween; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. As the substrate used recombinant PHAS-1/4BP1 (phosphorylated heat - and acid-resistant protein-1/4E-binding protein-1 (phosphorylated heat and acid stable protein-1/4E binding protein-1)) rats (Calbiochem, 2 mg/ml). The reaction is stopped, causing the reaction mixture in the form of spots on the nitrocellulose, which was washed with a mixture of 1 M NaCl/1% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Available in other sets or systems to analyze the activity of mTOR. For example, you can use a test kit kinase LanthaScreen™ (Invitrogen) for testing inhibitors of mTOR set forth in this application. This analysis is based on the use of FRET-platform with a temporal resolution of where to measure the phosphorylation EUR labeled with GFP (green fluorescent protein) under the action of mTOR kinase. Kinase reaction is carried out in a white 384-well microtiter tablet. The total reaction volume is 20 μl per well, and the reaction buffer has the following composition: 50 mm HEPES, pH 7.5; 0.01% Polysorbate 20; 1 mm EGTA; 10 mm MnCl2and 2 mm DTT. At the first stage in each well put 2 μl of a solution of test compound in 20% dimethyl sulfoxide, which results in obtaining a final DMSO concentration of 2%. Then add 8 ál per well of mTOR, diluted in reaction buffer to a final concentration of 60 ng/ml To run the reaction in each well was added 10 μl of a mixture of ATP/GFP-4EBP1 (diluted in p is a promotional buffer) to obtain a final concentration of 10 μm ATP and GFP-4EBP1 0.5 µm. The tablet is sealed and incubated for 1 hour at room temperature. The reaction is stopped by adding 10 μl per well of a mixture of Tb-anti-RT-AVR-antibody/EOTA (ethylenediaminetetraacetic acid) (diluted in buffer for TR-FRET) to obtain a final concentration of antibodies 1.3 nm and 6.7 mm EDTA. The tablet is sealed, incubated for 1 hour at room temperature and then read on a plate reader settings for TR-FRET LanthaScreen™. The data is analyzed and IC50 values of gain, using GraphPad Prism 5.

Example 23. Analyses of the expression and inhibition of growth factor receptor vascular endothelial.

The cross-activity or lack thereof of one or more compounds of the present invention in relation to the VEGF receptor can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain, recombinant KDR (kinase insertion domain-containing receptor (Invitrogen) receptor in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 0,1% instead of (2-mercaptoethanol); 10 μm ATP (2.5 to µci γ-32P-ATP), and 3 μg/ml BSA. As the substrate using poly-E-Y (Sigma; 2 mg/ml). The reaction is stopped, causing the reaction mixture in the form of spots on nitrocell the memory, which was washed with a mixture of 1 M NaCl/1% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 24. Analyses of the expression and inhibition iminovogo receptor B4 (h4)

The cross-activity or lack thereof of one or more compounds of the present invention in relation to h4 can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain, recombinant iminovogo receptor B4 (Invitrogen) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 0,1% TOGETHER; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. As the substrate using poly-E-Y (Sigma; 2 mg/ml). The reaction is stopped, causing the reaction mixture in the form of spots on the nitrocellulose, which was washed with a mixture of 1 M NaCl/1% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 25. Analyses of the expression and inhibition of the receptor for epidermal growth factor (EGFR)

The cross-activity or lack is their for one or more of the compounds of the present invention in relation to the EGFR kinase can be measured according to any method, known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain of recombinant human EGF receptor (Invitrogen) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl3; 0,1% TOGETHER; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. As the substrate using poly-E-Y (Sigma; 2 mg/ml).

The reaction is stopped, causing the reaction mixture in the form of spots on the nitrocellulose, which was washed with a mixture of 1 M NaCl/1% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 26. Analyses of the expression and inhibition of KIT Cross-activity or lack thereof of one or more compounds of the present invention in respect of the KIT kinase can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain, recombinant KIT (Invitrogen) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 1 mm DTT; 10 mm nCl2; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. As the substrate using poly-E-Y (Sigma; 2 mg/ml). The reaction is stopped, causing the reaction is mesh in the form of spots on the nitrocellulose, which was washed with a mixture of 1 M NaCl/1% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 27. Analyses of the expression and inhibition of RET Cross-activity or lack thereof of one or more compounds of the present invention in relation to the RET kinase can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain, recombinant RET (Invitrogen) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 2.5 mm DTT; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. Optimized peptide substrate for Abl EAIYAAPFAKKK used as photoacceptor (200 μm). The reaction is stopped, causing the reaction mixture in the form of spots on phosphocellulose plates are washed with 0.5% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 28. Analyses of the expression and inhibition of growth factor receptor of platelets (DERIVED)

The cross-activity or lack the influence of one or more compounds of the present invention in relation kinase DERIVED can be measured according to any method, known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain of recombinant PDGF receptor (Invitrogen) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 2.5 mm DTT; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. Optimized peptide substrate for Abl EAIYAAPFAKKK used as photoacceptor (200 μm). The reaction is stopped, causing the reaction mixture in the form of spots on phosphocellulose plates are washed with 0.5% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and the radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 29. Analyses of the expression and inhibition of Fms-like tyrosine kinase 3 (FLT-3)

The cross-activity or lack thereof of one or more compounds of the present invention in relation kinase FLT-3 can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain, recombinant FLT-3 (Invitrogen) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 2.5 mm DTT; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. Optimized peptide su the strata for Abl EAIYAAPFAKKK used as photoacceptor (200 μm). The reaction is stopped, causing the reaction mixture in the form of spots on phosphocellulose plates are washed with 0.5% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and transported radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 30. Analyses of the expression and inhibition of receptor tyrosine kinase TECH (THE)

The cross-activity or lack thereof of one or more compounds of the present invention in relation kinase TE can be measured according to any method known in the art, or by methods described below. Compounds described in this application can be tested in relation to the kinase domain, recombinant TA (Invitrogen) in the analysis, containing 25 mm HEPES, pH 7.4; 10 mm MgCl2; 2 mm DTT; 10 mm MnClz; 10 μm ATP (2.5 to µci µ-32P-ATP), and 3 μg/ml BSA. As the substrate using poly-E-Y (Sigma; 2 mg/ml). The reaction is stopped, causing the reaction mixture in the form of spots on the nitrocellulose, which was washed with a mixture of 1 M NaCl/1% phosphoric acid (approximately 6 times, each time by 5-10 minutes). The plate is dried and transported radioactive compound quantitatively measured by visualization using radionuclide phosphorus.

Example 31. Analysis of the asset is tion and proliferation of b-cells the Ability of one or more compounds which is the object of the invention to inhibit the activation and proliferation of b-cells is determined in accordance with standard techniques known in the art. For example, the method of analysis of cell proliferation in vitro, which measure the metabolic activity of living cells. The analysis is performed in 96-well microtiter tablet using the recovery of the dye Alamar Blue. B cells in the spleen of Balb/c purified using a gradient of Ficoll-Paque™ PLUS, with subsequent magnetic separation of cells using the set for the selection of b-cells MACS (Miletenyi). Cells seeded on the plates in a volume of 90 µl in the amount of 50,000 cells/well in the environment for b-cells (medium RPMI (Roswell Park Memorial Institute) + 10% FBS (fetal bovine serum)+ penicillin/streptomycin + 50 μm IME) + 5 mm HEPES). The connection described in this application, diluted in medium for b-cells and add to the volume of 10 µl. Tablets incubated for 30 min at 37°C and 5% CO2(final DMSO concentration of 0.2%). Then add 50 ál of the mixture to stimulate b-cells containing or LPS (lipopolysaccharide) (10 μg/ml), or F(ab')2antibodies ass against mouse IgM (5 μg/ml) plus recombinant IL4 (interleukin-4) mouse (2 ng/ml) in the medium for b-cells. Tablets incubated for 72 hours at 37°C and 5% CO2. To each well add Alamar Blue reagent in a volume of 15 ál and tablets Inka is irout for 5 hours at 37°C and 5% CO 2. The fluorescence of Alamar Blue read when eh/et (excitation at a wavelength of 560 nm, emission wavelength 590 nm) and IC50 values or AS calculated using GraphPad Prism 5.

Example 32. Analysis of proliferation of tumor cell lines

The ability of one or more compounds which are the object of the invention to inhibit the proliferation of tumor cell lines is determined in accordance with standard techniques known in the art. For example, it is possible to analyze cell proliferation in vitro, which measure the metabolic activity of living cells. This analysis is carried out in 96-well microtiter tablet using recovery Alamar Blue. Tumor cell lines of a person will receive from ATS (American type culture collection) (e.g., MCF7, U-87 MG; MDA-MB-468, PC-3), grow up confluentes state in bottles Kzt75 have trypsinization using 0,25% trypsin, washed once environment for tumor cells (DMEM (modified Dulbecco Wednesday Needle) + 10% FBS) and plated on plates in a volume of 90 µl in the amount of 5000 cells/well in the environment for tumor cells. The connection described in this application, is diluted in the environment for tumor cells and add to the volume of 10 µl. Tablets incubated for 72 hours at 37°C and 5% CO2. To each well add real the NT Alamar Blue in the volume of 15 ál and tablets incubated for 3 hours at 37°C and 5% CO 2. The fluorescence of Alamar Blue read when eh/et and IC50 values calculated using GraphPad Prism 5.

Example 33. Antitumor activity in vivo

You can evaluate compounds described in this application in a number of models of human cancers and mouse.

Models of tumors that are resistant to paclitaxel.

1. The model of ovarian cancer received on clinical material. This tumor model is created as a result of the tumor biopsy of a patient with ovarian cancer. Sampling of the tumor obtained from the patient.

Compounds described in this application, injected Nude mice bearing tumors with the established stage of development, using the scheme: every 2 days (5.

2. Xenograft ovarian cancer man Ath (mutant tubulin).

Ath is a model resistant to paclitaxel ovarian cancer man. It is from a sensitive source line A the result of co-incubation with paclitaxel and verapamil, agent, eliminating MDR (multiple drug resistance). It is shown that the mechanism of resistance to it is not related to the mechanism of MDR and due to the presence of mutations in a gene, encoding a protein of beta-tubulin.

Compounds described in this application can be injected into mice bearing tumors with the established stage of development, according to the scheme: every 2 days (5.

3. Xenotransplant is at cancer human colon NST/V46 (multidrug-resistant)

NST/VM46 represents MDR-resistant colon cancer from a sensitive source line ST. When growth in vivo in Nude mice NST/VM46 consistently demonstrates a high resistance to paclitaxel.

Compounds described in this application can be injected into mice bearing tumors with the established stage of development, according to the scheme: every 2 days (5.

4. Model murine sarcoma M

M is a murine fibrosarcoma, by nature resistant to paclitaxel in vivo.

Compounds described in this application can be injected into mice bearing tumors with the established stage of development, according to the scheme: every 2 days (5.

One or more compounds according to the invention can be used in combination with other therapeutic agents in vivo to xenografts of colon cancer human multidrug-resistant HCT/VM46 or for any other models known in the art, including models described in this application.

