Purine compounds inhibiting pi3k, and application methods

FIELD: biotechnologies.

SUBSTANCE: invention refers to new purine compounds of formula I and their pharmaceutically acceptable salts that have properties of an inhibitor of lipidic kinases including p110 alpha and other isoforms of PI3K. In formula I , R1 is chosen from H, C1-C12alkyl and -(C1-C12alkene)-(C5-C6 heterocyclyl), where heterocyclyl can contain 1-2 heteroatoms in a cycle, which are chosen from nitrogen, and in which alkyl and heterocyclyl are optionally replaced with one or more groups independently chosen from -NHCOCH3, -NHS(O)2CH3, -OH, -S(O)2N(CH3)2 and -S(O)2CH3; R2 is chosen from C1-C12alkyl, -(C1-C6alkene)-(C5-C6heterocyclyl) or -(C1-C6alkene)-C(=O)-(C5-C6heterocyclyl), in each of which heterocyclyl contains 1-2 heteroatoms chosen from nitrogen and oxygen, -(C1-C6alkene)-(C6aryl), where aryl is chosen from phenyl, and -(C1-C6alkene)-(C5-C6heteroaryl), where heteroaryl contains 1 atom of nitrogen, in which alkyl, heterocyclyl, aryl and heteroaryl are optionally replaced with one or more groups independently chosen from F, Cl, Br, I, CH3, -CF3, -CO2H, -COCH3, -CO2CH3, -CONHCH3, -NHCOCH3, -NH(SO)2CH3, -OH, -OCH3, -S(O)2N(CH3)2 and -S(O)2CH3; and R3 represents monocyclic heteroaryl chosen from derivatives of pyridine and pyrimidine, which are specified in Claim 1 of the invention formula.

EFFECT: applicability of a compound for treatment of proliferative diseases, such as cancer.

7 cl, 2 dwg 1 tbl, 59 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

This nepreodolenny application listed in the register 37 CFR § 1.53(b), claims priority 35 U.S.C. §119(e) of provisional application U.S. serial No. 61/057559 entered in the register on 30 may 2008, which entered entirely by reference.

The technical FIELD TO WHICH the PRESENT INVENTION

In General, the present invention relates to compounds with anticancer activity and, more specifically, to compounds which inhibit the activity of PI3 kinase. The present invention also relates to methods of using compounds forin vitro,in situandin vivodiagnosis or treatment of mammalian cells, or associated pathological conditions.

The prior art of the PRESENT INVENTION

Phosphatidylinositol (in the present invention are reduced to "PI") is one of several phospholipids found in cell membranes. In recent years it has become clear that PI plays an important role in the transmission of intracellular signals. Signal system cells by 3'-phosphorylated phosphoinositides associated with a number of cellular processes, such as malignant degeneration, signalling, growth factors, inflammation and immunity (Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsible for synthesis of these phosphorylated signaling products, f is spatialisation 3-kinase (also known as PI3 kinase, PI3-kinase or PI3K), was initially detected with an activity associated with viral oncogenic proteins and tyrosine kinases receptors of growth factors, which phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'-hydroxyl group inonitoring ring (Panayotou et al (1992) Trends Cell Biol 2:358-60).

Phosphoinositide 3-kinase (PI3K) is a lipid kinase that phosphorylate lipids at the 3-hydroxyl residue inonitoring ring phosphoinositol (Whitman et al (1988) Nature, 332:664). 3'-phosphorylated phospholipids (PIP3), synthesized PI3-kinases act as secondary messengers, adding to the number of kinase domains linking lipids (including homologous pleckstrin (PH) region), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). The binding of Akt to the membrane PIP3 causes movement of Akt to the plasma membrane, resulting in Akt in contact with PDK1, which is responsible for Akt activation. Phosphatase with antitumor activity, PTEN, dephosphorylates PIP3 and, therefore, acts as a negative regulator of Akt activity. PI3-kinase Akt and PDK1 are important in the regulation of many cellular processes, including cell cycle regulation, proliferation, survival, apoptosis and motility and are important components of the molecular mechanisms of diseases such as cancer, diabetes and immune the OE inflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips et al (1998) Cancer 83:41).

PI3 kinase is heterodimer consisting of p85 and p110 subunits (Otsu et al (1991) Cell 65:91-104; Hiles et al (1992) Cell 70:419-29). Found four different class I PI3K indicated PI3K α (alpha), β (beta), δ (Delta) and γ (gamma), each of which consists of various 110 kDa catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e. p110 alpha, p110 p110 beta and Delta, each interact with the same regulatory subunit, p85; whereas p110 gamma interacts with excellent regulatory subunit, p101. The way of expression of each of PI3K in human cells and tissues are also different.

The major isoform PI3-kinase in cancer is PI3-kinase class I p110 α (alpha) (US 5824492; US 5846824; US 6274327). Other isoforms are present in the cardiovascular and immune-inflammatory diseases (Workman P (2004) Biochem Soc Trans 32:393-396; Patel et al (2004) Proceedings of the American Association Cancer Research (Abstract LB-247) 95th Annual Meeting, March 27-31, Orlando, Florida, USA; Ahmadi K and Waterfield MD (2004) Encyclopedia of Biological Chemistry (Lennarz W J, Lane M D eds) Elsevier/Academic Press).

PI3 kinase/Akt/PTEN path represents an attractive target for development of anti-cancer drugs, because it is expected that these agents will inhibit the proliferation, suppressing the repression of apoptosis and overcoming resistance to cytotoxic agents in cancer cells. Together the t about the inhibitors of PI3 kinase (footsteps of Yaguchi et al (2006) Jour, of the Nat. Cancer Inst. 98(8):545-556; US 7173029; US 7037915; US 6608056; US 6608053; US 6838457; US 6770641; US 6653320; US 6403588; US 6703414; WO 97/15658; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 1417976; US 2004/053946; JP 2001247477; JP 08175990; JP 08176070). Certain thienopyrimidine compounds have p110 alpha binding, inhibiting PI3 kinase activity and inhibit the growth of cancer cells (WO 2006/046031; WO 2007/122410; WO 2007/127183; WO 2007/129161; US 2008/0269210; US 2008/0242665). Certain purine compounds have p110 Delta binding, inhibiting PI3 kinase activity (WO 2009/053716).

The ESSENCE of the PRESENT INVENTION

In General, the present invention relates to purine compounds of formula I with anti-cancer activity and, more specifically, the modulating and inhibiting PI3 kinase activity. Certain hyperproliferative disease characterized by a change in the functioning of PI3 kinase, such as mutations or increased expression of proteins. Accordingly, the compounds of the present invention may be suitable for the treatment of hyperproliferative diseases such as cancer. Compounds can inhibit tissue growth in mammals and may be suitable for the treatment of people with cancer.

The present invention also relates to methods of applying the purine compounds of formula I for thein vitro,in situandin vivodiagnosis or treatment of mammalian cells, organisms, or associated pathological conditions.

The compounds of formula I include the

and stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts. Different substituents R1, R2, R3, R4represent, as described in this invention.

Another aspect of the present invention relates to pharmaceutical compositions containing the purine compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more additional therapeutic agents.

Another aspect of the present invention relates to methods of inhibiting the activity of PI3 kinase, including contact PI3 kinase with an effective inhibitory amount of a compound of formula I, or a stereoisomer, geometric isomer, tautomer or a pharmaceutically acceptable salt.

Another aspect of the present invention relates to methods of preventing or treating hyperproliferative diseases or conditions modulated PI3 kinases, including the introduction to a mammal in need of this treatment an effective amount of the compounds of formula I, or its stereoisomer, geometric isomer, tautomer or a pharmaceutically acceptable salt. Examples e is the R hyperproliferative diseases or disorders include, but not limited to, cancer.

Another aspect of the present invention relates to methods of preventing or treating a hyperproliferative disease comprising the administration to a mammal in need of this treatment an effective amount of the compounds of formula I, or its stereoisomer, geometric isomer, tautomer or a pharmaceutically acceptable salt, single or in combination with one or more additional compounds having anti-hyperproliferative properties.

An additional aspect of the present invention is the use of compounds of the present invention for obtaining a medicinal product for the treatment or prevention of a disease or condition modulated PI3 kinase, in a mammal.

Another aspect of the present invention includes kits containing the compound of formula I, or a stereoisomer, geometric isomer, tautomer, MES, metabolite or pharmaceutically acceptable salt, Boxing, and not necessarily the leaflet in the package containing information on the medicinal product, or a label with instructions on how to carry out the treatment.

Another aspect of the present invention includes methods of preparation, methods of isolation and purification methods of the compounds of formula I.

Another aspect of the present invention includes a new temporarily the passed connection suitable for preparing compounds of formula I.

Additional advantages and new features of the present invention will be set forth in part in the description below, and will be clear to experts in the art upon familiarization with the following description or may be learned with practice of the present invention. The advantages of the present invention can be implemented and achieved through technical means, combinations, compositions and methods, partially indicated in the attached claims.

BRIEF DESCRIPTION of DRAWINGS

Fig. 1 shows the General method of obtaining polyfunctionalized purines.

Fig. 2 shows an alternative method of synthesis polyfunctionalized purines.

DETAILED DESCRIPTION of EXEMPLARY embodiments

Now will be described in detail certain embodiments of the present invention, examples of which are accompanied by the structures and formulas. Since the present invention will be described in accordance with the variants of implementation, it is clear that it is not expected that they limit the present invention data options for implementation. Conversely, it is assumed that the present invention includes all alternatives, modificat and and equivalents, which can be included in the scope of the present invention, as defined by the claims. Specialists known many methods and materials similar or equivalent to the methods and materials described in the present invention, which can be applied in the practical implementation of the present invention. The present invention is in no way limited to the methods and materials. If one or more of the entered literary references, patents and similar materials differ or contradict this application, including but not limited to defined terms, the use of terms, described techniques, or the like, the application defines them.

DEFINITION

The term "alkyl", as used in the present invention, refers to a monovalent hydrocarbon radical with saturated linear or branched chain, containing from one to twelve carbon atoms (C1-C12), in which the alkyl radical can optionally replace independently by one or more substituents described below. In another embodiment, the alkyl radical contains from one to eight carbon atoms (C1-C8or from one to six carbon atoms (C1-C6). Examples of alkyl groups include, but are not limited to, IU the sludge (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr,n-propyl, -CH2CH2CH3), 2-propyl (from-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu,n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (from-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (Deut-Bu,Deut-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-Bu,tert-butyl, -C(CH3)3), 1 pencil (npentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl(-CH(CH 3)C(CH3)3, 1-heptyl, 1-octyl and the like.

The term "alkylene", as used in the present invention, refers to devalentino hydrocarbon radical with saturated linear or branched chain, containing from one to twelve carbon atoms (C1-C12), in which alkalinity radical can optionally replace independently by one or more substituents described below. In another embodiment, alkalinity radical contains from one to eight carbon atoms (C1-C8or from one to six carbon atoms (C1-C6). Examples alkilinity groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-) and the like.

The term "alkenyl" refers to a monovalent hydrocarbon radical with a linear or branched chain containing from two to eight carbon atoms (C2-C8with at least one site of unsaturation, i.e. a carbon-carbon sp2a double bond, in which alkanniny radical can optionally replace, and includes radicals having "CIS" and "TRANS" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenic or vinyl (-CH=CH2), allyl (-CH2CH=CH2) and the like.

The term "albaniles" refers to ivalentine hydrocarbon radical with a linear or branched chain, containing from two to eight carbon atoms (C2-C8with at least one site of unsaturation, i.e. a carbon-carbon sp2a double bond, in which alkanniny radical can optionally replace, and includes radicals having "CIS" and "TRANS" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylaniline or vinile (-CH=CH-), allyl (-CH2CH=CH-) and the like.

The term "quinil" refers to a monovalent hydrocarbon radical with a linear or branched chain containing from two to eight carbon atoms (C2-C8with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond, in which alkynylaryl radical can optionally be replaced. Examples include, but are not limited to, ethinyl (-C≡CH), PROPYNYL (propargyl, -CH2C≡CH) and the like.

The term "akinyan" refers to devalentino hydrocarbon radical with a linear or branched chain containing from two to eight carbon atoms (C2-C8with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond, in which alkynylaryl radical optionally substituted. Examples include, but are not limited to, ethynylene (-C≡C-), propylen (propargyl, -CH2C≡C-) and the like.

The terms "carbocycle", "carbocyclic", "carbocyclic who also and cycloalkyl" refers to a monovalent non-aromatic, saturated or partially unsaturated ring containing from 3 to 12 carbon atoms (C3-C12in the form of a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycle containing from 7 to 12 atoms, can be positioned, for example, in the form of bicyclic[4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycle containing 9 or 10 ring atoms can be arranged in the form of bicyclic [5,6] or [6,6] system, or in systems with bridging bond, such as bicyclo[2,2,1]heptane, bicyclo[2,2,2]octane and bicyclo[3,2,2]nonan. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl and the like.

"Aryl" refers to a monovalent aromatic hydrocarbon radical containing 6 to 20 carbon atoms (C6-C20), obtained by removing one hydrogen atom from a single carbon atom of the original aromatic ring system. Some of the aryl groups represented in the sample structures in the form of "Ar". Aryl includes bicyclic radicals containing aromatic ring condensed with a feast upon the authorized, partially unsaturated ring, or aromatic carbocyclic ring. Standard aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl and the like. Aryl group optionally is substituted.

"Allen" refers to devalentino aromatic hydrocarbon radical containing 6 to 20 carbon atoms (C6-C20), obtained by removing two hydrogen atoms and two carbon atoms of the original aromatic ring system. Some allenbyi groups represented in the sample structures in the form of "Ar". Aralen includes bicyclic radicals containing aromatic ring condensed with a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Standard allenbyi groups include, but are not limited to, radicals derived from benzene (phenylene), substituted benzene, naphthalene, anthracene, biphenylene, Ingenier, indaniel, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl and the like. Allenbyi group optionally is substituted.

The terms "heterocycle", "heterocyclyl" and "heterocyclic ring" used in the present invention can be used interchangeably, and they refer to a saturated or partially unsaturated (theatergasse one or more double and/or triple bonds in the ring) the carbocyclic radical, containing from 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulphur and the remaining ring atoms are C, in which one or more ring atoms optionally substituted, for example, oxo (=O), mercapto or amino, etc. of the Heterocycle may be monocyclic containing from 3 to 7 ring members (2 to 6 carbon atoms and 1-4 heteroatoms selected from N, O, P and S), or bicyclic containing 7-10 annular member (4-9 carbon atoms and 1-6 heteroatoms selected from N, O, P and S), for example: bicyclic[4,5], [5,5], [5,6] or [6,6] system. The heterocycles described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclyl" also includes radicals where heterocyclic radicals condense saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydropyranyl, dihydropyran, tetrahydrothiopyran, piperidine (piperidinyl), morpholine (morpholinyl), calm surroundings is folino, dioxane, piperazinil, homopiperazine, azetidine, oxetane, titanyl, homopiperazine, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolopyrimidinones, imidazolidinyl, 3-azabicyclo[3,1,0]hexenyl, 3-azabicyclo[4,1,0]heptenyl, azabicyclo[2,2,2]hexenyl, 3H-indolyl, hemolysins, 1H-benzo[d]imidazol-2(3H)-one-5-yl and N-pyridylamine. Spiro group is also included in the scope of this definition. Examples of the heterocyclic group, substituted by one or more oxo (=O) group, are pyrimidinones and 1,1-dioxothiazolidine.

The term "heteroaryl" refers to a monovalent aromatic radical containing 5-, 6 - or 7 - membered ring, and it includes a condensed ring systems (at least one of which is aromatic, containing from 5 to about 20 ring atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridine), imidazolyl, imidazopyridines, pyrimidinyl (including, for example, 4-hydroxypyrimidine), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, tie the sludge, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, tetrahydroisoquinoline, indolyl, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properidine. Heteroaryl group optionally is substituted.

Heterocyclic or heteroaryl group may be attached via carbon (carbon-linked) or nitrogen (nitrogen-linked, where possible. By example and without limitation, heterocycles or heteroaryl, attached through a carbon, attached in position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5 or 6 pyridazine, in position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5 or 6 pyrazine, in position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, in position 2, 4 or 5 oxazole, imidazole or thiazole, position 3, 4 or 5 isoxazol, pyrazole or isothiazole, in position 2 or 3 of aziridine, in position 2, 3 or 4 azetidine, in position 2, 3, 4, 5, 6, 7 or 8 of a quinoline or position 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

By example and without limitation, heterocycles or heteroa the silts attached via nitrogen, attached in position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, in position 2 of a isoindole, or isoindoline in position 4 of the research and position 9 carbazole or β-carboline.

The term "monocyclic heteroaryl" refers to five - or six-membered, unsubstituted or substituted, monocyclic the heteroaryl radical which contains 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. the Monocyclic heteroaryl can be attached at C-4 and C-6 positions of pyrimidine ring according to formula I at any carbon atom (carbon-linked) R3group of monocyclic heteroaryl. Monocyclic heteroaryl radicals include, but are not limited to: 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 3-triazolyl, 1-triazolyl, 5-tetrazolyl, 1-tetrazolyl and 2-tetrazolyl. MES is cyclic heteroaryl optional override.

"Condensed bicyclic C4-C20heterocyclyl" and "condensed bicyclic C1-C20heteroaryl"containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur, differ only in their aromatic character, and contain two rings condensed among themselves, i.e. have a common link. Condensed bicyclic heterocyclyl and heteroaryl radicals may not substitute or replace and attach the C-4 and C-6 to the provisions of the pyrimidine ring according to formula I at any carbon atom (a carbon-attached) R3group condensed bicyclic C4-C20heterocyclyl or condensed bicyclic C1-C20heteroaryl group. Condensed bicyclic heterocyclyl and heteroaryl radicals include, but are not limited to: 1H-indazole, 1H-indole, indoline-2-it, 1-(indolin-1-yl)Etalon, 1H-benzo[d][1,2,3]triazole, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-benzo[d]imidazole, 1H-benzo[d]imidazol-2(3H) -, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrrolo[2,3-c]pyridine, 3H-imidazo[4,5-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, 7H-purine, 1H-pyrazolo[4,3-d]pyrimidine, 5H-pyrrolo[3,2-d]pyrimidine, 2-amino-1H-purine-6(9Hhe is, quinoline, hinzelin, cinoxacin, isoquinoline, of the quinoline-1(2 H)-he, 3,4-dihydroisoquinoline-1(2H)-he, 3,4-dihydroquinoline-2(1Hhe is, hinzelin-2(1Hhe is, cinoxacin-2(1Hhe is, 1,8-naphthiridine, pyrido[3,4-d]pyrimidine, pyrido[3,2-b]pyrazin, benzo[d][1,3]dioxol and 2,3-dihydrobenzo[b][1,4]dioxin.

The terms "treat" and "treatment" refers to therapeutic treatment and prophylactic or preventative measures, where the objective is to prevent or slow down(weakening) of undesired physiological change or disease, such as the development or spread of cancer. For the purposes of the present invention a positive or desired clinical results include, but are not limited to, relieving symptoms, reducing spread of disease, stabilization (i.e., no worsening) state of disease, halting or slowing the disease, weakening or temporary weakening of the morbid state, and remission (partial or complete)that can or cannot be detected. "Treatment" can also refer to a longer life compared to the life-expectancy if untreated. Subjects in need of treatment include subjects with a condition or disease, and subjects who are prone to have the condition or disease, or subjects who have the condition or illness should be prevented.

