Azabenzofuranyl compounds and methods of use

FIELD: chemistry.

SUBSTANCE: invention relates to azabenzofuranyl 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, halogen, CN, -(CR14R15)nC(=Y)OR11, - (CR14R15)nOR11, C1-C12 alkyl; W denotes or R5 and R6 are independently selected from H or C1-C12 alkyl; X1 is selected from R11, -OR11 and -S(O)2R11; if X1 denotes R11 or -OR11 from X1 and -R5 optionally taken together with a nitrogen atom with which they are bonded form a 4-6-member saturated or unsaturated ring containing 0-2 additional heteroatoms selected from O, S, where said ring is optionally substituted with one or more groups selected from oxo, -(CR19R20)nNR16R17, -(CR19R20)nOR16, (CR19R20)nS(O)2R16 and R21; X is selected from aryl, where said aryl is optionally substituted with one or more groups selected from halogen, CN, -Si(C1-C6alkyl), -(CR19R20)nOR16, -(CR19R20)nSR16, C1-C12alkyl; R11, R12 and R13 independently denote H, C1-C12alkyl, aryl, azetidine, pyrrolidinyl, piperidinyl, tetrahydropyranyl; R14 and R15 are independently selected from H or C1-C12 alkyl; n is independently selected from 0, 1; Y independently denotes O; where each of said alkyl, alkenyl, aryl and heteroaryl from R1, R2, R3, R4, R5, R6, X1, X2, R11, R12, R13, R14 and R15 is independently and optionally substituted with one or more groups independently selected from -(CR19R20)nC(=Y')OR16, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, - (CR19R20)nNR17SO2R16 and R21; each R16, R17 independently denotes H, C1-C12 alkyl, C2-C8alkenyl, aryl, or pyridinyl, where said alkyl, alkenyl or aryl is optionally substituted with one or more groups selected from -OH; R19 and R20 are independently selected from H, C1-C12 alkyl; R21 denotes C1-C12 alkyl, aryl, imidazolyl, pyridinyl, pyrazolyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperidinyl, or 2,2-dimethyl-1,3-dioxolanyl; each Y' independently denotes O. The invention also relates to specific compounds, a pharmaceutical composition based on the disclosed compounds, a method of inhibiting anomalous cell growth or a method of treating hyperproliferative disorders, inflammatory diseases and other diseases.

EFFECT: novel azabenzofuranyl derivatives which can be used in treating cancer and inflammatory diseases are obtained.

23 cl, 3 tbl, 34 ex

 

This application is an international patent application claiming priority from provisional application U.S. 60/839161, filed August 21, 2006, provisional patent application U.S. 60/871591, filed December 22, 2006, U.S. provisional application 60/917623, filed may 11, 2007, and U.S. provisional application 60/944741, filed June 18, 2007, the contents of which are fully included here as a reference.

The technical FIELD TO WHICH the INVENTION RELATES.

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

The LEVEL of TECHNOLOGY

In the research undertaken to understand how Ras transmit signals from extracellular growth, it was found that functional diagram MAP (mitogen-activated protein) kinase (MAPK) acts as the crucial link between related Ras membrane and nuclei. Functional diagram MAPK includes cascade acts phosphorylation, including three key kinases, namely Raf, MEK (MAP kinase) and ERK (MAP kinase). Active GTP-Ras lead to activation and indirect phosphorylation of Raf kinase. Then Raf phosphorylates MEK1 and 2 on two serine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahn et al., Methods in Enzymology 2001, 332, 417-431). Activated MEK then phosphorylates only the known substrates of MAP kinases, ERK1 and 2. ERK phosphorylation through MEK occurs Y204 and T202 for ERK1 and Y185 and T183 for ERK2 (Ahn et al., Methods in Enzymology 2001, 332, 417-431). Phosphorylated ERK timeresults and then move into the nucleus, where they accumulate (Khokhlatchev et al., Cell 1998, 93, 605-615). In the nuclei of ERK are involved in several important cellular functions, including, but not limited to, transport of cores, signal transduction, DNA repair, Assembly, and translocation of nucleosomes and the processing and translation of mRNA (Ahn et al., Molecular Cell 2000, 6, 1343-1354). In the end, 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 considerable evidence that genetic mutations and/or overexpression of protein kinase involved in the functional diagram MAP kinase, leading to uncontrolled cell proliferation and, ultimately, to the formation of tumors, proliferative diseases. For example, some cancer include mutations that cause continuous activation of the scheme operation, due to the continuous production of growth factors. Other mutations can adjust the tee to the defect in deactivation of the activated GTP-bound Ras complex, that again leads to the activation scheme of functioning of MAP kinase. Mutated, oncogenic forms of Ras is observed in 50% of cases of colon cancer and in >90% of cancer of the pancreas, as well as many other types of cancer (Kohl et al., Science 1993, 260, 1834-1837). Newly identified mutations skin disease more than 60% of malignant melanomas (Davies, H. et al., Nature 2002, 417, 949-954). These mutations in skin disease lead to constitutive active cascade of MAP kinases. Samples of primary tumors and cell lines also exhibit constitutive or overactivation operation scheme MAP kinase in cancer of the pancreas, colon, lung, ovarian and kidney (Hoshino, R. et al., Oncogene 1999, 18, 813-822).

MEK has proved itself as an attractive therapeutic target in the functional diagram of the cascade of MAP kinases. MEK, located in the forward direction from Ras and Raf, vysokospetsifichnymi in relation to phosphorylation of the MAP kinase; indeed, the only known substrates for MEK phosphorylation are the MAP kinases, ERK1 and 2. It was shown that inhibition of MEK has potential therapeutic benefit in some studies. For example, it was shown that small molecule MEK inhibitors inhibit the growth of human tumors in xenografts in Nude mice (Sebolt-Leopold et al., Nature Medicine 1999, 5 (7), 810-81); Trachet et al., AACR Apr. 6-10, 2002, Poster #5426; Tecle, H. IBC 2.sup.nd International Conference of Protein Kinases, Sep. 9-10, 2002), block static allodynia in animals (WO 01/05390 dated January 25, 2001) and inhibit the growth of active myeloid cell leukemia (Milella et al., J Clin Invest 2001, 108 (6), 851-859).

Some small molecule inhibitors of MEK was 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 tools for the treatment of various conditions of proliferative diseases, such as conditions associated with hyperactivity of MEK, as well as diseases modulated MEK cascade.

The INVENTION

The present invention relates in General to isobenzofuranone compounds of formula I (and/or solvate and salts) with anticancer and/or anti-inflammatory activity and more specifically with inhibitory activity against MEK kinase. Some of hyperproliferative and inflammatory disorders are characterized by modulating the functions of MEK kinase, such as mutations or overexpression of proteins. Accordingly, these compounds of the present invention and their compositions can be used in the treatment of hyperproliferative disorders such as cancer and/or inflammatory diseases such as rheumatoid arthritis.

where:

Z1 1or N;

Z2represents CR2or N;

Z3represents 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) (OR11), -(CR14R15)nSC(=Y)R11, -(CR14R15)nSC(=Y)OR11, -(CR14R15)nSC(=Y)NR11R12C1-C12of alkyl, C2-C8alkenyl, C2-C8the quinil, carbocycle, heterocyclyl, aryl and heteroaryl;

W represents

R5and R6independently selected from H or C1-C12of alkyl;

X1selected from R11, -OR11, -NR11R12, -S(O)R11and-S(O)2R11; where X1of R11or11,

R11or11of X1and R5not necessarily taken together with the nitrogen atom to which they are attached, form a 4-7-membered saturated or unsaturated ring containing 0-2 additional heteroatoms selected from 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-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR]9R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R2 )nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CRl9R20)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-C12alkyl, C2-C8alkenyl, C2-C8quinil, 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 containing 0-2 heteroatoms selected from O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from GoLoG is on, CN, CF3, -OCF3, -NO2C1-C6of alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(C1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

R14and R15independently selected from H, C1-C12of 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 each is shown alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl of R1, R2, R3, R4, R5, R6X1X2, R11, R12, R13, R14and R15independently optionally substituted by one or more groups independently wybranych from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(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)n S(O)2(OR16), -(CRl9R20)nSC(=Y')R16, -(CR19R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21;

each R16, R17and R18independently represents H, C1-C12alkyl, C2-C8alkenyl, C2-C8quinil, 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, oxo, CN, -OCF3, CF3, -NO2C1-C6of alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(C1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

or R16and R17together with the nitrogen atom to which they are attached, form a 3-8-membered saturated, unsaturated or aromatic ring containing 0-2 heteroatoms selected from O, S and N, where the aforementioned ring is optionally substituted by one or more groups selected from halogen, CN, -OCF3, CF3, -NO2C1-C6of alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(C1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)N(C 1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

R19and R20independently selected from H, C1-C12of alkyl, -(CH2)n-aryl, -(CH2)n-carbocycle, -(CH2)n-heterocyclyl and -(CH2)n-heteroaryl;

R21represents a C1-C12alkyl, C2-C8alkenyl, C2-C8quinil, carbocyclic, heterocyclic, aryl, or heteroaryl, where each member of R21optionally substituted by one or more groups selected from halogen, CN, -OCF3, CF3, -NO2C,-C6of alkyl, -OH, -SH, -O(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SO2(C1-C6alkyl), -CO2H, -CO2(C1-C6alkyl), -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHSO2(C1-C6alkyl), -N(C1-C6alkyl)SO2(C1-C6alkyl), -SO2NHsub> 2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -OC(O)O(C1-C6alkyl), -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)NH(C1-C6alkyl), -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)NH(C1-C6alkyl), -NHC(O)N(C1-C6alkyl)2, -NHC(O)O(C1-C6alkyl) and-N(C1-C6alkyl)C(O)O(C1-C6alkyl);

each Y' independently represents O, NR22or S; and

R22represents H or C1-C12alkyl.

The present invention includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or its solvate, hydrates and/or salts) and a carrier (a pharmaceutically acceptable carrier). The present invention also includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or its solvate, hydrates and/or salts) and a carrier (a pharmaceutically acceptable carrier), further comprising a second chemotherapeutic and/or second anti-inflammatory agent. Compositions of the present invention can be used for inhibiting abnormal cell growth or treating a hyperproliferative disorders in ml is capitalsim (for example, in humans). Compositions of the present invention can also be used for the treatment of inflammatory diseases in mammals (e.g. humans).

The present invention includes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorders in mammals (e.g. humans), 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, alone or in combination with a second chemotherapeutic agent.

The present invention includes 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, alone or in combination with a second anti-inflammatory agent.

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

A DETAILED DESCRIPTION of the PREFERRED VARIANT of the INVENTION

Next will be made detailed reference to some variants of the present invention, examples of which are illustrated with accompanying p is kiturami and formulas. Although the present invention is disclosed in connection with the above options, it should be understood that they in no way limit the present invention the specified options. On the contrary, the present invention includes all alternatives, modifications and equivalents that may be included in the scope of the present invention in accordance with the invention. Professionals will understand the many methods and materials similar or equivalent to those disclosed here, and which can be used in the practice of the present invention. The present invention is in no way limited to the disclosed methods and materials. In that case, if one or more of the literary references, patents and similar materials different from or opposed to a pending application, including, but not limited to, terminology, use of terms, the disclosed methods or the like, such application will be considered.

DEFINITION

The term "alkyl" in the sense used here, refers to a saturated unbranched or branched monovalent hydrocarbon radical containing from one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-repel (i-Pr, ISO-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, ISO-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1 pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-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 an unbranched or branched monovalent hydrocarbon glad the feces, containing from two to twelve carbon atoms with at least one site of unsaturation, i.e. a double bond carbon-carbon sp2in a hybrid state, where alkanniny radical includes radicals with "CIS" and "TRANS" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenic or vinyl (-CH=CH2), allyl (-CH2CH=CH2and so on

The term "quinil" refers to an unbranched or branched monovalent hydrocarbon radical containing from two to twelve carbon atoms with at least one site of unsaturation, i.e. a triple bond of carbon-carbon sp in a hybrid state. Examples include, but are not limited to, ethinyl (-C≡CH), PROPYNYL (propargyl, -CH2C≡CH), etc.

The terms "carbocycle", "carbocyclic", "carbocyclic ring" and "cycloalkyl" refers to univalent not aromatic, saturated or partially unsaturated ring containing from 3 to 12 carbon atoms in the form of a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycle containing from 7 to 12 atoms can be represented, for example, in the form of bicyclo[4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycle containing 9 or 10 atoms in the ring can be 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" refers to a monovalent aromatic hydrocarbon radical containing 6 to 18 carbon atoms, formed by removing one hydrogen atom from a simple carbon atom of the original aromatic ring system. Some of the aryl groups represented in the form of such 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, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl etc.

The terms "heterocycle," "heterocyclyl" and "heterocyclic ring" are used here interchangeably, and they refer to a saturated or partially unsaturated (i.e. soda is containing one or more double and/or triple bond within the ring) carbocyclic to radical, consisting of 3-18 atoms in the ring, in which at least one atom of the ring, which is a heteroatom, selected from nitrogen, oxygen and sulfur, and the remaining atoms in the ring are C, where one or more of the atoms in the ring optionally substituted independently one or more of the disclosed further substituents. A heterocycle may be a monocycle containing from 3 to 7 members in the ring (from 2 to 6 carbon atoms and from 1 to 4 heteroatoms selected from N, O, P and S), or bicyclo containing from 7 to 10 members in the ring (from 4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: bicyclo[4,5], [5,5], [5,6] or [6,6] system. Heterocycles disclosed in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclyl" also includes radicals where heterocyclic radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydropyranyl, dihydropyran, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, dioxane, piperazinil, Homo is piperazinyl, azetidinol, oxetanyl, tyltyl, homopiperazine, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolopyrimidines, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes and azabicyclo[2.2.2]hexanal. Spiroergometry also included in the scope of the specified definition. Examples of heterocyclic groups, where the atoms in ring substituted with oxo (=O) fragments, are pyrimidinones and 1,1-dioxothiazolidine.

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

Heterocyclic or heteroaryl group may be attached to carbon (as carbon) or nitrogen (nitrogen) wherever possible. So, for example, as an example, but not limitation, related to carbon heterocycles or heteroaryl can be linked to positions 2, 3, 4, 5, or 6 of a pyridine, clauses 3, 4, 5 or 6 pyridazine, positions 2, 4, 5, or 6 of a pyrimidine, positions 2, 3, 5, or 6 pyrazine, positions 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, positions 2, 4, or 5 oxazole, imidazole or thiazole, clauses 3, 4 or 5 isoxazol, pyrazole or isothiazole, clauses 2 or 3 of aziridine, positions 2, 3, or 4 azetidine, the provisions 2, 3, 4, 5, 6, 7 or 8 of a quinoline or provisions 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

So, for example, as an example, but not limitation, related nitrogen heterocycles or heteroaryl can be connected to position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-PIR is Zolina, 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+->-, S(O), and S(O)2.

The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or prevent activities, which implement the prevention of an object or a slow decrease (attenuation of undesired physiological change or disorder, such as the development or spread of cancer. For the purposes of this invention, beneficial or desired clinical results (or defined or not defined) include, but are not limited to, relieving symptoms, reducing the severity of disease, stabilized (i.e. not worsening) state of disease, delay or slowing of disease progression, improvement or temporary weakening of the morbid state, and remission (partial or full). The term "treatment" can also mean prolonging the duration of life compared with the expected duration in the absence of treatment. Those in need of treatment include those already present condition or violation, or t is x, who is prone to the appearance of such conditions or disorders, or those who need to prevent the emergence of such conditions or disorders.

"Therapeutically effective amount" means such amount of the compounds of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) relaxes, eases or eliminates one or more symptoms of the particular disease, condition or violation, or (iii) prevents or delays the occurrence of one or more of the symptoms disclosed here, the specific disease, condition or violation. In the case of cancer, a therapeutically effective quantity of a drug can reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., to some extent, slow and preferably stop) infiltration of cancer cells into peripheral organs; inhibit (i.e., to some extent, slow and preferably stop) tumor metastasis; to some extent, to inhibit tumor growth and/or to some extent weaken one or more of the symptoms associated with cancer. Depending on the extent to which the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cyto is oxycheck. For cancer treatment effectiveness can be measured, for example, estimating the time until progression of disease (TTP) and/or determining the degree of response (RR).

The term "abnormal cell growth" and "hyperproliferative disorders" is used in this application interchangeably. The expression "abnormal cell growth" in the sense used here, unless otherwise indicated, refers to such cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This growth includes, for example, an abnormal growth of: (1) tumor cells (tumors)that have proliferated due to the expression of the mutated tyrosine kinase or overexpression of the receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant activation of tyrosine kinase; (3) any tumors that proliferate at the expense of receptor tyrosine kinase; (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 the physiological state or describe the physiological condition of the mammal to the e is usually characterized by disordered growth of cells. The term "tumor" includes one or more of the cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignant disease. More particular examples of such cancers include squamous cancer cells(for example, cancer of the squamous epithelial cells), 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, cancer of the stomach or intestines, including cancer of the gastrointestinal tract, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, carcinoma of the salivary glands, kidney cancer or renal cancer, prostate cancer, cancer of the reproductive organs, thyroid cancer, liver carcinoma, anal carcinoma, carcinoma of the penis, acute leukemia, and cancers of the head/brain and neck.

"Chemotherapeutic agent" is a chemical compound that can be used for cancer treatment. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, ovartis), Machinemessiah (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, 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 CYTOXAN® cyclophosphamide; alkyl sulphonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimines and methylmelamine, including altretamin, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylaniline; acetogenins (especially bullatacin and bullatacin); camptothecin (including the synthetic analogue topotecan); bryostatin; callistemon; CC-1065 (including its synthetic analogues of adozelesin, carzelesin and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorpropamide, estramustine, ifosfamide, mechlorethamine, hydrochloride mechlorethamine, milfanal, novemberin, finasterin, prednimustine, trofosfamide, Wratislavia the mustards; nitrosoanatabine, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine and ranimustine; antibiotics such as e is adinoyi antibiotics (for example, calicheamicin, especially calicheamicin gamma I and calicheamicin omega I (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; spiramycin; as well as the chromophore of neocarzinostatin and related chromophores of antibiotic chromoprotein enediyne), aclacinomycin, actinomycin, autralian, azaserine, bleomycin, actinomycin, carubicin, karminomitsin, casinopolis, chromomycin, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino doxorubicin, cyanomethane doxorubicin, 2-pyrroline doxorubicin and deoxidation), epirubicin, zorubicin, idarubitsin marsellaise, mitomycin, such as mitomycin C, mycophenolat acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, colomycin, radiobeacon, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); analogs of folic acid, such as deeperin, methotrexate, peripherin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, timipre, tioguanin; pyrimidine analogues such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone, epitiostanol, menu is Josten, testolactone; anti-adrenali, such as aminoglutetimid, mitotane, trilostane; Replenisher folic acid, such as prolinea acid; Eagleton; glycoside aldophosphamide; aminolevulinic acid; eniluracil; amsacrine; bestobell; bisantrene; edatrexate; defaming; demecolcine; diazinon; alternity; acetate elliptinium; epothilone; etoposide; galliumnitride; hydroxyurea; lentinan; londini; maytansinoid, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitrean; pentostatin; penomet; pirarubicin; losoxantrone; podophylline acid; 2-acylhydrazides; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tinoisamoa acid; triaziquone; 2,2',2"-trihlortrietilamin; trichothecenes (especially T-2 toxin, verrucarin a, roridin a and anquetin); 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, the composition of paclitaxel-based nanoparticle albumin (American pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); Haralambos; GEMZAR® (gemcitabine); 6-tioguanin; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinblastine; etoposide (VP16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; deformational (DMFO); retinoids such as retinova acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

The definition of "chemotherapeutic agent" shall also include: (i) protivokomarinye agents, the action of which is to regulate or inhibit the effects of hormones on tumors such as anti-estrogens and selective modulators of estrogen receptors (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifenside), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and FARESTON® (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® (magistralata), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bikalutamid, leuprolide, and goserelin; as well as troxacitabine (1,3-dioxolane similar nucleosidase); (iv) inhibitors of protein kinases; (v) inhibitors lietkynes; (vi) antimicrob the e oligonucleotides, particularly those that inhibit expression of genes in signaling scheme involved in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozyme, such as the VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 inhibitors of gene expression; (viii) vaccines such as vaccines, gene therapy, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rII-2; a topoisomerase inhibitor 1, such as LURTOTECAN®; ABARELIX® rmRH; (ix) antiangiogenic agents such as beacomes (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above. Other antiangiogenic agents include inhibitors of MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloproteinase 9)inhibitors, COX-II (cyclooxygenase II) and inhibitors of VEGF receptor tyrosine kinase. Examples of useful inhibitors of matrix-metalloproteinases, which can be used in combination with the compounds/compositions of the present invention, are disclosed 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. Pat. No. 5863949, U.S. Pat. No. 5861510 and EP 780386, all of which are included here in its entirety for reference. Examples of inhibitors of VEGF receptor tyrosine kinase include 4-(4-bromo-2-foronline)-6-methoxy-7-(1-methylpiperidin-4-ylethoxy)hinzelin (ZD6474; Example 2 of WO 01/32651), 4-(4-fluoro-2-methylindol-5 is hydroxy)-6-methoxy-7-(3-pyrrolidin-1 ipropose)hinzelin (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds such as those 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 compositions of the present invention include inhibitors of PI3K (phosphoinositide-β kinase), such as those disclosed in the footsteps of Yaguchi et al. (2006) Jour, of the Nat. Cancer Inst. 98(8):545-556; US 7173029; US 7037915; US 6608056; US 6608053; US 6838457; US 6770641; US 6653320; US 6403588; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 1417976; US 2004/053946; JP 2001247477; JP 08175990; JP 08176070; US 6703414 and WO 97/15658, all of which are included here in its entirety for reference. Specific examples of these PI3K inhibitors include SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.).

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

"Anti-inflammatory agent is a compound that can be used in the treatment of inflammation. Examples of anti-inflammatory agents include protein therapeutic agents for injection, such as Enbrel®, Remicade®, Humira®, Kineret®. Other examples of anti-inflammatory agents include non-steroidal anti-inflammatory agents (NSAIDs)such as ibuprofen or aspirin (to reduce puffiness and ease the pain); disease modifying Antirheumatic drugs (DMARDs)such as methotrexate; 5-aminosalicylate (sulfasalazin and not containing sulfur agents; corticosteroids; immunomodulators such as 6-mercaptopurine ("6-MP"), azathioprine ("AZA"), cyclosporine, and biological response modifiers, such as Remicade.RTM. (infliximab) and Enbrel.RTM. (etanercept); fibroblast growth factors; growth factors derived from platelets; blockers of enzymes, such as Arava.RTM. (Leflunomide); and/or agents, protecting cartilage, such as hyaluronic acid, glucosamine and chondroitin.

The term "prodrug" in the sense used in this Declaration, the ke, refers to a precursor or derivative compound of the present invention, which is capable of being enzymatically or hydrolytically activated or can be converted into the more active the related form. See, for example, Wilman, "Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions, 14, pp.375-382, 615th Meeting 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 the present invention include, but are not limited to, the prodrugs containing ester, prodrugs containing phosphate, prodrugs containing thiophosphate, prodrugs containing sulfate, prodrugs containing peptide prodrugs, modified D-amino acid, glycosylated prodrugs, and prodrugs containing a β-lactam, prodrugs containing optionally substituted phenoxyacetamide, prodrugs containing optionally substituted phenylacetamide, 5-fortitudinous and other 5-ptoluidine prodrugs which can be converted into a more active, non-cytotoxic drugs. Examples of cytotoxic drugs that can be turned into proletarienne forms for use in the present invention include, but are not limited to, compounds of the present invention and chemotherapeutic agents, such as disclosed above.

"Metabolite" submitted is a product of a specific compound or its salt, formed as a result of metabolism in the body. Metabolites of compounds can be identified using well-known specialists routine methods, and to determine their activity, using various tests, such as those disclosed here. Such products can be obtained, for example, as a result of oxidation, hydroxylation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic degradation, etc. entered the compound. Accordingly, the present invention includes metabolites of compounds of the present invention, including the compounds obtained by the process that includes the interaction of the compounds of the present invention with a mammal for a period of time which is sufficient to form a product of its metabolism.

"Liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surface active agents which can be used for delivery to the mammal a drug (such as disclosed here inhibitors of MEK kinase and, optionally, a chemotherapeutic agent). Components of liposomes are typically arranged in a bilayer formation, similar to the grouping of lipids in biological membranes.

The term "investment package" refers to the nstruction, which is usually included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, method of administration, contraindications and/or warnings concerning the use of such therapeutic products.

The term "chiral" refers to molecules that do not possess the property of vzaimozavisimosti mirror images of each other, while the term "achiral" refers to molecules which have the property of vzaimozavisimosti mirror images of each other.

The term "stereoisomer" refers to compounds which have identical chemical compositions, but have different spatial orientation of the atoms that are not vzaimoprevrascheny while rotating around simple links.

The term "diastereoisomer" refers to a stereoisomer with two or more centers of chirality, molecules which do not represent a mirror image of each other. Diastereomers have different physical properties, such as, for example, melting point, boiling point, spectral characteristics and reactivity. A mixture of diastereoisomers can be separated using analytical high resolution procedures, such as crystallization, electrophoresis and chromatography.

The term "enantiomers" refers to on the mind of the stereoisomers of the compounds, which are not vzaimovliianie mirror images of each other.

Stereochemical definitions and conventions used here are usually in accordance with S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is assumed that all stereoisomeric forms of these compounds of the present invention, including, but not limited to, the diastereomers, the enantiomers and atropoisomeric, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compounds of the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center (centers). The prefixes d and 1 or (+) and (-) is used to denote the direction (sign) of rotation of plane-polarized light through the specified connection, and (-) or 1 meaning that the compound is levogyrate. Video in connection (+) or d means that the soy is inania is Pervouralsk. For specific chemical structure of these stereoisomers are identical, except that they are mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of such isomers is often called an enantiomeric mixtures. The mixture of enantiomers of 50:50 is called a racemic mixture or a racemate, which can be observed in cases of lack of stereoselectivity or stereospecificity in chemical reactions or processes. The terms "racemic mixture" and "racemate" refers to an equimolar mixture of two enantiomers devoid of optical activity.

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

The expression "pharmaceutically acceptable salt" in the sense used here, refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Representative salts include the, but not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannat, Pantothenate, bitartrate, ascorbate, succinate, maleate, genticin, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate "mesilate", aconsultant, bansilalpet, p-toluensulfonate, pamoate (i.e. 1,1'-methylene-bis-(2-hydroxy-3-aftout)), alkali metal salts (e.g. sodium and potassium), salts of alkaline earth metals (e.g. magnesium), and ammonium salts. Pharmaceutically acceptable salts may contain inclusions of other molecules such as acetate ions, succinate ions or other counterions. The counterion may be any organic or inorganic fragment, which stabilizes the charge of the original connection. Moreover, pharmaceutically acceptable salts may contain more than one charged atom in the structure. In cases where multi-charged atoms are part pharmaceutically acceptable salt, this salt, there can be many counterions. Consequently, the pharmaceutically acceptable salt can have one or more of the charged atoms and/or one or more of the counterions.

If the connection of the present invention is a base, the desired pharmaceutically acceptable the Yu salt can be obtained by any of the well-known specialists of ways, for example, treating the free base of such inorganic acid like hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesulfonate acid, phosphoric acid and the like, or such organic acids as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyrenoidosa acid, such as glucuronic acid or galacturonic acid, an alpha 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, a sulfonic acid such as p-toluensulfonate acid or econsultancy acid, or the like

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

"Pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients that make up the composition, and/or mammals, which they treat.

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

The term "protective group" refers to the Deputy, which is usually used to block or protect a particular functionality during the reaction with other functional groups of the compounds. For example, "amino-protective group" is a Deputy, attached to the amino group that blocks or protects the amino functionality of the compound. Suitable amino-protective groups include acetyl, triflora ethyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, the term "hydroxy-protective group" refers to the Deputy hydroxy-group that blocks or protects the hydroxy functionality. Suitable protective groups include acetyl and silyl. The term "carboxy-protective group" refers to the Deputy carboxy group that blocks or protects the carboxy functionality. Conventional carboxy-protective group include phenylsulfonyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluensulfonyl)ethyl, 2-(p-nitrobenzylidene)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl etc. For a General description of the protective groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound of the present invention" 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 their proletarienne form.

In the present invention proposed connection isobenzofuranyl formula I, as disclosed above, which you can use as kinase inhibitors, especially those that can be used as inhibitors of MEK kinase. Nastoyascheevremya includes connection formulae 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 are specified for formula I values.

In one embodiment of the present invention compounds have 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 are specified for formula I values.

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

In one embodiment of the present invention R1represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or C1-6alkyl 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 of the present invention R1represents H, halogen, CN, CF3C1-6alkyl, -NR11R12where R11and R12independently represent H or C1-C6alkyl, -OR11where R11represents H or C1-6alkyl, or-SR11where R11represents H or C1-6alkyl; 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, II-a, III-b, III-d, III-f and III-g.

In another embodiment of 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 another embodiment of 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 one embodiment of the present invention R2represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or C1-6alkyl 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 have the above values.

In another embodiment of the present invention R2represents H, halogen, CN, CF3C1-6alkyl, -NR11R12where R11and R12independently represent H or C1-6alkyl, -OR11where R11represents H or C1-6alkyl, or-SR11where R11represents H or C1-6alkyl; 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 have the above values.

2represents 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 have the above values.

In one embodiment of the present invention R3represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or C1-6alkyl 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 have the above values.

In another embodiment of the present invention R3represents H, halogen, CF3C1-6alkyl; 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 have the above values.

In another embodiment of 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, III-a, III-c, III-d, III-e, or III-i, or have the above values.

In another embodiment of the present invention R3represents H, F, Cl, CF3, 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 Il the III-i, or are the above values.

In one embodiment of the present invention R4represents H, halogen, CN, CF3, -NR11R12, -OR11, -SR11, -C(=O)NR11R12or C1-6alkyl 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 have the above values.

In another embodiment of the present invention R4represents H, halogen, CN, CF3, -NR22R12or-C(=O)NR11R12where R11and R12independently represent H or C1-6alkyl, -OR11where R11represents H or C1-6alkyl, or-SR11where R11represents H or C1-6alkyl; 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 have the above values.

In another embodiment of the present invention R4represents H, Br, Cl, CN, CF3, -NH2, -NH(CH3), -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -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 have the above values.

In another embodiment of the present invention R4pre is is a H, Br, Cl, CN, CF3, -NH2, -NH(CH3), -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -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 have the above values.

In another embodiment of the present invention R4represents a halogen, -OH, or C1-6alkyl, 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 have the above values.

In another embodiment of 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 have the above values.

In one embodiment of the present invention R5represents H or C1-6alkyl; and all other variables have the meanings specified for formula I, I-a to I-i or II-a to II-i, or have the above values.

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

In other variations which those of the present invention R 5represents H; and all other variables have the meanings specified for formula I, I-a to I-i or II-a to II-i, or have the above values.

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

In one embodiment of the present invention R6represents H or C1-6alkyl; and all other variables have the meanings specified for formula I, I-a to I-i, II-a to II-i, or III-a to III-i, or have the above values.

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

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

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

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

In one embodiment of the present invention X1is a OR11where R11represents H; and all other variables have the meanings specified for formula I or I-a to I-i; or have the above values.

In another embodiment of the present invention X1is a OR11where R11represents a C1-C12alkyl (for example, C1-6alkyl), substituted by one or more groups that are independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNRl6C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -( CR19R20)nNR18C(=Y')N R16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R17, -(CR19R20)nOS(O)2(OR16), -(CR19R20)nOP(=Y')(OR16)(OR17), -(CRsup> 19R20)nOP(OR16)(OR17), -(CR19R20)nS(O)R16, -( CR19R20)nS(O)2R10, -(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 to I-i, or have the above values.

In another embodiment of the present invention X1represents:

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

In another embodiment of the present invention X1represents; and all other variables have the meanings specified for formula I or I-a to I-i, or have the above values.

In another embodiment of the present invention X1represents a

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

In another embodiment of the present invention X1represents a

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

In another embodiment of the present invention X1represents a

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

In another embodiment of the present invention X1is a OR11where R11represents heterocyclyl (e.g., 4-6-membered heterocyclyl), optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CRl9R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(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), -CR 19R20)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, -(CRl9R20)nSC(=Y')OR16, -(CR19R20)nSC(=Y')NR16R17and R21; and all other variables have the meanings specified for formula I or I-a to I-i, or have the above values.

In another embodiment of the present invention X1is a OR11where R11is a 4-6-membered heterocyclyl containing one ring nitrogen atom, where the specified heterocyclyl optionally substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(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 to I-i, or have the above values.

In another embodiment of the present invention X1representsor; and all other variables have the meanings specified for formula I or I-a to I-i, or have the above values.

In another embodiment of the present invention X1represents a

and all other variables have the meanings specified for formula I or I-a to I-i, or there is t the above values.

In another embodiment of the present invention X1represents a

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

In one 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 cyclic ring containing 0-2 additional heteroatoms selected from O, S and N, where the specified cyclic ring optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2Rl6, -(CR19R20)nOC(=Y')R16, -(CR19R20)nOC(=Y')OR16, -(CR19R20)nOC(=Y')NR16R 17, -(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 to I-i, or have the above values.

In another embodiment of the present invention X1is an R11and X1and R5taken together with the nitrogen atom to which they are attached, form a 5-6-membered saturated cyclic ring containing 0-2 additional heteroatoms selected from O, S and N, where the specified cyclic ring optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR9 R20)n-SR16, -(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 to I-i, or have the above values.

In another embodiment of the present invention W is:

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

In another embodiment of the present invention W is:

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

In another embodiment of the present invention W is:

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

In one embodiment of the present invention X1is an R11and X1and R5taken together with the nitrogen atom to which they are attached, form a 4-membered saturated or unsaturated cyclic ring containing 0-1 additional heteroatom selected from O, S and N, where the specified cyclic ring optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CRI9R20)nC(=Y')OR]6, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNR17SO2R16, -(CR19R20)nOC(=Y')R16, -(CR19 R20)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 to I-i, or have the above values.

In another embodiment of the present invention W is:

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

In one 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 cyclic ring containing 0-2 additional heteroatoms selected from O, S and N, where the specified cyclic ring optionally substituted with one ilible group, selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(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 to I-i, or have specified the above values.

In another embodiment of 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 cyclic ring containing 0-2 additional heteroatoms selected from O, S and N, where the specified cyclic ring optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(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)2 R16, -(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 to I-i, or have the above values

In another embodiment of the present invention X1represents-OR11and-OR11of X1and R5taken together with the nitrogen atom to which they are attached, form a 5-6-membered saturated cyclic ring containing 0-2 additional heteroatoms selected from O, S and N, where the specified cyclic ring optionally substituted by one or more groups selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17-(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16R17, -(CR19R20)nNRsup> 17SO2R16, -(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 to I-i, or have the above values.

In another embodiment of the present invention W is:

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

In one 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 have the above values.

In another embodiment of the present invention X1is an R11where R 11represents 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 have the above values.

In another embodiment of the present invention X1is an R11where R11represents a C1-C12alkyl (for example, C1-C6alkyl), substituted by one or more groups independently selected from halogen, CN, CF3, -OCF3, -NO2, oxo, -Si(C1-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y,OR16, -(CR19R20)nC(=Y,)NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNRl6C(=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)2R 16, -(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-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or have the above values.

In another embodiment of the present invention X1represents:

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 have the above values.

In another embodiment of the present invention X1represents:

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 have the above values.

In another embodiment of 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 have the above values.

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

In one embodiment of the present invention W is a OR11(i.e. the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i), where R11from W represents H or C1-C12alkyl; and all other variables have the values indicated above.

In another embodiment of the present invention W is a OR11(i.e. the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i), where R11from W represents H; and all other variables have the values indicated above.

In another embodiment of the present invention W is a OR11(i.e. the formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i), where R11W represents C1-C6alkyl; and all other variables have the values indicated above.

In one 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-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n -SR16, -(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 to I-i, II-a to II-i, or III-a to III-i, or have the above values.

In another embodiment of the present invention X2represents:

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

In another embodiment of the present invention X2p is ecstasy:

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

In another embodiment of the present invention X2represents:

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

In another embodiment of the present invention X2represents:

; and all other variables have the meanings specified for formula I, I-a to I-i, II-a to II-i, or III-a to III-i, or have shown higher values.

In another embodiment of the present invention X2represents:

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

In another embodiment of the present invention X2represents a C6-C10aryl, substituted C1-C4by alkyl; and all other variables have the meanings specified for formula I, I-a to I-i, II-a to II-i, or III-a to III-i, or have the above values.

In another embodiment of the present invention X2represents:

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

In another embodiment of the present invention X2represents:

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

In another embodiment of the present invention X2represents:

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

In another embodiment of the present invention X2represents carbocyclic (for example, C4-C6carbocyclic) 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-C6alkyl), -(CR19R20)nC(=Y')R16, -(CR19R20)nC(=Y')OR16, -(CR19R20)nC(=Y')NR16R17, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)n-SR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR18C(=Y')NR16 R17, -(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, -(CRl9R20)nSC(=Y')NR16R17and R21; and all other variables have the meanings specified for formula I, I-a to I-i, II-a to II-i, or III-a to III-i, or have the above values.

In another embodiment of the present invention X2represents a C4-C6carbocyclic where specified carbocycle substituted-C(=Y')R16; and all other variables have the meanings specified for formula I, I-a to I-i, II-a to II-i, or III-a to III-i, or have the above values.

In another embodiment of the present invention X2represents a

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

Another variant of the present invention includes compounds disclosed in the examples 5-159, and connections are presented below:

Compounds of the present invention produced by the methods set forth in the schemes and in the examples or by methods known in the art. Raw materials and various intermediate compounds can be obtained from commercial sources, be obtained from commercially available compounds, or receive, using the well-known specialists of the synthesis methods (for example, those disclosed in WO 02/06213, WO 03/077855 and WO 03/077914).

For example, 5-isobenzofuranyl formula (I-b), (II-b) or (III-b) can be obtained using the synthesis methods presented in schemes 1, 2 and 3.

Scheme 1

The compounds of formula (IV) can be obtained using disclosed in the literature methods. These compounds can be subjected to interaction with methylglucose or ethylglycol in the presence of a base such as sodium hydride, in a suitable solvent such as N,N-dimethylformamide or 1,2-dimethoxyethane, at a temperature in the range 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), carrying out inter the operation with such a halogenation agent, as bromacil phosphorus, in pure form or in a suitable solvent such as toluene, at a temperature in the range from room temperature up 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 such a catalyst 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 in the range from room temperature up to the boiling point of the solvent under reflux. 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 in the range from -20°C to room temperature.

The compounds of formula (VIII) can be obtained from compounds of formula (VII), interacting with aniline (by introducing appropriate substituents R1), in the presence of such a catalyst as Tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, a base such as potassium phosphate, tert-piperonyl sodium, l,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, ligand, such as 9,9'-dimethyl-4,5-bis(definites is Ino)Xanten, 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 a temperature in the range from room temperature up to the boiling point of the solvent under reflux, or under microwave irradiation at a temperature in the range from 70°C to 150°C.

Alternative compounds of formula (VIII) can be obtained from compounds of formula (VI), interacting with compounds of the formula (IX) (obtained in accordance with the disclosures provided in the literature) in a suitable solvent such as toluene or 1,2-dimethoxyethane, at a temperature in the range from room temperature up to the boiling point of the solvent under reflux, or under microwave irradiation at a temperature in the range from 100°C to 180°C.

The compounds of formula (X) can be obtained from compounds of formula (VIII), interacting with bases such as sodium hydroxide, in an aprotic solvent such as ethanol or methanol, at a temperature in the range from room temperature up 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 with the availa able scientific C with scheme 8) or an amine, and so a suitable binding agent, as O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine, 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 room temperature, to obtain those compounds of the formula (XI). Alternatively, the compounds of formula (XI) can be obtained directly from compounds of formula (VIII), interacting 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 in the range from room temperature up to the boiling temperature under reflux.

Alternatively, the compounds of formula (VIII) can be obtained from compounds of formula (XIII) in accordance with scheme 2.

Scheme 2

The compounds of formula (XIII) can be obtained using disclosed in the literature methods. Compounds of General formula (XIV) can be obtained from compounds of formula (XIII), using the methods disclosed 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), is westlea interaction with compounds of the formula (XV) (by introducing appropriate substituents R1), using the methods disclosed above, to obtain compounds of the formula (VIII) from the compound of formula (VI). Alternatively, the compounds of formula (VIII) can be obtained from compounds of formula (XIV), interacting with compounds of the formula (XVI) (by introducing appropriate substituents R1), in the presence of a base such as sodium hydride or litigationrelated, in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide, at a temperature in the range from room temperature up to 150°C.

Alternatively, the compounds of formula (X) can also be obtained from compounds of formula (VII) in accordance with scheme 3.

Scheme 3

The compounds of formula (VII) can be converted into compounds of formula (XVII)using the disclosed methods of making compounds of formula (X) compounds of the formula (VIII).

The compounds of formula (XVII) can be attached to amines such as 2-amino-2-methyl-1-propanol using disclosed above to obtain compounds of the formula (XI) from compounds of formula (X), thus making the interaction with this agent, as thionyl chloride or phosphorus oxychloride, neat or in a suitable solvent such as dichloromethane, chloroform or diethyl ether, at a temperature in the range from room temperature up to the boiling point of the solvent under reflux, to obtain the compounds of f is rmula (XVIII).

The compounds of formula (XIX) can be obtained from compounds of formula (XVIII), interacting with aniline (by introducing 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, l,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)-l,l'-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 a temperature in the range from room temperature up to the boiling point of the solvent under reflux or under microwave irradiation at a temperature in the range from 70°C to 150°C.

Alternatively, the compounds of formula (XIX) can be obtained from compounds of formula (XVIII), interacting aniline (including appropriate substituents R1), in the presence of a base such as sodium hydride or litigationrelated, in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide, at a temperature in the range from room temperature up to 150°C.

The compounds of formula (X) can be obtained from compounds of formula (XIX), interacting with this is Isletas, as hydrogen chloride or acetic acid, in a suitable solvent such as water, at a temperature in the range from room temperature up to the boiling point of the solvent under reflux.

6-Isobenzofuranyl formula I-c, II-c or III-c can be obtained using the synthesis methods presented in figure 4.

Scheme 4

The compounds of formula (XX) can be obtained using the methods disclosed in the literature. They can be subjected to interaction with methylglucose or ethylglycol in the presence of a phosphine, such as triphenylphosphine, alkyl-azodicarboxylate, such as diethylazodicarboxylate or diisopropylcarbodiimide, aprotic solvent such as tetrahydrofuran or diethyl ether, at a temperature in the range from room temperature up to the boiling point of the solvent under reflux, to obtain compounds of the formula (XXI).

The compounds of formula (XXI) can react in the presence of such bases 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 compounds of the formula (XXII).

The compounds of formula (XXII) can be converted into compounds of formula (XXIII), interacting with such a halogenation agent, as bromacil phosphorus, in pure form or in the Ohm suitable solvent, as toluene, at a temperature in the range from room temperature up to 140°C. Alternatively, the compounds of formula (XXII) can be subjected to interaction with nonatherosclerotic in the presence of such grounds, as diisopropylethylamine, and such a catalyst 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 in the range from room temperature up to the boiling point of the solvent under reflux. In addition, the compounds of formula (VI) can be treated with anhydride triftormetilfullerenov acid in the presence of such bases as pyridine, in a solvent such as dichloromethane, at a temperature from -20°C to room temperature.

The compounds of formula (XXIV) can be obtained from compounds of formula (XXIII), interacting with aniline (by introducing appropriate substituents R1), in the presence of such a catalyst as Tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, a base such potassium phosphate, tert-piperonyl sodium, l,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)-l,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylene is about)biphenyl, 2-dicyclohexylphosphino-2',6'-(dimethoxy) - biphenyl-or three-butylphosphine in a suitable solvent such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at a temperature in the range from room temperature up to the boiling point of the solvent under reflux, or under microwave irradiation at a temperature in the range from 70°C to 150°C.

Alternatively, the compounds of formula (XXIV) can be obtained from compounds of formula (XXII), interacting with compounds of the formula (IX) (obtained using disclosed in the literature methods), in a suitable solvent such as toluene or 1,2-dimethoxyethane, at a temperature in the range from room temperature up to the boiling point of the solvent under reflux, or under microwave irradiation at a temperature in the range from 100°C to 180°C.

The compounds of formula (XXVI) can be obtained from compounds of formula (XXIV), interacting with such a base as sodium hydroxide, in such proton solvent like ethanol or methanol, at a temperature in the range from room temperature up 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 can be obtained in accordance with scheme 8) or an amine and with such a suitable binding agent, the AK O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine, 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 such an inert solvent as tetrahydrofuran, N,N-dimethylformamide or dichloromethane, at room temperature, to obtain those compounds of formula (XXVII). Alternatively, the compounds of formula (XXVI) can be obtained directly from compounds of formula (XXIV), interacting 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 in the range from room temperature up to the boiling temperature under reflux.

Furo[2,3-d]pyrimidines of formula I-f, II-f, III-f can be obtained using the synthesis methods presented in figure 5.

Scheme 5

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

The compounds of formula (XXXVI) can be obtained from the of soedinenii formula (XXIX), using methods similar to those disclosed for producing compounds of the formula (XI) from compounds of formula (IV), as shown in figure 1.

