UA76103C2 - Inhibitors of phosphatidyl-inositol- 3-kinase delta of human - Google Patents

Abstract

Methods of inhibiting phosphatidylinositol 3-kinase delta isoform ( ) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit , while not significantly inhibiting activity of other isoforms. Compounds are provided that inhibit activity, including compounds that selectively inhibit activity. Methods of using inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using inhibitory compounds to inhibit -mediated processes in vitro and in vivo.

Description

Description of the invention

This application claims the benefit of US Prior Application Serial No. Mob0/199655, filed Apr. 25, 2000, US Prior Application Serial No. Mob60/238057, filed Oct. 25, 2000).

The presented invention generally relates to phosphatidylinositol-3-kinase (PIZK) enzymes, and more precisely to selective inhibitors of the activity of PIZK and methods of using such materials.

Cell signaling by 3-phosphorylated phosphoinositides is involved in a variety of cellular processes, such as malignant transformation, growth factor signaling, inflammation, and 70 immunity (see Katepy et al., 9. Vioi Speth, 274:8347-8350 (1999)) , for review. The enzyme responsible for the production of these phosphorylated signaling products, phosphatidylinositol 3-kinase (PI-3-kinase; PIZK), was originally identified by activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI). and its phosphorylated derivatives by

C'-hydroxyl ring of inositol Rapauooy ei ai., Tgtepaz Seii! Vio! 2; 358-60 (1992)|. 12 Levels of phosphatidylinositol-3,4,5-trisphosphate (PIP3), the primary product of RIP-3-kinase activation, increase when cells are treated with a variety of agonists. The activation of RiI-3-kinase is therefore thought to be involved in a number of cellular reactions, including cell growth, differentiation and apoptosis (RagKeg ei aI., Sitepi Bioiodu, 5:577-99 (1995);

Uao ei ai., Zsiepse, 267:2003-05 (19953). Although the downstream targets of the phosphorylated lipids generated after activation of RiI-3 kinases are well defined, new evidence suggests that proteins that contain a pleckstrin homology domain and an EMME finger domain are activated upon binding to various phosphatidyl-inositol lipids | Zyettagk ei ai,, 9. Seyi Zsi, 112:4175-83 (1999); Iettop ei aiYi.,, Tgepaz Sei! Vioi, 7:237-42 (1997)| ip mio, some isoforms of protein kinase C (PKC) are directly activated by PIR with, and a related protein kinase of PKR, RKV, has been shown to be activated by PIL-3-kinase. )).

Currently, the family of RiI-3-kinase enzymes is divided into three classes based on their substrate specificity. Class I ROS can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidyl-inositol-4,5-diphosphate (PIP") to obtain phosphatidylinositol-3-phosphate / (PIP), phosphatidylinositol-3, 4-diphosphate and phosphatidylinositol-3,4,5-triphosphate, respectively. RIZK of class II phosphorylate RI and phosphatidylinositol-4-phosphate, and RIZK of class I can phosphorylate only RI.

Initial purification and molecular cloning of Pi-Z-kinase revealed that it is a heterodimer consisting of p85 and p110 subunits. Niyez ei ai., SeiII, 70:419-29 av (1992)). Later, four distinct class I ROKs, designated ROKs A, B, y, and D, were identified, each consisting of a distinct catalytic subelement and a regulatory subelement of size 11OkDa. More precisely, each of the three catalytic subelements, that is, p10A, p10B, and p110u, interacts with the same regulatory subelement, p85; and p110G interacts with a different regulatory subelement, p101. As described, the expression pattern of each of these RISK in human cells and tissues is also distinct.Although a wealth of information has accumulated in the recent past regarding the cellular functions of Ri-3-kinase in general, the role of each individual isoform is largely unknown.

Cloning of bovine p110A is described. This protein was identified as related to Zasspagotusea sehemizide: MraZa4r, a protein involved in vacuolar protein processing. The product of recombinant p110A, as also shown in 70, is associated with rvba, giving RAZK activity in transfected CO5-1 cells. |See Niyez ei ai., pp. Seii, 70,419-29 (1992). Cloning of the second human p110 isoform, designated as p1108B, (described in Ni ei aiYi., Moi Seii| Vioi, 13:7677-88 (1993)). This isoform has been shown to be associated in cells with p8v5 and is ubiquitously expressed because

p1108 mRNA was found in a number of human and mouse tissues, as well as in human umbilical vein endothelial cells, - 15 human Jurkat leukemic T-cells, 293 human embryonic kidney cells, mouse fibroblasts

ZT3, Nei a cells and MVT2 bladder carcinoma cells of rats. Such broad expression suggests that this (o) isoform is very important in the signaling pathway. - Identification of the isoform of p1iiOu Ri-Z-kinase (described by Sapigu ei a, 9 Vioi Speth, 272:19236-41 (1997)|.

It was observed that the human isoform p110) is expressed only in tissues. It is expressed at high levels in lymphocytes and lymphoid tissues, confirming that the protein may play a role in RiI-3-kinase c"-mediated signaling in the immune system. A detailed description of the p110y isoform can also be found (in US patents

MoMo5858753; 5822910; and 5985589). |See also, Mappaesergoesk ei ai., Rgos Mai Asai 5sii OBA, 94:4330-5 (1997) and international publication U/O 97/466881I. 5B In each of the RIZKA subtypes, B and y, subelement p85 affects the localization of PI-3-kinase in the protoplasm of membranes through the interaction of its ЗН2 domain with phosphorylated tyrosine residues (present in an acceptable environment

(F) sequence) in target proteins |(Cateyp et al., Sci., 83:821-30 (19953). Two isoforms of p85 have been identified, coreba, which is expressed ubiquitously, and p85B, which is first found in the brain and lymphoid tissues |Moiipia hey hey

Opsodepz, 7:789-93 (1992)). The association of the p8e5 subelement with the catalytic subelements p1t10A, B, or ybo of Ri-Z-kinase appears to be necessary for the catalytic activity and stability of these enzymes. In addition, the addition of Kaz proteins also up-regulates the activity of RiI-3-kinase.

Cloning of p110G revealed the following complexity in the family of RAZK enzymes (Ziouapom ei ai., Zsiepse, 269:690-93 (1995)). The p110H isoform is closely related to p110A and p1108 (45-4895 identity in the catalytic domain), but does not result in the use of p8v5 as a target subunit. Instead, p110H contains an additional 65 domain, designated the "pleckstrin (riesquihip)-homoloop domain" near its amino terminus.

This domain enables the interaction of p110H with the subelements of HV of heterotrimeric O-proteins, and this interaction leads to the regulation of their activity.

The regulatory subelement p101 for RIVK-gamma was first cloned in a pig, and then the human ortholog |Ktgidtapp ei ai,U was identified. Vioi Speth, 274:17152-8 (1999)). The interaction between the M-terminal region of p101 with

The M-terminal region of p110G appears to be critical for the activation of RIZKG through the above-mentioned VG.

A highly active RAZK polypeptide is described |In the international publication UUO 96/25488), which discloses the preparation of a chimeric condensed protein in which a 102-residue Rab fragment, known as the inter-ZH2 region (iIZH2), is condensed through a linker region with M- termination of mouse p110. The domain of p85 and IZN2 is probably able to activate RIZK activity in a manner comparable to that of an intact rach |Kiirrei ei a!., Moi! Sow! Vioi, 0. 14:2675-85(1994)).

Therefore, Ri-Z-kinases can be defined by their amino acid identity or by their activity.

Additional members of this growing gene family include more distantly related lipid and protein kinases, including Mre34 TOKI and TOK2 from bZasspagotuses segemiviae (and their mammalian homologues such as ECAR and ttTokK), the gene product of ataxic telangiectasia (ATK), and the catalytic subunit of DNA-dependent protein kinases 7/5. HDNE-PC). See in general, Nypieg, Seiyi, 83:1-4 (1995)).

RI-Z-kinase is also found to be involved in a number of aspects of leukocyte activation. Rv5-associated activity is shown for RiI-3-kinase, physically associated with the cytoplasmic domain of CO28, which is an important costimulatory molecule for the activation of T-cells in response to an antigen. Kiai, Ittipyu, 4:527-34 (1996)). Activation of T cells through CO28 lowers the threshold value for 2o activation by antigen and increases the intensity and duration of the proliferative reaction. This action is associated with an increase in the transcription of a number of genes, including interleukin-2 (1/2), an important factor in the growth of T cells (Rgazeg ei aIm,, Zsiepse, 251:313-16 (1991)). Mutation of CO28 so that it can no longer interact with Ri-Z kinase results in an inability to initiate production of 1/2, confirming the critical role of RiI-Z kinase in activation

T cells. high school

Specific inhibitors against individual members of an enzyme family provide an invaluable tool for deciphering the functions of each enzyme. Two compounds, IU294002 and wortmannin, are widely used as i) inhibitors of RiI-33-kinase. These compounds, however, are non-specific RIZK inhibitors that do not discriminate among the four members of class I Ri-3 kinases. For example, the IR values of wortmannin against each distinct Ri-3 kinase of class I RI-ZK are within 1- 1 TONNM. Similarly, the value of the IC for I 294002 against each of these RiI-3-kinases is approximately 100 µM (Rgitap et al. App Chem Biospet, 67:481-507 (1998)). Hence, the usefulness of these compounds in the study of the role of PI-3-kinases of a separate class is limited. at

Based on a study using wortmannin, evidence was obtained that the function of Ri-Z-kinase is also "required for some aspects of signaling by leukocytes through z-protein-coupled receptors. 64 (1994)). Moreover, it has been shown that wortmannin and I U294002 block ise) migration of neutrophils and release of superoxide. However, since these compounds do not distinguish between different isoforms of

RISK, it remains unclear how a particular isoform or isoforms of ROK are involved in this phenomenon.

Ed

And "t NI so no) z" and 1: en a zoyk t b: evil and "Mi kV. -ій і I: St she s" not Ts.

F) ime) 60 b5 not pak 7 z.

ZA y: I B ai "I

KE Y ik 1 TE x 15 . t he s ; : their a: that and Go 20 . ; AND:

From the point of view of the above, it is clear that the existing knowledge is insufficient in view of the structural and functional features of Ri-Z-kinase enzymes, including subcellular localization, activation states, substrate affinity, etc. Moreover, the function that these enzymes perform in normal and diseased tissues remains unclear. In particular, the function of RAZK in leukocytes has not been previously determined, and knowledge about its function in human physiology remains limited. The co-expression of other RAZK isoforms in these tissues has previously confounded attempts to separate the activities of each enzyme. Moreover, the separation of the activity of different RZK isoenzymes may not be possible without the identification of inhibitors that exhibit the characteristics of selective inhibition. C2

Indeed, the applicants are now unsure that such selective, or better, specific, inhibitors of the "RZK" isoenzymes have been demonstrated.

Therefore, in the state of the art, there is a need for further structural research of the polypeptide RIZK i. There is also a need for a functional study of RVC and. Moreover, our understanding of RZK requires further clarification of the structural interactions of P110 with its regulatory subunit and other proteins in the cell. There is also a need for selective or specific inhibitors of RZK isozymes in order to better to determine the functions of each isozyme In particular, selective or specific inhibitors of RZK are desirable to study the role of this isozyme and to develop pharmaceutical agents to modulate isozyme activity.

According to one aspect of the present invention, compounds are proposed that can inhibit the biological and c activity of human RISK. According to the second aspect of the invention, compounds are proposed that selectively inhibit tsRZKs, while having a relatively low inhibitory power against other isoforms of RZKs. According to the following "aspect of the invention, methods for determining the function of the RZK in a person are proposed. According to one more aspect of the invention, methods of selective modulation of the activity of the human RIZK are proposed, thereby facilitating the medical treatment of diseases mediated by the RIZK dysfunction. Other aspects and advantages of the invention will be readily apparent to one skilled in the art. b It has now been found that these and other aspects can be solved by the presented invention, which, according to one aspect, is a method of disrupting the function of leukocytes, which involves the interaction of leukocytes with a compound that selectively inhibits the activity of phosphatidylinositol 3-kinase-delta (RIZKi). in leukocytes. According to the method, leukocytes may include cells selected from the group consisting of neutrophils, B-lymphocytes, T-lymphocytes and basophils.

For example, in cases where leukocytes include neutrophils, the method may include disruption of at least one neutrophil function selected from the group consisting of stimulated superoxide release, stimulated exocytosis, and chemotactic migration. Preferably, the method does not substantially interfere with bacterial phagocytosis or destruction of bacteria by neutrophils. In cases where leukocytes include 29 B-lymphocytes, the method may include disruption of B-lymphocyte proliferation or antibody production (FI by B-lymphocytes. In cases where leukocytes include T-lymphocytes, the method may include disruption of T-lymphocyte proliferation. In cases, when leukocytes include basophils, the method may include interfering with the release of histamine by basophils.

In the methods of the invention, where a selective inhibitor of RISK is used, it is preferred that the compound be at least about 10-fold selective for inhibiting RISK in comparison to other isoforms

Type I RZK in cell-based studies. Preferably, the compound is at least about 20-fold selective for inhibition of RISK in comparison to other isoforms of RISK of type | in cell-based research. Even more preferably, the compound is at least about 50-fold selective for inhibition of β-RIZK, compared to other isoforms of type I RIZK in biochemical assays.

Preferred selective compounds useful in the methods include compounds having structure (1):

pvh () in TSI still rat and kih Sn; They are KO. ee Ne and CHIY en "MI p. o GA where A represents a substituted, as an option, monocyclic or dicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic;

X is selected from the group consisting of СНе?, СНоСНе? and SNAS (EU);

M is selected from the group consisting of 5, 50, 505, МН, О, С(-0), ОС(-0), С(О)0 and МНО(-О)СНоВ, or У is absent; high school

БЕ" and K?, independently selected from the group consisting of a hydrogen atom, C alkyl, aryl, heteroaryl, a halogen atom, МНО(-О)С. alkylenem(K?)", MO", OM, OSE" . -Ш(К2)», arylОС(-О)К2, S. lalkylens(-О)ОКа,

OS ldalkilens(:O)OKU,

Su. dalkilenos dalkylens(-FO)OKU, F(-0)-MKg5OKU, S. lalkylene(K 7)", Co valkenylene(K 7)", and, c-(-0)Mv S. dalkyleneOoK?, C(5O) MeS. dalkylenNei, OSao l-alkylensh(BK?)", OS. alkyleneCH(ОВК)СНоМ(Б2)",

OS lalkilennei, OS" dalkileno kg, OS" dalkilenmkK2S(-Ф0)OK, MKS, dalkilenim(t")", MK Ф(-О)KU, "-

ISS ho)", (OS. ldalkil)", MKU(5O»S. dalkil), BO2M(KU)", O5O»SE 5,

C) zalkilenarilu, S. lalkilennNei, S. valkilenoOk U, Si zalkileni(K U)", vok)", ise)

МНе-о)С, alkylene-aryl, C3.vcycloalkyl, C3.vheterocycloalkyl, aryl-OS. alkylene(K 2)", arylos(-O g, -

MNOSTsto)s . alkylene-C3 heterocycloalkyl, МНО(со)сС. zalkilennei, OS. dalkilenos and dalkilens(-O)OK,

S(O)S. dalkylene and MNO(-O)halogen. valkyla; or B" and B? together form a 3- or 4-ene alkylene or alkenylene chain component of a 5-" or b-membered ring, which optionally contains at least one heteroatom; From 70 BZ is selected from the group consisting of substituted, as an option, a hydrogen atom, C 4 alkyl, C C cycloalkyl, C C heterocycloalkyl, C alkylenecycloalkyl, C alkylenyl, C alkylenaryl, C arylSialkyl, C(-O)Ke, aryl, heteroaryl, C(-O )OKe, Ф(О)М(е), С(-5)М(К2)», 5О»MT?, 5ОЖ(КУ)», (OKU, (OM), С(:О)МКУС. dalkilenoО КУ , C(:O)MKUS. dalkylene, C(O)C. dalkylenaryl, 45. K(0)C. alkyleneheteroaryl, C..dalkylenaryl, as a variant substituted by one or more halogen atoms, -and 5ООМ(К7)» . C. lalkyleneheteroaryl, C. lalkyleneNei, C. lalkylens(O)-C. lalkylenearyl, with C. dalkylenes(O)-C. dalkyleneheteroaryl, C. lalkylens(-O)Nei, C. lalkylens(-O)M(K 2)", it is far away,

S. dalkilenmK "S(-O)Ke, Su dalkileno-Su dalkilenok", about S. lalkilen(K 2)", Si.lalkilens(-O0)-OKzg and S. zalkilenos. dalkilens(-F)O Ka; syu K? selected from the group consisting of a hydrogen atom, C. .alkyl,

Czacycloalkyl, C3.vheterocycloalkyl, C..alkylene(ke)", aryl, arylC.alkyl, C..alkylenaryl, heteroaryl, heteroarylsC. alkyl and C. alkylene heteroaryl; 59 or two KU groups together form a 5- or b-membered ring containing, as an option, at least one

F! heteroatom; to where selected from the group consisting of a hydrogen atom, C 4 alkyl, aryl, heteroaryl, aryls". alkyl, heteroaryls 4.alkyl, C. alkylenearyl and C. alkyleneheteroaryl;

It is represented by a 5- or b-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur atoms, and optionally substituted with C. alkyl or C (-O) OKU; and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof, wherein the compound exhibits at least about 10-fold selectivity for inhibition of RVC (|, c5 relative to other isoforms of RZK type-I! in a cell-based assay.

In particular, a second embodiment of the invention is a method of treating a medical condition mediated by neutrophils,

comprising administering to an animal in need thereof an effective amount of a compound that selectively inhibits the activity of phosphatidylinositol-3-kinase-delta (PSK) in neutrophils. Examples of medical conditions that can be treated according to the method include conditions defined by an undesirable neutrophil function selected from the group consisting of stimulated superoxide release, stimulated exocytosis, and chemotactic migration.

Preferably, according to the method, the phagocytic activity or destruction of bacteria by neutrophils is essentially uninhibited.

In particular, another embodiment of the invention is a method of disrupting the function of osteoclasts, which includes the interaction of osteoclasts with a compound that selectively inhibits the activity of phosphatidylinositol-3-kinase-delta (RISK) in 70 osteoclasts. According to the method, the compound may include a group that preferentially binds to bone.

In particular, another embodiment of the invention is a method of ameliorating a bone resorption disorder in an animal in need thereof, which includes administering to the animal an effective amount of a compound that inhibits the activity of phosphatidylinositol-3-kinase-delta (RISKU) in the animal's osteoclasts. A preferred bone resorption disorder to be treated by the method is osteoporosis.

In particular, another embodiment of the invention is a method of inhibiting the growth or proliferation of cancer cells of hematopoietic origin, which includes the interaction of cancer cells with a compound that selectively inhibits the activity of phosphatidylinositol 3-kinase-delta (RIZKu) in cancer cells.

The method may be useful in inhibiting the growth or proliferation of cancer cells selected from the group consisting of lymphoma, multiple myeloma, and leukemia.

In particular, another embodiment of the invention is a method of inhibiting the kinase activity of the polypeptide phosphatidylinositol-3-kinase-delta (RIZKi), which includes the interaction of the polypeptide RIZKu with a compound having the general structure (1).

Preferred compounds useful in the method include compounds selected from the group consisting of: c (1) o despite "SHE. in iy

And p and rank

But ve t y y av)

ЕК оо и ; that Y Ge) from r "pin r. neck and

SHE ay Shk z y Shen fe: TE eV I eat about. that

B. podi: Eh: in the direction of VYM (ke) шщ n 1 M шу Шче s ХИ No; h ZY 7 No

M nn i

From" them. she tsi and x | t t eh as (o) - syu" where U is selected from the group consisting of 5 and MN, or U is absent;

He is selected from the group consisting of H, a halogen atom, MO", OH, OSN", CH" and CE";

IS? selected from the group consisting of H, OSH" and a halogen atom;

GF) or B and 2? together with C-6 and C-7 of the quinazoline ring system represent a 5- or b-len aromatic 7 ring containing, as an option, one or more O, M, or 5 atoms;

VU is selected from the group consisting of C 16 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-FO)OC"OH" and morpholinyl;

VU is independently selected from the group consisting of MH 5, a halogen atom, C. alkyl, 5(C. alkyl), OH,

MH(C. alkyl), M(C.-alkyl)", MH(C. alkylenephenyl); and b5

70 rya: CIVIGE 4-1 or 2, provided that at least one of B" and EE? does not represent H, when 2? represents phenyl or 2-chlorophenyl.

Preferably, the compound is selected from the group consisting of: - (1)

N i 1 Y i t» she Ha

She diy She dra sho, 4 ni: IY o zo b. about MDE in | at. NYA Ya (va and o

Bk and U nt stylaya

I. I -.x

K. but I'm Ise)

Z and pi -

Ha ori - is st ;" where Y is selected from the group consisting of 5 and MH, or Y is absent; c' is selected from the group consisting of H, a halogen atom, OH, OSN", CH" and CE", - and BZ is selected from the group consisting of H, OSN" and a halogen atom; or K and K together with C-6 and C-7 of the quinazoline ring system represent a 5- or b-lene aromatic

Pho ring, optionally containing one or more O, M, or 5 atoms; - BO is selected from the group consisting of C 1 6 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, o 50 diphenyl, benzyl, pyridine, 4-methylpiperazinyl, C(-O)OHOH, and morpholinyl;

VU is independently selected from the group consisting of MH 5, a halogen atom, Sisalkyl, (Si alkyl), OH, c» MH(C. alkyl), M(C. alkyl)», MH(C. alkylenephenyl); and 4-1 or 2, provided that at least one of K'" and KZ does not represent a 6b-halogen or 6,7-dimethoxy group, and KZ does not represent 4-chlorophenyl.

GF) In particular, another embodiment of the invention is a method of disrupting the function of leukocytes, the method includes the interaction of white leukocytes with a compound having the general structure (1).

In particular, another embodiment of the invention is a class of compounds that have been identified as inhibiting the activity of RIZK in biochemical and cell-based studies and that are expected to have therapeutic utility in medical conditions in which RIZK activity is excessive. or unwanted Therefore, the invention provides a class of compounds having the structure (I).

Preferably, the compounds have a general structure (IM) b5

.- (M St.) ; that To - / a and m o. th th :

Shch y act t, Ne shch shch- ta chu

There is also | in. . more! h

А и Чо и с и, о where У is selected from the group consisting of 5 and МН, or У is absent; o d'o is selected from the group consisting of H, halogen atom, OH, OSN", CH" and CE"; (av)

БЕ" is selected from the group consisting of Н, ОСН" and a halogen atom, "- or Б"О and ЕК"! together with C-6 and C-7 of the quinazoline ring system represent a 5- or b--membered aromatic ring, containing, optionally, one or more O, M, or 5 atoms; ise)

B" is selected from the group consisting of C 1 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, -diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-O)OC"oH and morpholinyl;

VU is independently selected from the group consisting of MH 5, a halogen atom, C.isalkyl, 5(Sisalkyl), OH,

MH(C. alkylene), M(C. alkylene)z, MN(C. alkylenephenyl); and "4-1 or 2, provided that: t c (a) at least one of KU and K"! does not represent a 6-halogen or 6,7-dimethoxy group; "" (B) 2" does not represent a 4- chlorophenyl; and " (c) at least one of KO and B"Z does not represent H, when B 7 represents phenyl or 2-chlorophenyl, and X represents 5. - 15 These and other features and advantages of the presented invention will be clear from the detailed description below and the examples presented below. The detailed description and examples provide a better understanding of the invention, (o) but are not intended to limit the scope of the invention.- Fig. 1 shows the effect of a selective inhibitor of RIZK according to the invention on the activity of three RIZK isoforms.

Fig. 2 shows the effect of a selective inhibitor of RIZKa on the production of superoxide by human neutrophils in the presence of TME or Id. c» Fig. 3 shows the effect of a selective inhibitor of RIZKa on the production of superoxide by human neutrophils in the presence of TME or MI R.

Fig. 4 shows the effect of a selective RIZK inhibitor on human neutrophil elastase exocytosis in the presence of b5v MIR.

Fig. 5 shows the effect of the selective inhibitor RIZKiu on MI R-induced chemotaxis of human neutrophils.

F, Fig. b shows that the selective inhibitor of RIZKu does not affect phagocytosis and destruction of 5. ashgeiv by neutrophils. Figure 7 shows the effect of a selective inhibitor of RIZKa on the proliferation and production of antibodies by human B-lymphocytes. 60 Fig. 8 shows the effect of a selective inhibitor of RIZKa on the proliferation stimulated by anti-I9M B-lymphocytes of the mouse spleen:

Fig. 9 shows the effect of a selective inhibitor of RIZK on exocytosis of elastase in an animal model.

The invention provides compounds that selectively inhibit the activity of RIZKua. In addition, the invention provides methods of inhibiting the activity of RIZK, including methods of selective modulation of the activity of the RIZK isoenzyme in cells, especially leukocytes, osteoclasts and cancer cells. Methods include the use of ip miigo,

ip mimo and eh mimo.

Methods of selectively modulating RIZK activity in the clinic to alleviate diseases or disorders mediated by RIZK activity are particularly useful. Therefore, the treatment of diseases or disorders determined by excessive or unacceptable activity of RIZK can be carried out using selective RIZK modulators in accordance with the invention.

Other methods according to the invention include further characterization of the physiological role of the isozyme. Moreover, the invention provides pharmaceutical compositions including selective inhibitors

CUT Moreover, the invention provides industrial products comprising a selective RIZK inhibitor compound. 70 (or a pharmaceutical composition comprising the compound) and instructions for use of the compound. Details of these and other useful embodiments of the invention are described herein.

The methods described herein are useful due to the use of compounds that selectively inhibit, and preferably specifically inhibit, the activity of RIZK in cells, including ip myo, ip mimo, or ex mimo cells. Cells useful in the methods include those expressing an endogenous RIZKu, wherein enloggenicity indicates that the cells 75 express the RIZKu without recombinant introduction into the cells of one or more polynucleotides encoding a

RIZKy polypeptide or its biologically active fragment. The methods also include the use of cells expressing exogenous RIZKi, where one or more polynucleotides encoding RIZKi or its biologically active fragment are introduced into the cell using recombination methods.

A particular advantage is that the cells can be in vivo, that is, in a living subject, such as an animal or a human, where the RISK inhibitor can be used as a therapeutic agent to inhibit the activity

RISKS in the subject. Alternatively, cells can be isolated as single cells or in tissue, for ex vivo or in vivo methods. n my methods, also covered by the invention, may include the step of interaction of the RAZK enzyme or its biologically active fragment with the inhibitor compound according to the invention. high school

The RIZK enzyme may include a purified and isolated enzyme, where the enzyme is isolated from a natural source (eg, cells or tissues that normally express the RIZK polypeptide without modification by recombination methods) or isolated from cells modified by recombination methods to express an exogenous enzyme.

The term "selective RIZK inhibitor" as used herein refers to a compound that inhibits the RIZK isoenzyme (which is more effective than other RIZK isoenzymes of the RIZK family. A "selective RIZK inhibitor" compound is to be understood as more selective for RIZK than a compound of conventionally and commonly defined RIZK inhibitors , for example, about wortmannin or I U294002. Concomitantly, wortmannin and /M294002 are considered "non-selective RISK inhibitors"

Compounds of any type that selectively negatively regulate the expression or activity of RVC can be used as selective inhibitors of RVC in the methods of the invention. Moreover, compounds

Of any type that selectively negatively regulate the expression or activity of RIZK and reveal acceptable c. pharmacological properties, can be used as selective inhibitors of RVC in therapeutic methods according to the invention.

The relative effectiveness of compounds as inhibitors of enzyme activity (or other biological activity) can be established by determining the concentration at which each compound inhibits activity to a predetermined degree, and then by comparing the results. Typically, a better definition is the concentration that inhibits no) c 5090 activity in a biochemical assay, ie, 5095 inhibitor concentration or "ICeo". Determining the value of the ICoo can be carried out using conventional methods known in the state of the art. In general, the value of the ICoo can be determined by measuring the activity of this enzyme in the presence of a number of concentrations of the inhibitor during the study.

Experimentally obtained values of enzyme. activities are then plotted against the concentration of the inhibitor used. The concentration of the inhibitor that gives 5095 enzyme activity (compared to

The activity in the absence of any inhibitor) is taken as IR value 590 Similarly, other concentrations

Ge") of the inhibitor can be determined through an acceptable determination of activity. For example, in some cases it may be desirable to establish 9095. the concentration of the inhibitor, i.e., ICvo/etc.

Accordingly, a "selective RTZKu inhibitor" can alternatively be understood as a compound that exhibits 5090 au) 20 inhibitor concentration (ICeo value) with respect to RZKu that is at least 10-fold, preferably at least 20-fold, and more preferably at least 330-fold lower than the ICeo value for any or all other members of the class I RIZK family. The term "specific RIZK inhibitor" can be understood as referring to a selective RIZK inhibitor compound that exhibits an ICeo value with respect to RIZK, which is at least 50-fold, preferably at least 100-fold, more preferably at least 200-fold, and even more preferably at least 500-fold lower than the value of IC"o with respect to any or all other members of the RZK class family I. (F) Among other things, the invention provides methods of inhibiting the function of leukocytes. More specifically, the invention provides methods for inhibiting or suppressing the functions of neutrophils and T- and B-lymphocytes. With regard to neutrophils, it was unexpectedly found that inhibition of the activity of RISK inhibits the function of neutrophils. For example, it has been observed that the compounds according to the invention exhibit inhibition of classical functions of neutrophils such as stimulated superoxide release, stimulated exocytosis and chemotactic migration. However, it was further observed that the method according to the invention leads to the suppression of some functions of neutrophils, without essentially affecting other functions of these cells. For example, it has been observed that the phagocytosis of bacteria by neutrophils is essentially not inhibited by the selective RIZK inhibitor compounds according to the invention. 65 Therefore, the invention includes methods of inhibiting the functions of neutrophils, essentially without inhibiting the phagocytosis of bacteria. Neutrophil functions suitable for inhibition according to the method include any function that mediates the activity or expression of RiIZKa. Such functions include, without limitation, stimulated superoxide release, stimulated exocytosis or degranulation, chemotactic migration, adhesion to vascular endothelium (eg, neutrophil tethering/rolling, neutrophil activation, and/or neutrophil attachment to endothelium), transmural diapedesis or migration through endothelium to peripheral tissues. In general, these functions can be collectively referred to as "inflammatory functions" because they are usually related to the response of neutrophils to inflammation. The inflammatory functions of neutrophils can be distinguished from the bactericidal functions exhibited by these cells, such as phagocytosis and bacterial killing. Accordingly, the invention further includes methods of treating disease states in which one or more inflammatory functions of neutrophils are 7/0 abnormal or undesirable.

Further, the invention established that RIZKy plays a role in the stimulated proliferation of lymphocytes, including

B cells and T cells. Moreover, RIZK appears to play a role in stimulated antibody secretion

B cells. Selective RIZK inhibitor compounds according to the invention were used to establish that these phenomena can be reversed by RIZK inhibition. Therefore, the invention includes methods of inhibiting the proliferation of lymphocytes and 15 methods of inhibiting the production of antibodies by B-lymphocytes. Other methods permitted by the invention include methods of treating disease states in which one or more of these lymphocyte functions are abnormal or undesirable.

It has now been determined that the activity of RIZK can be inhibited selectively or specifically to facilitate the treatment of RIZK-mediated disease while reducing or eliminating the complications typically associated with concomitant inhibition of the activity of other class I RiIZ kinases. To illustrate this embodiment, the methods of the invention may be practiced using members of a class of compounds identified as exhibiting selective inhibition of RIZK over other RIZK isoforms.

The methods of this embodiment can be practiced using compounds having the general structure (PI).

The best methods use compounds that are empirically determined to exhibit at least 10-fold 25-fold selective inhibition of RAZK against other isoforms of RAZK. For example, methods can be practiced (3 using the following compounds: 5-chloro-3(2-fluorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-fluorophenyl) -5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-methoxyphenyl)-5-methyl-2-"9H-purin-y-ylsulfanylmethyl-ZH-quinazolin-4-one; Shk 30 3-(2,6-dichlorophenyl)-5-methyl-2-( "9H-purin-b-yl-sulfanylmethyl)-ZH-quinazolin-4-one; aw! 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 5-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; - 3-(2-chlorophenyl)-5-methyl-2-(9H- (Ce) 3-(3-methoxyphenyl-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one;

Zo 3-(2-chlorophenip)-5-fluoro-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; t

Z-benzyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one;

3-butyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-ZH- quinazolin-4-one; "

Z-morpholin-4-yl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; Z7Z 8-chloro-3-(2-chlorophenyl)-2-"9H-purin- 6-ylsulfanylmethyl)-ZN-quinazolin-4-one; c 3-(2-chlorophenyl)-6,7-difluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; ; z» 3-(2-methoxyphenyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; b-chloro-3-(2-chlorophenyl)-2-"9H-purin-6- ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(3-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(9H-purin-b6-ylsulfanylmethyl)-3-pyridin-4-yl-ZN-quinazolin-4-one; - 3-(2-chlorophenyl)-2--9H-purin-6-ylsulfanylmethyl)-trifluoromethyl-ZN-quinazolin-4-one; (Ge) 3-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; with 3-(4-methylpiperazin-1-yl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; 3-(2-chlorophenyl)-6-hydroxy-2-( 9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; (in 50 ethyl ester (5-fluoro-4-oxo-2-"9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3- yl|Ioacetic acid; 3-(2,4-dimethoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; c»3-diphenyl-2-yl-5-chloro-2 -"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZH-quinazolin-4-one ; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3-H-quinazolin-4-one; 99 2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2- yl-5-chloro-ZN-quinazolin-4-one;

HF) 5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; t 2-(6-aminopurin-9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 60 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-benzyl-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-butyl-ZN-quinazolin-4-one; bo 2-(6-aminopurin-9-ylmethyl)-3-morpholin-4-yl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one;

3-phenyl-2-(9H-purin-6-ylsulfonylmethyl)-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-isopropylphenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-ZN-quinazolin-4-one.

It is further determined that the methods according to the invention can preferably be practiced using members of the class of compounds exhibiting inhibitory activity of RIZKu, thus facilitating the inhibition of the activity of RVKu in diseases mediated by it. For example, in this embodiment, the methods according to the invention can be practiced, 7/0 using compounds having the general structure (I) пе () also че и хи: -3 с и щког ; ha re still No no

But - Kk. Ha

C. o o where A is optionally replaced by a monocyclic or dicyclic ring system containing at least two nitrogen atoms and at least one ring system is aromatic; co

X is selected from the group consisting of СНЕЕ, СНоСНЕ:? and SN-S (VU); at

M is selected from the group consisting of 5, ZO, 505, MH, 0, C(50), ОС(-0), С(-О)ОО and МНОС(-О)СНОЗ, or U is absent; "-

БЕ" and K?, independently selected from the group consisting of a hydrogen atom, C alkyl, aryl, heteroaryl, C halogen atom, МНО(-О)С. alkylenem(K?)", MO", OM, OSE" . -M(B 2)", arylos(-O)B2, Su lalkilens(:FOVa, -

OS dalkilens(-FO) OKU,

S. lalkilenosS. dalkilenes(-F)OKe, Fsh(-0)-MKke5OKU, Si dalkilene(K U)», Co valkenilenm(K 2)»

C(5O)MA S. dalkylenOvKU, /C(-0)-MK2S. 4-alkylenes, OS" dalalkylenemSh(K 2)", Si lalkylensH(OKU)SNoM(2), "

Os, ,y-alkylenNei OS» dealkylenoke, OS» alkylenmkeb(xO)Ote, Mass. /-alkylenimsh(Mke)», MKesF(ZO)MK, U c MKS OM), (OS. lalkyl)», 5202М(К2)20502)СЕ, "» C) zlkylenaryl, Si dalkylenNei, S. valkylenok "U, Si alkylene(Ck 2)», vok, "MNOT(-O)C, zalkylenaryl, C3.vcycloalkyl, C3 vheterocycloalkyl, aryl-OC. alkylene(k 2)", aryl(-O Be,

MNOSTsto)s . alkylene-C3 heterocycloalkyl, МНО(со)сС. zalkilennei, OS. dalkilenos and dalkilens(-O)OK,

B and B but -1 С(О)С. dalkylene and MNO(-O)halogen. valkyla; or KE! and B? together form a 3- or 4-ene alkylene or alkenylene chain component 5-

Me or b-membered ring, which optionally contains at least one heteroatom; - BZ is selected from the group consisting of optionally substituted hydrogen atom, C 4 alkyl, C 50 C cycloalkyl, C 3 heterocycloalkyl, C alkylenecycloalkyl, C alkylenyl, C alkylenearyl, arylSialkyl, C(5O)KU, aryl , heteroaryl, С(хО)OKU, сС(хО)М(КУ), С(-5)М(В)», 50282, 5ОЖ(ВЗ)»

Fe" (OKU, 5B-OMKU), S(:O) MKUS. dalkyleneO KU, С(:OMKUS. dalkylenei, С(-О)С, dalkylenarylu,

Ф(-О0)С, udalalkyleneheteroaryl, C.i.4alkylenaryl, as a variant, substituted by one or more halogen atoms, 5ООМ(К2), М(К?)», that), MKe5ООСЕЗ, СМ, МО», Ф(- O)Ke, OK, SidalkilenmSh(K?")" and

OS, /alkylene(K 2)", S. dalkyleneheteroaryl, S. lalkylenNei, S. lalkylens(O0)-S. alkS. dalkylenarylu, iF) S. dalkylens(0)-S. dalkylenheteroaryl, S. lalkylens(-O)Nei, S. lalkylens(-O)M(K 2)", Si dalkyleno ke, ime) S. dalkylenmMK 7C(-:O)KU, S. dalkylenOo-S. dalkilenok, Si lalkilenm(K 2)", Si dalkilens(-0)-OoKe and

S. dalkylenos) alkylenes(-F)Oae; because K? selected from the group consisting of a hydrogen atom, S. valkyl,

C-zacycloalkyl, C-heterocycloalkyl, C-alkyleneMm(K?)2, aryl, arylC-alkyl, C-alkylenearyl, heteroaryl, heteroaryls). alkyl and C. alkylene heteroaryl; or two KU groups together form a 5- or b-membered ring containing, as an option, at least one b5 Heteroatom;

IN? selected from the group consisting of a hydrogen atom, C 1 alkyl, aryl, heteroaryl, aryls. I ate

heteroaryls of 4-alkyl, C-alkylenearyl and C-alkyleneheteroaryl;

It is represented by a 5- or b-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur atoms, and optionally substituted with C. alkyl or C( -O) OKU; and their pharmaceutically acceptable salts and solvates (e.g. hydrates),

For example, the methods of the invention may employ compounds exhibiting inhibitory activity

RIZKu, which are listed below: 3-(2-isopropylphenyl)-5-methyl-2--9H-purin-6-yl-sulfanylmethyl)-ZH-quinazolin-4-one; 70 5-chloro-2-"9H-purin-b-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; 5-chloro-3-(2-fluorophenyl)-2-(9H-purin- b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-fluorophenyl)-5-methyl-2-(9H-purine-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-methoxyphenyl) -5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2,6-dichlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 5-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-methyl-2-(9H-purine -b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-5- fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one;

Z-benzyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one;

3-butyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-ZH- quinazolin-4-one;

Z-morpholin-4-yl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; 8-chloro-3-(2-chlorophenyl)-2-"9H-purin-6 -ylsulfanylmethyl)-ZN-quinazolin-4-one; Ge 3-(2-chlorophenyl)b, 7-difluoro-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; o 3-(3-methoxyphenyl)-2-(9H-purin- b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; b-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(3-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(9H-puryl-b6-ylsulfanylmethyl)-3-pyridin-4-yl-ZH- quinazolin-4-one; co 3-(2-chlorophenyl)-2--9H-purin-6-ylsulfanylmethyl)-trifluoromethyl-3H-quinazolin-4-one;

C-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; o 3-(4-methylpiperazin-1-yl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; - 3-(2-chlorophenyl)-6-hydroxy-2- (9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one; (5-fluoro-4-oxo-2-"9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl|acetic acid acids; what

3-diphenyl-2-yl-5-chloro-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; ich- 5-chloro-3-(2-methoxyphenyl)-2-(9H -purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZN-quinazolin-4-one; 2- (6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3-H-quinazolin-4-one; "2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2-yl- -chloro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-ZN-quinazolin-4-one; - c 2-(6- aminopurin-9-ylmethyl)-5-chloro-3-(2-fluoro-phenyl)-ZN-quinazolin-4-one; c 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2 -chlorophenyl-ZN-quinazolin-4-one; ,» 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6- aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro -ZN-quinazolin-4-one; - I 2-(6-aminopurin-9-ylmethyl)-3-benzyl-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl) -3-butyl-ZN-quinazolin-4-one;

F 2-(6-aminopurin-9-ylmethyl)-3-morpholin-4-yl-3H-quinazolin-4-one; - 2-(6-aminopurin-9-ylmethyl)-3-3-(2-chlorophenyl)-7-fluoro--ZN-quinazolin-4-one; 3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfonylmethyl)-ZH-quinazolin-4-one; o 3-phenyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4 - he; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 3-(4-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(2-chlorophenyl)-6,7-dimethoxy-2-("9H-purine- 6-ylsulfan)-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-7-nitro-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-6-bromo-3- (2-chlorophenyl)-ZN-quinazolin-4-one;

IF) 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-ZN-quinazolin-4-one; co b-bromo-3-(2-chlorophenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-2--9H-purin-6-ylsulfanylmethyl)-ZH-benzo|d)quinazolin-4-one; 60 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-ZN-quinazolin-4-one and 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-( 2-methoxy-phenyl)-ZN-quinazolin-4-one.

In addition, the invention provides compounds that are selective inhibitors of RIZKa activity. The compounds show inhibition of RIZK in a biochemical assay and selectively disrupt the functions of RIZK-expressing cells in a cell-based assay. As described herein, compounds of the invention have been shown to inhibit certain functions in neutrophils and other leukocytes, as well as osteoclast functions.