The phrase "therapeutically effective the sector number" refers to the amount of the compounds of the present invention, that (i) treats or prevents the particular disease, condition, or disorder, (ii) alleviates, relieves or eliminates one or more symptoms of the particular disease, condition or disorder, or (iii) prevents or slows down the occurrence of one or more symptoms of the particular disease, condition or disorder described in the present invention. In the case of cancer, a therapeutically effective quantity of a drug is able to reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) the penetration of cancer cells into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more symptoms associated with cancer. To some extent, the medicine may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. With regard to cancer therapy efficacy can be measured, for example, estimating the time to disease progression (TTP) and/or determining the speed of response (RR).

The terms "cancer" and "cancerous" refer to or describe the physiological condition in Lampedusa, which is typically characterized by unregulated cell growth. "Tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoplasma. More specifically, examples of data types of cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the abdominal cavity, hepatocellular cancer, colon cancer or stomach, including cancer of the gastrointestinal tract, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, cancer of the colon, rectum, endometrial or uterine carcinoma, carcinoma of the salivary gland, kidney cancer, prostate cancer, cancer of the external female genital organs, thyroid cancer, hepatocarcinoma, carcinoma of anal canal carcinoma of the penis, as well as cancers of the head and neck cancer.

"Chemotherapeutic agent" is a compound suitable for the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, raise the performance communications alkaloids spun tree, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers and kinase inhibitors. Chemotherapeutic agents include compounds used in targeted therapy and standard chemotherapy. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (CIS-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentacapital[4,3,0]non-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbuta-1-enyl)phenoxy]-N,N-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®) and doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD and rapamycin.

More examples of chemotherapeutic agents include: oxiplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), machinemessiah (GLEEVEC®, Novartis), XL-518 (MEK inhibitor, Exelixis, WO 2007/044515), ARRY-886 (MEK inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceiticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinovaya acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH 66336, Schering Plough), sorafenib (NEXA VAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™ (without cremator), compositions containing nanoparticle albumin associated with paclitaxel (American Pharmaceutical Partners, Schaumberg, II), vandetanib (aurothiomalate, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478 effect, AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), infospeed (TELCYTA®, Telik), thiotepa and cyclophosphamide (CYTOXAN®, NEOSAR®); alkyl sulphonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimines and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylaniline; acetogenins (especially bullatacin, bullatacin); camptothecin (including the synthetic analogue topotecan); bryostatin; callistemon; CC-1065 (including its adozelesin, carzelesin and bizelesin analogues); cryptophycins (in particular, cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorpropamide, estramustine, ifosfamide, mechlorethamine, hydrochloride mechlorethamine, melphalan, novemberin, finestein, prednimustine, trop shamed, uramustine; nitrosoanatabine, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine and ranimustine; antibiotics such as enediyne antibiotics (for example, calicheamicin, calicheamicin gamma 1I, calicheamicin omega I1 (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; spiramycin; and neocarzinostatin chromophore and related chromoprotein chromophores enediynes antibiotics, aclacinomycin, actinomycin, autralian, azaserine, bleomycin, actinomycin, carubicin, karminomitsin, casinopolis, chromomycin, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-1-norleucine, morphosyntactical, cyanomethaemoglobin, 2-pyrrolidinecarbonyl and desoxidation, epirubicin, zorubicin, idarubitsin, marsellaise, mitomycin, such as mitomycin C, mycofenolate acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, gelmicin, 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, sitrabi is, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; substances that suppress the activity of the adrenal glands, such as aminoglutetimid, mitotane, trilostane; compensator folic acid, such as prolinnova acid; Eagleton; aldophosphamide; aminolevulinic acid; eniluracil; amsacrine; astroball; bisantrene; edatrexate; defaming; demecolcine; diazinon; alternity; the acetate slipline; epothilone; etoposide; gallium nitrate; hydroxyurea; lentinan; londini; maytansinoid, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitrean; pentostatin; penomet; pirarubicin; losoxantrone; podofillina acid; 2-utilitized; procarbazine; PSK® polysaccharide complexes (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tinoisamoa acid; Trisagion; 2,2',2"-trihlortrietilamin; trichothecenes (especially T-2 toxin, verrucarin a, roridin A and unguided); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; Galitsin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 6-tioguanin; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NVELBINE®); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; deformational (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of "chemotherapeutic agent" are: (i) protivokomarinye agents, which act by regulating or inhibiting the hormone action on tumors such as antiestrogens and selective modulators of the estrogen receptor (SERM), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates the synthesis of estrogen in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutetimid, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RTVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bikalutamid, leuprolide, and goserelin; as well as troxacitabine (1,3-dioxolane nucleoside casinoby equivalent); (iv) inhibitors of protein kinases, such as MEK inhibitors (WO 2007/044515); (v) inhibitors of the lipid kinase; (vi) antisense oligonucleotides, cast the STI oligonucleotides, which inhibit expression of genes in signaling pathways associated with abnormal cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGF inhibitors of gene expression (e.g., ANGIOZYME®) and HER2 inhibitors of expression; (viii) vaccines such as vaccines for gene therapy, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase inhibitors 1, such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and loaded drug antibody gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibody with therapeutic activity as chemotherapeutic agents in combination with PI3K inhibitors the present invention include: alemtuzumab, apolizumab, utilityman, talisuna, bapineuzumab, bevacizumab, belarusemb martensen, cantuzumab mertansine, adeliza, certolizumab pegol, cefoperazone, Titus the MAB, daclizumab, eculizumab, efalizumab, epratuzumab, arizuma, felizola, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab is, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, natalizumab, nimotuzumab, nolasisana, numvisuals, ocrelizumab, omalizumab, palivizumab, pascolizumab, pectusinum, pertuzumab, pertuzumab, pexelizumab, palivizumab, ranibizumab, religiosum, reslizumab, reisevisum, rovelizumab, replisome, subrotunda, siplizumab, lintuzumab, takatsuka tetraxetan, ladiesman, talisman, tefibazumab, tocilizumab, torulosum, trastuzumab, tokotoukan celmoleukin, tulsidasa, omalizumab, uroxatral and visilizumab.

"Metabolite" is a product obtained by metabolism in the body of a particular compound or its salts. Metabolites of compounds can be detected using standard techniques known in the art, and their activity can be determined using tests such as the tests described in the present invention. These products can be formed, for example, oxidation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic degradation and the like, input connections. Accordingly, the present invention includes metabolites of compounds is the second of the present invention, including compounds formed in the process, including the contact connection of the present invention with a mammal for a period of time sufficient to obtain products of metabolism.

The term "leaflet" is used relative to the instructions usually contained in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, introduction, contraindications and/or warnings concerning the use of such therapeutic products.

The term "chiral" refers to molecules which have the property of analogiset mirror image of the molecule, while the term "achiral" refers to molecules, mirror image, which can be superimposed on each other.

The term "stereoisomers" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space.

"Diastereoisomer" refers to a stereoisomer with two or more chiral centers, and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. A mixture of diastereoisomers can be divided analytical techniques with high resolution is receiving, such as electrophoresis and chromatography.

"Enantiomers" refers to two stereoisomers of compounds that are not mirror images that can be superimposed on each other.

Stereochemical definitions and conventions used in the present invention, generally correspond to the S. P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. Assumes that all stereoisomeric forms of the compounds of the present invention, including, but neogranichivatsya, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center (centers). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane polarized light by the compound, with (-) or l indicates that the connection is is levogyrate. Connection with the prefix (+) or d is Pervouralsk. For a given chemical structure of these stereoisomers are identical, except that they are mirror images of each other. A specific stereoisomer may also be called an enantiomer, and a mixture of these isomers is often called an enantiomeric mixture. The mixture of enantiomers of 50:50 is called a racemic mixture or a racemate, which can occur in the absence of stereoselectivity, or stereospecificity chemical reaction or process. The terms "racemic mixture" and "racemate" refers to an equimolar mixture of two enantiomeric molecules that do not possess optical activity.

The term "tautomer or tautomeric form " refers to the structural isomers with different energies, which are vzaimoprevrascheny through the barrier with low energy. For example, proton tautomers (also known as prototroph the tautomers) include vzaimoprevrascheny via migration of a proton, such as keto-enol and Imin-Eminova isomerization. The valence tautomers include interconversion reorganizing some of the bonding electrons.

The phrase "pharmaceutically acceptable salt", as used in the present invention, refers to pharmaceutically acceptable organic or inorganic salts of the compounds of us who Otsego invention. Examples of salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromilow, jodido, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, realnuu, thanatou, Pantothenate, bitartrate, ascorbate, succinate, maleato, getsinto, fumaric, gluconate, glucuronate, charitou, formiate, benzoate, glutamate, methanesulfonate "mesilato", econsultancy, bansilalpet,p-toluensulfonate and pamoate (i.e. 1,1'-Methylenebis(2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salt may contain inclusions of other molecules, such as acetate ion, succinate ion, or other counterion. The counterion may be organic or inorganic particle, which stabilizes the charge of the original connection. In addition, pharmaceutically acceptable salt can have more than one charged atom in the structure. Examples in which several of charged atoms are part of a pharmaceutically acceptable salt, can have multiple counterions. Consequently, the pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

If the connection of the present invention is a base, the desired pharmaceutical is Eski acceptable salt can be obtained in any suitable way, available in the art, for example by treatment of the free base of an inorganic acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesulfonate acid, phosphoric acid and the like, or organic acid, such as acetic acid, triperoxonane acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, paranoidly acid, such as glucuronosyl acid or galacturonic acid,alpha-hydroxycitrate, such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamomea acid, sulfonic acid, such as p-toluensulfonate acid or econsultancy acid or the like.

If the connection of the present invention is an acid, the desired pharmaceutically acceptable salt may be obtained in a suitable way, for example, by treatment of the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkali earth metal hydroxide or the like. The sludge is istrative examples of suitable salts include, but not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts, obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The phrase "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients contained in the composition, and/or mammals, which should be treated.

"MES" refers to the associate or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

The term "protective group" refers to the Deputy, which is usually used to block or protect certain functional groups, while the other functional group of the compounds undergo reactions. For example, "protective group for the amino group" is a Deputy, attached to the amino group that blocks or protects linefunction connection. Suitable protective groups aminopentyl include acetyl, TRIFLUOROACETYL,tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, the "protective group hydroxypoly" refers to the Deputy hydroxy-group that blocks or protects hydroxypoly. Suitable protective groups include acetyl and silyl. "Protective group carboxyphenyl" refers to the Deputy carboxypropyl that blocks or protects carboxypentyl. Standard protective group carboxypentyl include phenylsulfonyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluensulfonyl)ethyl, 2-(p-nitrobenzylidene)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl and the like. As for a General description of the protective groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound of the present invention", "compounds of the present invention" and "compounds of formula I include compounds of formula I and stereoisomers, geometric isomers, tautomers, solvate, metabolites and pharmaceutically acceptable salts and prodrugs.

PURINE COMPOUNDS

The present invention relates to purine compounds and their pharmaceutical compositions, which are potentially suitable for treatment of diseases, conditions is/or disorders, modulating PI3 kinases. More specifically, the present invention relates to compounds of formula I

and stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, in which:

R1selected from H, C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, C6-C20aryl, -(C1-C12alkylen)-(C3-C12carbocycle), -(C1-C12alkylen)-(C2-C20heterocyclyl), -(C1-C12alkylene)-C(=O)-(C2-C20heterocyclyl), -(C1-C12alkylen)-(C6-C20aryl), and -(C1-C12alkylen)-(C1-C20heteroaryl), in which the alkyl, alkenyl, quinil, alkylen, carbocyclic, heterocyclic, aryl and heteroaryl optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3and-S(O)2CH3;

R2selected from C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, -(C1-C12alkylen)-(C3-C12carbocycle), -(C1 -C12alkylen)-(C2-C20heterocyclyl), -(C1-C12alkylene)-C(=O)-(C2-C20heterocyclyl), -(C1-C12alkylen)-(C6-C20aryl), and -(C1-C12alkylen)-(C1-C20heteroaryl), in which the alkyl, alkenyl, quinil, alkylen, carbocyclic, heterocyclic, aryl and heteroaryl optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3and-S(O)2CH3;

R3selected from C6-C20aryl, C2-C20heterocyclyl, attached through a carbon atom, and C1-C20heteroaryl, attached through a carbon atom, each of which is optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CH3, -CN, -CF3, -CH2OH, -CO2H, -CONH2, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -OH, -OCH3, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3and-S(O)2CH3;

R4selected from-NR10R13, -NR12C(=O)R10, -NR10(C1-C12alkyl)NR10R13, -NR10(C1-C12alkylen)OR10, -NR10(C1-C12alkylene)C(=O)NR10R13, -NR10(C1-C12alkylen)-(C3-C12carbocycle), -NR10(C1-C12alkylen)-(C2-C20heterocyclyl), -NR10(C1-C12alkylen)-(C6-C20aryl), and-NR10(C1-C12alkylen)-(C1-C20heteroaryl), in which the alkyl, alkylen, carbocyclic, heterocyclic, aryl and heteroaryl optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3and-S(O)2CH3;

R10, R11and R12independently selected from H, C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, C3-C12carbocycle, C2-C20heterocyclyl, C6-C20aryl and C1-C20heteroaryl, in which alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2-The CONCH 3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, -SCH3,-S(O)CH3,-CH2OCH3, -CH3and-S(O)2CH3;

or R10and R11together with the nitrogen atom to which they are attached, form a C2-C20heterocyclyl ring; and

R13selected from C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, C3-C12carbocycle, C2-C20heterocyclyl, C6-C20aryl and C1-C20heteroaryl, in which alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, -SCH3,-S(O)CH3,-OCH2CH2-N(CH3)2and-S(O)2CH3;

or R10and R13together with the nitrogen atom to which they are attached, form a C2-C20heterocyclyl ring.

Provided that when R1represents -(C1-C12alkylen)-(C2-C20heterocyclyl), R3is not an indole, which is not substituted or is substituted.

Examples of embodiments, R1include H, C1-C12alkyl such as CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3and-CH2CH(CH3)2C1-C12alkyl, substituted by one or more-OH or F, such as-C(CH3)2OH, -CH2CH2OH, -CH2CH2CH2OH and-CH2CH2CO2H and 2-morpholinoethyl.

Examples of embodiments, R1also include optionally substituted phenyl.

Examples of embodiments, R1also include -(C1-C12alkylen)-(C2-C20heterocyclyl), such as-CH2-(piperazine-1-yl), in which the piperazine-1-yl optionally substituted, such as-CH2-(4-(methylsulphonyl)piperazine-1-yl).

Examples of embodiments, R2include C1-C12alkyl such as CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3and-CH2CH(CH3)2C1-C12alkyl, substituted by one or more-OH or F, such as-C(CH3)2OH, -CH2CH2OH, -CH2CH2CH2OH and-CH2CH2CO2H, and 2-morpholinoethyl.

Examples of embodiments, R2also include -(C1-C12alkylen)-(C2-C20heteros CLIL), such as-CH2-(piperazine-1-yl), in which the piperazine-1-yl optionally substituted, such as-CH2-(4-(methylsulphonyl)piperazine-1-yl).

Examples of embodiments include those in which R3optionally substituted C6-C20the aryl. C6-C20aryl groups include phenyl, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene and 1,2,3,4-tetrahydronaphthyl, such as phenyl, substituted by one or more-OH.

Examples of embodiments include those in which R3represents a monocyclic heteroaryl selected from pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, furanyl, teinila, triazolyl and tetrazolyl.

Examples of embodiments include those in which R3represents a monocyclic heteroaryl selected from the structures:

in which the wavy line indicates the place of attachment.

Examples of embodiments include those in which R3represents a monocyclic heteroaryl selected from the structures:

in which the wavy line indicates the place of attachment.

Examples of embodiments include those in which R3isone monocyclic heteroaryl, selected from the structures:

in which the wavy line indicates the place of attachment.

Examples of embodiments include those in which R3represents a C1-C20heteroaryl substituted by one or more groups selected from F, -CF3, -NH2, -NHCH3, -OH, -OCH3, -NHC(O)CH3, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -CO2H, -CH2OH, -C(O)NH2and-CH3.

Examples of embodiments include those in which R3is attached via a carbon atom, condensed bicyclic C4-C20heterocyclyl or C1-C20heteroaryl chosen from:

in which the wavy line indicates the place of attachment.

Examples of embodiments include those in which R3choose from:

in which the wavy line indicates the place of attachment, and R14selected from F, Cl, Br, I, -CH3, -CN, -CF3, -CH2OH, -CO2H, -CONH2, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -OH, -OCH3, -SH, -NHC(=O)NHCH3and-S(O)2CH3.

Examples of embodiments include those in which R3is an attached via atom ug is erode, condensed bicyclic C4-C20heterocyclyl or C1-C20heteroaryl chosen from:

in which the wavy line indicates the place of attachment.

Examples of embodiments include those in which R3represents 1H-indazol-4-yl or 1H-indol-4-yl.

Examples of embodiments include those in which R4represents-NR10R13and in which-NR10R13forms C2-C20heterocyclyl ring, such as morpholinyl, 4-methylpiperazin-1-yl, 4-methylsulfonylmethane-1-yl or 4-(2-pyridyl)piperazine-1-yl.

Examples of embodiments include the structure:

In which R3represents a monocyclic heteroaryl chosen from:

in which the wavy line indicates the place of attachment, and in which R1selected from C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, C6-C20aryl, -(C1-C12alkylen)-(C3-C12carbocycle), -(C1-C12alkylen)-(C2-C20heterocyclyl), -(C1-C12alkylene)-C(=O)-(C2-C20heterocyclyl), -(C1-C12alkylen)-(C6-C20aryl), and -(C1-C12alkylene)-C 1-C20heteroaryl), in which the alkyl, alkenyl, quinil, alkylen, carbocyclic, heterocyclic, aryl and heteroaryl optionally substituted by one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3and-S(O)2CH3.

The compounds of formula I of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is assumed that all stereoisomeric forms of the compounds of the present invention, including, but not limited to, the diastereomers, the enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention.

In addition, the present invention encompasses all geometric isomers and isomers position. For example, if the compound of formula I contains a double bond or a condensed ring, CIS - and transforms, as well as mixtures thereof, are included in the scope of the present invention. And individual isomers, and mixture of isomers provisions are also included in the scope of the present invention.

In the structures shown in anastasimatarion, where the stereochemistry of a particular chiral atom is not shown, is assumed to be all stereoisomers, and they are included as compounds of the present invention. In the case where the stereochemistry shown a solid wedge or a dashed line represents a specific configuration, the stereoisomer shown and defined in this way.

Compounds of the present invention may exist in resolutional, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, and assumes that the present invention includes both solvated and nonsolvated forms.

Compounds of the present invention may also exist in different tautomeric forms, and all the form data is included in the scope of the present invention. The term "tautomer or tautomeric form" refers to the structural isomers of different energies, which are interconvertible through the barrier with low energy. For example, proton tautomers (also known as prototroph the tautomers) include vzaimoprevrascheny via migration of a proton, such as keto-enol and imino-enaminone isomerization. The valence tautomers include vzaimoprevrascheny reorganization of some of the bonding electrons.