Example 34. Stability analysis in the presence of microsomes

The stability of one or more compounds which are the object of the invention is determined in accordance with standard techniques known in the art. For example, the stability of one or more compounds which are the object of the invention is installed in analysis in vitro. In particular, it is possible to analyze the stability in the presence of microsomes in vitro, which measure the stability of one or more compounds, which is the object of the invention, when interacting with microsomes from the liver of mice, rats or humans. The interaction of microsomes with compounds is carried out in Eppendorf tube with a capacity of 1.5 ml Each vial contains 0.1 µl NADPH (adenine dinucleotide restored) (10.0 mg/ml); 75 μl of microsomes from the liver of mice, rats or humans (20.0 mg/ml); and 0.4 μl of 0.2 M phosphate buffer and 425 μl ddH2O (double-distilled water). The test tube with the negative control (without NADPH) contains 75 μl of microsomes from the liver of mice, rats or humans (20.0 mg/ml); and 0.4 μl of 0.2 M phosphate buffer and 525 μl ddH2O. the Interaction initiated by the addition of 1.0 ál 10.0 mm test compounds. The tubes with the reaction mixture incubated at 37°C. 100 μl of sample is withdrawn into a new Eppendorf tube containing 300 µl of cold methanol, 0, 5, 10, 15, 30 and 60 minutes from the start of the reaction. The samples are centrifuged at 15,000 rpm to remove protein. The supernatant was centrifuged sample is transferred into a new tube. The concentration of stable compounds in the supernatant after interaction with microsomes measured liquid chromatography/mass spectrometry (LC-MS).

Example 35. Analysis of the stability of the plasma is rovi

The stability of one or more compounds, which is the object of the invention, in the blood plasma is determined in accordance with standard techniques known in the art. See, for example, Rapid Commun. Mass Spectrom., 10: 1019-1026. The procedure below is an HPLC-MS/MS analysis using human blood plasma; it is also possible to use plasma of other species, including monkey, dog, rat and mouse. Frozen heparinized plasma human blood is thawed in cold water bath and before using centrifuged for 10 minutes at 2000 rpm at 4°C. the Connection, which is the object of the invention, add 400 microns concentrated solution to an aliquot of the pre-heated plasma to obtain the final volume for analysis 400 ál (or 800 ál to determine the half-life period) containing 5 μm test compound and 0.5% DMSO. The reaction mixture is incubated with shaking for 0 minutes and 60 minutes at 37°C or for 0, 15, 30, 45 and 60 minutes at 37°C to determine the half-life period. The reaction is stopped by transferring 50 μl of the incubation mixture in 200 µl chilled on ice acetonitrile and mixing by shaking for 5 minutes. The samples are centrifuged at 6000 (l for 15 minutes at 4°C and 120 μl of the supernatant is taken in the net probe the key. Then the samples are evaporated to dryness and subjected to analysis using HPLC-MS/MS.

Where desirable, simultaneously with the test compounds test one or more than one control connection or comparison (5 microns): one connection, propoxycaine, with low stability in plasma, and another connection, propantheline, with intermediate stability in plasma.

Samples re-dissolved in a mixture of acetonitrile/methanol/water (1/1/2, vol./about./about.) and analyzed using reversed-phase (RP) HPLC-MS/MS using the method of selective monitoring of reactions (SRM). Conditions for HPLC include double pump for LC with an autosampler, the combined operation, C12, column 2×20 mm and the gradient program. The peak areas corresponding to the analytes, register using HPLC-MS/MS. The ratio of parent compound remaining after 60 minutes, and the amount at time zero, expressed as a percentage, taking the stability in plasma. In the case of the half-life period it is determined from the initial slope of the linear plot of the logarithmic curve of the remaining compounds (%) of the time, suggesting the presence of first-order kinetics.

Example 36. Chemical stability

Chemical stability of one or more compounds which are the object of the invention is defined in soo is according to standard methods, known in the art. The following are the details of the typical methods of determining the chemical stability of the connection, which is the object of the invention. The standard buffer used for the analysis of chemical stability, is phosphate-saline buffer (PBS) with pH 7.4; you can use other suitable buffers. The connection, which is the object of the invention, add 100 microns concentrated solution to an aliquot of PBS (two times) to obtain the final volume for analysis 400 µl, containing 5 μm test compound and 1% DMSO (to determine the half-life of the prepared sample with the total volume of 700 μl). The reaction mixture is incubated with shaking for 0 minutes and 24 hours at 37°C to determine the half-life of the samples incubated for 0, 2, 4, 6 and 24 hours. The reaction is stopped by immediately adding 100 μl of the incubation mixture to 100 μl of acetonitrile and shaking on a vortex for 5 minutes. The samples are then stored at -20°C before carrying out HPLC-MS/MS analysis. Where desirable, the control connection or comparison, such as chlorambucil (5 μm), are tested simultaneously with interest connection, which is the object of the invention, since the connection is largely hydrolyzed within 24 hours. Samples Ana is serout using (RP)HPLC-MS/MS, using the method of selective monitoring of reactions (SRM). Conditions for HPLC include double pump for LC with an autosampler, the combined operation, C12, column 2×20 mm and the gradient program. The peak areas corresponding to the analytes, register using HPLC-MS/MS. The ratio of parent compound remaining after 24 hours, and the number at time zero, expressed in percent, is taken for chemical stability. In the case of the half-life period it is determined from the initial slope of the linear plot of the logarithmic curve of the remaining compounds (%) of the time, suggesting the presence of first-order kinetics.

Example 37. Analysis of Akt-kinase

Cells containing the path components Akt/mTOR, including, but not limited to, L6 cultured myoblasts, cells B-ALL, b-cells, T-cells, leukemia cells, bone marrow cells, R-transduced cells, cells from Philadelphia chromosome-positive (Ph+) and embryonic fibroblasts mouse, usually cultivated in media for growing cells, such as DMEM, supplemented with fetal bovine serum and/or antibiotics, and raise up confluentes state.

In order to compare the influence of one or more of the compounds described in this application on Akt activation, these cells Deplete the serum overnight and incubated with one and more than one connection, set forth in this application, or from about 0.1% DMSO for from about 1 minute to about 1 hour, then stimulated with insulin (e.g., 100 nm) for from about 1 minute to about 1 hour. Cells subjected to lysis by scraping them chilled in ice lyse buffer containing detergents, such as for example, sodium dodecylsulfate, and protease inhibitors (e.g., PMSF (phenylmethylsulfonyl-fluoride)). After bringing the cells into contact with lytic buffer solution is subjected to a brief exposure to ultrasound, clarify by centrifugation, separated using SDS-PAGE (polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate), transferred to nitrocellulose or PVDF (polyvinylidene fluoride) and subjected to Western blot turns using antibodies to phospho-Akt (pAkt) S473, phospho-Akt T, Akt, and (3-actin (Cell Signaling Technologies).

The result demonstrated that one or more compounds of the present description inhibit stimulated insulin phosphorylation of Akt in position S473. Alternatively, some compounds described in this application, additionally inhibit stimulated insulin phosphorylation of Akt in position T. This class of compounds can inhibit Akt is more effective than rapamycin, and can be attributed to the mTORC2 inhibitors or inhibitors of kinases, are located in the "upstream", such as RC or Akt.

Example 38. Signal transmission in the blood by kinases RC/Akt/mTor-mediated signal transmission measured in blood cells using the method phosflow (Methods Enzymol. 2007, 434:131-54). The advantage of this method is that by nature it is a method of analysis of a single cell, that gives the possibility of detecting cellular heterogeneity, and not the average population size. This allows simultaneous detection status signaling pathways in different populations, defined on other markers. In addition, the method phosflow is a quantitative method with high sensitivity. To test the influence of one or more compounds provided in this application, nefrackzionirovannam splenocytes or mononuclear cells peripheral blood stimulate antibodies against CD3 to initiate signal transmission involving T-cell receptors. After that, cells are fixed and stained for surface markers and intracellular phosphoproteins. It is expected that the inhibitors described in this application, inhibit anti-D3-mediated phosphorylation of Akt-8473 and S6, while rapamycin inhibited the phosphorylation of S6 and increases the phosphorylation of Akt in testing conditions.

Similarly, aliquots of whole blood incubated for 15 the minutes with the solvent (for example, 0,1% DMSO) or kinase inhibitors in different concentrations, and then add stimulating substances for carrying out cross-stitching T-cell receptor (TCR) (anti-CD3 with secondary antibody or b-cell receptor (BCR), using antibodies against the light chain Kappa (Fab'2-fragments). Approximately 5 and 15 minutes, the sample is fixed (for example, cold 4% paraformaldehyde and used for the method phosflow. Applied surface staining to distinguish between T - and b-cells, using antibodies to cell surface markers that are known in the art. The level of phosphorylation of kinase substrates such as Akt and S6, then measure incubare fixed cells labeled with antibodies specific to phosphorylated isoforms of these proteins. The population of cells is then analyzed using flow cytometry.

Example 39. Analysis of the formation of colonies

The bone marrow cells of the mouse directly in front of this transformed R-containing retrovirus BCR-Abl (referred to in this application as R-transduced cells) were seeded in the presence of various combinations of drugs for about 7 days in methylcellulose medium M with recombinant IL-7 of about 30% serum and count the number of formed colonies by visa is a high observation in the microscope.

Alternatively, the mononuclear cells of peripheral blood receive from patients with Philadelphia chromosome-positive (Ph+) and negative Philadelphia chromosome (Ph) according to the initial diagnosis or relapse. Living cells are isolated and enriched for CD19+ CD34+ B cells-the precursors. After staying overnight in liquid culture, cells plated on medium methocult GF+ N (Stem Cell Technologies) supplemented with cytokines (IL-3, IL-6, IL-7, G-CSF (granulocyte colony-stimulating factor), GM-CSF (granulocyte-macrophage colony-stimulating factor), CF, the ligand for Flt3 and erythropoietin) and known chemotherapeutic agents in various concentrations in combination with any of the compounds of the present description. The colony count after 12-14 days, using the microscope.This method can be applied to test for evidence of cumulative or synergistic activity.

Example 40. Effect of kinase inhibitors in leukemia cells in vivo

Female mice recipient irradiated with a lethal dose, using a source of γ-radiation, two separate doses with an interval of about 4 hours, about 5 Grams each. Approximately 1 h after the second dose mice injected I/V (intravenous) injection of approximately 1×106leukemic cells (e.g., Ph+ cells of human or mouse is whether R-transduced bone marrow cells). These cells are administered together with a radioprotective dose of approximately 5×106normal bone marrow cells from mice donor at the age of 3-5 weeks. Recipients give antibiotics in the water and is carried out daily monitoring. Mice who become ill after about 14 days, subjected to euthanasia and remove lymphoid organs for analysis. Treatment of kinase inhibitors begin approximately 10 days after the injection of leukemic cells and continue daily until until the mouse is not ill or to a maximum of approximately 35 days after the transplant. Inhibitors given with the use of oral lavage.

Cells peripheral blood collected approximately 10 days (before treatment) and after euthanasia (after treatment), lead into contact with the labeled antibodies against hCD4 (CD4) and counted using flow cytometry. This method can be used to demonstrate that, thanks to the synergic effect of one or more compounds set forth in this application, in combination with known chemotherapeutic agents significantly reduced the number of leukemic blood cells compared to treatment only known chemotherapeutic agents (e.g., Gleevec) in testing conditions.

Example 41. Treatment of mice that are models of the disease lupus/p>

In mice lacking the inhibitory receptor FcγRllb, preventing RK-mediated signaling in b cells, with a high probability of developing lupus. γPllb-knocked out mice (R2KO, Jackson Labs) are considered to be a suitable model for this disease in humans, because some patients with a diagnosis of lupus demonstrate reduced expression or function FcyRllb (S. Bolland and J. V. Ravtech, 2000. Immunity 12:277-285).