In general, the compounds according to the invention have the general structure (I), are their pharmaceutically acceptable salts,

or their prodrugs: nd () 70 g Y i-y X still ХХ шою

Z Me: M. C, y Y Ne where A represents a substituted, as an option, monocyclic or dicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic;

X is selected from the group consisting of SNEU, СНоСНЕ? and SNAS (EU);

M is selected from the group consisting of 5, 50, 502, МН, 0, (50), ОС(-0), С(-0)О and МНО(-О)СНо5, or У is absent; with

ВЕ" and К?, independently, selected from the group consisting of a hydrogen atom, С" alkyl, aryl, heteroaryl, a halogen atom, МНО(-О)Си alkylenemsch(t2)», MO», ОБ, ОСЕ5, Msch (2)», CM, ОосС(хО)Бе, с(хО)Бе, с(-:Форае, arylok, Nei, МВ2С(-О) Su alkylenes(-Ф)ОВ2, arylose alkylene-Ш(Б2)» , aryl(-O)B2, Si lalkylens(-FOOV,

OS dalkilens(-FO) OKU, p

Su. dalkylenosS dalkylens(-F)OKe, C(5O0)-MK25OKU, Si lalkylenm(K 2)", Co valkenylenm(K 7)",

С(50)-МВ2С, dalkilenovag, С(-0)-МВ2С. dalkilenNei, OS» dalkilenshch (В 2)», OS. 4 alkyleneCH(OV)CsNoM(B2)",

OS lalkilennei, OS» dalkilenmkK2S(-0)OK a, MKS. dalkileni (K 2)", mKkaFf-ozhKa; MAZS (OM(KU)), will settle down

M(ZO,S. alkyl)", MAKU(580"S. dalalkyl), OKU)", О5ОШСЕ", S. alkylenearyl, C1-4alkylene, so

S. valkilenoOk", S. zalkilenm(K 2)", vok)", MNO(o)sS. alkylenaryl, C3 -cycloalkyl,

From S. in heterocycloalkyl, aryl-OS. zalkilen(K 2)", arylos(O)vV?, MNesto)s. alkylene-C3 heterocycloalkyl, i.e

Mnes(so)s 4 zalkilenNei, OS. dalkylenos and dalkylens(-О)Ов2, С(О)С. dalkylene and MHC(-O)halogen. valkyla; or KE! and B? together they form a 3- or 4-ene alkylene or alkenylene chain component of a 5- or b-membered ring, which optionally contains at least one heteroatom;

BZ is selected from the group consisting of optionally substituted hydrogen atom, C 4 alkyl, C 4 cycloalkyl, C 3 heterocycloalkyl, C alkylenecycloalkyl, Co valkenyl, C alkylenaryl, "» arylSialkyl, C(-O) Ke, aryl, heteroaryl, С(-О)OKe, Ф(О)М(е), С(-5)М(К2)», 5О»МТ?, 5ОЖ(КУ)», " 5(-О КУ , (OK), FSH-O)MKUS. alkylene ke, F(-O)MKUS. more distant, F(-O)S. dalkylenaril,

Ф(-О)С, dalkyleneheteroaryl, C.4alkylenaryl, as a variant, substituted by one or more halogen atoms, -1 that 5О2М(К7)», М(Ке)», С(-О)OKe, MK?5ООСЕЗ, СМ , MO", (OKU, OKU, Si dalkilenshch(K?")" - and

OS, alkylene(K 2)", S. lalkylenheteroaryl, S. lalkylene, S. lalkylens(O)-S. lalkylenaryl,

F S. dalkilens(0)-S. dalkylenheteroaryl, S. lalkylens(-O)Nei, S. dalkylens(-OM(K U)", S. lalkylene KU, - S. dalkylenemv 2С(-О) 2, S..dalkylene-C u.dalkylenov 7, (ав) 50 Su. dalkylene(K 2)", Si. dalkylens(-0)-OKZg and S. lalkylenes and lalkylens(-O) OKaU; syu" K? is selected from the group consisting of a hydrogen atom, С. valkyla,

Czacycloalkyl, C3.vheterocycloalkyl, C..alkylene(ke)", aryl, arylC.alkyl, C..alkylenaryl, heteroaryl, heteroaryleo. alkyl and C. alkylene heteroaryl; or two KU groups together form a 5- or b-membered ring containing, as an option, at least one heteroatom;

IF) In? selected from the group consisting of a hydrogen atom, C 4 alkyl, aryl, heteroaryl, arylC. alkyl, heteroaryls 4.alkyl, C.alkylenearyl and C.alkyleneheteroaryl;

It is represented by a 5- or b-membered heterocyclic ring, saturated or partially or fully unsaturated, because it contains at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur atoms, and optionally substituted by C. alkyl or C (I-O) OKU; and their pharmaceutically acceptable salts and solvates (e.g. hydrates),

As used herein, the term "alkyl" includes straight or branched chain hydrocarbon groups containing a specified number of atoms. carbon, usually methyl, ethyl and propyl and butyl with a linear or branched 65 chain. The hydrocarbon group can contain up to 16 carbon atoms, preferably one to eight carbon atoms. The term "alkyl" includes "shunted alkyl," i.e., a C 1 -C 46 dicyclic or polycyclic hydrocarbon group, e.g.

norbornyl, adamantyl, dicyclo|2,2,2X)octyl, dicyclo|2,2,1)heptyl, dicyclo(3,2,|octyl, or decahydronaphthyl).

The term "cycloalkyl" is defined as a cyclic C3-Ca hydrocarbon group, for example, cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.

The term "alkenyl" is defined identically to "alkyl" except that it contains a carbon-carbon double bond. "Dcycloalkenyl" is defined similarly to cycloalkyl, except that the ring contains a carbon-carbon double bond.

The term "alkylene" refers to alkyl having a substituent. For example, the term "C. alkylenaryl" refers to alkyl containing one to three carbon atoms and substituted with aryl, 70 The term "halogen" or "halogen atom" is defined as fluorine, bromine, chlorine, and iodine.

The term "haloalkyl" is defined as alkyl substituted with one or more halogen substituents, fluorine, chlorine, bromine, iodine, or combinations thereof. Similarly, "Halocycloalkyl" is defined as cycloalkyl having one or more halogen substituents.

The term "aryl," alone or in combination, is defined herein as a monocyclic or polycyclic aromatic group, preferably a monocyclic or dicyclic aromatic group, for example, phenyl or naphthyl. Unless otherwise specified, "aryl" may be unsubstituted or substituted, for example, by one or more, and in particular one or three, halogen atoms, alkyl, phenyl, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio , alkylsulfinyl and alkylsulfonyl. Examples of aryls include phenyl, naphthyl, diphenyl, tetrahydronaphthyl, chlorophenyl, fluorophenyl, aminophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, carboxyphenyl, and the like. The terms "aryl-C 1-6 alkyl" and "heteroaryl-C 1-6 alkyl" are defined as aryl or heteroaryl having a C 1-6 alkyl substituent.

The term "heteroaryl" is defined herein as a monocyclic or dicyclic ring system containing one or two aromatic rings and containing at least one oxygen, nitrogen, or sulfur atom in the aromatic ring, which may be unsubstituted or substituted, e.g., by one or more , and in particular by one to three substituents of the type of halogen atom, alkyl, hydroxyl, hydroxyalkyl, hydroxy, alkoxyalkyl, haloalkyl, nitro group, amino group, alkylamino group, acylamino group, alkylthio group, alkylsulfinyl and alkylsulfonyl. Examples of heteroaryls include thienyl, furyl, opiridyl, oxazolyl, quinolyl, isoquinazolyl, indolyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. The term "Her" is defined as monocyclic, dicyclic and tricyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. The Her group may also contain an oxo group (:0) attached to the ring. "-

Non-limiting examples of Her groups include 1,3-dioxolane, 2-pyrazoline, pyrazolidine, pyrrolidine, piperazine, pyrroline, 2H-pyran, 4H-pyran, morpholine, thiopholine, piperidine, 1,4-dithiane, and 1,4-dioxane. re)

The term "hydroxyl" is defined as -OH. uh-

"Alkoxyl" is defined as -OH, where K is alkyl.

The term "Alkoxyalkyl" is defined as an alkyl in which the hydrogen atom is replaced by an alkoxy group,

The term "(alkylthio)alkyl" is defined similarly to alkoxyalkyl, except that a sulfur atom is present instead of an oxygen atom. "

The term "hydroxyalkyl" is defined as a hydroxy group attached to an alkyl, c The term "amino group" is defined as -MH" and the term "alkylamino group" is defined as -ME" where at least one K is alkyl and the second K is alkyl or hydrogen atom. ;" The term "acylamino group" is defined as KS(-O)M, where K is alkyl or aryl.

The term "alkylthio" is defined as -5K, where K is alkyl.

The term "alkylsulfinyl" is defined as K-505, where K is alkyl. -I The term "amino group" is defined as -MH", and the term "alkylamino group" is defined as -ME", where at least one K is alkyl and the second K is alkyl or a hydrogen atom.

Me, The term "acylamino group" is defined as KS(-O)M, where K is alkyl or aryl. - The term "alkylthio group" is defined as -5K, where K is alkyl.

The term "alkylsulfinyl" is defined as K-505, where K is alkyl. o The term "alkylsulfonyl" is defined as K-505, where K is alkyl. 4) The term "nitrogroup" is defined as -MO",

The term "trifluoromethyl" is defined as -SEz.

The term "trifluoromethoxyl" is defined as - OSE".

The term "cyano group" is defined as -CM.

In the best embodiments, X is selected from the group consisting of СН5», СНОСНо, СН-АСН, СН(СНУ), СНХСН(СН3) and

F) C(SNZ)". In the following preferred embodiments, Y is selected from the group consisting of C and MH, or Y is absent. ka Ring A can be monocyclic or dicyclic. Monocyclic A-ring systems are aromatic.

Dicyclic A-ring systems contain at least one aromatic ring, but both rings may be aromatic. Examples of A-ring systems include, but are not limited to, imidazolyl, pyrazolyl, 1,2,3-triazolyl, pyridizinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, purinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8 -naphthyridinyl, pteridinyl. 1H-indazolyl and benz-imidazolyl.

In the preferred group of compounds of formula (I), A represents, as an option, a substituted ring system selected from the group consisting of б5 иШ | - and and

Yes, that's it. and 5 s and so and nni as. her p 5 s with -I b t . o s SHI ay (9 inifnya: slu

ГФ) мчав ик) 6о 65 иШ | - and and

Yes, that's it. and 5 s and so and nni as. her p 5 s with -I b t . o s SHI ay (9 inifnya: slu

ГФ) мчав ик) 6о 65 иШ | - and and

Yes, that's it. and 5 s and so and nni as. her p 5 s with -I b t . o s SHI ay (9 inifnya: slu

ГФ) мчав ик) 6о 65 иШ | - and and

Yes, that's it. and 5 s and so and nni as. her p 5 s with -I b t . o s SHI ay (9 inifnya: slu

GF) ran ik) 6o 65

706 th and with still t: - В Е! pd iy dz i: i in hi 29 "prp vch Z o o o

Kk and S i t, cha

B - « du ih ee IN -

NYA tya Y y i -n . p and tears ;" -I (22) - o 50 What s» t y Bi:

ShK and 60 A-ring system, as an option, can be replaced by one to three substituents, and preferably by one to two substituents selected from the group consisting of M(K2)", and therefore halogen, C. alkyl, C(C .i.zalkilu), OKU, and b5 pe vo SCHE sa LYA: ak i" IY

In the second best group of compounds of the formulas (I), 2" and B, independently, represent a hydrogen atom, OBU, a halogen atom, C-alkyl, CEz, HO", MSH(K2)", MKS. alkylenem(K U)" and

OS) alkalizedOkKU. Certain substituents include, but are not limited to, Н,СОСН5,СИ, Вг, Е, СН3, СЕ5,МО",

HE, Moscow State University)",

MnSnasSna- o o and O(СНО»ОСН.СнНА. B! and B? can also form a ring together, for example, a phenyl ring.

In the best embodiment, KZ is selected from the group consisting, as an option, of substituted C 4 alkyl, aryl, heteroaryl, C 2 -cycloalkyl, C 2 -heterocycloalkyl, C(5O)OKU, C 1 -alkylene, C 1 -alkylene-cycloalkyl,

S. dalkilenarilu, Si dalkilens(-O)- so

S. lalkylenarilu, S. dalkylens(-O)OKe, Su dalkylen-C(O)M(K2)", Si dalkylenS(-O)Nei, Si lalkylenm(K?)" and are

S. dalkilenm"S(-O)K2., Certain groups of EZ include, but are not limited to - (Se) m. shi s with -I (22) - about 50 syu"

F) name) 60 b5 ee she o. TV login I o she Kai ey Ge)

Zo o - n-snU F h od, / her -

What With | - with . "» І 5 ssha -i yo - ih She m all over оге SHі і Z. se" і і і 2 і тях і 65 з ., а!

Group K" can be replaced by one to three substituents, for example, a halogen atom, OK, C. valkyl,

aryl, heteroaryl, MO", M(B2)", MK2502oSEZ, ME?С(-ОВЕ, С(-О0ОВ2, MVS. dalkylene(in 2), 802М(82)", SM,

C(chO)B2, S. lalkilen(K 2)" and OS. dalkilenm (B 2)". Certain substitutes for group E? including but not limited to

SI, E, Snu, SN(SNU)", OSN", SeN', MO", MNo, MNS(-O)SNz, SON and SHSNIISNoSNoM(SN 3)". --k : input and output.

No, you read Z

The purine ring structure and numbering of the ring structure are as follows: "and the wife is still I 5

Compounds according to the invention are presented below: so 3o 3-(2-isopropylphenyl)-5-methyl|-2-"9H-purine-b-ylylsulfanylmethyl)-ZH-quinazolin-4-one; (ab) 5-chloro-2 -"9H-purin-b-ylsulfanylmethyl)-3-o-tolyl-ZH-quinazolin-4-one; - 5-chloro-3-(2-fluorophenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-fluorophenyl)-5-methyl-2-"9H-purin-6-ylylsulfanylmethyl)-ZH-quinazolin-4-one; (Ce) 3-(2-methoxyphenyl)-5-methyl-2-" 9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2,6-dichlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; - 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 5-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-methyl-2-(9H-purine -b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; " du 3-(2-methoxyphenyl)-2-(9H-purine-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; with 3-(2- chlorophenyl)-5fluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one; 3-benzyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one; ; c» 3-butyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one;

3-morpholin-4-yl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; - 15 8-chloro-3-(2-chlorophenyl)-2-"9H-purin-6 -ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-6,7-difluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; (o) 3-(3-methoxyphenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; - b-chloro-3-(2-chlorophenyl)-2-"9H-purine -6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(3-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; (ab) 20 2-(9H-purin-b-ylsulfanylmethyl)-3-pyridin-4- yl-ZN-quinazolin-4-one; c» 3-(2-chlorophenyl)-8-trifluoromethyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one;

C-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(4-methylpiperazin-1-yl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; 3-(2-chlorophenyl)-6-hydroxy-2-(9H -purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; (B5-fluoro-4-oxo-2-"9H-purin-b6-ylsulfanylmethyl)-4H-quinazolin-3Z-yl|acetic acid ethyl ester;

HF) 3-(2-methoxyphenyl)-2-(9H-purin-b-ylsulfanylmetal)-ZN-quinazolin-4-one; 7 3-diphenyl-2-yl-5-chloro-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 5-chloro-3-(2-methoxyphenyl)-2-(9H- purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZN-quinazolin-4-one; 60 2- (6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3-H-quinazolin-4-one, 2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2-yl-5- chloro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9 -ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-ZN- 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-benzyl-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-butyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-morpholin-4-yl-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one; 21-(6-aminopurin-9-ylmethyl)-6b-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 3-(4-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 70 3-(2-chlorophenyl)-6,7-dimethoxy-2-(9H-purine- b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-nitro-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)b, 7-dimethoxy-ZN-quinazolin-4-one; b-bromo-3-(2-chlorophenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-ZN-quinazolin-4-one; and 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-3H-quinazolin-4-one.

The best compounds according to the invention have the structure (IM) and are presented below: 3-(2-isopropylphenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 5-chloro-2-"9H-purin-b-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; 5-chloro-3-(2-fluorophenyl)-2-(9H-purine-b6 -ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-fluorophenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2,6-dichlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 5-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-methyl-2-(9H- purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; i) 3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one;

Z-benzyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one;

3-butyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; c zo 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-6-ylsulfanylmethyl)- ZN-quinazolin-4-one;

3-morpholin-4-yl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; o 8-chloro-3-(2-chlorophenyl)-2-"9H-purin- 6-ylsulfanylmethyl)-ZN-quinazolin-4-one; "- 3-(2-chlorophenyl)-6,7-difluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; b-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; ise) 3-(3-xporphenyl)-2-(9H-purin-b6 -ylsulfanylmethyl)-ZN-quinazolin-4-one; 2-(9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one

C-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(4-methylpiperazin-1-yl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; " 3-(2-chlorophenyl)-6-hydroxy-2-( 9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; with c ethyl ester |(bfluoro-4-oxo-2-(9H-purin-b6-ylsulfanylmethyl)-4H-quinazolin-3-yl,| acetic acid; and?" 2-(6-aminopuryl-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZN-quinazolin-4-one 2-(6-aminopuryl-9-ylmethyl)-5-methyl-3-o -tolyl-ZN-quinazolin-4-one; 2-(6-aminopuryl-9-ylmethyl)-3-diphenyl-2-yl-5-chloro-ZN-quinazolin-4-one; -I 2-(6-aminopuryl-9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopuryl-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolin-4-one;

Me, 2-(6-aminopuryl-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one; - 2-(6-aminopuryl-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopuryl-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one; o 2-(6-aminopuryl-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one; 4) 2-(6-aminopuryl-9-ylmethyl)-3-benzyl-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopuryl-9-ylmethyl)-3-morpholin-4-yl-ZN-quinazolin-4-one; 2-(6-aminopuryl-9-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one; and 2-(6-aminopuryl-9-ylmethyl)-5-chloro-3 -o-tolyl-ZN-quinazolin-4-one.

The term "prodrug" refers to compounds that are rapidly converted into a compound having the above-defined

F) structural formula (I), for example, by hydrolysis. The creation of prodrugs is described in general by Nagata ei ai. (Edv.), ka boodtap apa OiYitape Tye RVIagtasoiodisai Vaziv oi TPegaretsiisv, 9 ey. 11-16 (1996). Further discussion is presented by Nidispi ei a!., Rgodgydz az Mome! Oeiimegu Zuvietv, MoI.14, ABSO Zutrozit Zegiez and bo Kospe (eds.), Viogemegvirie Sagiegtv ip Ogyd Oezidp, American Pharmaceutical Association and Regdatop

Rgezz (1987). In short, the use of drugs is accompanied by their elimination from the body or some biotransformation, in which the biological activity of drugs decreases or disappears. Alternatively, the biotransformation process may produce a metabolic by-product that is more active or equally active compared to the originally administered drug. Improved understanding of these biotransformation processes leads 65 to the creation of so-called "prodrugs", which after biotransformation become more physiologically active in their altered state. Prodrugs, therefore, include pharmacologically inactive compounds that are converted into biologically active metabolites. To illustrate, prodrugs can be converted into a pharmacologically active form by hydrolysis of, for example, an ester or amide bond, thus introducing or opening a functional group on the resulting product. Prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the compound's pharmacological properties, such as increased half-life. Alternatively, prodrugs can be designed to subject the functional group to covalent modifications, for example, with glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine, or become more potent than the parent compound. High molecular weight conjugates can also be secreted into the bile, be broken down by enzymes, and released back into the circulation, thus effectively increasing the biological half-life of the originally administered compound.

Methods of identifying negative regulators of RIZK activity,

The RIZKa protein, as well as its biologically active fragments, can be used to screen compounds for potential negative regulators by any of a variety of drug screening methods. 75 A negative regulator of RIZKa is a compound that reduces or destroys the ability of RIZKa to perform any of its biological functions. An example of such compounds is an agent that reduces the ability of the RIZKy polypeptide to phosphorylate phosphatidylinositol or target acceptable structures in the cell. Selective compounds that negatively regulate the activity of RIZK can be evaluated by comparing their activity against RIZK with their activity against other proteins. Selective negative regulators include, for example, antibodies and other proteins or peptides that specifically bind to RIZK polypeptides, oligonucleotides that specifically bind to RIZK polypeptides, and other non-peptide compounds (eg, isolated or synthetic organic molecules) that specifically interact with RIZK polypeptides. . Negative regulators also include compounds that are described above, but which interact with specific binding partners of the polypeptides of RIZK.

Currently, the best targets for the development of selective negative regulators of RIZK include, for example: c (1) cytoplasmic regions of RIZK polypeptides that contact other proteins and/or localize RIZKs in the cell; (2) regions of RIZK polypeptides that bind specific binding partners; (3) regions of the RZKu polypeptides that bind the substrate; (4) allosteric regulatory sites of RAZK polypeptides, which may or may not directly interact with the active site during a regulatory signal; - (5) regions of RIZKU polypeptides mediating multimerization. "-

For example, one goal for the development of modulators is to identify the regulatory interaction of rab with p110γ, which may be involved in the activation and/or subcellular localization of the p110γ group. Still other selective modulators include those that recognize specific regulatory or coding RIZK nucleotide sequences. /eats

Modulators of RIZK activity may be therapeutically useful in the treatment of a wide variety of diseases and physiological conditions in which aberrant RIZK activity is involved.

Accordingly, the invention provides methods for determining the potency of a test compound as an inhibitor of the RIZKy polypeptide, "the specified method includes the steps: (a) measuring the activity of the RIZKy polypeptide in the presence of a test compound; (B) Comparison of the activity of the RIZK polypeptide in the presence of the test compound with the activity of the RIZK polypeptide in the presence of an equivalent amount of a reference compound (e.g., a RIZK inhibitor compound according to the invention described herein), with the lower activity of the RIZK polypeptide , in the presence of the test compound than in the presence of the reference, indicates that the test compound is a more potent inhibitor than the reference compound, and a higher activity of the RIZKI polypeptide in the presence of the test compound than in the presence of the reference indicates that the test compound is less - And a more potent inhibitor than the reference compound.

In addition, the invention provides methods for determining the potency of a test compound as an inhibitor of the RAZK polypeptide, including the steps of: (a) determining the result of a control compound (for example, an RAZK inhibitor compound, according to the invention described herein) that inhibits the activity of the RAZK polypeptide ,y, as the control percent inhibition, thus determining the control amount of inhibitor for the control compound; (B) determining the amount of the test compound that inhibits the activity of the RIZK polypeptide as a control percentage of inhibition, thus determining the control amount of the inhibitor for the test compound; (c) comparing the control amount of inhibitor for the test compounds to the control amount of inhibitor for the control compound, where a lower control amount of inhibitor for the test compound than for the control compound indicates that the test compound is a more potent inhibitor than the control compound and a higher control amount the amount of inhibitor for the test compound than for the control compound indicates that the test compound is a less potent inhibitor than the control compound. According to one aspect, the method uses a control amount of inhibitor, which is an amount of a compound that inhibits the activity of a RizKy polypeptide named BO, bObo, 7095, or 80905. According to a second aspect, the method uses a control amount of inhibitor, which is an amount of a compound that inhibits the active polypeptide of RISKs at 9095, 9595, or 9995. These methods include determining 60 control amounts of the inhibitor compound in an ip mygo biochemical assay, in a cell-based ip mygo assay, or in an ip mimo assay.

The invention further provides methods for the identification of the negative regulatory activity of RBK, which includes the steps of: () measurement of the activity of the RAZK polypeptide in the presence and absence of a test compound and (ii) identification as a negative regulator of the test compound, which reduces the activity of RAZK, and competes with the compound according to with the invention 62 in relation to linking with RIZK nd. Moreover, the invention provides methods for the identification of compounds that inhibit RIZKa activity, comprising the steps of: (i) interaction of the RIZKi polypeptide with a compound according to the invention in the presence and absence of a test compound and (ii) identification of the test compound as a negative regulator of RIZKi activity , while the compound competes with the compound according to the invention in terms of binding to RIZK m.

The invention therefore provides a method of screening for possible negative regulators of the activity of RIZK in and/or for confirming the mode of action of such possible negative regulators. Such methods can be applied to other isoforms of RAZK in parallel with establishing the comparative activity of the test compound in relation to the isoform and/or in relation to the compound according to the invention.

According to these methods, the RZKu polypeptide can be a fragment of p110u that exhibits kinase activity, 70 that is, a fragment that includes the catalytic site of p110u. Alternatively, the RIZKy polypeptide may be a fragment of the p110y-binding domain of p85 and provide a way to identify allosteric modulators

CUT The methods can be used in cells expressing RIZKu or its subelements, enlogenically or exogenously. Accordingly, the polypeptide used in such methods can be free in solution, bound to a solid substrate, modified for detection on the surface of cells, or localized intracellularly. 75 Modulation of the activity or formation of binding complexes between the RAZK polypeptide and the tested agent can be further measured.

Human RISK polypeptides are those amenable to high-throughput screening in a biochemical or cell-based (CT) assay according to methods known and practiced in the art, including melanophore assay systems for studying receptor-ligand interactions, yeast-based assay systems, and mammalian cell expression systems. For an overview, |see. dauamiskgete and Covey, Sy Orip

Vioghesppoi, 8:629-34.(19,97)|.

Automated and miniaturized NT studies are also included as described, for example, in Neuviop and

Vapkv, Sigtg Orip Viobgesnpoi, 5:734-40 (1997)).

Such NT studies are used to screen libraries of compounds to identify specific compounds that exhibit the desired properties. Any library. of compounds may be used, including chemical (3) libraries, natural product libraries, and combinatorial libraries comprising random or discovered oligopeptides, oligonucleotides, or other organic compounds. Chemical libraries may contain known compounds, patented structural analogs of known compounds, or compounds identified in the screening of natural products. o 30 Natural product libraries are collections of materials isolated from natural sources, usually from microorganisms, animals, plants or marine organisms. Natural products are isolated from their source by fermentation of microorganisms, followed by isolation and extraction of the fermentation broth, or directly - - by extraction from microorganisms or tissues (plants or animals) themselves. Natural product libraries "o include polyketides, non-ribosomal peptides and their variants (including variants that do not occur in nature). For a 3o review | see. Sape eyi ai., Zsiepse, 282 :63-68 (1998)). in

Combinatorial libraries consist of a large number of related compounds, such as peptides, oligonucleotides, or other organic compounds as a mixture. Such compounds are relatively simple to create and obtain by traditional automated synthesis protocols, RSV, cloning, or proprietary synthetic methods. Peptide and oligonucleotide combinatorial libraries are of particular interest. Of 40 Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic s collections, recombinant, and polypeptide libraries. For a review of combinational chemistry and generated in this way

From" libraries, |see Muegs, Sy Orip Viogesnpoi, 8:701-07(1997)|.

As compounds have been identified as active as negative regulators of RZK functions, an optimization program can be applied in an attempt to increase potency and/or selectivity of activity. This structure-activity relationship (SAR) analysis typically involves an iterative series of selective modifications to the structure of compounds and their correlation with biochemical or biological activity. Families of related compounds can be designed as

Ge”) to all exhibit the desired activity, with some family members, namely those exhibiting suitable pharmacological profiles, potentially qualifying as therapeutic candidates.

Therapeutic uses of RIZK activity inhibitors, (ав) 20 The invention provides a method of selective or specific inhibition of RIZK activity therapeutically or prophylactically. The method includes the use of a selective or specific inhibitor of RIZKa activity in an amount effective for this purpose. This method can be used in the treatment of humans or animals that are or may be subjects with any condition whose symptoms or pathology are mediated by the expression or activity of RIZka. "Treatment" as used herein refers to preventing the onset of a disorder in an animal that may be (F.) prone to the disorder but not yet diagnosed with it; inhibiting the disorder, i.e. delaying its development; calming the disorder , i.e., causing its regression; or ameliorating the disorder, i.e., reducing the severity of symptoms associated with the disorder."Disorder" refers to definitions of medical disorders, diseases, conditions, syndromes, etc., without limitation.

The methods of the invention encompass various treatment regimens for an animal, preferably a mammal, preferably a primate, and even more preferably a human. Mammals that can be treated include, for example, domestic animals (pets), including dogs and cats; farm animals, including cattle, horses, sheep, pigs and goats; laboratory animals, including rats, mice, rabbits, guinea pigs, and non-65 human primates, and zoo animals. Non-mammals include, for example, birds, fish, reptiles and amphibians.

According to one aspect, the method according to the invention can be used for the therapeutic or prophylactic treatment of subjects who have, or may be subjects predisposed to, an inflammatory disorder. One aspect of the present invention derives from the involvement of RISK) in mediating aspects of the inflammatory process. Without being tied to any theory, it can be assumed that since inflammation includes processes that

Usually mediated by the activation and chemotactic transmigration of leukocytes (eg, neutrophils, lymphocytes, etc.) and because RISK can mediate such phenomena, RISK antagonists can be used to suppress disorders associated with inflammation. "Inflammatory disorder" as used herein may refer to any disease, disorder, or syndrome in which an excessive or dysregulated inflammatory response results in excessive inflammatory symptoms, damage to host tissue, or loss of tissue function. "Inflammatory disorder" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis. "Inflammation," as used herein, refers to a localized protective response induced by tissue injury or damage that aids in the decomposition, liquefaction, or sequestration of the injurious agent and the injured tissue. Inflammation is markedly associated with an influx of leukocytes and/or 75 chemotaxis of neutrophils. Inflammation can result from infection by pathogenic organisms and viruses and from noninfectious factors such as trauma or reperfusion after myocardial infarction or seizure, an immune response to a foreign antigen, and an autoimmune response. Accordingly, inflammatory disorders subject to the invention encompass disorders associated with responses of the specific defense system as well as responses of the non-specific defense system.

As used herein, the term "specific immune system" refers to a component of the immune system that responds to the presence of specific antigens. Examples of inflammation resulting from the response of the specific defense system include the classic response to foreign antigens, autoimmune diseases, and the delayed-type hypersensitivity reaction mediated by T cells. Chronic inflammatory diseases, rejection of solid transplanted tissue and organs, such as kidney and bone marrow transplants, and graft-versus-host disease (GVHD) are further examples of inflammatory responses of the specific immune system.

The term "nonspecific immune system" as used herein refers to inflammatory disorders that i) are mediated by leukocytes that are incapable of immunological memory (eg, granulocytes and macrophages). Examples of inflammation resulting, at least in part, from a nonspecific immune system response include inflammation associated with conditions such as adult (acute) respiratory distress syndrome (ADS) or multiple organ injury syndromes; reperfusion damage; acute glomerulonephritis; reactive arthritis; dermatosis with components of acute inflammation; acute purulent meningitis or other inflammatory disorders of the central nervous system, such as a seizure, thermal injuries; inflammatory disease of the intestines, syndromes associated with granulocyte transplantation; and cytokine-induced toxicity. "Autoimmune disease" as used herein refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own components. h- "Allergic disease" as used herein refers to any symptom, tissue damage or loss of tissue function due to allergy. "Arthritic disease" as used herein refers to any disease characterized by inflammatory joint lesions that may be of various etiologies. "Dermatitis" as used herein refers to any of a large family of skin diseases defined by inflammation of the skin, which may have a variety of etiologies. "Transplant rejection," as used herein, refers to any immune response directed against a transplanted tissue, such as an organ or cell (eg, bone marrow), characterized by loss of function of the transplanted and surrounding tissues, pain, swelling, leukocytosis and thrombocytopenia.

Therapeutic methods according to the present invention include methods of treating disorders associated with the activation of inflammatory cells. "Inflammatory cell activation" refers to a proliferative cellular response induced by a simulating -I exposure (including, but not limited to, cytokines, antigens, or autoantibodies), the production of soluble mediators (including, but not limited to, cytokines, oxygen radicals,

F enzymes, prostanoids, or vasoactive amines), or cell surface expression of new or increased mediators (including, but not limited to, major histosome antigens or cell adhesion molecules) in inflammatory cells (including, but not limited to, monocytes, macrophages, T- lymphocytes, B lymphocytes, o granulocytes (ie, polymorphonuclear leukocytes such as neutrophils, basophils, and eosinophils), mast cells, c» dendritic cells, Langerhans cells, and endothelial cells). Those skilled in the art will appreciate that activation of one or a combination of these phenotypes in these cells may contribute to the initiation, maintenance, or exacerbation of an inflammatory disorder.

Compounds according to the invention were found to be capable of inhibiting the release of superoxide by neutrophils.

Superoxide is released by neutrophils in response to any of a variety of stimuli, including signals of infection, as a mechanism for cell destruction. For example, superoxide release is known to be induced by tumor necrosis factor alpha (TMEA), which is released by macrophages, mast cells, and lymphocytes upon contact with bacterial cell wall components such as lipopolysaccharide (IP). TMEA is an extremely powerful and heterogeneous activator of inflammatory processes, being involved in the activation of neutrophils and various other types of cells, induction of leukocyte/endothelial cell adhesion, pyrexia, enhanced production of MHC class | and stimulation of angiogenesis. Alternatively, the release of superoxide can be stimulated by formyl-Mei-es-Rpe (MI R) or other peptides that block the M-terminus of formylated methionine. Such peptides are not normally found in eukaryotes, but they fundamentally characterize 65 bacteria, and signal the presence of bacteria to the immune system. Leukocytes expressing the MIR receptor, such as neutrophils and macrophages, stimulate migration up gradients of these peptides (ie, chemotaxis)

towards the localization of the infection. As demonstrated herein, the compounds of the invention inhibit the stimulated release of superoxide by neutrophils in response to TMEA or iMI R. Other functions of neutrophils, including stimulated exocytosis and directed chemotactic migration, are also shown to be inhibited by the RAZK inhibitors of the invention. Accordingly, the compounds of the invention may be expected to be useful in the treatment of disorders, such as inflammatory disorders, that are mediated by any or all of these neutrophil functions.

The presented invention makes possible methods of treatment of such diseases as arthritic diseases, such as rheumatoid arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis; Beckett's disease; 7/0 sepsis, septic shock, endotoxic shock, gram-negative sepsis, gram-positive sepsis and toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; ophthalmic disorders such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated ophthalmopathy; eosinophilic granuloma; lung or respiratory disorders such as asthma, chronic bronchitis, allergic rhinitis, AKS5, chronic inflammatory lung disease (eg, chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, and pulmonary hypoxia toxicity; reperfusion damage to the myocardium, brain, or limbs; fibrosis like cystic fibrosis; the formation of keloid tissues or the formation of scars; atherosclerosis; autoimmune diseases, such as systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, some forms of diabetes, Raynaud's syndrome; and transplant rejection disorders, such as SAD and allograft rejection;

Chronic glomerulonephritis; inflammatory bowel diseases such as chronic inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and necrotizing enterocolitis; inflammatory dermatoses, such as contact dermatitis, atopic dermatitis, psoriasis, or urticaria; fever and myalgia due to infection; inflammatory disorders of the central or peripheral nervous system, inflammatory disorders such as meningitis, encephalitis, and injury to the brain or spinal cord due to secondary trauma; Sørgensen's syndrome; diseases in which leukocytic diapedesis is involved; alcoholic hepatitis; bacterial pneumonia; disease mediated by an antigen-antibody complex; hypovolemic shock; type I diabetes; acute and delayed hypersensitivity; o painful conditions due to leukocytic dyscrasia and metastasis; thermal injuries; syndromes associated with granulocyte transfer; and cytokine-induced toxicity.

The method may be useful in the treatment of subjects who are or may be subjects of reperfusion injury, that is, injury obtained in a situation in which the tissue or organ undergoes a period of ischemia and then reperfusion. The term "ischemia" refers to localized tissue anemia due to obstruction of arterial blood flow. Temporary ischemia followed by reperfusion characteristically leads to neutrophil activation and transmigration through the endothelium of blood vessels in the damaged area. The accumulation of activated neutrophils, in turn, leads to the creation of reactive oxygen metabolites that damage the components of the involved EE,

35 tissue or organ. This phenomenon of "reperfusion injury" is commonly associated with conditions such as vascular attack (including global and focal ischemia), hemorrhagic shock, myocardial ischemia or infarction, organ transplantation, and cerebral vasospasm. To illustrate, reperfusion injury occurs during cardiac bypass or during cardiac arrest, when the heart, deprived of blood supply, experiences reperfusion. It is expected that inhibition of the activity of RISK will lead to a decrease in the degree of "reperfusion injury" in such situations. - c With regard to the nervous system, global ischemia occurs when the flow of blood into the brain is temporarily stopped. Global ischemia can occur from cardiac arrest. Focal ischemia occurs when part of the brain is deprived of normal blood supply. Focal ischemia can occur from thromboembolic occlusion of cerebral vessels, traumatic head injury, edema, or brain tumor. Even temporary global and focal ischemia can cause widespread neuronal damage. tissue damage occurs within hours or even days after the onset of ischemia, some permanent neural tissue damage may develop in the initial minutes after flow arrest

F blood to the brain. - Ischemia can also occur during myocardial infarction and other cardiovascular disorders in which the coronary arteries are blocked as a result of atherosclerosis, thrombosis, or spasm. Accordingly, the invention is contemplated to be useful in the treatment of cardiac tissue damage, particularly damage resulting from cardiac ischemia or reperfusion injury in mammals.

According to a second aspect, selective inhibitors of RIZK activity, such as compounds according to the invention, can be used in methods of treating bone diseases, especially diseases in which osteoclast function is abnormal or undesirable. As shown in example 6, below, compounds according to the invention inhibit the function of osteoclasts and myo. Accordingly, the use of such compounds and other selective RVC inhibitors may be valuable in the treatment of osteoporosis, Paget's disease, and related bone resorption disorders. According to the following aspect, the invention includes methods of using a compound of the RISK inhibitor to inhibit the growth or proliferation of cancer cells of hematopoietic origin, preferably cancer cells of lymphoid origin, and more preferably cancer cells related to B-lymphocytes or progenitors

B-lymphocytes or their derivatives. Types of cancer suitable for treatment using the method of the invention include, without limitation, lymphomas, for example, malignant neoplasms of lymphoid and reticuloendothelial tissues, such as Burkitt lymphoma, Hodgkins lymphoma, non-Hodgkins lymphomas, lymphocytic lymphomas, etc.; multiple myelomas, as well as leukemias, such as lymphocytic leukemias, chronic myeloid leukemias, etc. In a preferred embodiment, the compounds of the RIZKts inhibitor can be used to inhibit or control the growth or proliferation of chronic myeloid (myelogenous) leukemia cells.

According to a second aspect, the invention includes a method of inhibiting the function of basophils and/or mast cells and thus providing treatment options for diseases or disorders defined by excess or unwanted activity of basophils and/or mast cells. According to the method, compounds according to the invention can be used, which selectively inhibit the expression or activity of phosphatidylinositol-3-kinase-delta (RISK) in basophils and/or mast cells. Preferably, the method uses an inhibitor of RVKu in an amount sufficient to inhibit the stimulated release of histamine by basophils and/or mast cells. Accordingly, the use of such compounds and other selective RISK inhibitors may be valuable in the treatment of diseases characterized by histamine release, i.e., allergic disorders, including disorders such as chronic obstructive pulmonary disease (COPD), asthma, AKO5, emphysema, and related disorders.

Pharmaceutical compositions of RIZK activity inhibitors,

The compound according to the present invention can be used in its pure form, but usually the compound is used in the form of a pharmaceutical composition or formulation. Accordingly, the present invention also provides pharmaceutical compositions comprising a chemical or biological compound (an "agent") that is active as a modulator of the activity of RAZK. and a biocompatible pharmaceutical carrier, adjuvant, or medium. The composition may include the agent only as an active part or in combination with other agents, such as oligo- or polynucleotides, oligo- or polypeptides, drugs, or hormones in admixture with an excipient or other pharmaceutically acceptable carriers. Carriers and other ingredients may be considered pharmaceutically acceptable to the extent that they are compatible with the other ingredients of the composition and are harmless to the recipient thereof.

Methods of composition and use of pharmaceutical compositions can be found in Ketipdiop'z Rpagtaseciisa|!

Zsiepsez, 18(y Eida., Musk Rybijzpd So, Eaziop, RA, 1990. Pharmaceutical compositions according to the presented invention can be prepared using any conventional method, for example, mixing, dissolving, granulating, making a dragee, grinding into a powder, emulsifying . ip mimo and rate of elimination ip mimo of the applied agent Depending on the condition being treated, these pharmaceutical compositions can be formulated and applied systemically or topically.

Pharmaceutical compositions are formed with the content of suitable pharmaceutically acceptable carriers, they can, as an option, include excipients and auxiliary agents that facilitate the processing of active compounds into preparations that can be used pharmaceutically. The modality of application will generally be determined by the nature of the carrier. For example, compositions for parenteral use may include aqueous solutions of active compounds in a water-soluble form. Carriers suitable for parenteral use can be selected from saline, buffered saline, dextrose, water, and other physiologically compatible solutions. The best carriers for parenteral use are physiologically compatible buffers, such as Hank's solution, Ringer's solution, or buffered saline. For application to tissues or cells in the composition, penetrants suitable for penetration through a certain barrier are used. Such penetrants are generally known in the prior art. For preparations that include proteins, the composition may include stabilizing materials such as polyols (eg, sucrose) and/or surfactants (eg, nonionic surfactants), etc.

Alternatively, compositions for parenteral use may include dispersions or suspensions of active compounds obtained as acceptable oil suspensions for injections. Suitable lipophilic solvents or media include oils such as sesame oil and synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran, alternatively, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds in order to obtain highly concentrated solutions. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent can also be used as coatings or matrix structures, for example, methacrylic polymers such as the EOOCASUTO series) available from Copt Ategis Inc. (Rizsaiamzhau, M) - Emulsions such as oil-in-input and water-in-oil dispersions, optionally stabilized with an emulsifier o 50 or a dispersant (surface-active materials, surfactants), can also be used.

Suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and their mixtures.

Liposomes containing the active agent can also be used for parenteral administration. Liposomes are generally derived from phospholipids or other lipids. Compositions in the form of liposomes can also

Gee! contain other ingredients such as stabilizers, preservatives, excipients, etc. Preferred lipids include phospholipids and phosphatidylcholines (lecithins), natural and synthetic. Methods of obtaining liposomes are known in the prior art. |See, for example, Rgezsoi (Eid.), Meijodvs ip Sei! Vioiodu, Moi.KHIM, r. 33, Asadetis Rgezv,

Meme Hogk (1976). 60 Pharmaceutical compositions comprising the agent in doses suitable for oral use can be formulated using pharmaceutically acceptable carriers well known in the art. Preparations formulated for oral use can be in the form of tablets, pills, capsules, wafers, dragees, cakes, liquids, gels, syrups; pulps, elixirs, suspensions, or powders. By way of illustration, pharmaceutical preparations for oral use may be prepared by combining the active compounds with a solid excipient, alternatively, grinding the resulting mixture and transforming the mixture into granules, and then adding suitable excipients, if necessary, to obtain a tablet or dragee core. Oral compositions may employ liquid carriers of a type similar to that described for parenteral use, for example, buffered aqueous solutions, suspensions, and the like.

