Azabenzothiophenyl compounds and methods of use

FIELD: chemistry.

SUBSTANCE: invention relates to azabenzothiophenyl compounds of formula I

and salts thereof, where: Z1 denotes CR1; Z2 denotes N; Z3 denotes CR3; Z4 denotes CR4; R1, R3 and R4 are independently selected from H or halogen; W denotes , R5 and R6 denote H; X1 denotes -OR11; X2 denotes phenyl which is optionally substituted with one or two groups selected from halogen or (C1-C3)alkylsulphanyl; R11 denotes (C1-C12) alkyl, substituted by one or two groups independently selected from - (CR19R20)nOR16; n equals 0; R16 denotes H, (C1-C12) alkyl or (C2-C8) alkenyl. The invention also relates to a pharmaceutical composition based on said compounds, which can be used in medicine for treating hyperproliferative disorders.

EFFECT: high efficiency of using said compounds.

11 cl, 12 ex

 

Related applications

This application is an international patent application, seeking the priority of provisional patent application U.S. No. 60/839163, filed August 21, 2006, provisional application for U.S. patent No. 60/871600, filed December 22, 2006, and provisional application for U.S. patent No. 60/917624, filed may 11, 2007, included in this description by reference.

The technical field to which the invention relates.

The invention relates to isobenzofuranyl compounds with anticancer and/or anti-inflammatory activity and more specifically, to isobenzofuranyl compounds inhibiting the activity of the kinase MEK. The invention also relates to methods of using compounds for in vitro diagnosis, in situ and in vivo or treatment of mammalian cells or treatment of associated pathological conditions.

Background of invention

In the quest to understand how Ras transmits extracellular growth signals, metabolic pathway kinase MAR (mitogenactivated protein) (MARK) identified as a critical path between the membrane-bound Ras and nuclei. The metabolic pathway of MARK covers a cascade of phosphorylation events, including three key kinases, namely Raf, MEK (kinase of the MAP kinase) and ERK (MAP kinase). Active GTP-bound Ras leads to activation and indirect phosphorylation of Raf kinase. the ATEM Raf phosphorylates MEK and 2 on two serine residues (S218 and S222 in case MEK and S222 and S226 if MEC) (Ahn et al., Methods in Enzymology, 2001, 332, 417-431). Then activated MEK phosphorylates only known substrates of the kinase MAR, ERK1 and 2. Phosphorylation of ERK MEK occurs Y204 and T in the case of ERK1 and Y185 and T in the case of ERK2 (Ahn et al., Methods in Enzymology, 2001, 332, 417-431). Phosphorylated ERK dimerizes and then moves into the nucleus where it accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615). In the nucleus ERK is involved in several important cellular functions, including, but not limited to, nuclear transport, signal transduction, DNA repair, Assembly, and translocation of the nucleosome, and the processing and translation of mRNA (Ahn et al., Molecular Cell, 2000, 6, 1343-1354). In General, treatment of cells with growth factors leads to activation of ERK1 and 2, which leads to proliferation and in some cases differentiation (Lewis et al., Adv. Cancer Res., 1998, 74, 49-139).

There is serious evidence that genetic mutations and/or overexpression of its protein kinases involved in the cascade of reactions kinase MAR, leads to unregulated cell proliferation and, obviously, the formation of tumors in proliferative diseases. For example, some carcinomas contain mutations that result in continuous activation of this cascade due to the continuous production of growth factors. Other mutations can cause deactivation of the activated GTP-bound complex of Ras, and again lead to the activation of the cascade re the work kinase MAR. Mutated oncogenic forms of Ras was detected in 50% of cancers of the colon and more than 90% of cancers of the pancreas, as well as many other types of cancer (Kohl et al., Science, 1993, 260, 1834-1837). Recently, skin disease mutations identified in more than 60% of cases of malignant melanoma (Davies H. et al., Nature, 2002, 417, 949-954). Such skin disease mutations lead to constitutive active kinase cascade MAR. Samples of primary tumors and cell lines also show constitutive or overactivation ways of sharing kinase MAR for cancer of the pancreas, colon, lung, ovarian and kidney (R. Hoshino et al., Oncogene, 1999, 18, 813-822).

MEK identified as an attractive therapeutic target in the path of the exchange kinase MAR. MEK downstream signaling pathways Ras and Raf is highly specific for phosphorylation of the kinase MAR; indeed, the only known substrates phosphorylation of MEK kinases are MAR ERK1 and 2. Some studies have shown that inhibition of MEK has a potentially beneficial therapeutic effect. For example, it is shown that the small molecule MEK inhibitors inhibit the growth of human tumors in xenografts in Nude mice (Sebolt-Leopold et al., Nature Medicine, 1999, 5(7), 810-816); Trachet et al., AACR Apr., 6-10, 2002, Poster #5426; Tecle, H., IBC, 2.sup.nd International Conference of Protein Kinases, Sep., 9-10, 200), block static allodynia (allodynia) in animals (WO 01/053090 published 25 January 2001) and inhibit the growth of acute myeloid leukemia cells (Milella et al., J. Clin. Invest., 2001, 108(6), 851-859).

Some low molecular weight inhibitors of MEK are also discussed in, for example, WO 02/06213, WO 03/077855 and WO 03/077914. There is still a need for new inhibitors of MEK as an effective and safe therapeutic agents for the treatment of various proliferative diseases, such as conditions associated with hyperactivity of MEK, as well as diseases modulated by the MEK cascade.

The invention

The invention relates, in General, to isobenzofuranyl compounds of formula I (and/or their solvate and salts)that have anticancer and/or anti-inflammatory activity and more specifically, the activity of inhibiting the kinase MEK. Some of hyperproliferative and inflammatory disorders characterized by the modulation of the function of the kinase MEK, for example, due to mutations or overexpression of proteins. Accordingly, the compounds of this invention and their compositions useful in the treatment of hyperproliferative disorders such as cancer and/or inflammatory diseases such as rheumatoid arthritis.

where Z1represents CR1or N;

Z2represents CR2or N;

Z 3represents CR3or N;

Z4represents CR4or N;

where one or two of the Z1, Z2, Z3and Z4represent N;

R1, R2, R3and R4independently selected from H, halogen, CN,

CF3, -OCF3, -NO2, -(CR14R15)nC(=Y)R11, -(CR14R15)nC(=Y)OR11,

-(CR14R15)nC(=Y)NR11R12, -(CR14R15)nNR11R12, -(CR14R15)nOR11,

-(CR14R15)nSR11, -(CR14R15)nNR12C(=Y)R11, -(CR14R15)nNR12C(=Y)OR11,

-(CR14R15)nNR13C(=Y)NR11R12, -(CR14R15)nNR12SO2R11, -(CR14R15)nOC(=Y)R11,

-(CR14R15)nOC(=Y)OR11, -(CR14R15)nOC(=Y)NR11R12,

-(CR14R15)nOS(O)2(OR11), -(CR14R15)nOP(=Y)(OR11)(OR12),

-(CR14R15)nOP(OR11)(OR12), -(CR14R15)nS(O)R11, -(CR14R15)nS(O)2R11,

-(CR14R15)nS(O)2NR11R12, -(CR14R15)nS(O)(OR11), -(CR14R15)nS(O)2(OR11),

-(CR14R 15)nSC(=Y)R11, -(CR14R15)nSC(=Y)OR11, -(CR14R15)nSC(=Y)NR11R12,

(C1-C12)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, carbocycle,

heterocyclyl, aryl and heteroaryl;

W represents

R5and R6independently selected from H or (C1-C12)alkyl;

X1selected from R11, -OR11, -NR11R12, -S(O)R11and S(O)2R11; when X1is an R11or11, R11or11of X1and R5optionally taken together with the nitrogen atom to which they are attached, form a 4-7-membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6the alkyl), -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR6 C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21;

X2choose from carbocycle, heterocyclyl, aryl and heteroaryl;

R11, R12and R13independently represent H, (C1-C12)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, carbocyclic, heterocyclic, aryl or heteroaryl;

or R11and R12together with the nitrogen atom to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from the atoms O, S and N, where the specified ring neo is Astelin substituted by one or more groups, selected from halogen, CN, CF3, -OCF3, -NO2, (C1-C6)alkyl, -OH, -SH, -O(C1-C6)alkyl,

-S(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6alkyl)2,

-SO2(C1-C6)alkyl, -CO2H, -CO2(C1-C6)alkyl, -C(O)NH2,

-C(O)NH(C1-C6)alkyl, -C(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)CO(O)(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl,

-NHSO2(C1-C6)alkyl), -N(C1-C6alkyl)SO2(C1-C6)alkyl, -SO2NH2,

SO2NH(C1-C6)alkyl, -SO2N(C1-C6alkyl)2, -OC(O)NH2,

-OC(O)NH(C1-C6)alkyl, -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6)alkyl,

-NHC(O)NH(C1-C6)alkyl, -NHC(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)C(O)NH(C1-C6)alkyl,

-N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6)alkyl and

-N(C1-C6alkyl)C(O)O(C1-C6)alkyl;

R14and R15independently selected from H, (C1-C12)alkyl, aryl, carbocycle, heterocyclyl and heteroaryl;

m and n independently are selected from 0, 1, 2, 3, 4, 5 or 6;

Y independently represents O, NR11or S;

where is each specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl in R1, R2, R3, R4, R5, R6X1X2, R11, R12, R13, R14and R15optionally and independently substituted by one or more groups independently selected from halogen, CN,

CF3, -OCF3, -NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20) nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21;

each R16, R17and R18independently represents H, (C1-C12)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, carbocyclic, heterocyclic, aryl or heteroaryl where the specified alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl or heteroaryl optionally substituted by one or more groups selected from halogen, CN, -OCF3, CF3, -NO2, (C1-C6)alkyl, -OH, -SH,

-O(C1-C6)alkyl, -S(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl,

-N(C1-C6alkyl)2, -SO2(C1-C6)alkyl, -CO2H, -CO2(C1-C6)alkyl,

-C(O)NH2, -C(O)NH(C1-C6)alkyl, -C(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)C(O)(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl,

-NHSO2(C1-C6)alkyl, -N(C1-With6alkyl)SO2(C1-C6)alkyl, -SO2NH2,

SO2NH(C1-C6)alkyl, -SO2N(C1-C6alkyl)2, -OC(O)NH2,

-OC(O)NH(C1-C6)alkyl, -OC(O)N(C1-C6alkyl)2 , -OC(O)O(C1-C6)alkyl,

-NHC(O)NH(C1-C6)alkyl, -NHC(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)C(O)NH(C1-C6)alkyl,

-N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6)alkyl and

-N(C1-C6alkyl)C(O)O(C1-C6)alkyl;

or R16and R17together with the nitrogen atom to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN,

-OCF3, CF3, -NO2, (C1-C6)alkyl, -OH, -SH, -O(C1-C6)alkyl,

-S(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6alkyl)2,

-SO2(C1-C6)alkyl, -CO2H, -CO2(C1-C6)alkyl, -C(O)NH2,

-C(O)NH(C1-C6)alkyl, -C(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)C(O)(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl,

-NHSO2(C1-C6)alkyl, -N(C1-C6alkyl)SO2(C1-C6)alkyl, -SO2NH2,

SO2NH(C1-C6)alkyl, -SO2N(C1-C6alkyl)2, -OC(O)NH2,

-OC(O)NH(C1-C6 )alkyl, -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6)alkyl,

-NHC(O)NH(C1-C6)alkyl, -NHC(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)C(O)NH(C1-C6)alkyl,

-N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, NHC(O)O(C1-C6)alkyl and

-N(C1-C6alkyl)C(O)O(C1-C6)alkyl;

R19and R20independently selected from H, (C1-C12)alkyl, -(CH2)n-aryl, -(CH2)n-carbocycle, -(CH2)n-heterocyclyl and -(CH2)n-heteroaryl;

R21is a (C1-C12)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, carbocyclic, heterocyclic, aryl or heteroaryl, where each substituent R21optionally substituted by one or more groups selected from halogen, oxo, CN, -OCF3,

CF3, -NO2, (C1-C6)alkyl, -OH, -SH, -O(C1-C6)alkyl,

-S(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6alkyl)2,

-SO2(C1-C6)alkyl, -CO2H, -CO2(C1-C6)alkyl, -C(O)NH2,

-C(O)NH(C1-C6)alkyl, -C(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)C(O)(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl,

-NHSO2(C -C6)alkyl, -N(C1-C6alkyl)SO2(C1-C6)alkyl, -SO2NH2,

SO2NH(C1-C6)alkyl, -SO2N(C1-C6alkyl)2, -OC(O)NH2,

-OC(O)NH(C1-C6)alkyl, -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6)alkyl,

-NHC(O)NH(C1-C6)alkyl, -NHC(O)N(C1-C6alkyl)2,

-N(C1-C6alkyl)C(O)NH(C1-C6)alkyl,

-N(C1-C6alkyl)C(O)N(C1-C6alkyl)2,

-NHC(O)O(C1-C6)alkyl and-N(C1-C6alkyl)C(O)O(C1-C6)alkyl;

each Y' independently represents O, NR22or S; and

R22represents H or (C1-C12)alkyl.

The present invention relates to compositions (e.g., pharmaceutical compositions)containing the compound of formula I (and/or solvate and salt) and the media (pharmaceutically acceptable carrier). The present invention also relates to compositions (e.g., pharmaceutical compositions)containing the compound of formula I (and/or solvate and salt) and the media (pharmaceutically acceptable carrier, and optionally containing a second chemotherapeutic agent and/or the second anti-inflammatory agent. Compositions of the present invention are useful for inhibiting abnormal cell retaili treatment of hyperproliferative disorders in a mammal (for example, person). Compositions of the present invention are useful for the treatment of inflammatory diseases in a mammal (e.g. human).

The present invention relates to a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt) or compositions containing the specified connection, as such or in combination with a second chemotherapeutic agent.

The present invention relates to a method of treating inflammatory disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt) or compositions containing the specified connection, as such or in combination with a second anti-inflammatory agent.

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

Detailed description of examples of embodiments

Now will be described in detail some of the options done by the means of the invention, examples which explains the accompanying structures and formulas. Although the invention will be described in connection with the above variants of implementation, it should be borne in mind that it is not intended to be limiting of the invention specified options for implementation. On the contrary, it is assumed that the invention covers all alternatives, modifications and equivalents that may be included in the scope of the present invention, as defined in the claims. Specialist in the art will be able to present many methods and materials similar or equivalent to those described in this description that can be used in the practical implementation of the present invention. The present invention is in no way limited to the methods and materials. In the case when one or more of the included literature references, patents, and similar materials differ or conflict with this description, including, but without limitation, certain terms, the use of terms described methods or similar, it regulates the description.

Definitions

The term "alkyl", as used herein, refers to saturated linear or branched monovalent hydrocarbon radical with one to twelve carbon atoms. Examples of alkyl groups in luchot, but not limited to, 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(CH2CH2)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3) 2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 1-heptyl, 1-octyl etc.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical with two to twelve carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon double bond sp2where alkanniny radical includes radicals having orientation "CIS" and "TRANS", or, alternatively, the orientation of the "E" and "Z". Examples include, but are not limited to, ethylenic or vinyl (-CH=CH2), allyl (-CH2CH=CH2and so on

The term "quinil" refers to a linear or branched monovalent hydrocarbon radical with two to twelve carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon triple bond sp. Examples include, but are not limited to, ethinyl (CH≡CH), PROPYNYL (propargyl, -CH2With≡CH), etc.

The terms "carbocycle", "carbocyclic", "carbocyclic ring" and "cycloalkyl" refers to a monovalent non-aromatic saturated or partially unsaturated ring of from 3-12 carbon atoms as a monocyclic ring and 7-12 carbon atoms as a bicyclic ring. Bicyclic carbocycle with 7-12 atoms can be represented, for example, as bicikl is [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycle with 9 or 10 atoms in the ring can be represented as a bicyclo [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. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl etc.