RCO-mice developed volchanochnopodobny disease antinuclear antibodies, glomerulonephritis and proteinuria at the age of about 4-6 months. For these experiments as a reference connections use an analog of rapamycin RAD001 (supplied by LC Laboratories) and administered orally. It is shown that this compound alleviates symptoms of lupus in model B6.Sle1z.Sle3z (T. Wu et al. J. Clin. Invest. 117:2186-2196).

Mice that are models of the disease lupus, such as R2KO, BXSB or MLR/lpr, at the age of about 2 months is subjected to treatment for about two months. Mice given doses: solvent, RAD001 (about 10 mg/kg) or described in this application connections (from about 1 mg/kg to about 500 mg/kg). Over approximately the entire testing period selected blood and urine samples and analyze for antinuclear antibodies (dilutions in serum) or the concentration of protein in the urine). The serum that the same test for antibodies against ssDNA (single stranded DNA) and against dsDNA (double-stranded DNA) by ELISA (ELISA analysis). Animals subjected to euthanasia for 60 days and remove tissue to determine the weight of the spleen and kidney diseases. Glomerulonephritis assessed by staining sections of kidneys with H&E (hematoxylin and eosin). Other animals are examined approximately two months after the end of treatment, using the same endpoint.

This model, generally recognized in the art, can be used to demonstrate that kinase inhibitors described in this application can suppress or delay the beginning of the development of symptoms of lupus in mice that are models of the disease lupus.

Example 42. Analysis of bone marrow transplant in mice

Female mice recipient irradiated with a lethal dose, using a source of γ-radiation. Approximately 1 h after exposure doses to mice injected with approximately 1×106leukemic cells from early passages R-transduced cultures (for example, as described in Cancer Genet. Cytogenet. 2005 Aug, 161(1):51-6). These cells are administered together with a radioprotective dose of approximately 5×106normal bone marrow cells from mice donor at the age of 3-5 weeks. Recipients give antibiotics in the water and is carried out daily monitoring. Mice who become ill after about 14 days, subjected to euthanasia and remove lymphoid organs for flow cytometry and/or magnetic enriched with who I am. The treatment begins about 10 days and continue daily until until the mouse is not ill or to a maximum of approximately 35 days after the transplant. Drugs administered via gastric tube (p/o). In a trial experiment, identify the dose of a chemotherapeutic drug, nontherapeutic, but delaying the beginning of the development of leukemia for about one week or less; as controls use the processing solvent or treatment with a chemotherapeutic agent, for which previously in this model, it was shown that it delays the beginning of the development, but does not cure leucosolenia (e.g., imatinib at a dose of approximately 70 mg/kg twice a day). At the first stage we use R-containing cells expressing eGFP (enhanced GFP), and post-mortem analysis of the limit by counting the percentage of leukemic cells in the bone marrow, spleen and lymph nodes (LN) using flow cytometry. At the second stage we use R-bearing cells, expressing "not containing tail" form of human CD4, and post-mortem analysis includes magnetic sorting hCD4+ cells from the spleen and subsequent analysis by Western blot turns the key signaling endpoints: pAkt-T308 and S473; pS6 and revr-1. As controls for detection by Western blot turns sorted cells incubated the before lysis in the presence or in the absence of kinase inhibitors of the present description. If desired, use the "phosflow" for the detection of pAkt-8473 and R-S235/236 cells hCD4-gated without pre-sorting. Such studies signal is particularly useful if, for example, receiving drug therapy mice do not develop clinical leukemia at time of 35 days. Build graphs of the survival curve Kaplan-Meier and conduct statistical analysis methods known in the art. Results R-containing cells analyzed individually and cumulatively.

Once a week all mice selected samples of peripheral blood (100-200 µl), starting from the 10th day immediately before the beginning of treatment. The blood plasma is used to measure the concentrations of drugs and cells analyzed for markers of leukemia (eGFP or hCD4) and biomarkers of signal transmission, as set forth in this application.

This General analysis is known in the art, can be used to demonstrate that the effective therapeutic dose of the compounds described in this application can be used to inhibit the proliferation of leukemia cells.

Example 43. Cell culture, originating from the epithelial cells of the eye

The epithelial cells of the eyes receive no later than 5 days after the death of corneas stored in cold conditions in Optisol (Bausch and Lomb, Irvine, CA), or from a biopsy of cornea living donors. The tissue was washed with phosphate-saline buffer solution, incubated in a solution of dispute II (Roche Diagnostics, Basel, Switzerland) at 37°C for 30 minutes and epithelial carefully soskrebajut from the surface to separate the epithelium from below him stroma. The separated epithelium then incubated and pipeinput in a mixture with trypsin ethylenediaminetetraacetic acid to obtain a suspension of individual cells. Then the trypsin is neutralized culture medium for corneal epithelium. Culture medium for corneal epithelium consists of core media environment the Needle in the modification of Dulbecco:. F12 in the ratio 2:1, containing 10% irradiated fetal bovine serum, hydrocortisone (0.4 µ g/ml), cholera toxin (0.1 nmol), recombinant human insulin (5 μg/ml), epidermal growth factor (10 ng/ml) and antimicrobial agents: penicillin (100 international units(u)/ml), streptomycin (100 μg/ml) and amphotericin b (0.25 microgram/ml). Cells support subcultivation in the ratio of 1:4 after reaching 80% density. Epithelial cells from the eye are subjected to screening for inhibition of proliferation or toxicity, leading the test compound in contact with the cells and analyzing the viability of using a commercially available kit for the analysis using the MTT (3-(4-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) (Promega).

Example 44. Cell culture, originating from the endothelial cells of the eye

All tissue support at 4°C in the storage medium (Optical; Chiron Vision, Irvine, CA) for less than 10 days before the examination. The fabric is washed three times with DMEM containing gentamicin (50 mg/ml) and amphotericin b (1.25 mg/ml). The Central cornea is removed by means trephine diameter 8 mm, then the cells descemets membrane and the endothelial cells of the cornea with the back side peripheral surface of corneoscleral tissue is removed under preprofile magnifier and digested at 37°C for 1.5 to 16 hours using collagenase a (2 mg/ml) in the environment of the epithelium with the addition of hormones (SHEM), which is prepared by mixing equal volumes of HEPES-buffered DMEM and environment ham F12 with the addition of 5% FBS, 0.5% dimethyl sulfoxide, mouse EGF (2 ng/ml), insulin (5 μg/ml), transferrin (5 μg/ml), selenium (5 ng/ml), hydrocortisone (0.5 μg/ml), cholera toxin (1 nm), gentamicin (50 μg/ml) and amphotericin b (1,25 µg/ml). After digestion NSES (endothelial cells of the cornea of a person) form aggregates, which are harvested by centrifugation at 2000 rpm for 3 minutes to remove the solution for digestion. As control strips descemetocele membranes are also digested in solution dispute II (10 mg/ml) in SHEM and mixtures of trypsin and EDTA for up to 3 hours.

X is Annie selected aggregates NSES

The obtained aggregates of NSES stored in KSFM (containing no serum medium for keratinocytes) with a full set of supplements (the storage medium 1), DMEM/F12 with additives for KSFM (storage medium 2) or DMEM/F12 with additives to SHEM, but without FBS (storage medium 3). All of these medium does not contain serum, and one of the main differences between them lies in the concentration of calcium ions, which is 0.09 mm in the storage medium 1, and in environments for storing 2 and 3 is 1.05 mm. Aggregates NSES kept in the incubator for tissue cultures at 37°C for up to 3 weeks inclusive. Determine cell viability (analysis of Live and Dead; Invitrogen), and evaluated by subculturing them in SHEM.

Capacity of selected units NSEC

The obtained aggregates of NCES or immediately after digestion, or after storage in a storage medium further cultured in SHEM with additional growth factors such as bFGF (basic FGF) (40 ng/ml), TIME (the extract of the pituitary gland of the ox) (0.1 mg/ml) and NGF (nerve growth factor) (20 ng/ml), or without them on a plastic Cup at 37°C and 5% CO2.

Medium replaced every 2-3 days. Some units of NSES pretreated with a mixture of trypsin/EDTA at 37°C for 10 minutes for separation of endothelial cells before the above-mentioned cultivation.

Immunological staining

Units NS is To fill in the OST (the mixture to maintain the optimal temperature) and carry out the preparation of sections from the frozen state. Crisisi thickness of 4 μm is dried in air at room temperature (KG) for 30 minutes and fixed in cold acetone for 10 minutes at -20°C. the Slices used for immunological staining, re-hydratious in PBS and incubated in 0.2% Triton X-100 for 10 minutes. After three washes in PBS for 5 minutes each, and pre-incubation with 2% BSA to block nonspecific staining, sections are incubated with antibodies against laminin 5, collagen type IV, perlecan, ZO-1 and connexin 43 (dilution 1:100) for 1 hour. After three washes in PBS for 15 minutes slices incubated using conjugated with FITC (fluoresceinisothiocyanate) secondary antibody (antibody goat IgG against rabbit or mouse dilution 1:100) for 45 minutes. After three additional washes in PBS for 10 minutes each contrasting paint, using iodide of propecia (1:1000) or Hoechst 33342 (10 μg/ml), and then sign into the solution to prevent fading and analyzed using a fluorescent microscope. NSES cultured in 24-hole tablets or slide cameras, fixed in 4% paraformaldehyde for 15 minutes at KG and stained with antibodies against ZO-1 and connexin 43, as has already been described. For immunohistochemical staining for Ki67 endogenous peroxidase activity blokirujut,6% hydrogen peroxide for 10 minutes. Nonspecific staining block the normal 1% goat serum for 30 minutes. The cells are then incubated with the antibody against Ki67 (1:100) for 1 hour. After three washes in PBS for 15 minutes, cells incubated with biotinylated antibody rabbit against mouse IgG (1:100) for 30 minutes followed by incubation with ABC reagent (avidin reagent-bioteknologi complex) for 30 minutes. The reaction product are using DAB (3,3'-diaminobenzidine) for 5 minutes and examined using a light microscope.

Analysis of cell viability and TUNEL analysis

Analysis of cell viability and analysis using indirect terminal deoxyribonucleotidyltransferase (TdT) labeling conjugated with FITC dUTP (desacetyldiltiazem) single-stranded gaps at the ends (TUNEL) of DNA used for the determination of live and apoptotic cells, respectively. Aggregates NSES incubated with reagents for analysis of the viability of the cells for 15 minutes at KG. Live cells are distinguished by green fluorescent staining of the cell cytoplasm, and dead cells characteristic red fluorescence of nuclei. TUNEL analysis carried out in accordance with the manufacturer's instructions. Briefly, transverse sections of the aggregates NSES fixed in 4% paraformaldehyde for 20 minutes at RT and Khujand what are the permeability, using 1% Triton X-100. Then the samples are incubated for 60 minutes at 37°C with exogenous TdT and conjugated with fluorescein dUTP to repair single-strand breaks with 3'-hydroxy-DNA ends. Cells treated with Dnazol I as a positive control, whereas cells taken as a negative control incubated with buffer without enzyme rTdT. Nuclei of apoptotic cells have been labelled with a green fluorestsentnoi label.