Preferred oral compositions include tablets, dragees and gelatin capsules. These preparations may contain one of the excipients, including, without limitation: a) diluents, such as sugars, including lactose, dextrose, sucrose, mannitol, or - sorbitol; p) binders, such as magnesium aluminosilicate, corn, wheat, rice, potato, etc. starch; 70 c) cellulosic materials, such as methylcellulose, hydroxypropylmethylcellulose. and sodium carboxymethyl cellulose, polyvinylpyrrolidone, gums such as gum arabic and tragacanth, and proteins such as gelatin and collagen; a) disintegrants or solubilizing agents, such as cross-linked polyvinylpyrrolidone, starches, agar, alginic acid or its salts, such as sodium alginate, or gas-emitting compositions; e) lubricants, such as silicon oxide, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol; 7) flavors and sweeteners; d) dyes or pigments, for example, to identify the product or to determine the amount (dose) of the active compound; and

P) other ingredients such as preservatives, stabilizers, swelling agents, emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and buffers.

Gelatin capsules include tight-fitting capsules made from gelatin, as well as soft-shell capsules made from gelatin and a coating such as glycerin or sorbitol. Close-fitting capsules may contain the active ingredient in admixture with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers (i).

The dragee cores may be coated with a suitable coating, such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, glaze solutions, and suitable organic solvents or solvent mixtures.

Pharmaceutical compositions may include a salt of an active agent. Salts contribute to greater solubility in water or other protic solvents than in the corresponding free acids or bases. Pharmaceutically acceptable salts are well known in the art. Compounds containing acidic groups can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include, ise)

For example, cations of alkali metals (for example, sodium or potassium) and alkaline earth metals (for example, calcium or magnesium).

Compounds of structural formula (I) containing basic groups can form pharmaceutically acceptable acid addition salts with suitable acids. (For example, Vegde et al. describe in detail pharmaceutically acceptable salts of y). Rpalt Zsi, 66:1 (1977))Y. The salts can be obtained by the above during the final isolation and purification of the compounds according to the invention or separately by the reaction of the free functional basic group with a suitable acid.

Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, disulfate, bugarate, camphorate, camphorol-sulfonate, digluconate, glycerophosphate, hemi-sulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-dihydroxyethane-sulfonate (isothionate), lactate, maleate, methane -sulfonate or sulfate, nicotinate, -I 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate or hydrogen phosphate, glutamate, bicarbonate, p-toluenesulfonate and

Me. undecanoate Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. In light of the above, any reference herein to compounds of the present invention includes compounds of structural formulas (1)-(M), as well as pharmaceutically acceptable salts and solvates thereof, as well as prodrugs thereof.

The base-reactive salts can be obtained separately during the final isolation and purification of the compounds according to the invention, or separately by reaction of the carboxyl group with a suitable base, such as hydroxide, carbonate, or (F, hydrogen carbonate) of a pharmaceutically acceptable metal cation, or with ammonia or an organic primary, secondary, or tertiary amines.Pharmaceutically acceptable basic active salts include, but are not limited to, salts based on alkali metal or alkaline earth metal cations, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, and non-toxic salts of quaternary ammonium cations and amines, including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, diethylammonium, triethylammonium, etc. Other representative organic amines suitable for forming basic addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine , piperazine, etc.

Basic nitrogen-containing groups can be quaternized by such means as lower 65 alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, -bromides, and -iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain alkyl halides, such as decyl-; lauryl-,

myristyl and stearyl chlorides, -bromides and -iodides; aryl alkyl halides such as benzyl and phenethyl bromides; and other. Products with modified solubility or dispersibility are obtained in this way.

Compositions comprising a compound of the invention formulated in a pharmaceutically acceptable carrier

Can be received, placed in an acceptable container and . labeled to treat specific conditions. Accordingly, they are also considered a product of manufacture, such as a container containing a dosage form of a compound according to the invention and a label containing instructions for the use of the compound. Kits according to the invention are also considered. For example, a kit may include a dosage form of a pharmaceutical composition and a packaged insert containing instructions for use of the composition in the treatment of a 7/0 medical condition. In any event, conditions identified on the label may include treatment of inflammatory disorders, cancer, and the like.

Ways of using inhibitors of the activity of RIZK,

Pharmaceutical compositions comprising an inhibitor of RIZKa activity can be administered to a subject by any conventional route, including parenteral and enteral routes. intra-arterial, intraperitoneal, intramedullary, intramuscular, intra-articular, intrathecal and intraventricular injections. Enteral administration includes, for example, oral (including buccal and sublingual) and rectal administration. Transepithelial administration includes, for example, transmucosal administration and transdermal administration.

Mucosal administration includes, for example, enteral administration as well as nasal, inhalation and deep pulmonary administration; vaginal use; and rectal application.

Transdermal application includes passive or active transdermal or transdermal use, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or rubs. Parenteral administration can also be accompanied by the use of methods with Ge! using high pressure, for example, ROMMOEKUESTO. at

Surgical methods include implantation of a depot (reservoir) of compositions, osmotic pumps, etc.

A preferred route of administration for the treatment of inflammation may be local or topical delivery for localized disorders such as arthritis or systemic delivery for diffuse disorders such as intravenous delivery for reperfusion injury or for systemic conditions such as septicemia. For Ge) other diseases, including those in which the respiratory tract is involved, for example, chronic obstructive pulmonary disease, asthma, and emphysema, application can be achieved by inhalation or deep pulmonary application of sprays, aerosols, powders, etc. --

For the treatment of malignant diseases, especially leukemia and other diffuse types of cancer, parenteral administration is usually preferred. Compositions of compounds for their optimization for biodistribution after parenteral i-o use of RVC inhibitor compounds can be used before, during or after the use of chemotherapy, i-radiotherapy and/or surgery.

Moreover, the therapeutic index of a RISK inhibitor compound may be enhanced by modification or derivatization of the compound for targeted delivery to cancer cells expressing a marker that identifies the cells as such. For example, the compounds can be linked to an antibody that recognizes a marker that is selective or specific for cancer cells, so as to bring the compounds to the area adjacent to the cells for their local action, as previously described (see, e.g., Rie). egel ei ai., Ptypo! Kemu. 129:57 (1992); ThaiYi ei ai., Zsiepse, 261:212 h (1993); and Komiipgon-Vyzgga ei ai., Si Orip Opsoi, 4:1142 (1992)) . Tumor-directed delivery of these compounds enhances therapeutic utility, among other things, by minimizing potential non-specific toxicity that may result from radiation treatment or chemotherapy. According to the second aspect, the compounds of the RIZK inhibitor and radioisotopes or chemotherapeutic agents can be conjugated to the same anti-tumor antibodies. b For the treatment of bone resorptive disorders or osteoclast-mediated disorders, inhibitors of RISK can be delivered in any suitable manner. Focal application, such as intra-articular injections, may be desirable. In some cases, it may be desirable to combine the compound with a group that can target the compound to bone. For example, a RIZKa inhibitor can be conjugated to a compound with a high affinity for hydroxyapatite, which is the main component of bone. This can be achieved, for example, by adapting a method of combination with tetracycline designed for targeted delivery of estrogen to bone (Ogte ega!., VisogaMed Speth I ey, 4 (11):1375-80 (1994)).

In order to be therapeutically effective in modulating central nervous system targets, the agents used in the methods of the invention must readily cross the blood-brain barrier at peripheral

HF) use. Compounds that cannot cross the blood-brain barrier, however, can still be effectively administered intravenously. o As shown above, the characteristics of the agent itself and the composition of the agent can affect the physical state, stability, release rate, and clearance rate of the agent used. Such 60 pharmacokinetic and pharmacodynamic information can be gathered through preclinical studies of ip myo and ip mimo, further confirmed in humans during the course of clinical studies. Therefore, for any compound used in the method according to the invention, a therapeutically effective dose can be estimated first from the data of a biochemical study and/or a study based on cells. Further, the dosage can be formulated in animal models to obtain the desired circulating concentration limits that modulate the expression or activity of RIZKi. Following human studies, the following information regarding acceptable dosage levels and duration of treatment for various diseases and conditions will be determined.

The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical methods in cell cultures or experimental animals, for example, to determine the LD 50 (dose lethal to 5090 population) and EDeo (dose therapeutically effective in 5095 population). The dose ratio between the toxic and therapeutic effect is the "therapeutic index", which is usually expressed as the ratio

LD/ED. Compounds exhibiting large therapeutic indices, that is, the toxic dose is substantially higher than the effective dose, are preferred. Data obtained from such cell culture studies and additional animal studies can be used in the formulation of dosage limits for human use. The dosage of such compounds is mainly within the limits of circulating concentrations, which include the value of ED 50 with little or no toxicity.

With regard to the methods according to the invention, any effective regimens of administration that regulate the times of administration and the sequence of doses can be used. Dosage forms preferably include pharmaceutical dosage units comprising an effective amount of the agent. As used herein, an "effective amount" refers to an amount sufficient to modulate the expression or activity of a RISK in and/or result in a measurable change in a subject's physiological parameters following administration of one or more pharmaceutical dosage elements.

Exemplary dosage levels for humans are on the order of about 0.001 milligrams of active agent per kilogram of body weight (mg/kg) to about 100 µg/kg. Of course, dosage elements of the active agent include from about 0.01 mg to about 1000 Ω, preferably from about 0.1 mg to about 100 Ω, depending on the indication, route of administration, etc. Depending on the route of administration, the appropriate dose can be calculated according to body weight, body surface area, or organ size. The final dosage regimen will be determined by the leading physician from the point of view of accepted medical practice, taking into account various factors that modify the effect of drugs, for example, the specific activity of the agent, the features and severity of the disease, the reactivity of the patient, age, condition, weight, etc.

The body, gender and diet of the patient and the severity of any infection. Additional factors to consider include timing and frequency of administration, drug combinations, reactivity, and tolerance/response to therapy. The following elaboration of a dosage acceptable for a treatment involving any of the compositions mentioned herein will normally be made by a skilled artisan without undue experimentation, particularly in light of the dosage information and disclosed studies, as well as human pharmacokinetic clinical studies. Acceptable dosages can be summarized through the use of recognized studies to determine the concentration of the agent in body fluids or other samples together with dose response data. -

The frequency of receiving a dose will depend on the pharmacokinetic parameters of the drug and the route of administration. "-

Dosage and application are adjusted to ensure sufficient levels of the active ingredient or to maintain the desired effect. Accordingly, the pharmaceutical compositions may be administered as a single dose, multiple doses, discrete doses, continuous infusion, sustained release with a depot, or combinations thereof as required to maintain the desired minimum level of the agent. Short-acting pharmaceutical compositions (ie, with a short half-life) may be administered once daily or more frequently than once daily (eg, two, three, or four times daily). Long-lasting pharmaceutical compositions can be used every 3-4 days, every week, or once every two weeks. Pumps such as subcutaneous, intraperitoneal, or subdural pumps may be better for continuous infusion. 8 c The following examples provide an understanding of the invention and a background to the understanding of conventional methods well known to those skilled in the art, including examples relating to, for example, the construction of vectors and plasmids, "inserting genes encoding polypeptides into such vectors and plasmids" , or introduction of vectors and plasmids into host cells. Such methods are described in detail in a number of publications, including (for example, Zatbgook ei ai., Moiesshag Siopipd: A Garogayugu Mapitsai, Soi4 Zrgipu Nagrog Iarogagu Rgezz (1989), A!yvyrei! ei ai . (Edv.) pog Rgoosoiv ip Moiiesciag Vioiodu, 4 ey. add. UMpPeu 5 Bopv, Ips. (1999)), specific materials and conditions described below,

The drawings are intended to illustrate specific aspects of the invention without limiting its scope and content. - EXAMPLE 1

Preparation and purification of recombinant RIZKA, B and |, o Recombinant heterodimeric complexes of RIZKA, consisting of the catalytic subelement p110 and se» of the regulatory subelement rab were overexpressed using the baculovirus expression system

VAS-TO-VASF NT (BIVSO)/-VKI) and further purified for use in biochemical research. Four

RI-3-kinases of class I were cloned into baculovirus vectors as follows: rITou: RGASF-tagged variant of human r!10u (ZEO ZO MO: 1) | see SVapigu ei aY., U Vioi Speth, 272:19236-41 (1997)| was subcloned, using standard DNA recombination methods, into the Vatni-Hwai o site of the rEaziras NT insect cell expression vector (He TespoYodiez, Saipegzrigo, MO), so that the clone was in the (name) frame together with the Niz-tag of the vector. The RIH AS system is described in US patents MoMo4703004; 4782137; 4851341; and 5011912), and the reagents are available from Easetap Kodak Co. 60 p110A: Similar to the method used for p110 in described above, an RGASF-labeled variant of p110A, see Molecular Biology, Sepotevs, 24 (3):427-477 (1994))| subcloned in saiga Vatni-Nipa!n rEaviras NT (he

Tesppoiodieevz) so that the clone is in the frame together with the Niz-label of the vector. p1108B: Clone p11088 | see Ny.ei aiYi.,, Mo! Sow! Vioi, 13:7,677-88. (1993) amplified from the available human spleen cDNA library MAKATNOMF (Siopiesp, Rayu Ayo SA) according to the manufacturer's instructions, 65 using the following primers:

In the Primer

AbTTTSATAATOSSTSS-3 (5BO Y MO:3) 3 Primer 5-SATOOOSOSOSTTAASATSTOTASTSTTTSOSSAAASTOTOTO-3 (560 10 MOI) 5 primer was inserted into the GAS tag in frame together with the p110B sequence. After amplification, the sequence

EGASF-p110B was subcloned, using standard recombination methods, into the sites of EsokKI-MoM rEavzyras NTa (be Tespoiodiez), so that the clone was in frame with the Niz-tag of the vector. p11og: kKDNK p110G (see 5ioupam ei ai, Zsiepse, 269:690-93 (1995)) was amplified from the existing library

cDNA of human spleen (Siopiesi) according to the manufacturer's instructions, using the following primers:

U Primer 5'- AVAATOSSOSSOSSSATOSAOSSSTOSASALASTATAAASASSSS -3 (5201 MO:5) « w 3 Primer

U-SOSOOATSSTTTASOSTOAATOTTTTSTSTOSTTOTTTO-3 (5Е6О Ю МО: 6)

The GGASF tag was then attached to the 5'-end of the ri1OG sequence and cloned into the WatnNi-Zre! rEazibas NT (Iye Tesppoiodiev), using standard methods of DNA recombination, with the sequence of CM

RIG AsF-110U in a frame together with a Niz vector label. o reBA: a fragment of VatnNi-EsokK! RIG of ASFO-labeled DNA rVBA |see ZKoipik ei ai, SeiYi, 55:83-89 (1991) |) was subcloned into VatNi-EsokiI sites. vector rEazibas acai (I be Tesppoiodiyev).

Recombinant baculoviruses containing the above clones were generated using the manufacturer's protocol (He Thesppoiodieev). Baculoviruses expressing Niv-tagged catalytic subelement р10А, p1108, or Ар110;y and subelement p85 were co-infected into insect 521 cells. To improve the heterodimeric enzyme complex, an excess amount of baculovirus expressing the ра subelement was infected, and

Niz-labeled catalytic subelement p110 in complex with pv5 was purified on an affinity column with nickel. Since (7 p110H is associated with re85, 5121 cells were infected with recombinant baculoviruses expressing only "co

Bottom-marked p110G. In an alternative approach, ri10 can be cloned into a baculovirus for capability

From co-expression with its best binding partner p110G. in.

After 72 hours, post-infected 5121 cells (3 liters) were harvested and homogenized in hypotonic buffer (20 mM HEPES-KOH with pH7.8, 5 mM KSI, complete cocktail of protease inhibitors (Kospe Viospetisai!5, Ipaiaparoiiv, IM), using a Voshpse homogenizer. Homogenates centrifuged at 10009 for 15 minutes. The supernatants were further centrifuged at 100009 for 20 minutes, then ultra-centrifuged at 1000009 for 60 minutes. The soluble fraction was immediately loaded onto a nickel affinity column with a volume of 1Oml o) with NITKARF (Ragtasia, Rizsaiazhau, Moscow State University), equilibrated with 5 Oml of buffer A (50 mM HEPES-KOH pH 7.8, 0.5 M Mass, 10 mM "» imidazole). The column was washed extensively with buffer A and eluted with a linear gradient of 10-500 mM imidazole. " The free subelement ra5 was removed from the column during the washing step, and only the heterodimeric enzyme complex was eluted at 250 mM imidazole. Aliquots of nickel fractions were analyzed by gel electrophoresis on 1090 8OB5-polyacrylamide (ZO5-RACE) with ZURKOE Kea development (Moiiesshtsiag Rgobez, Ips., Eidepe, OK) and quantified using a ZTOKMO phosphovisualizer (Moiesshag Jubupatisv, Zippumaie, SA). Active fractions b were combined and directly loaded onto a heparin column with a volume of BbBml Ni-igar, pre-equilibrated with buffer B containing HOMM HEPES-KOH with pH 7.5, 50 mM Mass, 2 mM dithiothreitol (at). The column was washed with 50 ml of buffer B and eluted with a linear gradient of 0.05-2M Massey. A single peak containing a complex of 20 RIZK enzyme was eluted at 0.8M Mass. Analysis on a ZO5-polyacrylamide gel showed that the purified fractions of the RIZK enzyme contain a 1:1 stoichiometric complex of subelements p110 and p85.

Fe» The protein profile of the enzyme complex during heparin chromatography corresponded to the profile of kinase activity. Active fractions were combined and frozen under liquid nitrogen.

EXAMPLE 2 29 High-throughput screening (HT5) RIZK) and selectivity studies

GF) High-throughput screening of our own chemical library was performed to identify the activity of candidates for RIZK inhibitors. RIZKiu catalyzes the phosphotransfer from GAERIDtF to RIRORZ liposomes in the position ru RIR" of the lipid inositol ring. This reaction is Mossy-dependent and is quenched in high molarity potassium phosphate buffer with pHeO,O containing ZOM EDTA. When screening, this reaction is carried out in the presence or absence of library 60 compounds. The reaction products (and all unlabeled products) are transferred to a 96-well, pre-moistened PMOE filter plate, filtered and washed in high molarity potassium phosphate. A scintillating substance is added to the dried cell and the absorbed radioactivity is quantified.

Most of the research operations were performed using VIOMEKF 1000 robotic devices (WesKtap) and all tablets were read using the protocols of the liquid scintillation tablet counter 62 Uuaias.

Triple stock solutions of substrates and enzymes for research were made and stored in a cuvette (for robotic research) or a 9b-cell, M-bottom, polypropylene tablet (for non-mechanized research). The reagents were stable for at least 3 hours at room temperature.

The triple substrate for NTZ contained 0.6 mM Ma gATP, 0.10 mCi/ml G-H2RIATP (MEM, Riizrigoy, RA), bmM liposomes RR.O/RB (Amapii Royag Iiriaz, Ips., AMapia, SA), in 200 mM HEPES with pH 7.4.

The triplicate enzyme stock solution for NTZ contained 1.88 M RIZK in, 15 Ωkg/ml horse dO (used only as a stabilizer), 15 mM Massi», 3 mM OTT in 20 mM HEPES with pH 7 4. 70 Chemical high-throughput screening (HT) of library samples (each of containing a pool of 22 compounds) in dimethylsulfoxide (DMSO) was diluted to 18.75mM or 37.8mM in double-distilled water and 2µl of the dilutions were placed in the cells of a 96-cell polypropylene tablet for the study. The negative inhibitory control (or positive enzyme control) was DMSO diluted with water, and positive inhibitory controls used concentrations of I 294002 sufficient to provide 5095 and 75 10095 inhibition.

20 μl of ZXsubstrate was added to 20 μl of dilutions of the combined chemical library. The reaction was initiated by 20 μl

ZXenzyme, incubated at room temperature for 10 minutes. This dilution gave a final concentration of 200 μM ATP in the reaction volume. The reaction was stopped with 5 µM of quenching buffer (1.0 M potassium phosphate with pH 8V, O, ZOMM EDTA). A part of the quenching solution (1-8 Омкл) was then transferred to a pre-moistened RMOBE filter plate (Miyroge YAMAIIR MOV with subsequent washings of 200 мкл of 10095 methanol, water and, towards the end, 1.0 M washing buffer with potassium phosphate at pHa.0).

The PMOR filter tablet was sucked under a moderate vacuum (2-5 mm Hg), washed with 5200 μl of washing buffer and then dried by suction. The filter was then blotted, air-dried completely and inserted into

MUUayas a counting cassette with 5µl of Esozsipi scintillation cocktail added to the cell. The absorbed He radioactivity was quantified and the data analyzed, after normalization to the enzyme positive control (approximately 10095), to identify the point of the curve at 5095 inhibition values to estimate ICeo values for the inhibitors.

All 57 combined best cells were selected for deconvolution based on the combined criterion of a final activity of less than 4295 at the tested concentration and a total acceptable success rate of no more than 0.295. At 22 compounds per cell, all 1254 compounds were identified through this deconvolution and tested individually at 1 concentration of 27.7 µM to identify which compounds exhibited the desired activity. From this study, 73 compounds were selected and further investigated to generate IR curvature values of 5o. 34 compounds were selected for selectivity studies against RIZKA and RIZKV based on the obtained values of IKeo curvature (see the study protocol in example 11).

In selectivity studies, one compound y-3-(2-chlorophenyl)-2--9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one (compound Y-000) was selected as a relatively potent and selective compound. A catalog of studies and analyzes of the selectivity of many similar compounds with successful potency and/or selectivity yielded only one compound that had activity and selectivity similar to O-000. This compound was obtained from Sopigasi Zegmisez Sogrogayop (Catalog 57232154), and it differed from 0-000 in having a phenyl substituent instead of 2-chlorophenyl in 0-000. - "from n: -2.y is sho i Kv "ti t sodte I. STILL F : -i zhi 5 2 vd chn i: o, i.

Ge") . : yah x : |. y y 0 Sne.- I zhk

ЗЕ 7 ЕИ И, kn yu B-060 B: z ze:

As described above, the RiI-3-kinase I inhibitor U294002 (CaIriospet, Ha doMa, CA) does not have significant selectivity among the different Ri-3-kinase isoforms tested. In the conditions of our study, IU294002 inhibited all three isoforms of RiI-3-kinase with ICeo values of 0.3 µM. However, when compound 0-000 was tested against the same Ri-Z kinase isoforms, excellent selectivity was observed. Specifically, as shown in Fig. 1, O-000 inhibited the activity of the isoform tsu RIZK with an IC value of approximately 0.33 μM, while under similar conditions it did not inhibit the activity of A and B isoforms at the limit of 100 μM of the compound. These. the results show that Yu-000 selectively inhibits the activity of RIZKa.

EXAMPLES 3-7

Since RIZK is expressed at significant levels only in leukocytes, it is important to study the effect of a RIZK-selective inhibitor on leukocyte function. Accordingly, the effect of RIZKiu inhibition on several types of leukocytes was studied. Neutrophils were studied to determine the effect that selective inhibition of RIZK could cause (Example C, below). Unexpectedly, it was found that selective inhibition of RISK activity was significantly associated with inhibition of some, but not all, of the functional characteristics of activated 70 neutrophils. In addition, the effect of RIZKiu inhibition on B-cell and T-cell functions was also tested (Examples 4-5, below). Moreover, since RIZKu is also expressed in osteoclasts, the effect of inhibition of RIZKu on the function of these specialized cells was investigated (Example 6, below).

EXAMPLE Z

Determination of the role of RIZK in the function of neutrophils

The effect of the RIZK inhibitor according to the invention, i.e. O-000, on the functions of neutrophils, such as superoxide production, elastase exocytosis, chemotaxis and bacterial destruction, was tested.

A Obtaining neutrophils from human blood

Aliquots (8 ml) of heparinized blood from healthy volunteers were layered on Zml pads of 7.395 RISOY (Zidta, 5. I otsiv, Moscow) and 15.495 NURAOCEF (Zidta) and centrifuged at 900 rpm. for 30 minutes at room temperature in a table centrifuge (VesKtap). The neutrophil-enriched strip of the above RISOY G9-NURAOSHEF pad was collected and washed with Hank's balanced salt solution (HB5Z5) containing 0.196 gelatin. Final erythrocytes were removed by hypotonic lysis with 0.295 Mass. The resulting neutrophils were washed twice with HB525 containing 0.195 gelatin and used immediately.

B. Measurement of superoxide production by neutrophils p

Production of superoxide is one of the signs of neutrophil activation. A number of activators make it possible to produce superoxide by neutrophils. The effect of RTZKy inhibitor 0-000 on the production of superoxide by three different agonists: TMETA, dos and MI R, each of which represents separate classes of activators, was measured. The superoxide produced by neutrophils was measured by monitoring the change in absorbance during the reduction of cytochrome C using a modification of the method described by Ogeep eyi ai. ., Shk

Soiidap ei a!.) (1994)3), thus. Individual cells of a 96-cell plate were covered overnight at 49 av! 5 μl of a solution of 2 mg/ml human fibrinogen or db. Cells were washed with PB5 and the following reagents were added to each cell: 100 ml of NVZZ or superoxide dismutase (mg/ml), 100 ml of HVO or TMETA (5 ng/ml), 5 0 ml of cytochrome C (2.7 mg/ml) and 100 ml of purified neutrophil suspension human (21O0Ucells/ml). The tablet (F) was centrifuged for 2 minutes at 200 rpm and the absorbance was monitored at 55 Ohm for 2 hours.

To measure the relative amount of superoxide produced, values obtained from cells containing superoxide dismutase were subtracted from all others and normalized to values obtained from cells without any inhibitor.

As shown in Fig. 2, the RIZKy inhibitor ОО-000 inhibits TME-induced production of superoxide by neutrophils in a concentration-dependent manner. TME-induced superoxide production was reduced to half of its 2 maximal value at approximately 3 μM O-000. Fig.2 also shows that the production of superoxide induced by ido was slightly inhibited by O-000. In fact, even at 10 μM, this RIZK inhibitor has no effect on ;" superoxide production induced by.

Next, the effect of 0-000 on the production of superoxide, induced by a second powerful inducer, a bacterial peptide, formyl-Meni-ei-Rpe (MIR), was investigated. Similarly to TME-induced production of superoxide, and MIR-induced production of suleroxide was also inhibited by 0-000 (Fig. 3). These results show that the RIZK inhibitor 0-000 can reverse the stimulated specific induction of superoxide b production by neutrophils, indicating that RIZK is involved in this process. - C Measurement of neutrophil elastase exocytosis

In addition to superoxide production, activated neutrophils are also responsible for the release of several proteases that are relevant for tissue and cartilage damage during inflammation. As an indicator of the release of this protease, the effect of O-000 on elastase exocytosis was measured. Exocytosis of elastase was quantitatively determined by a modification of the method described by Ovzzapp. 9 Siip Ipmevi, 77:1939-1951 (1986)), thus. Purified human neutrophils (0.109) (treated with DMSO or serial dilutions of O-000 in DMSO) stimulated MI R in РВ5 containing O.O01 mg/ml cytochalasin B, 1.0 μM sodium azide (MamM), 5 μg/ml I-methionine and imkM MIR. for 90 minutes at 372C in a 96-well plate. At the end of the incubation period, the tablet was centrifuged for 5 minutes at 1000 rpm. and UOmcl of the supernatant layer of the liquid was transferred to 1Omcl of 10 mM solution of substrate co-peptide of elastase, MeO-v8ys-AIa-AIa-Pho-Mai-rIMA, where MeO-vys is methoxy-succinyl; pMA - p-nitroanilide (SaIriosnet, Zap Oiedo, SA). Absorbance at 41 Ohm was monitored for 2 hours in a 96-well 60 plate reader. To measure the relative amount of exocytosis of elastase, all absorbance values were normalized to the value obtained without any inhibitor. As shown in Fig. 4, the RIZK inhibitor, O-000, significantly inhibits MI R-induced elastase exocytosis and does so in a dose-dependent manner. Inhibition was half-maximal at a concentration of approximately 2-3 µM 0-000.

A. Measurement of MI-induced migration of human neutrophils because Neutrophils have an inherent ability to migrate through tissues and are one of the first cell types to arrive at sites of tissue inflammation or injury. The effect of 0-000 on the migration of neutrophils in the direction of the YAMI R concentration gradient was measured. One day before the migration study, b-cell plates were covered with recombinant condensed protein ISAM-1/Es (Map adeg Miegepei ei ai., Ittipyu, 3: 683-690 (1995)) (25μg/ml in a bicarbonate buffer with pHeO.3) and left overnight at 42 C. After washing with 195 agarose solution in KRMI-1640, 0.590 bovine serum albumin (BSA), without or with inhibitor, was added to the cells, and the plates were placed in a refrigerator before punching holes in the agarose gel to create plaques (1 a central hole surrounded by 6 peripheral holes per cell).

Human neutrophils were obtained as described above and resuspended in KRMI medium supplemented with 0.595 VZA at 510 cells/ml. After mixing equal volumes of neutrophil suspension and medium (DMSO or 70 serial dilutions of the test compound in DMSO), neutrophils were aliquoted into peripheral holes, and IMI P (5 μm) was added to the central hole. Tablets were incubated at 372C in the presence of 596 CO" for 4 hours, and then migration was stopped by adding 195 g of glutaraldehyde solution in O-RV5. After removing the agarose layer, the cells were washed with distilled water and dried.

The analysis of neutrophil migration was performed on an automated video installation with an inverted microscope (75 lens) Mikop OIARNOTF" using the program MIN 1.61, using the programs MKrozoy Ehse! and

Tarie Sigma 4 (55RB5 Ips., Spisado RI), the migration index was obtained for each of the studied conditions. The migration index was defined as the area under the curve representing the number of migrating neutrophils in relation to the net migration distance per cell.

As shown in Fig.5, the RIZKI 0-000 inhibitor has a strong effect on neutrophil migration, inhibiting this activity in a dose-dependent manner. The EC value of this compound in relation to the inhibition of neutrophil migration in these studies is approximately 17 µM. Based on visual inspection of the recorded cell paths in these studies, it was found that the total path length for neutrophils was not significantly affected by the test compound. Preferably, the compound affected neutrophil orientation or homing orientation, so that instead of migrating along the axis of the chemoattractant gradient, the cells migrated unidirectionally or less directionally. everything

E. Measurement of bactericidal ability of neutrophils o

The RIZKy-O-000 inhibitor has been found to affect some of the functions of neutrophils detailed above, and it will be interesting to see if the compound affects neutrophil-mediated killing of bacteria. The effect of 0-000 on the neutrophil-mediated destruction of Ziarpuiosossisis aigeis was studied according to the method that (described

Siak and Maizeei yr.7,23,4-7,23,6 in Moi.2, Ziyrr.b, Sip Rgoiosoiiv Iptypo! (Edv., Soiidap eyi a!) (19943). FO

Purified human neutrophils (5105 cells/ml) (treated with DMSO or 0-000 serial dilutions in DMSO) were mixed with autologous serum. Cells of 5. acgeiv grown overnight were washed, resuspended in HVO and added to neutrophils opsonized with serum at a ratio of 10:11. (7

Neutrophils were allowed to absorb bacteria by phagocytosis. incubation at 372 for 20 minutes. Unassimilated He) bacteria were destroyed with 10 units/ml of lysostaphin at 372С for 5 minutes and the joint mixture was rotated at 300. Samples were removed at various times up to 90 minutes and neutrophils were lysed by dilution in water. -

Viable bacteria were counted by plating an acceptable dilution on a trypticase-soy agar plate and counting 5. ashgeiz colonies after overnight growth.

As shown in Fig. b, neutrophil-mediated destruction of 5. acgeiz was similar in samples treated with DMSO (control) and O-000. These results indicate that the RIZK inhibitor has little effect on the ability of neutrophils to destroy 5. ashgeshv, confirming that RIZK is not involved in this function of neutrophils.

EXAMPLE 4: from» Determination of the role of RIZK in B-function of lymphocytes

The effect of the Ri-Z-kinase inhibitor on the functions of B cells, including classical indicators such as . production of antibodies and proliferation induced by a certain stimulating factor were also studied. -I A. Obtaining and stimulation of B-cells from human peripheral blood

Heparinized blood (200 ml) from healthy volunteers was mixed with an equal volume of ХО-РВ5 applied to

Me, 10100 ml of RISOYI!G-RAOSHEF (RNagtasia), and centrifuged at 1600 rpm. for 30 minutes at room temperature. Peripheral blood mononuclear cells (PBMC) were collected from the surface of the RISOIIHF/serum interface, 5g applied to 10 ml of fetal calf serum (EV5) and centrifuged at 800 rpm. for 10 minutes to remove platelets. After washing, the cells were incubated with OMMAI E Apiirodu Mich (B-cell kit) (Supai 4) Sogr., ake Byssevzv, MU) for 20 minutes at 4-82. After removal of unbound antibodies, RVI was mixed with coated anti-mouse IdS magnetic beads (Oupai) for 20 minutes at 4-892C with gentle shaking, followed by removal of labeled non-B cells on a magnetic bead separator. This operation was repeated one more time. B cells were resuspended in KRM1-1640 with 1095 EB5 and kept on ice until further use. o B. Measurement of antibody production by human B-cells (name) To study the production of antibodies, B-cells were divided into aliquots at 50-7510 cells/cell. in a 96-cell plate without or with an inhibitor, to which 1-2 (10 units/ml) and RAMZOQUIMO 60 "(SaiIriospet) Ziarpuiosossiz azgeiz cells (1:90000) were added. Part of the medium was removed after 24-36 hours and fresh medium (without or with the inhibitor) and I/-2 were added. Cultures were incubated at 372C in an incubator in the presence of CO" for an additional 7 days. Samples from each condition (in triplicate) were removed and analyzed for dO and IDM as measured by EG IZ A. In short, 96-cell plates of IMMIO! OM 4 were coated (5 Ωcl/cell) with 15 µg/ml donkey anti-human Ids (NA) (dChaskwop rptypoKezeagsi, MUezi Sgome RA), or 65 2μg/ml donkey antihuman IdSjIoM (Na) (daskwap rptypoKezeagsi) in bicarbonate buffer and left overnight at 42C . After 3 washes with a phosphate-buffered saline solution containing

0.195 TUUEEMO-80 (RV5T) (35µL/cell) and blocked with 395 goat serum in RBBT (10µL/cell) for 1 hour at room temperature, samples (100µL/cell) of B-cell-depleted medium diluted with RBZT were added. For tablets with dO, the dilution limits were 1:500-1:10000), and for tablets with DM - 1:50-1:1000. After 1 hour, the plates were exposed to biotin-conjugated anti-human Ids (10 ng/ml) or anti-human DM (200 ng/ml) (daskwap rptypoKezeagsi) for 30 minutes, then to streptavidin-NCR (1:20000) for 30 minutes, and at the end effects of a solution of TMB (1:100) with hydroperoxide (1:10000) for 5 minutes, with Х РВЗТ washings between stages. Color development was stopped with H 2504 solution and tablets were read on an EPIZA tablet reader. As shown in Fig. 7, O-000 significantly inhibited 7/0 antibody production. The effect on the production of IM was greater than on the production of Ids: half-maximal inhibition of the production of DM was observed at approximately 1μM versus approximately 7μM in comparison with the inhibition of the production of k.

S. Measurement of B-cell proliferation in response to stimulation of the surface of Y9M cells

In the above experiment, B cells were stimulated using FRAMES. The effect of 0-000 on the 7/5 proliferative response of B cells when stimulated with IM through their cell surface was also measured using an anti-(M) antibody. Mouse splenocytes (BaiIB/s) were plated in 96b-cell microtitre plates at 210 cells per cell in 1095 EB5B/VERMI. Acceptable dilutions of the test inhibitor in complete medium were added to the cells and the plates were incubated for 30-60 minutes before the addition of the stimulating factor. After pre-incubation with the test inhibitor preparation of goat antibody K(ar')", specific for

M-chain, (DM mouse) was added to the cells at a final concentration of 25 μg/ml. The plates were incubated at 372 for 3 days and ImKi | ZNI-thymidine was added to each cell until the final four hours of cultivation.

Plates were collected on glass fiber filters, washed, and absorbed radiolabels were determined using a beta counter (Maigih 96, RasKaga Ipzigitepi So., Yuom/pege Sgome, I) and expressed as pulses per minute (PPM). Ge

Fig.8 shows the effect of 0-000 on stimulated anti-I9M proliferation of B cells. The compound inhibited anti-IZ9M-stimulated B-cell proliferation in a dose-dependent manner. Approximately at iMm, proliferation decreased to half of its maximum value.

Since compound O-000 inhibits the proliferation of B cells, it is envisaged that this compound and other inhibitors of RISK could be used to inhibit the unwanted proliferation of B cells in the clinical setting. at

For example, in B-cell malignancy, B-cells at different stages of differentiation show unregulated proliferation. Based on the results shown above, it can be concluded that selective inhibitors of RIZKa. could be used to control, limit, or inhibit the growth of such cells. --

EXAMPLE 5 "co

Determination of the role of RIZK in T-function of lymphocytes

Proliferation of T cells in response to costimulation of SOZ-SU28 was measured. T-cells were purified from the blood of a healthy person by negative selection using antibody-coated magnetic beads according to the manufacturer's instructions and resuspended in KRMI. Cells were treated with DMSO or with a serial dilution of 0-000 in DMSO and placed at 10 cells/cell on a 96-well plate previously coated with goat anti-mouse db. Mouse monoclonal anti-COZ and anti-CO28 antibodies were then added to C7Z 70 of each cell at 0.2 ng/ml and 0.2 µg/ml, respectively. The plate was incubated at 372 for 24 hours and IZNI-thymidine (1 μCi/cell) was added. After another 18 hours of incubation, the cells were collected with an automatic cell harvester, washed, and the absorbed radioactivity was quantified.

Although the RIZKa inhibitor 0-000 inhibited anti-COZ- and anti-CO28-induced T cell proliferation, its effect did not exceed its effect on B cells or some neutrophil functions. Half-maximal inhibition of thymidine uptake was not achieved at the highest tested concentration, i.e., 10μM 0-000.

EXAMPLE 6) Determining the role of RIZK in the function of osteoclasts - To analyze the effect of the RIZK inhibitor and 0-000 on osteoclast cells in the bone marrow of mice, they were isolated and differentiated into osteoclasts by treating the cells with the macrophage colony-stimulating factor (MCF) and osteoprotegerin ligand (ORI) in serum -containing medium (AMEM) with 1095 inactivated ЕВ5 heating; Zidt) within 3 days. On the fourth day, when the osteoclasts became developed, the medium was removed and the cells were collected. Osteoclasts were placed on dentin plates at 10 cells/cell in a medium for cultivation, i.e., AME containing 195 serum and 295. VBA with 55 μg/ml ORS. and 1 omkg/ml toC5E-1.

Three hours later, the medium was replaced with 195 serum and 195 B5A, without osteopontin or with it (25 μg/ml) and RISK inhibitors (100 nM). The medium was replaced every 24 hours with fresh osteopontin and inhibitors. At 72 o'clock, the medium was removed and the dentin surfaces were washed with water to remove cell debris and co-stained with acid hematoxylin. Excess dye was washed away and well depth was quantified using confocal microscopy. As shown in Table 1, in two experiments, inhibitors of RiI-3-kinase 60 had an inhibitory effect on the function of osteoclasts. Non-specific inhibitors of I M294002 and wortmannin inhibited the activity of osteoclasts. However, the RIZKuy 0O-000 inhibitor had the strongest effect, as this compound almost completely inhibited the activity of osteoclasts in T0ONM. вв 100.5 1 4, вн0.22 5.706

EXAMPLE 7

Determination of the role of RVC) in the function of basophils

Evaluation of the effect of a compound according to the invention on basophil function was tested using a conventional histamine release assay, generally according to the method (described by Miga et al., in Ittipoi, 162:4198-206 (1999)), Briefly, enriched basophils were pre-incubated with a test -compounds at several concentrations from 0.1 to 0000NM, for 10 minutes at 37 C. Next, polyclonal goat 7/0 anti-human I9CHE (0.1 μg/ml) or MIR was added and allowed to incubate for an additional 30 minutes. The release of histamine into the supernatant liquid layer was measured using the method of automated fluorometry.

The two compounds shown below were tested. s (8) so "c) "- (Se) m. - s. and? -And (22) - about 50 syu"

F) has) 60 b5 that . She still has children in Yaki. shcha Sho and those NI g n f v. h

Mk and ІІ still S. t SHEU

M y s o o "- (Se)

ШИ and - 7. гай и и ! : . ; IS "

ШЭ She: iy roshe Be - "" ; : T.

B ka v. And also I: and KO ET that I I il y - d -I Ve y y p:

You are at 50 - and | her and her" | и и | more

X - A

And ik vo rimu Es oi SHHA

A dose-dependent decrease in histamine release was observed for 3-(2-chlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one (a-026) when basophils were stimulated with anti- GOING This inhibition of histamine release was essentially 10095 at 1000 nM, with an Ec value of approximately 25 nM. The second compound,

3-(2-chlorophenyl)-2-(1H-pyrazolo!|3,4-4|Ipyrimidin-4-ylsulfanylmethyl)-ZH-quinazolin-4-one (0-999), in which the purine ring structure is rearranged, was less effective in inhibiting the release of histamine. Neither compound produced any effect when basophils were stimulated with IMI R. In comparison, the nonselective inhibitor

RIZK 1294002, was tested at 0.1nM and 10000nM, showing close to 10095 inhibition of histamine release at the highest concentration.

These data indicate that inhibitors of the activity of Ri-Z-kinase delta can be used to suppress the release of histamine, which is one of the mediators of allergies. Since the activity of various RiI-3-kinases is required for the transport, secretion, and exocytosis of proteins in many of the above cell types, these data suggest that histamine release by other cells, such as mast cells, may also be impaired by delta-selective inhibitors. RI-3-kinase.

EXAMPLES OF CHEMICAL SYNTHESIS

Specific non-limiting examples of compounds according to the invention are presented below. It is known in the art that protecting groups can be applied where necessary according to general principles of synthetic chemistry. 7/5 These protecting groups are removed in the final stages of the synthesis under basic, acidic, or hydrogenolytic conditions well known to those skilled in the art. Using appropriate procedures and protection of any chemical functional group, the synthesis of compounds of structural formula (I) not specifically listed herein can be achieved by methods similar to those shown below in the schemes.

Unless otherwise specified, all starting materials were obtained from commercial suppliers and

Used without further cleaning. All reactions and chromatographic fractions were analyzed by thin layer chromatography (TLC) on 250 mm silica gel plates, visualized by ultraviolet (UV) light or iodine staining (12). Products and intermediates were purified by flash chromatography or reversed-phase high-performance liquid chromatography.