Furo[2,3-d]pyridazine of formulas I-h, II-h, III-h-furo[3,2-c]pyridazine formula I-g, II-g, III-g can be obtained using the synthesis methods presented in figure 6.

Scheme 6

The compounds of formula (L) can be obtained in accordance with the disclosures provided in the literature methods. The compounds of formula (LVI) can be obtained from compounds of formula (L), using methods similar to those disclosed for producing compounds of the formula (XI) from compounds of formula (IV), as shown in figure 1. Alternatively, the compounds of formula (LIV) can be obtained in accordance with scheme 7.

Scheme 7

The compounds of formula (LVIII) can be obtained using methods published in the literature. Compounds of General formula (LIV) can be obtained from compounds of formula (LIX), using the methods disclosed above, to obtain compounds of the formula (VIII) from compounds of formula (XIII).

Hydroxylamine formula (XII) can be obtained using the methods disclosed in the literature, or methods of synthesis is presented in figure 8.

Scheme 8

Primary or secondary alcohols of General formula (XXXVII) can be obtained using im is s, disclosed in the literature. The alcohols can be subjected to the interaction with N-hydroxyphthalimide using phosphine and such linking reagent, as diethylazodicarboxylate, to obtain compounds of General formula (XXXVIII). The compounds of General formula (XXXVIII) can remove the protective group using hydrazine or methylhydrazine, to obtain hydroxylamine General formula (XII-a). The compounds of formula (XII-a) can be modified further using reductive amination of aldehydes and ketones using a reducing agent as triacetoxyborohydride sodium, cyanoborohydride sodium or borane-pyridine, in a solvent such as dichloroethane at a temperature in the range from room temperature up to the boiling temperature under reflux. In addition, the compounds of formula (XH-a) can be modified 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 cross-linking reactions disclosed above, can be obtained using the methods disclosed in the literature or in accordance with scheme 9.

Scheme 9

where R1is a group with an optional substituent, and n= 0-4.

Substituted 4-chlornitrofen the ol can be subjected to interaction with hexamethyldisilane in such a solvent, as xylene, using a catalyst like tetrakis(triphenylphosphine)palladium, at a temperature in the range from room temperature up to the boiling temperature under reflux. The nitro-group can be recovered using the methods disclosed 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 such a catalyst as palladium-on-charcoal, and in a solvent such as ethanol or ethyl acetate, at room temperature.

Esters trifloromethyl General formula (XL)used in cross-linking reactions disclosed above, can be obtained using the methods disclosed in the literature or in accordance with scheme 10.

Scheme 10

X = halogen,

where R1is a group with an optional substituent, and n = 0-4.

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 so trialkylaluminium as trimethylsilane, to obtain trialkylsilyl (XLII). Trialkylsilanes can be further subjected to interaction, using known literature methods, to obtain triftormetilfullerenov or nonflow General formula (XL).

It should be taken into account, h what about in cases when there is a corresponding functional group, the compounds of formula (I), (II), (III) or any intermediate compounds used in their preparation, can be converted further one or more of the standard synthesis methods, using substitution reaction, oxidation, recovery, or splitting. Specific substitution reactions include the usual alkylation reaction, arilirovaniya, heteroarylboronic, acylation, sulfonylamine, halogenation, nitration, formirovanie and attach.

For example, groups of arilbred or chloride can be turned into arisitide using the Finkelstein reaction with the use of such a source of iodide, such as sodium iodide, using such a catalyst, such as copper iodide, and a ligand, TRANS-N,N'-dimethyl-1,2-cyclohexanediamine, in a solvent such as 1,4-dioxane, and heating the reaction mixture at the boiling point under reflux. Aryldialkyl can be turned into arisitide, treating the silane such a source of iodide, as monochloride iodine, in a solvent such as dichloromethane, with a Lewis acid (or without it), as tetrafluoroborate silver, at a temperature from -40°C up to the boiling temperature under reflux.

In the following example, the group of the primary amine (-NH2) you can alkilirovanii using the process of recovery alkyl is of overlap, using the aldehyde or ketone and a borohydride, for example triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as halogenated hydrocarbon such as 1,2-dichloroethane, or in this alcohol, as ethanol, optionally in the presence of acid such as acetic acid, at room temperature. The secondary amine group (-NH-) you can alkilirovanii similarly, using the aldehyde.

The following example groups, primary amine or secondary amine can be converted into amide group (-NHCOR', or-NRCOR') using the acylation. The acylation can be performed by interacting with the appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent such as dichloromethane, or when interacting with a corresponding carboxylic acid in the presence of a suitable binding agent, such as HATU (O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate), in a suitable solvent such as dichloromethane. Similarly, the amine group can be converted into sulfonamidnuyu group (-NHSO2R' or-NR"SO2R'), interacting with the corresponding sulphonylchloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane. The group's primary or secondary amine can p is vratiti groups, urea (-NHCONR'R" or-NRCONR'R"), interacting with the appropriate isocyanate in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane.

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

In the following example, the amine group (-CH2NH2) can be obtained by the reduction of NITRILES (-CN), for example, catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a substrate, such as coal, or Nickel of Renee, in a solvent such as ether, for example, a cyclic ether like tetrahydrofuran, at a temperature in the range from -78°C to the boiling point of the solvent under reflux.

In the following example, the amine group (-NH2) can be obtained from carboxylic acid groups (-CO2H) by transformation into the corresponding acylated (-CON ), Curtis rearrangement and hydrolysis of the resulting isocyanate (-N=C=O).

Aldehyde group (-CHO) can be converted into amine groups (-CH2NR'r R")) by reductive amination, using amine and a borohydride, for example triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as a halogenated hydrocarbon, for example dichloromethane, or alcohol, as ethanol, optionally in the presence of acid such as acetic acid, at room temperature.

In the following example, the aldehyde group can be converted into alkeneamine group (-CH=CHR')using a Wittig reaction or Wordsworth-Emmons using appropriate fosfory or phosphonate known to experts in standard conditions.

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

Ester group (-CO2R') can be transformed into the corresponding acid group (-CO2H) as a result of hydrolysis catalyzed by acid or base, depending on the nature of R. If R is tert-butyl, kataliziruet the second acid hydrolysis can be performed, for example, by treating such organic acid as triperoxonane acid, in an aqueous solvent, or by treatment of such inorganic acid like hydrochloric acid, in an aqueous solvent.

The carboxylic acid group (-CO2H) can be converted into amides (CONHR' or-CONR'R"), interacting with the corresponding amine in the presence of a suitable binding agent, such as HATU, in a suitable solvent such as dichloromethane.

In the following example, you can get a homolog of the carboxylic acid one carbon (i.e. turn-CO2H-CH2CO2H) by conversion into the corresponding acid chloride (-COCl) with subsequent synthesis Arndt-Eistert.

In the following example, the-OH group can be created from the corresponding complex ether (for example, -CO2R') or aldehyde (-CHO) recovery, using, for example, such a complex metal hydride, as sociallyengaged in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol. Alternatively, the alcohol can be obtained by restoring the appropriate acid (-CO2H)using, for example, sociallyengaged in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.

The alcohol group can be converted into a leaving group, such as the Toms halogen or sulfonyloxy group, such as alkylsulfonate, for example, tripterocalyx or arylsulfonate, for example p-toluensulfonate group, using well-known specialists of conditions. For example, the alcohol can be subjected to interaction with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to obtain the corresponding chloride. In this reaction can also use a base (e.g. triethylamine).

In another example, an alcohol, phenol or amide groups can be alkilirovanii by the addition of phenol or amide to 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 using a suitable base, for example sodium hydride, followed by addition of an alkylating agent, such as alkylhalogenide.

Aromatic halogen substituents in these compounds can be subjected to the exchange of the halogen-metal by treatment with a base, for example lithium base, 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 agent to enter the desired Deputy. So, e.g. the, the formyl group can be entered using N,N-dimethylformamide as the electrophilic agent. Aromatic halogen substituents can be alternatively subjected to the reactions catalyzed by metal (such as palladium or copper)for injection, for example, acid, ester, cyano, amide, aryl, heteroaryl, alkenyl, etkinlik, thio - or amino substituents. Suitable methods that can be used include methods disclosed heck, Suzuki, Steele, Buchwald or Hardwick.

Aromatic halogen substituents can also undergo nucleophilic substitution followed by reaction with such appropriate nucleophile, as amine or alcohol. It is beneficial to have such a reaction was carried out at elevated temperatures accompanied by microwave irradiation.

These compounds of the present invention are tested for their ability to inhibit MEK activity and activation (primary analysis) and in relation to their biological effects on growing cells (secondary analyses), as disclosed hereinafter. These compounds with the largest IR50less than 10 microns (more preferably less than 5 μm, even more preferably less than 1 μm, most preferably less than 0.5 μm) in the analysis of MEK activity of example la or lb, IR50less than 5 microns (Bo what it is preferably less than 0.1 μm, most preferably less than 0.01 μm) in the analysis of MEK activation in example 2, EC50less than 10 microns (more preferably less than 5 microns, most preferably less than 0.5 μm) in the analysis of cell proliferation in example 3, and/or EC50less than 10 microns (more preferably less than 1 μm, most preferably less than 0.1 μm) in the analysis of ERK phosphorylation in example 4, are compounds that can be used as inhibitors of MEK.

The present invention includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or solvate and salt) and the media (pharmaceutically acceptable carrier). The present invention also includes a composition (e.g., pharmaceutical composition)comprising a compound of formula I (and/or solvate and salt) and the media (pharmaceutically acceptable carrier), further comprising a second chemotherapeutic agent and/or the second anti-inflammatory agent, such as those disclosed here. Compositions of the present invention that can be used for inhibiting abnormal cell growth or treating a hyperproliferative disorders in mammals (e.g. humans). Compositions of the present invention can also be used for the treatment of inflammatory diseases in mammals (e.g. humans).

<> Compounds of the present invention and compositions of the present invention can also be used to treat autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, viral diseases, fibrotic diseases or neurodegenerative diseases in mammals (e.g. humans). Examples of such diseases/disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, retapamulin fibroplasia, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, kidney and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, rejection of transplanted organs, 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 concept of chronic pain for the purposes of the present invention includes, but is not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation, and postoperative pain.

Neuro is eticeskaja pain associated with many conditions which include, but are not limited to, inflammation, pain after operations, phantom pain, pain after burn, gout, trigeminal neuralgia, acute herpetic and post herpetic pain, causalgia, diabetic nephropathy, plexus avulsion, neuroma, vasculitis, viral infection, ruptured tissue damage, amputation of extremities, arthritic pain and destruction of nerves in the peripheral nervous system and Central nervous system.

Compounds and compositions of the present invention can also be used for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-kidney disease) in mammals (e.g. humans).

Compounds and compositions of the present invention can also be used to prevent implantation of blastocytes in mammals (e.g. humans).

The present invention includes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorders in mammals (e.g. humans), 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. Also in the present invention is included a method of treating inflammatory diseases in mammals (e.g. humans), including the introduction of a specified milk is itausa therapeutically effective amount of the compounds of formula I (and/or solvate and/or salt or composition thereof.

The present invention includes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorders in mammals (e.g. humans), 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 the second chemotherapeutic agent such as those disclosed here. The present invention also includes a method of treating inflammatory diseases in mammals (e.g. humans), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or solvate and/or salt or composition thereof in combination with a second anti-inflammatory agent such as those disclosed here.

The present invention includes a method of treating autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, viral diseases, fibrotic diseases or neurodegenerative diseases in mammals (e.g. humans), 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 further comprising a second therapeutic agent. Examples of such diseases/n the violations include, but not limited to, diabetes and diabetic complications, diabetic retinopathy, retapamulin fibroplasia, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis, and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, congestive heart failure, neurofibromatosis, rejection of transplanted organs, cachexia, shock, septic shock, heart failure, Alzheimer's disease, chronic or neuropathic pain, and viral infections such as HIV, hepatitis (B) (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein Barra.

The present invention includes a method of treating pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-kidney disease) in mammals (e.g. humans), 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 further comprising a second therapeutic agent.

The present invention includes a method of preventing implantation blastocytes in mammals (e.g. humans), including the introduction of a given mammal a therapeutically effective amount of the compounds of formula I (and/or its solve the tov and salt or composition thereof, and optionally further comprising a second therapeutic agent.

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

Consider also that the compounds of the present invention can make abnormal cells more susceptible to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, the present invention relates also to a method of sensitizing abnormal cells in mammals (e.g. humans) for the radiation treatment, which includes an introduction to the specified mammal such quantity of the compounds of formula I (and/or its solvate or salt or composition thereof that will be effective for sensitizing abnormal cells to treatment with radiation.

The introduction of these compounds of the present invention (hereinafter "the active connection (connection)") can be done by any method that enables delivery of such compounds to the site of action. These methods include methods of oral administration, intraduodenal injection, injection (including intravenous, subcutaneous, intramuscular, intravascular injection and infusion), topical, introduction by inhalation and rectal administration.

Enter the amount of the asset is th connection will depend on the subject to the treatment of the subject, the gravity of the violation or condition, rate of administration, location of the compound and the discretion of the attending physician. However, the effective dose is in the range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a person weighing 70 kg, this would amount to the amount of from about 0.05 to about 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, the dose levels below the lower limits of the above intervals can be more than adequate, 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 used as the sole pharmaceutical agent or in combination with one or more of the chemotherapeutic agents, such as those disclosed here. Such joint treatment can be achieved by simultaneous, sequential or separate administration of doses of the individual components of medicines.

The pharmaceutical composition may be, for example, in a form suitable for oral administration in the form of tablets, capsules, pills, powders, compositions with delayed allocation, solutions, aspen is s, preparations for parenteral injection in the form of sterile solutions, suspensions or emulsions for external use in the form of ointments or creams, or for rectal administration in the form of suppositories. The pharmaceutical composition may be in the form of a unit dose, appropriate for a single injection prescribed dose. The pharmaceutical composition may include a conventional pharmaceutical carriers or excipients and a compound in accordance with the present invention as an active ingredient. In addition, the composition may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

Representative forms for parenteral introduction include solutions or suspensions of the active compounds in sterile aqueous solutions, for example aqueous solutions of propylene glycol or dextrose. These dose forms if desired, appropriately supererogate.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions can optionally contain, in addition, additional ingredients, such as flavoring agents, binders, excipients, etc. So, for oral administration can be used tablets containing various excipients such as citric acid is acid, together with various leavening agents, such as starch, alginic acid and certain complex silicates, and binding agents, such as sucrose, gelatin and acacia. In addition, you can often use for the purposes of tabletting lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type can also be used to fill hard or soft gelatin capsules. Therefore, preferred materials include lactose or milk sugar and high molecular weight glycols. If oral administration is desired aqueous suspensions or elixirs, the active compound can be combined with various sweetening agents or fragrances, coloring agents or dyes and, if desired, with emulsifying or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of obtaining pharmaceutical compositions containing a specific number of active compounds known or will be apparent to experts in this field. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa.,15.sup.thEdition (1975).

EXAMPLES

Reduction
DBU1,8-diazabicyclo[5.4.0]undec-7-EN
DCMdichloromethane
DIADdiisopropylsalicylic
DIPEAdiisopropylethylamine
DMAP4-dimethylaminopyridine
DMFdimethylformamide
EDCI1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
HATUO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate
HClhydrochloric acid
HM-NIsolute® HM-N is a modified form of diatomaceous earth, which effectively absorbs water sample
HOBt1-hydroxybenzotriazole
IMSindustrial methylated spirits
IClmonochloride iodine
LDALicedei oprofiled
MeOHmethanol
NaHCO3sodium bicarbonate
NaOHsodium hydroxide
Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)
Pd2dba3Tris-(dibenzylideneacetone)dipalladium(0)

Si-SPEpre-Packed Isolute® silica cartridge for flash chromatography
Si-ISCOpre-filled ISCO® silica cartridge for flash chromatography
THFtetrahydrofuran
Xantphos9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

General terms experimentation

1H NMR spectra were recorded at room temperature using a spectrometer Varian Unity Inova (400 MHz) with 5 mm sensor for triple resonance. Chemical shifts are expressed in ppm relative to tetramethylsilane. Used the following abbreviations: br = broad signal, s = singlet, d = doublet, d = doublet of doublets, t = triplet, q = Quartet, m = multiplet.

High-performance liquid chromatography-massspectrometry (IHMS). Experiments to determine retention times (RT) and associated mass ions was performed using one of the following methods.

Method A: Experiments carried out on a Waters Micromass ZQ quadrupole mass spectrometer associated with the system Hewlett Packard HP1100 LC detector in the form of a diode matrix. In this system, use column Higgins Clipeus 5 micron C18 100×3.0 mm and a flow rate of 1 ml/min Initial solvent system is 95% water containing 0.1% formic acid (solvent A)and 5% acetonitrile containing 0.1% formic acid (solvent B), for 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 over the next 5 minutes.

Method B: Experiments carried out using a Waters Platform LC quadrupole mass spectrometer linked with the system Hewlett Packard HP 1100 LC with the detector in the form of a diode matrix and a 100-position auto-sampler, using a column Phenomenex Luna C18(2) 30×4.6 mm and a flow rate of 2 ml /min. and a solvent System is 95% water containing 0.1% formic acid (solvent A)and 5% acetonitrile containing 0.1% formic acid (races is varicel B), during the first 0,50 min followed gradients up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system can withstand constant over the next 0,50 minutes.

Method C: experiments carried out using a PE Sciex API 150 EX quadrupole mass spectrometer associated with the system Shimadzu LC-10AD, LC detector in the form of a diode matrix, and a 225-point sampler, column Kromasil C18 50×4.6 mm and a flow rate of 3 ml/min, the solvent System is a gradient starting with 100% water containing 0.05% TFA (solvent A), and 0% acetonitrile with 0,0375% TFA (solvent B), reaching 10% of solvent A and 90% solvent B over 4 minutes. The final solvent system can withstand constant over the next 0,50 minutes.

Method D: the experiments carried out using Shimadzu LCMS-2010A liquid chromatography-mass spectrometer associated with the system Shimadzu LC-10AD VP LC detector in the form of a diode matrix. Use column Kromasil 100 5 μm C18 50×4.6 mm and a flow rate of 2.5 ml/min Initially, the solvent system is 100% water containing 0.05% triperoxonane acid (solvent A), and 0% acetonitrile containing 0.05% triperoxonane acid (solvent B), followed by a gradient up to 10% solvent A and 90% solvent B over 8 minutes. The final solvent system can withstand post what annoy for an additional 2 minutes.

Method E: the Experiments carried out using Agilent Technologies liquid chromatography-mass spectrometer associated with the system Agilent Technologies Series 1100 LC with the detector in the form of a diode matrix. Use Bond column 3.5 μm SB-C18 30×2.6 mm and a flow rate of 0.5 ml/min Initial solvent system is 95% water containing 0.05% triperoxonane acid (solvent A)and 5% acetonitrile containing 0,0375% triperoxonane acid (solvent B), followed by a gradient up to 5% solvent A and 95% solvent B for 9 minutes. The final solvent system can withstand constant during the next 1 minute.

Microwave experiments carried out using a Personal Chemistry Emrys Iniatiator™ or Optimizer™, which uses a single-mode resonator and dynamic tuning, both provide reproducibility and control. The temperature can reach 40 to 250°C, and the pressure can reach up to 20 bar.

EXAMPLE 1a

MEK analysis (analysis of MEK activity)

Constitutively activated mutant MEK1 person, expressed in insect cells, used as a source of enzyme activity in the final concentration of 62.5 nm in the analysis of the kinase.

The analysis is carried out for 30 minutes in the presence of 50 μm ATP, using recombinant GST-ERK1 obtained inE. colias substratification substrate to define qualitatively and quantitatively, using HTRF reagents supplied Cisbio. They consist of anti-GST antibodies conjugated with allophycocyanin (XL665), and anti-phospho (Thr202/Tyr204) ERK antibodies conjugated with europium-Cryptocom. Anti-phospho antibody recognizes ERKl, razdvoennoj phosphorylated at Thr202 and Tyr204. If both antibodies bind with ERKl (i.e. if the substrate is phosphorylated), energy transfer from cryptate on allophycocyanin is followed by excitation at a wavelength of 340 nm, resulting in fluorescence emission which is proportional to the amount of phosphorylated substrate. Fluorescence detects, using fluorimeter. Compounds were diluted in DMSO before add in analytical buffer, and the final concentration of DMSO in the analysis is 1%.

The value of IR50defined as the concentration at which this compound provides 50% inhibition compared with the control. IR50values calculated using the software XLfit (version 2.0.5).

EXAMPLE 1b

MEK analysis (analysis of MEK activity)

Constitutively activated human mutant MEK1, expressed in insect cells, used as a source of enzyme activity at a final concentration of 15 nm in the analysis of the kinase.

The analysis is carried out for 30 minutes in the presence of 50 μm ATP, COI is lsua recombinant GST-ERK1, produced inE. colias the substrate. Phosphorylation of the substrate determine qualitatively and quantitatively, using HTRF reagents supplied Cisbio. They consist of anti-GST antibodies conjugated with allophycocyanin (XL665) and anti-phospho (Thr202/Tyr204) ERK antibodies, conjugated with europium-Cryptocom. These agents are used in final concentrations of 4 µg/ml and 0.84 μg/ml, respectively. Anti-phospho antibodies recognize ERK1, dual phosphorylated at Thr202 and Tyr204. If both antibodies are associated with ERK1 (i.e. if the substrate is phosphorylated), is the transfer of energy from cryptate on allophycocyanin, followed by excitation at a wavelength of 340 nm, which leads to fluorescence, which is proportional to the amount of phosphorylated substrate. Fluorescence detects, using fluorimeter.

Compounds were diluted in DMSO before adding to the analytical buffer, and the final concentration of DMSO in the above analysis is 1%.

The value of IR50defined as the concentration at which this compound provides 50% inhibition relative to control. Values IR50calculate, using the software XLfit (version 2.0.5).

Connection examples 5-18, 20-102, 105-109, 111-118, 120-133, 136-149 and 151-160 demonstrate value IR50less than 1 μm in the analysis, described in examples la or lb, the majority of these compounds demonstrate value IR50less than 5 microns.

EXAMPLE 2

skin disease analysis (analysis of activation of MEK)

Constitutive skin disease activated mutant 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 recombinant GST-MEK1 produced inE. colias the substrate. Phosphorylation of the substrate determine qualitatively and quantitatively, using HTRF reagents supplied Cisbio. They consist of anti-GST antibodies conjugated with allophycocyanin (XL665), and anti-phospho (Ser217/Ser221) MEK antibodies conjugated with europium-Cryptocom. Anti-phospho antibodies recognize MEK, a dual phosphorylated at Ser217 and Ser221 or single phosphorylated at Ser217. If both antibodies bind to MEK (i.e., if the substrate is phosphorylated), is the transfer of energy from cryptate on allophycocyanin with subsequent excitation at a wavelength of 340 nm, which leads to fluorescence, which is proportional to the amount of phosphorylated substrate. Fluorescence detects, using fluorimeter.

Compounds were diluted in DMSO before add in analytical buffer, and the final concentration of the MCO in the above analysis is 1%.

The value of IR50defined as the concentration at which this connection provides inhibition of 50% relative to control. The value of IR50calculate, using the software XLfit (version 2.0.5).

In the above analysis of the compounds of examples 5-19 show the value of IR50less than 5 microns.

EXAMPLE 3

Analysis of cell proliferation

Connection test in the analysis of cell proliferation using the following cell lines:

HCT116 human colorectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines support in DMEM/F12 (1:1) medium (Gibco), supplemented with 10% FCS at 37°C in humidified 5% CO2the incubator.

Cells were seeded in 96-well plates in a total of 2000 cells/well and after 24 hours they exhibit various concentrations of compounds in 0,83% DMSO. Cells cultured in the next 72 hours and to each well add an equal volume of CellTiter-Glo reagent (Promega). This leads to the lysis of the cells and causes the luminescence signal, which is proportional to the released quantity of ATP (and therefore proportional to the number of cells per well), which can be determined using a luminometer.

The value of EC50defined as the concentration at which this compound provides 50% inhibition of otnositelnaya. Value EC50calculate, using the software XLfit (version 2.0.5).

In the above analysis of the compounds of examples 5 to 13, 15-16, 18, 20-22, 24-25, 28, 31, 35, 38-39, 41, 109, 133-134, 138, 140-141, 160 demonstrate value EC50less than 10 microns in each of the cell lines.

EXAMPLE 4

Phospho-ERK cell analysis

Compounds are tested in cell phospho-ERK ELISA using the following cell lines:

HCT116 human colorectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines support in DMEM/F 12(1:1) medium (Gibco), supplemented with 10% FCS at 37°C in an incubator with 5% CO2a damp environment.

Cells were seeded in 96-well plates in a total of 2000 cells/well and after 24 hours they exhibit various concentrations of compounds in 0,83% DMSO. Cells were cultured further for 2 or 24 hours, fixed with formaldehyde (2% final concentration) and treated with methanol. After blocking TBST-3% BSA, fixed cells are incubated with primary antibody (anti-phospho ERK rabbit) overnight at 4°C. Cells incubated with propylimidazol (fluorescent DNA dye) and detection of cellular p-ERK carried out using anti-rabbit secondary antibody conjugated with the fluorescent dye Alexa Fluor 488 (Molecular probes). Emerging fluorescence analyzed using the Acumen Explorer TTP Labtech), laser scanning microplate of zitomer, and retrieved using the Alexa Fluor 488 signal normalize relative to the PI signal (proportional to the number of cells).

EC50defined as the concentration at which this connection provides a signal with an intensity equal to half the value between the baseline and maximum response. Value EC50calculate, using the software XLfit (version 2.0.5).

In the above analysis of the compounds of examples 5 to 13, 15-16, 18, 20-26, 28-29, 31, 35, 38-39, 41-48, 50, 55, 59-61, 68, 70, 73-74, 76, 79, 81-84, 87, 91, 95, 99, 109, 111, 113, 117, 118, 120, 122-124, 126-127, 131, 133, 134, 138-141, 144, 147, 152, 155-160 demonstrate value EC50less than 10 μm for each of the cell lines.

SYNTHESIS ISOBENZOFURANONE CENTERS

Ethyl 3-(4-bromo-2-forgenerating)furo[3,2-c]pyridine-2-carboxylate

Stage 1: 4-chloronicotinic acid

In accordance with the method Guillier et al. (1995) J. Org. Chem. 60(2):292-6 to a cold (-78°C) solution of LDA (21 ml of 1.6 M in hexano, 33.3 mmol) in anhydrous THF (70 ml) is added 4-chloropyridine (5.0 g, 33.3 mmol) in argon atmosphere. After 1 hour at -78°C the resulting solution was quickly poured on a layer of solid CO2contained in a 50 ml conical flask. After the solution is allowed to warm to room temperature, it is quenched with water (30 ml). Volatile org the organic 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 then adjusting the pH to 4 by adding concentrated hydrochloric acid. The precipitate was incubated for 30 minutes, then collected by filtration. The solid product is washed with cold diethyl ether (10 ml) to obtain specified in the connection header in the form of a solid white color (3.2 g, 61%).

Step 2: Ethyl 4-chloronicotinic

A suspension of 4-chloronicotinic acid (3.0 g, 19.0 mmol) in thionyl chloride (50 ml) is heated at the boil under reflux for 90 minutes. After cooling to room temperature the resulting solution was concentrated to dryness and then carry out azeotropic distillation with toluene (2×50 ml) to obtain a solid product. The obtained solid product is added in portions to a cooled (0°C) solution of ethanol (25 ml) and DIPEA (15 ml). The reaction mixture was stirred at room temperature for 4 hours, then concentrated in vacuo before adding water (75 ml). The resulting solution was 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 brown oil (33 g, 94%).1H NMR (CDCl3, 400 MHz) 9,03 (s, 1H), 7,58 (d, J=5.4 Hz, 1H), 7,41 (DD, J=5.4 Hz, 0.5 Hz, 1H), 4,45 (sq, J=7,3 Hz, 2H), USD 1.43 (t, J=7,3 Hz, 3H).

Step 3: Ethyl 3-hydroxyfuran[3,2-c]pyridine-2-carboxylate

To a cooled (0°C) solution of ethyl 4-chloronicotinate (910 mg, 4.9 mmol) and ethylglycol (of 0.48 ml, 5.1 mmol) in anhydrous DMF (17 ml), under nitrogen atmosphere, add sodium hydride (9.8 mmol, 60%, 392 mg). The reaction mixture is stirred for 16 hours (0°C to room temperature, then acidified by adding acetic acid (1.2 ml)and then concentrated to obtain a residue. Add water (23 ml) and the resulting mixture stirred for 5 minutes and during this time received a brown precipitate is collected by filtration and washed with water 3×30 ml to obtain specified in the connection header in the form of a solid light brown color. (875 mg, 86%).1H NMR (DMSO-D6, 400 MHz) 9,18 (d, J=1.2 Hz, 1H), at 8.60 (d, J=6.0 Hz, 1H), 7,66 (DD, J=6.0 Hz, 0.8 Hz, 1H), 4,32 (sq, J=7.2 Hz, 2H), 1,32 (t, J=7.2 Hz, 3H). IHMS (method B): RT- 1,42 min, M+H+= 208.

Stage 4: Ethyl 3-(tripterocalyx)-furo[3,2-c]pyridine-2-carboxylate

Mix a solution of ethyl 3-hydroxyfuran[3,2-c]pyridine-2-carboxylate (3.15 g, 15,204 mmol), N,N-bis(trifloromethyl)aniline (10,08 g, 28,24 mmol) and N,N-diisopropylethylamine (11,35 ml, 65,16 mmol) in dimethoxyethane (50 ml) is heated at 95°C for 35 minutes. Then the reaction mixture is cooled to room temperature and to the center under reduced pressure. Then the residue purified using flash chromatography (silica gel, 120 g column, ISCO, 45 ml/min, 0-60% ethyl acetate in hexane over 20 minutes) to obtain specified in the title compounds as a mixture of oil pale yellow/solid white (4.11 g, 79.7 per cent).1H NMR (CDCl3, 400M Hz) 9,07 (s, 1H), up 8.75 (d, 1H), to 7.59 (d, 1H), 4,54 (square, 2H), 1,47 (t, 3H). IHMS (5 min, method 2): RT= 2,93 min, M+H+= 339,6.

Stage 5: Ethyl 3-(4-bromo-2-forgenerating)-furo|3,2-c]pyridine-2-carboxylate

A suspension of ethyl 3-(tripterocalyx)-furo[3,2-c]pyridine-2-carboxylate (4.11 g, 12,11 mmol), 4-bromo-2-foronline (3,76 g, 19,38 mmol), Pd2dba3(925 mg, 1.01 mmol), Xantphos (591 mg, of 1.02 mmol) and K3PO4(4,95 g, 22,61 mmol) in toluene (60 ml) Tegaserod, barbotine nitrogen for 10 minutes, and then heated at 105°C for 24 hours. Then the reaction mixture is cooled to room temperature and diluted with ethyl acetate (100 ml). The resulting mixture was then filtered through celite 545 celite and washed with an additional 50 ml of ethyl acetate. The resulting filtrate is then concentrated and purified using flash chromatography (silica gel, 120 g column, ISCO, 45 ml/min, 0-70% ethyl acetate in hexane over 40 minutes), to obtain specified in the connection header in the form of a solid white color (2,96 g, 64.5 per cent).1H NMR (CDCl3, 400 MHz) at 8.60 (m, 2H), 7,66 (s, 1H), 7,50 (d, m, 1H), 7,39 (d, d, 1H), 7,30 (d, m, 1H), 716 (t, 1H), 4,49 (square, 2H), 1,47 (t, 3H). IHMS (5 min, method 2): RT= 2,47 min, M+H+= 378,9.

Ethyl 3-(2-fluoro-4-iodoaniline)-furo[2,3-c]pyridine-2-carboxylate

Stage 1: 3-amino-isonicotinoyl acid

In accordance with the method of Zhou et al. (2001) Bioorg. Med. Chem. Lett. 9(8):2061-2071 slowly added bromine (1,22 ml of 23.9 mmol) to a cooled (5°C) 2,5-called NaOH solution (60 ml, 150 mmol) and after stirring for 5 minutes add pyrrolo[3,4-c]pyridine-1,3-dione (3.5 g, 23.6 mmol). The temperature was raised to 80°C and the resulting mixture is stirred for 1 hour, then cooled to room temperature. Carefully add acetic acid (5,9 ml of 98.3 mmol) (N.B. there is a selection of gas) and the resulting solution was stirred for 10 minutes, resulting in a precipitate, which is collected by filtration. The solid product is washed with water (20 ml) and MeOH (20 ml), then dried to obtain specified in the connection header in a solid yellow color (2.1 g, 64%).

Stage 2: 3-hydroxyisoquinoline acid

To a suspension of 3-aminoisoquinoline acid (2.1 g, of 15.2 mmol) in water (35 ml) is added concentrated sulfuric acid (1.5 ml). The resulting solution was cooled to 5°C and intensively stirred before adding a solution of sodium nitrite (1,05 g, 15,2 shall mol) in water (10 ml). The resulting suspension is slowly heated up to 80°C and maintained at the specified temperature for 15 minutes, then cooled to 65°C and add acetic acid (1.5 ml). The pH of the resulting solution was adjusted pH to 4.5 by adding a concentrated solution of ammonia (approximately 3.5 ml), then the resulting mixture is placed in the refrigerator overnight. The precipitate is collected by filtration, washed with water (20 ml) and dried in vacuum to obtain specified in the connection header in a solid yellow color (1.85 g, 88%).1H NMR (d4-MeOH, 400 MHz) of 8.37 (s, 1H), of 8.09 (d, J=5.5 Hz, 1H), 7,81 (d, J=5.5 Hz, 1H).

Step 3: Ethyl 3-hydroxyazetidine

3-Hydroxyisoquinoline acid (1,83 g, 13,2 mmol) are heated at the boil under reflux for 48 hours in a mixture of ethanol (40 ml) and concentrated sulfuric acid (1.0 ml). The resulting mixture was cooled to room temperature and concentrated to obtain a residue. The residue is dissolved in water (10 ml) and neutralized by adding NaHCO3(approximately 2 g). The organic components extracted with DCM (3×20 ml) and the combined organic extracts are dried over magnesium sulfate and concentrated to obtain specified in the connection header in the form of a yellow oil, which solidifies upon standing (1,87 g, 85%).1H NMR (d4-MeOH, 400 MHz) the 10.40 (s, 1H), and 8.4 (s, 1H), 8,21 (d, J=5,20 Hz, 1H), 7.62mm (d, J=5,20 Hz, 1H), 4,47 (sq, J=6,44 Hz, 2H), 1,45 (t, J=6,44 Hz, 3H).

Stage 4: Ethyl 3-ethoxycarbonylmethylene

To a cold (5°C) solution of ethyl 3-hydroxyisovalerate (1,67 g, 1.0 mmol), ethylglycol (1,15 ml of 12.0 mmol) and triphenylphosphine (3,93 g, 15.0 mmol) in anhydrous THF (50 ml) added dropwise diisopropylethylamine (2,94 ml, 15.0 mmol). The reaction mixture was gradually warmed to room temperature, then stirred for an additional 1 hour. The resulting solution was concentrated and purified using flash chromatography (Si-SPE, pentane: diethyl ether, gradient 50:50 to 0:100)to obtain specified in the title compound as yellow oil (2.15 g, 85%). IHMS (method B): RT= 2,69 min, M+H+= 254.

Stage 5: Ethyl 3-hydroxyfuran[2,3-c]pyridine-2-carboxylate

A solution of ethyl 3-ethoxycarbonylmethylene (2.1 g, 8.3 mmol) in THF (50 ml) was carefully added to a cold (0°C) solution of tert-butoxide potassium (966 mg, 8.6 mmol) in THF (20 ml). After 30 minutes the reaction mixture was quenched by adding acetic acid (10 ml). In the evaporation of solvents are resin, which is dissolved in ethyl acetate (50 ml) and washed with water (2×10 ml). The organic layer is isolated and dried over anhydrous sodium sulfate. The resulting solution concentration is irout to obtain specified in the connection header in a solid yellow color (1.60 g, 94%). IHMS (method B): RT= 1,89 min, M+H+= 208.

Step 6: Ethyl 3-(nonattribute-1 sulfonyloxy)-furo[2,3-C]pyridine-2-carboxylate

To a stirred suspension of ethyl 3-hydroxyfuran[2,3-c]pyridine-2-carboxylate (1,16 g, the ceiling of 5.60 mmol) in DCM (15 ml) at 0°C is added DIPEA (1,32 ml, 7.5 mmol), and then nonatherosclerotic (1.25 ml, 6,9 mmol). After 10 minutes the reaction mixture is heated to room temperature and stirred for additional 20 hours. The reaction mixture was concentrated, the residue is dissolved in DCM (100 ml) and washed with water (50 ml), and then 1 N. NaOH solution (20 ml). Allocate the combined organic layer is dried over sodium sulfate and concentrated in vacuo.Purify using flash chromatography (Si-SPE, pentane: diethyl ether, gradient 80:20 to 50:50), receiving specified in the title compound in the form of solid white (895 mg, 33%). IHMS (method B): RT= 4,34 min, M+H+= 490.

Step 7: Ethyl 3-(4-bromo-2-forgenerating)-furo[2,3-C]pyridine-2-carboxylate

Degassed solution of ethyl 3-(nonattribute-1 sulfonyloxy)-furo[2,3-c]pyridine-2-carboxylate (838 mg, 1,71 mmol), 4-bromo-2-foronline (423 mg, of 2.23 mmol), Pd2dba3(78 mg, 0.09 mmol), Xantphos (99 mg, 0,17 mmol) and DBU (651 μl, to 4.28 mmol) in toluene (3.3 ml) is subjected to microwave irradiation at 150°C in ECENA 20 minutes. The reaction mixture was concentrated and the resulting residue absorb on HM-N before it is purified using flash chromatography (Si-SPE, pentane: diethyl ether, gradient 80:20 to 0:100)to obtain specified in the connection header in the form of a solid white (369 mg, 57%). IHMS (method B): RT= of 3.77 min, M+H+= 380/382.

Step 8: Ethyl 3-(2-fluoro-4-iodoaniline)-furo[2,3-C]pyridine-2-carboxylate

A mixture of ethyl 3-(4-bromo-2-forgenerating)-furo[2,3-c]pyridine-2-carboxylate (311 mg, 0.82 mmol), copper iodide(I) (8 mg, 0.04 mmol), sodium iodide (246 mg, of 1.64 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (13 μl, 0.08 mmol) in 1,4-dioxane (0.8 ml) is heated at 115°C for 26 hours in argon atmosphere. After the reaction mixture was cooled to room temperature, the mixture was concentrated, then purified using flash chromatography (Si-SPE, EtOAc)to obtain specified in the title compound as yellow oil (220 mg, 63%). IHMS (method B): RT= 3,91 min, M+H+= 427.

Ethyl 3-(2-fluoro-4-iodoaniline)-furo[3,2-c]pyridine-2-carboxylate

Stage 1: 2-fluoro-4-trimethylsilylmethylamine

4-chloro-2-ftorirovannom (6.0 g, 34,2 mmol) is added to a 100 ml round bottom flask followed by the addition of hexamethyldisilane (18,9 g, 129,0 mmol of 26.4 ml) and xylene (13 ml). P is obtained, the mixture is stirred with a magnetic stirrer, while nitrogen is bubbled into the solution through a glass pipette for 10 minutes or until until a solid product is dissolved completely.

Add tetrakis(triphenylphosphine)palladium(0) (l,0 g, 0.9 mmol), the flask connected with a reflux condenser and the reaction mixture is heated at boiling under reflux in 24-48 hours, while slowly passing a stream of nitrogen through the rubber membrane on top of the refrigerator. After cooling to room temperature the reaction mixture was diluted (40 ml) and filtered through a layer of silica gel (30 ml suspension SiO2ethyl ester, stuffed in 60 ml funnel of the sintered glass). The filter cake is washed with ethyl ether (60 ml) and the combined organic layers concentrated in vacuo, getting an orange oil, which was purified using flash chromatography (250 ml of silica gel, 98:1:1 hexane-CH2Cl2ethyl ether)to give 2-fluoro-4-trimethylsilylmethylamine (of 5.45 g, 75%) as oil yellow-orange color.

Then 2-fluoro-4-trimethylsilylmethylamine (of 5.45 g, 25.6 mmol)dissolved in ethanol (100 ml), move in shake flask Parra, rinsed with nitrogen, then load 10% Pd-C (0.4 g). The reaction mixture hydronaut for l hour in a Parr apparatus (45 f/inch square H2) and then filtered through a layer of celite. The filter cake about what to see with ethanol and the combined filtrates concentrated. The obtained residue is purified using flash chromatography (250 ml silica gel, 95:5 hexane-ethyl ether)to obtain specified in the connection header in the form of oil orange-brown color (or 4.31 g, 92%).

Step 2: Ethyl 3-(4-trimethylsilyl-2-forgenerating)-furo[3,2-c]pyridine-2-carboxylate

A suspension of ethyl 3-(tripterocalyx)-furo[3,2-c]pyridine-2-carboxylate (17.5 g, 51,58 mmol), 2-fluoro-4-trimethylsilylmethylamine (10 g, 54,26 mmol), Pd2dba3(2,98 g, 3,26 mmol), Xantphos (1,94 mg, 3,26 mmol) and K3PO4(15,83 g, 72,34 mmol) in toluene (100 ml) Tegaserod, barbotine nitrogen for 10 minutes in a 300 ml autoclave, and then heated at 105°C for 24 hours. The reaction mixture is then cooled to room temperature and diluted with ethyl acetate (200 ml). The resulting mixture was then filtered through celite 545 celite and washed with an additional 100 ml of ethyl acetate. The resulting filtrate is then concentrated and purified using flash chromatography on a column (silica gel, 0-55% ethyl acetate in hexane), to obtain specified in the connection header in a solid yellow color (17.9 g, 93,2 %). IHMS (method C): RT= 2,47 min, M+H+= 373.1H NMR (CDCl3, 400 MHz) 8,66 (d, 1H), to 8.57 (d, 1H), 7,52 (s, 1H), 7,45 (d, d, 1H), 7,30 (m, 2H), 4,50 (square, 2H), 1,49 (t, 3H).

Step 3: Ethyl 3-(2-fluoro-4-iodoaniline)-furo[3,2-C]pyridine-2-carboxylate/p>

16.0 g (72,49 mmol) AgBF4quickly weighed and placed in a 1000 ml round bottom flask, which is then closed with a rubber membrane. Then the flask was rinsed with dry gaseous N2within 10 minutes, after which the flask was cooled to -50°C, while maintaining the inert atmosphere. Into the flask, add 300 ml of dry dichloromethane and then the mixture is stirred for 15 minutes at -50°C in nitrogen atmosphere. To the reaction mixture were then added 9.0 g (24,16 mmol) ethyl 3-(4-trimethylsilyl-2-forgenerating)-furo[3,2-c]pyridine-2-carboxylate in 75 ml of dry dichloromethane and the mixture is stirred for 30 minutes at -50°C in nitrogen atmosphere. The color of the reaction mixture becomes a clear yellow. Then the reaction mixture is treated with 25 ml of ICl (1,0 M in CH2Cl2, 25 mmol) dropwise with stirring over 30 minutes. Adding ICl leads to the formation of precipitate (white/brown color reaction was yellow - red seats, when interacting with ICl color was returning from yellow to white). The reaction mixture was stirred at -50°C in nitrogen atmosphere for 30 minutes. According to LC/MS is that the reaction is complete. Then the reaction quenched at -50°C by adding 200 ml of a saturated solution of Na2S2C3and then 100 ml of water. The resulting mixture then is moved to a separating funnel and shaken. The resulting mixture is filtered across the filter paper. Then a solid black color on the filter paper was washed with dichloromethane and then drain. The resulting filtrate is then moved in a separating funnel. Contents are then quickly extracted with dichloromethane (3×100 ml). The combined dichloromethane layers then washed with 170 ml of 4 M NH4OH solution in a separating funnel. Then the dichloromethane layer is separated and bubbled with nitrogen to remove ammonia. Then dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid yellow color. The solid product is then converted into a powder and triturated c ether (2×30 ml) and then dried in vacuum to obtain 8.90 g specified in the connection header (solid yellow product, 86.4 per cent)). IHMS (method C): RT= 2,47 min, M+H+= 427.1H NMR (CDCl3, 400 MHz) 8,64 (d, 1H), 8,9 (d, 1H), 7,66 (s, 1H), 7,54 (d, d, 1H), 7,46 (d, d, m, 2H), 7,13 (t, 1H), 4,49 (square, 2H), 1,49 (t, 3H).

Ethyl 3-(4-iodobenzylamine)-furo[3,2-c]pyridine-2-carboxylate

Stage 1: Ethyl 3-minotoro|3,2-c]pyridine-2-carboxylate

To a stirred mixture of sodium hydride (60% suspension in mineral oil, 6.0 g, 150 mmol) in DMF (160 ml) at -10°C under nitrogen atmosphere add ethylglycol (14,5 ml, 150 mmol) over 5 minutes. After 35 minutes the reaction mixture is then cooled to -35°C and up to ablaut a solution of 4-chloronicotinamide (6,9 g, 50 mmol) in DMF (40 ml) for 5 minutes. The reaction mixture is then left to gradually heated for 1.5 hours to -5°C, before its quenched with a solution of a mixture of acetic acid:water (45 ml) : 400 ml) and then extracted with ethyl acetate (2×200 ml). Selected aqueous phase is alkalinized by adding solid sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic extracts washed with sodium bicarbonate solution (100 ml) and water (2×100 ml), then allocate the organic phase, dried (MgSO4), filtered and evaporated in vacuum.The resulting residue is purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 60:40 to 0:100, then ethyl acetate:methanol, 90:10), receiving specified in the title compound in the form of solid pale yellow color (6.25 g, 61%). IHMS (method B): RT= 1,45 min, M+H+= 207.

