Triazine, pyrimidine and pyridine analogues and use thereof as therapeutic agents and diagnostic samples

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

 

The technical FIELD

The present invention relates to a new therapeutic agents and diagnostic tests, including their pharmaceutically acceptable salts, prodrugs and metabolites, which are suitable for modulating the activity of a protein or enzyme, for modulating cellular activity, such as signal transduction, proliferation, differentiation, programmed cell death, migration and cytokine secretion. More specifically, the invention proposed compounds that inhibit, regulate, provide detection and/or modulate the activity of kinases, in particular, phosphoinositide-3-kinase (PI3K), target of rapamycin in mammals (mTOR), compounds that inhibit DNA-PK and ATM-kinase, their pharmaceutically acceptable salts and prodrugs, compositions of these new compounds, both alone and in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and application of these new compounds, as taken separately, or in combination with at least one additional therapeutic agent for the prevention or treatment of diseases, in particular diseases characterized by abnormal activity of serine/threonine kinases, receptor tyrosinekinase and lipid kinases. The invention also apply the methods of use of compounds for in vitro, in situ u in vivo diagnostics, development studies or treatment of mammalian cells or related pathological conditions.

The LEVEL of TECHNOLOGY

Protein kinase involved in the signal transmission, controlling the activation, growth, differentiation, survival and migration of cells in response to extracellular mediators or stimuli, including growth factors, cytokines or chemokines. In General, these kinases are divided into two groups: kinase that preferentially phosphorylate the tyrosine residues, and kinases that preferentially phosphorylate serine and/or threonine residues. Tyrosine kinase include membrane receptors growth factor, for example, the receptor for epidermal growth factor (EGFR), and cytosolic preceptory kinases, including the Src family kinase, kinase of the Syk family and kinase family of Ten.

Undesirable high activity of protein kinase plays a role in many diseases, including cancer, metabolic disorders, immunologic diseases and inflammatory disorders. These diseases may be caused directly or indirectly due to violations of the control mechanisms due to mutations, excessive expression or unwanted activation of the enzyme.

Proteincontaining - like receptor tyrosine kinase, and preceptories kinase is of great significance for the ctivitie and proliferation of cells of the immune system. Among the most amenable to early detection of effects in the activation of immunoreceptor in mastocyte, T-cells and b-cells, is encouraging preceptory tyrosinekinase.

Previously phosphoinositide-3-kinase (PI3K) were identified as lietkynes associated with viral oncogenes [Whitman et al., Nature 315:239-242 (1985), Sugimoto et al., Proc. Natl. Acad. Sci. 81:2117-2121 (1984); Mascara et al., Proc. Natl. Acad. Sci. 81:2728-2732 (1984)], and in the last 20 years were obtained additional evidence for the relationship between cancer and PI3KCully et al., Nat. Rev., Cancer 6:184-192 (2006); Wimann et al., Curr. Opin. Cell Biol. 17:141-149 (2005); Vivanco et al., Nat. Rev., Cancer 2:489-501 (2002). Since that time, it is believed that PI3K modulate a wide range of cellular activity and play an important role in the control of growth and metabolism. Path marking PI3K genetically modified mice and studies of hereditary diseases in humans, such as the syndrome Caudina, tuberose sclerosis, ataxia-telangiectasia, X-linked myotubular myopathy and neuropathy Charcot-Marie-Tooth, provided additional information about the cellular system and the role of phosphoinositide signaling system. Dysregulation of levels of phosphoinositides and, in particular, products of class I PI3K, Ptdlns (3,4,5)P3, plays a role in the pathogenesis of cancer, chronic inflammatory, allergic diseases, metabolic disorders, diabetes and problems with cardio the vascular system.

PI3K are a family of enzymes that carry out phosphorylation at position 3'-Oh inonitoring ring of phosphoinositides. PI3K is divided into three classes on the basis of structural features and specificity in relation to the lipid substrate in vitro [Marone et al., Biochimica et Biophysica Acta 1784:159-185 (2008)]. PI3K class I form heterodimer, which consist of one of four closely related catalytic subunits of ~110 kDa and associated regulatory subunit belonging to two different families. In vitro they are able to turn PtdIns to PtdIns-3-P, PtdIns-4-P to PtdIns(3,4)P2 and PtdIns(4,5)P2 PtdIns(3,4,5)P3, but the substrate in vivo is a PtdIns(4,5)P2 [Cantley et al., Science 296:1655-1657 (2002)]. PI3K class I activated using a wide range of cell surface receptors, including the receptors of growth factors and receptors associated with G-proteins.

PI3K class II can fosforilirovanii PtdIns and PtdIns-4-P in vitro, but still relevant substrates in vivo are the subject of research. Specified class (170-200 kDa) enzyme contains three representatives, characterized C-terminal homology domain C2. Now for PI3K class II molecules adapters not identified. PI3K class III can fosforilirovanii exclusively PtdIns and develop, thus only PtdIns-3-p is the Only representative of the specified class performance is to place a Vps34, the prototype of which is S. cerevisiae Vps34p (using protein sorting mutant proteins 34), which, as we have seen, plays an important role in the migration of newly synthesized proteins from the Golgi apparatus vacuole in yeast cells, the equivalent of mammalian lysosomes in organelles [Schu et al., Science 260:88-91 (1993)].

Phosphoinositide-4-kinase (PI4K), are pastravanu position 4'-HE inonitoring ring of PtdIns and produce, thus, PtdIns-4-p is Specified, the lipid can then be further phosphorylated using PtdIns-4-P 5-kinase to generate PtdIns(4,5)P2, which represents the main source of phospholipase C and PI3K signal in the plasma membrane. There are four isoforms PI4K: P14KIIα and β and P14KIIIα and β. PI4KIII are most closely associated with PI3K.

Class PI3K-related protein, called PI3K class IV consists of high molecular weight enzymes with a catalytic core, similar PI3K and PI4K, and includes the target of rapamycin (mTOR, also known as FRAP), DNA-dependent protein kinase (DNA-PK), the mutated gene product of the ataxia-telangiectasia (ATM), ataxia associated with teleangiectasia (ATR), SMG-1 and transformation/transcription-associated domain protein (TRRAP). The first five representatives are active protein serine-trionychinae, which are involved in the control of cell growth and the control of genome/transcriptome [Maone et al., Biochimica et Biophysica Acta 1784:159-185 (2008)]. DNA-PK, ATM, ATR and SMG-1 is involved in the response to DNA damage. The only active kinase, is not involved in the DNA damage is mTOR, which is regulated by growth factors and nutrient availability and coordinates protein synthesis, growth and cell proliferation. The target of rapamycin (mTOR) forms a complex 1 and integrates the signal growth factor (through PI3K7PKB and cascade Ras/MAPK), energy status (LKB1 and AMRS) and the detection of nutrients. TOR positively regulated by PKB/Akt, which phosphorylates a negative regulator in TSC2 complex tuberose sclerosis (TSC), which leads to activation of the G Rheb and mTOR [Marone et al., Biochimica et Biophysica Acta 1784:159-185 (2008)]. At the same time, mTOR stimulates the translation of ribosomal proteins and, consequently, the biogenesis of ribosomes through activation of p70S6K[Wullschleger et al., Cell 124:471 (2006)]. Rapamycin derivative RAD001 and CCI-779 in contact with FKBP12 and very selectively block the activity of mTOR complex 1 (mTORC1). With the use of rapamycin and its derivatives have conducted many clinical trials, mainly in patients with a tumor characterized by enhanced signal transfer and hyperactive PI3K mTOR. Promising results were obtained for lymphoma cells in the mantle zone, endometrial cancer and renal cell carcinoma [Guertin et al., Cancer Cell 12:9 (2007)]. Rapamycin and its derivatives remain Aut anti-angiogenic activity, because they neutralize the effect of VEGF [on et al., Nat. Med. 8:128 (2002)], which opens up the possibility for the treatment, combined with conventional chemotherapy [Beuvink et al.), Cell 120:747 (2005)].

The path PI3K is a key signal transduction cascade that controls the regulation of growth, proliferation, survival, and migration of cells. PI3K are activated by many different stimuli, including growth factors, inflammatory mediators, hormones, neurotransmitters and antibodies and antigens [Wimann et al., Trends Pharmacol. Sci. 24:366-376 (2003)]. Isoforms of PI3K class 1: PI3Kα, β, and δ - contact one of R/P55/P50 regulatory subunits that contain two SH2 domain, which bind with high affinity to phosphorylated motifs Tyr-X-X-Met. These motifs are present in activated receptors growth factors, their substrates and in a number of proteins adapters. In accordance with the above description, the activation of the signaling cascade, PI3K/PKB has a positive effect on growth, survival and cell proliferation. Constitutive positive regulation of PI3K signal may have a destructive effect on cells, leading to uncontrolled cell proliferation, enhanced migration and growth, independent of adhesion. These phenomena are favorable not only to the formation of malignant tumors, but also the development of Pospolita the data and autoimmune diseases.

Path PI3 kinase/Akt/PTEN is an attractive target for development of anti-cancer drugs, because it can be expected that these agents will inhibit the proliferation, to pay the suppression of apoptosis and to suppress the resistance of cancer cells to cytokine agents. Inhibitors of PI3 kinase are presented in the literature [see, in particular, Marone et al., Biochimica et Biophysica Acta 1784:159-185 (2008), footsteps of Yaguchi et al. (2006), Jour. Of the Nat. Cancer Inst. 98(8):545-556; US 6770641; US 6653320; US 6403588; US 6703414; WO 9715658; WO 2006046031; WO 2006046035; WO 2006046040; WO 2007042806; WO 2007042810; WO 2004017950; US2004092561; WO 2004007491; WO 2004006916; WO 2003037886; US2003149074; WO 2003035618; WO 2003034997; WO 2007084786; WO 2007095588; WO 2008098058; US 2003158212; EP 1417976; US 2004053946; JP 2001247477; JP 08175990; JP 08176070]. Derivatives of 1,3,5-triazine and pyrimidine as pharmaceuticals were obtained in connection with their anti-cancer, anti-inflammatory, analgesic and antispasmodic activity. In particular, the well-known hexamethylmelamine or altretamin (GMM or N2N2N4N4N6N6-HEXAMETHYL-1,3,5-triazine-2,4,6-trimip), which was developed as an analogue of the antitumor agent triethylenemelamine (TEM); GMM acts as a prodrug of hydroxyethylnitrosamine (GEM: the metabolically active form GMM) [Johnson et al., Cancer, 42:2157-2161 (1978)]. GMM on the market in Europe for the indications for treatment of ovarian cancer, melcochita the CSOs lung cancer.

Known for some of the triazine compounds having activity of inhibiting PI3 kinase and inhibiting the growth of cancer cells [WO 02088112 (ER), "HETEROCYCLIC COMPOUNDS AND ANTITUMOR AGENT CONTAINING THE SAME AS ACTIVE INGREDIENT", Kawashima et al., Filing date: 26.04.2002; WO 05095389 (ER). "HETEROCYCLIC COMPOUND AND ANTI-MALIGNANT-TUMOR AGENT CONTAINING THE SAME AS ACTIVE INGREDIENT", Kawashima et al., Filing date: 30.03.2005; WO 06095906 (ER), "IMMUNOSUPPRESSIVE AGENT AND the ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENTS, Haruta et al., Date of application: 11.03.2005; WO 09905138 (ER), HETEROCYCLIC COMPOUNDS AND ANTITUMOR AGENT CONTAINING THE SAME AS ACTIVE INGREDIENT, Kawashima et al., Date of application: 24.07.1998]. The triazine compound ZSTK474, developed in research laboratories Zenyaku Kogyo, represents the first, introduced orally, the triazine compound which has a high activity against PI3K, which showed strong antitumor activity against xenografts of human cancer in mice without manifestations of critical toxicity [footsteps of Yaguchi et al., Journal of The National Cancer Institute, 98:545-556, (2006)]. ZSTK474 is an competing with ATP inhibitor isoforms of phosphatidylinositol 3-kinase class I [Kong et al., Cancer Sci, 98:1638-1642 (2007)].

Known to some pyrimidine compounds that bind R alpha with activity, inhibiting PI3 kinase and inhibiting the growth of cancer cells (Intellectual property of the company AstroZeneca: WO 07066103, WO 07080382, WO 08023159, WO 08023180, WO 08032027, WO 08032033, WO 0803036, WO 08032041, WO 08032072, WO 08032077, WO 08032086, WO 08032089, WO 08032091; Intellectual property company Genentech/Piramed/Roche: US2007009880, WO 07127183, WO 08073785, WO 07042810, WO 07122410, WO 07127175, WO 07129161, WO 08070740, WO 2006046031, WO 2006046040, WO 2007042806, WO 2007122410; Intellectual property Novartis: WO 07084786, WO 08098058).

To increase the spectrum of cancers that can be treated with the indicated compounds, and increase the anticancer activity of these compounds, active against PI3K and/or mTOR, the authors of the present invention conducted in-depth research derived based on triazine, pyrimidine and pyridine and received, thus new heterocyclic compounds represented by the formula (I) and formula (Ia) to (Ii), which show strong biological activity against lipid kinases.

Compared with PI3K inhibitors described Zenyaku Kogyo (WO 02088112 (EP 1389617), WO 2005095389 (EP 1741714), WO 2006095906 (EP 1864665), WO 09905138 (EP 1020462)], AstraZeneca (WO 07066103, WO 07080382, WO 08023159, WO 08023180, WO 08032027, WO 08032033, WO 08032036, WO 08032041, WO 08032072, WO 08032077, WO 08032086, WO 08032089, WO 08032091), Piramed/Genentech (US 2007009880, WO 07127183, WO 08073785, WO 07042810, WO 07122410, WO 07127175, WO 08070740, WO 2006046031, WO 2006046040, WO 2007122410), Yamanouchi/Piramed (WO 01083456) and Novartis (WO 07084786, WO 08098058) inhibitors according to the present invention differ in the inclusion of the N atom in the basic heterocyclic ring that provides the best biological activity relative to the target enzyme, and/or the inclusion of new what about the molecular fragment, making the molecule as a whole more active or more selective for the corresponding enzyme.

BRIEF description of the INVENTION

The invention relates in General to new derivatives based on triazine, pyrimidine and pyridine, and their use as therapeutic agents and diagnostic tests.

The invention also relates to kinase inhibitors and diagnostic assays to detect kinase.

The invention also relates to compounds, inhibiting phosphoinositide 3-kinase (PI3K) and target of rapamycin in mammals (mTOR), with anticancer activity, pharmaceutical compositions of these compounds, which are potentially applicable for the treatment of diseases, conditions and/or disorders modulated PI3K and mTOR kinases. Compounds can inhibit tumor growth in mammals and can be used to treat patients suffering from cancer.

The invention also relates to methods of using compounds for the diagnosis of T. vitro, in situ and in vivo or treatment or mammalian cells, organisms, or associated pathological conditions.

Specifically, in one aspect of the present invention proposed the compounds of formula (I).

More specifically, in one aspect of the present invention proposed triazine compounds of formulas (Ia) to (Id), pyrimidine compounds of formula is t (If) to (Ii) and pyridine compounds of formula (Ie) and (If) to (Ii):

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide derivatives and pharmaceutically acceptable salts.

In another aspect of the present invention proposed a pharmaceutical composition comprising a triazine or pyrimidine or pyridine compound of the formula (I) or one of the formulas (Ia) to (Ii) and a pharmaceutically acceptable carrier. The pharmaceutical composition may additionally contain one or more additional therapeutic agent selected from anti-proliferative agents, anti-inflammatory agents, immunomodulatory agents, neurotropic factors, agents for treating blood disorders, an agent for treating diabetes and agents for treating immunodeficiency disorders.

In another aspect of the present invention, methods of inhibiting the activity of PI3K kinases, including PI3K interaction of the kinase with an effective inhibiting amount of the compounds of formula (I) or one of the formulas (Ia) to (Ii) or its stereoisomer, geometric Isom the RA, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salts or prodrugs.

In another aspect of the present invention proposed methods of prevention or treatment of diseases or disorders modulated PI3 kinases, including the introduction to a mammal in need of specific treatment, an effective amount of the compounds of formula (I) or one of the formulas (Ia) to (Ii) or its stereoisomer, geometric isomer, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salts or prodrugs. Examples of such diseases, conditions or disorders include, but are not limited to, hyperproliferative disorders (e.g., cancer, including melanoma and other skin cancers), neurodegeneration, cardiac hypertrophy, pain, migraine, neurotraumatic disease, stroke, diabetes, gepatomegalia, cardiovascular disease, Alzheimer's disease, cystic fibrosis, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic diseases, inflammation, neurological disorders, diseases related to hormones, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone lesions, hyperproliferative disorders, infectious diseases, state SV is related with cell death, platelet aggregation induced by thrombin, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions, including activation of T cells, and abnormalities of the Central nervous system.

In another aspect of the present invention proposed methods of prevention or treatment of hyperproliferative disorders, comprising the administration to a mammal in need of specific treatment, an effective amount of the compounds of formula (I) or one of the formulas (Ia) to (Ii) or its stereoisomer, geometric isomer, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salt or prodrug, individually or in combination with one or more additional compounds having antihypercholesterolemic properties.

In another aspect of the present invention proposed a method of using compounds according to the present invention for treatment of a disease or condition modulated PI3 kinase and/or mTOR, mammalian.

An additional aspect of the present invention includes the use of compounds according to the present invention in obtaining drugs for 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 is (I) or one of the formulas (Ia) to (Ii) or a stereoisomer, geometric isomer, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salt or prodrug; the container and possibly the instruction manual or insert with indications for treatment.

Another aspect of the present invention includes methods of preparation, methods of isolation and purification methods of the compounds of formula (I) or one of the formulas (Ia) to (Ii).

Another aspect of the present invention includes new intermediate compounds applicable for producing compounds of formula (I) or one of the formulas (Ia) to (ii).

Additional advantages and new features of the present invention proposed, in particular, in the following description, and, in particular, will become clear to experts in the art after considering the following description or may be learned in the practical study of the present invention. The advantages of the present invention may be realized and obtained by means of the combinations, compositions and methods specifically noted in the attached claims.

DETAILED DESCRIPTION of a TYPICAL IMPLEMENTATION OPTIONS

Please refer to the detailed description of specific variants of realization of the present invention, examples of which are illustrated in the accompanying structures or formulas. While the invention together describe the variants of implementation, it should be understood that they are listed as not limiting the invention under these implementation variants. On the contrary, the invention covers all alternatives, modifications and equivalents that may be included in the scope of present invention defined by the claims.

Specialist in the art will understand the methods and materials similar or equivalent to that described in the present application, 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 described in this application.

If one or more reference publication, patents, and similar materials, different from or contradicts this application in relation to, including but not limited to, the specific terms, use of terms, described techniques and so on, should be taken into account solely the content of this application.

DEFINITION

The term "alkyl", as used in this application, refers to saturated linear or branched monovalent hydrocarbon radical containing from one to twelve carbon atoms (C1-C12), where the alkyl moiety may be independently substituted by one or more Deputy, described below. In another embodiment, the implementation of skinny radical contains from one to eight carbon atoms (C1-C8), or from one to six carbon atoms (C1-C6). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (I-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (I-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (sec-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-Bu, tert-butyl, -C(CH3)3), 1 pentyl (n-pentyl, -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 (-CH2CH2CH2CH2CH3), 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-2-pentyl (-CH(CH3)(CH2CH3 )2), 2-methyl-3-Patil (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-distil-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and so on

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing from two to eight carbon atoms (C2-C8) containing at least one unsaturated site, i.e., carbon-carbon sp2 double bond, where alkanniny radical may be substituted by one or more Deputy described in this application, 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=CH2and so on

The term "quinil" refers to a linear or branched monovalent hydrocarbon radical containing from two to eight carbon atoms (C2-C8) containing at least one unsaturated site, i.e., carbon-carbon, sp triple bond, where alkynylaryl radical may be independently substituted by one or more Deputy described in this application. Examples include, but are not limited to, ethinyl (-C≡CH), PROPYNYL (propargyl, -CH2With≡CH), and so on, the Term "halogen" (and halo) preferably represents chlorine or fluorine, but it can also represent bromine or iodine.

The terms "carbocycle", "carbocyclic", "carbocyclic ring" and "cycloalkyl" refers to a monovalent, non-aromatic, saturated or partially unsaturated ring containing from 3 to 12 carbon atoms (C3-C12) in the monocyclic ring or 7 to 12 carbon atoms in the structure of the bicyclic ring. Bicyclic carbocycle containing from 7 to 12 atoms can be grouped, for example, in the form of bicyclo[4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycle containing 9 or 10 atoms in the ring can be grouped in the form of a bicyclo [5,6] or [6,6] system, or bridged systems 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 cyclopen-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 so on

"Aryl" means 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 system. Some of the aryl groups represented in tipis the data structures, as "Ar". Aryl includes bicyclic radicals containing aromatic ring condensed with a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical 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 etc., Aryl groups are possible independently substituted by one or more Deputy described in this application.

The terms "heterocycle", "heterocyclyl" and "heterocyclic ring", which in this application are used interchangeably, refer to a saturated or partially unsaturated (i.e. containing one or more double and/or triple bond within the ring) carbocyclic to radical containing from 3 to 20 atoms in the ring, in which at least one atom of the ring is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms are atoms, where one or more atoms of the ring may independently substituted by one or more Deputy described next. A heterocycle may be a monocycle containing from 3 to 7 members in the ring (from 2 to 6 carbon atoms and from 1 to 4 heteroatoms selected from N, O, P and S) or Bicycle, containing up to 10 members in the ring (from 4 to 9 carbon atoms and 1 to 6 heteroatoms, selected from N, O, P and S), for example: bicyclo[4,5], [5,5], [5,6] or [6,6] system. The heterocycles described in the work of Leo A. Pak: "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), especially in Sections 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclyl" also includes radicals where heterocyclic radicals are fused with a 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, morpholine, thiomorpholine, dioxane, piperazinil, homopiperazine, azetidine, oxetane, titanyl, homopiperazine, oxetanyl, tepanil, oxazepines, diazepampill, thiazepines, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dihydroindol, dihydrofurane, pyrazolopyrimidines, imidazolines, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes, azabicyclo[2.2.2]hexanal, 3H-indolealkylamines and N-pyridyl urea. Also in the scope of this definition includes spirography Examples of the heterocyclic group, in which 2 carbon atoms of the ring substituted by an oxo (=O) groups are pyrimidinones and 1,1-dioxothiazolidine. Heterocyclic groups described in this application are possible independently substituted by one or more Deputy described in this application.

The term "heteroaryl" refers to a monovalent aromatic radical of 5-, 6 - or 7-membered ring and includes a condensed system of rings (at least one of which is aromatic), consisting of 5-20 atoms, containing one or more heteroatom 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, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, tetrahydroisoquinoline, indolyl, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, triazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazolyl, hintline, honokalani, naphthyridines and properidine. Heteroaryl groups are in which can be independently substituted one or more Deputy described in this application.

Heterocyclic or heteroaryl groups may be associated with carbon (linked via a carbon atom or nitrogen (linked via the nitrogen atom), where binding is possible. As an example and not for limitation, linked through a carbon atom heterocycles or heteroaryl attached in position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5 or 6 pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5 or 6 pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 oxazole, imidazole or thiazole, position 3, 4 or 5 isoxazol, the pyrazole or isothiazole, position 2 or 3 of aziridine, position 2, 3 or 4 azetidine, position 2, 3, 4, 5, 6, 7 or 8 of a quinoline or position 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

As an example and not for limitation, linked through the nitrogen atom heterocycles and heteroaryl 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, position 2 - isoindole or isoindoline, position 4 of the research and position 9 carbazole or β-carboline.

The term "monocyclic heteroaryl" refers to the five - or chesticles the mu unsubstituted or substituted monocyclic the heteroaryl radical, which contains 1, 2, 3 or 4 heteroatoms in the ring independently selected from N, O and S. the Monocyclic heteroaryl can be attached at position C-2 of the pyrimidine ring according to formula Ia-Ii on any carbon atom (linked via a carbon atom or nitrogen (linked via the nitrogen atom) monocyclic heteroaryl R3 group. 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. Monocyclic heteroaryl is possible independently substituted by one or more Deputy described in this application.

The terms "treat" and "treatment" refers to therapeutic treatment and prophylactic or preventative measures, where the aim is to prevent or slow down (weakening) unwanted pathological changes or disturbances, such as the development or spread of cancer. For the objectives of the present invention is favorable or gelatinlike results include, but not limited to, reduction of symptoms, reducing the severity of the disease, stable (i.e., not worsening) state of disease, delay or slowing of disease progression, relief or mitigation of a disease state, and remission of disease (partial or full), detected or redetection. "Treatment" can also mean increased survival compared with the expected survival rate without treatment. Patients in need of treatment include patients suffering from painful conditions or disorders, and patients who are prone to painful condition or violation, or patients who require prevention of the disease condition or of the breach.

The phrase "therapeutically effective amount" means an amount of compound according to the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) reduces, simplifies or eliminates one or more symptom of a particular disease, condition or violation, or (iii) prevents or delays the manifestation of one or more symptoms of the particular disease, condition or violation described in this application. In the case of cancer, a therapeutically effective quantity of a drug can reduce the number of cancer cells; minisat the size of the tumor, to inhibit (i.e., slow to some extent and preferably stop) the penetration of cancer cells in the peripheral organs, inhibit (i.e., slow to some extent and preferably stop) tumor metastasis, inhibit, to some extent, tumor growth and/or alleviate to some extent one or more symptoms caused by the cancer. Depending on the extent to which the drug may prevent growth and/or kill existing cancer cells, the drug may be cytostatic and/or cytotoxic. The effectiveness of cancer treatment can be measured, for example, by determining the time to progression (TTP) and/or determine the speed of response (RR).

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. "Tumor" includes one or more cancer cell. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid leukemia. More specific examples of these 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, gastric or digestive tract, including cancers of the gastrointestinal tract, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial carcinoma or cancer, cancer of the salivary glands, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, carcinoma of the penis and head and neck cancer.

"Chemotherapeutic agent" is a chemical compound that is applicable for the treatment of cancer. Examples of known chemotherapeutic agents include trastuzumab, pertuzumab, erlotinib (TARCEVA®, Genetech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sunitinib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesilate (GLEEVEC®, Novartis), pinsonat (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (NEXAVAR, Bayer Labs) and gefitinib (IRESSA®, AstraZeneca), AG1478 effect, alkylating agents, such as thiotepa and CYTOXAN® (cyclophosphamide; alkyl sulphonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimines and methylmelamine, including altretamin, treat lomellin, triethylenephosphoramide, triethylenethiophosphoramide and trimethylamine; acetogenin; camptothecin (including the synthetic analogue topotecan);bryostatin; callistemon; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins; dolastatin; duocarmycin (including sinteticheskie analogues, KW-2189 and SW-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; attestee the mustards such as chlorambucil, chlornaphazine, chlorpropamide, estramustine, ifosfamide, mechlorethamine, hydrochloride mechlorethamine, melphalan, novemberin, finestein, prednimustine, trofosfamide, uramustine; nitrocefin, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine and ranimustine; antibiotics such as enediyne antibiotics (for example, calicheamicin, specifically calicheamicin gamma and calicheamicin omega; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; spiramycin; and the chromophore neocarzinostatin and related chromophores chromoproteins enediynes antibiotics), aclacinomycin, antipoison, autralian, azaserine, bleomycin, actinomycin, carubicin, karminomitsin, calcination, chromomycin, dactinomycin, daunorubicin, demoralizing, 6-diazol-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morphosyntactical, cyanomethaemoglobin, 2-pyrrolidinecarbonyl and deok doxorubicin), epirubicin, zorubicin, idarubitsin, marsellaise, mitomycin, such as mitomycin C, mycophenolate acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, colomycin, radiobeacon, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites 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 analogues such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, propionate of dromostanolone, epitiostanol, mepitiostane, testolactone; anti-adrenal agents, such as aminoglutetimid, mitotane, trilostane; DOPOLNITEL folic acid, such as prolinnova acid; Eagleton; glycoside aldophosphamide; aminolevulinic acid; eniluracil; amsacrine; astroball; bisantrene; edatrexate; defaming; demecolcine; diastop; alternity; the acetate slipline; epothilone; etoposide; gallium nitrate; hydroxyurea; lentinan; londini; maytansinoid, such as taitensis and ansamitocins; mitigate; mitoxantrone; mopidamol; nitrean; pentostatin; penomet; pirarubicin; losoxantrone; podofillina acid; 2-those who hydrazide; procarbazine; PSK® polysaccharide complex; razoxane; rhizoxin; sizofiran; spirography; tinoisamoa acid; triaziquone; trichothecenes; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; Galitsin; arabinoside; taxoid, for example, TAXOL® (paclitaxel; Bristol-Myers Squibb), ABRAXANE™ (not containing cremophor), procastinate compositions paclitaxel. created with the inclusion of albumin, and TAXOTERE® (docetaxel, docetaxel; Sanofi-Aventis); chlorambucil; GEMZAR® (gemcitabine); 6-tioguanin; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinblastine; etoposide; ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CF-11; topoisomerase inhibitor RFS 2000; deformational (DFMO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above compounds.