The present invention also includes isotopically-labeled compounds of altoadige of the invention, which are identical to the compounds mentioned in the present invention, not counting the fact that one or more atoms replaced by an atom having an atomic weight or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element, as shown, included in the scope of the compounds of the present invention, and their use. Examples of isotopes that can be introduced into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N15N15O,17O,18Oh ,32P,33P,35S18F,36Cl123I and125I. Certain isotopically-labeled compounds of the present invention (e.g., compound labeled with3H and14C) are suitable for analyses on tissue distribution of compound and/or substrate. Tritium (3H) and carbon-14 (14C) isotopes are suitable because of the ease of their production and detection. In addition, the substitution of heavier isotopes such as deuterium (i.e.,2H), may provide some therapeutic benefits due to the greater metabolic stability (e.g., prolonged half-life ofin vivoor decrease the data amount of the required dose) and hence, may be preferred in some circumstances.

Positron-emitting isotopes, such as15O,13N11C and18F, are suitable for studies using positron emission tomography (PET) to study the filling of the receptor substrate. Isotope-labeled compounds of the present invention can generally be obtained by methods analogous to methods described in the schemes and/or in the examples of the present invention below, the isotopic substitution-its reagent isotope-labeled reagent.

RECEIVING PURINE COMPOUNDS of FORMULA I

Purine compounds of formula I can be obtained by synthetic methods, which include a technique similar to that well known in chemical engineering techniques, especially with regard to the description relating to the present invention. The original connection is typically available from commercial sources such as Aldrich Chemicals (Milwaukee, WI), or easily determined using methods well known to experts in the art (for example, to obtain ways, generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including the application (also available in the online database Beilstein).

In certain embodiments of the implement is connected to the I formula I can be obtained easily, using well-known procedures for the production of purines (World et al (2007) Tetrahedron Lett. 48(16):2823-2827; Cerna et al (2006) Organic Letters 8(23):5389-5392; Chang et al (2006) J. Med. Chem. 49(10):2861-2867; Yang et al (2005) J. Comb. Chem. 7:474-482; Liu et al (2005) J. Comb. Chem. 7:627-636; Hocek et al (2004) Synthesis 17:2869-2876; World et al (2003) Tetrahedron Lett. 44:8361-8363; World et al (2002) Tetrahedron Lett. 43:8071-8073; Booth et al (1987) J. Chem. Soc, Perkin Trans. 1: Organic and Bio-Organic Chem. 7: 1521-1526; Booth et al (1981) J. Chem. Soc, Chemical Communications 15:788-789; Yoneda et al (1976) J. Chem. Soc, Perkin Trans. 1: Organic and Bio-Organic Chem. 14: 1547-1550; Taylor et al (1971) J. Org. Chem. 36(21):3211-3217; Lister, J. H.; Fenn, M. D. The Purines, Supplementary 1, John Wiley & Sons, 1996, Volume 54; The Chemisty of Heterocyclic Compounds, Editors Weissberger, A.; Taylor, E. C, Wiley Interscience, 1971, Volume 24; Legraverend, M.; Grierson, D. S. (2006) Bioorg. Med. Chem. 14:3987-4006; Hocek, M. (2003) Eur. J. Org. Chem. 245-254;US 7122665; US 6743919; US 5332744; US 4728644; US 3016378; US 2008/0058297; US 2003/0139427; WO 2008/043031); and other heterocycles, which are described in: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, for example, Volume 3; Liebigs Annalen der Chemie, (9); 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958); Arzneimittel-Forschung, 40(12); 1328-31, (1990), each of which is specifically enter via the link. Transformations carried out in synthetic chemistry, and methods of using the protective groups (protection and release), suitable for the production of purine compounds, and the necessary reagents and intermediates known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John iley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

The compounds of formula I can be obtained separately or in the form of libraries of compounds containing at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of formula I can be obtained by combinatorial approach 'split and mix' or parallel synthesis of many compounds, or applying a chemical reaction in solution or solid phase chemistry, by procedures known to specialists in this field of technology. Thus, according to further aspect of the present invention the present invention relates to a library of compounds containing at least 2 compounds, or their pharmaceutically acceptable salts.

Purine compound can be obtained by using 2,4,8-triglochin as the source connection. Three chargroup you can substitute different substituents. More specifically, the reactive group (i.e., chlorine in position 4) replace morpholino group in order to get morpholinopropan.

With illustrative purposes in Fig. 1 and 2 illustrate the General methods of obtaining the purine compounds of formula I, as well as key intermediates. As for the more detailed descriptions of the individual reaction stages, see General methods and examples. Specialisting the art clear other synthetic methods can be used to produce compounds of the present invention. Although the specific source of compounds and reagents are shown and discussed in Fig. 1 and 2, in the General methods and examples can easily be applied to other source compounds and reagents to obtain a number of derivatives and/or reaction conditions. In addition, many compounds of the examples collected in this way, you can further modify this description, using standard chemical reactions, well known to specialists in this field of technology.

Upon receipt of the compounds of formula I may be necessary to protect reactive functions (e.g., primary or secondary amine) of intermediates. The need for this protection will vary depending on the nature of the reactive functions and conditions ways to get. Suitable protective groups aminopentyl include acetyl, TRIFLUOROACETYL,tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc). The need for this protection is easily determined by experts in the field of technology. As for a General description of the protective groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Fig. 1 shows the General method of obtaining polyfunctionalized PUR is new, beginning with the protection of N-9 nitrogen atom 2,6-dichloro-9H-purine tetrahydropyranyl group (THP). The substitution of the more reactive chlorine group, a morpholine gives 4-(2-chloro-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-6-yl)morpholine. C-8 proton is removed by a strong base and is subjected to reaction with various electrophiles (R1). After the release of the processing of a weak acid N-9 alkylate various electrophiles (R2). Condensation Suzuki C-2 atom of chlorine according to the General procedure A using various boronated palladium reagents and catalysts gives C6-C20aryl attached via carbon atom C2-C20heterocyclyl and attached via carbon atom C1-C20heteroaryl as R3.

Fig. 2 shows an alternative method of obtaining polyfunctionalized purines. 2,6-dichloro-9H-purine protect on N-9 THP and more reactive chlorine substituted morpholine to obtain 4-(2-chloro-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-6-yl)morpholine. Condensation Suzuki using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine and a palladium catalyst gives 5-(6-morpholino-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-2-yl)pyrimidine-2-amine. Protection pyrimidine amino group in the form ofbis-Boc amino, and the removal of the THP group by hydrolysis of a weak acid allows Prov is going alkylation of N-9 different electrophiles (R 2). Processing TFA leads to the removal of the Boc group.

METHODS of SEPARATION

In the methods of producing compounds of the present invention may be preferable to separate the reaction products from each other and/or from the parent compounds. Target products of each stage or series of stages separated and/or purified to the required degree of homogeneity of the techniques common in the art. Usually this division includes multi-phase extraction, crystallization from a solvent or mixture of solvents, distillation, sublimation or chromatography. Chromatography may include any number of ways, including, for example: methods and systems with reversed and normal phase; exclusion chromatography; ionoobmennoe chromatography; liquid chromatography high, medium and low pressure; analytical small-scale chromatography; chromatography with pseudoviruses layer (SMB) and preparative thin-layer or thick-layer chromatography, and methods small-scale thin-layer chromatography, flash chromatography.

Another class of methods division includes the processing of the mixture with a reagent that selectively bind to or otherwise allowing separation of the target product, unreacted starting compound, the reaction by-products or the like. These reagents include adsorbents or absorbents, still is as activated carbon, molecular sieve, ion-exchange environment or similar. Alternatively, the reagents can be an acid in the case of lead compounds, the base case of acidic compounds, binding reagents, such as antibodies, binding proteins, selective chelating agents such as crown ethers, reagents for ion extraction liquid/liquid (LIX) or similar. The selection of the suitable methods of separation depends on the properties of the original and derived compounds, such as melting point and molecular weight by distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of compounds in acidic and basic environments in multi-phase extraction and the like.

Diastereomer mixture can be separated into individual diastereomers because of their physical chemical differences by methods known to experts in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary substance, such as a chiral alcohol or the acid chloride of the acid of Mosera), the distinction of the diastereomers and converting (e.g., hydrolysis) of individual diastereoisomers in the corresponding pure enantiomers. To the ome, some compounds of the present invention can be atropoisomeric (for example, substituted barely) and believe that they are part of the present invention. Enantiomers can also be divided using chiral HPLC column.

Individual stereoisomer, for example enantiomer, containing no second stereoisomer, can be obtained by separation of the racemic mixture using a method such as formation of diastereomers using optically active reagents for separation (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds of the present invention can be divided and highlight any suitable means, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral reagents for obtaining derivatives, separation of the diastereomers and converting into pure stereoisomers; and (3) separation almost not containing or enriched stereoisomers directly in the chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

According to the method (1) diastereomeric salt can be obtained by reaction of enantiomerically pure chiral bases, that is as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetric compounds containing acid functionality, such as carboxylic acid and sulfonic acid. Separation of the diastereomeric salts can be accomplished by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds adding chiral carboxylic or sulfonic acids, such as camphorsulfonic, tartaric acid, mandelic acid or lactic acid, can lead to the formation of diastereomeric salts.

Alternatively, by method (2), the substrate that you want to highlight, is reacted with one enantiomer of the chiral compound to form diastereomer pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be obtained by the reaction of asymmetric compounds with enantiomerically pure chiral reagents for producing derivatives such as derivatives of menthol, followed by separation of the diastereomers and hydrolysis to obtain pure or enriched enantiomers. The method of determining optical purity involves obtaining chiral esters, such as esters of menthol, for example (-) of mental chloroformate in the presence of a base, or ester Moser, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. J. Org. Chem. (1982) 47:415), racemic mixtures, and analysis1H NMR spectrum in the presence of two atropisomers enantiomers or diastereomers. Stable diastereomers atropisomers compounds can be divided to allocate direct and reversed-phase chromatography, following the methods of separation atropisomers of naphthylisoquinoline (WO 96/15111). According to the method (3) racemic mixture of two enantiomers can be separated by chromatography using chiral stationary phases Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by the methods used to distinguish between other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

BIOLOGICAL ANALYSIS

The determination of the activity of PI3 kinase activity of the compounds of formula I can be done near direct and indirect detection methods. Specific examples of compounds described in this invention, it is possible to explore on their PI3K binding activity (Example 52) andin vitroactivity relative to tumor cells (Example 53). Range PI3K binding activities ranged from less than 1 nm (nanomolar) to about 10 μm (mcmanamy). Specific examples of the compounds of the present invention have the IC50the size of PI3K binding activity m is Nisha, than approximately 10 nm. Certain compounds of the present invention have the IC50values activity against tumor cells less than approximately 100 nm.

The cytotoxic or cytostatic activity of the compounds of formula I of examples were measured: location line proliferating tumor cells of a mammal in a medium for cell culture, the addition of the compounds of formula I, the cultivation of cells during the period of time from about 6 hours to about 5 days; and measuring cell viability (Example 53). Testsin vitroon the basis of cells was used to measure viability, i.e. proliferation (IC50), cytotoxicity (EC50) and induction of apoptosis (activated caspase).

Activityin vitrocompounds of formula I of examples was measured by analysis of cell proliferation, CellTiter-Glo®fluorescent analysis of the viability of the cells, commercially available from Promega Corp., Madison, WI (Example 53). This way a homogeneous analysis is based on the recombinant expression of the luciferaseColeoptera(US 5583024; US 5674713; US 5700670)and determine the number of living cells in culture based on the quantitative evaluation of ATP present, an indicator of metabolically active cells (Crouch et al (1993) J. Immunol. Meth. 160:81-88; US 6602677). CellTiter-Glo®the analysis is performed in 96 or 384-well format on the heckling it suitable for automatic screening high throughput (HTS) (Cree et al (1995) Anticancer Drugs 6:398-404). Methods of homogeneous analysis involves adding a single reagent (CellTiter-Glo®the reagent directly to cells grown in provided with a serum environment. Washing of the cells, remove the medium and the large number of stages using pipettes are not required. The system can detect a minimum of 15 cells/well in 384-well format using 10 minutes after adding the reagent and mixing.

Homogeneous format "add-mix-measure" results in the lysis of cells and generation of a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the culture. Analysis of CellTiter-Glo®generates a luminescent signal type luminescence obtained in luciferase reaction, which has a period of palasathenea, usually more than five hours, depending on the cell type and the used environment. The number of viable cells is expressed in relative luminescence units (RLU). The substrate, luciferin fireflies, undergoes oxidative decarboxylation of recombinant luciferase fireflies with concomitant conversion of ATP to AMP and generation of photons. Increased period of palasathenea eliminates the use of dispensers for reagents and provides the flexibility of processing and a large number of tablets in a continuous or periodic mode. This analysis of cell proliferation can be applied in various advance formats, such as 96 - or 384-well format. Data can be registered on luminometer or CCD device for the display of images obtained with the camera. The output luminescence present in relative light units (RLU)measured over time.

Antiproliferative action of the compounds of formula I of examples was measured by CellTiter-Glo®analysis (Example 53) relatively few lines of tumor cells, including PC3, Detroit 562 and MDAMB361.1. Value EC50was determined for the test compounds. The range of activities of cellsin vitrowas from approximately 100 nm to approximately 10 μm.

Certain properties of absorption, distribution, metabolism and excretion were measured for certain compounds of the examples of the analysis, including: Caco-2 permeability (Example 54), clearance by hepatocytes (Example 55), inhibition of cytochrome P450 (Example 56), induction of cytochrome P450 (Example 57), binding to plasma proteins (Example 58) and blocking hERG channels (59).

The compounds of formula I of examples No. 101-156 in the Table, received, okharakterizovali and tested on PI3K activity according to the methods of the present invention, and they have the following structures and corresponding names (ChemDraw Ultra, Version 9.0.1, CambridgeSoft Corp., Cambridge MA).

Table 1
NoStructureName
1012-(9-(2-hydroxyethyl)-2-(1H-indol-4-yl)-6-morpholino-9H-purine-8-yl)propan-2-ol
1022-(2-(2-amino-4-methylpyrimidin-5-yl)-9-(2-hydroxyethyl)-6-morpholino-9H-purine-8-yl)propan-2-ol
1032-(2-(2-aminopyrimidine-5-yl)-9-butyl-6-morpholino-9H-purine-8-yl)propan-2-ol
1042-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9-propyl-9H-purine-8-yl)propan-2-ol

1053-(2-(2-aminopyrimidine-5-yl)-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purine-8-yl)propan-2-ol
1062-(2-(2-aminopyrimidine-5-the l)-9-(2-hydroxyethyl)-6-morpholino-9H-purine-8-yl)propan-2-ol
1071-(4-((2-(aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)piperidine-1-yl)alanon
1081-(3-((2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)pyrrolidin-1-yl)alanon

109(R)-3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(3-hydroxypyrrolidine-1-yl)propane-1-he
110(S)-3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(3-hydroxypyrrolidine-1-yl)propane-1-he
1111-(3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanol)-N-methylpiperidin-4-carboxamid
1123-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(4-methylsulphonyl)piperazine-1-yl)propan-2-he

1133-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-morpholinopropan-1-he
1143-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid
1155-(9-(4-(methylsulphonyl)benzyl)-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine
116methyl 4-((2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)benzoate

1175-(6-morpholino-9-(2-morpholinoethyl)-9H-purine-2-yl)pyrimidine-2-amine
1185-(9-(3-methoxybenzyl)-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine
119methyl 3-((2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-Puri is-9-yl)methyl)benzoate
1203-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propan-1-ol

1212-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)ethanol
1221-(2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetyl)-N-methylpiperidin-4-carboxamid
1232-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(4-(methylsulphonyl)piperazine-1-yl)alanon
1242-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-morpholinoethyl

1252-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetic acid
126 methyl 2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetate
1275-(9-methyl-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine
1285-(9-methyl-6-morpholino-9H-purine-2-yl)pyridine-2-amine
1294-(2-(1H-indazol-4-yl)-9-methyl-9H-purine-6-yl)morpholine

1302-(2-(2-aminopyrimidine-5-yl)-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol
1312-(2-(6-aminopyridine-3-yl)-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol
1322-(2-(1H-indazol-4-yl)-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol
1334-(2-(1H-indazol-4-yl)-9-2-methoxyethyl)-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine
134N-(4-(9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-6-morpholino-9H-purine-2-yl)phenyl)ndimethylacetamide

1355-(9-methyl-8-((4-methylsulphonyl)piperazine-1-yl)methyl)-6-morpholino-9H-purine-2-yl)pyridine-2-amine
1364-(2-(2-methoxypyridine-5-yl)-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine
1374-(9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-2-(pyridin-3-yl)-9H-purine-6-yl)morpholine
1384-(2-(1H-indazol-4-yl)-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine
1394-(2-(2-(3-hydroxyphenyl)-6-morpholino-9H-purine-9-yl)acetyl)piperazine-2-he

1402-(2-(3-hydroxyphenyl)-6-morpholino-9H-purine-9-yl)-N-methylacetamide
1413-(6-morpholino-9-(pyridin-4-ylmethyl)-9H-purine-2-yl)phenol
1423-(9-(4-terbisil)-6-morpholino-9H-purine-2-yl)phenol
1433-(9-benzyl-6-morpholino-9H-purine-2-yl)phenol
1443-(9-(2-hydroxyethyl)-6-morpholino-9H-purine-2-yl)phenol

1453-(9-isobutyl-6-morpholino-9H-purine-2-yl)phenol
1465-(8-((4-(dimethylamino)piperidine-1-yl)methyl)-9-ethyl-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine
147 5-(8-((4-(azetidin-1-yl)piperidine-1-yl)methyl)-9-ethyl-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine
1485-(8-((4-(azetidin-1-yl)piperidine-1-yl)methyl)-9-ethyl-6-morpholino-9H-purine-2-yl)-4-methylpyrimidin-2-amine
1492-(4-((2-(2-amino-4-methylpiperidin-5-yl)-9-ethyl-6-morpholino-9H-purine-8-yl)methyl)piperazine-1-yl)-2-methylpropanamide

1505-(8-((4-(dimethylamino)piperidine-1-yl)methyl)-9-ethyl-6-morpholino-9H-purine-2-yl)-4-methylpyrimidin-2-amine
1515-(8-(1,4'-bipiperidine-1'-ylmethyl)-9-ethyl-6-morpholino-9H-purine-2-yl)-4-methylpyrimidin-2-amine
1525-(8-(1,4'-bipiperidine-1'-ylmethyl)-9-ethyl-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine
153 5-(9-ethyl-6-morpholino-8-((4-morpholinopropan-1-yl)methyl)-9H-purine-2-yl)-4-methylpyrimidin-2-amine
1545-(9-ethyl-6-morpholino-8-((4-morpholinopropan-1-yl)methyl)-9H-purine-2-yl)pyrimidine-2-amine

155N-(1-((2-(2-amino-4-methylpyrimidin-5-yl)-9-ethyl-6-morpholino-9H-purine-8-yl)methyl)piperidine-4-yl)-N-methylmethanesulfonamide
156N-(1-((2-(2-aminopyrimidine-5-yl)-9-ethyl-6-morpholino-9H-purine-8-yl)methyl)piperidine-4-yl)-N-methylmethanesulfonamide

INTRODUCTION COMPOUNDS of FORMULA I

Compounds of the present invention can be entered by any route appropriate to the condition that should be treated. Appropriate ways include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, local (including buccal and sublingual), vaginal, intraperitoneal, intra-lungs and intranasal route of administration. With regard to local immune is suppressive therapy connection, you can enter inside the affected tissues, including spraying or otherwise contact the owner with the inhibitor prior to transplantation. It is clear that the preferred route of administration will vary, for example, depending on the condition of the patient. When the compound is administered orally, it can be obtained in the form of pills, capsules, tablets, etc. with a pharmaceutically acceptable carrier or auxiliary substance. When the compound is administered parenterally, it can be mixed with pharmaceutically acceptable for parenteral administration and receive standard injectable dosage forms, as described below.