The following abbreviations are used in the examples of synthesis: ad (hydrogen), H 20 (water), СНСИз (chloroform), НС счов (hydrochloric acid), MeOH (methanol), MaOH (sodium hydroxide), MaOMe (sodium methoxide), ТРА, (trifluoric acid), CoCO»z (potassium carbonate), OSI» (thionyl chloride), СНоСиИ» (methylene chloride), ЕЯАС i) (ethyl acetate), DMF (dimethylformamide), EN (ethanol), DMSO (dimethylsulfoxide), ManСООz (hydrocarbon sodium), TLC (thin-layer chromatography), HPLC (high-performance liquid chromatography), NOVT (hydroxybenzotriazole), EOS (ethyldiethylaminopropylcarbodiimide), OIEA. (diisopropylethylethane) and NOAc (acetic acid

From Acid).

Y. General methods of

Method A "-

Thionyl chloride was added to a rapidly stirred solution of anthranilic acid or benzoic acid in benzene and the mixture was stirred at reflux for 5-18 hours. The reaction mixture was concentrated in vacuo and purified twice with benzene. The formed oil was dissolved in SNS, and acceptable aniline was added to this solution. The reaction mixture was heated to reflux and stirred to completion as determined by TLC where the reaction mixture was cooled to ambient temperature. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by chromatography and/or recrystallization from MeonH to obtain amides Ia-Ig. "

Method B in c Chloroacetyl chloride was added to a rapidly stirred suspension of amide in glacial acetic acid. Reactionary. the mixture was heated to 1202C and stirred at this temperature until completion, which was determined by TLC. "" After rapid cooling, the reaction mixture was concentrated in vacuo. The crude residue was purified by extraction, chromatography and/or recrystallization to obtain chlorides 2a-2g.

Method C - a mixture of chloride, nitrogen or sulfur nucleophile, for example, mercaptopurine or adenine monohydrate and. COSOz in DMF was stirred at room temperature for 15-72 hours. The resulting suspension would be poured into water and kept at 42C for several hours. The crude solid product was filtered, washed with water and purified by chromatography or recrystallization to obtain the final products.

EXAMPLE 8 o Obtaining intermediates; Amides c» 2-amino-M-(2-chlorophenic)-4,5-dimethoxybenzamide (1a)

Prepared according to method A using 4,5-dimethoxyanthranilic acid (5.0g, 25.4mmol) and BOC (5.0ml, 76.0mmol) in benzene (100ml) followed by 2-chloroaniline (b/7ml , 63.5 mmol) and SNCIz (7 Bbml). The product was washed with an aqueous solution of MnSO 3 (225 ml) and HCl (0.5 M, 75 ml) and purified by chromatography in СНоСИ» to obtain 4.3 g of a brown foam. (55905). IR NMR (SOSIz) p: 8.42 (aa, 9-1.5,8.3Hz, 1H); 8.32 (Bg 8, 1H); 7.40 (aa, o-14,8,0hz, 1); 7.31 (and 0-1.4.7.9Hz, 1); 7.05 (and 9-1.5,7.7Hz, 71Н); 7.03 (in, 1H); 6.24 (in, 1H); where 3.8 8 (8, ZN); 3.87 (in, ZN). MS (ER): t/: 307.0 (M). 2-amino-5-bromo-N-(2-chlorophenyl)benzamide (15) 60 Prepared according to method A using 2-amino-5-bromobenzoic acid (5.0g, 23.1mmol) and OSI" (7, 0ml, 95.9mmol) in benzene (50ml), followed by 2-chloroaniline (7.3ml, 69.0mmol) and SNCI (50ml). The product was purified by two chromatographies in CHCl 2 to obtain 1.48 g of a yellow-orange solid product (2096). "H NMR (SOCIz) w: 8.36 (da, 9U-1.2, 8.2Hz, 1H); 8.20 (rg 85, 1H); 7.62 (9, 9U-2.1Hz, 1H ); 7.42 (aa, 2-1.3, 8.0 Hz, 1H); 7.34 (ad, 2-2.2, 8.8 Hz, 1H); 7.28-7.33 (t, 1H); 7.09 (ai, 9-1.4, 7.7Hz, 1H); 6.62 (a, 9-8.7Hz, 1H); 5.57 (Bg8,2H). bo 2-amino -M-(2-chlorophenyl)-4-fluorobenzamide (1c)

Obtained according to method A using 2-amino-4-fluorobenzoic acid (1.15 g, 7.41 mmol) and

OSI" (1.4ml, 18.5mmol) in benzene (25ml), followed by 2-chloroaniline (1.6ml, 14.8mmol) and SNSdz (25ml). The product was chromatographed with СНоСдо, and the date was triturated in hexanes to obtain 1.02 g of a whitish solid product (5295). "YAN YMR (SOSI»z) w 12.91 (bBg 8, 1H); 8.72 (aa, 9-2.7, 12Gu, 1H); 8.34 (aa, 9-64, 9.2Hz, 1Hn); 8.29 (aa, o-5.9, 8.8Hz, tn); 7.81 (aa, 9-62, 88Hz, 1); 7.28 (a 0-24, 34Hzc, 1) ; 7.21 (aa, 0-24, 9.oHz, 1); 6.92 (aa, 0-2.4, 7.3, 91Hz, 1); 6.54 (ada, 0-24, 7 .8, 8.8HzC, 1H); 6.45 (aa, 9-24, 11Hz, 1); 5.93 (rg in, 2H). MS (ER): t/2 265.0 (M). 2-amino-5-chloro-N-(2-chlorophenyl)benzamide (19)

Prepared according to method A using 2-amino-5-chlorobenzoic acid (2.0g, 11.7mmol) and OCI (2.2ml, 29.2mmol) in benzene (50ml) followed by 2-chloroaniline (2, 5ml, 23.3mmol) and SNCIIz (5Oml). The product was purified by recrystallization from MeOH to obtain 1.72 g of a dark yellow solid product (5296). "H NMR (SOSIv) IT 8.37 (aa, 9-1.5, 8.3Hz, 1); 8.22 (Bg 8, 1H); 7.48 (a, 9-2.3.Hz, 1H); 7.42 (aa, o-1.5, 81Hz, yin); 7.31 (a; 3-1.4, 7.8Hz, 1H); 7.22 (da, 2-24, 8 ,8Hz, 1H); 7.09 (ac o-1.5, 7.7Hz, 1H); 6.67 (a, U-8.8Hz, 1H); 5.56 (rg 5, 2H), 2 -amino-M-(2-chlorophenyl)-6-fluorobenzamide (1e)

Prepared according to method A using 2-amino-b-fluorobenzoic acid (2.0g, 12.9mmol) and ZOSIZ (2.3ml, 32.2mmol) in benzene (50ml) followed by 2-chloroaniline (2.7ml , 25.8 mmol) and SNSI" (5 Oml). The product was purified by chromatography in a mixture of EtOAc/hexanes to obtain 2.06 g of a pale orange solid product (60965)... H NMR (SOCI3) r: 9.00 (a, 9-17Hg, 1H); 8.47 (a, 9-8.3Hz, 1H); 7.41 (a, O-v, oGHz, 1); 7.30 (6 9-7.9Hz, 1H); 7.10-7.20 (t, 1H); 7.07 (5.9-7.7Hz, 1H); 6.49 (a, 2-8.3Hz, 1H); 6.03 (Bg in, 2H). MS (ER): t/2 265.0 (M). 2-amino-6-chloro-N-(2-chlorophenyl)benzamide (18)

Prepared according to method A using 2-amino-b-chlorobenzoic acid (2.5 g, 14.bmmol) and OCI (2.7ml, 3b.4mmol) in benzene (75ml) followed by 2-chloroaniline (C , iml, 29.1 mmol) and SNCIz (75 ml). The product was chromatographed in СНоСи» to obtain 1.05 g of a yellow-orange solid product (2695). NN NMR (SOSIZ) w: 8.54. (а, У-8, гу, 1Н); 8.30 (Bgo8, 1H); 7.41 (aa, 9-1.5, 80Gu, 1); 7.33 (6 9U-7.8Hz, 1H); 7.10 o'clock (B 9-8, hz, 1); 7.09 (and 0-1.1 7.8 Hz, yin); 6.78 (aa, 9-04,7,9Hz, 1H); 6.63 (aa, 9-0.98.2Hz, 1H); 4.69 (rg 5, 2H). MS (ER): t/2 303.0 (M"22), 281.0 (M). 2-amino-M-(2-chlorophenyl)-6-methylbenzamide (19) (ze)

Prepared according to method A using 2-amino-6-methylbenzoic acid (2.5g, 16.5mmol) and OCI (3 mmol, 4133mmol) in benzene (/bml) followed by 2-chloroaniline (3, B5ml , 33, Ommol) and SNCIz (75 ml). The product was chromatographed in СНоСи» to obtain 2.19 g of a brown oil (5195). "H NMR (SOCI5) w 8.58 (4, 0-7

U-8.1gu, 71Н); 7.99 (rg 85, 1H); 7.40 (aa, 9-1.4, 8.0Hz, 1NU 7.34 (B 9-7.7Hz, 1H)U 711 (6 9-7.8Hz, 1); "o 7.09 (a 0-1.5, 7.7 NU, 1n); 6.64 (а, 9-7.5Hz, 1Н); 6.59 (j, 9-8.1 NU, 1n); 4.29 (rg 8, 2H); 2.45 (in, ЗН).

MS (ER): t/2 283.0 (M"22). - 2-amino-3-chloro-M-(2-chlorophenyl)benzamide (1)

Prepared according to method A using 2-amino)-3-chlorobenzoic acid (1.0 g, 5.82 mmol) and OCI (1.1 mL, 14.0 mmol) in benzene (25 mL), followed by 2-chloroaniline (1 ,2ml, 11.7mmol) and SNCIz (25ml). The product was recrystallized from MeOH to give 1.29 g of a yellow solid (7896). "H NMR (SOSI") 8: 8.43 - (aa, 20-14, 8.3Hz, 1); 8.30 (rgov8, 1); 7.47 (ad, o-1.1, 8, oGu, 1H); 7.42 (a, 9-8.0Hz, 2); 7.33 (ab 9-14, c 7.9Hz, 1H); 7.09 (ai, 91.5, 7.7Hz , 1H); 6.68 (i, 9-7.9Hz, 1H); 6.13 (Bg in, 2H). MO (ER): t/2 281.0 (M). -M-diphenyl-2-yl-6-chlorobenzamide (11)

Prepared according to method A using 2-amino-b-chlorobenzoic acid (2.0g, 11.7mmol) and OCI (2.1ml, 29.3mmol) in benzene (bOml) followed by 2-aminodiphenylamine (4, 15g, 24.5mmol) and SNSYz (bOml). Product -I was chromatographed in СНоСі» to obtain 2.16 g of a foamy dark amber residue (5796). "H NMR (SOSI»v) IT 8.48 (a, -82Hz, 1); 7.79 (rg 8, 1); 7.34-7.46 (t, 6H); 7.20-7.30. (t, 2H); 7.00 (5 O-81Hzc, 71H); 6.63 b (aa, 9-0.6, 7.9Hz, 1H); 6.54 (9, 9-8.3Hz, 1H); 4.58 (rg 5, 2H). MO (ER): t/2 323.1 (ti) - 2-amino-6-chloro-M-o-tolylbenzamide (11)

Prepared according to method A using 2-amino-b-chlorobenzoic acid (1.0g, 5.83mmol) and OCI (1.1ml, 14.mmol) in benzene (30ml) followed by o-toluidine (14ml , 12.8 mmol) and SNCIz (ZOml). The product was chromatographed in SiOCl to obtain 840 mg of an oily yellow product (5596). "H NMR (SOSIv) w 7.96 (a, 9-7.9HzC, 1H); 7.60 (rgo8, 1), 7.23-7.30 (t, 2H); 7.14 (5 9 -7.5Hz, 1); 7.11 (5 9-8.3Hz, 1H), 6.78 (a, 9-7.9Hz, 1H); 6.64 (a, 9U-8.2Hz, 1H ), 4.73 (Bg 8, 2H), 2.35 (in, ЗН). MS (ER):t/2 261.0 (M). oo 2-amino-6-chloro-M-(2- fluorophenyl)benzamide(ic) o Prepared according to method A using 2-amino-b6-chlorobenzoic acid (2.0g, 11.7mmol) and ZOC (2.ml, 29.1mmol) in benzene (bOml), and then 2-fluoraniline (2.3 mL, 234 mmol) and SNCI1z3 (bOml). The product was chromatographed in CHNOST" to obtain 1.05 g of a yellow solid product (3496). "H NMR (SOCI3) w 8.45 (6 9U- 8.0 Hz, 71 N); 8.01 (rg 8, 1H); 7.02-7.22 (t, 4H); 6.78 (aa, 9-0.5, 7.9Hz, 71Н); 6.64 (aa, 2-08, 82Hz, bo 1H); 74.73 (Bg 5, 2H). MS (ER): t/2 265.0 (M). 2-amino-6-chloro-M-(2-methoxyphenyl)benzamide (11)

Prepared according to method A using 2-amino-b6-chlorobenzoic acid (2.0 g, 11.7 mmol) and OCI (2.ml, 29.1 mmol) in benzene (bOml) followed by o-anisidine (2, bml, 23.4 mmol) and SNCI3 (bOml). The product was chromatographed in SiOCl to obtain 2.61 g of a dark yellow oil (8195). "H NMR (SOSIv) w: 8.53 (aa, 9-1.7, 7.9 Hz, 7H; 8.39 (rg8, 71); 7.11 (а 0-1.6, 7.8. Hz, 71); 7.09 (5 -81Hz, 1H); 7.02 (a 9-14,

7.8 Hz, 1); 6.92 (yes, U-1.4, 8.0Hz, 1H); 6.62 (yes, 9-0.9, 8.2Hz, 1H); 4.66 (Bg in, 2H); 3.87 (in, ZN). MS (ER): t/: 277.0 (MU, 2-amino-M-(2-chlorophenyl)-3-trifluoromethylbenzamide (1t)

Obtained according to method A, using 3-trifluoromethylanthranilic acid (2.0 g, 9.75 mmol) and

OSI" (1.vml, 24.4mmol) in benzene (50ml), followed by 2-chloroaniline (2.1ml, 19.5mmol) and SNCl3 (50ml). The product was purified by recrystallization from MeonN to obtain 2.38 g of yellow crystals (7895). "H NMR (SOSI") and: 8.40 (aa, 3-14, 8.3Hz, 71); 8.25 (rg 85, 1), 7.71 (a, 0-7.8Hz, 1H) ; 7.60 (a, o-7.8Hz, 1H); 7.43 (aa, 9-14, 8.oHz, 1); 7.34 (a oo-1.3, 7.9Hz, 71) ; 7.11 (ab o-1.5, 7.7Hz, 1); 6.77 (5 9-7.8Hz, 1); 6.24 (rg 5, 2H). MO 70. (ER): t/2 315.0 (MU). (2-Chlorophenyl)amine of 3-aminonaphthalene-2-carboxylic acid (1n)

Prepared according to method A using 3-amino-2-naphthoic acid (2.0g, 10.7mmol) and OCI (1.bml, 26.7mmol) in benzene (50ml) followed by 2-chloroaniline (2, 3ml, 21.4mmol) and SNCI3 (5Oml). The product was recrystallized from MeonH to give 1.71 g of a brown solid (54965). "H NMR (SOSIv) IT t 10.88 (rg 5, 1); 9.21 (b, 1H); 8.91 (b, 1H); 8.70 (aa, 9-1.0, 8, 3HC, 1); 7.95-8.01 (t, 1H; 7.87-7.94 (t, 1H); 7.60-7.68 (t, 2H); 7.41 (aa,0 -1.3, 8.0Hz, 71); 7.34 (ab o-1.2, 7.8Hz, 1.07 (a 0-1.4, 7.7Hz, МН).

MS (85): t/2 2971 (M. 2-amino-M-(2-chlorophenyl)-4-nitrobenzamine (10)

Prepared according to method A using 4-nitroanthranilic acid (5.0g, 27.5mmol) and 5OCI'' (5.0ml, 68.bmmol) in benzene (150ml) followed by 2-chloroaniline (5.8ml, 55, 0 mmol) and SNCIz (150 ml). The product was purified by chromatography on SiOCl, followed by recrystallization from MeOH to give 2.20 g of an orange-brown solid (3195). "NYMR (SOSIZv) w: 8.41 (aa, 0-1.3, 8.3Hz, 1H) 8.91 (Bg in, 1H); 7.67 (a, 9-8v6hz, 1H); 7, 57 (a, 9-2y1gu, 1H); 7.52 (da, 9-22, 8.5HZ, 1H); 7.44 (aa, 9U-1.3, 8VYGu, 1 sc 7.35 (a, 9-1.3,7.9Hz, 1H); 7.13 (a, 9-1.4, 7.8Hz, 1H); 5.88 (g c, 2H). MS (ER): t/2 292.0 (M). 2-amino-M-(2-chlorophenyl)-5-hydroxybenzamide (Tr) and)

Prepared according to method A using 2-amino-5-hydroxybenzoic acid (5.0 g, 32.7 mmol) and

OSI" (6b.Oml, 81.bmmol) in benzene (15Oml), followed by 2-chloroaniline (b.9ml, 65.4mmol) and SNCl3 (150ml). The product was purified by two chromatographies in a mixture of Meon/Cn 5Si" to obtain 99 Ωg of a brown solid CO product (1290). "H NMR (MeOnH-aiv) w 7.92 (aa, 0-1.6, 81hz, tn); 7.48 (aa, 9-1.5, 7, Ihz, 1H); 7.34 (a o -1.5, 7.7Hz, 1); 7.20 (a 9-1.7, 7.7Hz, 1H); 7.16 (a, 9-2.7Hz, 71H); 6.83 ( aa, o-2.7, 8.7Hz, 1); 6.76 (a,

U8.7Hz, 1H); 6,24 (Bg in, 2H). MS (ER): t/2 263.0 (M). -- 2-amino-M-(2-chlorophenyl)-4,5-difluorobenzamide (14) so

Prepared according to method A using 4,5-difluoroanthranilic acid (2.0g, 11.bmmol) and OCI (2ml, 28.9mmol) in benzene (bOml) followed by 2-chloroaniline (2.4ml, 23, 2mmol) and SNCIIz (bOml). The product was purified by two chromatographies in CH2SiO2 and EtOAc/hexanes to obtain 769 mg of a yellow solid product (2396). "N

NMR (SOCI3) w: 8.69-8.82 (t, 1H); 8.00 (aa, 9-84, 9.0Hz, 1H), 7.90 (aa, ju-8.9, 12Hz, 1H); 7.3 9 (aa,

U-6.8, 10Hz, 1H); 6.53 (yes, 2-6.6, 12Hz, 1H); 6.41 (Bg 5, 2H); 5.79 (rg in, 1H). MS (ER): t/2 283.1 (M). « 20 2-amino-M-(2-chlorophenyl)-5-fluorobenzamide (1g) with

Prepared according to method A using 2-amino-5-fluorobenzoic acid (1.0g, 6.45mmol) and BOC (1.2ml, 16.1mmol) in benzene (30ml), followed by 2-chloroaniline-( 1.4ml, 12.9mmol) and SNCIz (30ml). The product :z" was triturated in СНоСі" to obtain 985 mg of a mustard-yellow solid product (5896). "H NMR (SOCI35) w 7.66 (aa, 9u-2.9, 8.7Hz, 1H); 7.52-7.55 (t, 1H); 7.32-7.37 (t, ZN ); 7.09 (ab 9-30, 8.5Hz, 1H); 6.71 (aa, 9-43, 8.7Hz, 1H). MS (ER): t/2 305.0 (M'40 ).-I EXAMPLE 9

Obtaining intermediates; Chlorides. b 2-chloromethyl-3-(2-chlorophenyl)-6,7-dimethoxy-ZN-quinazolin-4-one (2a) - Obtained according to method B with ta (2.95 g, 9.6 mmol) and chloroacetyl chloride (2 .3ml, 28.0mmol) in acetic acid (ZOml). Purified by extraction from an aqueous solution of K».COzZ and recrystallization from isopropanol to give 1.61 g of a brown crystalline solid (4695). "H NMR (SOSIV5) w: 7.59-7.66 (t, 2Н); со 7.45-7.56 (t, ЗН); 7.20 (v, 1Н); 4.37 (а, 20-12Hz, 1); 4.08 (a, 9U-12Hz, 1H); 4.04 (c, ZN); 4.00 (z, ZN). MS (ER): t/2 365.0 ( M). b-bromo-2-chloromethyl-3-(2-chlorophenyl)-ZN-quinazolin-4-one (25) 29 Prepared according to method B from 16 (500 Ωg, 1.54 mmol) and chloroacetyl chloride (0.37 ml , 4.61 mmol) in vinegar

GF! acid (1 Oml). Purified by recrystallization from isopropanol to give 490mg of an off-white solid product (8396). "H NMR (SOSIZ") w 8.43 (4, 9-2.3Hz, 1H); 7.91 (aa, yu-2.3, 8.7Hz, 1H); 7.67 (a, 9- 8, IHz, 1H); o 7.60-7.65 (t, 1H); 7.47-7.56 (t, 2H); 7.52 (5 9U-5.3Hz, 1); 7, 47-7.56 (t, 1H); 4.37 (a, 9U-12Hz, 1H), 4.06 vo (a, 9-12Hz, 1). MS (ER): t/2 385:0 ( M). 2-chloromethyl-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one (2c)

Prepared according to method B with 1c (500mg, 1.89mmol) and chloroacetyl chloride (0.45ml, 5.67mmol) in acetic acid (10ml). Purified by extraction from aqueous K»CO»z and then recrystallization from isopropanol to give 501 mg of a yellow crystalline solid (8296). "H NMR (SOSIV5) w: 8.32 (aa, 9-60, 8.9Gu, in 1); 7.59-7.66 (t, 1H); 7.50-7.55 (t, ZN ); 7.44 (ai, 9-24, 9.4Hz, 1H); 7.27 (46 9-2.5,8.5Hz, 1H); 4.37 (a,

U-12Hz, 1H); 4.07 (ad, 9-12Hz, 1H). MS (ER): t/2 323.0 (M).

b-chloro-2-chloromethyl-3-(2-chlorophenyl)-ZN-quinazolin-4-one (24)

Prepared according to method B from 14 (500 Ωg, 1.78 mmol) and chloroacetyl chloride (0.42 mL, 5.3 Ωmmol) in acetic acid (1 Ω). Purified by recrystallization from isopropanol to give 555 mg of a yellow solid (9295). "H NMR (SOSI»z) w 8.27 (a, 9-1.9Gu, 1H); 7.74-7.78 (t, 2H); 7.60-7.66 (t, 1H); 7.48-7.57 (t, ZN); 4:37 (a, U9-12Hz, 1H), 4.07 (a, 9-12Hz, 1H). MO (ER): t/2 339.0 (M). 2-chloromethyl-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one (2e)

Prepared according to method B with Te (500mg, 1.89mmol) and chloroacetyl chloride (0.45ml, 5.67mmol) in acetic acid (LOml). Purified by extraction from aqueous K20CO3 and recrystallization from isopropanol to give 40 mg of an off-white crystalline solid (7095). "H NMR (SOSIv) w: 7.76 (ab yu-5.3, 8.2Gu, 1H); 7.56-7.65 (t, 2H); 7.47-7.56 (t, ZN ); 7.16-7.25 (t, 1H); 4.35 (a, 9-12Hz, 1Hn), 4.07 (a, 9d-12Hz, 1n). MO (ER): t/2 323 .0 (M) 5-chloro-2-chloromethyl-3-(2-chlorophenyl)-ZN-quinazolin-4-one

Obtained according to method B from 17 (1.00g, 3.5bmmol) and chloroacetylchlorosciu (0.85ml, 10.7mmol) in 795 acetic acid (15ml), purified by recrystallization from isopropanol to give 791mg of an off-white crystalline solid (6595). TN nMR (SOS) 5: 7.70 (in, 1nH); 7.68 (a, 9-38 Hz, 1); 7.61-7.65 (t, 1H); 7.55 (aa, 0-2.7, 6bHz, 1H); 7.51 (a, 9-3 1HC, 1H); 7.50 (in, 2H); 4.35 (a, 9-12Hz, 1); 4.05 (a, 2-12 Hz, t). MS (ER): t/2 339 (M). 2-chloromethyl-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one (29)

Prepared according to method B from 19 (2.18g, 8.3bmmol) and chloroacetyl chloride (2.0ml, 25.1mmol) in acetic acid (40ml). Purified by two chromatographies in СНоSiO and Е(Одс/hexanes), followed by recrystallization from isopropanol to obtain 638 mg of a whitish crystalline solid product (2496). "H NMR (DMSO-ext.) w 7.73-7:80 (t, ZN); 7.58-7. 64 (t, ZN); 7.41 (a, 9-7.4GHz, tn); 440 (a, 9-12Gu, 1H), 4.26 (a, 9U-12Hz, 1 ); mp 2.74 (in, 3H). MS t/l: 319.0 (M): o 8-chloro-2-chloromethyl-3-(2-chlorophenyl)-ZH-quinazolin-4-one (2H )

Prepared according to method B from 1p (50mg, 1.78mmol) and chloroacetyl chloride (0.49ml, 6.13mmol) in acetic acid (10ml). Purified by extraction from aqueous K»CO»z and then recrystallization from isopropanol to give 448 mg of yellow solid (7495). "H NMR (SOCI3) w 8.23 (aa, 9-1.4, 8.0Hz, 1H); 7.90 (aa, so 0-14, 7.8Hz, 1); 7.61-7, 66 (t, 1H); 7.51-7.55 (t, ZN); 7.47 (5 9U-8.0Hz, 1n); 4.48 (a, 9-12Hz, 1H), 4.12 o (a, 9-12Hz, 1H). MO (ER): t/2 339.0 (M).

Z-diphenyl-2-yl-5-chloro-2-chloromethyl-ZN-quinazolin-4-one (2i) -

Obtained according to method B with Li (2.0g, b6.20mmol) and chloroacetylchloryl (1.5ml, 18.bmmol) in acetic acid (30ml). Purified by chromatography in СНоСі» followed by recrystallization from isopropanol for

From obtaining 1.44 g of whitish solid product (6195). "H NMR (SOCIv8) 5: 7.61-7.64 (t, 1H); 7.58-7.59 (t, 1H); - 7.54-7.57 (t, 2H); 7, 52-7.53 (t, 1H); 7.45-7.52 (t, 2H); 7.24 (v, BN); 3.92-4.03 (t, 2H). MS(ER) : t/2 381.0(M7) 5-chloro-2-chloromethyl-3-o-tolyl-ZN-quinazolin-4-one (21)

Obtained according to method B from 1) (75mg, 2.88mmol) and chloroacetyl chloride (0.69ml, 8.6mmol) in acetic acid (15ml). Purified by chromatography in CHClCl, followed by recrystallization from isopropanol to give 34 mg of an off-white solid product (3795). "H NMR (SOSIv5) w: 7.69 (a, 9U-2.1hz, 71H); 7.68 (ad,

Y U-7.4Hz, 71N); 7.54 (yes, 0-22, 7.0Hz, 1); 7.35-7.47 (t, ZN); 7.21-7.25 (t, 1); 4.27 (a, 9-12Hz, 1H); 4.11 "» (a, 9-12HzC, 1H); 2.18 (c, ЗН). MO (ER): t/:2 319.0 (M). 5-chloro-2-chloromethyl-3- (2-fluorophenyl)-ZN-quinazolin-4-one (2K).

Obtained according to method B from 1K (1.0g, 3.7v8mmol) and chloroacetyl chloride (0.90ml, 11.3mmol) in acetic acid (20ml). Purified by chromatography at SNSI to obtain 484 mg of pale pink solid product b (4095). "H NMR (SOSI"v) w: 7.69 (v, 1H); 7.68 (a, 9-3.2Hz, 1H); 7.56 (a, U-3.0Hz, 1H); 7 .54 (a, U-3.0Hz, 1H); 7.40-7.47 (t, 1); 7.35-7.38 (t, 1H); 7.27-7.32 (t, 1H); 4.35 (a, 9-12Hz, 1H); 4.18 (a, 9-12Hz, 1H). MS (ER): - t/2 323.0 o 50 5-chloro-2-chloromethyl -3-(2-methoxyphenyl)-ZN-quinazolin-4-one (21)

Obtained according to method B 11 (2.6g, 9.41mmol) and chloroacetyl chloride (2.2ml, 28.2mmol) in acetic acid (40ml). Purified by chromatography on CHClCl, followed by recrystallization from isopropanol to give 874 mg of a pale yellow solid (2895). "H NMR (SOSI»v) sho 7.55-7.74 (t, 2H); 7.47-7.54 (t, 2); 7.34 (aa, 0o-1.7, 7.8Hz , 1); 7.13 (ab o-1.2, 7.7Hz, 1); 7.08 (aa-1.0, 84Hz, 1); 4.29 (a, 9-12Hz, 99 1H) ; 4.11 (9, 9-12Hz, 1H); 3.80 (z, ZN). MS (ER): t/2 335.0 (M).

HF) 2-chloromethyl-3-(2-chlorophenyl)-8-trifluoromethyl-ZN-quinazolin-4-one. (2t) yuyu Obtained according to method B from 1t (500Ωmg, 1.59mmol) and chloroacetyl chloride (0.3v8ml, 4.77mmol) in acetic acid (1Oml). Purified by recrystallization from isopropanol to obtain 35O9mg of a white solid product in (6196): "H NMR (SOS) w 8.51 (aa, 9-1.0, 8.0Hz, 1H); 8.14 (a, 0-7 ,3Hz, 1H); 7.65 (aa, 9-2.5, 5, b6Hz, 1H); 7.62 (a, 20-3.9Hz, 1); 7.48-7.60 (t, ZN); 4.44 (a, 9-12Hz, 1H), 4.12 (da, 9-12Hz, 1H). MS (ER): t/:2 373.0 (MU. 2-chloromethyl-3- (2-chlorophenyl)-ZN-benzo (d) quinazolin-4-one (2p)

Prepared according to method B from 1p (500mg, 1.6vmmol) and chloroacetyl chloride (0.40ml, 5.05mmol) in acetic acid (1Oml). Purified by chromatography over SiO2 followed by recrystallization from isopropanol to give 232 mg of a light brown solid (3990). "IN NMR (SOS) w: 8.92 (in, 1H); 8.29 (in, 1H); 8.81 (a, yu-8,3,1H); 8.32 (a, 9U-8 ,3Hz, 1H); 7.51-7.69 (t, 4H); 7.55 (a, 9-52Hz, 1H); 7.53 (a, 9-3.8Hz, 1);

4.43 (ad, 9-12Hz, 1H), 4.12 (d, 9-12Hz, 1H). MS (ER): t/:2 355.0 (M). 2-Chloromegyl-3-(2-chlorophenyl)-7-nitro-ZN-quinazolin-4-one (20)

Prepared according to method B from 10 (500 µg, 1.71 mmol) and chloroacetyl chloride (0.41 mL, 5.14 mmol) in acetic acid (1 mL). Purified by extraction from an aqueous solution of CoCO3, followed by two chromatographies in СНоСи» to give 338 mg of a yellow oil (5695). "H NMR (SOSI»z) w 8.64 (a, 9-2.2Hz, 1H); 8.48 (a, 9-8.8Hz, 1H); 8.z2(aa, o-2.2 ,8.7Hz, 1); 7.66 (aa, 9-2.5,6.0, Hz, 1H); 7.52-7.59(t, ЗН); 4.41 (94.0- 12Hz, 1H),4,1F(a-12Hz, 1H). MS (ER): t/2 350.0 (M). 2-chloromethyl-3-(2-chlorophenyl)-4-oxo-3,4 -acetic acid dihydro-quinazolin-b6-yl ester (2p)

Obtained according to method B from 1p (67Omg, 2.55mmol) and chloroacetylchloryl (0.61ml, 7.65mmol) in acetic acid (TOml). Purified by chromatography at 0.396 Meon/cSnsi'' followed by recrystallization from isopropanol to give 52 µg of the acetate as pale peach crystals (5795). "H NMR (SOSIv) w: 8.00 (a, 9-2.7Hz, 1H); 7.82 (a, 2-8.8Hz, 1H); 7.60-7.66 (t, 1H) ; 7.56 (yes, 9-2.7, 8.8Hz, 1); 7.51 (5 9Я-4.7Hz, 2H); 7.50 (c, 1H); 4.38 /5 (a . -(2-chlorophenyl)-6,7-difluoro-ZN-quinazolin-4-one (24)

Prepared according to method B from 14 (70 Ωg, 2.4 μmmol) and chloroacetyl chloride (0.bΩc, 7.4 μmmol) in acetic acid (12 mL). Purified by chromatography over CH2Cl2, followed by recrystallization from isopropanol to give 219 mg of a yellow crystalline solid (2696). "H NMR (SOSI»v) w: 8.07 (aa, 9U-8.5,9.7Hz, 1H), 7.64 h (aa, 9-2.5, 5.6Hz, 1H); 7 .60 (aa, 9-3.5, 11Hz, 1H); 7.55 (a, 9-2.9Hz, ZNU; 7.52 (9, U-1.9Gu, 1H); 7.49-7 .51 (t, 1H); 4.36 (9, 2-12Hz, 1H), 4.06 (a, 9-12Hz, 1H). MS (ER): t/2 341.0 (M). 2 -chloromethyl-3-(2-chlorophenyl)-6-fluoro-ZN-quinazolin-4-one (2g)

Prepared according to method B from 1 g (850 mg, 3.21 mmol) and chloroacetyl chloride (0.77 mL, 9.6 mmol) in acetic acid (15 mL). Purified by extraction from an aqueous solution of KSO", and then by chromatography in a mixture of E(OAc/hexanes. su

A second chromatography in acetone/hexanes gave 125 mg of a white solid (1295). "H NMR (SOCI38) w o 7.95 (aa, 9-2.9, 8.2 Hz, 1); 7.81 (aa, 0-48, 9.0 Hz, 71H); 7.61-7 .66 (t, 1); 7.57 (aa, o-2.7, 8.6Hz, MH); 7.57 (aa, 0-2.7, 8.bHz, 1); 7.52 ( ad, 0-32, 6.9Hz, 1H); 7.52 (rg 8, 2H); 4.38 (y, 0-12Hz, tn), 4.08 (a,

U-12Hz, 1H). MS (ER): t/:2 323.0 (M).

EXAMPLE 10 me)

Obtaining compounds of the RIZK inhibitor in O

Compound Yu-001 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-ZN-quinazolin-4-one --

Prepared according to method C using intermediate 2a (200mg, 0.54bmmol), adenine (81mg, He 0O,b01mmol), KSO' (83mg, 0.601mmol) and BMR (4ml). The crude product was recrystallized from ethanol (EUN) to obtain 16b4mg of a beige, solid product (65965), m.p. 281.5-282.7 C (decomposes). "H NMR - (DMSO-ar) w: 8.06 (in, 1H); 8.04 (in, 1H); 7.76-7.81 (t, 1H); 7.70-7.76 ( t, 1H); 7.60-7.67 (t, 2H); 7.45 (c, 1H); 7.22 (c, 2H); 6.90 (z, 1H); 5.08 (a . ,9, 156.2, 155.4, 152.9, 150.0, 149.7, 149.4, 143.0, 141.9, 133.7, 132.1, 131.9, 131.2 , " 130.8, 129.3, 118.4, 113.6, 108.4, 105.8, 56.5, 56.1, 44.7. MO (ER): t/2 464.1 ( MU Analysis, calculated: for 8 s SooH.vSIM7O» with 0.1C2H2O.0.05KS: C, 56.47; H, 3.97; SI, 7.88; M, 20.76. Found: C, 56 .54; H, 4.05; SI, 7.77; M, 20.55. a Compound 0-002 "» 2-(6-aminopurin-o-ylmethyl)-6-bromo-3-(2-chlorophenyl) )-ZN-quinazolin-4-one

Obtained according to method C using intermediate 25 (10mg, 0.2b6mmol), adenine (Zmg, 0.286bmmol, K»CO3 (40mg, 0.28bmmol) and DMF (2ml). The crude product was recrystallized from EUN to give 52mg of a whitish solid product (4195), temp. pl. 284.2-284.7 "С (decomposed). "NN NMR o (DMSO-ar) w 8.24 (a, 9-2.0Hz, 71Н); 8, 05 (in, 1H); 8.03 (in, 1H); 7.98 (aa, 9U-1.9, 8, bHz, 1H); 7.74-7.83 (t, with 2H); 7 .59-7.68 (t, 2H); 7.46 (9, 9-8.7Hz, 1H); 7.22 (in, 2H); 5.12 (9, 9-17Hz, 1H); 4 .94 (9, 9-17 Hz, 1). C NMR (DMSO-iv) million: 159.5, 156.2, 152.9, 152.0, 150.1, 145.8, 141.85, 138.4, 133.1, 132.2, 131.9, 131.1, 130.9, (av) 50 130.1, 129.4, 128.9, 122.4, 1204, 1184, 450. MS (ER) t/2 482.0 (M'). Analysis, calculated: for syu SooN.zSIVgM,0.0, CS: C, 49.01; H, 2.67; SI, 7.96; M, 20 ,00. Found: C, 48.82; H, 2.82; SI, 8.00; M, 19.79.

Compound Yu-003 2-(6-aminopurin-o-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one

Obtained according to method C using intermediate 2c (10 Ω, 6.310 mmol); adenine (4 mg, 0.340 mmol), K»CO3 (47 mg, 0.340 mmol) and DMF (Iml). The crude product was recrystallized from EYN to obtain 57 mg of a beige solid product (4495), temp.pl. 216.8-217.2 S. "H NMR (DMSO-dv) w: 8.22 (aa, imo) 3-6.3, 8.7HC, 7Н); 8.05 (5, 71Н); 8 .03 (in, 1H); 7.78-7.80 (t, 2H), 7.61-7.64 (t, 2H); 7.46 (a; 0-21, 8.6Hz, 1H) 7.32 (a, 9-9.8Hz, 1H); 7.22 (c, 2H); 5.13 (0.9-17Hz, 1H); 4.95 (a, U-17Hz, 1H) C NMR (DMSO-dv) million 7: bo 166.1 (0, 9-253 Hz), 159.6, 155-8, 152.5, 149.7, 148.6 (y, 9-14 Hz) , 141.4, 132.8, 131.8, 131.6, 130.8, 130.5, 129.8 (y, 9-11 Hz), 129.0, 118.1, 117.4, 116.2 ( ad, 9-24Gu), 112.7 (8, 9-22Gu), 44.6. MS (ER): t/2 422.0 (M). Analysis, calculated: for С 20Н4зСИЕМ7О.0.1320.0.15КСИ : C, 55.25; H, 3.06; SI, 9.38; M, 22.55. Found: C, 55.13;

H, 2.92; SI, 9,12; M, 22.30.

Compound Yu-004 bo 2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one

Prepared according to method C using intermediate 24 (10mg, 0.294mmol), adenine (44mg, 0.3233mmol), K»CO3 (45mg, 0.3233mmol) and DMF (1ml). The crude product was recrystallized from EUN to obtain 5 BOmg of a yellow solid product (3995), temp.pl. 294.5-294.8 "C (decomposes). H NMR (DMSO-ag) w 810 (a, 9-2.2Gu, 1H); 8.05 (in, 1H); 8.03 (in, 1H); 7.86 (aa, 9-24, 8.8Hz, 1H); 7.75-7.82 (t, 2H); 7.59-7.67 (t, 2H); 7.53 (4.9U-8.7Hz, 1H); 7,22 (Bg 8, 2H); 5.13 (a, 9-17Hz, 1H); 4.95 (a, 9U-17Hz, 1). WITH

NMR (IDMSO-th in) million: 159.7, 156.2, 152.9, 151.9, 150.1, 145.5, 141.8, 135.7, 133.1, 132.3, 132.2, 131.9, 131.1, 130.9, 130.0, 129.4, 125.9, 122.0, 118.4, 44.9. MS (ER): t/2 438.0 (M). Analysis, calculated: for

СооН.8СИ,М7О: С, 54.81; H, 2.99; M, 22.37. Found: C, 54.72; N, 2.87; M, 22,18. Compound Yu-005 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5fluoro-ZN-quinazolin-4-one

Prepared according to method C using intermediate 2e (200mg, 0.619mmol), adenine (92mg, 0.681mmol), KSO' (94mg, 0.680mmol) and DMF (4ml). The crude product was chromatographed in a mixture of МЕОН/СН-СИ»/5 to obtain 168 mg of a whitish solid purge (6496), temp.pl. 159-172 "C (gradually decomposes). "N

NMR (DMSO-γ) ts: 8.10 (8.1H); 8.08 (in, 1H); 7.73-7.89 (t, ZN); 7.57-7.71 (t, 2H); 7.37-7.48 (t, 2H); 7.34 (a, 9-11Gu, 1H); 7.30 (4.9U-8.3Hz, 1H); 5.14 (9, 9-17Hz, 1H); 4.94 (a, 9-17 Hz, 1H). ZS NMR (DMSO-dv) million: 160.8 (a, 20-264Hz), 157.5 (0.90-4.2Hz), 155.8, 152.4, 152.4, 150.0, 148.7, 142.1, 136.4 (y, 0-11Hz), 133.0, 132.2, 132.1, 131.2, 130.9, 129.4, 123.8 (y, 9 -3.6 Hz), 118.4, 114.5 (a, 9-20 Hz), 110.2 (a, 9-6.0 Hz), 44.9. MO (ER): t/x 422.0 (M). Analysis, calculated: for C 20H413SIEM,O: C, 56.95; H, 3.11; SI, 8.40; M, 23,24. Found: C, 54.62; H, 3.32; SI, 9.40; M, 21,29.

Compound Yu-006 2-(6-aminopurin-o-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one

Obtained according to method C, using intermediate 21 (30mg, 0.8833mmol), adenine (131mg, cm 0.972mmol), K»CO» (134mg, 0.972mmol and DMF (4ml). The crude product was chromatographed in a mixture of MeOH/CHNOCl» (5) and recrystallized from EUN to obtain 188 mg of pale orange crystalline solid product (4996), mp 245.7-246.0 (starts to evaporate at 2202). "H NMR (DMSO-div) w: 8, 06 (in, 1H); (t, ZN); 7.41 (a, 90-8.1Hz, 1H); 7.26 (rg in, 2H) 5.11 (a,

U-17GHz, 1); 4.93 (a, 9-17 GHz, 1H). C NMR (DMSO-dv) mln.": 158.5, 156.2, 152.9, 152.2, 150.1, 149.2, 1354, o 3o 133.3, 133.2, 132.1 , 132.0, 131.2, 130.4, 129.4, 127.3, 118.4, 117.7, 44.9. MS (ER): t/2 438.0 (M). Analysis, "2 was calculated: for С 20Н413СИ2М70.0.1СоНо.05НО: С, 54.67; Н, 3.11; СИ, 15.98; M, 22.09. Found: С, 54.35; -

H, 3.00; SI, 15.82; M, 22,31.

