N4-phenylquinazoline-4-amine derivatives and related compounds as receptor tyrosine kinase type erbb inihibitors for treating hyperproliferative diseases

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

 

Cross-reference to related applications

[0001] This application claims the priority of provisional patent application U.S. No. 60/736289 registered on 15 November 2005, and provisional application for U.S. patent No. 60/817019, registered on June 28, 2006, each of which is incorporated herein by reference in their entirety.

The level of technology

1. The technical field to which the invention relates.

[0002] This invention relates to new inhibitors of the receptor tyrosinekinase type I and related kinase, pharmaceutical compositions containing such inhibitors, and methods for producing these inhibitors. Inhibitors are suitable for the treatment of hyperproliferative diseases such as cancer and inflammation, in mammals, especially in humans.

2. Description of the prior art

[0003] the Family of receptor tyrosinekinase type I consists of four closely related receptors: EGFR (ErbB1 or HER1), ErB2 (HER2), ErbB3 (HER) and ErbB4 (HER4) (Reviewed in Riese and Stern, Bioessays (1998) 20:41-48; Olayioye et al., EMBO Journal (2000) 19:3159-3167; and Schlessinger, Cell (2002) 110:669-672). This is a single-pass transmembrane glycoprotein receptors containing the extracellular landscapelaumu region and intracellular domain transmission signal. In addition, all of the receptors contain active intracellular tyrosine kinase domain, except ErB3, kinase domain which does not show enzymatic asset is awn. These receptors transmit extracellular signals through cytosol to the nucleus upon activation. The activation process is initiated by the binding of ligand to the extracellular domain of the receptor is one of a number of different hormones. When the binding of the ligand induced Homo - or heterodimerization, which leads to activation of the tyrosine kinase domain and phosphorylation of tyrosines in the intracellular domains of signal transmission. Since there is no known ligand for ErbB2 not described and ErbB3 there is no active kinase domain, these receptors must heterodimerization to cause a reaction. Phosphotyrosine then call the recruitment of the necessary cofactors for the initiation of several different cascades of signal transmission, including the cascades ras/raf/MEK/MAPK and RC/ACT. Caused the exact signal will depend on the ligands present as intracellular domains of signaling differ in which transmission signals are activated. These transmission signals can lead to cell proliferation and survival of cells through inhibition of apoptosis.

[0004] Some researchers have demonstrated the role of EGFR and ErbB2 in the development of cancer (reviewed in Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232; Klapper, et al., Adv. Cancer Res. (2000) 77:25-79; and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184). Squamous cell cancer of the head, neck and lung Express the high levels of EGFR. In addition, constrictive active EGFR detected in gliomas, cancer of the breast and cancer of the lungs. Overexpression of ErbB2 occurs in approximately 30% of all cancers of the breast. She also participated in other cancer diseases, including colon cancer, ovarian cancer, urinary bladder, stomach, esophagus, lung, uterus and prostate. Overexpression of ErbB2 was also correlated with poor prognosis in cancer the human disease, including metastatic disease and early relapse.

[0005] the Family of receptors tyrosinekinase type I was given special attention, and this family was included in the active area of cancer research (Reviewed in Mendelsohn and Baselga, Oncogene (2000) 19:6550-6565; and Normanno et al., Endocrine-Related Cancer (2003) 10:1-21). For example, in U.S. patent No. 6828320 describes some of substituted quinoline and hintline as inhibitors proteincontaining.

[0006] Several inhibitors of transmission path signals EGFR and ErbB2 have shown clinical efficacy in the treatment of cancer. HERCEPTIN® (HERCEPTIN), humanitariannet version monoclonal antibodies against ErbB2, was approved for use in breast cancer in the United States in 1998. IRESSA®(IRESSA) and TARCEVA®(V) are having small molecules, commercially available EGFR inhibitors. In addition, several other antibodies and small molecules, which are aimed at p is eravana transmission signals tyrosinekinase receptor type I, are in clinical and preclinical development. For example, ERBITUX®(RIU), human-mouse chimeric monoclonal antibody against EGFR, is available for the treatment of irinotecan-refractory colorectal cancer.

The invention

[0007] This invention provides compounds that inhibit receptor tyrosine kinase type I. Such compounds are used as therapeutic agents for diseases that can be treated by inhibition of the receptor tyrosinekinase type I. They may also act as inhibitors sericinus, trionychinae and inhibitors of kinases with dual specificity. In General, the invention relates to compounds of formula 1

[0008] and their solvate, metabolites and pharmaceutically acceptable salts and prodrugs, where B, G, a, E, R1, R2, R3, m and n have values here, where, when specified compound of formula I is represented by the formula

[0009] and R3is other than Q or Z, where Q and Z have the values defined here, then E is not benzofuranyl, indolinyl, girasolereale, hyalinella or izokhinolinom ring.

[0010] In the next aspect the present invention provides a method of treating diseases or medical conditions, OPOS duemig receptor tyrosine kinases type I, which includes the introduction of a warm-blooded animal an effective amount of the compounds of formula 1 or its metabolite, MES or pharmaceutically acceptable salts or prodrugs.

[0011] In the next aspect the present invention provides a method of inhibiting the production of receptor kinase type I, which includes the introduction of a warm-blooded animal an effective amount of the compounds of formula 1 or its metabolite, MES or pharmaceutically acceptable salts or prodrugs (prodrug).

[0012] In the next aspect the present invention provides a method of providing inhibitory effect against receptor kinase type I, which includes the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its metabolite, MES or pharmaceutically acceptable salts or prodrugs.

[0013] In the following aspect the present invention provides a method of treatment or prophylaxis of a condition mediated by the receptor kinase type I, which includes the introduction of a number of compounds effective for the treatment or prevention of a condition mediated by the receptor kinase type I, or pharmaceutical compositions comprising such a connection, a person or an animal in need this, where the specified compound is a compound of formula I or f is rmaceuticals acceptable salt or split prodrug in vivo. State, mediated by the receptor kinase type I, which can be treated according to the methods of this invention include, but are not limited to, hyperproliferative disorders such as cancer of the head and neck, lung, breast, colon, ovarian, bladder, stomach, kidney, skin, pancreas, leukemia, lymphoma, cancer of the esophagus, uterus or prostate, among other types of hyperproliferative disorders.

[0014] the compounds of formula I can be applied mostly in combination with other known therapeutic agents.

[0015] the Invention relates also to pharmaceutical compositions comprising an effective amount of an agent selected from the compounds of formula I or its pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salts or prodrugs.

[0016] the Invention also provides the use of compounds of formula I as a drug for the treatment or prophylaxis of a condition mediated by the receptor kinase type I.

[0017] an Additional aspect of the invention is the use of compounds of formula I in obtaining drugs for treatment or prevention of a condition mediated by the receptor kinase type I.

[0018] the invention further proposes that fits all models of the s for the treatment or prevention of a condition, mediated receptor kinase type I, and this set includes a compound of formula I or its MES, metabolite or pharmaceutically acceptable salt or prodrug, a container, and optionally a flyer insert in the packaging or label containing information about the treatment. The kits can additionally include a second connection or a drug comprising a second pharmaceutical agent suitable for the treatment of specified diseases or disorders.

[0019] the invention further includes methods of preparation, methods of separation and purification methods of the compounds of this invention.

[0020] Additional advantages and new features of this invention will be set forth in part in the description which follows, and in part will become apparent to the person skilled in the art when considering the following description, or will be studied in practice of the invention. Advantages of the invention may be realized and attained by means of the combinations, compositions and methods specified in the attached claims.

Detailed description of the invention

[0021] Now will be given detailed references to some embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in connection with listing the military options implementation it should be clear that these implementation options are assumed not to limit the invention. On the contrary, it is assumed that the invention includes all alternatives, modifications and equivalents that may be included in the scope of the present invention defined by the claims. The person skilled in the art can know many methods and materials similar or equivalent to the methods described here and substances that can be used in practice of the present invention. The present invention is in no way limited to the described herein methods and substances. If one or more of the incorporated literature and similar substances differ from this application or contradict him, including, but not limited to defined terms, the use of terms, described techniques, or the like, the application adjusts it.

[0022] DEFINITION

[0023] the Term "alkyl", used here, refers to saturated monovalent hydrocarbon radical with unbranched or branched chain, having from one to twelve carbon atoms, where the alkyl radical may be optionally substituted independently by one or more substituents described below. Examples of alkyl groups include, but are not limited to perechisleny is m, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (ISO-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (ISO-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (sec-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-Bu, tert-butyl, -C(CH3)3), 1 pentyl (n-pentyl, CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH2)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-trimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-trimethyl-2-butyl (-CH(CH3)C(CH3) 3, 1-heptyl, 1-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0024] the Term "alkyl" includes saturated monovalent hydrocarbon radical with unbranched or branched chain, containing from one to six carbon atoms (for example, C1-C6alkyl)where the alkyl radical may be optionally substituted independently by one or more substituents described below.

[0025] the Term "alkenyl"used here refers to a monovalent hydrocarbon radical with unbranched or branched chain, having from two to twelve carbon atoms and at least one unsaturated site, i.e. a carbon-carbon sp2-double bond, where alkanniny radical may be optionally substituted independently by one or more described here substituents and includes radicals with "CIS"and "TRANS"orientations, or alternatively, "E"and "Z"orientations, Examples include, but are not limited to, ethylenic or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

[0026] the Term "quinil"used here refers to a monovalent hydrocarbon radical with unbranched or RA is extensive chain having from two to twelve carbon atoms and at least one unsaturated site, i.e. a carbon-carbon sp2a triple bond, where alkynylaryl radical may be optionally substituted independently by one or more described here substituents. Examples include, but are not limited to, ethinyl (-C≡CH) and PROPYNYL (propargyl, -CH2C≡CH).

[0027] the Terms "cycloalkyl," "carbocyclic and carbocycle"used herein are interchangeable and refer to a monovalent non-aromatic saturated or partially unsaturated cyclic hydrocarbon radical, having from three to ten carbon atoms. Examples of monocyclic carbocyclic radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl and cyclododecyl. Cycloalkyl may be optionally substituted independently at one or more substitutable positions of different groups. The term "cycloalkyl" also includes polycyclic (e.g. bicyclic or tricyclic) cycloalkyl patterns, where the polycyclic structure neoba is consequently include saturated or partially unsaturated cycloalkyl, condensed with a saturated or partially unsaturated cycloalkyl or heterocyclyl ring or aryl or heteroaryl ring. Bicyclic carbocycle having 7-12 atoms, can be classified, for example, as a bicyclo[4,5], [5,5], [5,6] or [6,6]system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonan.

[0028] the Term "heteroalkyl"used here refers to saturated monovalent hydrocarbon radical with unbranched or branched chain, having from one to twelve carbon atoms, where at least one of the carbon atoms replaced by a heteroatom selected from N, O or S, and where the radical may be a carbon radical or heteroatomic radical (i.e., the heteroatom may be in the middle or at the end of the radical). Heteroalkyl radical may be optionally substituted independently by one or more described here substituents.

[0029] the Term "heteroalkyl"used here refers to a monovalent hydrocarbon radical with unbranched or branched chain, having from two to twelve carbon atoms and containing at least one double bond, such as Attila, propenyl and the like, in which at least one of the carbon atoms replaced by a heteroatom selected from N, O, or S, ihde radical may be a carbon radical or heteroatomic radical (i.e. the heteroatom may be in the middle or at the end of the radical). Heteroalkyl radical may be optionally substituted independently by one or more described here, radicals, and includes radicals having "CIS"and "TRANS"orientations, or alternatively, "E"and "Z"orientation.

[0030] the Term "heteroalkyl"used here refers to a monovalent hydrocarbon radical with unbranched or branched chain, having from two to twelve carbon atoms and containing at least one triple bond. Examples include, but are not limited to, ethinyl, PROPYNYL, and the like, in which at least one of the carbon atoms replaced by a heteroatom selected from N, O or S, and where the radical may be a carbon radical or heteroatomic radical (i.e., the heteroatom may be in the middle or at the end of the radical). Heteroalkyl radical may be optionally substituted independently by one or more described herein radicals.

[0031] the Terms "heterocycle" and "heterocyclyl"used here interchangeably, refer to a saturated or partially unsaturated carbocyclic the radical with 3-8 atoms in the ring, of which at least one atom of the ring is a heteroatom independently selected from nitrogen atom, oxygen and sulfur, PR is the remaining ring atoms are atoms, where one or more ring atoms may be optionally substituted independently by one or more substituents described below. The radical may be a carbon radical or heteroatomic radical. The term "heterocyclyl" includes heterocyclics. "Heterocyclyl" also includes radicals where heterocyclyl radicals condensed with a saturated, partially unsaturated or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Examples heterocyclyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydropyranyl, dihydropyran, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, dioxane, piperazinil, homopiperazine, azetidine, oxetane, titanyl, homopiperazine, oxetanyl,tepanil, oxazepines, diazepines, thiazepines, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolopyrimidines, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes, azabicyclo[2.2.2]hexanal, 3H-indolyl, finalizing and N-pyridylamine. In the scope of this definition also includes sparadically. Heterocyclyl radical which may be C-attached or N-attached, when it is possible. For example, a group formed from pyrrole, may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). In addition, the group formed from imidazole, may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). Examples of heterocyclic groups in which 2 carbon atoms of the ring substituted by oxopropyl (=O), are isoindoline-1,3-dionyl 1,1-dioxo-thiomorpholine. Heterocyclyl groups are unsubstituted or, as specified, substituted in one or more substitutable positions of the various groups.

[0032] as an example, but not limited to, attached through a carbon atom heterocycles attached in position 2, 3, 4, 5 or 6 in the case of a pyridine, position 3, 4, 5 or 6 in the case of pyridazine, position 2, 4, 5, or in the case of a pyrimidine, position 2, 3, 5 or 6 in the case of pyrazine, position 2, 3, 4 or 5 in the case of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 in the case of oxazole, imidazole or thiazole, position 3, 4 or 5 in the case of isoxazol, pyrazole or isothiazole, position 2 or 3 in the case of aziridine, position 2, 3 or 4 in the case of azetidine, position 2, 3, 4, 5, 6, 7 or 8 in the case of a quinoline or position 1, 3, 4, 5, 6, 7 or 8 in the case of isoquinoline. The following examples are linked through a carbon atom of the heterocycle is clucalc 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

[0033] as an example, but not limited to, attached via the nitrogen atom of the heterocycle attached at the position 1 in the case of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, in position 2 in the case of a isoindole, or isoindoline in position 4 in Suche of the research and in the position 9 in the case of carbazole or β-Carolina. Even more typically linked through the nitrogen atom heterocycles include 1-ezyrider, l-azetidin, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl,

[0034] the Term "arylalkyl"used here means the alkyl part has the values listed above), substituted by one or more aryl parts (also have the values specified above). Examples arylalkyl radicals include aryl-C1-3-alkali, such as, but not limited to, benzyl, phenylethyl, and the like.

[0035] the Term "heteroaromatic"used here means the alkyl part is C is achene, above), substituted heteroaryl part (also has the values listed above). Examples heteroarylboronic radicals include 5 - or 6-membered heteroaryl-C1-3-alkali, such as, but without limitation, oxazolidinyl, pyridylethyl and the like.

[0036] the Term "geterotsiklicheskikh"used here means the alkyl part has the values listed above), substituted heterocyclyl part (also has the values listed above). Examples geterotsiklicheskikh radicals include 5 - or 6-membered heterocyclyl-C1-3-alkali, such as, but not limited to, tetrahydropyranyl.

[0037] the Term "cycloalkenyl"used here means the alkyl part has the values listed above), substituted cycloalkyl part (also has the values listed above). Examples cycloalkenyl radicals include 5 - or 6-membered cycloalkyl-C1-3-alkali, such as, but not limited to, cyclopropylmethyl.

[0038] the Term "substituted alkyl", used here, refers to alkyl, in which one or more hydrogen atoms are independently replaced with a substituent. Typical substituents include, but are not limited to, F, Cl, Br, I, CN, CF3, OR, R, =O, =S, =NR, =N+(O)(R)=N(OR),=N+(O)(OR),=N-NRR', -C(=O)R, -C(=O)OR, -C(=O)NRR', -NRR', -N+RR'R", -NR)C(=O)R', -N(R)C(=O)OR', -N(R)C(=O)R NR'r", -SR, -OC(=O)R, -OC(=O)OR, -OC(=O)NRR', -OS(O)2(OR), -OP(=O)(OR)2, -OP(OR)2, -P(=O)(OR)2, -P(=O)(OR)R NR'r", -S(O)R, -S(O)2R, -S(O)2NR, -S(O)(OR), -S(O)2(OR), -SC(=O)R, -SC(O)OR, =O,- SC(=O)NRR', where each R, R' and R" are independently selected from H, alkyl, alkenyl, quinil, aryl and heterocyclyl. Alchemilla, Alchemilla, allyl, saturated or partially unsaturated cycloalkyl, heteroalkyl, heterocyclyl, arylalkyl, heteroallyl, heterocyclisation, cycloalkylation, aryl and heteroaryl groups described above may also be similarly substituted.

[0039] the Term "halogen"as used here, includes fluorine (F), bromine (Br), chlorine (Cl) and iodine (I).

[0040] the Symbol "a"is used here, means one or more.

[0041] In the compounds of the present invention, where used this symbol as (CR13R14)qvalues of R13and R14can vary in each case, when q is greater than 1. For example, when q is 2, the group (CR13R14)qmay be a group-CH2CH2- or-CH(CH3)C(CH2CH3)(CH2CH2CH3)- or any number of similar groups within the scope of the definitions of R13and R14.

[0042] the INHIBITORS of ErbB

[0043] This invention relates to compounds which are applicable for the inhibition of cocktail recipes. what were tyrosinekinase type I, such as EGFR (HER1), ErbB2 (HER2), ErbB3 (HER3,), ErbB4 (HER4), VEGFR2, Flt3 and FGFR. The compounds of this invention can also be used as inhibitors of serine-, trainingin and kinase dual specificity, such as Raf, MEK and R. Such compounds are used as therapeutic agents for diseases that can be treated by inhibition of the transmission signal receptor tyrosinekinase type I and path signaling serine-, trainingin and kinase dual specificity.

[0044] In some embodiments implementing the present invention relates to compounds which are suitable for inhibiting the receptor tyrosinekinase type I, such as EGFR (HER1), ErbB2 (HER2), ErbB3 (HER3, and ErbB4 (HER4).

[0045] In one embodiment, the invention includes compounds of formula I

[0046] and their solvate, metabolites and pharmaceutically acceptable salts, where

[0047] A represents O, C(=O), S, SO or SO2;

[0048] G represents N or C-CN;

[0049] represents a condensed 6-membered aryl ring or a condensed 5 or 6 membered heteroaryl ring;

[0050] E represents a

,,

,,;

[0051] X represents N or CH;

<> [0052] D1D2and D3are independently N or CR19;

[0053] D4and D5are independently N or CR19and D6represents O, S or NR20where at least one of the D4and D5cannot be CR19;

[0054] D7D8D9and D10are independently N or CR19where at least one of the D7D8D9and D10represents N;

[0055] R1represents H or alkyl;

[0056] each R2represents independently halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, deformedarse, triptoreline, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, cycloalkenyl, -S(O)p(alkyl), S(O)p(CR13R14)q-aryl, aryl, arylalkyl, heteroaryl, heteroaromatic, saturated or partially unsaturated heterocyclyl, geterotsiklicheskikh, -O(CR13R14)q-aryl, -NR15(CR13R14)q-aryl, -O(CR13R14)q heteroaryl is, -NR13(CR13R14)q-heteroaryl, -O(CR13R14)q-heterocyclyl or-NR15(CR13R14)q-heterocyclyl where the specified alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)R18, -NR13C(O)R15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, NR14C(NCN)NR15R13, -OR15, aryl, heteroaryl, arylalkyl, heteroallyl, saturated and partially unsaturated heterocyclyl and geterotsiklicheskikh, and where these aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl or heterocyclisation rings can be additionally substituted by one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, NR15R and OR15;

[0057] each R3represents independently Q, Z, halogen, cyano, nitro, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroaromatic, triptoreline, deformedarse, formatosi, trifluoromethyl, deformity, vermeil, OR15, NR15R16, NR15OR16, NR15C(=O)OR18, NR15C(=O)R16, SO2NR15R16, SR15, SOR15, SO2R15C(=O)R15C(=O)OR15, OC(=O)R15C(=O)NR15R16, NR15C(=O)NR16R17, NR15C(=NCN)NR16R17or NR15C(=NCN)R16,

[0058] where these alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroaromatic optionally substituted by one or more groups independently selected from halogen, oxo, cyano, nitro, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroaromatic, triptoreline, deformedarse, formatosi, trifloromethyl, diformate, formatie, OR15, NR15 16, NR15OR16, NR15C(=O)OR18, NR15C(=O)R16, SO2NR13R16, SR15, SOR15, SO2R15C(=O)R15C(=O)OR15, OC(=O)R15C(=O)NR15R16, NR15C(=O)NR16R17, NR15C(=NCN)NR16R17, NR15C(=NCN)R16, (C1-C4alkyl)NRaRband NR15C(O)CH2ORa,

[0059] or R3is a 5-6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S, SO and SO2, and replaced with-M1-M2-M3-M4or-M1-M5where M1represents a C1-C4alkyl, in which CH2optionally substituted by the group C(=O); M2represents NReor CReRf; M3represents a C1-C4alkyl; M4represents CN, NReS(O)0-2Rf, S(O)0-2NRgRh, CORgRh, S(O)0-2Rfor CO2Rfand M5represents NRgRhwhere Re, Rf, Rgand Rhare independently N or C1-C4alkyl, or Rgand Rhtogether with the nitrogen atom to which they are attached, form a 5 - or 6-membered ring, optionally containing 1 or 2 additional heteroatoms selected from N, O, S, SO and SO2and if any is westwoodi in the ring nitrogen atom optionally substituted C 1-C4alkyl group, and the ring may optionally have one or two oxo or thioxanthenes;

[0060] Q is a

;

[0061] Z is selected from

,,,

,

[0062] and their tautomers;

[0063] W and V are independently O, NR6, S, SO, SO2, CR7R8, CR8R9or C=O;

[0064] W2represents O or S;

[0065] Y is S, SO, SO2, CR7R8or CR8R9,

[0066] provided that when W represents O, NR6, S, SO or SO2then V is a CRW,

[0067] when V represents O, NR6, S, SO or SO2then each of W and Y is CR8R9;

[0068] R8brepresents N or C1-C6alkyl;

[0069] each of R6, R8, R8aand R9represents independently hydrogen, trifluoromethyl, alkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroaromatic or geterotsiklicheskikh, where these alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh not necessarily Emesene one or more groups, independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, OR15, NR15R16, SR15, S(=O)R15, SO2R15, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh,

[0070] or R8and R8atogether with the atom to which the are attached, form a 3-6-membered carbocyclic ring;

[0071] R7represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, geterotsiklicheskikh, -NR15SO2R16-SO2NR15R16, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR15C(O)OR18, -NR15C(O)R16, -C(O)NR15R16, -NR15R16, -NR15C(O)NR16R17, -OR15, -S(O)R15, -SO2R15or SR15where these alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups which, independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, -NR15SO2R16, -SO2NR15R16, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR15C(O)OR18, -NR15C(O)R16, -C(O)NR15R16, -NR15R16, -NR15C(O)NR16R17, -OR15, -S(O)R15, -SO2R15, SR15, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh;

[0072] R10represents hydrogen, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, geterotsiklicheskikh, -NR15C(O)OR18, -NR15C(O)R16, -NR15R16or15where these alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, geterotsiklicheskikh optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, busy and often is the rule unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, -NR15SO2R16, -SO2NR15R16, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR15C(O)OR18, -NR15C(O)R16, -C(O)NR15R16, -NR15R16, -NR15C(O)NR16R17, -OR15, -S(O)R15, -SO2R15, SR15, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh;

[0073] or R6and R8together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where these carbocyclic and heterocyclic rings are optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[0074] or R7and R8together with the ohms, to which they are attached, form a 3-10-membered saturated or partially unsaturated cycloalkyl or heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where these carbocyclic and heterocyclic rings are optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[0075] or R8and R9together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated cycloalkyl or heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where these carbocyclic and heterocyclic rings are optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl us the seal and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[0076] or R6and R10together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where specified heterocyclic ring optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[0077] or R8and R10together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where indicated the heterocyclic ring is optionally substituted by one or more groups, independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[0078] each R12represents independently halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, deformedarse, triptoreline, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR13R14, -NR13C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, cycloalkenyl, S(O)p(alkyl), S(O)p(CR13R14)q-aryl, aryl, arylalkyl, heteroaryl, heteroaromatic, saturated or partially unsaturated heterocyclyl, geterotsiklicheskikh, -O(CR13R14)q-aryl, -NR15(CR13R14)q-aryl, -O(CR13R14)q-heteroaryl, -NR13(CR13R14)q-heteroaryl, -O(CR13R14)q-heterocy is poured or-NR 15(CR13R14)q-heterocyclyl, where these alkyl, alkeline, alkyline, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)OR18, -NR13C(O)R15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, NR14C(NCN)NR15R13, -OR15, aryl, heteroaryl, arylalkyl, heteroallyl, saturated and partially unsaturated heterocyclyl and geterotsiklicheskikh, and where these aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl or heterocyclisation rings can be additionally substituted by one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, NR15R13and OR15;

[0079] R13and R14are independently hydrogen or alkiline

[0080] R13and R14together with the atoms to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl ring, where these alkyl, cycloalkyl and heterocyclyl part is optional substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORb, NR3CO2R6, NRaCORb, SO2NRaRb, SRa, SORa, SO2RandS-S-RaC(=O)RaC(=O)ORandOS(=O)RaC(=O)NRaRb, NRaC(=O)Rband NRaC(=O)NRbRc;

[0081] R15, R16and R17are independently H, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic or geterotsiklicheskikh where the specified alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected salkil, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, heteroaryl, halogen, oxo, ORa, NRaRb, NRaORb, NRaCO2R6, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORa, OC(O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc; OC(=O)NRaRband C(=O)CH2ORa;

[0082] or any two of R15, R16and R17together with the atom to which they are attached, form a heterocyclic ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where specified heterocyclic ring optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, vermeil, formatosi, deformedarse, triptoreline, azido, aryl, ORa, NRaRb, SRa, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh,

[0083] or R13and R1 together with the atom to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl ring, where the specified alkyl, cycloalkyl and heterocyclyl optionally substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rband NRaC(=O)NRbRc;

[0084] R18is a CF3, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic or geterotsiklicheskikh where the specified alkyl, alkenyl, quinil, cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from alkyl, alkenyl, quinil, Goethe is valkila, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, halogen, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc,

[0085] or R15and R18with the atoms to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl ring, where the specified alkyl, cycloalkyl and heterocyclyl optionally substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc;

[0086] each R19represents independently H, halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, format the XI, deformedarse, triptoreline, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15-NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR13C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, cycloalkenyl, -S(O)p(alkyl), S(O)p(CR13R14)q-aryl, aryl, arylalkyl, heteroaryl, heteroaromatic, saturated or partially unsaturated heterocyclyl, geterotsiklicheskikh, -O(CR13R14)q-aryl, -NR15(CR13R14)q-aryl, -O(CR13R14)q-heteroaryl, -NR13(CR13R14)q-heteroaryl, -O(CR13R14)q-heterocyclyl or-NR15(CR13R14)q-heterocyclyl, where these alkyl, alkeline, alkyline, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)OR18, -NR13CO)R 15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, NR14C(NCN)NC15R13, -OR15, aryl, heteroaryl, arylalkyl, heteroallyl, saturated or partially unsaturated heterocyclyl and geterotsiklicheskikh, and where these aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl or heterocyclisation rings can be additionally substituted by one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, NR15R13and OR15;

[0087] each R20represents independently1-C4alkyl, saturated or partially unsaturated cycloalkyl, trifluoromethyl, deformity or vermeil;

[0088] Ra, Rband Rcare independently H, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, or heteroaryl;

[0089] or NRaRbforms a 5-6-membered heterocyclic ring having 1-2 nitrogen atom in the ring and optionally substituted (C1-C3by alkyl);

[0090] or NRbNcforms a 5-6-membered g is teracycline ring, having 1-2 nitrogen atom in the ring;

[0091] j is 0, 1, 2 or 3;

[0092] m is 1, 2, 3, or 4;

[0093] n is 0, 1, 2, 3, or 4;

[0094] q is 0, 1, 2, 3, 4, or 5 and

[0095] p is 0, 1 or 2;

[0096] where, when the specified connection formula 1 represented by the formula

[0097] and R3is not a Q or Z, then E cannot be benzofuranyl, indolinyl, girasolereale, hyalinella or izokhinolinom ring.