Step 2: Ethyl 3-(4-iodobenzylamine)-furo[3,2-c]pyridine-2-carboxylate

Degassed solution of ethyl 3-minotoro[3,2-c]pyridine-2-carboxylate (206 mg, 1.0 mmol), 1,4-diiodobenzene (3.3 g, 10.0 mmol), Pd2dba3(24 mg, 26 μmol), Xantphos (30 mg, 52 μmol) and potassium phosphate (424 mg, 2.0 mmol) in toluene (10 ml) is stirred and heated to 105°C in argon atmosphere for 42 hours. The cooled reaction mixture was poured into an aqueous solution of ameriglide and extracted with ethyl acetate (3×70 ml). Obyedinenny the extracts washed with water (2×100 ml), then brine (50 ml) before release organic phase is dried (MgSO4), filtered and evaporated in vacuum.After treatment, the formed precipitate using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 60:40)are specified in the title compound in the form of solids not quite white (100 mg, 24%). IHMS (method B): RT= 3,16 min, M+H+= 409.

Ethyl 3-(2-chloro-4-iodoaniline)-furo[3,2-c]pyridine-2-carboxylate

Stage 1: Ethyl 3-(4-bromo-2-chlorpheniramine)-furo[3,2-c]pyridine-2-carboxylate

Degassed solution of ethyl 3-(nonattribute-1 sulfonyloxy)-furo[3,2-c]pyridine-2-carboxylate (500 mg, of 1.02 mmol), 4-bromo-2-Chloroaniline (275 mg, of 1.33 mmol), Pd2dba3(47 mg, 0.05 mmol), Xantphos (59 mg, 0.10 mmol) and DBU (388 μl, 2.56 mmol) in toluene (2.0 ml) is subjected to microwave irradiation at 150°C for 10 minutes. The reaction mixture was concentrated and the resulting residue absorb on HM-N before it is purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 0:100)to obtain specified in the connection header in the form of a solid white color (183 mg, 47%). IHMS (method B): RT= 3,54 min, M+H+= 395/397.

Step 2: Ethyl 3-(2-chloro-4-iodoaniline)-furo[3,2-C]pyridine-2-carboxylate

A mixture of ethyl 3-(4-bromo-2-chlorpheniramine)-furo[3,2-c]pyridine-2-carboxylate (183 mg, 0.46 mmol), copper iodide(I) (4 mg, 0.02 mmol), sodium iodide (139 mg, of 0.93 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (7 μl, 0.04 mmol) in 1,4-dioxane (0.5 ml) is heated at 115°C for 44 hours in argon atmosphere. The reaction mixture is cooled to room temperature, then add the copper iodide (4 mg, 0.02 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (7 μl, 0.04 mmol) and continue heating at 115°C for 18 hours in an argon atmosphere. The reaction mixture is then cooled to room temperature, diluted with dichloromethane and washed with 10% solution of ammonia in water, water, then brine. The organic extract is dried over sodium sulfate, filtered and concentrated in vacuo to obtain a residue, which is purified using flash chromatography on a column of silica gel (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 0:100)to obtain specified in the connection header in the form of solid substances not quite white (115 mg, 57%). IHMS (method B): RT = 3,97 min, M+H+= 443.

Ethyl 3-(2,6-debtor-4-iodobenzylamine)-furo[3,2-c]pyridine-2-carboxylate

Stage 1: Ethyl 3-(4-bromo-2,6-dipertanyakan)-furo[3,2-C]pyridine-2-carboxylate

Degassed solution of ethyl 3-(nonattribute-1 sulfonyloxy)-the UB[3,2-c]pyridine-2-carboxylate (500 mg, of 1.02 mmol), 4-bromo-2,6-diferencia (277 mg, of 1.33 mmol), Pd2dba3(47 mg, 0.05 mmol), Xantphos (59 mg, 0.10 mmol) and DBU (388 μl, 2.56 mmol) in toluene (2.0 ml) is subjected to microwave irradiation at 150°C for 10 minutes. The reaction mixture was concentrated and the resulting residue absorb on HM-N before it is purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 0:100)to obtain specified in the connection header in the form of a solid white (89 mg, 22%). IHMS (method B): RT= 3,38 min, M+H+= 397/399.

Step 2: Ethyl 3-(2,6-debtor-4-iodobenzylamine)-furo[3,2-C]pyridine-2-carboxylate

A mixture of ethyl 3-(4-bromo-2,6-dipertanyakan)-furo[3,2-c]pyridine-2-carboxylate (165 mg, 0.42 mmol), copper iodide (4 mg, 0.02 mmol), sodium iodide (125 mg, 0.83 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (7 μl, 0.04 mmol) in 1,4-dioxane (0.5 ml) is subjected to microwave irradiation at 180°C for 15 minutes. Add additional portion of copper iodide (4 mg, 0.02 mmol), sodium iodide (60 mg, 0.40 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (7 μl, 0.04 mmol) to the reaction mixture, which is again subjected to microwave irradiation at 180°C for 15 minutes. The reaction mixture was diluted with dichloromethane and washed with 10% solution of ammonia in water, water then brine. The organic extract is dried over sodium sulfate, filtered and to the center to obtain a precipitate, which is purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 0:100)to obtain specified in the connection header in the form of solid substances not quite white (137 mg, 74%). IHMS (method B): RT= 3,48 min, M+H+= 445.

Ethyl 3-(2,5-debtor-4-iodobenzylamine)-furo[3,2-c]pyridine-2-carboxylate

Stage 1: Ethyl 3-(4-bromo-2,5-dipertanyakan)-furo[3,2-c]pyridine-2-carboxylate

Degassed solution of ethyl 3-(nonattribute-1 sulfonyloxy)-furo[3,2-c]pyridine-2-carboxylate (500 mg, of 1.02 mmol), 4-bromo-2,5-diferencia (277 mg, of 1.33 mmol), Pd2dba3(47 mg, 0.05 mmol), Xantphos (59 mg, 0.10 mmol) and DBU (388 μl, 2.56 mmol) in toluene (2.0 ml) is subjected to microwave irradiation at 150°C for 10 minutes. The reaction mixture was concentrated and the resulting residue absorb on HM-N before it is purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 0:100)to obtain specified in the connection header in the form of a solid white color (231 mg, 57%). IHMS (method B): RT= 3,22 min, M+H+= 397/399.

Step 2: Ethyl 3-(2,5-debtor-4-iodobenzylamine)-furo[3,2-c]pyridine-2-carboxylate

A mixture of ethyl 3-(4-bromo-2,5-dipertanyakan)-furo[3,2-

c]pyridine-2-carboxylate (222 mg, 0,56 mmol), copper iodide (5 mg, 0.03 mmol), sodium iodide (168 m is, 1.12 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (10 μl, 0.06 mmol) in 1,4-dioxane (0.5 ml) is heated at 110°C for 18 hours. Added copper iodide (5 mg, 0.03 mmol) and TRANS-N,N'-dimethyl-1,2-cyclohexanediamine (10 μl, 0.06 mmol) are added to the reaction mixture, which is again heated at 110°C for 6 hours. The reaction mixture is cooled, diluted with dichloromethane and washed with 10% solution of ammonia in water, water, then brine. The organic extract is dried over sodium sulfate, filtered and concentrated to obtain residue, which is purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 0:100)to obtain specified in the connection header in the form of a solid white color (170 mg, 68%). IHMS (method B): RT= 3,30 min, M+H+= 445.

7-bromo-3-(2-fluoro-4-iodoaniline)-furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: Ethyl 7-bromo-3-hydroxy-furo[3,2-C]pyridine-2-carboxylate

To a solution of ethyl 4,5-dibranchiata (2,68 g, 8,67 mmol) and ethylglycol (0,90 g, 8,67 mmol) in DMF (25 ml) at 0°C (ice/water), add sodium hydride (1.04 g, 26 mmol, 60% dispersion in oil). The reaction mixture was stirred at 0°C for 15 minutes before you leave to come to room temperature for 2 hours. The reaction mixture was cooled to 0°Spared fact, how add 1 M HCl (18 ml, 18 mmol). The precipitate is filtered and washed with water to obtain specified in the connection header in the form of solid substances not quite white (2.35 g, 95%). IHMS (method B): RT= 2,96 min, M+H+= 285/287.

Stage 2: 3,7-dibromofuran[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl 7-bromo-3-hydroxyfuran[3,2-c]pyridine-2-carboxylate (1,14 g, 4.0 mmol) and brookie phosphorus (5.6 g, a 19.5 mmol) is heated at 140°C for 2 hours. The reaction mixture is cooled to room temperature before you add the crushed ice (about 30 ml). The resulting mixture was neutralized by adding solid NaOH before the pH is adjusted to pH 3.0, carefully adding 1 M HCl. The precipitate is filtered and then washed with water, then with dichloromethane to obtain specified in the connection header in the form of a solid white color (1.2 g, 90%). IHMS (method B): RT= 2,62 min, M+H+= 320/322/324.

Stage 3: 3,7-dibromofuran[3,2-c]pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethylethyl)amide

A mixture of 3,7-dibromofuran[3,2-c]pyridine-2-carboxylic acid (1.2 g, 3,74 mmol and carbonyldiimidazole of 0.85 g of 5.24 mmol) in acetonitrile (18 ml) is heated at 50°C for 2 hours. To the reaction mixture add the next portion of carbonyldiimidazole (0.035 g, 0.5 mmol), and heated n and 50°C continued for 1 hour. After cooling to room temperature, to the resulting solution was added 2-amino-2-methylpropan-1-ol (0,30 ml of 3.13 mmol). The reaction mixture is left to stand at room temperature for 19 hours, then heated at 50°C for 1 h before concentrated in vacuo.After treatment, the formed precipitate using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 80:20 to 0:100) receive specified in the title compound in the form of solid light yellow (0,53 g, 72%). IHMS (method B): RT= 2.57 m min, M+H+= 391/393/395.

Stage 4: 3,7-dibromo-2-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)-furo[3,2-c]pyridine

To a solution of (2-hydroxy-1,1-dimethylethyl)amide 3,7-dibromofuran[3,2-c]pyridine-2-carboxylic acid (0,53 g, 1.35 mmol) in dichloromethane (10 ml) is added thionyl chloride (0.25 ml, of 3.43 mmol). The resulting mixture was stirred at room temperature for l hour, then heated at the boil under reflux for 2 hours before cooled to 0°C. the resulting mixture was neutralized 1 M NaOH (15 ml)and the aqueous layer was extracted with dichloromethane (2×15 ml). The organic layer is collected, dried over magnesium sulfate and concentrated in vacuo to obtain a precipitate. After treatment, the formed precipitate using flash chromatography (Si-SPE, dichloromethane the ZAT is ethyl acetate) receive specified in the title compound in the form of resin, pale yellow (250 mg, 50%). IHMS (method B): RT= 3,11 min, M+H+= 373/375/377.

Stage 5: [7-bromo-2-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)-furo[3,2-c]pyridine-3-yl]-(2-fluoro-4-iodophenyl)Amin

To a solution of 3,7-dibromo-2-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)furo[3,2-c]pyridine (250 mg, 0.67 mmol) and 4-iodo-2-foronline (474 mg, 2 mmol) in THF (2 ml) add a solution litigationrelated in THF (2 ml, 1 M solution). The reaction mixture is heated at 50°C for 4 hours, then cooled to room temperature and diluted with water (15 ml). The aqueous layer was extracted with dichloromethane (2×10 ml)and the combined organic extracts dried over MgSO4and concentrated in vacuo to obtain a precipitate. After treatment, the formed precipitate using flash chromatography (Si-SPE, cyclohexane:tert-butyl methyl ether, gradient 1:1 to 1:2) get mentioned in the title compound in the form of a solid light brown color (150 mg, 42%). IHMS (method A): RT=13,97 min, M+H+= 530/532.

Stage 6: 7-bromo-3-(2-fluoro-4-iodoaniline)-furo[3,2-c]pyridine-2-carboxylic acid

A mixture of [7-bromo-2-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)furo[3,2-c]pyridine-3-yl]-(2-fluoro-4-iodophenyl)amine (110 mg, 0.2 mmol) and 1 M HCl (2 ml, 2 mmol) is heated at 100°C for 4 hours, then cooled and concentrated in vacuo.The precipitate Rast is oraut in methanol (3 ml) and added dropwise 2.5 M NaOH in methanol (0.4 ml, 1 mmol), then water (1 ml). The resulting mixture is heated at 75°C for 1 hour before was added 1 M aqueous NaOH solution (1 ml, 1 mmol), and heating continued for 2 hours. The reaction mixture was concentrated in vacuo and the remaining aqueous layer was washed with ethyl acetate (2×2 ml). The aqueous layer was then acidified to pH 4 using 1 M HCl (~1.5 ml), concentrated in vacuo to approximately half volume and left to stand at room temperature. The precipitate is collected by filtration and washed with water (1 ml), then ethyl acetate (1 ml) to obtain specified in the connection header in the form of a solid yellow-brown (66 mg, 69%). IHMS (method B): RT= 3,34 min, M+H+= 477/479.

Ethyl 5-(2-fluoro-4-iodoaniline)furo[2,3-d]pyrimidine-6-carboxylate

Stage 1: Ethyl 4-hydroxypyrimidine-5-carboxylate

To the previously prepared solution of sodium (1.70 g, 73,9 mmol) in absolute ethanol (300 ml) was added 1,3,5-triazine (6.0 g, 74,1 mmol) and diethylmalonate (11.3 ml, 74,1 mmol). The reaction mixture is heated at the boil under reflux. After heating for 3 hours, the reaction mixture was cooled to room temperature and concentrate under reduced pressure to obtain a precipitate. The precipitate is dissolved in water (300 ml), and then cooling the t to 5°C and acidified by adding hydrochloric acid (6 ml). The mixture was incubated for 48 hours at 5°C and filtered. The obtained solid product is washed with water before dried under reduced pressure to obtain specified in the connection header in the form of a solid beige color (3.0 g, 24%).1H NMR (d6-DMSO, 400 MHz) of 8.47 (s, 1H), of 8.37 (d, 1H), 4,22 (sq, J=7.2 Hz, 2H), 1.26 in (t, J=7.2 Hz, 3H).

Step 2: Ethyl 4-chloropyrimidine-5-carboxylate

To a suspension of ethyl 4-hydroxypyrimidine-5-carboxylate (3.0 g, 17.6 mmol) in toluene (35 ml) add diisopropylethylamine (3.4 ml, at 19.6 mmol) and phosphorus oxychloride (1.8 ml, at 19.6 mmol) dropwise under nitrogen atmosphere. The reaction mixture is heated to 70°C and stirred for two hours, then cooled to 5°C. was Added 1 M aqueous sodium hydroxide solution (26 ml)and the resulting mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water, saturated sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated to obtain specified in the title compound as brown oil (2,56 g, 77%).1H NMR (CDCl3, 400 MHz) 9,13 (s, 1H), remaining 9.08 (s, 1H), 4,47 (sq, J=6,9 Hz, 2H), 1,44 (t, J=6.9 Hz, 3H).

Step 3: Ethyl 4-ethoxycarbonylmethoxy-5-carboxylate

To a suspension of sodium hydride (60% in mineral oil, 602 mg, 15.1 mmol) in the same THF (55 ml) at 5°C in nitrogen atmosphere add ethylglycol (1.6 ml, 16.5 mmol). The reaction mixture was stirred at 5°C for 30 minutes before added dropwise a solution of ethyl 4-chloropyrimidine-5-carboxylate (2,56 g of 13.8 mmol) in anhydrous THF (20 ml). The reaction mixture was stirred at 5°C for 30 minutes. To the reaction mixture are added acetic acid (3 ml), then concentrated in vacuo.The precipitate is dissolved in ethyl acetate and washed with water, then brine before dried over sodium sulfate and concentrated under reduced pressure to obtain a precipitate. The precipitate absorb on HM-N and purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:00 to 40:60)to obtain specified in the title compound as yellow oil (2.67 g, 76%).1H NMR (CDCl3, 400 MHz) 9,05 (s, 1H), 8,82 (s, 1H), of 5.05 (s, 2H), to 4.41 (sq, J=7,1 Hz, 2H), 4,24 (sq, J=7,1 Hz, 2H), 1,40 (t, J=7,1 Hz, 3H), of 1.28 (t, J=7,1 Hz, 3H).

Stage 4: Ethyl 5-hydroxyfuran[2,3-d]pyrimidine-6-carboxylate

To a solution of ethyl 4-ethoxycarbonylmethoxy-5-carboxylate (2,12 g, 8.3 mmol) in anhydrous THF (80 ml) at 5°C in an inert atmosphere add tert-piperonyl sodium (1.40 g). The reaction mixture is stirred for 30 minutes at 5°C and add 1 M hydrochloric acid solution. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer is isolated and washed with the water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain specified in the connection header in the form of a solid white color (934 mg, 54%).1H NMR (CDCl3, 400 MHz) which 9.22 (s, 1H), 9,14 (s, 1H), 4,51 (sq, J=7,3 Hz, 2H), 1,47 (t, J=7,3 Hz, 3H).

Stage 5: Ethyl 5-triftoratsetilatsetonom[2,3-d]pyrimidine-6-carboxylate

To a solution of ethyl 5-hydroxyfuran[2,3-d]pyrimidine-6-carboxylate (1.2 g, 5.8 mmol) and diisopropylethylamine (1.5 ml, 8,7 mmol) in dimethoxyethane (25 ml) is added N-phenyltrichlorosilane (2.3 g, 6.4 mmol). The reaction mixture is heated at boiling under reflux and stirred for 1 hour, then cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in ethyl acetate, then washed with water, saturated aqueous sodium bicarbonate and saline. The organic layer is dried over sodium sulfate, filtered, absorb on HM-N and purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 100:0 to 50:50)to obtain specified in the title compound as a colourless oil (1.5 g, 77%).1H NMR (CDCl3, 400 MHz) 9,23 (s, 2H), 4,54 (sq, J=7.2 Hz, 2H), 1,47 (t, J=7.2 Hz, 3H).

Step 6: Ethyl 5-(2-fluoro-4-trimethylsilyl-phenylamino)furo[2,3-d]pyrimidine-6-carboxylate

Degassed solution of ethyl 5-triftoratsetilatsetonom[2,3-d]pyrimidine-6-carboxylate (1.5 g, 4.4 mmol), 2-fluoro-4-trimethylsilylmethylamine (888 mg, 4.8 mmol), Pd2dba3(202 mg, 0.22 mmol), Xantphos (127 mg, 0.22 mmol) and K3PO4(1.9 grams, 8,8 mmol) in toluene (20 ml) is heated to boiling under reflux and stirred for 4 hours under nitrogen atmosphere. The reaction mixture is cooled to room temperature and filtered through celite and the filter cake washed with ethyl acetate. The organic layer is washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is dissolved in dichloromethane, to absorb HM-N and purified using flash chromatography (Si-SPE, ethyl acetate:cyclohexane, gradient 0:100 to 40:60)to obtain specified in the connection header in the form of oil, which crystallized upon standing (1.2 g, 75%). IHMS (method B): RT= 4,39 min, M+H+= 374.

Step 7: Ethyl 5-(2-fluoro-4-iodoaniline)furo[2,3-d]pyrimidine-6-carboxylate

To a solution of ethyl 5-(2-fluoro-4-trimethylsilylmethylamine)-furo[2,3-d]pyrimidine-6-carboxylate (1.2 g, 3.2 mmol) in dichloromethane (10 ml) at 5°C, add a solution of monochloride iodine (674 mg, 4.2 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at 5°C for 1 hour lane is on the, how to add a saturated aqueous solution of sodium thiosulfate. The organic layer is isolated and washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue triturated with hot ethanol, incubated over night at room temperature. The precipitate is collected by filtration, then washed with cold ethanol before dried in vacuum, to obtain specified in the connection header in the form of a solid white color (864 mg, 63%).1H NMR (CDCl3, 400 MHz) remaining 9.08 (s, 1H), to 8.70 (s, 1H), 7,78 (s, 1H), EUR 7.57 (DD, J=9.6 Hz, 1.9 Hz, 1H), 7,51 (DDD, J=8,4 Hz, 1.7 Hz, 1.7 Hz, 1H), 7,03 (DD, J=8,2 Hz and 8.2 Hz, 1H), 4,49 (sq, J=7,4 Hz, 2H), 1,46 (t, J=7.4 Hz, 3H).

Ethyl ester of 3-((2-fluoro-4-iodophenyl)methylamino)furo[3,2-C]pyridine-2-carboxylic acid

Sodium hydride (60% dispersion in mineral oil, 45 mg, 1.12 mmol) is added in portions to a stirred solution of ethyl ester of 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (430 mg, 1.0 mmol) and iodomethane (310 μl, to 4.98 mmol) in DMF (3 ml) under inert atmosphere. The resulting mixture is stirred for 3 hours, then quenched with brine and extracted with ethyl acetate (3×40 ml). The combined organic extracts washed with brine, dried (MgSO4), filter and concentrate the vacuum .The resulting residue is purified using flash chromatography (Si-SPE, gradient 40:100 to 100:100 ether)to obtain specified in the connection header in the form of a solid yellow (57 mg, 13%). IHMS (method B): RT= 3,26 min; (M+H+440.

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

Degassed solution of ethyl ester of 3-triftoratsetilatsetonom[3,2-c]pyridine-2-carboxylic acid (300 mg, 0.88 mmol), 4-bromo-2-foronline (201 mg, 0.97 mmol), Pd2dba3(40 mg, 0,044 mmol), Xantphos (59 mg, 0,044 mmol) and trehosnovnogo potassium phosphate (373 mg, of 1.76 mmol) in toluene (5 ml) is heated at boiling under reflux in an argon atmosphere for 16 hours. The reaction mixture was filtered and concentrated in vacuo.The resulting residue is purified using flash chromatography (Si-SPE, pentane:diethyl ether, gradient 80:20 to 50:50)to obtain specified in the connection header in a solid yellow color (177 mg, 51%). IHMS (method B): RT= 3,76 min, M+H+= 395/397.

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

Degassed solution of ethyl ester of 3-minotoro[3,2-c]pyridine-2-carboxylic acid (300 mg, of 1.46 mmol), 4-bromo-3-portaluri (277 μl, 2,19 mmol), Pd2dba3(67 mg, 0073 mmol), Xantphos (84 mg, 0.15 mmol) and trehosnovnogo phosphate potassium (620 mg, of 2.92 mmol) in toluene (10 ml) is heated at boiling under reflux in an argon atmosphere for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified using flash chromatography (Si-SPE, pentane:diethyl ether, gradient 100:0 to 75:25), to obtain specified in the connection header in a solid yellow color (252 mg, 55%). IHMS (method B): RT= 3,14 min, M+H+= 315.

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

Stage 1: 4-bromo-3-fermentation

4-Bromo-3-forbindelsesfaneblad (324 μl, 2,19 mmol) is added dropwise to a solution of triphenylphosphine (1.73 g, to 6.58 mmol) in a mixture of dimethylformamide (125 ml) and dichloromethane (5 ml). The resulting solution was stirred at room temperature for 16 hours, then was added 1 M aqueous solution of hydrochloric acid (5 ml) and the layers separated. The organic layer was concentrated in vacuo and the resulting residue is placed in a 1 M aqueous sodium hydroxide solution (10 ml). The resulting suspension is filtered through celite ®and the filtrate washed with ether (10 ml × 3), then neutralized by adding 1 M aqueous hydrochloric acid solution (10 ml). The resulting solution was extracted with ether (10 ml× 3), and the combined organic extracts dried (Na2SO4), then concentrated in vacuo to obtain specified in the title compound as a colourless oil (225 mg, 50%).1H NMR (CDCl3, 300 MHz) 7,47 (1H, DD, J=8,4, 7.5 Hz), 7,06 (1H, DD, J=8,9 and 2.2 Hz), 6,93 (1H, DDD, J=8,4, 2,1, 0.7 Hz), 3,54 (1H, users).

Stage 2: 1-bromo-2-fluoro-4-methylsulfonylbenzoyl

A solution of 4-bromo-3-fermentative (225 mg, of 1.09 mmol) in tetrahydrofuran (3 ml) cooled to 0°C. sodium Hydride (60% dispersion in mineral oil, 52 mg of 1.31 mmol) is added, and the mixture was stirred for 5 minutes. Then add iodomethane (78 μl, 1.25 mmol)and the resulting mixture is left to warm to room temperature while stirring for 20 minutes. Dichloromethane (10 ml) is added and the reaction mixture is quenched using 1 M aqueous solution of hydrochloric acid. The layers separated, and the organic layer washed with water, dried (MgSO4), then concentrated in vacuo.The residue is purified using flash chromatography (Si-SPE, pentane: diethyl ether, gradient 100:0 to 90:10)to obtain specified in the connection header in the form of oil bright yellow (208 mg, 86%).1H NMR (CDCl3, 400 MHz) the 7.43 (1H, DD, J=8,4, 7,2), 7,00 (1H, DD, J=9,4, 2,3), 6,91 (1H, DDD, J=8,4, 2,1, 0,7), 2,48 (3H, s).

Step 3: Ethyl ester of 3-(2-fluoro-4-methylsulfanyl-phenylamino)furo[3,2-c]pyridine-2-carboxylic acid is you

Degassed solution of ethyl ester of 3-minotoro[3,2-c]pyridine-2-carboxylic acid (121 mg, 0.59 mmol), 1-bromo-2-fluoro-4-methylsulfonylbenzoyl (195 mg, 0.88 mmol), Pd2dba3(27 mg, 0,030 mmol), Xantphos (34 mg, 0,059 mmol) and trehosnovnogo potassium phosphate (250 mg, 1.18 mmol) in toluene (3 ml) is heated at boiling under reflux in an argon atmosphere for 60 hours. The reaction mixture is filtered and the resulting filtrate was concentrated in vacuo.The resulting residue is purified using flash chromatography (Si-SPE, pentane: diethyl ether, gradient 100:0 to 50:50)to obtain specified in the connection header in a solid yellow color (128 mg, 63%). IHMS (method B): RT= 3,24 min, M+H+= 347.

Ethyl ester of 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridineboronic acid

Stage 1: 4,5-dichloropyridine-3-carbaldehyde

To a solution of Diisopropylamine (of 10.73 ml, 75,9 mmol) in THF (60 ml) at -40°C, add n-utility (47,45 ml, 75,9 mmol, 1,6 M in hexano), and the resulting solution was stirred for 15 minutes at -40°C before cooling to -70°C. a Solution of 3,4-dichloropyridine (10.7 g, 72,3 mmol) in THF (30 ml) is added dropwise to maintain the temperature below -65°C. the Reaction mixture was stirred at -70°C within 2 hours the before however, as added DMF (6,74 ml, and 86.8 mmol). Then the reaction mixture was stirred at -40°C for 1 hour and then allowed to warm to -5°C before gently add saturated aqueous solution of ammoniaand (50 ml) with rapid stirring for 3 minutes. Then divide the mixture between saturated aqueous solution of ammoniaand (150 ml)and dichloromethane (150 ml)and the resulting layers emit. The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined organic layers are dried over magnesium sulfate, and then concentrated in vacuo.In the purification using flash chromatography (Si-SPE, dichloromethane:ethyl acetate, gradient 100:0 to 94:6) receive specified in the title compound in the form of a waxy solid white (8,01 g, 63%).

Stage 2: the Reaction of 4,5-dichloropyridine-3-carbaldehyde

A solution of 4,5-dichloropyridine-3-carbaldehyde (8,01 g, 45,51 mmol) in ethanol (50 ml) is added to the rapidly stirred solution of hydroxylaminopurine (3,48 g, 50,06 mmol) in water (50 ml). The reaction mixture was stirred at room temperature for 45 minutes, then divide between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml)and the combined organic layers are dried over magnesium sulfate before concentrating in vacuo to obtain is shown in the title compound in the form of a solid white color (8,3 g, 96%).

Stage 3: 4,5-dichloronicotinic

To a suspension of oxime 4,5-dichloropyridine-3-carbaldehyde (7,84 g, 41,05 mmol) in dichloromethane (150 ml) add carbonyldiimidazole (7,99 g, 49,26 mmol). The resulting mixture was then heated at boiling temperature under reflux for 1.5 hours before it is cooled, then washed with saturated aqueous sodium bicarbonate (70 ml) and water (70 ml). The organic layer is dried over magnesium sulfate and concentrated in vacuo.After treatment, the formed precipitate using flash chromatography (Si-SPE, cyclohexane:dichloromethane, gradient 20:80 to 0:100) receive specified in the title compound in the form of solid white (0,53 g, 72%). IHMS (method B): RT= 2,86 min, the ions are absent.

Stage 4: Ethyl ester of 3-amino-7-chlorpro[3,2-c]pyridine-2-carboxylic acid

To a solution of ethylglycol (1,48 ml, 15.7 mmol) in DMF (15 ml) at -10°C add sodium hydride (0,63 g, 15.7 mmol, 60% dispersion in oil). The resulting mixture was stirred at the same temperature for 35 minutes, then cooled to -40°C. a Solution of 3,4-dichloronicotinic (0,906 g of 5.24 mmol) in DMF (5 ml) is added dropwise before leaving the reaction mixture to warm to -15°C for 30 minutes, then to -5°C for 1 hour. The resulting mixture is poured into a mixture of 10:1 water/acetic acid (25 ml), diluted with water (25 ml) and extracted with ethyl acetate (2×30 ml). The aqueous phase is brought to pH 8 with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (2×25 ml). The combined organic layers are dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, ethyl acetate:triethylamine 98:2), receiving specified in the title compound in the form of solid yellow (0,60 g, 48%). IHMS (method B): RT= 2,79 min, M+H+- 241, 243.

Stage 5: Ethyl ester of 7-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridineboronic acid

To a solution of ethyl ester of 3-amino-7-chlorpro[3,2-c]pyridine-2-carboxylic acid (4,16 g, 17.3 mmol) in toluene (100 ml) is added cesium carbonate (11,27 g, 34.6 mmol)and the resulting mixture Tegaserod (argon/vacuum). Add 2-fluoro-4-trimethylsilylethynyl ether triftormetilfullerenov acid (7,1 g of 22.5 mmol), Pd2dba3(395 mg, 0,432 mmol) and Xantphos (0.5 g, 0,865 mmol) and the reactor rinsed with argon. The reaction mixture is heated at the boiling point under reflux for 19 hours, cooled and poured into a saturated aqueous solution of ammoniaand (150 ml). The aqueous layer was extracted with ethyl acetate (3×60 ml), the combined organic layers are dried over magnesium sulfate and concentrate their vacuum .Purify using flash chromatography (Si-SPE, cyclohexane:dichloromethane gradient 1:0 to 0:1), obtaining specified in the title compound in the form of solid pale yellow color (5,13 g, 73%). IHMS (method B): RT= 4,80 min, M+H+= 407, 409.

Step 6: Ethyl ester of 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridineboronic acid

To a solution of ethyl ester of 7-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridineboronic acid (250 mg, of 0.615 mmol) in dichloromethane (25 ml) at 0°C add monochloride iodine (1.23 ml of 1.23 mmol, 1 M solution in dichloromethane) and the resulting solution was stirred at the same temperature for 1 hour. Add a saturated solution of sodium thiosulfate (5 ml)and the resulting mixture was poured into saturated aqueous sodium thiosulfate solution (25 ml). The aqueous layer was extracted with dichloromethane (2×25 ml), the combined organic layers washed with brine, dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, cyclohexane:dichloromethane gradient 1:0 to 0:1), obtaining mentioned in the title compound in the form of a waxy solid yellow (0,22 g, 78%). IHMS (method B): RT= 4,30 min, M+H+= 461, 463.

Ethyl ester of 7-cyano-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridylcarbinol the acid

Stage 1: Ethyl ester of 7-cyano-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridineboronic acid

To a solution of ethyl ester of 7-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridineboronic acid (0.64 g, 1.57 mmol) in DMF (15 ml) is added cyanide zinc (II) (0,22 g, 12,63 mmol)and the resulting mixture Tegaserod (argon/vacuum). Then add Pd2dba3(72 mg, 0,079 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,l'-biphenyl (S-Phos, 65 mg, 0,158 mmol), and the reactor rinsed with argon, closed and then heated to 150°C under microwave irradiation for 30 minutes. The reaction mixture is cooled, the volatiles are removed, and carry out azeotropic distillation of the residue with toluene (3×15 ml). Purify the resulting residue using flash chromatography (Si-SPE, cyclohexane:dichloromethane gradient 1:0 to 0:1 then 10% ethyl acetate in dichloromethane)to give specified in the title compound in the form of solid pale yellow ones (0.46 g, 74%). IHMS (method B): RT= to 4.52 min, M+H+= 398.

Step 2: Ethyl ester of 7-cyano-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridineboronic acid

To a solution of ethyl ester of 7-cyano-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridineboronic acid and 0.46 g of 1.16 mmol) in dichloromethane (40 ml) at 0°C add monochloride iodine (2,32 m is, 2.32 mmol, 1 M solution in dichloromethane)and the resulting mixture is stirred at the same temperature for 30 minutes. Add a saturated solution of sodium thiosulfate (5 ml)and the resulting mixture is poured into saturated sodium thiosulfate solution (35 ml). The aqueous layer was extracted with dichloromethane (2×25 ml)and the combined organic layers washed with brine, dried over magnesium sulfate, and then concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:ethyl acetate gradient of 10:0 to 10:1), obtaining mentioned in the title compound in the form of a waxy solid yellow (0.36 g, 69%). IHMS (method B): RT= 4,10 min, M+H+= 452.

Ethyl ester of 3-(2-fluoro-4-triisopropylbenzenesulfonyl)furo[3,2-]pyridine-2-carboxylic acid

Stage 1: (4-bromo-3-forbindelse)triisopropylsilane

To a solution of (4-bromo-3-forfinal)methanol (410 mg, 2.0 mmol) and imidazole (163 mg, 2.4 mmol) in DMF (10 ml) add triisopropylsilane (0,472 ml, 2.2 mmol). The reaction mixture was stirred at room temperature for 18 hours and then separated between ethyl acetate and water. The organic layer emit, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo The resulting residue is purified using flash chromatography (Si-SPE, pentane), getting mentioned in the title compound as a colourless oil (643 mg, 89%).1H NMR (CDCl3, 400 MHz) of 7.48 (DD, J=8,1, 7,0 Hz, 1H), 7,16 (d, J=9.7 Hz, 1H), 6,99 (d, J=8.7 Hz, 1H), 4,78 (s, 2H), 1.04 million-1,24 (m, 21H).

Step 2: Ethyl ester of 3-(2-fluoro-4-triisopropylbenzenesulfonyl)furo[3,2-c]pyridine-2-carboxylic acid

Degassed solution of ethyl ester of 3-minotoro[3,2-c]pyridine-2-carboxylic acid (206 g, 1.0 mmol), (4-bromo-3-forbindelse)triisopropylsilane (433 mg, 1.2 mmol), Pd2dba3(36 mg, 0,039 mmol), Xantphos (46 mg, 0.08 mmol) and K3PO4(297 mg, 1.4 mmol) in toluene (1 ml) is heated to 110°C, then stirred for 4 hours. The reaction mixture is cooled to room temperature, then diluted with EtOAc and filtered through a layer of celite. The obtained filtrate was concentrated in vacuo to obtain the oil black. The oil obtained is purified using flash chromatography (Si-SPE, MeOH: DCM, gradient 0:100 to 5:95), getting mentioned in the title compound as yellow oil (166 mg, 34%). IHMS (method B): RT= 5,39 min, M+H+= 487.

Ethyl ester of 3-(2-fluoro-4-methoxybenzylamine)furo[3,2-C]pyridine-2-carboxylic acid

Stage 1: 1-bromo-2-fluoro-4-methoxybenzoyl

To a solution of 4-bromo-3-forfe the ol (500 mg, 2,62 mmol) in anhydrous THF (10 ml) was added in several portions sodium hydride (60% dispersion in mineral oil, 115 mg, is 2.88 mmol). The reaction mixture is stirred for 20 minutes before add iodomethane (0,500 ml, 8.0 mmol). The resulting mixture was stirred at room temperature for 16 hours before divide between EtOAc and water. The organic layer emit, washed with saturated sodium bicarbonate solution then brine, dried (Na2SO4), filtered and concentrated to obtain specified in the connection header in the form of oil, pale yellow (518 mg, 96%).1H NMR (CDCl3, 400 MHz) 7,41 (DD, J=8,8, 8.0 Hz, 1H), 6,69 (DD, J=10,3, 2.8 Hz, 1H), is 6.61 (DDD, J=8,8, 2,8, 1.0 Hz, 1H), 3,79 (s, 3H).

Step 2: Ethyl ester of 3-(2-fluoro-4-methoxybenzylamine)furo[3,2-C]pyridine-2-carboxylic acid

Degassed solution of ethyl ester of 3-minotoro[3,2-c]pyridine-2-carboxylic acid (206 g, 1.0 mmol), 1-bromo-2-fluoro-4-methoxybenzene (246 mg, 1.2 mmol), Pd2dba3(46 mg, 0,050 mmol), Xantphos (58 mg, 0.10 mmol) and K3PO4(254 mg, 1.2 mmol) in toluene (5 ml) is heated to 110°C, then stirred for 18 hours. The reaction mixture is cooled to room temperature, then diluted with EtOAc and filtered through a layer of celite. The obtained filtrate was concentrated in vacuo to obtain the oil black. The oil obtained is purified using flash XP is matography (Si-SPE, MeOH:DCM, gradient 0:100 to 10:90), getting mentioned in the title compound as yellow oil (130 mg, 39%). IHMS (method B): RT= 2,93 min, M+H+= 331.

Ethyl 3-(4-bromo-2,5-dipertanyakan)furo[3,2-C]pyridine-2-carboxylate

Degassed solution of ethyl 3-tripterocalyx)furo[3,2-c]pyridine-2-carboxylate (678 mg, 2.00 mmol), 4-bromo-2,5-diferencia (670 mg, up 3.22 mmol), Pd2dba3(147 mg, 0,160 mmol), Xantphos (97,0 mg, has 0.168 mmol) and finely ground powder K3PO4(793 mg, 3,74 mmol) in toluene (7.5 ml) is heated in a sealed ampoule at 105°C during the night. The reaction mixture is cooled to room temperature, then diluted with ethyl acetate (15 ml) and filtered through a layer of silica gel (15 ml ethyl ether). After washing of filter cakes with additional ethyl acetate (20 ml), the obtained filtrate is dried over magnesium sulfate and concentrated in vacuo to obtain a brown oil. The residue is purified using flash chromatography (silica gel, using a 5:3:2 hexane-methylene chloride-ethyl ether)to obtain specified in the connection header in the form of a solid yellow-brown (329 mg, 41%).

Uhtilby ester 3-(2-fluoro-4-iodophenoxy)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: Ethyl ester of 3-(2-fluoro-4-NITR is phenoxy)furo[3,2-c]pyridine-2-carboxylic acid

Ethyl 3-hydroxyfuran[3,2-c]pyridine-2-carboxylate (2.70 g, 13,0 mmol), then 3,4-diplomarbeit (2,89 ml of 26.1 mmol)and 18-crown-6 (3,45 g, 13,0 mmol) are added to a suspension of potassium hydride (1.10 g, a 27.4 mmol) in DMF (30 ml) at room temperature. The reaction mixture is heated at 100°C for 2 hours, then cooled to room temperature and poured into a mixture of water/salt solution. The aqueous layer was extracted 3 times with EtOAc, then the combined organic layers washed with brine, dried over Na2SO4and concentrate. The residue is purified on a chromatographic column with silica gel (30-80% EtOAc:Hex) to obtain specified in the title compound (442 mg, 10% yield) as yellow syrup. IHMS (method C): RT= 2,07 min, M+H+= 347.1H NMR (CDCl3, 400 MHz) 8,83 (d, J=1.2 Hz, 1H), 8,72 (d, J=6.0 Hz, 1H), 8,17 (DD, J=10,0, 2.4 Hz, 1H), 8,03 (DDD, J=9,2, is 2.8, and 1.6 Hz, 1H), to 7.59 (DD, J=5,6, and 0.8 Hz, 1H), was 7.08 (DD, J=9,2, 8.0 Hz, 1H), 4,36 (sq, J=7.2 Hz, 2H), 1.28 (in t, J=7.2 Hz, 3H).

Step 2: Ethyl ester of 3-(4-amino-2-pertenece)furo[3,2-C]pyridine-2-carboxylic acid

Powder Fe (299 mg, are 5.36 mmol) are added to a solution of ethyl ester of 3-(2-fluoro-4-nitrophenoxy)furo[3,2-c]pyridine-2-carboxylic acid (460 mg, 1.3 mmol) in ethanol (8 ml) and 2 n aqueous HCl (8 ml). The reaction mixture is heated to 50°C, then cooled to room temperature. Neprotahoval is her iron is removed with a magnet, then the reaction mixture was concentrated in vacuo. Add 10 ml of water and 10 ml of ethanol, then solid sodium bicarbonate (1.5 g). Add 3.2 g of silica gel and the volatiles removed in vacuum. The residue is purified on a chromatographic column with silica gel (40-80% EtOAc:Hex) to obtain specified in the title compound (130 mg, 31% yield) in the form of foam is not quite white. IHMS (method C): RT= 1,35 min, M+H+= 317.1H NMR (CDCl3, 400 MHz) 8,54 (d, J=3.6 Hz, 1H), 8,16 (d, J=0.8 Hz, 1H), 7,45 (DD, J=5,6, and 0.8 Hz, 1H), to 7.09 (t, J=8,8 Hz, 1H), 6,53 (DD, J=12,4, 2.8 Hz, 1H), 6,44 (DDD, J=8,8, is 2.8, and 1.6 Hz, 1H), 4,47 (sq, J=7.2 Hz, 2H), 3,81 (user., 2H), 1,42 (t, J=7.2 Hz, 3H).

Step 3: Ethyl ester of 3-(2-fluoro-4-iodophenoxy)furo[3,2-c]pyridine-2-carboxylic acid

Sodium nitrite (1,18 ml, 0,382 M aqueous solution) is added dropwise to a suspension of ethyl ester of 3-(4-amino-2-pertenece)furo[3,2-c]pyridine-2-carboxylic acid (130 mg, 0.41 mmol) in 2 M aqueous HCl solution (3.5 ml) at 0°C. the Reaction mixture is stirred for 45 minutes at 0°C, and then add sodium iodide (1,18 ml, 1,39 M aqueous solution of 1.64 mmol). The reaction mixture was stirred over night at 0°C to room temperature. Add sodium hydroxide (7 ml, aqueous solution) and Na2S2C3(5 ml saturated aqueous solution)and the aqueous layer was extracted three times CH2Cl2. The combined organic layers dried over Na2SO4, filtered and conc is the shape. The residue is purified on a chromatographic column with silica gel (30-70% EtOAc:Hex) to obtain specified in the title compound (60 mg, 30% yield) as a solid white color. IHMS (method C): RT= to 2.29 min, M+H+= 428.1H NMR (CDCl3, 400 MHz) 8,63 (d, J=6,4 Hz, 1H), 8,53 (d, J=1.2 Hz, 1H), 7,58 (DD, J=a 9.6, 2.0 Hz, 1H), 7,52 (DD, J=6,0, 1.2 Hz, 1H), 7,37 (dt, J=8,8, and 1.6 Hz, 1H), 6,86 (t, J=8,4 Hz, 1H), to 4.41 (sq, J=7.2 Hz, 2H), of 1.34 (t, J=7.2 Hz, 3H).

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

Stage 1: 4,5-debromination acid

5-Bromonicotinic acid (25,25 g, 125 mmol) was stirred as a solution in dry tetrahydrofuran (500 ml) under nitrogen atmosphere and cooled to -70°C. the resulting mixture is added dropwise within 1 hour sitedisability (1.8 M), 144 ml, 260 mmol). After complete addition, the resulting solution was stirred for 2.5 hours at - 55°C, then cooled to -70°C and treated in portions over 30 minutes, 1,2-dibromotetrachloroethane (50 g, 154,5 mmol). After stirring for 30 minutes the resulting mixture is left to warm to -20°C within 2 hours before carefully adding water (150 ml). The organic solvent is then removed in vacuo, and the residue diluted with water (500 ml), then washed with ethyl acetate before acidifying the aqueous layer to pH3,00 concentrated HCl. The precipitate is collected by filtration and dried at 60°C in vacuum to obtain specified in the title compound (14.2 g). The obtained filtrate is extracted with ethyl acetate, the extract washed with water, dried (MgSO4), filtered and concentrated in vacuo to obtain specified in the title compound (18.6 g, total yield 32,8 g, 93%).1H NMR (DMSO-d6, 400 MHz) of 8.92 (s, 1H), 8,73 (s, 1H).