The term "aryl" means a monovalent aromatic hydrocarbon radical with 6 to 18 carbon atoms, formed by removing one hydrogen atom from a single carbon atom of the original aromatic ring system. Some of the aryl groups represented in the examples of the structures as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring condensed with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, radicals formed from benzene (phenyl), substituted benzene, naphthalene, anthracene, indenyl, indanyl formed from 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene etc.

The terms "heterocycle","heterocyclyl" and "heterocyclic ring" are used herein interchangeably and refer to a saturated or partially unsaturated (i.e. with one or more double and/or triple bonds within the ring) carbocyclic the radical with 3-18 atoms in the ring, in which at least one atom in the ring is a heteroatom selected from nitrogen atoms, oxygen and sulfur, and the remaining atoms in the ring are atoms, where one or more atoms in the ring may be optionally independently substituted by one or more substituents described below. A heterocycle may be a monocycle having 3-7 atoms in the ring (2-6 carbon atoms and 1-4 heteroatoms selected their atoms N, O, P and S) or bicycl with 7-10 atoms in the ring (4-9 carbon atoms and 1-6 heteroatoms, selected atoms N, O, P and S), for example bicyclo[4,5], [5,5], [5,6] or [6,6] system. The heterocycles described in Paquette, Leo A, “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to the present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960), 82: 5566. "Heterocyclyl" also includes radicals where heterocyclic radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, Tetra droperidol, 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, pyrazolopyrimidines, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes and azabicyclo[2.2.2]hexanal. Spirography also included in the scope of this definition. Examples of heterocyclic groups in which 2 atoms in ring substituted groups, oxo (=O)are pyrimidinones and 1,1-dioxothiazolidine.

The term "heteroaryl" refers to a monovalent aromatic radical of a 5 - or 6-membered ring and includes a condensed cyclic system (at least one of which is aromatic) 5-18 atoms, containing one or more heteroatoms independently selected from nitrogen atoms, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridine), imidazolyl, imidazopyridines, pyrimidinyl (including, for example, 4-hydroxypyrimidine), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolin, pyrrolyl, hin is lineal, ethenolysis, indolyl, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzooxazole, hintline, honokalani, naphthyridines and properidine.

Heterocyclic or heteroaryl group can join in on the carbon atom (the carbon-accession) or nitrogen (nitrogen-accession), where possible. As an example, but not limitation, attached to the carbon atom heterocycles or heteroaryl attached in position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5 or 6 pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5 or 6 pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 oxazole, imidazole or thiazole, position 3, 4 or 5 isoxazol, pyrazole or isothiazole, position 2 or 3 of aziridine, position 2, 3 or 4 azetidine, position 2, 3, 4, 5, 6, 7 or 8 of a quinoline or position 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

As an example, but not limitation, attached to a nitrogen atom heterocycles or heteroaryl attached in position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, Piras is Lina, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of the research and position 9 carbazole or β-carboline.

The term "halogen" refers to F, Cl, Br or I. the Heteroatoms present in heteroaryl or heterocyclyl include the oxidized forms such as the N+→O-, S(O), and S(O)2.

The terms "treat" and "treatment" refer to both therapeutic measures properties and prophylactic or preventative measures, when the object is necessary to prevent or slow down (lessen undesired physiological change or disorder, such as the development or spread of cancer. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reducing the extent of disease, stabilization (i.e., the absence of worsening) state of disease, elimination or slowing disease progression, reducing the intensity or attenuation of a morbid state, and remission (full or partial), detectable or not detectable. "Treatment" can also mean a longer lifespan than expected if treatment is not given. Those in need of treatment include individuals who have already meetsomeone or disorder, and also susceptible to acquiring the disease condition or disorder, or individuals who have the condition or disorder must warn.

The expression "therapeutically effective amount" means an amount of compound of the present invention that (i) treats or prevents a disease, condition or disorder, (ii) facilitates reduces the intensity or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the occurrence of one or more symptoms of a particular disease, condition or disorder described herein. In the case of cancer, a therapeutically effective quantity of a drug may decrease the number of cancer cells; reduce the tumor size; inhibit (i.e., to weaken to some extent and preferably stop) infiltration of cancer cells to distant organs; inhibit (i.e., to weaken to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth and/or alleviate to some extent one or more symptoms associated with cancer. On the extent to which the drug may prevent growth and/or kill existing cancer cells, the but it may be cytostatic and/or cytotoxic. The effectiveness of cancer treatment can be measured, for example, assessing the time to disease progression (TTP) and/or determining the response rates (RR).

The term "abnormal cell growth" and "hyperproliferative disease" in this description are interchangeable. The term "abnormal cell growth" in this description, unless otherwise specified, refers to cell growth that is independent of normal regulatory mechanisms (e.g., lack of contact inhibition). The term includes, for example, abnormal growth (1) tumor cells (tumors)that proliferate by the expression of mutated tyrosine kinase or overexpression of the receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant activation of tyrosine kinase; (3) any tumors that proliferate at the expense of the receptor tyrosinekinase; (4) any tumors that proliferate due to aberrant activation of the serine/trionychinae; and (5) benign and malignant cells of other proliferative diseases in which aberrant activation of the serine/trionychinae.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in a mammal, which is specifically characterized by unregulated cell growth is m "Tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancy. More particular examples of such cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric cancer, including cancer of the gastrointestinal tract, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, endometrial cancer or uterine cancer, salivary gland cancer kidneys, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, carcinoma of the penis, acute leukemia, and cancers of the head/brain and neck cancer.

"Chemotherapeutic agent" is a chemical compound used in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (tarceva®, Genetech/OSI Pharm.), bortezomib (velcade®, Millennium Pharm.), fulvestrant (faslodex®, AstraZeneca), sutent (SU11248, Pfizer), letrozole (femara®, Novartis), of imatinib mesilate (gleevec®, Novartis), RTK/ZK 222584 (Novartis), oxaliplatin (eloxatin®, Saofi), 5-FU (5-fluorouracil, leucovorin, rapamycin (sirolimus, rapamune®, Wyeth), lapatinib (tukerb®, GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs) and gefitinib (iressa®, AstraZeneca), AG1478 effect, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and cyclophosphamide cytoxan®; alkyl sulphonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylaniline; acetogenin (in particular, bullatacin, bullatacin); camptothecin (including the synthetic analogue topotecan); bryostatin; callistemon; CC-1065 (including its synthetic analogues of adozelesin, carzelesin and bizelesin); cryptophycin (in particular, cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard gas analogues, such as chlorambucil, chlornaphazine, chlorpropamide, estramustine, ifosfamide, mechlorethamine, hydrochloride oxide mechlorethamine, melphalan, novemberin, finestein, prednimustine, trofosfamide, uracil mustard; nitrosoanatabine, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine and ranimustine; antibiotics such as andinavia antibiotics (for example, calicheamicin, cast the STI, calicheamicin-gamma and calicheamicin-omega (Angew. Chem. Intl. Ed. Engl. (1994), 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; spiramycin; and the chromophore neocarzinostatin and related chromophores chromatiaceae antibiotics), aclacinomycin, actinomycin, autralian, azaserine, bleomycin, actinomycin, carubicin, karminomitsin, casinopolis, chromomycin, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-L-norleucine, adriamycin® (doxorubicin, morphosyntactical, cyanomethaemoglobin, 2-pyrrolidinecarbonyl and desoxidation), epirubicin, zorubicin, idarubitsin, marsellaise, mitomycin, such as mitomycin C, mycofenolate acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, colomycin, idarubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); analogs of folic acid, such as deeperin, methotrexate, peripherin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, timipre, tioguanin; pyrimidine analogues such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, propionate dromostanolone, epitiostanol, mepitiostane, testolactone; and tatenergojsc means, such as aminoglutetimid, mitotane, trilostane; the means to add folic acid, such as prolinnova acid; Eagleton; glycoside aldophosphamide; aminolevulinic acid; eniluracil; amsacrine; astroball; bisantrene; edatrexate; defaming; demecolcine; diazinon; Alfonsin; the acetate slipline; epothilone; etoposide; gallium nitrate; hydroxyurea; lentinan; londonin; maytansinoid, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitrean; pentostatin; penomet; pirarubicin; losoxantrone; podofillina acid; 2-acylhydrazides; procarbazine; polysaccharide complexes PSK® (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tinoisamoa acid; creation; 2,2',2”-trihlortrietilamin; trichothecenes (in particular, the toxin T-2, verrucarin And, roridin and unguided); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; Galitsin; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoid, for example, taxol® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), abraxane™ (cremophor-free), nanocomposite of paclitaxel-based albumin (American Pharmaceutical Pertners, Schaumberg, Illinois), and taxotere® (docetaxel; Rhne-Poulenc Rorer, Antony, France); chlorambucil; gemzar® (gemcitabine); 6-tioguanin; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); IFOAM is d; mitoxantrone; vincristine; navelbine® (vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (xeloda®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; deformational (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above funds.

In the definition of "chemotherapeutic agent" also includes (i) antihormone means, which act on the tumor as a regulating or inhibiting the action of hormones, such as antiestrogens and selective estrogen receptor modulators (SERM), including, for example, tamoxifen (including nolvadex®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and fareston® (citrate toremifene); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates the production of estrogen in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megase® (acetate megestrol), aromazin® (exemestane; Pfizer), formestane, fadrozole, rivizor® (vorozole), femara® (letrozole, Novartis), and arimidex® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bikalutamid, leuprolide and goserelin; as well as troxacitabine (similar to 1,3-deoxyanthocyanins); (iv) inhibitors of protein kinases; (v) inhibitors lietkynes; (vi) antisense to oligonu leotide, in particular, oligonucleotides that inhibit expression of genes in cascades of signaling involved in aberrant cell proliferation, such as, for example, RKS-alpha, Ralf and H-Ras; (vii) ribozymes such as inhibitors of VEGF expression (for example, angiozime®), and inhibitors of HER2 expression; (viii) vaccines such as vaccines for gene therapy, for example, allovectin®, leuvectin®, and vexid®; proleukin® rIL-2; topoisomerase inhibitors 1, such as lurtotecan®, abarelix® rmRH; (ix) antiangiogenic agents such as bevacizumab (avastin®, Genetech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above funds. Other antiangiogenic tools include inhibitors of MMP-2 (metalloproteinase matrix 2), inhibitors of MMP-9 (metalloproteinase matrix 9)inhibitors, COX-II (cyclooxygenase II) inhibitors of tyrosine kinase VEGF receptors. Examples of the used inhibitors metalloproteinases matrix that can be used in combination with the compounds/compositions of the present invention, is described in WO 96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606046, EP 931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, U.S. patent No. 5863949, U.S. patent No. 5861510 and EP 780386, all of which are included in this description by reference. Examples of tyrosine kinase inhibitors of VEGF receptors include 4-(4-bromo-2-foronline)-6-methoxy-7-(1-methylp predin-4-ylethoxy)hinzelin (ZD6474; example 2 in WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1 ipropose)hinzelin (AZD2171; example 240 within WO 00/47212), vatalanib (RTK; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and such compounds as disclosed in PCT publication nos WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354).

Other examples of chemotherapeutic agents that can be used in combination with the compounds of the present invention include inhibitors of PI3K (phosphoinositide-3-kinase), such as described in footsteps of Yaguchi et al. (2006), in Jour. of the Nat. Cancer Inst., 98(8): 545-556; US 7173029; US 7037915; US 6608056; US 6608053; US 6838457; US 6770641; US 6653320; US 6403588; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; W) 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 141796; US 2004/053946; JP 2001247477; JP 0817990; JP 08176070; US 6703414 and WO 97/15658, all of which are included in this description by reference. Specific examples of such inhibitors include PI3K SF-116 (a PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (a PI3K inhibitor, Exelixis, Inc.).

The term "inflammatory disease"as used herein, includes, but is not limited to, rheumatoid arthritis, atherosclerosis, congestive heart failure, inflammatory bowel disease (including Crohn's disease and ulcerative colitis, and other diseases), chronic obstructive pulmonary disease, fibrotic liver disease and kidney disease is Ron, skin diseases such as psoriasis, eczema and scleroderma, osteoarthritis, multiple sclerosis, asthma, diseases and disorders associated with complications of diabetes, fibrotic failure in organs such as lungs, liver, kidneys, and complications due to inflammation of the cardiovascular system, such as acute coronary syndrome.

"Anti-inflammatory agent" is a compound useful for the treatment of inflammation. Examples of anti-inflammatory drugs include protein drugs for injection, such as Enbrel®, Remicade®, Humira®, Kineret®. Other examples of anti-inflammatory drugs include non-steroidal anti-inflammatory drugs (NSAID)such as ibuprofen or aspirin (which reduce swelling and relieve pain); disease modifying Antirheumatic drugs (DMARDs)such as methotrexate; 5-aminosalicylate (sulfasalazin and means that does not contain sulfur); corticosteroids; immunomodulators such as 6-mercaptopurine ("6-MP"), azathioprine ("AZA"), cyclosporine, and biological response modifiers, such as remicad.RTM. (infliximab) and Enbrel.RTM. (etanercept); fibroblast growth factors; platelet-derived growth factors, enzyme inhibitors, such as Arava.RTM. (Leflunomide); and/or means, protecting cartilage, such as hyaluronic acid, glucosamine and x is droidin.

The term "prodrug", as used herein, refers to a precursor or derivative compound of the present invention, which can be activated or enzymatically or hydrolytically, or to become more active in its original form. See, for example, Wilman, “Prodrugs in Cancer Chemotherapy”, Biochemical Society Transactions, 14, pp.375-382, 615thMeeting Belfast (1986)and Stella et al., “Prodrugs: A Chemical Approach to Targeted Drug Delivery”, Directed Drug Delivery, Borchardt et al. (ed.), pp.247-267, Humana Press (1985). Prodrugs of this invention include, but are not limited to, the prodrugs containing esters, phosphate-containing prodrugs, thiophosphoramide prodrugs, sulfadimidine prodrugs, peptideatlas prodrugs, and prodrugs based on modified D-amino acids, glycosylated prodrugs, β-lactosidase prodrugs, and prodrugs containing optionally substituted phenoxyacetamide, prodrugs containing optionally substituted phenylacetamide, 5-fertilizin and other prodrugs based on 5-ptoluidine, which can be converted into the more active cytotoxic free drug. Examples of cytotoxic drugs that can be converted in the form of prodrugs for use in this invention include compounds according to this invention and chemotherapeutics is their money, such as described above, and other medicines.

"Metabolite" is a product obtained by metabolism in the organism a compound or its salt. Metabolites of compounds can be identified using conventional methods known in this field, and their activity determined using tests such as described in this description. Such products may result, for example, oxidation, hydroxylation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic degradation, etc. entered the compound. Accordingly, the invention includes metabolites of compounds of the present invention, including the compounds obtained by the process comprising contacting compounds of this invention with the body of a mammal for a time sufficient to obtain a product of its metabolism.

"Liposome" is a small vesicles composed of various types of lipids, phospholipids and/or surfactant, which is applicable for delivery of a drug (such as MEK inhibitors disclosed herein, and optionally a chemotherapeutic drug) in the body of a mammal. Components of liposomes are usually placed in two layers, like the tra is of lipids in biological membranes.

The term "liner in the package" is used in relation to instructions, usually included in commercial packages of therapeutic products, that contain information about the indications, utility, application, introduction, contraindications and/or warnings concerning the use of such therapeutic products.

The term "chiral" refers to molecules that have the property cannot be collocated with the corresponding mirroring, while the term "achiral" refers to molecules that can be combined with the corresponding mirroring.

The term "stereoisomer" refers to compounds which have identical chemical composition, but different orientations of their atoms in space that cannot be transmuted into one another by rotation around a simple connection.

The term "diastereoisomer" refers to a stereoisomer with two or more centers of chirality, molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. A mixture of diastereoisomers can be divided analytical methods high resolution, such as crystallization, electrophoresis and chromatography.

