Aromatic sulfonohydroxamic acid as metalloprotease inhibitor

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to treatment of patients suffering from diseases associated with pathologic activity of matrix proteases. Treatment involves administration of compounds depicted by general formula (I).

EFFECT: increased treatment efficiency.

136 cl, 448 ex

 

The technical field to which the invention relates.

The present invention relates to inhibitors of proteases (proteases) and, in particular, to the use of derivatives of aromatic sulfamethoxasole acid, which, among other things, are selective inhibitors of matrix metalloproteinases, intended for the treatment of conditions associated with pathological activity of matrix metalloproteinases, by selective inhibitors, compositions of inhibitors of proteases, to intermediate products intended for the synthesis of proteinase inhibitors, and to a method for inhibitors of proteinases.

Background of invention

Connective tissue components of the extracellular matrix and basal membrane, are necessary components of the body of all mammals. These components represent a biological material that provides rigidity, differentiation, accession, and in some cases, and the elasticity of biological systems, including humans and other mammals. Components of connective tissue include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. They are biochemical components or are components of such structures, such as skin, bone, teeth, tendons, cartilage, basal membrane, crowton the e vessels, the cornea and the vitreous body.

In normal conditions the processes of transformation and/or repair of the connective tissue under the control of and are in equilibrium. Violation by any reason of this balance leads to many painful conditions. Inhibition of enzymes responsible for the imbalance, it provides a control mechanism indicated decomposition of the tissue and, therefore, is a method of treatment of these diseases.

The decomposition of the connective tissue or components of the connective tissue occurs under the influence of enzymes proteases that are released from the located in the tissue cells and/or of established inflammatory or neoplastic cells. The main class of enzymes carrying out this function are dependent on zinc metalloproteinases (metalloprotease).

Enzymes metalloprotease divided into classes, some members of which have adopted several different names. Their examples are the collagenase I (the matrix metalloprotease-1 (MMP-1), fibroblast collagenase, EC 3.4.24.3), collagenase II (MMP-8, neutrophil collagenase, KF 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3, KF 3.4.24.17), stromelysin 2 (MMP-10, KF 3.4.24.22), proteoglycans, matrilysin (MMP-7), gelatinase A (MMP-2, gelatinase with a molecular mass of 72 kDa collagenase of Basel the second membrane, KF 3.4.24.24), gelatinase B (MMP-9, gelatinase with a molecular mass of 92 kDa, EC 3.4.24.35), stromelysin 3 (MMM-11), metalloelastase (MMP-12, CMA, macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym of the concept of "the matrix metalloprotease"and attached to this acronym numbers allow to distinguish from each other the various specific representative groups MMP.

Uncontrolled decomposition of the connective tissue by metalloprotease is the cause of many pathological conditions. Their examples are rheumatoid arthritis, osteoarthritis, septic arthritis, corneal ulceration, epidermal or gastric, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease. Can also be violations of the processes of reparation of damage. This may cause the violation of the healing process, resulting in a weak repair, adhesion and scarring. The last of these disorders can lead to lack of physical and/or temporary disability, for example to the appearance of adhesions after surgery.

Metalloprotease also involved in the biosynthesis of tumor necrosis factor (TNF) and inhibit the production or activity of TNF and related compounds, which is an important clinical treatment of diseases. For example, TNF-α is a cytokine, which, as currently anticipated, initially produced in the form associated with cell molecules with a molecular mass of 28 kDa. Then there is a selection active form with a molecular mass of 17 kDa, which can cause many harmful effects in vitro and in vivo. For example, TNF can cause and/or influence inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, infections caused by mycobacteria, meningitis, fever, psoriasis, cardiovascular/pulmonary effects, such as postischemic perfusion injury, congestive heart failure, hemorrhage, coagulation, alveolar injury due to hyperoxia, radiation damage and acute phase reactions such as those that occur with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic secretion of active TNF can cause cachexia and anorexia. TNF can lead to death and odnovremenno with that TNF can help control the growth of tumor cells.

TNF-α -convertase is metalloprotease involved in the formation of soluble TNF-α . Inhibition of TNF-α -convertase (TAS) inhibin is no production of active TNF-α . Compounds that inhibit the activity of MMP, and the production of TNF-α described in WO 94/24140, WO 94/02466 and WO 97/20824. It is established that compounds that inhibit such MSEs, as collagenase, stromelysin, gelatinase also have the ability to inhibit the secretion of TNF (Gearing and other, Nature 376. 555-557 (1994), McGeehan et al., Nature 376. 558-561 (1994)). There is a need for effective inhibitors of MMP. In addition, there remains a need for agents which are effective inhibitors of TNF-α -convertase.

MMPs are also involved in other biochemical processes in mammals. They are involved in the regulation of ovulation postpartum involution of the uterus, possibly in implantation in the cleavage of APP (β -amyloid precursor protein) with the formation of amyloid plaques and inactivation of the inhibitor α1protease (α1-PI). Inhibition of these metalloprotease allows you to regulate fertility and to treat or prevent Alzheimer's disease. Furthermore, increasing and maintaining levels of endogenous or introduced drugs, which is the inhibitor of semipretioase, or biochemical agent, such as α1-PI, helps in the treatment or prevention of diseases such as emphysema, lung diseases, inflammatory diseases and diseases associated with aging, such as loss of elasticity, alasti the surface of the skin or body.

The specific inhibition of MMP may also be appropriate in other cases. Cancer treatment and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of such approaches to the treatment of diseases when the selective inhibition of this enzyme or enzymes, as stromelysin, gelatinase a or b or collagenase III, likely much more important than inhibition of collagenase I (MMP-1). The drug, which is not inhibited collagenase I, may have the most valuable therapeutic profile. Another important disease in which the degradation of cartilage in inflamed joints, probably at least partly due to MMP-13, released from such cells as stimulated chondrocytes is osteoporosis, the greatest effect in the treatment of which can be achieved through the use of drugs, one of the mechanisms of action is the inhibition of MMP-13 (see, for example, Mitchell and others, J. Clin. Invest., 97: 761-768 (1996) and Reboul, etc., J. Clin. Invest., 97: 2011-2019 (1996)).

The number of known inhibitors of metalloprotease. Their examples include natural biochemical agents, such as tissue inhibitors of metalloproteinases (TIMP), α2-macroglobulin and their analogs or derivatives. These endogenous inhibitors are protein molecules with large molecular mass is th, which form inactive complexes with metalloprotease. Described a number of peptidebinding compounds of smaller size, which inhibit metalloprotease. It is established that mercaptoimidazole derivatives inhibit ACE in vitro and in vivo. Angiotensinase enzyme (ACE) is involved in the production of angiotensin II, compounds that are effective vasoconstrictor agent in mammals, and inhibition of this enzyme leads to lower blood pressure.

Inhibitors of metalloprotease (MMP), which is an amide - or peptidyltransferase compounds bearing Tilney group, known for example from WO 95/12389, WO 96/11209 and patent US 4595700. Inhibitors of MMP bearing hydroxamate group, known from numerous publications, such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0780386, which describes compounds having a carbon skeleton, and in WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074, which describes hydroxamate with peptidyl skeletons or peptideprophet skeletons, and such compounds are also described in the articles Schwartz and others, Progr. Med. Chem., 29: 271-334 (1992), and Rasmussen and others, Pharmacol. Ther., 75(1): 69-75 (1997) and Denis and others, Invest. New Drugs, 15(3): 175-185 (1997).

One potential problem associated with known inhibitors of MMP, is that such compounds often have the same or similar inhibitory effect against all the farm is tov MMP. For example, for the connection of class peptidebinding hydroxamates known as batimastat, it was found that the values of the IC50range from about 1 to about 20 nmol (nm) in respect of each of such MSEs as MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9. For marimastat, another peptidebinding of hydroxamate, which is another broad-spectrum inhibitor of MMP, it was found that the spectrum of its inhibitory activity very close to that of batimastat except that the value of the IC50marimastat against MMP-3 is 230 nm (Rasmussen and others, Pharmacol. Ther., 75(1): 69-75 (1997)).

Preliminary analysis of the data obtained in phase I/II in the study of patients in whom the application of marimastat achieved success rapidly progressing dense treatment of malignant tumors (colon, pancreas, ovarian, prostate), showed dose-dependent decrease in the level carcinoma antigens that were used as indirect markers of biological activity. Although marimastat and showed a certain level of activity in relation to these markers, however, it was discovered toxic side steps. The most common associated with medication toxic effect of marimastat identified in clinical trials, provided the camping pain of skeletal muscles, rigidity, commonly affecting the small joints of the hands, spreading forth of the arm and shoulder. A short break in 1-3 weeks in treatment with a subsequent decrease doses allows you to continue treatment (Rasmussen and others, Pharmacol. Ther., 75(1): 69-75 (1997)). Perhaps the reason for this is the absence of a specific inhibitory action against MMP.

In WO 98/38163, published September 3, 1998, describes a large group of inhibitors of MMP and TACE of the class hydroxamates. Compounds described in WO 98/38163 contain one or two substituent adjacent to the functionally active hydroxamates, and the Deputy, which may be an aromatic sulfonyloxy group at the adjacent position in relation to one or to both of these substituents.

In WO 98/37877, published September 3, 1998, describes compounds that contain 5-7-membered heterocyclic ring in the adjacent position relative to the functionally active hydroxamate and may contain aromatic sulfonyloxy group adjacent to the heterocyclic ring.

Although many of the known MMP inhibitors, such as batimastat, marimastat and hydroxamate described in WO 98/37877 and WO 98/38163, and have a broad spectrum activity against MMP, however, these compounds do not possess a strong selective effect from the point of view of their inhibitory activity. This lack is their selectivity can be the cause of pain skeletal muscle rigidity, found in their application. In addition, it may be therapeutically useful to apply a medicinal product, which is the election from the point of view of activity in comparison with the commonly used active compounds to the treatment could be more accurately directed to a pathological condition available to the host mammal. Below is described a method of treating a host mammal having a condition associated with pathological activity of the matrix of metalloprotease, with the use of a compound that selectively inhibits one or more of MMP, but is less active against at least MMP-1.

Summary of the invention

The present invention relates to a method of treatment, including the introduction of the owner of the mammal, which has a condition associated with pathological activity of the matrix of metalloprotease, the effective number of considered aromatic sulfamethoxasole acid, which is an inhibitor of metalloprotease. This molecule shows, among other things, a very high inhibitory activity against one or more enzymes metalloprotease (MMPs)such as MMP-2, MMP-9 and MMP-13, but has substantially less inhibitory activity of at least about the wearing of MMP-1. The term "substantially smaller" mean for this connection are given below in this description of the experience for the assessment of inhibition of in vitro correlation values IC50in respect of one or more MMPs, such as MMP-2, MMP-9 or MMP-13, and its value IC50against MMP-1, for example IC50MMP-2, IC50MMP-1 is less than about 1:10, preferably less than about 1:100 and most preferably less than about 1:1000. The invention also relates to certain compounds that selectively inhibit the activity of one or more of such MSEs as MMP-2, MMP-9 and MMP-13, but have substantially less inhibitory activity against at least MMP-1, as well as to compositions containing such a MMP inhibitor as an active ingredient. The invention also relates to intermediate products, intended for the production of the considered molecules of aromatic sulfamethoxasole acid, and to a method for producing aromatic molecules sulfamethoxasole acid.

In General, one of the objects of the present invention is a method of treatment comprising introducing an effective amount considered aromatic sulfamethoxasole acid, an inhibitor of metalloprotease, which selectively inhibits the activity of matrix the x metalloprotease, the owner of a mammal having a condition associated with pathological activity metalloprotease. Applied enzyme inhibitor has a structure represented by the following formula (I)or its pharmaceutically acceptable salt:

where R1and R2both terms refer hydride or R1and R2together with the atoms to which they are attached, form a 5-8-membered ring containing in the ring one, two or three heteroatoms, represents oxygen, sulfur or nitrogen.

R3in the formula I denotes optionally substituted aryl or optionally substituted heteroaryl moiety. When R3denotes a substituted aryl or heteroaryl radical, the Deputy is chosen from the group comprising aryl, heteroaryl, aralkyl, heteroalkyl, aryloxy, aaltio, Alcoxy, heteroaromatic, alcoxialchil, aryloxyalkyl, arachnology, arylcarboxylic, aralkylated, aryloxyalkyl. aralconsult, unilateral, arylhydrazines, alkylaryl, alltoall, alkylthiomethyl, aralkylated, kalkiliya, sulfoxide or sulfon any of titlestyle, and condensed ring structure comprising two or more 5-6 membered rings selected from the group comprising aryl, heteroaryl the first, carbocyclic and heterocyclic radicals.

Deputy associated with aryl or heteroaryl radical, which includes the radical R3itself may be substituted by one or more substituents; i.e. replacing Deputy optionally is substituted. When the aryl or heteroaryl radical is replaced and the replacement fragment (group, Deputy or radical) is itself substituted, the last Deputy independently from each other selected from the group of cyano, perfluoroalkyl, triptoreline, triptoreline, haloalkyl, triptorelin, arelaxation, aryloxyalkyl, the hydroxy-group, halogen, alkyl, alkoxy-, nitro-group, thiol, hydroxycarbonyl, aryloxy, killigrew, aralkyl, aryl, arylcarboxamide, heteroaromatic, heterogroup, heteroalkyl, cycloalkyl, heterocyclics, heterocycly, heterocyclimamines, cycloalkane, cycloalkene-, heteroaromatic, heteroalkyl, Alcoxy, Uralkali, aralkylamines, heterologous, heteroaryl, arylazo, hydroxycarbonylmethyl, alkoxycarbonylmethyl, alkanoyl, arylcarbamoyl, arkanoid, alkanoyloxy, arachnodactyly, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkyl, alkoxycarbonyl, aryloxyalkyl, arylthioureas the sludge, aryloxyalkanoic, killiechassie, hydroxycarbonylmethyl, hydroxycarbonylmethyl, alkoxycarbonyl, alkoxycarbonylmethyl, amino, where the amino nitrogen is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, arelaxation, alkoxycarbonyl, arylcarbamoyl, arkanoid, heteroarylboronic, heteroalkyl and alkanoyl, or (III) where the nitrogen of the amino group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring containing 0-2 additional heteroatoms, represents a nitrogen, oxygen or sulfur, and the ring is (a) unsubstituted or (II) substituted with one or two groups independently from each other selected from the group including aryl, alkyl, heteroaryl, aralkyl, heteroalkyl, hydroxy-, alkoxygroup, alkanoyl, cycloalkyl, heteroseksualci, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, condensed with benzene ring heteroseksualci, hydroxyethoxyethyl, arelaxation, hydroxycarbonyl, aryloxyalkyl condensed with a benzene ring geterotsiklicheskikh condensed with a benzene ring cycloalkylcarbonyl, geterotsiklicheskikh and cycloalkyl boil, carbonylation,

where the nitrogen carbonylation is (I) unsubstituted or (II) is a reactive amine amino acids, or (III) is substituted by one or two radicals selected from the group comprising alkyl, hydroxyalkyl, hydroxycitronellal, cycloalkyl, aralkyl, triptorelin, heteroseksualci condensed with a benzene ring heteroseksualci condensed with a benzene ring cycloalkyl and N,N-dialkylamino acylaminoalkyl group, or (IV) the nitrogen carboxamidine and two adjacent substituent to form a 5-8-membered heterocycle-, heteroaryl, or condensed with a benzene ring geteroseksualnoe ring, which itself can be unsubstituted or may be substituted by one or two radicals independently from each other selected from the group comprising alkyl, alkoxycarbonyl, a nitrogroup, heteroseksualci, the hydroxy-group, hydroxycarbonyl, aryl, aralkyl, heteroalkyl

and amino, where the amino nitrogen is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group including alkyl, aryl and heteroaryl. or (III) where the nitrogen of the amino group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring,

and aminoalkyl is inuu group where the nitrogen aminoalkyl is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising alkyl, aryl, aralkyl, cycloalkyl, arelaxation, alkoxycarbonyl and alkanoyl, or (III) where the nitrogen aminoalkyl and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring.

In a preferred embodiment, R and R together with the atoms to which they are attached, form a 6-membered ring.

The radical R3preferably has a length exceeding the length Pintilei group[-(CH2)4CH3-the chain] and more preferably greater than a length of about hexylene group[-(CH2)5CH3-the chain]. The radical R3preferably has a length smaller than the length of coseley group[-(CH2)19CH3chain], and more preferably a length less than the length of stearley group[-(CH2)17CH3-the chain]. Preferably the group R3contains 2 or more 5-6 membered rings. Consider the group R3when rotating around the axis passing through the associated with SO21-position and associated with a Deputy at the 4-position of the 6-membered ring or through associated with the SO21-position and connected with the Deputy 3-or 4-position 5-membered ring, forms a three-dimensional space, the largest of which in the direction perpendicular to the specified axis, the rotation is Oia, equal to the length from approximately one furnishing ring to about two phenyl rings.

It is preferable that the radical R3represented an aryl or heteroaryl group with one ring, which is a 5 - or 6-membered, and is itself substituted at its 4-position, when it is a 6-membered ring, or 3 or 4 position, when it is a 5-membered ring, optionally substituted by a Deputy selected from the group including another aryl or heteroaryl group with one ring, With3-C14alkyl group, N-piperidino group, N-piperazino group, fenoxaprop, thiophenoxy, 4-dipyridyl group, phenylisopropyl and benzamidoxime. Deputy 5 - or 6-membered aryl or heteroaryl group can be substituted as indicated above.

The preferred compound that is intended for use in the present method has a structure corresponding to the following formula II, or pharmaceutically acceptable salt:

where

R14denotes a hydride, a pharmaceutically acceptable cation or C(W)R5where W denotes O or S, and R15selected from the group including1-C6alkyl, aryl, C1-C6alkoxygroup, heteroaryl1-C6alkyl, C3-the 8cycloalkyl-C1-C6alkyl, aryloxy-, ARS1-C6alkoxygroup, ARS1-C6alkyl, heteroaryl and amino1-C6alkyl, where the nitrogen aminoalkyl is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising From1-C6alkyl, aryl, ARS1-C6alkyl, C3-C8cycloalkyl-C1-C6alkyl, ARS1-C6alkoxycarbonyl,1-C6alkoxycarbonyl and C1-C6alkanoyl, or (III) the nitrogen aminos1-C6alkyl group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring,

m is 0, 1 or 2,

n is 0, 1 or 2

p is 0, 1 or 2,

the sum m+n+p is equal to 1, 2, 3,or 4

(a) one of the substituents X, Y and Z are selected from the group comprising C(O)NR6, O, S, S(O), S(O)2and NS(O)2R7and the other two substituent from the group comprising X, Y and Z denote CR8R9and CR10R11or

(b) X and Z or Z and Y together form the fragment chosen from the group comprising NR6C(O)NR6S(O)NR6S(O)2, NR6S, NR6O, SS, NR6NR6and OS(O), with one remaining Deputy from the group comprising X, Y and Z represents CR8R9or

(C) n is 0 and X, Y and Z together form a frag is UNT, selected from the group including

where

wavy lines denote communication with the atoms of the depicted ring, R6and R6'independently from each other selected from the group including hydride, With1-C6alkanoyl,6aryl-C1-C6alkyl, aroyl, bis(C1-C6alkoxy-C1-C6alkyl)-C1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl,1-C6littoralis,1-C6triptorelin,1-C6perforamce-C1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, C3-C6cycloalkyl,3-C8heteropatriarchal,3-C8geterotsiklicheskikh,6aryl, C5-C6heterocycle,5-C6heteroaryl,3-C8cycloalkyl-C1-C6alkyl, C6aryloxy-C1-C6alkyl, heterokaryosis1-C6alkyl, heteroaryl1-C6alkoxyl1-C6alkyl, heteroaromatic1-C6alkyl, C6arylsulfonyl,1-C6alkylsulfonyl, C5-C6heteroarylboronic is, carboxy1-C6alkyl, C1-C4alkoxycarbonyl-C1-C6alkyl, aminocarbonyl,1-C6alkylaminocarbonyl,1-C6ellimination,1-C6heterocyclimamines,6aaltio-C1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, C6aaltio-C3-C6alkenyl,1-C4alkylthio-C3-C6alkenyl,5-C6heteroaryl-C1-C6alkyl, Gialos1-C6alkanoyl, hydroxys1-C6alkanoyl, tools1-C6alkanoyl,3-C6alkenyl,3-C6quinil,1-C4alkoxy-C1-C4alkyl, C1-C5alkoxycarbonyl, aryloxyalkyl, NR8R9-C1-C5alkylsulphonyl, hydroxys1-C5alkyl, aminocarbonyl, where the nitrogen in aminocarbonyl is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, hydroxyaminobuteroyl, aminosulfonyl, where the nitrogen in aminosulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From 1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, amino1-C6alkylsulfonyl, where the nitrogen aminos1-C6alkylsulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, and aminos1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl,

R7selected from the group including arylalkyl, aryl, heteroaryl, heterologous,1-C6alkyl, C3-C6quinil,3-C6alkenyl,1-C6carboxyethyl and C1-C6hydroxyl,

R8and R9and R10and R11independently from each other selected from the group including hydride, hydroxy-group, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroarm1-C6alkyl, C2-C6quinil,2-C6alkenyl, tools1-C6alkyl, C1-C6is kiltia-C 1-C6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, arakaki1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarbonyl1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, arietis1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl, or where R8and R9or R10and R11together with the atoms to which they are attached, form a carbonyl group, or R8and R9or R10and R11or R8and R10together with the atoms to which they are attached, form the 5-8-membered carbocyclic ring or a 5-8-membered heterocyclic ring, containing one or two heteroatoms that are nitrogen, oxygen or sulfur, provided that only one of the radicals R8and R9or R10and R11denotes a hydroxy-group,

R12and R12'independently from each other selected from the group including hydride, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroalkyl,1-C6quinil,1-C6alkenyl, tools1-C6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, arakaki1-C6alkyl, amino1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarbonyl1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, arietis1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1-the 6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl,

R13selected from the group including hydride, benzyl, phenyl, C1-C6alkyl, C1-C6quinil,2-C6alkenyl and C1-C6hydroxyalkyl, and

G-A-R-E-Y is a Deputy, which preferably has a length exceeding the length Pintilei group, and more predpochtitelno has a length exceeding the length hexylene group. Deputy G-A-R-E-Y preferably has a length smaller than the length of coseley group, and more preferably less than the length of stearley group.

This Deputy G denotes aryl or heteroaryl group;

And are selected from the group including

(1) -O-,

(2) -S-,

(3) -NR17-,

(4) -CO-NR17-or-NR17-CO-, where R17denotes hydrogen, C1-C4alkyl or phenyl,

(5) -CO-O - or-O-CO-,

(6) -O-CO-O-,

(7) -HC=CH-,

(8) -NH-CO-NH-,

(9) -C=C-,

(10) -NH-CO-O-or-O-CO-NH-,

(11) -N=N-.

(12) -NH-NH-and

(13) -CS-N(R18)-or-N(R18)-CS-, where R18denotes hydrogen, C1-C4alkyl or phenyl, or

(14) a is absent, a G directly connected inen to R,

R denotes a fragment selected from the group comprising alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci, aralkyl, heteroalkyl, geterotsiklicheskikh, cycloalkenyl, cycloalkenyl, geterotsiklicheskikh, aryloxyalkyl, heteroepitaxial, alltoall, heteroalicyclic, cycloalkylcarbonyl and geterotsiklicheskikh, where aryl or heteroaryl, or cycloalkyl, or heterologously Deputy is (I) unsubstituted or (II) substituted with one or two radicals selected from the group comprising halogen, alkyl, perfluoroalkyl, performace, performancegroup, triptorelin, amino group, alkoxycarbonyl, alkoxy, C1-C2alkylenedioxy, hydroxyarylalkyl, hydroxycarbonylmethyl-, nitro-, hydroxy-group, hydroxyalkyl, alkanolamines and alkoxycarbonyl, and R does not denote an alkyl or alkoxyalkyl when And denotes-O - or-S-,

E is chosen from the group including

(1) -CO(R19)- or -(R19)CO-, where R19denotes heteroseksualci or cycloalkyl,

(2) -CONH-or-HNCO-,

(3) -CO-,

(4) -SO2-R19or R19-SO2-,

(5) -SO2and

(6) -NH-SO2- or-SO2-NH, or

(7) E is absent and R is directly attached to Y, and Y is absent or selected from the group including g grid, alkyl, alkoxygroup, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, Alcoxy, heterokaryosis, heteroalkyl, performace, performancegroup, triptorelin, alkenyl, heteroseksualci, cycloalkyl, trifluoromethyl, alkoxycarbonyl and aminoalkyl, where aryl or heteroaryl, or heterocytolysine group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising alkanoyl, halogen, the nitro-group, aralkyl, aryl, alkoxy and amino groups, where the nitrogen in the amino group is (I) unsubstituted or (II) substituted with one or two groups independently from each other selected from the group comprising a hydride, alkyl and aralkyl. Especially preferred compound that is intended for use in the proposed method, has a structure corresponding to the following formula III, or represents its pharmaceutically acceptable salt:

where m, n, p, X, Z, Y and R14have the meanings indicated above for formula II, and the values of the radical R, which are given below, are a subset of the values shown previously for Deputy G-A-R-E-Y.

Thus, R3denotes the radical, including aryl or heteroaryl group with one ring, which is - or 6-membered, and is itself substituted at the 4-position, when it is a 6-membered ring, and 3 - or 4-position, when it is a 5-membered ring, Deputy, selected from the group consisting of thiophenoxy-, 4-chlorophenoxy-, 3-chlorophenoxy-, 4-methoxyphenoxy-, 3-benzodioxol-5-yloxy-, 3,4-dimethylphenoxy-, 4-pertenece-, 4-fortifies, phenoxy-, 4-triftormetilfosfinov-, 4-triptoreline-, 4-(triptoreline)phenoxy-, 4-(triptoreline) thiophenoxy-, 4-chloro-3-pertenece-, 4-isopropoxyphenoxy-, 4-isopropylphenoxy-, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy-, 4-chloro-3-methylphenoxy-, 3-methylphenoxy-, 4-ethoxyphenoxy-, 3,4-divergence-, 4-chloro-3-methylphenoxy-, 4-fluoro-3-chlorophenoxy-, 4-(1H-1,2,4-triazole-1-yl)phenoxy-, 3,5-divergence-, 3,4-dichlorophenoxy-, 4-cyclopentyloxy-, 4-bromo-3-methylphenoxy-, 4-bromophenoxy-, 4-methylthiophene-, 4-phenyleneoxy-, 4-benzylphenol-, 6-hyalinelike-, 4-amino-3-methylphenoxy-, 3-methoxyphenoxy-, 5,6,7,8-tetrahydro-2-naphthalenyloxy-, 3-hydroxymethylbenzene, N-piperidyl, N-piperazinil and 4-benzyloxybenzyl.

A more preferred compound that is intended for use in the proposed method, has a structure corresponding to the following formula IV, or represents its pharmaceutically acceptable salt:

where R3has the values specified above for the ormula I, more preferably above for formula II (where the group R3is a Deputy G-A-R-E-Y), and more preferably also the values specified for formula III, and Z is chosen from the group comprising O, S, NR6, SO, SO2and NSO2R7where R6selected from the group including hydride, With1-C5alkyl, C1-C5alkanoyl, benzyl, benzoyl,3-C5quinil,3-C5alkenyl,1-C3alkoxy-C1-C4alkyl, C3-C6cycloalkyl, heteroaryl1-C6alkyl, C1-C5hydroxyalkyl,1-C5carboxyethyl,1-C5alkoxy-C1-C5alkylsulphonyl and NR8R9-C1-C6alkylsulphonyl or NR8R9-C1-C6alkyl, where R8and R9independently of one another denote hydride, With1-C5alkyl, C1-C5alkoxycarbonyl or arils1-C5alkoxycarbonyl, or NR8R9together form a heterocyclic ring containing 5 to 8 atoms in the ring, and R is chosen from the group vkluchaysya arylalkyl, aryl, heteroaryl, heterocycle-From1-C6alkyl, C3-C6quinil,1-C6alkenyl,1-C6carboxyethyl and C1-C6hydroxyalkyl.