The dose used to treat patients, which people may vary in the range from about 10 mg to about 1000 mg of the compounds of formula I. the Standard dose may be from about 100 mg to about 300 mg of the compound. Dose can be administered once a day (QID), twice daily (BID), or more often, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism and excretion of the specific compound. In addition, the toxicity characteristics may influence the dosage and mode of administration. With the introduction of oral pills, capsules or tablets can be taken orally daily or less frequently within agreed with the eye. The mode can be repeated for a number of cycles of therapy.

The treatment of COMPOUNDS of FORMULA I

Compounds of the present invention are suitable for the treatment of hyperproliferative diseases, conditions and/or disorders, including, but not limited to, diseases, conditions and disorders characterized by an increased expression of lipid kinases such as PI3 kinase. Accordingly, another aspect of the present invention includes methods of treating or preventing diseases or conditions that can be treated or prevented by inhibition of lipid kinases, including PI3. In one embodiment, the method includes the introduction of the required treatment to the mammal a therapeutically effective amount of the compounds of formula I, or its stereoisomer, geometric isomer, tautomer or a pharmaceutically acceptable salt. In one embodiment, the patient being a man, treating a compound of formula I and pharmaceutically acceptable carrier, ancillary medicinal substance or Foundation where the above-mentioned compound of the formula I is contained in a quantity sufficient to marked inhibition of PI3 kinase activity.

Types of cancer that are treated according to the methods of the present invention include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer,testicular cancer, cancer of the genitourinary tract, esophagus cancer, cancer of the larynx, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoakantoma, lung cancer, squamous cell carcinoma, both carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, Pappalardo carcinoma, seminoma, melanoma, sarcoma, carcinoma of the bladder, carcinoma of the liver and bile duct carcinoma of the kidney, myeloid disorders, lymphoid disorders, cancer "hairy" cell cancer of the oral cavity and pharynx, cancer of the lips, tongue cancer, cancer of the mouth opening, cancer of the small intestine, cancer of the colon, rectum, colon cancer, cancer of the brain and Central nervous system, Hodgkin's disease and leukemia.

Another aspect of the present invention relates to the compound of the present invention for use in treating diseases or conditions described in the present invention, a mammal, such as man, suffering from a given disease or condition. It also relates to the use of compounds of the present invention to obtain drugs for the treatment of diseases and conditions described in the present invention, in warm-blooded belly is s, such as a mammal, for example a person suffering from the disease.

The PHARMACEUTICAL COMPOSITION

In order to apply the compound of the present invention for therapeutic treatment (including prophylactic treatment) of mammals, including humans, they are usually formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

According to this aspect of the present invention relates to pharmaceutical compositions containing the compound of the present invention together with a pharmaceutically acceptable diluent or carrier.

The standard composition was prepared by mixing the compounds of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to experts in the art and include substances such as carbohydrates, waxes, soluble in water and/or measurable swelling polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. Specific applicable carrier, diluent or excipient will depend on the path and goals, which will be used for the connection of the present invention. Solvents are usually chosen on the basis of the solvents known in the art is the art as safe (GRAS) for administration to a mammal. Usually, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (such as PEG 400, PEG 300), etc. and mixtures thereof. The compositions also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifiers, suspendida substances, preservatives, antioxidants, agents for applying a transparent coating, regulators flowability, auxiliary substances used in the production process, dyes, sweeteners, flavouring agents, food additives and other known additives to give the drug an attractive appearance (i.e. the compound of the present invention or pharmaceutical composition) or facilitate the receipt of pharmaceutical products (i.e. medicines).

The composition can be obtained using standard methods of dilution and mixing. For example, the bulk drug substance (i.e., the compound of the present invention or stabilized form of the compound (e.g., complex with cyclodextrins derivative or other known complexing agents)) rest the accelerate in a suitable solvent in the presence of one or more auxiliary substances, described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the medicinal product and facilitate patient compliance with the prescribed mode.

The pharmaceutical composition (or formulation) for the application can be packaged in various ways, depending on the applied method for the introduction of medicines. Usually the product for sale includes a container containing a pharmaceutical composition in suitable form. Suitable packaging are well known to experts in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The package may contain a sticker to protect against inept handling to prevent unauthorized access to the contents of the package. In addition, the package contains a liner that describes the contents of the package. The liner may also contain suitable precautions.

The pharmaceutical compositions of the compounds of the present invention can be obtained for various routes and types of administration. For example, the compound of formula I having the desired degree of purity may optionally be mixed with pharmaceutically pickup is acceptable diluents, carriers, excipients or stabilizers (Remington''s Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) in the form of lyophilised compositions, the powder obtained by grinding, or aqueous solution. Getting the recipe can be carried out by mixing at room temperature and at a suitable pH, and when the desired degree of purity with physiologically acceptable carriers, i.e. carriers, which are nontoxic to recipients at the used dosing and concentrations. The pH of the composition depends on the specific application and concentration of the compound, but may vary from about 3 to about 8. Composition in acetate buffer at pH 5 is the appropriate option for implementation.

The connection can usually be stored in the form of a solid composition, a freeze-dried composition or aqueous solution.

The pharmaceutical compositions of the present invention will be obtained to measure and enter in some way, i.e. quantity, concentration, mode, rate, environment and routes of administration, consistent with good medical practice. Factors that must be considered in this context include the particular disorder that should be treated, the particular mammal, which need to be treated, the clinical condition of the individual patient, the cause of the disease, place of delivery agent, which is about the introduction, the mode of administration and other factors known to practitioners. "Therapeutically effective amount" of a compound that will enter will be determined by these factors, and it represents the minimum number necessary for the prevention, mitigation or treatment of hyperproliferative diseases.

As a General rule, the initial pharmaceutically effective amount of the inhibitor, administered parenterally per dose will be in the range of about 0.01 to 100 mg/kg, namely about 0.1 to 20 mg/kg body weight of the patient per day, with the standard initial range of the applied compound is from 0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxic to patients when applied dosages and concentrations, and they include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyltrimethylammonium; hexamethylene; benzylaniline, benzathine; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol; low molecular weight (less than about 10 residues of aminotic is from) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; soleobrazutaya counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be incorporated into the microcapsules obtained, for example, methods of accumulation or polymerization on the phase boundary, for example, hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery system tools (for example, liposomes, albumen microspheres, microemulsions, nanoparticles and nanocapsules) or in microemulsion. These techniques describe in Remington''s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

It is possible to obtain compositions with delayed release of the compounds of formula I. Suitable examples of compositions with delayed release include a semi-permeable matrices of solid hydrophobic polymers containing the unity of formula I, where the matrices are in the form of molded articles, e.g. films, or microcapsules. Examples of matrices with a slow release include polyesters, hydrogels (for example, poly(2-hydroxyethylmethacrylate), or poly(vinyl alcohol)), polyactide (US 3773919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable copolymers of lactic acid-glycolic acid, such as the LUPRON DEPOT™ (injectable microspheres composed of copolymer of lactic-glycolic acid and leuprolide) and poly-D-(-)-3-hydroxybutiric acid.

The composition includes compositions suitable for administration ways, discussed in detail in the present invention. It is convenient to obtain compositions in a standard dosage form, and you can get them in any of the ways well known in the pharmaceutical field. Techniques and formulations generally may be found in Remington 's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). These methods include the stage of mixing the active ingredient and carrier, which consists of one or more accessory ingredients. Typically, the composition will receive a uniform and thorough mixing of the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product.

The compositions of the compounds of formula I, the approach is appropriate for oral administration, you can get in the form of a discrete unit forms, such as pills, capsules, sachets or tablets, each contains a predetermined quantity of compounds of formula I. Pressed tablets can be obtained by pressing on a suitable machine the active ingredient in granular form, such as powder or granules, optionally mixed with a binder, lubricant, additive, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be obtained by molding in a suitable machine a mixture of the powdered active ingredient, moistened with an inert liquid diluent. The tablets may optionally be covered or they can cause risks and need not be formulated so as to provide slow or controlled release of the active ingredient. Tablets, molded tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups or elixirs can be obtained for oral administration. The compositions of the compounds of formula I, intended for oral administration, can be obtained according to any method known in the field of pharmaceutical compositions, and these compositions can contain one or more agents is s, including sweeteners, flavourings, colourings and preservatives, in order to give an attractive appearance. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable auxiliary substance, which is suitable for receiving the tablets are acceptable. Data excipients may constitute, for example inert diluents such as calcium carbonate or sodium, lactose, calcium phosphate or sodium; agents for granulating and disintegrating agents such as corn starch or alginic acid, binders, such as starch, gelatin or gum; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may not cover or be covered by known methods, including microencapsulation to slow down the destruction and adsorption in the gastrointestinal tract and thereby provide a delayed action over a longer period of time. For example, you can apply a material that slows the rate of release of the active ingredient, such as glycerol monostearate or distearate glycerol alone or with a wax.

For treatment of the eye or other external tissues, for example, throat and skin, the formulations are preferably applied in the form of ointments for topical use or cream containing the active is the first ingredient(ingredients) in the amount for example, 0,075-20%/century When receiving ointment active ingredients can be applied or paraffin, or mixed with water ointment base. Alternatively, the active ingredients can be formulated in a cream with a cream base oil in the water. If desired, the aqueous phase of the cream base may contain a polyhydric alcohol, i.e. an alcohol containing two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. Preferably, the compositions for topical application contains a compound which enhances absorption or penetration of the active ingredient through the skin or other exposed surfaces. Examples of data agents that enhance penetration through the skin, include dimethyl sulfoxide and related analogues. The oil phase of the emulsions of the present invention may consist of the known ingredients in a known ratio. While the phase may contain only the emulsifier, it is desirable that it contained a mixture of at least one emulsifier with a fat or oil and grease, and oil. It is preferable to add a hydrophilic emulsifier together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferable to add the oil, and grease. Together, the emulsifier(emulsifying agents) with the sludge is without stabilizer(stabilizer) are so-called nonionic emulsified wax, and the wax together with the oil and fat forms a so-called emulsified ointment base which forms the oily dispersed phase of the cream compositions. Emulsifiers and stabilizers of emulsions suitable for use in the compositions of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, ministerului alcohol, glycerol monostearate, and sodium lauryl sulfate.

Aqueous suspensions of the compounds of formula I contain the active substance in a mixture with excipients suitable for receiving water suspensions. Data excipients include suspendresume agents, such as carboxymethylcellulose sodium crosscarmellose, povidone, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum, and dispersing or wetting agents such as natural gums (e.g., lecithin), a condensation product of alkalinized with a fatty acid (for example, polyoxyethylenated), a condensation product of ethylene oxide with an aliphatic alcohol with a long hydrocarbon chain (for example, heptadecafluorooctyl), a condensation product of ethylene oxide with a partial ester derived from fatty acids and lexicological (for example, monooleate polyoxyethylenesorbitan). The aqueous suspension may also contain one Il is more preservatives, such as ethyl orncutp-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

Pharmaceutical compositions of compounds of formula I can be in the form of injectable preparation, such as sterile injectable aqueous or oily suspension. This suspension can be formulated according to known prior art, using suitable dispersing or wetting agents, and suspendresume agents such as those mentioned above. Sterile injectable drugs may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent that is acceptable for parenteral administration, such as a solution in 1,3-butanediol, or you can get them in the form of lyophilized powder. Among the acceptable vehicles and solvents that can be used include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fatty oils can usually be used as a solvent or suspendida environment. For these purposes, you can apply any aseptic fatty oils, including synthetic mono - or diglycerides. You can also use fatty acids such as oleic acid, to obtain injectable preparato is.

The amount of active ingredient that can be mixed with the media to produce a single dosage form will vary depending on the patient treated and the particular route of administration. For example, the composition with the gradual release intended for oral administration to humans may contain from about 1 to 1000 mg of the active substance is mixed with an appropriate and suitable number of media, which can vary from approximately 5 to approximately 95% of the total weight of the composition (weight:weight). The pharmaceutical composition can be obtained in order to ensure ease of measurement quantities for injection. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order to observed the infusion of a suitable volume at a rate of approximately 30 ml/hour.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic and liquid phases, which make the composition isotonic with blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspendresume agents and thickeners.

HDMI is tion, suitable for the local introduction of the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in the composition at a concentration of about 0.5-20% V/V, for example about 0.5-10% V/V, for example about 1.5%/C.

Compositions suitable for local injection in the mouth include lozenges, containing the active ingredient in a flavored basis, usually sucrose and gum or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and gum; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

Compositions for rectal injection can be represented by a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Composition suitable for intra-lungs or nasal administration, have a particle size, for example, in the range of 0.1 to 500 microns (including particle sizes in the range from 0.1 to 500 microns in increments, such as 0.5, 1, 30 microns, 35 microns, etc), which is administered by rapid inhalation through the nasal canal or by inhalation through the mouth so as to reach the alveolar sacs Suitable compositions include aqueous or oily solutions of the active ingredient. Compositions suitable for administration using aerosol or dry powder, can be obtained according to standard methods and can be delivered with various therapeutic agents such as compounds previously used for the treatment or prevention of diseases, as described below.

Compositions suitable for vaginal administration, can be represented by compositions in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient carriers known that they are appropriate in a given field of technology.

The composition can be packaged in a package for one dose or more doses, for example sealed ampoules and vials and may be stored in a lyophilized condition requiring only the addition of sterile aqueous carrier such as water for injection immediately before use. Solutions and suspensions are prepared for immediate injection, derived from sterile powders, granules and tablets of the previously described type. The preferred compositions for single dosing are compositions containing a daily dose or unit daily poddaszu as listed above in the present invention, or a suitable part of the active ingredient.

In addition, the present invention relates to veteran rnym songs containing at least one active ingredient, as defined above, together with suitable for veterinary purposes by the media. Suitable for veterinary purposes carriers are substances suitable for the purposes of introduction of the composition, and they can be solid, liquid or gaseous substances, which, otherwise, are inert or acceptable in the veterinary field and are compatible with the active ingredient. Data veterinary compositions can be entered parenteral, oral or in any other desired way.

COMBINATIONAL THERAPY

The compounds of formula I can be used separately or in combination with other therapeutic agents for the treatment of diseases or disorders described in the present invention, such as a hyperproliferative disease (e.g., cancer). In certain embodiments of the implementation of the connection of the formula I is mixed with a second compound which has protivovospalitelnoe activity or activity that is suitable for the treatment of hyperproliferative diseases (e.g. cancer), to obtain pharmaceutical compositions for combination therapy or dosing regimen as in combination therapy. A second connection pharmaceutical compositions for combination therapy or mode of dzirovani is, in combination therapies, preferably has an activity that is complementary to the activity of the compounds of formula I such that they do not have an adverse effect on each other. Preferably, these compounds were present in combinational therapy in an amount that is effective for the intended purpose. In one embodiment, the composition of the present invention contains a compound of formula I or a stereoisomer, geometric isomer, tautomer, MES, metabolite, or pharmaceutically acceptable salt, or prodrug in combination with a chemotherapeutic agent such as described in the present invention.

Combinational therapy can be performed using the simultaneous or sequential administration. The sequential introduction of the composition for combination therapy, you can enter two or more injections. The combined introduction includes a joint introduction, using different compositions or a single pharmaceutical composition, and the consequent introduction in any order, wherein preferably there is a time period while both (or all) active agents simultaneously exhibit biological activity.

The appropriate dose of any of the above simultaneously introduced agents are dose used in the present, and they could the t to be reduced, due to the combined action (synergy) of the new discovered agent and other chemotherapeutic agents or drugs.

Combinational therapy can provide "synergy" and to be "synergistic", i.e. the effect achieved with the use of active ingredients is greater than the sum of the effects that are the result of separate use of the compounds. A synergistic effect can be achieved when the active ingredients are: (1) mixed in the same composition and administered or delivered simultaneously in a mixed, single dosage of the composition; (2) delivered by alternation or in parallel as separate compositions; or (3) some of the other modes. Upon delivery by treatment with alternating introduction of a synergistic effect can be achieved when the compound is administered or delivered sequentially, for example, by different injections in separate syringes at separate pills or capsules, or separate injections. Usually, during therapy with alternating introduction of an effective dose of each active ingredient is administered sequentially, i.e. periodically, while in combination therapy, effective dosages of two or more active ingredients are administered together.

In a specific embodiment, the anti-cancer therapy, the compound of formula I or e is about stereoisomer, geometric isomer, tautomer, MES, metabolite or pharmaceutically acceptable salt or prodrug can be mixed with other chemotherapeutic, hormonal agents or agents based on antibodies, such as agents described in this invention, as well as combined with surgical therapy and radiotherapy. Thus, combination therapy according to the present invention includes the introduction of at least one compound of formula I or its stereoisomer, geometric isomer, tautomer, MES, metabolite or pharmaceutically acceptable salt, or prodrug, and the use of at least one other way of treating cancer. The number of compounds(compounds) of formula I and the other pharmaceutically active chemotherapeutic agent(agents) and the modes of their administration will be selected in order to achieve the desired effect of combination therapy.

METABOLITES of COMPOUNDS of FORMULA I

Also included in the scope of the present invention the products of metabolismin vivoformula I, described in the present invention. These products can be formed, for example, oxidation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic cleavage, and such input connection. Accordingly, this is completed with the invention includes metabolites of compounds of formula I, including compounds obtained by the process comprising the contact connection of the present invention with a mammal for a period of time sufficient to obtain products of its metabolism.

Metabolic products generally identify obtaining radiochango (for example,14C or3H) isotope compounds of the present invention, the introduction of parenteral dose, which can be detected (for example, greater than about 0.5 mg/kg) to an animal such as rat, mouse, Guinea pig, monkey, or to man, allowing for sufficient time for the flow of metabolism (typically from about 30 seconds to 30 hours) and recovery of the products of its transformation from urine, blood or other biological samples. These products are easy to distinguish because they are labeled (others allocate the use of antibodies which are able to bind to epitopes on the surface of metabolites). Patterns of metabolites determined by standard methods, such as MS, LC/MS or NMR analysis. Typically, the analysis of metabolites carried out in the same way as the standard studies of the metabolism of drugs, well-known specialists in this field of technology. The products of metabolism, because they cannot be detected otherwisein vivoare useful in diagnostic assays for therapeutic dzirovani the compounds of the present invention.