The term "enantiomers" refers the I to the two stereoisomers of the compounds, which are incompatible mirror images of each other.

Stereochemical definitions and rules used in this description correspond to the work of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons,Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is assumed that all stereoisomeric forms of the compounds of the present invention, including, but not limited to, the diastereomers, the enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate plane-polarized light. When describing an optically active compounds of the prefixes D and L, R and S are used to denote the absolute configuration of the molecule about its chiral(s) centre(s). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or l means that the connection is levogyrate. The connection to the prefix (+) or d is Pervouralsk. For a given chemical structure of such stereoisomers are identical, except for the receiving, they are mirror images of each other. A specific stereoisomer can also be attributed to the enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. The mixture of enantiomers of 50:50 is called a racemic mixture or a racemate, which can occur when a chemical reaction or process no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The term "tautomer or tautomeric form" refers to the structural isomers of various energy that can vzaimoperekrehivayutsya via a low energy barrier. For example, proton tautomers (also known as prototroph the tautomers) by migration of the proton involved in vzaimoprevrascheny, such as keto-enol and imino-Eminova isomerization. Valence tautomers are involved in vzaimoprevrascheny by reorganizing some of the bonding electrons.

The expression "pharmaceutically acceptable salt", as used herein, refers to pharmaceutically acceptable organic or inorganic salts of the compounds of this invention. Examples of salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisu ifaty, phosphates, hydrogen phosphates, isonicotinate, lactates, salicylates, hydronitrate, tartratami, oleates, tannate, Pantothenate, bitartrate, ascorbate, succinate, maleate, entityname, fumarate, gluconate, saharty, formate, benzoate, glutamate, methanesulfonate, mesylates", econsultancy, bansilalpet, p-toluensulfonate, pamoate (i.e. 1,1'-Methylenebis(2-hydroxy-3-naphthoate), alkali metal salts (e.g. sodium and potassium), salts of alkaline earth metals (e.g. magnesium), and ammonium salts. Pharmaceutically acceptable salt may include the inclusion of other molecules such as acetate ion, succinate ion, or other counterion. The counterion may be an organic or inorganic particle, which stabilizes the charge on the source connection. Moreover, pharmaceutically acceptable salt can have a number of charged atoms in its structure. When multiply charged atoms are part of a pharmaceutically acceptable salt, can be several counterions. Consequently, the pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

If the connection of the present invention is a base, the desired pharmaceutically acceptable salt may be obtained by any suitable method available in this area, for example by processing the Oh free base inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesulfonate acid, phosphoric acid, etc. 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, paranoidly acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluensulfonate acid or econsultancy acid, or similar connection.

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

The expression "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients that make up the composition, and/or the body of a mammal, which is subjected to the treatment.

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

The term "hydrate" refers to a complex in which the solvent molecule is water.

The term "protective group" refers to the Deputy, which is usually used to lock or protect certain functional groups at the time when the reaction take other groups of compounds. For example, "aminosidine group" represents a Deputy, attached to the amino group that blocks or protects the functional amino compounds. the right aminosidine groups include acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl (VOS), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, the term "hidroxizina group" refers to the Deputy hydroxy-group that blocks or protects the functional hydroxy-group connections. Suitable protective groups include acetyl and silyl. The term "carboxyamide group" refers to the Deputy carboxypropyl that blocks or protects the functional carboxypropyl connection. Normal carboxyamide group include phenylsulfonyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluensulfonyl)ethyl, 2-(p-nitrobenzylidene)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl and similar groups. General description of the protective groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound in this invention" and "compounds of the present invention" and "compounds of formula I, unless otherwise indicated, include compounds of formula I and stereoisomers, geometric isomers, tautomers, solvate, metabolites, salts (e.g., pharmaceutically acceptable salts and prodrugs.

The present invention relates to isobenzofuranyl compounds of formula I, described above, are useful as kinase inhibitors, particularly as inhibitors of the kinase MEK. Infusion is her invention includes compounds of formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h and III-i, and all other variables have the meanings indicated for formula I.

In the embodiment of the present invention the compounds are compounds of formula I-b, I-f, I-g, I-h, II-b, II-f, II-g, II-h, III-b, III-f, III-g, III-h, and all other variables have the meanings indicated for formula I.

In the embodiment of the present invention the compounds are compounds of formula III-c, and all other variables have the meanings indicated for formula I.

In the embodiment of the present invention R1represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or (C1-C6)alkyl, and all other variables have the meanings specified for formula I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f and III-g.

In another embodiment, the present invention R1represents H, halogen, CN, CF3, (C1-C6)alkyl, -NR11R12where R11and R12independently represent H or (C1-C6)alkyl, -OR11where R11represents H or (C1-C6)alkyl, or-SR11where R11represents H or (C1-C6)alkyl; and the CE other variables have the meanings indicated for formula I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f and III-g.

In another embodiment, the present invention R1represents H, Cl, CN, CF3, methyl, -NH2, -NH(CH3), -N(CH3)2, -OH or-och3; and all other variables have the meanings specified for formula I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f and III-g.

In yet another embodiment, the present invention R1represents H; and all other variables have the meanings specified for formula I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f and III-g.

In the embodiment of the present invention R2represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or (C1-C6)alkyl, and all other variables have the meanings specified for formula I, I-a, I-C, I-d, I-e, I-i, II-a, II-C, II-d, II-e, II-i, III-a, III-C, III-d, III-e, or III-i, or the above values.

In another embodiment, the present invention R2represents H, halogen, CN, CF3, (C1-C6)alkyl, -NR11R12where R11and R12independently represent H or (C1-C6)alkyl, -OR11where R11represents H or (C1-C6)alkyl, or-SR11where R11represents H or (C1-C6)is lkyl; and all other variables have the meanings specified for formula I, I-a, I-C, I-d, I-e, I-i, II-a, II-C, II-d, II-e, II-i, III-a, III-C, III-d, III-e, or III-i, or the above values.

In another embodiment, the present invention R2represents H, Cl, CN, CF3, methyl, -NH2, -NH(CH3), -N(CH3)2, -OH or-och3; and all other variables have the meanings specified for formula I, I-a, I-C, I-d, I-e, I-i, II-a, II-C, II-d, II-e, II-i, III-a, III-C, III-d, III-e, or III-i, or the above values.

In the embodiment of the present invention R3represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or (C1-C6)alkyl, and all other variables have the meanings specified for formula I, I-a, I-C, I-d, I-e, I-i, II-a, II-C, II-d, II-e, II-i, III-a, III-C, III-d, III-e, or III-i, or the above values.

In another embodiment, the present invention R3represents H, halogen, CF3, (C1-C6)alkyl; and all other variables have the meanings specified for formula I, I-a, I-C, I-d, I-e, I-i, II-a, II-C, II-d, II-e, II-i, III-a, III-C, III-d, III-e, or III-i, or the above values.

In yet another embodiment, the present invention R3represents H, F, CF3or methyl; and all other variables have the meanings specified for formula I, I-a, I-C, I-d, I-e, I-i, II-a, II-C, II-d, II-e, II-i, IIIa, III-C, III-d, III-e, or III-i, or the above values.

In yet another embodiment, the present invention R3represents H, F, Cl, methyl or CN; and all other variables have the meanings specified for formula I, I-a, I-C, I-d, I-e, I-i, II-a, II-C, II-d, II-e, II-i, III-a, III-C, III-d, III-e, or III-i, or the above values.

In the embodiment of the present invention R4represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or (C1-C6)alkyl, and all other variables have the meanings specified for formula I, I-a, I-b, I-C, I-e, I-g, I-h, II-a, II-b, II-C, II-e, II-g, II-h, III-a, III-b, III-C, III-e, III-g, III-h, or the above values.

In another embodiment, the present invention R4represents H, halogen, CN, CF3, -NR11R12or-C(=O)NR11R12where R11and R12independently represent H or (C1-C6)alkyl, -OR11where R11represents H or (C1-C6)alkyl, or-SR11where R11represents H or (C1-C6)alkyl; and all other variables have the meanings specified for formula I, I-a, I-b, I-C, I-e, I-g, I-h, II-a, II-b, II-C, II-e, II-g, II-h, III-a, III-b, III-C, III-e, III-g, III-h, or the above values.

In another embodiment, the present invention R4represents H, Br, CN, CF3, -NH2, -NH(CH3), -N(CH3)2, -C(O)NH2, -C(O)NH(CH3), C(O)N(CH3)2, -OH or-och3; and all other variables have the meanings specified for formula I, I-a, I-b, I-C, I-e, I-g, I-h, II-a, II-b, II-C, II-e, II-g, II-h, III-a, III-b, III-C, III-e, III-g, III-h, or the above values.

In another embodiment, the present invention R4represents H, Br, Cl, CN, CF3, -NH2, -NH(CH3), -N(CH3)2, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -OH or-och3; and all other variables have the meanings specified for formula I, I-a, I-b, I-C, I-e, I-g, I-h, II-a, II-b, II-C, II-e, II-g, II-h, III-a, III-b, III-C, III-e, III-g, III-h, or the above values.

In another embodiment, the present invention R4represents halogen, HE or (C1-C6)alkyl, optionally substituted with halogen and all other variables have the meanings specified for formula I, I-a, I-b, I-C, I-e, I-g, I-h, II-a, II-b, II-C, II-e, II-g, II-h, III-a, III-b, III-C, III-e, III-g, III-h, or the above values.

In another embodiment, the present invention R4independently represents Cl, Br, Me, Et, F, CHF2, CF3or-OH; and all other variables have the meanings specified for formula I, I-a, I-b, I-C, I-e, I-g, I-h, II-a, II-b, II-C, II-e, II-g, II-h, III-a, III-b, III-C, III-e, III-g, III-h, or the above values.

In the embodiment, the infusion is his invention R 5represents H or (C1-C6)alkyl; and all other variables have the meanings specified for formula I, (I-a)-(I-i) or (II-a)to(II-i)or the above values.

In another embodiment, the present invention R5represents H or methyl; and all other variables have the meanings specified for formula I, (I-a)-(I-i) or (II-a)to(II-i)or the above values.

In another embodiment, the present invention R5represents H; and all other variables have the meanings specified for formula I, (I-a)-(I-i) or (II-a)to(II-i)or the above values.

In another embodiment, the present invention R5represents methyl; and all other variables have the meanings specified for formula I, (I-a)-(I-i) or (II-a)to(II-i)or the above values.

In the embodiment of the present invention R6represents H or (C1-C6)alkyl; and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention R6represents H or methyl; and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention R6predstavljaet a N; and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention R6represents methyl; and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In the embodiment of the present invention X1is a OR11(i.e. of the formula (II-a)to(II-i)); and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1is a OR11where R11represents H; and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1is a OR11where R11is a (C1-C12)alkyl (for example, (C1-C6)alkyl), substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3,

-NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R7 ,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents a

and all other variables kayttajani, specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I or (I-a)-(I-I), or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I or (I-a)-(I-I), or the above values.

In another embodiment, the present invention X1is a OR11where R11represents heterocyclyl (e.g., 4-6-membered heterocyclyl), optionally substituted by one or more groups independently selected Shalagina, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6)alkyl,

-(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17,

-(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nSR16,

-(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17,

-(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16,

-(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21;

and all other variables have the meanings specified for formula I or (I-a)(I-i), or the above values.

In another embodiment, the present invention X1is a OR11where R11is a 4-6-membered heterocyclyl with 1 nitrogen atom in the ring, where specified heterocyclyl optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3,

-NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR6 R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In the embodiment of the present invention X1is an R11and X1and R5taken together with the nitrogen atom to which they are attached, form a 5-7-membered saturated or unsaturated ring having 0-2 additional heteroatom is a, selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen,

CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19Rsup> 20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1is an R11and X1and R5taken together with the nitrogen atom to which they are attached, form a 5-6-membered saturated ring having 0-2 additional heteroatoms selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, CF3,

-OCF3, -NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)n OP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention W is a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention W is a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention W is a

;

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In the embodiment of the present invention X1the submitted is an R 11and X1and R5taken together with the nitrogen atom to which they are attached, form a 4-membered saturated or unsaturated ring having 0-1 additional heteroatom selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen,

CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR 19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention W is a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In the embodiment of the present invention X1represents-OR11and-OR11of X1and R5taken together with the nitrogen atom to which they are attached, form a 4-7-membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16,

-(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16,

-(CR19R20)nSR16, -(CR19R )nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17,

-(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16,

-(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention X1represents-OR11and-OR11of X1and R5taken together with the nitrogen atom to which they are attached, form a 5-7-membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo,

-Si(C1 -C6)alkyl, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16,

-(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16,

-(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17,

-(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16,

-(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another Varian is the first implementation of the present invention X 1represents-OR11and-OR11of X1and R5taken together with the nitrogen atom to which they are attached, form a 5-6-membered saturated ring having 0-2 additional heteroatoms selected from the atoms O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen,

CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR 16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In another embodiment, the present invention W is a

and all other variables have the meanings specified for formula I or (I-a)-(I-i), or the above values.

In the embodiment of the present invention X1is an R11; and all other variables have the meanings specified for formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or the above values.

In another embodiment, the present invention X1is an R11where R11represents H; and all other variables have the meanings specified for formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or the above values.

In another embodiment, the present invention X1is an R11where R11is a (C1-C12)alkyl (for example, (C1-C6)alkyl), substituted by one or more groups independently chosen is from halogen, CN, CF3, -OCF3,

-NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all

other variables have the meanings specified for formula I, I-a, I-b, Ic, I-d, I-e, I-f, I-g, I-h, I-i, or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or the above values.

In another embodiment, the present invention X1represents a

and all other variables have the meanings specified for formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or the above values.

In another embodiment, the present invention X1represents-S(O)2R11and all other variables have the meanings specified for formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or the above values.

In another embodiment, the present invention X1represents-S(O)2R11where R11represents H or methyl; and all other variables have the meanings specified for formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or the above values.

In another embodiment, the present invention W is a OR11(i.e. the compound has the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i), where R11W represents H or (C1-C12)alkyl; and all the other variables have the values indicated above.

In another embodiment, the present invention W is a OR11(i.e. the compound has the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i), where R11W represents H; and all other variables have the values indicated above.

In another embodiment, the present invention W is a OR11(i.e. the compound has the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i), where R11W is a (C1-C6)alkyl; and all other variables have the values indicated above.

In the embodiment of the present invention X2represents aryl (e.g. phenyl), where the indicated aryl optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo,

-Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16,

-(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16,

-(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17,

-(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16,

-(CR19R20/sup> )nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2representsand all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2is a (C6-C10)aryl, substituted(C1-C4)alkyl; and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents carbocyclic (for example, (C4-C6)carbocyclic) or heterocyclyl (e.g., 4-6-membered heterocyclyl)where the specified carbocyclic or heterocyclyl optionally substituted by one or more groups independently selected from halogen, CN, CF3,

-OCF3, -NO2, oxo, -Si(C1-C6)alkyl, -(CR19R20)nC(=Y')R16,

-(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17,

-(CR19R20)nOR16, -(CR19R20)nSR16, -(CR19R20)nNR16C(=Y')R17,

-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17,

-(CR19R20)nNR17SO2R16-(CR 19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16,

-(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16),

-(CR19R20)nOP(=Y')(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),

-(CR19R20)nS(O)R16, -(CR19R20)nS(O)2R16, -(CR19R20)nS(O)2NR16R17,

-(CR19R20)nS(O)(OR16), -(CR19R20)nS(O)2(OR16), -(CR19R20)nSC(=Y')R16,

-(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and

all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2is a (C4-C6)carbocyclic, substituted-C(=Y')R16; and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above values.

In another embodiment, the present invention X2represents a

and all other variables have the meanings specified for formula I, (I-a)-(I-i), (II-a)to(II-i) or (III-a)to(III-i), or the above value is s.