In the definition of "chemotherapeutic agent" also includes (i) protivokomarinye agents that participate in the regulation or ophiuroidea of hormone action on tumors such as anti-estrogens and selective receptor modulators (MAYOR), including, for example, tamoxifen (including NOLVADEX® tamoxifen citrate), raloxifene, droloxifene and FARESTON® (citrate toremifene); (ii) inhibitors aroma the basics, which inhibit the enzyme aromatase, which regulates the production of estrogen in the adrenal glands, such as, for example, 4(5)-imidazoles, MEGASE® (acetate megestrol), AROMASIN® (exemestane, Pfizer), forestation, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole, Novartis), and ARIMIDEX® (anastrozole, AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide; (iv) inhibitors of protein kinases; (v) inhibitors lietkynes; (vi) antimicrobic oligonucleotides, particularly oligonucleotides, which inhibit expression of genes in signaling pathways that occur when disturbed cell proliferation, such as, for example, RKS-alpha, Rafl and H-Ras; (vii) ribozymes such as inhibitors of the expression of VEGF (e.g., ANGIOZYME®) and inhibitors of HER2 expression; (viii) vaccines such as vaccines, used in gene therapy, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2, an inhibitor of topoisomerase 1, such as LURTOTECANE®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above compounds.

The term "prodrug", as used in this application refers to a precursor or derivative form of a compound according to the present invention, which may be less cytotoxic to the cells compared to the reference compound or medicine, and is capable of enzymatic or hydrolytic the key to be activated or to become more active in its original form. prodrugs according to the present invention include, but are not limited to, phosphate-containing prodrugs, thiophosphoramide prodrugs, sulfadimidine prodrugs, peptideatlas prodrug, prodrug, modified D-amino acids, glycosylamine prodrugs, β-lactosidase prodrugs, possibly substituted phenoxyacetaldehyde prodrugs, 5-fortitudinous and other 5-ptoluidine prodrugs that can be converted into the more active cytotoxic free drug. Examples of cytotoxic drugs that can be transformed into the form of prodrugs for use in the present invention include, but are not limited to, compounds according to the present invention and the chemotherapeutic agents, similar to those described above.

"Metabolite" is a product resulting from metabolism in the body specific compounds or salts thereof. Metabolites of compounds can be determined using standard techniques known in the art, and their activity can be determined using studies similar to those described in this application. These products can be obtained, for example, oxidation, recovery, hydrolysis, amidation, is amidarone, esterification, deesterification, enzymatic degradation, and so on, input connections. Accordingly, the invention includes metabolites of compounds according to the present invention, including compounds produced by a process that includes the interaction of the compounds according to the present invention with a mammal for a time sufficient to obtain its metabolic product.

"Liposome" is a small vesicles composed of various GIP lipids, phospholipids and/or surfactant, which are applicable for delivery of a drug (such as inhibitors of PI3K and mTOR kinases described in this application, and, perhaps, a chemotherapeutic agent) to a mammal. The components of the liposomes, as a rule, are distributed in the bilayer formation, similar to the distribution of lipids in biological membranes.

The term "instructions for use" is used as a link to the instructions, usually supplied in 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 that do not coincide with the molecule, Kotor, which is mirroring, while the term "achiral" refers to molecules that consist of the molecule, which is their mirror reflection.

The term "stereoisomers" refers to compounds which have identical chemical composition, the different distribution of the atoms or groups in space.

"Diastereoisomer" refers to a stereoisomer, which contains two or more of the center of chirality, whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. A mixture of diastereoisomers can be separated by the application of analytical procedures with high resolution, such as electrophoresis and chromatography.

"Enantiomers" refers to two stereoisomers of compounds that are mismatched mirroring each other.

Stereochemical definitions and conventions used in this application, as a rule, taken from a paper by S. P. Parker, Ed., McRaw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and the work of Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Compounds according to the present invention may contain asymmetric or chiral centers, and exist, therefore, in different stereozoom the situations forms. Understand that all stereoisomeric forms of the compounds according to the present invention, including, but not limited to, diastereomer, enantiomer and atropoisomeric, 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., 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 describe the absolute configuration of the molecule about its chiral(s) centre(s). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of the connection plane-polarized light, and (-) or l indicates that the connection is levogyrate. Connection with the prefixes (+) or d is Pervouralsk. For a given chemical structure, 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. 50:50 mixture of enantiomers is called a racemic mixture or racemate.

The term "tautomer or tautomeric form" refers to the structural isomers with different energy States, which convert the I to each other, passing through a low energy barrier. For example, proton tautomers include mutual transformations due to the migration of a proton, such as keto-enol and Imin-enaminone isomerization.

The term "pharmaceutically acceptable salt" used in this application, refers to pharmaceutically acceptable organic or inorganic salts of the compounds according to the present invention. Typical salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannat, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate "mesilate", aconsultant, bansilalpet, p-toluensulfonate, pamoat. Pharmaceutically acceptable salt may contain an insert of another molecule, such as an acetate ion, succinate ion and other counterions. The counterion may be any organic or inorganic group which stabilizes the charge of the original connection. In addition, pharmaceutically acceptable salt may contain more than one charged atom in the structure. If a part of the pharmaceutically acceptable salt are a few of charged atoms, the salt can region in order to give more counterions. Thus, the pharmaceutically acceptable salt may contain one or more charged atom and/or one or more of the counterion.

If the connection according to the present invention is a base, target pharmaceutically acceptable salt may be obtained by any suitable method 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, phosphoric acid, etc. or organic acid, such as acetic acid, triperoxonane acid, maleic acid, succinea acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, xalilov acid, glycol acid, salicylic acid, paranosema acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, acid, such as p-toluensulfonate or econsultation and so on

If the connection according to the present invention is an acid, CE is the Wake pharmaceutically acceptable salt can be obtained in any suitable way, for example, by treatment of the free acid with an inorganic or organic base, such as amine, a hydroxide of an alkali metal or a hydroxide of alkaline-earth metal, etc. Illustrative examples of suitable salts include, but are 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 derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients making up the composition and/or mammal that is being treated for the specified structure.

"MES" refers to the associate or complex of one or more solvent molecules and compounds according to 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 a water.

The term "protective group" refers to the Deputy, which,as a rule, used to lock or protect a specific function, in which reactive remain other functional group compounds. For example, "amino-protective group" is a Deputy, attached to the amino group that blocks or protects aminopentyl connection. Suitable amino-protective groups include acetyl, TRIFLUOROACETYL, t-butoxycarbonyl (VOS), benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (Fmoc). For a detailed description of the protective groups and their applications see T. W. Greene, Protective Groups I Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound according to the present invention" and "compounds according to the invention" and "compounds of formula (I) or one of the formulas (Ia) to (Ii) include the compounds of formula (I) or one of the formulas (Ia) to (Ii) and their stereoisomers, geometric isomers, tautomers, solvate, metabolite, N-oxide derivatives and pharmaceutically acceptable salts and prodrugs. The term "mammal" includes, but is not limited to, humans, mice, rats, Guinea pigs, monkeys, dogs, cats, horses, cows, pigs and sheep.

ANALOGUES TRIAZINE, PYRIMIDINE AND PYRIDINE, AND THEIR USE AS THERAPEUTIC AGENTS AND DIAGNOSTIC SAMPLES

In the present invention proposed triazine, pyrimidine and pyridine compounds is their pharmaceutical compositions which are applicable as therapeutic agents, and new diagnostic tests. In addition, these compounds are potentially applicable for the treatment of diseases, conditions and/or disorders modulated by protein kinases and libidinously. More specifically, the present invention proposed the compounds of formula I,

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide derivatives and pharmaceutically acceptable salts, where:

Q=N, G=N, U=N (compounds of formulas (Ia) to (Id) based on triazine);

Q=C, G=C, U=N (compounds of formula (Ie) on the basis of the pyridine);

Q=C, U=C, G=N (compounds of formula (Ie) on the basis of the pyridine);

U=C, G=C, Q=N (compounds of formula (Ie) on the basis of the pyridine);

Q=CRz, G=N, U=N (condensed compounds of formula (If) to (Ii) on the basis of pyrimidine); or

Q=CRz, G=C, U=N (condensed compounds of formula (If) to (Ii) on the basis of the pyridine);

where Rzselected from the group consisting of:

(1) hydrogen, (2) cyano, (3) halogen, (4) methyl, (5) trifloromethyl, (6) sulfonamide, (7) sulfone, (8) linker fragment (hydrophobic linkers, hydrophilic linkers (Paglierani of linkers), tseplyaesh in the light of linkers, tseplyaesh in the redox reactions of linkers), (9) linker fragment covalently who knit TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups), (10) F, Cl, Br, I, -C1-C6-alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10, C1-C12 of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl and C1-C20heteroaryl; or (C3-C12carbocycle,2-C20heterocyclyl,6-C20aryl or C1-C20heteroaryl; where the specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl are possibly substituted one and the and more group independently selected from F, Cl, Br, I, CN, CF3, -NO2, oxo, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -(CR14R15)nC(=Y)NR10R11, -(CR14R15)nRC(=Y)OR10, (CR14R15)nNR12SO2R10, -(CR14R15)nOR10, -(CR14R15)nR10, -(CR14R15)nSO2R10, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12SO2R10, =NR12OR10, -OC(=Y)R10, -OC(=Y)OR10, -OC(=Y)NR10R11, -OS(O)2(OR10), -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), SR10, -S(O)R10, -S(O)2R10, -S(O)2NR10R11, -S(O)(OR10), -S(O)2(OR10), -SC(=Y)R10, -SC(=Y)OR10, -SC(=Y)NR10R11possibly substituted C1-C12of alkyl, possibly substituted C2-C8alkenyl, possibly substituted C2-C8the quinil, possibly substituted C3-C12carbocycle, possibly substituted C2-C20heterocycle, possibly substituted C6-C20aryl and possibly substituted C1-C20heteroaryl;

X represents a CRx or O, S, NRywhere Rxand Ryindependently selected from the group SOS is oasa from:

(1) hydrogen, (2) cyano, (3) halogen, (4) methyl, (5) trifloromethyl, (6) sulfonamide, (7) sulfone, (8) linker fragment (hydrophobic, hydrophilic, tseplyaesh PA light, tseplyaesh in the redox reactions of linkers), (9) linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups);

the linker fragment is selected from the group consisting of:

possibly substituted C1-C20of alkyl, possibly substituted by a halogen-substituted C1-C20of alkyl, possibly substituted C1-C20alkoxy, possibly substituted by a halogen-substituted C1-C20alkoxy, possibly substituted C1-C20Paglinawan of alkyl;

TAG-molecule selected from the group sostojashie from:

the dye molecules, fluorophore dyes (e.g., BODIPY derivatives or rhodamine), Biotin, polymeric resins or reactive group (for example, acrylamide, iodated, forcefed, chloracetamide, bromoacetamide, reactive to light chemical groups, carboxamide of oxirane, redox reactive chemical groups);

R3x, R3y, R3zand R3pindependently selected from the group consisting of: bodoro is a, F, Cl, Br, I, -C(C1-C6alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10-, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl and C1-C20heteroaryl; or group, in which3-C12carbocyclic,2-C20heterocyclyl, C6-C20aryl or1-C20heteroaryl are substituted on adjacent carbon atoms of the research and form a condensed bicyclic morpholinyl;

where the specified alkyl, alkenyl, quinil, carbocyclic, heteros CLIL, aryl and heteroaryl are possibly substituted by one or more group independently selected from F, Cl, Br, I, CN, CF3, -NO2, oxo, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -(CR14R15)nC(=Y)NR10R11, -(CR14R15)nC(=Y)OR10, (CR14R15)nNR12SO2R10, -(CR14R15)nOR10, -(CR14R15)nR10, -(CR14R15)nSO2R10, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12SO2R10, =NR12OR10, -OC(=Y)R10, -OC(=Y)OR10, -OC(=Y)NR10R11, -OS(O)2(OR10), -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), SR10, -S(O)R10, -S(O)2R10, -S(O)2NR10R11, -S(O)(OR10), -S(O)2(OR10), -SC(=Y)R10, -SC(=Y)OR10, -SC(=Y)NR10R11possibly substituted C1-C12of alkyl, possibly substituted C2-C8alkenyl, possibly substituted C2-C8the quinil, possibly substituted C3-C12carbocycle, possibly substituted C2-C20heterocycle, possibly substituted C6-C20aryl and possibly substituted C1-C20heteroaryl;

R1selected from the group consisting of:

(1) H, F, Cl, Br, I, (2) cyano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted, alkenyl, (7) substituted and unsubstituted quinil, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12) -C(C1-C6alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl or C1-C20g is tetraaryl;

R2selected from the group consisting of:

(1) hydrogen, (2) cyano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted, alkenyl, (7) substituted and unsubstituted quinil, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12) -COR2a, (13) -CO2R2a, (14) -CONR2aR2b, (15) -NR2aR2b, (16) -NR2aCOR2b, (17) -NR2aSO2R2b, (18) -OCOR2a, (19) -OR2a, (20) -SR2a, (21) -SOR2a, (22) -SO2R2aand (23) -SO2NR2aR2b; (24) of the linker fragment (hydrophobic linkers, hydrophilic linkers, tseplyaesh in the light of linkers, tseplyaesh in the redox reaction of linkers), (25) linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups);

where R2aand R2bindependently selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted alkyl, (C) substituted or unsubstituted aryl, (d) substituted or unsubstituted heteroaryl, (e) substituted or unsubstituted heterocyclyl and (f) substituted or unsubstituted cycloalkyl,

where R 10, R11and R12independently represent H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil,3-C12carbocyclic,2-C20heterocyclyl,6-C20aryl or C1-C20heteroaryl,

or R10, R11together with the nitrogen atom to which they are attached may form a3-C20heterocyclic ring may contain one or more additional atoms in the ring selected from N, O or S, where the aforementioned heterocyclic ring possibly substituted by one or more group independently selected from oxo, CF3, F, Cl, Br, I, C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl and C1-C20heteroaryl;

where R14and R15independently selected from H, C1-C12the alkyl or -(CH2)n-aryl,

or R14and R15together with the atoms to which they are attached, form a saturated or partially unsaturated With3-C12carbocyclic ring

where

Y represents O, S or NR12;

m is 0, 1, 2, 3, 4, 5 or 6;

n is 1, 2, 3, 4, 5 or 6; and

t is 2, 3, 4, 5 or 6.

Preferably

X represents O ring containing X is the Wallpaper morpholine) and/or R 3x, R3y, R3z, R3pindependently selected from the following structures:

where the wavy line indicates the place of attachment in position 4 of the main ring (triazine or pyrimidine or pyridine ring).

In another aspect of the present invention R1represents a substituted or unsubstituted heterocyclyl Il is substituted or unsubstituted-O-heterocyclyl. In another aspect, R1represents a substituted or unsubstituted morpholinyl, more specifically, R1is linked via the N atom of morpholinyl.

In another aspect, R1includes substituted or unsubstituted, geterotsiklicheskikh or substituted or unsubstituted heteroaromatic.

In another aspect, R1represents a substituted or unsubstituted tetrahydropyran or substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R1represents an unsubstituted 4-tetrahydropyranyloxy.

In another aspect, R1includes substituted or unsubstituted tetrahydropyran. In a more specific aspect tetrahydropyran includes 4 tetrahydropyranyloxy.

In another aspect, R1represents a substituted or unsubstituted tetrahydrofuran, or a substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R1represents unsubstituted 3-tetrahydropyranyloxy.

In another aspect, R1represents phenyl, whereby phenyl is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulphonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfonyl, 2-amino-2-methylpropanamide, 2-aminoacetyl, 2-hydroxyacetamido, is ethylsulfonyl, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4-methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In some embodiments of R1represents pyridyl, thiazolyl, isoxazolyl, oxadiazolyl or pyrimidyl, and heterocyclic group is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulfonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfamyl, 2-amino-2-methylpropanamide, 2-aminoacetyl, 2-hydroxyacetamido, methylsulfonylamino, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4 methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In another aspect of the present invention R2represents a substituted or unsubstituted heterocyclyl or substituted or unsubstituted-O-heterocyclyl.

In another aspect, R2includes substituted or unsubstituted, geterotsiklicheskikh, or substituted or unsubstituted heteroaromatic.

In another aspect, R2represents a monocyclic heteroaryl group selected from pyridyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, furanyl is, tanila, tetrazolyl, where the monocyclic heteroaryl group is a possibly substituted by one or more group selected from F, Cl, Br, I, -CN, -NR10R11, -OR10, -C(O)R10, -NR10C(O)R11, -N(C(O)R11)2, -NR10C(O)NR10R11, -C(=O)OR10, -C(=O)NR10R11, C1-C12 of alkyl and (C1-Say)-OR10.

In a specific embodiment, the implementation of R2selected from the following structures:

where the wavy line indicates the place of attachment in position 4 of the main ring (triazine or pyrimidine or pyridine ring), and

where monocyclic hetaeras the aryl group is a possibly substituted by one or more group selected from F, Cl, Br, I, -NR10R11, -OR10, -C(O)R10, -NR10C(O)R11, -N(C(O)R11)2, -NR10C(O)NR10R11, -C(=O)OR10, -C(=O)NR10R11and C1-C12the alkyl.

In specific embodiments of R2selected from the following structures:

where the wavy line indicates the place of attachment in position 4 of the main ring (triazine or pyrimidine or pyridine ring), and

where the monocyclic heteroaryl group is a possibly substituted by one or more group selected from F, Cl, Br, I, -NR10R11, -OR10, -C(O)R10, -NR10C(O)R11, -N(C(O)R11)2, -NR10C(O)NR10R11, -C(=O)OR10, -C(=O)NR10R11and C1-C12the alkyl.

In specific embodiments of R2represents a monocyclic or bicyclic heteroaryl group selected from the following structures:

where the wavy line indicates the place of attachment.

In specific embodiments of monocyclic or bicyclic heteroaryl group is substituted by one or more group selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -och3-C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -Cho, -CH2OH, -C(=O)NHCH3, -C(=O)NH2and CH3.

In one aspect of the present invention proposed compounds with General formula (Ia):

and stereoisomers, geometric isomers, tautomers, with livity, the metabolites, N-oxide derivatives and pharmaceutically acceptable salts, where

X, R3x, R3y, R3z, R3p. R1and R2similar to the previously defined for formula (I).

Preferences, specific aspects and embodiments, the above for X, R3x, R3y, R3z, R3p, R1and R2formula (I), is used for these substituents in the formula (Ia).

In another aspect of the present invention proposed the compounds having General formula (Ib):

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide derivatives and pharmaceutically acceptable salts, where

R3x, R3y, R3z, R3pand R2similar to the previously defined for formula (I),

R4x, R4y, R4zand R4pdo not depend on each other and selected from the group consisting of:

F, Cl, Br, I, -C1-C6alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12 OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl and C1-C20heteroaryl, or group, in which3-C12carbocyclic,2-C20heterocyclyl,6-C20aryl or C1-C20heteroaryl are substituted on adjacent atoms of the research and form a condensed bicyclic morpholinyl;

where the specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl possibly substituted by one or more group independently selected from F, Cl, Br, I, CN, CF3, -NO2, oxo, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -CR14R15)nNR10R11, -(CR14R15)nC(=Y)NR10R11, -(CR14R15)nC(=Y)OR10, (CR14R15)nNR12SO2R10, -CR14R15)nOR10, -(CR14R15)nR10, -(CR 14R15)nSO2R10, -NR10R11, -NR12C(=Y)R10, -R12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12SO2R10, =NR12OR10, -OC(=Y)R10, -C(-Y)OR10, -OC(=Y)NR10R11, -OS(O)2(OR10), -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), SR10, -S(O)R10, -S(O)2R11, -S(O)2NR10R11, -S(O)(OR10), -S(O)2(OR10), -SC(=Y)R10, -C(=Y)OR10, -SC(=Y)NR10R11possibly substituted C1-C12of alkyl, possibly substituted C2-C8alkenyl, possibly substituted C2-C8the quinil, possibly substituted C3-C12carbocycle, possibly substituted C2-C20heterocycle, possibly substituted C6-C20aryl and possibly substituted C1-C20heteroaryl;

where R10, R11and R12independently represent H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil,3-C12carbocyclic,2-C20heterocyclyl,6-C20aryl or C1-C20heteroaryl,

or R10, R11together with the nitrogen atom to which they are attached, may form a3-C20heterocyclic ring may contain one or more additional atom in the ring, SEL is p N, O or S, where the aforementioned heterocyclic ring possibly substituted by one or more group independently selected from oxo, (CH2)mOR10, (CH2)mNR10R11, CF3, F, Cl, Br, I, SO2R10C(=O)R10, NR12C(=Y)R11C(=Y)NR10R11C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl and C1-C20heteroaryl,

where R14and R15independently selected from H, C1-C12the alkyl or -(CH2)n-aryl,

or R14and R15together with the atoms to which they are attached, form a saturated or partially unsaturated With3-C12carbocyclic ring

where

Y represents O, S or NR12;

m is 0, 1, 2, 3, 4, 5 or 6,

n is 1, 2, 3, 4, 5 or 6 and

t is 2, 3, 4, 5 or 6

Preferences, specific aspects and embodiments, are presented for R3x, R3y, R3z, R3p, R1and R2in the formula (I), is used for these substituents in the formula (Ib).

In another aspect of the present invention proposed the compounds having General formula (Ic):

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide p is osvitnye and pharmaceutically acceptable salts, where

R3x, R3y, R3z, R3pand R2similar to the previously defined for formula (I),

Yarepresents O, S, NH or a direct bond,

R'1selected from the group consisting of:

(I) H, F, Cl, Br, I, (2) cyano, (3) nitro, (4) halogen, (5) substituted or unsubstituted alkyl, (6) substituted or unsubstituted, alkenyl, (7) substituted or unsubstituted quinil, (8) substituted or unsubstituted aryl, (9) substituted or unsubstituted heteroaryl, (10) substituted or unsubstituted heterocyclyl, (11) substituted or unsubstituted cycloalkyl, (12) -C(C1-C6alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10, -S(O)2NR10R1 , -SC(=Y)R10, -SC(=Y)OR10C1-C12of alkyl, C2-C8alkenyl,2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl or C1-C20heteroaryl, (13) linker fragment (hydrophobic linkers, hydrophilic linkers, tseplyaesh in the light of linkers, tseplyaesh in the redox reaction of linkers), (14) linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, biotype, a variety of polymer granules and various reactive groups), where R10, R11, R12, R14, R15, Y, m, n and t are defined above for formula (I).

Preferences, specific aspects and the embodiments presented above for R3x, R3y, R3z, R3pand R2in the formula (I), is used for these substituents in the formula (Ic).

In another aspect of the present invention R'1represents a substituted or unsubstituted heterocyclyl or substituted or unsubstituted-O-heterocyclyl. In another aspect, R'1represents a substituted or unsubstituted morpholinyl; more specifically R'1represents unsubstituted bound through the N atom, morpholinyl; more specifically, X is a direct bond. In another more than the specific implementation of R 1is a 4-tetrahydropyranyl; more specifically, X represents O. In another embodiment, the implementation of R1is a 3-tetrahydrofuranyl; more specifically, X represents O.

In another aspect, R'1includes substituted or unsubstituted, geterotsiklicheskikh or substituted or unsubstituted heteroaromatic.

In another aspect, R'1represents a substituted or unsubstituted tetrahydropyran or substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R'1is a 4-tetrahydropyranyloxy.

In another aspect, R'1includes substituted or unsubstituted tetrahydropyran. In a more specific aspect tetrahydropyran includes 4 tetrahydropyranyloxy.

In another aspect, R'1represents a substituted or unsubstituted tetrahydrofuran, or a substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R'1represents unsubstituted 3-tetrahydropyranyloxy.

In another aspect, R'1represents phenyl, whereby phenyl is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulfonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfonyl, 2-amino-2-methylpropanamide, 2-aminoate the amide, 2-hydroxyacetamido, methylsulfonylamino, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4-methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In specific embodiments of R'1represents pyridyl, thiazolyl, isoxazolyl, oxadiazolyl or pyrimidyl, and heterocyclic group is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulfonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfonyl, 2-amino-2-methylpropanamide, 2-aminoacetyl, 2-hydroxyacetamido. methylsulfonylamino, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4-methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In another embodiment, the implementation of R'1selected from the group consisting of: (1) substituted or unsubstituted morpholinyl, (2) substituted or unsubstituted tetrahydropyranyl and (3) substituted or unsubstituted tetrahydrofuranyl.

In a more specific implementation R'1is a bound through the N atom of morpholinyl. In another more specific embodiment, the implementation of R'1is a 4-tetrahydropyranyl. In another embodiment, the implementation of R'1the stand is made by a 3-tetrahydrofuranyl.

In another aspect of the present invention proposed the compounds having General formula (Id):

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide derivatives and pharmaceutically acceptable salts, where

R3x, R3y, R3z, R3pand R2such as previously defined for formula (I),

W represents CRwor N, where Rwselected from the group consisting of:

(1) hydrogen, (2) piano, (3) halogen, (4) methyl, (5) trifloromethyl, (6) sulfonamide;

R5selected from the group consisting of:

(1) hydrogen, and (2) halogen,

R6selected from the group consisting of:

(1) hydrogen, (2) cyano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted, alkenyl, (7) substituted and unsubstituted quinil, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, 12) -COR3a, (13) -NR3aR3b, (14) -NR3aCOR3b, (15) -NR3aSO2R3b, (16) -OR3a, (17) -SR3a, (18) -SOR3a, (19) -SO2R3aand (20) -SO2NR3aR3b,

where R3aand R3bindependently selected from the group consisting of: (a) hydrogen, (b) substituted or unsubstituted alkyl, (C) for EDINOGO or unsubstituted aryl, (d) substituted or unsubstituted heteroaryl, (e) substituted or unsubstituted heterocyclyl and (substituted or unsubstituted cycloalkyl, and

R7selected from the group consisting of:

(1) hydrogen, (2) substituted and unsubstituted alkyl, and (3) substituted and unsubstituted cycloalkyl, (4) methyl, (5) ethyl, (6) trifloromethyl, (7) sulfonamida, (8) acetate, (9) linker fragment (hydrophobic linkers, hydrophilic linkers, tseplyaesh in the light of linkers, tseplyaesh in the redox reaction of linkers), (10) linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups).

Preferences, specific aspects and the embodiments presented above for R3x, R3y; R3z, R3pand R2in the formula (I), applied to the above substituents of the formula (Id).

In a more specific implementation W represents CH.

In another embodiment, the implementation of W represents N. In a more specific embodiment, the implementation of R6is a =O.

In another embodiment, the implementation of R6selected from the group consisting of:

(1) cyano, (2) nitro, (3) halogen, (4) hydroxyl, (5) amino and (6) trifloromethyl.

In another embodiment, the implementation of R6is the Wallpaper trifluoromethyl. In another embodiment, the implementation of R6represents cyano.

In another aspect of the present invention proposed a compound having the General formula (Ie):

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide derivatives and pharmaceutically acceptable salts, where

Q=C, G=C, U=N;

Q=C, U=C, G=N; or

V=C, G=C, Q=N,

X, R3x, R3y, R3z, R3pand R2defined above in formula (I),

Yarepresents O, S, NH or a direct bond,

R'1selected from the group consisting of:

(1) H, F, Cl, Br, I, (2) piano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted, alkenyl, (7) substituted and unsubstituted quinil, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12) -C(C1-C6alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10,-C(=Y)NR 10R11, -C(=Y)NRnOR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl or1-C20heteroaryl, (13) linker fragment (hydrophobic linkers, hydrophilic linkers, tseplyaesh in the light of linkers, tseplyaesh in the redox reaction of linkers), (14) linker fragment, with Cavallero associated TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups), where R10, R11, R12, R14, R15, Y, m, n and t are defined above for formula (I).

Preferences, specific aspects and embodiments, the above for X,

R3x, R3y, R3z, R3pand R2in the formula (I), is used for these substituents in the formula (Ie).

In another aspect of the present invention R'1is own the th substituted or unsubstituted heterocyclyl or substituted or unsubstituted-O-heterocyclyl. In another embodiment, the implementation of R'1represents a substituted or unsubstituted morpholinyl; more specifically R'1represents unsubstituted bound through the N atom of morpholinyl; more specifically, X is a direct bond. In another more specific embodiment, the implementation of R1is a 4-tetrahydropyranyl; more specifically, X represents O. In another embodiment, the implementation of R1is a 3-tetrahydrofuranyl; more specifically, X represents O.

In another aspect, R'1includes substituted or unsubstituted, geterotsiklicheskikh or substituted or unsubstituted heteroaromatic.

In another aspect, R'1represents a substituted or unsubstituted tetrahydropyran or substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R'1represents an unsubstituted 4-tetrahydropyranyloxy.

In another aspect, R'1includes substituted or unsubstituted tetrahydropyran. In a more specific aspect tetrahydropyran includes 4 tetrahydropyranyloxy.

In another aspect, R'1represents a substituted or unsubstituted tetrahydrofuran, or a substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R'1represents unsubstituted 3-tetrahydropyranyloxy.

In another aspect, R' 1represents phenyl, whereby phenyl is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulfonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfonyl, 2-Amio-2-methylpropanamide, 2-aminoacetyl, 2-hydroxyacetamido, methylsulfonylamino, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4-methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In specific embodiments of R'1represents pyridyl, thiazolyl, isoxazolyl or pyrimidyl, and heterocyclic group is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulfonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfonyl, 2-amino-2-methylpropanamide, 2-aminoacetyl, 2-hydroxyacetamido, methylsulfonylamino, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4 methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In another embodiment, the implementation of R'1selected from the group consisting of: (1) substituted or unsubstituted morpholinyl, (2) substituted or unsubstituted tetrahedron is Anil and (3) substituted or unsubstituted tetrahydrofuranyl.