Compound Yu-007 (Ce) 2-i6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one m

Prepared according to method C using intermediate 29 (250 mg, 0.78 mmol), adenine (116 mg, 0.8 mmol), CoCO 3 (119 mg, 0.862 mmol), and DMF (4 mL). The crude product was recrystallized from EYN to obtain 9 mg of a pale yellow solid product (2895), temp.pl. 190.7-190.920. "H NMR (DMSO-aiv) w: 8.05 (in, 1H), 8.03 (in, 1H); 7.76-7.79 (t, 1H); 7.71-7.74 (t , 1H); 7.59-7.-67 (t, 1H); 7.34 (a, 0-7.4Hz, 1H); 7.28 (a, « h-8.2Hz, 1H); 7 .24 (Bg in, 2H); 5.07 (y, 9-17Hz, 1H); 4.92 (y, 9U-17Hz, 1H); 2.73 (y, ZN). C NMR (DMSO-dv )mln"!: OSHZ with 161.1, 156.2, 152.8, 150.9, 150.1, 148.3, 141.9, 141.0, 134.6, 133.6, 132.2 , 131.95 131.3, 130.8, 130.3, and 129.3, 125.9, 119.1, 118.4, 44.8, 22.8. MO (ER): t/2 418.1 (M). Analysis, calculated: for C 24H46SIM7O.NhO: C, I 57.87; H, 4.16; SI, 8.13; M, 22.49. Found: C, 57.78; H, 3.99; SI, 8.38; M, 22,32.

Compound Yu-008 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one -| Prepared according to method C using intermediate 2 (10mg, 0.294mmol), adenine (44mg, 0.324mmol), KSO' (45mg, 0.324mmol) and DMF (ml). The crude product was chromatographed in a mixture of MeOnH/CH»oCl» to obtain 5mg of a pale yellow solid product (3995), temp.pl. 273.3-273.52C (decolorizes). "H NMR - (DMSO-4av) w: 8.11 (aa, 9U-1.3, 8.0 Hz, 1H); 8.08 (8, 1H); 8.05 (v, 1H); 8, 00 (aa, 9-1.3, 7.8Hz, tn), 7.79-7.83 av) 50 (t, 2H), 7.63-7.66 (t, 2H); 7.56 ( Her, 9U-7.9Hz, 1H); 7.21 (g in, 2H); 5.17 (a, U9-17Hz, 1H); 4.97 (a, U9-17Hz, 1). CS NMR c » (DMSO-iv)mln"!: 160.2, 156.1, 152.8, 152.2, 150.2, 143.3, 142.0, 135.6, 133.1, 132.3, 131.9, 131.1, 131.0, 130.9, 129.4, 128.4, 126.0, 122.5, 1184, 450. MS (ER): t/2 438.0 (M' ). Analysis, calculated: for

SooN.zsSIDM,0.0.1СН.О.0.6Н2О.0.15КСИ: C, 52.09; H, 3.18; M, 21.15. Found: C, 51.85; H, 2.93; M, 21.01.

Compound Yu-009 2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2-yl-5-chloro-ZN-quinazolin-4-one

F) Prepared according to method C using intermediate 2i (40O0mg, 1.05mmol), adenine (155mgH, co 1.15mmol), K»CO3 (15Omg, 1.15mmol) and DMF (bml). The crude product was recrystallized from EYN to obtain 344 mg of a white solid product (6896), temp.pl. 299.9-300.1 "C (decolorizes). 1H NMR 6bo (DMSO-ar) m: 8.08 (8.1H); 7.89 (5, 1H); 7.58-7.73 (t, 5H); 7.51 (a, uUy, 9Hz, 1H); 7.46 (a, 9U-7.5Hz, 2H), 727-741 (t, ZN), 7.14-7.27 (t, ZN); 5.14 (d, U-17Hz, 1H); 4.82 (d, 9-17Gu, 1H). 3C NMR (DMSO-dv) mln.": 159.6, 156.2, 152.8, 152.5, 150.0, 149.0, 141.7, 140.2, 137.7, 135.0 , 133.3, 133.2, 131.8, 130.7, 1301, 129.8, 129.5, 128.8, 128.6, 128.4, 127.1, 118.4, 117.6 , 453. MS (ER): t/72 480.1 (Mk). Analysis, calculated: for

SovNivSIM7O: C, 65.07; N, 3.78; SI, 7.39; M, 20.43. Found: C, 64.77; H, 3.75; SI, 7.43; M, 20.35. because Compound I-010

5-chloro-2-"9H-purin-b-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one

Prepared according to method C using intermediate 2) (200mg, 0.62bmmol), b-mercaptopurine monohydrate (9mg, 0.54bmmol), CoCO3 (95mg, 0.689mmol) and DMF (4ml). The crude product was recrystallized from EYN to obtain 125 mg of a whitish solid product (4695), temp.pl. 213.9 96. tn

NMR (DMSO-y6) w: 13.53 (Bg 8, 1H); 8.49 (85, 1H); 8.44 (in, 1H); 7.78 (5 9-7.9Hz, tn); 7.63 (a, 9U-8.2Hz, 1H); 7.59 (6.9-7.7Hz, 1H); 7.49 (a, 9U-6.9Hz, 1H); 7.24-7.41 (t, ZN); 4.32445 (t, 2H); 2.14 (c, ZN). ZS NMR (DMSO-4 mln. 158.9, 157.2, 154.2, 151.5, 149.6, 143.5, 136.1, 135.9, 1351, 133.2, 131.3, 130.3, 1300, 129.9, 129.1, 127.6, 127.1, 32.4, 17.5. MS (ER): t/2 438.0 (M). Analysis, calculated: for C24Ni5SIMO8: C, 58.00; 70 H, 3.48; SI, 8.15; M, 19.32; 5, 7.37. Found: C, 58.05; H, 3.38; SI, 8 .89; M, 18.38; 5.7.00. 5-chloro-3-(2-fluorophenyl)-2-(9H-purin-b-yl-sulfanylmethyl)-ZN-quinazolin-4-one

Prepared according to method C using intermediate 2K (210mg, 0.6500mmol), b-mercaptopurine monohydrate (122mg, 0.715mmol), CoCO3 (99mg, 0.715mmol) and DMF (4ml). The crude product was recrystallized from EN to obtain 240 mg of a whitish solid product (8495), temp.pl. 244.0 20. "N

NMR (DMSO-y6) w: 13.56 (Bg 8, 1H); 8.50 (85, 1H); 8.45 (a, 1H); 7.81 (5 U-8.0Hz, 1); 7.74 (5 9-7.7Hz, 1H); 7.67 (9.9U-8.1GHz, 1H); 7.62 (a, 9-7.7Hz, 1H); 7.46-7.55 (t, 1H); 7.29-7.42 (t, 2H); 4.47-4.59 (t.2H). ZS NMR (DMSO-yv) mln. 158.4, 157.3 (a, 9-249 Hz), 156.4, 153.8, 151.0, 1491, 143.2, 135.0, 132.9, 131.8. (and,

U-8.0Hz), 130.8, 129.9, 126.7, 125.3 (a, 9-3.5Hz), 123.6 (a, 9-13Hz), 117.0, 116.2 (a, 9-19Hz), 31.7. MO (ER): t/2 439.0 (M"). Analysis, calculated: for C 20H42SiEMEO5: C, 54.74; H, 2.76; SI, 8.08; M, 19.15; 5, 7.31.

Found: C, 54.42; H, 2.88; SI, 8.08; M, 18.87; 5, 7,08. 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolyl-4-one

Prepared according to method C using intermediate 2K (210 mg, 0.65 mmol), adenine (97 mg, 0.715 mmol), K 2 CO 3 (99 mg, 0.715 mmol) and DMF (4 mL). The crude product was recrystallized from EUN for He to obtain 137 mg of a yellow-brown solid product (5096), temp.pl. 295.6-295.82C (decomposes). "H NMR o (DMSO-α6) p: 8.05 (in, 1H); 8.04 (in, 1H); 7.75 (5 9U-7.6Hz, 1H); 7.74 (6 9U- 7.9Hz, 1H); 7.62-7.69 (t, 1H); 7.61 (a, y9-7.6Hz, 1H); 7.47-7.55 (t, 1H); 7, 48 (a, 9U-7.8Hz, 1); 7.41 (a, 9-8.0Hz, 1H); 7.24 (Bg 8, 2H); 5.19 (a, 9-17GHz, 71H) ; 5.03 (a, 9-17 GHz, 1). C NMR (DMSO-div) million: 158.7, 157.6 (0, 9-250 Hz), 156.2, 152.8, 152.4 , 150.0; 149.2, 141.8, 135.4, 133.3, 132.5 (0.9-8.0Hz), 131.0, 130.4, 127.3, 126.2 ( y, y9-3.5Hz), 123.1 o (a, 9-14Hz), 118.4, 117.6, 117.2 (a, 9-19Hz), 451. MS (ER): t/2 422.0 (M). Analysis, calculated: for o

SooN.ZSIeM.,0.0.05So NO: C, 56.92; H, 3.16; SI, 8.36; M, 23,12. Found; C, 56.79; H, 3.20; 01, 8.46; M, 22.79. -

Compound Yu-013

Z-diphenyl-2-yl-5-chloro-2-"9H-purin-6-ylsulfanyl-methyl)-ZN-quinazolin-4-one (Ce)

Prepared according to method C using intermediate 2i (40O0mg, 1.0bmmol), β-mercaptopurine M monohydrate (196bmg, 1.15mmol), CoCO3 (159mg, 1.1bmmol) and DMF (BbBml). The crude product was chromatographed in a Meon/SnosCl mixture and then recrystallized from EUN to obtain 439 mg of a pale yellow crystalline solid product (8495), m.p. 222.0-222.52С (with decomposition). NN NMR (DMSO-ar) w: 13.56 (rg 8, 1H); 8.55 (8.1H); 8.45 (8.1H); 7.73 (5 U-8.0Hz, 1H); 7.64 (a, 9U-7.7Hz, 1H); "7.50-7.59 (t, 4H); 7.41-7.48 (t, 1H); 7.25-7.38 (t, 5H); 4.41 (9, U-16Hz, 1H); 4.16 (4 d-16Hz, 1H). C NMR - c (DMSO-iv) million: 160.2, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134, 1, 133.3, 131.5, 1305, "» 130.3, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ER) : t/2 497.0 (MU). Analysis, calculated: for "Со6Н.7СИМО: С, 62.84; H, 3.45; SI, 7.13; M, 16.91; 5, 6.45. Found: C, 62.60; N, 3.47; SI, 7.15; M, 16.65; 5, 6, 41.

Compound Yu-014 15 5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-b-yl-sulfanylmethyl)-ZH-quinazolin-4-one and Obtained according to method C using intermediate 21 (25 , 0.74 mmol), β-mercaptopurine monohydrate (He) (140 mg, 0.821 mmol), K»CO3 (113 mg, 0.821 mmol) and DMF (4 ml). The crude product was recrystallized from EYN to obtain 254 mg of a whitish solid product (7690), temp.pl. 237.0 90 (with 5Or Bozkladanam; decolorized at 154.6 C). "H NMR (DMSO-dv) w: 13.53 (riv, 1H); 8.52 (8, 1H) 8.45 (v, o 1); 7.78 (5 9U-7.9Hz, 1) ; 7.64 (a, o-8.0Hz, yin); 7.59 (a, 9-7.7Hz, 1H); 7.48 (a, 0-7.3Hz, 1); 7.42 ( i, se" U-7.7GHz, 1H); 7.15 (a, 9-8.2Hz, 1H); 7.03 (i, 9-7.5Hz, 1H); 4.45 (v, 2H ); 3.76 (in, ZN). C NMR (DMSOdv) ppm: 158.9, 157.1, 154.8, 154.7, 151.5, 149.6, 143.6, 135.1 , 133.2, 131.3, 130.4, 130.0, 127.0, 124.8, 121.2, 117.8, 112.7, 56.1, 32.0. MS (ER): t/2 451.0 (M). Analysis, calculated: for С 24Ни5СИМ6О25.0.15С25Н650.0.05КСИ:

С,55,43; N, 3.47; SI, 8.07; M, 18.21; 5, 6.95. Found: C, 55.49; H, 3.68; SI, 7.95; M, 17.82; 5, 6,82. o Compound Yu-015 3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-b-yl-sulfanylmethyl)-ZH-quinazolin-4-one obtained according to method C, using intermediate 2e (200 mg . The crude product was recrystallized from EYN to obtain 152 mg of a white solid product (5695), temp.pl. 222.7-223.8 "C (decolorizes). IN NMR (DMSO-α) p: 13.56 (Bg8, 1H); 8.48 (a, 1H); 8.44 (in, 1H); 7.89 (ab 9U-5,6,81Hz, 13; 7.76 (aa, o-1.6, 7.3Hz, 71); 7.67 (a, 9-74Hz, 1); 7.56 (a, 0-81 Hz, 1); 7.47 (B 90-71 Hz, 1), 7.41-7.53 (t, 2H) 7.37 (da, U-8.7, 11Gu, 1H ); 4.38-4.52 (t, 2H). NMR NMR (DMSO-dv) mln.": 160.9 (4, 9U-264Hz), 157.6, 156.8, 154.1, 151 ... ,8, 123.6, 114.4 (a, 9-20Hz), 110.2, 32.0. MS (ER): t/2 439.0 (M). Analysis, calculated: for -BO0-

SooN.oSIEM.O5.0.5SoNYO: C, 54.61; H, 3.27; SI, 7.68; M, 18,19; 5, 6. 94. Found: C, 54.37; H, 3.26; SI, 7.89; M, 18.26; 5, 6.55.

Compound Yu-016 3-(2-chlorophenyl)-6,7-dimethoxy-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one

Prepared according to method C using intermediate 2a (200mg, 0.54bmmol), b-mercaptopurine monohydrate (102mg, 0.6b01mmol), CoCO3 (8mg, 0.b0immol) and DMF (B5ml). The crude product was recrystallized from EN to obtain 172 mg of a whitish solid product (6590), temp.pl. 160-180 FS (gradually decomposes). "H NMR (DMSO-dv) w 13.55 (Bg 8, 1H); 8.49 (b, 1H); 8.44 (b, 1H); 7.72 (a, 70. 3-6.9Hz , 1H); 7.66 (9, U-6.9Hz, 1H) 7.38-7.54 (t, ЗН); 7.22 (v, 1H); 4.36-4.52 (t, 2H); 3.94 (in, ZN); 3.89 (in, ZN).. ZS

NMR (DMSO-iv) ppm: 160.1, 155.4, 151.5, 151.1, 1494, 143.2, 134.6, 132.3, 131.6, 131.5, 130.4 , 128.7, 113.6, 108.4, 105.8, 56.5, 56.1, 32.0. MS (ER) t/72 481.1 (M'). Analysis, calculated: for СооН., СИМ.О35.0.50.Н.О.0.05КСИ: С, 54.41; H, 3.97; SI, 7.33; M, 16.55; 5, 6, 32. Found: C, 54.43; H, 750..3.94; SI, 7.69; M, 16.69; 5, 6,52.

Compound Y-017 b-bromo-3-(2-chlorophenyl)-2-(9H-purin-6b-yl-sulfanylmethyl)-ZN-quinazolin-4-one

Prepared according to method C using intermediate 25 (200mg, 0.519mmol), b-mercaptopurine monohydrate (97mg, 0.570mmol), Co»CO3 (7O9mg, 0.572mmol) and DMF (BbbBml). The crude product was recrystallized from EUN to obtain 123 mg of a whitish solid product (47905), temp.pl. 212-242 C (gradually decomposes). "H NMR (DMSO-dv) w: 13.07 (Bg 85, 1H); 8.48 (c, 1H); 8.44 (c, 1H); 8.24 (a,

U-2.3Hz, 1H); 8.06 (aa, 0-2.3, 8.7Hz, 1); 7.76 (ai, o-1.9, 7.4 NE, 1n); 7.70 (a, 0-8.7Hz, 71N); 7.66 (a,

U-81GHz, 1H); 7.51 (yes, 9-21, 7.9Hz, 1); 7.46 (ad, 9-1.9, 7.9Hz, 1H); 4.47 (c, 2H). ZS NMR (DMSO-dv) million: 159.7, 156.8, 153.6, 151.5, 146.1, 143.6, 138.5, 134.0, 132.1, 131.8, 131.5, 130.5, 130.2, 129.9, 128.95..YDC CM 128.8, 122.2, 120.3, 32.0. MS (ER): t/:2 499.0 (MU). Analysis, calculated: for С»20Н412СИВгМ6О5.0,2С2НеО.0,О5КСИ: d)

C, 47.79; H, 2.59; M, 16.39; 5, 6, 25. Found: C, 47.56; H, 2.54; M, 16.25; 5, 6,58.

Compound Yu-018 3-(2-chlorophenyl)-"9H-purin-6-ylsulfanylmethyl)-trifluoromethyl-ZN-quinazolin-4-one

Prepared according to method C using intermediate 2t (200 mg, 0.53 mmol), i, b-mercaptopurine monohydrate (1000 mg, 0.588 mmol), CoCO 3 (82 mg, 0.593 mmol) and DMF (4 mL). The crude product was recrystallized from EN to obtain 148 mg of a white solid product (5695), temp.pl. 218.5-219.496. "N

NMR (DMSO-5) r: 13.52 (rg 8, 1H); 8.48 (c, 1H); 8.44 (in, 1H); 8.43 (a, 9-6.0 Hz, tn); 8.26 (a, 9-7.5Hz, - 1H); 7.84 (ad, 9-25, 6.7Hz, 1H); 7.70-7.75 (t, 2H); 7.51-7.59 (t, 2H); 4.40-4.55 (t, 2H). "ZS NMR (DMSO-dv) mln. 1: |se) 160.0, 157.2, 154.2, 151.4, 149.6, 144.4, 1434, 133.8, 133.0 (ad , 9U-5.1Hz), 132.0, 131.95 131.6, 131.4, ich- 130.6, 129.0, 127.3, 125.2 (yes, 9U-30Hz), 123, 6 (a, 9-273 Hz), 121.8, 32.6. MS (ER): t/2 489.0 (M). Analysis, calculated: for C 24H42SIRZMEO5: C, 51.59; H, 2, 47; SI, 7.25; M, 17.19; 5, 6.56. Found: C, 51.51; H, 2.55; SI, 7.37; M, 17.05; 5, 6, 38.

Compound Y-019 "3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-benzo|d)quinazolin-4-one shsh c Obtained according to method C, using intermediate 2n (200 mg, 0.56 mmol), b-mercaptopurine b-monohydrate (105mg, 0.619mmol), CoCO3 (8bmg, 0.619mmol) and DMF (4ml). The crude product a was recrystallized from EUN to obtain 128mg of a dark yellow solid product (48905). mp 247.8-254.496 (decomposed). 1N NMR (DMSO-αiv) tsh: 13.56 (Bg 8, 1H); 8.90 (85, 1H); 8.50 (v, 1H); 8.46 (c, 1H); 8.34 (c, 1H); 8.27 (a, 9-8.2Hz, t1Hn); 8.16 (a, 9-82Hzc, tn); 7.81 ( aa, 0-16, 7.3Hz, 1); 7.70 (5 9-7.5Hz, 1); - 7.61-7.74 (t, 2H); 7.49 (B 9-7, 5Hz, 1H); 7.44-7.53 (t, 1H); 4.44-4.56 (t, 2H). C NMR (DMSO-yv) ppm: 161.3,

FO 151.6, 151.5, 143.95 142.2, 136.7, 134.4, 131.8, 131.6, 130.5, 129.7, 129.3, 128.8, 128, 3, 128.3, 1271, 125.2, 119.5, 32.4. MO (ER): t/2 471.0 (M"). Analysis, calculated: for C2/H5SIMgO5.0.2САНО.0.05КСИ: С, 60.57; - Н, 3.37; СИ, 7, 69; M, 17.37; 5, 6.63. Found: C, 60.24; H, 3.46; SI, 7.50; M, 17.34; 5, 6.69. av | 250 Compound 0-020 b-chloro-3-(2-chlorophenyl)-2-(9ZH-purin-b-yl-sulfanylmethyl)-ZH-quinazolin-4-one c» Obtained according to method C, using intermediate 24 (200Omg, 0.587mmol), b-mercaptopurine monohydrate (11mg, 0.6b4bmmol), CoCO3 (9mg, 0.6b5immol) and DMF (B5ml). The crude product was recrystallized from EN to obtain 113mg of a yellow crystalline solid (42905), mp 59 237.1-238-22С (decomposed). "H nNMR (DMSO-γ) w: 13.55 (rg 5, 1Н); 8.48 (c, 1H); 8.44 (85, 1H); 8.11 (c, (F) 1H); 7.94 (4.9U-8.3Hz, 1H); 7.78 (a, 9U-8.1Hz, 2H); 7.66 (a, 9U-6.7Hz, 1H); 7.48-7.56 (t, 2H); 4.48 (c, 2H). ZS nMR co (DMSO-iv) million: 159.8, 156.8, 153.5, 151.5, 145.8, 143.6, 135.7, 134.0, 132.2, 132.1 , 131.5, 130.5, 1302, 129.8, 128.8, 125.8, 121.92 32.0. MS (ER); t/2 455.0 (M'). Analysis, calculated: for 60 Со9Н.оСИ,М.О5.0,1С.НЭО.06НОО 015КСИ: С, 50.34; H, 2.89; SI, 15.82; M, 17.44; With, 6.65. Found: C, 50.02; H, 2.63; C1, 15.51; M, 17.39; 5, 6,81.

CompoundYur-021 8-chloro-3-(2-chlorophenyl)-2-(9ZH-purin-6b-yl-sulfanylmethyl)-ZH-quinazolin-4-one

Prepared according to method C using intermediate 2p (200mg, 0.589mmol), b-mercaptopurine monohydrate (124mg, 0.72bmmol), CoCO3 (100mg, 0.72bmmol) and DMF (4ml). The crude product was recrystallized from EN to obtain 202 mg of a white solid product (7595), temp.pl. 211.9-212.7 "S

(decomposes). IR nMR (DMSO-α) r: 13.54 (rg 85, 1H); 8.47 (c, 1H); 8.44 (in, 1H); 8.12 (a, 2-7.9Hz, 1H); 8.07 (a, 9-7.6 Hz, 1); 7.78 (a, 9-7.5 Hz, 1); 7.67 (a, 9-7, hz, 1); 7.58 (5 9-7.9 Hz, 1H); 7.42-7.54 (t, 2H); 4.52 (in, 2H). ZS NMR (DMSO-yv) million: 1603, 156.9, 153.9, 151.5, 149.7, 143.5, 135.7, 134.0, 132.1, 2 131.8, 131.4 , 131.1, 130.5, 130.3, 128.9, 128.3, 126.1, 122.4, 32.5. MS (ER): t/2 455.0 (M"). Analysis, calculated: for Co20Ni2SiOMeO5: C, 52.76; H, 2.66; SI, 15.57; M, 18.46; 5.7 ,04. Found: C, 52.65; H, 2.79; SI, 15.32;

M, 18.47; 5, 7, 18.

Compound OYU-022 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-b-yl-sulfanylmethyl)-ZN-quinazolin-4-one

Prepared according to method C using intermediate 2c (200mg, 0.619mmol), b-mercaptopurine monohydrate (11mg, 0.6b8immol), K2CO3 (95mg, 0.687mmol) and DMF (4ml). The crude product was recrystallized from EN to obtain 14 mg of a white solid product (5395), temp.pl. 151.4-154.2 "6 (decolorizes). IN nMR (DMSO-α) c: 13.55 (rg 5, 1H); 8.48 (85, 1H); 8.44 (in, 1H); 8.23 (yes, 9-63, 8.7Hz, 7.77 (yes, 9-1.7.7.4Hz, 1H); 7.64 (a, 9-7.4Hz, 1H); 7, 57 (a, 9-9.8Hz, 1H); 7.45-7.52 (t, 4.48 (85.23). C NMR (DMSO-yv)mln"!: 169.0 (4, 9 -253Hz), 162.6, 159.3, 157.0, 154.0, 152.2, 151.7 (0.9-13Hz), 146.1, 136.5, 134.7, 134.2 , 134.0, 133.0, 132.6 (0, 9-11Hz), 131.3, 120.2, 118.9 (a, 0-24Hz), 115.3 (a, 90-22Hz), 346. MO (ER): t/2 439.0 (M"). Analysis, calculated: for C 20H42SiEMkO5.0.4H25O 0.15KSI: C, 52.52; H, 3.22; SI, 8.57 ; M, 17.67. Found: C, 52.25; H, 3.11; SI, 8.20; M, 17.69.

Compound Yu-023 3-(2-chlorophenyl)-7-nitro-2-"ZH-purin-6-yl-sulfanylmethyl)-ZH-quinazolin-4-one

Prepared according to method C using intermediate 20 (216 mg, 0.617 mmol), b-mercaptopurine monohydrate (11 mg, 0.6 mg), CoCO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was recrystallized from EN to obtain 212 mg of a yellow crystalline solid product (7490), temp.pl. He 218.0-218.32С (decomposes). "H NMR (DMSO-dv) w: 13.56 (rg 85, 1H); 8.49 (b, 1H); 8.42 (b, 1H); 8.38-8.45 (5) (t , 2H); 8.31 (4, U-8.4Hz, 1H); 7.81 (a, U-6.5Hz, 1H); 7.68 (a, U-6.7Hz, 1H); 7 .43-7.58 (t, 2H); 4.53 (z, 2H). SS NMR (DMSO-yv) ppm: 157.7, 154.4, 153.3, 149.8, 149.3 , 147.6, 145.2, 141.4, 131.5, 129.8, 129.7, 129.2, 12854, 127.1, 126.7, 122.7, 120.3, 1194, 299 MS (ER): t/2 466.0 (M). Analysis, calculated: for so

SooN.oSIM,O.5.0.4S.NYO.0.05KSI: C, 51.19; H, 2.97; 0.7.63; M, 20.09; 5, 6,57. Found: C, 51.27; H, 2.88;

SI, 7.40; M, 20.04; 5, 6,52. at

Compound 0-024 "- 3-(2-chlorophenyl)-6-hydroxy-2-"9H-purin-6-yl-sulfanylmethyl)-ZH-quinazolin-4-one

Prepared according to method C using intermediate 2p (200mg, 0.552mmol), p-mercaptopurine monohydrate (117mg, 0.6b85mmol), CoCO3 (9B5mg, 0.687mmol) and DMF (4ml). The crude product was recrystallized from EYN to obtain 182 mg of a white solid mixture of the desired product and the acetyl derivative.

Part of this material (120 mg) was suspended in a mixture of MeonN (2 ml) and an aqueous solution of MansSoO»z (saturated, 1 ml) and was stirred rapidly for 4 hours. The mixture was concentrated in a vacuum, suspended in water (1 Oml) and stored at 42C overnight. The white solid product was collected and dried to 10 Zmg (66905), room temp. 186-214 " (gradually decomposes). H NMR (DMSO-dv) w 8.48 (in, 1H); 845 (c, 1H); 7.71 (a, o-6.8Hz, 1H); - p 7.62-7; 64 (t, 2H); 7.43-7.51 (t, 2H); 7.40-7.43 (t, 1H); 7.35 (9.9-8.8 Hz, 1H); 4.39-4.52 (t, 23). ZS NMR "" (DMSO-a million): 160.6, 157.1, 156.2, 151.4, 150.8, 149.3, 144.1, 140.2, 134.5, 132.2, 131 ,6, 131.4, 1304, " 129.3, 128.7, 124.8, 121.7, 109.8, 32.0. MS (ER): t/2 437.0 (MU). Analysis , calculated: for (2 15 СооН.зСИМ5О.5.0,1С.ХНО.6НХО: C, 49.68; H, 3.88; SI, 7.26; M, 17.21; 5, 6.57. Found : C, 49.43; H, 3.62; -I SI, 7.32; M, 17.07; 5, 6.58.

Compound Yu-025

Me, 5-chloro-3-(2-chlorophenyl)-2-(3H-purin-b-yl-sulfanylmethyl)-3H-quinazolin-4-one - Prepared according to method C using intermediate 21 (30mg, 0, 883mmol), 20b-mercaptopurine monohydrate (165mg, 0.972mmol), K»CO3 (134mg, 0.972mmol) and OMR (4ml). The crude product was recrystallized from EUN to obtain 341 mg of a pale orange crystalline solid product (85965), se» temp.pl. 233.7-234.42С (decomposes). "H NMR (DMSO-α) w: 13.58 (rg 85, 1H); 8.50 (b, 1H); 8.47 (b, 1H); 7.77-7.85 (t, 2H) ; 7.68 (a, U-8.1Hz, 2H); 7.65 (a, 9U-7.7Hz, 1H); 7.41-7.56 (t, 2H); 4.45 (9, 9-1.2 Hz, 23). C NMR (DMSO-v) mln"!: 158.7, 156.8, 153.8, 151.5, 149.6, 143.5, 1354, 134.1, 133.3, 132.2, 131.6, 130.5, 130.2, 29 128.8, 127.1, 117.6, 32.0. MS (ER): t/2 455.0 (M"). Analysis, calculated: for С 20Н42СИ"М6О5.СоНеО.0.3Но: С,

F! 52.14; H, 3.70; SI, 13.99; M, 16.58; 5, 6,33. Found: C, 52.07; H, 3.37; SI, 13.40; M, 16.65; 5, 6, 42.

Compound Yu-026 about 3-(2-chlorophenyl)-5-methyl-2-(-9H-purin-b-yl-sulfanylmethyl)-ZN-quinazolin-4-one

Prepared according to method C using intermediate 29 (30mg, 0.940mmol), b-mercaptopurine monohydrate (17bmg, 1.0mmol), Co»CO3 (142mg, 1.03mmol) and DMF (bml). The crude product was recrystallized from EN to obtain 324 mg of a white solid product (7995), temp.pl. 227.8-230.1 "C (decomposes). IN NMR (DMSO-yv) w: 13.57 (Bg 85, 1H); 8.49 (in, 1H); 8.47 (c, 1H); 7.69-7.78 (t, 2H); 7.66 (a, 9-7.3Hz, 1H); 7.55 (a, 9U-7.9Hz, 1H); 7.39-7.52 (t, 1H); 7.36 (4, U-6.9Hz, 1H); 4.38-4.50 (t, 2H); 2.74 (in, ZN). C bv5 NMR (DMSO-ydv)mln"!: 161.2, 156.3, 152.4, 151.5, 148.6, 143.9, 141.0, 134.6, 134.5, 132, 3, 131.7, 131.4, 130.4, 130.2, 128.7, 125.7, 119.0, 32.0, 22.8. MS (ER): t/2: 435.0 (M'). Analysis, calculated: for

С.4Н.БСИМ»О5.0.65СоНо.0.1НО: С, 57.40; H, 4.13; SI, 7.60; M, 18.01; 5, 6.87. Found: C, 57.11; N, 3.96; SI, 7.45; M, 17.79; 5, 6,90.

Compound OYU-027 3-(2-chlorophenyl)-6,7-difluoro-2-(("9H-purin-b-yl-sulfanylmethyl)-ZH-quinazolin-4-one

Prepared according to method C using intermediate 24 (200mg, 0.58bmmol), b-mercaptopurine monohydrate, (11mg, 0.645mmol), CoCO3 (89mg, 0.645mmol) and DMF (4ml). The crude product was recrystallized from EN to obtain 14 mg of a pale yellow crystalline solid product (53965), temp.pl. 207.82 (decolorizes; evaporates at 136 2С). "H NMR (DMSO-α) w: 13.57 (rg 5, 1H); 8.49 (v, 70 1n); 8.46 (5, 1); 8.11 (5 9-94Hz, tn) ; 7.88 (aa, 0-73, 11Hz, yin); 7.77 (aa, o-1.7, 7.3Hz, 1); 7.67 (a,

U-7.4Hz, 1H); 7.42-7.55 (t, 2H); 4.48 (c, 2H). C NMR (DMSO-dv) mln"!: 159.5 (a, U-2.5 Hz), 154.6 (ai, 9-14, 255 Hz), 154.0 (a, 9-1.5 Hz), 151.5, 149.3 (aa, 90-14, 250Hz), 145.1 (90, 90-12Hz), 143.95 133.9, 132.1, 131.8, 131.4, 130.5 , 128.9, 118.0 (y, 0-4.9Hz), 115.8 (a, 9-18Hz), 114.6 (a, 9-20Hz), 32.0. MS (ER): t /2 457.0 (MU.

Analysis, calculated: for С 20Н44СИРоМ.ОЗ: С, 52.58; H, 2.43; SI, 7.76; M, 18.40; 5, 7,02. Found: C, 51.81;

H, 2.37; SI, 7.49; M, 18.04; 8, 7.55.

Compound Yu-028 3-(2-chlorophenyl)-6-fluoro-2-(9H-purine-bil-sulfanylmethyl)-ZN-quinazolin-4-one

Obtained according to method C using intermediate 2g (118mg, 0.3b5mmol), b-mercaptopurine monohydrate (bZmg, 0.402mmol), Co»CO3 (5bmg, 0.402mmol) and DMF (2ml). The crude product was recrystallized from EYN to obtain 10 mg of a whitish crystalline solid product (64905), room temp. 232.8-233.02С. (discolors). TN nMR (DMSO-α) r: 13.56 (rg 8, 1H); 8.48 (8.1H); 8.44 (8.1H); 7.81-7.86 (t, ZN); 7.76 (a, 9-7.5Hz, 1H); 7.67 (a, 9-7.5Hz, 1H); 7.40-7.54 (t, 2H); 4.48 (bg z, 23). SS NMR (DMSO-4 mln. 160.8 (a, 9-247Hz), 160.2 (a, 9-3.3Hz), 156.9, 152.3 (0, 9U-1.9Hz), 151 ,5, 149.7, 1440, s 143.6, 134.1, 132.1, 131.7, 131.5, 130.5, 130.4, 130.2, 128.8, 124.0 (4, u0-24Hz), 122.0 (a, 0-8.7Hz), 111.7 o (a, 9-24Hz), 32.0. MS (ER): t/2 439.0 (M). Analysis , calculated: for С2оНиоСИЕМ6О5.0.2СоНо.0.1Н20: С, 54.46;

H, 3.00; SI, 7.88; M, 18.68. Found: C, 54.09; H, 2.73; SI, 7.80; M, 18.77.

Compound Yu-029 2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZN-quinazolin-4-one so

Thionyl chloride (2.2 mL, 30 mmol) was added to a stirred solution of 2-amino-β6-methylbenzoic acid (1.51 g, 3 mmol) in benzene (5 mL) and the mixture was refluxed for 18 hours.

After cooling, the solvent was removed under vacuum and washed twice with benzene (25 ml). The residue was dissolved in "-

SNI" (5 Oml) and treated with 2-isopropylaniline (2.83 ml, 20 mmol). The pulp was further heated at reflux for 3 hours. At this time, the reaction was determined to be complete by TLC (5095 ethyl acetate/hexane). After cooling to room temperature, the reaction mixture was poured onto a 4-cm tampon - silica gel and washed with a mixture of 2095 ethyl acetate/hexane. The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in HOAc (50ml) and treated with chloroacetyl chloride (1.bml, 200mmol) and the mixture was heated at reflux for 18 hours. The reaction mixture was cooled and concentrated in vacuo. The remaining HOAc was removed by azeotropic distillation with toluene (25 ml) three times. The residue was dissolved in toluene (MOml) and passed through a 4-cm pad of silica gel, washing with a mixture of 20905 ethyl acetate/hexane. The product containing fractions were identified by LC-MS (MS (ER): t/2 327 (Mec)) and concentrated in vacuo to give 975 mg (3090) as a white foam. White foam chloride I (45mg, 1.3bmmol) was dissolved in DMF (10ml) and treated with adenine (275mg, 2.04mmol) and K2CO3 (281mg, 2.04mmol) and the mixture was stirred overnight at room temperature. The suspension was then poured into 200 ml of water, stirred at room temperature for 30 minutes, then cooled in the refrigerator for 30 minutes. - The formed solid product was collected by vacuum filtration and recrystallized from EUN to obtain

He» 285mg (4995) of whitish solid blowdown, temp.pl. 258.0-258.22С. "H NMR (DMSO-aiv) w: 8.19 (b, 1H), 8.09 (b, 1H), 7:60 (t, 3H), 7.45 (t, 2H), 7.23 ( t, ZN), 5.11 (a, 9-17.5 Hz, 1H), 4.71 (a, 9-17.5 Hz, 1H); 2.68 (c, ZN), which 2.73 ( a, 9-6.9Hz, 1H), 1.34 (a, U-6.8Hz, ZN), 1.13 (94, 9-6.8Hz, ZN). C NMR (DMSO-dv) mln. : 161.9, 156.2, (av) 50 152.8, 151.6, 150.1, 148.4, 1461, 142.2, 140.8, 134.3, 133.7, 130.6 , 130.0, 129.0, 127.7, 127.6, 125.8, 119.2, 118.4, 44 8, 28.3, 24.4, 23.3, 22.9. MO ( ER) t/2 426.4 (Mk). Analysis, calculated: for SodNozM,O: C, 67.75; c" H, 5.45; M, 23.04. Found: C, 67.60; H , 5-.45; M, 22.82.

Compound Y-0O30 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one 99 Thionyl chloride (2.2 ml, 0 mmol) was added to a stirred solution of 2-amino- b6-methylbenzoic acid

HF) (1.51 g, tOmol) in benzene (5Oml) and the mixture was heated at reflux for 18 hours.

After cooling, the solvent was removed under vacuum and washed twice with benzene (25 ml). The residue was dissolved in

SnCl3 (5.0ml) and treated with o-toluidine (2.13ml, 20mmol). The pulp was further heated at reflux for 3 hours. At this time, the reaction was determined to be complete by TLC (5095 ethyl acetate/hexane). After cooling to room temperature, the reaction mixture was poured onto a 4-cm pad of silica gel and washed with 20905 ethyl acetate/hexane. The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in HOAc (50ml) and treated with chloroacetyl chloride (1.bml, 200mmol) and the mixture was heated at reflux for 18 hours. The reaction mixture was cooled and concentrated in vacuo. The remaining HOAc was removed by azeotropic distillation with toluene (25 ml) three times. The residue was dissolved in toluene (MOml) and passed through a 4-cm pad of silica gel, washing with a mixture of 2095 ethyl acetate/hexane. The product containing fractions were identified by LC-MS |MS (ER): t/2 299 (M)) and concentrated in vacuo to give 47 mg (1690) as a white foam. A white foam chloride (47mg, 1.57mmol) was dissolved in DMF (10ml) and treated with adenine (423mg, 3.14mmol) and KCO (43mg, 3.14mmol) and the mixture was stirred overnight at room temperature. The suspension was then poured into 200 ml of water, stirred at room temperature for 30 minutes, then cooled in the refrigerator for 30 minutes. The formed solid product was collected by vacuum filtration and recrystallized from EUN to obtain 12 mg (2095) of a whitish solid product, temp.pl. 281.5-282; 7 "C (decomposes). "H NMR (DMSO-a,) w 8.07 (8, 1H); 8.05 (8.1H); 7.61 (5 9-7.8Hz, 1H), 7.48 (t, 4H), 7.25 (t, ЗН), 5.09 (a, 70. 4-17.4Hz, 1H); 4.76 (a, 9-17.4Hz, 1H), 2.73 (in, ЗН), 2.18 (in, ЗН). C NMR (DMSO-dv) million: 161.3, 156.2, 152.8, 151.4, 150.0, 148.5, 142.2, 140.9, 1361, 1354, 134.3, 131.7, 130.1, 130.6, 129.0, 128.0, 125.8, 119.2, 118.5, 44.8, 22.9, 17.4. MS (ER): t/2 398.2 (M). Analysis, calculated: for C 22Hlo9M7O: C, 66.49; N, 4.82; M, 24.67. Found: C, 66.29; N, 4.78; M, 24.72.

Compound Yu-031 3-(2-fluorophenyl-5-methyl-2-(9H-purin-6b-yl-sulfanomethyl)-ZH-quinazolin-4-one

Thionyl chloride (2.2ml, 30mmol) was added to a stirred solution of 2-amino-b6-methyl-benzoic acid (1.51g, 10mmol) in benzene (50ml) and the mixture was heated at reflux for 18 hours.