Step 2: Ethyl ester of 4,5-debromination acid

4,5-debromination acid (32,8 g of 116.7 mmol) was stirred as a suspension in acetonitrile (550 ml) at room temperature and treated with portions of 1,1'-carbonyldiimidazole (29,87 g, 180 mmol) for 10 minutes. The resulting mixture is stirred for 3 hours at room temperature. After 3 hours, add ethanol (78 ml), and stirring is continued for another 48 hours. The resulting solution was then filtered and the resulting filtrate is evaporated in vacuum to obtain a brown oil. The oil obtained is dissolved in ethyl acetate, and the resulting solution was washed with water, then brine and then dried over magnesium sulfate, filtered and evaporated in vacuum to obtain a brown oil. The oil obtained is purified using flash chromatography (SiO2eluent dichloromethane)to obtain specified in the title compound (20.6 g, 57 %).1H YAM WHO (CDC1 3, 400 MHz) 8,80 (s, 1H), up 8.75 (s, 1H), of 4.45 (q, 2H, J=7,0 Hz)of 1.39 (t, 3H, J= 7,0 Hz).

Step 3: Ethyl ester of 7-bromo-3-hydroxyfuran[3,2-c]pyridine-2-carboxylic acid

The solution ethylglycol (6.30 ml, with 66.5 mmol) in dry DMF (50 ml) is added dropwise to a stirred suspension of sodium hydride (8.00 g, 60% dispersion, 200 mmol) in dry DMF (80 ml), cooled to maintain the temperature below 10°C. After the addition the mixture is stirred for 30 minutes before added dropwise ethyl ester of 4,5-debromination acid (20,60 g, with 66.5 mmol) in solution in dry DMF (50 ml), again while maintaining the temperature below 10°C. the Obtained dark red/brown solution was left to slowly warm to room temperature over 1.5 hours before quenched and acidified to pH 3.00 and an aqueous solution of 1 M HCl. Resulting solid precipitate is collected by filtration, the residue is washed with water, then with cold acetone and dried in vacuum at 45°C to obtain specified in the connection header (11,98 g, 63%).1H NMR (DMSO-d6, 400 MHz) 9,13 (s, 1H), 8,76 (s, 1H), 4,35 (square, 2H, J=7,3 Hz)of 1.33 (t, 3H, J=7,3 Hz). IHMS (method B): Rx= 2,82 min, M+H+= 286, 288.

Stage 4: Ethyl ester of 7-bromo-3-triftoratsetilatsetonom|3,2-c]pyridine-2-carboxylic acid

Triftormetilfullerenov the initial anhydride (8,32 ml, 49,66 mmol) in dry DCM (70 ml) is added dropwise to a stirred solution of the ethyl ester of 7-bromo-3-hydroxyfuran[3,2-c]pyridine-2-carboxylic acid (12,80 g of 44.7 mmol) and pyridine (10,88 ml, 128 mmol) in dry DCM (400 ml) at 5-10°C. the resulting mixture was stirred for 1.5 hours at 5-10°C, and then left to slowly warm to room temperature for 3 hours before being left to stand for 16 hours. The resulting mixture was diluted with DCM, washed with 1 M aqueous HCl, water, saturated aqueous NaHCO3and a salt solution before dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the oil light brown color. The oil obtained is purified using flash chromatography (SiO2, dichloromethane)to obtain specified in the connection header in a solid yellow color (11,84 g, 63%).1H NMR (CDCl3, 400 MHz) 8,96 (s, 1H), 8,83 (s, 1H), 4,55 (square, 2H, J=7,2 Hz), 1,47 (t, 3H, J=7.2 Hz).

Stage 5: Ethyl ester of 7-bromo-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2-carboxylic acid

Ethyl ester of 7-bromo-3-triftoratsetilatsetonom[3,2-c]pyridine-2-carboxylic acid (11,84 g, 28.3 mmol) stirred in dry toluene (160 ml) with Pd2(dba)3(1.0 g, 1.20 mmol), Xantphos (0,572 g, 1.0 mmol) and trehosnovnoy potassium phosphate (11,25 g, 53,75 mmol). The MCA is ü Tegaserod before how add a solution of 2-fluoro-4-trimethylsilylmethylamine (5,38 g, 29,54 mmol) in dry toluene (10 ml). The resulting mixture was again Tegaserod before heated at 115°C for 4 hours. The reaction mixture was separated between ethyl acetate and water, then filtered and the resulting layers emit. The organic layer is washed with water, then brine, dried over magnesium sulfate, filtered and evaporated in vacuo to obtain a solid brown color. The solid product was then purified using flash chromatography (SiO2, 30% cyclohexane in DCM)to obtain specified in the connection header in the form of a solid pale yellow color (7,1 g, 55%).1H NMR (CDCl3, 400 MHz) 8,66 (s, 1H), and 8.50 (s, 1H), 7,73 (s, 1H), 7,27 (m, 3H), 4,50 (square, 2H, J=7,0 Hz)of 1.47 (t, 3H, J=7,0 Hz)to 0.29 (s, 9H). IHMS (method B): R, = 4,81 min, M+H+= 451,453.

Step 6: Ethyl ester of 3-(2-fluoro-4-trimethylsilylmethylamine)-7-phenylfuro[3,2-c]pyridine-2-carboxylic acid

Ethyl ester of 7-bromo-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2-carboxylic acid (100 mg, 0.22 mmol) is stirred suspension at room temperature in ethanol (2 ml) with phenylboronic acid (30 mg, 0,242 mmol) in argon atmosphere. After stirring for 20 minutes, add Pd(OAc)2(2 mg, 0.66 mmol), triphenylphosphine (0.5 mg, 0.002 mmol) and 2 M aqueous Na2CO32, 30% cyclohexane in DCM) to obtain specified in the connection header in the form of a solid pale yellow color (31 mg, 31%).1H NMR (CDCl3, 400 MHz) 8,73 (s, 1H), 8,61 (s, 1H), 7,87 (d, 2H, J=7,80 Hz), 7,72 (s, 1H), to 7.59-7,44 (m, 3H), 7,35-7,25 (m, 3H), 4,33 (square, 2H, J=7,0 Hz) was 1.43 (t, 3H, J=7,0 Hz) of 0.30 (s, 9H). IHMS (method B): Rx= 4,91 min, M+H+= 449.

Step 7: Ethyl ester of 3-(2-fluoro-4-iodoaniline)-7-phenylfuro[3,2-c]pyridine-2-carboxylic acid

Ethyl ester of 3-(2-fluoro-4-trimethylsilylmethylamine)-7-phenylfuro[3,2-c]pyridine-2-carboxylic acid (30 mg, 0,067 mmol) is stirred in a solution of DCM (2 ml) at 0-5°C and added dropwise 1 M ICl in DCM (130 μl, 0.13 mmol). The resulting mixture was stirred at 0-5°C for 2 hours before was added 1 M aqueous solution of Na2S2O3(1 ml). The resulting layers are separated and the organic layer washed with water, then salt RAS is a thief, dried over magnesium sulfate, filtered and evaporated in vacuo to obtain specified in the title compound (quantitative).1H NMR (CDCl3, 400 MHz) of 8.75 (s, 1H), 8,58 (s, 1H), 7,87 (d, 2H, J=7,80 Hz), to 7.67 (s, 1H), to 7.59-7,44 (m, 5H), 7,05 (t, 1H, J=8,50 Hz), 4,47 (square, 2H, J=7,10 Hz), USD 1.43 (t, 3H, J=7,10 Hz). IHMS (method B): RT= 4,40 min, M+H+= 503.

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

Stage 1: Ethyl ester of 3-(2-fluoro-4-trimethylsilylmethylamine)-7-methylfuran[3,2-c]pyridine-2-carboxylic acid

Ethyl ester of 7-bromo-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2-carboxylic acid (1.0 g, 2.2 mmol) is stirred with potassium carbonate (456,5 mg, 3.3 mmol), tetrahetarenoporphyrazines(0) (255 mg, 0.22 mmol) and trimethylboroxine (305 μl, 2.2 mmol) in dry 1,4-dioxane (5 ml). The reaction mixture Tegaserod before heated at 110°C in argon atmosphere for 6 hours, then cooled to room temperature and left to stand for 16 hours. The reaction mixture was diluted with dichloromethane and water. The organic layer emit, washed with water, then brine, dried over magnesium sulfate, then filtered and evaporated in vacuo to obtain a precipitate. The crude residue purified using flash chromatography (SiO2, 30% qi is logican in DCM, then 1% methanol in DCM)to obtain specified in the connection header in the form of a solid pale yellow color (710 mg, 83%).1H NMR (CDCl3, 400 MHz) and 8.50 (s, 1H), scored 8.38 (s, 1H), of 7.70 (s, 1H), 7,32-7,22 (m, 3H), 4,48 (square, 2H, J=7,0 Hz)to 2.54 (s, 3H ), of 1.46 (t, 3H, J=7,0 Hz)to 0.29 (s, 9H). IHMS (method B): RT= 4,12 min, M+H+= 387.

Step 2: Ethyl ester of 3-(2-fluoro-4-iodoaniline)-7-methylfuran[3,2-C]pyridine-2-carboxylic acid

Ethyl ester of 3-(2-fluoro-4-trimethylsilylmethylamine)-7-methylfuran[3,2-c]pyridine-2-carboxylic acid (710 mg, of 1.84 mmol) is stirred in a solution of DCM (25 ml) at 0-5°C and added dropwise 1 M ICl in DCM (3.5 ml, 3.5 mmol). The resulting mixture was stirred at 0-5°C for 2 hours before was added 1 M aqueous Na2S2O3(12 ml). The resulting layers separated, and the organic layer washed with water, brine, then dried over magnesium sulfate, filtered and evaporated in vacuo to obtain a precipitate. The crude residue purified using flash chromatography (SiO2gradient of 0-1% MeOH in DCM) to obtain specified in the connection header in the form of a solid pale yellow color (448 mg, 55%).1H NMR (CDCl3, 400 MHz) of 8.47 (s, 1H), 8,39 (s, 1H), 7,65 (s, 1H), 7,52 (DD, 1H, J=9,8, 1.9 Hz), 7,44 (dt, 1H, J=8,4, 1.3 Hz), 7,00 (t, 1H, J=8.5 Hz), 4,48 (square, 2H, J=7.0 Hz), 2,53 (s, 3H), of 1.46 (t, 3H, J=7.0 Hz). IHMS (method B): RT= 3,39 min, M+H+= 441.

Ethyl ester of 2-((R)-2,2-dimethyl[1,3]dioxolane-4-and methoxycarbonyl)-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-7-carboxylic acid

Stage 1: 7-ethyl ester of 2-benzyl ester 3-hydroxyfuran[3,2-c]pyridine-2,7-dicarboxylic acid

To a solution of diethyl ether 4-chloropyridin-3,5-dicarboxylic acid (250 mg, 0,971 mmol) and benzylglycine (145 μl, 1,019 mmol) in DMF (5 ml) at 0°C, add sodium hydride (97 mg, 2,43 mmol, 60% dispersion in mineral oil). The resulting mixture was left to warm to room temperature and stirred for 3 hours, then quenched by adding acetic acid (1 ml). The resulting mixture was then concentrated in vacuo and the resulting residue triturated with water and filtered. The obtained solid product is recrystallized from methanol/water to obtain specified in the connection header in the form of a solid pale yellow color (120 mg, 36%). IHMS (method B): RT= 3,29 min, M+H+= 342.

Stage 2: 7-ethyl ester of 2-benzyl ester 3-triftoratsetilatsetonom[3,2-c]pyridine-2,7-dicarboxylic acid

To a solution of 7-ethyl ether of 2-benzyl ester 3-hydroxyfuran[3,2-c]pyridine-2,7-dicarboxylic acid (120 mg, 0,352 mmol) and pyridine (85 μl, 1,056 mmol) in dichloromethane (1.5 ml) at 0°C is added dropwise triftormetilfullerenov anhydride (63 μl, of 0.37 mmol). The reaction mixture was stirred at room temperature is PE within 90 minutes then divide between dichlormethane (30 ml) and 0.1 M HCl (10 ml). The organic layer is isolated and washed with saturated sodium bicarbonate solution (10 ml), then brine (10 ml). Selected organic layer is dried over magnesium sulfate before being concentrated in vacuo to obtain specified in the title compound as a colourless oil (88 mg, 53%).1H NMR (CDCl3, 400 MHz) 9,27 (1H, s), 9,17 (1H, s)of 7.48 (2H, m), 7,38 (3H, m), of 5.48 (2H, s)to 4.52 (2H, square, J=7,2 Hz), USD 1.43 (3H, t, J=7.2 Hz).

Stage 3: 7 ethyl ester 2-benzyl ester 3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2,7-dicarboxylic acid

To a solution of 7-ethyl ether of 2-benzyl ester 3-triftoratsetilatsetonom[3,2-c]pyridine-2,7-dicarboxylic acid (88 mg, 0,186 mmol) and 2-fluoro-4-trimethylsilylmethylamine (41 mg, 0,223 mmol) in toluene (1.5 ml) is added potassium phosphate (55 mg, 0.26 mmol) before the mixture Tegaserod. To the obtained mixture is added Pd2dba3(8.5 mg, 0,0093 mmol) and Xantphos (11 mg, 0,0186 mmol) and the reactor rinsed with argon. The reaction mixture is heated at the boiling point under reflux for 1.5 hours, cooled, filtered through celite®, washed with ethyl acetate. The obtained filtrate was washed with saturated aqueous sodium bicarbonate (10 ml), then dried over magnesium sulfate, concentri the comfort in vacuum. Purify the resulting residue using flash chromatography (Si-SPE, cyclohexane:tert-butyl methyl ether, gradient 1:0 to 3:1), obtaining mentioned in the title compound in the form of a solid yellow (48 mg, 51%). IHMS (method B): RT= 4,89 min, M+H+= 507.

Stage 4: 7-ethyl ester 3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2,7-dicarboxylic acid

To a solution of 7-ethyl ether of 2-benzyl ester 3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2,7-dicarboxylic acid (48 mg, 0,0949 mmol) in ethyl acetate (2 ml) under nitrogen atmosphere, add palladium-on-coal (12 mg, 10% palladium on charcoal). The resulting suspension is stirred at room temperature for 2 hours in hydrogen atmosphere. The reaction mixture was filtered through celite®, washed with ethyl acetate, and the obtained filtrate was concentrated in vacuo to obtain specified in the title compound as a colourless oil (34 mg, 86%). IHMS (method B): RT= or 4.31 min, M+H+= 417, [M-H]-= 415.

Stage 5: Ethyl ester of 2-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethoxycarbonyl)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-7-carboxylic acid

To a solution of ethyl ester of 2-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethoxycarbonyl)-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-7-carboxylic acid (37 mg, 0068 mmol) in dichloromethane (2 ml) at -5°C add monochloride iodine (136 μl, 0,136 mmol, 1 M solution in dichloromethane) and the resulting solution was stirred at the same temperature for 1 hour. Add a saturated solution of sodium thiosulfate (5 ml)and the resulting mixture is then poured into a saturated solution of sodium thiosulfate (15 ml). The aqueous layer was isolated and extracted with dichloromethane (2×25 ml) before the combined organic layers washed with brine, dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:ethyl acetate, gradient 1:0 to 0:1 then 15% methanol in dichloromethane)to give specified in the title compound in the form of a waxy solid yellow (29 mg, 71%). IHMS (method B): RT= 3,92 min, M+H+= 600.

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

Stage 1: Ethyl ester of 2-dimethylcarbamoyl-3-hydroxyfuran[3,2-c]pyridine-7-carboxylic acid

To a solution of diethyl ether 4-chloropyridin-3,5-dicarboxylic acid (430 mg, 1,67 mmol) and 2-hydroxy-N,N-dimethylacetamide (189 mg, of 1.84 mmol) in DMF (7 ml) at 0°C. add sodium hydride (200 mg, 5,01 mmol, 60% dispersion in mineral oil). The resulting mixture was left to warm to room temperature, and displacement is more for 2.5 hours. The reaction mixture was quenched by adding acetic acid (1 ml). The resulting mixture was then concentrated in vacuo and the resulting residue triturated with water and filtered to obtain specified in the connection header in the form of a solid pale yellow color (200 mg, 43%). IHMS (method B): RT= 2,73 min, M+H+= 279.

Step 2: Ethyl ester of 2-dimethylcarbamoyl-3-triftoratsetilatsetonom[3,2-c]pyridine-7-carboxylic acid

To a solution of ethyl ester of 2-dimethylcarbamoyl-3-hydroxyfuran[3,2-c]pyridine-7-carboxylic acid (440 mg, was 1.58 mmol) and pyridine (0,38 ml, 4,74 mmol) in dichloromethane (7 ml) at 0°C add triftormetilfullerenov anhydride (0,29 ml of 1.74 mmol) dropwise. The reaction mixture was stirred at room temperature for 120 minutes, then divide between dichloromethane (50 ml) and 0.1 M HCl (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (20 ml), then brine (20 ml). The combined organic layers are dried over magnesium sulfate before concentrating in vacuo to obtain specified in the title compound as a colourless oil (144 mg, 22%). IHMS (method B): RT= 3,39 min, M+H+= 411.

Step 3: Ethyl ester of 2-dimethylcarbamoyl-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-7-carboxylic acid

To restorational ether 2-dimethylcarbamoyl-3-triftoratsetilatsetonom[3,2-c]pyridine-7-carboxylic acid (144 mg, 0.351 mmol) and 2-fluoro-4-trimethylsilylmethylamine (90 mg, 0,492 mmol) in toluene (3 ml) is added potassium phosphate (149 mg, 0.70 mmol) before the mixture Tegaserod. To the reaction mixture add Pd2dba3(16.1 mg, 0,0176 mmol) and Xantphos (20 mg, 0.035 mmol) and the reactor rinsed with argon. The reaction mixture was then heated at boiling temperature under reflux for 3 hours, cooled and filtered through Hyflo, washed with ethyl acetate. The obtained filtrate was washed with saturated sodium bicarbonate solution (30 ml), the organic layer is dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, cyclohexane:tert-butyl methyl ether, gradient 3:1 to 1:1), obtaining specified in the title compound in the form of solid pale yellow color (84 mg, 54%). IHMS (method B): RT= 4,58 min, M+H+= 444.

Ethyl ester of 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

Stage 1: Ethyl ether 4-chloro-5-fornicating acid

A suspension of 4-chloro-5-fornicating acid (0.36 g, of 2.06 mmol) in thionyl chloride (3 ml) is heated at 80°C for 2 hours until, until you dissolve a large part of the solid product. The reaction mixture was concentrated in vacuo, and the implementation is given in the azeotropic distillation of the residue with toluene (2×20 ml). The precipitate is dissolved in ethanol (5 ml) and diisopropylethylamine (1,76 ml, 10,31 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and washed with 0.1 M HCl, then saturated sodium bicarbonate solution and saline. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:ethyl acetate, gradient 1:0 to 92:8), receiving specified in the title compound as a colourless oil (415 mg, 99%).1H NMR (CDCl3, 400 MHz) of 1.43 (3H, t, J=7,1 Hz), 4,46 (2H, square, J=7,1 Hz), at 8.60 (1H, d, J=0.8 Hz), 8,86 (1H, s).

Step 2: Ethyl ester of 7-fluoro-3-hydroxyfuran[3,2-C]pyridine-2-carboxylic acid

To a solution of ethyl ester of 4-chloro-5-fluoro-nicotinic acid (400 mg, 1,975 mmol) and ethylglycol (196 μl, 2,074 mmol) in DMF (10 ml) at 0°C, add sodium hydride (158 mg, 3.95 mmol, 60% dispersion in mineral oil)and the resulting mixture left to warm to room temperature, then stirred for 2 hours. The reaction mixture was quenched by adding acetic acid (1.5 ml). The resulting mixture was then concentrated in vacuo and the resulting residue triturated with water to obtain specified in the header is connected to the I in the form of a solid pale yellow color (460 mg, quantitatively). IHMS (method B): RT= 2,59 min, M+H+= 226.

Step 3: Ethyl ester of 7-fluoro-3-triftoratsetilatsetonom[3,2-C]pyridine-2-carboxylic acid

To a solution of ethyl ester of 7-fluoro-3-hydroxyfuran[3,2-c]pyridine-2-carboxylic acid (460 mg, 1.97 mmol) and pyridine (of 0.48 ml, 5,91 mmol) in dichloromethane (10 ml) at 0°C is added dropwise triftormetilfullerenov anhydride (612 mg, 2,17 mmol). The reaction mixture was stirred at room temperature for 90 minutes, then divide between dichloromethane (50 ml) and 0.1 M HCl (20 ml). The organic layer is isolated and washed with saturated sodium bicarbonate solution (20 ml), then brine (20 ml). The combined organic layers are dried over magnesium sulfate before concentrating in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane), getting mentioned in the title compound as a colourless oil (470 mg, 67%). IHMS (method B): RT= 3,76 min, M+H+= 358.

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

To a solution of ethyl ester of 7-fluoro-3-triftoratsetilatsetonom[3,2-c]pyridine-2-carboxylic acid (470 mg, 1,32 mmol) and 2-fluoro-4-trimethylsilylmethylamine (337 mg, of 1.84 mmol) in toluene (15 ml)is added potassium phosphate (558 mg, 2,63 mmol)and the resulting mixture Tegaserod. To the reaction mixture add Pd2dba3(of 60.5 mg, of 0.066 mmol) and Xantphos (76,5 mg, 0,132 mmol) and the reactor rinsed with argon. The reaction mixture is heated at the boiling point under reflux for 4 hours, cooled and filtered through Hyflo, washing with ethyl acetate. The obtained filtrate was washed with saturated sodium bicarbonate solution, the organic layer is dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:ethyl acetate gradient 1:0 to 9:1), obtaining specified in the title compound in the form of solid pale yellow color (490 mg, 95%). IHMS (method B): RT= 4,70 min, M+H+= 391.

Stage 5: Ethyl ester of 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 7-fluoro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2-carboxylic acid (490 mg, 1,256 mmol) in dichloromethane (8 ml) at -10°C add monochloride iodine (of 2.51 ml, 2.51 mmol, 1 M solution in dichloromethane) and the resulting solution is stirred at a temperature between -10°C and 0°C for 2 hours. Add a saturated solution of sodium thiosulfate (5 ml)and the resulting mixture is then poured into a saturated solution of sodium thiosulfate (15 ml). The aqueous layer was allocated, then extracted with dichloromethane (3×25 ml before as the combined organic layers washed with brine, dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, cyclohexane:ethyl acetate gradient 1:0 to 3:1 and then dichloromethane)to give crude material. The crude material is triturated with cyclohexane to obtain specified in the connection header in the form of a waxy solid yellow (250 mg, 45%). IHMS (method B): RT= 4,13 min, M+H+= 445.

Ethyl ester of 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridineboronic acid

Stage 1: the oxime of 4-chloro-5-herperidin-3-carbaldehyde

To a cooled (-78°C) solution of 3-fluoro-4-chloropyridine (11,0 g, 84 mmol) in THF in an atmosphere of nitrogen was added dropwise sitedisability (1.8 M solution (47 ml, 84 mmol)and the resulting solution is stirred at a temperature of from -70 to -80°C for 18 hours. Added dropwise DMF (of 7.68 g, 1.25 EQ.) and stirring is continued at -78°C for 30 minutes before maintain the reaction mixture in a mixture of ice/2 M HCl. The resulting solution was extracted with ethyl ether and the organic layer is subjected to back extraction using 2 M HCl, two water solution should be stored separately. Each aqueous extract is treated with the hydrochloride hydroxyl is on (8,76 g, 126 mmol) and adjusted to pH 5 using potassium carbonate. After stirring for 1 hour the mixture is extracted with ethyl acetate (×2), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to obtain specified in the connection header in the form of a solid yellow-brown (11,07 g, 76%). IHMS (method B): RT= 2,49 min, M+H+175.

Stage 2: 4-chloro-5-fornicationis

To a suspension of the oxime of 4-chloro-5-herperidin-3-carbaldehyde (6.8 g, 39,0 mmol) in dichloromethane (150 ml) add carbonyldiimidazole (9.5 g, 58,5 mmol). The resulting mixture is then heated at the boil under reflux for 30 minutes, then cooled to room temperature before washed with saturated aqueous sodium bicarbonate, then with water. The organic layer is dried over sodium sulfate and concentrated in vacuo, then the resulting residue triturated in a mixture of diethyl ether/cyclohexane to obtain specified in the connection header in a solid yellow color (of 4.05 g, 79%).1H NMR (CDCl3400 MHz) 8,71 (1H, d, J= 0.4 Hz), to 8.70 (1H, s).

Step 3: Ethyl ester of 3-amino-7-torture[3,2-C]pyridine-2-carboxylic acid

4-chloro-5-fornicationis (4.0 g, 25.6 mmol) was dissolved in DMF (50 is l) and treated with potassium carbonate (17.8 g, 128 mmol), then acylglycerol (of 3.64 ml, 38.4 mmol). The resulting reaction mixture is heated at 80°C for 50 minutes, then cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with water (×2), dried (Na2SO4), filtered and concentrated in vacuo.The obtained solid product is triturated with diethyl ether to obtain specified in the connection header in the form of solid substances not quite white (3.58 g, 63%). IHMS (method B): RT= 2,65 min, M+H+= 225.

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

Degassed solution of ethyl ester of 3-amino-7-torture[3,2-c]pyridine-2-carboxylic acid (2.5 g, 11.1 mmol), 2-fluoro-4-trimethylsilylethynyl ether triftormetilfullerenov acid (4,2 g, 13.3 mmol), Pd2dba3(508 mg, 0,56 mmol), Xantphos (642 mg, 1.12 mmol) and CS2CO3(7.2 g, of 22.2 mmol) in toluene (25 ml) is heated at boiling under reflux for 1 hour. The reaction mixture is cooled to room temperature, then filtered through a layer of celite®, washing with ethyl acetate. The obtained filtrate was concentrated in vacuo, and the resulting residue purified using flash chromatography (Si-SPE, gradient 0-30% ethyl acetate in cyclohexane)to give the residue Krasnoarmiisk color. The residue is triturated with methanol to obtain specified in the connection header in the form of a solid yellow (2.5 g, 58%). IHMS (method B): RT= 4,71 min, M+H+

Stage 5: Ethyl ester of 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridineboronic acid

To a solution of ethyl ester of 7-fluoro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridineboronic acid (2.5 g, 6.4 mmol) in dichloromethane (60 ml) at 0°C add monochloride iodine (2,08 g, 12.8 mmol, solution in dichloromethane) and the resulting solution stirred and left to heat for 45 minutes. The solid precipitate is filtered off, the residue remain, and the obtained filtrate was washed with saturated aqueous sodium thiosulfate, dried (Na2SO4), filtered and concentrated in vacuo to obtain a residue. Remains after filtration and concentration are combined and triturated with diethyl ether to obtain a solid pale yellow-brown (2.58 g, 91%). IHMS (method B): RT= 4,14 min, M+H+= 445.

Uhtilby ether 4-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: Ethyl ester of 2,4-dichloronicotinic acid

To a solution of Diisopropylamine (2.4 ml and 16.9 mmol) in THF (40 ml) at -78°C in an inert atmosphere, to ablaut n-utility a (10.6 ml, of 16.9 mmol, 1,6 M in hexano) and the resulting solution was stirred for 15 minutes at -78°C. is Added dropwise 2,4-dichloropyridine (1.8 ml and 16.9 mmol)and the reaction mixture stirred at -78°C for 2 hours before adding achilleifolia (4,0 ml of 40.4 mmol). The reaction mixture was then stirred at -78°C for 1 hour and then allowed to warm to room temperature. The resulting mixture was then divided between water and ethyl acetate, and the resulting layers emit. The organic layer was washed with saturated sodium bicarbonate solution, then brine, dried over magnesium sulfate, and then concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, pentane:diethyl ether gradient 1:0 to 4:1), obtaining mentioned in the title compound as a colourless oil (1.6 g, 43%).1H NMR (CDCl3, 400 MHz) to 8.34 (1H, d, J=5.4 Hz), 7,33 (1H, d, J=5.4 Hz), 4,49 (2H, square, J=7,1 Hz), USD 1.43 (3H, t, J=7,1 Hz).

Step 2: Ethyl ether 4-chloro-3-hydroxyfuran[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 2,4-dichloronicotinic acid (1.6 g, 7,3 mmol) and ethylglycol (to 0.72 ml, 7.6 mmol) in DMF at 0°C in an inert atmosphere portions add sodium hydride (60% in mineral oil, 584 mg, 14.6 mmol). The reaction mixture was stirred at 0°C for 3 hours, quenched cautiously adding the criminal code of usnow acid (about 5 ml), diluted with water and extracted with ethyl acetate. The organic layer emit, washed with water, then brine, dried over sodium sulfate and concentrated to obtain specified in the connection header in a solid yellow color (1.75 g, 100%). IHMS (method B): RT= 2,99 min, M+H+= 242.

Step 3: Ethyl ether 4-chloro-3-triftoratsetilatsetonom[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl ether 4-chloro-3-hydroxyfuran[3,2-c]pyridine-2-carboxylic acid (1.8 g, 7.5 mmol), N-phenyl-triftoratsetofenona (5.0 g, 14.0 mmol) and diisopropylethylamine (5.5 ml, and 32.3 mmol) in dimethoxyethane (30 ml) was stirred at 90°C for 48 hours, cooled to room temperature and concentrate under reduced pressure. The resulting residue is purified using flash chromatography (Si-SPE, cyclohexane:ethyl acetate, gradient 1:0 to 1:1), to obtain specified in the connection header in the form of a solid pale yellow color (1.06 g, 38%). IHMS (method B): RT= 3,94 min, M+H+= 374.

Stage 4: Ethyl ether 4-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2-carboxylic acid

Degassed solution of ethyl ether 4-chloro-3-triftoratsetilatsetonom[3,2-c]pyridine-2-carboxylic acid (810 mg, 2,17 mmol), 2-fluoro-4-trimethyl what janelforeman (306 mg, to 1.67 mmol), Pd2dba3(31 mg, 0.03 mmol), Xantphos (58 mg, 0.10 mmol) and cesium carbonate (817 mg, of 2.50 mmol) in toluene (17 ml) is heated at boiling under reflux in an argon atmosphere for 16 hours. The reaction mixture was filtered through celite® and concentrated in vacuo.The resulting residue is purified using flash chromatography (Si-SPE, pentane: diethyl ether, gradient 1: 0 to 0:1), to obtain specified in the connection header in the form of a solid white color (558 mg, 82%). IHMS (method B): RT= with 4.64 min, M+H+= 407.

Stage 5: Ethyl ether 4-chloro-3-(2-fluoro-4-iodoaniline)-furo[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 4-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2-carboxylic acid (265 mg, of 0.65 mmol) in dichloromethane (6.5 ml) at 0°C add monochloride iodide (1.3 ml, 1.3 mmol, 1 M solution in dichloromethane)and the resulting solution was stirred at the same temperature for 1 hour. Add a saturated solution of sodium thiosulfate (5 ml) and the resulting mixture was poured into a saturated solution of sodium thiosulfate (25 ml). The aqueous layer was extracted with dichloromethane (2×25 ml), the combined organic layers washed with brine, dried over magnesium sulfate and concentrated in vacuo to obtain specified in the connection header in a solid yellow color (239 mg, 80%). The CMS (method B): R T= 4,22 min, M+H+= 461.

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

Stage 1: Ethyl ester of 3-(2-fluoro-4-trimethylsilylmethylamine)-4-methylfuran[3,2]pyridine-2-carboxylic acid

To a solution of ethyl ester of 4-chloro-3-(2-fluoro-4-trimethylsilylmethylamine)furo[3,2-c]pyridine-2-carboxylic acid (406 mg, 1.0 mmol) in dioxane (5 ml) add trimethylboroxine (of 0.14 ml, 1.0 mmol), tetrakis(triphenylphosphine)palladium (115 mg, 0.1 mmol) and potassium carbonate (207 mg, 1.5 mmol) before the mixture Tegaserod and heated at the boil under reflux for 6 hours. The reaction mixture is cooled to room temperature and filtered through a layer of celite®, which was washed with ethyl acetate. The filtrates are combined and concentrated in vacuo to obtain a residue, which was purified using flash chromatography on silica gel (Si-SPE, pentane:diethyl ether 1:0 to 0:1). Specified in the title compound obtained as oil pale yellow (221 mg, 57%). IHMS (method B): RT= 3,53 min, M+H+= 387.

Step 2: Ethyl ester of 3-(2-fluoro-4-iodoaniline)-4-methylfuran[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 3-(2-fluoro-4-trimethylsilylmethylamine)-4-methylfuran[3,2-C]pyridine-2-carboxylic acid (215 mg, 056 mmol) in dichloromethane (5 ml) at 0°C add monochloride iodide (1.1 ml, 1.1 mmol, 1 M solution in dichloromethane)and the resulting solution was stirred at the same temperature for 1 hour. Add a saturated solution of sodium thiosulfate (5 ml)and the resulting mixture is then poured into a saturated solution of sodium thiosulfate (25 ml). The aqueous layer was extracted with dichloromethane (2×25 ml), the combined organic layers washed with brine, dried over magnesium sulfate and concentrated in vacuo.In the purification of the obtained residue using flash chromatography on silica gel (Si-SPE, cyclohexane:dichloromethane, gradient 1:0 to 0:1)receive specified in the title compound in the form of solid yellow (241 mg, 98%). IHMS (method B): RT= 2,99 min, M+H+= 441.

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

Ethyl ester of 3-triftoratsetilatsetonom[3,2-c]pyridine-2-carboxylic acid (1.26 g, 3,71 mmol) and 2-fluoro-4-methylsulfinylphenyl (816 mg, 5,20 mmol) dissolved in toluene (25 ml) and add Pd2(dba)3(170 mg, 0,19 mmol), then added Xantphos (214 mg, and 0.37 mmol) and trehosnovnoy potassium phosphate (1,57 g, 7,42 mmol). The resulting mixture was thoroughly Tegaserod and rinsed with argon and then stirred in an argon atmosphere at 120°C for 16 hours. After cooling, the mixture is filtered through celite®and then concentrated. In R. the result of purification of the obtained residue, using flash chromatography on silica gel (Si-SPE, ether:pentane, gradient 1:4 to 1:0), get mentioned in the title compound in the form of a solid yellow-corcavado color (770 mg, 60%). IHMS (method B): RT= 3,29 M+H+= 347.

Ethyl ester of 7-Fluoro-3-(2-fluoro-4-methylsulfonylamino)furo[3,2-c]pyridine-2-carboxylic acid

Degassed solution of ethyl ester of 3-amino-7-torture[3,2-c]pyridine-2-carboxylic acid (0.2 g, 0.89 mmol), 1-bromo-2-fluoro-4-methylsulfonylbenzoyl (0.34 g, 1.5 mmol), Pd2dba3level (0.041 g, 0.045 mmol), Xantphos (0,052 g 0,089 mmol) and K3PO4(0,38 g, 1.8 mmol) in toluene (5 ml) is heated at the boil under reflux for 18 hours. The reaction mixture is cooled to room temperature, then filtered through a layer of Hyflo, washing with ethyl acetate. The obtained filtrate was concentrated in vacuo and the resulting residue purified using flash chromatography (Si-SPE, gradient 0-10% ethyl acetate in dichloromethane)to give specified in the title compound in the form of solid yellow (0.18 g, 55%). IHMS (method B): RT= 3,95 min, M+H+= 365.

Ethyl ester of 7-chloro-3-(2-fluoro-4-methylsulfanyl-phenylamino)furo[3,2-C]pyridine-2-carboxylic acid

Degassed solution of ethyl ester of 3-amino-7-chlorpro[3,2-c]pyridine-2-karbonvansty (0.1 g, 0.42 mmol), 1-bromo-2-fluoro-4-methylsulfonylbenzoyl (0.16 g, 0.71 mmol), Pd2dba3(0,019 g 0,021 mmol), Xantphos (0,024 g 0,042 mmol) and K3PO4(0.18 g, 0.83 mmol) in toluene (2.5 ml) is heated at the boil under reflux for 18 hours. The reaction mixture is cooled to room temperature, then filtered through a layer of Hyflo, washing with ethyl acetate. The obtained filtrate was concentrated in vacuo, and the resulting residue purified using flash chromatography (Si-SPE, gradient 0-10% ethyl acetate in dichloromethane)to give specified in the title compound in the form of solid pale yellow color (0,087 g, 54%). IHMS (method B): RT= 4,14 min, M+H+= 379.

The SYNTHESIS of REPRESENTATIVE AMINES AND HYDROXYLAMINES

Hydrochloride cyclopropanemethylamine

Received in accordance with Marquez et al. (2005) Synth. Comm. 35(17):2265-2269.

O-((R)-2,dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine

Obtained according to Bailey et al. (1991) J. Med. Chem. 34(1):57-65.

O-(2-Vinyloxyethyl)hydroxylamine

Received in accordance with WO 0206213.

N-Methyl-O-(2-vinyloxyethyl)hydroxylamine

Formaldehyde (37% wt./weight. in water, 80 μl, 1.0 mmol) are added to a chilled (0°C) solution of O-(2-vinyloxyethyl)hydroxylamine (105 mg, 1,mmol) in ethanol (1 ml). The resulting mixture was stirred for 30 minutes before you add the pair-toluensulfonate pyridinium (250 mg, 1.0 mmol) and cyanoborohydride sodium (70 mg, 1.1 mmol). The resulting suspension allowed to warm to room temperature and stirred for 20 hours. The solvent is evaporated, the residue diluted with ethyl acetate (25 ml) and washed with brine (20 ml), dried (MgSO4), filtered, then evaporated, obtaining the desired product in the form of oil (84 mg, 71%).1H NMR (CDCl3, 400 MHz) 6,44-6,55 (m, 1H), to 4.98 (s, 1H), 4,16-4,24 (m, 1H), 3,98-4,06 (m, 1H), 3,82-of 3.96 (m, 4H), at 2.59 (s, 3H).

4-(tert-Butyldimethylsilyloxy)isoxazolidine

tert-Butyldimethylchlorosilane (0.5 g, is 3.21 mmol) is added to a stirred solution of the hydrochloride isoxazolidine-4-ol (0.40 g, 3,18 mmol) in DMF (3 ml) and the resulting mixture is left under stirring at room temperature for 2.5 hours. The solvent is evaporated and the residue is divided between ethyl acetate (50 ml) and water (20 ml). The organic phase is allocated, washed with water (3×20 ml) then brine (20 ml), dried (MgSO4, filtered and evaporated, obtaining the desired product as colourless oil (0,62 g, 96%).1H NMR (CDCl3, 400 MHz) 5,52 (s, 1H), 4,60 with 4.65 (m, 1H), 3,45-3,62 (m, 1H), 3,80-of 4.05 (m, 1H), 2,80 was 3.05 (m, 2H), 0,80 (s, 9H), and 0.08 (s, 6H).

Tpet-butyl ether (S)-3-aminoantipyrine-1-carboxylic acid

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Step 1: Tert-butyl ether (S)-3-(1,3-dioxo-1,3-dihydroindol-2-yloxy)pyrrolidin-1-carboxylic acid

Tert-butyl ether (R)-3-hydroxypyrrolidine-1-carboxylic acid (1,37 g, 7,31 mmol) dissolved in THF (20 ml), add 2-hidroxizina-1,3-dione (1.19 g, 7,31 mmol) and triphenylphosphine (1.92 g, 7,31 mmol), then added dropwise diisopropylethylamine (1,33 ml of 8.04 mmol) for 10 minutes. The reaction mixture is left under stirring at room temperature for 18 hours, then the solvent is evaporated. The residue is purified using flash chromatography (Si-SPE, DCM:EtOAc, gradient 100:0 to 80:20), receiving specified in the title compound as a colourless oil (1,43 g, 59%).1H NMR (CDCl3, 400 MHz) 7,86 (m, 2H), to 7.77 (m , 2H), 4,94-5,02 (m, 1H), 3,66-a-3.84 (m, 2H), 3,50-the 3.65 (m, 2H), 2,24 of-2.32 (m, 1H), 1.93 and-2,05 (m, 1H), 1,49 (s, 9H).

Step 2: Tert-butyl ether (S)-3-aminoantipyrine-1-carboxylic acid

Methylhydrazine (0,23 ml, 4.40 mmol) is added dropwise over 5 minutes to a solution of tert-butyl methyl ether (S)-3-(1,3-dioxo-1,3-dihydroindol-2-yloxy)pyrrolidin-1-carboxylic acid (1,43 g, 4.3 mmol) in DCM (12 ml). The resulting mixture was stirred at room temperature for 1 hour, then evaporated. The residue is suspended in diethyl ether (10 ml) and the solid product filtered off. The resulting filtercontainer, getting listed in the title compound as a colourless oil (0,86 g, 99%).1H NMR (CDCl3, 400 MHz) are 4.24-4.26 deaths (m, 1H), 3,60-3,66 (m, 1H), 3,44-of 3.54 (m, 1H), 3,30-of 3.42 (m, 2H), 2,03-2,12 (m, 1H), 1,84 is 1.96 (m, 1H), of 1.46 (s, 9H).

Hydrochloride of 2-aminooxy-2-methylpropan-1-ol

Stage 1: Ethyl ester of 2-(N-Boc-aminooxy)somaclonal acid

To a solution of N-Boc-hydroxylamine (5,2 g, 39,05 mmol) in ethanol (100 ml) add potassium hydroxide (2,6294 g, 46,86 mmol) and stirred at room temperature until until the potassium hydroxide is dissolved. Add ethyl ester 2-promisable acid (6,87 ml, 46,86 mmol) and refluxed overnight. After 1 hour, observe the formation of a white precipitate. The reaction mixture is cooled to room temperature and then filtered. The white solid precipitate is removed, and the filtrate concentrated. The obtained oily residue is divided between water (75 ml) and ether (3×100 ml). The combined ether layers are dried over sodium sulfate, filtered and the filtrate concentrated to obtain the heading compound as a clear oil (9,543 g, 99 %). IHMS (method C): RT= 2,55 min, M+H+= 2247,9.1H NMR (CDCl3, 400 MHz) 4,20 (square, 2H), 1,50 (s , 6H), 1,498 (s, 9H), of 1.30 (t, 3H).

Stage 2: 2-(N-Boc-aminooxy)-2-methylpropan-1-ol

It races the thief ethyl ester 2-(N-Boc-aminooxy)somaclonal acid (2.35 g, 9.5 mmol) in anhydrous ethyl ether (100 ml) at 0°C under nitrogen atmosphere add to 1.0 M litererally in tetrahydrofuran (17,106 ml, 17 mmol) and stirred at 0°C under nitrogen atmosphere for 5 hours. Add a few granules of CO2(dry ice), then water (25 ml) at 0°C. the Reaction mixture was then stirred overnight and allowed to warm to room temperature in the process. The ether layers decanted and keep aside. The solid white product is triturated c ether and the resulting ether is combined with the ether layer obtained before. The solid white product is then removed. The combined ether layers are dried over sodium sulfate, filtered and concentrated to obtain specified in the connection header in the form of a solid white color ( 1,94 g, 99.5%pure).1H NMR (CDCl3, 400 MHz) 3,40 (s, 2H), 1,50 (s,9H), of 1.20 (s, 6H).

Stage 3: Hydrochloride 2-aminooxy-2-methylpropan-1-ol

To a solution of 2-(N-Boc-aminooxy)-2-methylpropan-1-ol (1,94 g of 9.45 mmol) in anhydrous dichloromethane (10 ml) is added 4 M HCl in dioxane (47,26 ml, 200 mmol) at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue triturated c ether (3×30 ml) to obtain specified in the connection header in the form of oily/solid white (HCl salt). The obtained oily the/white solid is dried in vacuum and used as it is, at the stage of accession (1.10 g, 82.2 per cent).1H NMR (DMSO-d6, 400 MHz) 3.58 (s, 2H), 3,48 (s, 2H), of 1.34 (s, 6H).

1 Aminooxy-2-methylpropan-2-ol

Stage 1: 2-(2-hydroxy-2-methylpropoxy)isoindole-1,3-dione

To a solution of N-hydroxyphthalimide (18,3 g, 112 mmol) and 1,2-epoxy-3-methylpropane (9.50 ml, 107 mmol) in anhydrous DMF under nitrogen atmosphere at room temperature is added triethylamine (16.1 ml, 115 mmol). The reaction mixture turns from yellow to dark red. The reaction mixture was then heated at 85°C during the night. The reaction mixture is cooled to room temperature and concentrate under reduced pressure. The resulting residue is divided between water (100 ml) and ether (3×75 ml). The combined ether layers washed with water (2×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a yellow oil (26,8 g). The oil obtained is then treated with dichloromethane (35 ml), resulting in unreacted N-hydroxyphthalimide falls in the form of a white precipitate, which is filtered off and removed. The obtained filtrate is purified using flash column chromatography (120 g silica gel, ISCO, 45 ml/min, 0-10% methanol in dichloromethane for 50 minutes), to obtain specified in the connection header in the form of a solid white color (13,4 g, 533 %). IHMS (method C): RT= 1,70 min, M+H+= 236,1.1H NMR (CDCl3, 400 MHz) to 7.84 (m, 2H), 7,78 (m, 2H), 4,15 s, 2H), 1.39 in (s, 6H).

Stage 2: 1 aminooxy-2-methylpropan-2-ol

To a solution of 2-(2-hydroxy-2-methylpropoxy)isoindole-1,3-dione (3,70 g, 15.7 mmol) in anhydrous dichloromethane (25 ml) under nitrogen atmosphere at 0°C add methylhydrazine (0,879 ml, 16,50 mmol) and stirred for 2 hours at 0°C. by adding methylhydrazine occurs pale yellow color, then a white precipitate. The reaction mixture was filtered after 2 hours at 0°C and the solid product removed. The resulting filtrate is concentrated under reduced pressure to obtain specified in the connection header in the form of oil, pale yellow (1.65 g, 100%). IHMS (method C): RT= 0,34 min, M+H+= 106,1.1H NMR (DMSO-d6, 400 MHz) of 3.60 (s, 2H), 1,22 (s, 6H).