[0098] In some embodiments, implementation of the proposed compounds of formula 1

[0099] and their solvate, metabolites and pharmaceutically acceptable salt,

[00100] where

[00101] A represents O, C(=O), S, SO or SO2;

[00102] G represents N or C-CN;

[00103] is a condensed 6-membered aryl ring or a 5-6-membered heteroaryl ring;

[00104] E represents a

,,

,or;

[00105] X represents N or CH;

[00106] D1D2and D3are independently N or CR19;

[00107] D4and D5are independently N or CR19and D6represents O, S or NR20where at least one of the D4and D5is not CR ;

[00108] D7D8D9and D10are independently N or CR19where at least one of the D7D8D9and D10represents N;

[00109] R1represents H or alkyl;

[00110] each R2represents independently halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, triptoreline, triptoreline, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR5C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, cycloalkenyl, -S(O)p(alkyl), S(O)p(CR13R14)q-aryl, aryl, arylalkyl, heteroaryl, heteroaromatic, saturated or partially unsaturated heterocyclyl, geterotsiklicheskikh, -O(CR13R14)q-aryl, -NR15(CR13R14)q-aryl, -O(CR13R14)q-heteroaryl, -NR13(CR13R14)q-heteroaryl, -O(CR13R14)q-heterocyclyl or-NR15(CR13R14)-heterocyclyl where the specified alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, arylalkyl, heteroaryl, heteropar Lucilla, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)OR18, -NR13C(O)R15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, -NR14C(NCN)NR15R13, -OR15, aryl, heteroaryl, arylalkyl, heteroallyl, saturated or partially unsaturated heterocyclyl and geterotsiklicheskikh, and where these aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl or heterocyclisation rings can be additionally substituted by one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, NR15R13and OR15;

[00111] each R3represents independently Q, Z, halogen, cyano, nitro, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, the reel, arylalkyl, heteroaryl, heteroaromatic, triptoreline, deformedarse, formatosi, trifluoromethyl, deformity, vermeil, -OR15, NR15R16, -NR15OR16, -NR15C(=O)OR18, -NR15C(=O)R16, SO2NR15R16, SR15, SOR15, -SO2R15C(=O)R15C(=O)OR15, OC(O)R15C(=O)NR15R16, -NR15C(=O)NR16R17, NR15C(=NCN)NR16R17or NR15C(=NCN)R16,

[00112] where the specified alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroaromatic optionally substituted by one or more groups independently selected from halogen, oxo, cyano, nitro, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroaromatic, triptoreline, deformedarse, formatosi, trifloromethyl, diformate, formatie, -OR15, NR15R16, -NR15OR16, -NR15C(=O)OR18, -NR15C(=O)R16, SO2NR15R16, SR15, SOR15, -SO2R15C(=O)R15C(=O)OR15, OC(=O)R15C(=O)NR15R16, -NR15C(=O)NR16R17, NR15C(=NCN)NR16Rsup> 17and NR15C(=NCN)R16

[00113] Q represents

;

[00114] Z is selected from

,,,,

[00115]

[00116] and their tautomers;

[00117] W and V are independently O, NR6, S, SO, SO2, CR7R8, CR8R9or C=O;

[00118] Y is S, SO, SO2, CR7R8or CR8R9,

[00119] provided that when W represents O, NR6, S, SO or SO2then V is a CR8R9,

[00120] and when V represents O, NR6, S, SO or SO2then W and Y are each, CR8R9;

[00121] each of R6, R8, R8aand R9are independently hydrogen, trifluoromethyl, alkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroaromatic or geterotsiklicheskikh, where these alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially nanosys the frame heterocyclyl, cycloalkenyl, cyano, nitro, OR15, NR15R16, SR15, S(=O)R15, SO2R15, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[00122] R7represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, geterotsiklicheskikh, -NR15SO2R16, -SO2NR15R16, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR15C(O)OR18, -NR15C(O)R16, -C(O)NR15R16, -NR15R16, -NR15C(O)NR16R17, -OR15, -S(O)R15, -SO2R15or SR15where these alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptorelin and, azido, -NR15SO2R16, -SO2NR15R16, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR15C(O)OR18, -NR15C(O)R16, -C(O)NR15R16, -NR15R16, -NR15C(O)NR16R17, -OR15, -S(O)R15, -SO2R15, SR15, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh;

[00123] R10represents hydrogen, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, geterotsiklicheskikh, NR15C(O)OR18, -NR15C(O)R16, -NR15R16or15where these alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, geterotsiklicheskikh optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, -NR15SO2R16, -SO2NR15R16, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR15C(O)OR18, -NR15C(O)R16 , -C(O)NR15R16, -NR15R16, -NR15C(O)NR16R17, -OR15, -S(O)R15, -SO2R15, SR15, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh;

[00124] or R6and R8together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where these carbocyclic and heterocyclic rings are optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[00125] or R7and R8together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated cycloalkyl or heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6, where is the s carbocyclic and heterocyclic rings are optionally substituted by one or more groups, independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[00126] or R8and R9together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated cycloalkyl or heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where these carbocyclic and heterocyclic rings are optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[00127] or R6and R10together with the atoms to which they are attached, is brisout 3-10-membered saturated or partially unsaturated heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where specified heterocyclic ring optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR15, NR15R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[00128] or R8and R10together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where specified heterocyclic ring optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, OR1515R16, SR15, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh;

[00129] each R12represents independently halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, deformedarse, triptoreline, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR13C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, cycloalkenyl, -S(O)p(alkyl), -S(O)p(CR13R14)q-aryl, aryl, arylalkyl, heteroaryl, heteroaromatic, saturated or partially unsaturated heterocyclyl, geterotsiklicheskikh, -O(CR13R14)q-aryl, -NR15(CR13R14)q-aryl, -O(CR13R14)q-heteroaryl, -NR13(CR13R14)q-heteroaryl, -O(CR13R14)q-heterocyclyl or-NR15(CR13R14)q-heterocyclyl, where these alkyl, alkeline, alkyline, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups, independent is selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)OR18, -NR13C(O)R15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, -NR14C(NCN)NR15R13, -OR15, aryl, heteroaryl, arylalkyl, heteroallyl, saturated and partially unsaturated heterocyclyl and geterotsiklicheskikh, and where these aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl or heterocyclisation rings can be additionally substituted by one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, NR15R13and OR15;

[00130] R13and R14are independently hydrogen or alkyl, or

[00131] R13and R14together with the atoms to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl ring, where these alkyl, cycloalkyl and heterocyclyl part is optional substituted with one or a few is Kimi groups, selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc;

[00132] R15, R16and R17are independently H, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic or geterotsiklicheskikh, where these alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups selected from alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, heteroaryl, halogen, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa , SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc,

[00133] or any two of R15, R16and R17together with the atom to which they are attached, form a heterocyclic ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where specified heterocyclic ring optionally substituted by one or more groups independently selected from oxo, halogen, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkenyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, aryl, ORa, NRaRb, SRa, heteroaryl, arylalkyl, heteroallyl and geterotsiklicheskikh,

[00134] or R13and R15together with the atom to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl ring, where these alkyl, cycloalkyl and heterocyclyl optionally substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatec and, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc;

[00135] R18is a CF3, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic or geterotsiklicheskikh, where these alkyl, alkenyl, quinil, cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, heteroaryl, halogen, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)Ra C(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc,

[00136] or R15and R18together with the atoms to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl ring, where these alkyl, cycloalkyl and heterocyclyl optionally substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rband NRaC(=O)NRbRc;

[00137] each R19represents independently H, halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, deformedarse, triptoreline, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR13C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, alkyl, alkenyl, quinil, saturated or partially unsaturated C is cloaker, cycloalkenyl, -S(O)p(alkyl), S(O)p(CR13R14)q-aryl, aryl, arylalkyl, heteroaryl, heteroaromatic, saturated or partially unsaturated heterocyclyl, geterotsiklicheskikh, -O(CR13R14)q-aryl, -NR15(CR13R14)q-aryl, -O(CR13R14)q-heteroaryl, -NR13(CR13R14)q-heteroaryl, -O(CR13R14)q-heterocyclyl or-NR15(CR13R14)q-heterocyclyl, where these alkyl, alkeline, alkyline, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)OR18, -NR13C(O)R15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, -NR14C(NCN)NR15R13, -OR15, aryl, heteroaryl, arylalkyl, heteroallyl, saturated or partially unsaturated heterocyclyl and geterotsiklicheskikh, and where these aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl or geterotsiklicheskikh can be optionally substituted by one or more groups, selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl, alkyl, alkenyl, quinil, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, NR15R13and OR15;

[00138] each R20represents independently1-4alkyl, saturated or partially unsaturated cycloalkyl, trifluoromethyl, deformity or vermeil;

[00139] Ra, Rband Rcare independently H, alkyl, alkenyl, quinil, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl or heteroaryl;

[00140] j is 0, 1, 2 or 3;

[00141] m is 1, 2, 3 or 4;

[00142] n is 0, 1, 2, 3, or 4;

[00143] q is 0, 1, 2, 3, 4, or 5 and

[00144] p is 0, 1 or 2;

[00145] where, when the compound of formula I is represented by the formula

[00146] and R3is not Q or Z, then E is not benzofuranyl, indolinyl, girasolereale, hyalinella or izokhinolinom ring.

[00147] In some embodiments, the implementation of the compounds of the formula I G is a n

[00148] In some embodiments, the implementation of the compounds of the formula I R1represents N.

[00149] In some embodiments, the implementation of the compounds of the formula I a represents O.

[00150] In some of the options which the implementation of the compounds of formula I And represents S.

[00151] In some embodiments, the implementation of the compounds of formula I represents a condensed 6-membered aryl ring.

[00152] In some embodiments, the implementation of the compounds of formula I represents a

[00153] In some embodiments, the implementation of formula I has the structure

[00154] where R1, R2, R3, G, A, E and n have the meanings specified above.

[00155] In some embodiments, the implementation of the compounds of formula I represents a condensed 5 or 6 membered heteroaryl ring. In specific embodiments, the implementation represents a condensed tianocore.

[00156] In some embodiments, the implementation of the compounds of formula I represents a

or

[00157] In some embodiments, the implementation of formula I has the structure

[00158] where R1, R2, R3, G, a, E and n have the meanings specified above.

[00159] In some embodiments, the implementation of formula I has the structure

[00160] where R1, R2, R3, G, A, E and n have the meanings specified above.

[00161] In some embodiments, the implementation of the compounds of the formula I E is a

, or

[00162] the Exemplary embodiments of E include, but are not limited to the above, the bicyclic heteroaryl ring selected from the

,,,,,

,,and;

[00163] where k is 0, 1, 2 or 3. Examples of groups R12include, but are not limited to, amino, C1-C4alkoxy, saturated or partially unsaturated cycloalkyl, CN, trifluoromethyl, deformity and vermeil. Examples of groups R19include, but are not limited to, N, amino, C1-C4alkoxy, saturated or partially unsaturated cycloalkyl, CN, trifluoromethyl, deformity and vermeil. Examples R20include, but are not limited to, C1-C4alkyl, saturated or partially unsaturated cycloalkyl, trifluoromethyl, deformity and vermeil.

[00164] In other embodiments, implementation of R12represents a halogen.

[00165] In other embodiments, implementation of R20represents N.

[00166] In specific embodiments, the implementation of R12represents N.

[00167] In nektarinukiniai implementation of R 19represents N or C1-C6alkyl. In specific embodiments, the implementation of R19represents H or methyl.

[00168] In some embodiments, the implementation of R20represents N or C1-C6alkyl. In specific embodiments, the implementation of R20represents H, methyl or ethyl.

[00169] In specific embodiments, the implementation of E is selected from structures

,,,,,

,,,,,

,,

[00170] In some embodiments, the implementation of the compounds of the formula I E is a

or

[00171] In one embodiment, at least one of the D1D2and D3represents N.

[00172] the Exemplary embodiments of E. further include a heteroaryl ring selected from the following, but not limited to,

,,,

, and,

[00173] where the value of each R19does not depend on the other. Examples of groups R12include, but are not limited to, amino, C1-C4alkoxy, saturated or partially unsaturated cycloalkyl, CN, trifluoromethyl, deformity and vermeil. Examples of groups R19include, but are not limited to, N, amino, C1-C4alkoxy, saturated or partially unsaturated cycloalkyl, CN, trifluoromethyl, deformity and vermeil.

[00174] In some embodiments, the implementation of R12represents a halogen. In some embodiments, the implementation of j is 0 or 1. A concrete example of R12is F.

[00175] In some embodiments, the implementation of R19represents H, C1-C6alkyl or halogen. Specific examples of R19include H, methyl, Cl, and Br.

[00176] Specific examples of E include:

,,,,

,,,,

,,

[00177] In one embodiment, the compounds of formula I select the s compounds in which E is selected from the groups E1, E2, E3, E4, E5, E6, E7 and E8:

[00178] In some embodiments, the implementation of E is selected from the groups E1, E2 and E3, and j is 0 or 1. In some embodiments, the implementation of the groups E1, E2 and E3, R12represents a halogen. In some embodiments, the implementation of the groups E1, E2 and E3, R19selected from H, halogen, or C1-C6the alkyl. In some embodiments, the implementation of the groups E1, E2 and e R20represents N. Specific examples of compounds which are selective against ErbB2, include the compounds of formula I in which E is selected from the group

[00179] In another embodiment, the proposed compounds of formula I in which E is selected from E1, E2 and E3, provided that R3in the formula I is-NR15C(=O)(CH=CH)R16awhen R16arepresents H, alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated gets recycler, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic or geterotsiklicheskikh, where these alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from alkyl, alkenyl, quinil, heteroalkyl, heteroalkyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, heteroaryl, halogen, oxo, ORa, NRaRb, NRaORbNRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaWith(=O)RaC(=O)ORa, OC(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc, OC(=O)NRaRband C(=O)CH2ORa.

Found that some compounds belonging to this group are very potent inhibitors of ErbB2 and are very selective for ErbB2 compared with EGFR. Used here, the term "very selective" refers to the compound, which IC50for EGFR, at least 20 times higher than the IC50for ErbB2, when determining their cellular analyses of phosphorylation of ErbB2 and EGFR, as described in examples b and C. Discovered that the concrete is connected to the I of this invention have values IC 50for EGFR, which is at least 50 times higher than the IC50for ErbB2. As the next example shows that the specific compounds of this invention have the value of the IC50for EGFR, which is at least 100 times larger than the IC50for ErbB2.

[00180] In accordance with this invention provides compounds of formula I, which are very potent inhibitors of ErbB2 and are very selective for ErbB2 relative to the EGFR. These connections will enable the treatment of cancers that can be treated by inhibition of ErbB2, such as cancer, in which the expression or overexpression of ErbB2, a relatively selective manner, and thereby minimize the potential side effects associated with inhibition of other kinases, such as EGFR.

[00181], However, found that compounds of the formula I, in which R3represents-NR15C(=O)(CH=CH)OR16aand R16arepresents H or substituted or unsubstituted With2-C6-alkyl, are inhibitors as ErbB2 and EGFR. In addition, it is believed that such compounds bind irreversibly with ErbB2 and EGFR.

[00182] In some embodiments, the implementation of the compounds of formula I, m is 1.

[00183] In some embodiments, the implementation of the compounds of the formula I R3is a OR15. In some the x variants of implementation, R15represents alkyl, alkenyl or quinil, where these alkyl, alkenyl and quinil optionally substituted by one or more groups independently selected from saturated and partially unsaturated cycloalkyl, heteroaryl, saturated and partially unsaturated heterocyclyl, ORa, SO2Raand NRaRb.

[00184] In some embodiments, the implementation of the compounds of the formula I R3is a OR15and R15represents a

[00185] (i) H;

[00186] (ii)3-C6cycloalkyl, optionally substituted OR3;

[00187] (iii) cycloalkenyl;

[00188] (iv) C1-C6alkyl, optionally substituted by one or two groups independently selected from-ORa, -OC(O)Ra, -CO2Ra, -SO2Ra, -SRa, -C(O)NRaRb, -NRaRb, -NRaC(O)Rb-OC(O)NRaRband NRaC(O)NRbRc;

[00189] (v) a 5-6-membered heterocyclic ring having a heteroatom ring selected from N and O, and optionally substituted-C(O)RandC1-C6by alkyl, -C(O)NRaRb, -SO2Raor C(O)CH2CRa;

[00190] (vi) geterotsiklicheskikh where the specified heterocyclic part is a 5-6-membered ring containing 1 or 2 heteroatoms in the ring independently selected from N and O, and optionally substituted C1 -C6by alkyl, halogen, ORandor oxo;

[00191] (vii) a 5-6 membered heteroaryl ring having from 1 to three nitrogen atoms of the ring, and optionally substituted C1-C6by alkyl or halogen; or

[00192] (viii) heteroallyl where the specified heteroaryl part is a 5-6 membered ring having 1-2 nitrogen atom of the ring, and optionally substituted C1-C6the alkyl.

[00193] In some embodiments, the implementation of R3is a HE.

[00194] the Examples OR15when R15represents a C3-C6cycloalkyl group, optionally substituted ORawhere Rarepresents N or C1-C6alkyl, include cyclohexanone and Cyclopentanone, optionally substituted, for example 2-hydroxycyclopent.

[00195] the Examples OR15when R15represents cycloalkenyl group include-O-(C3-C6cycloalkyl)(CH2)pwhere p is 1, 2 or 3. A concrete example is 1 cyclopropylmethoxy.

[00196] the Examples OR15when R15represents a C1-C6alkyl group include CH3O - CH3CH2O-.

[00197] the Examples OR15when R15represents a C1-C6alkyl group, substituted with one or two ORagroups, and Ra represents H, C1-C6alkyl or benzyl, include CH3O(CH2)2O-CH3CH2O(CH2)2O - (CH2)2O-, HOCH2CH(OH)CH2O-CH3CH(OH)CH2O-, NOSE(CH3)2CH2O-, (PhCH2O)CH2CH2O - and (PhCH2)OCH2CH(OH)CH2O-.

[00198] the Examples OR15when R15represents a C1-C6alkyl group substituted by-OC(O)Randinclude-O-(CH2)pOC(O)Rawhere R is 1-6 and Randrepresents N or C1-C6alkyl. A concrete example is-O-(CH2)2OC(O)CH3.

[00199] the Examples OR15when R15represents a C1-C6alkyl group, substituted-CO2Rainclude-O- (CH2)pCO2R3where R is 1-6 and Randrepresents N or C1-C6alkyl. A concrete example is-O-(CH2)CO2CH3.

[00200] the Examples OR15when R15represents a C1-C6alkyl group, substituted-SO2Randinclude-O-(CH2)pSO2R8where R is 1-6 and Randrepresents a C1-C6alkyl. A concrete example is-O(CH2)3SO2CH3.

[00201] the Examples OR15when R15is a Csub> 1-C6alkyl group, substituted-SRandinclude O-(CH2)pSRawhere R is 1-6 and Randrepresents a C1-C6alkyl. A concrete example is-O(CH2)3SCH3.

[00202] the Examples OR15when R15represents a C1-C6alkyl group, substituted-C(O)NRaRbinclude-O-(CH2)pC(O)NRaRbwhere R is 1-6 and Raand Rbare independently N or C1-C6alkyl or NRaRbis a 5-6-membered heterocycle having 1-2 nitrogen atom in the ring and optionally substituted C1-C6the alkyl. Specific examples OR15include (CH3)2NC(O)CH2O-CH3NHC(O)CH2O-, NH2C(O)CH2O - and

[00203] the Examples OR15when R15represents a C1-C6alkyl group substituted by-NRaC(O)Rbinclude-O(CH2)pNRaC(O)Rbwhere R is 1-6 and Raand Rbare independently N or C1-C6alkyl. Specific examples OR15include-O(CH2)2NHC(O)CH3and-O(CH2)2NHC(O)CH2CH3.

[00204] the Examples OR15when R15represents a C1-C6alkyl group, Thames is NUU-NR aRbinclude-O-(CH2)pNRaRbwhere R is 1-6 and Randand Rbare independently N or C1-C6alkyl (e.g. methyl or ethyl). Specific examples OR15include-O(CH2)3N(CH3)2and-O(CH2)2N(CH3)2.

[00205] the Examples OR15when R15represents a C1-C6alkyl group substituted by-OC(O)NRaRbinclude-O-(CH2)p-OC(O)NRaRbwhere R is 1-6 and Raand Rbare independently N or C1-C6alkyl. A concrete example is-O(CH2)2OC(O)N(CH3)2.

[00206] the Examples OR15when R15represents a C1-C6alkyl group substituted by-NRaC(O)NRaRbinclude-O-(CH2)p-NRaC(O)NRbRC, where p is 1-6, Raand Rbare independently N or C1-C6alkyl, and Rcrepresents H, C1-C6alkyl or-O(C1-C6alkyl) or NRbRcis a 5-6-membered heterocycle having 1-2 nitrogen atom in the ring (for example, pyrrolidinyl). Specific examples OR15include

,and

[00207] the measures OR 15when R15is a 5-6-membered heterocyclic ring having a heteroatom ring selected from N and O, and optionally substituted-C(O)RaWith1-C6the alkyl, oxo, -C(O)NRaRb, -SO2Raor-C(O)CH2ORainclude pyrrolidinyl, piperidinyl and tetrahydro-2H-perylene ring, optionally substituted-C(O)(C1-C6by alkyl), oxo, C1-C6by alkyl, -C(O)N(C1-C6by alkyl)2, -SO2(C1-C6by alkyl) and-C(O)CH2O(C1-C6by alkyl). Specific examples include :

,,,,

,,,,

,,.

[00208] the Examples OR15when R15represents heterocyclisation group include O-(heterocyclyl)(CH2)pwhere R is 1-6 and heterocyclyl is a 5-6-membered heterocyclic ring having 1-2 nitrogen atom of the ring, and optionally substituted by one or two groups selected from C1-C6of alkyl, halogen, HE, O-(C1-C6of alkyl and oxo. Por the measures of heterocyclic rings include pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, personalne and imidazolidinone ring, optionally substituted by one or two groups independently selected from methyl, F, HE, and oxo. Specific examples OR15include

,,,

,,,

,,,

,,.

[00209] the Example OR15when R15represents a heteroaryl group includes a group in which heteroaryl is pyridinyl group, optionally substituted C1-C6by alkyl or halogen. Specific examples include 2-methylpyridin-4-yloxy, 2-chloropyridin-4-yloxy and 2-methylpyridin-4-yloxy.

[00210] the Example OR15when R15represents heteroallyl group include-O-(CH2)p(heteroaryl), where p is 1-6, and heteroaryl group is optionally substituted C1-C6the alkyl. Examples of heteroaryl groups include 5-6 membered ring having 1-3 nitrogen atom, such as imidazolyl and 1,2,4-triazolyl. A specific example is s OR 15include

,and

[00211] In some embodiments, the implementation of R3represents a 5-membered heterocyclic ring, associated with the ring through the nitrogen atom and optionally having a second heteroatom in the ring, selected from N and O. In some embodiments, the implementation of a heterocyclic ring substituted by one or two groups independently selected from C1-C6of alkyl, oxo and (CH2)1-2NRaRbwhere Raand Rbare independently N or C1-C6alkyl. Specific examples OR15include

,,,,

[00212] In some embodiments, the implementation of R3is a 5-6-membered heteroaryl ring having 1-3 nitrogen atom, where the specified heteroaryl linked to the ring through the nitrogen atom of the ring. The example includes 1H-pyrazolyl, for example 1H-pyrazole-1-yl.

[00213] In some embodiments, the implementation of the compounds of the formula I R3represents Z. In some embodiments, the implementation of Z selected from the

,,,

[00214] and their tautomers. Examples of tautomers of the above groups Z include tautomers, in which R6represents hydrogen, and can be represented by the following structures:

,,,,

and.

[00215] In some embodiments, the implementation of Z selected from the

,,and

[00216] In some embodiments, the implementation of W represents O or S.

[00217] In some embodiments, the implementation of the W2represents O or S.

[00218] In some embodiments, the implementation of the V represents CR8R9.

[00219] In some embodiments, the implementation of Z selected from the

,,,

,.

[00220] In some embodiments, the implementation of R6represents N or C1-C6alkyl.

[00221] In some embodiments, the implementation of R8and R8aare independently N or C1-C6alkyl, optionally substituted ORawhere Rais the th N or C 1-C6alkyl. In other embodiments, implementation of R8and R8atogether with the atom to which they are attached, form a3-C6cycloalkyl ring.

[00222] In some embodiments, the implementation of Z selected from the

,,,

,,,

,,,

,.

[00223] In some embodiments, the implementation of R3represents NR15C(=O)R16. Examples R16include, but are not limited to, alkyl, alkenyl or quinil, where these alkyl, alkenyl and quinil optionally substituted NRaRb.

[00224] In other embodiments, implementation of R3represents-NR15C(=O)R16where R15represents H or methyl and R16represents a C2-C6alkenyl, optionally substituted NRaRb. Examples of its include-NR15C(=O)-CH=CH2R16awhere R16arepresents H or substituted or unsubstituted C1-C6alkyl. Specific examples of R3include-NHC(=O)-CH=CH2and-NHC(=O)-CH=CHCH2N(CH3) 2.

[00225] In other embodiments, implementation of R3represents-NR15C(=O)R16where R15represents H or methyl and R16is a 5-6-membered heterocyclic ring having one or two heteroatoms in the ring and optionally substituted C1-C6the alkyl. Examples of heterocyclic rings include piperidinyl, tetrahydrofuranyl and tetrahydropyranyl ring, optionally substituted C1-C6the alkyl. Specific examples of R3include

,and

[00226] In other embodiments, implementation of R3represents-NR15C(=O)R16where R15represents H or methyl and R16represents a C1-C6alkyl, optionally substituted by one or more groups independently selected from C1-C6the alkyl and ORa. In some embodiments, the implementation of Rarepresents N or C1-C6alkyl. Specific examples of R3include CH3C(O)NH-, (CH3)2C(O)NH-, CH3CH2C(O)N(CH3)- ,- CH3OCH2C(O)NH-, CH3OCH2C(O)N(CH3)- ,- CH3CH(OCH3)C(O)NH-, CH3OCH2CH2C(O)NH-, CH3OCH(CH3)C(O)NH - and CH3OCH2CH(CH3)C(O)NH-.

p> [00227] In some embodiments, the implementation of R3represents-C(=O)NR15R16. In some embodiments, the implementation of R15and R16independently represent N or C1-C6alkyl. A concrete example of R3is-C(=O)N(CH3)2.IN other variants of implementation of R15and R16together with the atom to which they are attached, form a 6-membered heterocyclic ring, optionally having a second heteroatom selected from N and O, and optionally substituted C1-C6the alkyl. Examples of heterocyclic rings include piperazinil or morpholinyl, optionally substituted stands. Specific embodiments of R3include-C(=O)(4-morpholinyl) and-C(=O)(1-methylpiperazin-4-yl).

[00228] In some embodiments, the implementation of R3represents the SO2R15. In some embodiments, the implementation of R15represents a C1-C6alkyl or phenyl group, optionally substituted C1-C6the alkyl. Specific examples of R3include 4-methylbenzenesulfonate or econsultant.

[00229] In some embodiments, the implementation of R3represents SOR15. In some embodiments, the implementation of R15represents a C1-C6alkyl. A concrete example of R3is ethyl is sulfinyl.

[00230] In some embodiments, the implementation of R3represents SR15. In some embodiments, the implementation of R15represents a C1-C6alkyl. A concrete example of R3is EtS.

[00231] In some embodiments, the implementation of R3represents a halogen. A concrete example of R3is bromide.

[00232] In some embodiments, the implementation of R3represents-CO2R15. In some embodiments, the implementation of R15represents a 6-membered heterocyclic ring having one or two nitrogen atom in the ring (for example, piperidinyl or piperazinil). In some embodiments, the implementation of a heterocyclic ring substituted C1-C6the alkyl (for example, the stands). A specific example of R3represents-CO2-(1-methylpiperazine).