Example 45. Cell culture cells of the retina

Eyes are cut in half along the equator and neural retina excised from the rest of the eyes in buffered saline solution in accordance with standard methods known in the art. Briefly, the retina, ciliary body and vitreous body excised from the anterior half of the eye in one piece and the retina carefully disconnect from the transparent vitreous body. Each retina sever using papain (Worthington Biochemical Corporation, Lakewood, N. J.), and then inactivate fetal bovine serum (FBS) and add Tnkase I (134 units Konitza/ml). Enzymatic disconnected cells are triturated and collected by centrifugation, resuspended in a mixture of the modified Dulbecco eagle medium (DMEM)/F12 medium (Gibco BRL, Invitrogen Life Technologies, Carlsbad, Calif.), containing insulin (25 μg/ml), transferrin (100 μg/ml), 60 μm putrescine, 30 nm with the flax, 20 nm progesterone, penicillin (100 u/ml), streptomycin (100 μg/ml), 0.05 M Hepes and 10% FBS. Disconnected the primary cells of the retina scatter covered with poly-D-lysine and Matrigel (BD, Franklin Lakes, N. J.) glass cover, which is placed in a 24-hole plates to tissue cultures (Falcon Tissue Culture Plates, Fisher Scientific, Pittsburgh, Pa.). The support cells in culture for 5 days up to one month in 0.5 ml of medium (as above, except only 1% FBS) at 37°C and 5% CO2.

Immunocytochemical analysis

Cells of the neural retina cultured for 1, 3, 6, and 8 weeks in the presence and absence of the test compounds of the present invention and cells analyzed using immunohistochemistry for each time point. Immunocytochemical analysis carried out in accordance with standard techniques known in the art. The photoreceptors sticks identify, using the tagging of specific rhodopsin antibody (mouse monoclonal, diluted 1:500; Chemicon, Temecula, Calif.). Antibody to the protein of neurofilament average molecular weight (rabbit polyclonal to protein NFM, diluted 1:10000, Chemicon) used to identify ganglion cells; antibody to β3-tubulin (G7121, mouse monoclonal, diluted 1:1000, Promega, Madison, Wis.) used for General identification of intermediate neurons and ha is glioznogo cells, and antibodies to calbindin (AB, rabbit polyclonal, diluted 1:250, Chemicon) and calretinin (AB, rabbit polyclonal, diluted 1:5000, Chemicon) used to identify subpopulations of calbindin and calretinin-expressing intermediate neurons in the inner nuclear layer. Briefly, cultures of retinal cells fixed with 4% paraformaldehyde (Polysciences, Inc, Warrington, Pa.) and/or ethanol, washed in phosphate-salt buffer, Dulbecco (DPBS) and incubated with primary antibody for 1 hour at 37°C. the cells are Then washed with DPBS, incubated with secondary antibody (Alexa 488 - or Alexa 568-conjugated secondary antibodies (Molecular Probes, Eugene, Oreg.)) and washed with DPBS. Nuclei stained with 4',6-diamidino-2-phenylindole (DAPI, Molecular Probes) and the culture was washed with DPBS, remove the glass cover glass and fix them using Fluoromount-G (Southern Biotech, Birmingham, Ala.) on slides for examination and analysis.

Example 46. Analysis of angiogenesis using the "tube" (plug) of Matrigel

Matrigel containing the test compound, is injected under the skin or into the eyes, where it hardens with the formation of the "tube". "Tube" is extracted through 7-21 days from the animal and examined histologically to determine the extent of penetration in her blood vessels. Angiogenesis assessed by quantification of vessels in histological the x slices. Alternatively, spend the measurement of plasma using fluorescence using labeled fluoresceinisothiocyanate (FITC) dextran 150. It is expected that these results will be marked with one or more compounds set forth in this application, which inhibit angiogenesis, and therefore it is expected that they will be useful in the treatment of ophthalmic disorders associated with aberrant angiogenesis and/or aberrant vascular permeability.

Example 47. Analysis of angiogenesis in the cornea

In the cornea do deepening, and "tube" containing inducing angiogenesis a composition (e.g., VEGF, FGF, or tumor cells), as introduced in this deepening causes sprouting of new vessels from the peripheral limbus vascular network. Substances with slow release, such as ELVAX (copolymer of ethylene-vinyl) or Hydron, used for the introduction of the angiogenesis-inducing substances into the groove in the cornea. Alternatively, use a sponge material.

The effect of the assumed inhibitors on locally induced (for example, sponge implant) angiogenese reaction in the cornea (e.g., under the action of FGF, VEGF or tumor cells). The test compound is administered orally, systemically or directly into the eyes. System introduction exercise bolus injection or, more effectively, put the m use method, provides slow release, such as implantation of osmotic pumps filled with the tested inhibitor. Introduction to eye perform any of the methods described in this application, including, but not limited to, eye drops, local introduction of a cream, emulsion or gel, intravitreal injection.

Vascular response recorded through direct observation during the experiment on mice, using the stereomicroscope.Accurate visualization of the vascular network of the cornea is achieved thanks to the introduction of labeled fluorochroman dextran with a large molecular weight. Quantitative determination is carried out by measuring the area of penetration of blood vessels, promote blood vessels over time towards the angiogenic stimulus or, in the case of using fluorescence, by analyzing the histograms or the number of image elements in excess of specific (background) threshold.

It is expected that these results will be marked with one or more compounds set forth in this application, which inhibit angiogenesis, and therefore it is expected that they will be useful in the treatment of ophthalmic disorders associated with aberrant angiogenesis and/or aberrant vascular permeability.

Example 48. Analysis of angiogenesis using microtiter tablet is

Analysis tablet is prepared by placing at the bottom of each hole collagen "tube" with 5-10 cell spheroids on one collagen "tube", with each spheroid contains 400-500 cells. Each collagen "tube" cover medium for storage, making for 1100 μl per well, and stored for future use (1-3 days at 37°C, 5% CO2). The tablet is sealed with the closing. Test compounds are dissolved in 200 ál medium for analysis, with at least one hole contains VEGF as a positive control, and at least one hole as a negative control contains no VEGF or test compounds. Analysis tablet removed from the incubator and storage medium carefully removed with a pipette. Environment for analysis containing the test compound, applied with a pipette on collagen "tube". "Tube" placed in the incubator with humidity (37°C, 5% CO2) for 24-48 hours. Quantitative assessment of angiogenesis spend, counting the number of processes, measuring the average length of shoots or determining the cumulative length of shoots. In order to analyze later analysis can be maintained by removing environment for analysis, add to each well 1 ml of 10% paraformaldehyde in sbalansirovanna salt solution (BSS), Henk and storage at 4°C. the Coolant is given, the results will enable us to identify compounds that inhibit angiogenesis in a variety of types of test cells, including cells, originating from the eye.

Example 49. Analysis independent T-cell activation b-cell TNP-picollo (TNP-F)

To test the effect of compounds of the present invention for suppression independent of T-cell production of antibodies used analysis of activation of b-cells TNP-picollo, as set forth in this application. Compounds of the present invention was dissolved in an appropriate solvent (for example, containing 5% 1-methyl-2-pyrrolidinone, 85% of polyethylene glycol 400, 10% of Solutia (solutor)). Compounds were injected into mice at the age of 4-10 weeks orally approximately 1 hour before treatment TNP-picollo. To study the effect of these compounds on the activation of b-cells, one party mice were combined into groups according to the following table:

no groupNumber of mice/ groupConnection introduced for the treatmentGroupInjection of antigen in 1-ecutIntroduction connections starting from the 1st day to the 7th day
TNP-F Method(mg/kg)MethodMode
14SolventOnly antigen200 μl (0.5 mg/ml)in a/b0p/o2 times a day for 7 days
28-Only antigen0
38Connection # 7Standard30
48Connection # 53Antigen + connection.1
583
6810
7830
88/td> 60

Four animals in group 1 and eight animals in groups 2 to 7 were subjected to euthanasia in CO22 hours after the last injection of the compounds on the 7th day. Produced immediate blood through a puncture in the heart and the blood was kept at 37°C for 1 h, so that it points down, and then incubated overnight at 4°C to reduce thrombus. The next day he collected the serum by decantation and centrifugation at 3000 rpm for 10 minutes the Collected serum was then frozen at -80°C for further analysis.

Serum samples were analyzed by ELISA for antibody titers against TNP, as set forth in this application. Wells of microtiter tablet Nunc Maxisorb covered with a solution of TNP-BSA in the amount of 100 μl/well at a concentration of 10 μg/ml in phosphate-buffered saline (PBS). Tablet Maxisorb were incubated for 1.5 hours at room temperature and the solution was removed. To each well was added 200 μl/well blocking buffer (1% BSA in PBS) and incubated for 1 h at room temperature. The tablet was washed once with 200 μl/well of 0.05% tween-20 in PBS (buffer flushing). To each well of the first column (1) microtiter tablet was added diluted 1:2 serum in blocking buffer from each mouse. The serum in each well Kolo is Ki 1 then diluted 3 times in blocking buffer and added in column 2. The serum in each well of column 2 was diluted 3 times in blocking buffer and added to column 3. This procedure was repeated for all twelve columns microtiter tablet. Microtiter tablet were incubated for 1 h at room temperature. Serum was removed from the tablet and the tablet thrice washed with buffer for washing. To each well was added 100 μl/well conjugated with HRP (horseradish peroxidase) antibodies goat against mouse lgG3, diluted 1:250 in blocking buffer and incubated for 1 h at room temperature. Conjugated with HRP antibodies against mouse lgG3 was removed from the microtiter tablet and the plate was washed six times with buffer for washing. To each well was added the substrate for HRP (200 μl of a solution of ABTS (2,2'-Azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) + 30% N3O2+10 ml citrate buffer), 100 μl/well, incubated for 2 to 20 minutes in the dark and the number of anti-TNP lgG3 was determined spectrophotometrically at 405 nm. Similarly, the number of anti-TNP IgM and total number of Abl (antibodies) against TNP was determined using conjugated with HRP antibodies against IgM and mouse conjugated with HRP antibodies against mouse Ig, respectively.

The results, shown in Fig.2 also shows that in the conditions of the test compound No. 7 and No. 53 exhibit 3,4 - and 6.5-fold decrease, the respectively, levels lgG3 mice compared with the solvent control at a dose of 30 mg/kg Fig.2 also shows that in the conditions of the test compound No. 53 shows 29,9-fold lower levels lgG3 mice compared with the solvent control at a dose of 60 mg/kg

Example 50. Analysis of the developing-induced collagen type II arthritis in rats

To study the effect of compounds of the present invention to autoimmune disease arthritis used the model of the developing collagen-induced arthritis. Female Lewis rats were injected with collagen to 0 days. Bovine collagen type II was prepared in the form of a solution at a concentration of 4 mg/ml in 0.01 N. acetic acid. Equal volumes of a solution of collagen and incomplete Freud's adjuvant was mulgirigala, mixing by hand until until a drop emulsifiable substances did not begin to keep its shape in the water. Each rodent by subcutaneous injection was administered on 300 ál of the mixture, in each moment of injection distributing it on three sites on the back.

Oral administration of the compounds was started at 0 days and continued for 16 days inclusive, by the solvent (5% NMP, 85% PEG 400, 10% Solutol) or compounds of the present invention in a solvent or control (e.g., methotrexate) with 12 hour intervals once sucky. Rats were weighed at 0, 3, 6, 9-17 days and measurements of the ankle joints with calipers were performed on 9-17 days. Spent the final measurement of body weight and then the animals were subjected to euthanasia on the 17th day. After euthanasia the blood was collected and separated hind legs and knee joints. Next, the blood was processed for pharmacokinetic experiments and ELISA analysis for antibodies against collagen type II. Hind paws were weighed and then together with the knee joints were stored in 10% formalin. Legs and knee joints were then processed for holding microscopy. Also weighed the liver, spleen and thymus. Sciatic nerves were prepared for histopathological studies.