In a more specific implementation R'1is a bound through the N atom of morpholinyl. In another more specific embodiment, the implementation of R'1is a 4-tetrahydropyranyl. In another embodiment, the implementation of R'1is a 3-tetrahydrofuranyl.

In another aspect of the present invention proposed a connection with one of the General formulas (If) and (Ig):

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide derivatives and pharmaceutically acceptable salts, where

G represents N or G is a C,

X, R3x, R3y, R3z, R3pand R2defined above for formula (I),

Ybrepresents O, S or SO2,

Z represents N or CRqwhere Rqselected from the group consisting of:

(1) the linker fragment (hydrophobic linkers, hydrophilic linkers, tseplyaesh in the light of linkers, tseplyaesh in the redox reaction of linkers), (2) the linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups)

R8selected from the group consisting of:

(1) H, F, Cl, Br, I, (2) cyano, (3) nitro, (4 halogen, (5) substituted and unsubstituted alkyl, (b) substituted and unsubstituted, alkenyl, (7) substituted and unsubstituted quinil, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12) -C(C1-C6alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NRnOR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl or1-C20heteroaryl, (13) linker fragment (HYDR is fobih of linkers, hydrophilic linkers, tseplyaesh in the light of linkers, tseplyaesh in the redox reaction of linkers), (14) linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups), where

R11and R12independently represent H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil,3-C12carbocyclic,2-C20heterocyclyl,6-C20aryl or C1-C20heteroaryl,

R10selected from the group consisting of:

(1) hydrogen, (2) cyano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted, alkenyl, (7) substituted and unsubstituted quinil, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12) -COR2a, (13) -CO2R2a, (14) -CONR2aR2b, (15) -NR2aR2b, (16) -NR2aCOR2b, (17) -NR2aSO2R2b, (18) -OCOR2a, (19) -OR2a, (20) -SR2a, (21) -SOR2a, (22) -SO2R2aand (23) -SO2NR2aR2b, (24) of the linker fragment (hydrophobic linkers, hydrophilic linkers, tseplyaesh in the light of the linkers, saleemah in the redox reaction of linkers), (25) of the linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups);

where R2aand R2bindependently selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted alkyl, (C) substituted or unsubstituted aryl, (d) substituted or unsubstituted heteroaryl, (e) substituted or unsubstituted heterocyclyl and (f) substituted or unsubstituted cycloalkyl,

or R10, R11together with the nitrogen atom to which they are attached, may form a3-C20heterocyclic ring may contain one or more additional atoms in the ring selected from N, O or S, with the specified heterocyclic ring possibly substituted by one or more group independently selected from oxo, CF3, F, Cl, Br, I, C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl and C1-C20heteroaryl;

where R14and R15independently selected from H, C1-C12the alkyl or -(CH2)n-aryl,

or R14and R15together with the atoms to which they are attached, form a saturated or partially unsaturated With3-C12arboricides ring,

where

Y represents O, S or NR12;

m is 0, 1, 2, 3, 4, 5 or 6;

n is 1, 2, 3, 4, 5 or 6; and

t is 2, 3, 4, 5 or 6.

Preferences, specific aspects and embodiments, the above for X, R3x, R3y, R3z, R3pand R2in the formula (I), applied to the above substituents of formulas (If) and (Ig).

In a particular aspect of the present invention R8represents a substituted or unsubstituted heterocyclyl or substituted or unsubstituted-O-heterocyclyl. In another aspect, R8represents a substituted or unsubstituted morpholinyl; more specifically, R8represents unsubstituted bound through the N atom of morpholinyl.

In another aspect, R8includes substituted or unsubstituted, geterotsiklicheskikh or substituted or unsubstituted heteroaromatic.

In another aspect, R8represents a substituted or unsubstituted tetrahydropyran or substituted or substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R8represents an unsubstituted 4-tetrahydropyranyloxy.

In another aspect, R8includes substituted or unsubstituted tetrahydropyran. In a more specific implementation tetrahydropyran includes 4 tetrahydropyranyloxy.

In another aspect, R8represents a substituted or illegal is ewenny tetrahydrofuran or a substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R8represents unsubstituted 3-tetrahydropyranyloxy.

In another aspect, R8represents a possibly substituted phenyl, whereby phenyl is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulfonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfonyl, 2-amino-2-methylpropanamide, 2-aminoacetyl, 2-hydroxyacetamido, methylsulfonylamino, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4-methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In specific embodiments of R8represents a possibly substituted pyridyl, possibly substituted thiazolyl, possibly substituted isoxazolyl, possibly substituted oxadiazolyl or possibly substituted pyrimidyl.

In another embodiment, the implementation of R8selected from the group consisting of: (1) substituted or unsubstituted morpholinyl, (2) substituted or unsubstituted tetrahydropyranyl and (3) substituted or unsubstituted tetrahydrofuranyl.

In a more specific embodiment, the implementation of R8is a bound through the N atom of morpholinyl. In another more specific embodiment, the implementation of R8is a 4-tetrahydropyran is l; in another embodiment, the implementation of R8is a 3-tetrahydrofuranyl.

For the application of R10see the General reaction scheme 45.

In another aspect of the present invention proposed compounds with General formula (Ih) and (Ii):

and stereoisomers, geometric isomers, tautomers, solvate, metabolites, N-oxide derivatives and pharmaceutically acceptable salts, where

G represents N or G is a C,

X, R3x, R3y, R3z, R3pand R2defined above for formula (I),

Ye represents O, S, SO2, NH or a direct bond,

L represents S, N, or N-oxide,

R9selected from the group consisting of:

(1) H, F, Cl, Br, I, (2) cyano, (3) nitro, (4) halogen, (5) substituted and unsubstituted alkyl, (6) substituted and unsubstituted, alkenyl, (7) substituted and unsubstituted quinil, (8) substituted and unsubstituted aryl, (9) substituted and unsubstituted heteroaryl, (10) substituted and unsubstituted heterocyclyl, (11) substituted and unsubstituted cycloalkyl, (12) -C(C1-C6alkyl)2NR10R11, -(CR14R15)tNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -CH(OR10R10, -(CR14/sub> R15)nOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NRnOR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2-The other12, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil,3-C12carbocycle,2-C20heterocyclyl,6-C20aryl or1-C20heteroaryl, (13) linker fragment (hydrophobic linkers, hydrophilic linkers, tseplyaesh in the light of linkers, tseplyaesh in the redox reaction of linkers), (14) linker fragment covalently bound TAG-molecules (TAG may be a fluorophore, Biotin, various polymer granules and various reactive groups), where R10, R11, R12, R14, R15, Y, m, n and t are defined above for formula (I).

In another aspect of the present invention R9represents a substituted or unsubstituted, heterotic the sludge or substituted or unsubstituted-O-heterocyclyl. In another aspect, R9represents a substituted or unsubstituted morpholinyl; more specifically, R9represents unsubstituted bound through the N atom, morpholinyl.

In another aspect, R9includes substituted or unsubstituted, geterotsiklicheskikh or substituted or unsubstituted heteroaromatic.

In another aspect, R9represents a substituted or unsubstituted tetrahydropyran or substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R9represents an unsubstituted 4-tetrahydropyranyloxy.

In another aspect, R9includes substituted or unsubstituted tetrahydropyran. In a more specific aspect tetrahydropyran includes 4 tetrahydropyranyloxy.

In another aspect, R9represents a substituted or unsubstituted tetrahydrofuran, or a substituted or unsubstituted, tetrahydropyranyloxy. More specifically, R9represents unsubstituted 3-tetrahydropyranyloxy.

In another aspect, R9represents a possibly substituted phenyl, whereby phenyl is unsubstituted or substituted by one or more group selected from N-methylcarbamate, isopropylbenzylamine, methylsulfonyl, 2-hydroxy-2-methylpropanamide, 2-hydroxypropanoic, 2-methoxyacetate, (propane-2-ol)sulfonyl, 2-amino-2-methylpropanamide, 2 am is loacated, 2-hydroxyacetamido, methylsulfonylamino, 2-(dimethylamino)ndimethylacetamide, amino, acetylamino, carboxamide, (4-methylsulfonylamino)-1-methyl, (4-methylpiperazine)-1-methyl, hydroxymethyl and methoxy.

In specific embodiments of R9represents a possibly substituted pyridyl, possibly substituted thiazolyl, possibly substituted isoxazolyl, possibly substituted oxadiazolyl or possibly substituted pyrimidyl.

In another embodiment, the implementation of R9selected from the group consisting of: (1) substituted or unsubstituted morpholinyl, (2) substituted or unsubstituted tetrahydropyranyl and (3) substituted or unsubstituted tetrahydrofuranyl.

In a more specific embodiment, the implementation of R9is a bound through the N atom of morpholinyl. In another more specific embodiment, the implementation of R9is a 4-tetrahydropyranyl; in another embodiment, the implementation R9 represents a 3-tetrahydrofuranyl.

Compounds according to the present invention may contain asymmetric or chiral centers, and exist, therefore, in different stereoisomeric forms. Understand that all stereoisomeric forms of the compounds according to the present invention, including, but not limited to, the diastereomers, the enantiomers and atropoisomeric, as well as mixtures thereof, such as the rat is ical mixture, form part of the present invention.

In addition, the present invention encompasses all geometric and positional isomers. For example, if the connection according to the invention contains a double bond or a condensed ring, CIS - and TRANS-forms, as well as mixtures thereof embraced within the present invention. Individual positional isomers and mixtures of positional isomers also fall within the scope of the present invention.

In the structures presented in this application, when the stereochemistry of each specific chiral atom is not specified, all stereoisomers are covered and included as compounds according to the present invention. When the stereochemistry of concrete using wedge-shaped or dashed line that represents a specific configuration that is specified in the stereoisomer is, therefore, specified and described.

Compounds according to the present invention may exist in undissolved and dissolved forms in pharmaceutically acceptable solvents such as water, ethanol, and so on, understand that the invention encompasses dissolved and undissolved form.

Compounds according to the present invention can also exist in different tautomeric forms (tautomers) and all of these forms fall within the scope of this and is gaining.

The present invention also embraces compounds according to the present invention, labeled isotopes, which are the same as described in the present application taking into account the fact that one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the atom, usually occurring in nature. All isotopes of any particular atom or element, as well as their application, which are described fall within the scope of the present invention. Typical isotopes that can be incorporated into compounds according to the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N15N15Oh,17Oh,18Oh,32P,33P,35S18F,36Cl123I and125I. Specific compounds according to the present invention, labeled with isotopes (e.g., compounds labeled3H and14C) are applicable for the study of the distribution connection and/or substrate tissue. Tritium (3N) isotopes and isotope carbon-14 (14C) are applicable as a consequence of the ease of obtaining and detection. Also, the substitution of heavier isotopes such as deuterium (i.e,2H) may, if it is the input to a specific therapeutic benefits, resulting in increased metabolic stability (e.g., increased half-life in the body or lower the required dosage) and, hence, may be preferred in some cases. Emitting a positron isotopes, such as15Oh,13N11C and18F, suitable for positron emission tomography (PET) to determine the extent of employment substrate receptor. Compounds according to the present invention, labeled isotopes, can usually be obtained using procedures similar to the procedures described in the Schemes and/or in the Examples of this application are presented below, using the substitution reagent is not labeled isotopes, reagent-labeled isotopes.

Obtaining the COMPOUNDS ACCORDING to the PRESENT INVENTION

Compounds according to the present invention can be synthesized using the synthesis methods, which include methods that are well known in the field of chemistry, especially in light of the description contained in this application. The initial substance, usually available from commercial sources such as Aldrich Chemicals or can be easily obtained using methods well known to experts in the art (for example, obtained by methods generally described in the work of Luis F. Fiser and Marie Fisher (Louis F, Fieser and Mary Fieser), Reagentsfor Organic Syntheis, v. 1-19, Wiley, N. Y. (1967-1999 ed.) or Beilsteins Handbuch der Organischcn Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin, including the application (also available in an online database Beilstein)).

In specific embodiments of the compounds according to the present invention can easily be obtained using techniques well-known to get triazines and other heterocycles, which are described in: Comprehensive Heterocyclic Chemistry, Editors Katritzky and Rees, Pergamon Press, 1984.

Compounds according to the present invention can be obtained individually or as a series of compounds containing at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. A series of compounds according to the present invention can be obtained by using the combined approach "split and mix" split and mix) or by multiple parallel syntheses using mortar chemistry or chemistry of solids, using techniques well-known to specialists in this field of technology. Thus, in accordance with another aspect of the present invention proposed a series of compounds containing at least 2 compounds or their pharmaceutically acceptable salts.

To illustrate the Diagrams 1-52 presents General methods for producing compounds according to the present invention, as well as key intermediates. For a more detailed description of the specific Rea the operating stages, see the Examples later in this application. Specialists in the art will understand that for the synthesis of compounds according to the present invention can use other methods of synthesis. Although the specific source materials and reagents provided in the diagram and described below, they can be easily replaced by other source materials and reagents to obtain various derivatives and/or conditions of the reactions. In addition, many of the compounds obtained by the methods described below can be further modified in light of the present description using appropriate chemistry, well known to specialists in this field of technology.

Upon receipt of the compounds according to the present invention may be the necessary protection required for future stages of functions (for example, primary or secondary amine) of intermediates. The need in this protection varies depending on the nature required in future stages of the functions and methods of obtaining. Suitable amino-protective groups include acetyl, TRIFLUOROACETYL, t-butoxycarbonyl (VOS), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc). The need in this protection will be easy to back out to the experts in this field of technology. For a General description of the protective groups and their applications, see the work of the T. C. green (T. W. Greene), Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

SCHEMES for preparing COMPOUNDS ACCORDING to the PRESENT INVENTION

Scheme 1 shows a General method of obtaining intermediate triazine compound 2 of 2,4,6-trihalogen-1,3,5-triazine reagent (1), where Hal represents Cl, Br or I, a R1defined for compounds of formulas Ia-d, or its predecessors, or prodrugs.

Figure 2 presents a General method of obtaining intermediate triazine compound 3 of 2,4,6-trihalogen-1,3,5-triazine reagent (1), where Hal represents Cl, Br or I, a R1defined for compounds of formulas Ia-d, or its predecessors, or prodrugs.

Figure 3 presents a General method for selective substitution of the halide of the bis-halogenating intermediate compound 2-morpholine in an organic solvent to obtain an intermediate morpholinothio compounds 4, where Hal represents Cl, Br or I, a R1defined for compounds of formulas Ia-d, or its predecessors, or prodrugs.

Scheme 4 shows a General method for selective replacement of two Gulidov of Tris-halogenating 1 morpholine in an organic solvent to obtain bis-morpholinothio premiato the different compounds 5, where Hal represents Cl, Br or I.

Figure 5 presents a General method to combine Suzuki 1-halogenating intermediate compounds 3 and reagent circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) connections (7) of formula Ia, where Hal represents Cl, Br or I, a R1and R2described for compounds of formula 1A, or precursors or prodrugs. For an overview of the Suzuki reaction, see Miyaura et al., (1995), Chem. Rev. 95:2457-2843; Suzuki, A., (1999), J. Were Obtained. Chem. 576:147-168; Suzuki, A. in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich, P. J. Stang, Eds., VCH, Weinheim, DE (1998), pp 49-97. The palladium catalyst may be any catalyst that is generally used for cross-combination Suzuki, such as PdCl2(PPh3)2Pd(PPh3)4Pd(OAc)2, PdCl2(dppf)-DCM, Pd2(dba)3/Pt-Bu)3Owens et al., 2003 Bioorganic & Med. Chem. Letters 13:4143-4145; Molander et al., 2002 Organic Letters 4(11): 1867-1870; US 6448433).

Figure 6 presents a General method to combine Suzuki intermediate 1-halogencontaining connection 4 and the cyclic heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) compounds (8) of formula Ia, where Hal represents Cl, B or I, a R1and R2described for compounds of formula Ia, or its precursors or prodrugs.

Figure 7 presents a General method to combine Suzuki intermediate 1-halogenic-morpholinothio connection 5 and the cyclic heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) compounds (9) of formula Ib, where Hal represents Cl, Br or I, a R2described for compounds of formula Ib, or precursors or prodrugs.

Figure 8 presents a General method of obtaining intermediate triazine compounds 10 of 2,4,6-trihalogen-1,3,5-triazine reagent (1), where Hal represents Cl, Br or I; and R'1and Yadefined for compounds of formula Ic, or precursors or prodrugs.

Figure 9 presents a General method of obtaining intermediate creativesage connection 11 of 2,4,6-trihalogen-1,3,5-triazine reagent (1), where Hal represents Cl, Br or I; and R'1and Yadefined for compounds of formula Ic, or precursors or prodrugs.

Figure 10 presents a General method of obtaining intermediate triazine compounds 12 of 2,4,6-trihalogen-1,3,5-createnewelement (1), where Hal represents Cl, Br or I; and R'1and Yadefined for compounds of formula Ic, or precursors or prodrugs.

Figure 11 presents a General method of obtaining intermediate triazine compound 12 from the intermediate triazine compounds 13, where Hal represents Cl, Br or I; and R'1and Yadefined for compounds of formula Ic, or precursors or prodrugs.

Figure 12 presents a General method to combine Suzuki intermediate triazine compounds 11 and cyclic heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) compounds (14), where Hal represents Cl, Br or I, a R'1and Yadefined for compounds of formula Ic, R2defined for compounds of formula I, or its precursors or prodrugs.

Figure 13 presents the General method of combining Suzuki intermediate triazine compounds 12 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) connection (15), where Hal represents Cl, Br or I, a R'1and Yadefined for compounds of formula Ic, R2identify Elen for compounds of formula I, or its precursors or prodrugs.

Figure 14 presents a General method to combine Suzuki intermediate triazine compounds 12 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) compounds (16), where R'1and Yadefined for compounds of formula Ic, R5, R6and W are defined for compounds of formula Id, or precursors or prodrugs.

In figure 15 provides a General way of combining Suzuki intermediate triazine compounds 12 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) compounds (17), where R'1and Yadefined for compounds of formula Ic, R5, R6, R7and W are defined for compounds of formula Id, or precursors or prodrugs.

Scheme 16 shows a General way to obtain the triazine compounds 17 of triazine compounds 16, where R'1and Yadefined for compounds of formula Ic, R5, R6, R7and W are defined for compounds of formula Id, or precursors or prodrugs.

In the Diagram freistellen common way of obtaining intermediate pyridine compound 19 of 2,4,6-trialgenericviagraho reagent (18), where Hal represents Cl, Br or I, a R1defined for compounds of formula I, or its precursors or prodrugs.

Figure 18 presents a General method of obtaining intermediate pyridine compound 20 of 2,4,6-trialgenericviagraho reagent (18), where Hal represents Cl, Br or I, a R1defined for compounds of formula I, or its precursors or prodrugs.

Figure 19 presents a General method of obtaining intermediate pyridine compounds 21 of 2,4,6-trialgenericviagraho reagent (18), where Hal represents Cl, Br or I, a R1defined for compounds of formula I, or its precursors or prodrugs.

Figure 20 presents a General method of obtaining intermediate pyridine compounds 22 of 2,4,6-trialgenericviagraho reagent (18), where Hal represents Cl, Br or I, a R1defined for compounds of formula I, its precursors or prodrugs.

Figure 21 presents a General method of obtaining intermediate pyridine compound 21 from dehalogenating reagent 19, where Hal represents Cl, Br or I, a R1defined for compounds of formula I, or its precursors or prodrugs.

Figure 22 presents a General method of obtaining intermediate pyridine compounds 22 of dehalogenating reagent 19, where Hal represents Cl, Br or I, a R1defined for compounds of formula I, or its precursors or prodrugs.

In Scheme 23 presents a General method of obtaining intermediate pyridine compound 21 from dehalogenating reagent 20, where Hal represents Cl, Br or I, and R1defined for compounds of formula I, its precursors or prodrugs.

Figure 21 presents a General method of obtaining intermediate pyridine compounds 23 of 2,4,6-trialgenericviagraho (18) and morpholino reagents, where Hal represents Cl, Br or I, or precursors or prodrugs.

Figure 22 presents a General method of obtaining intermediate pyridine compound 24 of 2,4,6-trialgenericviagraho (18) and morpholino reagents, where Hal represents Cl, Br or I, or precursors or prodrugs.

In Scheme 23 presents a General method of obtaining intermediate pyridine compounds 25 of 2,4,6-trialgenericviagraho (18) and morpholino reagents, where Hal represents Cl, Br or I.

Figure 24 presents a General method of obtaining intermediate pyridine compounds 26 of 2,4,6-trialgenericviagraho (18) and morpholino reagents, where Hal represents Cl, Br or I.

In Scheme 25 shows the General way of combining Suzuki intermediate 1-halogenopyrimidines connection 21 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) compounds (27) of the formula I, where Hal represents Cl, Br or I; a R1and R2defined for compounds of formula I or its precursors or prodrugs.

The Circuit 26 provides a General way of combining Suzuki intermediate 1-halogenopyrimidines connection 22 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) compounds (28) of the formula I, where Hal represents Cl, Br or I; a R1and R2defined for compounds of formula I or its precursors or prodrugs.

The Circuit 27 provides a General way of combining Suzuki intermediate dimorpholinyldiethyl connection 25 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=and the keel) 6 obtaining cyclic heteroaryl (Well) compounds (29) of the formula I, where Hal represents Cl, Br or I; a R2defined for compounds of formula I or its precursors or prodrugs.

The Circuit 28 provides a General way of combining Suzuki intermediate dimorpholinyldiethyl connection 26 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) connection (30) of the formula I, where Hal represents Cl, Br or I; a R2defined for compounds of formula I or its precursors or prodrugs.

In Scheme 29 presents a General method of obtaining intermediate pyridine compounds 32 of 2,4,6-trialgenericviagraho reagent (18), where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, or precursors or prodrugs.

In Scheme 30 presents a General method of obtaining intermediate pyridine compounds 33 of 2,4,6-trialgenericviagraho reagent (18), where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, or precursors or prodrugs.

In Scheme 31 presents a General method of obtaining intermediate pyridine compound 34 from dihalogenide the new reagent, where Hal represents Cl, Br or I; and R'1and Yadefined for compounds of formula Ie, R1defined for compounds of formula I, or its precursors or prodrugs.

In Scheme 32 presents a General method of obtaining intermediate pyridine compound 34 from dehalogenating reagent (32), where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, R1defined for compounds of formula I, or its precursors or prodrugs.

In Scheme 33 presents a General method of obtaining intermediate morpholinopropan connection 36 of dehalogenating reagent, where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, or precursors or prodrugs.

In Scheme 34 presents a General method of obtaining intermediate morpholinopropan connection 37 from dehalogenating reagent, where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, or precursors or prodrugs.

In Scheme 35 presents a General method of obtaining intermediate morpholinopropan connection 36 of morpholinobutyrophenone R the agent 23, where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, or precursors or prodrugs.

Scheme 36 presents a General method of obtaining intermediate morpholinopropan connection 37 from morpholinobutyrophenone reagent 24, where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, or precursors or prodrugs.

In Scheme 37 presents a General method of obtaining intermediate morpholinopropan connection 38 of morpholinobutyrophenone reagent 24, where Hal represents Cl, Br or I; a R'1and Yadefined for compounds of formula Ie, or precursors or prodrugs.

The Circuit 38 provides a General way of combining Suzuki intermediate pyridine compounds 34 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) connection 39 of the formula I, where Hal represents Cl, Br or I; R'1and Yadefined for compounds of formula Ie, a R1and R2defined for compounds of formula I, or their precursors or prodrugs.

the and Circuit 39 provides a General way of combining Suzuki intermediate pyridine compounds 35 and the circular heteroarylboronic acid (R 15=H) or its ether complex (Ri5=alkyl) 6 obtaining cyclic heteroaryl (Well) connections 40 formula I, where Hal represents Cl, Br or I; R'1and Yadefined for compounds of formula Ie, a R1and R2defined for compounds of formula I, or their precursors or prodrugs.

The Circuit 40 provides a General way of combining Suzuki intermediate pyridine compounds 36 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) connection 41 of the formula Ie, where Hal represents Cl, Br or I; R'1and Yadefined for compounds of formula Ie, a R2defined for compounds of formula I, or their precursors or prodrugs.

The Circuit 41 provides a General way of combining Suzuki intermediate pyridine compounds 37 and the circular heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) connections 42 of the formula Ie, where Hal represents Cl, Br or I; R'1and Yadefined for compounds of formula Ie, a R2defined for compounds of formula I, or their precursors or prodrugs.

In Scheme 42 presents the Yong common way of combining Suzuki intermediate pyridine compounds 38 and the circular heteroarylboronic acid (R 15=H) or its ether complex (R15=alkyl) 6 obtaining cyclic heteroaryl (Well) connections 43 of the formula Ie, where Hal represents Cl, Br or I; R'1and Yadefined for compounds of formula Ie, a R2defined for compounds of formula I, or their precursors or prodrugs.

Scheme 43 presents a General method of obtaining intermediate triazolopyrimidines and oxazolopyridine compounds 48 and 49 from 5-carboxykinase ether, 4-aminothiazole (X=S) and oxazole (X=O), and 4-carboxykinase ether, 5-aminothiazole (X=S) and oxazole (X=O), respectively reagents 44 and 45, where Ybrepresents O or S, Hal represents Cl, Br or I;

R8and R10defined for formula If-g.

In Scheme 44 presents a General method for selective substitution of the 7-halide intermediate bis-halogeensoojendeid and bis-galactosylceramide compounds 48 and 49 morpholine with the basic conditions in an organic solvent to obtain 5-halogen-7-morpholinomethyl and oxazolopyridine compounds 50 and 51, where Ybrepresents O or S, Hal represents Cl, Br or I; a R8defined for formula If-g.

In Scheme 45 presents a General method of obtaining derivatives with respect to position 2 of the thiazole is pyrimidine and oxazolopyridine compounds 52 and 53, in which R8represents H. Processing 52 and 53 literalism reagent for removal of the proton in position 2 and then adding Alliluyeva reagent R10C(O)Z, where Z is a leaving group such as halide, NHS ester, carboxylate or dialkylamino, leads to the production of 5-halogen-7-morpholino-2-acylethanolamines and oxazolopyridine connections 54 and 55, where Ybrepresents O or S, Hal represents Cl, Br or I; a R10defined for formula If-g.

The Circuit 46 provides a General way of combining Suzuki intermediate 5-halogenopyrimidines connection (50 and 51) and the cyclic heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) with 6 receiving 5-cyclic heteroaryl (Well)-7-morpholinosydnonimine and oxazolopyridine compounds (52 and 53) formula If-g, where Ybrepresents O or S, Hal represents Cl, Br or I; a R10defined for compounds of formula If-g, or precursors or prodrugs. For an overview of the Suzuki reaction, Miyaura et al., 1995 Chem. Rev. 95:2457-2483; Suzuki, A., 1999, J. Were Obtained. Chem. 576:147-168; Suzuki, A. in Metal-Catalyzed Cross-Coupling Reactions, Diedrich P., P. J. Stang, Eds., VCH, Weinheim, DE (1998), pp 49-97. The palladium catalyst may be any catalyst that is generally used for cross-combinations Suzuki, t is coy as PdCl 2(PPh3)2Pd(PPh3)4Pd(OAc)2, PdCl2(dppf)-DCM, Pd2(dba)3/Pt-Bu)3Owens et al., 2003 Bioorganic & Med. Chem. Letters 13:4143-4145; Molander et al., 2002 Organic Letters 4(11): 1867-1870; US 6448433).

In Scheme 47 presents a General method for oxidation of sulfur in the cell thieno - and triazolopyrimidine compounds 56 and 57 by means of cytochromes. After oxidation of sulfur in typeparameter connections 54 (IP Piramed/Roche) thiophene ring acts as an activated system Michael, where possible nucleophilic attack position 7, and therefore, it is possible to quickly modification in the cell thienopyrimidines connections 54. Compared with thienopyrimidine triazolopyrimidine connections 55 are more chemically stable due to the N-atom in position 7, when this is not possible nucleophilic attack after oxidation of sulfur.

Scheme 48 presents a General method of obtaining the linker-TAG-modified condensed pyrimidine compounds 59 of the intermediate morpholinothio connection 58, where the Well is a cyclic heteroaryl fragment, Yband Z are defined for compounds of formula If-g, linker and TAG defined for compounds of formula I, or precursors or prodrugs.

In Scheme 49 presents General the second method of obtaining a condensed pyrimidine intermediate compounds 64 and 65, for example, 2-carboxamide, 3-aminobenzophenone and 3-aminopyridine (X=Oh, L=C) and 2-carboxamide, 3-aminoazotoluene and 3-aminothiophene (X=S, L=S), respectively, compounds 60 and 61, where Ycrepresents O or S, Hal represents Cl, Br or I; a R9and L defined for formula Ih-i.

The following diagram illustrates the General process for the selective substitution of 4-halide interim condensed bis-halogenopyrimidines compounds 66 and 67 morpholine in basic conditions in an organic solvent to obtain a condensed 2-halogen-4-morpholinobutyrophenone compounds 68 and 69, where Ycrepresents O or S, Hal represents Cl, Br or I; and R9and L defined for formula Ih-i.