Another variant of implementation of the present invention includes compounds described in examples 5-12, and the connections are listed below:

Compounds of the present invention receive according to the methods described below in the schemes and in the examples or by methods known in this field. The initial substance and various intermediate compounds can be obtained from commercial sources, be obtained from commercially available compounds or receive using well-known synthetic methods (for example, the methods described in WO 02/06213, WO 03/077855 and WO 03/077914).

For example, 5-anabantoidei formula (I-b), (II-b) or (III-b) can be obtained by using paths of synthesis shown in schemes 1, 2 and 3.

Scheme 1

The compounds of formula (IV) can be obtained using the methods described in the literature. They can be subjected to interaction with methylthioribose or aterciopelados in the presence of a base such as sodium hydride, in a suitable solvent such as N,N-dimethylformamide or 1,2-dimethoxyethane, at temperatures from -50°C to room temperature, to obtain the compounds of formula (VI).

The compounds of formula (VI) can be converted into compounds of formula (VII) usaimage the action, with a halogenation agent, such as oxybromide phosphorus, pure or in a suitable solvent, such as toluene, at a temperature of from room temperature to 140°C. Alternatively, the compounds of formula (VI) can be subjected to interaction with nonatherosclerotic in the presence of a base, such as diisopropylethylamine, and a catalyst, such as N,N-dimethyl-4-aminopyridine, in a solvent such as dichloromethane, at room temperature, N-phenyltrimethylammonium in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as 1,2-dimethoxyethane, at a temperature of from room temperature to the temperature of reflux distilled the solvent. In addition, the compounds of formula (VI) can be treated with anhydride triftormetilfullerenov acid in the presence of a base, such as pyridine, in a solvent such as dichloromethane, at a temperature from -20°C to ambient temperature.

The compounds of formula (VIII) can be obtained from compounds of formula (VII) interaction with aniline (incorporating appropriate substituents R1) in the presence of a catalyst such as Tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, a base such as potassium phosphate, tert-piperonyl sodium, 1,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, ligand, such as 9,9'-dimethyl-4,5-bis(diphenylphosphino)xanthene, 2,2'-bis(diphenyl spine)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',6'-(dimethoxy)biphenyl or tributylphosphine, in a suitable solvent, such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at temperatures from room temperature to the temperature of reflux distilled solvent or when exposed to microwave irradiation at a temperature of from 70°to 150°C.

Alternatively, the compounds of formula (VIII) can be obtained from compounds of formula (VI) interaction with compounds of the formula (IX) (obtained using the methods described in the literature), in a suitable solvent, such as toluene or 1,2-dimethoxyethane, at a temperature of from room temperature to the temperature of reflux distilled solvent or when exposed to microwave irradiation at a temperature of from 100°C. to 180°C.

The compounds of formula (X) can be obtained from compounds of formula (VIII) interaction with base, such as sodium hydroxide, in proton solvent such as ethanol or methanol, at temperatures from room temperature to the boiling temperature under reflux.

The compounds of formula (X) can be subjected to interaction with functionalized hydroxylamine of the formula (XII) (commercially available or obtained according to the scheme 6) or an amine and a suitable agent combinations, such as hexaphosphate O-(7-azaban triazol-1-yl)-N,N,N',N'-tetramethylurea, the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or N,N'-dicyclohexylcarbodiimide, in the presence of N-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base, such as diisopropylethylamine or triethylamine, in an inert solvent, such as tetrahydrofuran, N,N-dimethylformamide or dichloromethane, at about room temperature, to obtain the compounds of formula (XI). Alternatively, the compounds of formula (XI) can be obtained directly from compounds of formula (VIII) interaction with an amine or hydroxylamine DNHR in the presence of a Lewis acid such as trimethylaluminum in a solvent such as DCM, at a temperature of from room temperature to the boiling temperature under reflux.

Alternatively, the compounds of formula (VIII) can be obtained from compounds of formula (XIII) according to the scheme 2.

Scheme 2

The compounds of formula (XIII) can be obtained using the methods described in the literature. Compounds of General formula (XIV) can be obtained from compounds of formula (XIII) using the methods described above to obtain compounds of the formula (VI) from compounds of formula (IV).

The compounds of formula (VIII) can be obtained from compounds of formula (XIV) interaction with compounds of the formula (XV) (incorporating appropriate substituents R1) using the methods of sannich above to obtain compounds of the formula (VIII) from compounds of formula (VI). Alternatively, the compounds of formula (VIII) can be obtained from compounds of formula (XIV) interaction with compounds of the formula (XVI) (incorporating appropriate substituents R1) in the presence of a base such as sodium hydride or hexamethyldisilazane lithium, in a suitable solvent, such as tetrahydrofuran or N,N-dimethylformamide, at a temperature of from room temperature to 150°C.

Alternatively, the compounds of formula (X) can also be obtained from compounds of formula (VII) according to scheme 3.

Scheme 3

The compounds of formula (VII) can be converted into compounds of formula (XVII) using the methods described above to obtain compounds of the formula (X) compounds of the formula (VIII). The compounds of formula (XVII) can be subjected to reaction combination with amines, such as 2-amino-2-methyl-1-propanol, using the methods described above to obtain compounds of the formula (XI) from compounds of formula (X), with subsequent interaction with this agent, as thionyl chloride or phosphorus oxychloride, pure or in a suitable solvent, such as dichloromethane, chloroform or diethyl ether, at temperatures from room temperature to the temperature of reflux distilled solvent to obtain compounds of the formula (XVIII).

The compounds of formula (XIX) can be obtained from compounds of formula (XVIII) interaction is m aniline (incorporating appropriate substituents R1) in the presence of a catalyst, such as Tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, a base such as potassium phosphate, tert-piperonyl sodium, 1,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, ligand, such as 9,9'-dimethyl-4,5-bis(diphenylphosphino)xanthene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',6'-(dimethoxy) - biphenyl or tributylphosphine, in a suitable solvent, such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at temperatures from room temperature to the temperature of reflux distilled solvent or when exposed to microwave irradiation at a temperature of from 70°to 150°C.

Alternatively, the compounds of formula (XIX) can be obtained from compounds of formula (XVIII) interaction with aniline (incorporating appropriate substituents R1) in the presence of a base such as sodium hydride or hexamethyldisilazane lithium, in a suitable solvent, such as tetrahydrofuran or N,N-dimethylformamide, at a temperature of from room temperature to 150°C. Compounds of formula (X) can be obtained from compounds of formula (XIX) by interaction with an acid, such hydrogen chloride or acetic acid, in a suitable solvent such as water, at a temperature of from room temperature to the temperature of reflux distilled solvent.

6-Anabantoidei formula I-c, II-c and III-c can be obtained using the ways of synthesis, shown in figure 4.

Scheme 4

The compounds of formula (XX) can be obtained using the methods described in the literature. They can be subjected to interaction with methylglucose or ethylglycol in the presence of a phosphine, such as triphenylphosphine, alkylcarboxylic, such as diethylazodicarboxylate or diisopropylethylamine, in an aprotic solvent such as tetrahydrofuran or diethyl ether, at temperatures from room temperature to the temperature of reflux distilled solvent to obtain compounds of the formula (XXI).

The compounds of formula (XXI) can be subjected to interaction in the presence of a base such as sodium hydride, in a suitable solvent such as N,N-dimethylformamide or 1,2-dimethoxyethane, at temperatures from -50°C to room temperature, to obtain the compounds of formula (XXII).

The compounds of formula (XXII) can be converted into compounds of formula (XXIII) by interaction with a halogenation agent such as oxybromide phosphorus, pure or in a suitable solvent, such as toluene, at a temperature of from room temperature to 140°C. Alternatively, the compounds of formula (XXII) can be subjected to interaction with nonatherosclerotic in the presence of a base, such as diisopropylethylamine, and a catalyst, such as N,N-d is methyl-4-aminopyridine, in a solvent such as dichloromethane, at room temperature, N-phenyltrimethylammonium in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as 1,2-dimethoxyethane, at a temperature of from room temperature to the temperature of reflux distilled solvent. In addition, the compounds of formula (VI) can be treated with anhydride triftormetilfullerenov acid in the presence of a base, such as pyridine, in a solvent such as dichloromethane, at a temperature from -20°C to ambient temperature.

The compounds of formula (XXIV) can be obtained from compounds of formula (XXIII) interaction with aniline (incorporating appropriate substituents R1) in the presence of a catalyst such as Tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, a base such as potassium phosphate, tert-piperonyl sodium, 1,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, ligand, such as 9,9'-dimethyl-4,5-bis(diphenylphosphino)xanthene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',6'-(dimethoxy)biphenyl or tributylphosphine, in a suitable solvent, such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at temperatures from room temperature to the temperature of reflux distilled solvent or when exposed to microwave irradiation is placed at a temperature of from 70°to 150°C.

Alternatively, the compounds of formula (XXIV) can be obtained from compounds of formula (XXII) interaction with compounds of the formula (IX) (obtained using the methods described in the literature), in a suitable solvent, such as toluene or 1,2-dimethoxyethane, at a temperature of from room temperature to the temperature of reflux distilled solvent or when exposed to microwave irradiation at a temperature of from 100°C. to 180°C.

The compounds of formula (XXVI) can be obtained from compounds of formula (XXIV) by interaction with a base such as sodium hydroxide, in proton solvent such as ethanol or methanol, at temperatures from room temperature to the boiling temperature under reflux.

The compounds of formula (XXVI) can be subjected to interaction with functionalized hydroxylamine of the formula (XII) (commercially available or obtained according to the scheme 6) or an amine and a suitable agent combinations, such as hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea, hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or N,N'-dicyclohexylcarbodiimide, in the presence of N-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base, such as diisopropylethylamine or triethylamine, in an inert solvent, such as tetrahydrofuran, N,N-dimethylformamide or dichloromethane, at about the rooms is the first temperature, obtaining compounds of formula (XXVIII). Alternatively, the compounds of formula (XXVI) can be obtained directly from compounds of formula (XXIV) by interaction with the amine or hydroxylamine DNHR in the presence of a Lewis acid such as trimethylaluminum in a solvent such as DCM, at a temperature of from room temperature to the boiling temperature under reflux.

Thieno[2,3-d]pyrimidines of the formula I-f, II-f, III-f can be obtained by using paths of synthesis shown in scheme 5.

Scheme 5

The compounds of formula (XXVIII) can be obtained according to methods described in the literature. They can be subjected to interaction with a halogenation agent such as phosphorus oxychloride, pure or in a suitable solvent, such as toluene, at a temperature of from room temperature to the boiling temperature under reflux, to obtain the compounds of formula (XXIX).

The compounds of formula (XXXVI) can be obtained from compounds of formula (XXXIX) using the methods described for preparing compounds of the formula (XI) from compounds of formula (IV), as shown in figure 5.

Hydroxylamine formula (XII) can be obtained using the methods described in the literature, or synthetically shown in scheme 6.

Scheme 6

The primary or torinia alcohols of General formula (XXXVII) can be obtained using methods described in the literature. They can be subjected to interaction with 1-hydroxyphthalimide using phosphine and reagent combinations, such as diethylazodicarboxylate, to obtain the compounds of General formula (XXXVIII). Of the compounds of General formula (XXXVIII) can remove the protective group using hydrazine or methylhydrazine and get hydroxylamine General formula (XII-a). Compounds of General formula (XII-a) can be modified further by reductive amination with aldehydes or ketones using a reducing agent such as triacetoxyborohydride sodium, cyanoborohydride sodium or borane-pyridine, in a solvent such as dichloroethane at a temperature of from ambient temperature to the boiling temperature under reflux. In addition, compounds of General formula (XII-a) can be modified further by alkylation with alkylhalogenide in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, to obtain hydroxylamine General formula (XII-b).

Anilines of General formula (XXXIX)used in the reaction cross-combinations described above can be obtained using the methods described in the literature or according to scheme 7.

Scheme 7

Substituted 4-chloronitrobenzene can be subjected to interaction with hexamethyldisilane the om in the solvent, such as xylene, using a catalyst such as tetrakis(triphenylphosphine)palladium, at a temperature of from room temperature to the boiling temperature under reflux. The nitro-group can be restored using the methods described in the literature, such as the reaction in an atmosphere of hydrogen at a pressure of from 1 to 5 atmospheres in the presence of a catalyst such as palladium-on-carbon, in a solvent such as ethanol or ethyl acetate, at room temperature.

Trifloromethyl esters of General formula (XL)used in the reaction cross-combinations described above can be obtained using the methods described in the literature or according to scheme 8.

Scheme 8

Halogenfrei General formula (XLI) can be subjected to the interaction with two equivalents of alkyllithium reagents, such as n-utility, in a solvent such as THF, followed by quenching with trialkylaluminium, such as trimethylsilane, obtaining trialkylsilyl (XLII). Then trialkylsilanes can be communication using the techniques described in the literature, obtaining triftormetilfullerenov or nonathletes General formula (XL).

It should be borne in mind that when you have the appropriate functional group to be connected to the I formula (I), (II), (III) or any intermediate compounds used in their preparation, can be further derivateservlet one or more standard methods of synthesis using substitution reactions, oxidation, recovery, or splitting. Specific treatment for substitution reactions include conventional methods of alkylation, arilirovaniya, heteroarylboronic, acylation, sulfonylamine, halogenoalkane, nitration, formirovanie and combinations.

For example, arilbreds or chloride group can be converted to arylidene group using the Finkelstein reaction using sources of iodine, such as sodium iodide, and a catalyst such as copper iodide, a ligand such as TRANS-N,N'-dimethyl-1,2-cyclohexanediamine, in a solvent such as 1,4-dioxane by heating the reaction mixture up to the boiling temperature under reflux. Aryldialkyl can be converted to arisitide processing silane source of iodine, such as monochloride iodine, in a solvent such as dichloromethane, with or without a Lewis acid, such as Teterboro silver, at a temperature from -40°C up to the boiling temperature under reflux.

In another example, a primary amino group (-NH2) you can alkilirovanii using the method of reductive alkylation using an aldehyde and the and ketone and borohydride, for example triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, or an alcohol, such as ethanol, optionally in the presence of acid, such as acetic acid, at ambient temperature. Secondary amino group (-NH-) you can alkilirovanii in a similar way using aldehyde.

In another example, primary or secondary amino group can be converted to the amide group (-NHCOR', or-NRCOR') by acylation. Acylation can be achieved by interaction with the appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by interaction with a corresponding carboxylic acid in the presence of a suitable agent combinations, such as HATU (hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea), in a suitable solvent such as dichloromethane. Similarly, the amino group can be converted to sulfonamidnuyu group (-NHSO2R' or-NR”SO2R') interaction with the corresponding sulphonylchloride in the presence of a base, such as triethylamine, in a suitable solvent such as dichloromethane. Primary or secondary amino group can be converted to the urea group (-NHCONR'R” or-NRCONR'R”) interaction with relevant from anatom in the presence of a base, such as triethylamine, in a suitable solvent such as dichloromethane.

Amine (-NH2) can be obtained by restoring the nitro group (-NO2), for example, catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a carrier, such as charcoal, in a solvent such as ethyl acetate or an alcohol, e.g. methanol. Alternatively, the conversion can be performed chemical recovery using, for example, metal, such as tin or iron, in the presence of acid, such as hydrochloric acid.

In another example, the amino group (-CH2NH2) can be obtained by recovering the nitrile (-CN), for example, catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a carrier, such as charcoal or Raney Nickel, in a solvent such as simple ether, e.g. a cyclic simple ether, such as tetrahydrofuran, at temperatures from -78°C to the temperature of reflux distilled solvent.

In another example, the amino group (-NH2) can be obtained from the carboxylic groups (-CO2N) by conversion into the corresponding acylated (-CON3), Curtis rearrangement and hydrolysis of the resulting isocyanate (-N=C=O).

Aldehyde group (-Cho) can be transformed into the in the amino group (-CH 2NR'r R”) by reductive amination using an amine and borohydride, such as triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, or an alcohol, such as ethanol, optionally in the presence of acid, such as acetic acid, at ambient temperature.