[00233] In some embodiments, the implementation of R3is substituted or unsubstituted C1-C6alkyl group. In some embodiments, the implementation of an alkyl group substituted by a group OR15where R15represents H or (C1-C6alkyl), such as -(C1-C6alkyl)and -(C1-C6alkyl)O(C1-C6alkyl). Specific examples of R3include -(CH2)3HE and -(CH2)3OCH3.

[00234] In some variants of the implementation of R 3represents a C3-C6alkylamino group. In some embodiments, the implementation Alchemilla group substituted OR15. In some embodiments, R15represents H or (C1-C6alkyl), Specific examples of R3include

,and

[00235] In some embodiments, the implementation of R3represents a C3-C6alkylamino group substituted by-NR15C(O)CH2ORa. In some embodiments, the implementation of R15represents N or C1-C6alkyl, In some embodiments, the implementation of R3represents N or C1-C6alkyl. A concrete example of R3is

[00236] In some embodiments, the implementation of R3represents a C3-C6alkylamino group, a substituted 6-membered heterocyclic ring having one or two heteroatoms in the ring independently selected from N, O and SO2. In some embodiments, the implementation of the heterocyclic ring has at least one nitrogen atom ring and attached to the alkyl group through a nitrogen atom. Specific examples of R3include

and

[00237] In some embodiments, about what westline R 3is a group-NR15C(O)NR16R17. In some embodiments, the implementation of R15, R16and R17independently represent N or C1-C6alkyl. Specific examples of R3include

and

[00238] In some embodiments, the implementation of R3is a group-NR15C(O)NR16R17in which R15represents N or C1-C6alkyl, and R16and R17together with the nitrogen atom to which they are attached, form a 5-6-membered heterocyclic ring, optionally having a second heteroatom selected from N and O. Examples include pyrrolidinyl, morpholinyl and piperazinilnom rings. In some embodiments, the implementation of a heterocyclic ring substituted C1-C6the alkyl. Specific examples of R3include

,,,

[00239] In some embodiments, the implementation of R3represents heterocyclisation group. Examples of it include (CH2)p-(heterocycle), where p is 1-6, and the heterocycle is a 6-membered heterocyclic ring having a nitrogen atom in the ring and optionally having a second at the m ring, selected from N and SO2. A concrete example of R3is

[00240] In some embodiments, the implementation of R3is a 5-6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S, SO and SO2and substituted by a group of M1-M2-M3-M4where M1M2M3and M4have the values defined here.

[00241] In some embodiments, the implementation of the 5-6-membered heterocyclic ring is furanyl, dihydrofurane, thienyl, imidazolyl, tetrazolyl, triazolyl, pyridinyl, pyrrolyl, pyrimidinyl, isoxazolyl or oxadiazolyl. In a specific embodiment, the heterocyclic ring is furanyl.

[00242] In some embodiments, the implementation of M1represents CH2CH2CH2With(O) or CH2C(O). In a specific embodiment, M1represents CH2.

[00243] In some embodiments, the implementation of M2represents NH or N(C1-C6alkyl). In specific embodiments, the implementation of M2represents NH or NMe.

[00244] In some embodiments, the implementation of M3represents a methylene, ethylene or propylene.

[00245] In some embodiments, the implementation of M4represents SORf, SO2Rf, NReSOsub> 2Rf, SO2NRgRh, CO2Rfor CONRgRhwhere Rf, Rgand Rhindependently represent N or C1-C4alkyl.

[00246] Specific examples of R3when he is a 5-6-membered heterocyclic ring, substituted by a group of M1M2M3and M4include:

,,,

,,

[00247] In a particular embodiment, R3represents a

[00248] In some embodiments, the implementation of n is 1 and R2represents halogen, CN, trifluoromethyl, deformity, vermeil,1-C4alkyl, C1-4alkoxy or cycloalkyl.

[00249] In some embodiments, the implementation of the phrase "R6and R8together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclic ring" refers to a ring formed from the radicals R6and R8attached to different atoms on the same functional group, such as in the group Q or Z, which have the values specified above. Formed heterocyclic ring may be a condensed ring or spirocycles ring.

[00250] In some embodiments, the implementation of the phrase "R7and R8together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated cycloalkyl or heterocyclic ring" refers to spirocyclohexane ring formed from the radicals R7and R8attached to the same carbon atom, for example, such as in the group Z, which has the values listed above, when W represents CR7R8. In other embodiments, implementation of the ring may be a condensed ring formed by the atom R7that is part of a group CR7R8and atom R8attached to the adjacent carbon atom of the group Z.

[00251] In some embodiments, the implementation of the phrase "R8and R9together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated cycloalkyl or heterocyclic ring" refers to spirocyclohexane ring formed from the radicals R8and R9attached to the same carbon atom, for example, such as in the group Z, which has the values listed above, where V represents CR8R9. In other embodiments, implementation of the ring may be a condensed ring formed by the atom R9group CR8R9and the atom is m R 8attached to the adjacent carbon atom of the group Z.

[00252] In some embodiments, the implementation of the phrase "R6and R10together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclic ring" refers to a ring formed NR6and the groups R10group Q, which has the values listed above.

[00253] In some embodiments, the implementation of the phrase "R8and R10together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclic ring" refers to a ring formed by N-R8and atoms, R10group Q, which has the values listed above.

[00254] In some embodiments, the implementation of the phrase "R13and R14together with the atoms to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclic ring" refers to a carbocyclic ring formed from the radicals R13and R14attached to the same carbon atom, such as in a group having the formula - S(O)p(CR13R14)q-, -O(CR13R14)q-aryl, -NR15(CR13R14)q-aryl, -O(CR13R14)q-heteroaryl, -NR13(CR13R14)q-heteroa the sludge, -O(CR13R14)q-heterocyclyl or-NR15(CR13R14)q-heterocyclyl, or the heterocyclic ring formed by the radicals R13and R14attached to different atoms in the same group, such as in a group having the formula-NR14C(O)NR15R13, -NR13C(NCN)NR15R14, -NR13(CR13R14)q-heteroaryl or-NR15(CR13R14)q-heterocyclyl.

[00255] In some embodiments, the implementation of the phrase "R13and R15together with the atom to which they are attached, form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclic ring" refers to a heterocyclic ring formed by the radicals R13and R15attached to different carbon atoms in the same group, such as in a group having the formula-NR13C(NCN)NR15R14, -NR15(CR13R14)q-aryl, or-NR15(CR13R14)q-heterocyclyl.

[00256] In some embodiments of the invention, the phrase "any two of R15, R16and R17together with the atom to which they are attached, form a heterocyclic ring" refers to a heterocyclic ring formed from the radicals R15and R16attached to odnomu the same nitrogen atom, such as in a group having the formula NR15R16, SO2NR15R16C(=O)NR15R16or the radicals R16and R17attached to the same nitrogen atom, such as in a group having the formula NR15C(=O)NR16R17. In other embodiments, the implementation of the phrase refers to the heterocyclic ring formed from the radicals R15and R16attached to different atoms of the same group, such as group NR15OR16, NR15C(=O)R16, NR15C(=NCN)NR16R17or NR15C(=NCN)R16.

[00257] it Should be clear that when consistently applied, two or more radicals to determine the substituent attached to the structure, it is believed that the first named radical is a limit, and it is believed that the last mentioned radical is attached to the structure. So, for example, radical arylalkyl attached to the structure via an alkyl group.

[00258] the compounds of this invention can have one or more asymmetric centers; therefore, such compounds can be obtained in the form of individual (R)- or (S)-stereoisomers or in the form of mixtures. I mean unless otherwise noted, the description or the name of the connection in the description and claims includes SEB is both an individual enantiomer, their diastereomer mixture, racemic or other mixture. In accordance with this invention includes all such isomers, including diastereomeric mixture, pure diastereomers and pure enantiomers of the compounds of this invention.

[00259] the Term "enantiomer" refers to two stereoisomers of compounds that are nesovmestimymi mirror images of each other. The term "diastereoisomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity.

[00260] the Compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the invention. The term "tautomer or tautomeric form" refers to the structural isomers of different energies, which are vzaimoprevrascheny because of the low barrier energy. For example, proton tautomers (also known as prototroph the tautomers) include interconversion via migration of a proton, such as keto-enol and Imin-enaminone isomerization. Valence isomers include mutual transformations of the reorganization of some of the bonding electrons.

[00261] In the structures shown here,when any particular stereochemistry of chiral atom is not certain, it refers to all stereoisomers and all stereometry included as compounds of the invention. When the stereochemistry of the compounds is indicated by a solid wedge or a dashed line, indicating a specific configuration, such stereoisomer thus indicated and specified.

[00262] in Addition to compounds of formula I of the invention includes a solvate, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable salts of such compounds.

[00263] the Phrase "pharmaceutically acceptable" indicates that the substance or composition is chemically and/or toxicologically compatible with the other ingredients that make up the drug, and/or the treated mammal.

[00264] "MES" refers to an Association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[00265] "Pharmaceutically acceptable prodrug" is a compound that can be converted under physiological conditions or by solvolysis to the specified compound or pharmaceutically acceptable salt of such a connection is possible. Prodrugs include compounds in which the amino acid residue or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues are covalently linked via an amide or ester bond with the free amino-, hydroxy-group or carboxylic acid group of compounds of the present invention. Amino acid residues include, but are not limited to 20 existing in nature, amino acids, usually denoted by the symbols of the three letters, and also include phosphoserine, posttraining, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demazin, isodesmosine, gamma carboxyglutamate, hippuric acid, octahedron-2-carboxylic acid, a statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminoiminomethyl acid, citrulline, homocysteine, homoserine, methylalanine, para-benzylpenicillin, phenylglycine propargylglycine, sarcosin, methanesulfonic and tert-butylglycol. Specific examples of the prodrugs of this invention include compounds of formula I covalently attached to a phosphate residue or a valine residue.

[00266] also Included additional types of prodrugs. For example, a free carboxyl group of the compounds of formula I can be converted into the amide group of Il the group Olkiluoto of ester. As another example, compounds of the present invention, which includes free hydroxy-group, can be converted into proletarienne derived by transforming the hydroxy-group in the group, such as, but not limited to, group, phosphate ester, hemisuccinate, diethylaminoacetate or phosphorylmethylcarbamoyl group, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Also included urethane prodrugs of hydroxy - and amino groups, and carbonate prodrugs, sulfate esters and sulfate esters of hydroxy groups. The invention also includes derivatives of hydroxy groups, such as (acyloxy)methyl and (acyloxy)ethyl ethers, in which the acyl group may be alkilany ester, optionally substituted by groups including, but not limited to a specified functional group of simple ether, amine and carboxylic acid, or the acyl group is a complex ester of the amino acids as described above. Prodrugs of this type is described in J. Med. Chem., 1996, 39, 10. More specific examples include prodrugs, in which the hydrogen atom of the alcohol group substituted by such a group, as (C1-C6)alkanoyloxy, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonylmethyl, N 1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C6)alkanoyl, ariell and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoaniline group independently selected from the natural L-amino acids, P(O)(OH)2, -P(O)(O)(C1-C6)alkyl)2or glycosyl (the radical resulting from the removal of the hydroxyl group hemiacetal form of carbohydrate).

[00267] Free amines of compounds of formula I can also be turned into a derivative in the form of amides, sulfonamides or phosphoramidon. All of these proletarienne parts can contain groups, including, but not limited to the above, the functional group of simple ether, amine and carboxylic acid. For example, a prodrug can be obtained by replacing the hydrogen atom in the amino group, such a group as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R'each independently is a (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, -C(OH)C(O)OY where Y is H, (C1-C6)alkyl or benzyl, -C(OY0)Y1where Y0is a (C1-C4)alkyl and Y1is a (C1-C6)alkyl, carboxy(C1 -C6)alkyl, amino(C1-C4)alkyl or mono-N - or di-N,N-(C1-C6)acylaminoalkyl, -C(Y2)Y3, where Y2represents H or methyl and Y3is a mono-N - or di-N,N-(C1-C6)alkylamino, morpholino, piperidine-1-yl or pyrrolidin-1-yl.

[00268] Additional examples proletarienne derivatives, see, for example, in the publications a) Design of Prodrugs, edited by N. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and N. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p.113-191 (1991); (C) N. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) N. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[00269] "Pharmaceutically acceptable salt", if not specified otherwise, includes salts which retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. The compound of this invention can have a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases or acids with the formation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable Sol is th include such salts, obtained by the reaction of compounds of the present invention with a mineral or organic acid or inorganic base, such salts include the sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, phosphates, monohydrogenphosphate, dihydrophosphate, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, Butin-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalates, sulfonates, cellsurface, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycollate, tartratami, methansulfonate, propanesulfonate, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelate. Because the individual connection of the present invention may include more than one acidic or basic part, the compounds of the present invention may include mono-, di - or tricoli individual connections.

[00270] If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be obtained by any suitable method available in this area, for example,by treatment of the free base Ki the pilot connection for example, inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyrenoidosa acid, such as glucuronic acid or galacturonic acid, an alpha hydroxycitrate, such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluensulfonate acid or econsultancy acid, or the like.

[00271] If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be obtained by any suitable method, for example by treatment of the free acid with an inorganic or organic base. Examples of suitable inorganic salts include salts formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Examples of suitable salts of organic bases include, for example, ammonium salts, deben is Ramone, benzylamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)ammonium, phenylethylenediamine, dibenziletilendiaminom and similar salts. Other salts of acid groups of compounds can include, for example, salts formed with procaine, quinine and N-methylglucamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.

[00272] the compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be suitable as intermediates for preparation and/or purification of the compounds of the formula I and/or for separating enantiomers of compounds of formula I.

[00273] the Present invention also includes the isotope-labeled compounds of the present invention, which are identical to the compounds described here, except that one or more atoms replaced by an atom having an atomic mass or atomic number different from the atomic mass or atomic number of the atom, usually found in nature. All isotopes of any specified particular atom or element included in the scope of the compounds of the invention and their applications. Examples of isotopes that can be introduced into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, KIS is aroda, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N15N15Oh,17O,18Oh,32P,33P,35S18F,36Cl123I and125I. Some labeled isotopes of the compounds of the present invention (e.g., compound labeled with3H and14C) are suitable for analyses determine the distribution connection and/or substrate tissue. The isotope tritium (i.e.3N) and carbon-14 (i.e.14C) are applicable due to the ease of obtaining them and detectiveyoshi. In addition, the substitution of heavier isotopes such as deuterium (i.e.2H), can provide some therapeutic advantages resulting from higher metabolic stability (e.g., increased half-life in vivo or lower the required dose), and therefore in some cases may be preferred. Positron emitting isotopes, such as15Oh,13N11C and18F, are suitable for the study of positron emission tomography (PET)to study the degree of occupancy of the receptor substrate. Labeled isotope compounds of the present invention are usually obtained by methods similar to the methods described in the schemes and/or in the examples below, with the replacement of its isotope is eagent on isotope-labeled reagent.

[00274] the METABOLITES of the COMPOUNDS of FORMULA I

[00275] In the scope of the present invention includes also formed in vivo metabolic products described herein compounds of formula I. "Metabolite" is a pharmacologically active product formed in the body through metabolism of the compounds or salts thereof. Such products may result, for example, oxidation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, glukuronidirovania, enzymatic cleavage, and the like entered connection. Accordingly, the invention includes metabolites of compounds of formula I, including compounds, formed by the process comprising contacting the compounds of this invention with the body of a mammal over a period of time sufficient for the formation of its metabolic product.

[00276] the Metabolic products generally identify obtaining a radiolabelled (e.g.,14With or3H) compounds of the invention, the parenteral its detectable dose (e.g. greater than about 0.5 mg/kg) to a mammal such as rat, mouse, Guinea pig, pig, monkey, or human), holding metabolism in sufficient time (usually about 30 seconds before 30pm) and the allocation of its transformation products from the urine, blood or other biological samples. These products are easy to distinguish because they are labeled (other products emit through the use of antibodies capable of binding epitopes of surviving metabolite). Patterns of metabolites determined in the usual method, for example by analysis of MS, LC/MS or NMR. In General, the analysis of metabolites spend the same method as in the conventional studies of the metabolism of drugs, well-known specialist in this field. Metabolic products, because otherwise they are not found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

[00277] the SYNTHESIS of COMPOUNDS of FORMULA I

[00278] the compounds of formula I can be synthesized by synthetic routes that include processes analogous to methods well known in the chemical industry, especially in light of the existing descriptions. The initial compounds are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI), or easily determined using methods well known to specialists in this field (e.g., methods, generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, N.Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).

[00279] the Compounds the Oia formula I can be obtained in the form of individual compounds or compound libraries, includes at least 2, for example 5-1000 compounds or 10-100 compounds. Libraries of compounds of formula I can be obtained by combinatorial method "splitting and connection of multiple parallel syntheses using methods of synthesis or solution phase or solid phase, known to the person skilled in the art. Thus, according to further aspect of the invention there is proposed a compound library comprising at least 2 compounds or their pharmaceutically acceptable salts.

[00280] For illustrative purposes in schemes 1-7 shows a General method of preparing compounds of the present invention, as well as key intermediates. For a more detailed description of the individual stages of the reactions, see the section below examples. The person skilled in the art should understand that for the synthesis of compounds of the invention can use other synthetic way. Although the schemes are listed and discussed below certain source materials and reagents, they can easily be replaced by other source materials and reagents, to obtain various derivatives and/or different reaction conditions. In addition, many of the compounds obtained by the methods described below can be further modified in the light of this description with the use of conventional chemical methods, x is the well-known specialist in this field.

[00281] scheme 1 illustrates the synthesis of N-linked" khinazolinov compounds (4) of the present invention, where a and E have the values defined here. According to the scheme 1 4-aniline-6-nitroquinazoline (3) can be obtained by reaction of the appropriate aniline (2) hinazolinam (1), substituted in position 4 of a suitable leaving group such as chloride, under standard conditions combinations. The reaction mix can be carried out in various solvents such as t-BuOH, IPA or DCE, and it may require elevated temperatures and may require the use of weak bases, such as EtN(i-Pr)2. In one example, the reaction is carried out in a mixture of IPA and DCE heated to 80°C. the Recovery of the nitro group of the compound (3) you can perform a variety of standard protocols, recovery, known in this field, such as Pd/C and H2Pd/C and hydrazine, Pt/C with NaOH and H2, Zn/AcOH, Zn/NH4Cl or Fe/HOAc. In one example, the recovery performed by the system Pd/C and H2. When R2represents halogen, you can perform recovery of Pt/C with NaOH and H2or Zn/NH4Cl. The resulting aniline can be combined with halides or subjected to interaction with other suitable electrophiles, such as aldehydes, acid anhydrides, etc. to obtain the compound (4). These reactions may require the SQL application of a suitable base and/or high temperatures.

[00282] Scheme 2 illustrates an alternative way to obtain the "N-linked" khinazolinov compounds (4), where a and E have the values defined here. According to scheme 2, the 4-chloro-6-iodination (5) can be used instead of 4-chloro-6-nitroquinazoline (1) in scheme 1 to obtain 4-aniline-6-iodination (6). Mediated by palladium reaction cross combinations formed iodination (6) with the appropriate amine R15NH2to obtain compounds 4 can be accomplished by treatment with palladium catalyst, for example Pd(OAc)2Pd(PPh3)4, PdCl2(dppf)2Pd2(dba)3, phosphine ligand and a base in a suitable organic solvent, such as THF, DME or toluene. In one example, the reaction mix performed using Pd2(dba)3, X-PHOS and Cs2CO3in THF and heated to 65°C. figure 2 shows the receipt-related compounds (7). These analogues can be obtained from compound (6) mediated by palladium cross-reactions combination with baronowie acids or ORGANOTIN compounds under the conditions of the Suzuki reaction or still, well known in this field.

[00283] In scheme 3 is illustrated by way of obtaining "N-linked" oxazolidinedione compounds where a and E are specified ZV is camping values. According to the scheme 3 amidon (8) with a suitable condensing aniline (2) in the presence of acid, such as the SPLA, in a suitable organic solvent, such as isopropylacetate (IPAc) to give the thiourea (9). The oxazoline (10) can be obtained by cyclization of thiourea in various conditions, such as treatment of thiourea (9) TsCl and aqueous NaOH in THF.

Radenotes H, R15or a protective group

Scheme 4

[00284] In scheme 4 illustrates the synthesis of linked simple broadcasting group hintline (13) of the present invention, where a and E have the above values. According to the scheme 4 4-chloro-6-oxiconazole (11) can be subjected to reaction with a suitable aniline (2) in the standard combination of conditions as described in scheme 1, to obtain the compounds (12). Oxygen connection part (11) it is possible to substitute different groups of Rawhere Rarepresents H, R15or appropriate hydroxyamino group, such as acyl group. After the reaction with aniline optional protective group can be removed at suitable conditions, such as ammonia in the Meon with the case of the acetate protective group. Hydroxyl group of compound (12) can be combined with a suitable alkylhalogenide R15-X in the presence of a suitable base, such as K2CO3Cs2CO3or Cs(OH)sub> 2in organic solvents, such as DMF or acetone, to obtain compound 13. In one example, the alkylation is carried out by connection R15-Br using Cs2CO3as the base in DMF. In the alternative case, R15-OH can be used instead of R15-X, if alcohol group was converted into an activated leaving group, such as tosylate. In another method, a hydroxyl group 12 can be combined with alcohol R15-OH under standard conditions of Mitsunobu, such as DIAD/PPh3in THF to obtain compound 13.

[00285] In scheme 5 is illustrated a method of obtaining aniline intermediates (2A) and (2b), suitable for use in schemes 1-4, phenols (14) and (14) respectively. Phenols (14) and (15) are commercially available or known in the literature or they can be obtained by the person skilled in the art standard methods. Phenol (14) can be subjected to reaction with optionally substituted 4-peritrabecular (16) and a suitable base, such as K2CO3, NaH or Cs2CO3in the polar organic solvent such as DMF, at elevated temperature to obtain the product of the combination of (17). In one example, the phenol (14) is subjected to interaction with optionally substituted 4-peritrabecular (16) in the presence of Cs2CO3 in DMF at 80°Sniagrab compound (17) can be restored to the desired aniline compound (2A) using conventional recovery methods, such as Pd/C and H2Pd/C and hydrazine, Pt/C with NaOH and H2, Zn/AcOH, Zn/NH4Cl or Fe/HOAc. In one example, the recovery is performed using Pd/C and H2(40 psi). When R2represents halogen, recovery can be done using Pt/C with NaOH and H2or Zn/NH4Cl. The same method of the compound (2b) can be obtained from phenol (15).

[00286] In scheme 6 illustrates a method of obtaining a phenolic intermediate compound (14a), suitable for use in scheme 5. Chloropyridin (18) can be subjected to interaction with hydrazine, for example, in pyridine at 80°C. the Resulting compound can then be subjected to interaction with the equivalent of a carboxylic acid, such as triethylorthoformate or trimethoxymethane, and acid, such as HCl, SPLA or 4-methylbenzenesulfonic acid. In one example, the cyclization is carried out trimethoxymethane and 4-methylbenzenesulfonic acid to obtain a triazole. The benzyl group can be removed under standard conditions, for example using Pd/C and H2pick (14a).

[00287] In scheme 7 illustrates a method of obtaining phenolic p is Megalochori compound (14b), suitable for use in scheme 5. Appropriately substituted acetal can be subjected to interaction with DMF and POCl3obtaining dimethylaminobenzaldehyde intermediate connection.

The transformation of this intermediate compound in pyrazolopyrimidine you can perform the processing optionally substituted 1H-pyrazole-3-amine in the base at an elevated temperature, e.g., NaOMe in Meon at 60°C. Benzyl group can be removed to obtain (14b) under standard conditions, such as Pd/C and H2.

[00288] In scheme 8 is illustrated obtaining aniline intermediate compounds (2C) and (2d), suitable for use in schemes 1-4. According to scheme 8 mediated palladium reaction cross-combination of 2-chloro-4-benzyloxypyridine (18) with a suitable amine to obtain the compound (19) can be accomplished by treatment with palladium catalyst, for example Pd(OAc)2Pd(PPh3)4, PdCl2(dppf)2Pd2(dba)3, phosphine ligand and a base in a suitable organic solvent, such cactf, DMF or toluene. In one example, the combination performed using LHMDS with Pd2(dba)3, X-PHOS and Cs2CO3in THF and heated to 65°C.

The resulting 2-aminopyridine can optionally be protected as the BOC-carbamate under standard conditions, in the example Boc 2O in t-BuOH. The benzyl group of compound (19) can be removed under standard conditions, such as Pd/C and H2. The resulting phenol is then subjected to interaction with optionally substituted 4-peritrabecular (16)as described in scheme 5, thus obtaining the product of the combination of (20). The BOC group of compound (20) can be removed with acid, for example TFA in DCM. 2-Aminopyridine (21), freed from the protective groups can be converted to a derived imidazopyridine reaction with appropriately substituted 2-halogenocarboxylic connection. For example, the compound (21) can be subjected to interaction with either chloroacetaldehyde, chloroacetone or 2-chloropropanol in THF by heating to boiling under reflux. The conversion of compound (21) in triazolopyridine you can reach the two-stage procedure, which involves the condensation of (21) with dimethylacetal of dimethylformamide to obtain a derivative of N,N-dimethylformamide, which is then subjected to interaction with hydroxylaminsulphate acid, thus obtaining triazolopyridine. The recovery of the corresponding nitro group can be accomplished as described in scheme 5, to obtain the compounds (2C) and (2d).

[00289] In scheme 9 illustrates an alternative synthesis of intermediate aniline compounds (2E) and (2f), suitable for the application of the Oia in schemes 1-4. According to scheme 9 2-chloro-5-hydroxypyridine subjected to interaction with optionally substituted 4-peritrabecular (16)as described in scheme 5. Chlorinated (22) can be transformed into derivatives (23) in conditions mediated by palladium cross combinations, as described in scheme 8. The conversion of compound (23) in imidazopyridine or triazolopyridine can be performed in suitable conditions described in scheme 8. The recovery of the corresponding nitro groups can be performed as described in scheme 5, to obtain the compounds (2E) and (2f).

[00290] In scheme 10 illustrates an alternative synthesis of intermediate aniline compound (2g), suitable for use in schemes 1-4. According to scheme 10 finalsilence benzododecinium heterocycles (14) and (25) can be subjected to interaction with dimethylthiocarbamate and a base such as NaH in THF, heated to boiling under reflux. The rearrangement of the formed THIOCARBAMATE performed by heating at an elevated temperature, for example at 200°C. in diphenyl simple ether. The product is then hydrolyzing in basic conditions, such as the line in the Meon, when heated to boiling under reflux. Thiol (24) can then be subjected to interaction with optionally substituted 4-peritrabecular (16) as described in scheme 5. The restoration of the nitro group can be performed as described in scheme 5, for example, with the use of Fe/HOAc or Zn/NH4Cl, obtaining compound (2g). Alternative synthesis of aniline (2g) involves the reaction of halogen-substituted condensed heterocyclic compounds (25), where X represents Br, s (i-Pr)3SiSH and palladium catalyst, for example Pd(PPh3)4in THF and the mixture heated to boiling under reflux. The resulting protected thiol (26) can be decillionth and subject interaction with optionally substituted 4-peritrabecular (16) in situ with a source of fluoride, such as CsF in DMF. The restoration of the nitro group to obtain (2g) perform the standard reaction conditions.

[00291] In scheme 11 illustrates the method of obtaining aniline (2h), suitable for use in schemes 1-4. According to scheme 11, the acid chloride of acid (27) is subjected to interaction with the 2-pyridone and the base, for example with Et3N in DCM, while receiving ester (28). Bronevoy acid (29) is derived from halogen-substituted condensed heterocycle (25) under standard conditions, for example by treatment of n-BuLi at low temperature followed by the addition In(OMe)3. Compound (28) is then combined with Bronevoy acid (29) when mediated by palladium conditions Perekrestok the combination, for example, using Pd(OAc)2, PPh3and dioxane and heated to 50°C (Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org. Lett. 2004, 6, 3597). The resulting nitrosoaniline can be restored to standard conditions as described in scheme 5, such as Fe/HOAc or Zn/NH4Cl, to obtain the compound (2h).