The Circuit 51 provides a General way of combining Suzuki 2-halogenopyrimidines intermediate compound (70 and 71) and the cyclic heteroarylboronic acid (R15=H) or its ether complex (R15=alkyl) with 6 receiving the condensed 2-cyclic heteroaryl (Oh)-4-morpholinobutyrophenone compounds (72 and 73) of formula Ih-i, where Ycrepresents O or S, Hal represents Cl, Br or I; a R9and L defined for formula Ih-i, or precursors or prodrugs. For an overview of the Suzuki reaction, see: Miyaura et al., 1995 Chem. Rev. 95:2457-2483; Suzuki, A., 1999, J. Were Obtained. Chem. 576:147-168; Suzuki A in Metal-Catalyzed Cross-Coupling Reactions, Diedrich F., Stang, P. J., Eds., VCH, Weinheim, DE (1998), pp 49-97. The palladium catalyst may be any catalyst that is generally used for cross-combinations Suzuki, such as PdCl2(PPh3)2Pd(PPh3)4Pd(OAc)2, PdCl2(dppf)-DCM, Pd2(dba)3/Pt-Bu)3(Owens et al., 2003 Bioorganic & Med. Chem. Letters 13:4143-4145: Molander et al., 2002 Organic Letters 4(11): 1867-1870; US 6448433).

In Scheme 52 presents a General method of obtaining the linker-TAG-modified condensed pyrimidine compounds 75 of the intermediate morpholinothio connection 74, where the Well is a cyclic heteroaryl fragment, Ycand L are defined for compounds of formula Ih-i binding fragment and TAG defined for compounds of formula I, or their precursors or prodrugs.

A COMMON technique to OBTAIN

General procedure a Substituting triazines:

A solution of 2,4,6-trichloro-1,3,5-triazine (1,00 g, 5,42 mmol, 1.0 EQ.) in dioxane (15 ml) at room temperature was treated with diisopropylethylamine (of 1.03 ml, 5,96 mmol, 1.1 EQ.) and was added dropwise aminopyridine (1.1 EQ.) and was stirred for 2 hours. Evaporated dioxane in vacuo and divided the remainder between the H2O (15 ml) and CH2Cl2(15 ml). Separated the organic layer and the aqueous layer was additionally extracted with CH2 Cl2(2×10 ml). The combined extracts were dried (MgSO4) and concentrated in vacuum. Purification using column chromatography allowed us to obtain the title compound.

General procedure a-1 Replacement triazines:

A solution of bis-chlordiazepoxide compound (100 mg, 390 mol, 1.0 EQ.) in dioxane (1 ml) at room temperature was treated with diisopropylethylamine (0.10 ml, 590 mol, 1.5 EQ.) and morpholine (0.05 ml, 590 mol, 1.5 EQ.) and stirred at room temperature for 2 hours. Evaporated dioxane in vacuo and shared the remainder in H2O (5 ml) and CH2Cl2(5 ml). Separated the organic layer and the aqueous layer was additionally extracted with CH2Cl2(2×2 ml). The combined extracts were dried (MgSO4) and concentrated in vacuum. Purification using column chromatography allowed us to obtain the title compound.

Note: for some compounds necessary was the addition of an additional amount of research (0.3 EQ.) after 12 hours of the completion of the reaction, then the reaction mixture was heated at 70°C for 8 hours.

General procedure a-2 Substitution triazines:

247 mg NaH (60% in mineral oil, or 10.3 mmol, of 0.95 EQ.) was added to a solution of 2-pyrimidinemethanol (940 Il, 9,76 mmol, 0.90 or equiv.) in THF (20 ml) at room temperature, which was stirred for 30 minutes. After cooling to -78°C but drops) was added 2,4,6-trichloro-1,3,5-triazine (2.00 g, 10,84 mmol, 1.0 EQ.) and leaving the reaction mixture to warm to room temperature and was stirred for 3 hours. Was added a saturated aqueous solution of NH4Cl (20 ml) and the mixture was extracted with EtOAc (20 ml). The organic phase was dried (MgSO4) and evaporated in vacuo. Column chromatography allowed us to obtain the target product.

A common technique In Combination Suzuki:

The reaction mix by Suzuki is applicable for joining cyclic heteroaryl in position 6 of the triazine or a pyridine ring (see Diagrams 7 and 27), in position 5 or 6 of the pyrimidine ring (see Scheme 46 and 51). As a rule, 4,4'-(6-chloro-1,3,5-trizip-2,4-diyl)dimorpholino(77), 4,4'-(6-chloropyridin-2,4-diyl)dimorpholino (79), 4-(5-chlorothiazole[4,5-d]pyrimidine-7-yl)morpholine (81) and 2-chloro-4-morpholinomethyl[3,2-d]pyrimidine (83) can be combined with pinacoline ether Bronevoy acid (4.0 equiv.) in 1,2-dimethoxyethane and 2M Na2CO3(3:1) for 15 minutes. Added a catalytic amount, or more, palladium reagent, such as dichloro 1,1'-bis(diphenylphosphino)ferrocene palladium(II) (0,025 EQ.) and glass vessel, resistant to pressure, prodably gaseous argon and sealed. Instead pinacoline ether Bronevoy acid can be applied p is lichnye boranova acid or esters Baranovich acids. Also alternatively, the nitrogen of the pyrimidine-2-amine can be protected, for example, tetrahydropyranyloxy group. Then the reaction mixture was heated at 90°C for 15 hours or more, cooled and diluted with ethyl acetate. The organic solution was washed with a mixture of water: Na2CO3: NH4OH (conc. 32% solution of NH4OH in water)=5:4:1, NH4Cl (feast upon.) and brine, dried MgSO4, filtered and concentrated. The residue was purified using flash column-chromatography on silica gel or, if necessary, using reversed-phase HPLC.

A General method With Amide combination of:

7 Morpholino-5-(pyrimidine-5-yl)thiazolo[4,5-d]pyrimidine-2-carboxylic acid (84) or pyridinecarboxamide 86 was treated with 1.5 EQ. HATU, 3 EQ. the alkylamine (R-NH2and 3 EQ. DIPEA in DMF to achieve a concentration equal to about 0.1 M. the Reaction mixture was stirred until completion of the reaction, and once was extracted in ethyl acetate and a saturated solution of bicarbonate. The organic layer was dried, filtered and concentrated to obtain the crude intermediate compound. Specified intermediate compound was purified using column chromatography or preparative TLC to obtain product 85 or 87.

General procedure C-1 Amide combination of:

4-(2-(Piperazine-1-ylmethyl)-5-(pyrimidine-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine (88) or pyridinesulfonamide 90 was treated with 1.5 EQ. HATU, 3 EQ. carboxylic acid (RCO2H) and 3 EQ. DIPEA in DMF to achieve a concentration equal to about 0.1 M. the Reaction mixture was stirred until completion of the reaction, and once was extracted in ethyl acetate and a saturated solution of bicarbonate. The organic layer was dried, filtered and concentrated to obtain the crude intermediate, which was used without additional purification or which is optionally purified using preparative TLC.

General procedure D Reductive amination:

7 Morpholino-5-(pyrimidine-5-yl)thiazolo[4,5-d]pyrimidine-2-carbaldehyde (92) or pyridinesulfonamide 94 was dissolved to achieve a 0.2 M concentration in dichloroethane. To the specified solution was added 1.5 to 2.0 equivalents of amine (R, R"NH), 10 equivalents of triethylorthoformate and 1 equivalent of acetic acid. Leave the mixture was mixed for 2 to 6 hours before the addition of 1.5 equivalents triacetoxyborohydride sodium. After 12-16 hours of stirring, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted several times with ethyl acetate. Specified intermediate compound was purified on C is imagele or used crude in the following reaction stages.

General method E Education sulfonamida:

7 Morpholino-5-(pyrimidine-5-yl)thiazolo[4,5-d]pyrimidine-2-sulphonylchloride (96) suspended in 1 ml of methylene chloride before addition of 2 EQ. amine (R, R"NH) and 3 EQ. DIPEA. The completion of the reaction was monitored using TLC until completion. The crude reaction mixture was diluted with ethyl acetate, was extracted with a saturated solution of ammonium chloride and once was extragonadal in ethyl acetate. The organic layers were combined and concentrated dry. The crude intermediate sulfonamidnuyu compound 97 was directly used in the subsequent combination of Suzuki.

General method F Synthesis of aldehyde:

To a suspension of 4-(5-(pyrimidine-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)research (6,85 mmol, 1.0 EQ.) in dry THF (40 ml) at -78°C was added a 2.5 M solution of n-utility (n-BuLi) in hexane (1.2 EQ.). After stirring for 1 hour was added dry DMF (1.5 EQ.). The reaction mixture was stirred for 1 hour at -78°C, then slowly warmed up to room temperature. After additional incubation for 2 hours at room temperature the reaction mixture was poured into a mixture of ice/water to obtain a precipitate, which was collected by filtration and air-dried to obtain the title compound.

The METHODS SECTION IS of

In the methods for producing compounds according to the present invention the separation of the reaction products from each other and/or from the original substances can be beneficial. Target products of each stage or series of stages separated and/or purified (hereinafter - share) to the required degree of homogeneity by using conventional in the art methods. Typically, these include separation of multi-phase extraction, crystallization from a solvent or mixture of solvents, distillation, sublimation or chromatography. Chromatography may include a number of ways, including, for example, reversed-phase and normal-phase chromatography; exclusion chromatography; ion exchange chromatography; methods and equipment liquid chromatography high, medium and low pressure; analytical chromatography for the determination of small amounts of compounds; chromatography on pseudopodium layer (SMB) and preparative thin - or thick-layer chromatography, and methods thin-layer chromatography, flash chromatography for the determination of small quantities of substances.

Another class of methods division includes the processing of the mixture with a reagent selected for binding or other separation method of the target product, unreacted educt, the side reaction product, etc. from reage what you include adsorbents and absorbents, such as activated carbon, molecular sieves, ion-exchange environment, etc. As an alternative, the reagents can be an acid in the case of basic substances, the base case of acid substances, binding reagents, such as antibodies, binding proteins, selective chelators, such as crown-ethers, extracting ions reagents in the system liquid/liquid (LIX), and so on

The selection of the suitable methods of separation depends on the nature of the contained substances. For example, the boiling point and molecular weight distillation and sublimation, the presence or absence of polar functional groups in chromatography, stability substances in acidic and basic medium under multiphase extraction, and so on, the Specialist in the art will apply the methods most appropriate to effect the required separation.

Diastereomeric mixtures can be separated into individual diastereomers on the basis of differences in chemical properties using methods known to experts in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomer mixture through the interaction with an appropriate optically active compound (e.g., chiral auxiliary substance is, such as a chiral alcohol or acid chloride of Mosera), separating the diastereomers and converting (e.g., hydrolysis) the individual diastereomers to the corresponding pure enantiomers. Also, some compounds according to the present invention can be atropoisomeric (for example, substituted barely) and be considered as part of the present invention. Enantiomers can also be separated using chiral HPLC column.

A single stereoisomer, e.g., enantiomer, essentially not containing their stereoisomers may be obtained by reconstitution of racemic mixtures with the use of a method such as formation of diastereomers using optically active pererastaya agents (e.g Eliel and S. Vilaine (Eliel, E. and Wilen, S.) "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994; K. H. Lochmuller (Lochmuller, C. H., 1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds according to the present invention can be separated and selected by any suitable means, including: (1) formation of ion diastereomeric salts with chiral compounds and separation by using fractionally crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivateservlet reagents, separation of the diastereomers and converting into pure stereoisomers, and (3)separating essentially pure stereoisomers or stereoisomers, mainly containing one of the isomers, directly in the chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology", Irving C. Weiner (Irving W. Wainer), Ed., Varcel Dekker, Inc., New York (1993).

In method (1) diastereomeric salts can be obtained by the interaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and so on, with asymmetric compounds containing acid functionality, such as carboxylic acids and sulfonic acids. Can be obtained diastereomer salt to separate by means of fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic, tartaric acid, almond acid or lactic acid, can lead to diastereomeric salts.

Alternatively, in method (2), the substrate, it is necessary to pererastaet, interacts with one of the enantiomers of chiral compounds with the formation of diastereomeric pairs (e.g Eliel and S. Vilaine (Eliel, E. and Wilen, S.) "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994, page 322). Diastereomers connection can be obtained through the interaction of asymmetric compounds with enantiomerically pure chiral derivateservlet reagents such the AK metrovia derivatives, the subsequent separation of the diastereomers and hydrolysis to obtain a pure enantiomer or an enantiomer, mainly containing one of the isomers. The method of determining optical purity involves obtaining chiral esters, such as metalowy ester, for example, (-) methylchloroform, in the presence of a base, or a complex ester Moser, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. J. Org. Chem. (1982) 47:4165), or racemic mixtures, and analysis1H NMR spectrum for the presence of two atropoisomeric enantiomers or diastereomers. Stable diastereomers atropoisomeric compounds can be separated and allocated using normal - and reversed-phase chromatography, then the methods of separation atropoisomeric naphthyl-isoquinolines (WO 96/15111). In method (3) racemic mixture of two enantiomers can be separated using chromatography using a chiral stationary phase ("Chiral Liquid Chromalography" (1989) C. J. Lo (W. J. Lough), Ed., Chapman and Hall, New York; Okamoto (Okamoto) J. Chromatogr., (1990), 513:375-378). Saturated or purified enantiomers can be distinguished by the methods that are used to distinguish between other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

INTRODUCTION COMPOUNDS ACCORDING to the PRESENT INVENTION

Compounds according to the present invented the Yu can be entered in any way, suitable for conditions requiring treatment. Suitable methods include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, local (including transbukkalno and sublingual), vaginal, intraperitoneally, intra-lungs and intranasal. For local immunosuppressive treatment compounds can be introduced by interstitial injection, including spraying or other interactions of the graft and the inhibitor prior to transplantation. It should be understood that the preferred route of administration may vary, for example, depending on the condition of the patient. In oral introduction the connection may be included in pills, capsules, tablets, etc. with a pharmaceutically acceptable carrier or excipient. When parenteral connection cannot enter into composition with pharmaceutically acceptable parenteral carrier and in an injectable dosage form, as shown below.

Dosage for treatment of patients-people can vary from about 10 mg to about 1000 mg of the compounds of formulas Ia-d. A typical dose may be from about 100 mg to about 300 mg of the compound. The dose can be entered once a day (QID), twice daily (BID) or more is frequent, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism and excretion of the specific compound. In addition, the toxicity factors may influence the dosage and scheme administration. During oral introduction of the pill, capsule or tablet can be entered daily or less often during a specific period of time. The treatment regimen can be repeated for several cycles of treatment.

METHODS of TREATMENT with COMPOUNDS ACCORDING to the PRESENT INVENTION

Compounds according to the present invention are applicable for the treatment of diseases, conditions and/or disorders, including, but not limited to, diseases characterized by increased expression of libidinis, for example, PI3 kinase. Accordingly, another aspect of the present invention includes methods of treatment or prevention of diseases or conditions that can be treated or prevented by the inhibition lietkynes, including PI3. In one embodiment, the implementation of the method comprises the administration to a mammal in need of specific treatment, a therapeutically effective amount of compounds of formulas Ia-d, or its stereoisomer, geometric isomer, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salts or prodrugs.

Diseases and conditions that may be treated in accordance with the tvii with the methods according to the present invention, include, but are not limited to, cancer, stroke, diabetes, gepatomegalia, cardiovascular disease, Alzheimer's disease, cystic fibrosis, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, diseases related to hormones, conditions associated with organ transplantation, immunological disorders, destructive bone lesions. hyperproliferative disorders, infectious diseases, conditions associated with cell death, platelet aggregation caused by thrombin, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions, including activation of T cells, and abnormalities of the Central nervous system. In one embodiment, the implementation of the patient-a person treated by a compound of formulas Ia-d and a pharmaceutically acceptable carrier, adjuvant or substance carrier, where the specified substance formulas Ia-d is present in the amount of visible inhibition of the activity of PI3 kinase.

Cancers that can be cured in accordance with the methods according to the present invention, include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, cancer of the male genital glands, cancer of the genitourinary tract, esophagus cancer, cancer of the larynx, glioblastoma, neuroblastoma, cancer of the VC is dka, skin cancer, keratoakantoma, lung cancer, epidermoid carcinoma, both carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, carcinoma of the bladder, carcinoma of the liver and bile duct carcinoma of the kidney, disorders of the spinal cord, lymphatic disorders, hairy cell leukemia, cancer of the oral cavity and pharynx, cancer of the lips, tongue cancer, oral cancer, cancer of the pharynx, cancer of the small intestine, cancer of the colon and rectum, colon cancer, rectal cancer, cancer of the brain and Central nervous system cancer, Hodgkin's and leukemia.

Cardiovascular diseases that can be treated in accordance with the methods according to the present invention, include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction and congestive heart failure.

Neurodegenerative diseases that can be treated in accordance with the methods according to the present invention, include, but are not limited to, Alzheimer's disease, Parkinson's disease, amiotrophic lateral sclerosis, the disease Huntingt is on and cerebral ischemia, also Neurodegenerative diseases caused by injury, glutamate neurotoxicity and hypoxia. Inflammatory diseases that can be treated in accordance with the methods according to the present invention, include, but are not limited to, rheumatoid arthritis, psoriasis, contact dermatitis and hypersensitivity of the delayed type.

In another aspect of the present invention proposed a connection according to the present invention, used for the treatment of diseases or conditions described in this application, a mammal, for example, a man suffering from the specified disease or condition. Also proposed the use of compounds according to the present invention for obtaining a medicinal product for the treatment of diseases and conditions described in this application, in warm-blooded animals such mammals, for example, people suffering from such disorders.

PHARMACEUTICAL COMPOSITIONS

For application of the compounds according to the present invention for therapeutic treatment (including prophylactic treatment) of mammals including humans, the substance is generally included in the composition, in accordance with conventional pharmaceutical practice, the pharmaceutical composition. In accordance with the aspect of the present invention offer the pharmaceutical composition, containing compound according to the present invention together with a pharmaceutically acceptable diluent or carrier.

A typical composition is produced by mixing the compounds according to 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, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. Specific applicable carrier, diluent or excipient depends on the methods and purposes for which the connection according to the present invention is applied. Solvents are generally selected from solvents that are defined by experts in the field of technology as safe (GRAS) for administration to a mammal. In General, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that dissolve or mix with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (such as PEG 400, PEG 300), etc. and mixtures thereof. The compositions can also contain one or more buffers, stabilizing agent, a preservative, an antioxidant, radiopaque agents, glide is you, substances to improve the processing properties, dyes, sweeteners, flavouring agents, flavoring agents and other known additives to provide a convenient dosage form of a drug (i.e., compounds according to the present invention or pharmaceutical composition) or aid in the production of the pharmaceutical product (i.e., medications).

The compositions can be obtained with the use of suitable methods of dissolution and mixing. For example, the mass of drug substance (i.e., compounds according to the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more filler described above. The connection according to the present invention, as a rule, is part of the pharmaceutical dosage form that provides an easily controllable dosage of the drug and provides patient compliance with prescribed treatment.

Applied pharmaceutical composition (or composition) can be packaged in different ways depending on the method used for the introduction of the drug. Typically, the product distribution includes container, contents is ASCII stored in the pharmaceutical composition in an appropriate form. Suitable containers are well known to experts in the art and include packaging, such as bottles (plastic and glass), shaped sachets, ampoules, bags, metal cylinders etc., the Container may also include a device for protection against inept use to prevent inadvertent access to the contents of the package. In addition, the container has a label, which describes the contents of the container. The tag may also contain appropriate warnings.

The pharmaceutical compositions of the compounds according to the present invention can be obtained for different methods and types of administration. For example, the compound of formulas Ia-d, with the necessary degree of purity, may be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remingrton''s Pharmaceutical Sciences (1980) 16ththEdition, L. Ed. Osol (Osol, A. Ed.)) in the form of a lyophilized composition, milled powder, or an aqueous solution, the composition can be obtained by mixing at ambient temperature at the appropriate pH, and at the required degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic for patients in the applied dosages and concentrations. the pH of the composition depends mainly on the particular application and is concentratie connection but may vary from about 3 to about 8. Suitable embodiment is a composition in acetate buffer with a pH equal to 5.

The connection according to the present invention, used for tasks of this application, is preferably sterile. In particular, the compositions used for the introduction into the body, must be sterile. The specified sterilization easily carried out by filtration through sterile filtration membranes.

Connection, as a rule, can be stored in the form of a solid composition of lyophilized composition or in the form of an aqueous solution.

The pharmaceutical compositions according to the present invention should be formulated, dosed, and introduced the method, i.e., in amounts, concentrations, schedules, course of treatment, the media and the method of administration, appropriate appropriate medical practice. Considered in this context include the particular disorder that is treated, the particular mammal that is being treated, the clinical condition of the individual patient, the cause of the violation, place of introduction of the drug, route of administration, the scheme of administration and other factors known to medical practitioners. "Therapeutically effective amount" of a compound that must be entered based on the following conditions, such as the minimum amount which, necessary for the prevention, delay or treatment of disorders of the blood's clotting mechanism. The specified amount is preferably lower than the amount that is toxic to the patient or makes the patient much more prone to bleeding.

As a General rule, the initial pharmaceutically effective amount of the inhibitor, administered parenterally, per dose is in the range of about 0.01 to 100 mg/kg, more specifically, from about 0.1 to 20 mg/kg of patient per day, with the typical initial range of concentration of the applied compound is from 0.3 to 15 mg/kg/day.

Suitable diluents, carriers, napolitani and stabilizers are nontoxic to patients in the applied dosages and concentrations, and include buffers such as phosphate, citric and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as chloride of octadecyltrimethoxysilane; chloride hexadecane; benzalkonium chloride, chloride benzene; phenol, butyl or benzyl alcohol; alkylarene, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (containing less than about 10 residues) polypeptides; proteins, such as serum albumin, m is tin 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; salt forming counterions such as sodium; metal complexes (e.g., complexes of Zn-protein); and/or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Active pharmaceutical ingredients may also be included in the composition of the microcapsules obtained, for example, by using coacervation or inter-phase polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly(methylmethacrylate)tion of microcapsules, respectively, in colloidal drug-delivery systems (e.g. liposomes, albumin microspheres, microemulsions, nanoparticles and apocaps) or microemulsion. These methods are described in Remington's Pharmaceutical Sciences 16thedition, A. ed. Osol (Osol, A. Ed., 1980).

Can be obtained preparations of the compounds of formulas Ia-d sustained-release. Suitable examples of drugs with impaired release include semi-permeable matrices of solid hydrophobic polymers containing a compound of formulas Ia-d, and the matrix are in the de-shaped products, for example, films, or microcapsules. Examples of matrices with a slow release include prilojenie esters, hydrogels (for example, poly(2-hydroxyethylmethacrylate) or polyvinyl alcohol), polylactide (U.S. patent No. 3773919), copolymers of L-glutamic acid and gamma ethyl-L-glutamate, non-biodegradable ethylene-vinyl acetate, degradable copolymers of lactic and glycol acid, such as the LUPRON DEPOT™ (injectable microspheres composed of copolymer of lactic and glycol acid and leuprolide) and poly-D-(-)-3-hydroxybutanoic acid.

The compositions include compositions suitable for administration by the methods described in this application. The compositions may suitably be in the dosage form and may be obtained by any method well known in the pharmaceutical field. The methods and formulations generally may be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). These methods include the stage of carrying out of the interaction of the active ingredient and carrier, which contains one or more auxiliary ingredient. In General, the compositions obtained a homogeneous and uniform interaction of the active ingredient and liquid carriers or finely dispersed solid carriers or both types of media, and then if necessary make the products form.

Compositions of the compounds of formulas Ia-d, the right to oral administration, can be obtained in the form of separate particles, such as pills, capsules, shaped sachets or tablets, each containing a specified number of compounds of formulas Ia-d.

Molded tablets can be obtained by pressing in a suitable device is the active ingredient in free-flowing form such as powder or granules, possibly mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be obtained by molding in a suitable device of the mixture powder of the active ingredient, uverennogo inert liquid diluent. The pill may may contain shell or be a divisible tablet and it is possible to enter into such a composition that provides a slow and controlled release of the active ingredient.

Tablets, molded tablets, lozenges, aqueous or oil suspensions, dispersed powders or granules, emulsions, hard or soft capsules, for example, gelatin capsules, syrups or elixirs can be obtained for oral administration. Formulations of the compounds of formulas Ia-d, intended for oral administration can be obtained in accordance with any method known in this field of technology, pharmaceutical production is omposite, and these compositions can contain one or more agent, including sweeteners, flavourings, colourings and preservatives, to obtain a product with a pleasant appearance. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable carrier which is suitable for manufacture of tablets, are acceptable. These fillers can represent, for example, inert diluents, such as calcium carbonate or sodium, lactose, calcium phosphate or sodium; granulating and improve raspadaemost tablets substances such as corn starch or alginic acid; binding agents such as starch, gelatin or gum; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be bezobolochnye or contain membrane obtained by the use of known methods, including microencapsulation to delay decomposition and adsorption in the gastrointestinal tract and provide, therefore, a delayed action over an extended period of time. For example, you can apply a substance that delay time of the release, such as glycerylmonostearate or glycerylmonostearate individually or together with wax.

For treatment of the eye or other external bodies, for example, mouth or skin, the formulations are preferred is sustained fashion used in the form of a cream or ointment for local application, containing the active(s) ingredient(s) in an amount equal to, for example, of 0.075 to 20% (wt./mass.). In the case of entering in the composition of ointments active ingredients can be used with paraffin or mixed with water-based ointments. As an alternative, the active ingredients can be included in the cream oily or water-based cream.

If necessary, the aqueous phase is the basis of the cream may contain polyhydroxy 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. Compositions for topical application may preferably include a compound which enhances absorption or penetration of the active ingredient into the skin or other skin surface. Examples of these amplifiers penetration into the skin include dimethylsulfoxide and analogues based on it.

The oily phase of the emulsions according to the present invention may consist of the known ingredients in a known manner. While the phase may contain an emulsifier, preferably a phase contains a mixture of at least one emulsifier and fat or oil, or grease and oil. Preferably, the hydrophilic emulsifier is used together with a lipophilic emulsifier, which acts as a stabilizer. Also repectfully is the content and oil and grease. In addition, the emulsifier(s) with stabilizer(s) or without stabilizers, form the so-called emulsifying wax, and the wax, taken in conjunction with oil and grease, forms the so-called emulsifying materials, which forms an oily dispergirovannoyj phase compositions cream. Emulsifiers and emulsion stabilizers suitable for use in the compositions according to the present invention include Tween® 60, Span® 80, cetosteatil alcohol, benzyl alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate.

Aqueous suspensions of the compounds of formulas Ia-d contain the active substance in a mixture with excipients suitable for the manufacture of aqueous suspensions. These fillers contain suspendisse agent, such as sodium carboxymethyl cellulose, croscarmellose, pavido, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum, and dispersing agents or humectants, such as natural phosphatic (e.g., lecithin), a condensation product of accelerated and fatty acids (for example, polyoxyethylenated), a condensation product of ethylene oxide and long chain aliphatic alcohol (for example, heptadecafluorooctyl), the condensation product of ethylene oxide and incomplete complex ester derived from a fatty acid of the anhydride hexitol (for example, the polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl-p-hydroxybenzoate, one or more colouring agents, one or more flavoring and one or more sweetener, such as sucrose or saccharin.

The pharmaceutical compositions of the compounds according to the present invention can be in the form of a sterile injectable preparation, such as a sterile aqueous or oily suspension. This slurry may enter into the composition in accordance with methods known in the art, for example with suitable/dispersing agents or moisturizers and suspendresume agents, which are presented above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, can also be obtained in the form of lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, ringer's solution and weak solution of sodium chloride. In addition, as a solvent or suspeciously environment, you can apply sterile fatty oil. For this purpose you can use any light fatty oils, including mono - or di is literaly. In addition, to obtain injectively compositions similarly, you can use fatty acids such as oleic acid.

The amount of active ingredient that can be mixed with the media to produce a single dosage form varies depending on the patient being treated and the particular route of administration. For example, the composition of the sustained-release formulation intended for oral administration to humans may contain from about 1 to 1000 mg of active substance included in the composition together with the appropriate and suitable amount of carrier which may vary from about 5% to about 95% of the total mass of the composition (weight: weight). The pharmaceutical composition can be obtained to provide easily dosed quantities for injection. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 µg of active ingredient per milliliter of solution for infusion of a suitable volume at a rate equal to about 30 ml/hour.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and dissolved substances, which make the composition isotonic with the blood of the patient; and aqueous and non-aqueous sterile suspensions, to whom that may contain suspendresume agents and thickeners.

Formulations suitable for topical introduction to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, specifically in aqueous solvent of the active ingredient. The active ingredient is preferably present in said composition at a concentration of approximately from 0.5 to 20% (wt./mass.), for example, from about 0.5 to 10% (wt./mass.), for example, about 1.5% (wt./mass.)

Formulations suitable for local injection in the mouth include lozenges, containing the active ingredient in a flavored basis, usually sucrose or gums or tragacanth gum; pastes contain the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and gum; solutions for rinsing the mouth contain the active ingredient in a suitable liquid carrier.

Compositions for rectal injection can be in the form of suppositories in a suitable basis, containing, for example, cocoa butter or a salicylate.

Formulations suitable for intra-lungs or nasal injection have a particle size of, for example, in the range from 0.1 to 500 microns (including particle sizes in the range from 0.1 to 500 microns with an interval, such as 0.5, 1, 30 microns, 35 microns, etc), which are introduced with a rapid inhalation through the nasal passage or by inhalation through the mouth, that is s thus to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for administration in the form of an aerosol or powder, can be obtained in accordance with appropriate methods and may be delivered in conjunction with other therapeutic agents such as compounds previously used for the treatment or prevention of the disorders described below.