In another example, the aldehyde group can be converted to alkeneamine group (-CH=CHR')using a Wittig reaction or Wadsworth-Emmons, using the appropriate phosphonate under standard conditions known to specialists in this field.

Aldehyde groups can be obtained by reduction of the ester groups (such as CO2Et) or NITRILES (-CN) using hydride diisobutylaluminum in a suitable solvent, such as toluene. Alternatively, the aldehyde group can be obtained by oxidation of the alcohol group with a suitable oxidizing agent, known to specialists in this field.

Ester group (-CO2R') can be converted into the corresponding acid group (-CO2N) catalyzed by acid or base hydrolysis, depending on the nature of R. If R is a tert-butyl, hydrolysis, acid catalyzed, can be realized, for example, by treatment with an organic acid, such the AK triperoxonane acid, in aqueous solvent or by treatment with inorganic acid, such as hydrochloric acid, in an aqueous solvent.

Carboxyl group (-CO2N) can be converted to amide groups (-CONHR' or-CONR'R”) interaction with the corresponding amine in the presence of a suitable agent combinations, such as HATU, in a suitable solvent such as dichloromethane.

In another example, carboxylic acids can be homologously one carbon atom (i.e., from-CO2N to CH2CO2N) by conversion into the corresponding acid chloride (-COCl), followed by synthesis according to the Arndt-Eistert.

In another example, the group-IT can be obtained from the corresponding ester (for example, -CO2R') or aldehyde (-Cho) groups recovery using, for example, metal hydride complex such as alumalite lithium in diethyl ether or tetrahydrofuran or sodium borohydride in a solvent such as methanol. Alternatively, you can get alcohol recovery of the appropriate acid (-CO2N) using, for example, lithium aluminum hydride, in a solvent such as tetrahydrofuran, or using borane in a solvent such as tetrahydrofuran.

The alcohol group can be converted to the deleted group, such as halogen atoms, or sulfonyloxy such to the to alkylsulfonate, for example, tripterocalyx, or arylsulfonate, for example, p-toluensulfonate, using conditions known to specialists in this field. For example, the alcohol can be subjected to interaction with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane), to obtain the corresponding chloride. When the interaction is also possible to use a base (e.g. triethylamine).

In another example, an alcohol, phenol or amide groups can be alkilirovanii combination of phenol or amide with an alcohol in a solvent such as tetrahydrofuran, in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, aminobutiramida or diethylazodicarboxylate. Alternatively, the alkylation can be accomplished by deprotonation with a suitable base such as sodium hydride, followed by addition of an alkylating agent, such as alkylhalogenide.

Aromatic halogenated substituents in the compounds can be subjected to the exchange of halogen for metal processing base, for example a lithium base such as n-butyl or tert-utility, optionally at a low temperature, e.g. around -78°C., in a solvent such as tetrahydrofuran, and then extinguish electrophilic compound for introducing the desired substituent. So, in the example, you can enter a formyl group used as the electrophile N,N-dimethylformamide. Alternatively, the halogenated aromatic substituents can be subjected to reactions catalyzed by metals (such as palladium or copper)for injection, for example, acid, ester, cyano, amide, aryl, heteroaryl, alkenyl, etkinlik, thio - or aminosalicyclic. Suitable methods that can be used include techniques described heck, Suzuki, Steele, Buchwald or Hardwick.

Aromatic halogenated substituents also can be subjected to nucleophilic substitution, following the interaction with an appropriate nucleophile such as an amine or alcohol. Such interaction can be mainly carried out at elevated temperature in the presence of microwave irradiation.

Compounds of the present invention were tested for their ability to inhibit the activity and activation of MEK (primary analysis) and their biological effects on cell growth (secondary analyses), as described below. Connection with IC50less than 10 microns (preferably less than 5 μm, even more preferably, less than 1 μm, most preferably less than 0.5 μm) in the analysis of the activity of MEK in example 1A or 1b, with IC50less than 5 microns (preferably less than 0.1 μm, most preferably less than 0.01 μm) in the analysis of activation of MEK in example 2, IC50less than 10 microns (preferably less than 5 microns, most preferably less than 0.5 μm) in the analysis of cell proliferation MEK in example 3, and/or IC50less than 10 microns (preferably less than 1 μm, most preferably less than 0.1 μm) in the analysis of ERK phosphorylation in example 4, can be used as inhibitors of MEK.

The present invention relates to compositions (e.g., pharmaceutical compositions)containing the compound of formula I (and/or solvate and salt) and the media (pharmaceutically acceptable carrier). The present invention also relates to compositions (e.g., pharmaceutical compositions)containing the compound of formula I (and/or solvate and salt) and the media (pharmaceutically acceptable carrier, and optionally containing a second chemotherapeutic agent and/or the second anti-inflammatory agent, such as described in this description. Compositions of the present invention are useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (e.g. human). Compositions of the present invention are also useful for treatment of inflammatory diseases in a mammal (e.g. human).

Compounds and compositions of the present invention is also useful for the treatment of autoimmune diseases, destructive the th bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (e.g. human). Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia associated with age macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, kidney disease and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, rejection of an organ transplant, cachexia, shock, septic shock, heart failure, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis b virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV). Chronic pain for the purposes of the present invention include, but are not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation, arthritis, and post-operative pain. Neuropathic pain is associated with a number of conditions that include, but are not limited to, inflammation, postoperative pain, phantom pain, pain from burns, pedag is, trigeminal neuralgia, acute herpetic and post herpetic pain, causalgia, diabetic neuropathy, avulsion plexus, neuroma, vasculitis, viral infection, crush, damage, compression, tissue damage, amputation of extremities, arthritic pain and damage to the nerves between the peripheral nervous system and Central nervous system.

Compounds and compositions of the present invention is also useful for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-kidney disease) in a mammal (e.g. human).

Compounds and compositions of the present invention is also useful for the prevention of implantation of blastocyte in a mammal (e.g. human).

The present invention relates to a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof. The present invention also relates to a method of treating inflammatory disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of compounds of formulas which I (and/or its solvate or salt or composition thereof.

The present invention relates to a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof in combination with a second chemotherapeutic agent such as described in this description. The present invention also relates to a method of treating inflammatory disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof in combination with a second anti-inflammatory agent, such as described in this specification.

The present invention relates to a method of treatment of autoimmune diseases, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof, and optionally the second therapeu the practical tools. Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia associated with age macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, kidney and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, rejection of an organ transplant, cachexia, shock, septic shock, heart failure, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis b virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr (EBV).

The present invention relates to a method of treating pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-kidney disease) in a mammal (e.g. human), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof, as well as optional second therapeutic agent.

The present invention relates to a method of preventing implantation of blastocyte in a mammal (e.g. human), including the introduction of specified mlekopitayushchikh effective amount of the compounds of formula I (and/or its solvate or salt or composition thereof, as well as not necessarily involving the introduction of a second therapeutic agent.

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

It is also assumed that the compounds of the present invention can give abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention also relates to a method of sensitizing abnormal cells in a mammal (e.g. human) in the treatment of radiation, including the introduction of a given mammal amount of the compounds of formula I (and/or its solvate or salt or composition thereof, effective for sensitizing abnormal cells to treatment with radiation.

Introduction compounds of the present invention (hereinafter in this description of "active(s) connection(s)") can be done by any method that enables delivery of the compounds in the scene. Such methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), local path, inhalation and rectal administration.

The number is entered active compound will depend on the subject, which they were treated, the severity of the disorder or condition, the route of administration, placement, connection and choice and prescriptions of the doctor. However, the effective dosage is in the range from about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg/kg/day in a single dose or divided doses. For a person weighing 70 kg, this may represent an amount of about 0.05 to 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, adequate can be dose below the lower limit of the above-mentioned interval, while in other cases it is possible to use even higher doses without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.

The active compound can be applied as a sole therapy or in combination with one or more chemotherapeutics, for example, the means described in this description. This combined treatment can be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

The pharmaceutical composition may be, for example, in a form suitable for oral administration in the form of tablets, capsules the crystals, pills, powder, compositions with delayed release, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration in the form of ointment or cream or for rectal administration in the form of a suppository. The pharmaceutical composition may be in unit dosage forms suitable for a single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the connection of the present invention as an active ingredient. In addition, the composition may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

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

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions can, if desired, contain additional ingredients such as corrigentov, binders, excipients and the like components. So, in the case of oral administration in tablets containing different the s excipients, such as citric acid, may also be used various disintegrant, such as starch, alginic acid and certain complex silicates, and binders such as sucrose, gelatin and Arabic gum. In addition, for the purposes of tabletting often used lubricants such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be used in soft and hard filled gelatin capsules. Therefore, preferred materials include lactose or milk sugar and high molecular weight glycols. When oral administration is desirable aqueous suspensions or elixirs, the active ingredient therein may be combined with various sweetening matter or korrigentami tinted substances or dyes and, if desired, emulsifiers or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerol or a combination thereof.

Methods of obtaining pharmaceutical compositions with a certain amount of active compounds known or will be apparent to experts in the field. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

Examples

Abbreviations

DBU/td> 1,8-Diazabicyclo[5.4.0]undec-7-EN
DCMDichloromethane
DIPEADiisopropylethylamine
DMAP4-Dimethylaminopyridine
DMFDimethylformamide
EDCI1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide
HATUHexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea
HClHydrochloric acid
HM-NIsolute® HM-N is a modified form of diatomaceous earth, which can effectively absorb water sample
HOBt1-Hydroxybenzotriazole
LDADiisopropylamide lithium
MeOHMethanol
NHCO3Sodium bicarbonate

Sodium hydroxide
Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)
Pd2dba3Tris(dibenzylideneacetone)dipalladium(0)
PdCl2(PPh3)2Dichlorobis(triphenylphosphine)palladium(II)
Si-SPECartridge for flash chromatography, pre-filled silica Isolute®
THFTetrahydrofuran
Xanthos9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene

General terms experimentation

Spectra1H NMR recorded at ambient temperature using a spectrometer Varian Unity Inova (400 MHz) with a 5 mm probe triple resonance. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations are used: ush = broadened signal, s = singlet, d = doublet, DD = double doublet, t = triplet, K = Quartet, m = multiplet.

Experiments with vysokoeffektivnoi liquid chromatography-mass spectrometry (GHMC) to determine retention time (RTand mass associated the x ions is carried out using one of the following methods.

Method a : Experiments performed on a quadrupole mass spectrometer (Waters Micromass ZQ connected to the LC system Hewlett Packard HP1100 with the detector diode matrix. Use column 100×3.0 mm, Higgins Clipeus, C18, 5 μm, flow rate 1 ml/min Initial solvent system consists of 95% water containing 0.1% formic acid (solvent A)and 5% acetonitrile containing 0.1% formic acid (solvent B), within the first minute, followed by a gradient up to 5% solvent a and 95% solvent b over the next 14 minutes. The final solvent system can withstand constant for another 5 minutes.

Method C. the Experiments carried out on a quadrupole mass spectrometer Waters Platform LC connected to the LC system Hewlett Packard HP1100 with the detector diode matrix and 100-position auto sampler using column 30×4.6 mm, Phenomena Luna C18(2), and a flow rate of 2 ml/min. and a solvent System is a 95% solvent a and 5% solvent b for the first 0.50 minutes followed by a gradient up to 5% solvent a and 95% solvent b over the next 4 minutes. The final solvent system can withstand constant within 0.50 minutes.

Experiments with microwave irradiation is performed with the use of the initiator Personal Chemistry Emrys Initiator or Optimizer, which uses single-mode p is Senator and dynamic adjustment of the field, both give the reproducibility and adjustment. You can reach the temperature of 40-250°C and raise the pressure up to 20 bar.

Example 1A

Analysis of MEK (analysis activity MEK)

Constitutively activated mutant human MEK expressed in insect cells, used as a source of enzyme activity at a final concentration in the analysis of the kinase at 62.5 nm.

The analysis is carried out for 30 minutes in the presence of 50 μm ATP, using as substrate the recombinant GST-ERK1 produced in E. coli. Phosphorylation of the substrate to detect and determine quantitatively using HTRF reagents supplied Cisbio. The reagents comprise antibodies against GST conjugated with allophycocyanin (XL665), and antibodies against phospho(Thr202/Tyr204)-ERK, conjugated with europium-Cryptocom. Antibodies against phospho recognize ERK1, dephosphorylating at Thr202 and Tyr204. When both antibodies are associated with ERK1 (i.e. when the substrate is phosphorylated), is the transfer of energy from cryptate to allophycocyanin after excitation at 340 nm, resulting in the emission of fluorescence is proportional to the amount of phosphorylated substrate. Fluorescence find using advance of fluorimetry.

Compounds diluted in DMSO before addition to buffer for analysis, and the final is the second concentration of DMSO in the analysis is 1%.

IC50defined as the concentration at which this connection reach 50% inhibition from control. The value of the IC50calculate using software XLift (version 2.0.5).

Example 1b

Analysis of MEK (analysis activity MEK)

Constitutively activated mutant human MEK expressed in insect cells, used as a source of enzyme activity at a final concentration in the analysis of kinase 15 nm.

The analysis is carried out for 30 minutes in the presence of 50 μm ATP, using as substrate the recombinant GST-ERK1 produced in E. coli. Phosphorylation of the substrate to detect and determine quantitatively using HTRF reagents supplied Cisbio. The reagents comprise antibodies against GST conjugated with allophycocyanin (XL665), and antibodies against phospho(Thr202/Tyr204)-ERK, conjugated with europium-Cryptocom. They are used at a final concentration of 4 μg/ml and 0.84 μg/ml, respectively. Antibodies against phospho recognize ERK1, dephosphorylating at Thr202 and Tyr204. When both antibodies are associated with ERK1 (i.e. when the substrate is phosphorylated), is the transfer of energy from cryptate to allophycocyanin after excitation at 340 nm, resulting in the emission of fluorescence is proportional to the amount of phosphorylated su the stratum. Fluorescence find using advance of fluorimetry.

Compounds diluted in DMSO before addition to buffer for analysis, and the final concentration of DMSO in the analysis is 1%.

IC50defined as the concentration at which this connection reach 50% inhibition from control. The value of the IC50calculate using software XLift (version 2.0.5).

Compounds of examples 5-8 and 10-12 show the IC50less than 10 microns in the analysis described in example 1A or 1b, the majority of these compounds show IC50less than 5 microns.

Example 2

Analysis of skin disease analysis of activation of MEK)

Constitutively activated mutant skin disease, expressed in insect cells, used as a source of enzyme activity.

The analysis is carried out for 30 minutes in the presence of 200 μm ATP, using as substrate the recombinant GST-MEK1 produced in E. coli. Phosphorylation of the substrate to detect and determine quantitatively using HTRF reagents supplied Cisbio. The reagents comprise antibodies against GST conjugated with allophycocyanin (XL665), and antibodies against phospho(Ser217/Ser221)-MEK conjugated with europium-Cryptocom. Antibodies against phospho recognize MEK, dephosphorylating at Ser217 and Ser221 or monophosphorylated at Ser217. is when both antibodies are associated with MEK (i.e. when the substrate is phosphorylated), is the transfer of energy from cryptate to allophycocyanin after excitation at 340 nm, resulting in the emission of fluorescence is proportional to the amount of phosphorylated substrate. Fluorescence find using advance of fluorimetry.

Compounds diluted in DMSO before addition to buffer for analysis, and the final concentration of DMSO in the analysis is 1%.

IC50defined as the concentration at which this connection reach 50% inhibition from control. The value of the IC50calculate using software XLift (version 2.0.5).

In this analysis, the compounds of examples 5-7 and 10 show the IC50less than 5 microns.

Example 3

Analysis of cell proliferation

Compounds of experience in the analysis of cell proliferation using the following cell lines:

NST - colorectal carcinoma person (ATSS);

A - malignant melanoma of man (ATSS).

Both cell lines retain in media DMEM/F12 (1:1) (Gibco) supplemented with 10% FCS at 37°C in a humid chamber with 5% CO2.