Even more preferred group of compounds, the art is meant for use according to the proposed method, has a structure corresponding to the following formula V, or a pharmaceutically acceptable salt of this group of compounds:

where Z has the meanings given above for formula IV, W and Q independently of one another represent oxygen (O)NR6or sulfur (S), where R6has the values specified for formula IV, and q is 0 or 1, and when q is 0, triptorelin group attached directly to indicated phenyl end.

The use of compounds of formulas I-V or a pharmaceutically acceptable salt of one of these compounds is discussed in the previously described method. In addition, the compounds of formulas II, III, IV and V and their pharmaceutically acceptable salts are the compounds of the present invention.

The present invention also relates to a precursor or intermediate connection, suitable for obtaining compounds of formulas I-V. This intermediate compound has the structure corresponding to the following formula VI:

where m, n, p, X, Z and Y have the meanings indicated above for formula II, g is 0, 1 or 2 and R24means R3as this radical defined for formula I, III or IV, Deputy G-A-R-E-Y of formula II (formula VIA) or denotes R3'in which aryl or heteroaryl group substituted linking what", reactive in relation to linking with another fragment (formula VIB), such as replacing the nucleophile leaving group D.

Examples replaced by the nucleophile leaving group D are halogen (fluorine, chlorine, bromine or iodine), nitro, azido, phenylsulfonyl, aryloxy-From1-C6alkoxygroup,1-C6alkylsulfonate or arylsulfonate group and tizamidine ammonium group, in which three substituent independently from each other selected from the group including aryl, ARS1-C6alkyl or C1-C6alkyl.

R20means (a) -O-R, where R21selected from the group including hydride, With1-C6alkyl, aryl, ARS1-C6alkyl and pharmaceutically acceptable cation, or (b) -NH-O-R22where R22means selectively removable protective group such as 2-tetrahydropyranyl,1-C6acyl, aroyl, benzyl, para-methoxybenzeneboronic (MOZ), benzyloxycarbonyl,1-C6alkoxycarbonyl,1-C6alkoxy-CH2-With1-C6alkoxy-C1-C6alkoxy-CH2-, tizamidine silyl group or ortho-nitroaniline group, the resin for the synthesis of peptides, etc. Tizamidine silyl group may be substituted With1-C6Ala is scrap, the aryl or ARS1-C6the alkyl.

Particularly preferred precursor or intermediate compound of formula VI is an intermediate compound of formula VII

where m, n, p, g, X, Z, Y, D, and R20have the meanings indicated above for formula VI.

The present invention achieves a number of advantages due to the proposed compounds and compositions useful as inhibitors of the activity of matrix metalloproteinases, i.e. due to such compounds and compositions that are effective for the inhibition of metalloproteinases, causing diseases and disorders associated with uncontrolled destruction of the connective tissue.

The present invention achieves a number of advantages, in particular due to the proposed connection and compositions effective against selective inhibition of certain metalloproteinases, such as one or more MMP selected from the group including MMP-2, MMP-9 or MMP-13, which is associated with pathological conditions such as, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal ulceration, epidermal or gastric, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease.

Another advantage is achieved according to the invention due to its proposed connections compositions and methods effective in the treatment of such pathological conditions through selective inhibition of metalloproteinases, such as MMP-2, MMP-9 or MMP-13 that are associated with the specified condition, with minimal side effects resulting from inhibition of other metalloproteinases such as MMP-1, the activity of which is necessary or desirable for the proper functioning of the body.

Another advantage is achieved according to the invention due to its proposed process for the preparation of such compounds.

The following advantage is achieved according to the invention due to its proposed method of treatment of a pathological condition associated with abnormal activity of matrix metalloproteinases.

Another advantage is achieved according to the invention due to its proposed process for the preparation of these compositions.

Other advantages and objectives of the invention are obvious to those skilled in the art from the following description.

Detailed description of the invention

According to the present invention, it was found that certain aromatic sulfamethoxasole acid (hydroxamate) are effective for the inhibition of matrix metalloproteinase ("MMP"), which is probably related to decontrol the units or any other pathological destruction of the connective tissue. In particular, it was found that such certain aromatic sulfamethoxasole have efficacy in inhibiting one or more enzymes, such as MMP-2, MMP-9 and MMP-13, which may be particularly significant tissue destruction, if present or generated in abnormal quantities or concentrations and, thus, show abnormal activity. This concept of pathological activity includes the ability to facilitate the penetration of tumors or tumor cells through the basement membrane and the development of new or enhanced blood supply, i.e. angiogenesis.

In addition, it was found that these aromatic sulfamethoxasole have a selectivity in relation to inhibition of one or more of MMP-2, MMP-9 and MMP-13 while lacking the pronounced inhibitory activity against other collagenases, which are important for normal body functions, such as the processes of transformation and repair tissue. In particular, it was found that the aromatic sulfonyloxy according to the invention or its pharmaceutically acceptable salt are particularly active in relation to inhibition of one or more of the M MP-2, MMP-9 and MMP-13 in vitro, suggesting the presence of activity in vivo. In addition, having a selective effect is one or more of MMP-2, MMP-9 and MMP-13 that is specified aromatic sulfonyloxy or its salt have limited or minimal inhibitory activity against MMP-1 in vivo.

Thus, there is a marked difference in the activity of the connection, which is used in this way in relation to one or more of MMP-2, MMP-9 and MMP-13 and against MMP-1. This significant difference is detected using analysis of inhibition in vitro, which is described in the examples. Significant difference in activity is that the value of the IC50connections for one or more of MMP-2, MMP-9 and MMP-13 is about 0.1 of the value IC50connection against MMP-1 and more preferably from 0.01 to value against MMP-1 and most preferably of 0.001 or more of its value against MMP-1. So, for some compounds, the ratio of selective action in assessing the values IC50exceeded the values obtained in a similar experience, 100000 times. This selective action is illustrated below in tables in which the data on inhibition.

Consider the connection also can inhibit the activity of MMP-2 compared with MMP-9 or MMP-13 and MMP-1. Similarly, consider the connection can inhibit the activity of MMP-13 and MMP-2 and have manchaspainaug to inhibit the activity of MMP-1 and MMP-9. Furthermore, this compound can inhibit the enzyme activity of MMP, but to be less impact on the secretion of tumor necrosis factor.

Without going into theoretical details, the advantages of the selective action of the considered compounds can be estimated on the basis of therapeutic value of the compounds. For example, it is assumed that the inhibition of MMP-1 is undesirable due to its role as a constitutive enzymes (enzymes "household"), promotes the maintenance of normal processes of transformation and repair of connective tissue. Inhibition of MMP-1 may lead to toxicity or side effects, such as destruction of the joint or connective tissue and pain. On the other hand, it is assumed that MMP-13 is directly involved in the destruction of joint components in such diseases as osteoporosis. So, it is highly desirable is an effective and selective inhibition of MMP-13 in comparison with the inhibition of MMP-1 as an inhibitor of MMP-13 in addition to its anti-inflammatory action may have a positive effect on the progressive development of the disease in the patient.

Inhibition of MMP-2 and MMP-9 may be desirable for the inhibition of tumor growth, metastasis, invasion and/or angiogenesis. PR is fil selective inhibition of MMP-2 and MMP-9 compared with MMP-1 may provide a therapeutic advantage.

Another advantage of the considered compounds is selective with respect to the selection of tumor necrosis factor and/or selection of the receptor of tumor necrosis factor, which is for the doctor one more chance to choose the most effective drug for a particular patient. Not based on any theory, it is possible to assume that there are several aspects of this type of selective action that should be taken into account.

First, the presence of tumor necrosis factor may be desirable to control the development of malignant tumors in the body, if TNF is not present in excessive amounts, causing toxic effects. So, uncontrolled inhibition allocation TNF can have negative consequences and in fact can be considered as a harmful side effect even in patients with cancer patients. In addition, it may also be desirable selectivity in respect of inhibiting the selection of the receptor of tumor necrosis factor. The presence of this receptor may be desirable to maintain a controlled level of necrosis of tumors in a mammal by binding excess TNF.

Consider the connection, which is a selective inhibitor of MMP, following the above process may be the Vedeno in different ways and to provide the required therapeutic blood levels of the active against the enzyme inhibitor. The connection may be, for example, oral (in the stomach (IG), oral (PO)or intravenous (IV) route. Oral route of administration is preferred if the patient is in an outpatient setting, not hospitalized, physically capable and responsible enough to self-medication through a certain period of time. This applies even to the case where the treatment involves taking more than one medication in the treatment of more than one disease. On the other hand, intravenous drugs are preferred in the hospital, at this dose and the associated level in the blood is well controllable. Consider the inhibitor may also be introduced into the composition for intramuscular (IM) injection. This way, it may be desirable to introduce prodrugs or for the regular administration of medication to a patient who is either physically weak or poorly compliance regime and the treatment regimen, or when you require a constant level of medication in the blood.

Thus, in one of the embodiments of the present invention proposed a method of treatment involves the introduction of an effective amount considered aromatic sulfamethoxasole acid, an inhibitor of metallopro is teas, or its pharmaceutically acceptable salt of the owner of the mammal, which has a condition associated with pathological activity of the matrix of metalloprotease.

Consider aromatic sulfonyloxy, which compound is an inhibitor, which is used according to this variant of the method, inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13 and has substantially less inhibitory activity against at least MMP-1 in the previously mentioned experience in vitro, which is described in detail below. Aromatic sulfonyloxy, which compound is an inhibitor, which is used according to the considered variant of the method has a structure corresponding to the formula below I:

in which the substituents have the following meanings.

In one embodiment, the implementation of R1and R2both indicate the hydride. In another embodiment, R1and R2together with the atoms to which they are attached, form a 5-8-membered ring containing in the ring one, two or three heteroatoms, represents oxygen, sulfur or nitrogen.

Preferably, R1and R2together with the atoms to which they are attached, form a 5-8-membered ring containing in the ring one or two heteroatoms, although R1and R 2together with the atoms to which they are attached can form a 5-8-membered ring containing in the ring one, two or three heteroatoms. Heterocyclic ring itself may have as substituents up to six With1-C6the alkyl group or groups, including another 5-8-membered carbocyclic or heterocyclic ring, an amino group, or may contain one or two oxo(carbonyl) groups. R3in the formula I denotes optionally substituted aryl or optionally substituted heteroaryl moiety. The radical R3selected from the group including aryl, heteroaryl, aralkyl, heteroalkyl, Alcoxy, heteroaromatic, alcoxialchil, aryloxyalkyl, arachnology, arylcarboxylic, aralkylated, aryloxyalkyl, aralconsult,

unilateral, arylhydrazines, alkylaryl, alltoall, alkylthiomethyl, aralkylated, kalkiliya, sulfoxide or sulfon any of titlestyle and condensed ring structure comprising two or more 5-6 membered rings selected from the group comprising aryl, heteroaryl, carbocyclic and heterocyclic radical.

Deputy included in the radical R3itself may be unsubstituted or may be substituted by one or more substituents, independently from each other selected from the group including cyano, perfluoroalkyl, triptorelin, the hydroxy-group, halogen, alkyl, alkoxy-, nitro-group, thiol, hydroxycarbonyl, aryloxy, killigrew, aralkyl, aryl, heteroaromatic, heterogroup, heteroalkyl, cycloalkyl, heterocyclics, heterocycly, heterocyclimamines, cycloalkane, cycloalkene, heteroaromatic, heteroalkyl, Alcoxy, Uralkali, aralkylamines, heterologous, heteroaryl, arylazo, hydroxycarbonylmethyl, alkoxycarbonylmethyl, alkanoyl, arylcarbamoyl, arkanoid, alkanoyloxy, arachnodactyly, hydroxyalkyl, hydroxyalkoxy, alkylthio-alkoxyalkyl, alkoxycarbonyl, aryloxyalkyl, arylthioureas, aryloxyalkyl, killiechassie, hydroxycarbonylmethyl, hydroxycarbonylmethyl, alkoxycarbonyl, alkoxycarbonylmethyl, amino, where the amino nitrogen is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, arelaxation, alkoxycarbonyl, arylcarbamoyl, arkanoid, heteroarylboronic, heteroalkyl and alkanoyl, or (III) where the nitrogen of the amino group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring the, containing 0-2 additional heteroatoms, represents a nitrogen, oxygen or sulfur, and the ring is (a) unsubstituted or (II) substituted with one or two groups independently from each other selected from the group including aryl, alkyl, heteroaryl, aralkyl, heteroalkyl, hydroxy-, alkoxygroup, alkanoyl, cycloalkyl, heteroseksualci, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, condensed with benzene ring heteroseksualci, hydroxyethoxyethyl, arelaxation, hydroxycarbonyl, aryloxyalkyl condensed with a benzene ring geterotsiklicheskikh condensed with a benzene ring cycloalkylcarbonyl, geterotsiklicheskikh and cycloalkylcarbonyl group,

carbonylation, where the nitrogen carboxamide is (I) unsubstituted or (II) is a reactive amine amino acids, or (III) is substituted by one or two radicals selected from the group comprising alkyl, hydroxyalkyl, hydroxycitronellal, cycloalkyl, aralkyl, triptorelin, heteroseksualci condensed with a benzene ring heteroseksualci condensed with a benzene ring cycloalkyl and N,N-dialkylamino acylaminoalkyl group, or (IV) the nitrogen carboxamidine and two adjacent substituent to form a 5-clonoe heterocycle-, heteroaryl, or condensed with a benzene ring cycloalkyl ring, which itself may be unsubstituted or may be substituted by one or two radicals independently from each other selected from the group comprising alkyl, alkoxycarbonyl, a nitrogroup, heteroseksualci, the hydroxy-group, hydroxycarbonyl, aryl, aralkyl, heteroalkyl

and the amino group,

where the amino nitrogen is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group including alkyl, aryl and heteroaryl, or (III) where the nitrogen of the amino group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring,

and aminoalkyl group where the nitrogen aminoalkyl is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising alkyl, aryl, aralkyl, cycloalkyl, arelaxation, alkoxycarbonyl and alkanoyloxy group, or (III) where the nitrogen aminoalkyl and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring. The compound of the formula I can also be used in the form of pharmaceutically acceptable salts.

The radical R3has a length greater than the length Pintilei group [a-(CH2)4CH3-the chain] and more preferably not the decisive length about hexylene group [-(CH 2)5CH3-the chain]. The radical R3has a length smaller than the length of coseley group [eicosyl-(CH2)19CH3chain], and more preferably a length less than the length of stearley group [a-(CH2)17CH3-the chain]. Consider the group R in rotation around the axis passing through the associated with SO21-position and associated with a Deputy at the 4-position of the 6-membered ring, or through associated with the SO21-position and connected with the Deputy 3-or 4-position 5-membered ring, forms a three-dimensional space, the largest of which in the direction perpendicular to the specified axis of rotation, equal to the length from approximately one furnishing ring to about two phenyl rings.

If, for example, associated with the SO2group, the radical R denotes a 4-phenoxyphenyl, this connection can be considered as peroxidisulphate derivative, i.e. the required 5-8-membered N-hydroxycarboxylic. Examples of such compounds which should be mentioned are the following:

N-hydroxy-1-methyl[4-(phenoxyphenylacetic)]-4-piperidinecarboxylic,

N-hydroxy[4-(phenoxyphenylacetic)]tetrahydro-2H-Piran-4-carboxamid,

N-hydroxy-1-methyl - [2,6-dioxo-4-(phenoxyphenylacetic)]-4-piperidinecarboxylic,

N-hydroxy-2,2-dimethyl[5-(phenoxyphenylacetic)]-1,3-dioxane-5-carboxamid,/p>

N-hydroxy-1,2-dimethyl-6-oxo[4-(phenoxyphenylacetic)]-4-piperidinecarboxylic,

N-hydroxy-2,2,6,6-tetramethyl[4-(phenoxyphenylacetic)]-4-piperidinecarboxylic,

N-hydroxy-1,3-dimethyl[5-(phenoxyphenylacetic)]hexahydro-5-pyrimidinecarboxylic,

2-amino-N-hydroxy[5-(phenoxyphenylacetic)]-1,4,5,6-tetrahydro-5-pyrimidinecarboxylic,

N-hydroxy-1,1-dioxo[4-(phenoxyphenylacetic)]-1(λ 6),2,6-tadisina-4-carboxamid,

N-hydroxy-2-oxo[5-(phenoxyphenylacetic)]hexahydro-5-pyrimidinecarboxylic,

N-hydroxy[2-(phenoxyphenylacetic)]tetrahydro-2-furancarboxylic,

N-hydroxy-1-methyl[2-(phenoxyphenylacetic)]-2-pyrrolidinecarboxamido,

N-hydroxy-2-methyl[4-(phenoxyphenylacetic)]-4-piperidinecarboxylic,

N-hydroxy[3-(phenoxyphenylacetic)]-8-azabicyclo[3.2.1]Octan-3-carboxamide,

N-hydroxy-1,1-dioxo[4-(phenoxyphenylacetic)]hexahydro-1 (λ 6)-thiopyran-4-carboxamid,

N-hydroxy[3-(phenoxyphenylacetic)]tetrahydro-3-furancarboxylic,

N-hydroxy[3-(phenoxyphenylacetic)]-3-pyrrolidinecarboxylic,

monohydrochloride N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl)]-1-(2-PROPYNYL)-4-piperazinecarboxamide,

nanomeasurement N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl)]-1-(2-PROPYNYL)-4-piperazinecarboxamide,

tetrahydro-N-hydroxy-4-[[4-[4-[(trifluoromethyl]phenoxy]phenyl]sulfonyl]-2H-Piran-4-ka is boxlid,

the hydrochloride of N-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl]phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide,

the dihydrochloride of N-hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl]phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide,

the dihydrochloride of N-hydroxy-1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl]phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide,

the dihydrochloride hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-(triptoreline)phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide,

monohydrochloride N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(triptoreline)phenoxy]phenyl]sulfonyl)]-4-piperazinecarboxamide,

monohydrochloride N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl)]-4-piperazinecarboxamide,

monohydrochloride N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]sulfonyl)]-4-piperazinecarboxamide,

monohydrochloride 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl)]-4-piperazinecarboxamide etc.

Some examples of groups R1and R2, which together form specified heterocyclic ring, are presented in the following tables, as well as in the descriptions of these 5-8-membered rings and in the specific examples, as several of these derivatives aromatic sulfamethoxasole acid.

In a more preferred embodiment, in formula I, R 1and R2together with the atoms to which they are attached, form a 5-8-membered ring containing in the ring one, two or three heteroatoms. More preferably the ring is a 6-membered ring which contains one heteroatom, located in position 4 relative to the position in which joined the group SO2. Other preferred compounds intended for use according to this method, have a structure corresponding to one or more of the following formulas II, III, IV or V.

In one of the embodiments the compound that is intended for use according to this method has a structure corresponding to the following formula II:

where

R14denotes a hydride, a pharmaceutically acceptable cation or C(W)R15where

W represents O or S, and

R15selected from the group including1-C6alkyl, aryl, C1-C6alkoxygroup, heteroaryl1-C6alkyl, C3-C8cycloalkyl-C1-C6alkyl, aryloxy-, ARS1-C6alkoxygroup, ARS1-C6alkyl, heteroaryl and amino1-C6alkyl, where the nitrogen aminoalkyl is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the GRU is dust, include1-C6alkyl, aryl, ARS1-C6alkyl, C3-C8cycloalkyl-C1-C6alkyl, ARS1-C6alkoxycarbonyl,1-C6alkoxycarbonyl and C1-C6alkanoyl, or (III) the nitrogen aminos1-C6alkyl group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring,

m is 0, 1 or 2,

n is 0, 1 or 2,

p is 0, 1 or 2,

the sum m+n+p is equal to 1, 2, 3,or 4

(a) one of the substituents X, Y and Z are selected from the group comprising C(O)NR6, O, S, S(O), S(O)2and NS(O)2R7and the other two substituent X, Y, and Z denote CR8R9and CR10R11or

(b) X and Z or Z and Y together form the fragment chosen from the group comprising NR6C(O)NR6S(O)NR6S(O)2, NR6S, NR6O, SS, NR6NR6and OS(O), with one remaining Deputy from the group comprising X, Y and Z represents CR8R9or

(C) n is 0 and X, Y and Z together form a fragment selected from the group including

where the wavy lines indicate the connection with the atoms of the depicted ring is, R6and R6'independently from each other selected from the group including hydride, With1-C6alkanoyl,6aryl-C1-C6alkyl, aroyl, bis(C1-C6alkoxy-C1-C6alkyl)-C1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl,1-C6perfluoroalkyl, C1-C6triptorelin,1-C6perforamce-C1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, C3-C6cycloalkyl,3-C8heteroseksualci,3-C8heteroseksualci-carbonyl, C6aryl, C5-C6heterologous,5-C6heteroaryl,3-C8cycloalkyl-C1-C6alkyl, C6aryloxy-C1-C6alkyl, heterokaryosis1-C6alkyl, heteroaryl1-C6alkoxyl1-C6alkyl, heteroaromatic1-C6alkyl, C6arylsulfonyl,1-C6alkylsulfonyl, C5-C6heteroarylboronic, carboxy1-C6alkyl, C1-C6alkoxycarbonyl-C1-C6alkyl, aminocarbonyl,1-C6alkylaminocarbonyl,6ellimination,5-C6heterocyclimamines-Nile, With6aaltio-C1-C6alkyl, C1-C6alkylthio-C1-C6alkyl,C 6aaltio-C3-C6alkenyl,1-C4alkylthio-C3-C6alkenyl,5-C6heteroaryl-C1-C6alkyl, Gialos1-C6alkanoyl, hydroxys1-C6alkanoyl, tools1-C6alkanoyl,3-C6alkenyl,3-C6quinil,1-C4alkoxy-C1-C4alkyl, C1-C5alkoxycarbonyl, aryloxyalkyl, NR8R9-C1-C5alkylsulphonyl, hydroxys1-C5alkyl, aminocarbonyl, where the nitrogen in aminocarbonyl is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, hydroxyaminobuteroyl, aminosulfonyl, where the nitrogen in aminosulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, amino1-C6alkylsulfonyl, where the nitrogen aminos1-C6alkylsulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group on what to make With 1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, and aminos1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl,

and aminos1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl,

R7choose from a group comprising benzyl, phenyl, C1-C6alkyl, C3-C6quinil,3-C6alkenyl and C1-C6hydroxyalkyl,

R8and R9and R10and R11independently from each other selected from the group including hydride, hydroxy-group, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroarm1-C6alkyl, C2-C6quinil,1-C6alkenyl, tools1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1 -C6alkyl, C1-C6alkoxy-C1-C6alkyl, arakaki1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarbonyl1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, arietis1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl, or where R8and R9or R10and R11together with the atoms to which they are attached, form a carbonyl group, or R8and R9or R10and R11or R8and R10together with the atoms to which they are attached, form a 5-8-membered carbocyclic ring or a 5-8-membered heterocyclic ring containing one who does two heteroatoms, which are nitrogen, oxygen or sulfur, provided that only one of the radicals R8and R9or R10and R11denotes a hydroxy-group,

R12and R12’independently from each other selected from the group including hydride, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroalkyl,2-C6quinil,2-C6alkenyl, tools1-C6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, aryloxy1-C6alkyl, amino1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarbonyl1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, arietis1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1-C6alkyl, where the nitrogen aminoalkyl the th group is (I) unsubstituted or (II) substituted with one or two radicals, independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl,

R13selected from the group including hydride, benzyl, phenyl, C1-C6alkyl, C2-C6quinil,2-C6alkenyl and C1-C6hydroxyl, and

G-A-R-E-Y is a Deputy, which preferably has a length exceeding the length Pintilei group, and more preferably has a length exceeding the length hexylene group. Deputy G-A-R-E-Y preferably has a length smaller than the length of coseley group, and more preferably, less than the length stearley group.

In this alternate:

G denotes aryl or heteroaryl group,

And are selected from the group including

(1) -O-,

(2) -S-,

(3) -NR17-,

(4) -CO-NR17- or-NR17-CO-, where R17denotes a hydrogen atom, a C1-C4alkyl or phenyl,

(5) -CO-O - or-O-CO-,

(6) -O-CO-O-,

(7) -HC=CH-,

(8) -NH-CO-NH-,

(9) -C=C-,

(10) -NH-CO-O-or-O-CO-NH-,

(11) -N=N-,

(12) -NH-NH and

(13) -CS-N(R18)- or-N(R18)-CS-, where R18denotes a hydrogen atom, a C1-C4alkyl or phenyl, or

(14) a is absent and G directly attached to R, R denotes a fragment selected from the group comprising alkyl, alkoxyalkyl, aryl, heteropar is l, cycloalkyl, heteroseksualci, aralkyl, heteroalkyl, geterotsiklicheskikh, cycloalkenyl, cycloalkenyl, geterotsiklicheskikh, aryloxyalkyl, heteroepitaxial, alltoall, heteroalicyclic, cycloalkylcarbonyl and geterotsiklicheskikh, where aryl or heteroaryl or cycloalkyl or heterologously Deputy is (I) unsubstituted or (II) substituted with one or two radicals selected from the group comprising halogen, alkyl, perfluoroalkyl, performace, performancegroup, triptorelin, amino group, alkoxycarbonyl, alkoxy, C1-C2alkylenedioxy, hydroxyarylalkyl, hydroxycarbonylmethyl-, nitro-, hydroxy-group, hydroxyalkyl, alkanolamines and alkoxycarbonyl, and R does not denote an alkyl or alkoxyalkyl when And denotes-O - or-S-, E is chosen from the group including

(1) -CO(R19)- or -(R19)CO-, where R19means geterotsyklicescoe or cycloalkyl group,

(2) -CONH - or-HNCO-,

(3) -CO-,

(4) -SO2-R19or R19-SO2-,

(5) -SO2-,

(6) -NH-SO2- or-SO2-NH, or

(7) E is absent and R is directly attached to Y, and Y is absent or selected from the group including hydride, alkyl, alkoxygroup, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroc and-, aryloxy, Alcoxy, heterokaryosis, heteroalkyl, performace, performancegroup, triptorelin, alkenyl, heteroseksualci, cycloalkyl, trifluoromethyl, alkoxycarbonyl and aminoalkyl, where aryl or heteroaryl, or heterocytolysine group is (I) unsubstituted or (II) replaced by one or two radicals independently from each other selected from the group comprising alkanoyl, halogen, the nitro-group, aralkyl, aryl, alkoxy and amino groups, where the nitrogen in the amino group is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising a hydride, alkyl and aralkyl.

Deputy-G-A-R-E-Y preferably contains 2-4 carbocyclic or heterocyclic ring, including aryl or heteroaryl group G. More preferably, each of these rings is 6-membered. In a more specific preferred embodiments, the substituents in the compound of the formula II have the following meanings: (a) (a denotes-O - or-S-, (b) R represents aryl, heteroaryl, cycloalkyl or heteroseksualci, (C) E is absent and (g) Y is chosen from the group comprising a hydride, alkyl, alkoxy, performace and performancegroup.