Formulations suitable for vaginal introduction may be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers which are known in the art, as appropriate.

The compositions can be packaged in disposable containers or reusable containers, for example sealed ampoules and vials, and can also be stored in dried cold (lyophilized) condition requiring only the addition of sterile liquid carrier, for example, water, immediately before use as injection. Prepared for immediate injection solutions or suspensions obtained from sterile powders, granules and tablets previously described species. The preferred dosage formulations are compositions containing a daily dose or unit podozerova presented earlier, or their respective share of the asset in the second ingredient.

The invention also proposed veterinary compositions containing at least one active ingredient, as described earlier, together with a veterinary carrier. Veterinary carriers are substances that are applicable to the introduction of the composition, and can be a solid, liquid or gaseous substances which are inert or applicable for veterinary purposes and are compatible with the active ingredient. These veterinary compositions can be entered parenterally, orally, or any other suitable method.

COMBINATION THERAPY

Compounds according to the present invention can be applied individually or in combination with other therapeutic agents for the treatment of diseases or disorders described in the present application, such as a hyperproliferative disorder (e.g., cancer). In some embodiments of the compound of formulas Ia-d are combined in a pharmaceutical combination composition or combined dosage regimen, such as combination therapy, with a second compound which has antihypercholesterolemic properties or which is applicable to the treatment of hyperproliferative disorders (e.g., cancer). The second compound of the pharmaceutical combination composition or combined mode is Osinovaya preferably active, supplementing the activity of the compounds of formulas Ia-d so that they do not impact negatively on each other. These compounds suitable means are present in combination in amounts that are effective for the purposes intended. In one implementation options of the composition according to the present invention contains a compound of formulas Ia-d, or a stereoisomer, geometric isomer, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salt or prodrug, in combination with a chemotherapeutic agent described in this application.

Combination therapy can be applied in a simultaneous or sequential mode of dosage. The sequential introduction of combination can be entered using two or more injections. The combined introduction includes co-administration, using separate formulations or a single pharmaceutical composition, and the consequent introduction in any order, and it is preferable that period of time, so that both (or all) of the active agent at the same time demonstrated their biological activity

Suitable dosages for any of the above added together agents represent the dosage used in the present time that can be reduced as a result of a combination of the CSO action (synergy) defined in this application agents and other chemotherapeutic agents or treatments.

Combination therapy may provide "synergy" and to be "synergistic" effect, i.e. the effect achieved when the active ingredients used together, which is more strong in comparison with the amount of effects that occur from the separate use of the compounds. A synergistic effect may be attained when the active ingredients are: (1) are members of the same composition and introduced or delivered simultaneously in a combined dosage composition; (2) delivered separately or simultaneously in different compositions; or (3) enter into certain other dosage regimes. Sequential therapy, a synergistic effect can be achieved when the compound is administered or delivered sequentially, for example, by using different injections in separate syringes and separate pills or capsules or separate infusions. In General, during sequential therapy effective dose of each active ingredient is administered sequentially, i.e., series, whereas combination therapy effective dose of two or more active ingredients are administered together.

In a specific embodiment, the implementation of anti-cancer therapy compounds of formulas Ia-d, or a stereoisomer, geometric isomer, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salt or poleca the STV, can be combined with other chemotherapeutic, hormonal agents or antibodies described in this application and can also be combined with surgical treatment or radiotherapy. Combined therapy according to the present invention, thus, includes the introduction of at least one compound of formulas Ia-d, or its stereoisomer, geometric isomer, tautomer, MES, metabolite, N-oxide derivative or pharmaceutically acceptable salt or prodrug, and the use of at least one other way of treating cancer. The amount of compound(s) of formulas Ia-d and the other(s), pharmaceutically acceptable(s) chemotherapy(their) agent(s) and the relative times of the target to achieve the target of a combined therapeutic effect.

METABOLITES of the COMPOUNDS ACCORDING to the PRESENT INVENTION

The products of metabolism in the body of the compounds of formulas (I) and (Ia) to (II) described in this application fall within the scope of the present invention. These products can be obtained, for example, oxidation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic degradation, and so on, entered the compound. Accordingly, the invention encompasses metabolites of compounds of formulas (I) and (Ia) to (Ii), the key connection the resulting process involving the interaction of the compounds according to the present invention and of a mammal for a time period sufficient to yield a metabolic product of the connection.

Metabolic products are usually determined by obtaining compounds according to the present invention, radiolabelled (e.g., H or C), the introduction of the specified connection parenterally in a detectable dose (e.g. greater than 0.5 mg/kg) to an animal such as rat, mouse, Guinea pig, monkey, or human, keeping within a period of time sufficient to pass metabolism (usually from 30 seconds to 30 hours) and highlighting the transformation products from the urine, blood or other biological samples. These products are easy to distinguish because they are labeled (other isolated by using antibodies that bind epitopes remaining in the metabolite). Metabolic patterns determine the appropriate way, e.g. with MS, MCHP or NMR analysis. In General, the analysis of metabolites carried out in a manner analogous to conventional studies of the metabolism of drugs that are well known to specialists in this field of technology. As metabolic products in any other case can't be found in the organization is the mechanism, they are applicable for diagnostic studies, therapeutic dosing of the compounds according to the present invention.

PRODRUGS of the COMPOUNDS ACCORDING to the PRESENT INVENTION

In addition to the compounds according to the present invention, the invention also includes pharmaceutically acceptable prodrugs of these compounds. Prodrugs include compounds in which amino acid residue, or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues, covalently joined through an amide or ester bonds with free amino, hydroxy or carboxyl group of the compounds according to the present invention. Amino acid residues include, but are not limited to, 20 existing in nature, amino acids, generally designated by three letter symbols and also include phosphoserine, phosphation, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demazin, isodesmosine, gamma carboxyglutamate, hippuric acid, octahedron-2-carboxylic acid, a statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, arpitan, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminobutanoic acid, Zhigulin, homocysteine, homoserine, methylalanine, para-benzylpenicillin, phenylglycine, propargylglycine, arcsin, methioninamide and tert-butylglycol.

Also covered additional types of prodrugs. For example, a free carboxyl group of the compounds according to the present invention can be converted into amide or ester with alkyl. As another example, compounds according to the present invention containing free hydroxyl groups can be converted into prodrugs by transforming the hydroxyl group, including, but not limited to, selenophosphate ether, hemisuccinate, dimethylamino acetate or phosphorylmethylcarbamoyl group, described in Advanced Drug Delivery Reviews, (1996) 19:115. Also included urethane prodrugs of hydroxyl and amino groups, such as the carbonate prodrugs, sulfate esters and sulfate esters of hydroxyl groups. Also involved in the conversion of hydroxyl groups in (acyloxy)methyl and (acyloxy)ethyl esters, in which the acyl group can be a difficult alkyl ether possibly substituted by groups including, but not limited to, ether, amine or carboxyl function, or in which the acyl group is an ester of the amino acids described above. Prodrugs of the specified type described in J. Med. Chem., (1996), 39:10. More specific examples include replacement of the ATO is and hydrogen of an alcohol group on the group, such as (C1-C6)alkanoyloxy, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonylmethyl, N-(C1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, ariell and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl groups independently selected from natural L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2or glycosyl (radical obtained by removing hydroxilic group hemiacetal form of carbohydrate).

For more examples, derivatives, prodrugs, see, for example, (a) Design of Prodrugs, edited by N. Bundgaard, Elsevier, 1985, Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder et al., Academic Press, 1985; b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and N. Bundgaard, Chapter 5 "Design and Application of Prodrugs, edited by N. Bundgaard p.113-191 (1991); (C) N. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) N. Bundgaard et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is incorporated into the present application by reference.

PRODUCTS

In another embodiment, the implementation of the proposed product, or a "kit" containing substances that are applicable for the treatment of diseases and disorders described above. In one implementation options of the kit includes a container containing the connection fo the mule Ia-d, or a stereoisomer, geometric isomer, tautomer, MES, metabolite, N-accidnet derivative or a pharmaceutical salt or the prodrug. The kit can further comprise a label or instructions for use, located on the container or associated with it. The term "instructions for use" is used to refer to the instructions, usually attached to commercial packages of therapeutic products, that contain information about the indications, usage, dosage, introduction, contraindications and/or warnings relating to the use of these therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blisters, etc., the Container can be obtained from a variety of substances, such as glass or plastic. The container may contain a compound of formulas Ia-d, or a composition containing a specified compound that is effective for treating the condition and may contain a sterile access port (for example, the container may be a container or vial intravenous solution containing tube, penetrable by a needle for subcutaneous injection). At least one active agent composition is a compound of formulas Ia-d. Tag or instruction manual indicates that the composition is used to treat the selected state, such as cancer. In addition,the label or instructions for use can show the patient, in need of a specific treatment, is a patient suffering from disorders, such as hyperproliferative violation, neurodegeneration, cardiac hypertrophy, pain, migraine or neurotraumatic disease or phenomenon. In one implementation options of the label or instructions for use indicate that a composition comprising a compound of formulas Ia-d, can be used to treat disorders caused by abnormal cell growth. The label or instructions for use can also show that the composition can be used to treat other disorders. As an alternative or in addition, the product may further comprise a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, ringer's solution and dextrose. The product may also contain other substances that are important from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

The kit can also contain a guide to introducing the compound of formulas Ia-d and, if present, the second pharmaceutical composition. For example, if the set contains a first composition comprising a compound of formulas Ia-d and the second pharmaceutical composition, the kit may optionally contain p is breeding for simultaneous, sequential or separate introduction of the first and second pharmaceutical compositions to a patient in need of specific treatment.

In another embodiment, the implementation sets are suitable for delivery of solid dosage forms for oral administration of the compounds of formulas Ia-d, such as tablets or capsules. The specified set preferably contains a number of unit dosage forms. These kits can contain a card containing dosage designed for the intended application. An example of such a set is a "blister". Blister packs are well known in the packaging industry, they are widely used for packaging of pharmaceutical dosage forms. If necessary, you may be prompted memo, for example, in the form of numbers, letters, or other marks or schedule of administration of the medicine, which displays the days in the regimen, in which you can enter the dosages.

In accordance with one implementation options of the set may contain (a) a first container containing a compound of formulas Ia-d; and possibly (b) a second container containing a second pharmaceutical composition, where the second pharmaceutical composition comprises a second compound with anti-hyperproliferative activity. As an alternative or additionally, the kit may further comprise a third container containing farmaci is almost acceptable buffer, such as bacteriostatic water for injection (BWFJ), phosphate-buffered saline, ringer's solution and dextrose. The kit may also contain other substances that are important from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

In some other implementations, when the set contains the composition of the compounds of formulas Ia-d and the second therapeutic agent, the kit may include a container for the content of individual compositions, such as an individual bottle or a separate package with the inner surface of the foil, however, the separate compositions may also be contained within a single undivided container. Typically, the kit contains guidelines for the implementation of separate components.

Particularly preferred form of a mosaic, in which the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), injected with different intervals in the dosage or when titration of the individual components of the combination determined by the treating physician.

An EXAMPLE of BIOLOGICAL RESEARCH

Identification of the potential detection of PI3K/PI3K-related kinases (PIKK) of the compound of formula I may make next direct and indirect detection methods. A particular model compounds described what s in this application, examined for activity, blocking phospho RKV, and activity against tumor cells in vitro. Range phospho RKV activities ranged from less than 1 nm (nanomolar) to about 10 μm (micromolar). Other typical compounds according to the present invention had values IC50for activity, blocking phospho RKV equal to less than 10 nm. Specific compounds according to the present invention had values IC50for activity against tumor cells, equal to less than 100 nm.

The cytotoxic or cytostatic activity of typical compounds of formula I was determined by: - keeping proliferating tumor cell lines mammals in the cell culture medium, adding the compounds of formula I, culturing cells for from about 6 hours to about 3 days; and measuring cell viability. Cell research was used to determine viability, i.e., proliferation (IC50), cytotoxicity (EC50) and inducing apoptosis (activated caspase).

The activity of compounds of the formula I in vitro was determined using intracellular studies on the type of Western, developed in the laboratory of the University of Basel. The analysis in this way was carried out in micromicrofarad tablets, which ensured receptive the TB screening high throughput (HTS). To the medium was added inhibitors and incubated. Antibodies diluted in FSB/T against RCV Ser473 (Cell signaling) and RCO (received as a gift from E. Hirsch (E. Hirsch)) or pS6 Ser 235/236 (Cell Signalling) were incubated overnight, and then used a secondary labeled fluorescently antibodies (LI-COR), and the plates were scanned on the device for reading Odyssey to determine the relationship RCV/RKV.

The following compounds have proved particularly significant biological activity:

- 4,4'-(6-(pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenol,

- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-3-ol,

- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-amine,

- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-amine,

- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine,

- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine,

- N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)acetamide", she

- N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-yl)acetamide", she

- N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-yl)acetamide", she

- N(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)acetamide", she

- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-(trifluoromethyl)pyridin-2-amine,

- 4,4'-(6-(1H-indazol-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 4,4'-(b-(1H-indol-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 4,4'-(6-(1H-benzo[d]imidazol-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 4,4'-(6-(1H-benzo[d]imidazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 4,4'-(6-(1H-indol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 4,4'-(6-(1H-indazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 4,4'-(6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,

- 5-(4-morpholino-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)pyridine-2-amine,

- 5-(4-morpholino-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)pyrimidine-2-amine,

- 4-(4-(1H-indol-4-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine,

- 4-(4-(1H-indazol-4-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine,

- 4-(4-(1H-benzo[d]imidazol-4-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine,

- 4-(4-(1H-benzo[d]imidazol-5-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine,

- 4-(4-(1H-indazol-5-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine,

- 4-(4-(1H-indol-5-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine,

- 3-(4-morpholino-6-(pyridine-2-ylmethylamino)-1,3,5-triazine-2-yl)phenol,

- 4-(6-aminopyridine-3-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine,

- 4-(2-aminopyrimidine-5-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine,

- 4-(1H-indol-5-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine,

- 4-(1H-indazol-5-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine,

- 4-(1H-benzo[d]imidazol-5-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine,

- 4-(1H-benzo[d]imidazol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-three is Zin-2-AMIP,

- 4-(1H-indol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine,

- 4-(1H-indazol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine,

- 3-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol,

- 3-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol,

- 3-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol,

- 3-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol,

- 3-(2-((4-(methylsulphonyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol,

- 5-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine,

- 5-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-amine,

- 5-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine,

- 5-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine,

- 4-(5-(1H-indazol-4-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 4-(5-(1H-indazol-4-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 4-(5-(1H-indazol-4-yl)-2-((4-(methylsulphonyl)piperazine-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 4-(5-(1H-indol-4-yl)thiazolo[4,5-e]pyrimidine-7-yl)morpholine,

- 4-{5-(1H-benzo[d]imidazol-4-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 4-(5-(1H-benzo[d]imidazol-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 4-(5-(1H-indol-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 4-(5-(1H-indol-5-yl)-2-((4-meth is piperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 4-(5-(1H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine,

- 2-(1H-benzo[d]imidazol-5-yl)-4-morpholinomethyl[3,2-d]pyrimidine,

- 2-(1H-indol-5-yl)-4-morpholinomethyl[3,2-d]pyrimidine,

- 2-(1H-indazol-5-yl)-4-morpholinomethyl[3,2-d]pyrimidine,

- 6-(1H-indazol-5-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren,

- 6-(1H-benzoimidazol-5-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren,

- 6-(1H-indol-5-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren,

- 2-(1H-indol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine,

- 2-(1H-indazol-4-yl)-4-morpholinomethyl [3,2-d]pyrimidine,

- 2-(1H-benzo[d]imidazol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine,

- 6-(1H-indazol-4-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren,

- 6-(1H-indazol-4-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren,

- 6-(1H-benzoimidazol-4-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren,

- 6-(1H-indol-4-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren,

- 5-(8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)pyrimidine-2-ylamine,

- 3-[2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl] phenol,

- 5-(8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)pyridin-2-ylamine,

- 5-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)pyridine-2-amine,

- 5-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)pyrimidine-2-amine, and

3-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)phenol.

Among the above link is 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine and 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine have excellent biological properties, which make them very promising therapeutic agents (see Table 6 below).

DETAILED description of the INVENTION

Hereinafter the invention will be described in more detail with reference to specific implementation options and examples of the present invention, which are typical, but not limiting the invention.

Table 1 presents the structures and corresponding names by IUPAC (using ChemDraw Ultra Version 11.0.1 and earlier and later versions of the software, CambridgeSoft Corp., Cambridge MA) typical compounds No. 1-259 of formula (Ia), (Ib) or (Id).

Table 1
No.StructureName
14,4'-(6-(pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
24,4'-(6-(pyridin-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
34,4'-(6-(3-herperidin-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
4 4,4'-(6-(4-herperidin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
53-(4,6-dimorpholino-1,3,5-triazine-2-yl)aniline
6N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)ndimethylacetamide

6.1N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)acrylamide
6.22-chloro-N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)ndimethylacetamide
6.32-bromo-N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)ndimethylacetamide
6.4N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)-2-iodated
6.5N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)nicotinamide
6.66-amino-N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)nicotinamide
6.72-amino-N-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)pyrimidine-5-carboxamide
74-(4,6-dimorpholino-1,3,5-triazine-2-yl)aniline

8N-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)ndimethylacetamide
8.1N-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)acrylamide
8.22-chloro-N-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)ndimethylacetamide
8.3N-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)acrylamide
8.4 1-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl)-3-metalmachine
93-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenol
9.1(R)-3-(4-(2-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)phenol

9.23-(4-((2R,6S)-2,6-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)phenol
9.31 -(4-(4-(3-hydroxyphenyl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)IRAP-2-EN-1-he
9.4(Z)-1-(4-(4-(3-hydroxyphenyl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)but-2-EN-1-he
9.52-chloro-1-(4-(4-(3-hydroxyphenyl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)alanon
103-(4,6-dimer is Olya-1,3,5-triazine-2-yl)phenyl acetate
115-(4,6-dimorpholino-1,3,5-triazine-2-l)pyridine-3-ol
124,4'-(6-(3-methoxyphenyl)-1,3,5-triazine-2,4-diyl)dimorpholino

134,4'-(6-(3-(tert-butyldimethylsilyloxy)phenyl)-1,3,5-triazine-2,4-diyl)dimorpholino
144-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenol
154-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenyl acetate
165-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-ol
175-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl acetate
18 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-ol
195-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-ylacetic

205-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-methylpyridin-2-ol
215-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-methylpyridin-2-ilaclar
225-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyridin-2-ol
235-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyridin-2-ylacetic
245-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyrimidin-2-ol
255-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyrimidin-2-ylacetic
265-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4,6-dimethylpyrimidin-2-ol

275-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-ol
285-(4-morpholino-6-(piperazine-1-yl)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidin-2-ol
295-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-ylacetic
305-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-(trifluoromethyl)pyridin-2-ol
315-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-(trifluoromethyl)pyridine-2-ylacetic
325-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-ol
33 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridine-2-ylacetic

344,4'-(6-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
355-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-amine
36N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)ndimethylacetamide
37tert-butyl 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-ylcarbamate
385-(4,6-dimorpholino-1,3,5-triazine-2-yl)Nijmegen-2-amine
38.15-(4-(4-methylpiperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)pyrimidine-2-amine
38.2 5-(4-(4-(methylsulphonyl)piperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)Nijmegen-2-amine

38.31-(4-(4-(2-aminopyrimidine-5-yl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)prop-2-EN-1-he
38.41-(4-(4-(2-aminopyrimidine-5-yl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)-2-chlorethane
38.55-(4-morpholino-6-(1,4-oxazepan-4-yl)-1,3,5-triazine-2-yl)pyrimidine-2-amine
39N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-yl)ndimethylacetamide
40tert-butyl 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-ylcarbamate
415-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-methylpyridin-2-amine
42 N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-methylpyridin-2-yl)ndimethylacetamide

435-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyridin-2-amine
43.11-(4-(4-(6-amino-4-methylpyridin-3-yl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)prop-2-EN-1-he
43.21-(4-(4-(6-amino-4-methylpyridin-3-yl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)-2-chlorethane
43.3(R)-4-methyl-5-(4-(2-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)pyridine-2-amine
43.45-(4-((2R,6S)-2,6-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-methylpyridin-2-amine
43.54-methyl-5-(4-(4-methylpiperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)pyridine-2-amine
43.64-methyl-5-(4-(4-(methylsulphonyl)piperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)pyridine-2-amine

44N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyridin-2-yl)ndimethylacetamide
455-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyrimidin-2-amine
45.1(R)-4-methyl-5-(4-(2-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)pyrimidin-2-amine
45.25-(4-((2R,6S)-2,6-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-methylpyrimidin-2-amine
45.31-(4-(4-(2-amino-4-methylpyrimidine-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-yl)prop-2-EN-1-he
45.41-(4-(4-(2-and the Ino-4-methylpyrimidin-5-yl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)-2-chlorethane
45.54-methyl-5-(4-(4-methylpiperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)pyrimidine-2-amine

45.64-methyl-5-(4-(4-(methylsulphonyl)piperazine-1-yl)-6-morpholino-1,3,5-triazine-2-yl)pyrimidine-2-amine
45.74-methyl-5-(4-morpholino-6-(1,4-oxazepan-4-yl)-1,3,5-triazine-2-yl)pyrimidine-2-amine
45.84-methyl-5-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazine-2-yl)pyrimidine-2-amine
46N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-methylpyrimidin-2-yl)ndimethylacetamide
475-(4,6-dimorpholino-1,3,5-Terezin-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
47A1-(5-(4,6-Dimo is folino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-yl)guanidine
48N-(5-(4,6-dimorpholino-1,3,5-Terezin-2-yl)-4-(trifluoromethyl)pyrimidine-2-yl)ndimethylacetamide

49tert-butyl 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(triptorelin)pyrimidine-2-ylcarbamate
505-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
515-(4-(4-methylpiperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
51.15-(4-(4-(methylsulphonyl)piperazine-1-yl)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine
525-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-(trifluoromethyl)pyridin-2-amine
53 N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-6-(trifluoromethyl)pyridin-2-yl)ndimethylacetamide
545-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine

54A1-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)guanidine
55N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)ndimethylacetamide
56tert-butyl 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridine-2-ylcarbamate
575-(4-morpholino-6-(piperazine-1-yl)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
585-(4-(4-methylpiperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
58.1 5-(4-(4-(methylsulphonyl)piperazine-1-yl)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
595-(4-((3R,5S)-3,5-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine

605-(4-((3R,5S)-3,5-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
615-(4-((3R,5R)-3,5-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
625-(4-((3R,5R)-3,5-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
63(R)-5-(4-(3-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
64 (S)-5-(4-(3-methylmorpholine)-6-morpholino-1,3,5-trizip-2-yl)-4-(trifluoromethyl)pyridin-2-amine
655-(4-((2S,6R)-2,6-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
665-(4-((2S,6R)-2,6-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine

675-(4-((2R,6R)-2,6-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
685-(4-((2R,6R)-2,6-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
695-(4-((2R,5R)-2,5-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
705-(4-((2R,5S)-2,5-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl-4-(trifluoromethyl)pyridin-2-amine
715-(4-((2S,5S)-2,5-dimethylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
72(S)-5-(4-(2-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
73(S)-5-(4-(2-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridine-2-AMIP

74(R)-5-(4-(2-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
75(R)-5-(4-(2-methylmorpholine)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
76N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)butyramide
77 N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)pentanone
78N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)hexanamide
79N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)heptanoic
80N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)heptanoic

81N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-yl)heptanoic
82N-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)-2-(2-methoxyethoxy)ndimethylacetamide
832-(2-(2-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridine-2-ylamino)-2-oksidoksi)ethoxy)acetic acid
84N-(2-amino-ethyl)-2-(2-(2-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridine-2-ylamino)-2-oksidoksi)ethoxy)ndimethylacetamide
85Bodipy = Tag molecule
86N-(2-(2-(2-(2-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridine-2-ylamino)-2-acetoxy)ethoxy)acetamido)ethyl)-5-((3aS,4S,6aR)-2-oxohexyl-1H-thieno[3,4-d]imidazol-4-yl)pentanone
Biotin = Tag molecule

87= solid polymers
885-(4-(4-(2-aminoethyl)piperazine-1-yl)-6-morpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
89Bodipy = Tag molecule
90Bodpy = Tag molecule

91N-(2-(4-(4-(2-amino-4-(trifluoromethyl)pyrimidine-5-yl)-6-morpholino-1,3,5-triazine-2-yl)pyrazin-1-yl)ethyl)-5-((3aS,4S,6aR)-2-oxohexyl-1H-thieno[3,4-d]imidazol-4-yl)pentanone
Biotin = Tag molecule
92N-(2-(4-(4-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholino-1,3,5-triazine-2-yl)piperazine-1-yl)ethyl)-5-((3aS,4S,6aR)-2-oxohexyl-1H-thieno[3,4-d]imidazol-4-yl)pentanone
Biotin = Tag molecule
934,4'-(6-(1H-pyrazole-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
944,4'-(6-(furan-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
954,4'-(6-(1-methyl-1H-pyrazole-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
964,4'-(6-(1-methyl-1H-pyrazole-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

974,4'-(6-(1H-pyrazole-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
984,4'-(6-(4,5-dihydrofuran-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
994,4'-(6-(2-bromopyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
100(3-(4,6-dimorpholino-1,3,5-Gruzii-2-yl)pyridine-2-yl)methanamine
1014,4'-(6-(5-bromopyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1024,4'-(6-(2-chloropyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1034,4'-(6-(6-chloropyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

td align="center">
1044,4'-(6-(6-herperidin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1054,4'-(6-(6-nitropyridine-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1064,4'-(6-(thiophene-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1074,4'-(6-(thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1084,4'-(6-(4-methylthiophene-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1094,4'-(6-(4-methylthiophene-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1104,4'-(6-(5-methylthiophene-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1114,4'-(6-(3,5-dimethylisoxazol-4-yl)-1,3,-triazine-2,4-diyl)dimorpholino
1124,4'-(6-(3,5-dimethyl-1H-pyrazole-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1134,4'-(6-(6-methoxypyridine-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1144,4'-(6-(2,4-dimethoxypyrimidine-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1155-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N,N-dimethylpyrimidin-2-amine
1164,4'-(6-(1H-indol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1174,4'-(6-(6-fluoro-1H-indol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1184,4'-(6-(5-fluoro-1H-indol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
119 4,4'-(6-(6-(trifluoromethyl)-1H-indol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1204,4'-(6-(2-(trifluoromethyl)-1H-indol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1214,4'-(6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1224,4'-(6-(1H-benzo[d]imidazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1234,4'-(6-(1H-indazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1244,4'-(6-(5-fluoro-1H-indazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1254,4'-(6-(6-fluoro-1H-indazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
126 4,4'-(6-(6-(trifluoromethyl)-1H-indazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1274,4'-(6-(1H-indazol-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1284,4'-(6-(1H-benzo[d]imidazol-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1294,4'-(6-(1H-indol-5-yl)-1,3,5-trianii-2,4-diyl)dimorpholino
1304,4'-(6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1314,4'-(6-(1-methyl-1H-indol-5-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1324,4'-(6-(N-carbazole-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1333-(4-(2-aminopyrimidine-5-yl)-6-morpholino-1,3,5-three is Zin-2-yl)phenol
134ethyl 2-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)-1H-pyrazole-1-yl)acetate
1354,4'-(6-(2-(piperazine-1-yl)pyridine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1364,4'-(6-(6-(piperazine-1-yl)pyridine-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1371-(6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrazin-2-yl)pyridine-2(1H)-he
1384,4'-(6-(thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1394,4'-(6-(2-methylthiazole-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1404,4'-(6-(2-tert-butylthiazole-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
141 4-(4,6-dimorpholino-1,3,5 - greasin-2-yl)-N,N-dimethylthiazol-2-amine
1424-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N-ethyl-N-Metelitsa-2-amine
1434-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N,N-dietitians-2-amine
1444,4'-(6-(2-(pyrrolidin-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1454,4'-(6-(2-(piperidine-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1464,4'-(6-(2-morpholinomethyl-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1474,4'-(6-(2-(4-methylpiperidin-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
148 4,4'-(6-(2-(3-methylpiperidin-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1494,4'-(6-(2-(2-methylpiperidin-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1501-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)thiazol-2-yl)pyridine-2(1H)-he
1514,4'-(6-(2-(1H-pyrazole-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1524,4'-(6-(2-(1H-imidazol-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1534,4'-(6-(2-(2-methyl-1H-imidazol-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1544,4'-(6-(2-(4-methyl-1H-imidazol-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
155 4,4'-(6-(2-(3-methyl-1H-pyrazole-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1564,4'-(6-(2-(4-methyl-1H-pyrazole-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1574,4'-(6-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
157.14-(1-(4,6-dimorpholino-1,3,5-triazine-2-yl)-1H-imidazol-4-yl)-2,6-dimethoxyphenol
157.24-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)furan-2-yl)-2,6-dimethoxyphenol
157.32,6-dimethoxy-4-(5-(4-(4-methylpiperazin-1-yl)-6-morpholino-1,3,5-triazine-2-yl)furan-2-yl)phenol
157.44-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-1,2,4-oxadiazol-3-yl)-2,6-dimethoxyphenol