The knee and ankle joints were fixed in 1-2 days and decalcification within 4-5 days. Ankles cut into two equal parts in the longitudinal direction, the knee joints were cut into two equal parts along the frontal plane. Then the joints were processed, secured, made the cut and were stained with toluidine blue.

Evaluation of the joints was performed in accordance with the following criteria.

Inflammation of the knee and ankle joints

0 - normal.

1 - minimal infiltration of inflammatory cells in synovial/periarticular tissue.

2 - light invasion into the walkie-talkie.

3 - moderate infiltration with moderate edema.

4 - marked infiltration with marked edema.

5 - strong infiltration with severe edema.

Pannus ankle joint is normal.

1 - minimal infiltration of pannus in cartilage and Podhradie bone.

2 - light infiltration (less than 1/4 of tibia or Tarsus in the marginal zones).

3 - moderate infiltration (1/4-1/3 of tibia or small bones of the Tarsus in the marginal zones).

4 - marked infiltration (1/2-3/4 of tibia or Tarsus in the marginal zones).

5 - strong infiltration (more than 3/4 of tibia or Tarsus in the marginal zones, a strong violation of the overall structure).

Pannus knee joint

0-normal.

1 - minimal infiltration of pannus in cartilage and Podhradie bone.

2 - light infiltration (extends up to 1/4 of the surface or Podhradie area of tibia or femur).

3 - moderate infiltration (extends in the range from more than 1/4 but less than 1/2 of the surface or Podhradie area of tibia or femur).

4 - marked infiltration (extends in the range from 1/2 to 3/4 of the surface of the tibia or femur).

5 - strong infiltration (covers more than 3/4 of the surface).

Loss of cartilage (galinstan the th joint, with an emphasis on small bones of the Tarsus)

0 - normal.

1 - minimum attenuation staining toluidine blue from minimal to mild, with no apparent reduction in the number of chondrocytes or destruction of collagen.

2 - slight - slight weakening staining toluidine blue light (surface), the Focal character, a decrease in the number of chondrocytes and/or destruction of collagen.

3 - mild - moderate degree of weakening staining toluidine blue with moderate (on a thickness of the middle zone), multifocal nature, a decrease in the number of chondrocytes and/or destruction of collagen, with the defeat of the small bones of the Tarsus 1/2-3/4 depth.

4 - visible - visible weakening staining toluidine blue with a noticeable (thickness to deep zone), multifocal nature, a decrease in the number of chondrocytes and/or destruction of collagen, loss of cartilage through the entire thickness of 1 or more small bones of the Tarsus.

5 - severe - significant diffuse attenuation staining toluidine blue with a significant (at a thickness of the demarcation line), multifocal nature, a decrease in the number of chondrocytes and/or destruction of collagen.

Loss of cartilage (knee, with emphasis on the medial condyles of the femur):

0 - normal.

1 - minimum attenuation painting that is vidinova blue from minimal to mild, with no apparent reduction in the number of chondrocytes or destruction of collagen.

2 - slight - slight weakening staining toluidine blue light (surface), the focal character, a decrease in the number of chondrocytes and/or destruction of collagen.

3 - mild - moderate degree of weakening staining toluidine blue with moderate (on a thickness of the middle zone), from multifocal to diffuse character, a decrease in the number of chondrocytes and/or destruction of collagen.

4 - visible - visible weakening staining toluidine blue with a noticeable (thickness to deep zone), from multifocal to diffuse character, a decrease in the number of chondrocytes and/or destruction of collagen on the surface of one of the femur with a complete loss of, or loss of close to full.

5 - severe - significant diffuse attenuation staining toluidine blue with a significant (at a thickness of the demarcation line), multifocal nature, a decrease in the number of chondrocytes and/or destruction of collagen on both thighs and/or large Shin bone.

Resorption of bone (ankle)

0 - normal.

1 - minimal - small areas of resorption, barely visible under low magnification, rare osteoclasts.

2 - easy - more numerous areas of resorption, barely visible under low magnification, osteoclasts more numerous, less than 1/4 of a large ber is new bone or bones of the Tarsus in the marginal zones subjected to resorption.

3 - moderate - obvious resorption of medullary trabecular or cortical bone without deep, full thickness defects of the surface layer, loss of some medullary trabeculae, lesion apparent at low magnification, osteoclasts more numerous, struck from 1/4 to 1/3 of tibia bone or bones of the Tarsus in the marginal zones.

4 - visible - deep, full thickness defects in cortical bone, often with distortion of profile of remaining cortical surface, marked loss of medullary portion of the bone, numerous osteoclasts, amazed 1/2-3/4 of tibia or bones of the Tarsus in the marginal zones.

5 - strong - deep, full thickness defects in cortical bone, often with distortion of profile of remaining cortical surface, marked loss of medullary portion of the bone, numerous osteoclasts, affected more than 3/4 of tibia or bones of the Tarsus in the marginal zones of strong deformation of the overall structure.

Bone resorption (knee)

0 - normal.

1 - minimal - small areas of resorption, barely visible under low magnification, rare osteoclasts.

2 - easy - more numerous areas of resorption, some loss of subchondral bone, including 1/4 of the surface of the tibia or femur (medial or lateral)

3 - moderate - apparent resorption Podhradie bones, including more than 1/4 but less than 1/2 of the surface of the tibia or femur (medial or lateral).

4 is noticeable clearly noticeable resorption Podhradie bones, including not less than 1/2 but less than 3/4 of the surface of the tibia or femur (medial or lateral).

5 is a strong deformation of the entire joint, caused by the destruction involving more than 3/4 of the surface of the tibia or femur (medial or lateral).

Statistical analysis body weight/feet, parameters AUC (area under the curve) for paws and histopathological parameters were assessed using t-test t-test or other relevant criteria (analysis of variance ANOVA with postexperimental test), with significance level set to 5%. The percentage of inhibition mass paws and AUC was calculated using the following formula:

% inhibition=(a - b/A) (100, where

And represents the average value for the control object of the disease minus the average value for the norm;

Represents a mean value for treatment of objects minus the average value for the norm.

The results shown in Fig.3 demonstrate the effect of compound No. 53 at doses of 10, 30 and 60 mg/kg at 12-hour intervals in testing conditions on the average di is the meter of the ankle joint in time in the model of the developing-induced collagen type II arthritis in rats. In comparison with the control in the form of a single solvent or a control in the form of methotrexate, the compounds of the present invention showed a significant decrease in induced arthritis increase the diameter of the ankle joint in time.

The results shown in Fig.4 demonstrate the effect of compounds No. 7 and No. 53 on the histopathology of the ankle joint in categories: inflammation, pannus, cartilage damage and bone resorption, as described previously in testing conditions. The results indicate a significant reduction in one or more categories under the action of one of the compounds of the present invention (i.e. compounds No. 53) in testing conditions. In Fig.4 also shows that a dose of 60 mg/kg in test conditions, there is a statistically significant decrease in all categories histopathology ankle identified for one of the compounds of the present invention (i.e. compounds No. 53). This is proof that one or more compounds of the present invention may be useful for treating and alleviating symptoms of arthritis.

The results shown in Fig.5 demonstrate the effect of compounds No. 7 and No. 53 in testing conditions on the histopathology of the knee joint. The results demonstrate a dose-dependent decrease in histopathology and knee joint. This is proof that one or more compounds of the present invention may be useful for treating and alleviating symptoms of arthritis.

The results shown in Fig.6 demonstrate the effect of compounds No. 7 and No. 53 in testing conditions on the levels of antibodies against collagen type II in the serum. The results also indicate a significant reduction in levels of antibodies against collagen type II in the serum at levels of dose of compound No. 53, equal to 10, 20 and 60 mg/kg, which is evidence that one or more compounds of the present invention may be useful not only for treating and alleviating symptoms of arthritis, but can also be useful for inhibiting the autoimmune response.

The results shown in Fig.7 demonstrate the effect of compound No. 7 in doses of 10, 30 and 60 mg/kg at 12-hour intervals in testing conditions on the average diameter of the ankle joint in time. In comparison with the control in the form of a single solvent or a control in the form of methotrexate, the compound under test conditions showed a significant decrease in induced arthritis increase the diameter of the ankle joint in time.

Example 51. Analysis of the set induced by collagen type II arthritis in rats

To study on sosovicka the effectiveness of the compounds of the present invention in the inhibition of inflammation, destruction of cartilage and bone resorption is installed on the 7th day induced collagen type II arthritis in rats the compound is administered orally once or twice a day for 6 days.

Female Lewis rats were anestesiology and were injected with collagen, prepared and injected as described previously, for 0 days. On the 6th day the animals were anestesiology and did the second injection of collagen. Measuring with calipers normal (pre-disease) of the right and left ankle joints was performed on the 9th day. Usually arthritis appeared on 10-11 days, and rats randomized into groups exposed to the treatment. Randomization was performed after clearly established swollen ankle and had good evidence of bilateral disease.

After the selection of animals for participation in this study, treatment was initiated, using the oral route of administration. Animals received a solvent control (Enbrel) or doses of the compounds two times a day or once a day (2x/day or 1x/day, respectively). The introduction was carried out in 1-6 days, using the amount of 2.5 ml/kg (2x/day) or 5 ml/kg (1x/day) for oral solution. Rats were weighed at 1-7 days after the establishment of arthritis and each day measurements of ankle joints with calipers. The final value of the body weight was determined on the 7th day and the animals were subjected to euthanasia.

The results shown in Fig.8, showing a significant reduction in the increase of the average diameter of the ankle joint in time for connection No. 53 at its introduction once a day under test conditions. The results shown in Fig.9, also showing a significant reduction in the increase of the average diameter of the ankle joint in time for connection No. 53 with the introduction of it twice a day under test conditions. This is proof that the compounds of the present invention may be useful for the treatment of autoimmune diseases such as arthritis.

Example 52. Analysis of arthritis induced by adjuvant

Intrathecal catheterization in rats

Shot by isoflurane Lewis rats (200-250 g) were implanted intrathecal (t) catheter. After a recovery period of 6 days for experiments used all animals except those that showed abnormalities of sensation or motor activity (less than 5% of the total). To implement and/t insertion through the catheter was injected 10 μl of drug or saline, followed by 10 μl of isotonic saline solution.

Induced adjuvant arthritis and drug therapy

The Lewis rats were immunized at the base of the tail, using 1 ml of complete adjuvant's adjuvant (CFA), 0 days through few days after implantation of the catheter (n is equal to 6/group). Drug therapy (e.g., one or more than one compound of the present invention or solvent) is usually started on the 8th day and continued daily until the 20th day. Clinical signs of arthritis, usually appear on the 10th day, and the swelling of the paws was determined every second day using plethysmometry water offset.

The results, shown in Fig.10, through the medium of change of volume of the paws for these schemes the introduction show that in the conditions of the test compound No. 53 shows a dose-dependent reduction of the increase in the average volume of paws on the results of the measurements in this model system induced adjuvant arthritis. These results are evidence that one or more compounds of the present invention may be useful for treating one or more diseases or conditions set forth in this application.

The results, shown in Fig.11, show that the compound No. 53 does not show toxicity or other adverse reactions in testing conditions that assessed by the absence of mass reduction.