A more preferred compound that is intended for use according to this method has a structure according to dtweedie the following formula III:

where R3denotes a radical comprising 5-or 6-membered aryl group or heteroaryl group with one ring, which is substituted in the 4-position, when it is a 6-membered ring, and 3 - or 4-position, when it is a 5-membered ring, Deputy, selected from the group consisting of thiophenoxy-, 4-chlorophenoxy-, 3-chlorophenoxy-, 4-methoxyphenoxy-, 3-benzodioxol-5-yloxy-, 3,4-dimethylphenoxy-, 4-pertenece-, 4-fortifies, phenoxy-, 4-triftormetilfosfinov-, 4-triptoreline-, 4-(triptoreline)phenoxy-, 4-(triptoreline) thiophenoxy-, 4-chloro-3-pertenece-, 4-isopropoxyphenoxy-, 4-isopropylphenoxy-, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl) phenoxy-, 4-chloro-3-methylphenoxy-, 3-methylphenoxy-, 4-ethoxyphenoxy-, 3,4-divergence-, 4-chloro-3-methylphenoxy-, 4-fluoro-3-chlorophenoxy-, 4-(1H-1,2,4-triazole-1-yl)phenoxy-, 3,5-divergence-, 3,4-dichlorophenoxy-, 4-cyclopentyloxy-, 4-bromo-3-methylphenoxy-, 4-bromophenoxy-, 4-methylthiophene-, 4-phenyleneoxy-, 4-benzylphenol-, 6-hyalinelike-, 4-amino-3-methylphenoxy-, 3-methoxyphenoxy-, 5,6,7,8-tetrahydro-2-naphthalenyloxy-, 3-hydroxymethylene - and 4-benzyloxybenzyl,

R14denotes a hydride, a pharmaceutically acceptable cation or C(W)R15where W denotes O or S, and R are selected from the group including -C6alkyl, aryl, C1-C6alkoxygroup, heteroaryl1-C6alkyl, C3-C8cycloalkyl-C1-C6alkyl, aryloxy-, ARS1-C6alkoxygroup, ARS1-C6alkyl, heteroaryl and amino1-C6alkyl, where the nitrogen aminoalkyl is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising From1-C6alkyl, aryl, ARS1-C6alkyl, C1-C6cycloalkyl-C1-C6alkyl, ARS1-C6alkoxycarbonyl,1-C6alkoxycarbonyl and C1-C6alkanoyl, or (III) the nitrogen aminos1-C6alkyl group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring; m is 0, 1 or 2, n is 0, 1 or 2, p is 0, 1 or 2, the sum of m+n+p is equal to 1, 2, 3,or 4

(a) one of the substituents X, Y and Z are selected from the group comprising C(O)NR6, O, S, S(O), S(O)2and NS(O)2R7and the other two substituent X, Y, and Z denote CR8R9and CR10R11or

(b) X and Z or Z and Y together form the fragment chosen from the group comprising NR6C(O)NR6S(O)NR6S(O)NR6S, NR6O, SS, NR6NR6and OS(O), with one remaining Deputy from the group comprising X, Y and Z represents CR8R 9or

(C) n is 0 and X, Y and Z together form a fragment selected from the group including

where the wavy lines indicate the connection with the atoms of the depicted ring, R6and R6'independently from each other selected from the group including hydride, With1-C6alkanoyl,6aryl-C1-C6alkyl, aroyl, bis(C1-C6alkoxy-C1-C6alkyl)-C1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl,1-C6perfluoroalkyl, C1-C6triptorelin,1-C6perforamce-C1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, C3-C6cycloalkyl,3-C8heteroseksualci,3-C8heteroseksualci-carbonyl, C6aryl, C5-C6heterologous,5-C6heteroaryl,3-C8cycloalkyl-C1-C6alkyl, C6aryloxy-C1-C6alkyl, heterokaryosis1-C6alkyl, heteroaryl1-C6alkoxyl1-C6alkyl, heteroaromatic1-C6alkyl, C6aryl sulfonyl,1- 6alkylsulfonyl, C5-C6heteroarylboronic, carboxy1-C6alkyl, C1-C4alkoxycarbonyl-C1-C6alkyl, aminocarbonyl,1-C6alkylaminocarbonyl,6ellimination,5-C6heterocyclimamines,6aaltio-C1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, C6aaltio-C3-C6alkenyl,1-C4alkylthio-C3-C6alkenyl,5-C6heteroaryl-C1-C6alkyl, Gialos1-C6alkanoyl, hydroxys1-C6alkanoyl, tools1-C6alkanoyl,3-C6alkenyl,3-C6quinil,1-C4alkoxy-C1-C4alkyl, C1-C5alkoxycarbonyl, aryloxyalkyl, NR8R9-C1-C5alkylsulphonyl, hydroxys1-C5alkyl, aminocarbonyl, where the nitrogen in aminocarbonyl is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, hydroxyaminobuteroyl, aminosulfonyl, where the nitrogen in aminosulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals, an independent who from each other selected from the group include1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, amino1-C6alkylsulfonyl, where the nitrogen aminos1-C6alkylsulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, and aminos1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl,

R7choose from a group comprising benzyl, phenyl, C1-C6alkyl, C3-C6quinil,3-C6alkenyl,1-C6carboxyethyl and C1-C6hydroxyalkyl, R8and R9and R10and R11independently from each other selected from the group including hydride, hydroxy-group, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroarm1-C6alkyl, C2-C6quinil,2-C6alkenyl, tools1-C6alkyl, C1-C6alkylthio-C1-the 6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, arakaki1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarb-Niels1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, aaltio1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl, or where R8and R9or R10and R11together with the atoms to which they are attached, form a carbonyl group, or R8and R9or R10and R11or R8and R10together with the atoms to which they are attached, form a 5-8 member of the second carbocyclic ring or a 5-8-membered heterocyclic ring, containing one or two heteroatoms that are nitrogen, oxygen or sulfur, provided that only one of the radicals R8and R9or R10and R11denotes a hydroxy-group,

R12and R12'independently from each other selected from the group including hydride, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroalkyl,1-C6quinil,1-C6alkenyl, tools1-C6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, aryloxy1-C6alkyl, amino1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarbonyl1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, arietis1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1- 6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl,

R13selected from the group including hydride, benzyl, phenyl, C1-C6alkyl, C1-C6quinil,2-C6alkenyl and C1-C6hydroxyalkyl. And in this case, means that the compound of formula III can be applied in the form of pharmaceutically acceptable salts.

Preferred variants of the compounds of formula III are the same options as in the case of the compounds of formula II are, independently of each other including the following conditions: (a) the sum of m+n+p is 1 or 2 and more preferably equal to 2, (b) Z represents O, S or NR6() R6selected from the group including3-C6cycloalkyl,1-C6alkyl, C3-C6alkenyl,3-C6quinil,1-C6alkoxy-C1-C6alkyl, amino1-C6alkyl, aminosulfonyl, heteroaryl1-C6alkyl, aryloxyalkyl and C1-C6alkoxycarbonyl, and (d) m=n=0, p=1 and Y represents NR6. Another preferred variant, the compounds of formula II and compounds of formula III are options when R 14means hydride or when W group C(W)R15prodrugs denotes Oh, where R15stands With1-C6alkyl, aryl, C1-C6alkoxygroup, heteroaryl1-C6alkyl, C3-C6cycloalkyl-C1-C6alkyl or alloctype.

Even more preferred compound that is intended for use according to this method has a structure corresponding to the following formula IV:

where

R3has the values specified above for formulas I, III, more preferably has the meanings specified for formula II (where the radical R3is a Deputy G-A-R-E-Y), most preferably R3has the values specified for formula III,

Z is chosen from the group comprising O, S, NR6, SO, SO2and NSO2R7,

where R6selected from the group including hydride, With1-C6alkyl, C1-C6alkanoyl, benzyl, benzoyl,3-C5quinil,3-C5alkenyl,1-C3alkoxy-C1-C4alkyl, C3-C6cycloalkyl, heteroaryl1-C6alkyl, C1-C5hydroxyalkyl,1-C5carboxyethyl,1-C5alkoxy-C1-C5alkylsulphonyl and NR8R9-C1-C5alkylsulphonyl or NR8 R9-C1-C5alkyl, where R8and R9independently of one another denote hydride, With1-C5alkyl, C1-C5alkoxycarbonyl or arils1-C5alkoxycarbonyl, or NR8R9together form a heterocyclic ring containing 5 to 8 atoms in the ring, and

R7selected from the group including arylalkyl, aryl, heteroaryl, heterologous,1-C6alkyl, C3-C6quinil,3-C6alkenyl,1-C6carboxyethyl and C1-C6hydroxyalkyl. Most preferably Z represents O or NR6. And in this case, means that the compound of formula III can be applied in the form of pharmaceutically acceptable salts.

A more preferred group of the considered compounds for use according to this method has a structure corresponding to the formula below V:

where Z has the meanings given above for formula IV, W and Q independently of one another represent oxygen (O), NR or sulfur (S), where R6has the values given above for formula IV, and q is 0 or 1, and when q is 0, Q is absent, and triptorelin group directly attached to the specified phenyl ring. And in this case, means that the compound of formula IV, m is should be used in the form of pharmaceutically acceptable salts.

Especially preferred compounds within the group represented by the formula V have the structure corresponding to the formula below:

Also particularly preferred are the following compounds:

Several particularly preferred compounds having a structure corresponding to formula I-V, below, in tables and in the examples.

As noted above, the compounds of formulas II, III, IV and V and their pharmaceutically acceptable salts are compounds falling under the scope of the invention.

In the preferred embodiment, connected to the SO2group, the radical R3represents an aryl or heteroaryl group having one 5-6 membered ring that is substituted for one another aryl group or heteroaryl group with one ring or alkyl or alkoxygroup with chain length from 3 to about 16 ATO is s C (more preferably with a length of up to about 14 carbon atoms), phenoxypropane, thiophenoxide [C6H5-S-], phenylisopropyl [C6H5-N2-], N-piperidino [C5H10N], N-piperazino [NC4H9N-] or benzimidazol [NHC(O)C6H5]. In this case, connected with the SO2the aryl group or heteroaryl group, R3with one ring substituted at its 4-position, if it is a 6-membered ring, and substituted in the 3-or 4-position, if it is a 5-membered ring.

Connected with SO2the aryl group or heteroaryl group of the radical R3preferably substituted in its 4-position, if it is a 6-membered ring, and substituted in the 3-or 4-position, if it is a 5-membered ring. Especially preferred as the Deputy is an aryl or heteroaryl group with one ring, phenoxy, thiophenoxy, phenylisopropyl, N-piperidyl, N-piperazin or benzamidoxime, which can be unsubstituted or can itself be substituted.

These 4 - and 3-positions in the ring are numbered starting from the accession Deputy in accordance with the officially valid numbering of the provisions adopted in the nomenclature heteroaryl derivatives as shown below in the present description. Thus, preferred are individual atoms, such as halogen atoms (fluorine, chlorine is, bromine or iodine), or deputies, which contain in the chain of one to about five atoms other than hydrogen, such as phenyl,1-C4alkyl, trifluoromethyl, tripterocarpa, cryptostigmata or carboxyethyl, although can be applied and the deputies, having a greater length, such that the total length does not exceed the length coseley group.

Examples of particularly preferred substituted connected with SO2-a group of radicals R include 4-(phenyl)phenyl[biphenyl], 4-(4’-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl[4-(phenylthio)phenyl], 4-(Otopeni)phenyl, 4-[(4’-triptoreline)phenoxy]phenyl, 4-[(4’-triptoreline)thiophenyl]phenyl, 4-[(4’-trifluoromethyl) phenoxy]phenyl, 4-[(4’-trifluoromethyl)thiophenyl]phenyl, 4-[(4’-triptoreline)phenoxy]phenyl, 4-[(4’-triptoreline)thiophenyl]phenyl, 4-[(4’-phenyl)-N-piperidyl]phenyl, 4-[(4’-acetyl-N-piperazin]phenyl and 4-(benzamido)phenyl.

Since the considered associated with the SO2group aryl or heteroaryl radical, R3itself is preferably substituted 6-membered ring, to facilitate understanding of the locations of the substituents in the present description uses two nomenclature systems. In the first system uses a number of provisions of the ring, directly related to the SO2group, while the second system uses symbols ortho-, meta-or para-position of one of the substituents 6-membered ring, United linked with SO2group aryl or heteroaryl radical. Although, as a rule, for aliphatic ring systems not used the item in the form of ortho-, meta - or para-position, likely much easier to understand the structure of compounds described in the present description, in conjunction with the numbering system for the first ring, associated with the SO2-group. If the radical R3does not denote a 6-membered ring, the position of substituents is numbered from the communication position with an aromatic or heteroaromatic ring. For the names of specific compounds used officially the current item.

Thus, the 1-position described above related to the SO2group aryl or heteroaryl radicals denotes the situation in which SO2group attached to the ring. These 3 - and 4-positions of the rings are numbered starting from the accession of the Deputy regarding joining SO2groups in accordance with the officially valid numbering of the provisions adopted in the nomenclature heteroaryl derivatives.

With regard to the longest chain of atoms of the radical R3including his own Deputy, its total length exceeds the length of the saturated chain of 5 carbon atoms (pentilla group), preferably a radical has a length, previews the long saturated chains, consisting of 6 carbon atoms (exilda group), i.e. the length of the radical roughly corresponds reptiles chain or exceeds it. The radical R3also has a length smaller than the length of the saturated chain, comprising from about 20 carbon atoms[esokilina group (icoil formerly eicosyl)], more preferably from about 18 carbon atoms (sterelny group). Most preferably, the chain length R3is from about 8 to about 12 carbon atoms, although the ring structures and substituents can be present a much greater number of atoms. The demands on their length will be discussed below.

In General, without specific fragments from which it is constructed, the radical R3(the group or the fragment has a length exceeding the length Pintilei group. In addition, the radical R3also has a length smaller than the length of coseley (dedelley) group. This means that R3represents a radical having a minimum length greater than the length of the saturated chain of 5 carbon atoms, and preferably greater than the length hexylene group, but shorter than the length of the saturated chain of 20 carbon atoms, and preferably chain consisting of 18 carbon atoms. Most preferably, R3has a length greater than the length octiles group, but less is Yu, than the length of laurelei group.

In particular, the group R3has a minimum length equal to hexylene group only when the Deputy includes two rings, which can be condensed or just covalently linked to each other ekzoticheskoy communication. If R3does not contain two linked or condensed ring, for example, if the radical R3includes alkyl or second, third or fourth annular Deputy, R3has a length greater than the length hexylene group. Examples of these two ring systems of the groups R3are 2-naftalina group or 2-hyalinella group (each with 6 carbon atoms in the chain) and 8-polylina group (with 5 carbon atoms in the chain). Not based on any theory, it is possible to assume that the presence of multiple rings in the radical R3increases the selectivity profile of the enzymatic activity of the inhibitor.

Length of chain radicals measured along the longest linear chain of atoms in the radical, optionally along the atoms of the skeleton of the ring. To facilitate calculations of each atom in the chain, such as carbon, oxygen, sulfur and nitrogen, a is carbon atom.

The length of the chains can be easily determined by using published data about the bond angles, bond lengths and radii of atoms, which are optionally used DL the image and measuring required, usually zigzag chains or by building models using commercially available kits, which angles, bond length and the radii of the atoms are in compliance with published data. The length of the radicals (Deputy) can also be defined with a slightly lower accuracy, if we assume that all atoms have bond length, corresponding to the saturated carbon atom that bonds have the same length as saturated links and that all corners of unsaturated bonds are the same as the angles for saturated links, although the above measurement methods are preferred. For example, when using this method of measurement phenyl and Peregrina group have a length corresponding to the length of the chain, consisting of 4 carbon atoms, as well as propoxylate, while the length biphenylenes group corresponds to the chain length of about 8 carbon atoms.

In addition, the group R3when rotating around the axis passing through the associated with SO21-position and associated with a Deputy at the 4-position of the 6-membered ring or through associated with the SO21-position and connected with the Deputy 3-or 4-position 5-membered ring, forms a three-dimensional space, the largest of which in the direction perpendicular to the specified axis of rotation, equal to the length from approximately the aqueous furnishing ring to about two phenyl rings.

Thus, the group R3has a size corresponding to 2-naftalina Deputy or 8-parinello Deputy, when measured by the above criterion, based on the evaluation of the radius of rotation, and using the above methods. On the other hand, 1-naftalina group or a 7-or 9-polylina group is too large radius of rotation and does not fall under the designation R3.

As a consequence of such requirements for the length and radius of rotation, is particularly preferred as radicals R3are such radicals R3as 4-(phenyl)phenyl[biphenyl], 4-(4’-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl[4-(phenylthio)phenyl], 4-(Otopeni)phenyl, 4-[(4’-triptoreline)phenoxy]phenyl, 4-[(4’-triptoreline)thiophenyl]phenyl, 4-[(4’-trifluoromethyl)phenoxy]phenyl, 4-[(4’-trifluoromethyl)thiophenol]phenyl, 4-[(4’-triptoreline)phenoxy]phenyl, 4-[(4’-triptoreline)thiophenyl]phenyl, 4-[(4’-phenyl)-N-piperidyl]phenyl, 4-[(4’-acetyl-N-piperazin]phenyl and 4-(benzamido)phenyl. These substituents themselves can be substituted in the second ring relative to the SO2group in the meta - or para-position or both positions by one atom or by Deputy, the longest chain which can be up to 5 atoms, excluding hydrogen atom.

Not based on any theory, I believe that the length associated with the SO2group Deputy radical R 3probably plays a role in the overall activity of the considered compounds with inhibitory activity against enzymes MMP. The length of the radical R3probably also plays a role in the selective activity of compounds with inhibitory activity against certain enzymes MMP.

In a particularly preferred embodiment, R3refers to a group PhR23where Ph denotes phenyl. Phenyl ring (Ph) group PhR23substituted at its para-position (4-position by a group R23that can be a another aryl or heteroaryl group with one ring, piperidino group, piperazinilnom group, fenoxaprop, thiophenoxy [C6H5-S-], phenylisopropyl [C6H5-N2-]or benzimidazole [-NHC(O)C6H5].

In one of the embodiments in a particularly preferred aromatic sulfamethoxazolum the compounds having inhibitory activity, the substituent R23denotes fenoxaprop and is itself substituted at its para-position of the fragment chosen from the group comprising halogen, C1-C4alkoxygroup,1-C4alkyl group, dimethylaminopropyl, carboxyls1-C3alkylenes group1-C4alkoxycarbonyl-C1 -C3alkylenes group, triptoreline, cryptometer, triptorelin group and carboxamide1-C3alkylenes group, or substituted meta - and para-positions by methylendioxyphenyl. Obviously, any substituent R23may be substituted by a fragment of the numbers listed above. It is preferable that substitution in the para-position.

The present invention also relates to an intermediate product suitable for obtaining compounds of formulas I-V. This intermediate compound has the structure corresponding to the following formula VI:

where q is 0, 1 or 2,

R20means (a) -O-R21where R21selected from the group including hydride, With1-C6alkyl, aryl, ARS1-C6alkyl and pharmaceutically acceptable cation, or (b) -NH-O-R22where R22means selectively removable protective group such as 2-tetrahydropyranyl,1-C6acyl, aroyl, benzyl, para-methoxybenzyl (MOZ), CARBONYLS1-C6alkoxygroup, tizamidine silyl group or ortho-nitroaniline group, resin for peptide synthesis and the like, and tizamidine silyl group substituted With1-C6the alkyl, aryl or ARS1-C6the alkyl,

m is 0, 1 or 2,

n is 0, 1 or 2,

p RA is but 0, 1 or 2,

the sum m+n+p is equal to 1, 2, 3,or 4

(a) one of the substituents X, Y and Z are selected from the group comprising C(O)NR6, O, S, S(O), S(O)2and NS(O)2R7and the other two substituent from the group comprising X, Y and Z denote CR8R9and CR10R11or

(b) X and Z or Z and Y together form the fragment chosen from the group comprising NR6C(O)NR6S(O)NR6S(O)2, NR6S, NR6O, SS, NR6NR6and OS(O), with one remaining Deputy from the group comprising X, Y and Z represents CR8R9or

(C) n is 0 and X, Y and Z together form a fragment selected from the group including

where the wavy lines indicate the connection with the atoms of the depicted ring, R6and R6'independently from each other selected from the group including hydride, With1-C6alkanoyl,6aryl-C1-C6alkyl, aroyl, BISS1-C6alkoxy-C1-C6alkyl)-C1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl,1-C6perfluoroalkyl, C1-C6triptorelin,1-C6perforamce-C1-C6 alkyl, C1-C6alkoxy-C1-C6alkyl, C3-C6cycloalkyl,3-C8heteroseksualci,3-C8geterotsiklicheskikh,6aryl, C5-C6heterologous,5-C6heteroaryl,3-C8cycloalkyl-C1-C6alkyl, C6aryloxy-C1-C6alkyl, heterokaryosis1-C6alkyl, heteroaryl1-C6alkoxyl1-C6alkyl, heteroaromatic1-C6alkyl, arylsulfonyl,1-C6alkylsulfonyl, C5-C6heteroarylboronic, carboxy1-C6alkyl, C1-C4alkoxycarbonyl-C1-C6alkyl, aminocarbonyl,1-C6alkylaminocarbonyl,6ellimination,1-C6heterocyclimamines,6aaltio-C1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, C6aaltio-C3-C6alkenyl,1-C4alkylthio-C3-C6alkenyl,5-C6heteroaryl-C1-C6alkyl, Gialos1-C6alkanoyl, hydroxys1-C6alkanoyl, tools1-C6alkanoyl,3-C6alkenyl,3-C6quinil,1-C4alkoxy-C1-C4alkyl, C1-C5alkoxycarbonyl, aryloxyalkyl, NR8, R 9-C1-C5alkylsulphonyl, hydroxys1-C5alkyl, aminocarbonyl, where the nitrogen in aminocarbonyl is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, hydroxyaminobuteroyl, aminosulfonyl, where the nitrogen in aminosulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, amino1-C6alkylsulfonyl, where the nitrogen aminos1-C6alkylsulfonyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl, and aminos1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, C3-C8cycloalkyl and C1-C6alkanoyl

R7choose from a group comprising benzyl, phenyl, C1-C6alkyl, C3-C6quinil,3-C6alkenyl and C1-C6hydroxyalkyl,

R8and R9and R10and R11independently from each other selected from the group including hydride, hydroxy-group, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroarm1-C6alkyl, C2-C6quinil,2-C6alkenyl, tools1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, arakaki1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarbonyl1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, arietis1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1-C6 alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl, or where R8and R9or R10and R11and the carbon atom to which they are attached, form a carbonyl group, or where R8and R9or R10and R11or R8and R10together with the atoms to which they are attached, form a 5-8-membered carbocyclic ring or a 5-8-membered heterocyclic ring containing one or two heteroatoms that are nitrogen, oxygen or sulfur, provided that only one of the radicals R8and R9or R10and R11denotes a hydroxy-group,

R12and R12'independently from each other selected from the group including hydride, With1-C6alkyl, aryl, ARS1-C6alkyl, heteroaryl, heteroalkyl,2-C6quinil,2-C6alkenyl, tools1-C6alkyl, cycloalkyl, cycloalkyl1-C6alkyl, heterocyclics1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, aryloxy1-C6alkyl, amino1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1 -C6alkyl, hydroxys1-C6alkyl, hydroxycarbonyl1-C6alkyl, hydroxycarbonyl1-C6alkyl, aminocarbonyl1-C6alkyl, aryloxy1-C6alkyl, heterokaryosis1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, arietis1-C6alkyl, heteroaromatic1-C6alkyl, the sulfoxide or sulfon any of these titlestyle, perfors1-C6alkyl, trifloromethyl1-C6alkyl, Gialos1-C6alkyl, alkoxycarbonyl1-C6alkyl and amino1-C6alkyl, where the nitrogen aminoalkyl group is (I) unsubstituted or (II) substituted with one or two radicals independently from each other selected from the group comprising From1-C6alkyl, ARS1-C6alkyl, cycloalkyl and C1-C6alkanoyl,

R13selected from the group including hydride, benzyl, phenyl, C1-C6alkyl, C2-C6quinil,2-C6alkenyl and C1-C6hydroxyalkyl, and

R24means R3as defined in formulas I, III, IV, or designates, the Deputy G-A-R-E-Y of formula II (formula VIA).

Alternatively, R24means R3', aryl or heteroaryl group that is substituted by linking Deputy, reactio nesposobnim in relation to linking with another fragment (formula VIB), such as replacing the nucleophile leaving group D.

Examples replaced by the nucleophile leaving group D are halogen (fluorine, chlorine, bromine or iodine), nitro, azido, phenylsulfonyl, aryloxy-From1-C6alkoxygroup,1-C6alkylsulfonate or arylsulfonate group and tizamidine ammonium group, in which three substituent independently from each other selected from the group including aryl, ARS1-C6alkyl or C1-C6alkyl. Additional connecting the substituents include a hydroxyl group and amino group, which may be associated with containing the carbonyl fragments with the formation of esters, urethanes, carbonates, amides and ureas, but are not limited to these substituents. Similarly, carboxyl binding Deputy can be used to obtain a complex ether, tiefer or amide. So connecting Deputy suitable for connecting termination Deputy containing aryl or heteroaryl group such Deputy, as described above, the Deputy G-A-R-E-Y, through the formation of covalent bonds.

The compound of formula VI may be associated with another fragment for binding to the Deputy R3with the formation of compounds in which newly formed GRU is PA R 3addressbook in formulas I, III, IV or G-A-R-E-Y-. An example of such reactions combination is nucleophilic substitution with the formation of ethers and thioethers, as well as with the formation of ester, amide, urea, carbonate, urethane and the like ties.

Particularly preferred precursor intermediate compounds of formula VI is an intermediate compound of the following formula VII:

where m, n, p, g, X, Z, Y, D and R have the meanings indicated above for formula VI.

Thus R20preferably represents-NH-O-R, where R22means selectively removable protective group such as 2-tetrahydropyranyl,1-C6acyl, aroyl, benzyl, para-methoxybenzyl (MOZ), CARBONYLS1-C6alkoxygroup, ortho-nitroaniline group, the resin for the synthesis of peptides, the so-called Merrifield''s Peptide Resin company Sigma Chemical Co., and so, while preferred is 2-tetrahydropyranyl. Thus, it is clear that the group-NH-O-R (R20in formulas VI and VII is the product of the reaction of hydroxylamine, the oxygen associated with the selectively removable protective group and a carboxyl group.

In the connection of each of the formulas VI and VII of the letter "g" in the form of a subscript is used to indicate the oxidation state of the sulfur atom. When g is 0, the CE atom is s is a non-oxidized state and the specified connection, as a rule, is a sulfide reaction product containing sulphur Sinton, as illustrated below in the examples. When g is 1, the sulfur is oxidized to the sulfoxide, and when g is 2, the sulfur is oxidized to the sulfone, which is also illustrated below. Compounds of formula VI or VII, in which g is 0 or 1, as a rule, are intermediate products to produce similar compounds in which g is 2, and the intermediate product is preferably sulfona.

Thus, the preferred intermediate product has the structure corresponding to the following formula VIIA

In the present description in the designation of molecules or groups of molecular descriptors can be combined to write the words or phrases that indicate structural group, or combined to identify structural groups. These descriptors are used in the present description. Examples of such commonly used concepts are aralkyl (or arylalkyl), heteroalkyl, heteroseksualci, cycloalkenyl, oralmaxillofacial and the like, Specific examples of compounds falling under the latter concept is oralmaxillofacial is6H5-CH2-CH2-O-CH2-O-(C=O), where C6H5denotes phenyl. It should also be noted that in this on the region of the structural group can be more than one word or phrase, for example heteroarylboronic can also be called heteroarylboronic. Such combinations are used in the present description, when the description of the processes, compounds and compositions of the present invention, and below are other such examples. The following list should not be considered as exhaustive or limiting, since it is given as illustrative examples of words or phrases (concepts)that are used in the context of the present description.

In the context of the present description, the term "alkyl" alone or in combination refers to an alkyl radical with a straight or branched chain, containing from 1 to about 12 carbon atoms, preferably from 1 to about 10 carbon atoms and more preferably from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl etc.

The concept of "alkenyl" alone or in combination refers to a hydrocarbon radical straight or branched chain, containing one or more double bonds and from 2 to about 12 carbon atoms, preferably from 2 to about 10 carbon atoms and more preferably from 2 to about 6 carbon atoms. Examples of acceptable alkenyl radicals include ethynyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadien the sludge, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl etc.

The concept of "quinil" alone or in combination refers to a hydrocarbon radical straight or branched chain, containing one or more triple linkages and from 2 to about 12 carbon atoms, preferably from 2 to about 10 carbon atoms and more preferably from 2 to about 6 carbon atoms. Examples of acceptable etkinlik radicals include ethinyl, 2-PROPYNYL, 3-PROPYNYL, decenyl, 1-butenyl, 2-butenyl, 3-butenyl, etc.