157.54-(3-(4,6-dimorpholino-1,3,5-triazine-2-yl)-1,2,4-oxadiazol-5-yl)-2,6-dimethoxyphenol
157.64-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-1,3,4-oxadiazol-2-yl)-2,6-dimethoxyphenol
157.74-(5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-1,3,4-thiadiazole-2-yl)-2,6-dimethoxyphenol
1584,4'-(6-(6-chloropyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1594,4'-(6-(2-methylpyridin-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1604-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-amine
1614,4'-(6-(2-(trifluoromethyl)pyridine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

4-(4,6-dimorpholino-1,3,5-triazine-2-yl)picolinate
1634-(4,6-dimorpholino-1,3,5-triazine-2-yl)picolinate
164methyl 4-(4,6-dimorpholino-1,3,5-triazine-2-yl)picolinate
1654,4'-(6-(pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1664,4'-(6-(6-methylpyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1674,4'-(6-(5-methylpyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1684,4'-(6-(4-methylpyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1694,4'-(6-(6-chlorp ridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1704,4'-(6-(6-branigin-2-yl)- 1,3,5-triazine-2,4-diyl)dimorpholino
1714,4'-(6-(6-methoxypyridine-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1724,4'-(6-(5-methoxypyridine-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1734,4'-(6-(6-ethoxypyridine-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1744,4'-(6-(6-propoxyphen-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1754,4'-(6-(6-isopropoxypyridine-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1764,4'-(6-(6-tert-butoxypropan-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1774,4'-(6-(6-cyclobutadiene-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1784,4'-(6-(6-(cyclopentyloxy)pyridine-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1794,4'-(6-(6-(tetrahydrofuran-3-yloxy)pyridine-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1804,4'-(6-(6-(cyclohexyloxy)pyridine-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1816-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-amine
1826-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-ol
1836-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-3-amine

184 N-(6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-3-yl)ndimethylacetamide
184tert-butyl 6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-3-ylcarbamate
1852-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-4-amine
1866-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N,N-dimethylpyridin-2-amine
1876-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N-ethyl-N-methylpyridin-2-amine
1886-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N,N-diethylpyrazine-2-amine
1894,4'-(6-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

1904,4'-(6-(6-(piperidine-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4 diyl)dimorpholino
1914,4'-(6-(6-morpholinopropan-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1924,4'-(6-(6-(4-methylpiperidin-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1934,4'-(6-(6-(3-methylpiperidin-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1944,4'-(6-(6-(2-methylpiperidin-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
195tert-butyl 4-(6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)piperazine-1-carboxylate
1964,4'-(6-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
1971 -(6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)pyridine-2(1H)-he

1981-(6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)piperidine-2-he
1991-(6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)pyrrolidin-2-he
2004,4'-(6-(6-(1H-pyrrol-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2014,4'-(6-(6-(1H-pyrazole-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2024,4'-(6-(6-(1H-imidazol-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2034,4'-(6-(6-(2-methyl-1H-imidazol-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2044,4'-(6-(6-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
205 4,4'-(6-(6-(3-methyl-1H-pyrazole-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

2064,4'-(6-(6-(4-methyl-1H-pyrazole-1-yl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2074,4'-(6-(4-chloropyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2084,4'-(6-(5-chloropyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2096-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-3-ol
2106-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2(1H)-he
211(6-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-yl)methanol
212(6(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-3-yl)methanol

213(2-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-4-yl)methanol
2145-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-3-ol
215methyl 6-(4,6-dimorpholino-1,3,5-triazine-2-yl)Nicolet
216methyl 6-(4,6-dimorpholino-1,3,5-triazine-2-yl)nicotinate
2176-(4,b-dimorpholino-1,3,5-triazine-2-yl)picolinate
2186-(4,6-dimorpholino-1,3,5-triazine-2-yl)nicotinamide
2192-(4,6-dimorpholino-1,3,5-triazine-2-yl)isonicotinamide

220 4,4'-(6-(6-herperidin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2214,4'-(6-(5-herperidin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2224,4'-(6-(4-herperidin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2234,4'-(6-(5-fluoro-6-methylpyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2244,4'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2254,4'-(6-(5-(trifluoromethyl)nereden-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2264,4'-(6-(4-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

227 4-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N,N-dimethylpyrimidin-2-amine
2284-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N,N-diarylpyrimidine-2-amine
2294-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N-ethyl-N-methylpyrimidin-2-amine
2304,4'-(6-(2-(pyrrolidin-1-yl)pyrimidine-4-yl)-1,3,5-triazin-2,4-diyl)dimorpholino
2314,4'-(6-(2-(piperidine-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2324,4'-(6-(2-morpholinopropan-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2334,4'-(6-(2-(4-methylpiperidin-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2344,4'-(6-(2-(3-methylpiperidin-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,-diyl)dimorpholino

2354,4'-(6-(2-(2-methylpiperidin-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2364,4'-(6-(2-(4-methylpiperazin-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2374,4'-(6-(2-(piperazine-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2384,4'-(6-(2-(1H-pyrazole-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2394,4'-(6-(2-(1H-imidazol-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2404,4'-(6-(2-(2-methyl-1H-imidazol-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2414,4'-(6-(2-(4-methyl-1H-imidazol-1-yl)nor is kidin-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2424,4'-(6-(2-(3-methyl-1H-pyrazole-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

td align="center"> 249
2434,4'-(6-(2-(4-methyl-1H-pyrazole-1-yl)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2441-(4-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-yl)pyridine-2(1H)-he
2454-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-carbonitrile
2464,4'-(6-(2-methoxypyridine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2474,4'-(6-(2-ethoxypyridine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2484,4'-(6-(2-propoxyimino-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
4,4'-(6-(2-isopropoxypyridine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2504,4'-(6-(2-tert-butoxyphenyl-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

2514,4'-(6-(2-(cyclopentyloxy)pyrimidine-4-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2524,4'-(6-(6-methoxypyridazine-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2536-(4,6-dimorpholino-1,3,5-triazine-2-yl)-N,N-dimethylpyridin-3-amine
2544,4'-(6-(6-(1H-imidazol-1-yl)pyridazin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2554,4'-(6-(6-(1H-pyrazole-1-yl)pyridazin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
25 4,4'-(6-(6-(2-methyl-1H-imidazol-1-yl)pyridazin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
2573-(4,6-dimorpholino-1,3,5-triazine-2-yl)benzonitrile

2584-(4,6-dimorpholino-1,3,5-triazine-2-yl)benzonitrile
2594,4'-(6-(6-morpholinopropan-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino

Table 2 presents the structure and the corresponding names by IUPAC (using ChemDraw Ultra Version 11.0.1 and earlier and later versions of the software, CambridgeSoft Corp., Cambridge MA) typical compounds No. 260-385 formula (Ie).

Table 2
No.StructureName
2603-(4-morpholino-6-(2-(pyridin-3-yl)ethylamino)-1,3,5-triazine-2-infenal
2613-(4-morpholino-6-(2-(pyridin-2-yl)ethylamino)-1,3,5-triazine-2-yl)phenol
2623-(4-morpholino-6-(2-(pyridin-4-yl)ethylamino)-1,3,5-triazine-2-yl)phenol

2634-(3-AMINOPHENYL)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine
2644-(3-AMINOPHENYL)-6-morpholino-N-(2-(pyridi-3-yl)ethyl)-1,3,5-triazine-2-amine
2654-(3-AMINOPHENYL)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine
2664-(4-AMINOPHENYL)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine
2674-(4-AMINOPHENYL)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2684-(4-AMINOPHENYL)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine
2694-(6-aminopyridine-3-yl)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine

2704-(6-aminopyridin-3-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2714-(6-aminopyridine-3-yl)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine
2724-(2-aminopyrimidine-5-yl)-6-morpholino-N-(2-(nereden-2-yl)ethyl)-1,3,5-triazine-2-amine
2734-(2-aminopyrimidine-5-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2744-(2-aminopyrimidine-5-yl)-6-morpho is Ino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine
2754-(b-amino-4-methylpyridin-3-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2764-(6-amino-4-methylpyridin-3-yl)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine

2774-(6-amino-4-methylpyridin-3-yl)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine
2784-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine
2794-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-AMI
2804-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine
281 4-(2-amino-4-(trifluoromethyl)pyrimidine-5-yl)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine
2824-(2-amino-4-(trifluoromethyl)pyrimidine-5-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2834-(2-amino-4-(trifluoromethyl)pyrimidine-5-yl)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine

284N-(5-(4-morpholino-6-(2-(pyridin-2-yl)ethylamino)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-yl)ndimethylacetamide
285N-(5-(4-morpholino-6-(2-(pyridin-3-yl)ethylamino)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-yl)ndimethylacetamide
286N-(5-(4-morpholino-6-(2-(pyridin-2-yl)ethylamino)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-yl)ndimethylacetamide
287 4-(1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2884-(1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine
2894-(1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine
2904-(6-fluoro-1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine

2914-(6-fluoro-1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2924-(6-fluoro-1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine
2934 morpholino-N-(2-(pyridin-2-yl)ethyl)-6-(6-(trifluoromethyl)-1H-indol-4-yl)-1,3,5-triazine-2-amine
294 4 morpholino-N-(2-(pyridin-3-yl)ethyl)-6-(6-(trifluoromethyl)-1H-indol-4-yl)-1,3,5-triazine-2-amine
2954-(5-fluoro-1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
296N,N-dimethyl-4-(4-morpholino-6-(2-(pyridin-3-yl)ethylamino)-1,3,5-triazine-2-yl)-1H-indole-6-sulfonamide

2974-(6-(methylsulphonyl)-1H-indol-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
2984 morpholino-N-(2-(pyridin-3-yl)ethyl)-6-(6-(trifluoromethyl)-1H-indol-4-yl)-1,3,5-triazine-2-amine
2994 morpholino-N-(2-(pyridin-3-yl)ethyl)-6-(2-(trifluoromethyl)-1H-indol-4-yl)-1,3,5-triazine-2-amine
3004 morpholino-N-(2-(pyridin-3-yl)ethyl)-6-(2-(trifluoromethyl)-1H-benzo is[d]imidazol-4-yl)-1,3,5-triazine-2-amine
3014-(4-morpholino-6-(2-(pyridin-3-yl)ethylamino)-1,3,5-triazine-2-yl)-1H-indole-2-carbonitrile
3024-(1H-indazol-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
3034-(6-fluoro-1H-indazol-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine

3044 morpholino-N-(2-(pyridin-3-yl)ethyl)-6-(6-(trifluoromethyl)-1H-indazol-4-yl)-1,3,5-triazine-2-amine
3054-(1H-benzo[d]imidazo-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
3064-(6-fluoro-1H-benzo[d]imidazol-4-yl)-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine
307 4 morpholino-N-(2-(pyridin-3-yl)ethyl)-6-(6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-1,3,5-triazine-2-amine
3083-(4-morpholino-6-(4-(triptoreline)phenylamino)-1,3,5-triazine-2-yl)benzamid
3093-(4-(methyl(4-(triptoreline)phenyl)amino)-6-morpholino-1,3,5-triazine-2-yl)benzamid
3403-(4-(4-methylpiperazin-1-yl)-6-(4-(triptoreline)phenylamino)-1,3,5-triazine-2-yl)benzamid

3413-(4-(methyl(4-(triptoreline)phenyl)amino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-yl)benzamid
342
343
344

3453-(4-morpholino-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)phenol
3463-(4-morpholino-6-(nereden-2-ylmethylamino)-1,3,5-triazine-2-yl)phenol
3473-(4-(benzylamino)-6-morpholino-1,3,5-triazine-2-yl)phenol
3483-(4-(benzyloxy)-6-morpholino-1,3,5-triazine-2-yl)phenol
3493-(4-morpholino-6-(pyridine-3-admetox)-1,3,5-triazine-2-yl)phenol
3503-(4-morpholino-6-(pyridine-3-instilling)-1,3,5-triazine-2-yl)phenol
3513-(4-morpholino-6-{pyridin-4-ylethoxy)-1,3,5-triazine-2-yl)phenol
3523-4-morpholino-6-(pyridine-4-ylmethylamino)-1,3,5-triazine-2-yl)phenol

3535-(4-morpholino-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)pyridine-2-amine
3545-(4-morpholino-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)pyrimidine-2-amine
3555-(4-morpholino-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
3565-(4-morpholino-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
3574-(6-aminopyridine-3-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3584-(2-aminopyrimidine-5-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3594-(2-amino-4-(Tr is permitil)pyrimidine-5-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine

3604-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3614-(4-(1H-indol-4-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
361.14-(4-(1H-indol-4-yl)-6-((pyridine-2-ylmethyl)thio)-1,3,5-triazine-2-yl)morpholine
361.24-(4-(1H-indol-4-yl)-6-((pyridine-2-ylmethyl)sulfonyl)-1,3,5-triazine-2-yl)morpholine
361.34-(4-(pyridine-2-ylethoxy)-6-(2-(trifluoromethyl)-1H-indol-4-yl)-1,3,5-triazine-2-yl)morpholine
3624-(1H-indol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3634-(6-fluoro-1H-indol-4-yl) - morpholine-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine

3644-(5-fluoro-1H-indol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3654-(7-fluoro-1H-indol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-AMI
3664-(4-(1H-indazol-4-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
2674-(1H-indazol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
2684-(1H-benzo[d]imidazol-4-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3694-(4-(1H-benzo[d]imidazol-4-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
3704-(4-(1H-indol-5-yl)-6-(pyridine-2-Ilmatar and)-1,3,5-triazine-2-yl)morpholine

3714-(1H-indol-5-yl)-6-morpholino-N-(pyridine-2-instil)-1,3,5-triazine-2-amine
3724-(4-(1H-indazol-5-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
3734-(1H-indazol-5-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3744-(4-(1H-benzo[d]imidazol-5-yl)-6-(birdin-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
3754-(1H-benzo[d]imidazol-5-yl)-6-morpholino-N-(nereden-2-ylmethyl)-1,3,5-triazine-2-amine
3764-(4-(1H-benzo[d]imidazol-6-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
3774-(1H-benzo[d]imidazol-6-yl)-6-morpholino-N-(is iridin-2-ylmethyl)-1,3,5-triazine-2-amine

/tr>
3784-(4-(1H-indazol-6-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
3794-(1H-indazol-6-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3804-(1H-indol-6-yl)-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine
3814-(4-(1H-indol-6-yl)-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine
3824-(4-(pyridine-2-ylethoxy)-6-(pyridin-3-yl)-1,3,5-triazine-2-yl)morpholine
3834 morpholino-N-(pyridine-2-ylmethyl)-6-(pyridin-3-yl)-1,3,5-triazine-2-amine
3844 morpholino-N-(pyridine-2-ylmethyl)-6-(pyrimidine-5-yl)-1,3,5-triazine-2-amine

3854-(4-pyridine-2-ylethoxy)-6-(pyrimidine-5-yl)-1,3,5-triazine-2-yl)morpholine

Table 3 presents the structure and the corresponding names by IUPAC (using ChemDraw Ultra Version 11.0.1 and earlier and later versions of the software, CambridgeSoft Corp., Cambridge MA) typical compounds No. 386-473 formula (If) or (Ig).

Table 3
No.StructureName
3864-(5-(1H-indol-4-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
3874-(5-(1H-indol-4-yl)thiazolo[5,4-d]pyrimidine-7-yl)morpholine
3884-(5-(1H-indol-4-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazole[4,5-d]pyrimidine-7-yl)morpholine
389 4-(5-(1H-indol-4-yl)-2-((4-methylsulphonyl)piperazine-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine

4-(5-(1H-indazol-4-yl)thiazolo[5,4-d]pyrimidine-7-yl)morpholine
3904-(5-(1H-indol-4-yl)-2-(methylsulphonyl)thiazolo[4,5-d]pyrimidin-7-yl)morpholine
3915-(1H-indol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine
3925-(1H-indol-4-yl)-7-morpholinomethyl[5,4-d]pyrimidine
3935-(1H-indol-4-yl)-2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine
3945-(1H-indol-4-yl)-2-((4-(methylsulphonyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine
3954-(5-(1H-indazol-4-yl)thiazolo[4,5-d]pyrimidin-7-yl)morpholine
396

3974-(5-(1H-indazol-4-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
3984-(5-(1H-indazol-4-yl)-2-((4-(methylsulfonyl)piperazine-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
3994-(5-(1H-indazol-4-yl)-2-(methylsulphonyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4005-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine
4015-(1H-indazol-4-yl)-7-morpholinomethyl[5,4-d]pyrimidine
4025-(1H-indazol-4-yl)-2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine
403 4-(5-(1H-benzo[d]imidazol-4-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine

4044-(5-(1H-benzo[d]imidazol-4-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4054-(5-(1H-benzo[d]imidazol-4-yl)-2-((4-(methylsulphonyl)piperazine-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4064-(5-(1H-benzo[d]imidazol-4-yl)-2-(methylsulphonyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4075-(1H-benzo[d]imidazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine
4085-(1H-benzo[d]imidazol-4-yl)-2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine
4094-(5-(1H-indol-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4104-(5-(1H-indol-5-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine

4114-(5-(1H-indol-5-yl)-2-((4-(methylsulphonyl)piperazine-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4125-(1H-indol-5-yl)-7-morpholinomethyl,5-d]pyrimidine
4135-(1H-indol-5-yl)-2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine
4145-(1H-indol-5-yl)-2-((4-(methylsulphonyl)piperazine-1-yl)revenged)-7-morpholinomethyl[4,5-d]pyrimidine
4154-(5-(1H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4164-(5-(1H-indazol-5-iltiazem[5,4-d]pyrimidine-7-yl)morpholine
4174-(5-(1H-indazol-5-yl)-2-((4-steeperthan-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine

4184-(5-(1H-indazol-5-yl)-2-((4-(methylsulphonyl)piperazine-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4195-(1H-indazol-5-yl)-7-morpholinomethyl[4,5-d]pyrimidine
4205-(1H-indazol-5-yl)-2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine
4214-(5-(1H-benzo[d]imidazol-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4224-(5-(1H-benzo[d]imidazol-5-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4234245-(1H-benzo[d]imidazol-5-yl)-2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine

4254-(5-(1H-indazol-6-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4264-(5-(1H-indazol-6-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4275-(1H-indazol-6-yl)-7-morpholinomethyl[4,5-d]pyrimidine
4284-(5-(N-carbazole-2-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4294-(5-(N-carbazole-2-yl)-2-((4-methylpiperazin-1-yl)methyl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
430 5-(N-carbazole-2-yl)-7-morpholinomethyl[4,5-d]pyrimidine
4314-(5-(1H-pyrazole-4-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine

432N-(5-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-yl)ndimethylacetamide
433N-(5-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-yl)ndimethylacetamide
434N-(5-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-yl)ndimethylacetamide
435N-(4-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenyl)ndimethylacetamide
436N-(4-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenyl)ndimethylacetamide
4374-(5-(pyridin-3-yl) who Asolo[4,5-d]pyrimidine-7-yl)morpholine
4384-(5-(pyrimidine-5-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine

4394-(5-(6-morpholinopropan-3-yl)thiazolo[4,5-d]pyrimidine-7-yl)morpholine
4407 morpholino-5-(6-morpholinopropan-3-yl)oxazolo[4,5-d]pyrimidine
4413-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
A3-(2-((4-(2-hydroxyethyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
441b2-(4-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)ethanol
S3-(2-((diethylamino)ethyl)-7-morpholinomethyl[4,5-d]pyrimidine-yl)Fe is ol

441dN-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)-N-Ethylenediamine
441e3-(2-((dimethylamino)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
441f1-(5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)-N,N-dimethylethanamine
4423-(2-hexyl-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
4433-(2-(2-(2-(aminoethoxy)ethoxy)ethyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol

443.1
444
445

446= solid polymers
445= solid polymers
446(3aS,4S,6aR)-4-(6-((2-(2-(2-(3-gidroksimetil)-4-morpholinothio[3,2-d]pyrimidine-6-yl)ethoxy)ethoxy)methylamino)-5-oxohexyl)tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-he

4473-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
A1-(4-((5-(3-hydroxyphenyl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)prop-2-EN-1-he
AA(E)-1-(4-((5-(3-hydroxyphenyl)-7-morpholinothio the lo[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)but-2-EN-1-he
447b2-fluoro-1-(4-((5-(3-hydroxyphenyl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)alanon
S2-chloro-1-(4-((5-(3-gidroksimetil)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)alanon

447d2-bromo-1-(4-((5-(3-hydroxyphenyl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)alanon
447e1-(4-((5-(3-hydroxyphenyl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazin-1-yl)-2-utatane
447f1-(4-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)pron-2-EN-1-he
447g(E)-1-(4-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)but-2-EN-1-he
447h1-(4-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)-2-floratone

447i1-(4-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)papership-1-yl)-2-chlorethane
447j1-(4-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)-2-brometane
447k1-(4-((5-(1H-indazol-4-yl)-7-morpholinomethyl[4,5-d]pyrimidine-2-yl)methyl)piperazine-1-yl)-2-utatane
4483-(2-((4-(methylsulphonyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
4493-(2-(methylsulphonyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
4503-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol

4513-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol
4525-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-amine
4535-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-amine
4545-(2-((4-(methylsulphonyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-amine
4555-(2-(methylsulphonyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-amine
4565-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyridin-2-amine
457 5-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine

4585-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine
4595-(2-((4-(methylsulphonyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine
4605-(2-(methylsulphonyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine
4615-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine
4625-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)pyrimidine-2-amine
4635-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyridin-2-amine
4645-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyridin-2-amine

4655-(2-((4-(methylsulphonyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyridin-2-amine
4665-(2-(methylsulphonyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyridin-2-amine
4675-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyridin-2-amine
4685-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyridin-2-amine
4695-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyrimidine-2-amine
470 5-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyrimidine-2-amine
4715-(2-((4-(methylsulfonyl)piperazine-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyrimidine-2-amine

4725-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyrimidine-2-amine
4735-(2-((4-methylpiperazin-1-yl)methyl)-7-morpholinomethyl[4,5-d]pyrimidine-5-yl)-4-(trifluoromethyl)pyrimidine-2-amine

Table 4 presents the structure and the corresponding names by IUPAC (using ChemDraw Ultra Version 11.0.1 and earlier and later versions of the software, CambridgeSoft Corp., Cambridge MA) typical connection 5 No. 474-537 formula (Ih) or (Ii).

Table 4
No.StructureName
474 2-(1H-indol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine
4752-(b-fluoro-1H-indol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine
4762-(5-fluoro-1H-indol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine

4774 morpholino-2-(6-(trifluoromethyl)-1H-indol-4-yl)benzofuro[3,2-d]pyrimidine
4786-(1H-indol-4-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4796-(6-fluoro-1H-indol-4-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4808-morpholine-4-yl-6-(6-trifluoromethyl-1H-indol-4-yl)-9-oxa-1,5,7-diazafluoren
481 2-(1H-indol-4-yl)-4-morpholine-4-albenza[4,5]thieno[3,2-d]pyrimidine
4826-(1H-indol-4-yl)-8-morpholine-4-yl-9-thia-1,5,7-diazafluoren
483b-(1H-indol-4-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren

3-(7-(4-methylpiperazin-1-ylsulphonyl)-4-morpholinomethyl[3,2-d]pyrimidine-2-yl)phenol
4846-(6-fluoro-1H-indol-4-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4852-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-6-(6-trifluoromethyl-1H-indol-4-yl)-9-oxa-1,5,7-diazafluoren
4862-(1H-indazol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine
A3-(4-morpholinothio[3,2-d]pyrimidine-2-yl)phenol
486b
4872-(6-fluoro-1H-indazol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine
4884-morpholine-2-(6-(trifluoromethyl)-1H-indazol-4-yl)benzofuro[3,2-d]pyrimidine

4896-(1H-indazol-4-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4906-(1H-indazol-4-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4916-(6-fluoro-1H-indazol-4-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4926-(1H-indazol-4-yl)-2-(4-methanesulfonylaminoethyl-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4936-(1H-indazol-4-yl)-8-morpholine-4-yl-9-thia-1,5,7-diazafluoren
4946-(1H-benzoimidazol-4-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4952-(1H-benzo[d]imidazol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine

4962-(1H-indol-5-yl)-4-morpholinomethyl[3,2-d]pyrimidine
4976-(1H-indol-5-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4986-(1H-indol-5-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
4992-(1H-indazol-5-yl)-4-morpholinothio[3,2-d]pyrimidine
500 6-(1H-indazol-5-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
5016-(1H-indazol-5-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
5022-(1H-benzo[d]imidazol-5-yl)-4-morpholinomethyl[3,2-d]pyrimidine

5036-(1H-benzoimidazol-5-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
5042-(1H-indazol-6-yl)-4-morpholinomethyl[3,2-d]pyrimidine
5056-(1H-indazol-6-yl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
5066-(1H-indazol-6-yl)-2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren
5075084-morpholine-4-yl-2-(1H-pyrazole-4-yl)benzo[4,5]thieno[3,2-d]pyrimidine
5098-morpholine-4-yl-6-(1H-pyrazole-4-yl)-9-thia-1,5,7-diazafluoren

5108-morpholine-4-yl-6-(1H-pyrazole-4-yl)-9-oxa-1,5,7-diazafluoren
5114 morpholino-2-(1H-pyrazole-4-yl)benzofuro[3,2-d]pyrimidine
511.12-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinomethyl[3,2-d]pyrimidine
511.22-(2-(deformity)-1H-benzo[d]imidazol-1-yl)-4-morpholinomethyl[3,2-d]pyrimidine
511.34 morpholino-2-(2-(trifluoromethyl-1H-benzo[d]imidazol-1-yl)benzofuro[3,2-d]pyrimidine
5124-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)aniline
5134-(8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)phenylamine

5145-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)pyridine-2-amine
5155-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)pyrimidine-2-amine
5165-(8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)pyrimidine-2-ylamine
5175-(8-morpholine-4-yl-9-oxa-1,5,7-createplugin-6-yl)-4-triptorelin-2-ylamine
517.14-methyl-5-(4-morpholinothio[3',2':4,5]furo[33,2-d]pyrimidine-2-yl)pyridine-2-amine
5185-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)-4-(trifluoromethyl)pyridin-2-amine
518.14-methyl-5-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)pyridine-2-amine

5195-(4-morpholinomethyl[3,2-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
5205-(8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)-4-cryptomaterial-2-ylamine
521N-(5-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)pyridine-2-yl)ndimethylacetamide
522N-[5-(8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)pyridin-2-yl]ndimethylacetamide
5234 morpholino-2-(pyridin-3-yl)benzofuro[3,2-d]pyrimidine
5248-morpholine-4-yl-6-pyridin-3-yl-9-oxa-1,5,7-diazafluoren
5254 morpholino-2-(pyrimidine-5-yl)benzofuro[3,2-d]pyrimidine

5264 morpholino-2-(6-morpholinopropan-3-yl)benzofuro[3,2-d]pyrimidine
526.1N-(3-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)phenyl)nicotinamide
526.26-amino-N-(3-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)phenyl)nicotinamide
526.32-amino-N-(3-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)phenyl)pyrimidine-5-carboxamide
526.4N-(3-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)phenyl)pyrimidine-5-carboxamide
3-(8-morpholine-4-yl-2-pentyl-6-oxa-1,5,7-diazafluoren-6-yl)phenol
5283-(2-hexyl-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)phenol

5293-{2-[2-(2-ethoxyethoxy)ethyl]-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl}phenol
5303-{2-[2-(2-aminoethoxyethanol)ethyl]-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl}phenol
5313-[2-(2-dimethylaminoethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl]phenol
5323-(2-dimethylaminomethyl-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)phenol
5333-(2-diethylaminomethyl-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl)phenol/td>
5343-[2-(4-methylpiperazin-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl]phenol
5353-[2-(4-methanesulfonylaminoethyl-1-ylmethyl)-8-morpholine-4-yl-9-oxa-1,5,7-diazafluoren-6-yl]phenol

536
537= solid polymers

Table 5 presents the structures and corresponding names by IUPAC (using ChemDraw Ultra Version 11.0.1 and earlier and later versions of the software, CambridgeSoft Corp., Cambridge MA) typical compounds No. 538-590 formula (Ie).