Cells were seeded in 96-well tablets at 2000 cells/well and after 24 hours they are subjected to the influence of various concentrations of compounds in 0,83% DMSO. Cells grown for 72 hours in each well to relax the Ute equal volume of reagent CellTiter (Promega). This leads to the lysis of cells and generates a luminescent signal proportional to the amount of released ATP (and, hence, proportional to the number of cells per well)that can be detected by using advance of luminometer.

EC50defined as the concentration at which this connection is achieved 50% inhibition from control. Value EC50calculate using software XLift (version 2.0.5).

In this analysis, the compounds of examples 5 and 10 show EC50less than 10 microns in any of the cell lines.

Example 4

Analysis based on cells with phospho-ERK

Connection experience in ELISA phospho-ERK cells using the following cell lines:

NST - colorectal carcinoma person (ATSS);

A - malignant melanoma of man (ATSS).

Both cell lines retain in media DMEM/F12 (1:1) (Gibco) supplemented with 10% FCS at 37°C in a humid chamber with 5% CO2.

Cells were seeded in 96-well tablets at 2000 cells/well and after 24 hours they are subjected to the influence of various concentrations of compounds in 0,83% DMSO. Cells are grown for 2 hours or 24 hours, fixed with formaldehyde (final concentration 2%) and impregnated with methanol. After blocking TBST-3% BSA, fixed cells are incubated with primary antibodies (anti-rabbit phospho-ERK)over night at 4°C. Cells incubated with iodide of propecia (fluorescent DNA dye) and carry out the detection of cellular p-ERK using anti-rabbit secondary antibodies conjugated with fluorescent dye Alexa Fluor 488 (molecular probes). Fluorescence analyzed using a laser scanning cytometer for microplate Acumen Explorer (TTP Labtech), and the signal Alexa Fluor 488 normalize the signal PI (proportional to the number of cells).

EC50defined as the concentration at which this connection is achieved by passing half of the signal between the baseline and maximum response. Value EC50calculate using software XLift (version 2.0.5).

In this analysis, the compounds of examples 5 and 10-12 show EC50less than 10 microns in any of the cell lines.

Example 5

4-Chloronicotinic acid

According to the method in Guillier et al. (1995), J. Org. chem., 60(2): 292-6, to a cooled (-78°C) solution of LDA (21 ml, 1.6 m in hexane, 33.3 mmol) in anhydrous THF (70 ml) in an argon atmosphere add 4-chloropyridine (5.0 g, 33.3 mmol). After keeping at -78°C for 1 hour the solution is quickly poured on a layer of solid CO2contained in a 250 ml conical flask. After the reaction solution warms to room temperature, the solution was quenched with water (30 ml). Flying the content of inorganic fillers solvents are removed in vacuo and the remaining aqueous suspension is extracted with diethyl ether (3×100 ml). The aqueous phase is cooled to 0°C. and adjusted pH to 4 by adding concentrated hydrochloric acid. The precipitate was incubated for 30 minutes and then separated by filtration. The solid is washed with cold diethyl ether (10 ml) to obtain the specified title compound as a white solid (3.2 g, 61%).

Ethyl-4-chloronicotinic

A suspension of 4-chloronicotinic acid (3.0 g, 19.0 mmol) in thionyl chloride (50 ml) is refluxed for 90 minutes. After cooling to ambient temperature the solution is concentrated to dryness, then the residue is subjected to azeotropic distillation with toluene (2×50 ml) to obtain a solid substance. The obtained solid is added in portions to a cooled (0°C.) mixture of ethanol (25 ml) and DIPEA (15 ml). The reaction mixture was stirred at room temperature for 4 hours, then concentrated in vacuo and water is added (75 ml). The solution is extracted with ethyl acetate (2×75 ml)then the combined organic phases are dried over sodium sulfate and then concentrated to obtain specified in the title compound as a brown oil (3.3 g, 94%).1H NMR (CDCl3, 400 MHz) 9,03 (c, 1H), 7,58 (d, J=5.4 Hz, 1H), 7,41 (DD, J=5.4 Hz, 0.5 Hz, 1H), 4,45 (kV, J=7,3 Hz, 2H), USD 1.43 (t, J=7,3 Hz, 3H).

Ethyl ester of 3-hydroxyimino[3,2-c]pyridine-2-carbon is acid

To a cooled (5°C.) solution of ethyl-4-chloronicotinate (1.55 g, 8.4 mmol) and ethyl ether mercaptohexanol acid (2.6 ml of 23.4 mmol) in anhydrous DMF (30 ml) under stirring in an argon atmosphere add on parts for 20 minutes, sodium hydride (21,7 mmol, 60% dispersion in oil, 868 mg). Stirring is continued at 5°C for 10 minutes and then for 1.5 hours at room temperature. Then the reaction quenched by adding water (5 ml), the reaction mixture is acidified by adding acetic acid (1 ml), then concentrated and receive the remainder. The residue is treated with ethyl acetate (150 ml) and water (100 ml). The layers are separated and the aqueous phase is extracted with DCM (100 ml). The combined organic phases are dried over sodium sulfate, filtered and evaporated to obtain a solid substance. The solid is triturated in a mixture of diethyl ether:pentane (1:1, 15 ml) to obtain the specified title compound as a yellow solid (1.5 g, 81%). IHMS (method B): RT=2,21 min, M+N+=224.

Ethyl ester of 3-(nonattribute-1 sulfonyloxy)thieno[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 3-hydroxyimino[3,2-c]pyridine-2-carboxylic acid (1.3 g, of 5.82 mmol) and DMAP (35 mg, 0.29 mmol) in DCM (10 ml) under stirring at 0°C is added DIPEA (2.5 ml, 14.0 mmol) and nonafterburning arid (1,36 ml, 7.56 mmol). After 10 minutes the reaction mixture is heated to room temperature and stirred for further 20 hours. The reaction mixture was diluted with DCM (50 ml) and washed with water (30 ml). The organic phase is separated, dried over sodium sulfate, filtered and evaporated to obtain a brown oil. The oil is purified flash chromatography (Si-SPE, pentane:diethyl ether, gradient from 100:0 to 70:30) to obtain specified in the title compounds as colorless oil, which crystallized upon standing (420 mg, 14%). IHMS (method B): RT=4,46 min, M+N+=508.

Ethyl ester of 3-(4-bromo-2-forgenerating)thieno[3,2-c]pyridine-2-carboxylic acid

Degassed solution of ethyl ester of 3-(nonattribute-1 sulfonyloxy)thieno[3,2-c]pyridine-2-carboxylic acid (206 mg, of 1.08 mmol), 4-bromo-2-foronline (206 mg, of 1.08 mmol), Pd2dba3(38 mg, 0.04 mmol), Xanthos (48 mg, 0.08 mmol) and DBU (316 μl, of 2.08 mmol) in toluene (1 ml) was exposed to microwave irradiation at 150°C for 10 minutes. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (30 ml). The resulting solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to obtain a solid residue. The solid residue purified flash chromatography (Si-SPE, pentane:diethyl ether, gradient from 90:10 is about 70:30) to obtain the specified title compound as a white solid (210 mg, 64%). IHMS (method B): RT=3,78 min, M+N+=395/397.

Ethyl ester of 3-(2-fluoro-4-ilfenomeno)thieno[2,3-c]pyridine-2-carboxylic acid

A mixture of ethyl ester of 3-(4-bromo-2-forgenerating)thieno[3,2-c]pyridine-2-carboxylic acid (209 mg, of 0.53 mmol), copper iodide(I) (5 mg, was 0.026 mmol), sodium iodide (159 mg, 1.06 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (8,5 μl, 0,053 mmol) in 1,4-dioxane (1.0 ml) is heated at 105°C for 24 hours in an argon atmosphere. Added copper iodide(I) (5 mg, was 0.026 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (8,5 μl, 0,053 mmol) and continue heating for another 24 hours. As soon as the reaction mixture cooled to room temperature, it is treated with ethyl acetate (30 ml) and a mixture of 10% V/V ammonia 0,880/water (20 ml). The layers are separated and the aqueous phase is extracted with DCM (30 ml). The combined organic layer is dried over sodium sulfate, filtered and evaporated, then the residue purified flash chromatography on Si-SPE (elution with mixtures of pentane:diethyl ether, gradient from 90:10 to 70:30) to obtain the specified title compound as a yellow solid (174 mg, 74%). IHMS (method B): RT=3,97 min, M+N+=443.

((R)-2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl ester of 3-(2-fluoro-4-is adreniline)thieno[2,3-c]pyridine-2-carboxylic acid (50 mg, 0.11 mmol), 1H. aqueous NaOH solution (to 0.12 ml, 0.12 mmol) and ethanol (2 ml) is heated at 65°C for 45 minutes. The reaction mixture was concentrated and then subjected to azeotropic distillation with toluene (2×2 ml) to give a solid residue. The solid residue is dissolved in anhydrous THF (2 ml) and added O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (27 mg, 0.23 mmol), EDCI (27 mg, 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59 μl, 0.34 mmol). After stirring for 19 hours, the solvent is evaporated and the residue treated with ethyl acetate (30 ml) and water (20 ml). The organic layer is dried over sodium sulfate, filtered and evaporated to obtain a yellow oil. The oil is purified flash chromatography (Si-SPE, pentane:ethyl acetate, gradient from 80:20 to 50:50) to obtain the specified title compound as a yellow solid (18 mg, 30%). IHMS (method B): RT=3,09 min, M+N+=544.

((R)-2,3-Dihydroxypropane)amide 3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid

((R)-2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid (18 mg, 0.03 mmol) dissolved in methanol (1 ml) and add concentrated hydrochloric acid (1 drop). The mixture is stirred for 2 hours and then evaporated to dryness to obtain a residue. The residue is treated with water feast upon the s ' solution of NaHCO 3(10 ml), water (20 ml) and DCM (20 ml). The organic layer is separated, dried over sodium sulfate, filtered and evaporated to obtain yellow solid. The solid is purified flash chromatography (Si-SPE, DCM:MeOH, gradient from 98:2 to 92:8), obtaining specified in the title compound as a yellow solid (8 mg, 50%). IHMS (method A): RT=6,32 min, M+N+=504.1H NMR (d4-MeOH, 400 MHz) 8,56 (s, 1H), 8.34 per (d, J=5.7 Hz, 1H), 7,87 (d, J=5.7 Hz, 1H), 7,45 (DD, J=10.5 Hz, 1.8 Hz, 1H), 7,27 (d, J=8.5 Hz, 1H), is 6.61 (DD, J=8,5 Hz, 8.5 Hz), 3,89-of 3.94 (m, 1H), 3,76-of 3.85 (m, 2H), 3.45 points-of 3.54 (m, 2H).

Example 6

((R)-2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(4-bromo-2-forgenerating)thieno[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl ester of 3-(4-bromo-2-forgenerating)thieno[3,2-c]pyridine-2-carboxylic acid (36 mg, 0.09 mmol), 1H. aqueous NaOH (0.10 ml, 0.10 mmol) and methanol (2 ml) is heated at 65°C for 45 minutes. The reaction mixture was concentrated and then subjected to azeotropic distillation with toluene (2×2 ml) to give a solid residue. The solid residue is dissolved in anhydrous THF (2 ml) and added O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (22 mg, 0.18 mmol), EDCI (22 mg, 0.12 mmol), HOBt (17 mg, 0.13 mmol) and DIPEA (48 μl, 0.28 mmol). After stirring overnight at ambient temperature the reaction mixture was concentrated in vacuo and the floor is given a yellow residue. The resulting residue is dissolved in ethyl acetate (30 ml), the solution washed with water (20 ml) and then with saturated salt solution (10 ml)then the organic layer is separated, dried over sodium sulfate and concentrated in vacuo to obtain a yellow oil. The oil is purified flash chromatography (Si-SPE, pentane:ethyl acetate, gradient from 90:10 to 50:50) to obtain the specified title compound as a yellow oil (18 mg, 41%). IHMS (method B): RT=3,03 min, M+N+=496/498.

((R)-2,3-Dihydroxypropane)amide 3-(4-bromo-2-forgenerating)thieno[3,2-c]pyridine-2-carboxylic acid

A solution of ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(4-bromo-2-forgenerating)thieno[3,2-c]pyridine-2-carboxylic acid (18 mg, being 0.036 mmol) in methanol (1 ml) is loaded into the cartridge isolute® SCX-2 (5 g). Then the cartridge was washed with methanol (15 ml), then elute the desired product using a 2M solution of ammonia in Meon, then the collected eluent concentrate and get the rest. The residue is purified flash chromatography (Si-SPE, DCM:MeOH, gradient from 100:0 to 94:6) to obtain the specified header connection in the form of not-quite-white solid (9 mg, 53%). IHMS (method A): RT=5,59 min, M+N+=456/458.1H NMR (d4-MeOH, 400 MHz) 8,60 (c, 1H), 8,40 (d, J=5.7 Hz, 1H), 7,94 (d, J=5.7 Hz, 1H), 7,39 (DD, J=10,6 Hz, 2.2 Hz, 1H), 7,16 (d, J=8.5 Hz, 1H), 6,80 (DD, J=8.5 Hz, 1H), 4,01-4,10 (m, 1H), 3,89-4,00 (m, 2H), 3,57-to 3.67 (m, 2 is).

Example 7

Ethyl ester of 3-chlorisondamine acid

A suspension of 3-chlorisondamine acid (1.0 g, 6,35 mmol) in thionyl chloride (10 ml) is refluxed for 2.5 hours. After cooling to ambient temperature the solution is concentrated to dryness, then the residue is subjected to azeotropic distillation with toluene (10 ml) and receive oil. The oil obtained is added dropwise during 10 minutes to a cooled (0°C.) mixture of ethanol (15 ml) and DIPEA (5 ml). The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and water is added (20 ml). The solution is extracted with ethyl acetate (30 ml), the organic phase is dried over sodium sulfate and then concentrated to obtain specified in the title compound as an orange oil (1.1 g, 94%).1H NMR (CDCl3, 400 MHz) 8,72 (s, 1H), 8,59 (d, J=4.9 Hz, 1H), 7,63 (DD, J=4,9 Hz, 0.5 Hz, 1H), of 4.44 (q, J=7,3 Hz, 2H), 1,42 (t, J=7,3 Hz, 3H).

Ethyl ester of 3-hydroxyimino[2,3-c]pyridine-2-carboxylic acid

To a cooled (5°C.) solution of ethyl ester of 3-chlorisondamine acid (1,11 g, 6.0 mmol) and ethyl ether mercaptohexanol acid (1.8 ml, and 16.7 mmol) in anhydrous DMF (20 ml) under stirring in an argon atmosphere add on parts for 20 minutes, sodium hydride (15.6 mmol, 60% of isperia in oil, 622 mg). Stirring is continued at 5°C for 20 minutes and then for 18 hours at room temperature. Then the reaction quenched by adding water (5 ml), the reaction mixture is acidified by adding acetic acid (1 ml), then concentrated and receive the remainder. The residue is treated with ethyl acetate (150 ml) and water (50 ml). The organic phase is dried over sodium sulfate, filtered and evaporated to obtain a yellow oil. The oil is purified flash chromatography (Si-SPE, pentane:ethyl acetate, gradient from 80:20 to 30:70) to obtain the specified title compound as a yellow solid (1,33 g, 99%). IHMS (method B): RT=2.57 m min, M+N+=224.

Ethyl ester of 3-(nonattribute-1 sulfonyloxy)thieno[2,3-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 3-hydroxyimino[2,3-c]pyridine-2-carboxylic acid (950 mg, 4.26 deaths mmol) and DMAP (26 mg, 0.21 mmol) in DCM (12 ml) under stirring at 0°C is added DIPEA (1.8 ml, 10.2 mmol) and nonatherosclerotic (0,99 ml of 5.53 mmol). After 10 minutes the reaction mixture is heated to room temperature and stirred for further 20 hours. The reaction mixture was diluted with DCM (30 ml) and washed with water (20 ml). The organic phase is dried over sodium sulfate, filtered and evaporated, to obtain yellow oil. The oil is purified flash chromatography (Si-SPE, pentane:diethyl ether, gradiented 90:10 to 65:35), obtaining specified in the title compounds as colorless oil, which crystallized upon standing (678 mg, 31%). IHMS (method B): RT=4,49 min, M+N+=508.