The term "carbonyl" or "oxoprop" separately or in combination, refers to-C(=O)-group in which the two remaining connection (valence) can be substituted independently from each other. It is implied that the concept of the carbonyl also includes gidratirovannuyu carbonyl group-C(OH)2-.

The term "thiol" or "sulfhydryl" separately or in combination, refers to-SH group. The concept of "tighrope" or "tearepa" alone or in combination refers to a simple Tiefenau group, i.e., simple ester group in which the oxygen of simple ether is replaced by a sulfur atom.

The term "amino", alone or in combination refers to amine or-NH2-the group in which the term "monosubstituted amino group" separately or in combination, refers to a substituted amine, i.e. a group-N(H) (Deputy), in which one hydrogen atom is replaced by a Deputy, and to understand what their "disubstituted amine" refers to a group-N(Deputy) 2in which two hydrogen atoms of an amino group substituted by the substituents, independently from each other selected from a particular group of deputies.

Amines, amino, and amides are compounds that can be designated as primary (I° ), secondary (II° ) or tertiary (III° ), or unsubstituted, monosubstituted or N,N-disubstituted depending on the degree of substitution of the nitrogen of the amino group. Quaternary amine (ammonium) (IV° ) denotes the nitrogen to 4 substituents [-N+(Deputy)4], which is positively charged and which accompanies the counterion, and the term "N-oxide" means that one Deputy represents oxygen, and this group can be marked as [-N+(Deputy)3"Oh-], i.e. the charges are internally balanced.

The term "cyano" separately or in combination, refers to-C-triple bond-N-group, i.e. a (-C≡ N). The concept of "asiagraph" separately or in combination, refers to-N triple bond-N-group, i.e. a (-N≡ N). The term "hydroxyl" separately or in combination, refers to-IT-group. The term "nitro-group" separately or in combination, refers to-NO2-group. The concept of "Isograph" separately or in combination, refers to-N=N-group in which relationships in the limit positions can be independently from each other substituted.

The concept of "Gerasimova" otdeljnoye in combination denotes-NH-NH-group, in which these remaining two links (valences) can be independently from each other substituted. The hydrogen atoms of hydratherapy can be independently from each other substituted by substituents and the nitrogen atoms can form an acid additive salt, or may form a Quaternary base.

The concept of "sulfonyl" separately or in combination, refers to-SO2-the group in which these remaining two links (valences) can be independently from each other substituted. The concept of "sulfoxide" separately or in combination, refers to-SO-group, in which these remaining two links (valences) can be independently from each other substituted.

The concept of "sulfon" separately or in combination, refers to-SO2-the group in which these remaining two links (valences) can be independently from each other substituted. The concept of "sulfenamid" alone or in combination refers to a group-SON=in which these remaining three bonds (valences) can be independently from each other substituted. The term "sulfide" separately or in combination, refers to-S-group in which these remaining two links (valences) can be independently from each other substituted.

The concept of "alkoxygroup" alone or in combination refers to a radical of simple alkyl ether where the term alkyl has the above knowledge is possible. Examples of suitable radicals a simple alkyl esters include methoxy, ethoxy-, n-propoxy, isopropoxy, h-butoxy, isobutoxy-, second -, butoxy-, tert-butoxypropan etc.

The concept of "cycloalkyl" alone or in combination refers to a cyclic alkynyl radical containing from 3 to about 8 carbon atoms. The concept of "cycloalkenyl" means an alkyl radical as defined above, substituted cycloalkyl radical containing from 3 to about 8, preferably from 3 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Heterocyclic (heterocycle-or heterocyclic fragment getrollbackonly, heterocyclicamines, getrollbackonly or geteroseksualnoe group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic a heterocycle that contains one or more heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. This fragment optionally may be substituted by one or more ring carbon atoms by halogen, alkyl, alkoxy, exography, etc. and/or secondary atom of nitrogen (i.e.- NH-) ring - alkyl, alcoxycarbenium, alkanoyl, aryl or arylalkyl and the atom is tertiary nitrogen (i.e. =N-) - oxydipropyl, attached through a carbon atom. Can also be attached atom of the tertiary nitrogen with 3 alternates with the formation of N-oxide [=N(O)-group].

The term "aryl" alone or in combination signifies a 5 - or 6-membered carbocyclic aromatic containing ring fragment or the condensed ring system containing two or three rings, which contain in a cycle of only carbon atoms, i.e. carbocyclic aryl radical. Examples of carbocyclic aryl radicals include phenyl, indenyl and naphthyl.

The concept of "heteroaryl" alone or in combination signifies a 5 - or 6-membered aromatic containing ring fragment or condensed ring system (radical)containing two or three rings, which contain in a loop (Ah) carbon atoms, and one or more heteroatoms, such as sulfur, oxygen and nitrogen. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinil, morpholinyl, thiomorpholine, pyrrolyl, imidazolyl (for example, imidazol-4-yl, 1-benzyloxycarbonylamino-4-yl and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl (e.g., 2-indolyl and the like), chinoline (for example, 2-chinoline, 3-chinoline, 1 oxido-2-chinoline and the like), from chinoline (for example, 1-ethenolysis, 3-ethenolysis etc.), tetrahydroquinoline (for example, 1,2,3,4-tetrahydro-2-chinolin etc.), 1,2,3,4-tetrahydroisoquinoline (for example, 1,2,3,4-tetrahydro-1-oxoethylidene etc.), honokalani, β -carboline, 2-benzofuranyl, benzothiophene, 1-, 2-, 4 - or 5-benzimidazolyl and similar radicals.

If aryl or heteroaryl radical is a replacement fragment (group Deputy or radical), then he can be replaced, while the latter Deputy is the Deputy, independently from each other selected from the group of cyano, perfluoroalkyl, triptoreline, triptoreline, haloalkyl, triptorelin, arelaxation, aryloxyalkyl, the hydroxy-group, halogen, alkyl, alkoxy-, nitro-group, thiol, hydroxycarbonyl, aryloxy, killigrew, aralkyl, aryl, arylcarboxamide, heteroaryl hydroxy-, heterogroup, heteroalkyl, cycloalkyl, heterocyclic-, heterozygotic, heterocyclimamines, cycloalkyl hydroxy, cycloalkyl, heteroaromatic, heteroalkyl, Alcoxy, Uralkali, aralkylamines, heterologous, heteroaryl, arylazo, hydroxycarbonylmethyl, alkoxycarbonylmethyl, alkanoyl, arylcarbamoyl, arkanoid, alkanoyloxy, arachnodactyly, hydroxyalkyl, hydroxyalkoxy, alkylthio-, ALK is calcultor, alkoxycarbonyl, aryloxyalkyl, arylthioureas, aryloxyalkyl, killiechassie, hydroxycarbonylmethyl, hydroxycarbonylmethyl, alkoxycarbonyl, alkoxycarbonylmethyl-,

the amino group,

where the amino nitrogen is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, arelaxation, alkoxycarbonyl, arylcarbamoyl, arkanoid, heteroarylboronic, heteroalkyl and alkanoyl, or (III) where the nitrogen of the amino group and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring containing 0-2 additional heteroatoms, represents a nitrogen, oxygen or sulfur, and the ring is (a) unsubstituted or (b) substituted by one or two groups independently from each other selected from the group including aryl, alkyl, heteroaryl, aralkyl, heteroalkyl, hydroxy-, alkoxygroup, alkanoyl, cycloalkyl, heteroseksualci, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, condensed with benzene ring heteroseksualci, hydroxyethoxyethyl, arelaxation, hydroxycarbonyl, aryloxyalkyl condensed with a benzene ring geterotsiklicheskikh condensed with the benzene ring to which lcom cycloalkylcarbonyl, geterotsiklicheskikh and cycloalkylcarbonyl, carbonylation,

where the nitrogen carbonylation is (I) unsubstituted or (II) is a reactive amine of an amino acid, or is (III) substituted by one or two radicals selected from the group comprising alkyl, hydroxyalkyl, hydroxycitronellal, cycloalkyl, aralkyl, triptorelin, heteroseksualci condensed with a benzene ring heteroseksualci condensed with a benzene ring cycloalkyl and N,N-dialkylamino acylaminoalkyl group, or (IV) the nitrogen carboxamidine and two adjacent substituent to form a 5-8-membered heterocycle-, heteroaryl, or condensed with a benzene ring geteroseksualnoe ring, which itself can be unsubstituted or may be substituted by one or two radicals independently from each other selected from the group comprising alkyl, alkoxycarbonyl, a nitrogroup, heteroseksualci, the hydroxy-group, hydroxycarbonyl, aryl, aralkyl, heteroalkyl

and amino, where the amino nitrogen is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group including alkyl, aryl and heteroaryl, or (III) where the nitrogen of the amino group and two adjacent substituent to form a 5-8-membered hetero is iclo or heteroaryl ring,

and aminoalkyl group where the nitrogen aminoalkyl is (I) unsubstituted or (II) substituted with one or two substituents, independently from each other selected from the group comprising alkyl, aryl, aralkyl, cycloalkyl, arelaxation, alkoxycarbonyl and alkanoyl, or (III) where the nitrogen aminoalkyl and two adjacent substituent to form a 5-8-membered heterocycle or heteroaryl ring. The concept of "aralkyl" separately or in combination, means an alkyl radical as defined above in which one hydrogen atom substituted aryl radical, as defined above, such as benzyl, 2-phenylethyl, etc.

The concept of "arelaxation" alone or in combination refers to a radical of the formula aralkyl-O-C(O)-, in which the concept of "aralkyl" has the above meaning. Example alcoxycarbenium radical is benzyloxycarbonyl.

The concept of "alloctype" refers to a radical of the formula aryl-O-, in which the term "aryl" has the above values. Example aryloxy is fenoxaprop.

The concept of "heteroalkyl" and "heteroanalogues" denote similar in structure to aralkyl and alloctype radicals, which are formed from heteroaryl radicals. Examples of such radicals include 4-picoline and 2-pyrimidinamine respectively.

The concept of "alkanoyl" or "alkylaryl" the Department is Ino or in combination represent acyl radical, formed from alkenylboronic acid. Examples of such radicals include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylmalonyl etc.

The concept of "cycloalkylcarbonyl" means an acyl group derived from a monocyclic or containing bridge cycloalkylcarbonyl acid, such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, etc. or obtained from condensed with the monocyclic benzene cycloalkylcarbonyl acid, which is optionally substituted, for example, alkanolamines, such as 1,2,3,4-tetrahydro-2-naphtol, 2-acetamido-1,2,3,4-tetrahydro-2-naphtol.

The concept of "arkanoid" or "aralkylamines" refers to an acyl radical derived from a substituted aryl alkenylboronic acid, such as phenylacetyl, 3-phenylpropionyl (hydroxycinnamic), 4-phenylbutyl, (2-naphthyl)acetyl, 4-chlorohydroquinone, 4-aminohydrocinnamic, 4-methoxycinnamyl etc.

The concept of "aroyl" or "arylcarbamoyl" refers to an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include radicals of aromatic carboxylic acids, optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl) benzoyl, 1-naphtol, 2-naphtol, 6-carboxy-2-naphtol, 6-(benzyloxy arbonyl)-2-naphtol, 3-benzyloxy-2-naphtol, 3-hydroxy-2-naphtol, 3-(benzyloxycarbonyl)-2-naphtol etc.

The concept of "cycloalkylcarbonyl" denotes the acyl group of the formula cycloalkyl-O-CO-, where "cycloalkenyl" has the above values. The concept of "aryloxyalkyl" denotes the acyl radical of the formula aryl-O-alkanoyl, where "aryl" and "alkanoyl" have the above values. The concept of "heterocyclisation" denotes an acyl group having the formula heterocycle-O-CO-, where "heterostropha" has the above values.

The concept of "heterocyclochain" denotes the acyl radical of the formula "substituted heterostropha alcantarea acid", where "heterostropha" has the above values. The concept of "heteroarylboronic" denotes the acyl radical represented by the formula heteroaryl-O-CO-, where "heteroaryl" has the above values.

The concept of "aminocarbonyl" (carboxamide) alone or in combination denotes a substituted amino group, carbonyl (carbamoyl) group derived from the amine by interacting with a carboxylic acid where the amino group (the nitrogen amidopropyl) is unsubstituted (-NH2or may be substituted primary or secondary amino group containing one or two substituent selected from the group comprising a hydride, alkyl, aryl, aralkyl, cycloalkyl cycloalkenyl etc., as specified above. Hydroxamate is an N-hydroxycarboxylic.

The concept of "aminoalkanoic" means an acyl group derived from alkenylboronic acid, substituted amino, where the amino group may be primary or secondary amino group containing substituents, independently from each other selected from the group comprising a hydride, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl etc.

The term "halogen" denotes fluorine, chlorine, bromine or iodine. The concept of "haloalkyl" denotes an alkyl radical, with the above values, in which one or more hydrogen atoms replaced by halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromacil, vermeil, deformity, trifluoromethyl, 1,1,1-triptorelin etc.

The term "perfluoroalkyl" means an alkyl group in which each hydrogen atom replaced by a fluorine atom. Examples of such performanceline groups in addition to the above trifloromethyl are performatic, perforator, perforater and peritonitis.

The concept of "performancehttp" alone or in combination refers to a radical of simple perforaciones ether, where "perfluoroalkyl" is the above values. Examples of such performancepro in addition to this tripometer (F3C-O-) are perforbalance, perforator is epoxy-, performancex and performancegroup.

The concept of "performancegroup" alone or in combination refers thioester perferably radical, in which "perfluoroalkyl" is the above values. Examples of such performancegroup in addition to this trypomastigote (F3C-S-) are performativity, performapply, performability and perpendiculaire.

The term "aromatic ring" in combination with, for example, aromatic ring, substituted by sulfonol, or aromatic ring, substituted sulfoxide, denotes aryl or heteroaryl, as defined above.

The term "pharmaceutically acceptable" when used as an adjective in the context of the present description denotes that the variable concept, used as a noun suitable for use in a pharmaceutical product. Pharmaceutically acceptable cations include metal ions and organic ions. Preferred metal ions include ions of salts of alkali metals (group Ia), salts of alkaline-earth metals (group IIA) ions and other physiologically acceptable metal, but is not limited to them. Examples of ions include ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc from the usual for their valences. The preferred organization is practical ions include protonated tertiary amines and cations of Quaternary ammonium, including, in particular, trimethylamine, diethylamine, N,N’-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples of pharmaceutically acceptable acids include hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonate acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, solomonow acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, provisorio acid, salewoman acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid and the like, but not limited to.

Obtaining the required connections

The following reaction schemes "M" denotes a leaving group such as halogen, complex phosphate ester or complex sulfate the ether.

The following diagrams a-b and schemes 1-19 illustrates the chemical processes and transformations that can be used to obtain compounds suitable for use according to the invention, i.e. compounds of formulas I, II, III, IV and V and similar cyclic compounds with inhibitory activity. In addition, illustrates the formation of compounds of formula VI and formula VII. The compounds of formula VI is of the formula VII can be used as intermediates for producing compounds of formula I, II, III, IV and V or prodrugs or inhibitors of MMP.

In the diagrams And In the symbols J, independently of one another denote R20or other suitable for the synthesis of groups such as amides, anhydrides, mixed anhydrides and the like, the Symbol n denotes 0, 1 or 2, and the scheme preferably denotes 1 or 2. In these schemes n corresponds to g in formulas VI and VII, and a represents 0, 1 or 2. The symbol m denotes 1 or 2. The symbols r independently of one another denote 1, 2 or 3. The symbol R denotes a protective group, which may also be representative of the group R In scheme And to facilitate positional isomers depicted in the standard manner with communication passing through the ring. In the subsequent schemes, usually shown only one of the positional isomers, it is understood that these structures and reaction schemes include positional isomers characteristic of the above formulas I, II, III, IV, V, VI and VII. Similarly, the symbol In denotes O, S, SO, SO2and NR6. The symbols C and C’ independently of one another denote an electrophilic group or a group capable of participating in the condensation reaction. In this regard, it should also be noted that the 6-membered ring are included solely for illustrative purposes and processes and/or reagents are applicable and are a combination that allows you to get a 5-8-membered ring systems is.

The patterns shown in the diagrams 1-19, also correspond to the compounds representing another group of compounds of the present invention. The aromatic ring in the diagram In denotes aryl and heteroaryl. Fragments-A-R-E-Y have the above meaning. Are given as illustrations reactions involving spiroheterocyclic the nitrogen atom, may not be suitable for compounds comprising sulfur or oxygen.

Scheme And

In stage 1 scheme a illustrates the recovery heteroaryl connection with the formation of carboxyl derivative. Typically, the first product is a heterocyclic containing hydrogen Amin, if the original product is used aromatic radical, or represents a containing R6a heterocycle, as if the original product is used partially unsaturated heterocycle.

The compound of formula 2 can be treated in several ways depending on the requirements of the chemist. In stage 2, the nitrogen can be protected by obtaining, for example, carbobenzoxy- (Z) or tert-butoxycarbonyl derived. Such acylation reaction can be carried out according to methods well known in the field, especially in the field of synthesis of amino acids and peptides. The% is with acylation with reagents, containing activated carboxyl group or activated sulfonyloxy group, to obtain these compounds perform similarly. Examples of such alleluya groups are carbonylated, halides, anhydrides, mixed anhydrides, derivatives, carbodiimide or other less traditional activated ester group, such as a derivative of hydroxybenzotriazole (HOBT). These reactions acylation can take place in the presence of a base, including a weak base, such as triethylamine or N-ethylmorpholine. Getting some activated ester reagents and their application to obtain other compounds of the invention are described below. It should again be emphasized that denoted by the symbol R groups, which serve as a selectively removable protective group, can also be part of the group R6.

In stage 4 of scheme a illustrates the process of alkylation or acylation of compounds of formula 2 to obtain the compounds of formula 5. The process of alkylation or acylation in the present description. Stage 5 group J if necessary, can be replaced. An example of such a substitution is the exchange of ester on Tgp-protected hydroxamate when turning Tgp-protected hydroxamate in hydroxamate or turning to the slots in protected hydroxamate or similar

At stages 3, 7 and 8 shows the receipt of sulfur-containing derivatives of these compounds or intermediates of these compounds. In the above stages of the original product (for example compounds of formula 2, 5 and 6) may be processed by the base for deprotonation of the alpha carbon in order to obtain functionally active carbonyl. This anion may be subjected to interaction with containing sulfur electrophile with getting sulfone, sulfoxide or sulfide. These electrophiles can be presented, for example, in such forms as R24S-SR24, R24SO2Cl, R24SCl, R24SOCl, R24S(O)-SR24and the like, where R24has the above values, or may denote aryl or heteroaryl containing sulfur product, including connecting Deputy, i.e. R3that can be used to obtain one containing R24groups. To produce anion needed basis, and may require a strong base, such as one referred to in the present description amides, hydrides or Akilov metals. Apply nephratonia solvents, preferred are bipolar aprotic solvents along with the use of an atmosphere of inert gas. The following diagrams to simplify, as a rule, it is assumed that R24means R .

It should be noted that using these processes, depending on the original product get sulfides (simple thioethers), sulfoxidov or sulfones. In addition, the sulfides can be oxidized with the formation of sulfoxidov or sulfones, and sulfoxidov can be oxidized with formation of the corresponding sulfonic derivatives. The selection process for the synthesis stage on which you want to change the oxidation state of sulfur, and the decision about changing the oxidation state of sulfur is carried out by a specialist in the field of chemistry. Methods of oxidation of sulfur are described below.

On stage 6, 9, 10 and 12 of the circuit And independently from each other are illustrated by the mutual conversion of the groups denoted by the symbol J. Examples of such mutual conversions include replacement of ester on hydroxamic acid or derivative of hydroxamic acids, the conversion of carboxylic acid derivative with an activated carbonyl function or hydroxamic acid or derivative of hydroxamic acids (a prodrug, or a protected derivative) or the removal of the protective group hydroxamates derived. Obtaining compounds with an activated carbonyl function, their interaction with nucleophiles, such as hydroxamic acid, a protected hydroxamate or prodrugs based hydroxamic acids described below, the extent of transformation of protected derivatives of hydroxamic acid hydroxamic acid. Obtaining, for example, products that are derived from hydroxybenzotriazole/carbodiimide, as described below. Gets or hydrolysis of esters, amides, amide derivatives, acid chlorides, acid anhydrides, mixed anhydrides, etc. are methods of synthesis are well known in this field, and therefore they are not discussed in detail in the present description. On stage 6 illustrates the conversion of compounds of formula 4 to the compound of formula 9 without performing prior conversion to the compound of formula 7.

Scheme B

In scheme B shows an alternative way of obtaining these compounds. The reagent of the arrow shown in the above stage 1, is a reagent with two active groups in addition to the heteroatoms (In)specified earlier. And in this case is given to illustrate the reagent is chosen to simplify the description of the reaction, this implies that can be used reagents that determine the position of the heteroatom to allow connection to the ring size, consisting of 5, 7, and 8 members. These reagents can be easily selected by the specialists in this field.

The symbols C and C’ in the reagent listed in stage 1, independently from each other represent an electrophilic group, or a group, the cat heaven can turn into the electrophile. Such groups include halides, sulfonic acid esters, epoxides, diepoxides, hydroxyl group, etc. This reagent reacts with nucleophilic anion of sulfur-containing carbonyl compounds, such as compound of formula 1. The anion formed by deprotonation of compounds of formula 1, and examples of bases suitable for this deprotonation below. The processing of the above electrophilic reagent is carried out in conditions of alkylation, well known in this field and are considered in the present description. The product of this reaction may be either a compound of formula 2, or a compound of formula 3, i.e. the reaction may optionally be carried out as a reaction in a single tube, or as a two-stage process.

In stage 3 is illustrated the mutual conversion indicated by the symbol J groups, which optionally carried out in the same way as described above for scheme A. In stage 4 using the reagent, in which, for example, denotes a nucleophile, as above, but With’ denotes an electrophile or nucleophile, such as hydroxyl, thiol, or R6the amino group. It should be noted that the characters’ can denote independently from each other nucleophile or electrophile, when m is 2, i.e. when m is 2, there is an implied condition that the groups With’ them is whether the same value. When m is 2, the processing of the second mole of base is for the specialist-chemist alternative method of obtaining the compounds of formula 5. When’ denotes a hydroxyl, thiol or R6-an amino group, a m is 2, a person skilled in the art may condensing the compound of formula 4, for example, aldehyde or ketone, reducing conditions or with subsequent restoration of obtaining the compounds being considered. As mentioned above, the compound in which m is 2, can be obtained in one stage (the process in one test tube) or in two stages, allowing the specialist in the field of chemistry to choose, should be declared to be the reagent(s) are the same (one tube) or different (two-stage process).

In scheme B also illustrates the mutual conversion of the groups denoted by the symbol J, the degree of oxidation of sulfur and the group at the nitrogen atom, i.e. the R group through which it is possible to obtain the compounds being considered. These methods and processes discussed above in the description of reaction scheme A.

Schema

In the diagram illustrated In nucleophilic substitution group D, with the above values. This reaction is carried out in a manner analogous to the method of carrying out substitution reactions, which are considered in the present description. The oxidation of sulfur chosen specialist who this field, however sulfoxide or sulfonic groups are preferred, and sulfon is the most preferred. The substitution can be carried out either before or after the interaction of methylene located behind a carbonyl group, with the receipt of spiroheterocyclic group.

At stages 1, 2 and 3 also shows that although nucleophilic substitution can be carried out using one of the nucleophile (NF), the product of this reaction can be modified using methods well known in the field, with the receipt in accordance with the present description of the group-A-R-E-Y, as defined above.

An example of such a method, when D represents fluoride, provided to illustrate and not limit the scope of invention. Fluoride leaving group can be directly replaced by the anion of 4-cryptomaterial, 4-cryptomaterial, 4-cryptomaterial etc. with obtaining the considered connection, which is an example carried out in a single vial retrieval method using as starting product the compounds of formula 4. Other compounds including a group-A-R-E-Y-, can be obtained by substitution of fluoride leaving groups on ammonia with getting amine, which can then be subjected to acylation methods described, for example, by using 4-triftormetilfullerenov, the floor is rising as the reaction product of another of the considered connection.

If it is desirable or necessary, functionally active group, R6may be substituted and/or optionally modified by the person skilled in the art in the joints or in the diagrams stages with the aim of obtaining the considered compounds. Mention should be made of mutual conversion bifunctional groups representing a protective group, intended for short-term or long-term protection, in other groups of R6. In this area is well known to many other conventional and/or acceptable conversion, including obtaining synthetic intermediates. Some people do not limit the invention examples of such transformations or reactions include the reaction of recovery, reactions of nucleophilic substitution/replacement, exchange reactions or obtaining carboxylic or sulfonic acids, amides, esters, halides, mixed anhydrides, and the like, the reaction of electrophilic substitution/replacement, oxidation reaction, reaction conversion ring/chain reaction open ring, the condensation reaction, including reaction using sulfonylurea or carbonyl groups and/or carbon-hydrogen bonds, which are influenced by any or both of these groups. Specialist in the art can choose a suitable m is the method of obtaining or transformation of the considered compounds and the order of the reaction(s). It should be noted that if a certain sequence or method will be junk, you should select and use an alternative method. You can also make a choice in favor of getting/adding groups in one stage using a convergent strategy inhibition or obtain a nite group, R6using a stepwise approach.

Thus, in General, the choice of the starting materials and the reaction conditions may change, which is well known to specialists in this field. As a rule, the appropriate method is not limited to one set of conditions, if necessary, may apply their variations. Conditions are optionally selected depending on a particular purpose, such as obtaining small quantities or large-scale retrieval. In any case, the use of more dangerous to humans, or more dangerous to the environment products or reagents, as a rule, should be kept to a minimum. Examples of such products are diazomethane, diethyl ether, salts of heavy metals, dimethyldisulfide, chloroform, benzene, etc.

These reactions, if necessary, can be conducted in an atmosphere of dry inert gas, such as nitrogen or argon. Certain reactions, known to specialists in this field, can be carried out in a dry atmosphere, such ka the atmosphere of dry air, while other stages of the synthesis, for example the hydrolysis of ester or amide with aqueous acid or base, can be performed in the atmosphere of the laboratory air. In addition, some stages of the synthesis can be carried out in vessels designed for carrying out reactions under pressure, when the pressure is higher, equal or lower than atmospheric pressure. The use of such vessels allows you to control gaseous reactants such as hydrogen, ammonia, trimethylamine, methylamine, oxygen, etc. and allows you to protect flowing reaction from the action of air or moisture. The above is not exhaustive, and it is clear that specialist chemist may be developed and may apply additional or alternative methods, conditions, reactions or system.

Are given as illustrations of the reaction, usually carried out in the temperature range from -25° to the temperature of reflux distilled solvent in an atmosphere of inert gas, such as nitrogen or argon. The solvent or solvent mixture can vary widely depending on the reagents and other conditions, and they can include these polar or bipolar aprotic solvents, or mixtures of these solvents. Reactions, such as reactions of metallation or education anion with a strong is of Sevani, if necessary, can be carried out at low temperatures such as the temperature of the dry ice/acetone or liquid nitrogen.

In some cases, amines, such as triethylamine, pyridine or other directionspanel Foundation can serve as reagents and/or solvents and/or co-solvents. In some cases these reactions and other reactions shown in the above schemes, to maintain or conservation groups in other parts of the molecules (molecules) in positions that do not require the presence of reactive(s) centre (s), apply a protective group. Examples of such groups that the specialist can support or maintain, include amines, other hydroxyl groups, thiols, acids, etc. Such protective groups may include acyl groups, arylalkyl group, carbamoyl groups, ethers, simple alkoxyalkyl esters, simple cycloalkylation, arylalkyl groups, silyl groups, including tizamidine silyl group, ester group, etc. are Examples of such protective groups include acetyl, TRIFLUOROACETYL, tetrahydropyran (Tgp), benzyl, tert-butoxycarbonyl (BOC or t-BOC), benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethyl (MEM). The receipt of such protected compounds, and a method of removal of the protective groups well is swesty in this area. The protective group can also be used as substituents in the compounds, which is used as a medicine and not a synthetic intermediate product.