[00292] In scheme 12 shows a method of obtaining compounds of formula I, where a and E have values here, the ring is benzododecinium ring and R3represents a group Z having the formula

[00293] where R8brepresents H or methyl.

[00294] In scheme 13 shows a method of obtaining compounds of formula I, where a and b have the values defined here, the ring is benzododecinium ring and R3represents a group Z having the formula

[00295] the compounds of formula I can be obtained using methods of the reactions known in the field, or by methods similar to the methods known in this field. The invention also provides methods of making compounds of formula I, including:

[00296](a) reaction of compounds of formula (F1)

[00297] with the compound of the formula (F2)

[0098] in which Z represents a leaving atom or group;

or

[00299] (b) for compounds of formula I in which G represents N, the reaction of the compound of the formula (F3)

[00300] in which R represents a tertiary amino group, for example di(1-6C)alkylamino, such as dimethylamino, with the compound of formula (F1), followed, if necessary, converting the compounds of formula I into another compound of formula I with another group, R3.

[00301] More specifically, the invention provides methods for producing compounds of formula I, including:

[00302] (C) for compounds of formula I, in which R3is an-otherxand Rxis an R15or OC(O)R15and R15has the values specified for formula I, by reaction of the corresponding compounds of formula I, where R3represents-NH2with an alkylating agent or allermuir agent R15-X1where R15-X1is a acid or its reactive derivative (such as R15C(O)Cl), or, when X1represents a leaving group such as halogen group, optionally in the presence of a base; or

[00303] (d) for compounds of formula I, in which R3is an-other15and R15has the values specified for formula I, by reaction of the corresponding compounds of formula I, where R3 represents an iodide group, with a compound having the formula R15NH2in the presence of palladium catalyst and phosphine ligand; or

[00304] (e) for compounds of formula I, in which R3is an R15and R15has the values specified for formula I, by reaction of the corresponding compounds of formula I, where R3represents an iodide group, with a compound having the formula R15B(OH)2or R15SnBus in the presence of palladium catalyst and phosphine ligand; or

[00305] (f) for compounds having formula I, in which R3is a OR15and R15represents alkyl, alkenyl or quinil, by reaction of the corresponding compounds of formula I, where R3HE is a, R15-X2where R15represents alkyl, alkenyl or quinil and X2represents a leaving group, in the presence of a base; or

[00306] (g) for compounds having formula I, in which R3is a OR15and R15represents alkyl, alkenyl or quinil, by reaction of the corresponding compounds of formula I, where R3represents-OR15aand-OR15arepresents a sulfate group, such as toiletry group, with a compound having the formula R15OH, in the presence of a base; or

[00307] (h) for compounds having formula I, in which R3represents a group of the formula (F3)

[00308] the reaction of the corresponding compounds of formula I, in which R3represents an iodide group, with a compound having the formula (F4)

[00309] in the presence of a palladium catalyst, a phosphine ligand and a base; or

[00310] (i) compounds having the formula I, in which R3represents a group of formula (F5)

[00311] where R6represents methyl, cyclization of the corresponding compounds of formula I, in which R3represents a group of formula (F6)

[00312] where R6represents methyl, in the presence of a base and sulphonylchloride, such as Teilhard; or

[00313] (j) for compounds having formula I, in which R3represents a group of formula (F5)

[00314] where R6represents H, by cyclization of the corresponding compounds of formula I, in which R3represents a group of formula (F6), where R6represents H, in the presence of diisopropylcarbodiimide and phosphine ligand, such as h3;

or

[00315] (k) for compounds having formula I, kotorogo R 3represents a group of formula (F7)

[00316] where R6represents H, reaction of a corresponding compound having the formula I, in which R3represents a group of formula (F6) and R6represents H, in the presence of a base and sulphonylchloride.

[00317] it Is believed that some of the intermediate compounds described in the above schemes and examples, are new and proposed as the following aspects of the invention. In particular, this invention further provides a compound of formula (F1)

[00318] where R1, R2, A, E and n have the meanings indicated for formula I. the compounds of formula (F1) are applicable for pharmaceutical compounds, such as compounds of formula I, which are inhibitors of ErbB.

[00319] Upon receipt of the compounds of formula I may be required to protect remote functional groups (e.g., primary or secondary amines, alcohols, etc.) intermediates. The need for such protection will vary depending on the nature of remote functional groups and methods of obtaining. Suitable aminosidine group (NH-Pg) include acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl (VOS), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl is l (Fmoc). The need for such protection is easily determined by the person skilled in the art. General description of the protective groups and their use, see publication .W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New. York, 1991.

[00320] SEPARATION METHODS

[00321] In any of the synthetic methods for preparing compounds of formula I may be convenient separation of the reaction products from each other and/or from starting materials. Required products each stage or series of stages separated and/or purified to the required degree of homogeneity techniques, common in this area. Such separation include, for example, multiphase extraction, crystallization from a solvent or mixture of solvents, distillation, sublimation or chromatography. Chromatography may include any number of methods, including, for example, methods and apparatuses chromatography with reversed phase and normal phase chromatography with the exception of the size of molecules; ion exchange chromatography; liquid chromatography with high medium and low pressure; analytical chromatography of small quantities; chromatography with simulated moving bed (SMB) and preparative thin-layer chromatography, thick-layer chromatography, and methods thin-layer chromatography of small quantities and flash chromatography.

[00322] Another class of methods for separation includes about the development of the reaction mixture with a reagent selected for binding or otherwise, transform to separate the desired product, unreacted educt, the side reaction product or the like. Such reagents include adsorbents, such as activated carbon, molecular sieves, ion exchange medium or the like. Alternatively, the reagents can be acid in the case of the basic substance, the base case of acid substances, binding reagents, such as antibodies, binding proteins, selective hepatoblastoma agents, such as crown-ethers, reagents ion extraction system liquid-liquid (LIX) or the like.

[00323] the Selection of the appropriate method(s) of separation depends on the nature of the involved substances. For example, the boiling point and molecular weight by distillation and sublimation, the presence or absence of polar functional groups in chromatography, stability substances in acidic and basic environments with multi-phase extraction, and the like. Specialist in this field will apply methods most appropriate to achieve the desired separation.

[00324] Diastereomer mixture can be divided into their individual diastereomers on the basis of their physical chemical differences by methods well known to specialists in this field, such as chromatogra the Oia and/or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary substance, such as a chiral alcohol or Mosher acid chloride), separating the diastereomers and converting (e.g., hydrolysis) of individual diastereoisomers in the corresponding pure enantiomers. In addition, some of the compounds of the present invention can be atropisomers (for example, substituted barely), and consider them as part of the present invention. Enantiomers can also be divided using HPLC with chiral column.

[00325] Individual stereoisomer, for example enantiomer is essentially not containing a stereoisomer, can be obtained by separation of the racemic mixture using a method such as formation of diastereomers using optically active separating agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., J. Chromatogr., (1975) 113(3):283-302). Racemic mixtures of chiral compounds of the invention can be divided and highlight any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric salts with chiral forming p is otvodkami reagents, separation of the diastereomers and converting into pure stereoisomers, and (3) isolation of essentially pure or enriched stereoisomers directly under chiral conditions. Cm. Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekkr, Inc., New York (1993).

[00328] In the method (1) diastereomeric salt can be obtained by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetric compounds having acidic functional group such as carboxylic acid and sulfonic acid. Diastereomeric salt can be divided by fractional crystallization or ion chromatography. When the separation of optical isomers of amino compounds, the addition of chiral carboxylic acids or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid, can lead to the formation of diastereomeric salts.

[00327] In the alternative case of method (2) the substance that you want to share, is subjected to the interaction with one enantiomer of chiral compounds with the formation of diastereomeric pairs (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p.322). Diastereomeric compounds can be obtained by the interaction of the asymmetric compounds with enantiomerically pure chiral forming the derivative reagents, such as methylpropane, followed by separation of the diastereomers and hydrolysis of obtaining pure or enriched enantiomers. The method of determining optical purity involves obtaining chiral esters, such as metalowy ester, for example, (-)-methylchloroform, in the presence of base, or Mosher ester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165) racemic mixture and analysis by spectroscopy1H NMR to determine the presence of two atropisomers enantiomers or diastereomers. Stable diastereomers atropisomers compounds can be divided to allocate chromatography with normal or reversed phase separation methods atropisomers of naphthylisoquinoline (WO 96/15111). Method (3) racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be characterized by the methods used to establish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[00328] the METHODS of TREATMENT with COMPOUNDS of the FORMULA I

[00329] the Compounds of the present invention can be applied as a preventive or therapeutic agent is for the treatment of diseases, mediated by modulation or regulation of the receptor tyrosinekinase and/or serine-, trainingin and/or kinase dual-specificity of type I. it is Assumed that "effective amount" refers to an amount of a compound that when administered to a mammal in need of such treatment, is sufficient to effect the treatment of a disease mediated by the activity of one or more receptor tyrosinekinase and/or serine-, trainingin and/or kinase dual-specificity of type I. for example, a therapeutically effective amount of compounds selected from the compounds of formula I or its MES, metabolite, or pharmaceutically acceptable salts, or prodrugs, is a quantity sufficient to modulate, regulate, or inhibiting the activity of one or more receptor tyrosinekinase and/or serine-, trainingin and/or kinase dual-specificity of type I, so that a pathological condition that is mediated by such activity was restored to a normal state or have been eased.

[00330] the Term "treatment" ("treal" or "treatment"refers to both therapeutic treatment and prophylactic or preventive measures, aimed at prevention or deceleration (decrease undesired physiological change or disturbance. For the purposes of this from the retene beneficial or desired clinical results include, but not limited to, relieving symptoms, reducing the extent of disease, stabilized (i.e. not worsening) state of disease, delay or slowing of disease progression, reducing the intensity of symptoms or weakening of the pathological state, and remission (whether partial or total), whether preventable or not detectable. "Treatment" can also mean prolonging life expectancy compared with the expected life expectancy without treatment. Subjects in need of treatment include subjects who already have this condition or violation, as well as entities which have a tendency to the occurrence of such condition or breach, or entities in which such condition or violation should be avoided. The term "treatment" includes both preventive, i.e. preventive and palliative treatment.

[00331] the Compounds of the present invention possess anti-proliferative effect against cell properties, which are believed to be called their inhibitory activity against receptor tyrosine kinase class I. In accordance with this it is expected that the compounds of the present invention are suitable for treatment of diseases or medical conditions, oposreduemyh or only partially enzymes, receptor tyrosine kinases class I, i.e. such compounds can be used for production of inhibitory effect against the receptor tyrosinekinase class I in the body of warm-blooded animal in need of such treatment. Thus, the compounds of the present invention provide a method of treating the proliferation of malignant cells characterised by inhibition of enzymes receptor tyrosinekinase class I, i.e. compounds can be used for production of anti-proliferative actions, mediated only partially or inhibition of the receptor tyrosine kinase class I. According to this it is expected that the compounds of the present invention are suitable for the treatment of cancer by providing antiproliferative actions, especially in the treatment of sensitive receptor tyrosinekinase grade 1 cancers, such as breast cancer, lung, colon, rectum, stomach, prostate, bladder and ovaries. It is also expected that compounds of the present invention are suitable for the treatment of other diseases with cell proliferation, such as psoriasis.

[00332] accordingly one aspect of the present invention relates to pharmaceutical compositions for the treatment of hyperproliferative diseases or abnormal cell growth in a mammal, which includes those who piticescu effective amount of the compounds of the present invention or its MES, metabolite, or pharmaceutically acceptable salt, or prodrug, and a pharmaceutically acceptable carrier.

[00333] the Term "abnormal cell growth" and "hyperproliferative violation" is used in this invention interchangeably.

[00334] the Term "abnormal cell growth", used here, unless otherwise noted, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). It includes, for example, abnormal growth (1) tumor cells (tumors)that proliferate the expression of the mutated tyrosine kinase or overexpression of the receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which activation takes place aberrant tyrosine kinase; (3) any tumors that proliferate receptor tyrosine kinases; (4) any tumors that proliferate activation of aberrant serine/trionychinae, and (5) benign and malignant cells of other proliferative diseases in which activation takes place aberrant serine/trionychinae.

[00335] In one embodiment, the abnormal cell growth is cancer. According to this, the invention provides methods for treating cancer, comprising the introduction is of the mammal, in need, a therapeutic amount of a composition of this invention.

[00336] In some embodiments, the implementation of specified cancer selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, linfocitos lymphoma, bladder cancer, cancer of the kidney or ureter, carcinoma renal cell carcinoma renal pelvis, neoplasm Central nervous system (CNS), primary CNS lymphoma, spinal tumours, gliomas, brain stem, pituitary adenomas, or a combination of one or more of the above cancers.

[00337] the Invention relates also to pharmaceutical compositions for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and induced diabetes renal Soboleva is e) or treating pain in a mammal, which includes a therapeutically effective amount of the compounds of the present invention or its MES, metabolite, or pharmaceutically acceptable salt, or prodrug, and a pharmaceutically acceptable carrier.

[00338] the Invention relates also to a method of treating pancreatitis or kidney disease, or treating pain in a mammal, as described above, which includes the introduction of the specified mammal therapeutically effective amounts of compounds of the present invention or its MES, metabolite, or pharmaceutically acceptable salt, or prodrug in combination with a pharmaceutically acceptable carrier.

[00339] the Invention relates also to pharmaceutical compositions for the prevention of implantation of blastocytes a mammal which comprises a therapeutically effective amount of the compounds of the present invention or its MES, metabolite, or pharmaceutically acceptable salt, or prodrug, and a pharmaceutically acceptable carrier.

[00340] the Invention relates also to a method of preventing implantation of blastocytes the mammal, which includes the introduction of the specified mammal therapeutically effective amounts of compounds of the present invention or its MES, metabolite, or pharmaceutically acceptable salt, or Strait is the drugs and pharmaceutically acceptable carrier.

[00341] the Invention relates also to pharmaceutical compositions for the treatment of diseases associated with vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of the compounds of the present invention or its MES, metabolite, or pharmaceutically acceptable salt, or prodrug, and a pharmaceutically acceptable carrier.

[00342] the Invention relates also to a method of treatment of a disease associated with vasculogenesis or angiogenesis in a mammal, which includes the introduction of the specified mammal therapeutically effective amounts of compounds of the present invention or its MES, metabolite, or pharmaceutically acceptable salt, or prodrug, and a pharmaceutically acceptable carrier. Examples of such diseases include, but are not limited to, tumor angiogenesis, chronic inflammatory disease or other inflammatory condition, such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retrolental fibroplasia associated with aging macular degeneration, hemangioma, glioma, melanoma, sarcoma Galoshes and cancer of the ovaries, breast, lung, pagelogin the th cancer, prostate, colon and epidermoid (epidermoid cancer).

[00343] the Invention relates also to pharmaceutical compositions for the treatment of a disease or condition associated with an inflammatory disease, autoimmune disease, destructive bone disorders, proliferative disorders, infectious diseases, viral disease, fibrotic disease or neurodegenerative disease in a mammal which comprises a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier. Examples of the aforementioned diseases and/or conditions include, but are not limited to, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia associated with aging macular degeneration, hemangioma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, allergic reactions, including asthma, allergic rhinitis and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, acute coronary SYN is rum, congestive heart failure, osteoarthritis, neurofibromatosis, organ rejection in transplantation, cachexia and pain.

[00344] Patients that can be treated by the compositions of the present invention include, for example, patients who have been diagnosed as having psoriasis, restenosis, atherosclerosis, national Department of standardization, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecological tumors (e.g., sarcoma of the cervix, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer of the endocrine system (e.g., thyroid cancer, parathyroid cancer, or cancer of the adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of children, limfocitna lymphoma, bladder cancer, cancer of the kidney or ureter (e.g., carcinoma renal cell carcinoma renal pelvis) or neoplasm Central nervous system (e.g., primary CNS lymphoma, tumors of the spine, glioma stem brain or pituitary adenomas).

[00345] Further suggested that the connection is of the formula I for use as a drug for the treatment of diseases and conditions, as described above, in a mammal, such as a person suffering from this disorder. The proposed application of the compounds of formula I in the manufacture of a medicine for the treatment of diseases and conditions described above, in a mammal, such as a person suffering from this disorder.

[00346] COMBINATION THERAPY

[00347] the Compounds of the present invention can be used in combination with one or more additional drugs, such as described below. The dose of the second drug can appropriately be selected on the basis of the clinically used dose. The proportion of compounds of the present invention and a second drug can appropriately be determined depending on subject of administration, route of administration, subject to the treatment of the disease, clinical condition, combination, and other factors. When the subject of the introduction is, for example, the second drug can be used in an amount of 0.01-100 mass parts by mass of the connection part of the present invention.

[00348] In some embodiments of the invention a method of treating abnormal cell growth in a mammal comprises the administration to the mammal of an amount of the compounds of formula I,

[00349] which is effective in the treatment of anomie is inogo cell growth in combination with an antitumor agent, selected from the following categories:

[00350] (i) antiproliferative/antineoplastic (anti-neoplastic) drugs and their combinations used in medical Oncology, such as alkylating agents (for example CIS-Platin, carboplatin, cyclophosphamide, nitrogen mustard gas analogue, melphalan, chlorambucil, busulfan and nitrosoanatabine); antimetabolites (for example antifolates such as ftorpirimidinu like 5-fluorouracil and tegafur, raltitrexed, methotrexate, citizenoriented, hydroxyurea, or one of the preferred antimetabolites described in the application for European patent application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoindole-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid); antitumor antibiotics (for example anthracyclines like adriamycin, bollicine, doxorubicin, daunomycin, epirubicin, idarubitsina, mitomycin-C, dactinomycin and mithramycin); antimitoticescoe agents (for example Vinca alkaloide, such vincristine, vinblastine, vindesine and vinorelbine, and taxaide like Taxol and Taxotere); topoisomerase inhibitors (for example, epipodophyllotoxins, such etoposide and teniposide, amsacrine, topotecan and computacin) and inhibitors of the mitotic kinesin KSP;

[00351] (ii) cytostatic agents such as antiestrogens (for example tamoxifen, t is Reifen, raloxifene, drological and idoxifene); positive regulators of estrogen receptor (for example, fulvestrant); antiandrogens (for example, bikalutamid, flutamide, nilutamide, cyproterone acetate and CASODEX™ (4'-cyano-3-(4-perpenicular)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide)); the LHRH antagonists or LHRH agonists (for example goserelin, laporan, buserelin); progesterones (for example, megestrol acetate), aromatase inhibitors (for example, aseanstats, letrozole, varsol and exemestane); inhibitors of 5α-reductase such as finasteride; and inhibitors R, such as inhibitors, are described in the publications U.S. patent No. 2004/0176325, 2004/0180896 2004/0192635;

[00352] (iii) agents which inhibit the invasion of cancer cells (for example, inhibitors of metalloproteinases, such marimastat, and inhibitors of receptor function of the plasminogen activator urokinase);

[00353] (iv) inhibitors of the function of growth factor, such as antibodies, growth factor, antibody growth factor receptor (e.g., anti-erB2-antibody tristanusa [HERCEPTIN™] and the anti-erbB1-antibody cetuximab [S]), inhibitors farnesyltransferase, tyrosine kinase inhibitors and inhibitors sprintringtones (for example, inhibitors of the epidermal growth factor family tyrosinekinase, such as N-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-what ethoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) and 6-acrylamide-N-(3-chloro-4-forfinal)-7-(3-morpholinopropan)hinzelin-4-amine (CI 1033)); inhibitors of the family isolated from platelet growth factors; inhibitors family of growth factors hepatocyte and MEK inhibitors, such as PD325901 and such compounds as described in published U.S. patent 2004/0116710;

[00354] (v) antiangiogenic agents, such as agents that inhibit the action of factor vascular endothelial growth (for example, antibodies against factor vascular endothelial growth bevacizumab [AVASTIN™], compounds such as described in PCT publication nos WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that act by other mechanisms (for example, linomide, inhibitors of the function of integrin αvβ3 inhibitors of MMP inhibitors SOH-2 and angiostatin);

[00355] (vi) agents vascular damage, such as combretastatin A4 and compounds described in PCT publications No. WO 99/02166, WO 0/40529, WO 00/41669, WO 01/92224, WO 02/04434 WO 02/08213;

[00356] (vii) therapy using antisense chains (e.g., therapy, which is directed to the targets listed above, such as ISIS 2503 and antisense antibodies against gas);

[00357] (viii) methods of gene therapy, including, for example, GVAX™, how to replace aberrant genes such as aberrant p53 or aberrant BRCAI or BRCA2, GDEPT (gene-directed enzyme proletarienne therapy), t is the cue ways as the use citizendiumat, timedancing or enzyme bacterial nitroreductase, and ways to improve the tolerance of the patient to chemotherapy or radiotherapy such as gene therapy multidrug resistance;

[00358] (ix) interferon, and

[00359] (x) immunotherapy methods, including, for example, carried out in ex-vivo and in-vivo method for enhancing the immunogenicity of tumor cells, such as transfection with cytokines such as interleukin-2, interleukin 4 or granulocyte macrophage colony-stimulating factor, methods of reducing anergy of T cells, methods of using transfected immune cells such as transfetsirovannyh cytokine dendritic stand, ways of using cytokine transfected lines of tumor cells and methods of using antiidiotypic antibodies.

[00360] In one embodiment, the second compound of the pharmaceutical combination of the drug or regimen medicines has complementary activities to the compounds of formula I, so that they do not adversely effect each other. Such medicines are suitable present in combination in amounts that are effective for the intended purpose. Accordingly, in another aspect of this is bretania proposed composition, includes the compound of formula I or its MES, metabolite, or pharmaceutically acceptable salt, or prodrug in combination with a second drug, such as described here is the second drug.

[00361] the Compound(I) of formula I and the additional pharmaceutically active agent(s) can be entered together in the same pharmaceutical composition or separately, and when introduced separately, the introduction can be performed simultaneously or sequentially in any order. This gradual introduction may be close in time or remote in time. The amount of compound(s) of formula I and the second agent(s) and the relative times of administration should be chosen so as to achieve the desired combined therapeutic effect.

[00362] Suitable dosages for any of the above agents joint injection doses are used at the present time, and can be reduced due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments.

[00363] Combination therapy can provide "synergy" and may be "synergistic", i.e. will provide action when the active ingredients used together, stronger than the sum of the actions that are the result of applying the compounds razdel is. A synergistic effect can be achieved when the active ingredients (1) are part of the same drug and they are administered or delivered simultaneously in a combined uniform dosage of the drug; (2) delivered by alternation or in parallel as separate drugs or (3) by some other regimen. When delivering alternating therapy, a synergistic effect can be achieved when the compound is administered or delivered sequentially, for example, different users in different syringes. In General, during alternating therapy effective dose of each active ingredient is administered sequentially, i.e. periodically, whereas combination therapy effective dose of two or more active ingredients are administered together.

[00364] the Compounds of the present invention can be applied, for example, in combination with an additional drug(s), such as a therapeutic agent for

[00365] the introduction of the COMPOUNDS of FORMULA I

[00366] the Compounds of the invention can be entered by any means, suitable for being treated condition. Appropriate ways include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), percutaneous, rectal, nasal, local (including transbukkalno, sublingual the first), vaginal, intraperitoneal, intra-lungs and intranasal route. It should be clear that the preferred path may vary, for example, depending on the condition of the recipient. When the compound is administered orally, it may be made in the composition of the drug in the form of pills, capsules, tablets and so on with a pharmaceutically acceptable carrier or excipient. When the compound is administered parenterally, it can be made with a pharmaceutically acceptable parenteral carrier, and in a unit dosage injectable dosage form, as described in detail below.

[00367] PHARMACEUTICAL

[00368] To apply the compounds of formula I or its pharmaceutically acceptable salt, MES, metabolite or prodrug for therapeutic treatment (including prophylactic treatment) of mammals including humans, it is usually produced according to standard pharmaceutical practice in the form of pharmaceutical compositions. According to this aspect of the invention there is proposed a pharmaceutical composition that includes a compound of formula I or its pharmaceutically acceptable salt, MES, metabolite or prodrug in combination with a pharmaceutically acceptable diluent or carrier.

[00369] the Pharmaceutical compositions of the invention produce, dispense, and introduce a method ie apply quantity, concentration, scheme introduction, course of treatment, fillers and route of administration that is compatible with suitable medical practice. The factors discussed in this context include the particular exposed treatment violation, the concrete being treated animal, the clinical condition of the individual patient, the cause of the violation, place of delivery of the agent, route of administration, the scheme of administration and other factors known to practitioners in medicine. A therapeutically effective amount of the compound that is administered will be determined by such factors, and it is the minimum amount necessary to prevent, reduce the intensity of symptoms or disorders. The compound of the present invention is usually produced in the form of pharmaceutical dosage forms, which provide an easily controllable dosage of the drug and allow the patient to follow the treatment and the treatment regimen.

[00370] the Composition for use here is preferably sterile. In practice, the drugs that are used for administration in vivo, must be sterile. Such sterilization is easily performed, for example, by filtration through sterile membranes for filtration. The connection is usually stored in the form of solid compositions, liofilizirovannogo preparation or in the form of water is Astor.

[00371] the Pharmaceutical preparations of the compounds of the present invention can be manufactured for various routes and types of administration. For example, the compound of formula I having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington''s Pharmaceutical Sciences (1980) 16ththedition, Osol, A. Ed.) to obtain the form of liofilizirovannogo drug, milled powder, or an aqueous solution. Preparation can be carried out by mixing the compounds at ambient temperature and under suitable pH and when the desired degree of purity with physiologically acceptable carriers, i.e. carriers, which are nontoxic to recipients at the dosages and concentrations. the pH of the drug depends largely on the particular application and the concentration of the compound, but may be in the range of from about 3 to about 8. The drug in acetate buffer at pH 5 is a suitable embodiment. Drugs can be obtained with the use of accepted methods of dissolving and mixing. For example, the bulk drug substance (i.e., the compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexing agent) solution of the Ute in a suitable solvent in the presence of one or more excipients.

[00372] Specific applicable carrier, diluent or excipient will depend on the method and purpose for which the compound of the present invention is applied. Solvents are usually chosen based solvents, which are known to specialists in this area as safe (GRAS) for administration to a mammal. In General, safe solvents are non-toxic solvents, such as water and other non-toxic solvents that are soluble in water or miscible with it. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (such as PEG 400, PEG 300), etc. and mixtures thereof. Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations and include buffers like phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as chloride of octadecyltrimethoxysilane; chloride hexadecane; benzalkonium chloride, chloride benzene; phenol, butyl or benzyl alcohol; alkylarene, such as methyl or propyl paraben; catechin; resorcinol; cyclohexanol; 3-pentanol and p-cresol); polypeptides of low molecular weight (less than about 10 residues); proteins such as serum album is h, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; soleobrazutaya counterions such as sodium; complexes with metals (for example, complexes of Zn-protein) and/or nonionic surfactants such as tween™, pluronic™ or polyethylene glycol (PEG). Drugs may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspendida agents, preservatives, antioxidants, agents which impart opacity, agents, give the slip, auxiliary substances for processing, dyes, sweeteners, fragrances, corrigentov and other known additives to provide the best view of the medicinal product (i.e. compounds of the present invention or pharmaceutical composition) or aid in the manufacture of pharmaceutical products (i.e. medicines). Active pharmaceutical ingredients may also be "captured" in the microcapsules obtained, for example, methods of the mi koatservatsii or interfacial polymerization, for example hydroxymethylcellulose or gelatin-microcapsules and poly(methylmethacrylate) microcapsules, respectively, in colloidal systems for delivery of a drug (for example, liposomes, albumen the microspheres, microemulsions, nanoparticles and nanocapsules) or in microemulsion. Such techniques are described in the publication Remington's Pharmaceutical Sciences 16thedition, Osol, A. Ed. (1980). "Liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is suitable for delivery of a drug (such as compounds described herein, and optionally a chemotherapeutic agent) to a mammal. Components of liposomes are typically located in the bilayer formation, similar to the lipid structure of biological membranes.

[00373] you Can get drugs from steadfastly supported the release of the compounds of formula I. Suitable examples of drugs with steadfastly supported release include semi-permeable matrices of solid hydrophobic polymers containing a compound of formula I, and the matrices are in the form of molded articles, e.g. films, or microcapsules. Examples of matrices with steadfastly supported release include polyesters, hydrogels (for example, poly(2-hydroxyethyl the acrylate) or poly(vinyl alcohol), the polylactide (U.S. patent No. 3773919), copolymers of L-glutamic acid and gamma ethyl-L-glutamate, indestructible copolymers of ethylene and vinyl acetate, destructible copolymers of lactic acid and glycolic acid, such as the LUPRON DEPOT™ (injectable microspheres composed of a copolymer of lactic acid and glycolic acid and acetate leuprolide) and poly-D-(-)-3-hydroxipropionic acid.