Table 5
No.StructureName
5384,4'-(2,3'-bipyridine-4,6-DII Prov.) dimorpholino

5392,6'-dimorpholino-3,4'-piperidin
5403-(4,6-demoralization-2-yl)phenol
5413-(2,6-demoralization-4-yl)phenol
5424,6-dimorpholino-2,3'-bipyridine-5'-ol
5432',6'-dimorpholino-3,4'-piperidin-5-ol
5445-(4,6-demoralization-2-yl)-4-(trifluoromethyl)pyrimidine-2-ol
5455-(2,6-demoralization-4-yl)-4-(trifluoromethyl)pyrimidine-2-ol

5464,6-is morpholino-4'-(trifluoromethyl)-2,3'-bipyridine-6'-ol
5472',6'-dimorpholino-4-(trifluoromethyl)-3,4'-bipyridine-6-ol
5484,6-dimorpholino-2,3'-bipyridine-6'-amine
5492',6'-dimorpholino-3,4'-bipyridine-6-amine
550N-(4,6-dimorpholino-2,3'-bipyridine-6'-yl)ndimethylacetamide
551N-(2',6'-dimorpholino-3,4'-bipyridine-6-yl)ndimethylacetamide
5525-(4,6-demoralization-2-yl)pyrimidine-2-amine

5535-(2,6-demoroleprovider-4-yl)pyrimidine-2-amine
554N-(5-(4,6-dimorpholino-2-yl)pyrimid the h-2-yl)ndimethylacetamide
555N-(5-(2,6-demoralization-4-yl)pyrimidine-2-yl)ndimethylacetamide
5562'-methyl-4,6-dimorpholino-2,3'-bipyridine-6'-amine
5572-methyl-2',6'-dimorpholino-3,4'-bipyridine-6-amine
558N-(2'-methyl-4,6-dimorpholino-2,3'-bipyridine-6'-yl)ndimethylacetamide
559N-(2-methyl-2',6'-dimorpholino-3,4'-bipyridine-6-yl)ndimethylacetamide

5604'-methyl-4,6-dimorpholino-2,3'-bipyridine-6'-amine
5614-methyl-2',6'-dimorpholino-3,4'-bipyridine-6-amine
562N-(4'-meta the-4,6-dimorpholino-2,3'-bipyridine-6'-yl)ndimethylacetamide
563N-(4-methyl-2',6'-dimorpholino-3,4'-bipyridine-6-yl)ndimethylacetamide
5645-(4,6-demoralization-2-yl)-4-methylpyrimidin-2-amine
5655-(2,6-demoralization-4-yl)-4-methylpyrimidin-2-amine
566N-(5-(4,6-demoralization-2-yl)-4-methylpyrimidin-2-yl)ndimethylacetamide

567N-(5-(2,6-demoralization-4-yl)-4-methylpyrimidin-2-yl)ndimethylacetamide
5685-(4,6-demoralization-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine
5695-(2,6-demoralization-4-yl)-4-(trifluoromethyl)pyrimidine-2-amine
570N-(5-(4,6-demoralization-2-yl)-4-(trifluoromethyl)pyrimidine-2-yl)ndimethylacetamide
571N-(5-(2,6-demoralization-4-yl)-4-(trifluoromethyl)pyrimidine-2-yl)ndimethylacetamide
5724,6-dimorpholino-2'-(trifluoromethyl)-2,3'-bipyridine-6'-amine
5732',6'-dimorpholino-2-(trifluoromethyl)-3,4'-bipyridine-6-amine

574N-(4,6-dimorpholino-2'-(trifluoromethyl)-2,3'-bipyridine-6'-yl)ndimethylacetamide
575N-(2',6'-dimorpholino-2-(trifluoromethyl)-3,4'-bipyridine-6-yl)ndimethylacetamide
5764,6-dimorpholino-4'-(trifluoromethyl)-2,3'-bipyridine-6'-amine
477 2',6'-dimorpholino-4-(trifluoromethyl)-3,4'-bipyridine-6-amine
578N-(4,6-dimorpholino-4'-(trifluoromethyl)-2,3'-bipyridine-6'-yl)ndimethylacetamide
579N-(2',6'-dimorpholino-4-(trifluoromethyl)-3,4'-bipyridine-6-yl)ndimethylacetamide
5804,4'-(6-(1H-indol-4-yl)pyridine-2,4-diyl)dimorpholino

5814,4'-(4-(1H-indol-4-yl)pyridine-2,6-diyl)dimorpholino
5824,4'-(6-(1H-benzo[d]imidazol-4-yl)pyridine-2,4-diyl)dimorpholino
5834,4'-(4-(1H-benzo[d]imidazol-4-yl)pyridine-2,6-diyl)dimorpholino
5844,4'-(6-(1H-indazol-4-yl)pyridine-2,4-diyl)dimorpholino
58 4,4'-(4-(1H-indazol-4-yl)pyridine-2,6-diyl)dimorpholino
5864,4'-(6-(1H-indazol-5-yl)pyridine-2,4-diyl)dimorpholino
5864,4'-(4-(1H-indazol-5-yl)pyridine-2,6-diyl)dimorpholino

5874,4'-(6-(1H-benzo[d]imidazol-5-yl)pyridine-2,4-diyl)dimorpholino
5884,4'-(4-(1H-benzo[d]imidazol-5-yl)pyridine-2,6-diyl)dimorpholino
5894,4'-(6-(1H-indol-5-yl)pyridine-2,4-diyl)dimorpholino
5904,4'-(4-(1H-indol-5-yl)pyridine-2,6-diyl)dimorpholino
5914,4'-(6-(1H-indazol-6-yl)pyridine-2,4-Hai is)dimorpholino
5924,4'-(4-(1H-indazol-6-yl)pyridine-2,6-diyl)dimorpholino

EXAMPLES of preparing COMPOUNDS ACCORDING to the PRESENT INVENTION

The chemical reactions described in the Examples can easily be adapted for some other inhibitors lietkynes according to the present invention, alternative methods of producing compounds according to the present invention also fall within the scope of the present invention. For example, the synthesis of typical compounds according to the invention can be successfully carried out as a result of modifications, obvious to experts in the art, for example, using the appropriate protection of the interacting groups, by using other suitable reagents known in the art, different from those described in this application reagents, and/or by the exercise of ordinary modifications of the conditions of the reactions. As an alternative, understand that other reactions described in this application or known in the art, is applicable to other compounds according to the present invention.

In the Examples described below, unless otherwise specified, all temperatures are expressed in degrees Celsius. Reagents acquired is Ali from commercial suppliers, such as Aldrich Chemical Company, Fluorochem, Acros, Lancaster, TCI or Maybridge, and was used without further purification, unless otherwise stated. The reactions below are conducted, as a rule, when a positive pressure of nitrogen or argon or with the use of drainage tubes (unless otherwise stated) in anhydrous solvents, and the reaction flask, as a rule, were equipped with a rubber membrane for the introduction of substrates and reagents via syringe. Glassware was dried in an oven or by heating. Column chromatography was performed using silica gel Merck. Spectra1H NMR were obtained on a Bruker instrument operating frequencies of 400 MHz, 500 MHz and 600 MHz. Spectra1H NMR was obtained in deuterated solutions CDCl3d6-DMSO, CH3OD or d6-acetone (expressed in ppm), using chloroform as the control solution (to 7.25 ppm) or TMS (0 ppm). If mark multipletness signals, use the following abbreviatory: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened peak), dd (doublet of doublets), dt (doublet of triplets). Constants of spin-spin interaction, when given, is expressed in Hertz (Hz).

Example P1

4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino:

The acid chloride cyanuric acid (1,00 g, 5,42 mmol, 1.0 EQ.) was dissolved in DMF (5 ml) and to the reactions which authorized the mixture at 0°C was slowly added morpholine (2,11 ml, 24.4 mmol, 4.5 equiv.) was stirred for 20 minutes at the same temperature, poured into water and was filtered colorless precipitate was washed with hexane and diethyl ether and dried to obtain the title compound as a colourless solid (860 mg, 56%). Data analysis:

1H-NMR (400 MHz, CDCl3): δ 3.78-3.69 (M, m).

13C-NMR (100 MHz, CDCl3): δ 170.10, 164.88, 67.28, 66.98, 44.23.

ESI-MS (70 eV, m/z): calculated for C11H16ClN5O2[M+H]+: 286, 360 experimental.

X-ray analysis of the structure of 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was confirmed by x-ray analysis.

Example P2

5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-amine:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 2-aminopyridine-5-Bronevoy acid during the time of the reaction is equal to 15 hours. Chromatography (methylene chloride/methanol 97:3) has led to 69% of the title compound as a pale yellow solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 9.06 (s, 1H), 8.36 (dd, J=2.28, 8.59 Hz, 1H), 6.50 (d, J=8.59 Hz, 1H), 4.82 (s, 2H), 3.87-3.73 (m, 16H), 2.22 (s, 1H), 1.23 (s, 1H).

13With NMR (100 MHz, CDCl3): δ 169.42, 165.37, 160.56, 150.02, 138.31, 123.91, 107.89, 67.27, 44.01, 25.27.

ESIMC (70 eV, m/z): calculated d the I C 16H21N7O2[M+H]+: 344.38, experimental 344.30.

Example P3

3-(4,6-dimorpholino-1,3,5-triazine-2-yl)feel:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 3-hydroxyphenylpropionic acid during the time of the reaction is equal to 15 hours. Chromatography (hexane/ethyl acetate 1:1) allowed to obtain the title compound as a colourless solid.

Data analysis:

1H NMR (400 MHz, DMSO): δ 9.51 (s, 1H), 7.77-7.74 (m, 2H), 7.23 (t, J=8.08 Hz, 1H), 6.90-6.88 (m, 1H), 3.81-3.55 (m, 16H), 1.25 (s, 1H).

13With NMR (100 MHz, DMSO): δ 170.27, 165.60, 165.47, 158.12, 138.99, 130.01, 119.73, 119.36, 115.56, 66.86, 44.10.

ESI-MS (70 eV, m/z): calculated for C17H21N5O3[2M]+: 685.32, experimental 685.8.

Example P4

4-(4,6-dimorpholino-1,3,5-triazine-2-yl)aniline:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 4-aminophenylarsonic acid during the time of the reaction, equal to 24 hours. Chromatography (hexane/ethyl acetate 6:4) allowed us to obtain the title compound as a yellow solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 8.21 (d, J=8.59, 2H), 6.68 (d, J=8.84, 2H), 3.93-3.73 (m, N), 3.71-3.68 (m, H).

13With NMR (100 MHz, CDCl3): δ 170.59, 165.62, 149.97, 130.45, 127.82, 114.54, 67.32, 67.29, 44.04, 44.01.

ESI-MS (70 eV, m/z): calculated for C17H21N5O3[M+H]+: 343.18, experimental 343.40.

Example P5

3-(4,6-dimorpholino-1,3,5-triazine-2-yl)aniline:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 3-aminophenylarsonic acid during the time of the reaction is equal to 15 hours. Column chromatography (hexane/ethyl acetate 1:1) allowed to obtain the title compound as a colourless solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 7.80-7.77 (m, 1H), 7.72-7.71 (m, 1H), 7.22 (t, J=7.83 Hz, 1H), 6.82-6.79 (m, 1H), 3.90-3.74 (m, 18H).

13With NMR (100 MHz, CDCl3): δ 170.91, 165.64, 146.68, 138.86, 129.47, 119.26, 118.53, 115.21, 67.29, 44.03.

ESI-MS (70 eV, m/z): calculated for C17H22N6O2[M+H]+: 343.18, experimental 343.30.

Example P6

3-(4,6-dimorpholino-1,3,5-triazine-2-yl)benzonitrile:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 3-cyanophenylacetic acid during the time of the reaction is equal to 15 hours. Column chromatography (hexane/ethyl acetate 1:1) has resulted in a 57% t Colnago connection in the form of a colorless solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 8.68-8.67 (m, 1H), 8.61-8.59 (m, 1H), 7.76-7.74 (m, 1H), 7.57 (t, J=7.83 Hz, 1H), 3.95-3.76 (m, 17H).

13C NMR (100 MHz, CDCl3): δ 168.79, 165.47, 139.09, 134.64, 132.83, 132.64, 129.36, 119.30, 112.73, 67.23, 44.06.

ESI-MS (70 eV, m/z): calculated for C18H20N6O2[M+H]+: 353.16, experimental 353.50.

Example P7

4-(4,b-dimorpholino-1,3,5-triazine-2-yl)benzonitrile:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 4-cianfarini acid during the time of the reaction is equal to 15 hours. Column chromatography (hexane/ethyl acetate 1:1) allowed to receive 40% of the title compound as a colourless solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 8.47 (d, J=8.34, 2H), 7.71 (d, J=8.08, 2H), 3.93-3.75 (m, 16H), 1.35 (s, 1H).

13With NMR (100 MHz, CDCl3): δ 169.14, 165.50, 142.09, 132.33, 129.20, 123.67, 119.23, 114.79, 67.22, 44.13, 44.08, 25.27.

ESI-MS (70 eV, m/z): calculated for C18H20N6O2[M+H]+: 353.16, the required mass is not defined.

Example P8

4,4'-(6-(pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino:

In accordance with the General methodology And 4,4'-(b-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with peacelover ether 3-pyridineboronic the acid during the time of the reaction, equal to 15 hours. Column chromatography (hexane/ethyl acetate 1:1) allowed to obtain gatuline compound as a colourless solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 9.53 (s, 1H), 8.70-8.68 (m, 1H), 8.61-8.57 (m, 1H), 7.36-7.32 (m, 1H), 3.92-3.75 (m, 1H), 1.92 (s, 1H).

13C NMR (100 MHz, CDCl3): δ 169.24, 165.40, 152.25, 150.54, 136.04, 133.24, 123.40, 67.23, 44.06.

ESI-MS (70 eV, m/z): calculated for C16H20N6O2[M+H]+: 329.16, experimental 329.20.

Example P9

4,4'-(6-(6-morpholinopropan-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 6-(morpholine-4-yl)pyridine-3-Bronevoy acid during the time of the reaction is equal to 15 hours. Column chromatography (hexane/ethyl acetate 1:1) allowed to obtain the title compound as a colourless solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 9.19-9.18 (m, 1H), 8.39 (dd, J=2.40, 8.97 Hz, 1H), 6.61 (d, J=8.71 Hz, 1H), 3.87-3.81 (m, N), 3.74 (t, J=4.8 Hz, 8H), 3.62 (t, J=4.92, 4H), 1.66 (s, 1H).

13With NMR (100 MHz, CDCl3): δ 169.49, 165.40, 161.08, 149.99, 137.78, 123.05, 105.67, 67.27, 67.08, 45.68, 44.02.

ESI-MS (70 eV, m/z): calculated for C20H27N7O3[M+H]+: 414.22, experimental 414.40.

Example P10

5-(4,4,5,5-Tetra is ethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine:

In a dry 25 ml flask was added 5-bromo-4-(trifluoromethyl)pyridin-2-amine (300 mg, 1,24 mmol, 1.0 EQ.), potassium acetate (366 mg, 3.73 mmol, 3.0 equiv.) bis(pinacolato)DIBORANE (348 mg, 1.37 mmol, 1.1 EQ.) and dioxane (8 ml). After the solution was purged argon for 15 minutes and added complex dichloride 1,1-bis(diphenylphosphino)ferrocene-palladium(II) and dichloromethane (50,8 mg, 60 mol, of 0.05 EQ.). The reaction mixture is boiled under reflux at 115°C. oil bath for 8 hours in an argon atmosphere. After cooling to room temperature, dioxane was removed in vacuum. Added ethyl acetate and the resulting suspension was treated with ultrasound and filtered. For washing solids was applied an additional amount of ethyl acetate. The combined organic extracts were concentrated, and the crude substance was partially purified using chromatography on silica gel (hexane/ethyl acetate 6:4). After removal of solvent was added hexane, were decantation and the resulting colourless solid was dried in high vacuum for three days.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 6.71 (s, 1H), 4.86 (s, 2H), 1.33 (s, 12H), 1.27 (s, 2H), 1.24 (s, 2H).

19F (400 MHz, CDCl3): δ -64.24.

ESI-MS (70 eV, m/z): calculated for C12H16BF3N2O2[M+H]+: 289.13, experimental 289.10.

Example P11

5-(4,6-dimorpholino-1,3,5-trizip-2-yl)-4-(trifluoromethyl)pyridin-2-amine:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine during the time of the reaction is equal to 15 hours. Chromatography (dichloromethane/methanol 97:3) allowed to obtain the title compound in the form of colorless oily substance.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 6.78 (s, 1H), 4.93 (s, 2H), 3.85-3.73 (m, 16H), 1.73 (s, 1H), 1.24 (s, 1H).

13C NMR (125 MHz, CDCl3): δ 169.90, 164.71, 159.49, 152.65, 138.30, 122.34, 105.40, 105.35, 66.81, 43.59, 24.87.

19F (400 MHz, CDCl3): δ -60.95.

ESI-MS (70 eV, m/z): calculated for C17H20F3N7O2[M+H]+: 412.16, experimental 412.20.

Example R

4,4'-(6-(5-herperidin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 3-herperidin-5-Bronevoy acid during the time of the reaction is equal to 15 hours. Chromatography (hexane/ethyl acetate 1:1) allowed to receive 31% of the title compound.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 9.36-9.35 (m, 1H), 8.55 (d, J=3.03 Hz, 1H), 8.31-8.28 (m, 1H), 3.94-3.75 (m, 16H).

13With NMR (100 MHz, CDl 3): δ 165.30, 146.30, 142.65, 140.68, 140.45, 122.69, 122.50, 67.29, 67.20, 44.04.

19F (400 MHz, CDCl3): δ -128.86, -128.88.

ESI-MS (70 eV, m/z): calculated for C16H19FN6O2[M+H]+: 347.16, experimental 347.50.

Example P13

5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-amine:

In accordance with the General methodology And 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholino was subjected to reaction combination with pinacoline ether 2-aminopyrimidine-5-Bronevoy acid during the time of the reaction, equal to 17 hours. Chromatography (hexane/ethyl acetate 1:1) allowed to obtain the title compound as a colourless solid.

Data analysis:

1H NMR (400 MHz, CDCl3): δ 9.17 (s, 2H), 5.37 (s, 2H), 3.87-3.74 (m, 17H), 1.63 (s, 3H).

ESI-MS (70 eV, m/z): calculated for C15H20N8O2[M+H]+: 345.17, experimental 345.80.

Example P14

4,6-dichloro-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine:

In accordance with the General method As 2,4,6-trichloro-1,3,5-triazine were subjected to reaction in combination with a 2-aminomethylpyridine during the time of the reaction is equal to 2 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C9H8Cl2N5[M+H]+: 256.01, experimental is Talina 256.

Example R

In accordance with the General method As 2,4,6-trichloro-1,3,5-trizip were subjected to reaction in combination with a 3-aminomethylpyridine during the time of the reaction is equal to 2 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C9H8Cl2N5[M+H]+: 256.01, experimental 256.

Example P16

4,6-dichloro-N-(pyridine-4-instil)-1,3,5-triazine-2-amine:

In accordance with the General method As 2,4,6-trichloro-1,3,5-triazine were subjected to reaction in combination with a 4-aminomethylpyridine during the time of the reaction is equal to 2 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C9H8Cl2N5[M+H]+: 256.01, experimental 256.

Example R17

4,6-dichloro-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine:

In accordance with the General method As 2,4,6-trichloro-1,3,5-tritip was subjected to reaction combination with 2-(2-amino-ethyl)pyridine during the time of the reaction is equal to 2 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): caters the Naya for C 10H10Cl2N5[M+H]+: 270.02, experimental 270.

Example P18

4,6-dichloro-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine:

In accordance with the General method As 2,4,6-trichloro-1,3,5-triazine was subjected to reaction combination with 3-(2-amino-ethyl)pyridine during the time of the reaction is equal to 2 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C10H10Cl2N5[M+H]+: 270.02, experimental 270.

Example P19

4,6-dichloro-N-(2-(pyridin-4-yl)ethyl)-1,3,5-triazine-2-amine:

In accordance with the General methodology And 2.4,b-trichloro-1,3,5-triazine was subjected to reaction combination with 4-(2-amino-ethyl)pyridine during the time of the reaction is equal to 2 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C10H10Cl2H5[M+H]+: 270.02, experimental 270.

Example P20

4,6-dichloro-N-(2-(piperidin-1-yl)ethyl)-1,3,5-triazine-2-amine:

In accordance with the General method As 2,4,6-trichloro-1,3,5-triazine was subjected to reaction combination with 1-(2-amino-ethyl)piperidine during the time of the reaction is equal to 2 hours. Cleaning is by using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C10H16Cl2N5[M+H]+: 276.07, experimental 276.

Example P21

4,6-dichloro-N-(2-morpholinoethyl)-1,3,5-triazine-2-amine:

In accordance with the General method As 2,4,6-trichloro-1,3,5-triazine was subjected to reaction combination with N-(2-amino-ethyl)morpholine during the time of the reaction is equal to 2 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C9H14Cl2N5O [M+H]+: 278.05, experimental 278.

Example P22

4-chloro-6-morpholino-N-(pyridine-2-ylmethyl)-1,3,5-triazine-2-amine:

In accordance with the General method was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C9H14Cl2N5O [M+H]+: 278.05, experimental 278.

Example R23 is applied

4-chloro-6-morpholino-N-(pyridi-3-ylmethyl)-1,3,5-trizip-2-amine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): RA is a matter for C 13H16ClN6O [M+H]+: 307.10, experimental 307.

Example R24

4-chloro-6-morpholino-N-(pyridine-4-ylmethyl)-1,3,5-triazine-2-amine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C13H16ClN6O [M+H]+: 307.10, experimental 307.

Example P25

4-chloro-6-morpholino-N-(2-(pyridin-2-yl)ethyl)-1,3,5-triazine-2-amine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C14H18ClN6O [M+H]+: 321.12, experimental 321.

Example R

4-chloro-6-morpholino-N-(2-(pyridin-3-yl)ethyl)-1,3,5-triazine-2-amine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C14H18ClN6O [M+H]+: 321.12, experimental 321.

Example P27

4-chloro-6-morpholino-N-(2-(pyridin-4-yl)these who)-1,3,5-triazine-2-amine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C14H18ClN6O [M+H]+: 321.12, experimental 321.

Example P28

4-chloro-6-morpholino-N-(2-(piperidine-1-yl)ethyl)-1,3,5-triazine-2-amine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C14H24ClN6O [M+H]+: 327.17, experimental 327.

Example R29

4-chloro-6-morpholino-N-(2-morpholinoethyl)-1,3,5-triazine-2-amine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C13H22ClN6O2[M+H]+: 329.14, experimental 329.

Example R30

2,4-dichloro-6-(pyridine-2-ylethoxy)-1,3,5-triazine:

In accordance with the General procedure a-2 4,6-dichloro-N-(2-(piperidine-1-yl)ethyl)-1,3,5-triazine-2-amine was subjected to reaction in combination with a 2-pyridinemethanol during the course the e time of the reaction, equal to 3 hours. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C9H7Cl2N4O [M+H]+: 256.99, experimental 257.

Example P31

4-(4-chloro-6-(pyridine-2-ylethoxy)-1,3,5-triazine-2-yl)morpholine:

In accordance with the General procedure a-1 was obtained target compound. Purification using column chromatography allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C13H15ClN5O2[M+H]+: 256.99, experimental 257.

Example R

4-(4,6-dichloro-1,3,5-triazine-2-yl)morpholine:

The acid chloride cyanuric acid (10.0 g, a 54.2 mmol, 1.0 EQ.) was dissolved in methylene chloride (60 ml) to the reaction mixture at -50°C slowly (dropwise) was added morpholine (4,70 ml, 54,2 mmol, 1.0 EQ.), was stirred for 20 minutes at the same temperature and poured into water. After extraction with methylene chloride and ethyl acetate (2×), the organic layers were dried MgSO4and concentrated. Additional purification was performed using flash chromatography (1:1 hexane/ethyl acetate) to give the title compound as a colourless solid (of 3.56 g, 28%).

Data analysis:

1H-NMR (400 MHz, CDCl3): δ 3.76-3.74 (8 is, m).

ESI-MS (70 eV, m/z): calculated for C7H8Cl2N4O [M+Na]+(258); experimental 258.

X-ray analysis of the structure of the title compounds was confirmed by x-ray analysis.

Alternate method 1 synthesis of 4-(4,6-dichloro-1,3,5-triazine-2-yl)research in accordance with EP 1020462 B1:

The acid chloride cyanuric acid (10.0 g, 54.0 per mmol) dissolved in acetone (100 ml) was cooled to -5°C, slowly but drops were added triethylamine (4,70 ml, is 49.0 mmol) and then slowly dropwise added morpholine (7.50 g, 54.0 per mmol). The reaction mixture was stirred at the same temperature for one hour, then stirred at room temperature for one hour. The reaction solution was poured into water (500 ml). Precipitated crystals were collected by filtration, washed with a small amount of acetone and dried with getting to 9.70 g (yield: 69%) of 2,4-dichloro-6-morpholino-1,3,5-triazine in the form of colorless crystals with a melting point equal to 155°-157°C.

Alternative 2 synthesis of 4-(4,6-dichloro-1,3,5-triazine-2-yl)research in accordance with EP 1020462 B1:

An aqueous solution of the research (120 mmol, 2.0 EQ.) slowly dropwise added to a solution of the acid chloride cyanuric acid (a 60.2 mmol, 1.0 EQ.) in the dimethyl ether of ethylene glycol (130 ml) at a temperature of from -15°C to -5°C. the Reaction mixture was stirred at -15°C within 2 hours, and then at room temperature for 20 hours. After removal of solvent the residue was extracted with CH2Cl2. The extract was washed with saline, dried MgSO4and concentrated to obtain the title compound as colorless crystals (yield: 63%).

Data analysis:

1H-NMR (400 MHz, CDCl3): δ 3.60-3.80 (8H, m).

ESI-MS (70 eV, m/z): calculated for C7H8Cl2N4O [M+] (234); experimental 234.

X-ray analysis of the structure of the title compounds was confirmed by x-ray analysis.

Example P33

4-(4-chloro-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-yl)morpholine:

4-(4,6-dichloro-1,3,5-triazine-2-yl)morpholine (1.40 g, 5,96 mmol, 1.0 EQ.) was dissolved in dichloromethane (21 ml). In the reaction mixture at 0°C was added N-methylpiperazine (727 l, 6,56 mmol, 1.1 EQ.) and was stirred for 30 minutes at the same temperature. The solvent evaporated under reduced pressure, and purified using flash chromatography allowed us to obtain the title compound as a white solid (690 mg, 39%).

Data analysis:

1H-NMR (400 MHz, CDCl3): δ 3.78-3.68 (17H, m), 2.42 (4H, t, J=5.3, J=5.05), 2.32 (3H, s), 0.87-0.72 (1H, m).

13C-NMR (100 MHz, CDCl3): δ 170.05, 164.92, 164.69, 46.51, 44.24, 43.75, 43.68.

ESI-MS (70 eV, m/z): calculated for C12H19ClN6O [M+H]+ (299); experimental 299.

Example P34

A mixture of methyl 4-aminothiazol-5-carboxylate (1.0 equiv.) and urea (5 EQ.) was heated at 190°C for 2 hours. The hot reaction mixture was poured into a solution of sodium hydroxide and nerastvorimaya substance was removed by filtration. The mixture is then acidified (HCl, 2N) with getting thiazolo[4,5-d]pyrimidine-5,7(4H,6N)-dione as a white precipitate, which was collected by filtration and dried in air.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C5H4N3O2S [M+H]+(170); experimental 170.

The mixture thiazolo[4,5-d]pyrimidine-5,7(4H,6N)-dione (9,49 g of 56.5 mmol) and phosphorus oxychloride (150 ml) was boiled under reflux for 6 hours. Then the reaction mixture was cooled and POCl3evaporated under reduced pressure. The crude product was washed with diethyl ether and NaHCO3. Then the mixture was filtered to obtain 5,7-dichlormethane[4,5-d]pyrimidine as a white solid.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C5H2Cl2N3S [M+H]+(206); experimental 206.

A mixture of 5,7-dichlormethane[4,5-d]pyrimidine (1.0 EQ.), the research (2.2 EQ.) and Meon was stirred at room temperature for 1 hour. Then the reaction mixture was filtered, the item is washed with water and Meon obtaining 4-(5-chlorothiazole[4,5-d]pyrimidine-7-yl)research in the form of a white solid (100%).

Data analysis:

ESI-MS (70 eV, m/z): calculated for C9H10ClN4OS [M+H]+(257); experimental 257.

An alternative synthesis scheme

Example R35

4-(2-(3-(tert-butyldimethylsilyloxy)phenyl)thieno[3,2-d]pyrimido-4-yl)morpholine:

3-(4-Morpholinothio[3,2-d]pyrimidine-2-yl)phenol (obtained according to Hayakawa et al., Bioorganic & Med. Chem. 14:6847-6858 (2006)) (540 mg, 1,72 mmol, 1.0 EQ.) was dissolved in DMF (5 ml). To the resulting solution were added imidazole (936 mg, of 13.8 mmol, 8.0 EQ.) and TBDMSC1 (909 mg, of 6.02 mmol, 3.5 EQ.) and the mixture was heated at 70°C for 3 hours. DMF is evaporated under reduced pressure, and purified using flash chromatography (hexane: ethyl acetate, gradient from 100% to 50% hexane in EtOAc) allowed to obtain the title compound as a white solid.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C22H30H3O2SSi [M+H]+(428); experimental 428.

Example R36

4-(5-(3-(tert-butyldimethylsilyloxy)phenyl)thiazolo['4,5-d]pyrimidine-7-yl)morpholine:

3-(7-morpholinomethyl[4,5-d]pyrimidine-5-yl)phenol (1.0 EQ.) was dissolved in DMF (5 ml). To the specified solution was added imidazole (8.0 EQ.) and TBDMSCl (3.5 EQ.) and the mixture was heated at 70°C for 5 hours. Evaporated DMF under reduced pressure, and purified using flash x is omatography (hexane: ethyl acetate, a gradient from 100% to 50% hexane in EtOAc) allowed to obtain the title compound as a white solid.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C21H29N4O2SSi [M+H]+(428); experimental 428.

Example P37

Tert-butyl 2-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)ethylcarbamate:

4-(2-(3-(Tert-butyldimethylsilyloxy)phenyl)thieno[3,2-d]pyrimidine-4-yl)morpholine (166 mg, 388 mol, 1.0 EQ.) was dissolved in dry THF (3 ml) at room temperature and was added to the round bottom dvuhgolosy flask, which was heated in vacuum and purged with nitrogen. Then the solution was cooled to -78°C. and was added dropwise n-BuLi (315 al, 1.6 M solution in hexane, 1.3 EQ.). After stirring for 20 minutes to the reaction mixture was added 2-(Boc-amino)ethylbromide (130 mg, 582 mol, 1.5 EQ.) and the reaction mixture was stirred at -78°C for 20 minutes, then was heated to room temperature. The reaction mixture was additionally stirred at room temperature overnight.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C29H43N4O4SSi [M+H]+(571.27); experimental 571.