After cooling, the solvent was removed in vacuo and washed twice with benzene. (25ml). The residue was dissolved in

CHO" (5 Oml) and treated with 2-fluoroaniline (1.93 ml, 20 mmol). The pulp was further heated at reflux for 3 hours. At this time, the reaction was determined to be complete by TLC (5095 ethyl acetate/hexane). After cooling to room temperature, the reaction mixture was poured onto a 4-cm pad of silica gel and washed with 2095 U(OdAc/hexane). The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in HOAc (5 Oml) and treated with chloroacetyl chloride (1, bml, 20Omol) and the mixture was heated at reflux for 18 hours. The reaction mixture was cooled and concentrated in vacuo. The NOAc residue was removed by azeotropic distillation with toluene (25ml) g) three times. The residue was dissolved in toluene (MOml) and passed through a 4-cm pad of silica gel, washing with a mixture of 20O 9O ethyl acetate/hexane. The product containing fractions were identified by LC-MS |MS (ER): t/2 303 (M'k)) and concentrated in vacuo to give 1.12g (37905) as a white foam. A white foam chloride (455mg, 1.560mmol) was dissolved in DMF (10ml) and treated with b-mercaptopurine monohydrate (510mg, 3.0mmol) and K»CO»z o (d14mg, 3.0mmol) and the mixture was stirred overnight at room temperature . The suspension was then poured into about 200 ml of water, stirred at room temperature for 30 minutes, then cooled in the refrigerator for 30 minutes. The formed solid product was collected by vacuum filtration and recrystallized from (7

EUN to obtain 487 mg (7796) of a whitish solid product, temp.pl. 151.9-152.2 "S. "H NMR (DMSO-dv) and He) 8.48 (85, 1HO, 8.44 (5, 1M), 7.70 (t, 2H); 7.48 (t, 2H), 7.33 ( t, ZN), 4.55 (a, 9U-15.1Hz, tn); 4.48 (a,

U-15.1 GHz, 1), 2.73 (v, ZN). C NMR (DMSO-yv) million: 161.3, 157.8 (y, 9-249.1 Hz), 156.9, 152.8, 151.5, te 149.6, 148.6, 143, 6, 140.9, 134.7, 131.9 (a, 9-8.0Hz), 131.4, 130.2, 125.6 (a, 9-36Hz), 125.5, 124.4 ( and,

U-13.5Hz), 118.8, 116.6 (a, 9-19.6Hz), 56.4, 22.9. MS (ER): t/2 419.5 (M'). Analysis, calculated: for

S. Khnibem.O5.0,15.SoNhO: C, 60.14; N, 3.77; R, 4.47; M, 19.76; Z, 7.54, Found: С, 59.89; N,Z,88; R, 4.42; "

M, 19,42; 5.7,23. - c Compound Y-032 c 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-ZN-quinazolin-4-one "» Obtained according to method C, using 2) (200 mg, 0.62bmmol), adenine (9Zmg, 0.689mmol), CoCO3 (95mg, 0.689mmol) and DMF (Zmp). The crude product was chromatographed in a mixture of MeOH/CH»oCl» to obtain 101 mg of a whitish solid product (39965), temp.pl . 262.0-266.59С. "H NMR (DMSO-div) w: 8.08 (8, 1Н); 8.07 (in, 1H); - 7.70 (5 u-8.0 Hz, 1); 7.58 (aa, 9-06, 7.9Hz, 1H); 7.43-7.57 (t, 4H); 7.36 (yes, 9-0.7, 8.0Hz, 1H); 7.26 (rg b c, 2H); 5.12 (a, U-18Hz, 1); 4.78 (a, U-18Hz, 1H); 2.20 (in, ZN). ZS NMR-(DMSO-iv) million: 158.7, 156.2, 152.9, 152.7, 150.0, 149.4, 142.1, 1361, 1351, 135.0, 133.2 , 131.8, 130.3, 130.1, 128.95 128.1, 127.2, 118.5, - 117.9, 44.9, 17.4. MS (ER): t/2 418.1 (MU). Analysis, calculated: for С 24Н.6СИМеО.0.1н20.0.05КСИИ: С, 59.57; H, (av) 50 3.86; SI, 8.79; M, 23,16. Found: C, 59.65; H, 3.80; SI, 8.70; M, 22.80.

Compound Yu-0O33 c» 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxy-phenyl)-ZH-quinazolin-4-one

Prepared according to method C using 21 (25mg, 0.74bmmol), adenine (111mg, 0.821mmol), K»CO»z (113mg, 0.821mmol) and DMF (4ml). The crude product was chromatographed in a mixture of Meon/SnHhCSiI and 99 was recrystallized from EN to obtain 124 mg of a brown solid product (3895), temp.pl. (F. 257.0-257.120. "H NMR (DMSO-yv) w: 8.06 (8, 71H); 8.01 (v, 1H); 7.71 (5 9U-8.0Hz, 1H) 7.57 (aa, 9-09, ko 7.9HzC, 1); 7.52-7.59 (t, 1H); 7.50 (da, -1.6,7.8Hz, 1H); 7.38 (ai, 9-11, 82Hz, 1); 7.27 (aa, 3-0,6,8,3Hz, 1H); 7.24 (Bg 5, 2); 7.17 (a 9-0.9, 7.6Hz, 1); 5.07 (a, 9dU-17Hz, 1H); 4.97 (a, 9-17Hz, 1); 3.79 (c, vo ZN). 132 NMR (DMSO-dv) ppm: 158.8, 156.2, 154.7, 153.2, 152.8, 150.1, 149.3, 142.0, 135.1, 133.2, 131 ,8, 130.1, 130.1, 127.2, 123.8, 121.6, 118.4, 117.9, 113.1, 56.2, 44.8. MS (ER): t/ 2,434.0 (M). Analysis, calculated: for C 21H46SIM,O".0.5H20.0.04KSI: C, 56.57; H, 3.84; SI, 8.27; M, 21.99 Found: C, 56.29; H, 3.75; SI, 8.21; M, 21.61.

The following compounds were prepared generally according to the methods described above and are intended to further illustrate certain embodiments of the compounds of the invention: 3-(2,6-dichlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH -quinazolin-4-one (a-034) -B4-

3-(2-isopropylphenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one (а-035) 3-(2-methoxyphenyl)-2-(9H-purine) -β6-ylsulfanylmethyl)-ZN-quinazolin-4-one (a-036)

Z-benzyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-037)

C-butyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-038)

Z-morpholin-4-yl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate (a-039) 3-(3-methoxyphenyl)-2-(9H-purin-b6 -ylsulfanylmethyl)-ZH-quinazolin-4-one (a-040) 3-(3-chlorophenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-041) 2- (9H-purin-b6-ylsulfanylmethyl)-3-pyridin-4-yl-3H-quinazolin-4-one (а-042) 70 3-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl) -ZN-quinazolin-4-one (a-043)

C (4-methylpiperazin-1-yl)-2-"9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate (a-044) ethyl ester |5-fluoro-4-oxo-2- -9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl|acetic acid (a-045) 3-(2-methoxyphenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one (a-046) 3-(2-methoxyphenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-047) 2-(6-aminopurine- 9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-ZN-quinazolin-4-one (a-048) 2-(6-aminopurin-9-ylmethyl)-3-benzyl-5-fluoro-ZN -quinazolin-4-one (a-049) 2-(6-aminopurin-9-ylmethyl)-3-butyl-ZN-quinazolin-4-one (a-o0550) 2-(6-aminopurin-9-ylmethyl) -3Z-morpholin-4-yl-ZN-quinazolin-4-one, acetate (a-051) 3-(4-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one (a-052).

Additional compounds according to the present invention were obtained by the following methods of synthesis.

The following intermediates were obtained by the above-described method A. ! o niya a a sly ni, iy ah (8) i, y eh TE z. 8 ts ss sk p; In o.

Z Ya Beh Y Bai Ga") floor sx "-

For K - cyclopropyl -

3B Kk - cyclopropylmethyl

Cs K - phenethyl for Kk - cyclopentyl "

Ze K - 3-(2-chloro)pyridyl with 70 ZK - 4-(2-methyl)benzoic acid with Za K - 4-nitrobenzyl: z» Zp K - cyclohexyl

With K - E-(2-phenyl)cyclopropyl

Additional compounds according to the presented invention (a-053-0-070), having 15 core structure: -I (22) - 4 5. o - c» and DC. time

Her. them - ; and to AL » for Mt vv Y t ;

Z, zhi B; i I bo Z. sema 00050000 bo 0-053 /|cyclopropyl s rova |cyclopropyl methit 18.

BoBt Fet 0118

Be (cyclolenty 8. 0:ovo 0-061 13-(2-chloro)pyridyl (v. 0p-062 |3-(2-chloro)pyridyl 2053 a-ometite) beshoina kisshiv V. rova (cyclopretya V. 065 ov Annrobenia B. i5 vt (cyclovyt B. 0-070 | E-(2-phenyl) cyclopropyl IV. s 7 o so (av) «-- (Se) v. - . it - (o) -y (av) Sat» ko 60 b5

AND

I yu KN g. and KE village

What I She V ("in)

E t. g su M « 3: 7 s V "z -I a AJ, for another 50 h with che i NS o Kach Z yuyu m u Kona:

What happened in 1965

I yu KN g. and KE village

What I She V ("in)

E t. g su M « 3: 7 s V "z -I a AJ, for another 50 h with che i NS o Kach Z yuyu m u Kona:

That aa riya in 65 s

I yu KN g. and KE village

What I She V ("in)

E t. g su M « 3: 7 s V "z -I a AJ, for another 50 h with che i NS o Kach Z yuyu m u Kona:

What aa ria at 65

Obtained according to method C, using Za (100mg, 0.4mmol), 2-amino-β6-mercaptopurine (8Omg,

O.48mmol) and KSO" (77mg, 0.5bmmol). The product was purified by trituration in water. "H NMR (DMSO-dv) w: 7.89 (a,

U-0Hz, 1); 7.54 (5 9-74 Hz, 1); 7.34 (a, 9-8, hz, 1); 7.19 (a, 9-7.2 Hz, 1); 6.28 (c, 2H); 4.94 (in, 2H); 2.70 (in, ZN); 1.24 (a, 9U-6.5Hz, 2H); 0.91 (8, 2H). MS (ER): t/2 380 (MAN), 190.

C-cyclopropylmethyl-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one. (a-054)

Obtained according to method C, using ZB (30mg, 1.14mmol), b-mercaptopurine monohydrate (214mg, 1.2bmmol) and KSO" (189mg, 1.37mmol). The product was purified by trituration with water, and then by recrystallization from

Meon. "H NMR (DMSO-dv) w: 13.60 (rg 8, 1H); 8.72 (8, 1H); 8.48 (v, 1H); 7.63 (5 9-7.8Hz, 1H ); 7.42 (a, 70 3-8.0 Hz, 1); 7.28 (a, 9-7.3 Hz, 71); 5.01 (c, 2H); 4.11 (a, 0- 6.8 Hz, 2H); 2.78 (8, ZN); 1.35 (quintet,

U-6.2Hz, 1H); 0.44-0.59 (t, 4H). MS (ER): m/2 379 (MAN), 325. 2-(6-aminopurin-9-ylmethyl)-3-diclopropylmethyl-5-methyl-ZN-quinazolin-4-one. (a-055)

Prepared according to method C using ZB (ZOOmg, 1.14mmol), adenine (17Omg, 1.2bmmol) and K»CO»z (189mg, 1.37mmol). The product was purified by trituration with water, followed by recrystallization from MeOH. "H NMR 75 (DMSO-yv) w 8.21 (8, 1H); 810 (v, 1H); 7.52 (B 9-7.7Hz, 71H); 7.18-7.31 (t, ЗН); 7.06 (а, 9У-81Hz, 1Н); 5.6.8 (в, 2Н); 4.14 (а, 9-6.8HzС, 2Н); 2.77 (в, ЗН) ; 1.34 (quintet, 9U-6.4Hutz, 1H); 0.45-0.60 (t, 4H). MS (ER): t/2 362 (MAN), 308. 2-(2-amino -9ZH-purin-6-ylsulfanylmethyl)-3-cyclo-propylmethyl-5-methyl-ZH-quinazolin-4-one (a-056)

Obtained according to method C, using ZB (280mg, 1.1mmol), 2-amino-6-mercaptopurine (20Omg, 1.2mmol). and KSO" (180 mg, 1.0 mmol). The product was purified by trituration with MeOH. "H NMR (DMSO-dv) w 12.70 (bho85, 71); 7.95 (v, 1); 7.64 (5 -7.8Hz, 1); 7.44 (a, 0-7, 9Hz, 1); 7.28 (a, 9-7.4Hz, 1H); 6.41 (c, 2H); 4.91 (c, 2H); 4.05 (j, 9U-6.8Hz, 2H); 2.78 (v, ЗН); 1.26-1.43 (t, 1H); 0.36-0.56 (t, 4H). MS (ER): t/2 394 (M. H), 340. 5-methyl-3-phenethyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-057)

It was obtained according to method C, using Zc (75 Ω, 2.4 mmol), b-mercaptopurine monohydrate (442 mg, 2.6 mmol of urine) and CoCO»z (398 mg, 2.9 mmol). The product was purified by trituration with water. "H NMR (DMSO-dv) w 138.61 o) (5, 1H); 8.71 (b, 1H); 848 (b, 1H); 7.65 (5 9-7.7 Hz, 1); 7.44 (a, 0-7.9Hz, 1H); 7.16-7.35 (t, 6H); 4.89 (c, 2H); 4.29 (rgi, 9-7.9Hz, 2H ); 3.08 (g i, 9U-7.8Hz, 2H); 2.81 (z, ZN). MS (ER): t/2 429 (M.H), 105. 2-(2-amino -9UN-purin-6-ylsulfanylmethyl)-5-methyl-3-phenethyl-ZN-quinazolin-4-one (a-058) c zo Obtained according to method C, using Cc (75 Ωg, 2.4 mmol), 2- amino-6-mercaptopurine (435mgH, 2.bmmol) and KSO" (398mg, 2.9mmol). The product was purified by trituration with water. "H NMR (DMSO-dv) δ 12.61 o (5, 1H); 7.95 (in, 1); 7.65 (5 9-7.7Hz, 71); 7.45 (a, 9U-7.9HZ, 71Н); 7.14-7.32 (t, 6H); 6.44 (c, 2H); 481 "-- (in, 2H); 4.24 (hy, 9-7.9Hz, 2H); 3.04 (Bgi 9U-7.8Hz, 2H); 2.81 (from, ZN). MS (ER): t/2 444 (MAN), 340.

C-cyclopentyl-5-methyl-2-(9H-purine-b-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-059)

Obtained according to method C, using Za (10mg, 0.3bmmol), b-mercaptopurine monohydrate (73mMG, Ycc

0.4 mmol) and CoCO3 (100 mg, 0.72 mmol). The product was purified by recrystallization from MeOH. "H NMR (DMSO-dv) and 13.62 (rgv5, 1H); 8.77 (v, 1H); 8.48 (v, 1H); 7.62 (5 9-7.7 Hz, 71H); 7.42 (a, ju-7.8Hz, 2H); 7.26 (a, 9-7 4Hz, 1H); 5.03 (v, 2H); 4.80 (quintet, U-8.0Hz, 1H); 2.76 (v, ЗН); 2.12-2.31 (t, 2H); 1.79-2.04 (t, 4H); 1.44-1.58 " (t, 2H ). ) t s Obtained according to method C, using Za (10 mg, 0.5 mmol), adenine (58 mg, 0.4 mmol) and CoCO3 with (100 mg, 0.72 mmol). The product was purified by recrystallization from MeonH. "H NMR (DMSO-dv) w 8.15 (in, 1H); 8.11" (in, 1); 7.52 (5 9-7.7 Hz, 1H); 7.16-7.31 (t, ZN); 7.10 (a, 9-8.0 Hz, 2H); 5.68 (c, 2H); 4.78 (quintet,

U-8.3 Hz, 1); 2.74 (in, ZN); 2.09-2.32 (t, 2H); 1.86-2.04 (t, 2H); 1.68-1.86 (t,2H); 1.43-1.67 (t, 2H). MS (ER): t/: 376 (M.N), 308,154. and 3-(2-chloro-pyridin-3-yl)-5--methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one. (a-061)

Ge") Obtained according to method C using Ze (500 Ωg, 1.bmmol), b-mercaptopurine monohydrate (289mg, 1./mmol) KSO" (262mg, 1.9mmol). The product was purified by trituration in water. MS (ER): m/2 436 (MAN), 200. - 2-(6-aminopurin-9-ylmethyl)-3-(2-chloro-pyridin-3-yl)-5--methyl-ZN-quinazoline -4-on(a-062) av! 20 Prepared according to method C using Ze (500mg, 1.bmmol), adenine (23Omg, 1.7mmol) and CoCO3 Co (262mg, 1.9mmol). The product was purified by trituration in water. "H NMR (DMSO-dv) w: 8.59 (aa, 9U-1,7,4,8Hz, 1H); 8.22(aa, 9-1,7,7,8HzC, 1H): 8.025 ( c, 1H); 8.017 (c, 1H); 7.60-7.72 (t, 2H); 7.35 (9U-82HC, 2H); 7.22 (c, 2H); 5.12 (a .

3-methyl-4-(15-methyl-4-oxo-2-"9H-purin-6-ylsulfanyl-methyl)-4H-quinazolin-3-yl]-benzoic acid (a-063)

Obtained according to method C, using ZI (400mg, 1.17mmol), b-mercaptopurine monohydrate (219mg, (F) 1.29mmol) and CoCO»z (226mg, 1.64mmol). The product was purified by recrystallization from MEON "H NMR (DMSO-iv). 8:

GI 13.54 (rg 85, 1H); 8.44 (5.1H); 8.42 (in, 1H);. 7.80 (in, 2H), 7.71 (5 9U-7.7Hz, 71H); 7.59 (a, 9-8.6Hz, 1H); 7.52 (a, 9-7.9Hz, 1H); 7.34 (a, 0-74 NA, 1); 446 (a, 0-154Hz, 1H); 4.34 (а, ю0-15.7Hz, 1); 3.17 (a, in U-4.4Hz, 1H); 2.73 (in, ZN); 2.17 (in, ZN). MS (ER): t/2 459 (MAN)

C-cyclopropyl-5-methyl-2-"9H-purine-b-ylsulfanyl-methyl)-ZH-quinazolin-4-one (a-064)

Obtained according to method C, using Za (100mg, 0.4Omol), b-mercaptopurine monohydrate (9Omg,

0.5 mmol) and CoCO3 (97 mg, 0.7 mmol). The product was purified by trituration with water. "H NMR (DMSO-dv) w: 8.69 (a,

U-0.8Hz, 1H); 8.47 (c, 1); 7.57 (a, 9-7.9Hz, 1H); 7.37 (a, 9u-81GHz, 1); 7.23 (a, 9-7.3Hz, 1H); 5.08 (in, 65 2Н); 3.06-3.18 (t, 1H); 2.74 (in, ZN); 1.14-1.36 (t, 2H); 0.92-1.06 (t, 2H). 2-(6-aminopurin-9-ylmethyl)-3-cyclopronyl-5-methyl-ZN-quinazolin-4-one (a-065)

Prepared according to method C using Za (100mg, 0.400mmol), adenine (94mg, 0.7mmol) and K»CO»z (121mg, 0.88mmol). The product was purified by trituration with water. "H NMR (DMSO-dv) w: 8.19 (a, U-0.9Hz, 1H); 8.09 (a, 9-1.0Hz, 71); 7.48 (5 9-7.8Hz . t, 1H); 2.73 (v, 3H); 1.18-1.38 (t, 2H); 0.94-1.09 (t, 2H). 5-methyl-3-(4-nitrobenzyl )-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-066)

Prepared according to method C using Za (200mg, 0.58mmol), b-mercaptopurine monohydrate (148mg, 0.87mmol) and CoCO3 (16Omg, 1.1bmmol). The product was purified by trituration in MeOnH: "H NMR (DMSO-aiv) w 13.44 (Bbg 85, 71Н); 8.50 (85, 1Н); 8.31 (b, 1Н); 8.03 (а, 9 -8.6Hz, 2), 7.58 (5 9U-7.9Hz, 1H); 7.37 (a, 9U-8.3Hz, ZN); 710..7.22 (0, 20-7, 5HC, 1H); 5.44 (in, 2H); 4.70 (in, 2H); 2.6 6. (8, ZN). MS (ER): t/2 460 (M.N).

C-cyclohexyl-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl-ZH-quinazolin-4-one (a-067)

Obtained according to method C, using ZP (15mg, 0.52mmol), b-mercaptopurine monohydrate (97mg, 0.57mmol) and KSO" (86mg, 0.2mmol). The product was purified by trituration in MeOH. "H NMR (DMSO-aiv) w: 13.66 (bg 85, 1); 8.82 (v, 1H); 8.50 (v, 1H); 7.62 (5 9-7.7Hz, 1 ); 7.42 (a, 2-8.0Hz, 1); 7.26 (a, 9-7.3Hz, 19H); 19 5.01 (c, 2H); 4.11 (Bg 8, 1H ); 2.75 (v, ZN); 2.38-2.65 (t, 2H); 1.58-1.p90 (t, 4H); 1.37-1.57 (t, 1H); 0.71-1.26 (t, ZN). MS (ER): t/2 407 (MAN), 325. 2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-ZN- quinazolin-4-one (a-068)

Prepared according to method C using ZP (15mg, 0.52mmol), adenine (77mg, 0.57mmol) and CoCO3 (Vbmg, 0.62mmol). The product was purified by trituration in MeOH. "H NMR (DMSO-vv) w 8.15 (8, 2H); 7.54 (u

U-7.9 Hz, 71 N); 7.06-7.35 (t, 4H); 5.65 (from, 2H); 4.09 (rg 8, 1H); 2.73 (in, ZN); 1.41-1.90 (t, 6H); 0.99-1.34 (t, 4H). MO (ER): t/2 390 (MAN) 308. 2-(2-amino-9UN-purin-6-ylsulfanylmethyl)-3-cyclohexyl-5-methyl-ZN-quinazolin-4-one (a-069)

Obtained according to method C, using Zp (150mg, 0.52mmol), 2-amino-b-mercaptopurine (95mg, 00.57mmol) and K»CO»z (8bmg, 0.6b2mmol). The product was purified by reversed-phase HPLC (C18 Iip column, 4.62500mm, 4.7ml/min, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, Ho) detector at 220). MS (ER): m/2 422 (MAN), 340, 170. 5-methyl-3-(E-2-phenyl-cyclopropyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4 -on. (a-070)

Obtained according to method C, using Zi and b-mercaptopurine monohydrate. The product was purified with reversed-phase HPLC, (column C18 I pa, 4.6250 mm, 4.7 ml/minute, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 220). MO (ER): t/: 441. (av)

Additional compounds of the invention are listed below along with the synthesis route for compound Yu-071-0-118. -

Method O (Se) m. "shi s;" -And (22) - about 50 syu"

F) ime) 60 b5 syvyv t b y ay But! iz ye ak "Y I? And you

Sha Shk ak and El, z sh chu sey y ts cha: Shkya Ye : y v tesyvavvai

Riy ad Eh nya eat Still tea y y y Eh Mo u shik ih i K-. general zo Kak o oda Yu -

I i nd i t y E shchi sa niv A s vyh z-d t iv. fe What Mi and r on AI / o . TT co

Эепамб EE: because ! Y OK Tanya o: s with B ba ov. 65 Method E method

NNYA E zovivay z u v sh. o ssh: "- ;I'm looking for it; I'm looking for it; and 3

And and that and with and with zay; and there are also 7 tons of TT

Method: о ий Я Ге Г 7 ; E Y Z kn Her and Eh how I eat Y: aa ove stump ba ov. 65 The method is self-explanatory. at. і 4 o s ШХ Ч What is with "» Kk is ZY: ayv TI ze ne shny shi ShK nyu S a tai -i I S ; ! Mi What with fe pe even With

Щ SЯ nn o 20 t TT so a " І как 60 E І их Z ІІ І чо о: рн з о ІХ чах M vo nn dya ч B nn ba ov. 65 Method Yur: A mixture of amide 4a or 45, EMOS- of glycyl chloride and glacial acetic acid was heated to 1202 for 1-4 hours. The resulting mixture was concentrated in vacuo and purified by flash chromatography to afford the protected cyclized amine. This material was combined with 10 equivalents of octanethiol and a catalytic amount of OVI in THF and stirred at ambient temperature to the consumption of the starting material, which was determined by LC-MOS. The reaction mixture was poured directly into a flash chromatographic column (equilibrated in SNSi") and eluted at 0-596o Meon/SNsi" to obtain the free amine, for or 50. Compound 5c was obtained similarly , using (4) EMOS-alanyl chloride instead of EMOS-glycyl chloride.

Method E: Equimolar amounts of 5a or 56, acceptable b-chloropurine and SIEA were combined with EN in a small flask and heated to 802C. The reaction mixture was monitored regularly by LC-MS and purified as indicated.

Method P: A mixture of amide 4B5, acetoxyadetylchloryl and glacial acetic acid was heated to 120°C and stirred for 2 hours. The cooled reaction mixture was filtered and the solid products were washed

СНоСИ» to obtain the cyclized acetate as a white solid product. This material was combined with K»CO3 in aqueous methanol and stirred for one hour, then concentrated in vacuo. The solids formed were triturated with water to give a white solid. g s what y ; with Him

OO | | 3-(2-chlorophenyl)-5-fluoro-2-KU9H-purine-b-ylamino)-methyl|-3H-quinazolin-4-one. (a-072)

Obtained according to method E, using 55 (5mg, 0.165mmol) and b-chloropurine (26bmg, 0.165mmol) in 10 ml of EUN. After 5 days, the reaction mixture was purified by HPLC (column C18 I pa, 4.6250 mm, 4.7 ml/minute, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector, at 220A). "N

NMR (DMSO-5) p: 12.99 (pg 8, 1H); 8,14 (Bg 85, 1H); 8.12 (c, 1H); 7.85 (and 9U-5.7, 81Hz, 1H); 7.68-7.79 "9 (t, ZN); 7.57 (5 9U-62Hz, 1); 7.57 (а, 9У-7, игц, тн); 7.50 (a, O-81hz, 1H); 7.35 (ad, 9-8.4, 10.7 Hz, 1); 4.15-4.55 (t, 2H). MS (ER): t/2 422 (M.N), 211. o "- zv , M shk still i- ! I n F 2 k

U: that U

unit what

2-((2-amino-9H-purin-6-ylamino)methyl|-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one (a-074) - Obtained according to the method E, using 55 (5Omg, 0.1b65mmol) and 2-amino-b-chloropurine (28mgH, about 50 0.165mmol) in iml EN.After 5 days, the reaction mixture was purified by HPLC (column C18 I pa, 4.625O0mm, 4 ,7ml/minute, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, c" detector, at 220A). "H NMR (DMSO-iv) w 12.13 (g 8, 1H); 7, 86 (a 9-5.6, 8.2Hz, 1H); 7.76-7.83 (t, 2H); 7.68 (rgo8, 1); 7.61 (5 9-5.7hz, 1H ); 7.61 (a, 9-7.2Hz, 1); 7.53 (a, 9-8.2Hz, tn); 7.35 (da, 9-82, 10.9Hz, 1H); 5 .66 (Bg 5, 2H); 4.164.50 (t, 1H); 4.09 (ad, U-5.3Hz, 2H). MS (ER): t/2 437 (MAN), 219. , С .: Й -Я ю Я Я B. 65 | and, and-th

5-methyl-2-CUE-purin-6b-ylamino)methyl|-3-o-tolyl-ZN-quinazolin-4-one. (a-071)

Prepared according to method E using β-chloropurine (11 mg, 0.072 mmol) and 5a (20 mg, 0.072 mmol).

After 5 days, the reaction was quenched with water and the formed suspension was filtered. Solid products were purified using

HPLC (column C18 I ipa, 4.6250 mm, 4./ml/minute, 10-7595 acetonepril/water for 15 minutes, 10090 acetonepril for 18 minutes, detector at 220A). "H NMR (DMSO-α) w 12.98 (Bg 8, 1H); 8.14 (Bg 58, 1H); 8.10 (8, 1H); 7.58-7.79 (t, 2H) ; 7.37-7.48 (t, 4H); 7.26-7.36 (t, 2H); 3.93-4.39 (t, 2H); 2.75 (v, ЗН); 2 ,18 (85, ZN). MO (ER): t/2 398 (MAN), 199. then with SI and "V | Sh i Y with i and A

WITH

And, What 2-K2-amino-9UN-purin-6-ylamino)methyl|-5-methyl-3-o-tolyl-ZN-quinazolin-4-one. (a-073)

Obtained according to method E, using Ba (189mg, 0.677mmol) and 2-amino-b-chloropurine (115mg, c 0.677) in 3ml EJUN. After 3 days, the reaction mixture was filtered to remove excess purine and the filtrate was purified by HPLC (C18 IPA column, 4.625 Ohm, 4.7 ml/minute, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 220A) to obtain 7 mg of product as the TEA salt. "N

NMR (DMSO-Idv) y: 8.88 (Bho8, 1H); 8.21 (8.1H); 7.71 (B 9-7.7Hz, 1H); 7.45-7.56 (t, 2H); 7.38-7.44 (t,

ZNU; 7.35 (a, 9-7.5 Hz, 1H); 7.30 (rg ov, 1H); 4.40 (ai, o-4.5, 17.5 Hz, 1); 4.27 (yes, 9-53, 17.4Hz, 1); 2.75 "s (8, ZN); 2.0 9 (in, ZN). MS (ER): t/2 413 (MAN), 207, 163. o a. B , - :z" and "7: z and M - 2-K2-fluoro-9H-purine-b-ylamino)methyl|-5-methyl-3-o-tolyl-ZH-quinazolin-4-one. (a-076) o 20 Obtained according to method E, using ba (20mg, 0.072mmol) and 2-fluoro-6b-chloropurine (16bmg, 0.094mmol) in iml EUN. After 18 hours, the reaction mixture was purified by HPLC (column C18 I cpa, c» 4.625O0mm, 4.7ml/min., 10-75906 acetonpril/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 2202) and further recrystallized with EN to give 14 mg of product as a yellow solid. IN NMR (DMSO-α) ts: 13.12 (Bg 8, 1H); 8.40 (rBgo5, 1); 8.15 (c, 1H); 7.66 (5 U-7, I7 GHz, 1); 59 7.35-7.49 (t, 4H); 7.31 (0.9-7.2 Hz, 1H); 4.00-4.22 (t, 2H); 3.17 (in, 1H); 2.74 (in, ZN); 2.18 (in, ZN). MS

GF) (ER): t/2 416 (MAN), 208. name) 60 b5

70 " MORE : U. t (2-chlorophenyl)-dimethylamino-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-075) 0-015 (100mg, 0.228mmol) was combined with ammonium hydroxide (28-3095, iml) in DMF (2ml) and heated to 80260.

After 2 days, the reaction mixture was purified by HPLC (column C18 I pa, 4.6250 mm, 4.7 ml/min, 10-7590 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 220 29) to obtain the product as a yellow solid, approximately 2 mg. IN YaMe (DMSO-d5) w: 13.52 (rg in, 1H); 8.46 (5, 18); 8.42 (in, 1NK-7.69 (aa, 0-2,1,7,3Hz, 71H); 7.62 (aa, -1,6.7Hz, 1H); 7.61 (5 9 -8.0HzC, 1); 7.37-7.48 (t, 2H); 7.05 (a, 90-7.9Hz, 1H); 6.96 (a, 9-7.8Hz, 1H) ; 432-4.45 (t, 2H); 2.80 (in, 6H). MO (ER): t/2 464 (MN), 232. and in: | He

E Ii "i o

I E s ts s

From Kk Uch ("in") | NO I і- "ee: Y zv sht, y v. I Y "g MU K. U y Y Sh still dove, I sh

SA k: ziinnniya is eV «

M gm shi "z 5-(2-benzyloxyethoxy)-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-078) " To a solution of 2- of benzyloxyethanol (0.3 mL) in DMF (1.0 mL) was added Mann (5 mg, 2.08 mmol). After stirring for 5 minutes, 0.5 mL was added to a solution of IS-87185 (5 mg, 0.114 mmol) in anhydrous DMF (0. 75ml). The reaction mixture was heated to 502C and stirred for 3 days. Purification by HPLC (column - C18 I opa, 4.6250mm, 4.7ml/minute, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18

F minutes, detector at 2202), gave the product as a heterogeneous solid, 150 µg. MS (ER): t/2 571 (MAN), 481. o is She ku F from her; I know that I know them and by r, and 65 and m 2

3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl ester of b-aminopurine-9-carboxylic acid (a-079)

Phosgene (2M/toluene, ZbmCl, 0.072 mmol) was added to a solution of 3b (20 mg, 0.0 bbmmol) in SiOCl (500 μl) at 09C, followed by adenine (10 mg, 0.072 mmol) and OIEA (25 μl, 0.145 mmol). The reaction mixture was allowed to reach ambient temperature and stirred for 8 days. Purification by HPLC (column C18 I pa, 4.625 Ω, 4.7 ml/min, 10-75906 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 2202) gave the product as a mixture. "H NMR (DMSO-dv) w: 11.04 (Bg 5, 1H); 8.61 (b, 1H); 8.40 (b, 1H); 7.85-7.95 (t, 1H) ; 7.76 (aa, 9-54.9 ,6HCts, 1); 7.70-7.78 (t, 1H); 7.52-7.63 (t, ЗН); 7.38 (Y 9 -83, 70. .10.6HzC., 1H); 4.76-4.89 (t, 2H). MO (ER): t/2 466 (MAN), 331, 305 for is DE ac. Is . и | « : ! I pi IY S uh Ks DI: y r | se y

V / E- 7 in She 8 so with KY. at

IM-3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl|-2-(9H-purin-b-ylsulfanyl)-acetamide (a-077) - (9H-purine-b-ylsulfanyl)-acetic acid (bZmg, 0.29bmmol), 565 (108mg, 0.35bmmol), EOS (b8mg, with 0.355mmol), NOVT (48mg, 0.355mmol), BIEA (b2μl , 0.355 mmol) and DMF (1 mL) were combined in a flask and stirred at ambient temperature for one hour. The reaction mixture was diluted with EtOAc (20 mL) and washed with dilute brine (21 mL). The organic phase was concentrated in vacuo and chromatographed in 590 MeOH/ClClCl to give 9 mg of product as a viscous, peach-colored foam. DMSO-ar) w 12.88 (rgo8, 1H); 8.72 (v, 1H); 8.62 (6 9-5.00Hz, 71H); 8.49 (v, 1H); 7.88 ( and 9-56, 82Hz, "1NU; 7.73-7.78 (t, 1); 7.67-7.72 (t, 1H); 7.57-7.65 (t, 2H); 7 .38 (a, 9-8.1Hz, 1Hn); 7.36 (ad, 9-83, 111Hz, Z n 40 1Nu; 4.11-4.24 (t, 2H); 3.96 (ad, 9-5.0, 17.4Hz, 1H); 3.78 (44, 9-5.2, 17.4Hz, 1H). MS (ER): t/2 496 (M.H), 248.

Kish jan i et - Zh x shk y s» com. 2-(1--2-fluoro-9H-purin-6b-ylamino)ethyl|-5-methyl-3-o-tolyl-ZH-quinazolin-4-one (a-080) and F) Obtained according to method E , using 5c (5mg, 0.17mmol) and 2-fluoro-b-chloropurine (35mg, co 0.204mmol) in 1.2ml of EUN. Purification by HPLC (column C18 I sp, 4.625 Ωm, 4.7 mL/min, 10-7590 acetonitrile/water for 15 min, 10095 acetonitrile for 18 min, detector at 220 g) gave the two 60 atropisomers as white solids. The data for one of them are as follows: "H NMR (DMSO-dv) w: 8.48 (g a, U-6.4Hz, 1H); 8.17 (v, 1); 7.69 (5 9-7, 8Hz, 71); 7.53 (a, 9-7.8Hz, 1); 7.44 (a, o0-7.6Hz, 2); 7.33 (a, 9-7 2Hz, 2); 7 ... (а, 9-6.7 Hz, ЗН).

MS (ER): t/2 430 (MAN), 215. b5

STILL in the 17th and about. - K dyan and equal: their yo Ken yai sho

I "I I 5-methyl-2-11-(9H-purin-b-ylamino)ethyl/|-3-o-tolyl-N-quinazolin-4-one (a-081)

Obtained according to method E, using 5c (50mg, 0-17mmol) and b-chloropurine (32mg, 0.204mmol) in 1.2ml EN. Purification by HPLC (column C18 I pa, 4.62500 mm, 4.7 ml/min, 10-7595 acetonitrile/water for 15 min, 10095 acetonitrile for 18 min, detector at 2202) gave the two atropisomers as yellow solids. The data for one of them are as follows: IN NMR (DMSO-iv) ts: 8.3 9 (rg 85, 1Н); 8.34 (in, 1H); 8.18 (in, 183; 7.71 (f 9-7.7Hz, 71H); 7.56 (a, 2-7.9Hz, tn); 7.49 (a, 9-6.9Hz, 1 ); 7.28 -7.43 (t, ZN); 7.20 (bBg in, 1H); 5.06 (Bg 5, 1H); 2.73 (in, ZN); 2.04 (in, ZN); 1.51 (a, 9-6.6Hz, ZN), MS (ER): t/2 412 (MAN) 206. almost: te tv x s ! 8 SI ; w h; days o dib i i и зай и" таж ог и ий и о и given base SIY и OO "V zn V y -ai me) pe Be. I and | Щ НИ: well; dm F"

The following compounds according to the presented invention (4-082-0-109) were obtained by method C, using m 2-chloromethyl-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (10 mg), an acceptable nucleophile XN ( 20mg, excess) and potassium carbonate (1Omg) in DMF (0.25ml). The reaction mixture was stirred for 16 h at room temperature, quenched with water, and the crude solid was collected by filtration and air-dried. The crude material was dissolved in O0.bml DMSO and purified by reversed-phase HPLC (column C18 I pa, 4.6250 mm, 4.7 ml/min, 10-7595 acetonitrile/water « 20 for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 220 g). Acceptable fractions from c were concentrated in a vacuum, obtaining the final products. 2-(6-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a-082)

Ge) a dn o senia I s»

Output: 8.mg.

TN nMR (300 MHz, adm) w: 8.13 (8, 1H), 8.11 (v, 1H), 7.60 (5 9-7.8Hz, 1H), 7.54-7.38 (t . (а, 9-17.4 HZ, 1), 3.33 (c, 6Н), 2.73 (5, ЗН), 2.20 (5, ЗН). IR MS (ER positive) t/2-426 (M--1). o What are x: these. -yi ra 65 Output: 3, Zmg

TN nMR (300 MHz, a-DdMsSO) 12.06 (in, 1H); 8.12 (c, 1H); 7.60 (5 9-7.8Hz, 1H); 7.55-7.38 (t, 4H),

7.30 (a, 0o-74hz, tn); 7.15 (a, 9-7.9Hz, 1), 5.26 (a, 9-17.4HuC, 1H), 4.94 (a, 0-17.4Hz, 1), 2.73 (in , ZN), 2.32 (8, ZN), 2.24 (in, ZN). Alkylation at the M position of the purine was determined arbitrarily on the basis of the shift in the signal of methylene protons along the way due to the effect of carbonyl, IR MS (ER pos.) t/2-413 (M 1). 5-methyl-2-(2-methyl-b-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-ZN-quinazolin-4-one. (a-084) yu Zh MK Ov shi and ne shu

What

Isolated from the same reaction mixture as 0-083. Exit: From BMG. "H NMR (Z00Mhz, as-DMSO) 12.17 (8, 1H), 7.96 (z, 1H), 7.63 (5 9-7.8Hz, 1H), 7.57-7.39 ( t, 4H), 7.32 (a,

U-7.4Hz, tn), 7.26 (a, u9-8.1Hz, 1Hn), 5.08 (a, 0-17.2Hz, 1), 4.70 (a, u0-17.2Hz , 1), 2.73 (5, ZN), 2.27 (in,

ZN), 2.17 (in, ZN). 1 K MS (ER positive) t/2-413 (M'-1). 2-(aminodimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a-085)

In window: MNYH sch

AI what - . Kk : o: che u

Ge: p so

Yield: 6b, 7mg. o "IN YAMe (З00МГЦц, ас-ДдМСо) w: 7.66 (v, TNO, 7.61 (y, 9-7.8Gu, 1H), 7.55-7.40 (t, 4H), 7 .32-7.26 (t, 2H), 6.74 (in, 2H), 4.94 (0.9-17.2Hz, 1), 4.63 (0.9-17.2GHz, 1) , 4.63 (y, 9-17.2 Hz, 1), 2.97 (in, 6H), 2.73 (in; (77

ZN), 2.17 (in, ZN), 2.08 (85, ZN). I K MS (ER positive) t/2-441 (M--1). Ge) 2-(2-amino-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZH-quinazolin-4-one (а4-086)

Kh i i. ' 2 more shi s from the eye ;" AND

Yield: 9.5 mg. -I TN nMR (300 MHz, a-DdMsSO) w: 12.54 (in, 1H), 7.89 (in, 1H), 7.69 (5 9U-7.8Hz, 71), 7.51 ( a, U-68, oHz, b 13, 7.51 (a, 9-8.0Hz, 1), 7.43 5 O-39Hz, 1H), 7.34-7.26 (t, 4H), 6.16 (v, 2H), 4.32 (quartet AB, y-14.8Hz, 8"-23.7), 2.74 (v, ZN), 2.09 (v, ZN). IR MS (ER positive) t/2-430 (M'-1). - 2-(4-amino-1,3,5-triazol-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZH- quinazolin-4-one (a-087)

GF) Sh y t 7

Output: 5,vmg. 60 "NN yaYMe (Z00MGhCs, a-dmMsSo) w: 8.10 (v, 1H), 7.70 (5 9-7.6Hz, 1H), 7.58 (v, 1H), 7.52 (9 , U-8.0 Hz, 1H), 7.48-7.26 (t, 6H), 4.08 (v, 2H), 2.73 (v, ZN), 2.09 (v, ZN). I.K MS (ER positive) t/2-391 (M'1). 5-methyl-2-(7-methyl-7H-purin-b6-ylsulfanylmethyl)-3-o-tolyl-ZH-quinazolin- 4-on (4088) b5

Oven and: :

F: | output: Z, mg. "NN yaYAMe (Z00MGhCs, a-dmMsSo) w: 8.52 (8, 1H), 8.49 (v, 1H); 7.70 (5 9-7.8Hz, 1H), 7.50 (9, U-7.8Hz, 1H), 7.45 (a, 9-7.1Hz, 1), 7.35-7.20 (t, 4H), 4.41 (quartet AB, ddv-15.3Hz, 5M-19.2Hz), 4.08. (in, ZN), 2.73 (in, ZN), 2.12 (in, ZN). IR MS (ER pos.) t/2-406 (M' -1).5-methyl-2-(2-oxo-1,2-dihydro-pyridin-4-ylsulfanylmethyl)-3-o-tolyl-ZH-quinazolin-4-one (a-089)

M lk; test Yav chni Ya

SAME and "V

More

M.Sc

Ku o

Yield: 2.4 mg.