3 Aminooxy-3-methylbutane-1-ol

Stage 1: 2-(3-hydroxy-3-methylbutoxy)isoindole-1,3-dione

To a solution of N-hydroxyphthalimide (3.13 g, 19.2 mmol) and 3-hydroxy-3-methylbutane (2.00 g, 19.2 mmol) in anhydrous dichloromethane under nitrogen atmosphere at room temperature add apirat boron TRIFLUORIDE (2,43 ml, 19.2 mmol) and stirred over night. The reaction mixture turns black after 18 hours and the white precipitate is formed (N-hydroxyphthalimide). To the reaction mixture EXT is make a saturated solution of sodium bicarbonate (3 ml) and stirred for 5 minutes at room temperature. The reaction mixture was then filtered and the white solid product is removed. The obtained filtrate is concentrated, and the resulting black precipitate is again dissolved in 25 ml of dichloromethane and filtered. The solid white product is removed, and the resulting filtrate concentrated to obtain a black residue. The residue is dissolved in dichloromethane (5 ml) and purified using flash column chromatography (silica gel, 80 g, ISCO, 30 ml/min, 0-100% ethyl acetate in hexane over 45 minutes), to obtain specified in the title compound as yellow oil (228 mg, 4,75%). IHMS (method C): RT= 1,77 min, M+H+= 250,2.1H NMR (CDCl3, 400 MHz) 7,83 (m, 2H), 7,78 (m, 2H), 3,95 (t, 2H), 2,00 (t, 2H), 1,45 (s, 6H).

Stage 2: 3-aminooxy-3-methylbutane-1-ol

To a solution of 2-(3-hydroxy-3-methylbutoxy)isoindole-1,3-dione (228 mg, of 0.91 mmol) in anhydrous dichloromethane (2 ml) under nitrogen atmosphere at 0°C add methylhydrazine (0.05 ml, 0.96 mmol), stirred for 1 hour and allowed to warm to room temperature in the process. In the add methylhydrazine occurs pale yellow color, then a white precipitate is formed. The reaction mixture was filtered after 2 hours at 0°C, and the solid product removed. The resulting filtrate is concentrated under reduced pressure to obtain specified in the connection header in the form of a solid pale yellow color (95 mg, 87%). IHMS (method C): RT=0,34 min, M+H+= 120.1H NMR (DMSO-d6, 400 MHz) of 3.75 (t, 2H)and 1.83 (t, 2H), 1,24 (s, 6H).

Hydrochloride O-pyridine-2-almatygidrogeologiya

Stage 1: N-Boc-aminoacetyl(pyridin-2-yl)

To a solution of N-Boc-hydroxylamine (5.0 g, of 37.6 mmol) in ethanol (100 ml) add potassium hydroxide (4,63 g, 82,61 mmol) and stirred at room temperature until until the potassium hydroxide will not go into solution. To the solution add the hydrobromide of 2-pommerellen (11,398 g, 45,06 mmol) and refluxed overnight. After 1 hour, observe the formation of a white precipitate. The reaction mixture is cooled to room temperature and then filtered. The solid white product is removed and the resulting filtrate concentrated. The obtained oily residue is divided between water (75 ml) and ether (3×100 ml). The combined ether layers are dried over sodium sulfate, filtered and the resulting filtrate concentrated to obtain the product as a yellow oil (6.0 g). The oil obtained is dissolved in dichloromethane (10 ml) and purified using flash column chromatography (silica gel, 120 g, ISCO, 45 ml/min, 0-100 % ethyl acetate in hexane over 40 minutes), to obtain specified in the connection header in the form of a solid white color (1.78 g, 21.2 percent). IHMS (method C): RT= 1,13 min, M+H+= 225,2.1H I Is R (CDCl 3, 400 MHz) 8,61 (d, m, 1H), 7,73 (t, d, 1H), 7,52 (s, 1H), 7,46 (l, t, 1H), free 5.01 (s, 2H), 1.50 in (c, 9H).

Stage 2: Hydrochloride O-pyridine-2-almatygidrogeologiya

To a solution of N-Boc-aminoacetyl(pyridin-2-yl) (860 mg, 3.8 mmol) in anhydrous dichloromethane (2 ml) is added 4 M HCl in dioxane (of 5.06 ml, 20 mmol) at room temperature and stirred for 2 hours. To the reaction mixture add a simple ether (25 ml) and stirred for 5 minutes. The solvent is decanted, and the residue is treated with ether (25 ml), then stirred and then decanted again. This procedure is repeated one more time, and the precipitate (solid white color), dried in vacuum to obtain specified in the connection header in the form of a solid white color (688 mg, 91%). IHMS (method C): RT= 0,36 min, M+H+= 125,0.1H NMR (DMSO-d6, 400 MHz) to 8.70 (m, 1H), with 8.05 (m, 1H), 7,60 (m, 2H), 5,20 (s, 2H).

Hydrochloride, O-(1-phenylethyl)hydroxylamine

Synthesized from 1-(bromacil)benzene according to the method used for the synthesis of hydrochloride of O-pyridine-2-almatygidrogeologiya. IHMS (method C): RT= 0,92 min, M+H+= 138,2.1H NMR (DMSO-d6, 400 MHz) 10,90 (s, 2H), 7,45 (m, 5H), 5.25-inch (square, 1H), 1,50 (d, 3H).

O-[2-(tert-Butyldimethylsilyloxy)propyl]hydroxylamine

Stage 1: (2-benzyloxy-1-methylethoxy)tert-Buti is dimethylsilane

Tert-butyldimethylsilyloxy (517 mg, of 3.43 mmol) are added to a solution of 1-benzyloxypyridine-2-ol (518 mg, of 3.12 mmol), imidazole (318 mg, of 4.66 mmol) and 4-DMAP (95 mg, 0.78 mmol) in CH2Cl2(3 ml). The reaction mixture was stirred at room temperature for 16 hours, then add 2 g of silica gel and the volatiles removed in vacuum. The residue is purified on a chromatographic column with silica gel (0-5% EtOAc:Hex) to obtain specified in the connection header (713 mg, 82% yield) as a clear oil.

Stage 2: 2-(tert-butyldimethylsilyloxy)propan-1-ol

To a solution of (2-benzyloxy-1-methylethoxy)of tert-butyldimethylsilyl (640 mg, 2.3 mmol) in ethyl acetate (10 ml) is added 20% Pd-on-coal (64 mg). The reaction mixture is recovered and rinsed H2then stirred in an atmosphere of H2within 3 hours. The reaction mixture was then filtered through celite and concentrate to obtain specified in the title compound (430 mg, 99% yield) as a clear oil which is used without further purification in the next stage.

Stage 3: 2-[2-(tert-butyldimethylsilyloxy)propoxyethanol-1,3-dione

DEAD ones (0.46 ml, to 2.94 mmol) is added dropwise to a solution of 2-(tert-butyldimethylsilyloxy)propan-1-ol (430 mg, and 2.26 mmol), triphenylphosphine (593 mg, and 2.26 mmol who) and N-hydroxyphthalimide (369 mg, of 2.26 mmol) in THF (10 ml) at 0°C. After stirring for 10 minutes at 0°C, the reaction mixture is heated to room temperature and stirring is continued for another 48 hours. The reaction mixture was filtered through a coarse glass funnel and concentrated in vacuo. The residue is purified on a chromatographic column with silica gel (0-40% EtOAc:Hex) to obtain specified in the title compound (139 mg, 18% yield) as a solid white color.

Stage 4: O-[2-(tert-butyldimethylsilyloxy)propyl]hydroxylamine

N-methylhydrazine (23 μl, 0.43 mmol) are added to a solution of 2-[2-(tert-butyldimethylsilyloxy)propoxy]isoindole-1,3-dione (135 mg, 0.40 mmol) in CH2C12(3 ml). After stirring for l hour at room temperature, the white precipitate is filtered off and the reaction mixture was concentrated in vacuo to obtain specified in the title compound (76 mg, 92% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz) 5,48 (user., 2H), Android 4.04 (m, 1H), to 3.58 (DD, 1H), 3,52 (DD, 1H), 1,13 (d, 3H), of 0.89 (s, 9H), and 0.09 (s, 6H).

O-[2-(tert-Butyldimethylsilyloxy)-1-methylethyl]hydroxylamine

Stage 1: 1-(tert-butyldimethylsilyloxy)propan-2-ol

Tert-butyldimethylsilyloxy (4.1 g, 27 mmol) are added to a solution of propane-1,2-diol (2.0 ml, 27 mmol) and triethylamine (4,93 ml, 3.4 mmol) in CH 2Cl2. After stirring over night at room temperature the reaction mixture was washed once each with an aqueous solution of HCl, water and 1:1 saturated solution of NaHCO3and a salt solution. The organic layer is dried over Na2SO4, then filtered and concentrated. Crude specified in the title compound used without further purification in the next stage.

Stage 2: 2-[2-(tert-butyldimethylsilyloxy)-1-methylethoxy]isoindole-1,3-dione

DEAD (of 1.86 ml of 11.8 mmol) is added dropwise to a solution of 1-(tert-butyldimethylsilyloxy)propan-2-ol (1.73 g, 9.09 mmol), triphenylphosphine (2.38 g, 9.09 mmol) and N-hydroxyphthalimide (1.48 g, 9.09 mmol) in THF (45 ml) at 0°C. After stirring for 10 minutes at 0°C the reaction mixture was brought to room temperature and stirring is continued for another 48 hours. The reaction mixture was filtered through a coarse glass funnel and concentrated in vacuo. The residue is purified on a chromatographic column with silica gel (0-40% EtOAc:Hex) to obtain specified in the title compound (1.80 g, 59% yield) as a clear oil.

Stage 3: O-[2-(tert-butyldimethylsilyloxy)-1-methyl-ethyl]hydroxylamine

N-methylhydrazine (310 μl, 5,74 mmol) are added to a solution of 2-[2-(tert-butyldimethylsilyloxy)-1-methylethoxy]isoindole-1,3-dione (1.80 g, are 5.36 mmol who) in CH 2Cl2(20 ml). After stirring for l hour at room temperature the white precipitate is filtered off and the reaction mixture was concentrated in vacuo to obtain specified in the title compound (682 mg, 62% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz) 5,39 (user., 2H), of 3.77-3,68 (m, 1H), to 3.67 (DD, 1H), 3,61 (DD, 1H), 1,13 (d, 3H), of 0.90 (s, 9H), and 0.08 (s, 6H).

O-(2-Phenyl-1,3-dioxine-5-yl)hydroxylamine

Stage 1: 2-(2-phenyl-1,3-dioxine-5-yloxy)isoindole-1,3-dione

Diethylazodicarboxylate of 0.85 ml, 5.41 mmol) is added dropwise to a solution of 2-phenyl-1,3-dioxine-5-ol (750 mg, 4,16 mmol), triphenylphosphine (1,09 g of 4.16 mmol) and N-hydroxyphthalimide (0,679 g, 4,16 mmol;) in THF (20 ml) at 0°C. Stirred over night at 0°C to room temperature, then concentrated in vacuo. Diluted with CH2Cl2, then filtered through a filter syringe with Whatman paper. Add 4 g of silica gel and concentrated in vacuo. The obtained residue purified on a chromatographic column with silica gel (30-70% EtOAc:Hex, flash 100% EtOAc) to obtain specified in the title compound (495 mg, 37% yield) as a solid white color.

Stage 2: O-(2-phenyl-1,3-dioxine-5-yl)hydroxylamine

N-methylhydrazine (87 μl,5,74 mmol) are added to a solution of 2-(2-phenyl-1,3-dioxine-5-yloxy)isoindole-1,3-dione is (495 mg, of 1.52 mmol) in CH2Cl2(10 ml). After stirring for 3 hours at room temperature, the white precipitate is filtered off and the reaction mixture was concentrated in vacuo to obtain specified in the title compound (272 mg, 92% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz) 7,50-7,46 (m, 2H), 7,40-7,35 (m, 3H), 5,44 (user., 2H), 5,41 (s, 1H) 4,48 was 4.42 (m, 2H), 4,01-3,93 (m, 1H), 3,66-of 3.60 (m, 2H).

N-(2-Aminoacetyl)methanesulfonamide

Step 1: Tert-butyl ether [2-(1,3-dioxo-1,3-dihydroindol-2-yloxy)ethyl]carbamino acid

To a suspension of N-(tertbutoxycarbonyl)ethanolamine (5.0 g, was 31.0 mmol), N-hydroxyphthalimide (5,1 g, was 31.0 mmol) and triphenylphosphine (8.5 g, a 32.6 mmol) in tetrahydrofuran (30 ml) at 0°C is added dropwise diisopropylethylamine (6.3 ml, with a 32.6 mmol). The reaction mixture was stirred and allowed to warm to room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the resulting product was then purified through column chromatography with silica gel (SiO2gradient of ethyl acetate:cyclohexane, 20:80 to 30:70) to obtain specified in the title compound as oil (14.2 g).1H NMR (CDCl3, 400 MHz) 7,87-a 7.85 (2H, m), 7,79-to 7.77 (2H, m), 4.26 deaths (2H, t, J=5.5 Hz), 3,47-of 3.43 (2H, m)of 1.47 (9H, s).

Stage 2: 2-(2-aminoethoxy)isoindole-1,3-dione

Tert-butyl ether [2-(1,3-dioxo-1,3-dihydroindol-2-yloxy)ethyl]carbamino acid (4.4 g, 8.6 mmol) is dissolved in a solution of hydrochloric acid in dioxane (4 n, 20 ml) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo.The resulting residue is dissolved in ethyl acetate (20 ml)and the resulting solution was washed with sodium hydroxide solution (20 ml, 1 n). The aqueous layer was allocated, then extracted with ethyl acetate (2×10 ml). The combined organic layers washed with brine and then dried over magnesium sulfate and concentrated in vacuo to obtain specified in the title compound as a colourless oil (1,96 g).1H NMR (CDCl3, 400 MHz) a 7.85 (2H, DD, J=5,4, 2,9 Hz), 7,72 (2H, DD, J=5,4, 3.0 Hz), 3,99-of 3.97 (2H, m), 3,86-a 3.83 (2H, m).

Stage 3: N-[2-(1,3-dioxo-1,3-dihydroindol-2-yloxy)ethyl]methanesulfonamide

To a solution of 2-(2-aminoethoxy)isoindole-1,3-dione (1,96 g, 8.1 mmol) in acetonitrile (20 ml) at 0°C add both methanesulfonanilide (0.63 ml, 8.1 mmol) and triethylamine (2.3 ml, 16.2 mmol). The reaction mixture was stirred at 0°C for 1 hour, then at room temperature for 1 hour. The reaction mixture is filtered and the resulting filtrate was concentrated in vacuo.The resulting residue is dissolved in ethyl acetate (20 ml) and washed with water (20 ml). Aq is th layer emit, then extracted with ethyl acetate (2×10 ml). The combined organic layers washed with brine, dried over magnesium sulfate and concentrated in vacuo to obtain specified in the connection header in the form of a solid white color (1.2 g, 44%).1H NMR (CDCl3, 400 MHz) 7,87 (2H, DD, J=5,5, 3.1 Hz), 7,79 (2H, DD, J=5,5, 3.2 Hz), 4,36 (2H, DD, J=4,82, to 4.62 Hz), 3,43-3,47 (2H, m), 3,05 (3H, s).

Stage 4: N-(2-aminoacetyl)methanesulfonamide

To a suspension of N-[2-(1,3-dioxo-1,3-dihydroindol-2-yloxy)ethyl]acanaloniidae (0.55 g, 1.92 mmol) in dichloromethane (15 ml) add methylhydrazine (0.1 ml, 1.92 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and during this time a white precipitate is formed. The reaction mixture is filtered and the resulting filtrate was concentrated in vacuo to obtain a residue. The residue is purified using flash chromatography (SiO2gradient of 1-5% methanol in dichloromethane)to obtain specified in the connection header in the form of a solid white color (204 mg, 68%).1H NMR (CDCl3, 400 MHz) of 3.80 (2H, t, J=4.9 Hz), 3,39 (2H, t, J=4,8 Hz)of 3.00 (3H, s).

N-cyclopropylmethyl-O-(2-vinyloxyethyl)hydroxylamine

A solution of O-(2-vinyloxyethyl)hydroxylamine (210 mg, 2.0 mmol) and cyclopropanecarboxaldehyde (140 mg, 2.0 mmol) in ethanol (2.0 ml) cooled to 0°C in nitrogen atmosphere, then dobavljeni p-toluensulfonate acid (0.5 g, 2.0 mmol) and cyanoborohydride sodium (0.15 g, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water, then brine, dried (Na2SO4), filtered and concentrated in vacuo to obtain a colorless oil, which was used crude in the next stage.

O-[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylmethyl]hydroxylamine

Stage 1: 2-[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylethoxy]isoindole-1,3-dione

Diisopropylsalicylic added dropwise to a cooled (0°C) solution of 2-(hydroxymethyl)-1-(p-tamilselvan)imidazole (of 0.60 g, 2.4 mmol), triphenylphosphine (0.65 g, 2.5 mmol) and N-hydroxyphthalimide (0.39 g, 2.4 mmol) in THF (20 ml). The reaction mixture was stirred and allowed to warm to room temperature for 40 hours. The reaction mixture was concentrated in vacuo and the residue is dissolved in dichloromethane (20 ml)causing precipitation in the form of a solid white color. The resulting product is collected by filtration and washed with dichloromethane (5 ml) to obtain specified in the connection header in the form of a solid white color (580 mg, 61%). IHMS (method B): RT= of 3.46 min, M+H+= 398.

Stage 2: O-[1-(toluene-4-sulfonyl)-1H-imidazol-2-ilma is Il]hydroxylamine

Methylhydrazine (40 μl, 0.75 mmol) are added to a solution of 2-[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylethoxy]isoindole-1,3-dione (300 mg, 0.75 mmol) in dichloromethane (3 ml)and the reaction mixture stirred at room temperature for 20 minutes. After approximately 10 minutes a white precipitate is formed. The reaction mixture is filtered and the resulting filtrate was concentrated in vacuo to approximately half volume. Add diethyl ether (5 ml), which causes the formation of a white precipitate. The reaction mixture is filtered and the resulting filtrate was concentrated in vacuo to obtain specified in the title compounds as colorless oil (230 mg, 114%). The resulting product is used without further purification. IHMS (method B): RT= 2,46 min, M+H+= 268.

Ghydrochloride (3S,4S)-pyrrolidine-3,4-diol

Stage 1: (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione

L-(+)-tartaric acid (1.51 g, 10,06 mmol) and benzylamine (1.08 g, 10,06 mmol) in meta-xylene (50 ml) is heated at boiling under reflux, while collecting water trapped in a Dean-stark. After stirring overnight, the reaction mixture was concentrated. The residue is placed in a minimum amount of THF/EtOH and purified using flash chromatography (gradient elution using 3:1 hexane-ethyl acetate, etilize is at, and 9:1 ethyl acetate-ethanol), receiving specified in the title compound in the form of solids brown (0,99 g, 44%).

Stage 2: (3S,4S)-1-benzylpyrrolidine-3,4-diol

(3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (0,98 g, 4.4 mmol) in THF (20 ml) is added slowly to a stirred solution of LiAlH4and 4.75 ml, 11.87 per mmol of a 2.5 M solution in THF) in THF, cooled to -5°C. After complete addition, the reaction mixture is heated to room temperature, then heated at the boil under reflux overnight. The reaction mixture is cooled to room temperature, then quenched using saturated aqueous solution of NH4Cl, up until the following additions will no longer cause the formation of bubbles. The reaction mixture was diluted with ethyl acetate (20 ml), filtered, and the solid product washed with ethyl acetate. The combined filtrates are concentrated and the resulting residue purified using flash chromatography (gradient elution, using EtOAc, 9:1 EtOAc-EtOH), getting mentioned in the title compound in the form of a solid yellow-brown (0.52 g, 61%).

Stage 3: Hydrochloride (3S,4S)-pyrrolidine-3,4-diol

(3S,4S)-1-benzylpyrrolidine-3,4-diol (0.52 g, 2.7 mmol) dissolved in ethanol (15 ml) and acetic acid (10 ml) and hydronaut (50 f/inch square H2) over 10% Pd-C (100 mg) in the apparatus is ATA Parra for 6 hours. After filtration through celite and washing of filter cakes with ethyl acetate, the combined filtrate and washings are concentrated. The residue is diluted with a mixture of 4 n HCl/dioxane (2 ml), methanol (5 ml), then toluene (40 ml) and concentrated. The residue is triturated with ethyl ether, receiving cleaners containing hydrochloride salt specified in the connection header in the form of a solid yellow-brown (0,37 g, 97%).1H NMR (D2O, 400 MHz) of 4.35 (d, J=3,4 Hz, 2H), 3,54 (DD, J=12,8 Hz and 3.4 Hz, 2H), 3,30 (d, J=12,8 Hz, 2H).

Ghydrochlorid 3 methylpyrrolidine-3-ol

Step 1: Tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate

The resulting solution (0,070 g, 0.38 mmol) of tert-butyl 3-oxopyrrolidin-1-carboxylate in anhydrous THF (2 ml) cooled to -78°C. and Then added dropwise a solution of 1 M methylacrylamide in butyl ether. The reaction mixture was stirred at -78°C for 4 hours and quenched with water (2 ml). After concentrating the reaction mixture under vacuum, the residue is divided between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. The residue is purified using flash chromatography (gradient elution using 1:1 hexane-ethyl acetate and ethyl acetate), obtaining the decree is Noah in the title compound (0,054 g, 70%).

Stage 2: the Hydrochloride of 3-methylpyrrolidine-3-ol

To tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate (0,027 g, 0.13 mmol) is added a solution of 4 n HCl/dioxane (1 ml) and the resulting mixture is stirred for 2 hours. The resulting solution was concentrated in vacuo. The residue is diluted with toluene (1 ml) and again concentrated, getting mentioned in the title compound as a colourless oil (0,018 g, 100%).

Hydrochloride (9H-fluoren-9-yl)methyl (3R,4R)-4-hydroxypyrrolidine-3-ylcarbamate

Stage 1: (9H-fluoren-9-yl)methyl (3R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-3-ylcarbamate

(3R,4R)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (0.05 g, 0.25 mmol) dissolved in 1,4-dioxane (1 ml), water (1 ml), and toluene (0.3 ml). Then slowly add 9-fluorenylmethoxycarbonyl (0,077 g, 0.30 mmol), then sodium bicarbonate (,083 g 0,99 mmol). The reaction mixture was stirred at room temperature overnight. After concentrating the reaction mixture under vacuum, the residue is divided between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. The obtained residue is purified using flash chromatography on silica gel (gradient elution, use the Zuya 1:1 hexane-ethyl acetate and ethyl acetate), getting listed in the title compound (0,090 g, 90%).

Stage 2: Hydrochloride (9H-fluoren-9-yl)methyl (3R,4R)-4-hydroxypyrrolidine-3-ylcarbamate

A solution of 4 n HCl/dioxane (1 ml) are added to (9H-fluoren-9-yl)methyl (3R,4R)-1-(tertbutoxycarbonyl)-4-hydroxypyrrolidine-3-ylcarbamate, and the resulting mixture is stirred for 2 hours. The resulting solution was concentrated in vacuo. The residue is diluted with toluene (1 ml) and again concentrated, getting mentioned in the title compound as a colourless oil (0,076 g, 100%).

Ghydrochloride (2R,3R)-2-(hydroxymethyl)pyrrolidin-3-ol

Stage 1: (2S,3R)-1-(tertbutoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid

(2S,3R)-1-(tertbutoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (1,76 g, 7,63 mmol) and NaHCO3(1.28 g, and 15.3 mmol) suspended in DMF (10 ml). To the resulting mixture add methyliodide (2.37 ml, 5,41 g, 38,13 mmol)and the mixture is then heated at 50°C during the night. After concentrating the reaction mixture under vacuum, the residue is divided between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. The residue is purified using flash chromatography on silica gel (gradient elution using 1:1 hexane-e is ylacetic and ethyl acetate), getting listed in the title compound as a colourless oil (1.66 g, 89%).

Stage 2: (2R,3R)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-carboxylate

To a stirred solution of (2S,3R)-1-(tertbutoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (0.36 g, of 1.47 mmol) in THF (5 ml) was added LiCl (0,19 g, 4.4 mmol), then NaBH4(0.17 g, 4.4 mmol). After adding ethanol (10 ml) the resulting mixture was stirred at room temperature overnight. The reactor is placed in a bath of ice and chilled milky white solution is acidified to pH 2-3 using 37% HCl. The resulting solution was concentrated, and the residue is divided between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. Purify the resulting oil by using flash chromatography (silica gel, ethyl acetate), obtaining of 0.30 g (95%) indicated in the title compounds as colorless oils.

Stage 3: Hydrochloride (2R,3R)-2-(hydroxymethyl)pyrrolidin-3-ol

A solution of 4 n HCl/dioxane (5 ml) are added to (2R,3R)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-carboxylate, and the mixture was stirred for 2 hours. The resulting solution was concentrated in vacuo. The residue is diluted with toluene (5 ml) and again concentrated, receiving the decree of the TES in the title compound as a colorless oil (0.21 g, 100%).

Ghydrochloride (3R,5R)-5-(hydroxymethyl)pyrrolidin-3-ol

Step 1: (2R,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

CIS-4-hydroxy-D-Proline (1.0 g, 7,63 mmol) and NaHCO3(1.6 g, 19,05 mmol) dissolved in H2O (16 ml), then added dropwise a solution of benzylbromide (1.25 ml, 1,49 g, 8,76 mmol) in toluene (4 ml) over a period of time of 15 minutes. After stirring at room temperature for 16 hours, the two phases are separated. Excess benzylchloride removed from the aqueous phase, washing with ether (4×5 ml). Acidifying the aqueous phase to pH 2 with concentrated HCl, which causes the precipitation of an oily product is extracted with ethyl acetate, repeating washing (3×5 ml) the aqueous layer. The combined organic layers are dried (MgSO4) and concentrate to obtain the heading compound as a viscous oil (2,02 g, 100%).

Stage 2: (2R,4R)-1-benzyl-2-methyl-4-hydroxypyrrolidine-1,2, in primary forms

(2R,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2,02 g, 7,63 mmol) and NaHCO3(1.28 g, and 15.3 mmol) suspended in DMF (10 ml). To the resulting mixture add methyliodide (2.37 ml, 5,41 g, 38,13 mmol)and the mixture is then stirred and heated at 50°C during the night. After concentration Rea the operating mixture under reduced pressure, the residue is divided between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. The residue is purified using flash chromatography on silica gel (gradient elution using 1:1 hexane-ethyl acetate and ethyl acetate), obtaining mentioned in the title compound as a colorless oil (1.9 g, 89%).

Stage 3: (2R,4R)-benzyl-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-carboxylate

To a stirred solution of (2R,4R)-1-benzyl 2-methyl-4-hydroxypyrrolidine-1,2-in primary forms (0,41 g of 1.47 mmol) in THF (5 ml) was added LiCl (0,19 g, 4.4 mmol), then NaBH4(0.17 g, 4.4 mmol). After adding ethanol (10 ml), the mixture was stirred at room temperature overnight. The reaction flask is placed in a bath of ice, and chilled milky white solution is acidified to pH 2-3 using 37% HCl. The resulting solution was concentrated, and the residue is divided between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. Purify the resulting oil by using flash-chromatography on silica gel (silica gel using ethyl acetate), to obtain specified in the title compound (0.35 g, 95%) as a colourless oil.

Stage 4: hydrochloride, (3R,5R)-5-(hydro shall simetal)pyrrolidin-3-ol

(2R,4R)-benzyl 4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-carboxylate (0.35 g, 1.4 mmol) dissolved in ethanol (30 ml) and move in a Parr shaker. After dobavleniya 10% Pd-C (0.07 g), the mixture was shaken in an atmosphere of hydrogen at 50 F./inch sq. for 0.5 hours on a Parr apparatus. The catalyst was removed by filtration through celite. The filter cake is washed with ethanol and the combined filtrate and washing was concentrated in vacuo to obtain a colorless oil. For ease of processing Amin in turn cleaners containing hydrochloride salt. To the residue is added a solution of 4 n HCl/dioxane (1 ml) along with adding more methanol (about 1 ml) to dissolve the residue. After adding the solvent is evaporated under reduced pressure. The solid product was diluted with toluene (20 ml) and again concentrated. At the end of the solid product triturated with ether, the ether removed, and the solid product dried in vacuum to obtain 0,186 g (87%) indicated in the title compound in a solid pink color.

Hydrochloride, (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol

To N-Boc-TRANS-4-hydroxy-L-prolinol (0,422 g, 1.94 mmol) is added a solution of 4 n HCl/dioxane (5 ml)and the resulting mixture is stirred for 1 hour. The resulting solution was concentrated in vacuo. The residue is diluted with toluene (10 ml) and again concentrate is their. The obtained white solid product triturated with ethyl ether, the ether removed, and the solid product is dried in vacuum, obtaining 0,29 g (97%) indicated in the title compounds as a colorless white solid product.1H NMR (D2O, 400 MHz) 4,65-of 4.67 (m, 1H), 3,99-4,06 (m, 1H), 3,93 (DD, J=12,5 Hz, 3.6 Hz, 1H), 3,71 (DD, J=12,5 Hz, 6.9 Hz, 1H), 3,44 (DD, J=a 12.7 Hz, 3.8 Hz, 1H), 3,32 (d, J=a 12.7 Hz, 1H), 2,11-2,17 (m, 1H), 1,92-to 1.98 (m, 1H).

Tert-butyl (3R,5R)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

Step 1: (2R,4S)-1-benzyl-2-methyl-4-hydroxypyrrolidine-1,2, in primary forms

To a stirred solution of (2R,4R)-1-benzyl-2-methyl-4-hydroxypyrrolidine-1,2-in primary forms (1.45 g, 5.2 mmol), triphenylphosphine (4.59 g, 17.5 mmol) and p-nitrobenzoic acid (2.6 g, 15.6 mmol) in dry benzene (10 ml) at room temperature is added dropwise diethylazodicarboxylate (to 2.57 ml, 17.5 mmol). The resulting solution was then stirred at room temperature for 6 hours, after which the volatile components are removed in vacuo and the residue purified using flash chromatography (silica gel, hexane-ethyl ester 1:1, and again hexane-ethyl ether-methylene chloride 2:1:1). The precipitate is dissolved in methanol (10 ml), add K2CO3(0.02 g, 0.14 mmol)and the resulting mixture is stirred for 1 hour at room temperature. After removal of yuchih components in vacuum, the residue is purified using flash chromatography (silica gel, gradient elution, ethyl ether to ethyl acetate), obtaining mentioned in the title compound as a colourless oil (0.33 g, 23%).

Stage 2: 4-methylbenzenesulfonate (3S,5R)-1-((benzyloxy)carbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl

(2R,4S)-1-benzyl-2-methyl-4-hydroxypyrrolidine-1,2, in primary forms (0.33 g, 1.18 mmol) and DMAP (0,43 g, 3,55 mmol) is dissolved in chloroform, and the resulting mixture is cooled to -5°C in a bath with a mixture of ice-ethanol. Add p-toluensulfonate (0.45 g, 2,24 mmol)and the reaction mixture was stirred, warming up to room temperature for 2 hours. After quenching with water (0.6 ml) and vigorous stirring for 10 minutes, the resulting layers separated, and the aqueous layer was extracted with methylene chloride (2×). The organic layers are dried (MgSO4), filtered through a layer of silica gel (7 ml ethyl ether), elute with ethyl ether and concentrated. The residue is purified using flash chromatography (gradient elution, hexane-ethyl ester 1:1 to ethyl ether), getting mentioned in the title compound as a colourless oil (0,49 g, 95%).

Stage 3: (2R,4R)-1-benzyl-2-methyl-4-azidopyridine-1,2, in primary forms

Sodium azide (0.33 g, 5,07 mmol) are added to 4-methylbenzenesulfonate (3S,5R)-1-((benzyloxy)to bonil)-5-(methoxycarbonyl)pyrrolidin-3-yl (0,49 g, 1.13 mmol) in DMF (8 ml)and the resulting mixture is heated at 50°C during the night. After concentration in vacuo the residue is divided between ethyl ether and water. The aqueous layer was extracted with ethyl ether, and the combined organic layers are dried (MgSO4) and concentrate. Purify the resulting oil by using flash chromatography (silica gel, using ethyl ether)to obtain 0.33 g (97%) indicated in the title compounds as colorless oils.

Stage 4: (3R,5R)-H(benzyloxy)carbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylcarbamate

Triphenylphosphine (0.33 g, 1.15 mmol) are added to a solution of (2R,4R)-1-benzyl-2-methyl-4-azidopyridine-1,2-in primary forms (0.33 g, a 1.08 mmol) in THF (4 ml) and water (2 ml). After stirring at 50°C over night add sodium bicarbonate (0,23 g, a 2.71 mmol), then di-tert-butyl dicarbonate (0,47 g, 2,17 mmol), and stirring is continued at 50°C for 4 hours. Volatiles are removed under reduced pressure, and the residue is divided between ethyl ether and water. The aqueous layer was extracted with ethyl ether, and the combined organic layers are dried (MgSO4) and concentrate. Purify the resulting oil by using flash-chromatography on silica gel (gradient elution, hexane-ethyl ester 1:1 to 3:7), to obtain 0,258 g (64%) indicated in the title compounds as colorless oils./p>

Step 5: Tert-butyl (3R,5R)-1-((benzyloxy)carbonyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

To a stirred solution of tert-butyl (3R,5R)-1-((benzyloxy)carbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylcarbamate (0.16 g, 0.42 mmol) in THF (1.5 ml) is added LiCl (0,054 g of 1.27 mmol) and NaBH4(0,048 g of 1.27 mmol). After adding ethanol (3 ml), the mixture was stirred at room temperature overnight and then quenched with water (1 ml). The resulting solution was concentrated, and the residue is divided between ethyl acetate (20 ml) and water (3 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml)and the combined organic layers washed with brine, dried (MgSO4) and concentrate. Purify the resulting oil by using flash chromatography (silica gel, ethyl ether)to obtain 0.11 g (74%) indicated in the title compounds as colorless oils.

Step 6: Tert-butyl (3R,5R)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

Tert-butyl (3R,5R)-1-((benzyloxy)carbonyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate (0.11 g, 0.31 mmol) dissolved in ethanol (20 ml), and transferred to a Parr shaker. After adding 10% Pd-C (0,030 g) the mixture is shaken in an atmosphere of hydrogen at 50 F./inch sq. for 0.5 hours in a Parr apparatus. The catalyst was removed by filtration through celite. The filter cake is washed with ethanol and the volume of yennie the filtrate and washing was concentrated in vacuo to obtain specified in the title compound as a colourless oil (0.07 g, 100%).

Ghydrochloride (2R,3S)-2-(hydroxymethyl)pyrrolidin-3-ol

Stage 1: (2S,3S)-1-(tertbutoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid

TRANS-3-hydroxy-L-Proline (2,62 g, 20.0 mmol) and sodium bicarbonate (5,04 g, 60 mmol) dissolved in water (20 ml). Add dioxane (20 ml), then di-tert-BUTYLCARBAMATE (8,72 g, 40 mmol). Stirring is continued at room temperature overnight. The reaction mixture was concentrated, and the residue is divided between ethyl ether (10 ml) and water (30 ml). The aqueous layer was washed again with ether, and the organic layers are removed. The gradual acidification of the aqueous phase with concentrated HCl causes the precipitation of an oily product is extracted with ethyl acetate repeated washings (3×10 ml) the aqueous layer. The combined organic layers washed with brine, dried (MgSO4and concentrate, getting mentioned in the title compound as a viscous oil (4,17 g, 90%).

Stage 2: (2S,3S)-1-tert-butyl-2-methyl-3-hydroxypyrrolidine-1,2, in primary forms

(2S,3S)-1-(tertbutoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (4,2 g, 18.2 mmol) and NaHCO3(3.1 g, 36,3 mmol) suspended in DMF (20 ml). Methyliodide (5.7 ml, 12.9 g, 91,0 mmol) are added to the mixture, which is then heated is at 50°C during the night. After concentrating the reaction mixture under vacuum, the residue is divided between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. The residue is purified using flash chromatography on silica gel (gradient elution, 1:1 hexane-ethyl ether to ethyl ether), getting mentioned in the title compound as a colorless oil (3.7 g, 82%).

Stage 3: (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-carboxylate

(2S,3S)-1-tert-butyl-2-methyl-3-hydroxypyrrolidine-1,2, in primary forms (0.54 g, of 2.20 mmol) dissolved in THF (8.0 ml). Add lithium chloride (0.28 g, 6,60 mmol) and sodium borohydride (0.25 g, 6,60 mmol), then ethanol (16.0 ml). The reaction mixture was stirred overnight, then quenched with water (4 ml) and concentrated. The residue is divided between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layers are combined washed with brine and dried (MgSO4). Flash chromatography treatment (50 ml silica gel, gradient elution, ethyl acetate to 9:1 ethyl acetate-ethanol) leads to obtain 0.5 g (100%) specified the title compound as a colourless solid.

Stage 4: Hydrochloride (2R,3S)-2-(hydroxymethyl)pyrrolidin-3-ol

To (2R,3's)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-carboxylate (0.50 g, 2,30 mmol) is added a solution of 4 n HCl/dioxane (6 ml) and the mixture was rotated for 2 hours. The resulting solution was concentrated in vacuo. The residue is diluted with toluene (20 ml) and again concentrated, getting mentioned in the title compound as a colorless oil (0.36 g, 100%).

Hydrochloride (2R,3R,4S)-2-(Hydroxymethyl)pyrrolidine-3,4-diol

Stage 1: (S)-1-(tertbutoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid

3,4-Degidro-L-Proline (1.0 g, 8,8 mmol) dissolved in H2O (9.0 ml) and sodium bicarbonate (2,23 g of 26.5 mmol). Add dioxane (9.0 ml), then di-credibilityof (3,86 g of 17.7 mmol). The reaction mixture was stirred overnight, then concentrated. The residue is divided between ethyl ether (20 ml) and water (25 ml)and the resulting layers separated. The aqueous layer was diluted with ethyl acetate (20 ml)and the resulting mixture is slowly acidified with concentrated HCl, intensively mixing the obtained mixture to be extracted precipitate in the organic layer. After acidification to ~ pH 2, and further extraction with ethyl acetate, the aqueous layer was saturated with salt and extracted again with ethyl acetate. The combined organic layers washed with brine, dried (MgSO4) and concentrate to obtain specified in the title compound (2.0 g, 100%) in VI is e viscous colorless oil.

Stage 2: (S)-1-tert-butyl-2-methyl-2H-pyrrole-1,2(5H)-in primary forms

(S)-1-(tertbutoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (0,85 g, 4.0 mmol) dissolved in ethyl ether (10 ml) and methanol (10 ml), then cooled to -5°C in a bath with a mixture of ice/ethanol. Trimethylsilyldiazomethane (4,4 ml of 2.0 M solution in hexane, to 8.8 mmol) is added dropwise. After stirring overnight, the volatiles removed under reduced pressure. The residue is divided between ethyl ether (20 ml) and water (5 ml)and the resulting layers separated. The organic layer was washed with saturated NaHCO3and brine, then dried (MgSO4), filtered through a layer of silica gel (7 ml), ethyl ether, and concentrated, obtaining mentioned in the title compound as a colourless oil (0,821 g, 91%).

Stage 3: (2S,3R,4S)-1-tert-butyl 2-methyl 3,4-dihydroxypyrrolidine-1,2, in primary forms

(S)-1-tert-butyl-2-methyl-2H-pyrrole-1,2(5H), in primary forms (0,83 g, 3.65 mmol) dissolved in tert-butyl alcohol (15 ml), tetrahydrofuran (4 ml)and water (1.3 ml). Added osmium tetroxide (0,37 ml 100 mg/ml solution of tert-butyl alcohol, 0.15 mmol), then N-oxide N-methylmorpholine (0.51 g, 4.4 mmol). The reaction mixture was stirred at room temperature for 5 hours, and then diluted with saturated sodium thiosulfate (5 ml), utilize the atom (15 ml) and water (5 ml). After separation of the layers the organic layer is washed again with sodium thiosulfate, then with saline, dried (MgSO4), filtered through a layer of silica gel (7 ml)using ethyl acetate (75 ml), and concentrated. The oil obtained is placed in a minimum amount of a mixture of ethyl ether/methylene chloride and purified using flash chromatography (gradient elution, hexane-ethyl acetate 3:7 to ethyl acetate), obtaining mentioned in the title compound as a colourless oil (0,83 g, 87%).

Stage 4: (3aR,4S,6aS)-5-tert-butyl 4-methyl-tetrahydro-2,2-dimethyl[1,3]dioxolo[4,5-c]pyrrole-4,5, in primary forms

(2S,3R,4S)-1-tert-butyl 2-methyl 3,4-dihydroxypyrrolidine-1,2, in primary forms (0,426 g, and 1.63 mmol) was dissolved in 2,2-dimethoxypropane (10 ml). Add pyridine p-toluensulfonate (0.02 g, 0.08 mmol)and the reaction mixture stirred at room temperature overnight. According to TLC, the reaction is fully completed. Add another 2.2-dimethoxypropane (5 ml)and the resulting mixture is heated with a Hairdryer until then, until the mixture boils and full volume is reduced to about 1/4 (takes about 5 minutes). The reaction mixture is diluted with ethyl ether (10 ml)and the resulting solution was extracted with saturated NaHCO3and brine, then dried (MgSO4), filtered and concentrated, obtaining oil is pale yellow in color. the donkey processing by means of flash chromatography (70 ml silica gel, gradient elution, hexane-ethyl ester 25:15-hexane-ethyl ester 1:1)receive specified in the header connection (0,402 g, 82%) as a colourless oil.

Stage 5: (3aR,4R,6aS)-tert-butyl tetrahydro-4-(hydroxymethyl)-2,2-dimethyl[1,3]dioxolo [4,5-c]pyrrole-5-carboxylate

(3aR,4S,6aS)-5-tert-butyl 4-methyl-tetrahydro-2,2-dimethyl[1,3]dioxolo[4,5-c]pyrrole-4,5, in primary forms (0.40 g, 1.3 mmol) dissolved in THF (5.0 ml) and treated sequentially with literorica (0.17 g, 4.0 mmol), sodium borohydride (0.15 g, 4.0 mmol) and ethanol (10 ml). The reaction mixture was stirred overnight, then quenched with water (3 ml) and concentrated. The residue is divided between ethyl acetate and water. After extraction of the aqueous layer again with ethyl acetate the combined organic layers washed with brine and dried (MgSO4). After flash chromatographic processing (50 ml silica gel, gradient elution, hexane-ethyl ether 6:4 to ethyl ether) to obtain 0.36 g (99%) indicated in the title compounds as colorless oils.

Stage 6: Hydrochloride (2R,3R,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol

(3aR,4R,6aS)-tert-butyl tetrahydro-4-(hydroxymethyl)-2,2-dimethyl[1,3]dioxolo [4,5-c]pyrrole-5-carboxylate (0.36 g, 1.3 mmol) was dissolved in 4 n HCl/dioxane (5 ml) and water (0.5 ml) and the reaction mixture was rotated at room temperature for 2 the aces. Then volatiles removed under reduced pressure to obtain oil pink color. The obtained residue was diluted with toluene (20 ml) and again concentrated to obtain a solid product, which was triturated with ethyl ether. The ether is removed, and the solid product dried in vacuum. Yield 200 mg (90%) specified in the connection header in a solid pink color.1H NMR (D2O, 400 MHz) 4,37-4,39 (m, 1H), 4,21 (DD, J=8.6 Hz, 4,1 Hz, 1H), 3,98 (DD, J=a 12.7 Hz, 3.5 Hz, 1H), 3,83 (DD, J=12,5 Hz, 6.0 Hz, 1H), 3,62 (DDD, J=8.6 Hz, 6.0 Hz, 3.5 Hz, 1H), 3,50 (DD, J=13,0 Hz to 4.1 Hz, 1H), 3,37 (DD, J=13,0 Hz, 2.0 Hz, 1H).

Hydrochloride (2R,3S,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol

Stage 1:

2,3,5-tri-O-benzyl-β-L-arabinose (0.5 g, 1,19 mmol) dissolved in ethanol (5 ml) under heating. Add sodium bicarbonate (249 mg, 2,96 mmol) in water (2.5 ml), then hydroxylamine hydrochloride (247 mg, 3,55 mmol). The heterogeneous mixture was stirred at room temperature for 5 hours. Then add hydroxylamine hydrochloride (100 mg, 1.44 mmol) and sodium bicarbonate (100 mg, 1,19 mmol) and the reaction mixture was stirred over night. Add sodium bicarbonate (0,084 g, l mmol)and the resulting mixture is heated to boiling for 5 minutes. After cooling to room temperature, the reaction mixture was concentrated. The resulting mass is about triturated with THF (20 ml) as long until a solid product is not converted into fine powder. The solid product is filtered and the resulting filtrate concentrated. The obtained residue is purified using flash chromatography (hexane:ethyl acetate 3:1)to obtain 0.45 g (87%) of product as a colorless oil.