Example R

2-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-4-morpholinothio[3,2-d]pyrimidin-6-yl)ethanamine:

Tert-butyl 2-(2-3-(tert-butyldimethylsilyloxy)phenyl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)ethylcarbamate (10.0 mg, 1.0 EQ.) was dissolved in 3 ml TFUCK:DHM (1:1). The reaction mixture was stirred at room temperature for 2 hours. Column chromatography on silica (DHM:Meon/95:5) allowed us to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C24H35N4O2SSi [M+H]+(471.22); experimental 471.

Example R

10-(3-(2-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)ethylamino)-3-oxopropyl)-5,5-debtor-1,3,7,9-tetramethyl-5H-dipyrrole[1,2-C:1',2'-f][1,3,2]diazaborine-4 s-5-MIA:

To a solution of 2-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)ethanamine (0,010895 mmol, 1.0 EQ.) in DMF (200 l) at room temperature was added Bodipy-NHS (0,011984 mmol, 1.1 equiv.) then DIPEA (0,02179 mmol, 2.0 EQ.). After 24 hours stirring at room temperature in the dark solvents were removed in high vacuum and the mixture was purified using flash chromatography (DHM:Meon/35:1). Additional purification using preparative TLC allowed to obtain the title compound.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C40H52BF2N6O3SSi [M+H]+(773); experimental 773.

Example R40

5,5-debtor-10-(3-(2-(2-(3-hydroxyphenyl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)ethyl) - Rev. Ino)-3-oxopropyl)-1,3,7,9-tetramethyl-5H-dipyrrole[1,2-C:1',2'-f]diazaborine-4 s-5-MIA:

To a solution of TBDMS-protected derivative of phenol (0,060269 mmol, 1.0 EQ.) in 3 ml of abs. THF, cooled to 0°C, was added a 1M solution of tetrabutylammonium fluoride (TBAF) in THF (0,120538 mmol, 2.0 EQ.). After stirring at 0°C for 40 minutes, the solvent was removed in vacuum and the residue was purified using flash chromatography (gradient, hexane: ethyl acetate), then the residue is triturated in a mixture of EtOAc/Meon obtaining the title compound as a colourless solid.

Data analysis:

ESI-MS (70 eV, m/z): calculated for C34H38BF2N6O3S [M+H]+(659); experimental 659.

Example R

Benzofuro[3,2-d]pyrimidine-2,4(1H,3H)-dione:

To a stirred solution of 3-amino-2,3-dihydrobenzofuran-2-carboxamide (and 82.2 mg, 0,461 mmol, 1.0 EQ.) in anhydrous toluene (8 ml) under inert atmosphere was added dropwise oxalicacid (70,2 mg, 553 mol, 1.2 EQ.). The resulting mixture was boiled under reflux (115°C) for 4 hours, then cooled and was additionally stirred for 16 hours. The crude reaction mixture was concentrated to half volume and filtered to obtain a colorless solid matter (of 41.5 mg, 45%). Data analysis:

1H-NMR (400 MHz, DMSO): δ 11.80 (s, 1H), 8.50-7.20 (m, 4H).

13C-NMR (125 MHz, DMSO): δ 162.2, 157.0, 152.7, 134.6, 128.4, 125.9, 125.1, 123.5, 121.1, 112.2.

Example P4

Ethyl 2-carbamoylmethyl-3-ylcarbamate:

3-amino-2,3-dihydrobenzofuran-2-carboxamide (200 mg, to 1.14 mmol, 1.0 EQ.) and ethylchloride (109 ml, to 1.14 mmol, 1.0 EQ.) in anhydrous toluene (10 ml) under inert atmosphere was heated under reflux (115°C) for 6 hours, then stirred at room temperature overnight. Solvent was removed and the residue was purified using chromatography (gradient from 100% hexane in EtOAc to 50%) to give a white solid (130 mg, 46%).

Data analysis:

1H-NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 8.45 (d,3JHH=8.1 Hz, 1H), 7.45-7.41 (m, 2H), 7.28-7.26 (m, 1H), 6.34 (s, br, 1H), 5.8 (s, br, 1H), 4.28 (q,3JHH=7.1 Hz, 2H), 1.35 (t,3JHH=7.1 Hz, 3H).

13C-NMR (100 MHz, CDCl3): δ 163.4, 154.0, 153.9, 129.6, 128.7, 126.7, 123.6, 122.0, 112.1.

ESI-MS (MeOH, 70 eV): calculated for C12H12N2O4[M+Na]+(271); experimental 271.

Example P43

Benzofuro[3,2-d]pyrimidine-2,4(1H,3H)-diol:

Ethyl 2-carbamoylbiphenyl-3-ylcarbamate (114 mg, 0,460 mmol, 1.0 EQ.) in 5% NaOH solution of 3.7 ml, 4,60 mmol, 10.0 EQ.) and EtOH (2.2 ml) was boiled under reflux for 1 hour. After cooling the mixture to room temperature, the product was besieged by adding HCl (conc., 37%) and a solid substance was collected by filtration and washed with water and Et2O. the Obtained compound (40 mg, 43%) was used in the next stage without additional purification.

Data analysis:

1H-NMR (500 MHz, DMSO): δ 12.03 (s, 1H), 11.43 (s, 1H), 8.00 (d,3JHH=7.3 Hz, 1H), 7.75 (d,3JHH=8.5 Hz, 1H), 7.64 (t,3JHH=7.3 Hz, 1H), 7.45 (t,3JHH=7.3 Hz, 1H)

13C-NMR (100 MHz, DMSO): δ 155.5, 154.9, 151.3, 133.3, 130.6, 129.8, 123.9, 121.6, 117.6, 112.9.

Example R

2,4-dichlorobenzoate[3,2-d]pyrimidine:

In benzofuro[3,2-d]Piramide-2,4(1H,3H)-dione (100 mg, 495 mol, 1.0 EQ.) in toluene (810 l) under inert atmosphere was added N,N-diisopropylethylamine (427 ml, 2.48 mmol, 5.0 EQ.). Then to the mixture was added dropwise phosphorus oxychloride (227 ml, 2.48 mmol, 5.0 equiv.) prior to heating the reaction mixture to 100°C for 22 hours. Then the mixture was concentrated in vacuo, added water (20 ml) and was extracted with a mixture of DGM, washed with saturated solution of NaHCO3. Remove the solvent in high vacuum and purified connection using chromatography (gradient from 100% hexane in EtOAc to 50% hexane) to give a colorless solid (68,3 mg, 58%).

Data analysis:

1H-NMR (500 MHz, DMSO): δ 8.28 (d,3JHH=7.3 Hz, 1H), 8.01 (d,3JHH=8.5 Hz, 1H), 7.93 (t,3JHH=7.9 Hz, 1H), 7.65 (t,3JHH=7.3 Hz, 1H).

13C-NMR (125 MHz, DMSO): δ 158.4, 153.3, 151.8, 143.6, 142.4, 133.9, 125.5, 122.8, 120.1, 113.5.

TCX (SiO2, hexane/EtOAc (1:1), Rf=0.88

Example P45/p>

2-chloro-4-morpholinomethyl[3,2-d]pyrimidine:

2,4-Dichlorobenzoate[3,2-d]pyrimidine (61 mg, 0,255 mmol, 1.0 EQ.) was dissolved in Meon (2 ml) was added morpholine (49,1 ml, 562 mol, 2.2 EQ.) The reaction mixture is boiled under reflux for 30 minutes, then cooled to room temperature. Remove the solvents in vacuo and the residue was purified using chromatography on silica gel (gradient from 100% hexane in EtOAc to 50% hexane) to give a colorless solid (59,4 mg, 80%).

Data analysis:

1H-NMR (400 MHz, DMSO): δ 8.06 (d,3JHH=7.3 Hz, 1H), 7.82 (d,3JHH=8.3 Hz, 1H), 7.71 (t,3JHH=7.8 Hz, 1H), 7.50 (t,3JHH=7.6 Hz, 1H), 4.00-3.99 (m, 4H), 3.77 (t,3JHH=5.1 Hz, 4H).

MC-ESI (Meon, 70 eV): calculated for C14H13ClN3O2[M+H]+(290); experimental 290.

Example P46

3-(4-morpholinopropan-2-yl)phenol:

Gaseous argon was purged mixture of 2-chloro-4-morpholinomethyl[3,2-d]pyrimidine (ASA66) (48.7 per mg, 168 mol, 1.0 EQ.) and pinacoline ester 3-gidroksistearinovoj acid (220 MM) (148 mg, 672 mol, 4.0 EQ.) in 1,2-dimethoxyethane and 2M Na2CO3(3:1) (4 ml) for 5 minutes. Added complex, dichloro 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) and dichloromethane (732 MM) (3,07 mg, 4,20 mol, of 0.025 EQ.) and the reaction to the offer was boiled under reflux (90°C) for a 15.5 hours. The red solution was cooled and diluted with EtOAc (6.5 ml). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc., 32% solution in water)=5:4:1 (6.5 ml), then NH4Cl (us.) and brine (2×), dried Na2CO3, filtered and concentrated. Purification via chromatography on silica gel allowed to obtain a colorless solid (49 mg, 85%).

Data analysis:

1H-NMR (400 MHz, DMSO): δ 9.52 (s, 1H), 8.14-8.12 (d,3JHH=7.0 Hz, 1H), 7.88-7.86 (m, 2H), 7.80-7.78 (d,3JHH=8.3 Hz, 1H), 7.68 (t,3JHH=7.7 Hz, 1H), 7.49 (t,3JHH=7.3 Hz, 1H), 7.27 (t,3JHH=7.6 Hz, 1H), 6.87-6.84 (m, 1H), 4.08 (t,3JHH=4.6 Hz, 4H), 3.81 (3JHH=4.8 Hz, 4H).

13C-NMR (100 MHz, DMSO): δ 158.9, 158.3, 156.7, 149.2, 148.9, 140.1, 134.8, 131.3, 130.2, 124.9, 122.8, 122.2, 119.6, 117.8, 115.4, 113.6, 66.9, 46.1.

MC-ESI (MeOH, 70 eV): calculated for C20H17N3O3[M+H]+(348); experimental 349.

Example R

5-(4-morpholinomethyl[3,2-d]pyrimidine-2-yl)pyridine-2-amine:

Gaseous argon was purged mixture of 2-chloro-4-morpholinomethyl[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 EQ.) and pinacoline ether 2-aminopyridine-5-Bronevoy acid (220 MM) (243 mg, 1.10 mmol, 4.0 EQ.) in 1,2-dimethoxyethane and 2M Na2CO3(3:1) (6 ml) for 5 minutes. Added complex, dichloro 1,1'-bis(diphenylphosphino)ferrocene-PAL is adiya(II) and dichloromethane (732 MM) (of 5.05 mg, 0,00690 mmol, of 0.025 EQ.) and the reaction mixture is boiled under reflux (90°C.) for 14 hours and 45 minutes, cooled and diluted with EtOAc (9 ml). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc., 32% solution in water)=5:4:1 (9 ml), then NH4Cl (us.) and brine (2×), dried Na2CO3, filtered and concentrated. Purification via chromatography on silica gel (gradient from = % MeOH in DHM to 5% MeOH in DHM) allowed us to obtain a colorless solid (4.40 mg, 5%).

Data analysis:

1H-NMR (400 MHz, DMSO): δ 8.96 (d, JHH=1.8 Hz, 1H), 8.37 (dd,3JHH=8,4 Hz4JHH=2.5 Hz, 1H), 8.12 (d,3JHH=7.6 Hz, 1H), 7.78 (d,3JHH=8.4 Hz, 1H), 7.67 (dt,3JHH=7.1 Hz,4JHH=1.3 Hz, 1H), 7.48 (t,3JHH=7.1 Hz, 1H), 6.58 (s, 1H), 6.56 (s, 2H), 4.06-4.05 (m, 4H), 3.81-3.80 (m, 4H).

MC-ESI (MeOH, 70 eV): calculated for C19H17N5O2[M+H]+(348); experimental 348.

Example R48

2-(1H-indol-4-yl)-4-morpholinomethyl[3,2-d]pyrimidine:

Gaseous argon was purged mixture of 2-chloro-4-morpholinomethyl[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 EQ.) and pinacoline ether indole-4-Bronevoy acid (243 MM) (267 mg, 1.10 mmol, 4.0 EQ.) in 1,2-dimethoxyethane and 2M Na2CO3(3:1) (6 ml) for 5 minutes. Added complex, dichloro 1,1'-bis(diphenylphosphino)fer the assess-palladium(II) and dichloromethane (732 MM) (of 5.05 mg, 0,00690 mmol, of 0.025 EQ.) and the reaction mixture is boiled under reflux (90°C.) for 15 hours and 30 minutes, cooled and diluted with EtOAc (20 ml). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc., 32% solution in water)=5:4:1 (9 ml), then NH4Cl (us.) and brine (2×), dried Na2CO3, filtered and concentrated. Purification using chromatography pas silica gel (gradient from 100% hexane in EtOAc to 50% hexane) allowed us to obtain a yellowish solid (89,0 mg, 87%).

Data analysis:

1H-NMR (400 MHz, DMSO): δ 11.26 (s, 1H), 8.20-8.17 (m, 2H), 7.76 (d,3JHH=8.4 Hz, 1H), 7.66 (dt,3JHH=6.0 Hz,4JHH=1.3 Hz, 1H), 7.55-7.53 (m, 2H), 7.50-7.47 (m, 2H), 7.22 (t,3JHH=7.8 Hz, 1H), 4.08 (t,3JHH=5.1 Hz, 4H), 3.81 (t,3JHH=5.0 Hz, 4H).

13C-NMR (100 MHz, DMSO): δ 161.2, 156.6. 149.3. 148.9, 138.0, 134.3. 131.1, 130.5, 127.2, 126.9, 124.8, 123.0, 122.2, 121.5, 121.3, 114.2, 113.5, 104.4, 66.9, 46.3.

MC-ESI (MeOH, 70 eV): calculated for C22H18N4O2[M+H]+(371); experimental 372.

Example R

2-(1H-indol-5-yl)-4-morpholinomethyl[3,2-d]pyrimidine:

Gaseous argon was purged mixture of 2-chloro-4-morpholinomethyl[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 EQ.) and pinacoline ether indole-5-Bronevoy acid (243 MM) (267 mg, 1.10 mmol, 4.0 EQ.) in 1,2-dimethoxyethane and 2M Na2CO3(3:1) 6 ml) for 5 minutes. Added complex, dichloro 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) and dichloromethane (732 MM) (5.05 mg, 0,00690 mmol, of 0.025 EQ.) and the reaction mixture is boiled under reflux (90°C.) for 15 hours, cooled and diluted with EtOAc (20 ml). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc., 32% solution in water)=5:4:1 (9 ml), then NH4Cl (us.) and brine (2×), dried Na2CO3, filtered and concentrated. Purification via chromatography on silica gel (gradient from 100% hexane in EtOAc to 70% hexane) allowed us to obtain a colorless solid (35 mg, 34%).

Data analysis:

1H-NMR (400 MHz, DMSO): δ 11.23 (s, 1H), 8.71 (s, 1H), 8.29 (dd,3JHH=8.6 Hz,4JHH=1.5 Hz, 1H), 8.17 (d,3JHH=7.6 Hz, 1H), 7.75 (d, 8.3 Hz, 1H), 7.65 (dt,3JHH=7.8 Hz,4JHH=1.0 Hz, 1H), 7.50-7.46 (m, 2H), 7.39 (t, JHH=2.8 Hz, 1H), 6.57 (s, 1H), 4.09-4.06 (m, 4H), 3.82.3.80 (m, 4H).

Example P50

Intracellular study of the inhibition of the Western type (Protocol definition phospho-RKV/RKV when A melanoma):

Inhibitory efficacy of compounds of formula I was determined by using cell research using the following method:

The cells were placed in 96-well plates (Packard) for 24 hours before the experiment. To the medium was added inhibitor or DMSO as a control sample (each sample in two eczema is larah) and incubated for 3 hours. For fixation, cells were treated with 4% para-formaldehyde for 20 minutes. After washing the FSB/0,1% Triton X-100, were filled 100% goat serum in FSB for 1 hour. Dissolved in the FSB antibodies against RCV Ser473 (Cell signaling) and RCO (received as a gift from E. Hirsch (E. Hirsch)) or pS6 Ser235/236 (Cell Signalling) were incubated in a shaker overnight at 4°C. After washing the FSB used secondary antibodies (LI-COR), diluted FSB at room temperature in the dark. The tablets were washed FSB before scanning device for reading tablets Odyssey.

Day 0

1. Put 80,000 cells/well in a black 96-well ViewPlate production Packard.

2. Put 200 l cell suspension per well using a multichannel pipette.

3. Investigated the homogeneity of the distribution under the microscope.

4. Incubated the cells for 24 hours.

Day 1

1. Carefully remove the medium and re-placed in the wells 100 l environment. Examined under the microscope loss of cells.

2. Added 1 l 100× concentrated DMSO or inhibitor.

3. Incubated for 3 hours at 37°C.

4. Added 60 l of paraformaldehyde 10% (final concentration 4%) and incubated at room temperature for 20 minutes.

5. Washed 3×5 minutes (200 l) FSB/0,1% Triton X-100.

6. Filled within 60 minutes (100 l) 10% FCS in the FSB at room temperature.

7. Incubated in ECENA night 50 l RCV Ser473 (1:500) and RCO (1:500) or pS6 Ser235/236 (1:500) in the FSB at 4°C in the shaker.

Day 2

1. Washed 3×5 minutes FSB.

2. Were incubated for 60 minutes 50 l secondary protivoryechiya antibodies IRDye800 (1:800) and protivorechivyh antibodies IRDye680 (1:500) in the FSB at room temperature in the dark in the shaker.

3. Washed 3×5 minutes FSB.

4. Investigated the tablet PA-reader tablets Odyssey.

Reagents:

Packard ViewPlate (black) #6005225

Anti-Phospho RKV Scr473 (Cell signaling cat.4058)

Anti-RKV (received as a gift from E. Hirsch, Turin)

Anti-R Ser 235/236 (Cell signaling cat.4856)

Goat protivoryechiya IRDye800 CW (LI-COR cat. 926-32211)

Goat protivorechivy IRDye680 (LI-COR cat. 923-32220)

Examples of conduct intracellular studies of inhibition of the Western type:

For more phosphorylated RKV defined on the scan Odyssey received higher values RCV/RKV, i.e. was less strong inhibition signal. Summary of the results obtained for some typical compounds represented in Table 7.

Confirmation permeability connection indirectly reflected with the use of this study. Compounds were applied to the apical surface of the cell monolayers, and the penetration of compounds into the cell cavity can be defined by determining the inhibition of PI3K.

Table 6:
Some biologically active inhibitors of PI3K:
(ZSTK474) was used as a control triazine compounds for the conducted experiments (Intellectual property Zenyaku) 4,4'-(6-(2-(deformity)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)dimorpholinoExample P3 3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenolExample P6 3-(4,6-dimorpholino-1,3,5-trizip-2-yl)benzonitrile

Example P7 4-(4,6-dimorpholino-1,3,5-triazine-2-yl)benzonitrileExample P8 4,4'-(6-(pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholinoExample P9 4,4'-(6-(6-morpholinopropan-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
Example P2 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-amineExample P4 4-(4,6-dimorpholino-1,3,5-triazine-2-yl)anilineNCA235 or 5-(2,6-disorganized-4-yl)-4-(trifluoromethyl) - IIiii-2-amine was used as a control pyrimidine compounds for the conducted experiments (IP Novartis)
Example P11 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amineExample P12 4,4'-(6-(5-herperidin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino
Table 7:
ExampleAAAA1205lu1205lu
RCV/RKVRCV/RKVS6 pS6pS6pS6
1 µm10 µm1 µm10 µmµm10 µm

Fig.1 and Fig.2 (see the end of the description).

The description should be considered as an illustration of the basics of this invention. Also, since a number of modifications and changes are obvious to experts in the art, the description does not limit the invention to the specific definitions and processes described above. Accordingly, all suitable modifications and equivalents may be considered as included in the scope of the present invention defined by the claims presented below.

The terms "contains", "containing", "include", "including" and "includes" when used in the specified description and the following claims are intended to clarify the availability of these features, numerical values, components, or steps, but do not preclude the presence or addition of one or more characteristics of the numerical values of the component stages or groups.

1. The compound of formula (Ib):

and its pharmaceutical is acceptable salt, where
R2represents a heteroaryl group of the structure:

where the wavy line indicates the place of attachment of the triazine ring, and
where specified monocyclic heteroaryl group is unsubstituted or substituted by one or more groups selected from F, Cl, Br, I, -NR10R11and C1-C12of alkyl;
or monocyclic heteroaryl group patterns

where the wavy line indicates the place of attachment of the triazine ring, and
where specified monocyclic heteroaryl group is unsubstituted or optionally substituted by one or more groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -och3-C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -Cho, -CH2HE, -C(=O)NHCH3, -C(=O)NH2and CH3;
R3x, R3y, R3zand R3prepresent hydrogen;
R4x, R4y, R4zand R4pindependently from each other selected from the group consisting of:
hydrogen, F, Cl, Br, I,- C(C1-C6alkyl)2NR10R11;
R10and R11represent hydrogen.

2. Connection on p. 1, characterized in that:
R3x, R3y, R3z, R3pand R4x, R4zand R4pimagine the battle hydrogen.

3. A compound selected from:
- 4,4'-(6-(pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino,
- 3-(4,6-dimorpholino-1,3,5-triazine-2-yl)phenol,
- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyridine-2-amine,
- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)pyrimidine-2-amine,
- 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine,
- 4-(4,6-dimorpholino-1,3,5-triazine-2-yl)aniline,
- 3-(4,6-dimorpholino-1,3,5-triazine-2-yl)aniline,
- 3-(4,6-dimorpholino-1,3,5-triazine-2-yl)benzonitrile,
- 4-(4,6-dimorpholino-1,3,5-triazine-2-yl)benzonitrile,
- 4,4'-(6-(6-morpholinopropan-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino, and
- 4,4'-(6-(5-herperidin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholino.

4. Connection on p. 1 selected from 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyridin-2-amine and 5-(4,6-dimorpholino-1,3,5-triazine-2-yl)-4-(trifluoromethyl)pyrimidine-2-amine.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of a compound according to any one of paragraphs.1-4, effective for inhibiting the activity of PI3K in a subject representing a human or animal, in the introduction he mentioned composition.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of a compound according to any one of paragraphs.1-4, effective for inhibiting the activity of mTOR, the entity representing a person or animal, when introducing him to the specified com is osili.

7. The method of modulating the activity of PDK, RCO and other PH-domain containing proteins are the effectors, including the conversion of a compound according to any one of paragraphs.1-4 in contact with the cell ex vivo.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula I and its pharmaceutically acceptable salt, wherein if a chemical valency permits, i represents 1 or 2, R1 represents H; a linear (C1-C4) alkyl group, R2 represents H, Cl or F, X represents either N, or CR3, R3 represents H; halogen; a linear (C1-C4) alkyl or (C1-C4) alkoxyl group, Y represents Z represents O or NRx, Rx represents H or a linear or branched (C1-C4) alkyl, k is equal to 2, 3 or 4, n and p independently represents 2, and a sum of n+p cannot exceed 4, T represents H or a linear (C1-C4) alkyl group; T′ represents a linear C1-C3 alkyl chain substituted by either (C1-C6)-dialkylaminogroup, or a 5-6-merous saturated heterocycle containing one nitrogen atom and optionally containing the second heteroatom specified in O, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; or a 5-merous saturated heterocycle containing one nitrogen atom, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; r represents zero, 1; R′ represents di(C1-C4)alkylamino, (C1-C4)alkoxy; except for the compounds specified in the clause. The invention also refers to a pharmaceutical composition based on the compound of formula (I), using the compound of formula (I) and to a method of treating diseases, in which the hedgehog signalling pathway modulation is effective.

EFFECT: there are prepared new heterocyclic compounds possessing t effective biological properties.

20 cl, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a new compound of formula or its pharmaceutically acceptable salt, wherein R1 represents (C1-C6)alkyl; an oxodihydropyridyl ring in the formula is optionally substituted by 1-3 groups optionally specified in fluorine, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkoxy; R2 represents (C1-C6)alkyl, phenyl, or tetrahydropyranyl optionally substituted by a group in the number of up to 1 independently specified in fluorine, hydroxy(C1-C6)alkyl and (C3-C6)cycloalkyl; R3 is specified in (C1-C6)alkyl optionally substituted by groups in the number of up to 3 independently specified in fluorine, cyano, R4, R4O-, (R4)2N-, R4C(=O)NR4-, (R4)2NC(=O)-, R4OC(=O)NR4-, R4S(=O)2NR4- and oxadiazolyl optionally substituted by (C1-C6)alkyl; R4 independently represents H or (C1-C6)alkyl. Also, the invention refers to a method of treating an individual by using the above compound, a method of inhibiting 11β-HSD1, and a compound-based pharmaceutical composition.

EFFECT: there are prepared new compounds effective in treating the diseases related to 11β-HSD1 activity or expression.

15 cl, 6 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 and R2 have the following values: (i) R1 and R2 together form =O; (ii) R1 and R2 together with carbon atom, which they are bound with, form duoxacycloalkyl; R1 represents hydrogen or halogen; and R2 represents halogen; (iv) R1 represents C1-6alkyl, where alkyl is optionally substituted with cyano, -RxS(O)qRv or -RxNRyRz; and R2 represents hydrogen; (v) R1 represents -OR12 or -NR13R14; and R2 represents hydrogen, deutero or phenyl, which is optionally substituted with halogen; R3 represents hydrogen, halogen, C1-6alkyl, cyano, halogen C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy; R4 and R5 represent hydrogen; R6 is independently selected from halogen, C1-6alkyl, halogenC1-6alkyl, -RxOR18 and -RxS(O)qRv; R7 independently represents halogen or -RxORw; R12 is selected from hydrogen and C1-6alkyl, R13 represents hydrogen; R14 is selected from hydrogen, C3-10cycloalkyl, -C(O)Rv and -C(O)ORw; R18 represents hydrogen, C1-6alkyl, or pyperidinyl, where R18 is optionally substituted with 1-3 Q1 groups, each Q1 is independenly selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl; Rx independently represents C1-6alkylene or simple bond; Rv and Rw represent hydrogen or C1-6alkyl; Ry and Rz represent hydrogen; n has value 0-4; p has value 0-5; and each q independently has value 0, 1 or 2. Invention also relates to compounds of formula (II) , where substituents have values, given in the invention formula, to pharmaceutical composition, possessing inhibiting activity with respect to JAK kinases, containing compounds of formula (I) or (II), methods of treating JAK-modulated disease, and application of compounds of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) as inhibitors of JAK kinases.

32 cl, 6 dwg, 2 tbl, 84 ex

FIELD: medicine, pharmaceutics.

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

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

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

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

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

26 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, in particular to method of obtaining 3-hetaryl-1,5,3-dithiazepinanes of general formula (1) , where ; ; ; ; ; ; ; ; , consisting in the following: N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine is subjected to interaction with hetarylamine [2-pyridinamine, 3-pyridinamine, 5-bromo-2-pyridinamine, 5-methyl-2-pyridinamine, 4-pyridinylmethylamine, 5-nitro-1,3-thiazol-2-amine, 6-nitro-1,3-benzothiazol-2-amine, 2-91h-indol-3-yl)-1-ethanamone, 5-methyl-1H-pyrazol-3-amine] in presence of catalyst CuCl2 in molar ratio N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:hetarylamine: CuCl2=10:10:(0.3-0.7) at temperature 55-65°C and atmospheric pressure in chloroform as solvent for 50-80 minutes.

EFFECT: elaborated is method of obtaining 3-hetaryl-1,5,3-dithiazepinanes, which can be applied as biologically active substances.

1 tbl, 1 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

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

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

22 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of nucleoside derivatives - 1,2,5-oxadiazoles of general structural formula I where R1 and R2 are selected from phenylsulphonyl, substituted with one or more halogen atoms, nitro groups, carboxy groups, alkyl halides, CH3, OCH3, OCF3; X is selected from N or N→O; or R1 and R2 form a group, where R', R", R'" and R'''' are independently selected from hydrogen; halogens; nitro groups, hydroxy group, carboxy group, CH3; CH2Br; OCH3; phenylsulphonyl; phenylthio group; or the following groups: R' and R" can also be merged into one of the following common rings for inhibiting human immunodeficiency virus (HIV) replication. The invention also relates to a pharmaceutical composition based on compounds of formula I and a method of inhibiting HIV-1 subtypes A and B integrase, including forms which are resistant to raltegravir.

EFFECT: detecting novel activity in compounds of formula I, which can be used in medicine as HIV replication inhibitors.

3 cl, 5 tbl, 4 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

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

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

6 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula (1): or pharmaceutically acceptable salts thereof, where: R1 denotes H, halogen; R2 denotes an 8-10-member bicyclic hydrocarbon group, optionally substituted, or a bicyclic heterocyclic group consisting of one or two atoms selected from nitrogen, oxygen and sulphur and 5-9 carbon atoms, optionally substituted, where the optional substitute is halogen, lower alkyl, OH, lower alkoxy, oxo, NO2, CN; R3 denotes H.

EFFECT: compounds have inhibiting action of production of IL-6, which enables use thereof in a pharmaceutical composition and when treating a range of diseases.

12 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

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