TN nMR (300 MHz, abs-DdMsO) w: 11.49 (in, 1H), 7.70 (5 9-7.8Hz, 1), 7.60 (p, 9U-6.0Hz, 1), 7 .53-7.48 (t, 2H), 7.46-7.28 (t, 4H), 6.31 (0.9-6.7Hz, 1), 4.05 (in, 2H), 2 .73 (8, ZN), 2.12 (in, ZN). IV MS (ER pos.) t/2-391 (M-n1). o 5-methyl-2-purin-7-ylmethyl-3-o-tolyl-ZN-quinazolin-4-one. (a-090) "- "in y - y 1, yes,

B in E and "

She ay t s . "» "IN nMR (Z00MgCs, a-dMsSo) w: 9.04 (v, 1H), 8.97 (v, 1H), 8.48 (v, 1H), 7.65-7.54 (t , 2H), 7.53-7.39 (t, p

ZNU), 7.31 (a, 0-74Hz, tn), 7.13 (a, o-8.0Hz, 1), 5.31 (a, 9-17.6Hz, 71Н), 5.16 ( a, 9-17.6 Hz, 1H), 2.73 (in,

ZN), 2.09 (in, ZN). Alkylation in the M position of purines was determined by increasing the MOE between the purine proton in position b-I 75 and methylene protons on the linker between purine and quinazolinone groups. YIK MS (ER pos.) t/2-383 (Mt). (He) 5-methyl-2-purin-9-ylmethyl-3-o-tolyl-ZN-quinazolin-4-one (а-091) - z | y " SCHI l ni She... Y

Fo in: SHY a, y . and in i I g

M nits: I have the same reaction that gave 0-090. H NMR (300 MHz, a6-DMSO) p: 9.17 (in, 1H), 8.86 (in, 1H), 8.55 (in, 13), 7.59 (5 9-7.8Hz, 1 ), 7.55-7.42 (t, 4H), 7.30 (a, o-7.4Hz, 1), 7.13 (a, 9-8.0Hz, 71), 5.26 (a ,

U-17.5Hz, 7H), 4.92 (a, 0-17.5Hz, 1), 2.73 (8, ЗН), 2.19 (в, ЗН). Alkylation in the MU position of purine 60 was confirmed by the loss of MOE enhancement between the purine protons in the b position and the linker methylene protons.

YIK MO (ER positive) t/2-383 (M'-1). 5-methyl-2-(9-methyl-9H-purin-b6-ylsulfanylmethyl)-3-o-tolyl-ZH-quinazolin-4-one (a-092) b5 c! se x B; Y 70 nia "NN yaYMe (Z00MGhCts, a-dmMsSo) w: 8.52 (8, 1H), 8.42 (v, 1H), 7.69 (5 9-7.7Hz, 1H), 7.50 (9, U-8.0Hz, 1H), 7.44 (a, 90-7.6Hz, 1), 7.36-7.27 (t, 4H), 4.38 (quartet AB, Odv-15 .5Hz, 5M-21.0Hz), 3.80 (v, ZN), 2.73 (v, ZN), 75.22.12 (v, ZN). YIK MS (ER pos.) t/2-429 ( M). 2-(2,6-diaminopyrimidin-4-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZH-quinazolin-4-one (a-093) 20 bi ka Kk sia

Ka To 1: p 25 I. (5) "НН яЯМе (З00МГхЦц, а-дмМсСО) ш 7/7О (Б о-7.7Hz, 1Н), 7.54 (а, 9-8.0Hz, 1Н) , 7.45-7.27 (t, 5H), 6.22 (Bg 8, 1H), 5.80 (Bg 5, 1H), 3.99 (AB quartet, uUdv-14.6Hz, 5M-26 ,9Hz, 2H), 2.73 (8, ZN), 2.08 (in, ZN). IR MO (ER so 30 pos.) t/2-405 (M.1). 5-methyl-2 -(5-methyl-/1,2,4Atriazolo|1,5-a|pyrimidin-7-ylsulfanylmethyl)-3-o-tolyl-ZH-quinazolin-4-one (а-094) (ав) т р і o Й 35 - p s. .73 (5 9-7.8 Hz, 1H), 7.55-7.35 (t, 4H), 7.18 (in, 1H), 427 (5, 2H), 2.74 (8, ЗН) , 2.55 (in, ZN), 2.08 (in, ZN). I K MS (ER positive) t/2-429. (M--1). 5-methyl-2-(2-methylsulfanyl-9UN-purin-6-ylsulfanyl-methyl)-3-o-tolyl-ZN-quinazolin-4-one (a-095) - gbisbeh and shk zah | tk yog B; и Ш бю» Ш 0:

Ж She 7 blue "IN nNMR (300MgCs, a-dMsSo) w: 13.30 (8, 1H), 8.29 (v, 1H), 7.72 (5 9U-7.6Hz, 1H), 7, 54 (a, U-7.8Hz, 1H), (F) 7.47 9a, 9-6.3Hz, 1H), 7.38-7.26 (t, 4H), 4.34 (quartet AB, dv-16.1Hz, 5M-23.6HzC, 2H), 2.74 (8, ZN), 2.32 (v, ka ZN), 2.10 (5, ZN). IR MS (ER pos.) t/2-461 (M'1). 2-(2-hydroxy-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZH-quinazolin-4-one (a-096) 60 b5 vach - chl / F ; in i;

TN nMR (300 MHz, as-dMSO) w 8.08 (in, 1H), 7.69 (5 9U-7.8Hz, 1H), 7.50 (Bha, U-68Hz, 2H), 7.33- 7.50 (t, 4H), 4.28 (quartet AB, ddv-15.5Hz, 5y"-21.3Hz, 2H), 2.74 (in, ЗН), 2.12 (in, ЗН). IR MS (ER positive) t/2-431 (M'1). 5-methyl-2-(1-methyl-1H-imidazol-2-ylsulfanyl-methyl)-3-o-tolyl-ZH-quinazoline- 4-on. (a-097) hv fu ! "y "y i y

TN NMR (300 MHz, 4d2-DMsSO) p: 7.691, 9-7.8Hz, 1H), 7.46-7.37 (t, BN), 7.32 (a, 9-7.3Hz, 1H), 7.20 (a,

U-1.0Hz, 1H), 6.48 (a, 9-1.0Hz), 3.83 (quartet AB, ddv-15.0Hz, 5"-18.8Hz, 1H), 3.55 (in , ZN), 2.73 (in, ZN), 2.09 s g (8, ZN). IR MS (ER positive) t/2-364 (M'n1). 5-methyl-3-o- Tolyl-2-(1H-(1,2,4|. triazol-3-ylsulfanylmethyl)-ZH-quinazolin-4-one (а-098) o

Ж І vAYay i "u cho o i E - і KE ih і- "IN nMR (Z00MgCs, a-dMsSo) w: 13.98 (8, 1H), 8.47 (v, 1H), 7.70 ( 6 9U-7.6Hz, 1H), 7.49 (a, U-7.9Hz, 1H), 7.44-7.31 (t, 5H), 4.04 (quartet AB, 2-15.5Hz . -(2-amino-6-chloropurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZH-quinazolin-4-one (а-099) - with no. what what: with M Я

WHAT about; and ap; more s What - В - ЖЭ / vo zay Z (o) 6 gyi y "a i t y sho Y y I o a. s s" YIK MO (ER pos.) t/2-432 (M'-1) 2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (а-100) is not available. t this. tn nMR (300 MHz, ab-DMSO) w 8.19 (v, ZN), 7.66 (5 -7.8 Hz, 71), 7.59-7.43 (t, 5H), 7 ... 4Hz, 6"-221HzC, 2H), 2.72 (in, ZN), 1.93 (8, ZN). Alkylation in the M position of the purine was confirmed by an increase in MOE between the following protons: 1) exocyclic amine protons and methylene protons; 2) exocyclic amine protons and toluylmethyl protons. I K MS (ER positive) t/2-398 (M 1). 2-(7-amino-I,2,3-triazolo|4/5-4|Ipyrimidin-3-yl-methyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a- 101)

Belief in 4 volumes | TYA: ke And still vu

TN nMR (300 MHz, as-dMSO) w 8.43 (rgo8, 1H), 8.19 (v, 1H), 8.10 (Bg 85, 1H), 7.62 (5 9-7.8Hz, 1H ), 7.49-7.28 (t, 5H), 7.22 (a, 9-81Hz, 71H), 5.49 (a, 0-17.0Hz, 1), 5.19 (a, 9 -17.0 Hz, MH), 2.73 (in, 1H), 2.11 (85, ZN). Alkylation in the MU position of the purine was determined by similarity to the NMR spectrum 0-030, 1K MS (ER positive) t/72-399 (M.-1). 2-(7-amino-1,2,3-triazolo|4,5-4|pyrimidin-1-yl-methyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a- 102) that m. -Sh... In my and about

Ha: re ЧЕ ж: Sh;, Ge.

And and with and Ge) to her Shk (c)

ALIVE AND "--

From the same reaction mixture as 0-101. "so" YAN NMR (Z00MHz, adm) w 82.7 (8, 1H), 8.20 (rg 85, 1H), 8.05 (Bg 85. 1), 7.70 (5 9-7.8Hz . in, ZN)). t

Alkylation at the M position of the purine was determined by similarity to the 0-100 NMR spectrum.

YIK MO (ER positive) t/2-399 (M'-1). 2-(6-amino-9H-purin-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (d4-103) D ii za za che E 7 ; ha at 20 "IN nNMR (300MgCs, a-dMsSo) w 12.62 (8, 1H), 7.93 (v, 1H), 7.69 (6 9-7.7Hz, 1H), 7.51 ( a, U-8.1Gu, 1H), (s 7.42 (aa, 20-7.6,1.7Hz, 1H), 7.35-7.15 (t, 6H), 4.12 (quartet AB, Odv-14.5Hz, 6y"-18.2Hz, 2H), 2.73 (8, ЗН), 2.10 (in, ЗН).

YIK MO (ER positive) t/2-430 (M'-1). 2-(2-amino-b6-ethylamino-pyrimidin-4-ylsulfanyl-methyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a-104)

F) ime) 60 b5 zado 70 . as -

Shchi "NN yaYAMe (Z00MGhCts, a-dmMsSo) shto (6 9-7.8Hz,. 1), 7.53 (a, 9U-8.0Hz, 1H), 7.44-7.31 (t, 5H ), 6.69 (Brg 8, 1), 5.83, (rg 8, 2H), 5.61 (c, 1), 4.03 (a, 0-14.6ГЦц, 1H), 3.95 (а, 2-14.6 HZ, 1Н), 3.22-3.11 (t, 2Н), 2.73 (в, ЗН), 2.08 (в, ЗН), 1.06 (I, 9 -7 1Hz, ZZN). IR MS (ER positive) t/2-433 (M'1). 2-(3-amino-5-methylsulfanyl-1,2,4-triazol-1-yl-methyl) -5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a-105)

He oo g 29 "I iy y o "K SCHE zuue Fo

Output: 5.Omg. at

TN nMR (300 MHz, a-meon) w 7.67 (5 9U-7.8 Hz, 71), 7.55-7.37 (t, 4H), 7.35-7.27 (t, 2H), 477 (y, - -17.1Hz, 1H), 4.60 (a, 9-17.1HzC, 1H), 2.80 (in, ЗН), 2.43 (in, ЗН), 2.14 ( in, ZN). "co

YIK MO (ER positive) t/2-393 (M'-1). 3 2-(5-amino-3-methylsulfanyl-1,2,4-triazol-Tylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a-106) c.

Е 20 hryvnias І и « а. Goodbye ps y;" with for what 15 | Mn -I Output: Oh, bmg.

Isolated from the same reaction mixture as O-105.

Me TN nMR (300 MHz, a,-meon) w: 7.67 (B 9U-7.6Hz, 1), 7.50-7.24 (t, 6H), 4.83 (a, 9-16, 5Hz, 1H), 4.70 (a, - -16.5HzC, 1H), 2.79 (in, ZN), 2.47 (in, ZZN), 2.14 (in, ZN) IR MS (ER pos.) t/2-393 (M'-1). o 50 b-methyl-2-(b-methylaminopurin-9-ylmethyl)-3-o-tolyl-ZN-quinazolin-4-one (a-107) sv 3 i g sl

In 2 years

GF) dey r re? ka vo she

Output: 5.Omg

TN nMR (300 MHz, a,-meon) w: 8.17 (8, 1H), 8.03 (v, 1H), 7.54-7.43 (t, 4H), 7.31-7.23 (t, 2H), 5.14 (a, -17.5Hz, 1H), 4.90 (a, 9-17.5HzC, 1H), 3.14 (Bg 5, ЗН), 2.79 (in , ZN), 2.22 (8, ZN). 65 YIK MO (ER pos.) t/2-412 (M.-1). 2-(6-benzylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one (a-108)

p ro z y

Ah / in z. etc

Ki -K N yk - that What. F. shk and ODN B and i:

Yield: 6b, 7mg. 75 TN NMR (300 MHz, a,-Meon) w: 8.13 (v, 1H), 8.04 (v, 1H), 7.58 (6 9-7.8 Hz, 1H), 7.51-7 .21 (t, 11), 515 (0, 9-17.5Hz, 1H), 4.91 (a, 9-17.5Hz, 1H), 4.83 (c, 2H, peak under HO), 2 .79 (in, ZN), 2.22 (in, ZN) IR MS (ER positive) t/2-488 (M'-1). 2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZH-quinazolin-4-one (a-109) p. Ben me Kk. n and I | And t pk

NN shchi 2. o

M sho SHY

Double amounts of all reagents. Yield: 14mMg o "YAN nNMR (Z00MHz, adm) w 8.53 (g 8, 2H), 8.01 (v, 1H), 7.64 (B 2-7.8Hz, 1H), 7.53- 7.40 (t, 4H), «-- 7.33 (a, o-74Hz, 1), 7.27 9a, 9-7.9Hz, 1H), 4.96 (a, 0-17.5Hz . M'-1).

Compounds 0-110-0-115 of the following general structure are obtained from the following intermediates E-1-E-3. ch- in there is She.

Ж What iy l t k ; (i ; -I pi a, s-m o Z-methyl 2-09 Nenurny: b-ipsulfaniamethyli-Z, Ihbenzokovkhinei-ev: av) yan neo ke sii still and de Ne still ts I I "y cha dz nis DYA and what and who and "vm

Y B h ; I 60 I 5-methyl-2-"9H-purin-6b-ylsulfanylmethyl)-3,1-benzoxazin-4-one

She and o 1 I 1 I

A 5 and it - -k B:

Iv that o Ba o 0 BI 00 to si. I - I I SHE! and pick rya not CHAK M . ru ShK sh No o

Step 1. A suspension of b-methylanthranilic acid (2g, 13.2mmol) in chloroacetyl chloride (12ml, large excess) was stirred at 1152 in a sealed flask for 30 minutes. The resulting solution was cooled to room temperature and treated with ether (about bml). After cooling at 4 C overnight, the resulting creamy precipitate was collected by filtration, washed with ether, and dried in vacuo to give the chlorine intermediate (1.39 g, 50965). at

TN YaMeR (Z00MHz, SOSIZz) w: 7.67 (B 9U-7.8Hz, 1), 7.46 (a, 9-7.9Hz, 1H), 7.35 (a, 9-7.6Hz, 1H), 4.39 (6, - 2H), 2.81 (85, ЗН). IC MO (ER positive) t/2-5210, (M--1). co

Stage 2. A mixture of chlorine intermediate (5mg, O0.25mmol), b-mercaptopurine monohydrate (43mg, 0.25mmol) and potassium carbonate (25mg, 0.25mmol) in dry DMF (0.5ml) was stirred at room temperature for 30 - minutes The mixture was poured into ethyl acetate (20 mL) and all insoluble material was filtered off and discarded.

The filtrate was concentrated in vacuo to remove all the ethyl acetate and the residue was treated with ether to give a light orange precipitate. The precipitate was collected by filtration, washed with ether and dried under vacuum to obtain intermediate E-1 (41mg, 5190)

TN NMR (Z00MHC, a6-DMSO) n: 8.64 (in, 1H, 8.39 (in, 1H), 7.73 (5 9-7.8 Hz, 1H), 7.44-7.37 ( t, 2H), 4.69 c) s (5, 2H), 2.69 (5, ЗН). IR MS (ER positive) t/2-326 (M'-1). z» Intermediate E-2 - z mir dya i i i i i

There is Gautier, and (there is) cha This g -- shchi zhi y z U t y Sh y her t TZ chi. t. sha and I and Zh r. What mk te Shk Z and same GE n B ; . cha z «oo I M o M. ku i, che so sela

Fe and Y:

Intermediate E-2 o A solution of 2-nitroacetanyl (1.0 g, 5.0 mmol) in EJN was purged with nitrogen, treated with RY(OH)" (2095 by mass at

C, 200 mg, catalyst) and shaken for 2 hours under a hydrogen atmosphere (20 psi). The catalyst was removed by filtration through a 0.22 µm cellulose acetate membrane (Sogpipe) and the filtrate was concentrated in vacuo to obtain a white crystalline solid (800 mg, 96905). bo "NN yaYAMe (Z00MGhCts, a-dmMsSo) w: 9.12 (v, 1H), 7.14 (da, 0-7,8,1.3Gu, 1H), 6.68 (a 9-7, 6.1.5Hz, 1H), 6.70 (aa, 9-8.0,1.3Hz, 1H), 6.52 (ac 9-7.5,1.4Hz, 1H), 4.85 ( Bg 5, 2H); 2.03 (5, ZN). IR MS (ER positive) t/2-151 (M'-1).

Intermediate E-3 b5

Ya. ZD M ches umer nou VIY A, pn y

Intermediate E-3

A mixture of 2-fluoro-nitrobenzene (1.41 g, 1 mmol) and MnSO3 in BEN (20 mL) was treated with (M,M,M'-trimethyl)-1,2-diaminoethane (1.1 g, 11 mmol) and stirred for 16 h at 8020. The solvent was removed in vacuo, the residue was treated with 0.1M Mahon solution (120ml) and the mixture was extracted with ethyl acetate (250ml). The organic layers were combined and washed with 20 mL of water (1) and brine (2), dried over sodium sulfate, and concentrated in vacuo to an orange liquid (2.2 g, 10090; EP MS: t/2-224, (M'-1).

This intermediate was dissolved in EUN, the solution was purged with nitrogen, treated with PaY(OH) at (2095 wt/cS., 18Omg, catalyst) and shaken for 2 hours under a hydrogen atmosphere (50 lb/sq.in.). The catalyst was removed by filtration through a 0.22 µm cellulose acetate membrane (Sogppipud) and the filtrate was concentrated in vacuo to obtain the red liquid product E-3 (1.8 g, 9590). "YAN NMR (Z00MHz, SOS) w: 8.64 (85, 1H), 7.03 (da, U-8.3, 1.4Gu, 1H), 6.91 (aa, 9-7.6, 7.2, 1.4Hz, 1H), 6.73-6.67 (t, 2H), 4.20 (Bg 8, 2H), 2.95 (i, 9-6.7Hz, 2H), 2 .68 (in, ZN), 2.41 (in 9-6.7 HZ, 71Н), 2.26 (in, 6Н).

YIK MO (ER pos.) t/2-194. (M.-1),

Compounds 0-110-0-115 were obtained as follows: directly o-megthyl-2-(9H-purshe-6-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one. (a-110) -: And and and. What about t | - x pam y y | at

A mixture of intermediate E-1 (40mg) and o-toluidine (0.3ml, large excess) was heated at 1002C in a sealed flask at room temperature for 16 hours. The reaction mixture was cooled, treated with 1N HCl (2ml) and ether (2ml) and the formed gray precipitate was collected by filtration, washed with ether and dried in air (19mg cheese). The crude solid product and - was dissolved in 0.bml DMSO and purified by HPLC (column C18 I pa, 4.625 Ωm, 4.7 ml/min, 10-7590 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 220 2). Acceptable fractions were concentrated in vacuo to give the final product as a white solid (4 mg).

TN NMR (300 MHz, 46-DMSO) w: 13.52 (8, 1H), 8.47 (v, 1H), 8.43 (v, 1H), 7.69 (5 9u-7.8Hz, 1H ), 7.50 (a, C 10 U-7.9HZ, 1H), 7.46-7.43 (t, 1H), 7.37-7.25 (t, 4H), 4.37 (quartet AB, ddv 154Hz, 5y"-22.4Hz, 2H), 2.74 (5, ЗН), s 2.12 (5, 3H). IR MO (ER pos.) t/2-415 (M'- 1). ; » 3-isobutyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one. (d-111) -. a. :

A mixture of intermediate E-1 (4Omg) and isobutylamine (0.4ml, large excess) was heated at 1202C in a sealed flask for 16 hours. The excess of isobutylamine was allowed to evaporate, the residue was dissolved in 1 ml of DMSO and purified in two steps using HPLC (C18 Izpa column, 4.6250 mm, 4.7 ml/min, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 220 g). Acceptable fractions were concentrated in vacuo to give the final product as a white solid (4mg). "NN NMR (30 MHz, a6-DMSO) cd: 13.75 (rg 8, 1H), 8.73 (8, 1H), 8.50 (v, 1H), 7.63 (B 9-7.7Hz . -7.5Hz, 2H), 2.77 (v, ZN), 2.30-2.15 (t, 1H), 0.98 (a, 5-6.7Hz, 1H). YIK MU (ER positive .) t/2-381 (M'-1). ko M-42-(5-methyl-4-oxo-2-"3H-purin-6-ylsulfanyl-methyl)-4H-quinazolin-3-yl| -phenyl)-acetamide (a-112) 60 b5 to A mixture of intermediate E-1 (8mg, 0.25mmol) and intermediate E-2 (75mg, 0.5mmol, 2eq.) was heated to melting in a sealed flask using a heating device . The reaction mixture was triturated with ether and the solids were collected by filtration. The crude material was dissolved in 1 ml of DMSO and purified in two steps using HPLC (column C18 I cpa, 4.6250 mm, 4.7 ml/min, 10-75956 acetonitrile/water for 15 minutes, 75 10095 acetonitrile for 18 minutes, detector at 2202) . Acceptable fractions were concentrated in vacuo to give the final product as a white solid. "H NMR (Z00MHC, ab-DMSO) w 13.52 (in, 1H), 9.52 (in, 1), 8.48 (5, ZN), 8.42 (in, ZN), 8.02 (a, 9-8.0Hz, 1), 7.69 (5 9U-7.8Hz, 1), 7.51 (a, 9-7.9HzC, 1), 7.A45-7.37 (t , 2H), 7.31 (a, 90-7.3Hz, 1), 7.19 (5 9-7.5Hz, 1H), 4.38 (v, 2H), 2.74 (v, ЗН , 1.93 (in, ZN). IC

MS (ER positive) t/2-458 (M'-1) 5-methyl-3-(E-2-methyl-cyclohexyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4 -he (a-113) and I (5)

A mixture of intermediate E-1 (8mg, 0.25mmol) and trans-2-methyl-1-aminocyclohexane (0.25ml, large excess) was heated under sealed conditions at 1002 for 16 hours. The reaction mixture was triturated with ether and the solids were collected by filtration. The crude material was dissolved in O0.bml DMSO and purified by HPLC (column C18 I pa, 4.6250 mm, 4.7 ml/min, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile i. for 18 minutes, detector at 2202 ). Acceptable fractions were concentrated in vacuo to give the final product as a white solid (1.5 mg). "H NMR (300 MHz, a-DdmMSO) w: 13.5 (Bg8v, 1H), 8.82 (8, 1H), 8.51 (v, - 13, 7. 63 (56 -7.7Hz, 1 ), 7.43 (a, 9-7.9Hz, 1), 7.27 (a, 2-74Hz, 1H), 5.11 (a, 9-14.5Hz, 1H), 3.78-3 .69 (t, 7), 2.73 (v, ZN), 2.55-2.40 (t, ZN), 1.88-1.46 (t, 4H), 1.31-1.11 (t, 1H), 0.90-0.65 (t, 1), 0.74 (40, 0 5-6.7Hz, ZN). IR MS (ER positive) t/2 421 (M'- 1).im 2-(b-methyl-4-oxo-2-(9H-purin-6-ylsulfanylmethyl) 4H-quinazolin-3-yl|-bSenzoic acid (а-114) that F «

Tsav! and And or and o)

A mixture of intermediate E-1 (8Omg, 0.25mmol), methylanthranilate (0.25ml, large excess) was heated in a sealed flask at 10092 for 16 hours. The reaction mixture was triturated with ether and the solid products were collected by filtration. The crude material was dissolved in O0.bml DMSO and purified by HPLC (column C18 I pa, b 4.625O0mm, 4.ml/min, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 2202). Acceptable fractions were concentrated in vacuo to give the final product as a white solid (mg). av | 20 TN nMR (300 MHz, a-DdMsSO) w: 13.51 (8, 71H), 8.51 (8, 1H), 8.42 (v, 1H), 8.11 (aa, 9U-74.11Hz . (t, ZN), 4.58 (a, -15.5 Hz, 1H), 4.35 (a, 9-15.5 Hz, 1H), 2.44 (5, ZN). IR MS (ER pos. ) t/2-445 (M'-1). 3-2-(2-dimethylaminoethyl)-methyl-amino|-phenyl)-5-methyl-2-(("9H-purin-b-ylsulfanylmethyl)-ZH- quinazolin-4-one (а-115) sti bo | F shk p

A mixture of intermediate E-1 (40 mg, 0.25 mmol) intermediate E-3 (0.2 ml, large excess) was heated in a sealed flask at 1009 for 16 hours. The reaction mixture was triturated with ether and the solids were collected by filtration. The crude material was dissolved in 1 ml of DMSO and purified by HPLC in two steps (column C18 I pa, 4.6250 mm, 4.7 ml/min, 10-7595 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, 0.05956 TEA in all solvents, detector at 2202). Acceptable fractions were concentrated in vacuo to give the final product as trifluoroacetate (11mgHg).

TN nMR (300 MHz, a-DdMSO) w 13.4 (Bg 85, 1H), 9.27 (8, 1H), 8.52 (8, 1H), 8.44 (in, 1H), 7.72 (6

U-7.8Hz, 1), 7.53 (a, 9-7.9Hz, 1H), 7.40-7.33 (t, 4H), 7.10-7.04 (t, 1H), 4.42 (v, ЗН), 3.5 (t, 2Н), 3.23-3.03 (t, ЗН), 2.75 (v, ЗН) 2.68-2.56 (t, 8Н ). IR MS (ER positive) t/2-501 (M'-1).

Compounds 0-116-0-118 are obtained as follows: 70 - whether Bonya Ya Ne esniy che g" -k i:

I STILL FIGHT! Щй ШЧИ | : and zhk in she SN : Ш Shch

AND; ii and m. g VA A: so zy cha, that and with V Kl at . ny: w -NOT: o 3-(2-chlorophenyl)-5-methoxy-2-((9H-purin-b-ylsulfanylmethyl) (a-116) (Kk-Me,x-O)

A mixture of 0-015 (25mg) in 0.5M MaOMe (2ml mixed with MeOH; large excess) was stirred at 502°C for 16 hours in a sealed flask. The reaction mixture was cooled to room temperature, treated with water (5 ml) and the formed precipitate was collected by filtration, washed with water and dried in air. The crude material was dissolved in 0.bml DMSO and purified by HPLC (column C18 I pa, 4.625O0mm, 4.6250mm, - 4.7ml/min, 10-7590 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector with at 2202). Acceptable fractions were concentrated in vacuo to give the final product as a white solid (5 mg). -

TN nMR (300 MGgCs, a-DdMSo) w: 13.52 (8, 71H), 8.48 (v, 1H), 8.44 (rg 5, 1), 7.77 (5 U-82Hz, 1H) , 7.71-7.60 (t, 2H), 7.51-7.34 (t, 2H), 7.23 (a, 0-82 Hz, 1), 7.10 (a, 9-84 Hz , 71H), 4.39 (quartet AB,

Udv-5.2Hz, 5y"-23.2Hz, 2H), 3.85 (v, ZN). 1 K MS (ER pos.) t/2-451 (M'1). « du 3-(2 -chlorophenyl)-5-(2-morpholin-4-ylethylamino)-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one (a-117) with

She and -I

A mixture of 0-015 (25mg) and 4-(aminoeth-2-1H)-morpholine (b65O0mg, large excess) was stirred at 509

Fo within 16 hours. The crude reaction mixture was purified by HPLC (column C18 I pa, 4.6250mm, - 4.7ml/minute, 10-7590 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 5or at 2202), Acceptable fractions were concentrated in a vacuum, obtaining the final product. NMR (Z00MHC, av-acetone) w: 8.57 (Bg 8, 1H), 8.47 (b, 1H), 8.37 (b, 1H), 7.72 (aa, 9U-7, 7, 1, bHz, 1H), c» 7.65 (aa, 9-80, 1.2Hz, 1), 7.57 (5 9U-81Hz, 71), 7.49 (a o-7.7 , 1.6Hz, tn), 7.40 (av ot, 1.5Hz, 1), 6.86 (aa, 0-7.4Hz, 1), 6.82 (a, 9-8.3Hz, 1H ), 4.55 (a, 9-15.0HzC, 1H), 4.42 (a, 9-15.1HuCs, 1), 4.05-3.90 (t,

AN), 3.9 0 (i, 9U-6.9Hz, 2H), 3.75-3.4 (t, 4H), 3.54 (i, 9-6.9Hz, 2H). IR MS (ER positive) t/2-549 (M'-1).

C-benzyl-8-methoxy-2-(9H-purine-b-ylsulfanylmethyl). ZN-quinazolin-4-one (a-118)

F) ime) 60 b5 and ke Shk 2 5 ;

N i ZI y Ye h. tsi cho : lk I i yayti y - sa onov: : vav tar a no Kk. ; and |. t te shchi: y " y pi RYM yy yy chn m ih pot t ЩХ I 70 І ON ne schi foni y; y v -I Te "Z l o.

Tel le Nizh Ka dn p.

Her and fe

Even in I Y aty "Ж ; And "live" and "B.:

A mixture of 020-043 (25mg) in 0.5M MaOMe (2ml mixed with MeOH; large excess) was stirred at 502 for 16 hours in a sealed flask. The reaction mixture was treated with 1N HCl (ml) and aliquots of this solution (05 bml each) were purified by HPLC (ICPA C18 column, 4.62500 mm, 4.7 ml/min, 10-7590 acetonitrile/water for 15 minutes, 10095 acetonitrile for 18 minutes, detector at 220 2). Acceptable fractions were concentrated in vacuo to give the final product as a white solid (6.bmgH).

TN nMR (300 MHz, ab-DdMsSO) w: 13.57 (8, 71H), 8.60 (8, 71H), 845 (v, 1H), 7.72 (5 U-81Hz, 1H), 7, 42-7.30 (t, 2H), 7.30-7.19 (t, ZN), 7.15 (a, 9-8.0Hz, 1H), 7.06 (a, 9U-8.3Hz , 71H), 543 (in, 2H), 4.80 (in, c 29 2H), 3.87 (5, ЗН). IR MS (ER positive) t/2-431 (M'1). Gee)

Compound O0-999 (comparative) 3-(2-chlorophenyl)-2-(1H-pyrazolo|3,4-4|Ipyrimidin-4-ylsulfanylmethyl)-ZN-quinazolin-4-one

An analogous compound, 3-(2-chlorophenyl)-2-(1H-pyrazolo|3,4-4|Ipyrimidin-4-ylsulfanylmethyl)-ZH-quinazolin-4-one, was also synthesized according to the described methods, except that that at the final stage mercaptopurine was replaced by 4-mercapto-1H-pyrazolo|Z,4-4|Ipyrimidine. Av

EXAMPLES

Biochemical studies of the power and selectivity of RIZK -

A. Biochemical studies using 20 μM ATP (He)

Using the method described in Example 2 above, the compounds of the invention were tested for inhibitory activity and potency against RIZKa and for selectivity against RIZKa compared to others in RIZK class I isoenzymes. In Table 2, IC values (μM) are given for RIZK' ( "Alpha"), RIZKV ("Beta"), RIZK

SGama") and RIZKoo ("Delta"). To illustrate the selectivity of the compounds, the ratios of the IR 50 values of the compounds RBKA, RVKV and RVC in relation to RVC are given, respectively, as "Alpha/dDelta ratio," "20 Beta/Delta ratio;, " and "Gamma/Delta ratio." with c Initial selectivity studies were performed identically to the protocol for selectivity studies in Example 2, except for the use of 100 μl of EsozsSipi for radiolabel determination. Subsequent selectivity studies were performed ;" similarly, using the same stock solutions of ХХ substrate except that they contained 0.05 mCi/ml

GR)ATF and ZmM RIR". Subsequent selectivity studies also used the same stock solutions of the 3X enzymes, except that they did not contain the SNM of any of the given RZK isoforms. -i For all selectivity studies, test compounds were weighed and dissolved to 10-50 mM stock solutions in 10095 DMSO (depending on their respective solubility) and stored at -209C. The compounds were melted (at room temperature or 372), diluted to 30 Ωm in water, from which a series of 3-fold dilutions in water was made. Of these dilutions, 20 µl was added to the assay cells alongside pure water, which was used as an enzyme control (positive) and a no-enzyme control (background). Further, the study was essentially carried out according to the protocol of the selectivity study in example 2. For cases in which the highest concentration was used in the study, that is, 100 μM, which did not inhibit the enzyme activity by at least 5095, the table shows the percentage of residual activity at this concentration ( that is, at 100 μM); In these cases, the actual ratio of activities for the compounds cannot be calculated due to the lack of the necessary data on the IC values of one compound. However, to gain some insight into the properties of these compounds, calculate the hypothetical activity ratios using the data for 100μM in place of the missing values. In such cases, the selectivity ratios should actually be greater than the hypothesized values, and this is indicated by the use of the greater than (») symbol. in

CompoundsAlpha Beta (Delta Gamma Alpha/Delta Ratio |(Beta/Delta Ratio Gamma/Delta Ratio

Po ss ni nn Pokinnny resiv yav | vv vve; in t 00000005 r-003| 92 5395) (A 22 »24 Staffing I 11721851 Dov in LE at 11118601 Real in OMV000000000001000008000000000000000000000 ovyayuozvi oo ov 10067 11110100yu000111100000853 buvet yuyu 00000025 sho (veto vyyu yuyu g 00111818

EE NI En NNY NIMY NN PI NN NO oy in in in 71117616 byu juzhovya la 00000065 molu lyu 115818 m lo; Oy) Liai 00111050 0000000040000000000000000000000000000000000000 REMA 25117818 is a din no TNC

Pet: Sunnet Nsui No Posson: - Ponna Ponna Pona - Wow Vent 00000010 F Without Heavy at 08001011 mi t61031755315 g» because you are in 91111151 that v/o ov) 00005811 svi yu mo vb60111ya801yu1100 - byu poyu | лю 00100010яю0001000000ю001

FRI

Ф бувиовяовт з 00000000 - bob slov 8 11111093 шо 00 мый клюв вв 01010000

Ф вело мя ю)0000022000000100000021000001000000080

Fe" Ii 2940 1.2 04 0.23 5.3 1.7 (F) ko bo b5

Compound 0-121 is 3-phenyl-2-"-9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one half: What ; a :: zhi y E y no Ci xx B 1 y

E MA I "V. "sl:

E «Sun: ai IY.

F: Mr. I

Acne and, and

B. Biochemical studies using 200 μM ATP

In Section A above, the compounds of the invention were tested to determine their IC 50 values for inhibition of the alpha, beta, delta and gamma isoforms of RISK using 20 μM ATP. The next screening was carried out to determine the values of IR 5o for the inhibition of four isoforms of RISK at a final concentration of 200 μM ATP, which is 10 times higher and essentially close to the normal physiological concentration of ATP in cells.

This protocol for establishing selectivity is identical to that described above, except that the 3X stock (8) ATP solution has a concentration of bO0µM. Data from this study are summarized in Table 3, below. The observed sensitivity to ATP concentration indicates that these RVC inhibitor compounds act as ATP competitors. (ze) from Table Z

Compound Alpha Beta Delta Gamma (|(Alpha/Delta Ratio Beta/Delta Ratio Gamma/Delta Ratio (αv)

YKBo YKBo YKBo YKBo - ooo | vtatya zBez6 0005 loyae oh and - oto eh 354 ooo? « p sh Without tzh|lo40016001800001000005 («c) is. o3v rigi t vaye be tu 111vv17771111611111111z611 b5

EXAMPLE 12

Data from a cell-based study for the inhibitory activity of PPK

Using the methods described above in Examples 3-5, the compounds of the invention were tested for their inhibitory activity and potency in studies of B and T cell-stimulated proliferation, neutrophil migration (NMP), and neutrophil (NMP) elastase release. The data of this study are presented below in Table 4. The values shown in Table 4 are the effective concentrations of the compounds (EC 50; µM). In the absence of a value, the study was not conducted. then

VSC mouse (ECbo) TSE mouse /RMM human (ECvo))!RMM human (ECvo) ost I NI ti NN PO POL iv bo) ot 13900000 bob og 0055000oayuy 00000000 tou 00420004 vvi byu oyayuya 00000005 2 boju oi 000000010095yu30000 evyu0 00000018 viz la siva bayum yav s o bo oeyyut 00080000 vela 01851 o». not from you 00111118

F

- God bless you 00000100 00080000 000002 00000100

PS NSTU UNN NIMY POL PO « yu vezvogyul gayu, 00003100 - s bolu 01000000100ayu40100020 » vvi layuy 0102850 bu ov 00000005 1 malya 01380001 - ov

F roy ozyum11ov5yua rovobyayu 150111oeyu?ye tr re! 2 o 16315111 o vali sho sh-ooiiiovye 11111

EXAMPLE 13

Study of the activity of RVC inhibitors in cancer cells

F! The effect of compounds according to the invention on the proliferation of cancer cells was evaluated by testing one of the compounds against cell lines of a panel of chronic myeloid leukemia (CML), including KO812, KUM ec4, K562 and MEO-O1. o The inhibitory activity of the compound (a-000, solution in DMSO) was determined as follows. The tested compound was added in a series of concentrations (0.001-20μM) to 96-cell microtiter plates with cells (1000-5000 60 cells/cell). Tablets were incubated for five days at 37 °C, during which control cultures without test compounds were . capable of at least two cycles of cell division. Cell growth was measured by absorbance

INi-thymidine for 18 hours, added on the third, fourth and fifth days. Cells were transferred to a filter, washed, and counted for radioactivity using a Maighich 96 beta counter (RaskKaga). The percentage of cell growth was measured as follows: bo (average number of incubated cells before Cell growth at a given inhibitor concentration) 100 (average number of cells without inhibitor)

ECo values in these experiments were determined by the concentration of the test compound, which gives a radioactivity count that is 5095 lower than that obtained using a control without inhibitor. Compound 0-000 showed inhibitory activity with EK 59 of approximately 2 μM for KO812 and KUM ec4 lines. The compound was found to have no effect on the КЛ62 and МЕС-О1 lines.

Inhibitors of RIZCoo according to the invention have been found to inhibit the growth of SMI cells and therefore could be useful in the treatment of benign or malignant tumors. The expression of RVC in currently 70 has been demonstrated mainly in cells of hematopoietic origin. However, it could be present in a wide variety of proliferating cells. Therefore, the compounds according to the invention could be used to induce regression of tumors and to prevent the formation of tumor metastasis in leukemia and solid tumor or in proliferation of non-tumor origin. When added, the compound could be used alone and in combination with other pharmacologically active compounds or in combination with 75 radiation as a sensitizing agent.

EXAMPLE 14

Measurement of elastase exocytosis during lavage of mouse air pockets

The effect of 0-030 on leukocyte influx and neutrophil elastase exocytosis was tested in animal models. The six-day model of air pockets is a model of ip mimo inflammation, which histologically resembles joint synovitis. A lining of formed mononuclear cells and fibroblasts develops, which has a close resemblance to the synovial cavity. The model represents an "acute" model of a chronic disease (for example, rheumatoid arthritis). This model makes it possible to evaluate IP bypassing means of blocking cell influx into the air pocket under the influence of an inflammatory stimulating factor. as with p with lips. ay: 7: you ay, from whom I and from which and check and N so 3o E I i o i KO - pln s Y 2 5 -

Shchi Riy y to - nn shko Z pt | (So) i g. - - In 2 to Zo what h "her they siy 8

B-03 about their XX "and -I

The test was carried out as follows: on day zero, a group of rats was shaved and injected subcutaneously with 1 Oml of air in the side (22) of each, forming a pocket. On the third day, 10 ml of air was injected again. Six hours before the control - TME infection on day six, one group of rats (n-b6) received 0-030 (10Omg/kg in PEG 400 medium) for 5 days orally, and the second group (n-12) received only the medium orally. Six hours after receiving the dose, the air pockets of both groups received 2.5 ng of TME. Twelve "Fo" hours after receiving the dose, the pockets were flushed with saline and the resulting lavage fluid was analyzed for leukocyte count and neutrophil elastase activity. In addition, blood was taken to determine the levels of O-030 in the circulating blood. The results were as follows: Rats treated with 0-030 for twelve hours had an average of 8.7 µM of the compound in the circulating blood and had an 8295 reduction in total" leukocytes in the lavage fluid compared to the medium control. The reduction in specific (F) leukocyte counts was : neutrophils (9095), eosinophils (6695) and lymphocytes (7090) Quantification

GI of neutrophil elastase revealed that 0O-030 treated rats had elastase levels that were slightly reduced (1595) compared to the medium control. In the second test, the side plane of the mouse was shaved using scissors and an air pocket was created by injecting Zml of air subcutaneously. On the third day, the air injection was repeated. On the sixth day, the animals were dosed with 0-030 (32 mg/kg in AVKARYI F) or only I AVKARYI F one hour before the control infection and two hours after the control infection with TMRa (0.5ng in iml PB5), or only PB5. РВ5 is a phosphate-buffered saline solution. Four hours after control infection with TME, the animals were anesthetized and the pockets were washed with 2 ml of 0.995 saline with 2 mM EDTA. 65 Washing fluids were centrifuged at 14,000 rpm. in a microcentrifuge. Fifty microliters of the supernatant liquid was used to measure elastase exocytosis by the method described above.

As shown in Fig.9, control infection with TME induced high levels of elastase exocytosis compared to animals with control infection with PB5. However, when control PB5-infected animals were treated with 0-030, a significant reduction in elastase activity was observed in air pocket lavages.

All publications and patent documents cited in this specification are presented as reference with respect to all that they disclose.

While the present invention has been described with certain references to certain preferred embodiments for clarity and understanding, it should be understood by those skilled in the art that the following changes and modifications may be practiced within the scope of the invention as defined in the following claims. Accordingly, no other limitations should be 7/0 Used with respect to the invention than those specifically set forth in the claims.