The FINISHED PRODUCT

In another embodiment, the present invention provides a ready-made or "set"containing substances suitable for the treatment of diseases and disorders described above. In one embodiment, the kit includes a container containing a compound of formula I or a stereoisomer, geometric isomer, tautomer, MES, metabolite or pharmaceutically acceptable salt or prodrug. The kit can further comprise a label or leaflet-leaflet inside the packaging. The term "leaflet-liner" is used relative to the instructions usually included in selling packages of therapeutic products, that contain information about the indications, usage, dosage, introduction, contraindications and/or warnings concerning the use of such therapeutic products. Suitable packaging include, for example, vials, test tubes, syringes, blister packing, etc. Packing can be obtained from various materials, such as glass or plastic. The package may contain the compound of formula I or a composition that is effective for treating the condition and may contain a sterile hole (for example, packaging can be a tank with a solution for intravenous or vial having a stopper, impervious to needles for p is decornoy injection). At least one active agent in the composition is a compound of formula I. the Label or leaflet-liner show that the composition is used for treating the selected condition, such as cancer. In addition, the label or leaflet-liner can show that the patient to be treated is a patient having a disease, such as a hyperproliferative disease, neurodegenerative disease, cardiac hypertrophy, pain, migraine or neurotraumatic disease or complication. In one embodiment, the label or leaflet show that the composition containing the compound of the formula I, can be used to treat diseases resulting from abnormal cell growth. The label or leaflet-liner can also show that the composition can be used to treat other diseases. Alternatively, or additionally, the finished product may further comprise a second package containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), saline phosphate buffer, ringer's solution and dextrose. It can also optionally contain other materials desirable from a commercial point of view and from the point of Isernia consumers, including other buffers, diluents, filters, needles, and W is the matrix.

The kit can further comprise instructions for administering the compounds of formula I and, if present, the second pharmaceutical composition. For example, if the set contains a first composition comprising a compound of formula I, and the second pharmaceutical composition, the kit may further comprise directions for the simultaneous, sequential or separate introduction of the first and second pharmaceutical compositions to the needy in the treatment of the patient.

In another embodiment, the kits are suitable for the delivery of solid oral forms of the compounds of formula I, such as tablets or capsules. This kit preferably contains a number of individual doses. Data sets may contain blister containing a dose, oriented in the order of their intended application. An example of such a set is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging of pharmaceutical unit dosage forms. Optionally, you can provide a memo, for example, in the form of numbers, letters, or other marks or liner-calendar indicating the days in the course of treatment, which is administered dose.

According to one variant of implementation, the set may contain (a) a first package contains a compound of formula I; and optionally b) a second package contained a second pharmaceutical composition, in which second pharmaceutical composition comprises a second connection with protivovospalitelnoe activity. Alternatively, or additionally, the kit may further comprise a third pack containing pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), saline phosphate buffer, ringer's solution and dextrose. It may additionally contain other materials desirable from a commercial point of view and from the point of view of the consumer, including other buffers, diluents, filters, needles and syringes.

In certain other embodiments, the implementation in which the set contains a composition of formula I and a second therapeutic agent, the kit may include a container for the separate compositions such as a divided bottle or package with divisions, made of foil, however, the separate compositions may also be contained in a single, undivided packaging. Typically, the kit contains instructions for the introduction of individual components. The set is especially preferred when the individual components preferably in different dosage forms (e.g., oral and parenteral), when they are introduced at different dosing intervals, or when titration of the individual components of the combination requires the treating physician.

BSIE the METHOD

General methods A.The reaction mix Suzuki

The reaction mix type Suzuki is suitable for connection of monocyclic heteroaryl, condensed bicyclic heterocycle, condensed bicyclic heteroaryl or phenyl in the second position of the pyrimidine ring 2-chloropurine21. For example,21can be mixed with 1.5 equivalents of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole24and dissolved in 3 equivalents of sodium carbonate in the form of a 1 molar solution in water and an equal volume of acetonitrile. Add a catalytic amount or more reagent containing low valent palladium, such as dichloride bis(triphenylphosphine)palladium (II). Instead of the specified indazol ether Bronevoy acid can be applied a number of Baranovich acids or Baranovich esters. Also alternatively, it is possible to protect the nitrogen atom of indazole, for example, N-THP-protected compound41. In some cases, you can use potassium acetate instead of sodium carbonate for pH control of the water layer. Then, the reaction mixture is heated to about 140-150°C under pressure in a microwave reactor, such as a Biotage Optimizer (Biotage, Inc.) within 10-30 minutes. The contents extracted with ethyl acetate or other organic solvent. After evaporation of the organic layer is the reaction products of the combination Suzuki, 6,8,9-substituted 2-(1H-indazol-4-yl)purine22or 6,8,9-substituted 2-(5-pyrimidine-2-amine)purine23you can purify on silica gel or reverse-phase HPLC. The substituents R1', R2', R4'can represent R1, R2, R4as defined, or a protected form or precursor.

A number of palladium catalysts can be used in reaction stage combination Suzuki to produce compounds, including examples of embodiments of the22and23. The reaction mix Suzuki is the reaction cross-combination, catalyzed by palladium, arylhalides, such as21with Bronevoy acid, such as24or25. Low valent, Pd(II) and Pd(O)catalysts can be used in the reaction combinations Suzuki, including PdC12(PPh3)2Pd(tert-Bu)3, PdCl2dppf-CH2Cl2Pd(PPh3)4Pd(OAc)/PPh3, Cl2Pd[(Pet3)]2, Pd(DIPHOS)2, Cl2Pd(Bipy), [PdCl(Ph2PCH2PPh2)]2, Cl2Pd[P(o-tol)3]2Pd2(dba)3/P(o-tol)3Pd2(dba)/P(furyl)3, Cl2Pd[P(furyl)3]2, Cl2Pd(PMePh2)2, Cl2Pd[P(4-F - Ph)3]2, Cl2Pd[P(C6F6)3]2, Cl2Pd[P(2-COOH-Ph)(Ph)2]2, Cl2Pd[P(4-COOH-Ph)(Ph)2]2and encapsulated Pd EnCat™ 30, Pd EnCat™ TPP30 and Pd(II)EnCat™ BINAP30 (US 2004/0254066).

A General method B.Replacement C-6 nitrogen

To 2,6-dichloropurine intermediate connection27in a solvent such as ethanol, add primary or secondary amine (R10R13NH, 1.1 EQ.) and dinucleophiles base, such as triethylamine (NEt3, 1.5 EQ., 63 μl). Alternatively, it is possible to use as solvent of acetonitrile and potassium carbonate can be added as a base. The reaction mixture was stirred at room temperature for approximately 1 hour or overnight, the volatile components removed in vacuo, and the residue partitioned between DCM and brine. If the mixture is insoluble, it can be treated with ultrasound, and the solid product collected by filtration. Drying over magnesium sulfate and evaporation of the solvent yields N-(2-globulin-6-yl)amine-substituted intermediate compound28often in the form of crystalline substances, or grinding. The substituents R1'and R2'can represent R1and R2as defined, or a protected form or precursor.

A General method C.Alkylation of N-9 nitrogen

9-H-Purine intermediate connection29dissolved in DMF and added dropwise to the reaction mixture 2 equivalent carbó the ATA cesium. The reaction is heated to 50°C, then added to the reaction mixture of 3 equivalents of alkylhalides R2'-X. the Reaction control TLC or LC/MS and mix until it is completed, usually a few hours. The reaction mixture was extracted with EtOAc and water and the organic layer is dried, filtered and concentrated, obtaining the crude 9-alkilirovanny purine30, which is used directly in the next step or purified by reversed-phase HPLC. The substituents R1', R3'and R4'can represent R1, R3and R4as defined, or a protected form or precursor.

A General method D.The removal of the THP

Usually, N-9-tetrahydropyranyl-substituted compound31you can process a catalytic amount ofpair-toluensulfonate acid (PTSA) in a solution of methanol and heated to approximately 50°C to remove tetrahydropyranyl (THP) group to obtain a compound32. The reaction can be controlled LC-MS or TLC. The substituents R1'and R3'can represent R1and R3as defined, or a protected form or precursor.

A General method E.Removal of Boc

Usually, Boc-substituted compound33treated with TFA or 4N HCl to remove thetert-butoxycarbonyl GRU is p (groups) and reaction control LC-MS until it is completed. Then, the crude product is concentrated and purified by reversed-phase HPLC to obtain the product 34 in the form of a pure solid residue. The substituents R1'and R2'can represent R1and R2as defined, or a protected form or precursor.

A General method F.The combination with the formation of amide

2,6,8-substituted 9-alkylcarboxylic35in which n is 1-12, treated with 1.5 EQ. HATU (2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate, an excess (such as 3 EQ.) the alkylamine (HNR10R11) and an excess (such as 3 EQ.) of cesium carbonate in dimethylformamide (DMF). Alternatively, you can use other condensing agents. The reaction is stirred until complete and extracted into ethyl acetate saturated solution of bicarbonate. The organic layer is dried, filtered and concentrated to obtain acylated, the crude intermediate compound, which is purified by reversed-phase HPLC to obtain the product36. The substituents R1'and R3'can represent R1and R3as defined, or a protected form or precursor.

EXAMPLES

The chemical reactions described in the examples can easily be adapted for some other PI3K in which autorow of the present invention, and it is implied that alternative methods of producing compounds of the present invention is included in the scope of the present invention. For example, the synthesis of missing examples of compounds according to the present invention can be successfully performed using modifications, obvious to experts in the art, for example, the appropriate protection of reactive functional groups, the use of other suitable reagents known in the art other than those described, and/or by a standard change of conditions of the reactions. Alternatively, other reactions described in the present invention, or known in the art, will be considered as having applicability for other compounds of the present invention.

In the examples described below, unless otherwise indicated, all temperatures are given in degrees Celsius. Reagents were obtained from commercial sources such as Sigma Aldrich Chemical Company, Lancaster, TCI or Maybridge, and they were used without further purification, unless otherwise noted. The reaction below is usually carried out at a gauge pressure of nitrogen or argon or with a drying tube (unless otherwise noted) in anhydrous solvents, and the reaction flask was usually supplied by a rubber membrane for the introduction of substrates and reagents via syringe. Glassware is left the house taking in the furnace and/or dried by heating. Column chromatography was performed on a Biotage system (manufacturer: Dyax Corporation)containing a column of silica gel or on a SEP-PAK® cartridge with silica gel (Waters).1H-NMR spectra were recorded at 400 MHz in deuterated solutions CDCl3d6-DMSO, CH3OD or d6-acetone (ppm), using chloroform as internal standard (is 7.25 ppm). With regard to the multiplicity of peaks, use the following abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet), ush (broadened), DD (doublet of doublets), dt (doublet of triplets). Constants of spin-spin interaction, when they are presented in Hertz (Hz).

EXAMPLE 1.2,6-dichloro-9-methyl-9H-purine4

EXAMPLE 2.4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indazol24- method 1

To a solution of 3-bromo-2-methylaniline (5.0 g, 26.9 mmol) in chloroform (50 ml) was added potassium acetate (of 1.05 EQ., of 28.2 mmol, 2,77 g). Was added while cooling in a mixture of water-ice acetic anhydride (2.0 EQ., of 53.7 mmol, 5,07 ml). The mixture is then stirred at room temperature for 10 minutes, after which a white gel-like residue. Added 18-crown-6 (0.2 EQ., 5.37 mmol, 1.42 g) followed by the addition of isoamylase (2.2 EQ., the 59.1 mmol, 7,94 ml) and the mixture is boiled under reflux in ECENA 18 hours. The reaction mixture was cooled and distributed between chloroform (3×100 ml) and saturated aqueous sodium bicarbonate (100 ml). The combined organic extracts washed with brine (100 ml), separated and dried (MgSO4).

The crude product was evaporated onto silica gel and purified by chromatography, elwira 20%-40% EtOAc-petroleum ether to obtain 1-(4-brominator-1-yl)alanonA(3,14 g, 49%) as an orange solid residue, and 4-bromo-1H-indazolB(2,13 g, 40%) as a pale orange solid residue.A:1H NMR (400 MHz, CDCl3) 2,80 (3H, s), 7,41 (1H, t, J=7,8gts), to 7.50 (1H, d, J=7,8gts), of 8.15 (1H, s), 8,40 (1H, d, J=7,8gts).B:1H NMR (400 MHz, CDCl3) to 7.25 (1H, t, J=7,3 Hz), 7,33 (1H, d, J=7,3 Hz), 7,46 (1H, d, J=7,3 Hz), 8,11 (1H, s), and 10.20 (1H, USS).

To a solution of 1-(4-brominator-1-yl)ethanoneA(3,09 g, 12.9 mmol) in MeOH (50 ml) was added 6N aqueous HCl (30 ml)and the mixture was stirred at room temperature for 7 hours. MeOH was evaporated, and the mixture was distributed between EtOAc (2×50 ml) and water (50 ml). The combined organic layers were washed brine (50 ml), separated and dried (MgSO4). The solvent was removed by evaporation under reduced pressure to obtain 4-bromo-1H-indazolB(2,36 g, 93%).

To a solution of 4-bromo-1H-indazoleB(500 mg, 2.54 mmol) and bis(pinacolato)Debora (1.5 EQ., 3,81 mmol) in DMSO (20 ml) was added potassium acetate (3.0 EQ., to 7.61 mmol, 747 mg; dried in a drying PI is tolete) and PdCl 2(dppf)2(3 mol%, 0,076 mmol, 62 mg). The mixture was degirolami purge with argon and was heated at 800C for 40 hours. The reaction mixture was cooled and distributed between water (50 ml) and ether (3×50 ml). The combined organic layers were washed brine (50 ml), separated and dried (MgSO4). The crude substance was purified by chromatography, elwira 30%-40% EtOAc-petroleum ether to obtain an inseparable 3:1 mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indazole24(369 mg, 60%) and indazole (60 mg, 20%), isolated as a yellow resin, which solidifies upon standing, giving off-white solid residue.1H ΝMR (400 MHz, d6-DMSO) of 1.41 (12H, s), 7,40 (1H, DD, J=8,4Hz, 6,GC), to 7.59 (1H, d, J=8,4 Hz), to 7.67 (1H, d, J=6,GC), 10,00 (1H, OSS), to 8.45 (1H, s), and indazol: 7,40 (1H, t), 7,18 (1H, t, J=7,Hz), to 7.50 (1H, d, J=9,1 Hz), to 7.77 (1H, d, J=7,Hz), of 8.09 (1H, s); admixture at 1.25.

EXAMPLE 3.4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indazol24- method 2

To a solution of 2-methyl-3-nitroaniline (2,27 g, 14,91 mmol) in acetic acid (60 ml) was added a solution of sodium nitrite (1.13 g, 1.1 EQ.) in water (5 ml). After 2 hours of dark-red solution is poured into ice/water and the resulting precipitate was collected by filtration to obtain 4-nitro-1H-indazolC(1.98 g, 81%).

A mixture of 4-nitro-1H-indazoleC(760 mg, and 4.68 mmol), palladium on coal (10%, cat.) and ethanol (30 ml) was stirred ATM is the field of hydrogen for 4 hours. Then, the reaction mixture was filtered through celite, and the solvent was removed in vacuum to obtain 1H-indazol-4-ylamineD(631 mg, 100%).

An aqueous solution of sodium nitrite (337 mg, 4,89 mmol) in water (2 ml) was added dropwise to a suspension of 1H-indazol-4-ylamineD(631 mg, 4,74 mmol) in 6M chloroethanol acid (7.2 ml) at a temperature below 0°C. After stirring for 30 minutes was added to the reaction mixture tetrafluoroborate sodium (724 mg). Received a viscous solution, which was filtered and washed quickly with water to obtain tetrafluoroborate salt 1H-indazol-4-pageE(218 mg, 20%) as a dark red solid residue.

Dry methanol (4 ml) was purged with argon for 5 minutes. To it was added tetrafluoroborate salt 1H-indazol-4-page (218 mg, of 0.94 mmol), bis(pinacolato)LIBOR (239 mg, 1.0 EQ.) and chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (20 mg).

The reaction mixture was stirred for 5 hours and then filtered through celite. The residue was purified using flash chromatography to obtain 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indazol24(117 mg).

EXAMPLE 4.1-(Tetrahydro-2H-Piran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol41(method A)

Stage A: Obtain 4-chloro-1H-indazole: In a 250 ml flask with a magnetic mesh is the left main coronary artery was added 2-methyl-3-Chloroaniline (8,4 ml, 9.95 g, 70,6 mmol), potassium acetate (8,3 g, 84,7 mmol) and chloroform (120 ml). This mixture was cooled to 0°C under stirring. To the cooled mixture was added dropwise over 2 minutes, acetic anhydride (20,0 ml, 212 mmol). The reaction mixture was heated to 25°C and was stirred for 1 hour. At this stage, the reaction mixture was heated to 60°C. was Added soliditet (18,9 ml, 141 mmol)and the reaction mixture was stirred over night at 60°C. After completion, was added water (75 ml) and TΗF (150 ml)and the reaction mixture was cooled to 0°C. was Added LiOH (20.7 g, 494 mmol)and the reaction mixture was stirred at 0°C for 3 hours. Was added water (200 ml), and the product was extracted with EtOAc (300 ml, 100 ml). The organic layers were combined, dried over MgSO4and concentrated in vacuum to obtain 4-chloro-1H-indazol 11,07 g (100%) as an orange solid residue.1H NMR (400 MHz, CDCl3) δ 8,18 (d, J=1Hz, 1H), 7,33 (d, J=8gts, 1H), 7,31 (t, J=Hz, 1H), 7,17 (DD, J=Hz, 1 Hz, 1H). LCMS (ESI position.) m/e 153 (M+1).

Stage B: Obtain 4-chloro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole: In a 1 l flask with a mechanical stirrer was added 4-chloro - 1H-indazol (75,0 g, 0,492 mol),p-toluensulfonate pyridinium (1.24 g, to 4.92 mmol), CH2Cl2(500 ml) and 3,4-dihydro-2H-Piran (98,6 ml of 1.08 mol). Under stirring the mixture was heated at 45°C for 16 hours. Analysis of the reaction mixture showed the formation of both isome is offering the product. Cooled the reaction mixture to 25°C and was added CH2Cl2(200 ml). Washed with a solution of water (300 ml) and saturated NaHCO3(250 ml). Dried the organic layer over MgSO4and concentrated to dryness. Purified crude product by dissolving in a mixture of EtOAc/hexane (4:6, 1 l) and the addition of SiO2(1.2 l). The mixture was filtered, and the filter residue was washed with a mixture of EtOAc/hexane (4:6, 2 l). The organic layers were concentrated in vacuo to obtain 4-chloro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol 110,2 g (95%) as an orange solid residue. Isomer 1:1H NMR (400 MHz, CDCl3) δ 8,10 (d, J=1 Hz, 1H), 7,50 (DD, J=Hz, 1 Hz, 1H), 7,29 (DD, J=9 Hz, 8 Hz, 1H), 7,15 (DD, J=8 Hz, 1 Hz, 1H) 5,71 (DD, J=9 Hz, 3 Hz, 1H) was 4.02 (m, 1H) 3,55 (m, 1H) of 2.51 (m, 1H) 2,02 (m, 2H) of 1.55 (m, 3H). LCMS (ESI position.) m/e 237 (M+1); Isomer 2:1H NMR (400 MHz, CDCl3) δ of 8.25 (d, J=1 Hz, 1H), 7.62mm (DD, J=9 Hz, 1 Hz, 1H), 7,20 (DD, J=9 Hz, 8 Hz, 1H), 7,06 (DD, J=8 Hz, 1 Hz, 1H) 5,69 (DD, J=9 Hz, 3 Hz, 1H) to 4.15 (m, 1H) 3,80 (m, 1H) 2,22 (m, 2H) 2,05 (m, 1H) of 1.75 (m, 3H). LCMS (ESI position.) m/e 237 (M+1).