Example 53. Pharmacokinetic analysis in rodents

To study the pharmacokinetics of the compounds of the present invention from the party in mice in which the Rast 4-10 weeks are groups in accordance with the following table:

no groupThe number of mice/ groupConnection introduced for the treatmentIntroduction connections, starting from the 1st day to the 7th day
(mg/kg)MethodMode
131p/o2 times a day for 7 days
233
3310
4330
5360

Compounds of the present invention is dissolved in an appropriate carrier (e.g., containing 5% 1-methyl-2-pyrrolidinone, 85% of polyethylene glycol 400, 10% of Solutia (Solutor)) and administered orally at intervals of 12 hours once a day. All animals subjected to euthanasia in CO22 hours after enclose inogo introduction connections. Carry out an immediate blood sampling and stored on ice for separation of plasma. The plasma emit by centrifugation at 5000 rpm for 10 minutes. The collected plasma freeze for conducting pharmacokinetic definition.

It is expected that the results will demonstrate the pharmacokinetic parameters, such as parameters of absorption, distribution, metabolism, excretion and toxicity of the compounds of the present invention.

Example 54. Basotect(Basotet) analysis (analysis using the test activation of basophils allergens)

Basotest-analysis is performed using a set of reagents for Basotest from Orpegen Pharma. Whole heparinized blood pre-incubated with test compound or solvent at 37°C for 20 minutes Then the blood incubated with stimulating buffer set for analysis (to premirovat cells to respond), then with the allergen (extract dust contains dust mites, or extracts of vegetable origin) within 20 minutes after the Process of degranulation stop by incubation of blood samples on ice. After that, the cells enter a label using anti-lgE-PE (phycoerythrin), for detection of basophilic granulocytes, and anti-gp53-FITC for detection Dr (glycoprotein expressed on activated basophils). After staining erythrocytes subjected to lysis way is adding a lytic solution. Cells are washed and analyzed using flow cytometry. Compounds 7 and 53, in the case when they are tested in this analysis, inhibit induced by allergen activation of basophilic granulocytes in the range submicromolar concentrations.

Example 55. Combined use of inhibitors I3δ and agents that inhibit the production or activity of IgE

Compounds of the present invention can be synergistic or additive efficacy when introduced in combination with agents that inhibit the production or activity of IgE.

Agents that inhibit the production of IgE, include, for example, one or more agents from THE-9874, 2-(4-(6-cyclohexyloxy-2-naphthyloxy)-phenylacetamide)benzoic acid, rapamycin analogues of rapamycin (i.e. replagal), inhibitors of TORC1, TORC2 inhibitors or any other compounds that inhibit mTORC1 and mTORC2. Agents that inhibit the activity of IgE, include, for example, antibodies against IgE, such as, for example, omalizumab and TNX-901.

One or more compounds which are the object of the invention is able to inhibit I3δ, effective in the treatment of autoimmune and inflammatory disorders (AIID), for example, rheumatoid arthritis. If any of the compounds cause an undesirable level of production lgE, you can choose to introduce in combination with agent is, which inhibits the production of lgE or activity lgE. In addition, the introduction of inhibitors I3δ or PI3Kδ/γ according to the present invention in combination with mTOR inhibitors can also lead to synergies through enhanced inhibition RK-way. To establish the effect of this combined treatment on AIID can be used in a variety of models in vivo and in vitro, including, but not limited to, (a) analysis of the production of antibodies by b-cells in vitro, (b) TNP-analysis of in vivo and (b) model of collagen-induced arthritis in rodents.

(a) Analysis using b-cells

Mice subjected to euthanasia, spleen extract and crushed through a nylon mesh to obtain a suspension of individual cells. Splenocytes are washed (after removal of erythrocytes by osmotic shock) and incubated with the microspheres, conjugated with antibodies against CD43 and against Mac-1, (Miltenyi Biotec). Contacting granule cells are separated from unbound cells using magnetic cell sorters. Unwanted cells are held in a magnetized column, and the remaining b-cells collect in the ongoing thread. Purified b cells stimulated with lipopolysaccharide or antibody against CD40 and interleukin 4. Stimulated b cells treated only with the solvent or solvent together with PI3Kδ inhibitors of the present invention, such as with the unity 53, inhibitors of mTOR such as rapamycin, realogy or inhibitors of mTORC1/C2, or without them. It is expected that these results will be demonstrated that in the presence only of mTOR inhibitors (e.g., rapamycin) effect on IgG - and lgE-the answer will be provided in the range from small to essentially zero. However, it is expected that in the presence of inhibitors RC(and mTOR In cells will demonstrate weakened lgG response compared with cells treated only with the solvent, and it is expected that cells will demonstrate weakened lgE-response compared to the response from b cells treated only inhibitors I3δ,

(b) TNP-analysis

Mice were immunized TNP-picollo or TNP-KHL (hemocyanin mollusk fissurella) and process: solvent, inhibitor I3δ, for example, the connection 53 of the present invention, a mTOR inhibitor, e.g. rapamycin, or inhibitor I3δ in combination with the mTOR inhibitor, such as rapamycin. Serum antigen-specific lgE measured by ELISA, using the tablets coated with TNP-BSA, and isotype-specific labeled antibodies. It is expected that mice treated only inhibitor of mTOR, will show little effect or substantially no effect on antigen-specific lgG3-response and no statistically significant improvement lgE-from the ETA compared with the solvent control. It is also expected that mice treated together inhibitors I3δ and mTOR inhibitors, will demonstrate a decrease in antigen-specific lgG3 response compared to mice treated only with solvent. In addition, mice treated with both inhibitors I3δ and mTOR inhibitors, will demonstrate improvement in lgE response compared to mice treated only inhibitor I3δ.

(C) Model of collagen-induced arthritis in rats, Female rats, Lewis anaesthetize and 0 days do collagen injections, which are prepared and injected as described previously. On the 6th day anaesthetize animals and make a second injection of collagen. Measuring with calipers normal (pre-disease) of the right and left ankle joints is performed on the 9th day. Usually arthritis appears on 10-11 days and rats randomizer on the group being treated. Randomization is performed after clearly establish swollen ankle and there is good evidence of bilateral disease.

After the selection of animals for participation in this study begin treatment. Animals receive solvent, inhibitor I3δ or inhibitor I3δ in combination with rapamycin. The introduction is carried out in 1-6 days. Rats weighed in 1-7 days after the establishment of arthritis and each day the item is avodat measurement of the ankle joints with calipers. The final values of body weight is determined on the 7th day and the animals are subjected to euthanasia.

It is expected that the combined treatment with the inhibitor I3δ and rapamycin will provide greater efficiency than treatment only inhibitor I3δ.

Although in this application is shown and described a preferred embodiment of the present invention, specialists in the art it will be obvious that such embodiments are given only as an example. Specialists in the art will immediately appear ideas numerous variations, changes and substitutions without deviating from the invention. It should be understood that in the practical application of the present invention may be used various alternatives to the embodiments of the invention described in this application. Assumes that the supplied formula defines the scope of the invention and thereby covers the methods and structures falling within the scope of this formula, and cash equivalents.

1. The compound of formula IV

or its pharmaceutically acceptable salt, where
Wa2represents CR5;
Wa3represents CR6;
Wa4represents N or CR7;
Wdis heteroaryl, selected from the group consisting of the:
,and,
where Wdpossibly substituted: (a) C1-C10the alkyl, which may substituted by one or more than one aminocarbonyl, 5-10-membered heterocyclyl, amino, (C1-C6alkyl)-C(O)-(HE)N-, (HE) (1-C6alkyl)N-C(O)- or (5-to 10-membered heterocyclyl)carbonyl; (b) cyano; (C) amino; (g) halogen; (l)2-C6the quinil, which itself is possibly substituted C3cycloalkyl; (e) HE-(C2-C6quinil)-; (f) phenyl, which itself is possibly substituted by one or more than one halogen, hydroxyl, C1-C6alkoxyl, aminocarbonyl, NH2(C1-C6alkyl)-, (C1-C6alkyl)-C(O)-NH-, (C1-C6alkoxyl)2P(O)O-, (OH)2P(O)O - or carboxyla; (h) a 5-10 membered heteroaryl, which itself is possibly substituted by one or more than one C1-C6the alkyl, HE-(C1-C6alkyl)-, (C1-C6alkyl)NH-, (C1-C6alkyl)-C(O)-NH-, (C1-C6alkyl)-NH-C(O)-NH -, or amino; (and) With2-C6alkenyl, which itself is possibly substituted 5-10-membered heterocyclyl, aminocarbonyl or 5-10-membered heterocyclyl)carbonyl; and
where heterocyclyl or heteroaryl groups have one or more ring heteroatoms selected from N, O and S;
In is the th C 1-C10alkyl, C3-C10cycloalkyl,3-C10heteroseksualci having from one to six ring heteroatoms selected from N, O and S, or a group of formula II

where Wcrepresents a C6-C10aryl or 5-18-membered heteroaryl having one or more ring heteroatoms selected from N, O and S; and
q is an integer 0, 1, 2, 3 or 4;
X is absent or represents -(CH(R9))z-;
z is equal to 1;
Y is absent;
R1represents (a) hydrogen, (b) C1-C10alkyl, which may substituted by one or more than one halogen, (C) C1-C8alkoxyl, (g) halogen, (d) hydroxyl, or (e) (5-10-membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen)-(C1-C6alkoxyl);
R2represents a C1-C10alkyl, C1-C8alkoxy, halogeno, hydroxyl or (5-10 membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen)-(C1-C6alkoxyl);
R3represents hydrogen, C1-C10alkyl or halogeno;
R5, R6, R7and R8represent hydrogen; and
in each case, R9independently represents hydrogen or C1-C10alkyl.

2. Connection on p. 1 of formula V

where, X, Y, Wd, R3, R5, R6, R7and R8are as defined in paragraph 1.

3. Connection on p. 1 of formula VI

where, X, Y, Wd, R3, R5, R6, R7and R8are as defined in paragraph 1.

4. Connection on p. 1 of formula VII

where, Wd, R3, R5, R6, Wa4and R8are as defined in paragraph 1.

5. Connection on p. 4, where Wa4represents N.

6. Connection on p. 1, where R1represents hydrogen, C1-C10alkyl or halogeno.

7. Connection on p. 6, where R1represents hydrogen, -CH3, -CH(CH3)2or-F.

8. Connection on p. 1, where R3represents halogeno.

9. Connection on p. 1, where R3represents a C1-C10alkyl.

10. Connection on p. 1, where R3represents-H, -CH3, -CH2CH3, -CF3, -Cl or-F.

11. Connection on p. 1, where X represents-CH2- or-CH(CH3)-.

12. Connection on p. 1, where X represents-CH2and Y is absent.

13. Connection on p. 1, where Wdrepresents.

14. Connection on p. 1, where Wdrepresents.

15. With the unity under item 1, where Wdrepresents.

16. Connection on p. 1 having the formula 6-a

where R12represents (a) C1-C10alkyl, which may substituted by one or more than one aminocarbonyl, 5-10-membered heterocyclyl, amino, (C1-C6alkyl)-C(O)-(HE)N-, (HE) (1-C6alkyl)N-C(O)- or (5-to 10-membered heterocyclyl)carbonyl; (b) cyano; (C) amino; (g) halogen; (l)2-C6quinil, which itself is possibly substituted C3cycloalkyl; (e) HE-(C2-C6quinil)-; (f) phenyl, which itself is possibly substituted by one or more than one halogen, hydroxyl, C1-C6alkoxyl, aminocarbonyl, NH2(C1-C6alkyl)-, (C1-C6alkyl)-C(O)-NH-, (C1-C6alkoxyl)2P(O)O-, (OH)2P(O)O - or carboxyla; (h) a 5-10 membered heteroaryl, which itself is possibly substituted by one or more than one C1-C6the alkyl, HE-(C1-C6alkyl)-, (C1-C6alkyl)NH-, (C1-C6alkyl)-C(O)-NH-, (C1-C6alkyl)-NH-C(O)-NH -, or amino; (and) With2-C6alkenyl, which itself is possibly substituted 5-10-membered heterocyclyl, aminocarbonyl or 5-10-membered heterocyclyl)carbonyl; and where heterocyclyl or heteroaryl groups have one or more ring heteroatoms, selected the data from N, O and S;
or its pharmaceutically acceptable salt.