Ethyl ester of 3-(4-bromo-2-forgenerating)thieno[2,3-c]pyridine-2-carboxylic acid

Degassed solution of ethyl ester of 3-(nonattribute-1 sulfonyloxy)thieno[2,3-c]pyridine-2-carboxylic acid (678 mg, of 1.33 mmol), 4-bromo-2-foronline (329 mg, at 1.73 mmol), Pd2dba3(61 mg, 0.07 mmol), Xanthos (78 mg, 0.14 mmol) and DBU (509 μl, 3.35 mmol) in toluene (3 ml) was exposed to microwave irradiation at 150°C for 10 minutes. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (70 ml). The resulting solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to obtain an orange oil. The oil is purified flash chromatography (Si-SPE, pentane:diethyl ether, gradient from 90:10 to 50:50), followed by crystallization from a mixture of ethyl acetate:pentane to obtain specified in the title compound as a white solid (353 mg, 67%). IHMS (method B): RT=4,08 min, M+N+=395/397.

Ethyl ester of 3-(2-fluoro-4-ilfenomeno)thieno[2,3-c]pyridine-2-carboxylic acid

A mixture of ethyl ester of 3-(4-bromo-2-forgenerating)thieno[2,3-c]feast the DIN-2-carboxylic acid (288 mg, 0.73 mmol), copper iodide(I) (7 mg, being 0.036 mmol), sodium iodide (219 mg, of 1.46 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (10.4 mg, 0,073 mmol) in 1,4-dioxane (1.0 ml) is heated at 105°C for 24 hours in an argon atmosphere. Added copper iodide(I) (7 mg, being 0.036 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (10.4 mg, 0,073 mmol) and continue heating for another 24 hours. The reaction mixture is cooled to room temperature and the mixture is treated with DCM (30 ml), concentrated aqueous ammonia solution (2 ml) and water (13 ml). The organic layer is separated, dried over sodium sulfate, filtered and evaporated, then the residue purified flash chromatography (Si-SPE, DCM) to obtain the specified title compound as a yellow solid (275 mg, 85%). IHMS (method B): RT=to 4.23 min, M+N+=443.

((R)-2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-ilfenomeno)thieno[2,3-c]pyridine-2-carboxylic acid

A mixture of ethyl ester of 3-(2-fluoro-4-ilfenomeno)thieno[2,3-c]pyridine-2-carboxylic acid (50 mg, 0.11 mmol), 1H. aqueous NaOH solution (to 0.12 ml, 0.12 mmol) and ethanol (2 ml) is heated at 65°C for 45 minutes. The reaction mixture was concentrated and then subjected to azeotropic distillation with toluene (2×2 ml) and obtain a solid residue. The solid residue is dissolved in anhydrous THF (4 ml) and added O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)g is doxylamin (27 mg, 0.23 mmol), EDCI (27 mg, 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59 μl, 0.34 mmol). After stirring for 19 hours, the solvent is evaporated and the residue treated with ethyl acetate (20 ml) and water (15 ml). The organic layer is separated, dried over sodium sulfate, filtered and evaporated to obtain a brown oil. The oil is purified flash chromatography (Si-SPE, pentane:ethyl acetate, gradient from 80:20 to 0:100) to obtain the specified title compound as an orange oil (40 mg, 66%). IHMS (method B): RT=3,30 min, M+N+=544.

((R)-2,3-Dihydroxypropane)amide 3-(2-fluoro-4-ilfenomeno)thieno[2,3-c]pyridine-2-carboxylic acid

((R)-2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-ilfenomeno)thieno[2,3-c]pyridine-2-carboxylic acid (40 mg, 0.07 mmol) dissolved in methanol (1 ml) and add concentrated hydrochloric acid (1 drop). The mixture is stirred for 2 hours and then evaporated to dryness to obtain a residue. The residue is treated with an aqueous saturated solution of NaHCO3(3 ml), water (20 ml) and DCM (20 ml). The organic layer is separated, dried over sodium sulfate, filtered and evaporated to obtain yellow solid. The solid is purified flash chromatography (Si-SPE, DCM:MeOH, gradient from 99:1 to 92:8) to obtain the specified title compound as a yellow solid (21 mg, 7%). IHMS (method A): RT=7,12 min, M+N+=504.1H NMR (d4-MeOH, 400 MHz) to 9.15 (s, 1H), scored 8.38 (d, J=5.7 Hz, 1H), 7,52 (DD, J=10,6 Hz, 2.0 Hz, 1H), 7,44 (DD, J=5.7 Hz, 1.0 Hz, 1H), 7,32 (DDD, J=8,5 Hz, 2.0 Hz, 1.0 Hz, 1H), 6,56 (DD, J=8,5 Hz, 8.5 Hz, 1H), 4,00-4,13 (m, 1H), 3,85-3,95 (m, 2H), 3,54-the 3.65 (m, 2H).

Example 8

((R)-2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(4-bromo-2-forgenerating)thieno[2,3-c]pyridine-2-carboxylic acid

A mixture of ethyl-3-(4-bromo-2-forgenerating)thieno[2,3-c]pyridine-2-carboxylate (63 mg, 0.16 mmol), 1N aqueous NaOH (0.17 ml, 0,17 mmol) and ethanol (2 ml) is heated at 65°C for 45 minutes. The reaction mixture was concentrated in vacuo, then the residue is subjected to azeotropic distillation with toluene (2×2 ml) and obtain a solid residue. The obtained solid residue is suspended in anhydrous THF (2 ml) and then added O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (38 mg, 0.32 mmol), EDCI (38 mg, 0.20 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (83 μl, 0.48 mmol). After stirring for 66 hours at ambient temperature the reaction mixture was concentrated in vacuo and receives a yellow residue. The resulting residue is dissolved in ethyl acetate (50 ml), the solution washed with water (20 ml)then the organic layer is separated, dried over sodium sulfate, then concentrated in vacuo and receives a yellow oil. The oil is purified flash chromatography (Si-SPE, pentane:tracecut, a gradient from 60:40 to 0:100) to obtain the specified title compound as a yellow foam (61 mg, 77%). IHMS (method B): RT=3,02 min, M+N+=496/498.

((R)-2,3-Dihydroxypropane)amide 3-(4-bromo-2-forgenerating)thieno[2,3-c]pyridine-2-carboxylic acid

A solution of ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(4-bromo-2-forgenerating)thieno[2,3-c]pyridine-2-carboxylic acid (61 mg, 0.12 mmol) and 1 drop of concentrated HCl in methanol (2 ml) was stirred at ambient temperature for 2 hours. The solvent is evaporated in vacuo and the resulting residue is treated with dichloromethane (20 ml), water (10 ml) and a saturated solution of NaHCO3(3 ml). The organic phase is dried over sodium sulfate and concentrated in vacuo to obtain a yellow oil. The obtained yellow oil purified flash chromatography (Si-SPE, DCM:MeOH, gradient from 99:1 to 92:8) followed by rubbing in a mixture of methanol/acetonitrile, getting mentioned in the title compound in the form of not-quite-white solid (15 mg, 26%). IHMS (method A): RT=6,01 min, M+N+=456/458.1H NMR (d4-MeOH, 400 MHz) 9,16 (d, J=0.8 Hz, 1H), scored 8.38 (d, J=5.8 Hz, 1H), 7,37-7,46 (m, 2H), 7,17 (DDD, J=8.6 Hz, 2.3 Hz and 2.2 Hz, 1H), 6,72 (DD, J=8.7 Hz, 8.7 Hz, 1H), 4,00-of 4.05 (m, 1H), 3,84-of 3.96 (m, 2H), 3,53-to 3.64 (m, 2H).

Example 9

(2 Venlafaxi)amide 3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl ester of 3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid (124 mg, 0.28 mmol), 1H. aqueous NaOH solution (to 0.30 ml, 0.30 mmol) and ethanol (4 ml) is heated at 65°C for 45 minutes. The reaction mixture was concentrated in vacuo, then the resulting residue is subjected to azeotropic distillation with toluene (2×2 ml) and obtain a solid residue. The solid residue is dissolved in anhydrous THF (4 ml) and then added O-(2-vinyloxyethyl)hydroxylamine (58 mg, 0,56 mmol), EDCI (67 mg, 0.35 mmol), HOBt (53 mg, 0,39 mmol) and DIPEA (147 μl, 0.84 mmol). After stirring for 18 hours at ambient temperature the solvent is evaporated, the resulting residue was diluted with water (20 ml), then extracted with ethyl acetate (30 ml) and then dichloromethane (30 ml). The combined organic layers dried over sodium sulfate, filtered and evaporated to obtain a yellow oil. The obtained yellow oil purified flash chromatography (Si-SPE, dichloromethane:methanol, gradient from 100:0 to 98:2) to obtain the specified title compound as a yellow solid (91 mg, 65%). IHMS (method B): RT=3,05 min, M+N+=500.

Example 10

(2 Hydroxyethoxy)amide 3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid

(2 Venlafaxi)amide 3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-ka is oil acid (91 mg, 0.18 mmol) dissolved in ethanol (2 ml) and added 1M hydrochloric acid (0.5 ml). The mixture is stirred for 2 hours, then evaporated to dryness and receive the remainder. The resulting residue is treated with an aqueous saturated solution of NaHCO3(3 ml), water (20 ml) and DCM (20 ml). The organic layer is separated, dried over sodium sulfate, filtered and evaporated to obtain yellow solid. The yellow solid is purified flash chromatography (Si-SPE, DCM:MeOH, gradient from 100:0 to 98:2) and then HPLC with reversed phase (Phenomenex Luna 5 phenyl/hexyl, of 0.1% TFA in water gradient with methanol 95:5 to 40:60) to obtain the specified title compound as a yellow solid (34 mg, 40%). IHMS (method A): RT=6,00 min, M+N+=474.1H NMR (d4-MeOH, 400 MHz) 8,68 (d, J=5.7 Hz, 1H), 7,98 (DD, J=5.7 Hz, 0.8 Hz, 1H), 7,55 (DD, J=10.5 Hz, 1.8 Hz, 1H), 7,35-7,40 (m, 1H), 6,7 (DD, J=8,5 Hz, 8.5 Hz, 1H), 3,98 (t, J=Hz, 2H), 3,74 (t, J=Hz, 2H).

Example 11

Ethyl ester of 3-amino-7-fortiana[3,2-c]pyridine-2-carboxylic acid

To a mixture of 4-chloro-5-fornicationis (1.0 g, 6.4 mmol) and potassium carbonate (4.4 g, 32 mmol) in DMF (15 ml) at 0°C is added dropwise ethyldiglycol (0,73 ml, 6.7 mmol). The reaction mixture was stirred at 0°C for 10 min, at room temperature for 20 min and then at 40°C for 30 is in. The reaction mixture is cooled to room temperature and treated with water and ethyl acetate. The organic layer is separated and washed with water, then with saturated salt solution, dried over sodium sulfate and concentrated, to obtain specified in the title compound as a yellow solid (1.5 g, quantitative). IHMS (method B): RT=3,41 min, M+N+=241.

Ethyl ester of 7-fluoro-3-(2-fluoro-4-trimethylsilylmethylamine)thieno[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl ester of 3-amino-7-fortiana[3,2-c]pyridine-2-carboxylic acid (360 mg, 1.5 mmol), 2-fluoro-4-trimethylsilylethynyl ether triftormetilfullerenov acid (411 mg, 1.3 mmol), Pd2dba3(69 mg, of 0.075 mmol), Xanthos (86 mg, 0.15 mmol) and Cs2CO3(685 mg, 2.1 mmol) in toluene (6 ml) was exposed to microwave irradiation at 160°C for 20 minutes. The reaction mixture was filtered through a layer of celite®. The filtrate is concentrated under reduced pressure, obtaining a residue which is subjected to flash chromatography (Si-SPE, pentane:diethyl ether, gradient from 100:0 to 90:10) to obtain the specified title compound as a yellow solid (338 mg, 55%). IHMS (method B): RT=5,20 min, M+N+=407.

Ethyl ester of 7-fluoro-3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid

To a cooled (0°C.) solution of ethyl ester of 7-fluoro-3-(2-fluoro-4-trimethylsilylmethylamine)thieno[3,2-c]pyridine-2-carboxylic acid (330 mg, 0.81 mmol) in DCM (10 ml) is added dropwise 1M solution of monochloride iodine in DCM (1.6 ml, 1.6 mmol). Upon completion of the addition the mixture is stirred at 0°C for 1 hour, and then the reaction quenched by adding a saturated solution of sodium thiosulfate (10 ml). The mixture is vigorously stirred for 10 min and treated with ethyl acetate and water. The organic layer is separated and washed with saturated sodium hydrogen carbonate solution, then with saturated salt solution, dried over sodium sulfate, filtered and concentrated to obtain specified in the title compound as a yellow solid (358 mg, 54%.). IHMS (method B): RT=4,72 min, M+N+=461.

(2 Vinyloxyethoxy)amide 7-fluoro-3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 7-fluoro-3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid (175 mg, 0.38 mmol) in IMS (4 ml) was added 1.0m aqueous sodium hydroxide solution (0.5 ml, 0.5 mmol). The reaction mixture is heated at 65°C for 1 hour, then cooled to room temperature and concentrated in vacuo. The resulting residue is subjected to azeotropic distillation with toluene (3×10 ml) and then the resulting residue is suspended in THF (5 m is). Then successively added O-(2-vinyloxyethyl)hydroxylamine (78 mg, from 0.76 mmol), N,N-diisopropylethylamine (0,26 ml of 1.52 mmol), EDCI (146 mg, from 0.76 mmol) and HOBt (103 mg, from 0.76 mmol) and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue is treated with water and ethyl acetate. The organic layer is separated and washed with saturated sodium hydrogen carbonate solution and saturated salt solution, dried over sodium sulfate, filtered and concentrated, obtaining a residue, which is purified column chromatography (Si-SPE, gradient 0-2% methanol in DCM) to obtain specified in the title compounds as a pale yellow solid (106 mg, 54%). IHMS (method B): RT=3,92 min, M+N+=518.

(2 Hydroxyethoxy)amide 7-fluoro-3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid

A solution of (2-vinyloxyethoxy)amide 7-fluoro-3-(2-fluoro-4-ilfenomeno)thieno[3,2-c]pyridine-2-carboxylic acid (100 mg, 0,19 mmol) in a mixture of methanol and DCM is loaded into the cartridge with 5 g SCX-2, which elute with methanol and then 2M ammonia solution in methanol. The appropriate fractions are combined and concentrated under reduced pressure. The remaining solid is purified column chromatography (Si-SPE, gradient 0-40% tert-butyldimethylsilyl ester in DCM then a mixture of 10% meta is ol in DCM) and get listed in the title compound as yellow solid (50 mg, 53%). IHMS (method A): RT=9,60 min, M+N+=492.1H NMR (CD3OD, 400 MHz) 3.58 (2H, t, J=4,89 Hz), a-3.84 (2H, t, J=4,91 Hz), 6.89 in (1H, t, J=8,76 Hz), 6,98 (1H, DD, J=to 8.41, 2,15 Hz), 7,21-7,26 (1H, m), 8,02 (1H, d, J=5,61 Hz), to 8.45 (1H, DD, J=8,25, 5,61 Hz), 8,53-8,59 (1H, m).