In many reactions and processes involved, which can act as reactants, reagents, deproteinised agents, acid acceptors, salt-forming reagents, solvents, co-solvents and the like, which can be used include, for example, metal hydroxides such as sodium hydroxide, potassium, lithium, cesium or magnesium oxides, such as oxides of sodium, potassium, lithium, calcium or magnesium, metal carbonates, such as carbonates of sodium, potassium, lithium, cesium, calcium or magnesium, bicarbonates of metals, such as sodium bicarbonate or potassium bicarbonate primary (I° ), secondary (II° ) or tertiary (III° organic amines, such as alkylamines followed, arylalkylamine, alkylenediamine, heterocyclic amines, or heteroaryl amines, ammonium hydroxides or Quaternary ammonium hydroxides. Not limiting the scope of invention examples of such amines include triethylamine, trimethylamine, Diisopropylamine, methyldiisopropanolamine, diazabicyclo, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine (N-MM), N,N’-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetrame repellin, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine etc. do Not limit the invention, examples of the hydroxides of ammonium, usually obtained from amines and water, may include ammonium hydroxide, a hydroxide of triethylamine, trimethylammonium hydroxide, a hydroxide of methyldiisopropanolamine, the hydroxide of tribenzylamine, the hydroxide of dimethylbenzylamine, the hydroxide morpholine, hydroxide N-methylmorpholine, hydroxide, N,N’-dimethylpiperazine, hydroxide N-ethylpiperidine etc. as not limiting the scope of the invention examples of Quaternary ammonium hydroxides can be a hydroxide of tetraethylammonium, the hydroxide of Tetramethylammonium, the hydroxyl of dimethylaminopropylamine, the hydroxide of benzylmethylamine, the hydroxide of methyldiethanolamine, the hydroxide of methyltrienolone, hydroxide, N,N-dimethylmorpholine, hydroxide, N,N,N’,N’-tetramethylpiperidine and hydroxide N-ethyl-N’-hexylpyridine etc.

Also suitable reagents are hydrides, amides and metal alcoholate, such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, the hydride diisobutylaluminum (DIBAL), sodium methoxide, tert-piperonyl potassium, atoxic calcium, atoxic magnesium, sodium amide, diisopropylamide potassium, etc. ORGANOMETALLIC deprotonized agents, such as agents, based on the Ala is La or aryl lithium, such as motility, finality, tert-utility, acetimidate or utility, Grignard reagents, such as bromatology or chloromethylene, kadmirovannye reagents, such as dimethylcadmium, etc. may also serve as grounds, contributing to the formation of salts, or catalysts of reactions. The Quaternary ammonium hydroxides or mixed salts may also be used to facilitate combinations of phase transfer or serve as agents of the phase transfer. Pharmaceutically acceptable base may be subjected to interaction with acids to produce considered pharmaceutically acceptable salts. It should also be noted that the optically active base can be used to obtain optically active salts that can be used for optical divisions.

Typically, the reaction medium can include one solvent, mixed solvents of the same or of different classes or serve as a reagent system consisting of a single or mixed solvent. The solvent can be a proton, aprotonnymi or bipolar aprotic. Not limiting the scope of invention examples of proton solvents include water, methanol (Meon), disturbancy or pure 95%or absolute ethanol, isopropanol, etc. Typical nephratonia actuarialy include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, methyl tert-butyl ether (TBME), aromatic compounds such as xylene, toluene or benzene, ethyl acetate (EA), methyl acetate, butyl acetate, dichloromethane, methylene chloride, ethylene dichloride (ejh), hexane, heptane, isooctane, cyclohexane, etc. Bipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAC), acetonitrile, DMSO, triamide of hexamethylphosphoric (GMFA), nitromethane, tetramethylrhodamine, N-organic, etc. do Not limit the invention by examples reagents that can be used as solvents or part of the system of mixed solvents are organic or inorganic mono - or multipotency acids or bases, such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazin, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines, intended for production of esters or amides, or thiol, intended to receive the products considered, and so on

Getting considered in this description of the connections may require oxidation of nitrogen or sulphur derivatives in the form of N-oxides or sulfo the seeds or sulfones. The reagents for this process can be included as not limiting the scope of invention examples peroxymonosulfate (Oxon, OXONE®), hydrogen peroxide, meta-chloroperbenzoic acid (m-HPBC), perventing acid, peracetic acid, prolocol acid, peroxide tert-butyl, hypochlorite tert-butyl, sodium hypochlorite, hypochlorous acid, meta-periodate sodium, periodno acid and the like, and to sulfones and sulfoxidov most suitable weaker agents. Can be selected either pure or mixed proton, nephratonia, bipolar aprotonin solvents such as methanol/water.

The oxidation can be conducted at temperatures from about -78° With up to about 50° typically in the range from -10° With up to about 40° s Sulfoxidov most expedient to obtain, using one equivalent of oxidant. When applying more active oxidizing agents may be useful, but not necessary, that the reaction proceeded in an atmosphere of inert gas from the degassing of solvents or without it. It should be noted that the oxidation of sulfides with getting sulfones can be carried out in one or in two stages through sulfoxide depending on the requirements of the specialist.

Recovery is a well-known process in this area, and most have tremendum method is hydrogenation. In such cases (catalytic reduction) can be applied to metal catalysts, such as Rh, Pd, Pt, Ni or the like with additional media, such as carbon, barium carbonate and the like, or without it. Solvents, if necessary, can be a proton or nephratonia pure solvents or mixed solvents. Of reduction reaction can be conducted at a pressure of from atmospheric pressure up to several atmospheres, and the preferred pressure is from atmospheric up to about 40 pounds per square inch (psi) or high pressure, achieved by using the device for the hydrogenation are well known in this field.

Reductive alkylation of amines or active methylene compounds is also an acceptable method of obtaining compounds. Such alkylation reaction can be carried out in the above-described conditions reductive hydrogenation using, for example, aldehydes or ketones. Reagents designed to transfer hydride, such as lambrogini sodium hydride aluminum, alumoweld lithium, borane, borohydride sodium hydride diisobutylaluminum and the like, are also suitable reagents for reductive alkylation. In a similar way can be restored acyl group with obtaining substituted AMI the s.

An alternative method of alkylation of carbon or nitrogen is direct alkylation. Such alkylation, as is well known in this field may involve the processing of activated carbon containing at least one atom of hydrogen, a base to obtain the corresponding anion, in addition electrophilic reagent and implementation SN2-interaction. Subject to alkylation of the amine is treated similarly, except that it may not be necessary deprotonation. The electrophiles include derivatives of Halogens, esters of sulfonates, epoxies, etc.

Bases and solvents for the alkylation reactions are the same as those described previously. Preferred are the Foundation, where competition with the electrophile is minimal. More preferred bases are metal hydrides, anions amides or ORGANOMETALLIC bases, such as n-utillity. Acceptable are described solvents, mixtures of solvents or mixtures of solvents/reagents, while nephratonia or bipolar aprotic solvents, such as acetone, acetonitrile, DMF and the like, are preferred examples.

Acids are used in many reactions during various synthetic processes is A. For example, for removal of the protective group TGPs with getting hydroxamic acids. The acid may be mono-, di - or trapatonni organic or inorganic acid. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, Hydrobromic acid, hydrofluoric acid, carbonic acid, phosphoric acid, para-toluensulfonate acid, triftormetilfullerenov acid, triperoxonane acid (TFA), DIPEROXY acid, benzoic acid, methanesulfonate acid, benzosulfimide acid, 2,6-dimethylbenzenesulfonyl acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, etc. They can also be a Lewis acid such as aluminum chloride, borontrifluoride, pentaploid antimony, etc. Acid in the form of protons can also be used for hydrolysis of esters, amides, etc. and also as catalysts in reactions of metabolism.

Protected carboxylic acid ester or amide can be converted also into hydroxamic acid or derivative of hydroxamic acid, such as a simple O-arylalkyl ether or a simple O-cycloalkylcarbonyl ether. In the case when using hydroxylamine, hydroxo the OIC acid can be obtained directly after processing ester or amide with one or more equivalents of hydroxylamine hydrochloride at room temperature or at an elevated temperature in a solvent or in solvents, usually in proton or partially proton solvent such as mentioned above. This exchange process can also be carried out with the addition of another acid as catalyst. Alternatively, to obtain in situ hydroxylamine from its hydrochloride can be used a base such as alcoholic salt solution used as a solvent, for example sodium methoxide in methanol, which can react with the ether or Amida. As mentioned above, the exchange reaction can occur involving protected hydroxylamine, such as tetrahydropyranyloxy (THONN2), benzylhydroxylamine (BnONH2and so, in the case where the products of the reactions shown in schemes a, B and C are derived hydroxamic acids, protected tetrahydropyranyl (TBM) or benzyl (EAP). Removing the protective groups, if required, for example, after further transformations in another part of the molecule, or after storage, perform standard methods, well known in this field, such as acid hydrolysis Tgp-group, as described above, or reductive removal of the benzyl group with hydrogen in the presence of a metal catalyst, such as palladium, platinum, palladium on coal or Nickel.

In the case when R 20denotes hydroxyl, i.e. when the intermediate product is a carboxylic acid, can be a standard reaction mix. For example, the acid may be converted into the acid chloride, mixed anhydride or activated ester, such as hydroxybenzotriazole, and subjected to treatment with hydroxylamine or protected hydroxylamine in the presence of non-competing grounds with getting acylated nitrogen compounds, which is the same product, which is described above. The combination of this nature are well known in this field and especially in the field related to the chemistry of peptides and amino acids.

Included in this description of the connections can carry one or more asymmetric carbon atoms and can therefore exist in the form of optical isomers, enantiomers, diastereoisomers, as well as in the form of racemic or narramissic mixtures. The connection may also exist in other isomeric forms, such as ortho-, meta - and para-isomers, CIS - and TRANS-isomers, SYN - and anisometry, E - and Z-isomers, tautomeric isomers, alpha - and beta-isomers, axial and Equatorial isomers and isomers obtained by slow rotation. The isomer can exist in equilibrium with the other isomer in mammals or in another experimental system. That the second connection may also exist in the form of a system with isomeric equilibrium with the solvent or water, for example in the form of gidratirovannoe ketone or aldehyde, which is well known in this field. All such isomers fall under the concept of "joint invention".

The above chemical reaction, usually considered in terms of the broadest possible application to obtain the compounds according to the invention. Sometimes it may be that the reaction is not applicable, as these are described, for each of the compounds falling under the scope of the invention. The connection to which this applies can be easily identified by experts in the field. In all such cases, either the reactions can be successfully performed using conventional modifications known to specialists in this field, such as adequate protection of the interacting groups, substitution to alternative conventional reagents, a common modification of the reaction conditions and the like, or to obtain relevant compounds can be used in other reactions mentioned in this description or is customary.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Scheme 13

In a similar way the following can be derived analogs

Scheme 14

Scheme 15

Scheme 16

Scheme 17

Scheme 18

Scheme 19

The following tables 1-150 presents several analysis derived aromatic sulfamethoxasole acids possessing inhibitory activity, or structural formula illustrating the group of substituents. Each group of compounds is illustrated in the form of a General formula or formulas, for which(s) followed by a series of preferred fragments or groups that represent different substituents, which may be attached in position accurately indicated on the total formula. The appropriate Vice characters, such as R1, R2and R3have the meanings given in each table and, as a rule, do not have these rapeslutty. One or two links (wavy line) is shown for those deputies, for which you must specify the relevant provisions of the accession in the illustrated connection. This system is well known for the transmission of information in the field of chemistry and is widely used in scientific papers and other documents. For example, in table 2, R1and R2together with the atoms to which they are attached, denote a variable group is shown in this table, the structural elements that can simultaneously replace R1and R2.

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Consider the connection with inhibitory activity applied for the treatment of a mammal, such as mouse, rat, rabbit, dog, horse, Primate, such as a monkey, chimpanzee or a person who has a condition associated with pathological activity of the matrix of metalloprotease.

Also discusses the use of the specified connection, which is the inhibitor of metalloprotease, for the treatment of painful conditions that can influence the activity of such metalloprotease as TNF-α -convertase.

Examples is aka illnesses are acute phase reactions of shock and sepsis, response to coagulation, bleeding and cardiovascular disorders, fever and inflammation, anorexia and cachexia.

For the treatment of painful conditions associated with abnormal activity of matrix metalloproteinases, the compound which is an inhibitor of MMP, can be used in the form of amine salts derived from inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulphate, aconsultant, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, virologic, 2-hydroxyethanesulfonic, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesilate, undecanoate.

In addition, the basic nitrogen-containing group with the aim of increasing the solubility in water can be quaternization with such agents as (ness.)alkylhalogenide, such as methyl-, ethyl-, propyl - and butylchloride, bromides and iodides, diallylsulfide, dimethyl-, diethyl-, dibutil and dimycolate, halides, long-chain, such as decyl-, l is uril-, myristyl and sterilgarda, bromides and iodides, aralkylated, type benzyl - and phenylethylamine, and others. Thus, if necessary, can be obtained from water or maslorastvorimye or dispersible products. Salt is produced by interaction of lead compounds with the desired acid.

Other used in the present invention compounds are acids, which can also form a salt. Examples of salts include salts of alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium, or salts of organic bases or basic Quaternary ammonium.

In some cases, the salts can also be used for separation, purification, or separation of the compounds according to the invention.

The total daily dose, administered to the mammal in a single or divided doses, may be, for example, from 0.001 to 30 mg/kg of body weight per day, more preferably from 0.01 to 10 mg. of the Composition of standard doses may contain such amounts or smaller multiples, making necessary the daily dose. Acceptable daily intake can be put into several smaller doses. By using multiple small doses can also increase the total daily dose, if required by the specialist who ordered the medication.

The regimen of medicines for the ecene painful condition with the compounds and/or compositions of the present invention is selected depending on numerous factors, including the type, age, weight, sex, diet and medical condition of the patient, severity of the disease, route of administration, pharmacological characteristics, such as the activity, efficacy, pharmacokinetic profile and toxicity profile of specific applicable connection, depending on whether you are using the system administration of medication and enter whether the connection is in the form of one part of combination medicines. Thus, specifically used regimen drug can vary significantly and as a result may deviate from the preferred of the above schema.

Compounds according to the invention can be used for the manufacture of pharmaceutical compositions. This composition can then be administered orally, parenterally, by using an aerosol for inhalation, rectally, or topically in the form of compositions containing the daily dose, which optionally include conventional non-toxic pharmaceutically acceptable excipients, adjuvants and carriers. The local application may also include the use of such methods transdermal applications, such as transdermal patches or device for iontophoresis. The term "parenteral" in the context of the present description includes subcutaneous injections, intravenous, intramuscular, intraperitoneal, intra the basal injection or infusion. The composition of medicines are described, for example, Hoover, John E., Remington''s Pharmaceutical Science, Mack Publishing Co. Easton, Pennsylvania, 1975, and Liberman H.A. and Lachman L. (editor), Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

Injectable preparations, for example sterile injectable aqueous or oily suspensions may be made by known in this field of technology with appropriate dispersing or wetting agents and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic acceptable for parenteral use diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used include water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment typically use non-volatile oil. For this purpose, can be applied to any clean, non-volatile oils, including synthetic mono - or diglycerides. In addition, for the preparation of injectable forms are used fatty acids such as oleic acid. Can be used dimethylacetamide, surfactants, including ionic and nonionic detergents, glycols. Can also be used a mixture of rest is ritala and wetting agents, such as the above.

Suppositories for rectal administration of medicinal remedies can be prepared by mixing the drug with acceptable not cause irritation excipients, such as cocoa butter, synthetic mono-, di - or triglycerides, fatty acids and polyethylene glycols, which are solid at ordinary temperatures, but can melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms of the compounds of the present invention, typically combined with one or more adjuvants that are acceptable for the appropriate route of administration. Oral introduction consider the derivative of aromatic sulfamethoxasole, which is the inhibitor may be smesto with lactose, sucrose, powdered starch, cellulose ethers and alkanovykh acids, alkylamino esters of cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, Arabic gum, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for conventional applications. Such capsules or tablets may with erati composition of controlled release, which can be obtained in the form of a dispersion of the active substance in the hypromellose. In the case of capsules, tablets and pills dosage forms may also include tabularasa agents, such as citrate, carbonate or bicarbonate of magnesium or calcium. In addition, pills and tablets can be manufactured with intersolubility coatings.

For therapeutic purposes compositions for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions can be obtained from the soluble powders or granules having one or more carriers or diluents, which as mentioned above may be used in compositions for oral administration. Consider the derivative of aromatic sulfamethoxasole, which is the inhibitor may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and/or various buffers. Other adjuvants and methods of introduction are well known and widely used in the pharmaceutical field.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, sod is readie inert diluents, usually used in this field, such as water. Such compositions can also include adjuvants such as wetting agents, emulsifiers and suspendresume agents, and sweetening agents, corrigentov and fragrances.

The amount of active ingredient that may be combined with carriers for single dosage form varies depending on subject to treatment of a mammal and the particular route of administration.

Preferred embodiments of the inventions

The above description allows you to implement the present invention without additional research in full. Thus, the following specific preferred embodiments of serve only to illustrate the invention and, therefore, do not limit the scope of the invention.

Example 1: Obtain N-hydroxy-2-[(4-phenoxyphenyl)sulfonyl]ndimethylacetamide

Stage A: To a solution of hydrate of 3-bronirovochnoy acid (1,95 g, 11.7 mmol), cooled to 0° With, in methanol (50 ml) was added 4-(phenoxy)sensation (2.35 g, 11.7 mmol). The solution was stirred for 15 min, then concentrated in vacuo. The residue was distributed between ethyl acetate and N2O and the organic layer was dried over magnesium sulfate. After concentration in vacuum perfectly and the crude sulfide in the form of solid yellow, which was used without further purification.

Stage B: To the solution obtained at the stage And the crude sulfide (1.2 g, <2.6 mmol) in a mixture of methanol/N2Oh, cooled to 0° C, was added Oxone®(3.5 g, 5,72 mmol). The solution was stirred for 1 h, after which the excess Oxone® was removed by filtration. The filtrate was concentrated and the residue was dissolved in ethyl acetate, washed with saturated solution of Panso3and saturated NaCl solution and dried over magnesium sulfate. After concentration in vacuo the resulting residue was dissolved in methanol and was added thionyl chloride (1.9 ml, 26 mmol). After chromatography (silica gel, ethyl acetate/hexane) received sulfon in the form of a solid (350 mg, 44%). MS (CI) MH+: calculated for C15H14About5S: 307 detected 307.

Stage b: To a solution of sulfone (350 mg, 1.1 mmol) in methanol (2 ml) and THF (THF, 2 ml) was added 50%aqueous solution of hydroxylamine (1 ml). The solution was stirred over night. After trituration with ethyl acetate had been specified in the title compound in the form of solid white (270 mg, 77%). Purity according to GHUR: >97%. MS (CI) MH+: calculated for C14H13NO5S: 308 detected 308.

Example 2: Obtain N-hydroxy-2-methyl-2-[(4-phenoxyphenyl)sulfonyl]propanamide

Stage A: To restore(phenoxy)bentolila (3.8 g, for 18.8 mmol) in methanol (60 ml), cooled to 0° C, was added tert-butylbromide (2,8 ml of 18.8 mmol) and triethylamine (2.6 ml, 19.0 mmol). The solution was stirred for 30 min and then concentrated in vacuum. The residue was distributed between ethyl acetate and N2Oh, the organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After concentration in vacuo received sulfide in the form of oil. To a solution of sulfide in dichloromethane (85 ml) for 15 min was added meta-chloroperbenzoic acid (13.8 g, 43.2 mmol). The solution was stirred at ambient temperature for 2 hours the Reaction was stopped by addition of an aqueous solution of Na2SO3. After 30 min the solution was filtered through Celite®. The filtrate is washed with 25%aqueous solution of hydroxylamine, 1 N. Hcl and saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfon in a solid white color (4.0 g, 68%).

Stage B: To the solution obtained at the stage And sulfone (3.2 g, 9.2 mmol) in THF (65 ml)cooled to 0° C, was added sodium hydride (730 mg of 60%dispersion in mineral oil, 18.4 mmol). After 10 min was added dropwise methyliodide (2,28 ml, to 36.8 mmol) and the mixture was stirred for 18 h at ambient temperature. The reaction was stopped by adding N2Oh and reacciona the mixture was concentrated in vacuum. The aqueous residue was diluted with ethyl acetate and the organic phase is washed with N2O and dried over Na2SO4. After concentration in vacuo was obtained dimethyl derivative in a solid whitish (3.2 g, 92%). Purity according to GHUR: 95%.

Stage b: To the solution obtained in stage B dimethyl derivative (3.2 g, 8.5 mmol) in anisole (10 ml) was added triperoxonane acid (30 ml) and the solution was stirred for 30 minutes After concentration in vacuum and subsequent trituration (diethyl ether) was obtained acid in a solid white color (750 mg, 28%). Purity according to GHUR: 99%. MS (CI) MH+: calculated for C16H16O5S: 321 detected 321.

Stage G: To a solution obtained at the stage In acid (723 mg, and 2.26 mmol) in DMF (DMF), and 4.5 ml) was added N-hydroxybenzotriazole· N2On (HOBT, 366 mg, a 2.71 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 476 mg, 2.49 mmol). After stirring the solution for 1 h at ambient temperature was added 50%aqueous hydroxylamine (0,40 ml, 6.8 mmol). After 15 min the solution was distributed between ethyl acetate and N2O. the Organic layer was washed N2Oh, saturated NaCl and dried over Na2SO4. After chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified the title compound as white foam (434 mg, 57%). Purity according to GHUR: 99%. MS (CI) M+Li-: calculated for C16H17NO5O: 342, found 342.

Example 3: Obtaining 1,1-dimethyl ester 4-[(hydroxyamino)carbonyl]-4-[(phenoxyphenyl)sulfonyl]-1-piperidinecarboxylic acid

Stage A: a Solution of 4-(phenoxy)bentolila (2,03 g, 10.0 mmol) in dimethyl sulfoxide (DMSO, 20 ml) was heated to 65° C for 5 h the Solution was allowed to stand for 18 h at ambient temperature. The solution was extracted with ethyl acetate and the combined organic layers were washed N2O and saturated NaCl and dried over magnesium sulfate. After concentration in vacuo received disulfide in the form of a yellow oil (2.3 g, quantitative yield).

Stage B: To a solution of utilisedictated (15.7 g, 0.1 mol) in THF (100 ml) dropwise over 20 min, the solution was added di-tert-BUTYLCARBAMATE (21.8 g, 0.1 mol) in THF (5 ml). The solution was stirred overnight at ambient temperature and then concentrated in vacuum, receiving light oil. The oil was filtered through silica gel (ethyl acetate/hexane, 7:3) and concentrated in vacuum, obtaining the BOC-protected piperidine derived (26,2 g, quantitative yield) as a clear colorless oil.

Stage b: To a solution of Diisopropylamine (2.8 ml, 20 mmol) in THF (30 ml), cooled to -78° With, on calendarall n-utility (12.5 ml, 20 mmol). After 15 min was added dropwise obtained in stage B of the BOC-protected piperidine derivative (2.6 g, 10 mmol) in THF (10 ml). After 1.5 h, the solution was cooled to -60° and added obtained at the stage And the disulfide (2.0 g, 10 mmol) in THF (7 ml). The solution was stirred for 2 h at ambient temperature. The solution was diluted with N2O and was extracted with ethyl acetate. The organic layer was washed N2O and saturated NaCl and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of an oil (1.8 g, 40%).

Stage G: To a solution obtained at the stage In sulfide (1.8 g, 3.95 mmol) in dichloromethane (75 ml), cooled to 0° With added meta-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 h, then was diluted with water and was extracted with dichloromethane. The organic layer is washed with 10%solution of Na2SO4N2O and saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfon in the form of solids (1,15 g, 59%).

Stage D: To the solution obtained in stage G of the sulfone (800 mg, and 1.63 mmol) in THF (9 ml) and ethanol (9 ml) was added NaOH (654 mg, 16.3 mmol) in N2About (3 ml). The solution was kept for 18 h at 65° C. the Solution was concentrated in vacuo and the residue was dissolved in N O. After acidification with 2 N. Hcl to pH 4 solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After concentration in vacuo got acid in the form of a white foam (790 mg, quantitative yield). Elemental analysis: calculated for C23H27NO7S: 59,86; N 5,90; N 3.04 FROM; S 6,95. Found: 59,49; N 6,37; N 2,81; S 6,59.

Stage E: To the solution obtained in stage D acid (730 mg, was 1.58 mmol) in DMF (9 ml) was added HOBT (256 mg, 1,90 mmol)and then EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0,521 ml, 4.7 mmol) and 50%aqueous solution of hydroxylamine (1,04 ml, 15.8 mmol). The solution was stirred for 20 h, after which was added in the form of additional portions of N-hydroxybenzotriazole· N2On (256 mg), EDC (424 mg) and 50%aqueous solution of hydroxylamine (1,04 ml). After stirring for 24 h the solution was diluted with N2O and was extracted with ethyl acetate, the organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified in the title compound in the form of solid white (460 mg, 61%).

Purity according to GHUR: >99%. Elemental analysis: calculated for C23H28N2O7S: C 57,97; H OF 5.92; N 5,88; S OF 6.73. Found: 57,95; N. Of 6.02; N 5,81; S 6,85.

When is EP 4: Getting monohydrochloride N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-piperazinecarboxamide

Stage A: a Solution of 4-(phenoxy)bentolila (2,03 g, 10.0 mmol) in DMSO (20 ml) was heated to 65° C for 5 h the Solution was allowed to stand for 18 h at ambient temperature. The solution was extracted with ethyl acetate and the combined organic layers were washed N2O and saturated NaCl and dried over magnesium sulfate. After concentration in vacuo received disulfide in the form of a yellow oil (2.3 g, quantitative yield).

Stage B: To a solution of utilisedictated (15.7 g, 0.1 mol) in THF (100 ml) dropwise over 20 min, the solution was added di-tert-BUTYLCARBAMATE (21.8 g, 0.1 mol) in THF (5 ml). The solution was stirred overnight at ambient temperature and then concentrated in vacuum, receiving light oil. The oil was filtered through silica gel (silica gel, ethyl acetate/hexane) and concentrated in vacuum, obtaining the BOC-protected piperidine derived (26,2 g, quantitative yield) as a clear colorless oil.

Stage b: To a solution of Diisopropylamine (2.8 ml, 20 mmol) in THF (30 ml), cooled to -78° C was added dropwise n-utility (12.5 ml, 20 mmol). After 15 min was added dropwise obtained in stage B of the BOC-protected piperidine derivative (2.6 g, 10 mmol) in THF (10 ml). After 1.5 h, the solution was cooled to -60° and added obtained at the stage And the disulfide(2.0 g, 10 mmol) in THF (7 ml). The solution was stirred for 2 h at ambient temperature. The solution was diluted with N2O and was extracted with ethyl acetate. The organic layer was washed N2O and saturated NaCl and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of an oil (1.8 g, 40%).

Stage G: To a solution obtained at the stage In sulfide (1.8 g, 3.95 mmol) in dichloromethane (75 ml), cooled to 0° With added meta-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 h, then diluted with H2O and was extracted with dichloromethane. The organic layer is washed with 10%solution of Na2SO3N2O and saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfon in the form of solids (1,15 g, 59%).

Stage D: To the solution obtained in stage G of the sulfone (800 mg, and 1.63 mmol) in THF (9 ml) and ethanol (9 ml) was added NaOH (654 mg, 16.3 mmol) in N2About (3 ml). The solution was kept for 18 h at 65° C. the Solution was concentrated in vacuo and the residue was dissolved in N2O. After acidification with 2 N. Hcl to pH 4 solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After concentration in vacuo was awarded to the slot in the form of a white foam (790 mg, quantitative yield). Elemental analysis: calculated for C23H27NO7S: 59,86; N 5,90; N 3.04 From; S of 6.95; found: 59,49; N 6,37; N 2,81; S 6,59.