Stage C: Obtain 1-(tetrahydro-2H-Piran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole41: In a 500 ml flask with a magnetic stir bar was added 4-chloro-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol (10.0 g, 42.2 per mmol), DMSO (176 ml), PdCl2(PPh3)2(6.2 g, 8,86 mmol), tricyclohexylphosphine (0,47 g, was 1.69 mmol), bis(pinacolato)LIBOR (16,1 g, and 63.4 mmol) and potassium acetate (12.4 g, to 0.127 mol). When paramasivan and the mixture was heated at 130°C for 16 hours. The reaction mixture was cooled to 25°C, was added EtOAc (600 ml) and washed with water (2×250 ml). The organic layer was dried over MgSO4and concentrated in vacuum to dryness. The crude product was purified by passing through a layer of SiO2(120 g), elwira 10% EtOAc/hexane (1 l) and 30% EtOAc/hexane (1 liter). The filtrate was concentrated in vacuum to obtain a 13.9 g (100%) of the product41a 20% (weight/weight) solution in ethyl acetate.1H NMR showed the presence of approximately 20% (weight/weight) of bis(pinacolato)Debora.1H NMR (400 MHz, CDCl3) δ of 8.37 (s, 1H), 7.62mm (DD, J=14 Hz, 2 Hz, 1H), 7,60 (DD, J=7 Hz, 1 Hz, 1H), 7,31 (DD, J=8 Hz, 7 Hz, 1H) 5,65 (DD, J=9 Hz, 3 Hz, 1H) of 4.05 (m, 1H) 3,75 (m, 1H) 2,59 (m, 1H) 2,15 (m, 1H) 2,05 (m, 1H) 1,75 (m, 3H) of 1.34 (s, 12H). LCMS (ESI position.) m/e 245 (M+1).

EXAMPLE 5.1-(Tetrahydro-2H-Piran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol41(method B)

Stage A: Obtain 4-nitro-1H-indazole: a Mixture of 2-methyl-3-nitroaniline (200 g, 1,315 mol), acetic acid (8000 ml) was cooled to 15-20°C, was slowly added over 30 minutes a solution of sodium nitrite (90,6 g 1,315 mol) in water (200 ml). After the addition the temperature of the reaction mixture was raised to 25-30°C, and the reaction mixture was stirred at this temperature for 2-3 hours. The reaction was controlled by TLC, and after completion of the reaction the product was filtered, and the residue was washed with acetic acid (1000 ml), Acetic acid kept in vacuum (550 mm Hg) at a temperature below 80°C, was added water (8000 ml), cooled to 25-30°C and was stirred for 30 minutes. The suspension was filtered and washed with water (1000 ml). The crude product was dried by heating to 70-80°C for 2 hours, then was dissolved in a mixture of 5% ethyl acetate/n-hexane (100:2000 ml) and was stirred for 1-1 .5 hours at ambient temperature. The suspension was filtered and washed with a mixture of 5% ethyl acetate/n-hexane (25:475 ml). The obtained product was dried in vacuum at a temperature below 80°C for 10-12 hours to obtain 4-nitro-1H-indazol in the form of a brown solid residue (150 g, 70%); TPL: 200-203°C;1H NMR (200 MHz, CDCl3) δ 13,4 (ush, 1H), and 8.6 (s, 1H), 8,2-of 7.95 (DD, 2H), and 7.4 (m, 1H). ESMS m/z 164 (M+1). Purity: 95% (HPLC).

Stage B: Obtain 4-amino-1H-indazole: a Mixture of 4-nitro-1H- indazole (200 g, 1,22 mol) and 10% palladium on coal (20,0 g) in EtOH (3000 ml) was first made at ambient temperature (the reaction was exothermic and the temperature increased to 50°C). After completion of the reaction the catalyst was removed by filtration. The solvent was evaporated in vacuum at a temperature below 80°C, cooled to room temperature, was added to the residuen-hexane (1000 ml) and was stirred for 30 minutes. Precipitated solid residue was filtered and washedn-hexane (200 ml). The product was dried at 70-80°C for 10-12 hours to obtain 4-amino-1H-indazol in the IDA brown solid residue (114 g, 70%), TPL: 136-143°C.1H NMR (200 MHz, CDCl3) δ 12 (ush, 1H), and 8.0 (s, 1H), 7,1-a 7.0 (DD, 2H), and 6.5 (d, 1H), 3,9 (m, 2H). ESMS m/z 134 (M+1). Purity: 90-95% (HPLC).

Stage C: Obtain 4-iodine-1H-indazole: a Mixture of 4-amino-1H-indazole (50.0 g, the 0.375 mol) in water (100 ml) and conc. chloroethanol acid (182 ml) was cooled to -10°C. To this mixture was added dropwise at -10°C for about 30-60 minutes a solution of sodium nitrite (51,7 g, 0.75 mol) in water (75 ml) (in the process of adding observed the formation of foam). In another flask were obtained at room temperature a mixture of potassium iodide (311 g of 1.87 mol) in water (3000 ml)and to this solution was added for about 30-40 minutes at 30-40°C cooled diazonium salt. The reaction temperature was maintained equal to 30°C within 1 hour after completion of the reaction was added ethyl acetate (500 ml) and the reaction mixture was filtered through celite. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×500 ml). The combined organic layers were washed with 5% hypo solution (2×500 ml), brine (500 ml), dried (Na2SO4) and concentrated. The crude product was purified by chromatography (silica gel, hexane, 15-20% ethyl acetate/hexane) to obtain 4-iodine-1H-indazole as an orange solid residue (23,0 g, 25%). TPL: 151-177 C:1H NMR (200 MHz, CDCl3) δ 12,4 (ush, 1H), and 8.0 (s, 1H), and 7.6 (DD, 2H), and 7.1 (d, 1H). ESMS m/z 245 (M+1). Purity: 95-98% (VE is X).

Stage D: Obtain 4-iodine-1-(2-tetrahydropyranyl)indazole: a Mixture of 4-amino-1H-indazole (250,0 g, 1,024 mol), 3,4-dihydro-2Η-Piran (126,0 g, 1.5 mol) and PPTS (to 2.57 g, 0.01 mol) in CH2Cl2(1250 ml) was heated at 50°C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (625 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2(250 ml). The combined organic layers were washed with water (625 ml), dried (Na2SO4) and concentrated. The crude residue was purified by chromatography (silica gel, hexane, 5-10% ethyl acetate/hexane) to obtain 4-iodine-1-(2-tetrahydropyranyl)indazole in the form of oil (807,0 g, 60%).1H NMR (200 MHz, CDCl3) δ of 8.5 (s, 1H), 7,8 (m, 1H), and 7.6 (d, 1H), 7,25 (m, 1H), 5,7 (DD, 1H), from 4.2 to 3.8 (DD, 1H), 2,2-2,0 (m, 4H) 2,0-1,8 (m, 4H). ESMS m/z 329 (M+1).

Stage E: Obtain 1-(tetrahydro-2H-Piran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole41: A mixture of 4-iodine-1-(2-tetrahydropyranyl)indazole (100 g, 0,304 mol), bis(pinacolato)Debora (96.4 g, 0,381 mol), PdCl2(dppf) (8,91 g, 0.012 mol) and potassium acetate (85,97 g, 0,905 mol) in DMSO (500 ml) was heated at 80°C for 2-3 hours. After completion the reaction mixture was cooled to room temperature and added water (1500 ml). The reaction mass was extracted into ethyl acetate (3×200 ml)and the combined organic layers were evaporated, dried (Na2SO4) and concentrated. Untreated whom the product was purified column chromatography (silica gel, hexane, 5-10% ethyl acetate/hexane) to obtain a41in the form of a viscous brown oil (70,0 g, 70%).1H NMR (CDCl3) δ of 8.5 (s, 1H), 7,8 (m, 1H), and 7.6 (d, 1H), 7,25 (m, 1H), 5,7 (DD, 1H), from 4.2 to 3.8 (DD, 1H), 2,2-2,0 (m, 4H) 2,0-1,8 (m, 4H) 1,4-1,2 (s, 12H). ESMS m/z 329 (M+1).

EXAMPLE 6.4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl)pyrimidine-2-ylamine42

To a solution of 4-methylpyrimidin-2-ylamine (8.0 g, 0,073 mol) in chloroform (320 ml) was addedN-bromosuccinimide (13,7 g 0,077 mol). The reaction mixture was stirred in the dark for 18 hours. LC/MS showed that the reaction was completed. The mixture was diluted with DCM, then washed with 1N aqueous NaOH solution and brine, dried over MgSO4, filtered and concentrated to obtain 5-bromo-4-methylpyrimidin-2-ylamine (12 g, yield: 86%)

A mixture of 5-bromo-4-methylpyrimidin-2-ylamine (5.0 g, 26 mmol), potassium acetate (7,83 g of 79.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7,43 g, 29.2 mmol) in dioxane (140 ml) was stirred for 20 minutes in nitrogen atmosphere. Was added to the reaction mixture of the chloride adduct of 1,1'-bis(diphenylphosphino)ferienparadies (II) and dichloromethane (1.08 g, of 1.33 mmol). The reaction mixture was heated at 115°C for 18 hours under nitrogen atmosphere. After the mixture was cooled and was added EtOAc. The resulting mixture, quenching Tivoli ultrasound and filtered. Additional amount of EtOAc was used for washing of the solid residue. The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated. The crude residue was purified by chromatography, elwira 20-100% EtOAc/hexane to obtain 4.5 g42(yield: 74%).1H-NMR (DMSO, 400 MHz); δ of 8.28 (s, 1H), 6,86 (USS, 2H), 2,35 (s, 3H), 1,25 (s, 12H). MS (ESI) m/e (M+H+) 236,15, 154,07.

EXAMPLE 7.2-(9-(2-hydroxyethyl)-2-(1H-indol-4-yl)-6-morpholino-9H-purine-8-yl)propan-2-ol101

2-(2-Chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purine-9-yl)acetic acid ethyl ester (165 mg) was treated with indole-4-Bronevoy acid according to the General procedure A and purified by reversed-phase HPLC to obtain 21 mg101in the form of a white solid connections. MS (Q1) 423,2 (M)+

EXAMPLE 8.2-(2-(2-amino-4-methylpyrimidin-5-yl)-9-(2-hydroxyethyl)-6-morpholino-9H-purine-8-yl)propan-2-ol102

2-(2-Chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purine-9-yl)acetate (300 mg) was treated with 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine according to the General procedure A and purified by reversed-phase HPLC to obtain 107 mg102in the form of a white solid connections. MS (Q1) 415,2 (M)+

EXAMPLE 9.2-(2-(2-aminopyrimidine-5-yl)-9-butyl-6-morpholino-9H-purine-8-yl)propan-2-ol103

<> 2-(2-Chloro-6-morpholino-9H-purine-8-yl)propan-2-ol (100 mg were treated with bromoethanol according to the General method C to obtain the crude intermediate compound 2-(9-butyl-2-chloro-6-morpholino-9H-purine-8-yl)propan-2-ol, which was treated with 2-aminopyrimidine-5-Bronevoy acid, pinacolone ether according to the General procedure A and purified by reversed-phase HPLC to obtain 55 mg103in the form of a white solid connections. MS (Q1) 413,3 (M)+.

EXAMPLE 10.2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9-propyl-9H-purine-8-yl)propan-2-ol104

2-(2-Chloro-6-morpholino-9H-purine-8-yl)propan-2-ol (100 mg) was treated with jumprope according to the General method C to obtain the crude intermediate compound 2-(2-chloro-6-morpholino-9-propyl-9H-purine-8-yl)propan-2-ol, which was treated with 2-aminopyrimidine-5-Bronevoy acid, pinacolone ether according to the General procedure A and purified by reversed-phase HPLC to obtain 34 mg104in the form of a white solid connections. MS (Q1) 399,3 (M)+.

EXAMPLE 11.3-(2-(2-aminopyrimidine-5-yl)-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purine-9-yl)propan-1-ol105

100 mg of 2-(2-chloro-6-morpholino-9H-purine-8-yl)propan-2-ol was treated with TBDMS-protected bromopropane according to the General method C. the Crude intermediate compound 2-(9-(3-(tert-butyldimethylsilyloxy)the filing)-2-chloro-6-morpholino-9 H-purine-8-yl)propan-2-ol was treated with 2-aminopyrimidine-5-Bronevoy acid, pinacolone ether according to the General procedure A and purified by reversed-phase HPLC to obtain 36 mg105in the form of a white solid connections. MS (Q1) 415,2 (M)+.

EXAMPLE 12.3-(2-(2-aminopyrimidine-5-yl)-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purine-9-yl)propan-1-ol106

2,6-Dichloropurine (3 g) was dissolved in 20 ml EtOAc was added 100 mg of PTSA. Was slowly added to a heterogeneous mixture dihydropyran (3 ml) and heated until the moment when the reaction mixture became homogeneous. Then the reaction mixture was extracted with saturated sodium bicarbonate solution three times. The organic layer was dried, filtered and concentrated to dryness. The crude 2,6-dichloro-9-(tetrahydro-2H-Piran-2-yl)-9H-purine was dissolved in MeOH, after which was added morpholine (3 EQ.). 4-(2-Chloro-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-6-yl)morpholine slowly fell out of solution within the next 3 hours, then it was filtered, collected and dried to obtain 4.26 deaths / g in the form of a white solid connections

4-(2-Chloro-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-6-yl)morpholine (2.76 g) was cooled in THF to -78°C. was Added dropwise within 20 minutes of a 2.5 M solutionn-BuLi in THF (1.5 EQ.). The reaction mixture was peremeci the Ali at -78°C for 30 minutes, then acetone was added (1,56 ml)and the reaction mixture was stirred for 2 hours, slowly warming to 0°C. Then the reaction mixture was extinguished with water and was extracted with ethyl acetate. The crude product 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-8-yl)propan-2-ol was concentrated and dissolved in MeOH. Then, THP group was removed according to the General method D. the Reaction mixture was concentrated, and the crude residue was dissolved in water, filtered, collected and dried over night in order to get of 2.23 g of 2-(2-chloro-6-morpholino-9H-purine-8-yl)propan-2-ol as a pale yellow solid residue

100 mg of 2-(2-chloro-6-morpholino-9H-purine-8-yl)propan-2-ol was treated with 2-Bromeliaceae according to the General method C. the Crude intermediate compound 2-(2-chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purine-9-yl)acetic acid ethyl ester was treated with 2-aminopyrimidine-5-Bronevoy acid, pinacolone ether according to the General procedure A and purified by reversed-phase HPLC to obtain 54 mg106in the form of a white solid connections. MS (Q1) 401,2 (M)+.

EXAMPLE 13.1-(4-((2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)piperidine-1-yl)alanon107

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (400 mg) was reacted withtert/i> -butyl 4-(methyl bromide)piperidine-1-carboxylate according to General method C to get thetert-butyl 4-((2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)piperidine-1-carboxylate (554 mg), which removed the Boc-protective group according to the General procedure D to obtain 5-(6-morpholino-9-(piperidine-4-ylmethyl)-9H-purine-2-yl)pyrimidine-2-amine (454 mg) as a yellow solid residue.

5-(6-Morpholino-9-(piperidine-4-ylmethyl)-9H-purine-2-yl)pyrimidine-2-amine (75 mg) was reacted with excess acetic acid, 2 EQ. HOBT, 5 EQ. diisopropylethylamine and 2 EQ. hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide in 1 ml of DMF. After completion, the reaction mixture was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was concentrated and purified by reversed-phase HPLC in order to get to 18.9 mg107in the form of a white solid connections. MS (Q1) 438,3 (M)+

EXAMPLE 14.1-(3-((2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)pyrrolidin-1-yl)alanon108

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (400 mg) was reacted withtert-butyl 3-(methyl bromide)pyrrolidin-1-carboxylate according to General method C to get thetert-butyl 3-((2-(2-(bis(tert-butoxy arbonyl)amino)pyrimidine-5-yl)-6-morpholino-9 H-purine-9-yl)methyl)pyrrolidin-1-carboxylate (496 mg), which removed the Boc-protective group according to the General procedure D to obtain 352 mg of 5-(6-morpholino-9-(pyrrolidin-3-ylmethyl)-9H-purine-2-yl)pyrimidine-2-amine as a yellow solid residue.

5-(6-Morpholino-9-(pyrrolidin-3-ylmethyl)-9H-purine-2-yl)pyrimidine-2-amine (75 mg) was reacted with excess acetic acid, 2 EQ. HOBT, 5 EQ. diisopropylethylamine and 2 EQ. hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide in 1 ml of DMF. After completion, the reaction mixture was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was concentrated and purified by reversed-phase HPLC in order to get to 40.1 mg108in the form of a white solid connections. MS (Q1) 424,2 (M)+.

EXAMPLE 15.(R)-3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(3-hydroxypyrrolidine-1-yl)propane-1-he109

3-(2-(2-(Tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid (50 mg) was reacted with (R-pyrrolidin-3-I according to the General method F, with subsequent removal of the Boc-protective group according to the General method E to get to 10.9 mg109in the form of a white solid residue by reversed-phase purification. MS (Q1) 440,2 (M)+

EXAMPLE 16.(S)-3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(3-hydroxypyrrolidine-1-yl)PR is pan-1-he 110

3-(2-(2-(Tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid (50 mg) was reacted with (S-pyrrolidin-3-I according to the General method F, with subsequent removal of the Boc-protective group according to the General method in order to obtain a 10.1 mg110in the form of a white solid residue by reversed-phase purification. MS (Q1) 440,2 (M)+

EXAMPLE 17.1-(3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanol)-N-methylpiperidin-4-carboxamid111

3-(2-(2-(Tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid (50 mg) was reacted withN-methylpiperidin-4-carboxamide according to the General method F, with subsequent removal of the Boc-protective group according to the General method E to get to 10.9 mg111in the form of a white solid residue by reversed-phase purification. MS (Q1) 495,3 (M)+

EXAMPLE 18.3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(4-(methylsulphonyl)piperazine-1-yl)propane-1-he112

3-(2-(2-(Tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid (50 mg) was reacted with 1-(methylsulphonyl) - piperazine according to General method F, with subsequent removal of the Boc-protective group according to the General method E to get to 33.8 mg112in the form of a white solid residue by reversed-phase purification. MS (Q1) from 517.2 (M)+/sup>

EXAMPLE 19.3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-morpholinopropan-1-he113

3-(2-(2-(Tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid (50 mg) was reacted with morpholine according to General method F, with subsequent removal of the Boc-protective group according to the General method E to get 24,9 mg113in the form of a white solid residue by reversed-phase purification. MS (Q1) 440,2 (M)+

EXAMPLE 20.3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid114

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (400 mg) was reacted with methyl 3-bromopropionate according to the General method C. the Product, 468 mg of the crude methyl 3-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propionate was reacted with 3 EQ. of lithium hydroxide in a solution of 1:1 THF/water. After THF was removed in vacuo, and the aqueous solution was acidified to pH 2 using concentrated HCl solution. The product precipitated as a white solid connection, and it was filtered to obtain 388 mg of 3-(2-(2-(tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propanoic acid, of 88 mg which removed the Boc-protective group according to the General method E to get to 15.5 mg114in the form of a white solid residue after treatment the n-phase purification. MS (Q1) 371,2 (M)+

EXAMPLE 21.5-(9-(4-(methylsulphonyl)benzyl)-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine115

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (100 mg) was reacted with 1-(chloromethyl)-4-(methylsulphonyl) - benzene according to the General method C, followed by removal of the Boc-protective group according to the General method E to get to 25.4 mg115in the form of a white solid residue by reversed-phase purification. MS (Q1) 467,2 (M)+

EXAMPLE 22.Methyl 4-((2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)benzoate116

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (100 mg) was reacted with methyl 4-(methyl bromide)benzoate according to the General method C, followed by removal of the Boc-protective group according to the General method E to get to 10.2 mg116in the form of a white solid residue by reversed-phase purification. MS (Q1) 447,2 (M)+

EXAMPLE 23.5-(6-morpholino-9-(2-morpholinoethyl)-9H-purine-2-yl)pyrimidine-2-amine117

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (100 mg) was reacted with 4-(2-bromacil)morpholine according to General method C, followed by removal of the Boc-protective group according to the General method E to get to 15.9 mg117in the form of a white solid residue by reversed-phase clean is key. MS (Q1) 412,2 (M)+

EXAMPLE 24.5-(9-(3-methoxybenzyl)-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine118

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (75 mg) was reacted with 1-(methyl bromide)-3-methoxybenzoyl according to the General method C, followed by removal of the Boc-protective group according to the General method E in order to obtain a 50.2 mg118in the form of a white solid residue by reversed-phase purification. MS (Q1) 419,2 (M)+

EXAMPLE 25.Methyl 3-((2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)methyl)benzoate119

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (75 mg) was reacted with methyl 3-(methyl bromide)benzoate according to the General method C, followed by removal of the Boc-protective group according to the General method E in order to obtain a 27.6 mg119in the form of a white solid residue by reversed-phase purification. MS (Q1) 447,2 (M)+

EXAMPLE 26.3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)propan-1-ol120

2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (75 mg) was reacted with 3-bromopropane-1-I according to the General method C, followed by removal of the Boc-protective group according to the General method E in order to obtain a 19.6 mg120in the form of a white solid residue by reversed-phase purification. MS (Q1) 357,2 (M)+

<> EXAMPLE 27.2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)ethanol121

2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl (75 mg) was reacted with 2-Bromeliaceae according to the General method C, followed by removal of the Boc-protective group according to the General method E in order to obtain 22 mg of121in the form of a white solid residue by reversed-phase purification. MS (Q1) 343,2 (M)+.