[00374] the Pharmaceutical compositions of the compounds of formula I may be in the form of a sterile injectable preparation, such as sterile injectable aqueous or oily suspension. This suspension can be manufactured according to known in the field methods of using such suitable dispersing or wetting agents and suspendida agents listed above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or the product obtained in the form of lyophilized powder. Among the acceptable fillers and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment can appropriately apply sterile fatty oil. For this purpose it is possible when Enate any mixed fatty oil, including synthetic mono - or diglycerides. In addition, when receiving injectable medication may likewise be applied fatty acids such as oleic acid.

[00375] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile solutions for injection, which may contain antioxidants, buffers, bacteriostatic and dissolved substances, which give the drug isotonicity in the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that can include suspendresume agents and thickening agents.

[00376] the Compositions of the invention may also be in a form suitable for oral use (for example, in the form of tablets, pellets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, in the form of fine powder or a liquid aerosol), for administration by insufflating (for example, in the form of a fine powder).

[00377] Suitable pharmaceutically acceptable excipients for the manufacture of tablets include, for example, inert diluents, such as lactose, sodium carbonate n is sodium, calcium phosphate or calcium carbonate, granulating and dezintegriruetsja agents such as corn starch or alginic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl - or propyl-p-hydroxybenzoate, and antioxidants, such as ascorbic acid. Preparations in the form of tablets can be uncoated or coated or to modify their disintegration and the subsequent absorption of the active ingredient in the gastrointestinal tract, or to increase their stability and/or enhance the appearance, and in any case the use of conventional agents for coatings and methods for this are well known in this field.

[00378] Compositions for oral administration can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

[00379] Aqueous suspensions generally contain the active ingredient in the form of a fine powder together with one or more suspendresume agents such as sodium salt Carbo is simmilarly, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum; dispersing or wetting agents such as lecithin or condensation products of oxide alkylene with fatty acids (for example, polyoxyethylenated), or condensation products of ethylene oxide with aliphatic alcohols, such as heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as monooleate of polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, such as monooleate polyethylenimine. Aqueous suspensions can also contain one or more preservatives (such as ethyl - or propyl-p-hydroxybenzoate), antioxidants (e.g. ascorbic acid), coloring agents, corrigentov and/or sweetening agents (such as sucrose, a sugar or aspartame).

[00380] Oil suspensions can be made by suspendirovanie active ingredient in a vegetable oil (such as peanut butter, olive oil, sesame oil or coconut oil) or mineral oil such as liquid paraffin). Oily suspensions may contain a thickening agent, such as the inverter is Linyi wax, hard paraffin or cetyl alcohol. To obtain a palatable oral preparation can be added sweetening agents, such as agents mentioned above, and corrigentov. These drugs can be protected from damage by the addition of an antioxidant such as ascorbic acid.

[00381] Dispersible powders and granules suitable for preparation of aqueous suspension by the addition of water, usually contain the active ingredient together with a dispersing or wetting agent, suspenders agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspendida agents are those agents that have already been specified above. Can also present additional excipients such as sugar derivatives, gives taste and smell and coloring matter.

[00382] the Pharmaceutical compositions of the invention may also be in the form of emulsions of the type oil-in-water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil such as liquid paraffin or a mixture of any of them. Suitable emulsifying agents may be, for example, exist in nature gums, such as Arabian gum or tragacanth gum, existing in nature phosphatides, such as soybean phosphatides, lecithin, esters Il is a partial esters, derived from fatty acids and anhydrides of hexitol (for example, monooleate sorbitan) and condensation products of these partial esters with ethylene oxide, such as monooleate of polyoxyethylenesorbitan. The emulsions may also contain sweetening, gives taste and smell and preservatives.

[00383] Syrups and elixirs can be made with sweetening agents such as glycerin, propylene glycol, sorbitol, aspartame or sucrose, and they may contain a means of reducing the irritation, preservative, corrigent and/or coloring agent.

[00384] the Preparations in the form of suppositories can be obtained by mixing the active ingredient with a suitable, not causing irritation, excipients, which is solid at ordinary temperature but becomes liquid at rectal temperature and therefore will melt in the rectum, releasing this drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Drugs suitable for vaginal insertion, can be presented as pessaries, tampons, creams, gels, pastes, foams or drugs in the form of sprays that contain, besides the active ingredient, such carriers as are known in this area are appropriate.

[00385] the topical Preparations such as creams, ointments, gel and aqueous or oil solutions or suspensions, usually get the combination of the active ingredient with conventional, suitable for local use filler or diluent using conventional techniques, well known in this field.

[00386] the Composition for percutaneous introduction can be in the form of transdermal patches for the skin, which are well known to specialists in this field.

[00387] Preparations suitable for intra-lungs or nasal administration, have a particle size, for example, in the range of 0.1 to 500 microns (including particle sizes in the range between 0.1 and 500 microns with such increments in microns, 0.5, 1, 30 microns, 35 microns, etc), they are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so that the drug has reached the alveolar sacs. Suitable preparations include aqueous or oily solutions of the active ingredient. Preparations suitable for administration as an aerosol or dry powder, can be obtained according to conventional methods and can be delivered with other therapeutic agents such as compounds are still used in the treatment or prevention of disorders as described below.

[00388] the Pharmaceutical composition (or product) for the application can be packaged in various ways, depending on the method used for the introduction of the drug. For example, from what the men for distribution may include a container, with the continuing therein pharmaceutical drug in a suitable form. Suitable containers are well known to specialists in this field and include materials such as vessels (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may include also an impermeable tube to prevent inadvertent access to the contents of the package. In addition, the container has a label, which describes the contents of the container. The label may also include appropriate warnings. Drugs can also be packaged in containers with a single dose or multiple doses, for example sealed ampoules and vials, they can be stored in a freeze dried (liofilizirovannom) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Improvised, we have the solutions and suspensions for injection is obtained from sterile powders, granules and tablets of the previously described type. The preferred uniform dosed drugs are drugs containing a daily dose or uniform daily curioso, as indicated here above, or an appropriate part of the dose of the active ingredient.

[00389] Invented the e further provides veterinary compositions, includes the compound of formula I, together with his veterinary carrier. Veterinary carriers are substances suitable for the purpose of introduction of the composition, they can be solid, liquid or gaseous substances, which in other respects are inert or acceptable in the veterinary field and are compatible with the active ingredient. These veterinary compositions can be entered parenteral, oral or in any other desired way.

[00390] the Amount of the compounds of this invention, which is combined with one or more excipients to obtain a dosage form for single use, will certainly vary depending on the exposed treatment of the subject, the severity of the violation or condition, rate of administration, distribution of compounds in the body and discretion establishes the connection of the attending physician. In one embodiment, the mammal in need of this, introducing a suitable amount of the compounds of formula I. In one embodiment, the compound is administered in amounts of between about 0.001 mg/kg body weight and about 60 mg/kg of body weight per day. In another embodiment, the introduction of a quantity between about 0.5 mg/kg body weight and about 40 mg/kg of body weight per day. In some cases, the level is higher doses and lower limit of the aforesaid range may be more than adequate, whereas in other cases it is possible to use even higher doses do not cause any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. For more information on routes of administration and regimens medication, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which, inter alia, incorporated herein by reference.

[00391] the Invention further provides veterinary compositions comprising a compound of formula I, together with his veterinary carrier. Veterinary carriers are substances suitable for the purpose of introduction of the composition, they can be solid, liquid or gaseous substances, which in other respects are inert or acceptable in the veterinary field and are compatible with the active ingredient. These veterinary compositions can be entered parenteral, oral or in any other desired way.

[00392] the Amount of the compounds of this invention, which is combined with one or more excipients to obtain a dosage form for single use, will certainly vary depending on the exposed treatment of the subject, the severity of the violation or condition, the speed of distribution of compounds in the body and discretion establishes the connection of the attending physician. In one embodiment, the mammal in need of this, introducing a suitable amount of the compounds of formula I. In one embodiment, the compound is administered in amounts of between about 0.001 mg/kg body weight and about 60 mg/kg of body weight per day. In another embodiment, the introduction of a quantity between about 0.5 mg/kg body weight and about 40 mg/kg of body weight per day. In some cases, the dose levels higher and lower limit of the aforesaid range may be more than adequate, while in other cases it is possible to use even higher doses do not cause any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. For more information on routes of administration and regimens medication, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which, inter alia, incorporated herein by reference.

[00393] PRODUCTS MANUFACTURING

[00394] In another embodiment, the proposed articles of manufacture, or "kit", containing substances suitable for the treatment of the above disorders. In one embodiment, the kit includes a container comprising a compound of formula I or its MES,metabolite, or a pharmaceutically acceptable salt, or prodrug. The kit can optionally include a label or leaflet insert in the package that contains the information about medicine and placed on the container or associated in other ways with the container. The term "leaflet-liner" is used to refer to instructions that are usually included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, introduction, contraindications and/or warnings relating to the use of such therapeutic products. In one embodiment, the label or leaflet inserts indicates that the composition comprising the compound of formula I, can be used to treat one or more of these diseases or disorders.

[00395] In one embodiment, the kit additionally includes a container. Suitable containers include, for example, bottles, vials, syringes, blister packs and the like. The container can be made of various materials such as glass or plastic. The container may contain a compound of formula I or a drug that is effective to treat one or more of these diseases or disorders, and may have a sterile hole for the ode (for example, the container may be a bag of intravenous solution or vial having a stopper pierceable hypodermic needle for injection).

[00396] the Kit may optionally include instructions for administration of the compounds of formula I and, if present, the second pharmaceutical product. For example, when the kit comprises a first composition comprising a compound of formula I, and the second pharmaceutical product, the kit may further comprise directions for the simultaneous, sequential or separate introduction of the first and second pharmaceutical compositions to the needy in this patient.

[00397] In another embodiment, the kits are suitable for the delivery of solid oral forms of the compounds of formula I, such as tablets or capsules. Such a set may include a number of standardized doses. Such kits can include a piece of cardboard with a dose oriented in the order of their intended application. An example of such a set is a "blister pack". Blister packs are well known in the packaging industry, and they are widely used for packaging pharmaceutical unified dosage forms. Desirable may be providing funds to aid memory, for example, in the form of numbers, letters, or other symbols or inserted to the langara, specifies the days of the regimen, which must be injected dose.

[00398] According to one variant of implementation, the article of manufacture may comprise (a) a first container containing a compound of the formula I and optionally (b) a second container contains a second pharmaceutical drug, where the second pharmaceutical preparation comprises a second connection with, for example, antihypercholesterolemic activity. Alternative or additionally, the article of manufacture may further include a third container that includes a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution and dextrose. The product may further include other materials desirable from a commercial and consumer standpoint, including other buffers, diluents, filters, needles and syringes.

[00399] In some other embodiments, the implementation in which the set includes a composition of formula I and a second therapeutic agent, the kit may include a container to accommodate the separate compositions such as a divided bubble or a divided foil bag, however, the separate compositions may also contain one undivided container. Usually on the PRS includes instructions for administration of the individual components. The form kit is particularly suitable when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when titration of the individual components of the combination is required prescribing the drug your doctor.

BIOLOGICAL EXAMPLES

Example

Enzymatic analysis of EGFR/ErbB2

[00400] 96-well tablets Thermo LabSystems Immulon 4HBX used for incubation over night at room temperature, cover with 100 μl per well of 0.25 mg/ml poly(Glu, Tyr), 4:1 (PGT) (Sigma Chemical Co., St. Louis, MO) in SFR (phosphate buffered saline). Excessive PGT removed by aspiration and the plate is washed three times with buffer for washing (0.1% tween-20 in SFR). The kinase reaction is carried out in 100 μl of 50 mm HEPES (pH 7,3)containing 125 mm NaCl, 24 mm magnesium chloride, 0.1 mm of orthovanadate sodium, 15 μm ATP (adenosine triphosphate) and 0.3 units/ml of EGFR (the receptor for epidermal growth factor) (BIOMOL Research Laboratories, Inc., Plymouth Meeting, PA). The compound in DMSO (dimethyl sulfoxide) is added to obtain the final concentration of DMSO is approximately 1%. Phosphorylation initiated by adding ATP and incubation carried out for 30 minutes at room temperature. The kinase reaction terminorum aspiration of the reaction mixture and subsequent washing buffer is La rinsing (see above). Phosphorylated PGT 30 detects the incubation 30 with 100 μl per well of HRP-conjugated antibodies against phosphotyrosine Ru (Zymed Laboratories, Inc., South San Francicso, CA)diluted to 0.2 μg/ml in 3% BSA and 0.05% tween-20 in SFR. The antibody is removed by aspiration and the plate is washed with buffer. The colorimetric signal is developed by adding 100 μl per well of substrate for peroxidase (HRP microwell TMB (Kirkegaard and Perry, Gaithersburg, MD) and stopped by adding 100 µl per well of 1 M phosphoric acid. The content of phosphotyrosine measured by optical density at 450 nm.

[00401] the Kinase ErbB2 is measured, as described above, using 250 ng/ml intracellular domain instead of erbB2 EGFR. The intracellular tyrosine kinase domain of ErbB2 (amino acids 691-1255) Express in the form of his-tagged protein in baculovirus and purified by chelation with Nickel, ion exchange chromatography and chromatography-based exceptions.

[00402] the Compounds of the present invention have 1C50from less than 1 nm to 50 mm.

The example In

Analysis of cellular phosphorylation of ErbB2

[00403] Cellular activity of the compounds is measured by the inhibition of phosphorylated erbB2 (p-erbB2) in cell lines WT that sverkhekspressiya erbB2 and, therefore, has a high basal levels of p-erbB2. Cells WT seeded in 96-well tablets and incubated over night in conditions of 37°C/% CO 2. The next day, the medium is replaced by medium without serum followed by the addition of compounds within 2 hours. Cells are lysed by the addition of a buffer for lysis and freezing at -80°C. Thawed and clarified lysates were then added to 96-well plates that are coated with antibody against erbB2. Phosphorylated erbB2 detects antibody of phosphotyrosine using ELISA format. Compounds of the present invention in this analysis have IC50less than 1 micron.

The example

Analysis of cellular phosphorylation of EGFR

[00404] In this analysis, we measure the inhibition of EGF-induced phosphorylated EGFR (pEGFR) in cell line A431, which sverkhekspressiya EGFR. Cells were seeded in 96-well tablets and incubated for 6-8 hours under conditions of 37°C/5% CO2before serum starvation overnight. The next day the connection is added dropwise within 1 hour before the 10-minute induction of EGF. Cells are lysed by the addition of a buffer for lysis and freezing at -80°C. Thawed and clarified lysates were then added to 96-well plates that are coated with antibodies against EGFR, p-EGFR then detects antibody against phosphotyrosine using ELISA format.

PREPARATIVE EXAMPLES

[00405] To illustrate the invention included the following examples. However, it should be clear that this is the examples do not limit the invention and are intended only to provide a way of carrying out the invention in practice. Professionals in this field should be clear that the described chemical reaction can be easily adapted to obtain other compounds of this invention, and it is believed that alternative methods of producing compounds of this invention are within the scope of the present invention. For example, the synthesis is not listed as examples of compounds according to the invention can be successfully carried out with the use of modifications, obvious to the person skilled in the art, for example, the protection of appropriately preventing the synthesis of the groups, the use of other suitable reagents known in this area, but other than described here, reagents, and/or creating a regular modifications of reaction conditions. In the alternative case can be approved by the others described here, the reaction or reactions known in this area as suitable for other compounds of the invention.

[00406] In the examples described below, unless otherwise noted, all temperatures are given in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and was used without further purification unless otherwise stated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE), toluene, dioxane and 1,2-differetn were purchased from Aldrich in securely germetizirovany, and they were used as such.

[00407] the Reaction below, usually held at a positive pressure of nitrogen or argon or with drying tube (unless noted) in anhydrous solvents, and the reaction vessels were usually equipped with rubber membranes for input substances and reagents via syringe. Glassware was dried in a drying Cabinet and/or drying by heating.

[00408] Column chromatography was performed on a Biotage System (Manufacturer: Dyax Corporation)having a column of silica gel, or the cartridge silica SepPak (Waters). Spectra1H NMR were recorded on a Varian instrument operating at 400 MHz. Spectra1H NMR of compounds were removed in the form of solutions in CDCl3CD3OD or d6-DMSO (indicated in ppm) using TMS as the reference standard (0,0 ppm). When you define a plurality of peaks, use the following abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet), user. (broadened), DD (doublet of doublets), dt (doublet of triplets). Constant interaction, when they are specified in Hertz (Hz).

Example 1

Synthesis of N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)-N4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenyl)hinzelin-4,6-diamine

[00409] stage a: obtaining N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine. A mixture of 2-amino-5-nitrobenzonitrile the (30.0 g, 184 mmol) and dimethoxy-N,N-dimethylethanamine (up 29.6 ml, 223 mmol) was heated to 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution is passed through a layer of silicon dioxide, washing the ethyl acetate layer. The filtrate is concentrated under reduced pressure, the residue is stirred with simple ether and filtered, thus obtaining the product (35,0 g, 87%) as a yellow solid.

[00410] stage: obtain N'-(4-amino-2-cyanophenyl)-N,N-dimethylformamidine. A solution of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (30.0 g, 137 mmol), cyclohexene (200 ml) and 10% Pd on coal (3.0 g) in methanol (1 l) was refluxed for 10 hours in an atmosphere of hydrogen. The hot solution is filtered through celite and the filtrate concentrated under reduced pressure. The residue is recrystallized from a mixture of dichloromethane/carbon tetrachloride, while receiving the product (23,4 g, 90%) as light grey crystals.

[00411] stage: obtain 1-(3-cyano-4-((dimethylamino)methylamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea. To a cooled (-10°C.) solution of thiocarbonyldiimidazole (211 g, 1,178 mol) in THF (1.5 l) slowly via cannula add a solution of N'-(4-amino-2-cyanophenyl)-N,N-dimethylformamidine (201,6 g 1,071 mol) in THF (1.5 l). After stirring at -10°C for 25 minutes to the mixture is added slowly a solution of 2-and the Ino-2-methylpropan-1-ol (120 g, 1.4 mol) in THF (500 ml). After heating to room temperature and stirring for 16 hours the mixture was washed with saturated sodium chloride (2×2 l). The combined aqueous layers extracted with MTBE (2 l) and ethyl acetate (4×1 l). The combined organic layers dried over MgCO4and concentrate under reduced pressure. The residue is crystallized from MTBE and ethyl acetate, thus obtaining the product (116,9 g, 34%) as a yellow solid.

[00412] stage D: getting oxime 1-(2,5-dihydroxyphenyl)ethanone. To a solution of 1-(2,5-dihydroxyphenyl)ethanone (10.0 g, 65,73 mmol) in ethanol (200 ml) is added hydroxylamine hydrochloride (13,7 g, 197,2 mmol). After heating to boiling under reflux for 16 hours the solvent is evaporated under reduced pressure. Add ethyl acetate (200 ml) and water and the mixture extracted with ethyl acetate (3 x). The combined organic layers are dried and concentrated, thus obtaining the product (10 g, 91%) as a yellow solid.

[00413] stage E: getting 2-methylbenzo[d]oxazol-5-ol. To a cooled (0°C.) solution of oxime 1-(2,5-dihydroxyphenyl)ethanone (1.0 g, 5,98 mmol) in DMF (30 ml) is added dropwise l3(0,661 ml, to 6.58 mmol). After stirring at 0°C for 1 hour and then at room temperature for 2 hours the mixture is washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic is such layers are dried and concentrated under reduced pressure, while receiving the crude product which is used without further purification.

[00414] stage F: obtaining 2-methyl-5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole. 2 Methylbenzo[d]oxazol-5-ol (0,86 g, 5,77 mmol), 1-fluoro-2-methyl-4-nitrobenzene (0,98 g, 6,34 mmol) and K2CO3(1,59 g, 11,53 mmol) are mixed in DMF and the mixture is heated to 50°C for 16 hours. The reaction mixture is cooled to room temperature and poured into ice water. The mixture is extracted with ethyl acetate (3 x). The combined organic layers washed with saturated salt solution, dried and concentrated under reduced pressure. The remainder chromatographic (20%-40% ethyl acetate in hexano), while receiving the product (0,671 g, 41%) as a yellow solid.

[00415] stage G: obtain 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine. To a solution of 2-methyl-5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole (671 mg, 2.36 mmol) in ethanol (10 ml) is added 10% palladium on coal (50 mg, 0,047 mmol). In the reaction mixture create an atmosphere of hydrogen until a pressure of 40 pounds per square inch and maintained it in these conditions for 2.5 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure. The remainder chromatographic, while receiving the product (0,411 g, 69%) as a yellow oil.

[00416] stage N: obtain 1-(1-hydroxy-2-methylpropan-2-yl)-3-(4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenylamino)x is Natolin-6-yl)thiourea. To a solution of 1-(3-cyano-4-((dimethylamino)methylamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (275 mg, 0,861 mmol) and 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine (241 mg, 0,947 mmol) in isopropylacetate (2 ml) is added acetic acid (0.2 ml, 3,44 mmol). After stirring at room temperature for 16 hours add hexane and the mixture is stirred for 30 minutes. The mixture is filtered, thus obtaining the crude product (281 mg, 62%) as a yellow solid.

[00417] stage I: getting N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)-N4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenyl)hinzelin-4,6-diamine. To a solution of 1-(1-hydroxy-2-methylpropan-2-yl)-3-(4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenylamino)hinzelin-6-yl)thiourea (156 mg, 0,295 mmol) and NaOH (71 mg, 1.77 mmol) in THF (5 ml) add taillored 113 mg, 0,590 mmol). After stirring at room temperature for 3 hours, water is added and the mixture extracted with ethyl acetate (2 x). The combined organic layers are washed with 1 M NaOH and then with a saturated solution of salt. The solution is dried and concentrated under reduced pressure. The yellow residue chromatographic, while highlighting white solid. The solid is triturated with simple ether and again chromatographic, thus obtaining the pure product (92 mg, 63%) as a white solid. Detects MS APCI (+)m/z 495 (M1); 1H NMR (400 MHz, DMSO-d6) δ 9,49 (user. s, 1H), 8,45 (s, 1H), 7,95 (user. s, 1H), 7,81 (user. s, 1H), 7,73 (user. m, 2H), 7,65 (s, 1H), 7.62mm (s, 1H), 7,46 (user. s, 1H), 7,12 (d, 1H), 6,97 (DD, 1H), 6,93 (d, 1H), 4,08 (m, 2H), 2,60 (s, 3H), of 2.21 (s, 3H), 1.28 (in C, 6N).

Example 2

N6-(4,4-Dimethyl-4,5-dihydrooxazolo-2-yl)-N4-(3-methyl-4-(2-methylbenzo[d]oxazol-6-yloxy)phenyl)hinzelin-4,6-diamine

[00418] Receive according to the method for example 1 using 1-(2,4-dihydroxyphenyl)ethanone instead of I-(2,5-dihydroxyphenyl)ethanone. Detects MS APCI (+)m/z 495 (M+1);1H NMR (400 MHz, DMSO-d6) δ 9,49 (s, 1H), 8,45 (s, 1H), 7,95 (user. s, 1H), 7,83 (user. s, 1H), 7,76 (user. s, 1H), 7,65 (user. s, 1H), to 7.61 (d, 1H, J=8 Hz), 7,20 (d, 1H, J=2 Hz), of 6.96 (d, 1H, J=8 Hz), 6,93 (DD, 1H, J=8 Hz, 2 Hz), 4.09 to (user. s, 2H), 2,58 (s, 3H), of 2.21 (s, 3H), 1.28 (in C, 6N).

Example 3

N6-(4,4-Dimethyloxazolidine-2-ilidene)-N4-(3-methyl-4-(2-methylbenzo[d]thiazole-5-yloxy)phenyl)hinzelin-4,6-diamine

[00419] Receive according to the method for example 1 using 2-methylbenzo[d]thiazole-5-ol instead of 2-methylbenzo[d]oxazol-5-ol. Detects MS APCI (+)m/z 511 (M+1);1H NMR (400 MHz, DMSO-d6) δ at 9.53 (s, 1H), of 8.47 (s, 1H), 8,02 (s, 1H), 8,00 (d, 1H, J=8 Hz), 7,83 (s, 1H), of 7.75 (d, 1H, J=7 Hz), 7,66 (d, 1H, J=8 Hz), 7,29 (d, 1H, J=2 Hz), was 7.08 (DD, 1H, J=8 Hz, 2 Hz), 7,03 (d, 1H, J=8 Hz), 4,08 (s, 2H), 2,77 (s, 3H), of 2.20 (s, 3H), 1.28 (in C, 6N).

Example 4

N6-(4,4-Dimethyloxazolidine-2-ilidene)-N4-(3-methyl-4-(2-methyl is Enzo[d]thiazol-6-yloxy)phenyl)hinzelin-4,6-diamine

[00420] stage A: getting 2-methylbenzo[d]thiazol-6-ol. To a cooled (-78°C) solution of 6-methoxy-2-methylbenzo[d]thiazole (0,861 g, 4,80 mmol) in dichloromethane (10 ml) was added BBr3(5 ml, 1.0 M solution in dichloromethane). After slow warming to room temperature and stirring for 16 hours the mixture is cooled to 0°C. and slowly quenched with methanol (20 ml). The reaction mixture is heated to room temperature and concentrate under reduced pressure. The residue is partitioned between saturated NaHCO3and with a mixture of dichloromethane/isopropyl alcohol (85/15). The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure, thus obtaining the crude product (0,351 g, 44%), which is used without further purification.

[00421] stage b: Specified in the header connection receive according to the method for example 1 using 2-methylbenzo[d]thiazol-6-ol instead of 2-methylbenzo[d]oxazol-5-ol. Detects MS APCI(+)m/z 511 (M+1);1H NMR (400 MHz, DMSO-d6) δ of 9.51 (s, 1H), 8,46 (s, 1H), 8,03 (user. s, 1H), 7,87 (d, 1H, J=9 Hz), 7,83 (s, 1H), of 7.75 (d, 1H, J=8 Hz), the 7.65 (d, 1H, J=8 Hz), 7,50 (d, 1H, J=2 Hz), 7,10 (DD, 1H, J=8 Hz, 2 Hz), 7,00 (d, 1H, J=8 Hz), 4,07 (s, 2H), was 2.76 (s, 3H), of 2.20 (s, 3H), 1.28 (in C, 6N).

Example 5

N6-(4,4-Dimethyloxazolidine-2-ilidene)-N4-(3-methyl-4-(quinoline-6-yloxy)phenyl)hinzelin-4,6-diamine

[00422] Receive according to the methodology for approx the RA 1 with the use of quinoline-6-ol instead of 2-methylbenzo[d]oxazol-5-ol. Detects MS APCI(+)m/z 491 (M+1);1H NMR (400 MHz, DMSO-d6) δ 9,54 (s, 1H), 8,78 (DD, 1H, J=5 Hz, 2 Hz), 8,48 (s, 1H), of 8.25 (d, 1H, J=9 Hz), with 8.05 (d, 1H, J=9 Hz), 7,89 (s, 1H), 7,82 (d, 1H, J=8 Hz), 7,66 (d, 1H, J=9 Hz), 7,56 (DD, 2H, J=9 Hz, 3 Hz), 7,46 (DD, 2H, J=9 Hz, 5 Hz), 7,16 (d, 2H, J=2 Hz), 7,10 (d, 1H, J=9 Hz), 4,08 (s, 2H), of 2.21 (s, 3H), 1,29 (C, 6N).

Example 6

N6-(4,4-Dimethyl-4,5-dihydrooxazolo-2-yl)-N4-(4-(isoquinoline-7-yloxy)-3-were)hinzelin-4,6-diamine

[00423] Receive according to the method for example 1 using isoquinoline-7-ol instead of 2-methylbenzo [(C)]oxazol-5-ol. Detects MS APCI(+)m/z 491 (M+1);1H NMR (400 MHz, DMSO-d6) δ 9,58 (s, 1H), 9,18 (s, 1H), 8,49 (s, 1H), to 8.41 (d, 1H), 8,04 (user. s, 1H), 8,03 (d, 1H), of 7.90 (s, 1H), a 7.85 (d, 1H), 7,81 (d, 2H), to 7.67 (d, 1H), 7,60 (DD, 2H), 7,28 (d, 1H), 7,12 (d, 1H), 4,08 (s, 2H), measuring 2.20 (s, 3H), 1,29 (C, 6N).