Stage E: To the solution obtained in stage D acid (730 mg, was 1.58 mmol) in DMF (9 ml) was added HOBT (256 mg, 1,90 mmol)and then EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0,521 ml, 4.7 mmol) and 50%aqueous solution of hydroxylamine (1,04 ml, 15.8 mmol). The solution was stirred for 20 h, after which was added in the form of additional portions of N-hydroxybenzotriazole· N2On (256 mg), EDC (424 mg) and 50%aqueous solution of hydroxylamine (1,04 ml). After stirring for 24 h the solution was diluted with N2O and was extracted with ethyl acetate, the organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography with reversed phase (silica gel, acetonitrile/N2Has received hydroxamate in a solid white color (460 mg, 61%). Purity according to GHUR: >99%. Elemental analysis: calculated for C23H28N2O7S: 57,97; N. Of 5.92; N 5,88; S of 6.73; found: 57,95; N. Of 6.02; N 5,81; S 6,85.

Stage G: the Solution obtained in stage E of hydroxamate (385 mg, 0,808 mmol) in ethyl acetate (25 ml), cooled to 0° was barbotirovany within 5 min of gaseous Hcl. After maturation for 30 min the solution was concentrated in vacuum. After trituration with diethyl ether there was obtained is indicated in the title compound in the form of solid white (330 mg, quantitative yield). MS (CI) MH+: calculated for C18H20O5S: 377 detected 377. Msvr (mass spectroscopy high resolution): calculated for C18H20N2O5S: 377,1171 found 377,1170. Elemental analysis: calculated for C18H20N2O5S· 1HCl· 0,25N2About: 51,35; N. Of 5.17; N 6,65; S 7.62mm; Cl 9,26; found: 51,58; N 5,09; N 6,55; S 8,02; Cl is 9.09.

Example 5: Obtaining (E)-N-hydroxy-2-[(4-phenoxyphenyl)sulfonyl]-3-phenyl-2-propenamide

Stage A: To a solution of 4-(phenoxy)bentolila (5,00 g of 24.7 mmol) in methanol (100 ml), cooled to 0° C, was added tert-butylbromide (3,99 ml of 24.7 mmol). After adding triethylamine (of 3.60 ml, from 25.8 mmol) the solution was stirred for 40 minutes the Solution was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate and washed with N2Oh, saturated NaCl and dried over Na2SO4. After concentration in vacuo received sulfide in the form of an oil (7.9 g, quantitative yield).

Stage B: To the solution obtained at the stage And sulfide (7.9 g, to 24.7 mmol) in methanol (180 ml) and N2O (20 ml) was added to Ohope® (38,4 g, 62.5 mmol) and the mixture was stirred for 22 hours the Mixture was acidified with 2,5 N. NaOH to pH 4 and poured, removing insoluble salts. Obtained by merging the product was concentrated to half volume and aspidella between ethyl acetate and N 2O. the Organic layer was washed N2Oh, saturated NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received sulfon in a solid yellow color (5,79 g, 67%).

Stage b: To a solution containing obtained in stage B sulfon (2,5064 g, 7.20 mmol) and benzaldehyde (0,748 ml, 7.36 mmol) in benzene (20 ml), was added acetic acid (0.15 ml) and piperidine (0.05 ml). The solution was heated for 2 h to a temperature of reflux distilled and the condensate was collected using traps Dean-stark. After incubation for 1.5 h at the temperature of reflux distilled solution was cooled to ambient temperature and was stirred for 18 hours the Solution was diluted with ethyl acetate, washed with N2Oh, saturated NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) and subsequent trituration (diethyl ether/hexane) received unsaturated sulfon in a solid white color (1.97 g, 73%). Purity according to GHUR: >98%.

Stage G: the Solution obtained at the stage of unsaturated sulfone (0,5053 g of 1.16 mmol) was barbotirovany gaseous Hcl for 1 h the Solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with N2O and dried over Na2SO4. After concentration in vacuo received acid oil (0,41 is, 93%).

Stage D: To the solution obtained in stage G of the acid (461 mg, to 1.21 mmol) was added thionyl chloride (3.0 ml) and the solution was heated for 1 h to 100° C. After concentration in vacuo was obtained acid chloride in the form of oil of amber (380 mg, 79%).

Stage E: To the solution obtained in stage D of the acid chloride (380 mg, 0.95 mmol) in THF (20 ml) was added 50%aqueous solution of hydroxylamine (1.7 ml, 9.5 mmol). The solution was stirred for 1 h at 0° C. the Solution was diluted with ethyl acetate, washed with N2Oh, saturated NaCl and dried over Na2SO4. After chromatography with reversed phase (silica gel, acetonitrile/N2O) and subsequent trituration (diethyl ether/hexane) has been specified in the title compound in the form of solid white (131 mg, 35%). Purity according to GHUR: >97%.

Example 6: Getting monohydrochloride N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: a Solution of 4-(phenoxy)bentolila (2,03 g, 10.0 mmol) in DMSO (20 ml) was heated for 5 h to 65° C. the Solution was kept for 18 h at ambient temperature. The solution was extracted with ethyl acetate, the combined organic layers were washed N2Oh, saturated NaCl solution and dried over magnesium sulfate. After concentration in vacuum p who were given the disulfide in the form of a yellow oil (2.3 g, quantitative yield).

Stage B: To a solution of utilisedictated (15.7 g, 0.1 mol) in THF (100 ml) dropwise over 20 min, the solution was added di-tert-BUTYLCARBAMATE (21.8 g, 0.1 mol) in THF (5 ml). The solution was stirred overnight at ambient temperature and then concentrated in vacuum, receiving light oil. The oil was filtered through silica gel (silica gel, ethyl acetate/hexane) and concentrated in vacuum, obtaining the BOC-protected piperidine derived (26,2 g, quantitative yield) as a clear colorless oil.

Stage b: To a solution of Diisopropylamine (2.8 ml, 20 mmol) in THF (30 ml), cooled to -78° C was added dropwise n-utility (12.5 ml, 20 mmol). After 15 min was added dropwise obtained in stage B of the BOC-protected piperidine derivative (2.6 g, 10 mmol) in THF (10 ml). After 1.5 h, the solution was cooled to -60° and added obtained at the stage And the disulfide (2.0 g, 10 mmol) in THF (7 ml). The solution was stirred for 2 h at ambient temperature. The solution was diluted with N2O and was extracted with ethyl acetate. The organic layer was washed N2O and saturated NaCl and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of an oil (1.8 g, 40%).

Stage G: To a solution obtained at the stage In sulfide (1.8 g, 3.95 mmol) in dichloromethane (75 ml), obladenno is near to 0° With added meta-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 h, then was diluted with water and was extracted with dichloromethane. The organic layer is washed with 10%solution of Na2SO4N2O and saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfon in the form of solids (1,15 g, 59%).

Stage D: the Solution obtained in stage G of the sulfone (of 3.56 g, 7.0 mmol) in ethyl acetate (100 ml), cooled to 0° was barbotirovany within 5 min of gaseous Hcl. After concentration in vacuum and subsequent trituration with diethyl ether there was obtained the hydrochloride of amine in the form of solids, white (3.5 g, quantitative yield). MS (CI) MH+: calculated for C30H23NO5S: 390 detected 390.

Stage E: To a solution containing obtained in stage D amine hydrochloride (2.6 g, 6 mmol) and K2CO3(1.66 g, 12 mmol) in DMF (50 ml), was added propargylamine (892 mg, 6 mmol) and the solution was stirred for 4 h at ambient temperature. The solution was diluted with N2O and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received propargylamine in the form of solid substances is STV white (2.15 g, 82%).

Stage G: To a solution obtained in stage E of propargylamine (2.15 g, 5 mmol) in THF (30 ml) and ethanol (30 ml) was added NaOH (2.0 g, 50 mmol) and the solution for 48 h and kept at 65° C. the Solution was concentrated in vacuo and the aqueous residue was acidified to pH 5. After vacuum filtration of the resulting precipitate got acid in a solid white color (2,04 g, quantitative yield).

Stage 3: To the solution obtained in stage G of the acid (559 mg, 1.4 mmol) in dichloromethane (5 ml) was added triethylamine (0,585 ml, 4.2 mmol) and 50%aqueous solution of hydroxylamine (0,925 ml, 14.0 mmol), and then hexaphosphate bromotris(pyrrolidino)phosphonium (Rouger®, 718 mg, 1.54 mmol). The solution was stirred for 4 h at ambient temperature. The solution was diluted with N2O and was extracted with dichloromethane. The organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography with reversed phase (silica gel, acetonitrile/N2Has received hydroxamate in a solid white color (140 mg, 25%). Elemental analysis: calculated for C21H22N2O5S: 60,85; N lower than the 5.37; N 6,76; S 7,74; found: 60,47; N To 5.35; N 6,61; S 7,46.

Stage I: To the solution obtained in stage 3 of hydroxamate (121 mg, 0,292 mmol) in methanol (2 ml), cooled to 0° C, was added acetylchloride (0,228 ml, 0,321 mmol) in meta is OLE (1 ml). After stirring for 30 min at ambient temperature the solution was concentrated in a stream of N2After trituration with diethyl ether has been specified in the title compound in the form of solid white (107 mg, 81%). Elemental analysis: calculated for C21H22N2About5S· Hcl· 0,3H2About: 55,27; N To 5.21; N 6,14; found: 54,90; N lower than the 5.37; N 6,07.

Example 7: Obtain N-[4-[[2-(hydroxyamino)-2-oxoethyl]sulfanyl]phenyl]benzamide

Stage A: To a suspension of 2-(4-aminophenylthio) acetic acid (20,00 g, 0,109 mmol) in methanol (100 ml), cooled to 0° C, was added dropwise thionyl chloride (24,0 ml, 0,327 mmol). Added another portion of methanol (100 ml) and the suspension was heated for 2 h to a temperature of reflux distilled. The solution was concentrated in vacuo and the residue was dissolved in N2O and neutralized with a saturated solution Panso3. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo was obtained methyl ester in the form of butter dark purple color (22,75 g, quantitative yield). Purity according to GHUR: 99%.

Stage B: To a solution containing obtained on the stage And methyl ether (5,00 g, 25,35 mmol) and triethylamine (7,07 ml, 50,70 mmol) in dichlo is methane (50 ml), added benzoyl chloride (3,24 ml, 27,89 mmol) and the solution was stirred for 2 h at ambient temperature. The solution was concentrated in vacuo and the residue was distributed between ethyl acetate, THF and N2O. the Organic layer was washed N2Oh, saturated NaCl and dried over Na2SO4. After concentration in vacuo received benzamid in a solid purple color (7,06 g, 92%). Purity according to GHUR: 98%. MS (CI) M+Li+: calculated for C16H15NO3S: 308 detected 308.

Stage b: To the solution obtained in stage B benzamide (of 4.00 g of 13.27 mmol) in THF (100 ml) and N2About (10 ml), cooled to 0° added Ohope® (monopersulfate potassium, 24,47 g, 39,81 mmol). The suspension was stirred overnight (about 18 hours) at ambient temperature. The mixture was filtered to remove the excess Ohope® and the filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with N2Oh, saturated NaCl and dried over Na2SO4. After concentration in vacuo received sulfon in a solid pink color (4.11 g, 93%). Purity according to GHUR: 98%. MS (CI) M+Li+: calculated for C16H15NO5S: 340 detected 340.

Stage G: To a solution obtained at the stage In sulfone (400 mg, 1.2 mmol) in THF (9 ml) was added 50%aqueous solution of hydroxy who amine (5.0 ml). The solution was stirred for 8 h and concentrated in vacuum. After trituration with hot diethyl ether has been specified in the title compound in the form of solids whitish (348 mg, 78%). Purity according to GHUR: 97%. MS (CI) MH+: calculated for C17H14N2O5S: 335 detected 335.

Example 8: Getting monohydrochloride N-[4-[[2-(hydroxyamino)-2-oxo-1-(piperidine-4-yl)ethyl]sulfonyl]phenyl]benzamide

Stage A: To a solution of diethanolamine (22,16 g, 0,211 mol) in THF (100 ml), cooled to 0° C, was added di-tert-BUTYLCARBAMATE (46,0 g, 0,211 mol) and the solution was stirred for 20 h at ambient temperature. The solution was concentrated in vacuo and the resulting residue was filtered through a pad of silica gel (5% methanol/95% dichloromethane)to give diol as a clear oil (45,06 g, quantitative yield). MS (CI) MH+: calculated for C9H19O4S: 206 detected 206.

Stage B: To a suspension of 2-(4-aminophenylthio)acetic acid (20,00 g, 0,109 mmol) in methanol (100 ml), cooled to 0° C, was added dropwise thionyl chloride (24,0 ml, 0,327 mmol). After adding another portion of methanol (100 ml) suspension for 2 h was heated to a temperature of reflux distilled. The mixture was concentrated in vacuo, the residue was dissolved in N2O and neutralized on Ishenim solution of NaHCO 3. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo was obtained methyl ester in the form of butter dark purple color (22,75 g, quantitative yield). Purity according to GHUR: 99%.

Stage b: To a solution containing obtained in stage B methyl ester (5,00 g, 25,35 mmol) and triethylamine (7,07 ml, 50,70 mmol) in dichloromethane (50 ml)was added benzoyl chloride (3,24 ml, 27,89 mmol) and the solution was stirred for 2 h at ambient temperature.

The solution was concentrated in vacuo and the residue was distributed between ethyl acetate, THF and N2O. the Organic layer was washed N2Oh, saturated NaCl and dried over Na2SO4. After concentration in vacuo received benzamid in a solid purple color (7,06 g, 92%). Purity according to GHUR: 98%.

Stage G: To the solution obtained in stage benzamide (of 4.00 g of 13.27 mmol) in THF (100 ml) and N2About (10 ml), cooled to 0° added Ohope® (24,47 g, 39,81 mmol). The suspension was stirred overnight (about 18 hours) at ambient temperature. The mixture was filtered to remove the excess Ohope® and the filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with N2Oh, saturated NaCl solution and dried over N is 2SO4. After concentration in vacuo received sulfon in a solid pink color (4.11 g, 93%). Purity according to GHUR: 98%.

Stage D: To a solution containing obtained on the stage And diol (of 1.03 g, 5.00 mmol) and obtained in stage g of methyl ester (2.00 g, 6,00 mmol) in THF (100 ml)was added 1,1’-(azodicarbon)dipiperidino (of 5.05 g, 20.00 mmol). To this suspension was added trimethylphosphine (20,00 ml, 1.0 M solution in THF, 20.00 mmol). The mixture was stirred for 1 h at ambient temperature, and then kept at 40° C for 18 hours, After cooling the suspension to ambient temperature was added diethyl ether and was removed by filtration of the insoluble solid particles. The filtrate was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate, washed with N2Oh, saturated NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received piperidine in the form of a solid yellow (600 mg, 24%). MS (CI) MN+: calculated for C25H30N2O7S: 503, 503.

Stage E: To the solution obtained in stage D of piperidine (950 mg, 1,89 mmol) in THF (10 ml) was added silanolate potassium (970 mg, 7.56 mmol) and the solution was stirred for 72 h at ambient temperature. The solution was washed N2Oh, was acidified using 1 M Hcl to pH 2 and extras who were garofali with ethyl acetate. The combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo got acid in a solid yellow color (772 mg, 84%).

Stage G: To a solution obtained in stage E acid (772 mg, 1.48 mmol) in DMF (9 ml) was added HOBT (240 mg, 1.77 mmol), 4-methylmorpholine (0,488 ml of 4.44 mmol), O-tetrahydropyranyloxy (538 mg, of 4.54 mmol) and EDC (397 mg, 2,07 mmol). The solution was stirred for 2 h at ambient temperature. After concentration in vacuo the residue was distributed between ethyl acetate and N2O. the Organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received-protected hydroxylamine in the form of a solid white color (608 mg, 70%). Purity according to GHUR: >99%.

Stage 3: To the solution obtained in stage G of the protected hydroxylamine (596 mg, 1.01 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4 M HCl in dioxane (2,50 ml, 10,14 mmol) and the solution was stirred for 50 min at ambient temperature. After trituration with diethyl ether there was obtained is listed in the title compound in the form of a solid white color (433 mg, 98%). Purity according to GHUR: 98%. MS (CI) MN+: calculated for C19H21N3About5S: 404 found 404.

Prima is 9: Getting monohydrochloride N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To a solution of utilisedictated (15.7 g, 0.1 mol) in THF (100 ml) dropwise over 20 min, the solution was added di-tert-BUTYLCARBAMATE (21.8 g, 0.1 mol) in THF (5 ml). The solution was stirred over night 15 (approximately 18 hours) at ambient temperature and then concentrated in vacuum, receiving light oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuum, obtaining the BOC-protected piperidine derived (26,2 g, quantitative yield) as a clear colorless oil.

Stage B: a Solution of 4-portifino (50,29 g, 390 mmol) in DMSO (500 ml) was heated for 6 h to 65° C. the Reaction was stopped with melting ice and the resulting solid was collected by vacuum filtration, getting disulfide in the form of a solid white color (34.4 g, 68,9%).

Stage b: To the solution obtained in stage a, the BOC-protected piperidino derivative (16 g, 62 mmol) in THF (300 ml), cooled to -50° C, was added diisopropylamide lithium (DAL) (41,33 ml, 74 mmol) and the solution was stirred for 1.5 h at 0° C. To this solution was added a disulfide obtained in stage B (15,77 g, 62 mmol) and the resulting solution was stirred for 20 h at ambient temperature. The reaction was stopped by addition of N2Oh and the solution was concentrated in VA is uume. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5 N. a solution of KOH, H2O and saturated NaCl solution. After chromatography (silica gel, hexane/ethyl acetate) received sulfide in the form of oil (18.0 g, 75%).

Stage G: To a solution obtained at the stage In sulfide (16.5 g, 43 mmol) in dichloromethane (500 ml), cooled to 0° C, was added 3-globerman-soyou acid (18.0 g, 86 mmol) and the solution was stirred for 20 hours the Solution was diluted with N2O and was extracted with dichloromethane. The organic layer is washed with 10%solution PA2SO3N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfon in the form of a solid (10.7 g, 60%).

Stage D: the Solution obtained in stage G of the sulfone (10 g, 24,0 mmol) in ethyl acetate (250 ml) was barbotirovany within 10 min of gaseous HCl, and then was stirred for 4 h at ambient temperature. After concentration in vacuo received amine hydrochloride in a solid white color (7,27 g, 86%).

Stage E: To the solution obtained in stage D amine hydrochloride (5,98 g of 17.0 mmol) in DMF (120 ml) was added potassium carbonate (4.7 g, 34,0 mmol), and then propylbromide (2,02 g of 17.0 mmol) and the solution was stirred for 4 h at ambient temperature. The solution distribution is whether between ethyl acetate and N 2Oh, the organic layer washed with N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received propargylamine in the form of a yellow oil (5.2 g, 86%).

Stage G: To a solution obtained in stage E of propargylamine in DMF (15 ml) was added thiophenol (0,80 ml, for 7.78 mmol) and s3(2,79 g, 8,56 mmol) and the solution was heated for 6 h to 70° C. the Solution was distributed between diethyl ether and N2O. the Organic layer was washed N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received S-phenoxyphenyl derived in the form of oil (1,95 g, 56%).

Stage C: the solution obtained in stage W S-phenoxyphenyl derived (1,81 g 4,06 mmol) in ethanol (21 ml) and N2O (3.5 ml) was added KOH (1,37 g, 24.5 mmol) and the solution was heated for 4.5 h to 105° C. the Solution was acidified with concentrated HCl to pH 1 and then concentrated, receiving acid in the form of a yellow residue, which was used without further purification (1,82 g).

Stage I: To a solution received in stage 3 acid (1,82 g 4,06 mmol) in acetonitrile (20 ml) was added O-tetrahydro-2H-Piran-2-alhydrogel (723 mg, 6,17 mmol) and triethylamine (of 0.67 ml, a 4.86 mmol). To this solution under stirring was added ED is (1.18 g, of 6.17 mmol) and the solution was stirred for 18 hours the Solution was distributed between H2O and ethyl acetate. The organic layer was washed N2Oh, a saturated solution of NaHCO3saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (1,32 g, 63%).

Stage: To the solution obtained at the stage And secure hydroxamate (9,65 g, to 18.7 mmol) in methanol (148 ml), cooled to 0° C, was added acetylchloride (4,0 ml, 56.2 mmol) and the solution was stirred for 45 min at ambient temperature. After concentration in vacuum and subsequent trituration with diethyl ether there was obtained is listed in the title compound in the form of a solid white color (8,10 g, 94%). MS (CI) MH+: calculated for C21H22N2O4S2: 431, found 431.

Example 10: Getting monohydrochloride 4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage E of example 9 propargylamine 10 (7.0 g, and 19.8 mmol) in DMF (30 ml) was added sesamol (5,52 g, 40 mmol) and potassium carbonate (5,52 g, 40 mmol) and the solution was heated for 48 h to 85° C. the Solution was distributed between ethyl acetate and N2O. the Organic is the second layer was dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of oil (9,38 g, quantitative yield).

Stage B: To the solution obtained at the stage And sulfide (2,72 g of 5.92 mmol) in ethanol (30 ml) and N2O (5 ml) was added potassium hydroxide (2.0 g, 36 mmol) and the solution was heated for 4 h to a temperature of reflux distilled. The solution was acidified to pH 3 using concentrated HCl. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile (30 ml). To the solution was added O-tetrahydro-2H-Piran-2-alhydrogel (1,05 g, 9.0 mmol), triethylamine (1 ml) and EDC (1,72 g, 9.0 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo, diluted with saturated solution of NaHCO3and were extracted with ethyl acetate. The organic layer was dried over magnesium sulfate.

After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of oil (2.86 g, 93%).

Stage b: To the solution obtained in stage B of protected hydroxamate (2.86 g, at 5.27 mmol) in methanol (40 ml) was added acetylchloride (1.13 g, 15.8 mmol) and the solution was stirred for 3 hours the Solution was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2On (HCl)) has been specified in the title compound in the form of solid white (2.2 g, 84%). MS (CI) MH+ : calculated for C22H22N2O7S: 459, found 459.

Example 11: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-(4-phenyl-1-piperidinyl)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution of Na (8,97 g, 390 mmol) in methanol (1 l) at 0° added 4-portifino (50 g, 390 mmol) and methylchloride (34,2 ml, 390 mmol) and the solution was stirred for 4 h at ambient temperature. The solution was filtered to remove salts and the filtrate was concentrated in vacuum, obtaining the sulfide as a colorless oil (75,85 g, 97%).

Stage B: To the solution obtained at the stage And sulfide (75,85 g, 380 mmol) in methanol (1 l) and H2O (100 ml) was added to Ohope® (720 g of 1.17 mol) and the solution was stirred for 2 hours, the Reaction mixture was filtered to remove excess salts and the filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with N2Oh, a saturated solution Panso3saturated NaCl solution and then dried over magnesium sulfate. After concentration in vacuo, got sulfon in a solid white color (82,74 g, 94%).

Stage b: To the solution obtained in stage B sulfone (28.5 g, 123 mmol) in N,N-dimethylacetamide (200 ml) was added potassium carbonate (37,3 g, 270 mmol), easy-bis(2-bromatology) ether (19.3 ml, 147 mmol), 4-dimethylaminopyridine (750 mg, 6 m is ol) and tetrabutylammonium bromide (1.98 g, 6 mmol) and the solution was stirred for 72 h at ambient temperature. The solution was poured into 1 N. HCl (300 ml) and the precipitate was collected by vacuum filtration. After recrystallization (ethyl acetate/hexane) received tetrahydropyrrolo derived in the form of a solid beige color (28,74 g, 77%).

Stage G: To a solution obtained at the stage In tetrahydropyrrolo derived (1,21 g, 4.0 mmol) in DMSO (10 ml) was added Cs2CO3(3,26 g, 10.0 mmol) and 4-phenylpiperidine (640 mg, 4.0 mmol) and the solution was heated for 2 h to 90° C. the Solution was diluted with N2O and was extracted with ethyl acetate. The organic layer was washed with 5%aqueous solution of KHSO4, a saturated solution of NaHCO3saturated NaCl solution and then dried over magnesium sulfate. After concentration in vacuo received amine in the form of a solid white color (1.2 g, 67%).

Stage D: To the solution obtained in stage g of amine (815 mg, of 1.84 mmol) in methanol (5 ml) and THF (5 ml) was added 50%aqueous NaOH solution (2 ml) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was diluted with H2O and acidified to pH 7. The precipitate was collected by vacuum filtration, getting acid in a solid white color (680 mg, 86%).

Stage E: To a solution obtained at the stage of the acid (620 mg, 1.44 mmol) in dichloromethane (10 ml) and DMF (3 ml) was added Rouger (810 mg, at 1.73 mmol), N-methylmorpholine (0.5 ml, 4.3 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (190 mg, of 1.59 mmol) and the solution was stirred for 4 h at ambient temperature. The solution was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with N2O and saturated NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (630 mg, 83%). MS (CI) MH+: calculated for C28H36N2About6S: 529 found 529.

Stage G: To a solution obtained in stage E protected hydroxamate (600 mg, to 1.14 mmol) in dioxane (1.5 ml) and methanol (1.5 ml) was added 4 N. HCl in dioxane (1.5 ml) and the solution was stirred for 2 h the Solution was poured into diethyl ether and the precipitate was collected by vacuum filtration, getting mentioned in the title compound in the form of a solid beige color (500 mg, 91%). MS (CI) M+Li+: calculated for C23H28N2O5S: 445, found 445.

Example 12: Obtain 1-acetyl-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 6 sulfone (2,75 g, 5.6 mmol) in THF (10 ml) and ethanol (10 ml) NaOH (2.25 g, 56 mmol) and the solution was heated to 70° C for 18 hours the Solution was concentrated in vacuo, the residue was dissolved in N2O and was extracted with diethyl ether. The aqueous solution was acidified to pH 2 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. After concentration in vacuo was obtained the crude acid solids. The acid solution in dichlormethane (6 ml) and triperoxonane acid (6 ml) was stirred for 1 h at ambient temperature. After concentration in vacuo received amine hydrochloride as a solid (2.3 g, quantitative yield).

Stage B: To the solution obtained in stage a of the amine hydrochloride (2.3 g, <5.6 mmol) in acetone (10 ml) and N2About (10 ml), cooled to 0° C, was added triethylamine (1,17 ml, 8.4 mmol) and acetylchloride (of 0.60 ml, 8.4 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo to remove acetone and the aqueous solution was extracted with diethyl ether. The aqueous solution was acidified to pH 2 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and after concentration under vacuum was obtained N-acetyl derivative in a solid white color (1.5 g, 65.2 percent).

Stage b: To the solution obtained in stage B of N-acetyl producing the CSO (0.6 g, for 1.49 mmol) in DMF (10 ml) was added EDC (401 mg, 2.1 mmol), and then 50%aqueous solution of hydroxylamine (0.9 ml) and 4-methylmorpholine (0.7 ml, 6.4 mmol)and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed N2O and dried over magnesium sulfate. After chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified in the title compound in the form of solid white (101 mg, 16%). MS (CI) MH+: calculated for C20H22N2O6S: 419, found 419.

Example 13: Getting monohydrochloride 4-[[4-(cyclohexylthio)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage E of example 9 propargylamine (6.5 g, 18.4 mmol) in DMF (10 ml) was added potassium carbonate (3,81 g, 27.6 mmol) and cyclohexylurea (3,37 ml, 27.6 mmol). The solution was heated for 6.5 h to 100° C. the Solution was diluted with N2O and was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of a yellow oil (6,05 g, 73%).