17. Connection on p. 16, which represents a C1-C10alkyl, C3-C10heteroseksualci having from one to six ring heteroatoms selected from N, O and S, or C3-C10cycloalkyl.

18. Connection on p. 1, where In is a
,
where Wc, R1, R2and q are as defined in paragraph 1.

19. Connection on p. 18, where Wcrepresents a C6-C10aryl.

20. Connection on p. 18, where Wcrepresents phenyl, pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidine-4-yl, pyrimidine-2-yl, pyrimidine-5-yl or pyrazin-2-yl.

21. Connection on p. 17, where In represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

22. Connection on p. 20, where the phenyl possibly substituted by one or more than one halogen or hydroxyl.

23. Connection on p. 18, where R1represents hydrogen.

24. Connection on p. 18, where R1represents a C1-C8alkoxy, hydroxy or C1-C10alkyl.

25. Connection on p. 18, where R1represents-F, -Cl, -CH3, isopropyl, -CF3or-och3.

26. Connection on p. 18, where q is 0 or 1.

27. Connection on p. 18, where R2represents halogeno or hydroxy.

28. Connection P1 or its pharmaceutically acceptable salt, where the connection is a








































img src="https://img.russianpatents.com/1190/11901754-s.jpg" height="36" width="135" />



,,,,
or.

29. Connection on p. 1 or its pharmaceutically acceptable salt, where the connection is a
,,or.

30. Connection on p. 1 or its pharmaceutically acceptable salt, where the connection is a
,or.

31. Connection on p. 1 or its pharmaceutically acceptable salt, where the connection is a

or
.

32. Connection on p. 1 or its pharmaceutically acceptable salt, where the connection is a
.

33. Connection on p. 1 or its pharmaceutically acceptable salt, where the connection is a
.

34. Connection on p. 1, where the connection is a

or
,
or its pharmaceutically acceptable salt.

35. The compound of formula VIII-A

or its pharmaceutically acceptable salt, where
Wdrepresentsor;
Rarepresents hydrogen;
R11represents amino;
R12represents (a) hydrogen, (b) C1-C10alkyl, (C) cyano, (g)2-C6quinil, which itself is possibly substituted by a hydroxyl or3-C6cycloalkyl, (d), halogeno, (e) phenyl, which itself is possibly substituted by one or more than one hydroxyl or halogen, (W) 5-6-membered heteroaryl containing 1-2 heteroatoms nitrogen, or (h)3-C6cycloalkyl;
Represents a grouping of formula II

Wcrepresents phenyl;
q is an integer 1;
X represents -(CH(R9))z-;
Y is absent;
z is equal to 1;
R1represents hydrogen;
R2represents a C1-C10alkyl or halogeno;
R3represents a C1-C10alkyl;
R5and R6represent hydrogen; and
each R9represents hydrogen.

36. Obedinenie on p. 35, where the connection is a

,,or,
or its pharmaceutically acceptable salt.

37. Connection on p. 35, where the connection is a

or,
or its pharmaceutically acceptable salt.

38. The compound of formula IX:

or its pharmaceutically acceptable salt, where
Wa1and Wa2independently represent CR5, N or NR4and Wa4independently represents CR7or S, where not more than two adjacent atoms in the ring are nitrogen or sulfur;
Wb5represents N;
Represents a C1-C10alkyl, 6-membered heteroseksualci having a heteroatom of nitrogen, With3-C6cycloalkyl or a grouping of formula II

where Wcrepresents phenyl or 6-membered heteroaryl having a heteroatom of nitrogen, and q is an integer 0, 1, 2, 3 or 4;
Wdis heteroaryl selected from the group consisting of
, and,
possibly substituted by one or more of: (a) (C1-C6alkyl)aminocarbonyl; (b) phenyl, which itself is possibly substituted by a hydroxyl or halogen; (C) halogen; (d) hydroxyl; (d)2-C6the quinil, which itself is possibly substituted by a hydroxyl or3-C6cycloalkyl; and (e) 5-10-membered heteroaryl with nitrogen heteroatom;
X is absent or represents -(CH(R9))z-;
z is equal to 1;
Y is absent;
R1represents hydrogen, C1-C10alkyl, possibly substituted by one or more than one halogen; C1-C6alkoxy or halogeno;
R2represents a C1-C10alkyl, possibly substituted by one or more than one halogen; C1-C6alkoxy or halogeno;
R4represents hydrogen or C1-C4alkyl, possibly substituted by one or more than one halogen;
R5and R7independently represent hydrogen or C1-C4alkyl, possibly substituted by one or more than one halogen;
and in each case, R9independently represents hydrogen or C1-C10alkyl.

39. Connection on p. 38 of the formula X

40. Connection on p. 39, where R4represents a C1-C4alkyl.

41. The is begins on p. 40, where R4represents methyl or ethyl.

42. Connection on p. 38 formula XII

43. Connection on p. 38 of the formula XIII or XIV

44. Connection on p. 38, where R1represents hydrogen and R2represents methyl, ethyl or propyl.

45. Connection on p. 44, propyl where represents isopropyl.

46. Connection on p. 38, where R1represents hydrogen and R2represents halogeno.

47. Connection on p. 38, where R1represents methyl, ethyl or propyl and q equal to 0.

48. Connection on p. 47, propyl where represents isopropyl.

49. Connection on p. 38, where R1represents halogen and q equal to 0.

50. Connection on p. 38, where R5represents hydrogen, methyl or-CF3.

51. Connection on p. 38, where R7represents hydrogen or methyl.

52. Connection on p. 38, where R9represents hydrogen or methyl.

53. Connection on p. 38 or its pharmaceutically acceptable salt, where the connection is a
















or.

54. Connection on p. 38, where the connection is a

or
,
or its pharmaceutically acceptable salt.

55. Pharmaceutical composition having inhibitory activity against R-kinase (phosphoinositide-3-kinase), containing pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to any one of paragraphs.1-54.

56. The composition according to p. 55, where the composition is in a liquid, solid, semi-solid form, gel form or aerosol form.

57. Method of inhibiting R-kinase in a subject, comprising introducing to a subject an effective amount of a compound according to any one of paragraphs.1-54.

58. The method according to p. 57, where the subject is suffering from a disorder that represents cancer, bone damage, inflammatory disease, immune disease, disease of the nervous system, metabolic disease, respiratory ill the tion, thrombosis or heart disease.

59. The method according to p. 58, where the subject is suffering from cancer.

60. The method according to p. 59 where the cancer is a breast cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, pancreatic cancer, bladder cancer, bone cancer, lung cancer, skin cancer, eye retinoblastoma, primary liver cancer, kidney cancer, thyroid cancer, cancer induced by viruses, cervical cancer, cancer of the Central nervous system, cancer of the peripheral nervous system, cancer of the oral cavity and oropharynx, stomach cancer, testicular cancer, cancer of the thymus gland, cancer of the rectum or colon cancer.

61. The method according to p. 60, where lung cancer is a non-small cell lung cancer (NSCLC) or small cell lung cancer.

62. The method according to p. 59 where the cancer is a lymphoma or leukemia.

63. The method according to p. 62, where the lymphoma is a diffuse In both lymphoma, b-cell immunoblastic lymphoma, small cell lymphoma of the unsplit cells, leukemia/lymphoma, caused(th) lymphotropic virus human type 1 (HTLV-1), T-cell lymphoma adult Hodgkin's disease, non-Hodgkin lymphoma or AIDS-associated lymphoma.

64. The method according to p. 62, where leukemia is an acute lymphocytic leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders is, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), b-cell acute lymphoblastic leukemia, T-cell acute lymphocytic leukemia, T-cell leukemia adult or myelodysplastic syndrome (MDS).

65. The method according to p. 59, where cancer is a cutaneous or intraocular melanoma (melanoma of the eye), sarcoma Galoshes, a disorder associated with fat cells, T-cell leukemia adult T-cell lymphoma in adults.

66. The method according to p. 57, where in combination with the medicinal product should be used the second therapeutic agent.

67. The method according to p. 66, where the second agent is an agent that inhibits the production of Ig(immunoglobulin)that is

68. The method according to p. 58, where the disorder is selected from inflammatory diseases and immune diseases where inflammatory and immune diseases selected from asthma, emphysema, allergies, dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus, graft versus host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, and multiple sclerosis.



 

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15 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

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,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

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7 cl, 1 tbl, 30 ex

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FIELD: chemistry.

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28 cl, 5 dwg, 225 ex

FIELD: chemistry.

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21 cl, 7 tbl, 250 ex

FIELD: medicine, pharmaceutics.

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14 cl, 8 dwg, 2 tbl, 33 ex

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23 cl, 1 tbl, 13 ex

FIELD: chemistry.

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14 cl, 3 tbl, 26 ex

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13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles of general formula (I)

where a R=CH3, R1=C6H5; b R=CH3, R1=4-CH3OC6H4; c R=CH3, R1=2-thienyl; d R=C6H5, R1=4-CH3OC6H4. The method is carried out by reacting 4-bromo-5-nitrophthalonitrile with esters of 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids in the presence of triethylamine, which is used as a deprotonating agent. The reaction takes place at temperature of 18…35°C and molar ratio of reactants (1):(2):(TEA)=1:1:2, for 12-30 hours in dimethylformamide solution. Further, the reaction mass is diluted with water, the water being in tenfold excess, at temperature T=0…25°C; the tarry residue released is decanted from the aqueous layer and recrystallised from alcohol; the precipitate of the end product is filtered and dried on air.

EFFECT: synthesis of compounds which are used as precursors for producing phthalocyanines.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula wherein each of R1 and R2 is independently selected from a group consisting of a hydrogen atom, nitro and NR6R7; R3 is C1-C8alkyl; each of R4 and R5 is independently selected from a group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylene)oxy; each of R6 and R7 is independently selected from a group consisting of a hydrogen atom, C1-C8alkyl, C(O)R8 and SO2R8;R8 is selected from a group consisting of a hydrogen atom, C1-C8alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkylsubstituted amino), C1-C8-alkyl, substituted with piperidine and C1-C8-alkyl, substituted with morpholine.

EFFECT: reduced PDE4 enzyme activity and treating PDE4 enzyme mediated diseases or conditions.