Stage 2:

A solution of oxime 2,3,5-tri-O-benzyl-β-L-arabinose (0.45 g, 1.0 mmol) in dry ethyl ether (5 ml) is added dropwise to a solution of LiAlH4(0.75 ml of 2.5 M in THF, of 1.85 mmol). The resulting mixture was stirred for an additional 2 hours at room temperature after the addition. Slowly add ethyl acetate (1.7 ml) to decompose excess LiAlH4then 0.75 ml of 4 n NaOH solution. The obtained turbid suspension is filtered through a layer of celite, and calinou cake is washed thoroughly with ether and ethyl acetate. The obtained filtrate and washings are concentrated, receiving a viscous oil. The oil obtained is transferred into ethyl acetate (20 ml) and washed with saturated NaHCO3and brine, then dried (MgSO4) and concentrate give crude amine in the form of oil, pale yellow (0,44 g, 100%). The obtained amine (,44 g, 1.0 mmol) dissolved in THF (3 ml) and water (1.5 ml). Add sodium bicarbonate (0,22 g, 2.6 mmol) and then di-tert-BUTYLCARBAMATE ones (0.46 g, 2.1 mmol). The reaction mixture was stirred overnight, then concentrated. The remainder R is sdelat between ethyl ether (20 ml) and water (10 ml), and the resulting layers separated. The aqueous layer was extracted again with ethyl ether, and the combined organic layers washed with brine, dried (MgSO4) and concentrate. After flash chromatography treatment (silica gel, hexane-ethyl ester 1:1) get to 0.29 g (52%) of Boc-amine as a colourless oil.

Stage 3:

Alcohol (0.29 grams, 0.55 mmol) and triethylamine (of 0.13 ml, 0.96 mmol) dissolved in methylene chloride (2.0 ml) and cooled to -5°C in a bath with a mixture of ice-ethanol. Add methanesulfonamide (64 μl, 0.83 mmol)and the reaction mixture is stirred for 2 hours. After quenching with water (0.2 ml) the resulting mixture is stirred for 30 minutes. The resulting layers separated, the aqueous layer washed with methylene chloride and the combined organic layers are dried (MgSO4) and concentrate. The residue is purified using flash chromatography (hexane-ethyl ether-methylene chloride 2:1:1), to obtain specified in the connection header (0,30 g, 91%).

Stage 4:

The compound N-Boc-O-mesilate (0,247 g, 0,412 mmol) dissolved in DMF (2.0 ml), then add sodium hydride (0,023 g, 60% dispersion in oil) directly to the resulting solution and the cloudy mixture was stirred at room temperature for 2.5 hours. According to TLC, the reaction was completed. The reaction mixture was diluted with ethyl the ether (8 ml), filtered directly through a layer of silica gel (7 ml ethyl ether), and the filter cake washed with c ether. After removal of volatiles under reduced pressure, the obtained residue is purified using flash chromatography on silica gel (hexane-ethyl ether-methylene chloride 3:1:1), to obtain 0,196 g (95%) pyrolidine product as a colourless oil.

Stage 5: (2R,3S,4S)-tert-butyl 3,4-dihydroxy-2-(hydroxymethyl)pyrrolidin-1-carboxylate

Tri-O-benzyl pyrrolidine (0.24 g, 0.47 mmol) was dissolved in methanol (50 ml) and added to a Parr shaker. After blowing nitrogen was added 10% Pd-C (150 mg), and the resulting mixture hydronaut in the Parr apparatus at 50 F./inch square H2within 4 hours. The reaction mixture was filtered through a layer of celite, the filter cake washed with methanol, and the resulting solution concentrated. Purify the obtained residue using flash chromatography on silica gel (silica gel, gradient elution, ethyl acetate to ethyl acetate : ethanol 9:1), obtaining the product-triol (0,103 g, 95%) as a colourless oil.

Stage 6: Hydrochloride (2R,3S,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol

N-Boc-pyrrolidine (0,103 g, 0,442 mmol) was dissolved in 4 n HCl/dioxane (3 ml) and rotate at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to p the receipt of a colorless oil. The residue is diluted with toluene (20 ml), again concentrated, then triturated with ethyl ether, trying to cause crystallization. The residue solidifies, the ether removed, and the solid product dried in vacuum to give crude specified in the title compound in the form of solid white (75 mg, 100%).1H NMR (D2O, 400 MHz) 4,39 (d, J=4.3 Hz, 1H), 4,32 (apparent s, 1H), 3,99-of 4.05 (m, 1H), a 3.87-3,93 (m, 2H), 3,66 (DD, J=13,0 Hz, 4.3 Hz, 1H), 3,30 (d, J=13,0 Hz, 1H).

EXAMPLE 5: ((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

Stage 1: ((R)-2-dimethyl-[1,3]dioxolan-4-emetogenic-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2 - carboxylic acid

A mixture of ethyl 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylate (60 mg, 0.15 mmol), 1 n aqueous sodium hydroxide solution (of 0.18 ml, 0.18 mmol) and methanol (2 ml) is heated at 65°C for 30 minutes. The reaction mixture was concentrated, and then carry out azeotropic distillation with toluene (3×10 ml) to obtain 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 (35 mg, 0.23 mmol), EDCI (28 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (61 μl, 0.35 mmol). After stirring overnight at 40°C, the residue absorb on HM-N and purified, ispolzovalas chromatography (Si-SPE, diethyl ether: MeOH, gradient 100:0 to 90:10)to obtain specified in the title compound as a white foam (30 mg, 48%). IHMS (method B): RT= 3,10 min, M+H+= 528.

Stage 2: ((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (30 mg, 0.06 mmol) dissolved in methanol (0.5 ml) and injected into Isolute® SCX-2 cartridge (5 g). Then the cartridge was washed with methanol (15 ml) and the desired product is then elute using 2 M NH3in MeOH and the eluate is collected and concentrated to obtain a residue. The remainder absorb on HM-N and purified using flash chromatography (Si-SPE, diethyl ether: MeOH, gradient 100:0 to 80:20)to obtain specified in the connection header in the form of a solid white color (18 mg, 64%). IHMS (method A): RT= 5,80 min, M+H+= 488.1H NMR (d4-MeOH, 400 MHz) 8,53 (d, J=5,9 Hz, 1H), 8,49 (d, J=1.0 Hz, 1H), 7.62mm (DD, J=5,9 Hz, 1.0 Hz, 1H), 7,60 (DD, J=10.3 Hz, 2.0 Hz, 1H), 7,51 (DD, J=8,5 Hz, 2.0 Hz, 1H), 7,06 (t, J=8,5 Hz, 1.0 Hz, 1H), 4,10 (m, 1H), 3.96 points (m, 2H), 3,63 (m, 2H).

EXAMPLE 6: ((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-brompheniramine)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-brompheniramine)furo[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl 3-(2-fluoro-4-brompheniramine)furo[3,2-c]pyridine-2-carboxylate (400 mg, 1.06 mmol), 1 n aqueous sodium hydroxide solution (l,11 ml, 1.11 mmol) and methanol (10 ml) is heated at 65°C for 30 minutes. The reaction mixture was concentrated in vacuo, then carry out azeotropic distillation with toluene (3×10 ml) to obtain a solid residue. The solid is dissolved in anhydrous THF (10 ml) and added O-((R)-2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)hydroxylamine (255 mg, 2,12 mmol), EDCl (254 mg, 1,32 mmol), HOBt (200 mg, 1.48 mmol) and DIPEA (556 μl, 3,18 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo to obtain a yellow precipitate. The resulting residue is dissolved in ethyl acetate (30 ml), washed with water (30 ml) then brine (30 ml) before the organic layer exhale, then dried over sodium sulfate and concentrated in vacuo to obtain a yellow oil. The oil obtained is purified using flash chromatography (Si-SPE, pentane: ethyl acetate, gradient 50:50 to 0:100)to obtain specified in the connection header in the form of foam is not quite white (370 mg, 73%).1H NMR (CDCl3, 400 MHz) which 9.22 (s, 1H), 7,95 (s, 1H), to 7.67 (m, 1H), 7,51 (m, 1H), 7,45-7,31 (m, 3H), 7,13 (t, J=8,4 Hz, 1H), 4,49 (m, 1H), 4,08-4.26 deaths (m, 3H), with 3.89 (m, 1H), 1,49 (s, 3H), of 1.40 (s, 3H).

Stage 2: ((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-brompheniramine)furo[3,2-C]pyridine-2-arbonboy acid

To ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-brompheniramine)furo[3,2-c]pyridine-2-carboxylic acid (50 mg, 0.10 mmol) is added a solution of 4 n HCl in methanol (1 ml), then the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture are added water (10 ml) and ethyl acetate (10 ml)and the organic layer isolated. The organic phase is washed with a saturated solution of NaHCO3(10 ml), then dried over sodium sulfate before concentrating in vacuo, receiving sediment. The residue is introduced into Isolute® SCX-2 cartridge (5 g). The cartridge is then washed with methanol (15 ml) before the desired product elute using 2 M ammonia in MeOH and the eluate is collected, then concentrated to obtain a residue. The residue is purified using flash chromatography (Si-SPE, DCM: MeOH, gradient 100:0 to 93:7) to obtain specified in the connection header in the form of a solid white (27 mg, 59%). IHMS (method A): RT= 5,55 min, M+H+= 440/442.1H NMR (d4-MeOH, 400 MHz) charged 8.52 (s, 1H), 8,44 (s, 1H), 7,60 (d, J=5,9 Hz, 1H), 7,44 (DD, J=8,8 Hz, 2.2 Hz, 1H), 7,32 (m, 1H), 7,19 (m, 1H), 4,06 (m, 1H), 3,91 (m, 2H)and 3.59 (m, 2H).

EXAMPLE 7: ((R)-2,3-dihydroxypropane)amide 3-(4-ethinyl-2-forgenerating)furo[3,2-c]pyridine-2-carboxylic acid

A mixture of ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-brompheniramine)furo[3,2-c]pyridine-2-carboxylic acid the (100 mg, 0.21 mmol), trimethylsilylacetamide (288 μl, of 2.08 mmol) and PdCl2(PPh3)2(7,3 mg, 0.01 mmol) in triethylamine (3.0 ml) is subjected to microwave irradiation at 150°C for 10 minutes. The reaction mixture was then diluted with ethyl acetate (5 ml) and the resulting solution washed with water (10 ml), then brine (5 ml)then the organic layer is dried over sodium sulfate and concentrated in vacuo to obtain a precipitate. The residue is dissolved in methanol (3 ml), add potassium carbonate (58 mg, 0.42 mmol)and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture was then evaporated to dryness, and the resulting residue is dissolved in ethyl acetate (20 ml). The organic phase is washed with water (10 ml), then brine (10 ml) and dried over sodium sulfate and concentrated in vacuo to sediment. The precipitate is dissolved in methanol (0.5 ml) and injected into Isolute® SCX-2 cartridge (5 g). The cartridge was washed with methanol (15 ml) before the desired product elute using 2 M triethylamine in MeOH and the eluate is collected, then concentrate to obtain specified in the connection header in the form of solids, white (19 mg, 24%). IHMS (method A): RT= 5,78 min, M+H+= 386.1H NMR (d4- MeOH, 400 MHz) 8,51 (m, 2H), 7,60 (d, J=5,9 Hz, 1H), 7,31 (DD, J=11.3 Hz, 1.8 Hz, 1H), 7.23 percent (DD, J=8,4 Hz, 1.6 Hz, 1H), 7,06 (t, J=8.5 Hz, 1H), 4,07 (m, 1H), 3,92 (m, 2H), 3,55 (m, 2), to 3.49 (s, 1H).

EXAMPLE 8: cyclopropylmethoxy 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

A mixture of ethyl 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylate (87 mg, 0.20 mmol), 1 n aqueous sodium hydroxide solution (of 0.21 ml, 0.21 mmol) and methanol (2 ml) is heated at 65°C for 60 minutes. The reaction mixture was concentrated in vacuo, then carry out azeotropic distillation with toluene (3×10 ml) to obtain a solid residue. The solid is dissolved in anhydrous THF (5 ml) and add hydrochloride cyclopropanemethylamine (49 mg, 0.40 mmol), EDCI (48 mg, 0.25 mmol), HOBt (36 mg, 0.27 mmol) and DIPEA (140 μl, 0.80 mmol). After stirring overnight at 40°C, the precipitate absorb on HM-N and purified using flash chromatography (Si-SPE, diethyl ether: MeOH, gradient 98:2 to 95:5) to obtain specified in the connection header in the form of solid substances not quite white (31 mg, 33%).1H NMR (CDCl3, 400 MHz) 8,84 (s, 1H), to 8.62 (s, 1H), 8,59 (d, J=5,9 Hz, 1H), to 7.99 (s, 1H), 7,51 (DD, J=9.7 Hz, 1.5 Hz, 1H), 7,43 (d, J=8.6 Hz, 1H), 7,38 (d, J=5,9 Hz, 1H), 6,98 (t, J=8,4 Hz, 1H), 3,90 (d, J=7.5 Hz, 2H), of 1.20 (m, 1H), 0,66 (m, 2H), and 0.37 (m, 2H).

EXAMPLE 9: ((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-iodoaniline)furo[2,3-C]pyridine-2-carboxylic acid

Stage 1: ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[23-c]pyridine-2-carboxylic acid

A mixture of ethyl 3-(2-fluoro-4-iodoaniline)furo[2,3-c]pyridine-2-carboxylate (220 mg, 0.52 mmol), 1 n aqueous sodium hydroxide solution (2.0 ml) and methanol (2.0 ml) is heated at boiling under reflux for 15 minutes. The reaction mixture condenses and carry out azeotropic distillation with toluene (3×10 ml) to obtain a solid residue. The solid is dissolved in anhydrous THF (8 ml) and added O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (149 mg, 1.04 mmol), EDCI (123 mg, 0.64 mmol), HOBt (98 mg, 0.73 mmol) and DIPEA (274 μl, 1.54 mmol). After stirring for 16 hours at room temperature, the precipitate absorb on HM-N and purified using flash chromatography (Si-SPE, diethyl ether: MeOH, gradient 100:0 to 90:10)to obtain specified in the title compound as brown oil (124 mg, 45%). IHMS (method B): RT= 3,39 min, M+H+= 528.

Stage 2: ((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-iodoaniline)furo[2,3-c]pyridine-2-carboxylic acid

((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[2,3-c]pyridine-2-carboxylic acid (25 mg, 0.05 mmol) dissolved in methanol (0.5 ml) and treated chromatography (Isolute® SCX-2, MeOH: 2 M NH3in MeOH, gradient 100:0 to 50:50). The residue is then absorb on HM-N and purified using flash chromatography on silica gel (Si-SPE, DCM: MeOH, gradient 5:5 to 80:20), to obtain specified in the connection header in the form of solids, white (19 mg, 78%). IHMS (method A): RT= 6,99 min, M+H+= 488.1H NMR (d4-MeOH, 400 MHz) 8,88 (s, 1H), 8,32 (d, J=5.5 Hz, 1H), 7,55 (DD, J=10.3 Hz, 2.0 Hz, 1H), 7,45 (DDD, J=8,5 Hz, 2.0 Hz, 1.0 Hz, 1H), 7,32 (DD, J=5,5 Hz, 1.0 Hz, 1H), 6.89 in (t, J=8.5 Hz, 1H), 4,11 (DD, J=9.9 Hz, 3.5 Hz, 1H), of 3.97 (m, 2H), 3,63 (m, 2H).

EXAMPLE 10: (2 hydroxyethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: (2-vinyloxyethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

To a solution of ethyl 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylate (6.50 g, of 15.2 mmol) in THF (92 ml) and methanol (31 ml) was added a 1.0 M aqueous sodium hydroxide solution (31 ml, 31 mmol). The reaction mixture is heated at 65°C for 1.5 hours, then cooled to room temperature and concentrated in vacuo. Carry out azeotropic distillation of the obtained residue with toluene (3×75 ml), and then suspended in THF (75 ml). Then successively added O-(2-vinyloxyethyl)hydroxylamine (1.86 g, 18.0 mmol), N,N-diisopropylethylamine (10.4 ml, 60,0 mmol), EDCI (5.75 g, 30.0 mmol), and HOBt (4,46 g, 33.0 mmol)and the reaction mixture stirred for 18 hours at room temperature. Then add to 18.9 g of silica gel, and the resulting mixture was concentrated in vacuo. Statomat on a chromatographic column with silica gel (0-7% methanol:CH 2Cl2) to obtain specified in the connection header in the form of a solid pale yellow: and 4.40 g, 60%. IHMS (method C): RT= 2,11 min, M+H+= 484.1H NMR (CDCl3, 400 MHz) 8,97 (s, 1H), 8,63 (s, 1H), at 8.60 (d, J=5.6 Hz, 1H), 7,98 (s, 1H), 7,52 (DD, J=a 9.6, 2.0 Hz, 1H), 7,44 (m, 1H), 7,39 (DD, J=6,0, 1.2 Hz, 1H), 7,00 (t, J=8,8 Hz, 1H), 6,56 (DD, J=14,4, 6,8 Hz, 1H), 4,34 (m, 2H), 4,28 (DD, J=14,0, 2.0 Hz, 1H), 4,12 (DD, J=6,4, 2.0 Hz, 1H), a 4.03 (m, 2H).

(2 hydroxyethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

To a suspension of (2-vinyloxyethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (4,40 g, 9,10 mmol) in a mixture of methanol (14,3 ml) and ethanol (51.9 ml) is added a 1.0 M aqueous solution of hydrochloric acid (18.2 ml, 18.2 mmol) at 0°C. After complete addition, the reaction mixture is brought to room temperature and stirred for 1.5 hours. Then add portions of solid sodium bicarbonate and 4.75 g of 56.5 mmol), and stirring is continued for 15 minutes. Add silica gel (14 g) and the resulting mixture was concentrated in vacuo. The solid residue purified on a chromatographic column with silica gel (0-10% methanol: CH2Cl2) to obtain specified in the connection header in the form of a solid pale yellow color: 4.12 g, 91%. IHMS (method C): RT=1,61 min, M+H+= 458.1H NMR (CDCl3, 400 MHz) 8,84 (s, 1H), 8,61 (s, 1H), at 8.60 (s, 1H), 7,94 (s, 1H), 7,53 (DD, J=a 9.6, 2.0 Hz, 1H), 7,43(m, 1H), 7,38 (DD, J=6,0, 1.2 Hz, 1H), 7,00 (t, J=8,4 Hz, 1H), 4,30 (b, 1H), 4,11 (m, 2H), 3,83 (user., 2H).

EXAMPLE 11: (2 vinyloxyethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

EXAMPLE 12: ((R)-2,3-dihydroxypropane)amide 3-(4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(4-iodobenzylamine)furo[3,2-C]pyridine-2-carboxylic acid

A mixture of ethyl 3-(4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylate (100 mg, 0.24 mmol), 1 n aqueous sodium hydroxide solution (260 ml) and ethanol (4 ml) is heated at 65°C for 3 hours. The reaction mixture condenses and carry out azeotropic distillation with toluene (3×20 ml) to obtain a solid residue. The solid residue is dissolved in anhydrous THF (7 ml)solution was added EDCI (57 mg, 0.30 mmol) and HOBt (45 mg, 0.33 mmol)and the resulting mixture is stirred for 30 minutes before finally added O-((R)-2,2-dimethyl)-[1,3]dioxolane-4-ylmethyl)hydroxylamine (71 mg, 0.48 mmol) and DIPEA (125 μl, to 0.72 mmol). After stirring for 16 hours at room temperature, the residue absorb on HM-N and purified using flash chromatography (Si-SPE, cyclohexane: ethyl acetate gradient of 50:50 to 0:100)to obtain specified in the connection header in the form of solid substances is tion is not quite white (103 mg, 84%). IHMS (method B): RT= 2,86 min, M+H+= 510.

Stage 2: ((R)-2,3-dihydroxypropane)amide 3-(4-iodobenzylamine)furo[3,2-c|pyridine-2-carboxylic acid

((R)-2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)amide 3-(4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid (100 mg, 0,19 mmol) is dissolved in methanol and purified through column chromatography (Isolute® SCX-2, EtOAc then EtOAc: MeOH: Et3N, 89:10:1). The resulting residue absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane: MeOH, gradient 100:0 to 90:10)to obtain specified in the connection header in the form of a solid pale yellow color (38 mg, 42%). IHMS (method A): RT= 6,16 min, M+H+= 470.1H NMR (d4-MeOH, 400 MHz) charged 8.52 (d, J=5,9 Hz, 1H), 8,48 (s, 1H), to 7.67 (d, J=8,8 Hz, 2H), 7,60 (DD, J=6.0 Hz, 0.8 Hz, 1H), 7,00 (d, J=8.7 Hz, 2H), 4.09 to (DD, J=9.9 Hz, 3.4 Hz, 1H), 3,93-4,00 (m, 2H), 3,61-to 3.64 (m, 2H).

EXAMPLE 13: ((R)-2,3-dihydroxypropane)amide 3-(2-chloro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

Stage 1: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-chloro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl 3-(2-chloro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylate (115 mg, 0.26 mmol), 1 n aqueous sodium hydroxide solution (of 0.27 ml, 0.27 mmol) and industrial methylated spirits (3.0 ml) is heated at 65°C for 60 mine is. The reaction mixture was concentrated, and then carry out azeotropic distillation with toluene (3×10 ml) to obtain a solid residue. The obtained solid residue was dissolved in anhydrous THF (5 ml)solution was added O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (75 mg, 0.51 mmol), EDCI (65 mg, 0.34 mmol), HOBt (49 mg, 0.36 mmol) and DIPEA (175 μl, of 1.02 mmol). The reaction mixture is stirred for 48 hours, and then concentrated under reduced pressure. The obtained residue absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 95:5)to obtain specified in the title compound as yellow oil (119 mg, 84%). IHMS (method B): RT= 3,14 min, M+H+= 544.

Stage 2: ((R)-2,3-dihydroxypropane)amide 3-(2-chloro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2-chloro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (119 mg, 0.22 mmol) dissolved in methanol (5.0 ml) and injected into Isolute® SCX-2 cartridge (5 g). Then the cartridge was washed with methanol (15 ml) and the desired product sequentially elute using 2 M NH3in MeOH. Eluent is collected and concentrated to obtain a residue. The remainder absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 90:10)to obtain specified in the connection header in the form of t is ejogo substance white (20 mg, 18%). IHMS (method A): RT= 7,02 min, M+H+= 504.1H NMR (d4-MeOH, 400 MHz) charged 8.52 (d, J=6.2 Hz, 1H), charged 8.52 (d, J=0.9 Hz, 1H), 7,81 (d, J=2.0 Hz, 1H), to 7.61 (DD, J=6.2 Hz, 0.9 Hz, 1H), 7,58 (DD, J=8,5 Hz, 2.0 Hz, 1H), 7,01 (d, J=8.5 Hz, 1H), 4.09 to of 4.05 (m, 1H), 3,98-3,88 (m, 2H,), 3,60-to 3.58 (m, 2H).

EXAMPLE 14: ((R)-2,3-dihydroxypropane)amide 3-(2,6-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2,6-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl 3-(2,6-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylate (137 mg, 0.31 mmol), 1 n aqueous sodium hydroxide solution (of 0.32 ml, 0.32 mmol) and industrial methylated spirits (5.0 ml) is heated at 65°C for 60 minutes. The reaction mixture was concentrated, and then carry out azeotropic distillation with toluene (2×10 ml) to obtain a solid residue. The solid residue is dissolved in anhydrous THF (5 ml) before add O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (89 mg, 0.61 mmol), EDCI (77 mg, 0.40 mmol), HOBt (58 mg, 0.43 mmol) and DIPEA (213 μl, 1,22 mmol). The reaction mixture is stirred for 16 hours and concentrated under reduced pressure. The remainder absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 95:5)to obtain specified in the header connect the deposits in the form of a yellow oil (63 mg, 37%). IHMS (method B): RT= 2,87 min, M+H+= 546.

Stage 2: ((R)-2,3-dihydroxypropane)amide 3-(2,6-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2,6-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid (63 mg, 0.11 mmol) dissolved in methanol (4.0 ml) and injected into Isolute® SCX-2 cartridge (5 g). Then the cartridge was washed with methanol (15 ml) and the desired product sequentially elute using 2 M NH3in MeOH. Eluent is collected and concentrated to obtain a residue. The resulting residue absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 90:10) to obtain specified in the connection header in the form of a solid white (17 mg, 31%). IHMS (method A): RT= 5,97 min, M+H+= 506.1H NMR (d4-MeOH, 400 MHz) 8,48 (d, J=6.0 Hz, 1H), compared to 8.26 (s, 1H), 7,55 (d, J=6.0 Hz, 1H), 7,54-7,49 (m, 2H), 4,08-of 4.05 (m, 1H), 3.96 points-a 3.87 (m, 2H), 3,60-to 3.58 (m, 2H).

EXAMPLE 15: ((R)-2,3-dihydroxypropane)amide 3-(2,5-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2,5-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

A mixture of ethyl 3-(2,5-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylate (163 mg, and 0.37 mmol), 1 n aqueous solution guide is sodium oxide (0,38 ml, 0.38 mmol) and industrial methylated spirits (4,0 ml) is heated at 65°C for 30 minutes. The reaction mixture was concentrated in vacuo, then carry out azeotropic distillation with toluene (2×10 ml) to obtain a solid residue. The solid residue is dissolved in anhydrous THF (5 ml) before add O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (106 mg, to 0.72 mmol), EDCI (91 mg, 0,470 mmol), HOBt (69 mg, 0.51 mmol) and DIPEA (250 μl, 1,45 mmol). The reaction mixture is stirred for 16 hours and concentrated under reduced pressure. The remainder absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 95:5)to obtain specified in the title compound as yellow oil (152 mg, 76%). IHMS (method B): RT= 3,01 min, M+H+= 546.

Stage 2: ((R)-2,3-dihydroxypropane)amide 3-(2,5-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 3-(2,5-debtor-4-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid (145 mg, 0.27 mmol) dissolved in methanol (5.0 ml) and injected into Isolute® SCX-2 cartridge (5 g). Then the cartridge was washed with methanol (15 ml), and the desired product sequentially elute using 2 M NH3in MeOH. Eluent is collected and concentrated to obtain a residue. The remainder absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane:met the Nol, gradient 100:0 to 90:10)to obtain specified in the connection header in the form of a solid white (75 mg, 56%). IHMS (method A): RT= of 6.49 min, M+H+= 506.1H NMR (d4-MeOH, 400 MHz) 8,61 (d, J=0.9 Hz, 1H), charged 8.52 (d, J=6,1 Hz, 1H), to 7.61 (DD, J=6,1 Hz, 0.9 Hz, 1H), to 7.59 (DD, J=10.1 Hz, 5.7 Hz, 2H), 6,94 (DD, J=8,4 Hz, 7.5 Hz, 1H), 4,07-a 4.03 (m, 1H), 3.96 points-a 3.87 (m, 2H), 3,63-3,55 (m, 2H,).

EXAMPLE 16: Tert-butyl ether 4-{(3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carbonyl]aminooxy}piperidine-1-carboxylic acid

A mixture of 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (398 mg, 1 mmol), HOBT (190 mg, 1.4 mmol) and EDCI (240 mg, 1.25 mmol) in THF (5 ml) is stirred for l hour. To the obtained mixture is added DIPEA (530 μl, 3.0 mmol) and tert-butyl ether 4-aminoantipyrine-1-carboxylic acid (432 mg, 2.0 mmol). After stirring overnight, the reaction mixture was concentrated in vacuo,dilute with ethyl acetate (30 ml) and washed with saturated solution of NaHCO3(10 ml). The organic layer emit, dried over sodium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100% to 95:5), receiving specified in the title compound in the form of foam, pale yellow (285 mg, 47%). IHMS (method A): RT= 10,43 min, M+H+= 597.1H NMR (CDCl3, 400 MHz) up 11,86 (s, 1H), 8,15 (s, 1H), 7,66 (DD, =10,8 Hz, 2.0 Hz, 1H), to 7.61 (d, J=8.6 Hz, 1H), 7,51 (m, 1H), 7,43 (DD, J=8 8 Hz, 1H), 7,32 (d, J=7.7 Hz, 1H), 7,27 (m, 1H), 6,86 (t, J=8,8 Hz, 1H), 4,88 (d (OSiR.), J=3,4 Hz, 1H), 4,60 (t (OSiR.), J=5.5 Hz, 1H), 3,17 (DDD, J=13,6, 8,8, and 3.7 Hz, 2H), 1,97-2,03 (m, 2H), 1,7-of 1.81 (m, 2H), and 1.63 (s, 9H).

EXAMPLE 17: (2-morpholine-4-ylethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

A mixture of 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (199 mg, 0.5 mmol), HOBt (95 mg, 0.7 mmol) and EDCl (125 mg, of 0.65 mmol) in THF (2 ml) is stirred for l hour. To the obtained mixture is added DIPEA (270 μl, 1.5 mmol) and O-(2-(tetrahydropyran-4-yl)ethyl)hydroxylamine (146 mg, 1.0 mmol). After stirring overnight the resulting solution was concentrated in vacuo,dilute with ethyl acetate (30 ml) and washed with saturated solution of NaHCO3(10 ml). The organic layer emit, dried over sodium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 95:5), receiving specified in the title compound in the form of foam, which crystallized from a mixture of ether/dichloromethane (75 mg, 28%). IHMS (method A): RT= 5,67 min, M+H+= 527.1H NMR (CDCl3, 400 MHz) 8,77 (s, 1H), 8,63 (d, J=0.7 Hz, 1H), 8,59 (d, J=5.8 Hz, 1H), to 7.99 (s, 1H), 7,51 (DD, J=9.7 Hz, 2.0 Hz, 1H), 7,42-7,46 (m, 1H), 7,37 (DD, J=6 0, 1.2 Hz, 1H), 6,99 (t, J=8.5 Hz, 1H), 4,20-4,12 (m, 2H,), 3,92-3 80 (m, 2H), 3,17 (DDD, J=13,6, 8,8, and 3.7 Hz, 2H), 2,03-of 1.97 (m, 2H), 1,81-1,7(m, 2H), 1,68-to 1.61 (m, 2H).

EXAMPLE 18: ((R)-2,3-dihydroxypropane)amide 7-bromo-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

Stage 1: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 7-bromo-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

A mixture of 7-bromo-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (50 mg, 0.21 mmol) and carbonyl diimidazole (35 mg, 0.21 mmol) in acetonitrile (2 ml) is heated at 50°C for 4 hours. The reaction mixture is then treated with a solution of O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (46 mg, 0.36 mmol) in acetonitrile (1 ml) and heated at 80°C for 3.5 hours before it is cooled and left to stand at room temperature. The reaction mixture is filtered, washed with ethyl acetate before the resulting filtrate is collected and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:ethyl acetate, gradient 1:0 to 4:1 to 0:1, then methanol)to give specified in the title compound in the form of solid light brown (11 mg, 20%). IHMS (method B): RT= 3,55 min, M+H+= 606/608.

Stage 2: ((R)-2,3-dihydroxypropane)amide 7-bromo-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

((R)-2,2-dimethyl[1,3]dioxolan-ylethoxy)amide 7-bromo-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (40 mg, of 0.066 mmol) was dissolved in 0,067 M methanolic HCl (2,79 ml, 0,198 mmol) and stirred at room temperature for 40 minutes. The reaction mixture was concentrated in vacuo, then carry out azeotropic distillation with toluene (2×15 ml). The resulting residue is dissolved in IMS (4 ml), and then add the potassium carbonate before stirred at room temperature for 4 minutes. The reaction mixture was filtered and washed with IMS, before the resulting filtrate is evaporated in vacuo to obtain a solid product. The obtained solid product is triturated with acetonitrile to obtain the desired product as a cream solid color (29 mg, 77%). IHMS (Method A): RT= 9,06 min, M+H+= 566/568.1H NMR (CD3OD): 8,68 (1H, s, of usher.), 8,42 (1H, s, of usher.), to 7.61 (1H, DD, J=10,2, 1.9 Hz), 7,52 (1H, m), 7,07 (1H, t, J=8.6 Hz), of 4.12 (1H, DD, J=10,0, 3,4 Hz)to 3.99 (1H, DD, J=10,0, 6,8 Hz), of 3.96 (1H, m), 3,63 (2H, m).

EXAMPLE 19: ((R)-2,3-dihydroxypropane)amide 5-(2-fluoro-4-iodoaniline)furo[2,3-d]pyrimidine-6-carboxylic acid

Stage 1: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 5-(2-fluoro-4-iodoaniline)furo[2,3-d]pyrimidine-6-carboxylic acid

A mixture of ethyl 5-(2-fluoro-4-iodoaniline)furo[2,3-d]pyrimidine-6-carboxylate (300 mg, 0.70 mmol), 1 n aqueous sodium hydroxide solution (0.75 ml, 0.75 mmol) and industrial metalero the data alcohol (8.0 ml) is heated at 65°C for 30 minutes. The reaction mixture was concentrated, and then carry out azeotropic distillation with toluene (3×10 ml) to obtain a solid residue. The solid residue is dissolved in anhydrous THF (5 ml) and added O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (106 mg, to 0.72 mmol), EDCI (91 mg, 0.47 mmol), HOBt (69 mg, 0.51 mmol) and DIPEA (250 μl, 1,45 mmol). The reaction mixture is stirred for 18 hours before concentrating under reduced pressure. The resulting residue absorb on HM-N and purified using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 95:5)to obtain specified in the title compound (124 mg, 67%). IHMS (method B): RT= of 3.46 min, M+H+= 529.

Stage 2: ((R)-2,3-dihydroxypropane)amide 5-(2-fluoro-4-iodoaniline)furo[2,3-d]pyrimidine-6-carboxylic acid

To a suspension of ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide (5-(2-fluoro-4-iodoaniline)furo[2,3-d]pyrimidine-6-carboxylic acid (124 mg, 0.23 mmol) in methanol (5.0 ml) is added concentrated hydrochloric acid (10 drops)and the resulting mixture is stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure, dissolved in methanol (5 ml) and add potassium carbonate or sodium (approximately 200 mg). The resulting mixture was stirred for 5 minutes to absorb HM-N and purified using flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 0:100, to obtain specified in the connection header in the form of a solid white color (60 mg, 54%). IHMS (method A): RT= a 7.85 min, M+H+= 489.1H NMR (d6- DMSO, 400 MHz) 8,96 (s, 1H), 8,77 (s, 1H), to 7.64 (DD, J=10,7 Hz, 1.9 Hz, 1H), 7,43 (DDD, J=8,5 Hz, 1.9 Hz, 0.9 Hz, 1H), 6,91 (DD, J=8,5 Hz, 8.5 Hz, 1H), 3,86-3,71 (m, 3H), 3,40-3,30 (m, 4H).

EXAMPLE 97: (1 methylpiperidin-4-yloxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

A mixture of piperidine-4-yloxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (80 mg, 0.16 mmol), pyridine p-toluensulfonate acid (40 mg, 0.16 mmol) and formaldehyde (0.05 ml, 10 M aqueous solution, 0.48 mmol) suspended in methanol (0.5 ml) and stirred in an argon atmosphere for 16 hours. Add cyanoborohydride sodium (30 mg, 0.47 mmol)and the resulting solution is stirred for l hour. The solvent is evaporated and the resulting residue is divided between ethyl acetate and sodium bicarbonate, the organic layer emit, washed with brine, dried (Na2SO4) and evaporated. The resulting product was then purified using flash chromatography (Si-SPE 2M methanolic ammonia:DCM, gradient 0:100 to 10:100)to obtain the product as a solid, pale yellow (50 mg, 61% yield). IHMS (method A): RT= 5,49 min; (M+H+511;1H NMR (CDCl3) a 1.88 (2H, m), of 2.08 (2H, m), 2,22 (2H, m), 2,31 (H, C), 2,78 (2H, m), 4,08 (1H, m), 6,98 (1H, t, J=8.5 Hz), 7,37 (1H, DD, J=5,9, 1.0 Hz), 7,44 (1H, m), 7,51 (1H, DD, J=9,8, 1.9 Hz), to 7.99 (1H, s), 8,59 (1H, d, J=5,9 Hz), 8,63 (1H, d, J=1.0 Hz).

EXAMPLE 98: (2 dimethylaminoethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

A mixture of (2-methylaminorex)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (45 mg, 99 mmol), formaldehyde (8 ml, 107 mmol), pyridine p-toluensulfonate acid (25 mg, 97 mmol) in ethanol (1 ml) was stirred at 0-5°C for 30 minutes. Add cyanoborohydride sodium (7 mg, 106 mmol)and the resulting solution was stirred for 30 minutes at room temperature. Add HCl (1 M, 200 μl)and the resulting solution is injected in an Isolute® SCX-2 cartridge (2 g), elwira methanolic ammonia. The appropriate fractions are combined and concentrated, obtaining a residue, which is purified further using flash chromatography (Si-SPE, gradient 2 M methanolic ammonia : DCM, 0:100 to 10:100)to obtain the product as a white foam (23 mg). IHMS (method A): RT= 5,12 min, M+H+484;1H NMR (CD3OD) 2,70 (6H, s), 3,11 (2H, m), is 4.15 (2H, m), to 6.80 (1H, t, J=8.7 Hz), 7,42 (1H, m), 7,53 (1H, DD, J=10,6, 1.9 Hz), to 7.61 (1H, DD, J=5,9, and 0.9 Hz), of 8.47 (1H, d, J=5,9 Hz), 8,56 (1H, d, J=0.9 Hz).

EXAMPLE 99: (2-fluoro-4-iodoaniline)-N-tert-butoxyphenol[3,2-c]pyridine-2-carboxamide

A mixture of ethyl ester of 3-(2-fluoro-4-Iodate is ylamino)furo[3,2-c]pyridine-2-carboxylic acid (251 mg, 0.59 mmol), 1 n aqueous NaOH solution (1.77 ml, 1.77 mmol), methanol (15 ml) and tetrahydrofuran (15 ml) is refluxed for 2 hours. The reaction mixture was concentrated in vacuo, then carry out azeotropic distillation of the resulting residue with toluene (3×15 ml) to obtain a solid residue. The solid residue triturated c ether (3×10 ml)and ether layers are removed. The obtained solid residue is dried in vacuum. Then the solid residue was dissolved in anhydrous DMF (5 ml) before type O-tert-butylhydroxyanisole (58 mg, 0,56 mmol), HATU (270 mg, 0.71 mmol) and DIPEA (470 μl, 2.36 mmol). After stirring for 18 hours at room temperature the solvent is evaporated and the resulting residue purified using preparative HPLC chromatographic column filled with silica gel to obtain specified in the connection header in the form of a solid white (80 mg, 23%). IHMS (method E): RT= 2,30 min, M+H+= 470.1H NMR (CDCl3, 400 MHz) 8,82 (d, 1H), 8,69 (s, 1H), 8,39 (s, 1H), 8,15 (s, 1H), 7,73 (d, 1H), to 7.59 (DD, 1H), 7,51 (d, m, 1H), 6,85 (t, 1H), 1,4 (2, 1H).

EXAMPLE 100: (3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-yl)(1-oxothiazolidine-3-yl)methanon

(3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-yl)(thiazolidin-3-yl)methanon dissolved in methanol (1 ml) and THF (1 ml) and cooled to -5°C. Add Oxon (21 mg ,035 mmol) in water (0.5 ml), and the reaction mixture was stirred and warmed to room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (3 ml) and water (1 ml) and a solid portion decanted. The resulting layers separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers washed with saturated aqueous NaHCO3and brine, dried (MgSO4) and concentrate. The oil obtained is purified using HPLC with reversed phase, receiving TFA salt specified in the connection header in a solid yellow color (to 6.8 mg). IHMS (method D): RT= 2.45 minutes, M+H+= 486.

EXAMPLE 101: (3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(1,1-diocletianopolis-4-yl)methanon

(3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-yl)(thiomorpholine-4-yl)methanon (19 mg, 0,039 mmol) dissolved in methanol (1 ml) and THF (1 ml), and cooled to -5°C. Add Oxon (30 mg, 0,049 mmol) in water (0.5 ml)and the reaction mixture is stirred while warming to room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (3 ml) and water (1 ml) and the solid product isolated. The resulting layers separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers washed with saturated aqueous NaHCO3and brine, dried (MgSO4) and concentrate. Received from the oil cleanse, using HPLC with reversed phase, receiving TFA salt specified in the connection header in the form of a solid yellow (1.5 mg). IHMS (method E) RT= 4,17, M+H+= 516.

EXAMPLE 102: (3-(2,5-debtor-4-(4-pyrazolyl)phenylamino)furo[3,2-C]pyridine-2-yl) ((R)-3-hydroxypyrrolidine-1-yl)methanon

Degassed solution of (3-(4-bromo-2,5-dipertanyakan)furo[3,2-c]pyridine-2-yl)((R)-3-hydroxypyrrolidine-1-yl)methanone (53 mg, 0.12 mmol), pinacolato ether 1-Boc-pyrazole-4-Bronevoy acid (53 mg, 0.18 mmol), Pd(PPh3)4(7,0 mg, 0,0061 mmol), and Na2CO3(29 mg, 0.27 mmol) in dimethoxyethane (2.0 ml), ethanol (0.7 ml), water (0.7 ml) is heated at boiling under reflux overnight. The reaction mixture is cooled to room temperature, filtered, and the solid product washed with ethyl acetate and dried, obtaining the crude product in the form of a solid yellow-brown (41 mg, 80%). IHMS (method D): RT= 1,44 min, M+H+= 426).1H NMR (DMSO-d6, 400 MHz) 8,77-8,82 (m, 2H), 8,66-8,68 (m, 1H), 8,07 (apparent s, 2H), to $ 7.91-to 7.93 (m, 1H), 7,73 for 7.78 (m, 1H), 7,10-to 7.15 (m, 1H), 4,32-to 4.41 (m, 1H), 3,89-Android 4.04 (m, 2H), 3,76-of 3.80 (m, 1H), 3,45-3,62 (m, 2H), 1,80-2,02 (m, 2H,).

EXAMPLE 104: Ethyl ester of 2-dimethylcarbamoyl-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-7-carboxylic acid

To a solution of ethyl ester of 2-dimethylcarbamoyl-3-(2-fluoro-4-trimet is seleniferous)furo[3,2-c]pyridine-7-carboxylic acid (84 mg, 0,19 mmol) in dichloromethane (3 ml) at -10°C add monochloride iodine (range 0.38 ml, 0.38 mmol, 1 M solution in dichloromethane)and the resulting solution was stirred at the same temperature for 1 hour. Add a saturated solution of sodium thiosulfate (5 ml)and the resulting mixture is then poured into a saturated solution of sodium thiosulfate (15 ml). The aqueous layer was allocated, then extracted with dichloromethane (2×25 ml) before the combined organic layers washed with brine, dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:tert-butyl methyl ether, gradient 1:0 to 1:3), receiving specified in the title compound in the form of solid yellow (87 mg, 92%). IHMS (method B): RT= 3,97 min, M+H+= 498.

EXAMPLE 105: Dimethylamide 3-(2-fluoro-4-iodoaniline)-7-hydroxymethylene[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl ester of 2-dimethylcarbamoyl-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-7-carboxylic acid (96 mg, rate of 0.193 mmol) in THF (4 ml) at -40°C is added dropwise linitiative (of 0.41 ml, 0.41 mmol, 1 M solution in THF). The resulting mixture was stirred at -40°C for 30 minutes before the reaction mixture is quenched by adding saturated aqueous solution of ammoniaand (20 ml). The aqueous layer was allocated, the ATEM extracted with dichloromethane (3×20 ml) before as the combined organic layers are dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:ethyl acetate gradient 1:0 to 0:1 then a mixture of ethyl acetate:methanol 85:15)to give crude material. The crude material is triturated with methanol to obtain specified in the connection header in the form of a solid white (34 mg, 39%).1H NMR (DMSO-D6, 400 MHz) of 3.07 (6H, s, of usher.), a 4.83 (2H, d, J=5.6 Hz), vs. 5.47 (1H, t, J=5.6 Hz), 6.87 in (1H, t, J=8.7 Hz), the 7.43 (1H, m), 7,66 (1H, DD, J=10,8, 2.0 Hz), 8,54 (2H, m), 8,56 (1H, s). IHMS (method A): RT= 6,74 min, M+H+= 456.

EXAMPLE 106: Dimethylamide 3-(2-fluoro-4-iodoaniline)-7-phenoxymethyl[3,2-c]pyridine-2-carboxylic acid

To a solution of dimethylamide 3-(2-fluoro-4-iodoaniline)-7-hydroxymethylene[3,2-c]pyridine-2-carboxylic acid (34 mg, of 0.075 mmol) and triphenylphosphine (20 mg, of 0.075 mmol) in THF (3 ml) was added phenol (of 7.75 mg, 0,083 mmol) and DIAD (18,5 μl, 0,094 mmol)and the resulting mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate (40 ml), washed with 1 M NaOH (15 ml) and brine (15 ml). The organic layer emit, dried over magnesium sulfate and concentrated in vacuo.Purify the resulting residue using flash chromatography (Si-SPE, dichloromethane:ethyl acetate, gradient 1:0 to 0:1 then ethyl acetate:methanol 85:15), receiving raw material. Repeated purification using flash chromatography (Si-SPE, ethyl acetate:dichloromethane:cyclohexane 1:4:1) results specified in the connection header in the form of a solid white (12 mg, 30%).1H NMR (CDCl3, 400 MHz) 3,26 (6H, s, of usher.), lower than the 5.37 (2H, s)6,94 (1H, t, J=8.6 Hz), 7,02 (3H, m), 7,33 (2H, m), 7,41 (1H, m), 7,49 (1H, DD, J=9,9, 1.9 Hz), 8,55 (1H, s), 8,66 (2H, apparent). IHMS (method A): RT= 12,30 min, M+H+= 532.