Stage B: To the solution obtained at the stage And sulfide (612 mg, 1.4 mmol) in ethanol (8,4 ml) and N2On (1,4 ml) EXT is ulali potassium hydroxide (470 mg, 8.4 mmol) and the solution boiled under reflux for 3 h the Solution was acidified to pH 3 and concentrated in vacuum. The residue was dissolved in acetonitrile (10 ml) and to this solution was added O-tetrahydro-2H-Piran-2-alhydrogel (230 mg, 2.0 mmol) and triethylamine (0.5 ml), and then EDC (380 mg, 2.0 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was diluted with saturated solution of NaHCO3and were extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of oil (246 mg, 34%).

Stage b: To the solution obtained in stage B of protected hydroxamate (246 mg, 0.47 mmol) in methanol (4 ml) was added acetylchloride (of 0.11 ml, 1.5 mmol) and the solution was stirred for 3 h at ambient temperature. After concentration in vacuo and chromatography with reversed phase (silica gel, acetonitrile/N2On(HCl)) has been specified in the title compound in the form of solid white (223 mg, quantitative yield).

Example 14: Getting monohydrochloride N-hydroxy-1-methyl-4-[(phenoxyphenyl)sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 6 sulfone (2.67 g, 5.5 mm is l) in dichloromethane (5 ml) was added triperoxonane acid (5 ml) and the solution was stirred for 2 h at ambient temperature. The solution was concentrated in vacuo and the residue triturated with diethyl ether, obtaining the crude triptorelin Amin. To a solution of the crude trifenatate amine in methanol (10 ml) was added formaldehyde (37%aqueous solution, 2.0 ml, 27.5 mmol) and branfireun (2.2 ml, 22 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with N2O and dried over magnesium sulfate. After concentration in vacuo was obtained N-methyl derivative in the form of a yellow oil (2.17 g, 98%).

Stage B: To the solution obtained at the stage And N-methyl derivative (2.17 g, 5.4 mmol) in ethanol (10 ml) and THF (10 ml) was added NaOH (2.0 g, 50 mmol) and the reaction mixture was stirred for 18 h at -65° C. the Solution was concentrated in vacuum. The residue was dissolved in N2O and was extracted with diethyl ether. The aqueous solution was acidified to pH 2 and the resulting solid was collected by vacuum filtration, getting acid in a solid white color (1.8 g, 90%).

Stage b: To the solution obtained in stage B acid (0.5 g, 1.3 mmol) in DMF (10 ml) was added EDC (1.06 g, 5.5 mmol), and then O-tetrahydro-2H-Piran-2-alhydrogel (490 mg, 4.2 mmol) and 4-methylmorpholine (0,76 ml) and the solution was stirred for 18 h at ambient temperature. Astor was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed N2O and dried over magnesium sulfate. After concentration in vacuo was obtained the crude protected hydroxamate. To a solution of crude hydroxamate in methanol (10 ml) was added acetylchloride (of 0.28 ml, 3.9 mmol) and the solution was stirred for 3 h at ambient temperature. The solution was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2(Of 0.0125% HCl)) has been specified in the title compound in the form of solid white (261 mg, 46%). MS (CI) MH+: calculated for C19H22N2S: 391, found 391.

Example 15: Getting monohydrochloride N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage E of example 9 propargylamine (2.00 g, to 5.66 mmol) in DMF (10 ml) was added cesium carbonate (4.7 g, 14.5 mmol) and 4-methoxythiophene (1.80 g, 14.5 mmol) and the solution was heated for 24 h to 95° C. the Solution was diluted with ethyl acetate and washed with 1 N. NaOH and saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received phenoxypropane in a solid white color (2.67 g, quantitative yield).

Stage B: To the solution obtained at the stage And phenoxypropanol (2,40 g's, 5.25 mmol)in which canola (30 ml) and N 2O (6 ml) was added potassium hydroxide (2.0 g, 31,37 mmol) and the solution was heated to the temperature of reflux distilled for 4 hours the Solution was acidified with concentrated HCl to pH 3 and the residue was collected by vacuum filtration, obtaining the crude acid, which was used without further purification.

Stage b: To the solution obtained in stage B acid (2.25 g, a 5.25 mmol) in acetonitrile (30 ml) was added triethylamine (1 ml) and O-tetrahydro-2H-Piran-2-alhydrogel (1,34 g, 9.0 mmol). After stirring the solution for 15 min was added EDC (1,72 g, 9.0 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. An ethyl acetate solution was washed with saturated NaHCO3N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (0,93 g, 33%).

Stage G: To a solution obtained at the stage In protected hydroxamate (0,93 g, 1.7 mmol) in methanol (15 ml) was added acetylchloride (0,36 ml, 5.1 mmol) and the solution was stirred for 3 hours the Solution was concentrated in vacuum, obtaining mentioned in the title compound in the form of a solid white color (650 mg, 82%). Elemental analysis: calculated for C22H24N2AboutHCl: 54,84; N 5,24; N Of 5.82; S 6,67; Cl to 6.67; found: 53,10; N 5,07; N 5,59; S? 7.04 baby mortality; Cl 6,32.

Example 16: Getting monohydrochloride 4-[[4-(4-butoxy-1-piperidinyl)phenyl]sulfonyl]-tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 11 tetrahydropyrrolo derived (1,95 g, 6,46 mmol) in dimethyl sulfoxide (DMSO, 25 ml) was added Cs2CO3(7,4 g, and 22.6 mmol) and 4-butoxyphenyl (1,25 g, 6,46 mmol) and the solution was heated for 1 h to 90° C. the Reaction solution was stopped by the addition of N2O and was extracted with ethyl acetate. The organic layer was washed with 5%aqueous solution of KHSO4, a saturated solution Panso3saturated NaCl solution and then dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/dichloromethane) received amine as yellow oil (1.85 g, 65%).

Stage B: To the solution obtained at the stage And amine (1.65 g, 3,76 mmol) in THF (10 ml) was added trimethylsilanol potassium (530 mg, 4,13 mmol) and the solution was stirred for 22 h at ambient temperature. The solution was concentrated in vacuo and the crude residue was used in subsequent reactions without further purification.

Stage b: To the solution obtained in stage B of the crude acid (1,74 g, 3,76 mmol) in dichloromethane (10 ml) was added Rouge is (2.10 g, 4,51 mmol), N-methylmorpholin (1,24 ml, 11.3 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (484 mg, 4.14 mmol)and the solution was stirred for 30 min at ambient temperature. The solution was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane/methanol) received protected hydroxamate in the form of a colorless oil (1.5 g, total yield in two stages 76%).

Stage G: To a solution obtained at the stage In protected hydroxamate (1,25 g, 2.4 mmol) in dioxane (3 ml) was added 4 n HCl solution in dioxane (3 ml) and the solution was stirred for 15 minutes After adding methanol (3 ml) solution was stirred for 5 h at ambient temperature. The solution was poured into diethyl ether and the precipitate was collected by vacuum filtration, getting mentioned in the title compound in the form of a solid white color (1.0 g, 88%). MS (CI) MH+: calculated for C21H32N2About6S: 441 detected 441.

Example 17: Getting monohydrochloride 1-cyclopropyl-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage D of example 6 amine hydrochloride (2,13 g, 5.0 mmol) in methanol (25 ml) was added molecular the sieve size 3E, acetic acid (2,86 ml, 50 mmol) and the solution was stirred for 5 minutes To this solution was added(1-ethoxysilane)oxy)trimethylsilane (between 6.08 ml, 30 mmol), and then lambrogini sodium (1,41 g of 22.0 mmol) and the solution was heated to the temperature of reflux distilled within 18 hours the Excess salts and molecular sieves was collected by filtration and the filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate and washed with 1 N. NaOH solution, N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received cyclopropylamine in a solid white color (1.90 g, 86%).

Stage B: To the solution obtained in stage a of cyclopropylamine (1.9 g, 4.2 mmol) in THF (12 ml) and ethanol (12 ml) was added NaOH (1,71 g, 4.3 mmol) in N2About (10 ml) and the solution for 20 h was heated to 62° C. the Solution was concentrated in vacuo, the residue was diluted with H2O and acidified 1 N. HCl solution to pH 5. The resulting solid was collected by vacuum filtration, getting acid in a solid white color (1,49 g, 82%). MS (CI) MH+: calculated for C21H23NO5S: 402 detected 402. Msvr: calculated for C21H23NO5S: 402,1375 found 402,1350.

Stage b: To the solution obtained in stage B acid (1,49 g, 3.4 mmol) in dichloromethane (50 ml) was added triethylene is (of 1.42 ml, of 10.21 mmol), and then 50%aqueous solution of hydroxylamine (2.25 ml, 34,0 mmol) and Rouger (3,17 g, 6.8 mmol)and the solution was stirred for 72 h the Mixture was diluted with H2Oh, the organic layer was separated, washed with saturated NaCl solution and dried over magnesium sulfate. After concentration in vacuum and subsequent chromatography with reversed phase (silica gel, acetonitrile/N2Has received hydroxamate.

The hydrochloride was obtained by dissolving the free base (830 mg, 2.0 mmol) in methanol (20 ml) followed by the addition of acetylchloride (0.17 ml, 2.0 mmol). The solution was stirred for 10 min at 0° C. the Formed solid was collected by vacuum filtration and washed with cold diethyl ether, obtaining mentioned in the title compound (595 mg, 66%). Msvr: calculated for C21H24N2About5S: 416,1407 found 416,1398. Elemental analysis: calculated for C21H24N2O5S: 55,68; 5,56 N; N 6,18; S 7,08; CL 7,83; found: 55,39; N 5,72; N 6,15; S 7,29; CL 8,17.

Example 18: Obtain N-hydroxy-1-(methylsulphonyl)-4-(phenoxyphenyl)sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage D of example 6 amine hydrochloride (1.06 g, 2.5 mmol) in dichloromethane (10 ml) was added triethylamine (from 0.76 ml, 5.5 mmol) and methanesulfonamide (0,23 ml, 3.0 mmol) and the solution is PE is amasyali for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was distributed between ethyl acetate and N2O. the Organic layer was washed N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received methanesulfonamide in the form of a solid (2.1 g, 58%).

Stage B: To the solution obtained in stage a of methanesulfonamide (2.0 g, 4,15 mmol) in ethanol (12 ml) and N2O (12 ml) was added NaOH (1.66 g, 41.5 mmol) and the solution was heated for 18 h to 65° C. the Solution was concentrated in vacuum and the remaining aqueous solution was acidified to pH 4. The solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After concentration in vacuo got acid in the form of a yellow foam (1,46 g, 80%).

Stage b: To the solution obtained in stage B acid (1,46 g, to 3.38 mmol) in dichloromethane (50 ml) was added triethylamine (1,41 ml, 10.1 mmol), 50%aqueous solution of hydroxylamine (2.2 ml, 33.8 mmol) and Rouger (3,16 g, 6,76 mmol)and the solution was stirred for 72 h at ambient temperature. The solution was diluted with N2Oh, the organic layer was separated, washed with saturated NaCl solution and then dried over magnesium sulfate. After chromatography with reversed phase (silica gel, acetonitrile/N2O) and subsequent trituration with diethyl ether, the m has been specified in the title compound in the form of a solid white color (160 mg, 11%). Elemental analysis: calculated for C19H22N2O7S2: 50,21; N 4,88; N 6,16; S 14,11; found: 48,72; N Are 5.36; N 5,61; S 12,81.

Example 19: Obtaining monohydrochloride 4-[[4-(cyclohexylthio)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 9 sulfone (10.1 g, 24,0 mmol) in DMF (20 ml) was added To a2CO3(5.0 g, 36,0 mol) and cyclohexylurea (4,4 ml, 36,0 mmol) and the solution was heated for 6.5 h to 85° C. the Solution was distributed between ethyl acetate and N2O. the Organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of oil (8.2 g, 67%).

Stage B: To a solution of sulfide (2,32 g, 4.5 mmol) in ethanol (10 ml) and THF (10 ml) was added NaOH (1,81 g, 45 mmol) in N2About (10 ml) and the solution was heated for 18 h to 65° C. the Solution was concentrated in vacuo and the aqueous residue was acidified to pH 2. The solution was extracted with dichloromethane and dried over magnesium sulfate. After concentration in vacuo got acid in a solid white color (830 mg, 38%).

Stage b: To the solution obtained in stage B acid (2.0 g, 4.0 mmol) in dichloromethane (25 ml) was added N-methylmorpholine (1,32 ml of 12.0 mmol), Rouger (2,12 g, 2,12 mmol) and 50%aq is th solution of hydroxylamine (2,6 ml, 40 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was diluted with N2O and the layers were separated. The organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/methanol) received hydroxamate in a solid white color (1.4 g, 70%).

Stage G: the Solution obtained at the stage At hydroxamate (1.31 g, 2,63 mmol) in ethyl acetate (70 ml), cooled to 0° was barbotirovany gaseous HCl for 30 minutes the Solution was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2On(Hcl)) has been specified in the title compound in the form of solid white (378 mg, 33%). Elemental analysis: calculated for C18H26N2O4S2: 49,70; N. Of 6.26; N 6,44; S 14,74; Cl 8,15; found: 48,99; N 6,34; N 6,24; S 14,66; Cl 8,56.

Example 20: Obtaining dihydrochloride tetrahydro-N-hydroxy-4-[[4-(4-phenyl-1-piperazinil)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 11 tetrahydropyrrolo derived (1,96 g, 6.5 mmol) in DMSO (20 ml) was added Cs2CO3(4.9 g, 15 mmol) and 4-phenylpiperazin (1.1 g, 7,15 mmol) and the solution was heated for 45 min to 90° C. the Reaction was stopped by addition of N2Oh and the mixture extragear the Vali with ethyl acetate. The organic layer was washed with 5%aqueous solution of KHSO4, a saturated solution Panso3saturated NaCl solution and then dried over magnesium sulfate. After concentration in vacuo, got amine in the form of a solid beige color (1.7 g, 59%).

Stage B: To the solution obtained at the stage And amine (1.5 g, to 3.38 mmol) in THF (20 ml) was added trimethylsilanol potassium (480 mg, 3.72 mmol) and the solution was stirred for 22 h at ambient temperature. After concentration in vacuo was obtained the crude acid additive salt, which can be used in the next stage without purification.

Stage b: To the solution obtained in stage B of acid additive salt (1,58 g, to 3.38 mmol) in dichloromethane (10 ml) and DMF (3 ml) was added Rouger (1.89 g, 4,06 mmol), N-methylmorpholine (1.1 ml, 10.1 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (435 mg, 3.72 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was distributed between ethyl acetate and N2Oh, the organic layer washed with N2O and saturated NaCl and then dried over Na2SO4. After chromatography (silica gel, dichloromethane/methanol) received protected hydroxamate in the form of a white foam (1.7 g, total yield in two stages 95%).

Stage G: To a solution obtained at the stage To secure the CSOs of hydroxamate (1.28 g, 2.4 mmol) in dioxane (5 ml) and methanol (5 ml) was added 4 N. HCl in dioxane (5 ml) and the solution was stirred for 2 h at ambient temperature. The solution was poured into diethyl ether and the precipitate was collected by vacuum filtration, getting mentioned in the title compound in the form of a solid white color (900 mg, 73%). MS (CI) MN+: calculated for C22H27N3O5S: 446 detected 446.

Example 21: Getting monohydrochloride 4-[[4-(cyclohexylthio)phenyl]sulfonyl]-1-cyclopropyl-N-hydroxy-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 9 sulfone (10.1 g, 24,0 mmol) in DMF (20 ml) was added To a2CO3(5.0 g, 36,0 mol) and cyclohexylurea (4,4 ml, 36,0 mmol) and the solution was heated for 6.5 h to 85° C. the Solution was distributed between ethyl acetate and N2O. the Organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of oil (8.2 g, 67%).

Stage B: the Solution obtained at the stage And sulfide (8,2 g of 17.0 mmol) in ethyl acetate (100 ml), cooled to 0° was barbotirovany within 30 min of gaseous HCl. The solution was concentrated in vacuum, obtaining the amine in the form of a solid white color (of 5.99 g, 79%). MS (CI) MH+: calculated for C 20H29NO4S: 412 detected 412.

Stage b: To the solution obtained in stage B amine (2.24 g, 5.0 mmol) in methanol (20 ml) was added acetic acid (2,86 ml, 50 mmol), and then (1-amoxicilpin)axithromycin (6,03 ml, 30 mmol) and borohydride sodium (1,41 g of 22.5 mmol) and the solution boiled under reflux for 18 hours the Solution was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 1N. NaOH solution, N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received cyclopropylamine in a solid white color (1.97 g, 87%).

Stage G: To a solution obtained at the stage In cyclopropylamine (1.9 g, 4.2 mmol) in ethanol (10 ml) and THF (10 ml) was added NaOH (1.68 g, 42.0 mmol) in N2About (10 ml) and the solution was heated for 18 h to 68° C. the Solution was concentrated in vacuo and the aqueous residue was acidified to pH 2. Collected the resulting solid was washed with diethyl ether, receiving acid in a solid white color (1,61 g, 81%). Msvr: calculated for C21H29NO4S2: 424,1616 found 424,1615.

Stage D: To the solution obtained in stage G of the acid (1,61 g, 3.0 mmol) in dichloromethane (30 ml) was added N-methylmorpholine (1.0 g, 9.0 mmol), Rouger (1.54 g, 3.3 mmol) and 50%aqueous solution of hydroxylamine (2.0 ml, 30 IMO the b) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuum. The residue was distributed between ethyl acetate and N2Oh, the organic layer washed with N2O and saturated NaCl solution and dried over magnesium sulfate. After filtration through a pad of silica (ethyl acetate/methanol) received hydroxamate in a solid white color (1.07 g, 80%).

Stage E: To the solution obtained in stage D of hydroxamate (1.07 g, 2.4 mmol) in cold methanol (2 ml) was added acetylchloride (0,27 ml, 3.6 mmol) and the solution was stirred for 30 minutes the Solution was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2On(HCl)) has been specified in the title compound in the form of a solid white color (245 mg, 21%).

Example 22: Obtaining monohydrochloride 4-[[4-[(4-forfinal)thio]phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 9 sulfone (6.0 g, 14.4 mmol) in DMF (30 ml) was added potassium carbonate (2,39 mg, 17.3 mmol) and 4-portifino (3.0 ml, 28.1 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was diluted with ethyl acetate and washed with 1 N. NaOH solution and with saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of solid substances is STV (6.6 g, 87%).

Stage B: To the solution obtained at the stage And sulfide (6.6 g, 12.6 mmol) in ethanol (90 ml) and N2O (20 ml) was added sodium hydroxide (5,04 g, 126 mmol) and the solution was kept for 18 h at 70° C. the Mixture was acidified to pH 4 and the solution was extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/ethanol) was obtained acid as a solid (4.8 g, 79%).

Stage b: To the solution obtained in stage B acid (4.8 g, 10.0 mmol) in DMF (30 ml) was added 4-methylmorpholine (3.03 g, 30.0 mmol), and then O-tetrahydro-2H-Piran-2-alhydrogel (7,45 g, 50.0 mmol) and Rouger (5,59 g, 12,0 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with N2O and saturated NaCl and then dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (4.0 g, 67%).

Stage G: the Solution obtained in stage G of protected hydroxamate (4.0 g, 6.7 mmol) in ethyl acetate (120 ml) was barbotirovany within 5 min of gaseous HCl, and then was stirred for 1.5 h at ambient temperature. The resulting solid was collected by vacuum filter is iej, getting listed in the title compound in the form of a solid white color (1.90 g, 64%). MS (CI) MH+: calculated for C18H19N2O4S2F: 411 detected 411.

Example 23: obtain the dihydrochloride of N-hydroxy-4-[[4-[4-(1H-imidazol-1-yl)phenoxy]phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage E of example 9 amine hydrochloride (3.00 g, 8,49 mmol) in DMF (13 ml) was added To a2CO3(2.35 g, 17,0 mmol) and 4-(imidazol-1-yl)phenol (2,72 g of 17.0 mmol) and the solution was heated for 64 h to 85° C. the Solution was concentrated in vacuo and the residue was distributed between ethyl acetate and N2O. the Organic layer was washed N2O and saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, chloroform/methanol) received complex ethyl ester as white foam (2,36 g, 56%).

Stage B: To the solution obtained in stage a complex ethyl ester (2,36 g, 5.33 mmol) in ethanol (2.8 ml) and N2(4.6 ml) was added KOH (1.80 g, 32.1 mmol) and the solution was heated for 4.5 h to 100° C. the Solution was acidified with concentrated HCl to pH 1 and then concentrated, receiving acid in the form of a solid reddish-brown color, which was used without further purification (2.87 in).

The study is In: To the solution obtained in stage B acid (2,87 g, 5.33 mmol) in acetonitrile (24 ml) was added O-tetrahydro-2H-Piran-2-alhydrogel (870 mg, 7,45 mmol), EDC (1,43 g, 7,45 mmol) and N-methylmorpholin (to 1.21 ml, 11.0 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated and the residue was diluted with H2O and was extracted with ethyl acetate. The organic layer was washed N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (chloroform/methanol) received-protected hydroxylamine in the form of a solid white color (1,62 g, 53%).

Stage G: To a solution obtained at the stage In a protected hydroxylamine (1.60 g, and 2.83 mmol) in methanol (23 ml) was added acetylchloride (and 0.61 ml, charged 8.52 mmol) and the solution was stirred for 1 h the Solution was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2On (HCl)) has been specified in the title compound in the form of solid white (975 mg, 62%). MS (Cl) MH+: calculated for C24H25N4O5S: 481, found 481. Elemental analysis: calculated for C24H25N4O5S· HCl: 52,08; N To 4.73; N 10,12; S 5,79; Cl 12,81; found: 51,59; N 4,84; N Of 10.93; S 5,51; Cl 11,98.

Example 24: Getting monohydrochloride 4-[[4-(4-forfinal)thiophenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

The study is A: To the solution obtained in stage E of example 9 propargylamine (4,06 g, 11,49 mmol) in DMF (20 ml) was added potassium carbonate (3,18 g, 22.98mm mmol) and 4-portifino (2,95 g, 22.98mm mmol) and the solution was stirred for 18 h at ambient temperature. The solution was diluted with ethyl acetate, washed with 1N. NaOH and saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of solids (4,46 g, 84%).

Stage B: To the solution obtained at the stage And sulfide (4,46 g, 9.7 mmol) in tetrahydrofurane (90 ml), N2O (30 ml) and ethanol (30 ml) was added NaOH (3,86 g, 97,0 mmol) and the solution was heated for 2 h to 65° C. the Solution was concentrated in vacuo and the residue was dissolved in N2O and acidified 2 N. HCl to pH 4. The resulting residue was collected by vacuum filtration, getting acid in a solid white color (4.0 g, 95%).

Stage b: To the solution obtained in stage B acid (4.0 g, 9.2 mmol) in DMF (50 ml) and 4-methylmorpholine (2.8 g, 27.7 mmol) was added O-tetrahydro-2H-Piran-2-alhydrogel (6,88 g of 46.1 mmol) and Rouger (5,16 g, 11.1 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroc the Amat in a solid white color (2.8 g, 56%).

Stage G: the Solution obtained at the stage In the protected amine (2.8 g, 5.1 mmol) in ethyl acetate (100 ml) was barbotirovany within 10 min of gaseous HCl and the solution was stirred for 1 h the Solution was concentrated in vacuum and the solid was recrystallized (ethanol), getting mentioned in the title compound in the form of a solid white color (1.12 g, 45%). MS (CI) MH+: calculated for C21H21N2O4S2F: 449, found 449.

Example 25: Obtain 4-[[4-[(4-chlorophenyl)thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 11 tetrahydropyrrolo derived (8.0 g, of 26.5 mmol) in THF (250 ml) was added trimethylsilyl potassium (10,2 mg, 79.5 mmol) and the solution was stirred for 1.5 hours the Reaction was stopped by addition of N2Oh, the solution was acidified to pH 2.5 and the solution was extracted with ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo was awarded an acid additive salt in a solid white color (5,78 g, 76%).

Stage B: To the solution obtained at the stage And the acid additive salt (5.4 g, to 18.7 mmol) in DMF (35 ml) was added HOBT (3.04 from g to 22.5 mmol), N-methylmorpholin (6.2 ml, 56.2 mmol), O-tetrahydro-2H-Piran-2-algidras the Lamin (6.8 g, to 58.1 mmol) and EDC (5.0 g, 26,2 mmol) and the solution was stirred for 3 h at ambient temperature. The solution was concentrated in vacuo, the residue was distributed between ethyl acetate and N2O and the organic layer washed with 5%aqueous solution of KHSO4N2Oh, a saturated solution Panso3saturated NaCl solution and then dried over Na2SO4. After concentrated in vacuo received protected hydroxamate in a solid white color (6,34 g, 87%).

Stage b: To a solution of para-chlorothiophenol (2,71 g, to 18.7 mmol) in DMF (10 ml) was added To a2CO3(2.6 g, to 18.7 mmol), and then obtained at stage B protected hydroxamate (2.9 g, 7.5 mmol) and the solution was kept for 5 h at 75° C. the Solution was concentrated in vacuo, the residue was distributed between ethyl acetate and N2Oh, the organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane/methanol) received sulfide in the form of a white foam (of 3.56 g, 93%). MS (CI) MH+: calculated for C23H26ClNO6S2: 512 detected 512.

Stage G: To a solution obtained at the stage In sulfide (3.5 g, 6.8 mmol) in dioxane (10 ml) was added 4n. a solution of HCl in dioxane (10 ml). After stirring for 10 min was added for 1 h with continuous stirring methanol (10 ml). Astor concentrated in vacuum. After recrystallization (acetone/hexane) has been specified in the title compound in the form of a solid white color (2.4 g, 83%). MS (CI) MH+: calculated for C18H18lN5S: 428, found 428.

Example 26: Obtaining monohydrochloride tetrahydro-N-hydroxy-4-[[4-[4-(1H-1,2,4-triazole-1-yl)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage B of example 25 protected carboxamide (2.9 g, 7.5 mmol) in DMF (10 ml) was added 4-(1,2,4-triazole-1-yl)phenol (2,47 g, 15 mmol) in DMF (5 ml), and then Cs2CO3(7,33 g of 22.5 mmol)and the solution was kept at 95° C for 5 h the Solution was concentrated in vacuo and the residue was distributed between ethyl acetate and N2O. the Organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane/methanol) received phenol in the form of a solid white color (3,16 g, 80%).

Stage B: To the solution obtained at the stage And phenol (2.8 g, 5.3 mmol) in dioxane (10 ml) was added 4n. a solution of HCl in dioxane (10 ml). After stirring for 5 min was added methanol (10 ml) and stirring was continued for 1 h Then the solution was poured into diethyl ether and the precipitate was collected by vacuum filtration, getting solid white (2,44 g, 96%)MS (CI) MN +: calculated for C20H20N4About6S:445, found 445.

Example 27: Obtaining monohydrochloride 1-cyclopropyl-4-[[4-[(4-forfinal)thio]phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: the Solution obtained in stage G of example 9 sulfide (7,06 g, 13.5 mmol) in ethyl acetate (150 ml) was barbotirovany within 7 min of gaseous HCl and the solution was stirred for 15 min at 0° C. the Solution was concentrated in vacuum, obtaining the amine in the form of a solid white color (to 6.43 g, quantitative yield).

Stage B: To the solution obtained at the stage And amine (6.4 g, a 13.9 mmol) in methanol (65 ml) was added acetic acid (of 7.96 ml, 139 mmol) and a portion of the molecular sieves size IS included in the weighing boat. To this mixture was added (1-amoxicilpin)axithromycin (16,8 ml, 84 mmol), and then lambrogini sodium (3,9 g, 62 mmol). The solution was heated to the temperature of reflux distilled for 6 hours the Solution was filtered and the filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with N2Oh, 2n. NaOH, saturated NaCl solution and dried over magnesium sulfate. After filtration through a pad of silica (hexane/ethyl acetate) received cyclopropylamine in a solid white color (of 6.49 g, quantitative yield).