21 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a compound of formula and to its pharmaceutically acceptable salt and its enantiomers, wherein D means pyridyl, which is substituted by 1-2 independently specified groups R38; M means , wherein * means an attachment position to D; and † means an attachment position to Z; Z means -O-; Ar means phenyl, which is optionally substituted by 0-4 groups R2; and G means ; wherein each R38 means -C0-C6-alkyl-(substituted by one group containing heterocyclyl, which means a monocyclic structure, and contains 5 to 7 atoms, wherein 1 or 2 atoms are independently specified in a group containing N, O and S optionally substituted by one or more oxo groups); in each specific case R2 is independently specified in -H and halogen; each R13 means -H; Q means cyclopropyl. The invention also refers to a pharmaceutical composition based on the composition of formula (I), a method for inhibiting the activity of protein kinase of the growth factor receptors and a method of treating choroidal neovascularisation.

EFFECT: there are prepared new compounds possessing the activity on protein kinase inhibitors.

7 cl, 8 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining compounds of formula . The compounds of formula 6 are intermediate products for obtaining dihydrothieno[3,2-d]pyrimidines, which produce an impact on the cardiovascular system, possess sedative action, or can be applied in treatment of inflammatory diseases of joints, skin, eyes or diseases of the peripheral or central nervous system, respiratory or gastrointestinal disorders. The method includes the following stages: a) interaction of reagents of formulas HS-CH2-CO2Ra and CHR5=CR4-CO2Ra with obtaining an intermediate product of formula ; and b) cyclisation of the intermediate product of formula 7 in a solvent in the presence of TiCl2(O-iPr)2, TiCl(O-iPr)3, TiCl3(O-iPr) and in the presence of a base-amine, with obtaining a product of formula 6. Ra stands for alkyl, R4 and R5 are independently selected from a group, including H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkylene, C5-C10-heteroaryl-C1-C6-alkylene, C3-C10-heterocycle and C5-C10-heteroaryl, -O-C1-C6-alkyl, -O-C6-C10-aryl, -O-C3-C10-heterocycle and -O-C5-C10-heteroaryl, -NR'R", fluorine, C1-C6-fluoroalkyl and C1-C6-fluoroalkoxygroup, where R' and R" are independently selected from a group, including H and C1-C6-alkyl, and where in each case the group can be optionally substituted with one or more groups, selected from a group, including OH, oxogroup, halogen, C1-C6-alkyl and O-C1-C6-alkyl. The method makes it possible to obtain the intermediate products 6, which do not require carrying out distillation and chromatographic purification between stages in realisation of processes suitable for wide-scale synthesis of dihydrothieno[3,2-d]pyrimidines.

EFFECT: invention results in higher total output of the final products as compared to that in realisation of methods of preceding level of technology.

6 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compound with structural formula (I) or to its pharmaceutically acceptable salt, where R represents cyanogroup. Invention also relates to method of obtaining said compound and to pharmaceutical composition against platelet aggregation based on the compound.

EFFECT: obtained is novel compound and based on its pharmaceutical composition, which can be applied in medicine for production of medication for prevention or treatment of diseases of cardiac and cerebral vessels, such as coronary syndromes, myocardial infarction and myocardial ischemia, caused by aggregation of platelets.

13 cl, 3 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to thieno[3,2-d]pyrimidine derivative of formula (I) or to its pharmaceutically acceptable salt: (I), where Y stands for -CH=CR1-, -C≡C- or -C(=O)NR1-; L stands for -C(=O)NR2-, -NR2C(=O)- or -NR2C(=O)NR2-; R1 and R2, each independently stands for H; R stands for H, a halogen atom, methyl or methoxy; E stands for phenyl or C3-10heteroaryl, which is non-substituted or substituted with 1-2 substituents, consisting of a group, which includes a halogen atom, -CF3, C1-6alkyl, hydroxy-C1-6alkyl, C3-8cycloalkyl, -(CH2)n-C1-6alkylamino, -(CH2)n-diC1-6alkylamino, -(CH2)nC1-6alkoxy, -(CH2)n-OS(=O)2-C1-6-alkyl, -(CH2)n-phenyl, -(CH2)n-C2-5heteroaryl and -(CH2)n-C4-6heterocycloalkyl, where C3-10heteroaryl represents pyridine, isoquinoline, indole or isoxazole, C2-5heteroaryl of radical -(CH2)n-C2-5heteroaryl represents imidazole or pyrrol, C4-6heterocycloalkyl of radical -(CH2)n-C4-6heterocycloalkyl represents piperazine, morpholine, diazepam, pyrrolidine or piperidine, and phenyl, heteroaryl and heterocycloalkyl each independently, is non-substituted or substituted with substituent selected from a group, which consists of C1-6alkyl, hydroxy-C1-6alkyl, a halogen atom and diC1-6alkylamino, n is equal to 0 or 1; and Z stands for H, -C(=O)R3, C1-6alkyl, hydroxyC1-6alkyl, C3-8cycloalkyl, piperidine, phenyl or pyridine, where piperidine, phenyl and pyridine, each independently, is non-substituted or substituted with C1-6alkyl, C1-6alkoxy or R3-piperazinyl and R3 represents C1-6alkyl or phenyl. The invention also relates to an intermediate compound for obtaining the claimed final compound of formula (I).

EFFECT: novel compound, which can be applied in medicine for the prevention or treatment of diseases, characterised by an anomalous growth of cells as a result of an excessive expression of proteinkinase, is obtained.

8 cl, 2 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I , which represents agent of in vivo visualisation of peripheral benzodiazepine receptor (PBR), where Q represents hydrogen or fluorine; X represents hydrogen or C1-4alkoxy; Y represents S; and R represents C1-6fluoroalkyl; and where, at least, one atom of said agent of in vivo visualisation of formula I represents radioisotope, suitable for in vivo visualisation and representing either gamma-emitting radioactive halogen or positron-emitting radioactive non-metal; and where if said radioisotope is a carbon radioisotope, it is carbonyl carbon.

EFFECT: obtaining novel derivatives.

15 cl, 2 dwg, 1 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I, including stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof: where Z1 is CR1; Z2 is CR2; Z3 is CR3 or N; Z4 is CR4 or N; where (i) X1 is N and X2 is S or (iv) X1 is S and X2 is CR7; R1, R2, R3, R4 and R7 are independently selected from H, F, Cl, Br, I, -CN, -CH2OR10, -(C1-C12 alkylene)NR10R11, -(C1-C12 alkylene)NR12C(=O)R10, -CO2R10, -C(=O)N(R10)OR11, -NR10R11, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)OR11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)R11, -C(=O)NR10(C1-C12 alkylene)R11, -C(=O)NR10(C1-C12 alkylene)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(-O)NR10R11, -NR12C(=O)(C1-C12 alkylene)NR10R11, NR12(C=O)C1-C12 alkylene)NR11(C=O)R12, -C≡CR10, C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-6 ring atoms, where 1-4 ring atoms are nitrogen atoms, and phenyl, where the heteroaryl and phenyl are optionally substituted with one or two groups selected from -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -CO2H, -CH2CO2CH3, -NH2 and -S(O)2CH3; A is selected from -C(=O)NR5R6, -C(=S)NR5R6, phenyl and C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-10 ring atoms, 1-4 of which are heteroatoms selected from nitrogen, oxygen or sulphur, C1-C20 heteroaryl and phenyl are optionally substituted with one or three groups independently selected from C1-C12 alkyl, -(C1-C12 alkylene)NR10R11, -CH3, oxo, -CO2CH3, -NH2, 1-methylpiperid-4-yl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, benzoimidazolyl, benzyl and phenyl, where the alkyl, benzoimidazolyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CF3, -CH2OH, -CH3, -C(=O)NHCH3, -NH2, -OH, -OCH3, -CH2OCH3, -C(=O)N(CH3)2, -N(CH3)2, -C(CH3)2OH, -CH(CH3)2, -CH2(1H-1,2,4-triazol-5-yl) and C(=O)4-methylpiperazin-1-yl; R5 is selected from C1-C12 alkyl, optionally substituted with one group independently selected -NH2, -NHCOCH3 and -OH; R6 is selected from pyridinyl and phenyl, each optionally substituted with one or two groups independently selected from F, Cl, Br, I, -CN, -CF3, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11 and -C(=O)NR10R11; R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-phenyl, cyclopentyl, pyridinyl and imidazolyl, where C1-C12 alkyl, cyclopentyl are optionally substituted with one or two groups independently selected from -CH2OH, -N(CH3)2, -NHCOCH3, -OH and -S(O)2CH3; or R10 and R11 together with a nitrogen atom to which they are bonded form a C5-C6 heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, or pyrazolyl, optionally substituted with one or two groups independently selected -CH3, -NH2, -N(CH3)2; -OH and oxo. The invention also relates to a pharmaceutical composition having PI3K inhibiting activity based on said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for treating cancer.

25 cl, 5 dwg, 2 tbl, 331 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to compounds of formula I:

, where X means S or CR5;Y means S or CR7; where one of X or Y means S; each of R2, R5, R6 and R7 has been independently chosen from a group including the following: a) halogen; b) R8, -O-R8, -(C1-C6)alkylene-R8, -(C1-C6)alkylene-O-R8; where in each case R8 has been independently chosen from a group containing H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl and aryl; R3 means -W-R31 and bond is an ordinary bond; where W means O and R31 means (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-; R4 means aryl or Het, where each aryl and Het optionally contains 1 to 5 substitutes, each of which has been independently chosen from a group containing halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -OH, -O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl and -N((C1-C6)alkyl)2, which can be used for treatment of HIV infection.

EFFECT: improving compound application efficiency.

15 cl, 4 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to dihydrothienopyrimidinesulphoxides of formula 1, and pharmaceutically acceptable salts thereof , where X denotes SO, R1 denotes H, R2 denotes H or a residue selected from C1-C10alkyl, which is optionally substituted with one or more residues selected from OR2.1, where R2.1 denotes H or C1-C6alkyl, R2.2 and R2.3 independently denote H or C1-C6alkyl, where Het is a 6-member monocyclic, saturated heterocycle containing 1 heteroatom selected from N or O, and where the hetaryl is a 5-11-member mono- or bicyclic, optionally anellated heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, S or O, and where the cycloalkyl can be saturated, or R2 denotes a monocyclic C3-cycloalkyl, which is optionally substituted with a residue selected from a branched or linear C1-C6alkanol, C1-C3alkylene-OR2.1, or R2 denotes phenyl which is optionally substituted with a halogen, or R2 denotes a residue selected from Het and hetaryl, each optionally substituted with one or more residues selected from halogen, OH, oxo group and OR2.1, C1-C6alkyl, and where R3 denotes a bicyclic 9-11-member unsaturated or partially saturated heterocycle which is optionally substituted with one or more residues selected from a group comprising F, O, Br, CF3, CN, OH, methyl, ethyl, propyl, isopropyl, -O-methyl, -O-ethyl, phenyl, NR2.2R2.3, where the phenyl is optionally substituted with F, Cl or Br. The invention also relates to pharmaceutical compositions based on said compounds, having phosphodiesterase 4 (PDE4) inhibiting activity.

EFFECT: obtaining novel compounds and pharmaceutical compositions based thereon, which can be used in medicine to treat respiratory or gastrointestinal complaints or diseases, inflammatory diseases of joints, skin or eyes, diseases of the peripheral or central nervous system or cancers.

20 cl, 1 tbl, 156 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically 4-((2-hydroxyethoxy)methyl)-5-methyl-2-methylmercapto-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one of formula (I) . The invention also relates to a method of producing and using said compound to treat West Nile fever.

EFFECT: obtaining a novel compound with useful biological activity.

3 cl, 2 tbl, 4 ex

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