Claims (1)

The formula of the invention 1. A method of leukocyte dysfunction, in which said leukocytes are treated with a compound that selectively inhibits the activity of phosphatidylinositol-33-kinase-delta (PSK) in said leukocytes relative to other phosphatidylinositol-3-kinase (PSK) type I isoforms in a cell-based study , and the specified compound has the structure: (8) or Y is absent; "- in" is selected from the group consisting of H, a halogen atom, OH, OSN, CH" and CE"; BZ is selected from the group consisting of H, OSH" and a halogen atom; ee, or B" and 8, together with C-6 and C-7 of the quinazoline ring system, represent a 5- or b--lens aromatic h- ring containing, as an option, one or more O, M, or 5 atoms; BO is selected from the group consisting of C 1 6 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-FO)OC"OH" and morpholinyl; "BZ is independently selected from the group consisting of MH", halogen atom, Si alkyl, Z(S. alkyl), OH, MN(S. alkyl), M(S. alkyl)", MN(S. alkylenephenyl); and c) c 4 - 1 or 2, "" or are its pharmaceutically acceptable salts and solvates, " provided that at least one of B' and C does not represent a β-halogeno- or 6,7-dimethoxy group, and BO does not represent 4-chlorophenyl. 2. The method according to claim 1, which is characterized by the fact that said leukocytes include cells selected from the group consisting of neutrophils, B-lymphocytes, T-lymphocytes and basophils. Gee! Q. The method according to claim 1, characterized in that said leukocytes include neutrophils, and said method includes disruption of at least one function of neutrophils selected from the group consisting of stimulated superoxide release, stimulated exocytosis, and chemotactic migration. o 20 4. The method according to claim 3, which is characterized by the fact that bacterial phagocytosis or destruction of bacteria by said neutrophils is essentially intact. c" 5. The method according to claim 1, which is characterized by the fact that the specified leukocytes include B-lymphocytes, and the specified method includes disruption of the proliferation of the specified B-lymphocytes or the production of antibodies by the specified B-lymphocytes. 6. The method according to claim 2, which is characterized by the fact that the specified method includes a violation of the proliferation of the specified 29 T-lymphocytes. GF) 7. The method according to claim 1, which differs in that the specified leukocytes include basophils, and the specified method includes disruption of the release of histamine by basophils. o 8. The method according to claim 1, which is characterized by the fact that the specified compound exhibits at least approximately 10-fold selectivity for inhibition of RISK,y, relative to other isoforms of RISK type I in a cell-based study. 60 9. The method according to claim 8, which is characterized by the fact that the specified compound exhibits at least approximately 20-fold selectivity for inhibition of RISK,y, relative to other isoforms of RISK type I in a cell-based study. 10. The method according to claim 9, which is characterized by the fact that the specified compound shows at least approximately 50-fold selectivity for inhibition of RIZK,y, relative to other isoforms of RIZK type I in a biochemical study. 11. The method according to claim 1, which differs in that the compound is selected from the group consisting of: b5 3-(2-isopropylphenyl)-5-methyl-2-(9H-purine-b6-ylsulfanylmethyl)-ZH-quinazoline -4-one; 5-chloro-2-"9H-purin-b-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; 5-chloro-3-(2-fluorophenyl)-2-(9H-purine-b6 -ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-fluorophenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-methoxyphenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl-ZH-quinazolin-4-one; 3-(2,6-dichlorophenyl)-5-methyl-2-(9H- purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 5-chloro -3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 70 3-(3-methoxyphenyl-2-(9H-purin-6-ylsulfanylmethyl-3H-quinazolin-4-one; 3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl) -ZH-quinazolin-4-one; Z-benzyl-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; Z-butyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH -quinazolin-4-one, 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-morpholin-4-yl-2-" 9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; 8-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-6,7-difluoro-2-(9H -purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one, 3-(2-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; b-chloro-3- (2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(3-chlorophenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; (9H-purin-6-ylsulfanylmethyl)-3-pyridin-4-yl-3H-quinazolin-4-one; (2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-trifluoromethyl-3H-quinazolin-4-one; 3-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H- quinazolin-4-one; 3-(4-methylpiperazin-1-yl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; ch 3-(2-chlorophenyl)-6-hydroxy-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; ethyl ester (5-fluoro-4-oxo-2-"9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl|Ioacetic acid; i) 3-(2,4-dimethoxyphenyl)-2-(9H -purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZN-quinazolin-4-one; c zo 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2-yl-5-chloro-3H-quinazolin-4-one; o 5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; "- 2-(6-aminopurin-9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolin-4-one; ise) 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 1-2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-benzyl-5-fluoro-ZN-quinazolin-4-one; « 2-(6-aminopurin-9-ylmethyl)-3-butyl-ZN-quinazolin-4-one; with c 2-(6-aminopurin-9-ylmethyl)-3-morpholin-4-yl-3H-quinazolin-4-one; . 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one; and?" 3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-phenyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4- he 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-isopropylphenyl)-ZN-quinazolin-4-one. and -I 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one. 12. The method of leukocyte dysfunction, which includes the interaction of leukocytes with a compound having the structure Фо гШХХЧы М - о хо де A represents a substituted, as an option, monocyclic or dicyclic ring system containing ГФ) at least two nitrogen atoms, and at least one ring of the system is aromatic; which X is selected from the group consisting of СН, СНоСНЕ? and SNAS (VU); M is selected from the group consisting of 5, ZO, 505, MH, 0, C(50), ОС(-0), С(-О)ОО and МНОС(-О)СНОЗ, or U is absent; 60 VE! and B are independently selected from the group consisting of hydrogen, C..alkyl, aryl, heteroaryl, halogen atom, МНО(-О)С. Zalkylenm(К?)», MO», OKU, OSE», M(KU)», SM, Oos(chOvU, с(5О)В2, С(-О)ОК2, arylOv?, Nei, MeЕ2С(-О0) S. zalkylens(-O)ОВ2, aryls. zalkylene-(B 2)", arylC(-O)Ke, S. lalkylens(-O)OKe, OS. dalkylens(-F)OKe, 65 S. lalkylenosS. dalkylens (-F)OKe, Fsh(-0)-MKke5OKU, S. lalkileni(K 7)", Co valkenylen(K 7)", cS(O)Mv es, dalkylenOvKU, C(5O)MK2S. dalkylenNei, OS" 4-alkyleneM(K?)", Os. dalkylensH(OK SNoM(B 2)", OS dalkylenNei, OS»odalkylenOmK", OS»dalkylenmKeS(-0)Oe, MKS. dalkylenim(t")", MA F(-oMKU, MASOK)", MO". dalkil)", MK U(5O05S. ldalkil), ZH02M(K2)", О5ОoСЕ", C) zalkylenarilu, S. lalkylenNei, S. valkylenob U, S. zalkyleni(K 7)", SOKU)", 2 MNO( -O)C, alkylenearyl, C3.vcycloalkyl, C3.vheterocycloalkyl, aryl-OC. Zalkylen(K 2)", arylos(-O Ve, MNOSTsto)s . alkylene-C3 heterocycloalkyl, МНО(со)сС. zalkilennei, OS. dalkilenos and dalkilens(-O)OK, С(О)С. dalkylene and MNO(-O)halogen. valkyla; or KE! and B? together they form a 3- or 4-ene alkylene or alkenylene chain component of a 5-7/0 or b-membered ring, which, as an option, contains at least one heteroatom; BZ is selected from the group consisting of a substituted, as an option, hydrogen atom, C 4.alkyl, C. vcycloalkyl, C. v. heterocycloalkyl, C. alkylenecycloalkyl, C. valkenyl, C. alkylenearyl, arylSialkyl, C(-O)Ke, aryl, heteroaryl, C(-O)OKe, F(O)M(e), C(- 5)M(K2)", 5O»MT?, 5ОЖ(KU)", 5(-O KU, (OK), FSH-O)MKUS. alkylene ke, F(-O)MKUS. more distant, F(-O)S. dalalkylenaryl, Ф(-О0)С, udalalkyleneheteroaryl, C.i.4alkylenaryl, as a variant, substituted by one or more halogen atoms, 5ООМ(К2), М(К?)», what), MKe5ООСЕЗ, СМ, МО», Ф (-O)Ke, OK, SidalkylenemS(K?)" and OS, alkylene(K 2)", C. dalkyleneheteroaryl, C. dalkylene, Si dalkyleneC(O)-C. lalkylenearyl, S. dalkilens(0)-S. dalkylenheteroaryl, S. lalkylens(-O)Nei, S. dalkylens(-O)M(K2)", Si. long-knee U, S. dalkilenemk "C(HO)Ke, S. lalkileno-S. lalkilenok?, S. lalkilene(K U)", Si lalkilens(-0)-OKe and S. dalkilenos in lalkilens(-O)OKe; KZ: selected from the group consisting of a hydrogen atom, C..alkyl, C.zacycloalkyl, C.sub.heterocycloalkyl, C..alkylene(ke)", aryl, arylC.alkyl, C..alkylenearyl, heteroaryl, heteroaryl. alkyl and C. alkylene heteroaryl; or two KU groups together form a 5- or b-membered ring containing, as an option, at least one i9) heteroatom; IN? selected from the group consisting of a hydrogen atom, C /.alkyl, aryl, heteroaryl, aryls. alkyl, 4.alkyl heteroaryls, C. alkylenearyl and C. alkyleneheteroaryl; It represents a 5- or b-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur atoms and optionally substituted with C. alkyl or S(-O) OKU; "-- and are pharmaceutically acceptable salts and solvates thereof, "so in an amount sufficient to inhibit the activity of phosphatidylinositol-3-kinase-delta in the specified leukocytes. 13. The method according to claim 12, which is characterized by the fact that the compound is selected from the group consisting of: - 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-ZH -quinazolin-4-one; 2-(6-aminopurin-o-ylmethyl)-6-bromo-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-o-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one; « 2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one; t c 2-(6-aminopurin-o-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; h 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one; » 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2-yl-5-chloro-3H-quinazolin-4-one; 5-chloro-2-"9H-purin-b-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; - 5-chloro-3-(2-fluorophenyl)-2-(9H-purine- b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; b 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolin-4-one; Z-diphenyl- 2-yl-5-chloro-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; - 5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; o 20 3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-6,7-dimethoxy-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; c» b-bromo-3-(2-chlorophenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-8-trifluoromethyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-2--9H-purin-6-ylsulfanylmethyl)-ZH-benzo|d)quinazolin-4-one; 22 b-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; He! 8-chloro-3-(2-chlorophenyl)-2-" 9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; where 3-(2-chlorophenyl)-7-nitro-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-6-hydroxy-2-(9H- Purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 60 5-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-methyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-6,7-difluoro-2(9H -purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 2- (6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-3-H-quinazolin-4-one; 65 (b-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl -ZN-quinazolin-4-one; (2-fluorophenyl)-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-ZN-quinazolin-4-one; 2-(2-amino-9UN-purin-6-ylsulfanylmethyl)-3-cyclopropyl-5-methyl-ZN-quinazolin-4-one; 3-cyclopropylmethyl-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-cdcyclopropylmethyl-5-methyl-ZH- quinazolin-4-one; 2-(2-amino-9UN-purin-6-ylsulfanylmethyl)-3-cdcyclopropylmethyl-5-methyl-3H-quinazolin-4-one; 5-methyl-3-phenethyl-2-"9Н -purin-b-ylsulfanylmethyl)-ZN-quinazolin-4-one; 2-(2-amino-9UN-purin-6-ylsulfanylmethyl)-5-methyl-3-phenethyl-3H-quinazolin-4-one; 70 3-cyclopentyl-5-methyl-2-"9H-purin-6b-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-cdcyclopentyl-5-methyl-ZH -quinazolin-4-one; 3-(2-chloropyridin-3-yl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin- 9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin-4-one; 3-methyl-4-15-methyl-4-oxo-2-(9H-purine- 6-ylsulfanylmethyl)-4H-quinazolin-3-yl|-benzoic acid; 3-cyclopropyl-o-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-3H-quinazolin-4-one; 2-(6- aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one; 5-methyl-3-(4-nitrobenzyl)-2-(9H-purin-b6-ylsulfanylmethyl)-3H-quinazoline -4-one; 3-cyclohexyl-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-33-cyclohexyl-5 -methyl-3H-quinazolin-4-one; (2-amino-9UN-purin-6-ylsulfanylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one; 5-methyl-3-(E -2-phenylcyclopropyl)-2-"9H-purin-6b-ylsulfanylmethyl)-ZH-quinazolin-4-one; (2-chlorophenyl)-5-fluoro-2-KUN-purin-6-ylamino)-methyl/|-ZN-quinazolin-4-one; 2-(2-amino-9UN-purin-6-ylamino)methyl|-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one; 5-methyl-2-KUZN-purin-6b-ylamino)methyl|-3-o-tolyl-ZN-quinazolin-4-one; ch 2-(2-amino-9H-purin-6-ylamino)methyl|-5-methyl-33-o-tolyl-3H-quinazolin-4-one; 2-K2-fluoro-9H-purine-b-ylamino)methyl-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; i) (2-chlorophenyl)-dimethylamino-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 5-(2-benzyloxyethoxy)-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-fluoro-4- oxo-3,4-dihydroquinazolin-2-yl methyl ester of b-aminopurine-9-carboxylic acids; IM-(3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2- ylmethyl (|-2-"9H-purin-6b-ylsulfanyl)-acetamide; o 2-(1--2-fluoro-9H-purine-b-ylamino)ethyl-|-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; "- 5-methyl-2-/1-(9H-purin-b-ylamino)ethyl/|-3-o-tolyl-ZN-quinazolin-4-one; 2-(6-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; ise) 5-methyl-2-(2-methyl-b-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one; n-5-methyl-2-(2-methyl-6b-oxo-1,6-dihydropurin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one; 2-(amino-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(amino--H-purin-b6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(4-amino-1,3,5-triazol-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; « 5-methyl-2-(7-methyl-7H-purin-6-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; with c 5-methyl-2-(2-oxo-1,2-dihydropyrimidin-7-4-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one; . 5-methyl-2-purin-7-ylmethyl-3-o-tolyl-ZN-quinazolin-4-one; and?" 5-methyl-2-purin-9-ylmethyl-3-o-tolyl-ZN-quinazolin-4-one; 5-methyl-2-(3-methyl-9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one; 2-(2,6-diaminopyrimidin-4-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; -I 5-methyl-2-(5-methyl-|1,2,A|triazolo|1,5-a|Ipyrimidin-7-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; 5-methyl-2-(2-methylsulfanyl-9UN-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one; Me, 2-(2-hydroxy-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; - 5-methyl-2-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-3-o-tolyl-ZH-quinazolin-4-one; 5-methyl-3-o-tolyl-2-(1H-(1,2,A)triazol-3-ylsulfanylmethyl)-ZH-quinazolin-4-one; o 2-(2-amino-6-chloropurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 4) 2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(7-amino-1,2,3-triazolo|4,5-4|-pyrimidin-3-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(7-amino-1,2,3-triazolo|4,5-4|-pyrimidin-1-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(6-amino-9UN-purin-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(2-amino-b6-ethylaminopyrimidin-4-ylsulfanylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; F) 2-(3-amino-5-methylsulfanyl-1,2,4-triazol-1-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; ka 2-(5-amino-3-methylsulfanyl-1,2,4-triazol-1-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2-(b-methylaminopurin-9-ylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; in 2-(6-benzylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one; 3Z-isobutyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)- M-(2-(5-methyl-4-oxo-2-"9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl|-phenyl))-acetamide; 65 5-methyl-3-(E-2-methylcyclohexyl)-2-"9H-purin-6b-ylsulfanylmethyl)-ZH-quinazolin-4-one; (b-methyl-4-oxo-2-(9H-purine -6-ylsulfanylmethyl)-4H-quinazolin-3-yl|-bSenzoic acid; 12-K2-dimethylaminoethyl)methylamino|-Zphenyl)-5-methyl-2-((9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-methoxy-2 -(9H-purin-b-ylsulfanylmethyl)-3H-quinazolin-4-one; 3-(2-chlorophenyl-)-5-(2-morpholin-4-ylethylamino)-2-"9H-purin-6- ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-benzyl-5-methoxy-2-"9H-purine-b-ylsulfanylmethyl)-ZH-quinazolin-4-one; 14. A method of improving a medical condition mediated by the activity of RAZK in leukocytes, in which a therapeutically effective amount of a compound that selectively inhibits the activity of phosphatidylinositol-3-kinase-delta in the specified leukocytes relative to other isoforms of phosphatidylinositol-3-kinase is administered to an animal in need of it ( RIZK) of type I in a cell-based study, and the specified compound has the structure: B) , in c da and 5 in M zhom Shen -e M M Kn where U is selected from the group consisting of 5 and MH, or U is absent; c c' is selected from the group consisting of H, a halogen atom, OH, OSN", CH" and CE"; o BZ is selected from the group consisting of Н, ОСН" and a halogen atom; or B" and KZ together with C-6 and C-7 of the quinazoline ring system represent a 5- or b--membered aromatic ring, optionally containing one or more O, M or 5 atoms; BO is selected from the group that consists of C 1 6 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, and) diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(xO)OSONH, and morpholinyl; o BZ is independently selected from the group consisting of MH", a halogen atom, Si zalkilu, Z(S. alkyl), OH, MN(S. alkyl), M(S. alkyl)", MN(S. alkylenephenyl); a - 4 - 1 or 2, Ge) or are its pharmaceutically acceptable salts and solvates, Zo provided that at least one of KE" and KZ does not represent a 6b-halo- or 6,7-dimethoxy group, and KU does not - represents 4 -chlorophenyl. 15. The method of claim 14, wherein said medical condition is determined by an undesirable neutrophil function selected from the group consisting of stimulated superoxide release, stimulated exocytosis, and chemotactic migration. 7 16. The method according to claim 15, which is characterized by the fact that the phagocytic activity or destruction of bacteria by said neutrophils is essentially intact. from 17. A method of disrupting the function of osteoclasts, in which the specified osteoclasts are subjected to the action of a compound that selectively inhibits the activity of phosphatidylinositol-3-kinase-delta in the specified osteoclasts relative to other isoforms of phosphatidylinositol-3-kinase (PIZK) type | in a study based on cells, and the indicated compound has -1 175 structure (8) , - M o -Щ s» e M zhom | З в Ше (Ф, с-м д) M Kn 60 where U is selected from the group consisting of 5 and МН, or U is absent; B" is selected from the group consisting of H, a halogen atom, OH, OSNa3, CH3 and SEZ; BZ is selected from the group consisting of H, OSN" and a halogen atom; or B" and 28 together with C-6 and C -7 of the quinazoline ring system represent a 5- or b-len aromatic 65 ring containing, as an option, one or more O, M or 5 atoms; BO is selected from the group consisting of C 1 6 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-FO)OC"OH" and morpholinyl; VZ is independently selected from the group consisting of MH", a halogen atom, Si alkyl, Z(S. alkyl), OH, MN(S. alkyl), M(S. alkyl)", MN(S. alkylenephenyl); and 4 - 1 or 2, or are its pharmaceutically acceptable salts and solvates, provided that at least one of B and KZ does not represent b-halogeno- or 6,7-dimethoxy groups, and in addition, provided that KZ does not represent 4 -chlorophenyl. 18. The method according to claim 17, characterized in that said compound includes a bone-binding group. 19. A method of improving a bone resorption disorder in an animal in need thereof, in which the animal is administered a therapeutically effective amount of a compound that inhibits the activity of phosphatidylinositol-3-kinase-delta (PIZK) in the osteoclasts of the animal relative to other isoforms of phosphatidylinositol-3-kinase (PIZK). of type I in a cell-based study, and the specified compound has the structure (8), 5 r h ЯК M - M жо M She si Shi --M s M kh o Kn de U is selected from the group consisting of 5 and MH, or Y is absent; He is selected from the group consisting of H, a halogen atom, OH, OSN", CH" and CE"; o BZ is selected from the group consisting of Н, ОСН" and a halogen atom; o or B" and 28 together with C-6 and C-7 of the quinazoline ring system represent a 5- or b--membered aromatic ring containing, optionally, one or more O, M or 5 atoms; -- BO is selected from a group consisting of C 1 6 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, "0 from diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-FO)OC"OH" and morpholinyl; M BZ is independently selected from the group that consists of MH", a halogen atom, C alkyl, C(Ci alkyl), OH, MH(C alkyl), M(C alkyl)", MH(C i alkylenephenyl); and 4 - 1 or 2 , or are its pharmaceutically acceptable salts and solvates, "provided that at least one of KK" and KZ does not represent b-halogeno- or 6b,7-dimethoxy groups, and in addition with the condition that KZ does not represent 4-chlorophenyl. c 20. The method according to claim 19, which differs in that the specified bone resorption disorder is osteoporosis. ,» 21. A method of inhibiting the growth or proliferation of chronic myelogenous leukemia cells, in which the cell is treated with a compound that selectively inhibits the activity of phosphatidylinositol-3-kinase-delta in cancer cells. research on the basis of cells, and the indicated -I compound has the structure Ф о ' 7 - Е Z em Shchy ("c) s" В as x М - Ф) | ii ko -M M bo Ж mn where U is selected from the group consisting of 5 and МN, or U is absent; He is selected from the group consisting of H, a halogen atom, OH, OSN", CH" and CE"; BZ is selected from the group consisting of H, OSH" and a halogen atom; b or B" and KZ together with C-6 and C-7 of the quinazoline ring system represent a 5- or b--membered aromatic ring, optionally containing one or more O, M or 5 atoms; BO is selected from the group, consisting of C16alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-FO)OC"OH" and morpholinyl; BZ is independently selected from the group consisting of MH" atom halogen, C 1 alkyl, Z(C 1 alkyl), OH, MH(C 1 alkyl), M(C 1 alkyl), MH(C 1 alkylenephenyl); and 4 - 1 or 2, or its pharmaceutically acceptable salts and solvates, provided that at least one of K' and KZ does not represent β-halogeno- or 6,7-dimethoxy groups, and in addition 70 provided that EZ does not represent 4-chlorophenyl. 22. The method of inhibiting the kinase activity of the phosphatidylinositol-3-kinase-delta polypeptide, in which the specified polypeptide is subjected to action with a compound having the structure (8) in. Г 3 M -- where A represents a substituted, as an option, monocyclic or dicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic; X is selected from the group consisting of СНЕ?, СНоСНЕ? and SN - C(VU); M is selected from the group consisting of 5, 5O, 505, МН, 0, (50), ОС(-0), С(-0)ОО, and МНС(-О)СНоЗ, or M SI is absent; oh VE! and K2, independently, selected from the group consisting of a hydrogen atom, Si. alkyl, aryl, heteroaryl, halogen atom, МНО(-О)С. zalkylenm(K?)", MO", OKU, OSEz, M(K)", SM, Oos(-Ove, с(-О)К2, сС(-FOKe, arylOk?, Nei, MK2С(-О)С . zalkylens(-O)OKe, aryl) zalkylene-M(K 2)", from arylC(-O)Ke, S. lalkylens(-O)OKe, OS. dalkylens(-F)OKe, o Su. dalkilenos dalkilens(-FO)OKU, Ф(-0)-МКг5OKU, S. lalkileni(K 7)», Sowalkenilenm(t?)», С(хО)Mt es. dalkilenote, /С(хО)МтеС. dalalkylene, OS» -alkylenem(B2)», OS. lalkylensn(ОВ)СНоМ(Б2)», se OS, /alkylenNei, OS» dalkyleno kg, OS» dalkylenmK2С(-Ф0)OK, MKS. dalkyleniSh(ke)», MKes(-oMKU, so MKS OMU)», (OS. dalkil)», MK U(505С.. lalkyl), З0О2М(К2)», О5О»СЕ», 3о С) alkylenearyl, С .lalkylenNei, C. alkyleneOk U, Si alkylene(K U)", vok)", - МНО(-О)С, alkylenearyl, C3.vcycloalkyl, C3.vheterocycloalkyl, aryl-OS. Zalkylen(K 2)", arylos(-O Ve, MNOSTsto)s . alkylene-C3 heterocycloalkyl, МНО(со)сС. zalkilennei, OS. dalkilenos and dalkilens(-O)OK, С(О)С. dalkylene and MNO(-O)halogen. valkyla; "or B" and B? together form a 3- or 4-ene alkylene or alkenylene chain component of a 5- in c or b-membered ring, which, as an option, contains at least one heteroatom; c BZ is selected from the group consisting of optionally substituted by a hydrogen atom, C 4 alkyl, "» C cycloalkyl, C 3 heterocycloalkyl, C alkylenecycloalkyl, C alkylenyl, C alkylenaryl, arylSialkyl, C(-O)Ke, aryl, heteroaryl, C(-O )OKe, F(O)M(e), C(-5)M(K2)", 5O»MT?, 5ОЖ(KU)", 8("FOra, (OK), FSH-O)MKUS. alkylene ke, F(-O)MKUS. more distant, F(-O)S. dalkylenaryl, Ш- Ф(-О)С, dalkylene heteroaryl, C.alkylenaryl, as a variant substituted by one or more halogen atoms, (o) 5ООМ(К7)», M(Ke)», С(-О)OKe, MK ?5OOSEZ, SM, MO", (OKU, OKU, S. dalkylensh(K?")" - and - OS, ualkylenish(K 2)", S. lalkylenheteroaryl, S. lalkylenNei, S. lalkylens(O)-S .alkylenearyl, about 50. S. dalkylens(O)-C. dalkyleneheteroaryl, S. dalkylens(-O)Nei, S. dalkylens(-O)M(K2)", Si. dalkylenok U, S. dalkilenemK "C(-O)Ke, Su dalkileno-Su dalkilenok U, s" S. lalkilene(K 2)", Si.lalkilens(-O0)-OKzg and S. zalkilenos. dalkilens(-F)O Ka ; K? is selected from the group consisting of a hydrogen atom, C-alkyl, C-zacycloalkyl, C-3-heterocycloalkyl, C--alkylene(ke)", aryl, aryl-C-alkyl, C--alkylenaryl, heteroaryl, heteroaryleo-alkyl and C . alkylene heteroaryl; F) or two KU groups together form a 5- or b-membered ring containing, as an option, at least one ka heteroatom; B? is selected from the group consisting of a hydrogen atom, C 4 alkyl, aryl, heteroaryl, aryl C 1 alkyl, for heteroaryl C 1 alkyl, C 1 alkylenearyl and C 1 alkylene heteroaryl; It represents a 5- or b-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of atoms of oxygen, nitrogen, and sulfur, and, as an option, substituted with C. valkyl or C(-O)OKU, and its pharmaceutically acceptable salts and solvates. 65 23. The method according to claim 22, which differs in that Ge is selected from the group consisting of H, a halogen atom, OH, OSN", CH»z and CEz;a BZ is selected from the group consisting of C-alkyl, phenyl, halophenyl, alkylphenyl, diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-O)CoHb and morpholinyl; where at least one of the EE! and B2 does not represent a 6b-halo- or 6,7-dimethoxy group, and BZ does not represent a-chlorophenyl. 24. A compound having the structure (8) в щ до - М - е М жо М -и Ше --М М Мн where У is selected from the group consisting of 5 and МН, or У is absent; He is selected from the group consisting of H, a halogen atom, MO", OH, OSN", CH" and CE"; IN? selected from the group consisting of H, OSH" and a halogen atom; or B and K5 together with C-6 and C-7 of the quinazoline ring system represent a 5- or b--len aromatic SM ring containing, as an option, one or more O, M, or 5 atoms; d) VU is selected from the group consisting of C 1 6 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-FO)OC"OH" and morpholinyl; VU is independently selected from the group consisting of MH 5, a halogen atom, C alkyl, 5(C alkyl), OH, MH(C alkyl), M(C alkyl)", MH(C alkylenephenyl) and o 1-3 1-3 2 1-3 Zo ,a | "in) shi z o Te) and - no sn.on 4 - 1 or 2, and are its pharmaceutically acceptable salts and solvates, provided that at least one of B" and БЕ? does not represent H, when E? represents phenyl or 2 -chlorophenyl 25. The compound according to claim 24, which differs in that it is selected from the group consisting of: c 3-(2-isopropylphenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin- 4-on; ; c» 5-chloro-2-"9H-purine-b-ylsulfanylmethyl)-3-o-tolyl-ZH-quinazolin-4-one; 5-chloro-3-(2-fluorophenyl)-2-(9H-purine -β6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-fluorophenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; - 3-(2-methoxyphenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2,6-dichlorophenyl)-5-methyl-2-( 9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; (2) 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4- - 5-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 3-(2-chlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; («c 3-(2-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; «co 3-(2-chlorophenyl)-5-fluoro-2-(9H- purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; Z-benzyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; Z-butyl-2-"9H-purin- 6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; Z-morpholin-4 -yl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; (F) 8-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; GI 3-(2-chlorophenyl)-6,7-difluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(3-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; b-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(3-chlorophenyl)-2-"9H-purin-6- ylsulfanylmethyl)-ZN-quinazolin-4-one; (9H-purin-6-ylsulfanylmethyl)-3-pyridin-4-yl-3H-quinazolin-4-one; (2-chlorophenyl)-8-trifluoromethyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)- ZN-quinazolin-4-one; 65 3-(4-methylpiperazin-1-yl)-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one, acetate; 3-(2-chlorophenyl)-6-hydroxy-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; ethyl ester (5-fluoro-4-oxo-2-"9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl|Ioacetic acid; 3-(2-methoxyphenyl)-2-(9H-purine-b6 3-diphenyl-2-yl-5-chloro-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2-yl-5-chloro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-ZN-quinazolin-4-one; 70 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-benzyl-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-butyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-morpholin-4-yl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one; (b-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; (4-chlorophenyl)-2-9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-6,7-dimethoxy-2-"9H-purin-b-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-nitro-2-"9H -purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-ZN-quinazolin-4-one; sc b-bromo-3-(2-chlorophenyl)-2-"9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-2-"9H-purin-b6- ylsulfanylmethyl)-ZH-benzo|dinazolin-4-one; i) 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one. and 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-3H-quinazolin-4-one. 26. The compound according to claim 24, which differs in that K 4 is selected from the group consisting of H, a halogen atom, CO OH, OSN", CH" and CE"; BZ is selected from the group consisting of C 4 alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, o diphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(-O)OC»OH, and morpholinyl; where -- (a) B and 27, independently, do not represent β-halo- or 6,7-dimethoxy groups; "so (B) 29 does not represent 4-chlorophenyl; and Zo (c) at least one of K7 and KO does not represent H, when B9 represents phenyl or 2-chlorophenyl, and X represents 5. 27. The compound according to claim 25, which differs in that it is selected from the group consisting of: 3-(2-isopropylphenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-ZH-quinazolin-4 - he; "5-chloro-2-"9H-purin-b-ylsulfanylmethyl)-3-o-tolyl-ZN-quinazolin-4-one; - 70 5-chloro-3-(2-fluorophenyl)-2-(9H- purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; c 3-(2-fluorophenyl)-5-methyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; : z» 3-(2,6-dichlorophenyl)-5-methyl-2-(9H-purin-b6-ylsulfanylmethyl)-3H-quinazolin-4-one; 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 5-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-5-methyl-2-(9H-purine -b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; and 3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; Ge") Z-benzyl-2-(9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; z-butyl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; av | 20 3-morpholin-4-yl-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one, acetate; 8-chloro-3-(2-chlorophenyl)-2-"9H-purin- 6-ylsulfanylmethyl)-ZN-quinazolin-4-one; c» 3-(2-chlorophenyl)-6,7-difluoro-2-(9H-purin-b6-ylsulfanylmethyl)-3H-quinazolin-4-one; b-chloro-3-(2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 3-(3-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl )-ZN-quinazolin-4-one; (9H-purin-6-ylsulfanylmethyl)-3-pyridin-4-yl-3H-quinazolin-4-one; HF) (2-chlorophenyl)-2-"9H-purin-6-ylsulfanylmethyl)-trifluoromethyl-3H-quinazolin-4-one; 3-benzyl-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)- ZN-quinazolin-4-one; o 3-(4-methylpiperazin-1-yl)-2-"9H-purin-6-ylsulfanylmethyl)-ZN-quinazolin-4-one, acetate; 3-(2-chlorophenyl)-6-hydroxy-2-(9H-purin-b6-ylsulfanylmethyl)-ZN-quinazolin-4-one; 60 ethyl ester (5-fluoro-4-oxo-2-"9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl|acetic acid; 3-diphenyl-2-yl-5-chloro-2-" 9H-purin-6-ylsulfanylmethyl)-ZH-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-diphenyl-2-yl-5-chloro-3H-quinazolin-4-one; bo 2-(6-aminopurin-9-ylmethyl)-3-(2-fluorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-benzyl-5-fluoro-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-butyl-ZN-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-morpholin-4-yl-ZN-quinazolin-4-one; 70 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-ZN-quinazolin-4-one and 2-(6-aminopurin-9-ylmethyl)-5-chloro-3 -o-tolyl-ZN-quinazolin-4-one. 28. The compound having the general structural formula (8) , in! G - fii H. where A represents a substituted, as an option, monocyclic or dicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic; X is selected from the group consisting of SNE?, CH-SNE? and SNAS (EU); M is selected from the group consisting of 5, ZO, 505, МН, 0, С(50), ОС(-0), С(-О)ОО and МНОС(-О)СНОЗ, or У сч is absent; Whew! and K2, independently, selected from the group consisting of a hydrogen atom, o C..alkyl, aryl, heteroaryl, halogen atom, МНО(-О)С. Zalkylenm(K)», MO», OKU, OSEz, M(K)», SM, Oos(chOvU, с(5О)В2, С(-О)ОК2, arylОв?, Nei, MeE2С(-О0)С. alkylene(-O)ОВ2, aryloxyalkylene-(B 2)", arylCs(-O) KU, S. dalkylens(-O)OKU, OS. dalkylens(-F)OKU, Ge) S. lalkilenosS. dalkylens(-F)OKe, Fsh(-0)-MKke5OKU, Si dalkylene(K U)", Co valkenylenm(K 2)", o cS(O)Mv es, dalkylenOvKU, C(5O)MK2S. dalkylenNei, OS» 4-alkyleneM(K?)», Os. dalkylensH(OK СНоМ(В 2)», OS, /alkylenei, OS» dalkyleno kg, OS» dalkylenmkK2С(-Ф0)OK, MKS. dalkyleniSh(ke)», MKes(-oMKU, - MKS OMU)», (OS . dalkyl)", MK U(505С.. lalkyl), З0О2М(К2)", О5О»СЕ", (Се) C) alkylenearyl, С. )", i- MNeso)c, alkylenaryl, C3-acycloalkyl, C3-heterocycloalkyl, aryl-OC. zalkylen(B 9)", arylos(-OR, MNOSTsto)s . alkylene-C3 heterocycloalkyl, MNOT(-o)-C. zalkilennei, OS. dalkilenos dalkilens(-O)OR, С(О)С. dalkylene and MNO(-O)halogen. valkyla; " or KE! and B? together form a 3- or 4-ene alkylene or alkenylene chain component of a 5- or b-membered ring, which, as an option, contains at least one heteroatom; C with BZ is selected from the group consisting of optionally substituted hydrogen atom, C 4 alkyl, C 3 C cycloalkyl, C 3 heterocycloalkyl, C dalalkylenecycloalkyl, C 3 valkenyl, C 4 alkylenaryl, arylSialkyl, C(-O) КУ, aryl, heteroaryl, С(-ФО)OKe, сС(-О)М(К2), С(-5М(К), 502, BOZHU)» 45. ZO), 5B-OMKU), S(:O)MKUS. dalkyleneO KU, C(:OMKUS. dalkylenei, C(-O)C, dalkylenaryl, -I Ф(-О0)С, udalkylenheteroaryl, C.i.4alkylenaryl, as a variant substituted by one or more halogen atoms, b» 5ООМ( K2), M(K?)", that), MKe5OOSEZ, SM, MO", F(-O)Ke, OK, SidalkylenmSh(K?)" and OS, /alkylene(K 2)", S. lalkyleneheteroaryl , S. lalkilennNei, S. lalkilens(O)-S. lalkilenarilu, - S. dalkilens(0)-S. dalkylenheteroaryl, S. lalkylens(-O)Nei, S. lalkylens(-O)M(Ke)", / Si.lalkylenoke, o 20 S. dalkylenmK "C(-O)Ke, Su dalkyleno-Su dalkylenok U, p » C. alkylene(K 2)", C. alkylenes(-O0)-OKzg and C. alkylenes. dalkylenes(-F)O Ka; K? is selected from the group consisting of a hydrogen atom, C. alkyl, Czacycloalkyl, C3-heterocycloalkyl, C1-alkyleneim(K?)", aryl, arylC1-alkyl, C1-alkylenaryl, 5-heteroaryl, heteroaryl-alkyl and C-alkylene heteroaryl; HF) or two KU groups together form 5- or b- -len ring optionally containing at least one heteroatom; o B is selected from the group consisting of a hydrogen atom, C 4 alkyl, aryl, heteroaryl, arylC 4 alkyl, heteroarylC 4 alkyl, C 1 alkylenearyl and C 1 alkylene heteroaryl 60 It is represented by a 5- or b-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur atoms, and optionally substituted by C. valkyl and because C6-O) OKU; and pharmaceutically acceptable salts and solvates thereof, provided that if X-X represents CH 55, then KZ does not represent SI SI SI EI SE. ; se, dream You ate She dream. but sn, and if Х-Х represents SNOZV, then EZ does not represent substituted -"СНАСН(ОН)ИСНоОН-phenyl. 29. A compound according to claim 28, characterized in that X is selected from the group consisting of CH 5 , СНоСН»о, СНАСН, СН(СН3), СНЬСН(СН»С) and С(СН3). 30. The compound according to claim 28, which differs in that Y is selected from the group consisting of Z and MH, or Y is absent. 31. The compound according to claim 28, which is characterized in that the A-ring system is selected from the group consisting of imidazolyl, pyrazolyl, 1,2,3-triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, purinyl , cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, 1H-indazolyl and benzimidazolyl. 32. The compound according to claim 28, which differs in that the A-ring system is selected from the group consisting of c 29 and in M ' m ! Oh, MO. M /y M t My A M-A-MNO n.s M Mo lem M m sn. at 33. The compound according to claim 28, which differs in that the A-ring system is replaced by one to three substituents - selected from the group consisting of M(K2)", a halogen atom, C. alkyl, C(C.4. alkyl), OKU, halogen atom and He) | ич- НО (8) 0 НО Ссн.ОоН - с 34. The compound according to claim 28, which differs in that the A-ring system is substituted by one to three substituents, "» selected from the group consisting of МН», МН( CH»), M(CHnaz)», MNHNoSeNv, MH(SeoNv), SI, E, CHz, CH», OH and n 45. НО -И (8) (22) а но сн.он о 50 35. The compound according to claim 28, which differs in that K 1 and K2 are independently selected from the group consisting of a hydrogen atom, OKU, of a halogen atom, Sivalkilu, SEz, MO", M(K?), ISS. alkylene")"" and OS, alkylenenk U, specific substituents include, but are not limited to, Н, ОСН з, СИ, Вг, Е, СНз, СЕз, MO», ОН, М(СН3з)», and m (8) M-SnNo.SNOMN HF) x 2-72 ime) and Oo(СНОоОСНоСНХ5. 60 36. The compound according to claim 29, which differs in that B and B? together form a five- or six-membered ring. 37. The compound according to claim 28, which differs in that K C is selected from the group consisting of C 1 alkyl, aryl, heteroaryl, C3.vcycloalkyl, C3. in heterocycloalkyl, C(-O)OKU, S. dalkylenei, S. lalkylenecycloalkyl, S. lalkylenaryl, S. lalkilens(-O)S. lalkylenarylu, Si lalkylens(-O)OKe, S.lalkylens(O)MSH(K)", Si lalkylens(-O)Nei, because S. dalkylenMS KU) and Su. dalkilenm Kk 2-(хО)КУ. 38. The compound according to claim 29, which is characterized by the fact that К З is selected from the group consisting of ОК 3. С. ООСНХ, СННХ(СНЗ)», - shk it it i -fIO - lk o - hm M--sn, Ky do mtyu sn,-S ne n, ; ta. nin it 39. The compound according to claim 28, which differs in that K Z is a substituted substituent selected from the group consisting of a halogen atom, OK 2, C..alkyl, aryl, heteroaryl, MO», MSH(К?)» . )". 40. The compound according to claim 28, which is characterized by the fact that KE is a substituted substituent selected from the group consisting of SI, E, СНз, СН(СНУ)», OSN», SeNev, MO», МН, МНОС(:О )SNU, SOON and MSNZUISNSNoM (СН 3)". 41. The method according to claim 1, which differs in that it is used for the treatment of the following diseases: i) ischemia, especially caused by cardiac arrest, myocardial infarction, obstruction of coronary arteries, thromboembolic occlusion of cerebral vessels, traumatic head injury, edema or brain tumor, i) ) reperfusion injury, especially associated with vascular attack, myocardial ischemia or infarction, organ transplantation and cerebral vasospasm, sii) bone diseases, especially osteoporosis, Paget's disease and disorders related to bone resorption, Ge) im) cancer of hematopoietic origin, especially a) lymphoma, especially Burkitt lymphoma, Hodgkins lymphoma, non-Hodgkin lymphoma, lymphocytic lymphoma, 5) multiple myeloma, c) leukemia, especially lymphocytic leukemia, chronic myeloid (myelogenous) leukemia, o m) diseases associated with the release of histamine, especially chronic obstructive pulmonary disease, asthma, av! AKOZ and emphysema. mi) arthritis, especially rheumatoid arthritis, monoarticular arthritis, osteoarthritis, gouty - arthritis, spondylitis, Ge) mii) Bakhket's disease, mii) sepsis, septic shock, endotoxic shock, gram-negative sepsis, gram-positive sepsis and - toxic shock syndrome, i) multiple organ injury syndrome, secondary to septicemia, trauma or hemorrhage, x) ophthalmic disorders, especially allergic conjunctivitis, vernal conjunctivitis, uveitis and thyroid-associated ophthalmopathy, - 70 x) ensinophilic granuloma, c xii) lung disorders or respiratory disorders, especially asthma, chronic bronchitis, allergic rhinitis, chronic bronchitis, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis and pulmonary oxygen toxicity, hii) fibrosis , especially cystic fibrosis, chemical) formation of keloid tissues or scars, Xu) atherosclerosis, Ge») chmi) autoimmune diseases, especially systemic lupus erythematosus (CE), autoimmune thyroiditis, multiple sclerosis, some forms of diabetes, Raynaud’s syndrome, - chmi) transplant rejection disorders, especially SAD and allotransplant rejection, av | 20 chmii) chronic glomerulonephritis, xih) inflammatory bowel diseases, especially chronic inflammatory bowel disease (IBD), Crohn's disease, c» ulcerative colitis and necrotizing enterocolitis, xxi) inflammatory dermatoses, especially contact rheumatism, atopic dermatitis, psoriasis or urticaria, xxi) fevers and myalgias due to infection, xiii) inflammatory disorders of the central or peripheral nervous system, inflammatory disorders such as HF) meningitis, encephalitis and brain or spinal cord injury due to secondary trauma, xiii) Sørgensen's disease, o xiii) diseases in which leukocyte diapedesis is involved . , xxxiii) thermal injuries, xxxiii) syndromes associated with the transfer of granulocytes, xxxiii) cytokine-induced toxicity. c schi 6) (ze) "c) "- (Se) m. - with . and? -I (o) - r SHY syu» ime) 60 b5