EXAMPLE 107: Sodium salt of 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

To a suspension of ethyl ester of 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridineboronic acid (100 mg, 0,277 mmol) in methanol (7 ml) was added 1 M NaOH (of 0.32 ml, 0.32 mmol) and the resulting mixture was stirred at 55°C for 3 hours. The resulting suspension is cooled to room temperature and stirred for 17 hours, then heated at 55°C for 2.5 hours. The reaction mixture was concentrated in vacuo and carry out azeotropic distillation of the residue with toluene (2×20 ml). The resulting residue is then triturated in water and filtered to obtain specified in the connection header in the form of a solid white (74 mg, 75%).1H NMR (CD3OD, 400 MHz) to 6.95 (1H, t, J=8.6 Hz), 7,44 (1H, DDD, J=8,4, of 1.8, 1.2 Hz) rate of 7.54 (1H, DD, J=10,4, 1.9 Hz), 8,48 (1H, s), 8,49 (1H, s). IHMS (method A): RT= 10,57 min, M+H+= 433./p>

EXAMPLE 108: Amide 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

To a solution of sodium salt of 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (60 mg, 0,110 mmol) and ameriglide (17.5 mg, 0.33 mmol) in DMF (1.5 ml) is added HATU (84 mg, 0.22 mmol) and diisopropylethylamine (75 μl, 0.44 mmol)and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water, then saturated sodium bicarbonate solution and then brine. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo.The resulting residue triturated with acetonitrile to obtain specified in the connection header in the form of a solid yellow (14 mg, 30%).1H NMR (CDCl3, 400 MHz) 5,69 (1H, s, of usher.), 6,30 (1H, s, of usher.), 6,98 (1H, t, J=8,4 Hz), 7,46 (1H, m), 7,53 (1H, DD, J=9,7, 1.9 Hz), 8,03 (1H, s), 8,46 (1H, s), 8,56 (1H, s). IHMS (method A): RT= 10,46 min, M+H+= 432.

EXAMPLE 109: (2 methanesulfonylaminoethyl)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

N-(2-aminoacetyl)methanesulfonamide (116 mg, 0.75 mmol), 3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (300 mg, 0.75 mmol), EDC (159 mg, 0.83 mmol), HOBT (112 mg, 0.83 mmol) and DIPEA (of 0.13 ml, 0.75 m is ol) suspended in THF (5 ml) before as added DMF (5 drops). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue is dissolved in ethyl acetate (20 ml), washed with aqueous saturated sodium bicarbonate solution (20 ml). The aqueous layer was washed with ethyl acetate (2×10 ml), the combined organic extracts washed with brine and dried over magnesium sulfate and concentrated in vacuo.The resulting residue is purified using flash chromatography on silica gel (SiO2, gradient 0-10% methanol in dichloromethane)to obtain specified in the connection header in the form of a solid pale yellow color (120 mg, 49%).1H NMR (CDCl3, 400 MHz) of 8.95 (1H, s), 8,61-8,59 (2H, m), to $ 7.91 (1H, s), 7,54 (1H, DD, J=9,6, 1.9 Hz), of 7.48 (1H, dt, J=8,4, 1.3 Hz), 7,37 (1H, DD, J=5,9, and 0.8 Hz), 7,03 (1H, t, J=8,4 Hz), 6,09-the 6.06 (1H, m), 4,17-to 4.15 (2H, m), 3,47-of 3.43 (2H, m), 3.04 from (3H, s). IHMS (method A): RT= 7,34 min, M+H+= 535.

EXAMPLE 138: ((R)-2,3-dihydroxypropane)amide 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

Stage 1: 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

A suspension of ethyl ester of 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (150 mg, 0.33 mmol) in IMS (10 ml) is treated with sodium hydroxide (1 M aqueous solution of 0.32 ml), and the reaction mixture is heated at 60°C for 3 hours. The resulting mixture is allowed to cool, then concentrated in vacuo, the crude residue is treated with water and the pH of the mixture adjusted to pH 5 using acetic acid. The resulting suspension is filtered, the residue is collected and dried in vacuo to obtain specified in the connection header in the form of a solid yellow (105 mg, 74%).1H NMR (DMSO-d6, 400 MHz) 8,63 (1H, s), to 8.45 (1H, s), of 7.69 (1H, d, J=10,28 Hz), 7,49 (1H, d, J=by 8.22 Hz), 7,03 (1H, s).

Stage 2: ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

A suspension of 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (177 mg, 0.41 mmol) in dry dichloromethane (6 ml) under nitrogen atmosphere cooled to 0°C and treated with DMF (1 drop) and oxalylamino (is 0.102 ml of 1.16 mmol). The reaction mixture is stirred for 1 hour, then the solvent is removed in vacuum.The resulting residue is again suspended in dichloromethane and treated dropwise with a solution of O-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethyl)hydroxylamine (101 mg, 0.69 mmol) and DIPEA (0,172 ml of 1.21 mmol) in dichloromethane (4 ml) before stirred for 3 hours. The reaction mixture was washed (water, brine), dried (Na2SO4), filter and concentrate in what the Aquum to obtain specified in the title compound as yellow foam (207 mg, 90%). This foam is used in the next stage without analysis and further purification.

Stage 3: ((R)-2,3-dihydroxy-propoxy)amide 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

A solution of ((R)-2,2-dimethyl[1,3]dioxolane-4-ylethoxy)amide 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2 carboxylic acid (280 mg, 0.49 mmol) in methanol/.HCl (0,14 ml .HCl(aq) in 25 ml of methanol) was stirred at room temperature until, while according to TLC nothing remains of the original material. The reaction mixture was concentrated in vacuo, and the residue is treated with dichloromethane (11 ml) and triethylamine (0,210 ml), stirring for 20 minutes before again concentrated in vacuo.The obtained solid residue is treated using HPLC with reversed phase (Phenomenex Luna 5 C18, 0.1% of HCO2H in water at a gradient of acetonitrile), to obtain specified in the connection header a solid pale yellow color (168 mg, 66%). IHMS (method A): RT= 8,87 min, M+H+= 522 (CD3OD, 400 MHz) 3,61 (1H, DD, J=11,4, a 5.3 Hz), the 3.65 (1H, DD, J=11,4, 5,1 Hz), of 3.94 (1H, m)to 3.99 (1H, DD, J=10,0, 6,8 Hz), 4,11 (1H, DD, J=10,0, 3.5 Hz), 7,07 (1H, t, J=8.6 Hz), 7,52 (1H, m), to 7.61 (1H, DD, J=10,2, 1.9 Hz), scored 8.38 (1H, s), 8,56 (1H, s).

EXAMPLE 139: (2 hydroxyethoxy)amide 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

Stage 1: 7-fluoro-3-(2-for-iodobenzylamine)furo[3,2-c]pyridine-2-carboxylic acid

Ethyl ester of 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (4,00 g, 9.0 mmol) is stirred in suspension in ethanol (150 ml) at room temperature before treated with 1 M NaOH, and heated at 60°C for 2 hours. The solvent is removed in vacuo, and the residue diluted with water (50 ml) and acidified to pH 4 glacial acetic acid. The obtained solid residue is collected by filtration, washed with water and dried at 40°C in vacuum (P2O5) to obtain specified in the title compound (3.75 g quantitatively). IHMS (method B) RT= 3,51 minutes, M+H+= 417.

Stage 2: (2-vinyloxyethoxy)amide 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid

7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (3.75 g, 9.0 mmol) is stirred in suspension in dry DCM (100 ml) in an argon atmosphere at 0°C and treated dropwise with oxalylamino (2,24 ml of 25.7 mmol)while maintaining the temperature below 5°C. the resulting mixture was stirred for 1 h before concentrated in vacuo.The residue is again suspended in dry DCM (100 ml) in an argon atmosphere at 0°C and treated dropwise with a solution of O-(2-vinyloxyethyl)hydroxylamine (1.40 g, and 14.3 mmol) and diisopropylethylamine (4,70 ml of 3.48 g, 27 mmol) in DCM (0 ml). The resulting solution was stirred and allowed to warm to room temperature within 3 hours before washed with water, then with saturated salt solution, dried (MgSO4), filtered and evaporated in vacuum, obtaining a residue, which is treated using flash chromatography on silica gel (SiO2gradient of 0-10% ethyl acetate in dichloromethane)to obtain specified in the connection header in a solid yellow color (2,41, 53%). IHMS (Method B) RT= 3.82 minutes, M+H+= 502.

Stage 3: (2-hydroxyethoxy)amide 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid

(2 vinyloxyethoxy)amide 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid (2,41 g, 4,80 mmol) suspended in ethanol (100 ml) and add concentrated hydrochloric acid (2.0 ml). The resulting mixture was stirred at room temperature for 1 hour before is neutralized by adding saturated aqueous sodium bicarbonate solution. The solvent is then removed in vacuo and the resulting residue dissolved in DCM, washed with water, dried (MgSO4), filtered and evaporated in vacuo to obtain a crude residue, which was purified using flash chromatography on silica gel (SiO2, gradient 0 to 2% methanol in dichloromethane)and then recrystallized (water-methanol) to obtain specified the CSOs in the title compound as yellow needles (0,837 g, 36%). IHMS (method A): RT= 9,15 min, M+H+= 476;1H NMR (DMSO-d6, 400 MHz) of 3.60 (2H, m), 3,88-3,93 (2H, m), 4,70 (1H, user. C)7,02 (1H, t, J=8,68 Hz), 7,46-7,49 (1H, m), 7,68 (1H, DD, J=10,55, with 1.92 Hz), at 8.36 (1H, s), 8,40 (1H, s)8,64 (1H, d, J=2,58 Hz), 11,95 (1H, s).

EXAMPLES 20-96 and 111-159

Compounds are presented in tables 2, 3, and 4 receive the General methods presented below.

Amides and hydroxamate obtained from the corresponding acid using the disclosed hereinafter, the method of joining. In some cases, intermediate acid are not allocated, the reaction mix is carried out, using crude carboxylate salt, obtained following the General method of saponification.

A common way of saponification

A mixture of ether carboxylic acids in aqueous NaOH (1-2 EQ.) and EtOH is heated at 70°C for 1 hour. The reaction mixture was concentrated in vacuo and carry out azeotropic distillation with toluene to obtain a crude carboxylate salt.

A common way combination

The corresponding salt of carboxylic acid or carboxylate are suspended in anhydrous THF before you add the appropriate hydroxylamine or amine (1-4 equiv.) EDCI (1-2 EQ.) or HATU (1-2 equiv.) HOBt (1-2 EQ.) and DIPEA (2-4 EQ.). In some cases, add DMF as co-solvent to increase the solubility. After stirring at room temperature until completion of the reaction (IHMS/TLC), the reaction mixture will contentresult in vacuum .The resulting residue is dissolved in ethyl acetate and washed with water before release organic layer, dried over sodium sulfate, then concentrated in vacuo and purified using one of the common cleaning methods disclosed hereinafter. If necessary, then remove all protective group using one of the conditions for removal of the protective groups which are disclosed below.

Common methods for removing protective groups

Method A: Aqueous HCl (1 n or 2 n) are added to a mixture of the protected substrate in an appropriate solvent at room temperature. The resulting mixture is stirred until until data analyses (TLC/JHMS) all source material used. The reaction mixture is neutralized, concentrated in vacuo and purified.

Method B: a Solution of the substrate in methanol injected into Isolute® SCX-2 cartridge. Then the cartridge was washed with methanol before elute the desired product, using 2 M ammonia in MeOH, and the eluent is collected, then concentrated to obtain a residue. The residue is purified.

Method C: TBAF in THF are added to a solution salelologa ether, the resulting mixture was stirred at room temperature until such time as according to the analyses (TLC/JHMS) all source material used. The reaction mixture was concentrated in vacuo and purified.

Method D: TFA are added to a substrate or in pure form or in the form of RA is down in DCM. The reaction mixture was stirred at room temperature until such time as according to the analyses (TLC/JHMS) all source material used. The reaction mixture was concentrated in vacuo and purified.

Method E: a 20% solution of piperidine in DME added to the substrate. The reaction mixture was stirred at room temperature until such time as according to the analyses (TLC/JHMS) all source material used. The reaction mixture was then concentrated.

Method F: 4 N. HCl solution in dioxane are added to a substrate. The reaction mixture was stirred at room temperature until such time as according to the analyses (TLC/JHMS) all source material used. The reaction mixture was then concentrated.

Method G: an Aliquot (3 mol equivivalent) their solution of HCl in methanol [concentrated HCl (0,14 ml) in methanol (25 ml)] is added to the combined substrate at room temperature. The resulting mixture is stirred until until data analyses (TLC/JHMS) all source material used. Content is evaporated to dryness, the residue dissolved in dichloromethane and treated with triethylamine (3 mol equivalents) at room temperature for 10 minutes the resulting mixture was then concentrated in vacuo and the residue purified.

Common cleaning methods

Method A: Si-SPE, or Si-ISCO, gradient ethyl acetate/cycle is hexane.

Method B: Si-SPE, or Si-ISCO, gradient ethyl acetate/DCM.

Method C: Si-SPE Il Si-ISCO, gradient methanol/DCM

Method D: Si-SPE, or Si-ISCO, gradient methanol/ethyl acetate.

Method E: HPLC with reversed phase Phenomenex Luna 5 phenyl/hexyl, of 0.1% TFA in water at a gradient of methanol.

Method F: HPLC with reversed phase Phenomenex Luna 5 phenyl/hexyl, of 0.1% TFA in water at a gradient of acetonitrile.

Method G: HPLC with reversed phase Phenomenex Luna 5 phenyl/hexyl, with 0.1% HCO2H in water at a gradient of methanol.

Method H: HPLC with reversed phase Phenomenex Luna 5 phenyl/hexyl, with 0.1% HCO2H in water at a gradient of acetonitrile.

Method I: the substrate Solution in methanol is introduced into Isolute® SCX-2 cartridge. Then the cartridge was washed with methanol before the target product elute using 2 M ammonia in MeOH.

Method J: Si-SPE, or Si-ISCO, gradient ethyl acetate/hexane.

Method K: HPLC with reversed phase Sunfire C18, of 0.05% TFA in water at a gradient of acetonitrile.

Method L: Si-SPE, or Si-ISCO, gradient ethanol/ethyl acetate.

Method M: Si-SPE, gradient ether/pentane, then the gradient of methanol/ether.

Deviations from the General ways:

1Triturated in hot methanol;2recrystallized from ethyl acetate;3triturated with diethyl ether;4recrystallized from diethyl ether;5recrystallized from 5% MeOH in CHCl3;6Si-SPE eluent ether/pentane, the ATEM methanol in ether; 7triturated with ethyl acetate,8ether omelet lithium hydroxide,9use column C18;10the reaction of lead in DMF;11recrystallization from a mixture of chloroform/methanol;12triturated with acetonitrile;13DMF is used as co-solvent in the reaction;14recrystallization from methanol;15final elution with 10% methanol in ethyl acetate;16the reaction mixture is heated at 55°C;17triturated with a mixture of diethyl ether/DCM.

TABLE 2
ExampleStructure/nameWay (way) Premiata-
the offered cleaning
The method of removal of the protective groupsEnd-to-end cleanupThe way IHMS, Rt, M+N+1H NMR (MD)
20
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (piperidine-4-yloxy)the amide monovariate, Sol
InA MeonI1 5,41, 497, A(DMSO-D6) was 1.69 (2H, m), at 1.91 (2H, m), 2,71 (2H, m), 3,10 (2H, m), 3,93 (1H, m)6,86 (1H, t, J=8,8 Hz), 7,44 (1H, m), of 7.64 (2H, m), and 8.5 (1H, d, J=5.8 Hz), 8,59 (1H, d, J=0.8 Hz), at 8.60 (2H, s, of user.)
21
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid amide
In,26,68, 398, A(DMSO-D6)? 7.04 baby mortality (1H, t, J=8.7 Hz), 7,50 (1H, m), 7,66 (1H, DD, J=5,9, and 0.9 Hz), of 7.70 (1H, DD, J=10,6, 1.9 Hz), 7,78 (1H, s, of usher.), 8,01 (1H, s, of usher.), scored 8.38 (1H, s), 8,54 (1H, s), 8,58 (1H, d, J=5,9 Hz)
22
3-[(2-fluoro-4-iodoaniline)methylamino]-furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
AndA IMSD6,40,
472, A
(CDCl3) to 3.58 (3H, s), of 3.78 (2H, m), 4.09 to (2H, m), 4,14 (1H, s, of usher.), of 6.99 (1H, t, J=8.6 Hz), 7,38 (1H, DD, J=5,9, and 0.9 Hz), 7,42 (1H, DD, J=10,9, 2.0 Hz), of 7.48 (1H, DDD, J=8,6, 2,0, 1.0 Hz), 8,23 (1H, s), 8,55 (1H, d, J=5,9 Hz), 9,27 (1H, s)

23
3-(2-fluoro-4-iodoaniline)furo[3,2]-pyridine-2-carboxylic acid (2-g is doxetaxel)methylamide
AndA IMSA7,24, 472, A(CDCl3) and 3.31 (1H, s, of usher.), to 3.58 (3H, s), 3,86 (2H, m), 4,19 (2H, m), 7,00 (1H, t, J=8.5 Hz), 7,39 (1H, DD, J=5,9, 1.0 Hz), 7,44 (1H, m), 7,52 (1H, DD, J=9,8, 1.9 Hz), and 8.5 (1H, s), 8,59 (1H, d, J=5,9 Hz), 8,61 (1H, s)
24
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid hydroxyamide
InA in MeOH35,93, 414, A(DMSO-D6) 6,98 (1H, t, J=8,8 Hz), 7,44 (1H, m), 7,68 (1H, DD, J=10,7, 1.9 Hz), 8,13 (1H, d, J=6.5 Hz), 8,54 (1H, s), 8,81 (1H, d, J=6.5 Hz), 9,01 (1H, s), 11,58 (1H, s, of user.)
25
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (tetrahydropyran-4-yloxy)amide
--C4of 7.82, 497, A(CDCl3) to 1.82 (2H, m), of 2.08 (2H, m), 3,50 (2H, m), a 4.03 (2H, dt, J=11,9, and 4.5 Hz), 4,25 (1H, m), of 6.99 (1H, t, J=8.5 Hz), 7,37 (1H, DD, J=5,9, and 0.9 Hz), 7,45 (1H, m), 7,52 (1H, DD, J=9,8, 1.9 Hz), to 7.99 (1H, s), and 8.6 (1H, d, J=5,9 Hz), 8,63 (1H, d, J=0.9 Hz), 8,72 (1H, s)

26
3-(4-bromo-2-chlorpheniramine)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
S, IA IMSI5of 6.96, 426/428, A(CD3OD) of 3.80 (2H, m), 4,07 (2H, m), 7,20 (1H, d, J=8.6 Hz), was 7.45 (1H, DD, J=8,6, and 2.3 Hz), the 7.65 (1H, DD, J=5,9, and 0.9 Hz), 7,71 (1H, d, J=2.3 Hz), 8,53 (1H, d, J=0.9 Hz), 8,56 (1H, d, J=5,9 Hz)
27
3-{[3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carbonyl]aminooxy}azetidin-1-carboxylic acid tert-butyl methyl ether
--In9,83, 568, A(CDCl3) a 1.45 (9H, s), 4,11 (2H, m), 4,17 (2H, m), 4,89 (1H, TT, J=6,4, 4.0 Hz), 7,01 (1H, t, J=8.5 Hz), 7,39 (1H, d, J=5.8 Hz), 7,47 (1H, m), 7,53 (1H, DD, J=9,7, 1.9 Hz), of 7.97 (1H, s), at 8.60 (1H, d, J=5.8 Hz), 8,61 (1H, s), of 8.95 (1H, s)
28
[3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl](4-hydroxyisoquinoline-2-yl]metano
ADA6,53, 470, A(DMSO-D6) 3,79 (1H, DD, J=11,40, 1.5 Hz), 3,90 (1H, DD, J=8,7, 1.8 Hz), 3,98 (1H, DD, J=8,7, 4.4 G is), of 4.00 (1H, DD, J=11,4, 5,5 Hz), 4.72 in (1H, m), 5,52 (1H, d, J=4.0 Hz), 7,01 (1H, t, J=8.7 Hz), δ 7,49 (1H, m), of 7.70 (1H, DD, J=a 10.5, 1.9 Hz), 7,73 (1H, DD, J=5,9, 1.0 Hz), 8,51 (1H, s), to 8.57 (1H, d, J=1.0 Hz), 8,58 (1H, d, J=5,9 Hz)

29
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid methoxime
--With47,14, 428,(CDCl3) of 3.94 (3H, s), 7,00 (1H, t, J=8.5 Hz), 7,37 (1H, DD, J=5,9, and 0.9 Hz), 7,45 (1H, m), 7,52 (1H, DD, J=9,8, 2.0 Hz), 7,98 (1H, s), 8,59 (1H, d, J=5,9 Hz), 8,63 (1H, s), 8,84 (1H, s)
30
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
And13,88, 362,(CD3OD) of 3.80 (2H, m), 3,85 (3H, s)4,07 (2H, m), at 6.84 (1H, DDD, J=8,8, is 2.8, 1.2 Hz), to 6.88 (1H, DD, J=12.1 is 2,8 Hz), 7,35 (1H, t, J=8,8 Hz), 7,55 (1H, DD, J=6,0, 0.9 Hz), with 8.05 (1H, s), 8,46 (1H, d, J=6.0 Hz)
31
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-aminoethoxy)amide
A, C DI4,78, 456,(CD3OD) of 3.14 (2H, m), 4,08 (2H, m), for 6.81 (1H, t, J=8.7 Hz), 7,39 (1H, m)to 7.50 (1H, DD, J=10,6, 2.0 Hz), to 7.61 (1H, DD, J=5,9, 1.0 Hz), to 8.45 (1H, d, J=5,9 Hz), to 8.57 (1H, d, J=1.0 Hz)

32
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid [2-(2-oxopyrrolidin-1-yl)ethoxy]amide
--(CDCl3) to 2.15 (2H, m), of 2.53 (2H, t, J=8.1 Hz), 3,53 (2H, t, J=7,1 Hz)to 3.67 (2H, t, J=5.0 Hz), 4,08 (2H, t, J=5.0 Hz), 6,98 (1H, t, J=8.5 Hz), 7,42 (1H, m), 7,46 (1H, DD, J=5,9, and 0.9 Hz), to 7.50 (1H, DD, J=9,8, 1,9 Hz), 8,02 (1H, s), to 8.57 (1H, d, J=5,9 Hz), 8,64 (1H, s)to 10.6 (1H, s)
33
3-(2-fluoro-4-hydroxymethylamino)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
AndWith,3,88, 362,(DMSO-D6) 3,62 (2H, t, J=5.5 Hz), 3,93 (2H, t, J=5,5 Hz)to 4.52 (2H, d, J=5.7 Hz), 4,74 (1H, s, of usher.), and 5.30 (1H, t, J=5.7 Hz), to 7.15 (1H, DD, J=8,3, 1.8 Hz), 7,25 (1H, DD, J=11,6, 1.8 Hz), 7,29 (1H, t, J=8,3 Hz), to 7.64 (1H, DD, J=5,8, and 0.9 Hz), by 8.22 (1H, s), 8,31 (1H, s), 8,55 (1H, d, J=5.8 Hz), 11,74 (1H, s, of user.)
34
3-(2-fluoro-4-methylphenylimino)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
I6A IMSI,H5,31, 346, A(DMSO-D6) was 2.34 (3H, s), 3,62 (2H, t, J=5.0 Hz), 3,93 (2H, t, J=5.0 Hz), 7,03 (1H, d, J=8.6 Hz), 7,17 (1H, DD, J=12.1 is of 1.7 Hz), 7.23 percent (1H, t, J=8.6 Hz), 7,63 (1H, d, J=5.8 Hz), 8,17 (1H, s), of 8.27 (1H, s), 8,54 (1H, d, J=5.8 Hz)

35
3-(2-fluoro-4-methylsulfonylamino)-furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
AHof 5.89
378, A
(CD3OD) 2,52 (3H, s), 3,80 (2H, t, J=4,7 Hz), 4,07 (2H, t, J=4,7 Hz), 7,11 (1H, DD, J=8,5, 2.0 Hz), 7,18 (1H, DD, J=11,2, 2.0 Hz), 7,28 (1H, t, J=8.5 Hz), 7,58 (1H, DD, J=5,9, and 0.9 Hz), 8,32 (1H, s), and 8.50 (1H, d, J=5,9 Hz)
36
(2-{[3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carbonyl]aminooxy}ethyl)-methylcarbamyl acid tert-butyl methyl ether
A,710,4
7, 51, A
(CDCl3) of 1.52 (9H, s)to 2.94 (3H, s), of 3.60 (2H, t, J=4.9 Hz), 4,07 (2H, t, J=4.9 Hz), 6,97 (1H, t, J=8.5 Hz), the 7.43 (2H, m)to 7.50 (1H, DD, J=9,8, 1.7 Hz), 8,02 (1H, s), 8,58 (1H, d, J=5,9 Hz), 8,65 (1H, s), 10,54 (1H, s)
37
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-methylaminorex)amide
DI75,43, 471, A(DMSO-D6) 2,52 (3H, s), 2,89 (2H, t, J=5.3 Hz), 3,91 (2H, t, J=5.3 Hz), at 6.84 (1H, t, J=8,8 Hz), the 7.43 (1H, d, J=8.5 Hz), to 7.64 (1H, DD, J=10,8, 1.9 Hz), the 7.65 (1H, d, J=5.8 Hz), 8,49 (1H, d, J=5.8 Hz), 8,58 (1H, s), 8,61 (1H, s, of user.)

38
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-pyrrolidin-3-yloxy)the amide monovariate, Sol
InDH5,63, 483, A(CDCl3) 2,2l (1H, m), of 2.45 (1H, m), 3,24 (1H, DD, J=13,1, 2,9 Hz), 3,55 (2H, m), a 3.87 (1H, d, J=13.1 Hz), to 4.98 (1H, t, J=3.3 Hz), 6,98 (1H, t, J=8.5 Hz), 7,34 (1H, DD, J=5,9, and 0.9 Hz), the 7.43 (1H, m)to 7.50 (1H, DD, J=9,8, 1.9 Hz), of 7.96 (1H, s), 8,55 (1H, d, J=5,9 Hz), 8,61 (1H, d, J=0.9 Hz)
39
7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
8InDD9,23, 483,(CDCl3) a 3.83 (2H, t), of 4.13 (2H, t), 4,22 (1H, s, of usher.), of 7.00 (1H, t, J=8,4 Hz), of 7.48 (1H, t), of 7.55 (1H, DD, J=9,6, 1.9 Hz), to 7.93 (1H, s), 8,42 (1H, s), to 8.57 (1H, s), 8,99 (1H, s)
40
7-cyano-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
InA MeonIn9,58, 492,(CD3OD) with 3.79 (2H, m), 4,07 (2H, m), was 7.08 (1H, t, J=8.6 Hz), 7,53 (1H, m), a 7.62 (1H, DD, J=10,2, 1.9 Hz), 8,67 (1H, s), 8,91 (1H, s)

41
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (azetidin-3-yloxy)the amide monovariate, Sol
InA dioxaneN5,07, 469,(CD3OD) 4,20 (2H, DD, J=12,2, 4,4 Hz), 4,34 (2H, DD, J=12,2, 6.5 Hz), 4,89 (1H, m), 6,98 (1H, t, J=8.6 Hz), of 7.48 (1H, m), EUR 7.57 (1H, DD, J=10,4, 1.9 Hz), to 7.61 (1H, d, J=6.0 Hz), and 8.50 (1H, s),8,51 (1H, d, J=6.0 Hz), 8,53 (1H, s)
42
(2-fluoro-4-iodoaniline)-N-isobutoxide[3,2-C]pyridine-2-carboxamide
--J2,35, 470,(CDCl3) is 8.75 (s, 1H), to 8.62 (s, 1H), 8,59 (d, 1H), to 7.99 (s, 1H), 7,50 (DD, 1H), 7,43 (d, 1H), 7,37 (d, 1H), 6,85 (t, 1H), 3,82 (d, 2H), 2,04 (m, 1H), 1,01 (s, 3H), and 1.00 (s, 3H),
43
(2-fluoro-4-iodoaniline)-N-isopropoxyphenol[3,2-C]pyridine-2-carboxamide
--J2,07, 456,(CDCl3) 8,64 (s, 2H), at 8.60 (d, 1H), 8,15 (s, 1H), 7,51 (DD, 1H), 7,43 (t, 2H), 6,97 (t, 1H), 4,25 (t, 1H), 1,195 (s, 3H), 1,19 (s, 3H)
44
(2-fluoro-4-iodoaniline)-N-benzyloxyphenol[3,2-C]pyridine-2-carboxamide
--J2,42, 504,(CDCl3) 8,68 (s, 1H), 8,63 (s, 1H), 8,58 (d, 1H), 8,10 (s, 1H), 7,54 (DD, 1H), 7,50-7,40 (m, 6H), was 7.36 (d, d, 1H), 7,0 (t, 1H), and 5.2 (s, 2H)

45
(2-fluoro-4-iodoaniline)-N-(3-hydroxypropoxy)furo[3,2-C]pyridine-2-carboxamide
JTo3,49,
472,
(CDCl3) 8,79 (d, 1H), 8,63 (s, 1H), 8,00 (s, 1H), 7.62mm (d, d, 1H), 7,58 (d, d, 1H), 7,52 (d, t, 1H), 7,0 (t, 1H), 4,27 (t, 2H), 3,35 (t, 2H), 2,00 (m, 2H)
46
(2-fluoro-4-iodoaniline)-N-[3-(pyridine-2-carboxamide)propoxy)furo-[3,2-C]pyridine-2-carboxamide
--To2,16, 576,(CDCl3) to 8.70 (s, 1H), 8,58 (d, m, 1H), charged 8.52 (t, 1H), 8,23 (l, t, 1H), 8,10 (s, 1H), to 7.93 (t, d, 1H), of 7.75 (d, d, 1H), to 7.59 (d, d, 1H), 7,53 (d, m, 1H), 7.5 (t, m, 1H), 6,97 (t, 1H), 4,22 (t, 2H), 3,8 (t, 2H), 2,10 (m, 2H)
47
(2-fluoro-4-iodoaniline)-N-[3-(nicotinamide)propoxy)]furo[3,2-C]pyridine-2-carboxamide
--To3,47, 576, E(DMSO) to 9.00 (s, 1H), up 8.75 (t, 1H), 8,68 (d, 1H), at 8.60 (d, 1H), 8,56 (s, 1H), at 8.36 (s, 1H), 8,19 (l, t, 1H), 7,68 (m, 2H), 7,50 (m, 2H), 7,02 (t, 1H), 4.00 points (t, 2H), 3,42 (m, 2H), and 1.9 (m, 2H)
48
(2-fluoro-4-iodoaniline)-N-[3-(isonicotinamide)propoxy)]-furo[3,2-C]pyridine-2-carboxamide
--To1,72, 576,(CDCl3) 9,10 (s, 1H), 8,70 (m, 3H), to 8.62 (d, 1H), at 8.60 (t, 1H), 7,98 (s, 1H), to 7.84 (d, d, 2H), 7,58 (d, d, 1H), 7,49 (d, m, 1H), 7,39 (d, m, 1H),? 7.04 baby mortality (t, 1H), 4,20 (t, 2H), 3,80 (m, 2H), 2.0 (m, 2H)

49
(2-fluoro-4-iodoaniline)-N-propoxyphene[3,2-C]pyridine-2-carboxamide
--To2,11, 456,(CDCl3) 8,76 (s, 1H), 8,64 (s, 1H), at 8.60 (d, 1H), 8,00 (s, 1H), 7,52 (d, d, 1H), 7,44 (d, d, 1H), 7,38 (d, d, 1H), 6,99 (t, 1H), of 4.05 (t, 2H), 1.8 m (m, 2H), of 1.05 (t, 3H)
50
(2-fluoro-4-iodoaniline)-N-idoxifene[3,2-C]pyridine-2-carboxamide
--To1,87, 442,(CDCl3) 8,77 (s, 1H), 8,64 (s, 1H), at 8.60 (d, 1H), 8,00 (s, 1H), 7,52 (d, d, 1H), 7,44 (d, d, 1H), 7,38 (d, d, 1H), 6,99 (t, 1H), 4,19 (square, 2H), 1,40 (t, 3H)
51
N-(2(benzyloxy)-2-methylpropoxy)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide
--To2,78, 576,(CDCl3) to 9.8 (s, 1H), at 8.60 (s, 1H), charged 8.52 (d, 1H), and 7.9 (s, 1H), 7,50 (d, d, 1H), 7,42 (m, 3H), 7,35 (m, 3H), of 7.00 (d, 1H), 6,95 (t, 1H), 4,60 (s, 2H), 4,0 (s, 2H), 1,40 (s, 6H)
52
2-hydroxy-2-methylpropyl-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylate
--Jto 2.06, 471,(CDCl3) to 8.62 (s, 1H), at 8.60 (d, 1H), and 7.5 (s, 1H), 7,55 (d, d, 1H), of 7.48 (m, 2H),? 7.04 baby mortality (t, 1H), and 5.30 (s, 2H), 4,30 (s, 2H), 1,40 (s, 6H)

53
N-(2-hydroxyethoxy)-3-(4-bromo-2-forgenerating)furo[3,2-C]pyridine-2-carboxamide
JATo1,67, 412,(DMSO) 11,90 (s, 1H), 8,62 (m, 2H), 8,40 (s, 1H), 7,80 (m, 1H), 7,60 (d, d, 1H), 7,30 (d, 1H), 7,15 (t, 1H), 3,90 (m, 2H), 3,60 (t, 2H)
54
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxy-1-methylethoxy)amide
J to 3.58, 472, E(DMSO-d6) 11,78 (users, 1H), 8,59 (d, J=6.0 Hz, 1H), 8,55 (s, 1H), at 8.36 (s, 1H), 7,72-to 7.67 (m, 2H), 7,49 (d, J=8,4 Hz, 1H), 7,00 (t, J=8,8 Hz, 1H), 4,68 (user., 1H), 3,99-3,93 (m, 1H), 3,49-3,47 (m, 2H), 1,18 (d, J=6.4 Hz, 3H)
55
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxypropoxy)amide
J3,76,
472, E
(DMSO-d6) 11,94 (users, 1H), at 8.60 (d, J=6.0 Hz, 1H), 8,55 (s, 1H), at 8.36 (s, 1H), 7,71 (DD, J=10,4, and 1.6 Hz, 1H), 7,68 (DD, J=6,0, 1.2 Hz, 1H), 7,49 (d, J=8,4 Hz, 1H), 7,00 (t, J=8,8 Hz, 1H), a 4.83 (user., 1H), a-3.84 (m, 1H), 3,71 (d, J=6.0 Hz, 2H), only 1.08 (d, J=6.4 Hz, 3H)

57
56
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxy-1-hydroxyethyloxy)amide
JATo3,35, 488, E(DMSO-d6) 11,94 (users, 1H), 8,64-8,61 (m, 2H), 8,44 (s, 1H), 7,81 (d, J=5.6 Hz, 1H), of 7.70 (DD, J=10,4, 2.0 Hz, 1H), 7,49 (d, J=8,4 Hz, 1H),? 7.04 baby mortality (t, J=8,8 Hz, 1H), 3,82 (quintet, J=4,8 Hz, 1H), 3,57 (d, J=4.8 Hz, 4H)

N-[3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carbonyl]methanesulfonamide
--Toof 3.77, 476, E(CDCl3) 8,77 (d, J=6,4 Hz, 1H), 8,63 (s, 1H), 8,10 (s, 1H), 7,63-7,52 (m, 3H), 7,06 (t, J=8,4 Hz, 1H), 3,49 (s, 3H)
58
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-piperidine-1-ylethoxy)amide
--To3,82, 525, E(CDCl3) 8,79 (d, J=6,4 Hz, 1H), to 8.70 (s, 1H), of 7.97 (s, 1H), to 7.77 (d, J=6,4 Hz, 1H), EUR 7.57 (DD, J=a 9.6, 2.0 Hz, 1H), 7,47 was 7.45 (m, 1H), 6,97 (t, J=8,4 Hz, 1H), 4,48 (ushort, J=5,2 Hz, 2H), 3,79 (userd, J=12.0 Hz, 2H), 3,39 (ushort, J=5,20 Hz, 2H), 2,82 (ushort, J=11,6 Hz, 2H), 2, 16-2,04 (m, 2H), 2.00 in with 1.92 (m, 3H), 1,58 of 1.46 (m, 1H)

59
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((R)- 3-hydroxypyrrolidine-1-yl)methanon
--J2,62, 468, D(CDCl3) 8,69 (apparent s, 1H), 8,65 (apparent s, 1H), 8,57(apparent d, J=5,9 Hz, 1H), of 7.48 (apparent DD, J=10.0 Hz, 1.9 Hz, 1H), 7,39-7,41 (m, 2H), 6,95 (apparent t, J=8.6 Hz, 1H), 4,59 with 4.65 (m, 1H), 4.09 to 4.26 deaths (m, 2H), 3,74-3,88 (m, 2H), 2,02-of 2.20 (m, 2H), 1.75 of (apparent s, 1H)
60
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((3S,4S)-3,4-dihydroxypyrrolidine-1-yl)methanon
--J3,32, 484, D(DMSO-d6) 8,68 (s, 1H), 8,57-8,59 (m, 2H), 7,69-7,76 (m, 2H), 7,47-to 7.50 (m, 1H), 7,01-7,05 (m, 1H), 5,24 at 5.27 (m, 2H), 3.96 points-4,07 (m, 3H), 3,83-3, 86 (m, 1H), 3,61-the 3.65 (m, 1H), 3.45 points-of 3.48 (m, 1H)

td align="center"> To
TABLE 3
ExampleStructure/nameWay (way) intermediate purificationThe method of removal of the protective groupsWay (ways) final cleaningThe way IHMS, Rt, M+N+
61
3-(2-fluoro-4-iodoaniline)-N-(3-hydroxypropyl)furo[3,2-C]pyridine-2-carboxamide
--To2,47, 456, D
62
3-(2-fluoro-4-iodoaniline)-N-(2-methoxyethyl)furo[3,2-C]pyridine-2-carboxamide
--To4,12, 456, D
63
3-(2-fluoro-4-iodoaniline)-N-isopropylthio[3,2-C]pyridine-2-carboxamide
--To3,41, 440, D
64
3-(2-fluoro-4-iodoaniline)-N-(2-cyclopropylethyl)furo[3,2-C]pyridine-2-carboxamide
--To3,81, 466, D
65
3-(2-fluoro-4-iodoaniline)-N-(3-(dimethylamino)propyl)furo[3,2-C]pyridine-2-carboxamide
--To2,20, 483, D
66
3-(2-fluoro-4-iodoaniline)-N-(2-(2-hydroxyethoxy)ethyl) - furo[3,2-C]pyridine-2-carboxamide
--To2,64, 486, D
67
N-(3-(1H-imidazol-1-yl)propyl-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide
--To1,41, 506, D
68
3-(2-fluoro-4-iodoaniline)-N-(1,3-dihydroxypropyl-2-yl)furo[3,2-C]pyridine-2-carboxamide
--To2,30, 472, D
69
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(thiazolidin-3-yl)methanon
--To4,98, 470, D
70
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((S)-3-hydroxypyrrolidine-1-yl)methanon
--To2,62, 468, D
71
(3-(4-bromo-2,5-dipertanyakan)furo[3,2-C]pyridine-2-yl)((R)-3-hydroxypyrrolidine-1-yl)methanon
--D3,83, 439, E
72
(3-(4-bromo-2-forgenerating)furo[3,2-C]pyridine-2-yl)((R)-3-hydroxypyrrolidine-1-yl)methanon
--D3,76, 421, E
73
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((3S,4R)-3,4-dihydroxypyrrolidine-1-yl)methanon
--To1,76, 484,
74
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((R)-3-aminopyrrolidine-1-yl)methanon
JDTo1,60, 467,
75
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((S)-3-hydroxypiperidine-1-yl)methanon
--1,97, 482,
76
(3-(2-fluoro-4-iodoaniline)-N-((S)-1-hydroxypropan-2-yl)furo[3,2-C]pyridine-2-carboxamide
--To1,94, 456,
77
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(2-(thiazol-yl)pyrrolidin-1-yl)methanon
--To2,37, 535,
78
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(3-(methylsulphonyl)pyrrolidin-1-yl)methanon
--To2,00, 530,
79
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((S)-2-(hydroxymethyl)pyrrolidin-1-yl)methanon
--To2,00, 482,
80
(3-(2-fluoro-iodobenzylamine)furo[3,2-C]pyridine-2-yl)(2-(hydroxymethyl)piperidine-1-yl)methanon
--To2,10, 496,
81
3-(2-fluoro-4-iodoaniline)-N-(2-hydroxyethyl)-N-methylfuran[3,2-C]pyridine-2-carboxamide
--To1,81, 456,
82
3-(2-fluoro-4-iodoaniline)-N-(2-hydroxyethyl)furo[3,2-C]pyridine-2-carboxamide
--To1,80, 442,
83
3-(2-fluoro-4-iodoaniline)-N,N-dimethylurea[3,2-C]pyridine-2-carboxamide
--To2,11, 426,
84
3-(2-fluoro-4-iodoaniline)-N-(2,3-dihydroxypropyl)furo[3,2-C]pyridine-2-carboxamide
--To1,75, 472,
85
3-(2-fluoro-4-iodoaniline)-N-((R)-1-hydroxypropan-2-yl)furo[3,2-C]pyridine-2-carboxamide
--To1,96, 456,
86
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(3-(hydroxymethyl)piperidine-1-yl)methanon
--To1,99, 496,
87
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((R)-2-(hydroxymethyl)piperidine-1-yl)methanon
--To2,07, 482,
88
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(4-hydroxypiperidine-1-yl)methanon
--To1,89, 482,
89
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((R)-3-(hydroxypiperidine-1-yl)methanon
-- To1,95, 482,
90
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(morpholino)metano
--To2,07, 468,
91
3-(2-fluoro-4-iodoaniline)-N-methylfuran[3,2-C]pyridine-2-carboxamide
--To1,88, 412,
92
3-(2-fluoro-4-iodoaniline)-N-(2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethyl) - furo[3,2-C]pyridine-2-carboxamide
--J2,38, 526,
93
3-(2-fluoro-4-iodoaniline)-N-(3,4-dihydroxybutyl)furo[3,2-C]pyridine-2-carboxamide
JATo1,75, 486,
94
3-(2-fluoro-4-iodoaniline)-N-(2-((S)2,2-dimethyl-1,3-dioxolane-4-yl)ethyl) - furo[3,2-C]pyridine-2-carboxamide
--J2,40, 526,
95
3-(2-fluoro-4-iodoaniline)-N-((S)-3,4-dihydroxybutyl)furo[3,2-C]pyridine-2-carboxamide
JATo1,74, 486,
96
3-(2-fluoro-4-iodoaniline)-N-isopentyl[3,2-C]pyridine-2-carboxamide
--To2,85, 468,

TABLE 4
ExampleStructure/nameWay (way) intermediate purificationThe method of removal of the protective groupsEnd-to-end cleanupThe way IHMS, Rt, M+N+1H NMR (MD)
111
3-(2-fluoro-4-iodoaniline)-N-phenyloxirane[3,2-C]pyridine-2-CT is the oksamid
--To5,04, 490, E(DMSO-d6) to 8.7 (m, 2H), charged 8.52 (s, 1H), 7,83 (d, 1H), 7.7 (d, d, 1H), 7.5 (d, m, 1H), 7,34 (m, 1H), and 7.1 (m, 4H)
112
3-(2-fluoro-4-iodoaniline)-N-(2-hydroxy-2-methylpropoxy)furo[3,2-C]pyridine-2-carboxamide
3,987, 486,1, E(CDCl3) of 9.21 (s, 1H), at 8.60 (m, 2H), 7,95 (s, 1H), 7,52 (d, m, 1H), 7,45 (d, m, 1H), 7,38 (d, m, 1H), 6.90 to (t, 1H), 3,97 (s, 2H), 1,32 (s, 6H)
113
N-(1-hydroxy-2-methylpropan-2-yloxy)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide
--J4,13, 486,1, E(DMSO) at 8.60 (d, 1H), 8,54 (s, 1H), scored 8.38 (s, 1H), 8,15 (s, 1H), of 7.96 (m, 1H), of 7.70 (t, 2H), 7,50 (d, m, 1H),? 7.04 baby mortality (t, 1H), 4.75 V (t, 1H), 3,3 (d, 2H), 1,2 (C, 6N)