EXAMPLE 28.1-(2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetyl)-N-methylpiperidin-4-carboxamid122

2-(2-(2-(Tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetic acid (35 mg) was reacted withN-methylpiperidin-4-carboxamide according to the General method F, with subsequent removal of the Boc-protective group according to the General method E, and the product was purified by reversed-phase HPLC in order to get to 10.3 mg122in the form of a white solid connections. MS (Q1) 481,2 (M)+.

EXAMPLE 29.2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-(4-(methylsulphonyl)piperazine-1-yl)alanon123

2-(2-(2-(tert-Butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetic acid (35 mg) was reacted with 1-(methylsulphonyl) - piperazine according to General method E, followed by removal of the Boc-protective group according to the General procedure D, and the product was purified by reversed-phase HPLC to ensure that the floor is given 9 mg 123in the form of a white solid connections. MS (Q1) 503,2 (M)+.

EXAMPLE 30.2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)-1-morpholinoethyl124

2-(2-(2-(Tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetic acid (35 mg) was reacted with morpholine according to General method F, with subsequent removal of the Boc-protective group according to the General method E, and the product was purified by reversed-phase HPLC to obtain 3.2 mg124in the form of a white solid connections. MS (Q1) to 426.2 (M)+

EXAMPLE 31.2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetic acid125

The crude 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetate (240 mg) was reacted with 3 EQ. of lithium hydroxide in 1:1 solution of THF/water. After THF drove in a vacuum, and the aqueous solution was acidified to pH 2 using concentrated HCl solution. The product precipitated as a fine white solid residue, and it was filtered to obtain 2-(2-(2-(tert-butoxycarbonylamino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetic acid (145 mg), 40 mg of which was subjected to General method E and was purified by reversed-phase HPLC to obtain 19.5 mg125in the form of a white solid connections. MS (Q1) 357,2 (M)+

EXAMPLE 32.Methyl 2-(2-(2-amino shall eremein-5-yl)-6-morpholino-9 H-purine-9-yl)acetate126

4-(2-Chloro-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-6-yl)morpholine (of 4.05 g) was reacted with 2-aminopyrimidine-5-Bronevoy acid, pinacolone ether according to the General procedure A to obtain of 4.75 g of 5-(6-morpholino-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-2-yl)pyrimidine-2-amine, which was boiled under reflux in the presence of catalytic amounts of dimethylaminopyridine, 4 EQ. Boc-anhydride and 3 EQ. of triethylamine in 60 ml of acetonitrile. After completion, the reaction mixture was cooled, concentrated to dryness and purified by chromatography with direct phase in order to obtain 6.11 g of 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-2-Il in the form of a light yellow solid residue.

2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-2-yl (2 g) was subjected to General procedure D for the selective removal of the THP protective group, and 300 mg of 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-2-yl reacted with methyl 2-bromoacetate according to the General method C to obtain methyl 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9H-purine-9-yl)acetate. Boc group of the crude methyl 2-(2-(2-(bis(tertBoo is oxycarbonyl)amino)pyrimidine-5-yl)-6-morpholino-9 H-purine-9-yl)acetate (60 mg) was removed according to the General method E, and the product was purified by reversed-phase HPLC to obtain 39 mg126in the form of a white solid connections. MS (Q1) 371,2 (M)+

EXAMPLE 33.5-(9-methyl-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine127

4-(2-Chloro-9-methyl-9H-purine-6-yl)morpholine (95 mg) was reacted with 2-aminopyrimidine-5-Bronevoy acid, pinacolone ether according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 26.1 mg127in the form of a white solid connections. MS (Q1) 313,2 (M)+

EXAMPLE 34.5-(9-methyl-6-morpholino-9H-purine-2-yl)pyridine-2-amine128

4-(2-Chloro-9-methyl-9H-purine-6-yl)morpholine (20 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine according to the General procedure A and the product was purified by reversed-phase HPLC in order to get to 9.3 mg128in the form of a white solid connections. MS (Q1) 312,3 (M)+.

EXAMPLE 35.4-(2-(1H-indazol-4-yl)-9-methyl-9H-purine-6-yl)morpholine129

4-(2-Chloro-9-methyl-9H-purine-6-yl)morpholine (20 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 13,8 mg129in the form of a white solid connections. MS (Q1) 336,2 (M)+

EXAMPLE 36.2-(2-(2-aminopyrimidine-5-yl)-9-methyl-6-morpholino-9H-purine-8-yl)PR is pan-2-ol 130

2-(2-Chloro-6-morpholino-9H-purine-8-yl)propan-2-ol (100 mg) was treated with iodomethane according to the General method C to obtain the crude intermediate compound 2-(2-chloro-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol, which was treated with 2-aminopyrimidine-5-Bronevoy acid, pinacolone ether according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 44 mg130in the form of a white solid connections. MS (Q1) 371,2 (M)+.

EXAMPLE 37.2-(2-(6-aminopyridine-3-yl)-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol131

2-(2-Chloro-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol (95 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine according to method A, and the product was purified by reversed-phase HPLC to obtain 89,3 mg131in the form of a white solid connections. MS (Q1) 370,3 (M)+

EXAMPLE 38.2-(2-(1H-indazol-4-yl)-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol132

4-(2-Chloro-9-methyl-9H-purine-6-yl)morpholine (233 mg) was cooled in 5 ml of anhydrous THF to -78°C before the addition of 2 EQ. a 2.5 M solutionn-butyl lithium. The reaction mixture was stirred for 1 hour at -78°C, after which was added 3 EQ. of acetone. Then the reaction mixture was heated to 0°C over 30 minutes. The reaction extinguished with water and was extracted with et is lacerata. The organic layer was concentrated to obtain crude 2-(2-chloro-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol (95 mg).

The crude 2-(2-chloro-9-methyl-6-morpholino-9H-purine-8-yl)propan-2-ol was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole according to method A, and the product was purified by reversed-phase HPLC to obtain 56.6 mg132in the form of a white solid connections. MS (Q1) 394,3 (M)+

EXAMPLE 39.4-(2-(1H-indazol-4-yl)-9-(2-methoxyethyl)-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine133

4-(2-chloro-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9-(tetrahydro-2H-Piran-2-yl)-9H-purine-6-yl)morpholine (250 mg) was treated withpair-toluensulfonate acid according to the General procedure D to obtain 4-(2-chloro-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine.

4-(2-chloro-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine (215 mg) was reacted with 2-bromatology ether according to the General method C to obtain 4-(2-chloro-9-(2-methoxyethyl)-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine (207 mg), which was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole according to the General procedure A and the product was purified by reversed-phase HPLC in order to get to 21.6 mg133in the form of a white solid residue. MS (Q1) 556,3 (M)sup> +.

EXAMPLE 40.N-(4-(9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-6-morpholino-9H-purine-2-yl)phenyl)ndimethylacetamide134

4-(2-Chloro-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine (50 mg) was reacted with 4-acetaminophenydrocodone acid according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 25,9 mg134in the form of a white solid residue. MS (Q1) 529,3 (M)+.

EXAMPLE 41.5-(9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-6-morpholino-9H-purine-2-yl)pyridine-2-amine135

4-(2-Chloro-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine (50 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine according to the General procedure A and the product was purified by reversed-phase HPLC in order to get to 29.1 mg135in the form of a white solid residue. MS (Q1) 488,3 (M)+.

EXAMPLE 42.4-(2-(2-methoxypyridine-5-yl)-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine136

4-(2-Chloro-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine (50 mg) was reacted with 2-methoxypyridine-5-Voronovo acid according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 5,5 mg136in the form of a white solid residue. MS (Q1) 504,3 (M)+.

EXAMPLE 43.4-(9-methyl-8-((4-(methylsulphonyl)Pipera the Jn-1-yl)methyl)-2-(pyridin-3-yl)-9 H-purine-6-yl)morpholine137

4-(2-Chloro-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine (50 mg) was reacted with pyridine-3-Voronovo acid according to the General procedure A and the product was purified by reversed-phase HPLC to obtain the 33.4 mg137in the form of a white solid residue. MS (Q1) 473,3 (M)+

EXAMPLE 44.4-(2-(1H-indazol-4-yl)-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine138

4-(2-Chloro-9H-purine-6-yl)morpholine (510 mg) was reacted with methyliodide according to the General method C to obtain 4-(2-chloro-9-methyl-9H-purine-6-yl)morpholine. 4-(2-Chloro-9-methyl-9H-purine-6-yl)morpholine (100 mg) was cooled 1.5 ml of anhydrous THF to -78 °C before the addition of 2 EQ. a 2.5 M solutionn-utility. The reaction was stirred for 1 hour at -78°C, after which was added 3 EQ. DMF. Then the reaction mixture was heated to 0°C over 30 minutes. The reaction extinguished by pouring in cold 0.25 M aqueous solution of HCl, and the orange solid was filtered, collected and dried to obtain 48 mg of the crude intermediate 2-chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde.

2-Chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde was treated with 1.1 EQ. 1-(methylsulphonyl)piperazine, 7 EQ. triethylorthoformate, 1 EQ. acetic acid in 2 ml of dichlorethane for 6 hours, after which was added to the reaction mixture of 1.1 EQ. triacetoxyborohydride sodium. The reaction mixture was extracted with dichloromethane and water, in order to obtain the crude intermediate compound 4-(2-chloro-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-9H-purine-6-yl)morpholine, which is then reacted with 1-(tetrahydro-2H-Piran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 41,8 mg138in the form of a white solid residue. MS (Q1) 512,2 (M)+.

EXAMPLE 45.4-(2-(2-(3-hydroxyphenyl)-6-morpholino-9H-purine-9-yl)acetyl)piperazine-2-he139

The crude 2-(2-(3-hydroxyphenyl)-6-morpholino-9H-purine-9-yl)acetic acid (50 mg) was reacted with piperazine-2-one according to General method F, and the product was purified by reversed-phase HPLC to obtain 1.9 mg139in the form of a white solid residue. MS (Q1) 438,2 (M)+.

EXAMPLE 46.2-(2-(3-hydroxyphenyl)-6-morpholino-9H-purine-9-yl)-N-methylacetamide140

4-(2-Chloro-9H-purine-6-yl)morpholine (75 mg) was reacted with methyl 2-bromoacetate according to the General method C. Methyl 2-(2-chloro-6-morpholino-9H-purine-9-yl)acetate was reacted with 150 mgtert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate according to the General method A. the Crude 2-(2-(3-hydroxyphenyl)-6-m is holino-9 H-purine-9-yl)acetic acid (50 mg) was reacted with methylamine according to the General method F, and the product was purified by reversed-phase HPLC to obtain 5.6 mg140in the form of a white solid connections. MS (Q1) 369,2 (M)+

EXAMPLE 47.3-(6-morpholino-9-(pyridin-4-ylmethyl)-9H-purine-2-yl)phenol141

4-(2-Chloro-9H-purine-6-yl)morpholine (75 mg) was reacted with 4-(methyl bromide)pyridine according to the General method C to obtain 4-(2-chloro-9-(pyridin-4-ylmethyl)-9H-purine-6-yl)morpholine, which was reacted with 150 mgtert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate according to the General procedure A and the product was purified by reversed-phase HPLC in order to get to 28.1 mg141in the form of a white solid residue. MS (Q1) 389,2 (M)+

EXAMPLE 48.3-(9-(4-terbisil)-6-morpholino-9H-purine-2-yl)phenol142

4-(2-Chloro-9H-purine-6-yl)morpholine (75 mg) was reacted with 1-(methyl bromide)-4-florasulam according to the General method C to obtain 4-(2-chloro-9-(4-terbisil)-9H-purine-6-yl)morpholine, which was reacted with 150 mgtert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 50 mg142in the form of a white solid residue. MS (Q1) 406,2 (M)+.

EXAMPLE 49.3-(9-benzyl-6-morpholino-9H-purine-2-yl)phenol143

4-(2-Chloro-9H-purine-6-yl)morpholine (75 mg) was reacted with (methyl bromide)benzene according to the General method C to obtain 4-(9-benzyl-2-chloro-9H-purine-6-yl)morpholine, which was reacted with 150 mgtert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate according to the General procedure A and the product was purified by reversed-phase HPLC to obtain 92,2 mg143in the form of a white solid residue. MS (Q1) 388,2 (M)+

EXAMPLE 50.3-(9-(2-hydroxyethyl)-6-morpholino-9H-purine-2-yl)phenol144

4-(2-Chloro-9H-purine-6-yl)morpholine (75 mg) was reacted with 2-Bromeliaceae according to the General method C to obtain 2-(2-chloro-6-morpholino-9H-purine-9-yl)acetic acid ethyl ester, which was reacted with 150 mgtert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate according to the General procedure A and the product was purified by reversed-phase HPLC in order to get to 59.4 mg144in the form of a white solid residue. MS (Q1) 342,2 (M)+

EXAMPLE 51.3-(9-isobutyl-6-morpholino-9H-purine-2-yl)phenol145

4-(2-Chloro-9H-purine-6-yl)morpholine (75 mg) was reacted with 1-iodine-2-methylpropanol according to the General method C. 4-(2-Chloro-9-isobutyl-9H-purine-6-yl)morpholine was reacted with 150 mgtert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate according to the General procedure A and the product was purified by reversed-phase In the LC for to get and 62.6 mg145in the form of a white solid connections. MS (Q1) 354,2 (M)+

EXAMPLE 52.p110α (alpha) PI3K Analysis linking

Analyses linking: experiments on primary polarization was performed on the Analyst HT 96-384 (Molecular Devices Corp, Sunnyvale, CA.). Samples for measurement of affinity with fluorescent polarization was obtained by adding solutions of 1:3 serial dilutions p110 alpha PI3K (Upstate Cell Signaling Solutions, Charlottesville, VA), starting from a final concentration of 20 μg/ml in the buffer of polarization (10 mm Tris pH 7.5, 50 mm NaCl, 4 mm MgCl2, of 0.05% Chaps and 1 mm DTT), 10 mm PIP2(Echelon-Inc, Salt Lake City, UT.) final concentration. After keeping for 30 minutes at room temperature the reaction was stopped by adding GRP-1 and PIP3-TAMRA probe (Echelon-Inc, Salt Lake City, UT.) 100 nm and 5 nm final concentrations, respectively. Registered with the standard filters with limited bandwidth for radominova fluorophore (λex=530 nm; λem=590 nm) in 384-well dark Proxiplates low volume (PerkinElmer, Wellesley, MA.) the values of fluorescence polarization was used to plot a function of protein concentration, and EC50values were obtained by casting the data to equation 4 parameters, using the software KaleidaGraph (Synergy software, Reading, PA). This experiment was also set an appropriate protein concentration for use in the next competition experiments with inhibitors.

The value of the IC50inhibitor was determined by addition of 0.04 mg/ml p110 PI3K alpha (final concentration), mixed with PIP2(10 mm final concentration) in wells containing a solution of 1:3 serial dilutions antagonists at a final concentration of 25 mm ATP (Cell Signaling Technology, Inc., Danvers, MA) in the buffer for polarization. After keeping for 30 minutes at room temperature the reaction was stopped by adding GRP-1 and PIP3-TAMRA probe (Echelon-Inc, Salt Lake City, UT.) 100 nm and 5 nm final concentrations, respectively. Registered with the standard filters with limited bandwidth for radominova fluorophore (λex=530 nm; λem=590 nm) in 384-well dark Proxiplates low volume (PerkinElmer, Wellesley, MA.) the values of fluorescence polarization was used to plot a function of the concentration of antagonist, and IC50values were obtained by casting the data to equation 4 parameters, using software Assay Explorer (MDL, San Ramon, CA.).

Alternatively, inhibition of PI3K was determined by radiometric analysis, using purified, recombinant enzyme and ATP at a concentration of 1 μm. The compound of formula I is serially diluted in 100% DMSO. Kinase reaction was kept for 1 hour at room temperature, and the reaction was stopped by adding PBS. Then IC50values were determined by applying the approximation Sigma is icalneu curve "dose-effect" (variable slope).

EXAMPLE 53.Analysis of cell proliferationin vitro

The effectiveness of the compounds of formula I) was evaluated by analysis of cell proliferation using the following Protocol (Promega Corp. Technical Bulletin TB288; Mendoza et al (2002) Cancer Res. 62:5485-5488):

1. An aliquot of 100 μl of cell culture containing about 104cells (PC3, Detroit562 or MDAMB361,1) in the medium was put into each well of the 384-well plate with opaque walls.

2. Received control wells containing medium without cells.

3. The connection was added to the experimental wells and maintained for 3-5 days.

4. The tablets were balanced to room temperature for about 30 minutes.

5. Added a volume of CellTiter-Glo reagent equal to the volume of medium with cell culture present in each hole.

6. The contents were mixed for 2 minutes on an orbital shaker to induce lysis of the cells.

7. The tablet is kept at room temperature for 10 minutes to stabilize the luminescence signal.

8. Luminescence was detected and resulted in curves as RLU=relative luminescence units.

Alternatively, cells were sown at the optimum density in 96-well tablet and kept for 4 days in the presence of the test compound. Then to the environment for analysis were added Alamar Blue™, and cells were kept at t the value of 6 hours before you check in at 544 nm excitation, 590 nm emission. EC50 values were calculated using the approximation of a sigmoid curve "dose-effect".