Example 7

N6-(4,4-Dimethyl-4,5-dihydrooxazolo-2-yl)-N4-(3-methyl-4-(quinoline-7-yloxy)phenyl)hinzelin-4,6-diamine

[00424] Receive according to the method for example 1 using quinoline-7-ol instead of 2-methylbenzo[d]oxazol-5-ol. Detects MS APCI(+)m/z 491 (M+1);1H NMR (400 MHz, DMSO-d6) δ 9,59 (s, 1H), 8,81 (DD, 1H, J=2 Hz, 5 Hz), 8,49 (s, 1H), 8.34 per (d, 1H, J=8 Hz), 8,04 (user. s, 1H), 8,02 (d, 1H, J=9 Hz), 7,89 (user. s, 1H), to 7.84 (d, 1H, J=9 Hz), 7,66 (d, 1H, J=9 Hz), the 7.43 (m, 3H), 7,16 (d, 1H, J=9 Hz), to 7.09 (d, 1H, J=2 Hz), 4,08 (s, 2H), 2,19 (s, 3H), 1,76 (C, 6N).

Example 8

N4-(4-(Benzo[d]thiazol-6-yloxy)-3-were)N6-(4,4-dimethyl-5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00425] stage A: Getting benzo[d]]thiazol-6-ol. The hydrobromide 6 methoxybenzo[d]thiazole (1,00 g 4,06 mmol) is dissolved in aqueous hydrogen bromide (10 ml of a 48% solution). After heating to boiling under reflux for 10 hours the mixture is cooled in an ice bath and diluted with water (50 ml). After setting the pH to 8 by slow addition of solid NaHCO3the mixture is filtered, the solid washed with water and dried in air, while receiving the product (0.35 g, 57%) as a white solid.

[00426] stage b: Specified in the header connection receive according to the method for example 1 using benzo[d]thiazol-6-ol instead of 2-methylbenzo[d]oxazol-5-ol. Detects MS APCI (+)m/z 497 (M+1);1H NMR (400 MHz, DMSO-d6) δ of 9.55 (s, 1H), 9,26 (s, 1H), of 8.47 (s, 1H), of 8.06 (d, 1H, J=9 Hz), 8,01 (user. s, 1H), a 7.85 (s, 1H), to 7.77 (d, 1H, J=8 Hz), 7,66 (d, 1H, J=8 Hz), to 7.61 (d, 1H, J=2 Hz), 7,20 (DD, 1H, J=9 Hz, 2 Hz), 7,03 (d, 1H, J=9 Hz), 4,07 (s, 2H), of 2.21 (s, 3H), 1.28 (in C, 6N).

Example 9

N4-(4-([1,2,4]Triazolo[4,3-a]pyridine-7-yloxy)-3-were)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00427] stage A: Obtain 4-(benzyloxy)-2-chloropyridine. To a cooled (0°C.) suspension of washed (hexane) of sodium hydride (14,07 g, 352 mmol) in THF (650 ml) is added dropwise a solution of benzyl alcohol (35.2 ml, 337 mmol) in THF (200 ml). After stirring for 15 minutes, dropwise add recipients who have a solution of 2-chloro-4-nitropyridine (50 g, 306 mmol) in THF (200 ml). After heating to boiling under reflux for 16 hours black suspension was diluted with water (200 ml) and concentrated to remove THF. The resulting mixture is diluted with more water and filtered. The filtrate is extracted with simple ether and ethyl acetate. The combined organic layers dried and concentrated. The remainder chromatographic (10% ethyl acetate in hexano), while receiving the product as an orange solid.

[00428] stage: obtain 1-(4-benzyloxy)pyridin-2-yl)hydrazine. To a solution of 4-(benzyloxy)-2-chloropyridine (4,89 g, 22,30 mmol) in pyridine (120 ml) is added hydrazine (45 ml, 22,30 mmol). After heating to boiling under reflux for 18 hours the mixture is concentrated, thus obtaining the crude product which is used without further purification.

[00429] stage: obtain 7-(benzyloxy-[1,2,4]triazolo[4,3-a]pyridine. To a solution of 1-(4-(benzyloxy)pyridin-2-yl)hydrazine (3,52 g, 16,35 mmol) in trimethoxymethane (20 ml, 16,35 mmol) is added 4-methylbenzenesulfonic acid (2,816 g, 16,35 mmol). After heating to 60°C for 2 hours, the reaction mixture was concentrated under reduced pressure. The remainder chromatographic (ethyl acetate and the mixture is 20:1 dichloromethane/methanol), thus obtaining the product (2,33 g, 63%).

[00430] stage D: receive [1,2,4]triazolo[4,3-a]pyridine-7-ol. To a solution of 7-(benzo is Loxy)-[1,2,4]triazolo[4,3-a]pyridine (0,512 g, of 2.27 mmol) in ethanol (30 ml) is added Pd/C (0.5 g). After stirring in nitrogen atmosphere of hydrogen from a cylinder within 3 hours the mixture is filtered through celite and washed with ethanol (30 ml). The filtrate is concentrated under reduced pressure and chromatographic (a mixture of dichloromethane/methanol, 20:1), thus obtaining the product.

[00431] stage that is Specified in the header connection receive according to the method for example 1 using [1,2,4]triazolo[4,3-a]pyridine-7-ol instead of 2-methylbenzo[d]oxazol-5-ol. Detects MC APCI(+)m/z 481 (M+1);1H NMR (400 MHz, CDCl3) δ 8,79 (s, 1H), 8,58 (s, 1H), 8,19 (m, 2H), a 7.85 (s, 1H), 7,74 (m, 3H), 7,53 (d, 1H), 7,12 (d, 1H), 6.89 in (DD, 1H), 6,79 (s, 1H), 4,14 (s, 2H), and 2.26 (s, 3H), of 1.46 (s, 6N).

Example 10

Synthesis of N4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00432] stage A: obtain 4-(benzyloxy)pyridine-2-amine. To a mixture of 4-(benzyloxy)-2-chloropyridine (1.10 g, 5,01 mmol), Pd2dba3(46 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (57 mg, 0,120 mmol) in THF (10 ml) was added LHMDS (6 ml of 1.0 M solution). After heating to 65°C for 30 minutes the mixture is cooled to room temperature and purified on silica gel. Product elute with a mixture of ethyl acetate/methanol, 20:1, while highlighting light Golden solid (0.97 g, 96%).

[00433] stage: Obtain tert-butyl 4-(is ensilage)pyridine-2-ylcarbamate. To a solution of 4-(benzyloxy)pyridine-2-amine (4.6 g, 22,97 mmol) in tert-BuOH (50 ml) was added boc-anhydride (5,57 g, 25.5 mmol). After heating to 50°C for 1 hour to the reaction mixture are added ethanol (200 ml). At room temperature the mixture is filtered, thus obtaining a solid product (of 5.89 g, 85%).

[00434] stage: obtain tert-butyl-4-hydroxypyridine-2-ylcarbamate. To a solution of tert-butyl 4-(benzyloxy)pyridine-2-ylcarbamate (of 5.89 g, a 19.6 mmol) in methanol added palladium on coal (1.04 g, 0,981 mmol). After stirring in an atmosphere of hydrogen from a cylinder at room temperature for 70 minutes, the solids removed by filtration. The filtrate is concentrated under reduced pressure and utverjdayut under high vacuum, thus obtaining the product (4.12 g, 99%) as a white solid.

[00435] stage D: obtain tert-butyl 4-(2-methyl-4-nitrophenoxy)pyridine-2-ylcarbamate. To a solution of tert-butyl-4-hydroxypyridine-2-ylcarbamate (4.12 g, a 19.6 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (3,34 g, 21.6 mmol) in DMF (40 ml) add K2CO3(4,06 g, 29,04 mmol). After heating to 65°C for 64 hours the mixture is cooled to room temperature and poured into ice water (200 ml). The reaction mixture is extracted several times with ethyl acetate. The combined organic layers are concentrated under reduced pressure. The remainder chromatographic (20% ethyl acetate in hexane is), while receiving the product (2,03 g, 30%).

[00436] stage E: obtain 4-(2-methyl-4-nitrophenoxy)pyridine-2-amine. To a solution of tert-butyl 4-(2-methyl-4-nitrophenoxy)pyridine-2-ylcarbamate (1.0 g, 2,90 mmol) in dichloromethane (28 ml) is added TFA (4 ml). Under stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure, thus obtaining the crude product which is used without further purification.

[00437] stage F: obtain 7-(2-methyl-4-nitrophenoxy)-N-imidazo[1,2-a]pyridine. To a solution of 4-(2-methyl-4-nitrophenoxy)pyridine-2-amine (0.71 g, 2,90 mmol) in dichloromethane (25 ml) is added a saturated NaHCO3(25 ml) followed by the addition of chloroacetaldehyde (1,14 g of 7.24 mmol). After stirring at room temperature for 16 hours the mixture is diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers dried and concentrated under reduced pressure. The remainder chromatographic, while receiving the product (0,61 g, 78%) as a sticky yellow solid.

[00438] stage G: obtain 4-(N-imidazo[1,2-peridin-7-yloxy)-3-methylbenzenamine. To a solution of 7-(2-methyl-4-nitrophenoxy)-N-imidazo[1,2-a]pyridine (0,59 g, 2,19 mmol) in ethanol added palladium on coal (0,116 g, 0.11 mmol). After stirring at room temperature in hydrogen atmosphere from the cylinder during the 16 hours, the solids removed by filtration. The filtrate is concentrated under reduced pressure and utverjdayut in high vacuum, thus obtaining the product (0.51 g, 97%) as a white foam.

[00439] stage N: obtain N4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine. To a mixture of 4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylbenzenamine (0.124 g, 0,518 mmol) and 1-(3-cyano-4-((dimethylamino)methylamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (0,151 g, 0,471 mmol) in isopropylacetate (2 ml) is added acetic acid (1 ml). After stirring at room temperature for 16 hours to the mixture add hexane and the yellow solid collected by filtration. To a solution of this product in THF (1 ml) add taillored (0,180 g, 0,942 mmol) and NaOH (2.8 ml of 1 M solution). After stirring at room temperature for 30 minutes to the mixture, water is added and the mixture extracted twice with ethyl acetate. The combined organic layers washed with NaOH (1 M) and a saturated solution of salt. The solution is dried, filtered and concentrated under reduced pressure. The yellow residue is triturated with a mixture of ethyl acetate/MTBE, while receiving the product (0.10 g, 44%) as a white solid. Detects MS APCI(+)m/z 480 (M+1);1H NMR (400 MHz, DMSO-d6) δ of 9.55 (s, 1H), 8,54 (d, 1H, J=7 Hz), 8,48 (s, 1H), 8,00 (user. s, 1H), to 7.84 (m, 3H), 7,66 (d, 1H, J=8 Hz), 7,50 (user. s, 1H), 7,43 (s, 1H), 7,12 (d, 1H, J=8 Hz), to 6.80 (DD, 1 is, J=7 Hz, 2 Hz), 6,53 (d, 1H, J=2 Hz), 4,08 (user. s, 2H), 2,19 (s, 3H), 1.28 (in C, 6N).

Example 11

N4-(4-([1,2,4]Triazolo[1,5-a]pyridine-7-yloxy)-3-were)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00440] stage A: obtain (Z)-N,N-dimethyl-N'-(4-(2-methyl-4-nitrophenoxy)pyridine-2-yl)formamidine. To a solution of 4-(2-methyl-4-nitrophenoxy)pyridine-2-amine (2,05 g, a 8.34 mmol) in ethanol (9 ml) is added dimethoxy-N,N-dimethylethanamine (1,18 ml, to 8.34 mmol). After heating to 80°C for 1 hour the mixture was concentrated under reduced pressure, thus obtaining the crude product as a dark oil.

[00441] stage: obtain 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine. To a cooled (0°C.) solution of (Z)-N,N-dimethyl-N'-(4-(2-methyl-4-nitrophenoxy)pyridine-2-yl)formamidine (1,00 g of 3.33 mmol) in methanol (5 ml) is added pyridine (0.54 ml, of 6.66 mmol) and hydroxylaminsulphate acid (0,427 g, 3,66 mmol). After stirring at room temperature for 2 hours, the residue is separated by filtration, thus obtaining the product (0,442 g, 49%) as a white solid.

[00442] stage C: the specified header connection receive according to the method for example 1 using [7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine instead of 2-methyl-5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole. Detects MS APCI(+)m/z 481 (M+1);1H NMR (400 MHz, CDCl3) δ 9,58(s, 1H), 8,93 (d, 1H), 8,49 (s, 1H), scored 8.38 (s, 1H), 7,92 (user. m, 2H), to 7.67 (user. s, 1H), 7,47 (user. s, 1H), 7,19 (d, 1H), 7,03 (DD, 1H), 6,79 (d, 1H), 4,08 (s, 2H), 2,19 (s, 3H), 1.28 (in C, 6N).

Example 12

N6-(4,4-Dimethyl-4,5-dihydrooxazolo-2-yl)-N4-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)hinzelin-4,6-diamine

[00443] stage A: obtain 4-(2-methyl-4-nitrophenoxy)-2-nitrobenzamide. To a solution of 1-fluoro-2-methyl-4-nitrobenzene (2,02 g, 13,0 mmol) and 4-amino-3-NITROPHENOL (2,22 g, 14.4 mmol) in DMF (20 ml) is added cesium carbonate (5,28 g, 16.2 mmol). After heating to 60°C for 10 hours the mixture is diluted with water (100 ml) and filtered. The precipitate is washed with water and air-dried, thus obtaining the product (3.28 g, 87%) as a dark solid.

[00444] stage: obtaining N-methyl-4-(2-methyl-4-nitrophenoxy)-2-nitrobenzamide. To a solution of sodium hydroxide (10.2 g 10.5 ml of water) is added toluene (15 ml), 4-(2-methyl-4-nitrophenoxy)-2-nitrobenzene (2.00 g, 6,92 mmol), dimethylsulfate (750 μl, 7,88 mmol) and tetrabutylammonium sulfate (0,277 g, 0,816 mmol). After stirring at room temperature, cooled (0°C.), the reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (100 ml). The organic layer is washed with water and saturated salt solution, dried over Na2SO4filter and concentrate under reduced pressure. The remainder chromatographic (dichloromethane)to give p and this product (1.90 g, 91%).

[00445] stage: obtain 4-(4-amino-2-methylphenoxy)-N1-methylbenzol-1,2-diamine. To a solution of N-methyl-4-(2-methyl-4-nitrophenoxy)-2-nitrobenzamide (1.90 g, 6,27 mmol) in ethyl acetate (10 ml) and ethanol (20 ml) is added 10% Pd/C (0,342 g, 0,321 mmol). After shaking under hydrogen pressure of 50 psi for 1 hour the mixture is filtered and the filtrate concentrated under reduced pressure, thus obtaining the product as a clear oil.

[00446] stage D: obtaining N-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)formamide. 4-(4-Amino-2-methylphenoxy)-N1-methylbenzol-1,2-diamine (1.52 g, and 6.25 mmol) was dissolved in formic acid (15 ml) and heated to boiling under reflux for 6 hours. After cooling to room temperature the mixture was diluted with water (100 ml) and neutralized with sodium bicarbonate. The mixture is partitioned between water and dichloromethane. The organic layer was washed with aqueous NaHCO3saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure, thus obtaining the product (1.70 g, 97%).

[00447] stage E: obtaining 3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzenamine. To a solution of concentrated aqueous HCl (10 ml) in methanol (10 ml) is added N-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)formamide (1.70 g, 6,04 mmol). After heating to boiling under reflux during 2 hours, the reaction mixture was cooled to room temperature and diluted with water (100 ml). The mixture is neutralized with sodium bicarbonate and extracted with dichloromethane. The organic solution is dried over Na2SO4, filtered and concentrated under reduced pressure, thus obtaining the product.

[00448] stage F: specified in the header connection receive according to the method for example 1 using 3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoylamino instead of 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine. Detects MS APCI(+)m/z 494 (M+1);1H NMR (400 MHz, DMSO-d6) δ 9,49 (s, 1H), 8,44 (s, 1H), 8,17 (s, 1H), 8,00 (user. s, 1H), 7,78 (s, 1H), 7,66 (m, 2H), 7,56 (s, 1H), was 7.08 (d, 1H), 6,98 (DD, 1H), 6,86 (d, 1H), 4,07 (s, 2H), of 3.84 (s, 3H), of 2.23 (s, 3H), 1.28 (in C, 6N).

Example 13

N6-(4,4-Dimethyl-4,5-dihydrooxazolo-2-yl)-N4-(3-methyl-4-(2-methyl-N-imidazo[1,2-a]pyridine-7-yloxy)phenyl)hinzelin-4,6-diamine

[00449] Receive according to the method of example 10 using chloroacetone instead of chloroacetaldehyde. Detects MS APCI(+)m/z 494 (M+H);1H NMR (400 MHz, DMSO-d6) δ of 8.47 (s, 1H), 8,43 (d, 1H), 7,87 (m, 3H), 7,66 (user. s, 1H), 7,56 (s, 2H), 7,10 (d, 1H), of 6.71 (DD, 1H), 6,45 (s, 1H), 4.09 to (s, 2H), of 2.25 (s, 3H), of 2.18 (s, 3H), 1,11 (C, 6N).

Example 14

N4-(4-(N-Imidazo[1,2-a]pyridine-6-yloxy)-3-were)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00450] stage A: getting 2-chloro-5-(2-methyl-4-nitrophenoxy)pyridine. To a suspension of 6-chloropyridin-3-ol (3,37 g, 26.0 mmol and K 2CO3(7,19 g, with 52.0 mmol) in DMF (200 ml) was added 1-fluoro-2-methyl-4-nitrobenzene (4.44 g, 28.6 mmol). After heating to 50°C for 16 hours, the reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate (2 X). The organic layer was washed with saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure, thus obtaining the product as a yellow oil.

[00451] stage: obtain 5-(2-methyl-4-nitrophenoxy)pyridine-2-amine. To a solution of 2-chloro-5-(2-methyl-4-nitrophenoxy)pyridine (1.13 g, 4,27 mmol), XPHOS (0,097 g, 0,205 mmol) and Pd2dba3(0,078 g, 0,0853 mmol) in THF (32 ml) was added LHMDS (8.53 ml, 8,53 mmol). After heating to 65°C for 1 hour the mixture is cooled to room temperature and stirred for 16 hours. The mixture is introduced into silicon dioxide and chromatographic (10% methanol in ethyl acetate), thus obtaining the product (0,336 g, 33%).

[00452] stage C: the specified header connection receive according to the method of example 10 using 5-(2-methyl-4-nitrophenoxy)pyridine-2-amine instead of 4-(2-methyl-4-nitrophenoxy)pyridine-2-amine. Detects MS APCI(+)m/z 480 (M+1);1H NMR (400 MHz, DMSO-d6) δ of 9.51 (s, 1H), 8,45 (s, 1H), 8,21 (s, 1H), to $ 7.91 (s, 1H), 7,83 (user. s, 1H), 7,73 (user. s, 1H), 7,66 (m, 2H), 7,60 (d, 1H), 7,55 (s, 1H), 7,15 (DD, 1H), 7,00 (d, 1H), 4,07 (s, 2H), and 2.27 (s, 3H), 1.28 (in C, 6N).

Example 15

N-(4-(N-Imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine

[00453] stage A: getting hinzelin-4,6-diol. A mixture of 2-amino-5-hydroxybenzoic acid (19,64 g, 128 mmol), 1,3,5-triazine (15.6 g, 192 mmol) and piperidine (9 ml, with 92.4 mmol) heated to 60°C. in methanol (60 ml) for 2 hours. After cooling to 0°C. the mixture is filtered. The solid is washed with cold methanol and dried in a high vacuum, thus obtaining the product (15 g, 72%) as a white solid.

[00454] stage: obtain 4-hydroxyquinazoline-6-racette. The mixture hinzelin-4,6-diol (20 g, 123 mmol) and acetic anhydride (186 ml, 1.97 mol) is heated to 100°C in pyridine (30 ml) for 2 hours. After cooling to room temperature, to the reaction mixture slowly add ice (200 g). The precipitate was separated by filtration, washed with cold water and dried in a high vacuum, thus obtaining the product (16,25 g, 65%) as a pale yellow solid.

[00455] the stage With: obtaining 4-chlorination-6-racette. To a solution of 4-hydroxyquinazoline-6-ilaclama (12.0 g, 58.8 mmol) in thionyl chloride (50 ml) is added DMF (0.5 ml). After heating to 90°C for 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluene, thus obtaining the product (11.8 g, 90%) as not quite white solid.

[00456] stage D: the doctrine of the hydrochloride of 4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-racette. A mixture of 4-chlorination-6-ilaclama (930 mg, 4,18 mmol) and 4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylbenzenamine (1.10 g, 4,60 mmol)dissolved in isopropanol (20 ml), heated to boiling under reflux for 2 hours. After cooling to room temperature the precipitate is collected by filtration and washed with isopropanol and simple ether. The precipitate is dried in air, while receiving the product (820 mg, 43%).

[00457] stage E: obtain 4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-ol. To a solution of the hydrochloride of 4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-ilaclama (820 mg, 1.78 mmol) in THF (30 ml) is added ammonium hydroxide (10 ml). After stirring at room temperature for several hours the precipitate is collected by filtration and washed with THF. The precipitate is dried in air, while receiving the product (581 mg, 85%) as a white solid.

[00458] stage F: obtaining N-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine. A mixture of 4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-ol (578 mg, of 1.27 mmol), cesium carbonate (1.60 g, 4,91 mmol), sodium iodide (190 mg, of 1.27 mmol) and 1-bromo-2-methoxyethane (150 μl, was 1.58 mmol) in DMF (10 ml) is heated to 80°C for 3 hours. After cooling to room temperature the mixture was partitioned between dichloro what ETANA and water. The organic layer was washed with water (4 X) and saturated salt solution, dried over Na2SO4filter and concentrate under reduced pressure. The remainder chromatographic (100:7:0,1, dichloromethane/methanol/triethylamine), while receiving the product (365 mg, 65%) as a foam. To 325 mg of this product dissolved in methanol (10 ml), add monohydrate tselovoe acid (280 mg). After stirring at room temperature for 45 minutes the mixture is concentrated under reduced pressure. The residue is triturated with simple ether, filtered and air-dried, thus obtaining the product (576 mg) in the form bistability salt. Detects MS APCI(+)m/z 442 (M+1);1H NMR (400 MHz, CD3OD) δ 7,46 (d, 1H, J=8 Hz), the 7.43 (s, 1H), 6,79 (DD, 2H, J=11 Hz, 2 Hz), is 6.54 (m, 2H), of 6.52 (s, 1H), of 6.49 (DD, 1H, J=9 Hz, 2 Hz), 6,45 (DD, 1H, J=9 Hz, 3 Hz), 6,38 (d, 4H, J=9 Hz), of 6.02 (DD, 1H, J=7 Hz, 2 Hz), of 5.99 (d, 1H, J=9 Hz), of 5.89 (d, 4H, J=9 Hz), 5,71 (d, 1H, J=3 Hz), of 3.07 (m, 2H), of 2.51 (m, 2H), of 2.15 (s, 3H), 1.04 million (C, 6N), of 0.95 (s, 3H).

Example 16

N-(4-(N-Imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-(cyclopropylmethoxy)hinzelin-4-amine

[00459] Receive according to the method of example 15 using (methyl bromide)cyclopropane instead of 1-bromo-2-methoxyethane. Detects MS APCI(+)m/z 438 (M+1);1H NMR (400 MHz, CDCl3) δ 8,97 (s, 1H), 8,67 (s, 1H), 8,07 (d, 1H, J=8 Hz), 7,82 (d, 1H, J=9 Hz), the 7.65 (d, 1H, J=2 Hz), to 7.50 (m, 3H), 7,44 (DD, 2H, J=9 Hz, 2 Hz), 6,93 (d, 1H, J=9 Hz), 6,74 (DD, 1H, J=7 Hz, 2 Hz), 654 (d, 1H, J=2 Hz), and 3.72 (d, 2H, J=7 Hz), 2,11 (s, 3H), 1,24 (m, 1H), 0,59 (m, 2H), 0,21 (m, 2H).

Example 17

(E)-N-(4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-yl)-4-(dimethylamino)but-2-ename

[00460] stage A: obtaining 6-nitroquinazoline-4-ol. A mixture of 2-amino-5-nitrobenzoic acid (1000 g, 5 mol) and acetate of formamidine (1000 g, 10 mol) is dissolved in methoxyethanol (4 l) and heated to 115°C for 16 hours. After cooling the mixture to room temperature, add ice water (5 l) and the mixture is stirred for 30 minutes before collecting the product (125 g, 14%) by filtration.

[00461] stage: obtain 4-chloro-6-nitroquinazoline. To a solution of 6-nitroquinazoline-4-ol (4,40 g, 23,01 mmol) and N-ethyl-N-isopropyl-propan-2-amine (11,89 g, 92,04 mmol) in dichloroethane (50 ml) add trichloride phosphorus (7,06 g, 46,02 mmol). After heating to 80°C for 16 hours the mixture is concentrated under reduced pressure. The residue is again concentrated using toluene (2×100 ml), while receiving the product.

[00462] stage With: obtaining N-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-nitroquinazoline-4-amine. To a solution of 4-chloro-6-nitroquinazoline (4,62 g, for 22.02 mmol) in a mixture of dichloromethane/tert-butanol (20 ml, 1:1) add 4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylbenzenamine (5,270 g, for 22.02 mmol). After heating to 80°C for 2 hours the mixture is cooled to 0°C and filtered. TBE is the substance was washed with cold dichloromethane (50 ml), while receiving the product as HCl salt. The solid is suspended in a mixture of dichloromethane/isopropanol (50 ml/8 ml) and washed with saturated NaHCO3(50 ml). The aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic layers dried over Na2SO4and concentrated, thus obtaining the product (7,05 g, 78%).

[00463] stage D: obtain N4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)hinzelin-4,6-diamine. To N-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-nitroquinazoline-4-amine (4,665 g to 11.31 mmol) in ethanol (100 ml) is added Pd/C (1 g). After stirring at room temperature in an atmosphere of hydrogen from a cylinder within 4 hours the mixture is filtered through celite and the solid washed with ethanol (100 ml). The filtrate is concentrated under reduced pressure, thus obtaining the product (to 3.89 g, 90%).

[00464] stage E: obtaining hydrochloride (E)-4-(dimethylamino)but-2-tailhold. The hydrochloride of (E)-4-(dimethylamino)but-2-ene acid (110 mg, 0,664 mmol) in acetonitrile (1.5 ml) add oxalidales (75,9 mg, 0,598 mmol) followed by addition of one drop of DMF. After heating to 60°C for 30 minutes the mixture is cooled to room temperature and concentrated to a total volume of 0.5 ml of the Resulting solution is used without further purification.

[00465] stage F: obtaining (E)-N-(4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)is insulin-6-yl)-4-(dimethylamino)but-2-enamide. To a cooled (0°C.) solution of hydrochloride (E)-4-(dimethylamino)but-2-tailhold (0,122 g, 0,664 mmol) is added dropwise a solution of N4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)hinzelin-4,6-diamine (to 0.127 g of 0.332 mmol) in NMP (1.5 ml). After stirring at 0°C for 2 hours to the mixture is added a saturated solution of NaHCO3(15 ml). The aqueous layer was extracted with ethyl acetate (2×10 ml). The combined organic layers dried over Na2SO4and concentrate under reduced pressure. The remainder chromatographic (dichloromethane/methanol/30% NH4OH, 20:1,5:0,01), while receiving the product (16 mg, 10%). Detects MS APCI (+)m/z 494 (M+1);1H NMR (400 MHz, CDCl3) δ 8,96 (s, 1H), 8,63 (s, 1H), of 8.09 (d, 1H, J=7 Hz), 7,66 (d, 1H, J=9 Hz), 7,55 (d, 2H, J=14 Hz), 7,46 (d, 1H, J=9 Hz), 7,40 (s, 1H), 7,38 (d, 1H, J=9 Hz), 7,02 (m, 1H), 6,83 (d, 1H, J=9 Hz), 6,77 (DD, 1H, J=8 Hz, 2 Hz), to 6.43 (s, 1H), 6,34 (d, 1H, J=14 Hz), is 3.08 (d, 2H, J=5 Hz), 2,24 (s, 6N), to 1.98 (s, 3H).