114
3-(2-fluoro-4-iodoaniline)-N-(4-hydroxy-2-methylbutane-2-yloxy)furo[3,2-C]pyridine-2-carboxamide
-4,03, 500,1, E(DMSO) of 8.90 (s, 1H), at 8.60 (t, 2H), 8,00 (s, 1H), 7,51 (d, m, 1H), 7,44 (d, m, 1H), 7,40 (d, d, 1H), 7,00 (t, m, 1H), 3,95 (t, 2H), 1,92 (t, 2H), 1,50 (s, 6H)
115
N-((pyridin-2-yl)methoxy)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide
--8,07, 505,1, E(DMSO) 8,58 (d, 1H), 8,55 (t, 2H), scored 8.38 (s, 1H), 7,85 (t, d, 1H), of 7.70 (d, d, 1H), to 7.67 (d, d, 1H), 7,63 (d, 1H), 7,50 (d, m, 1H), was 7.36 (m, 1H), 7,02 (t, 1H), free 5.01 (s, 2H)
116
N-(1-phenylethane)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide
--J13,55, 518,1, E(DMSO) 8,32 (s, 1H), compared to 8.26 (d, 1H), to 8.20 (s, 1H), 7,73 (s, 1H), 7.23 percent (d, d, 1H), 7,05-7, 18 (m, 7H), to 6.67 (t, 1H), 4,85 (square, 1H), 1,40 (d, 3H)

117
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((R)-2-hydroxypropoxy)amide
J 3,76, 472, E(DMSO-d6) 11,94 (users, 1H), at 8.60 (d, J=6.0 Hz, 1H), 8,55 (s, 1H), at 8.36 (s, 1H), 7,71 (DD, J=10,4, and 1.6 Hz, 1H), 7,68 (DD, J=6,0, 1.2 Hz, 1H), 7,49 (d, J=8,4 Hz, 1H), 7,00 (t, J=8,8 Hz, 1H), a 4.83 (user., 1H), a-3.84 (m, 1H), 3,71 (d, J=6.0 Hz, 2H), only 1.08 (d, J=6.4 Hz, 3H)
118
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-2-hydroxypropoxy)amide
J3,76,
472, E
(DMSO-d6) 11,94 (users, 1H), at 8.60 (d, J=6.0 Hz, 1H), 8,55 (s, 1H), at 8.36 (s, 1H), 7,71 (DD, J=10,4, and 1.6 Hz, 1H), 7,68 (DD, J=6,0, 1.2 Hz, 1H), 7,49 (d, J=8,4 Hz, 1H), 7,00 (t, J=8,8 Hz, 1H), a 4.83 (user., 1H), a-3.84 (m, 1H), 3,71 (d, J=6.0 Hz, 2H), only 1.08 (d, J=6.4 Hz, 3H)
120
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(3-hydroxy-3-methylpyrrolidine-1-yl)methanon
--J3,93, 482,1, D(DMSO-D6) 8,78-8,80 (m, 2H), 8,70-8,72 (m, 1H), of 7.96-7,98 (m, 1H), 7,75 for 7.78 (m, 1H), of 7.48-to 7.50 (m, 1H), 7,00-7,02 (m, 1H), 3,99-was 4.02 (m, 2H), 3,45-3,70 (m, 2H), 1,80-of 1.95 (m, 2H), 1.30 and 1.32 to (s, 3H)


(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((3R,4R)-3-amino-4-hydroxypyrrolidine-1-yl)methanon
121JEJ3,06, 483,1, D(DMSO-D6) 8,60 is 8.75 (m, 2H), 8,18 is 8.22 (m, 2H), 7,75 for 7.78 (m, 1H), 7,56-7,58 (m, 1H), 7,07-7,10 (m, 1H), 5,80-5,90 (users, 1H), 3,50-and 4.40 (m, 6H)
122
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(3-hydroxyazetidine-1-yl)methanon
--J3,61, 454,0, D(DMSO-D6) 8,66-8,68 (s, 1H), 8,62-8,65 (d, 1H), of 8.47 (s, 1H), 7,92-to 7.95 (m, 1H), 7,63-to 7.67 (m, 1H), 7,42-7,46 (m, 1H), of 6.96-7,01 (m, 1H), 4,70-4,75 (users, 1H), 4,50-4,58 (m, 1H), 4,21-the 4.29 (m, 2H), 3,49-3,51 (m, 2H)
123
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((2R,3R)-3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanon
--J1,96, 498,0, C(DMSO-D6) cent to 8.85-8,87 (users, 1H), 8,65-to 8.70 (m, 2H), 8,00-8,02 (d, 1H), 7,62-the 7.65 (m, 1H), 7,38-7,42 (d, 1H), 6.90 to-6,98 (m, 1H), 4,28-4,32 (m, 2H), 3,80-3,82 (m, 1H), 3,65-of 3.80 (m, 1H), 3,60-3,62 (m, 2H), 3,50 is 3.57 (m, 2H)

124
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((2R,3R,4R)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanon--J3,28, 514,1, D(DMSO-D6) 8,65-8,80 (m, 2H), of 7.90-to 7.99 (m, 1H), 7,71 for 7.78 (m, 1H), of 7.48-7,52 (m, 1H), 4,01-4,12 (m, 3H), 3.95 to 4.00 points (m, 1H), 3,78-3,82 (m, 1H), 3,61-of 3.77 (m, 2H)125
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(pyrrolidin-1-yl)methanon--J4,59, 452,1, D(DMSO-D6) 8,61-8,63 (s, 1H), charged 8.52-8,55 (m, 2H), 7,63-to 7.68 (m, 2H), 7,42 was 7.45 (m, 1H), 6,92-6,98 (m, 1H), 3,82-a-3.84 (m, 2H), 3,78-of 3.80 (m, 2H), 3, 43-3, 46 (m, 2H), 3,40-of 3.42 (m, 2H)126
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((2R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanon--Jto 3.58, 498, D(DMSO-D6) 8,65 (s, 1H), 8,54-8,56 (m, 2H), 7,66-7,72 (m, 2H), 7,44-7,47 (m, 1H), 6,95-6,99 (m, 1H), 5,50-of 5.55 (m, 1H), 4,90-4,96 (m, 1H), 4,00-of 4.25 (m, 2H), 3,54-3,66 (m, 3H), of 3.28 (1H), 2, 10-2,22 (m, 1H), 1,84-1,89 (m, 1H)

3,76, 470, D
127
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanon
--J3,33, 498, D(DMSO-D6) 8,77 (s, 1H), 8,67-to 8.70 (m, 2H), 7,93-to 7.95 (m, 1H), 7,69-7,73 (m, 1H), 7,45-7,47 (m, 1H), 6,97-7,03 (m, 1H), 4,33-4,37 (m, 1H), 4,24-to 4.28 (m, 1H), 3.7 to 4.1 (user., 2H), 3.72 points is 3.76 (m, 2H), to 3.58-3,63 (m, 1H), 3,48-of 3.53 (m, 1H), 1,99 e 2.06 (m, 1H), 1,87-of 1.93 (m, 1H)
128
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((2R,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)methanon
LFJ3,24, 497, D(DMSO-D6) 8,72 (users, 1H), 8,62-8,65 (m, 2H), 8,12 (users, 3H), 7,72 for 7.78 (m, 2H), 7,51-7,53 (m, 1H), 7,13-to 7.18 (m, 1H), 4,3 1-4,47 (m, 3H), 3,82-3,90 (m, 2H), 3,48-of 3.54 (m, 1H), 2.40 a-2,47 (m, 1H), 1,95-2,00 (m, 1H)
129
3-(2-fluoro-4-iodoaniline)-N-(3-hydroxypropyl)-N-methylfuran[3,2-C]pyridine-2-carboxamide
--J(CD3OD) 8,93 (s, 1H), 8,72-a total of 8.74 (m, 1H), 8,08-8,10 (m, 1H), 7,58-to 7.61 (m, 1H), 7,46-of 7.48 (m, 1H), 6,95-6,99 (m, 1H), 4,90 (s, 2H), 3,7-of 3.78 (m, 1H), 3,55-3,63 (m, 3H), 3,28-to 3.35 (m, 1H), 3,03-3,13 (m, 2H), 1,80-1,98 (m, 2H)

130
3-(2-fluoro-4-iodoaniline)-N-(1H-pyrazole-3-yl)furo[3,2-C]pyridine-2-carboxamide
--J4,15, 463, D(DMSO-D6) 10,08 (s, 1H), 8,68-8,79 (m, 1H), 8,66 (s, 1H), 8.30 to (d, 1H), of 7.90-a 7.92 (m, 1H), 7,72-7,74 (m, 1H), 7,50-7,52 (m, 1H), 7, 13-7,16 (m, 1H), 6,07 (d, 1H)
131
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanon
--J3,47, 498, D(CD3OD) 8,87-8,79 (m, 2H), 8.07-a 8, 12 (m, 1H), 7,62-the 7.65 (m, 1H), 7,51-rate of 7.54 (m, 1H), 7,06-7,11 (m, 1H), 4,90 (s, 2H), 4,40-of 4.66 (m, 2H), 4,10-to 4.23 (m, 2H), 3,52-3,90 (m, 3H), 2,22-to 2.41 (m, 1H), 1,95-2,07 (m, 1H)
132
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)((2R,3R,4S)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanon
--J3,24, 514, D(CD3OD) 8,78 (s, 1H), 8,7 (d, J=6,51 Hz, 1H), 8,07 (d, J=6,51 Hz, 1H), 7,62-the 7.65 (m, 1H), 7,52-rate of 7.54 (m, 1H), 7,15-7,19 (m, 1H), br4.61 (users, 1H), 4,48 (users, 1H), 4,36-4,39 (m, 1H), 4,33 (users, 1H), 4,25-4,27 (m, 1H), 4.09 to-4,17 (m, 2H), 4,01-of 4.05 (m, 1H), 3,94-3,98 (m, 1H), 3,64-3,82 (m, 2H)

133
3-(2-fluoro-4-iodoaniline)-7-phenylfuro[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
AndN99,98, 534,(CDCl3), a total of 8.74 (s, 1H), 8,68 (s, 1H), 8,51 (s, 1H), to 7.93 (s, 1H), 7,71 (d, 2H, J=7.5 Hz), EUR 7.57-the 7.43 (m, 6H), 7,03 (t, 1H, J=8,2 Hz), 4,07 (t, 2H, J=4.3 Hz), of 3.78 (t, 2H, J=4.3 Hz)
134
3-(2-fluoro-4-iodoaniline)-7-methylfuran[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
InAndN96,32, 472,(CDCl3) 8,87 (s, 1H), 8,39 (m, 2H), to $ 7.91 (s, 1H), 7,50 (DD, 1H J=9,70, 1.8 Hz), 7,42 (d, 1H, J=8,4 Hz), 6,98 (t, 1H, J=8,2 Hz), 4.09 to (t, 2H, J=4.3 Hz), 3,80 (t, 2H, J=4.3 Hz) to 2.46 (s, 3H)

135
2-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethoxycarbonyl)-3-(2-fluoro-4-trimethylsilylmethylamine)-furo[3,2-C]pyridine-7-carboxylic acid ethyl ester
--In4,43, 546,
136
2-((R)-2,dihydroxypropane-carbarnoyl)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-7-carboxylic acid ethyl ester
-GM9,16, 560,(CD3OD) of 1.46 (3H, t, J=7,1 Hz), and 3.72 (2H, m), Android 4.04 (1H, m), 4,10 (1H, DD, J=10,1, 5,2 Hz), 4,17 (1H, DD, J=10,1, 3,9 Hz), 4,51 (2H, square, J=7,1 Hz), to 6.88 (1H, t, usher.), the 7.43 (1H, d, J=8,4 Hz), 7,54 (1H, DD, J=10,6, 1.7 Hz), 8,65 (1H, s), 8,98 (1H, s)
137
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (1H-imidazol-2-ylmethyl)amide
10-I115,06,
478,
(DMSO-D6) of 4.49 (2H, d, J=5.7 Hz), for 6.81 (1H, s), 7,01 (1H, s),? 7.04 baby mortality (1H, d, J=8,9 Hz), 7,49 (1H, m), of 7.70 (2H, m), scored 8.38 (1H, s), 57 (1H , d, J=0.9 Hz), 8,59 (1H, d, J=5.8 Hz), 9,01 (1H, d, J=5.8 Hz), 11,78 (1H, s, of user.)

138
7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((R)-2,3-dihydroxypropane)amide
InGIn, M12cent to 8.85,
522, A
(CD3OD) 3,61 (1H, DD, J=1 to 1.4, 5.3 Hz), the 3.65 (1H, DD, J=11,4, 5,1 Hz), of 3.94 (1H, m)to 3.99 (1H, DD, J=10,0, 6,8 Hz), 4,11 (1H, DD, J=10,0, 3.5 Hz), 7,07 (1H, t, J=8.6 Hz), 7,52 (1H, m), to 7.61 (1H, DD, J=10,2, 1.9 Hz), scored 8.38 (1H, s), 8,56 (1H, s)
139
7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
InGIn, M9,15, 476, A(CD3OD) with 3.79 (2H, m)4,06 (2H, m), 7,07 (1H, t, J=8.6 Hz), 7,52 (1H, m), to 7.61 (1H, DD, J=10,2, 2.0 Hz), 8,29 (1H, s), and 8.50 (1H, d, J=2,8 Hz)
140
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (piperidin-3-yloxy)amide
InMH 5,61, 497, A(DMSO-D6) to 1.60 (1H, m), of 1.85 (2H, m), of 1.94 (1H, m)to 2.94 (1H, m), of 3.12 (1H, m), and 3.16 (2H, d, J=3.6 Hz), 4,10 (1H, m), of 6.99 (1H, t, J=8.7 Hz), 7,49 (1H, m), 7,68 (1H, DD, J=5,8, 1.0 Hz), 7,69 (1H, DD, J=10,7, 2,0 Hz), to 8.41 (1H, s, of usher.), 8,59 (1H, d, J=5.8 Hz), at 8.60 (1H, d, J=1.0 Hz)

141
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-1-pyrrolidin-2-ylethoxy)amide
InMH5,38, 497, A(DMSO-D6) to 1.61 (1H, m), 1,90 (2H, m), a 2.01 (1H, m), 3,17 (2H, t, J=7,1 Hz), 3,80 (1H, m), 3,93 (1H, DD, J=11,6, 8.6 Hz), was 4.02 (1H, DD, J=11,6, 4,1 Hz)6,94 (1H, t, J=8,8 Hz), 7,47 (1H, m), 7,66 (1H, DD, J=5,8, and 0.9 Hz), to 7.68 (1H, DD, J=10,7, 1.9 Hz), 8,56 (1H, d, J=5.8 Hz), at 8.60 (1H, d, J=0.9 Hz), 10,13 (2H, s, of user.)
142
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (1H-imidazol-4-ylethoxy)amide
13-lower than the 5.37, 494,(DMSO-D6) 8,54-charged 8.52 (2H, t), with 8.33 (1H, s), the 7.65 (1H, DD, J=10,6, 1.8 Hz), a 7.62 (1H, DD, J=5,7, and 0.9 Hz), 7,46-the 7.43 (1H, t), 6,99-to 6.95 (2H, t), a 4.86 (2H, s)
143
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid [(1H-imidazol-4-yl)ethyl)]amide
10-I145,20, 492,(DMSO-D6, TFA-D6) of 2.92 (2H, t, J=6.8 Hz), to 3.58 (2H, t, J=6.8 Hz), 7,01 (1H, t, J=8,8 Hz), 7,45 (1H, m), of 7.48 (1H, s), to 7.68 (1H, DD, J=10,5, 1.8 Hz), of 8.27 (1H, d, J=6.9 Hz), 8,91 (1H, DD, J=6,6, and 0.9 Hz), 9,01 (1H, s), 9,11 (1H, s)

144
3-(2-fluoro-4-iodoaniline)-4-methyl-furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
In6,05, 472,(CD3OD) 8,39 (1H, d, J=5,9 Hz), of 7.48 (1H, DD, J=10,5, 1.8 Hz), 7,47 (1H, d, J=5,9 Hz), 7,28 (1H, DDD, J=8,5, of 1.8, 1.0 Hz), 6,47 (1H, t, J=8.5 Hz), of 4.00 (2H, t, J=4.5 Hz), and 3.72 (2H, t, J=4.5 Hz), a 2.45 (s, 3H)
145
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid cyclopropylmethyl(2 vinyloxyethoxy)amide, monovariate
--And, F11,92, 536,(CD3OD) charged 8.52 (2H, s, of usher.), 7,60 1H, d, J=6.0 Hz), 7,56 (1H, DD, J=2.5 and 9.0 Hz), 7,47 (1H, m), 7,02 (1H, t, J=8.5 Hz), 6,44 (1H, DD, J=7,0, of 14.0 Hz), 4,30 (2H, m), 4,18 (1H, DD, J=2,0, of 14.0 Hz), of 3.96 (1H, DD, J=2,0, 8.0 Hz), 3,95 (2H, m)to 3.67 (1H, d, J=6.5 Hz), 1.04 million (1H, m)of 0.53 (2H, m), 0,34 (2H, m)
146
3-(2-fluoro-4-methylsulphonyl-phenylamino)furo[3,2-C]pyridine-2-carboxylic acid amide
--6,09, 318,(DMSO-D6) of 2.51 (3H, s), 7,10 (1H, d, J=9,2 Hz), 7,27 (2H, m), of 7.64 (1H, d, J=5.3 Hz), 7,72 (1H, s, of usher.), to 7.93 (1H, s, of usher.), of 8.28 (1H, s), scored 8.38 (1H, s, of usher.), 8,55 (1H, s, of user.)

147
4-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
And9,42, 492,(DMSO-D6) 11,95 (1H, users), scored 8.38 (1H, d, J=5.8 Hz), 7,76 (1H, user., C), 7,74 (1H, d, J=5,8), 7,52 (1H, DD, J=10,9, and 2.1 Hz), 7,24 (1H, DDD, J=8,4, 2,1, 1.2 Hz), 6.48 in (1H, t, J=8,9 Hz), of 4.66 (1H, users), 3,85 (2H, t, J=5,1 Hz), of 3.54 (2H, t, J=5,1 Hz)
148
Azetidin-1-yl(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)methanon/td>
--J4,11, 438,1, D(DMSO-D6) 8,58 at 8.60 (m, 2H), 8,50-charged 8.52 (s, 1H), 7,70-7,72 (m, 2H), 7,50-7,52 (m, 1H), 7,00-7,02 (m, 1H), 4,45-4,65 (users, 2H), 4,00-4,20 (users, 2H), 2,30-to 2.40 (m, 2H)
149
(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl)(3-(hydroxymethyl)azetidin-1-yl)methanon
--J3,67, 468,1 D(DMSO-D6) 8,70-8,72 (s, 1H), 8,68-to 8.70 (d, 1H), charged 8.52-8,56 (s, 1H), of 7.90-a 7.92 (d, 1H), 7,70-7,74 (m, 1H), of 7.48-7,52 m, 1H), 7,02-7,06 (m, 1H), 4,54 with 4.64 (m, 2H), 4,28-4,36 (users, 1H), was 4.02-4,10 (m, 1H), 3,76-3,84 (users, 1H), 3,56-of 3.60 (d, 2H), 2,78-2,84 (m, 1H)

150
[7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl]-((2S,4R)-4-hydroxy-2-hydroxyethylpyrrolidine-1-yl)methanon
--In158,82, 516(CDCl3) to 1.70 (1H, d, J=3,62 Hz), with 1.92 (1H, m)to 2.18 (1H, m), 3,70-of 3.77 (1H, m), a 3.87-3,93 (1H, m), 4.09 to (1H, m), the 4.29 (2H, m), 4,63 (2H, m), of 6.96 (1H, t, J=8,44 Hz), 7,44 (1H, d, J=8,46 Hz), 7,52 (1H, DD, J=9,75, to 1.86 Hz), 8,39 (1H, s), to 8.45 (1H, d, J=2.30 Hz), 8,54 (1H, is)
151
7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-pyrrolidin-3-yloxy)amide
InDN7,17, 517(DMSO-d6): 1,88 of 1.99 (1H, m), 2,12 (1H, s), 3,11-of 3.25 (3H, m)to 3.34 (1H, d, J=12,55 Hz), of 4.57 (1H, d, J=4,33 Hz), 6,85 (1H, t, J=8,78 Hz), 7,39-7,42 (1H, m), a 7.62 (1H, DD, J=10,71, 1,94 Hz), 8,21 (1H, s), and 8.50 (1H, s), 8,55 (1H, s)

152
7-chloro-3-(2-fluoro-4-methyl-sulfonyl-phenylamino)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
InAnd, MeonN8,84, 412(DMSO-d6): 3,62 (2H, t, J=4,94 Hz), 3,93 (2H, t, J=equal to 4.97 Hz), was 7.08 (1H, DD, J=to 8.41, 2,09 Hz), 7,22-7,30 (2H, m), of 8.28 (2H, d, J=14,40 Hz)8,64 (1H, s)
153
7-fluoro-3-(2-fluoro-4-methyl-sulfonyl-phenylamino)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide
InAnd, MeonN8,46, 396 (CDCl3) of 2.51 (3H, s), 3,81-of 3.85 (2H, m), 4.09 to to 4.14 (2H, m), 7,02-7,10 (2H, m), 7,21 (1H, t, J=8,32 Hz), 7,88 (1H, s), by 8.22 (1H, s), to 8.45 (1H, d, J=2,33 Hz), 8,97 (1H, s)

154
[3-(2-fluoro-4-iodoaniline)-7-methylfuran[3,2-C]pyridine-2-yl]-((2S,4R)-4-hydroxy-2-hydroxyethylpyrrolidine-1-yl)methanon
--A3of 5.82, 511(CDCl3) 1,85-2,07 (2H, m)to 2.18 (1H, DD, J=13,52, to 7.59 Hz), 2,47 (3H, s), of 3.73 (1H, DD, J=11,72, 6,28 Hz), 3,93 (1H, d, J=11, 73 Hz), EUR 4.00-4.09 to (1H, m), 4.26 deaths (1H, d, J=12,12 Hz), 4,57-to 4.73 (2H, m), to 6.95 (1H, t, J=8,50 Hz), 7,39-7,42 (1H, m), 7,47-7,52 (1H, m), at 8.36 (1H, s), of 8.47 (1H, s), 8,54 (1H, s)
155
7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((2S)-2-hydroxypropoxy)amide
AndC16With129,80, 489 (A)(CD3OD) of 1.18 (3H, d, J=6,47 Hz), with 3.79 (1H, DD, J=10,56, to 7.93 Hz), 3,93 (1H, DD, J=10,56, 3,51 Hz), a 4.03-4,11 (1H, m), 7,07 (1H, t, J=8,56 Hz), 7,53 (1H, DDD, J=8,39, 1,92, 1,10 Hz), to 7.61 (1H, DD, J=10,20, with 1.92 Hz), 8,29 (1H, s), and 8.50 (1H, d, J=2,79 Hz)
156
7-fluoro-3-(2-fluoro-iodobenzylamine)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethylmethoxy)amide
--And10,69, 504 (A)(DMSO-d6) of 1.17 (6H, s), 3,24 (2H, s), 4,69 (1H, s), 7,03 (1H, t, J=8,65 Hz), 7,46-7,49 (1H, m), 7,68 (1H, DD, J=10,54, with 1.92 Hz), 8,35 (1H, s), 8,42 (1H, s), 8,65 (1H, d, J=2.57 m Hz)

157
[7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl]-((R)-3-hydroxypyrrolidine-1-yl)methanon
--With1710,2, 486 (A)(DMSO-d6) 1,74 e 2.06 (2H, m), 3,39-the 3.65 (2H, m), 3,69-was 4.02 (2H, m), 4,35 (1H, m), 5,04 (1H, m), 7,01 (1H, t, J=8,71 Hz), 7,45-7,51 (1H, m), of 7.70 (1H, DD, J=10,52, with 1.92 Hz), 8,39 (1H, d, J=1,19 Hz)8,64 (1H, d, J=2,52 Hz), 8,67 (1H, s)
158
((3S,4S)-3,4-dihydroxypyrrolidine-1-yl)-[7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl]metano
--With178,75, 502 (A)(DMSO-d6) of 3.46 (1H, m), 3,63 (1H, m), 3,82 (1H, m), 3,90 is 4.13 (3H, m), 5,24 (2H, m), 7,03 (1H, t, J=8,67 Hz), of 7.48 (1H, d, J=to 8.45 Hz), of 7.70 (1H, DD, J=10,44, 1,93 Hz), scored 8.38 (1H, s), 8,65 (2H, d, J=or 4.31 Hz)
159
[7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((R)-2,3-dihydroxypropane)amide
In8,49, 506 (A)(CD3OD) 3,62 (2H, DD, J=5,11, and 3.72 Hz), 3,88-3,99 (2H, m), 4,05-4,11 (1H, m), 7,07 (1H, t, J=8,56 Hz), 7,52 (1H, DDD, J=8,39, 1,92, 1,10 Hz), to 7.61 (1H, DD, J=10,19, 1,91 Hz), of 8.28 (1H, s), 8,49 (1H, d, J=2,77 Hz)

160
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-yl]((2R,3S,4S)-3,4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanon
--J3,33, 514, D(DMSO-D6) 8,79 (users, 1H), 8,66-8,69 (m, 2H), to $ 7.91-to 7.93 (m, 1H), 7.68 per-7,71 (m, 1H), 7,44-7,46 (m, 1H), of 6.96-7,00 (m, 1H), 3,57-4,10 (m, 10H)

1. A compound selected from compounds of the formula I:

and its salts,
where Z1represents CR1;
Z2represents N;
Z3represents CR3;
Z4represents CR4;
R1, R3and R4independently selected from H, halogen, CN, -(CR14R15)nC(=Y)OR11, -(CR14R15)nOR111-C12of alkyl;
W representsor;
R5and R6independently selected from N or C1-C12of alkyl;
X1selected from R11, -OR11and-S(O)2R11; if X1is an R11or11, R11or11of X1and R5optionally taken together with the nitrogen atom to which they are attached, form a 4-6 membered saturated or unsaturated ring containing 0-2 additional heteroatoms selected from O, S, where the aforementioned ring is optionally substituted by one or more groups selected from oxo, -(CR19R20)nNR16R17, -(CR19R20)nOR16, (CR19R20)nS(O)2R16and R21;
X is selected from aryl, where the specified aryl optionally substituted by one or more groups selected from halogen, CN, -Si(C1-C6alkyl), -(CR19R20)nOR16, -(CR19R20)nSR16C1-C12alkyl;
R11, R12and R13independently represent H, C1-C12alkyl, aryl, azetidin, pyrrolidinyl, piperidinyl, tetrahydropyranyl;
R14and R15independently selected from N or C1-C12of alkyl;
n is independently chosen from 0, 1;
Y independently represents the;
where each specified alkyl, alkenyl, aryl and heteroaryl of R1, R2, R3, R4, R5, R6X1X2, R11, R12, R13, R14and R15independently optionally substituted by one or more groups independently selected from -(CR19R20)nC(=Y')OR16, -(CR19R20)nNR16R17, -(CR19R20)nOR16, -(CR19R20)nNR16C(=Y')R17, -(CR19R20)nNR16C(=Y')OR17, -(CR19R20)nNR17SO2R16and R21;
each R16, R17independently represents H, C1-C12alkyl, C2-C8alkenyl, aryl or pyridinyl, where the specified alkyl, alkenyl or aryl optionally substituted by one or more groups selected from-HE;
R19and R20independently selected from H, C1-C12of alkyl;
R21represents a C1-C12alkyl, aryl, imidazolyl, pyridinyl, pyrazolyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperidinyl, or 2,2-dimethyl-1,3-DIOXOLANYL;
each Y' independently represents O.

2. The compound according to claim 1, selected from formula I-b:

3. The compound according to claim 2, where X1choose from:

4. The compound according to claim 2, where X1choose from:

5. The compound according to claim 1, where X1is an R11and R11and R5taken together with the nitrogen atom to which they are attached, form:

6. The compound according to claim 1, where X2is:

7. The compound according to claim 1, where R1selected from N, CH3CN, -OR11and Cl.

8. The compound according to claim 1, where R3selected from N, CH3or F.

9. The compound according to claim 1, where R4selected from Br, Cl, CN, and-OR11.

10. The compound according to claim 1, where R4selected from Cl, Br, Me, Et, F, or-HE.

11. The compound according to claim 1, where R5represents H or methyl.

12. The compound according to claim 1, where R6represents H or methyl.

13. The compound according to claim 1, where W is a OR11.

14. The connection indicated in paragraph 13, where W is a HE.

15. A compound selected from
((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 3-(2-fluoro-4-brompheniramine)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 3-(4-ethinyl-2-forgenerating)furo[3,2-C]pyridine-2-carboxylic acid;
cyclopropylmethoxy 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
(2 hydroxyethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
(2-miniloc is etoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 3-(4-iodobenzylamine)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 3-(2-chloro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 3-(2,6-debtor-4-iodobenzylamine)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 3-(2,5-debtor-4-iodobenzylamine)furo[3,2-C]pyridine-2-carboxylic acid;
tert-butyl ether 4-{(3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carbonyl]aminooxy}piperidine-1-carboxylic acid;
(2-morpholine-4-ylethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 7-bromo-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
(1 methylpiperidin-4-yloxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
(2 dimethylaminoethoxy)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
(2-fluoro-4-iodoaniline)-N-tert-butoxyphenol[3,2-C]pyridine-2-carboxamide;
(2 methanesulfonylaminoethyl)amide 3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
((R)-2,3-dihydroxypropane)amide 7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid;
(2 hydroxyethoxy)amide 7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-c]pyridine-2-carboxylic acid;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic KIS is the notes (piperidine-4-yloxy)the amide monovariate, salt;
3-[(2-fluoro-4-iodoaniline)methylamino]-furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]-pyridine-2-carboxylic acid (2-hydroxyethoxy)methylamide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid hydroxyamide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (tetrahydropyran-4-yloxy)amide;
3-(4-bromo-2-chlorpheniramine)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-{[3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carbonyl]aminooxy}azetidin-1-carboxylic acid tert-butyl ether
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid methoxime;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-aminoethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid [2-(2-oxopyrrolidin-1-yl)ethoxy]amide;
3-(2-fluoro-4-hydroxymethylamino)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-methylphenylimino)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-methylsulfonylamino)-furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
(2-{[3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carbonyl]aminooxy}ethyl)-methylcarbamyl is islote tert-butyl ether;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-methylaminorex)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-pyrrolidin-3-yloxy)the amide monovariate, salt;
7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
7-cyano-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (azetidin-3-yloxy)the amide monovariate, salt;
(2-fluoro-4-iodoaniline)-N-isobutoxide[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-isopropoxyphenol[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-benzyloxyphenol[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-(3-hydroxypropoxy)furo[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-[3-(pyridine-2-carboxamide)propoxy)furo-[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-[3-(nicotinamide)propoxy)]furo[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-[3-(isonicotinamide)propoxy)]-furo[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-propoxyphene[3,2-C]pyridine-2-carboxamide;
(2-fluoro-4-iodoaniline)-N-idoxifene[3,2-C]pyridine-2-carboxamide;
N-(2-(benzyloxy)-2-methylpropoxy)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide;
N-(2-hydroxyethoxy)-3-(4-bromo-2-ftoh is ylamino)furo[3,2-C]pyridine-2-carboxamide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxy-1-methylethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxypropoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxy-1-hydroxyethyloxy)amide;
N-[3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carbonyl]methanesulfonamide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-piperidine-1-ylethoxy)amide;
3-(2-fluoro-4-iodoaniline)-N-phenyloxirane[3,2-C]pyridine-2-carboxamide;
3-(2-fluoro-4-iodoaniline)-N-(2-hydroxy-2-methylpropoxy)furo[3,2-C]pyridine-2-carboxamide;
N-(1-hydroxy-2-methylpropan-2-yloxy)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide;
3-(2-fluoro-4-iodoaniline)-N-(4-hydroxy-2-methylbutane-2-yloxy)furo[3,2-C]pyridine-2-carboxamide;
N-((pyridin-2-yl)methoxy)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide;
N-(1-phenylethane)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxamide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((R)-2-hydroxypropoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-2-hydroxypropoxy)amide;
3-(2-fluoro-4-iodoaniline)-7-phenylfuro[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-iodoaniline)-7-methylfuran[3,2-C]pyridine-2-carboxylic acid (2-guide is acetoxy)amide;
2-((R)-2,2-dimethyl[1,3]dioxolane-4-ylmethoxycarbonyl)-3-(2-fluoro-4-trimethylsilylmethylamine)-furo[3,2-C]pyridine-7-carboxylic acid ethyl ester;
2-((R)-2,3-dihydroxypropane-carbarnoyl)-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-7-carboxylic acid ethyl ester;
7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((R)-2,3-dihydroxypropane)amide;
7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (piperidin-3-yloxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-3-pyrrolidin-2-ylethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (1H-imidazol-4-ylethoxy)amide;
3-(2-fluoro-4-iodoaniline)-4-methyl-furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid cyclopropylmethyl(2 vinyloxyethoxy)amide, nonformat;
4-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
7-chloro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((S)-pyrrolidin-3-yloxy)amide;
7-chloro-3-(2-fluoro-4-methyl-sulfonyl-phenylamino)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxyethoxy)amide;
7-fluoro-3-(2-fluoro-4-methyl-sulfonyl-phenylamino)furo[3,2-C]pyridine--carboxylic acid (2-hydroxyethoxy)amide;
7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid ((2S)-2-hydroxypropoxy)amide;
7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-C]pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethylmethoxy)amide;
[7-fluoro-3-(2-fluoro-4-iodoaniline)furo[3,2-e]pyridine-2-carboxylic acid ((R)-2,3-dihydroxypropane)amide.

16. Pharmaceutical composition for inhibiting abnormal cell growth or treating a hyperproliferative disorders in a mammal, comprising a compound according to any one of claims 1, 3, and 5-12, and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to item 16, further comprising a second chemotherapeutic agent.

18. The pharmaceutical composition according to item 16, further comprising a second anti-inflammatory agent.

19. Method of inhibiting abnormal cell growth or treating a hyperproliferative disorders in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition according to any one of p or 17.

20. A method of treating inflammatory disease in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition according to any one of p or 18.

21. The method according to any one of p or 20, where the specified second chemotherapeutics is s or anti-inflammatory agent is administered to the specified mammal, either sequentially or consecutive.

22. A method of treating autoimmune diseases, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease, neurodegenerative disease, pancreatitis or kidney disease in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of the pharmaceutical composition according to item 16.

23. The method according to item 22, further comprising introducing a specified mammal a second therapeutic agent, where the specified second agent is administered to the specified mammal, either sequentially or consecutive.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

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: chemistry.

SUBSTANCE: invention relates to novel pyrazole derivatives of general formula I

and pharmaceutically acceptable salts thereof, where n equals 1 or 2, m equals 0, 1 or 2, A contains in the ring a group selected from -CR1=, -CR2=, -CR3=, -CR4= and -CR5=, where 0 or 1 in these groups is replaced with N, R1, R2, R3, R4 and R5 are independently selected from a group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6 heterocycloalkyl-C0-alkyl, where the said heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, C5heteroaryl-(C0-C4)alkyl, where the said heteroaryl contains 1-4 heteroatoms selected from nitrogen atoms, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12; -XN(XOR12)2, -XNR11XC(O)OR12 -XNR11XNR11C(O)R12 -XNR11XNR11R12, -XNR11C(O)R12, where each X is independently selected from a group comprising a chemical bond and C1-C4alkylene, each R11 is selected from a group comprising hydrogen and C1-C6alkyl, and R12 is selected from a group comprising hydrogen, C1-C6alkyl and phenyl, or R11 and R12 together with a nitrogen atom to which R11 and R12 are bonded form C6heterocycloalkyl. Said heteroaryl or heterocycloalkyl in R1, R2, R3, R4 or R5 optionally contains one substitute selected from a group comprising hydroxyl, cyano, C1-C6alkyl, hydroxyl(C1-C6)alkyl and carboxy, R6 and R7 independently denote hydrogen, R8 is selected from a group comprising C1-C6alkyl, halogen(C1-C3)alkyl, -CH2OR8a and -COOR8a or two R8 groups bonded to different carbon atoms, together form a (C1-C2)alkyl bridge, or two R8a groups bonded to one carbon atom form a (C3-C8)cycloalkyl group, where R8a is selected from a group comprising hydrogen and C1-C6alkyl, R9 is selected from a group comprising phenyl and C6heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen atoms, and C9heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, where the said phenyl or heteroaryl in R9 is optionally substituted with 1-2 substitutes independently selected from a group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14, where each of R13 and R14 is independently selected from a group comprising hydrogen and C1-C6alkyl, R10 denotes hydrogen, Y and Z are independently selected from a group comprising CR20 and N, where R20 denotes hydrogen, provided that compounds of formula I do not include compounds of formula II, which are described in claim 1, and provided that compounds of formula I do not include compounds which are: 1-(4-fluorophenyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)piperazine, 1- ((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(4-(trifluoromethyl)-(pyridin-2- yl)piperazine, 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)-(pyridin-2-yl)piperazine and 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-fluoropyridin-2-yl)piperazine. The invention also relates to specific compounds obtained.

EFFECT: novel pyrazole derivatives which can be used in treating diseases or disorders which are mediated by disrupted activation of the said compound are obtained.

8 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula 1: or its pharmaceutically acceptable salt; in which each R1 and R8 independently represents H or hydroxyl; each R2 and R9 independently represents H or hydroxyl; R5 represents H; each R3, R4, R6, R7, R13 and R14 independently represents H; or R1 and R2, taken together, form =O; or R4 and R5, taken together form double bond; or R5 and R6, taken together form double bond; R10 and R11, taken together form double bond; R12 represents H, alkyl, hydroxyl, aralkyl, halogenalkyl, alcoxyl,- -[(W)- N(R21)C(O)]qR21, -[(W)-N(R21)SO2]qR21, -[(W)-O]qR21 or -[(W)-N(R21)]qR21; where each W independently represent bivalent alkyl or aralkyl radical, and q is equal 1, 2, 3 or 4; each R15, R16 and R17 independently represent H; each R18 and R19 independently represents H; and each R21 independently represents H, alkyl, aryl or aralkyl. Invention also relates to pharmaceutical composition. Claimed invention provides cycloamine analogues which can be applied to counteract phenotypic effects of undesirable activation of Hedgehog pathway, such as acquiring function from Hedgehog, Ptc loss of function or mitigated acquired from function mutations.

EFFECT: compounds by claimed invention are especially applicable in cancer treatment.

19 cl, 1 tbl, 28 ex

FIELD: chemistry.

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

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

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula

wherein A, R1, R2, R3, R4, R5 and R6 are presented in the description, preparing and using them as pharmaceutically active compounds as immunomodulatory agents.

EFFECT: preparing the pharmaceutical composition showing agonist activity with respect to S1P1/EDG1 receptor and using it for prevention and treatment diseases or disorders associated with activated immune system.

20 cl, 244 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of a metal of group 4 or 5 of the periodic system specified in titanium, zirconium, hafnium, niobium and tantalum, or its oxide for preparing a drug used for treating or preventing a disease characterised by undesired expression and/or release of interferon-γ inducible protein of weight 10 kDa, IP-10 in a subject. The invention also refers to a method of treating or preventing the disease characterised by undesired expression and/or release of interferon-γ inducible protein of weight 10 kDa, IP-10, which implies the extraction of a biological fluid in a subject suffering said disease, the ex vivo contact of the biological fluid and the metal specified in titanium, zirconium, hafnium, niobium and tantalum, or its oxide, the fluid return after the contact with the metal to the subject stated above. The invention also provides the use of the method stated above or its oxide for the in vitro removal of interferon-γ inducible protein of weight 10 kDa, and a method for removing said protein. The invention also refers to a device for biological fluid purification which comprises a purification chamber with a fluid inlet and outlet and containing metal particles specified in titanium, zirconium, hafnium, niobium and tantalum, or its oxide, used for biological fluid purification, and a filter coupled with the fluid inlet and outlet to prevent said particles from escaping from the purification chamber.

EFFECT: invention provides the selective decrease of expression and release of chemokine, namely interferon-γ inducible protein of weight 10 kDa, IP-10.

25 cl, 6 tbl, 16 dwg

FIELD: medicine.

SUBSTANCE: The invention relates to pharmacology, in particular, to medication for preventing or treating herpes labialis or herpes genitalis. The homeopathic medication or biologically active additive with anti-viral effect or preventing or treating herpes labialis or herpes genitalis contains: Nisylen, Cepa, Euphrasia, Belladonna and Mericulis Solubilis, furthermore, the components are present with a certain dilution and amount. The combination of the said components is used for production of homeopathic medication or biologically active additive with anti-viral effect or preventing or treating herpes labialis or herpes genitalis.

EFFECT: production of medication which effectively treats herpes labialis or herpes genitalis.

14 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention is referred to the field of medicine, namely to dermatovenerology and immunology and can be used for treatment of patients with sexually transmitted urogenital infections caused by chlamydiae and/or micoplasma. It includes the infusion of antibiotics of macrolides group or immunotropic drug that is selected individually, for which purpose the sensitivity of patient to immunotropic drugs is determined. That is done by in vitro definition of interferons in the samples of peripheral blood and urogenital scrapings before and after addition of each studies drug. As the result the immunotropic drug selected for treatment is the one that induces the increase of interferon activity in studied material by no less than 4 U/ml compared to the baseline level in the samples of peripheral blood and urogenital scrapings.

EFFECT: method provides for etiologic recovery, prevention of disease relapses, particularly due to effective interferons production on systemic and local level.

1 dwg, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula in which is or (values of radicals are given in the claim), a method of producing said compounds, a pharmaceutical composition containing said compounds and therapeutic application thereof.

EFFECT: compounds are cysteine protease inhibitors and can be used in medicine.

25 cl, 1 tbl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly immunology, namely immunocorrection drugs, and can be used as an inducer of a granulocyte-macrophage colony-forming factor in cells of a mononuclear phagocyte system in vitro and for efferent therapy in pathological conditions accompanied by decrease in cell-mediated immunity. The drug represents oxidised dextrane of average molecular weight 35 - 65 kDa. The drug can be presented in the form of a solution or a nanoliposomal emulsion of the concentration of oxidised dextrane 1-5 wt %. The drug is applied by introduction in a cell culture of the mononuclear phagocyte system in an amount containing oxidised dextrane 125-250 mcg per culture medium 1 ml.

EFFECT: drug under the invention exhibits high biocompatibility.

8 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns an immunomodulatory drug preparation showing antiviral properties. Substance of the invention consists in the fact that the offered drug preparation contains sodium nucleinate 2 to 50 mg/ml, sodium chloride 3 to 10 mg/ml and apyrogenic water with pH making within 6.0 to 7.5.

EFFECT: preparation has a direct antiviral effect, suppresses reproductive ability of viruses.

2 cl, 3 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to allergology, and can be used for prevention of development of respiratory allergies in a subject. That is ensured by introduction of an effective amount of Lactobacillus rhamnosus GG (LGG) either in a pregnant mother's body, and/or postnatal in a feeding mother's body, or in a subject directly.

EFFECT: introduction of LGG allows preventing an early allergic sensitisation and the following development of respiratory allergies due to higher production of serum antibodies IgA in a subject, and also prevention of allergic inflammation in lungs and respiratory ways.

12 cl, 13 ex, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to optimised fused protein for blocking BLyS or APRIL, which contains extracellular region of N-end of truncated TACI (transmembrane activator and CAML-partner) and Fc sequence IgG. TACI segment of fused protein contains sequence of amino-end region of extracellular region, starting with 13-th amino acid residue, complete sequence of stem area from TACI and is obtained from native sequence of TACI between 12-th and 120-th amino acids. Segment Fc of immunoglobulin IgG of fused protein contains hinge region, CH2 region and CH3 region, TACI segment and Fc segment are fused either directly or through linker sequence. In addition, claimed is DNA sequence which codes fused protein, expression vector, host-cell, pharmaceutical composition, containing fused protein, and application of fused protein for blocking BLyS or APRIL. Obtained fused protein does not degrade in process of expression, possesses high biological activity and high level of expression.

EFFECT: fused protein in accordance with claimed invention can be used in treatment of diseases, associated with abnormal immunologic functions and in treatment of diseases caused by abnormal proliferation of B-lymphocytes.

10 cl, 6 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to immunomodulatory interleukin-1 drugs. An interleukin composition contains interleukin-1, a cyclooxygenase inhibitor - diclofenac, taken in certain proportions.

EFFECT: compositions exhibit higher efficacy and have no side effects.

6 cl, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I): X denotes a single bond or a binding group selected from -CO, -SO2-, -CS- or -CH2-; Y denotes a single bond or a divalent binding group obtained from a cyclic structure selected from benzene, pyridine, pyrimidine, pyrazole, imidazole, thiazole, thiophene, quinoline, benzoimidazole, benzothiazole, benzopyrazole, naphthalene and benzothiophene; X and Y are simultaneously single bonds; Z denotes a hydrogen atom or a substitute selected from a group A; m equals 1 or 2; n equals 0-3; in group A and group B, R, R' and R" can, respectively and independently, be identical or different and denote a hydrogen atom or -C1-6-alkyl; said -C1-6-alkyl can be substituted with a group selected from -OH, -O(C1-6-alkyl),-CONH2, -CONH(C1-6-alkyl), -CON(C1-6-alkyl)2, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2); Sus denotes a C3-C7 saturated or a C5-C10 unsaturated hydrocarbon ring or a nitrogen-containing C3-C7 heterocyclic ring containing 1-4 nitrogen atoms or containing an additional O, S atom; said C1-6 alkylene in groups A and B can be substituted in positions 1-3 with a -N(C1-6- alkyl)2 group, values of radicals R1, A1, T, B and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a PI3K inhibitor and a medicinal agent having PI3K inhibitor properties against a proliferative diseases such as a malignant tumour.

EFFECT: high efficiency of using the compounds.

21 cl, 645 ex

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