EXAMPLE 54.Caco-2 permeability

Caco-2 cells were sown on Millipore Multiscreen tablets at 1×105cells/cm2and were grown for 20 days. Then evaluated the permeability of the compounds. Compounds were applied to the apical surface (A) cell monolayers, and measured the penetration of compounds in basolateral (B) plot. The same was carried out in the reverse direction (B-A) for studies of active transport. Expected value of the permeability coefficient, Pappfor each connection, the speed of passage of compounds through the membrane. The compounds were grouped into groups with low (Papp</=1,0×106cm/s) or high (Papp>/=1,0×106cm/s) absorptive capacity on the basis of comparison with a control connection established for human absorption.

To assess the ability of compounds to be active outflow was determined attitude basolateral (B) to apollinea (A) transport, compared with A-B. the Value of B-A/A-B>/=1,0 show the presence of an active outflow from the cells.

EXAMPLE 55.Clearance by hepatocytes

Used suspension frozen human hepatocytes. Incubation was carried out at concentrations of compounds 1 mm or 3 mm at PLO is the tendency of cells to 0.5×10 6viable cells/ml Final concentration in DMSO in the incubation was approximately 0.25%. A control incubation was also performed in the absence of cells in order to identify any non-enzymatic decomposition. Duplicate samples (50 μl) was removed from the mixture for an incubation of 0, 5, 10, 20, 40 and 60 minutes (control sample only at 60 minutes) and added to MeOH containing internal standard (100 μl), to terminate the reaction. As control compounds can be applied tolbutamide, 7-hydroxycoumarin and testosterone. The samples were centrifuged, and the supernatant at each time point were pooled for analysis of LC-MSMS. From the graph ln relationship of peak areas (peak area for the parent compound/peak area to internal standard) versus time was calculated own clearance (CLint) as follows: CLmt(ál/min/million cells)=V×k, where k represents the rate constant of elimination, obtained from the gradient of ln concentration, constructed with respect to time; V is a volume component, obtained from the volume of incubation and expressed as µl of 106cells-1.

EXAMPLE 56.Inhibition of cytochrome P450

The compounds of formula I can be tested relatively CYP450 targets (1A2, 2C9, 2C19, 2D6, 3A4) with approximately 10 of concentration is x in two copies, with a maximum concentration of approximately 100 μm. Standard inhibitors (furafylline, sulfaphenazole, tranilcipromin, quinidine, ketoconazole) can be used as a control. The tablets can be read using BMG LabTechnologies PolarStar in fluorescent mode.

EXAMPLE 57.Induction of Cytochrome P450

Freshly isolated human hepatocytes from a single donor can be grown for 48 hours before adding the compounds of formula I with three concentrations and curing for 72 hours. Marker substrates for CYP3A4 and CYP1A2 add 30 minutes and 1 hour before the end of the incubation. After 72 hours the cells and the medium removed, and the degree of metabolism of each marker substrate quantify LC-MS/MS. The experiment control inducers of specific P450, maintained at the same concentration in triplicate.

EXAMPLE 58.Binding to plasma proteins

Solutions of compounds of the formula I (5 μm, and 0.5% final DMSO concentration) was received in the buffer, and 10% plasma (V/V in buffer). 96-well HT tablet for dialysis collected so that each hole was divided into two semi-permeable cellulose membrane. The buffer solution is added to one side of the membrane, and the solution of the plasma to the other side; then incubation was performed at 37°C for 2 hours in triplicate. Then the cells were removed, and the solution is for each group of compounds were combined into two groups (without plasma containing plasma), then were analyzed by LC-MSMS using two sets of calibration standards for solutions without plasma (6 points) and containing the plasma (7 points). Expected value of the unbound fraction for the connection.

EXAMPLE 59.Blocking hERG channels

The compounds of formula I was evaluated for its ability to modulate the outflow of rubidium from HEK-294 cells stably expressing hERG potassium channels by applying the standard method for the study of expiration. The cells were obtained in the medium containing RbCl, seeded in 96-well plates and grown overnight to obtain monolayers. The experiment started after aspiration of the medium and washing each well 3×100 μl pre-seasoned buffer (containing a low concentration [K+]) at room temperature. After the last extraction add to each well 50 µl of the working solution (2×) connection and kept at room temperature for 10 minutes. Then to each well was added 50 μl of buffer for stimulation (containing a high concentration of [K+]), giving final concentrations of the tested compounds. Then the tablets with cells kept at room temperature for an additional 10 minutes. Then 80 μl of supernatant from each well was transferred into equivalent wells of 96-hole tablet and analyzed using atomic emission the Oh spectroscopy. The connection is explored in the form of the IC50curves with 10 points obtained in duplicate, n=2, with a maximum concentration of 100 ám.

The preceding description is to be considered only as illustrating the principles of the present invention. Furthermore, since numerous modifications and changes will be obvious to experts in the field of technology, it is undesirable to limit the present invention to the exact construction and method shown, as described above. Accordingly, all suitable modifications and equivalents may be considered included in the scope of the present invention, as defined by the claims presented below.

It is assumed that the words "include", "including", "include", "contain" and "contains", when used in this description and in the subsequent claims, indicate the presence of a specified property, integers, components, or stages, but they do not preclude the presence or addition of one or more other properties, integers, components, stages or groups.

1. The compound of the formula I

and its pharmaceutically acceptable salts,
where R1selected from H, C1-C12the alkyl and -(C1-C12alkylen)-(C5-C6heterocyclyl), where heterocyclyl may contain 1-2 heteroatoms in the cycle selected from nitrogen, and in which alkyl, heterotic the Il optionally substituted by one or more groups, independently selected from-NHCOCH3, -NHS(O)2CH3, -OH, -S(O)2N(CH3)2and-S(O)2CH3;
R2selected from C1-C12of alkyl, -(C1-C6alkylen)-(C5-C6heterocyclyl) or(C1-C6alkylene)-C(=O)-(C5-C6heterocyclyl), each of which heterocyclyl contains 1-2 heteroatoms selected from nitrogen and oxygen, -(C1-C6alkylen)-(C6aryl, where aryl is selected from phenyl, and -(C1-C6alkylen)-(C5-C6heteroaryl), where heteroaryl contains 1 nitrogen atom, which alkyl, heterocyclyl, aryl and heteroaryl optionally substituted by one or more groups independently selected from F, Cl, Br, I, CH3, -CF3, -CO2H-PINES3, -CO2CH3,
-CONHCH3, -NHCOCH3, -NH(SO)2CH3, -OH, -och3, -S(O)2N(CH3)2and-S(O)2CH3;
R3represents a monocyclic heteroaryl chosen from:

in which the wavy line indicates the place of attachment.

2. The compound according to claim 1, in which R1choose from SN3, -CH2CH3,
-CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2- (CH3)2OH,
-CH2CH2OH, -CH2H 2CH2OH, -(C1-C6alkylen)-(C5-C6heterocyclyl), -CH2-(piperazine-1-yl), where the piperazine-1-yl optionally substituted, and-CH2-(4-(methylsulphonyl)piperazine-1-yl).

3. The compound according to claim 1, in which R2choose from SN3, -CH2CH3,
-CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2C1-C12alkyl, substituted by one or more-F, -(C1-C6alkylen)-(C5-C6heterocyclyl),
-CH2-(piperazine-1-yl), where the piperazine-1-yl optionally substituted, and-CH2-(4-(methylsulphonyl)piperazine-1-yl).

4. The compound according to claim 1, chosen from:
2-(2-(2-amino-4-metopirone-5-yl)-9-(2-hydroxyethyl)-6-morpholino-N-purine-8-yl)propan-2-ol;
2-(2-(2-aminopyrimidine-5-yl)-9-butyl-6-morpholino-N-purine-8-yl)propan-2-ol;
2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-9-propyl-N-purine-8-yl)propan-2-ol;
3-(2-(2-aminopyrimidine-5-yl)-8-(2-hydroxypropan-2-yl)-6-morpholino-N-purine-1-yl)propan-1-ol;
2-(2-(2-aminopyrimidine-5-yl)-9-(2-hydroxyethyl)-6-morpholino-N-purine-8-yl)propan-2-ol;
1-(4-((2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)methyl)piperidine-1-yl)ethanone;
1-(3-((2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)methyl)pyrrolidin-1-yl)ethanone;
(R)-3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)-1-(3-hydroxypyrrolidine-yl)propane-1-it;
(S)-3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)-1-(3-hydroxypyrrolidine-1-yl)propane-1-it;
1-(3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)propanol)-N-methylpiperidin-4-carboxamide;
3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)-1-(4-(methylsulphonyl)piperazine-1-yl)propane-1-it;
3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)-1-morpholinopropan-1-it;
3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)propanoic acid;
5-(9-(4-(methylsulphonyl)benzyl)-6-morpholino-N-purine-2-yl)pyrimidine-2-amine;
methyl 4-((2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)methyl)benzoate;
5-(6-morpholino-9-(2-morpholinoethyl)-9H-purine-2-yl)pyrimidine-2-amine;
5-(9-(3-methoxybenzyl)-6-morpholino-9H-purine-2-yl)pyrimidine-2-amine;
methyl 3-((2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)methyl)benzoate;
3-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)propan-1-ol;
2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)ethanol;
1-(2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)acetyl)-N-methylpiperidin-4-carboxamide;
2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)-1-(4-(methylsulphonyl)piperazine-1-yl)ethanone;
2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)-1-morpholinoethoxy;
2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl)acetic acid;
methyl 2-(2-(2-aminopyrimidine-5-yl)-6-morpholino-N-purine-1-yl) acetate;
5-(9-methyl-6-morphol the but-9H-purine-2-yl)pyrimidine-2-amine;
5-(9-methyl-6-morpholino-9H-purine-2-yl)pyridine-2-amine;
2-(2-(2-aminopyrimidine-5-yl)-9-methyl-6-morpholino-N-purine-8-yl)propan-2-ol;
2-(2-(6-aminopyridine-3-yl)-9-methyl-6-morpholino-N-purine-8-yl)propan-2-ol;
5-(9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-6-morpholino-N-purine-2-yl)pyridine-2-amine;
4-(2-(2-methoxypyridine-5-yl)-9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-N-purine-6-yl)research;
4-(9-methyl-8-((4-(methylsulphonyl)piperazine-1-yl)methyl)-2-(pyridin-3-yl)-N-purine-6-yl)research;
N-(1-((2-(2-amino-4-metopirone-5-yl)-9-ethyl-6-morpholino-N-purine-8-yl)methyl)piperidine-4-yl)-N-methylmethanesulfonamide; and
N-(1-((2-(2-aminopyrimidine-5-yl)-9-ethyl-6-morpholino-N-purine-8-yl)methyl)piperidine-4-yl)-N-methylmethanesulfonamide.

5. Pharmaceutical composition having anti-proliferative activity, containing a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier, control flowability, diluent or excipient.

6. A method of obtaining a pharmaceutical composition, comprising a mixture of compounds according to claim 1 with a pharmaceutically acceptable carrier.

7. The method of obtaining the compounds of formula I according to claim 1, including the interaction of the compounds of formula II:

with boronate a compound containing monocyclic heteroaryl, with the formation of compounds of formulas is I.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel pyrimidine-substituted purine compound of formula (I) or pharmaceutically acceptable salt of said compound, which possess inhibiting action with respect to mTOR and P13 kinases and can be applied in cancer treatment. Formula (I) compound corresponds to structural formula Formula (I)

EFFECT: invention relates to pharmaceutical composition which contains therapeutically effective quantity of said compound and pharmaceutically acceptable diluents, auxiliary substance or carrier, to method of inhibition of proteinkinase, selected from mTOR or P13 kinase, and to method of treatment or prevention of state in mammal, associated with inhibition of mTOR and/or P13 kinase activity.

11 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

The invention relates to new derivatives of 2-aryl-8-oxopiperidine formula (I) having a selective affinity towards BZw3receptor, the method thereof, pharmaceutical composition and means containing it, and also to the intermediate compound of formula (II) to obtain the derivatives of 2-aryl-8-oxopiperidine

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to an improved method for producing a purine compounds of General formula A, where X is hydrogen, hydroxy, chlorine, Ra and Rb denote hydrogen, acyl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

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

I-B I-C

I-D I-E

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

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

25 cl, 19 dwg, 8 tbl, 17 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to bicyclic heterocycles of formula I and formula II , in which radicals and symbols have values specified in the formula of the invention. These compounds have inhibiting activity in relation to MEK kinase. The invention also refers to a pharmaceutical composition for treatment of hyperproliferation disease or inflammatory disease, to a method for inhibition of abnormal growth of cells or treatment of hyperproliferation disorders and to a treatment method of inflammatory diseases of a mammal. Besides, the invention refers to use of a pharmaceutical composition for preparation of a medicinal agent for treatment of the above diseases of a mammal.

EFFECT: improving compound application efficiency.

19 cl, 29 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: pox virus of variolovaccine is proposed, which includes a defect F2L gene and a suicide gene. Pox virus has oncolytic activity. Besides, a reproduction method of such pox virus and its use for treatment of proliferative diseases or diseases with increased activity of osteoclasts is proposed.

EFFECT: improving compound application efficiency.

31 cl, 12 dwg, 3 tbl

FIELD: biotechnologies.

SUBSTANCE: an in vitro generation method of antigen-specific cytotoxic cells with activity against ovarian carcinoma cells is proposed. Simultaneously, a non-adhesive fraction of mononuclear cells (MNC) and mature dendritic cells (DC) are cultivated in presence of recombinant human interleukine-12 and recombinant human interleukine-18. MNC are extracted from peripheral blood of patients having ovarian carcinoma. Mature DC are obtained from monocytes of adhesive MNC fraction after two-day cultivation, and first, activation by lysate of autologous ovarian carcinoma cells, and then maturation of DC loaded with lysate during one day in presence of recombinant human TMF-α (tumor necrosis factor).

EFFECT: use of the invention provides reduction of a stage for obtaining mature DC, in vitro increases cytotoxicity of antigen-specific cytotoxic cells with antitumor activity and provides an immune response via T-helper to type 1 in respect to ovarian carcinoma, which can be used in ovarian carcinoma therapy.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology. What is disclosed is a vaccine representing four RNAs coding a prostate-specific antigen (PSA), a prostate-specific membrane antigen (PSMA), a prostate stem cell antigen (PSCA) and a six-transmembrane epithelial antigen of the prostate (STEAP). The vaccine is applicable for treating prostate carcinoma, preferentially neo-adjuvant and/or hormone resistant prostate carcinoma, as well as related diseases or disorders. Using the vaccine and a kit are also disclosed. The invention can be used in medicine.

EFFECT: preparing the vaccine for treating prostate carcinoma.

16 cl, 23 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a kit for lung cancer cell sensitisation to cisplatin. The declared kit comprises a first composition containing a therapeutically effective amount of sodium metaarsenite, and a second composition containing a therapeutically effective amount of cisplatin. Also, the invention refers to using the therapeutically effective amount of sodium metaarsenite for lung cancer cell sensitisation in a patient treated with cisplatin.

EFFECT: invention provides increasing the therapeutic effectiveness with a reduced risk of side effects.

10 cl, 4 tbl, 3 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination for treating a proliferative disease containing (a) the phosphoinositide3-kinase inhibitor 5-(2,6-dimorpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethylpyridin-2-ylamine (compound B) or a pharmaceutically acceptable salt thereof and (b) a compound that modulates the Ras/Raf/Mek pathaway specified in a group consisting of (i) a compound that modulates Raf kinase activity that is Raf265, SB590885, XL281 or PLX4032; (ii) a compound that modulates Mek kinase activity that is PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026, wherein the active ingredients in each case present in a free form or as a pharmaceutically acceptable salt or a hydrate thereof, and used simultaneously, separately or sequentially, a respective pharmaceutical composition or a combination drug, and a method of treating a proliferative disease in a homoithermic animal, principally a human.

EFFECT: what is shown is a synergism of the antineoplastic action of the declared combinations.

11 cl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound CL168 of general structural formula I where R is oxygen. The invention also relates to a method of producing a compound of formula I and use of the compound of formula I to produce a medicinal agent for preventing or treating tumorous and immunological diseases.

EFFECT: compound of formula I for producing a medicinal agent for preventing or treating tumorous and immunological diseases.

4 cl, 11 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulphonamide of formula A and/or a pharmaceutically acceptable salt thereof, having KDR and/or FGFR1 inhibitor properties. The compounds can be used to treat disorders associated with KDR mediated angiogenesis, such as cancer and age-related macular degeneration, or various cancerous diseases which respond to FGFR1 inhibition. Compound (A) corresponds to the structural formula (A) given below.

EFFECT: invention relates to crystalline forms I and II of said compound A and methods for production thereof, pharmaceutical compositions and a method of treatment.

38 cl, 8 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing acyclovir 2/3 hydrate, which involves mixing acyclovir with water in weight ratio of 1:5-50, dissolving at 50-100°C, filtering, cooling the filtrate at 0-30° to deposit crystals, collecting crystals by filtering and drying the crystals at 0-150°C for 0.5-24 hours to obtain acyclovir 2/3 hydrate having a stable crystalline structure.

EFFECT: preparation process is simple and suitable for industrial production.

10 cl, 4 dwg, 1 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: present invention refers to a prolonged release tablet containing theobromine and comprising a prolonged release layer and a fast release layer, wherein the prolonged release layer consists of 40-60 wt % of theobromine as an active ingredient and 14-19 wt % of a prolonged release base consisting of polyethylene oxide and hydroxypropyl methylcellulose, and the fast release layer consists of 10-30 wt % of theobromine as an active ingredient and 0.5-2 wt % of an aerating agent consisting of one or more ingredients specified in croscarmellose sodium, crospovidone and starch glycolate sodium salt.

EFFECT: prolonged release tablet according to the present invention effectively suppresses various types of cough symptoms if taken only once a day.

4 cl, 2 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel pyrimidine-substituted purine compound of formula (I) or pharmaceutically acceptable salt of said compound, which possess inhibiting action with respect to mTOR and P13 kinases and can be applied in cancer treatment. Formula (I) compound corresponds to structural formula Formula (I)

EFFECT: invention relates to pharmaceutical composition which contains therapeutically effective quantity of said compound and pharmaceutically acceptable diluents, auxiliary substance or carrier, to method of inhibition of proteinkinase, selected from mTOR or P13 kinase, and to method of treatment or prevention of state in mammal, associated with inhibition of mTOR and/or P13 kinase activity.

11 cl, 1 tbl, 3 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to cyclohexyl ammonium salt of 2-[3-methyl-7-(1,1-dioxotiethanyl-3)-1-ethyl xanthenyl-8-tio]acetic acid of the following formula: .

EFFECT: obtaining a new compound that shows antithromboembolic action and can be used in medicine.

2 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to using a purine derivatives for preparing drug preparations for treating chronic lymphocytic leukaemia and polycystic kidneys.

EFFECT: invention provides preparing the compounds possessing higher activity on lymphocytic leukaemia and polycystic kidneys.

8 cl, 3 dwg, 1 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a combined analgesic and anti-spasmodic drug containing caffeine and drotaverine hydrochloride, characterised by the fact that as active substances it additionally contains ketorolac or a compound thereof, such as ketorolac tromethamine and diphenylhydramine in the amount of: ketorolac or a compound thereof, such as ketorolac tromethamine 5 - 40 mg, caffeine 50 - 100 mg, diphenylhydramine 20 - 50 mg, drotaverine hydrochloride 40 - 80 mg.

EFFECT: invention provides developing the drug possessing strong analgesic action in moderate or severe pain syndromes, various cramping pains.

2 cl, 3 ex

Up!