Example 18

N-(4-(N-Imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-bratiano[2,3-d]pyrimidine-4-amine

[00466] stage A: obtaining 6-bratiano[2,3-d]pyrimidine-4-ol. To a solution of thieno[2,3-d]pyrimidine-4-ol (3.0 g, 20 mmol) in glacial acetic acid (40 ml) is added bromine (6.3 g, 39 mmol). After heating to 80°C for 1.5 hours, the reaction mixture was cooled to room temperature and poured into saturated NaHCO3and the ice. The solid is separated by filtration, washed in the water and dried, while receiving the product.

[00467] stage: obtain 6-bromo-4-chlorothieno[2,3-d]pyrimidine. To 6-bratiano[2,3-d]pyrimidine-4-Olu (3.0 g, of 19.7 mmol) is added phosphorus oxychloride (5 ml). After heating to 80°C for 1.5 hours, the reaction mixture was poured into saturated NaHCO3and the ice. The solid is separated by filtration, washed with water and dried, thus obtaining the product (4,06 g, 83%) as a brown solid.

[00468] stage With: obtaining N-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-bratiano[2,3-d]pyrimidine-4-amine. To a solution of 6-bromo-4-chlorothieno[2,3-d]pyrimidine (0,569 g, 2.58 mmol) and 4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylbenzenamine (0,60 g, 2.51 mmol) in a mixture of dihloretan/isopropanol (11 ml) is added DIEA (of 0.44 ml, 2.51 mmol). After heating to 60°C for 64 hours, the reaction mixture is treated with a mixture of isopropanol/dichloromethane. The organic solution is dried and concentrated under reduced pressure. The remainder chromatographic (gradient from 0% to 8% methanol/7 N. NH3/ethyl acetate). The crude product is purified optional liquid chromatography with reversed phase. Detects MS APCI (+)m/z 452, 454 (M+1, profile Br);1H NMR (400 MHz, DMSO-d6) δ RS 9.69 (s, 1H), 8,63 (d, 1H, J=7 Hz), charged 8.52 (s, 1H), 8,10 (s, 1H), 7,94 (s, 1H), 7,82 (d, 1H, J=3 Hz), 7,78 (DD, 1H, J=3 Hz, 9 Hz), to 7.59 (s, 1H), 7,16 (d, 1H, J=9 Hz), of 6.96 (DD, 1H, J=2 Hz, 7 Hz), 6,63 (s, 1H), 2,19 (s, 3H).

Example 19

(Z)-N4-(4-(Imidazo[1,2-a]pyridine-7-yloxy)-3-were)-N6-(3-methylthiazolidine-2-ilidene)hinzelin-4,6-diamine

[00469] stage a: obtaining N-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-isothiocyanatobenzene-4-amine. To a solution of N4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)hinzelin-4,6-diamine (0,292 g, 0,764 mmol) in a mixture of THF/dichloromethane (6 ml/3 ml) is added di(1H-imidazol-1-yl)retention (0,150 g, 0,840 mmol). After stirring at room temperature for 1 hour 80% of the solvent is evaporated and add DMF (4 ml). The reaction solution is stirred for a further 1 hour, thus obtaining the crude product.

[00470] stage b: 3-(4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-yl)-1-(2-hydroxyethyl)-1-methylthymine. To N-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-isothiocyanatobenzene-4-amine (0,324 g, 0,763 mmol) is added 2-(methylamino)ethanol (0,115 g, 1.53 mmol). After stirring for 2 hours the mixture is diluted with ethyl acetate (20 ml) and water (10 ml). The organic phase is dried over Na2SO4and concentrated, thus obtaining the crude product.

[00471] stage: obtain (Z)-N4-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-N6-(3-methylthiazolidine-2-ilidene)hinzelin-4,6-diamine. To a solution of 3-(4-(4-(imidazo[1,2-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-yl)-1-(2-hydroxyethyl)-1-methylthymine (0,38 g ,76 mmol) in THF (4 ml) is added NaOH (40%, 3.8 mmol) followed by addition of 4-methylbenzol-1-sulphonylchloride (to 0.29 g, 1.5 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The remainder chromatographic (dichloromethane/methanol/30% NH4OH, 20:1:0,02), while receiving the product. Detects MS APCI (+)m/z 482 (M+1);1H NMR (400 MHz, CDCl3) δ 8,65 (m, 2H), 8,18 (m, 2H), a 7.85 (d, 1H, J=7 Hz), and 7.7 (s, 1H), 7.62mm (m, 1H), 7,58 (s, 1H), 7,55 (s, 1H), 6,95 (m, 1H), 6,8 (m, 1H), of 6.68 (m, 1H), 4.26 deaths (m, 2H), 3,78 (m, 2H), 3,2 (s, 3H), 2,15 (s, 3H).

Example 20

N4-(4-(Imidazo[1,2-a]pyridine-7-yloxy)-3-were)-N6-(4-methylthiazole-2-yl)hinzelin-4,6-diamine

[00472] stage A: obtaining 6-iodination-4-ol. A mixture of 2-amino-5-iodobenzoyl acid (125 g, 475 mmol) and formamide (200 ml) is heated to 190°C for 2 hours. After cooling to room temperature the reaction mixture was poured into water (500 ml) and stirred for 2 hours. The solid is separated by filtration and dried in high vacuum, thus obtaining the product (108 g,83%).

[00473] stage: obtain 4-chloro-6-iodination. To a cooled (0°C.) suspension of 6-iodination-4-ol (107,6 g, 396 mmol) and DIEA (138 ml, 791 mmol) in dichloroethane (600 ml) is added POCl3(44,25 ml, 475 mmol). After heating to 90°C for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73,8 g) collecting filter is to be neglected. The filtrate is concentrated under reduced pressure and subjected twice to azeotropic distillation with toluene. Solid (8,3 g) triturated with isopropanol (450 ml) and cooled in an ice bath before picking up by filtering and drying in a high vacuum. Collect the two portions of the solids, while receiving the product (82,1 g, 71%) as a white solid.

[00474] stage C: obtain the hydrochloride of N-(4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-iodination-4-amine. To a solution of 4-chloro-6-iodination (6,07 g of 20.9 mmol) in isopropanol (83 ml) is added 4-(N-imidazo[1,2-a]pyridine-7-yloxy)-3-methylbenzenamine (5,00 g of 20.9 mmol). After heating to 80°C for 4 hours the mixture is cooled to room temperature and filtered. The solid is washed with cold isopropanol and recrystallized from isopropanol, thus obtaining the product (2.66 g, 24%) as a yellow solid.

[00475] stage D: obtain N4-(4-(imidazo[1,2-a]pyridine-7-yloxy)-3-were)-N6-(4-methylthiazole-2-yl)hinzelin-4,6-diamine. A solution of the hydrochloride of N-(4-(imidazo[1,2-a]pyridine-7-yloxy)-3-were)-6-iodination-4-amine (0.20 g, 0,378 mmol) and 4-methylthiazole-2-amine (0,086 g, 0,755 mmol) and 2-methylpropan-2-olate sodium (0,145 g and 1.51 mmol), Xanthos (0,016 g 0,028 mmol), Pd2dba3(0,017 g, 0.018 mmol) in toluene (3.6 ml) Tegaserod and seal. After heating to 100°C for 16 hours the mixture is diluted with water and ethyl acetate. The formed solid substance was separated by filtration, thus obtaining the product as a brown solid. Detects MS APCI (+)m/z 480 (M+1);1H NMR (400 MHz, DMSO-d6) δ 9,96 (s, 1H), 8,86 (s, 1H), 8,63 (s, 1H), 8,55 (d, 1H), 7,79 (m, 5H), 7,44 (s, 1H), 7,14 (d, 1H), 6,80 (DD, 1H), 6,55 (d, 1H), 2,50 (s, 3H), of 2.21 (s, 3H).

Example 21

N-(4-(Benzo[d]oxazol-6-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine

[00476] stage A: getting 2-aminobenzoyl-1,4-diol. To a solution of 2-nitrobenzene-1,4-diol (3.00 g, 19,34 mmol) in ethanol (100 ml) is added 10% palladium on coal (0,600 g, 0,564 mmol). After shaking in a hydrogen atmosphere under a pressure of 40 psi for 2 hours the mixture is filtered and the filtrate concentrated under reduced pressure, thus obtaining the product in the form of solids.

[00477] stage: obtain benzo[d]oxazol-5-ol. To a solution of 2-aminobenzoyl-1,4-diol (2,40 g, 19.2 mmol) in triethylorthoformate (10 ml) is added 3 drops of concentrated HCl. After heating to 65°C for 30 minutes and stirring at room temperature for 16 hours the mixture was poured into water and extracted with ethyl acetate (2 x). The organic phase was washed with HCl (2 BC) saturated NaHCO3, dried and concentrated under reduced pressure, thus obtaining the product (2,09 g, 81%) as a red-black solid.

[00478] stage: obtain 5-(2-methyl-nitrophenoxy)benzo[d]oxazole. To a solution of benzo[d]oxazol-5-ol (1.50 g, 11,10 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.89 g, 12,21 mmol) in DMF added cesium carbonate (1,81 g, 5,55 mmol) and potassium carbonate (2.30 g, 16,65 mmol). After heating to 50°C for 16 hours the mixture was poured into ice water and extracted with ethyl acetate (3 x). The combined organic layers washed with saturated salt solution, dried and concentrated under reduced pressure. The remainder chromatographic (30% ethyl acetate in hexano), while receiving the product (1,69 g, 56%) as a white solid.

[00479] stage D: obtain 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine. To a solution of 5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole (1.65 g, 6.12 mmol) in ethanol added Pd/C (0,130 g, 0,122 mmol). After stirring in an atmosphere of hydrogen at a temperature of 16 hours the mixture is filtered and the filtrate is concentrated, thus obtaining the product (0,81 g, 55%) as a yellow oil.

[00480] stage E: getting 4-chlorination-6-ol. A mixture of 4-chlorination-6-ilaclama (10.0 g, with 44.9 mmol) and ammonia (200 ml of a 7 n solution in methanol) is stirred together for 1 hour. The reaction mixture is concentrated to approximately 3 ml and triturated with diethyl ether, thus obtaining the product (6.50 g, 80%) as a reddish brown solid.

[00481] stage F: obtain 4-chloro-6-(2-methoxyethoxy)hintline. To a solution of 4-chlorination-6-ol (1,00 g, 5,54 mmol), Trife is lifespine (1.45 g, 5,54 mmol) and 2-methoxyethanol (0,421 g, 5,54 mmol) in dichloromethane (83 ml) add diisopropylethylamine (1.18 g, 5,54 mmol). After stirring at room temperature for 16 hours the mixture is concentrated under reduced pressure. The remainder chromatographic (30% ethyl acetate in hexane), thus obtaining the product (1,15 g, 87%) as a white solid.

[00482] stage G: N-(4-(benzo[d]oxazol-5-yloxy-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine. A solution of 4-chloro-6-(2-methoxyethoxy)hintline (0,199 g, 0.83 mmol) and 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine (0,200 g, 0.83 mmol) in isopropanol (2 ml) and DCE (2 ml) is heated to 80°C for 12 hours, after which the mixture is concentrated under reduced pressure. The residue is partitioned between saturated NaHCO3and EtOAc. The aqueous phase is extracted with 2 × EtOAc, the combined organic phase was washed with saturated salt solution, dried (Na2SO4), filtered and concentrated. The remainder chromatographic, while receiving the product (0,100 g, 27%) as not quite white solid. Detects MS APCI (+)m/z 443 (M+1);1H NMR (400 MHz, DMSO-d6) δ 9,59 (s, 1H), 8,76 (s, 1H), and 8.50 (s, 1H), of 7.96 (s, 1H), to 7.75 (m, 4H), 7,52 (DD, 1H), 7,26 (m, 1H), 7,10 (m, 1H), 6,97 (d, 1H), 4,30 (m, 2H), 3,76 (m, 2H), on 3.36 (s, 3H), 2,24 (s, 3H).

Example 22

N-(4-(Benzo[d]oxazol-5-yloxy)-3-chlorophenyl-6-(2-methoxyethoxy)hinzelin-4-amine

[00483] Produces the t according to the method of example 21 using 1-fluoro-2-chloro-4-nitrobenzene instead of 1-fluoro-2-methyl-4-nitrobenzene, except that the recovery nitro spend Zn/NH4Cl in the mixture Meon/THF. Detects MS APCI (+)m/z 463,3 (M+1).

Example 23

N-(4-(Benzo[d]oxazol-6-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine

[00484] Receive according to the method of example 21 using 2-aminobenzoyl-1,5-diol instead of 2-aminobenzoyl-1,4-diol. Detects MS APCI (+)m/z 443 (M+1);1H NMR (400 MHz, DMSO-d6) δ a 9.60 (s, 1H), 8,69 (s, 1H), and 8.50 (s, 1H), of 7.96 (s, 1H), 7,74 (m, 4H), 7,52 (DD, 1H), 7,29 (d, 1H), 7,05 (m, 2H), 4,30 (m, 2H), of 3.77 (m, 2H), on 3.36 (s, 3H), of 2.23 (s, 3H).

Example 24

N-(4-([1,2,4]Triazolo[1,5-a]pyridine-7-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine

[00485] Receive according to the method of example 21 using 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylbenzenamine instead of 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine. MS APCI (+)m/z 443,2.

Example 25

N-(4-([1,2,4]triazolo[1,5-a]pyridine-6-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine

[00486] stage A: obtain 4-([1,2,4] triazolo[1,5-a]pyridine-6-yloxy)-3-methylbenzenamine. Receive according to the method of example 11 using 5-(2-methyl-4-nitrophenoxy)pyridine-2-amine instead of 4-(2-methyl-4-nitrogenase)pyridine-2-amine.

[00487] stage b: N-(4-([1,2,4]triazolo[1,5-a]pyridine-6-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine. P is to obtain according to the method of example 21 using 4-([1,2,4]triazolo[1,5-a]pyridine-6-yloxy)-3-methylbenzenamine instead of 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine. MS APCI (+)m/z 443,3.

Example 26

6-(2-Methoxyethoxy)-N-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)hinzelin-4-amine

[00488] Receive according to the method of example 21 using 3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoylamino instead of 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine. Detects MS APCI (+)m/z 456 (M+1);1H NMR (400 MHz, CDCl3) δ 8,68 (s, 1H), a 7.85 (s, 1H), 7,83 (d, 1H, J=9 Hz), 7,56 (s, 1H), 7,53 (d, 1H, J=2 Hz), 7,49 (DD, 1H, J=9 Hz, 3 Hz), 7,38 (DD, 1H, J=9 Hz, 2 Hz), 7,34 (d, 1H, J=9 Hz), 7,30 (d, 1H, J=3 Hz)that was 7.08 (DD, 1H, J=9 Hz, 2 Hz), 6.87 in (d, 1H, J=9 Hz), to 4.23 (m, 2H), 3,85 (s, 3H), 3,80 (m, 2H), 3,47 (s, 3H), of 2.30 (s, 3H).

Example 27

N-(3-Chloro-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)-6-(2-methoxyethoxy)hinzelin-4-amine

[00489] Receive according to the method of example 26 using 1-fluoro-2-chloro-4-nitrobenzene instead of 1-fluoro-2-methyl-4-nitrobenzene, except that the restoration of the nitrogroup perform system Zn/NH4Cl in the mixture Meon/THF. Detects MS APCI (+)m/z 476,3 (M+1).

Example 28

The hydrochloride of N-(4-(benzo[d]thiazole-5-yloxy)-3-were-6-(2-methoxyethoxy)hinzelin-4-amine

[00490] stage A: obtain 4-(benzo[d]thiazole-5-yloxy)-3-methylbenzenamine. Receive according to the method of example 8 using 5-methoxybenzo[d]thiazole instead of 6-methoxybenzo[d]thiazole.

[00491] stage b: the floor is the group of N-(4-(benzo[d]thiazole-5-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine. Receive according to the method of example 21 using 4-(benzo[d]thiazole-5-yloxy)-3-methylbenzenamine instead of 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine.

Example 29

The hydrochloride of N-(4-(N-pyrazole[1,5-a]pyridine-6-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine

[00492] Receive according to the method of example 21 using pyrazolo[1,5-a]pyridine-6-ol (Miki, Y.; et al., J.Heterocycles, 1996, 43, 2249) instead benzo[d]oxazol-5-ol. Detect m/z MC APCI (+), 442,2 (M+1).

Example 30

N-(4-(Benzo[d]thiazol-6-yloxy)-3-were)-6-(2-methoxyethoxy)hinzelin-4-amine

[00493] Receive according to the method of example 21 using 4-(benzo[d]thiazol-6-yloxy)-3-methylbenzenamine instead of 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine.

Example 31

N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-forfinal)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00494] stage A: obtain (Z)-N'-(4-(benzyloxy)pyridin-2-yl)-N,N-dimethylformamidine. In a 250 ml odnogolosy, round-bottom flask is charged with 4-(benzyloxy)pyridine-2-amine (6,012 g, 30,02 mmol), dimethoxy-N,N-dimethylethanamine (5,535 ml, 39,03 mmol) and ethanol (100,1 ml). Add a few drops of TFA and the reaction mixture is heated to 50°C for 4 hours. The reaction mixture was cooled to ambient temperature and concentre the comfort. The crude product used in the next stage without purification.

[00495] stage: obtain (Z)-N'-(4-(benzyloxy)pyridin-2-yl)-N-hydroxybutylidene. In 100 ml odnogolosy, round-bottom flask is charged with (Z)-N'-(4-(benzyloxy)pyridin-2-yl)-N,N-dimethylformamide (7,66 g, 30.0 mmol), hydroxylamine hydrochloride (2,40 g, 34.5 mmol), propane-2-ol (33.3 ml) and THF (5 ml). The reaction mixture is heated to 50°C for 7 hours, then concentrated. The residue is triturated with a mixture of EtOAc/THF and filtered. The filtrate is concentrated and the residue triturated with dichloromethane, while receiving the product as a white solid.

[00496] stage: obtain 7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine. Triperoxonane anhydride (2,62 ml of 18.9 mmol) is added dropwise to a solution of (Z)-N-(4-(benzyloxy)pyridin-2-yl)-N-hydroxytriazine (4,37 g of 17.9 mmol) in THF (180 ml) and the mixture cooled to 0°C. the Ice bath is then removed and the reaction mixture is stirred for 12 hours. The reaction mixture is concentrated to approximately 15-25 ml, then poured into 400 ml ice 1 M NaOH.

The mixture is stirred for 1 hour. The resulting white solid is collected by filtration, washed with hexane and dried in high vacuum for 1 hour, thus obtaining the desired product.

[00497] stage D: receive [1,2,4]triazolo[1,5-a]pyridine-7-ol. In a 250 ml odnogolosy, round-bottom flask is loaded the t 7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine (3,20 g, of 14.2 mmol), Pd/C (0,756 g, 0,710 mmol) and THF (125 ml). The reaction mixture was stirred in an atmosphere of hydrogen for 16 hours, then filtered (paper GF) and concentrated to yield a white solid. The solid is triturated with EtOAc and collected by filtration, thus obtaining the desired product.

[00498] stage E: obtain tert-butyl-3-chloro-2,4-differenziata. 125 ml odnogolosy, round-bottom flask is charged with di-tert-butoxy-N,N-dimethylethanamine (48,2 ml, 201 mmol), 3-chloro-2,4-differentyou acid (9,67 g of 50.2 mmol) and DMF (50 ml). The reaction mixture is heated to 80°C for 48 hours. After cooling to ambient temperature the reaction mixture was diluted with saturated NaHCO3and EtOAc. The aqueous phase is extracted with EtOAc and the combined organic phases are washed with saturated NaHCO3and saturated salt solution, dried, filtered and concentrated, thus obtaining the desired product as a Golden oil (gold oil).

[00499] stage F: obtain tert-butyl 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-perbenzoate. In the ampoule download tert-butyl-3-chloro-2,4-differentat (0,210 g, 0,845 mmol), [1,2,4]triazolo[1,5-a]pyridine-7-ol (0,114 g, 0,845 mmol), cesium carbonate (0,413 g of 1.27 mmol) and DMF (1.7 ml).

The reaction mixture is heated to 80°C for 12 hours, then poured into ice water. The resulting solid is collected by filtration and clean the lash-chromatography, elwira with a gradient from 10% EtOAc/hexane up to 50% EtOAc/hexane, thus obtaining the desired product.

[00500] stage G: obtain 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-fermenting acid. A 25 ml flask is charged with tert-butyl 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-perbenzoate (to 0.060 g, 0.16 mmol) and dichloromethane (1.6 ml). The reaction mixture was cooled to 0°C and added dropwise 2,2,2-triperoxonane acid (0,50 ml, 0.16 mmol). The reaction mixture is stirred for 20 minutes, then heated to ambient temperature, stirred an additional 3 hours and then concentrated, thus obtaining the desired product as colorless oily residue.

[00501] stage N: obtain 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-forbindelsen. In a vessel load of 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-fermenting acid (0,090 g, 0,2925 mmol), triethylamine (0,1223 ml, 0,8776 mmol) and DMF (1.5 ml). Add diphenylphosphinite (0,1630 ml, 0,7313 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, then add water (0,2199 ml, 0,2925 mmol). The vessel is sealed and heated to 100°C for 1 hour, then cooled to ambient temperature and poured into a mixture of 1 N. NaOH/ice. The reaction mixture was extracted with EtOAc and the organic layer is dried, filtered and concentrated. The residue purified flash chromatography, algirus gradient from 100% EtOAc to 10% (from 6% NH 4OH) Meon/EtOAc.

[00502] stage I: getting N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-forfinal)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine. Receive in accordance with the method for example 1 using 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-chloro-2-forbindelsen instead of 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine. Detects MS APCI (+)m/z 519,3 (M+1, the profile of chlorine).

Example 32

N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-2-fluoro-3-were)-N6-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00503] Receive according to the method of example 31 using 2,4-debtor-3-methylbenzoic acid instead of 3-chloro-2,4-diferential acid. Detects MS APCI (+)m/z 499,3 (M+1).

Example 33

(R)-N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-were)-N6-(4-methyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine

[00504] Receive according to the method for example 1 using (R)-2-aminopropan-1-ol instead of 2-amino-2-methylpropan-1-ol and 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylbenzenamine instead of 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine. Detects MS APCI (+)m/z 467,3 (M+1).

Example 34

TRANS-2-(4-(4-([1,2,4]Triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-yloxy)Cyclopentanol

[00505] stage A: obtain hydrochloride of 4-(-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-ol. Receive according to the method of example 15 using 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylbenzenamine instead of 4-(imidazo[1,2-a]pyridine-7-yloxy)-3-methylaniline.

[00506] stage: obtain TRANS-2-(4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-yloxy)Cyclopentanol. In a 50 ml flask is charged hydrochloride 4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-ol (3,117 g 7,406 mmol), 6-oxabicyclo[3,1,0]hexane (0,6924 ml 7,777 mmol), monohydrate hydroxide caesium (2,736 g, 16,29 mmol), DMF (20 ml). The reaction mixture is heated to 92°C for 12 hours, then cooled to room temperature and diluted with 200 ml of water. The mixture is stirred for 24 hours. The resulting precipitate is collected by filtration, washed with water and dried in air, while receiving 2,80 g specified in the connection header in the form of racemic mixtures. Detects MS APCI (+)m/z 469,3 (M+1).

Example 35

(2-(4-(4-([1,2,4]Triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-ylamino)-4-methyl-4,5-dihydrooxazolo-4-yl)methanol

[00507] stage A: obtaining (E)-N'-(4-(3-(1-(tert-butyldiphenylsilyl)-3-hydroxy-2-methylpropan-2-yl)touraid)-2-cyanophenyl)-N,N-dimethylformamidine. Receive according to the method of example 1 using 2-amino-3-(tert-butyldiphenylsilyl)-2-methylpropan-1-ol instead of 2-amino-2-methylpropan-1-ol.

[00508] stage: obtain N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-were)-N6-(4-((tert-butyldiphenylsilyl)methyl)-4-methyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine. Receive according to the method of example 1, using (E)-N'-(4-(3-(1-(tert-butyldiphenylsilyl)-3-hydroxy-2-methylpropan-2-yl)touraid)-2-cyanophenyl)-N,N-dimethylformamide instead of 1-(3-cyano-4-((dimethylamino)methylamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea and 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylbenzenamine instead of 4-(imidazo[1,2-a]pyridine-7-yloxy)-3-methylaniline.

[00509] stage C: receive (2-(4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenylamine)hinzelin-6-ylamino)-4-methyl-4,5-dihydrooxazolo-4-yl)methanol. To a solution of N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-were)-N6-(4-((tert-butyldiphenylsilyl)methyl)-4-methyl-4,5-dihydrooxazolo-2-yl)hinzelin-4,6-diamine (2,866 g 3,900 mmol) in THF (60 ml) is added TBAF (7,799 mmol, 7,79 ml, 1 M in THF). The reaction mixture is stirred for 3 hours and then concentrated. The residue is purified flash chromatography, elwira a mixture of EtOAc/hexane/Meon, 9:1:1, with 0.1% H2O, while receiving specified in the header connection. Detects MS APCI (+)m/z 497.4 m (M+1).

Example 36

N-(4-([1,2,4]Triazolo[1,5-a]pyridine-7-yloxy)-3-were)-5-(2-methoxyethoxy)hinzelin-4-amine

[00510] stage A: obtain 5-(2-metakit the XI)hinzelin-4-ol. To a solution of 2-methoxyethanol (0,528 ml, 6,70 mmol) in DMF (6 ml) is added slowly 514 mg of 60% dispersion of NaH (0,308 g, 12.8 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Add 5-florinopolis-4(3H)-he (1.0 g, 6,09 mmol) and the reaction mixture is heated at 80°C for 2 hours. The reaction mixture was concentrated and the residue suspended in EtOH (75 ml) and then filtered through paper GF/f Filtrate concentrated, thus obtaining the desired product as a yellow solid.

[00511] stage: obtain 4-chloro-5-(2-methoxyethoxy)hintline. Receive according to the method of example 15 using 5-(2-methoxyethoxy)hinzelin-4-ol instead of 4-hydroxyquinazoline-6-racette.

[00512] stage With: obtaining N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-were)-5-(2-methoxyethoxy)hinzelin-4-amine. Receive according to the method of example 24 using 4-chloro-5-(2-methoxyethoxy)hintline instead of 4-chloro-6-(2-methoxyethoxy)hintline. Detects MS APCI (+)m/z 443,1 (M+1).

[00513] the Following compounds also receive according to the above methods.

[00514] the above description be considered merely as illustrative of the principles of the invention. Furthermore, since numerous modifications and changes should be readily apparent to experts in this field, one should not limit the invention to the exact structure and detected by the method as described above. In accordance with this, it is considered that all suitable modifications and equivalents are within the scope of the invention defined by the following claims.

[00515] it Is believed that the word "contains", "containing", "includes" and "including" when used in this description and in the following claims indicate the presence of these features, complete systems, components, or steps, but do not prevent the presence or addition of one or more other attribute of the Cove, complete systems, components, stages or groups.