Example 12

Ethyl ester of 3-(2-fluoro-4-methylsulfonylamino)thieno[3,2-c]pyridine-2-carboxylic acid

Degassed solution of ethyl ester of 3-(nonattribute-1 sulfonyloxy)thieno[3,2-c]pyridine-2-carboxylic acid (0.74 g, 1.5 mmol), 2-fluoro-4-methylsulfonylamino (0.12 g, from 0.76 mmol), Pd2dba3(0.035 g, of 0.038 mmol), Xanthos (0,044 g, 0,076 mmol) and K3PO4(0.32 g, 1.5 mmol) in toluene (10 ml) is refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and then filtered through a layer of gilt, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, the obtained residue is subjected to flash chromatography (Si-SPE, gradient 0-10% ethyl acetate in dichloromethane) to obtain the specified title compound as a yellow solid (0.16 g, 57%). IHMS (method B): RT=3,84 min, M+N+=363.

3-(2-Fluoro-4-methylsulfonylamino)thieno[3,2-c]pyridine-2-carboxylic acid

A suspension of ethyl ester of 3-(2-fluoro-4-methylsulfonylamino)thieno[3,2-c]pyridin-carboxylic acid (0,19 g, 0.52 mmol) in IMS (10 ml) is treated with sodium hydroxide (1M aqueous solution, 0.63 ml) and the reaction mixture is heated at 60°C for 3 hours. The resulting mixture was cooled and then concentrated in vacuo. The crude residue is treated with water and bring the mixture to pH 5 with acetic acid. The resulting suspension is filtered, the residue is separated and dried in vacuum to obtain specified in the title compound as a green solid (0,107 g, 56%), which is used in the next stage without additional purification.

(2 Vinyloxyethoxy)amide 3-(2-fluoro-4-methylsulfonylamino)thieno[3,2-c]pyridine-2-carboxylic acid

A suspension of 3-(2-fluoro-4-methylsulfonylamino)thieno[3,2-c]pyridine-2-carboxylic acid (0,107 g, 0.32 mmol) in dry dichloromethane (5 ml) under nitrogen atmosphere cooled to 0°C and treated with DMF (1 drop) and oxalylamino (of 0.081 ml, 0.96 mmol). The reaction mixture is stirred for 1 hour and then the solvent is removed in vacuum. The resulting residue is again suspended in dry dichloromethane (1 ml) and treated by adding dropwise a solution of O-(2-vinyloxyethyl)hydroxylamine (of 0.066 g, 0.64 mmol) and DIPEA (0,167 ml, 0.96 mmol) in dry dichloromethane (4 ml)and then stirred for 18 hours. The reaction mixture was washed (water, saturated salt solution), dried (MgSO4), filtered and concentrated in in the cosmology vacuum. The resulting residue is subjected to flash chromatography (Si-SPE, gradient 0-30% ethyl acetate in dichloromethane) to obtain the specified title compound as a yellow solid (0,024 g, 18%). IHMS (method B): RT=3,17 min, M+N+=420.

(2 Hydroxyethoxy)amide 3-(2-fluoro-4-methylsulfonylamino)thieno[3,2-c]pyridine-2-carboxylic acid

(2 Vinyloxyethoxy)amide 3-(2-fluoro-4-methylsulfonylamino)thieno[3,2-c]pyridine-2-carboxylic acid (20 mg, 0,048 mmol) dissolved in methanol (1 ml), treated with concentrated hydrochloric acid (0.01 ml, 0.12 mmol) and then stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue is subjected to HPLC with reversed-phase (0.1% of HCO2N in water, gradient of acetonitrile). The appropriate fractions are combined and dried by freezing to produce specified in the title compound (9 mg, 47%). IHMS (method A): RT=6,36 min, M+N+=394.1H-NMR (DMSO-d6, 400 MHz) 3.58 (2H, t, J=4,89 Hz), a-3.84 (2H, t, J=4,91 Hz), 6.89 in (1H, t, J=8,76), 6,98 (1H, DD, J=to 8.41, 2,15 Hz), 7,21-7,26 (1H, m), 8,02 (1H, d, J=5,61 Hz), to 8.45 (1H, DD, J=8,25, 5,61 Hz), 8,53-8,59 (1H, m).

1. The compound of the formula I

and its salts,
where Z1represents CR1;
Z2represents N;
Z3represents CR3/sup> ;
Z4represents CR4;
R1, R3and R4independently selected from H or halogen;
W represents a

R5and R6represent H;
X1represents-OR11;
X2represents phenyl, optionally substituted by one or two groups selected from halogen or (C1-C3)alkylsulfanyl;
R11is a (C1-C12) alkyl, substituted with one or two groups independently selected from - (CR19R20)nOR16;
n is 0;
R16represents H, (C1-C12) alkyl or (C2-C8) alkenyl.

2. The compound according to claim 1, where X1choose from

3. The compound according to claim 1, where X1choose from

4. The compound according to claim 1, where X2represents a

5. The compound according to claim 1, where R1selected from H or CL.

6. The compound according to claim 1, where R3selected from H or halogen.

7. The compound according to claim 1, where R4selected from H or halogen.

8. The connection according to claim 7, where R4selected from CL, Br, or F.

9. A compound selected from:

10. Pharmaceutical composition for treating hyperproliferate the main disorders, containing the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. Method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition of claim 10.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: method is realised by treating a compound of formula

with boronic acid or ether thereof of formula

,

in which two OR15 groups together with the boron atom with which they are bonded form a pinacolato boronate ester group in the presence of a Pd catalyst. The invention relates to a method of producing a pharmaceutically acceptable salt of thieno[3,2-d]pyrimidine of formula

.

The invention also relates to a pharmaceutical composition, having phosphatidyl inositol-3-kinase inhibitor activity, containing thieno[3,2-d]pyrimidine of formula (I) as an active ingredient, a method of preparing said composition and use of thieno[3,2-d]pyrimidine of formula (I) or pharmaceutically acceptable salt thereof in producing a medicinal agent for inhibiting phosphatidyl inositol-3-kinase.

EFFECT: use of the derivative as a phosphatidyl inositol-3-kinase inhibitor.

11 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing prasugrel hydrochloride which involves the following stages: (i) chlorination of a compound described by formula (III) by addition of an chlorinating agent, optionally drop-by-drop, in a solvent; (ii) reaction of the prepared compound of formula (IV) and a compound described by general formula (V) where R means a protective group for hydroxyl, or its salt in a solvent in the presence of a base; (iii) acetylation of the prepared compound described by general formula (II) by reaction with an acetylation agent in a solvent in the presence of a base and an acetylation catalyst; and (iv) addition of hydrochloric acid, optionally drop-by-drop, to the prepared compound described by formula (I) in a solvent to produce prasugrel hydrochloride described by formula (1a), and differs by the fact that at the stage (i) temperature during addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C, and reaction temperature after addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C. The invention also concerns a product containing prasugrel hydrochloride and CATP in an amount no more than 0.3 %, to the pharmaceutical composition suitable for prevention or treatment of thrombosis or embolism on the basis of the specified product.

EFFECT: production of low-CATP prasugrel hydrochloride.

31 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method of olanzapine purification which involves mixing olanzapine with an organic acid in an organic solvent or a mixture of organic solvents to prepare acid-additive olanzapine salt, precipitation and isolation of acid-additive olanzapine salt and transforming acid-additive olanzapine salt in olanzapine; the organic acid is carboxylic acid which is selected from the group including oxalic, fumaric and benzoic acid.

EFFECT: invention refers to methods for producing pure olanzapine, intermediate products and acid-additive olanzapine salts which in turn can find application for producing pure olanzapine used for preparing a drug for treating mental disorders and conditions.

38 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where X denotes S; R1 and R2 taken together with atoms to which they are bonded form a 5-member carbocycle, substituted with up to two substitutes selected from alkyl and CF3; R3 is selected from a group consisting of a hydrogen atom and C1-8-alkyl; R3a denotes a hydrogen atom; R4 denotes a hydrogen atom; R4a denotes a hydrogen atom; R5 denotes a hydrogen atom; R5a denotes a hydrogen atom; R6 denotes a hydrogen atom; R6a denotes a hydrogen atom; R7 denotes a hydrogen atom; or pharmaceutically acceptable salts thereof. The invention also relates to compounds of the given formula, compounds selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which modulate serotonin receptor activity.

6 cl, 19 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

Organic compounds // 2430921

FIELD: chemistry.

SUBSTANCE: invention relates to an azathiabenzo-azulene derivative of formula I

,

where R3 denotes C1-C6alkyl, R4 denotes OH, R5 denotes halogen and R6 denotes H or halogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having anti-inflammatory or analgesic action.

EFFECT: obtained compounds and pharmaceutical composition can be used to treat arthritis and arthritis-related conditions, and for relieving inflammation and pain associated with acute inflammation of body parts, primarily joints, as a result of injury or as a result of arthritic conditions or other diseased conditions.

17 cl, 8 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing prasugrel hydrochloride of the formula:

,

with low content of "ОХТР", involving preparation of free prasugrel containing "ОХТР" from 2-silyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, dissolving the obtained free prasugrel in an inert solvent and optionally adding hydrochloric acid in drops to the solution for reaction.

EFFECT: novel method of producing prasugrel with low content of impurities, specifically "ОХТР" by-product.

2 cl, 6 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydropyran-2-one of formula

, where R1 is selected from hydrogen, ORa, OCORa, OCOORa, NRaRb, NRaCORb and NRaC(NRa)NRaRb; each R2 and R3 are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl; each R41, R42, R43, R44, R45, R46, R47 and R48 are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl; each R5, R6 and R7 are optionally selected from hydrogen, CORa, COORa, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl, or R5 and R48 together with coupled atom N and atom C whereto attached can form substituted or unsubstituted heterocyclic group; each Ra and Rb are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and each dashed line means an optional additional bond; to its pharmaceutically acceptable salts, tautomers or stereoisomers.

EFFECT: development of the method for preparing an anticancer composition, and the method of treating cancer.

46 cl, 10 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline forms of 3-[[3,5-dribromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid, characterised by X-ray powder diffraction pattern with principal peaks either at 2θ = 16.1 ± 0.2, 20.1 ± 0.2, 20.7 ± 0.2, and 24.2 ± 0.2, or at 2θ = 9.0 ± 0.2, 14.7 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2 and 24.3 ± 0.2. The invention also relates to methods of obtaining the disclosed crystalline forms, a pharmaceutical composition having thyroid beta-receptor agonist properties, a method for selective agonist action on thyroid beta-receptor, use of said forms to produce a medicinal agent and a method of treating mammals suffering from thyroid dysfunction associated conditions.

EFFECT: obtaining novel crystalline forms of 3-[[3,5-dribromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid, having thyroid beta-receptor agonist properties.

19 cl, 3 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, and can be used for combination treatment of locally advanced non-small-cell lung cancer. That is ensured by thorax computed tomography to determine an area of parietal and visceral pleura. It is attended by lung reduction with mediastinal lymph node dissection. That is accompanied with intraoperative photoradiation therapy. It is ensured by intravenous introduction of Photoditasine 0.8-1.0 mg/kg of body weight, In 2 hours, a lymph node dissection region, bronchial and vascular stumps are exposed to light stimuli generated by a diode laser at wave length 662 s and power density 40 J/cm2 for a time estimated on account of the area of the lymph node dissection regions, the bronchial and vascular stumps. It is followed by light stimuli covering the parietal and visceral pleura at power density 4 J/cm2 for a time estimated on account of the area of the bronchial and vascular stumps.

EFFECT: method provides improved therapeutic effects ensured by destruction of the lesions both within the lymph node dissection region, and on the periphery of the lung root reduction and tumour cell resorption in the operative wound, prevention of developing recurrent tumour growth within the pleural cavity.

6 cl, 2 dwg, 3 tbl, 2 ex

Drug preparation // 2444362

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns an antineoplastic drug containing a compound of formula

,

a method for treating a tumour and using the compound of formula (1) for preparing the antineoplastic drug.

EFFECT: drug preparation shows high activity and high safety.

54 cl, 435 tbl, 2717 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fluorinated derivatives of 1,4-naphthoquinone of general formula (II), having cytotoxic effect on human cancer cells in a culture. In formula (II) R = NHCH2COOH, NHCH2COOC2H5, NH(CH2)5COOH, NH(CH2)3COOH, NH(CH2)2COOH, OOC(CH2)3NH2.

EFFECT: disclosed compounds can be used in medicine for therapy of malignant growths.

1 dwg, 4 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an immunodepressant based on a heterocyclic compound of formula

or to its pharmaceutically acceptable salt where X represents a nitrogen atom or CH, both or one of R1 or R2 represents a hydrogen atom, hydroxyl, a halogen atom, an amino group, C1-C6 alkoxy or C1-C6 alkyl: R3 represents a hydrogen atom, difluoromethyl, an amino group, methyl or hydroxymethyl; R4 or R5 represents a hydrogen atom or C1-C6 alkyl; R6 represents morpholino (optionally substituted by one or two C1-C6 alkyl groups), pyrrolidinyl (optionally substituted by hydroxy C1-C6 alkyl), piperidine (which is optionally substituted by an oxygen atom, hydroxyl, formyl or C1-C6 alkyl), piperazinyl (optionally substituted by one or two oxygen atoms, where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a groups consisting of formyl, C1-C6 hydroxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 oxoalkyl, furoyl, benzoyl, methoxybenzoyl, benzylcarbonyl, dimethylcarbamoyl, diethylcarbamoyl, morpholinocarbonyl and methoxyacetyl) or 1,4-diazepano (optionally substituted by one oxygen atom where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a group consisting of formyl, C1-C6 oxoalkyl). Also, the invention refers to a heterocyclic compound of general formula

and to an anticancer drug based on the compound of formula (II).

EFFECT: there are produced new immunodepressant based on the compound of formula (I) and compound of formula (II) which can be used as anticancer drugs.

12 cl, 8 tbl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition for injections contains a mixture of platinum complex of formula II and at least one cyclodextrin and/or at least one cyclodextrin derivative selected from a group comprising alpha-, beta- and gamma-cyclodextrins and their alkylated derivatives in mass ratios within 1:0.1 to 10:1 respectively, and optionally at least one pharmaceutically acceptable excipient. The composition is presented in the form of an aqueous solution prepared by adding an aqueous medium to cyclodextrin or its derivative that is followed by adding the platinum complex of formula ;

or adding the aqueous medium to the mixed platinum complex of formula II and/or at least one cyclodextrin derivative; or adding cyclodextrin or its derivative to the suspension of the platinum complex of formula II in the aqueous medium.

EFFECT: preparing the inclusion complex in the aqueous medium is considerable facilitation of the method for producing the complex and preparing the injected pharmaceutical composition.

3 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly oncology, and can be applied in treating non-muscle invasive bladder cancer. The method involves adjuvant intra-bladder therapy with chemopreparations pre-dissolved in Tisol, aqueous solution. The tumpours with a low risk of relapse and progression require single instillations immediately following the operation of doxorubicine 50 mg or mitomycin 40 mg pre-dissolved in 40% Tisol, aqueous solution 50 ml with the length of exposition 1 h. In the tumours with a medium risk of relapse and progression, the postoperative instillations are added with intra-bladder chemotherapy with doxorubicine 50 mg or mitomycin 40 mg pre-dissolved in Tisol, aqueous solution with the length of exposition 1 h once every 6 weeks.

EFFECT: use of the invention provides higher clinical effectiveness and decreases a degree of side effects due to the adjuvant intra-bladder therapy according to a degree of postoperative risk of relapse and progression of the tumour.

3 tbl, 1 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns a method for treating a proliferative disease associated with PAX/FKHR translocation by introducing N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j[1,7]benzodiazonin-11-yl]-H-methylbenzamide.

EFFECT: invention provides high clinical effectiveness.

4 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely a dosage form presented as suppositories for gynaecological and urological diseases. The suppositories for gynaecological and urological diseases contain a lipid complex of Elton lake mud dehydrated to 20-35%, PEG-1500 base, a preparation of Tykveol and T2 emulsifier in certain proportions, wt %.

EFFECT: suppositories present vaginal and rectal suppositories providing microbiological purity with no side and allergic reactions.

3 tbl

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