1. The compound of the formula I

or its pharmaceutically acceptable salt, where
And represents O or S;
G represents N;
Represents a 6-membered aryl or 5-6-membered heteroaryl ring containing a sulfur atom as a heteroatom;
E is a

,,
X represents N or CH;
D1D2and D3are independently N or CR19;
D4and D5are independently N or CR19and D6represents O, S or NR20where at least one of the D4and D5is not CR19;
D7D8D9and D10are independently N or CR19where at least one of the D7D8D9and D10represents N;
R1represents N or C1-C6alkyl;
each R2represents independently halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, deformedarse, triptoreline, azido,
-SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18,
-SO2NR15R14-NR 14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14,
-NR15R14C1-C12alkyl, C2-C12alkenyl, quinil, saturated or partially unsaturated With3-C10cycloalkyl,3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl),
-S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-3-alkyl, saturated or partially unsaturated 3-8-membered heterocyclyl, 5-6-membered heterocyclyl-C1-3-alkyl, -O(CRl3R14)q-phenyl, NR15(CR13R14)q-phenyl, - O(CR13R14)q-(5-6-membered heteroaryl), NR13(CR13R14)q-(5-6-membered heteroaryl, -O(CR13R14)q-(3-8-membered heterocyclyl) or-NR15(CR13R14)q-3-8-membered heterocyclyl)where the specified alkyl, Alchemilla, Alchemilla, cycloalkyl, phenyl, fenilalanina, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido,
-NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)ORsup> 15, -OC(O)R15, -NR13C(O)OR18,
-NR13C(O)R15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, -NR14C(NCN)NR15R13, -OR15, phenyl, 5-6-membered heteroaryl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl-C1-3-alkyl, saturated and partially unsaturated 3-8-membered heterocycle and a 5 to 6 membered heterocyclyl-C1-3-alkyl, and where mentioned phenyl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl or heterocyclisation rings can be additionally substituted by one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl, C1-C12of alkyl, C2-C12alkenyl,2-C12the quinil, saturated and partially unsaturated C3-C10cycloalkyl, saturated and partially unsaturated 3-8-membered heterocyclyl, NR15R13and OR15;
each R3is a Z;
Z is selected from
,,and
and their tautomers;
W represents O or S;
W2represents O or S;
V is CR8R9,
R8brepresents N or C1-C6alkyl;
each of R6, R8/sup> , R8aand R9represents independently hydrogen, trifluoromethyl, C1-C12alkyl, saturated or partially unsaturated With3-C10-cycloalkyl, saturated or partially unsaturated 3-8-membered heterocyclyl, phenyl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl, 5-6-membered heteroaromatic-C1-3-alkyl or 5-6-membered geterotsiklicheskikh-C1-3-alkyl, where these alkyl, cycloalkyl, heterocyclyl, phenyl, phenylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from oxo, halogen, C1-C12of alkyl, C2-C12-alkenyl,2-C12-quinil, saturated or partially unsaturated With3-C10cycloalkyl, saturated or partially unsaturated 3-8-membered heterocyclyl,3-C10-cycloalkenyl-C1-C12-alkyl, cyano, nitro, OR15, NR15R16, SR15, S(=O)R, SO2R15, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, phenyl, 5-6-membered heteroaryl, phenyl-C1-3of alkyl, 5-6-membered heteroaryl-C1-3-alkyl, 5-6-membered heterocyclyl-C1-3of alkyl,
or R8and R8atogether with the atom to which the are attached, form a 3-6-membered carbocyclic ring;
or R6 and R 8together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where these carbocyclic and heterocyclic rings are optionally substituted by one or more groups independently selected from oxo, halogen, C1-C12of alkyl, C2-C12alkenyl,2-C12the quinil, saturated or partially unsaturated With3-C10-cycloalkyl, saturated or partially unsaturated 3-8-membered heterocyclyl,3-C10-cycloalkyl-C1-C12-alkyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, phenyl, OR15, NR15R16, SR15, 5-6-membered heteroaryl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl-C1-3the alkyl and 5-6-membered heterocyclyl-C1-3-alkyl;
or R8and R9together with the atoms to which they are attached, form a 3-10-membered saturated or partially unsaturated cycloalkyl or heterocyclyl ring, optionally containing one or more additional heteroatoms selected from N, O, S, SO, SO2and NR6where these carbocyclic, heterotic the practical ring optionally substituted by one or more groups, independently selected from oxo, halogen, C1-C12of alkyl, C2-C12alkenyl,2-C12the quinil, saturated and partially unsaturated C3-C10cycloalkyl, saturated and partially unsaturated 3-8-membered heterocyclyl,3-C10-cycloalkyl-C1-C12-alkyl, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, phenyl, OR15, NR15R16, SR15, 5-6-membered heteroaryl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl-C1-3-Aquila and 5-6-membered heterocyclyl-C1-3-alkyl;
each R12represents independently halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, deformedarse, triptoreline, azido,
-SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR13C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14C1-C12alkyl, C2-C12alkenyl, C2-C12quinil, saturated or partially unsaturated With3-C10cycloalkyl,3-C10-cycloalkyl-C1-C12-alkyl, -S(O)p(C1-C12alkyl), S(O)p(CR13R14)q-enyl, phenyl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-3-alkyl, saturated or partially unsaturated 3-8-membered heterocyclyl, 5-6-membered heterocyclyl-C1-3-alkyl, -O(CR13R14)q-phenyl, -NR15(CR13R14)q-phenyl, -O(CR13R14)q-5-6-membered heteroaryl, -NR13(CR13R14)q-5-6-membered heteroaryl,
-O(CR13R14)q-3-8-membered heterocyclyl or-NR15(CR13R14)q-3-8-membered heterocyclyl, where these alkyl, alkeline, alkyline, cycloalkyl, phenyl, phenylalaline, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR13SO2R18,
-SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)OR18, -NR13C(O)R15,
-C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, -NR14C(NCN)NR15R13, -OR15, phenyl, 5-6-membered heteroaryl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl-C1-3-alkyl, saturated and partially unsaturated 3-8-membered heterocyclyl or 5-6-membered heterocyclyl-C1-3-is Lila, and where mentioned phenyl, heteroaryl, phenylalaline, heteroallyl, heterocyclyl or heterocyclisation rings can be additionally substituted by one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl,1-C12of alkyl, C2-C12alkenyl,2-C12the quinil, saturated or partially unsaturated With3-C10cycloalkyl, saturated or partially unsaturated 3-8-membered heterocyclyl, NR15R13and OR15;
R13and R14are independently hydrogen or C1-C12alkyl or
R13and R14together with the atoms to which they are attached, form a saturated or partially unsaturated With3-C10-cycloalkyl or a saturated or partially unsaturated 3-8-membered heterocyclyl ring, where these alkyl, cycloalkyl and heterocyclyl part is optional substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORbNRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-Ra, C(=O)RaC(=O)ORa, OC(=O)RaC(=O)NRaRb, NRaC(=O)Rband NRaC(=O)NRbRc;
R15are independently H, C1-C12alkyl, C2-C12alkenyl,2-C12quinil, C1-C12heteroalkyl,2-C12heteroalkyl,2-C12heteroalkyl, saturated or partially unsaturated With3-C10-cycloalkyl, saturated or partially unsaturated 3-8-membered heterocyclyl,3-C10-cycloalkyl-C1-C12-alkyl, phenyl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-3-alkyl or 5-6-membered heterocyclyl-C1-3-alkyl, where the specified alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, cycloalkenyl, phenyl, phenylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from C1-C12of alkyl, C2-C12alkenyl,2-C12the quinil,1-C12heteroalkyl,2-C12heteroalkyl, C2-C12heteroalkyl, saturated and partially unsaturated C3-C10cycloalkyl, saturated and partially unsaturated 3-8-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, halogen, oxo, ORa, NRaRb, NRaORbNRaC 2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORa, OC(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRcOS(=O)NRaRband C(=O)CH2ORa;
or R13and R15together with the atom to which they are attached, form a saturated or partially unsaturated With3-C10cycloalkyl or a saturated or partially unsaturated 3-8-membered heterocyclyl ring, where the specified cycloalkyl and heterocyclyl optionally substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORbNRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaWith(=O)ORaOS(=O)RaC(=O)NRaRb, NRaC(=O)Rband NRaC(=O)NRbRc;
R18is a CF3C1-C12alkyl, C2-C12alkenyl,2-C12quinil,1-C12heteroalkyl,2-C12heteroalkyl,2-C12heteroalkyl, saturated or partially unsaturated With3-C10cycloalkyl, nasy the military or partially unsaturated 3-8-membered heterocyclyl, With3-C10-cycloalkyl-C1-C12-alkyl, phenyl, phenyl-C1-3-alkyl, 5-8-membered heteroaryl, 5-6-membered heteroaryl-C1-3-alkyl or 5-6-membered heterocyclyl-C1-3-alkyl, where the specified alkyl, alkenyl, quinil, cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkenyl, phenyl, phenylalkyl, heteroaryl, heteroaromatic and geterotsiklicheskikh optionally substituted by one or more groups independently selected from C1-C12of alkyl, C2-C12alkenyl,2-C12the quinil,1-C12heteroalkyl,2-C12heteroalkyl,2-C12heteroalkyl, saturated or partially unsaturated With3-C10cycloalkyl, saturated or partially unsaturated 3-8-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, halogen, oxo, ORa, NRaRb, NRaORbNRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORa, OC(=O)RaC(=O)NRaRb, NRaC(=O)Rb, NRaC(=O)NRbRc,
or R15and R18with the atoms to which they are attached, form a saturated or partially unsaturated With3-C10cycloalkyl or a saturated or partially unsaturated 3-8-membered g is tetracyclinee ring, where specified cycloalkyl and heterocyclyl optionally substituted by one or more groups independently selected from halogen, cyano, nitro, trifloromethyl, diformate, formatie, formatosi, deformedarse, triptoreline, azido, oxo, ORa, NRaRb, NRaORb, NRaCO2Rb, NRaCORb, SO2NRaRb, SRa, SORa, SO2RaS-S-RaC(=O)RaC(=O)ORa, OC(=O)ORaC(=O)NRaRb, NRaC(=O)Rband NRaC(=O)NRbRc;
each R19represents independently H, halogen, cyano, nitro, trifluoromethyl, deformity, vermeil, formatosi, deformedarse, triptoreline, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR13C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14C1-C12alkyl, C2-C12alkenyl,2-C12quinil, saturated or partially unsaturated With3-C10cycloalkyl,2-C12cycloalkyl-C1-C12-alkyl, -S(O)p(C1-C12alkyl),
-S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-C3arylalkyl, 5-6-membered heteroaryl, 5 and 6 members of the hydrated heteroaryl-C 1-3-alkyl, saturated or partially unsaturated 3-8-membered heterocyclyl, 5-6-membered heterocyclyl-C1-3-alkyl, -O(CR13R14)q-phenyl,
-NR15(CR13R14)q-phenyl, -O(CR13R14)q-5-6-membered heteroaryl, -NRl3(CRl3R14)q-5-6-membered heteroaryl, -O(CR13R14)q-3-8-membered heterocyclyl) or-NR15(CRl3R14)q-(3-8-membered heterocyclyl), where these alkyl, alkeline, alkyline, cycloalkyl, phenyl, phenylalkyl, heteroaryl, heteroallyl, heterocyclyl and heterocyclisation part is optional substituted by one or more groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, NR13SO2R18, -SO2NR15R13, -C(O)R15, -C(O)OR15, -OC(O)R15, -NR13C(O)OR18, -NR13C(O)R15, -C(O)NR15R13, -NR15R13, -NR14C(O)NR15R13, -NR14C(NCN)NR15R13, -OR15, phenyl, 5-6-membered heteroaryl, phenyl-C1-3-alkyl, 5-6-membered heteroaryl-C1-3-alkyl, saturated or partially unsaturated 3-8-membered heterocyclyl and 5-6-membered heterocyclyl-C1-3-alkyl, and where mentioned phenyl, heteroaryl, phenylalaline, heteroallyl, g is teracycline or heterocyclisation rings can be additionally substituted by one or more groups, selected from halogen, hydroxyl, cyano, nitro, azido, formatie, diformate, trifloromethyl,1-C12of alkyl, C2-C12alkenyl,2-C12the quinil, saturated and partially unsaturated C3-C10cycloalkyl, saturated and partially unsaturated 3-8 membered heterocyclyl, NR15R13and OR15;
each R20represents independently1-C4alkyl, saturated or partially unsaturated With3-C10cycloalkyl, trifluoromethyl, deformity or vermeil;
Ra, Rband Rcare independently H, C1-C12alkyl, C2-C12alkenyl,2-C12quinil, saturated or partially unsaturated With3-C10cycloalkyl, saturated or partially unsaturated 3-8-membered heterocyclyl, phenyl, or 5-6-membered heteroaryl,
or NRaRbforms a 5-6-membered heterocyclic ring having 1-2 nitrogen atom in the ring and optionally substituted (C1-C3by alkyl),
or NRbRcforms a 5-6-membered heterocyclic ring having 1-2 nitrogen atom in the ring;
j is 0, 1, 2 or 3;
m is 1;
n is 0, 1, 2, 3 or 4;
q is 0, 1, 2, 3, 4 or 5 and
p is 0, 1 or 2;
where, when the specified connection formula I represented by formula

and R3not pre is is a Q or Z, then E cannot be benzofuranyl, indolinyl, girasolereale, hyalinella or izokhinolinom ring.

2. The compound according to claim 1, having the formula

3. The compound according to claim 1, having the formula

4. The compound according to claim 1, having the formula

5. The compound according to any one of claims 1 to 4, where E is selected from
,and

6. The compound according to claim 5, where E is selected from the structures:
,,,
,
and
where k is 0, 1, 2, or 3.

7. The connection according to claim 6, where E is selected from the structures:

8. The compound according to any one of claims 1 to 5, where E is selected from
and.

9. The connection of claim 8, where E is selected from the structures:
,,,
and,
where each R12and each group R19is independently is from another.

10. The connection according to claim 9, where E is selected from:


11. The compound according to claim 1 where Z is selected from the structures:
,,,
,
R6represents N or C1-C6alkyl and
R8and R8aindependently represent N or C1-C6alkyl, optionally substituted
ORawhere Rarepresents N or C1-C6alkyl,
or R8and R8atogether with the atom to which they are attached, form a3-C6cycloalkyl ring.

12. Connection to item 11, where m is 1 and R5selected from the structures:
,,
,,
,,,

13. The compound according to any one of claims 1 to 5, where
E is selected from
,and
R12is a halogen;
j is 0 or 1;
R19 represents H, C1-C6alkyl or halogen, and
R20represents N;

14. The pharmaceutical composition capable of inhibiting tyrosine kinase type 1, comprising the compound according to any one of claims 1 to 5 in an effective amount and a pharmaceutically acceptable carrier.

15. The compound of formula I according to claim 1 selected from the structures:


















or their pharmaceutically acceptable salt.

16. The connection 15 having the structure:

17. The connection 15, is within a structure:

18. The connection 15 having the structure:

19. The pharmaceutical composition capable of inhibiting tyrosine kinase type 1, comprising the compound according to any one of p-18 in an effective amount and a pharmaceutically acceptable carrier.

20. The compound according to claim 5, where Z is selected from the structures:
,,,
,,,
,,,
,

21. The connection of claim 8, where Z is selected from the structures:
,,,
,,,
,,,
,

22. The use of the compounds of formula I according to any one of claims 1 to 5 in the manufacture of a medicinal product for the treatment of hyperproliferative disease in a mammal.

23. The use of the compounds of formula I according to any one of p-18 in the manufacture of a medicinal product for the treatment of hyperproliferative disease in a mammal.

24. The compound of formula I according to any one of claims 1 to 5, having the properties of tyrosine kinase inhibitors of type I.

25. The compound of formula I according to any one of p-18, having the properties of tyrosine kinase inhibitors of type I.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds with affinity to MC4 receptors, of the general formula (I): , where A is -CH2- or -C(O)-; R1 is (C1-C8)alkyl; R2 is (C1-C8)alkyl; R3 is radical of the formula -(CH2)s-R'3; R'3 is 5-6-member heterocycloalkyl containing one or two nitrogen atoms and possibly one oxygen atom possibly substituted with (C1-C6)alkyl or benzyl; or radical of the formula -NW3W'3; W3 is hydrogen atom or (C1-C8)alkyl; W'3 is radical of the formula -(CH2)s'-Z3; Z3 is hydrogen atom, (C1-C8)alkyl; s and s' are independently an integer within 0 to 6; B is 5-6-member monocyclic unsaturated, aromatic or non-aromatic radical which can be condensed with 5-6-member unsaturated, aromatic or non-aromatic radical forming bicyclic condensed system, and B is possibly containing one or more equal or different heteroatoms selected out of O, S and N, and possibly substituted with one or more equal or different radicals selected out of halogen atom, nitro group, cyano group, oxy group, -XB-YB and phenyl possibly substituted with one substitute selected out of halogen atom and (C1-C6)alkyl; XB is a covalent bond, -O-, -S-, -C(O)-, -C(O)-O-; YB is (C1-C6)alkyl; or pharmaceutically acceptable salt of claimed compounds.

EFFECT: improved obtainment and application efficiency of compounds for production of drug for treatment of diseases related to MC4 receptor activation.

20 cl, 4 dwg, 2 tbl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , where R1 is C1-C7-alkyl; R2 is C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl; R3 is -NRaRb; possibly substituted phenyl, thiophenyl, furanyl, where the substitutes are selected from a group consisting of halogen, C1-C7-alkoxy, C1-C7-alkylsulphonyl and -C(O)O-C1-C7-alkyl; R4 is hydrogen or C1-C7-alkyl; R5 is hydrogen, halogen, C1-C7-alkyl, phenyl; or R5 together with R4 can form a ring selected from a group consisting of C5-C7-cycloalkyl, tetrahydrofuranyl, piperidine, tetrahydropyran, phenyl or pyridinyl, which can possibly be substituted with -C(O)O-C1-C7-alkyl; Ra and Rb together with the nitrogen atom to which they are bonded form piperidine; and to pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent based on the said compounds which has GABA-B receptor allosteric enhancement effect.

EFFECT: obtaining novel compounds and a medicinal agent based on the said compounds, which can be used in medicine for treating central nervous system disorders.

13 cl, 42 ex

FIELD: pharmacology.

SUBSTANCE: present invention relates to antagonists of serotonin 5-HT5 receptors with general formula 1 and their pharmaceutically acceptable salts and/or hydrates, particularly to substituted 3-sulphonyl-[1,2,3]triazolo[1,5-a]quinazolines and 3-sulphonyl-thieno[2,3-e][1,2,3]triazolo [1,5-a]pyrimidines, as active compounds for pharmaceutical compositions and medicinal agents, and methods of producing said compounds. In general formula 1 , Ar is a phenyl which is unsubstituted or substituted with halogen or at least one lower alkyl; R1 is a hydrogen atom or optionally substituted amine group, or optionally substituted 5-6 member azaheterocyclyl, bonded by a nitrogen atom to a carbon atom of a triazolopyrimidine ring with 1-2 heteroatoms selected from nitrogen, oxygen or sulphur, and optionally annulated with a benzene ring; where the substitutes are selected from hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C8cycloalkyl, alkoxy group, acyl, saturated or unsaturated optionally annulated 5-7 member heterocyclyl, where heteroatoms are selected from nitrogen, oxygen or sulphur, optionally substituted phenyl; R2 and R3 together with carbon atoms to which they are bonded form an optionally substituted benzene or thiophene ring, where substitutes are selected from C1-C5alkyl or halogen atom.

EFFECT: invention also relates to pharmaceutical compositions and medicinal agents, a method of treating or preventing development of CNS diseases mediated by action of serotonin 5-HT5 receptors, for example Alzheimer's disease.

20 cl, 6 dwg, 4 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

17 cl, 70 ex

The invention relates to new 3-substituted derivatives 3,4,5,6,7,8-hexahydropyrazino[4', 3': 4,5] -thieno[2,3-d] pyrimidine of the General formula I and their physiologically acceptable salts with selective action of antagonists 5HT1Band 5HT1Aand has inhibiting effect of reuse of serotonin

The invention relates to new biologically active chemical substance, namely 6-methyl-8-methoxymethyl-3-phenylisoxazole[3', 4': 4,5]thieno[2,3-b]pyridine of formula 1, showing the growth regulating and anti-stress activity

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in free form or in form of a pharmaceutically acceptable salt, where A is independently selected from CH and at least one nitrogen atom; D denotes CR3; R1 and R2 denote H, R3 denotes C1-C8-alkyl, R5 denotes , R5j and R5k are independently selected from H, C1-C8-alkyl and C3-C15-carbocyclic group, or R5j and R5k together with the nitrogen atom to which they are bonded form an optionally substituted 4-14-member heterocyclic group; R6 denotes H; W denotes a C6-C15-aromatic carbocyclic group; X denotes -CH2-; n assumes values from 0 to 3, a pharmaceutical composition based on said compounds and having CRTh2 receptor modulating activity, as well as a method for synthesis of compounds of formula I.

EFFECT: novel compounds which can be used as anti-inflammatory agents are obtained and described.

9 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in general formula I R1 denotes hydrogen atom, a halogen atom, hydroxy, lower alkyl, benzyloxy or -O-(CH2)-(CO)-(5-member heteroaryl with 2 heteroatoms selected from N, O), substituted with phenyl or lower alkyl; R2 denotes a hydrogen atom, a halogen atom, lower alkyl, lower alkynyl, amino, -NHC(O)Ra or -(CO)-Ra; R3 denotes a hydrogen atom, a halogen atom, cyano, lower alkyl, lower alkynyl, amino, -NHC(O)-Ra, -(CO)-Ra, 4- or 5-member heterocycloalkyl substituted with a =O group or a 5-member heteroaryl with 1-2 heteroatoms selected from N; R4 denotes a hydrogen atom or a 5-member heteroaryl with 2 heteroatoms selected from N; R5 denotes lower alkyl or C3-C7cycloalkyl; Ra denotes lower alkoxy, -(CH2)n-(6-member heteroaryl with 1 heteroatom selected from N), phenyl C3-C7-cycloalkyl or NR'R", where each of R' and R" independently denotes a hydrogen atom, lower alkyl, substituted hydroxy, lower alkynyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-member heterocycloalkyl with 1-2 heteroatoms selected from O, N) or -(CH2)n-(5- or 6-member heteroaryl with 1 heteroatom selected from N, O); n assumes values from 0 to 3. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare the medicinal agent.

EFFECT: high activity and selectivity towards GABA A receptor subunit α5.

18 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2,8-dimethyl-5-[2-(6-methyl-pyridyl-3)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole salts of general formula (1) exhibiting antidepressive and antihypoxic activity where n=1, 2 Y = (CH2COOH)2, HOOCCH(OH)CH2COOH, (HOOCCH2)2C(OH)COOH. Besides, the invention concerns a pharmaceutical agent.

EFFECT: ensured production of new biologically active compounds exhibiting antidepressive and antihypoxic activity.

6 cl, 5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I ; or to its pharmaceutically acceptable salts where n represents 0, 1 or 2; Y1 represents a bond or a group C(O); Y2, represents a bond, the groups C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, C1-2alkyl; R2 represents hydrogen, halogen, cyano, C1-4alkyl, C1-3alkoxy, halogen-substituted-C1-3alkyl, halogen-substituted-C1-3alkoxyl, C6aryl-C0alkyl, tetrazolyl, C3-6cycloalkyl-C0alkyl, C6-7heterocycloalkyl-C0-4alkyl where 1 or 2 carbon atoms in the ring are substituted by the groups selected from -O-, -NH-, -S(O) and -SO2-; and phenoxy groups; where said aryl and heterocycloalkyl groups R2 can be substituted by 1 or 2 radicals independently selected from C1-6alkyl; R3 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group and a group -NR6aR6b where R6a and R6b are independently selected from hydrogen and C1-4alkyl; R4 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group; R5 represents hydrogen or C1-3alkyl group; L represents a bivalent radical selected from ; ; ; ; ; ; ; ; ; ; ; ; and ; where asterisks the junctions of Y2 and R2; where any bivalent radical L can be substituted by 1 or 2 radicals independently selected from halogen, hydroxy, cyano, C1-4alkyl, C1-4alkyl carbonylamino, C1-4alkoxy, C1-4alkoxycarbonyl, halogen-substituted - C1-4alkyl, C1-3alkylsulfonyl, C1-3alkylsulfonyl-amino, cyano-substituted - C1-4alkyl and halogen-substituted -C1-4alkoxy radicals. Also, the invention refers to a method of Hedgehog path inhibition in a cell and to a method of undesired cell proliferation inhibition which involves the interaction of the compound of formula I and the cell.

EFFECT: new substituted imidazole derivatives which can be effective in treatment of some types of cancer are prepared.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a condensed cyclic aromatic compound having the formula [2] given below: , where each R1 R2, R3, R5-R8, R10-R13, R15-R18, R20 denotes a hydrogen atom, R4, R9, R14, R19 denote phenyl, optionally substituted with two substitutes selected from tertbutyl. The invention also relates to use of said compound as an organic light-emitting layer in an organic light-emitting device.

EFFECT: obtaining a substance which can be used to make a light-emitting device which is durable and has high radiation efficiency.

2 cl, 6 ex, 2 tbl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to new amino acid derivatives of formula (I), , in which R-groups have the following value: -R1 is -H;-R2 is -C(O)R15 or -SO2R15; -R3 is -H;-R4 is -H or -(1-4C)alkyl; -R6 is -H; -R7 is -H; -R8 is -H, cyanogroup, halogen, nitrogroup; -(1-6C)alkyl optionally substituted by amino group, hydroxyl or halogen; -heteroaryl representing a 5 or 6-members aromatic ring containing one or more heteroatoms N optionally substituted by -(1-4C) alkyl; -C(R16)NOR16, -C(O)N(R17)2, -C(O)R18 or -C(O)OR19; -R9 is -H; -R10 is -H or -(1-4C)alkyl; -R11 is -H; -R12 is -H; -R13 is -H; -R14 is -H; -R15 is -H; -(1-6C)alkyl, -(2-6C)alkynyl, -O(2-6C)alkyl) all optionally substituted by one or more, halogen, cyanogroup or 5-members heteroaryl where 5-members heteroaryl represents an aromatic ring containing one or more heteroatoms selected from a group including N, O or S; -(hetero)aryl representing 5 or 6-members aromatic ring system containing one or more heteroatoms selected from group including N, O or S, optionally substituted by -(1-4C)alkyl, halogen or NH2; -NH2, -(di)(1-4C)alkylamihogroup, -(1-4C)alkylamihogroup or -NR16OR16; R16 is -H or -(1-4C)alkyl; -R17 is -H or -(1-6C)alkyl optionally substituted by halogen, or 5 or 6-members heteroaryl or aryl optionally substituted by halogen, -(1-4C)alkyl or -(1-4C)alkoxygroup where heteroaryl represents an aromatic ring containing one or more heteroatoms selected from the group including N, O or S; -R18 is -H or -(1-4C)alkyl; -R19 is -H or -(1-6C)alkyl.

EFFECT: compounds of this invention are high-specific to glucocorticoid receptor and can be used for treating inflammatory diseases.

6 cl, 58 ex

FIELD: medicine.

SUBSTANCE: invention refers to aryl-izoxazole-4-yl-imidazo[1,5-a]pyridine derivatives of formula I and to their pharmaceutically acceptable acid addition salts. In formula I , R1 represents hydrogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom, cyano or -(CO)-Ra; Ra represents lower alkoxy or NR'R" where each of R' and R" independently represents hydrogen atom, 6-members heterocycloalkyl with the 1st heteroatom selected from O, or lower alkyl substituted by C3-C7-cycloalkyl. The invention also refers to a drug exhibiting affinity and selectivity to GABA(A) α5-receptor binding sites, containing one or more compounds of formula I and to an application of the compound of the invention in producing the drug exhibiting affinity and selectivity to GABA(A) α5-receptor binding sites.

EFFECT: improved efficacy of the drug.

7 cl, 2 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I): in which the radicals R1, R2, R3 and R4 independently represent hydrogen atom, halogen atom, hydroxy group, amino group, nitro group, an alkyl, alkenyl, cycloalkyl or aralkyl radical. And all these radicals can to be optionally substituted by haloalkyl or hydroxyalkyl, or radicals R2 and R3 in combination can represent a part of an aryl rings; R5 represents hydrogen atom, halogen atom, hydroxy group or thiol group, an alkyl, alkenyl, alkinyl, aryl, cycloalkyl, aralkyl radical or a 5-merous heteroaromatic ring containing 1, 2 heteroatoms selected from nitrogen and oxygen; the radicals R6 and R7 independently represent hydrogen atom, an alkyl or aryl radical; and X represents a group of formula where represents a bond or CH2, V represents O, W represents NH, a Y represents OH, or to its pharmaceutically acceptable salts, and besides to pharmaceutical composition based on said compound showing an inhibitory action on peptide deformylase (PDF).

EFFECT: new compounds which attract a great interest as new antibiotics are produced and described.

11 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

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