Stage b: To a solution of the obtained n the stage B cyclopropylamine (6.4 g, of 13.8 mmol) in ethanol (30 ml) and THF (30 ml) was added NaOH (5.5 g, 138 mmol) in N2O (23 ml) and the solution was heated for 12 h to 65° C. the Solution was concentrated in vacuum and the aqueous layer was acidified using 2n. HCl to pH 2. The resulting white precipitate was collected by filtration, getting acid in a solid white color (5,2 g, 97%). MS (CI) MH+: calculated for C21H22NO4S2F: 436, found 436.

Stage G: To a solution obtained at the stage In the acid of 2.27 g, 5.2 mmol) in DMF (60 ml) was added HOBT (845 mg, 6.2 mmol)and then N-methylmorpholine (1,71 ml, 15.6 mmol), EDC (1.40 g, 7,28 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (913 mg, 7.8 mmol) and the solution was stirred for 72 h at ambient temperature. The solution was concentrated in vacuo, the residue was dissolved in dichloromethane and washed with N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (1,95 g, 70%).

Stage D: To the solution obtained in stage G of protected hydroxamate (3.2 g, 6.0 mmol) in cold methanol (100 ml) was added acetylchloride (1.3 ml, 18.0 mmol) in methanol (30 ml) and the solution was stirred for 4 h at ambient temperature. The solution was concentrated in vacuo and the residue triturated with diethyl ether, the floor of the tea mentioned in the title compound in the form of a solid white color (2.86 g, 98%). MS (CI) MH+: calculated for C21H23N2O4S2F: 451 detected 451. Elemental analysis: calculated for C21H23N2O4S2F· 0,25N2About· HCl: 51,32; N 5,02; N 5,70; S Of 13.05; Cl 7,21; found: 50,99; N 4,91; N 5,65; S 13,16; Cl 7,83.

Example 28: Obtaining monohydrochloride N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propenyl)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage D of example 9 amine hydrochloride (4,78 g to 10.8 mmol) in DMF (25 ml) was added To a2CO3(2,98 g, 21.6 mmol) and allylbromide (0,935 ml, about 10.8 mmol) and the solution was stirred for 5 h at ambient temperature. The residue was distributed between ethyl acetate and N2Oh, the organic layer washed with N2O and saturated NaCl solution and dried over magnesium sulfate. After filtration through a pad of silica (hexane/ethyl acetate) received allylamine in the form of oil (4,80 g, quantitative yield).

Stage B: To the solution obtained at the stage And allylamine (4.8 g, the 10.8 mmol) in ethanol (25 ml) and THF (25 ml) was added NaOH (4.3 g, 108 mmol) in N2O (20 ml) and the solution was heated for 18 h to 65° C. the Solution was concentrated in vacuo and diluted with N2O. the Aqueous solution was acidified to pH 3. The precipitate was collected by vacuum filtration, getting acid in the de solid beige color (4.1 g, 84%). MS (Cl) MH+: calculated for C21H23NO4S2: 418 detected 418.

Stage b: To the solution obtained in stage B acid (4.1 g, 9.0 mmol) in DMF (90 ml) was added HOBT (1,46 g, 11.0 mmol)and then N-methylmorpholine (2,97 ml, 2.7 mmol), O-tetrahydro-2H-Piran-2-alhydrogel (1,58 g, 13.5 mmol) and EDC (2,42 g, 13,0 mmol) and the solution was stirred for 72 h, the Solution was concentrated in vacuum. The residue was dissolved in dichloromethane and washed with N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/methanol) received-protected hydroxylamine in the form of a solid white color (4.11 g, 88%).

Stage G: To a solution obtained at the stage In a protected hydroxylamine (4.11 g, 8.0 mmol) in ethyl acetate (100 ml), cooled to 0° C, was added acetylchloride (1,71 ml of 24.0 mmol) and the solution was stirred for 4 h at ambient temperature. The solution was concentrated in vacuum and after trituration with diethyl ether, obtaining mentioned in the title compound in the form of a solid white color (3,53 g, 95%). Elemental analysis: calculated for C21H24N4O4S2·HCl· 0,5H2About: 52,76; N. Of 5.48; N 5,86; S 13,42; Cl 7,42; found: 52,57; N 5,69; N 6,29; S 12,59; Cl 7,80.

Example 29: Obtaining monohydrochloride 1-cyclopropyl-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-is piperidinecarboxylate

Stage A: the Solution obtained in stage D of example 6 amine hydrochloride (2,13 g, 5.0 mmol) in DMF (10 ml) was added To a2CO3(1.4 g, 10.0 mmol) and bromelicola (of 0.48 ml, 5.0 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was distributed between ethyl acetate and N2Oh, the organic layer washed with N2O and saturated NaCl and then dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received cyclopropanemethylamine in the form of solids (2,09 g, 91%).

Stage B: To the solution obtained in stage a of cyclopropanemethylamine (2.0 g, 4.4 mmol) in ethanol (12 ml) and THF (12 ml) was added NaOH (1.75 g, 44 mmol) in N2About (10 ml) and the solution was heated for 18 h to 65° C. the Solution was concentrated in vacuo and the aqueous residue was acidified to pH 5. The precipitate was collected by vacuum filtration, getting acid in a solid white color (1,58 g, 79%). Msvr: calculated for C22H25NO5S: 414,1375 found 414,1334.

Stage b: To the solution obtained in stage B acid (1,58 g, 3.5 mmol) in dichloromethane (50 ml) was added triethylamine (of 1.46 ml, 10.5 mmol), and then 50%aqueous solution of hydroxylamine (2.3 ml, 35 mmol) and Rouger (3,26 g of 6.99 mmol) and the solution was stirred for 72 h at a temperature of environment is environment. The solution was washed N2Oh, saturated NaCl solution and dried over magnesium sulfate. After chromatography with reversed phase (silica gel, acetonitrile/N2Has received hydroxamate in a solid white color (3.2 g, quantitative yield).

Stage G: To a solution obtained at the stage At hydroxamate (1.5 g, 3.5 mmol) in cold methanol (20 ml) was added acetylchloride (0.25 ml, 3.5 mmol) in methanol (5 ml) and the solution was stirred for 15 min at 0° C. After stirring the solution for 30 min at ambient temperature, it was concentrated in vacuum. After trituration with diethyl ether there was obtained is listed in the title compound in the form of a solid white color (229 mg, 7%).

Example 30: Obtaining monohydrochloride N-hydroxy-1-(2-methoxyethyl)-4-[(4-phenoxyphenyl)sulfonyl]-4-piperazinecarboxamide

Stage A: the Solution obtained in stage D of example 6 amine hydrochloride (2.5 g, by 5.87 mmol) and K2CO3(1.6 g, 11,57 mmol) in N,N-dimethylformamide (25 ml) was added methyl-2-bromatology ether (0,66 ml, 7.0 mmol) and then stirred for 18 h at ambient temperature. Then N,N-dimethylformamide is evaporated in a high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. After concentration in which the Aquum received methoxyethylamine in the form of a gel light yellow (2,63 g, quantitative yield).

Stage B: the Solution obtained in stage a of methoxyethylamine (2,63 g, by 5.87 mmol) in tetrahydrofuran (18 ml) and ethanol (18 ml) was added NaOH (2.1 g, a 5.25 mmol) in water (6 ml). The solution was heated to the temperature of reflux distilled within 12 hours the Solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with simple ether (2× 100 ml) and acidified to pH 2. After vacuum filtration of the resulting precipitate got acid in a solid white color (2.4 g, quantitative yield).

Stage b: To the solution obtained in stage B acid (2.0 g, 4,33 mmol), containing N-methylmorpholine (1.8 ml, 16.4 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0,767 g, 6,44 mmol)in N,N-dimethylformamide (20 ml), was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (3.1 g, 16.2 mmol) and the solution was stirred for 20 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed N2O and dried over MgSO4. After concentration in vacuo received amide in the form of whitish foam (1.60 g, 71,1%).

Stage G: To a solution obtained at the stage In amide (1,58 g of 3.05 mmol) in methanol (20 ml), cooled to 0° C, was added acetylchloride (0,65 ml, to 9.15 mmol) and the resulting solution was stirred at the same temperature in those who tell 3 hours The solution was concentrated and after chromatography with reversed phase (columns C-18 silica, acetonitrile/N2With the addition of 0.01% HCl) was obtained the hydrochloride of hydroxamate in a solid white color (0.65 g, 45.5 per cent). Elemental analysis: calculated for C21H26N2About6S· HCl· 0,N2About: 52,06; N To 5.93; N 5,78; S 6,62; found: 51,94; N 5,67; N 5,91; S 6,66. Msvr: calculated for C21H26N2About6S: 435,1590 found 435,1571.

Example 31: Obtaining monohydrochloride N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(1-pyrrolidinyl)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 6 sulfone (2,75 g, 5.6 mmol) in tetrahydrofuran (10 ml) and ethanol (10 ml) was added NaOH (2.25 g, 56 mmol) in N2O (20 ml) and the solution was heated for 20 h to 70° C. the Solution was concentrated in vacuo and the residue was dissolved in N2O. the Aqueous layer was extracted with simple ether and acidified to pH 2, and then were extracted with ethyl acetate. The combined organic layers were again washed N2O and dried over MgSO4. After concentration in vacuo received BOC-protected acid in the form of a white foam (2.3 g, 88,8%).

Stage B: To a solution received at the stage AND the BOC-protected acid (2.3 g, to 4.98 mmol) in dichloromethane (6 ml) was added t everysunday acid (6 ml, 77,8 mmol) and the resulting solution was stirred for 1 h at ambient temperature. After concentration in vacuo received amine in the form of a white foam (2,44 g, quantitative yield).

Stage b: To a solution containing obtained in stage B amine (2.4 g, 4.9 mmol) and triethylamine (3.5 ml, 24.4 mmol) in acetone (15 ml) and N2About (15 ml), was added chlorocatechol (1.2 ml, 14.7 mmol) and the solution was stirred for 20 h at ambient temperature. The acetone evaporated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration in vacuo received chloracetamide in the form of a gel light yellow (2,78 g, quantitative yield).

Stage G: To a solution containing the receiving stage In chloracetamide (2,78 g is 4.93 mmol) and K2CO3(5 g, 36 mmol) in N,N-dimethylformamide (20 ml) was added pyrrolidine (3 ml, 36 mmol). Then the solution was stirred for 18 h at ambient temperature. Then N,N-dimethylformamid evaporated in high vacuum and after chromatography with reversed phase (columns C-18 silica, acetonitrile/N2With the addition of 0.01% HCl) received pyrrolidinedione (0.25 g, 10.7 percent).

Stage D: To the solution obtained in stage g of the amide of pyrrolidinyl (0.25 g, of 0.53 mmol), also contains Adamu N-methylmorpholin (0,14 ml, of 1.27 mmol), 1-hydroxybenzotriazole (0.17 g, 1.2 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0.15 g, of 1.26 mmol) in N,N-dimethylformamide (4 ml), was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (to 0.23 g, 1.2 mmol). Then the solution was stirred for 18 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3N2O and dried over MgSO4. After concentration in vacuo received Tgp-protected amide as white foam (0.25 g, 83,3%).

Stage E: To the solution obtained in stage D amide (0.25 g, 0,437 mmol) in methanol (4 ml), cooled to 0° C, was added acetylchloride (0.075 ml, 1.05 mmol) and the resulting solution was stirred for 2.5 h at ambient temperature. The solution was concentrated in vacuum and after chromatography with reversed phase (columns C-18 silica, acetonitrile/N2With the addition of 0.01% HCl) was obtained the hydrochloride of hydroxamate in a solid white color (80 mg, 29%). Elemental analysis: calculated for C24H29N3O6S· HCl· 0,N2About: 53,36; N 5,98; N 7,78; found: 53,61; N 5,71; N 7,94. Msvr: calculated for C24H29N3About6S: 488,1855 found: 488,1835.

Example 32: Obtaining monohydrochloride 1-cyclopropyl-N-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: a Solution of 4-portifino (50,29 g 0,39 mmol) in dimethylsulfoxide (500 ml) was heated for 5 h to 65° C. the Solution was cooled to ambient temperature and was poured into ice water with vigorous stirring. The precipitate was filtered and twice washed with water. After drying in high vacuum at ambient temperature received disulfide in the form of a yellow oil (34,39 g, 68,9%).

Stage B: a Solution of di-tert-BUTYLCARBAMATE (21.8 g, 0.1 mol) in tetrahydrofuran (5 ml) was added dropwise over 20 min to a solution of utilisedictated (15.7 g, 0.1 mol) in tetrahydrofuran (100 ml). The resulting solution was stirred overnight (about 18 hours) at ambient temperature and then concentrated in vacuum, obtaining protrace oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuum, obtaining the BOC-protected piperidine derived in the form of a clear colorless oil (26,2 g, quantitative yield).

Stage b: To the solution obtained in stage B of the BOC-protected piperidino derived (15,96 g, 62 mmol) in tetrahydrofuran (300 ml), cooled to -40° C, was added diisopropylamide lithium (41,33 ml, 74 mmol). Then the solution was stirred for 1 h at -40° and for 0.5 h at 0° C. Then the solution was again cooled to -40° and obavljale obtained at the stage And the disulfide (15,77 g, 62 mmol) in tetrahydrofuran (20 ml). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with N2O and was extracted with ethyl acetate. The organic layer was washed N2Oh, saturated NaCl solution and dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of oil (18.0 g, 75%).

Stage G: To a solution obtained at the stage In sulfide (16.5 g, 43 mmol) in dichloromethane (500 ml), cooled to 0° With added meta-chloroperbenzoic acid (18.5 g, 107 mmol). After 2 h, the solution was diluted with dichloromethane and washed with 1 N. COHN, H2O and dried over MgS4. After concentration in vacuo received sulfon in the form of a solid (21 g, quantitative yield)

Stage D: To a solution containing obtained in stage G sulfon (40 g, 96 mmol) and powdered To2CO3(26 g, 188 mmol) in N,N-dimethylformamide (200 ml), cooled to 0° C, was added tylenol (to 19.8 ml, 192 mmol) and then the resulting mixture was stirred for 36 h at ambient temperature. This solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed N2O and dried over magnesium sulfate. After chromatography (silica gel, ethyl acetate/hexane) received the BOC-protected sulfon of phenylthiophene in the de solid white (44,34 g, 91%).

Stage E: To the solution obtained in stage D of the BOC-protected sulfone of phenylthiophene (8.6 g, 17 mmol) in dichloromethane (30 ml), cooled to 0° With added triperoxonane acid (TFA, 30 ml) and the resulting solution was stirred for 2 h at ambient temperature. After concentration in vacuo received triptorelin amine in the form of a gel light yellow (8.7 g, quantitative yield).

Stage G: To a solution obtained in stage E of triptoreline amine (6 g, with 11.9 mmol) was added acetic acid (6.8 ml, 119 mmol). After stirring for 5 min at ambient temperature was added 1-adoxycycline)axithromycin (14,3 ml of 71.4 mmol), and then after 5 min was added to hydrate tianbian sodium (3,35 g, 53,55 mmol). After this, the solution was heated to the temperature of reflux distilled for 18 hours, the Methanol evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed 1 N. NaOH solution, N2O and dried over MgSO4. After concentration in vacuo received cyclopropylamine in the form of a whitish powder (4.9 g, 92.6 per cent).

Stage 3: To the solution obtained in stage G of cyclopropylamine (4,88 g, 10,95 mmol) in tetrahydrofuran (12.5 ml) and ethanol (12.5 ml) was added NaOH (4.3 g, 100 mmol) in water (25 ml). Then the solution was heated for 12 h to 50-55° and was stirred for 18 h at temperatures of the environment. The solution was acidified to pH 2 and after concentration in vacuo got acid in a solid white color mixed with NaCl. To a solution of this mixture in acetonitrile (50 ml), was added O-tetrahydropyranyl-Lamin (1,95 g, 16.3 mmol), N-methylmorpholin (2.4 ml, 21.9 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (3,14 g, 16.3 mmol). Then the solution was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed N2O and dried over MgSO4. After concentration in vacuo received tetrahydropyranyl (Tgp)-protected amide in the form of a solid white color (3.0 g, 53.1 per cent).

Stage I: To the solution obtained in stage 3 TBM-protected amide (3 g, 5.8 mmol) in methanol (45 ml), cooled to 0° C, was added acetylchloride (1.5 ml, 21.1 mmol) and the solution was stirred for 2.5 h at ambient temperature. After vacuum filtration of sludge received hydrochloride of hydroxamate in a solid white color (1,844 g, 68.3 per cent). Elemental analysis: calculated for C21H24N2O4S2·HCl: 53,78; N lower than the 5.37; N 5,97; S 13,67; found: 53,40; N 5,26; N 5,95; S 13,68.

Example 33: Obtaining monohydrochloride N-hydroxy-1-methyl-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To a solution containing obtained in stage E of example 32 triptorelin amine (2.67 g, 5,14 mmol) and 37%aqueous formaldehyde solution (2.0 ml, of 25.7 mmol) in methanol (20 ml), was added at ambient temperature branfireun (2,6 ml of 25.7 mmol). Then the solution was stirred for 18 h at ambient temperature. The solution was acidified to decompose excess reagent. The methanol is evaporated and the residue was distributed between the aqueous solution of NaHCO3and ethyl acetate. The layer of aqueous solution of NaHCO3were extracted with ethyl acetate. The combined organic layers were washed N2O and dried over MgSO4. After concentration in vacuo received methylamine in the form of whitish foam (1.6 g, 76%).

Stage B: To the solution obtained in stage a of methylamine (1.63 g, 3.88 mmol) in ethanol (20 ml) was added a solution of KOH (1.31 g, 23.2 mmol) in water (4 ml) and the resulting solution was heated for 8 h to 50° C for 4 h to 70° and was stirred for 18 h at ambient temperature. The solution was acidified and concentrated in vacuum, obtaining the acid in a solid white color mixed with NaCl. To a solution of this mixture in N,N-dimethylformamide (50 ml), was added O-tetrahydropyranyl (0,92 g, 7,76 mmol), N-methylmorpholin (1,05 ml, 7,76 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide is a (1.5 g, 7,76 mmol). The solution was stirred for 72 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3N2O and dried over MgSO4. After concentration in vacuo and chromatography

(on silica gel, dichloromethane/methanol) received Tgp-protected amide in the form of a solid white color (0,46 g, 24.2 per cent).

Stage b: To the solution obtained in stage B Tgp-protected amide (0,22 g, 0.45 mmol) in methanol (5 ml), cooled to 0° C, was added acetylchloride (0,096 ml, 13.5 mmol) and the resulting solution was stirred for 3 h at ambient temperature. The solution was concentrated in vacuum and after chromatography with reversed phase (columns C-18 silica, acetonitrile/N2With the addition of 0.01% HCl) was obtained the hydrochloride of hydroxamate in a solid white color (0.12 g, 60.6 per cent). Msvr: calculated for C19H22N2O4S2: 407,1099 found 407,1105.

Example 34: Obtaining monohydrochloride N-hydroxy-1-(1-methylethyl)-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: the Solution obtained in stage G of example 32, the BOC-protected sulfone (11,19 g, 22,12 mmol) in ethyl acetate (150 ml), cooled to 0° s barbotin the Wali within 20 min of gaseous HCl. The solution was stirred at the same temperature for 40 minutes After concentration in vacuo and trituration with simple ether was obtained amine hydrochloride (9.88 g, quantitative yield).

Stage B: To a solution containing obtained on the stage And amine hydrochloride (4.7 g, 10.6 mmol), triethylamine (2.0 ml, 14.4 mmol) and acetone (2.0 ml, for 27.2 mmol) in dichloromethane (100 ml)was added at ambient temperature triacetoxyborohydride sodium (5.7 g, 26.9 mmol)and then acetic acid (1.5 ml, 26.9 mmol). The solution was stirred for 18 h, and then distributed between 1 N. NaOH solution and simple ether. The aqueous layer was extracted with simple ether and the combined organic layers were washed 1 N. NaOH solution, N2O and dried over MgSO4. After concentration in vacuo received Isopropylamine in the form of a white foam (4,58 g, 96%).

Stage b: To the solution obtained in stage B of Isopropylamine (4,58 g, 10.2 mmol) in tetrahydrofuran (10 ml) and ethanol (10 ml) was added NaOH solution (2.1 g, a 5.25 mmol) in water (20 ml). The solution was heated for 13.5 h to 60° With, then was stirred for 18 h at ambient temperature. The solution was acidified and concentrated in vacuum, obtaining the acid in a solid white color mixed with NaCl. To a solution of this mixture in N,N-dimethylformamide (75 ml) was sequentially added 1-hydroxybenzotriazole (1,94 g,14.4 mmol), O-tetrahydropyranyl (1.8 g, 15.1 mmol), N-methylmorpholin (3,37 ml, 30.7 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (2,74 g of 14.3 mmol). Then the solution was stirred for 48 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3N2O and dried over MgSO4. After concentration in vacuum chromatography (on silica gel, dichloromethane/methanol) received Tgp-protected amide in the form of a solid white color (of 3.78 g, 71.3 per cent).

Stage G: To a solution obtained at the stage In Tgp-protected amide (1,15 g, 2.2 mmol) in methanol (20 ml) was added acetylchloride (0,096 ml, 13.5 mmol) and the resulting solution was stirred for 2.5 h at ambient temperature. The solution was concentrated in vacuum and after chromatography with reversed phase (columns C-18 silica, acetonitrile/N2With the addition of 0.01% HCl) was obtained the hydrochloride of hydroxamate in a solid white color (0,69 g, 66.3 per cent). Elemental analysis: calculated for C21H26N2O4S2·HCl· N2About: 51,58; N 5,98; N 5,73; S 13,11; found: 51,76; N Vs. 5.47; N 5,72; S 12,68.

Example 35: Obtaining monohydrochloride N-hydroxy-1-(2-methoxyethyl)-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To a solution containing obtained in stage a of example 34 amine hydrochloride (463 g, 9.43 mmol) and K2CO3(2,62 g, 19.0 mmol) in N,N-dimethylformamide (40 ml), was added methyl-2-bromatology ether (1.9 ml, at 20.2 mmol). The solution was stirred for 48 h at ambient temperature. Then N,N-dimethylformamide is evaporated in a high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. After concentration in vacuo received methoxyethylamine in the form of a white foam (4.26 deaths / g, 95.3 per cent).

Stage B: To the solution obtained in stage a of methoxyethylamine (4.26 deaths / g, 9.2 mmol) in tetrahydrofuran (5 ml) and ethanol (5 ml) was added a solution of NaOH (3.7 g, of 92.5 mmol) in water (9 ml). The resulting solution was heated for 12 h to 60° and was stirred for 18 h at ambient temperature. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with simple ether (2× 100 ml) and acidified to pH 2. After vacuum filtration of the resulting precipitate got acid in a solid white color (3.5 g, 87,5%).

Stage b: To the solution obtained in stage B acid (3.4 g, 7.8 mmol) in N,N-dimethylformamide (20 ml)containing N-methylmorpholine (2,6 ml of 23.4 mmol), 1-hydroxybenzotriazole (3,16 g and 23.4 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (1.85 g, 15,5 IMO the b) added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (4,47 g and 23.4 mmol). The solution was stirred for 36 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3N2O and dried over MgSO4. After concentration in vacuo received amide in the form of a solid whitish (2,98 g, 71,5%).

Stage G: To a solution obtained at the stage In amide (2,98 g, 5.6 mmol) in methanol (40 ml), cooled to 0° C, was added acetylchloride (1,19 ml of 16.8 mmol) and the resulting solution was stirred for 3 h at ambient temperature. The solution was concentrated in vacuum and after chromatography with reversed phase (columns C-18 silica, acetonitrile/N2With the addition of 0.01% HCl) was obtained the hydrochloride of hydroxamate in a solid white color (to 2.29 g, 84.6 per cent). Elemental analysis: calculated for C21H26N2O6S· HCl· 0,N2About: 50,12; N 5,77; N 5,57; S 12,74; found: 50,41; N. Of 5.85; N 5,73; S 12,83.

Example 36: Obtaining monohydrochloride 1-acetyl-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage D of example 32, the BOC-protected sulfone of phenylthiophene (7 g, 1,29 IMO the ü) in tetrahydrofuran (25 ml) and ethanol (25 ml) was added NaOH (5,1 g, 12.9 mmol) in N2About (50 ml). The solution was heated for 20 hours to a temperature of reflux distilled. After cooling, the solution was concentrated in vacuo and the residue was dissolved in N2O. the Aqueous layer was extracted with simple ether and acidified to pH 2 and then extracted with ethyl acetate. The combined organic layers were again washed N2O and dried over MgSO4. After concentration in vacuo received BOC-protected acid in the form of a white foam (3.9 g, 60%).

Stage B: To the solution obtained in stage a, the BOC-protected acid (2.3 g, to 4.98 mmol) in dichloromethane (6 ml) was added triperoxonane acid (6 ml, 77,8 mmol) and the solution was stirred for 1 h at ambient temperature. After concentration in vacuo received amine in the form of a white foam (2,44 g, quantitative yield).

Stage b: To a solution containing obtained in stage B amine (5.0 g, 12,08 mmol) and triethylamine (8.7 ml, 60,4 mmol) in acetone (20 ml) and N2O (20 ml), cooled to 0° C, was added acetylchloride (4.6 ml, 36 mmol) and the solution was stirred for 40 h at ambient temperature. The acetone evaporated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and dried over Mg2SO4. After concentration in vacuo received acetylated foam light is on yellow (5 g, quantitative yield).

Stage G: To a solution obtained at the stage In acetylamino (5 g, to 11.9 mmol) in N,N-dimethylformamide (50 ml)containing N-methylmorpholine (5,3 ml of 11.9 mmol), 1-hydroxybenzotriazole (4.8 g, 35,7 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (2.8 g, 23.5 mmol)were added hydrochloride 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (6.8 g, 35,7 mmol) and the solution was stirred for 20 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3, KHSO4N2O and dried over MgSO4. After concentration in vacuo received Tgp-amide in the form of a white foam (6,07 g, 98.2 per cent).

Stage D: To the solution obtained in stage G Tgp-amide (6,07 g, 11.7 mmol) in methanol (100 ml), cooled to 0° C, was added acetylchloride (2.5 ml, of 35.1 mmol) and the resulting solution was stirred for 3 h at ambient temperature. The solution was concentrated and after chromatography (silica gel, methanol/dichloromethane) was obtained the hydrochloride of hydroxamate in a solid white color (3,3 g, 65%). Elemental analysis: calculated for C24H29N3O6S· HCl· 0,N2About: 53,36; N 5,98; N 7,78; found: 53,61; N 5,71; N 7,94. Msvr: calculated for C24H29N3About6S: 488,1855 found 88,1835.

Example 37: Obtaining monohydrochloride 1-acetyl-4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To a solution containing obtained in stage G of example 32 sulfone (25 g, to 67.3 mmol) and powdered K2CO3(23.3 g, to 16.9 mmol) in N,N-dimethylformamide, was added at ambient temperature of sesamol (23,24 g, a 16.8 mmol) and the solution was heated for 24 h to 90° C. the Solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed 1 N. NaOH, H2O and dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received the BOC-protected sulfon of sesamol in the form of a white foam (33.6 g, 93,6%).

Stage B: To the solution obtained in stage a, the BOC-protected sulfone of sesamol (29,31 g, 54,93 mmol) in ethanol (60 ml) and tetrahydrofuran (60 ml) was added via an additional funnel over 20 min at ambient temperature NaOH (21,97 g, 544 mmol). The solution was heated for 9 h to 60° C, and then kept for 12 h at ambient temperature. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with simple ether and acidified to pH 2. Then it was extracted with ethyl acetate and the combined organic layers were washed N2O and dried over MgSO . After concentration in vacuo got acid in a solid white color (25,3 g, 91%).

Stage b: the Solution obtained in stage B acid (20,3 g, 40,15 mmol) in ethyl acetate, cooled to 0° was barbotirovany gaseous HCl. After 1.5 h by vacuum filtration of the white precipitate was obtained amine hydrochloride in a solid white color (16 g, 93,6%).

Stage G: To a solution containing obtained at the stage In amine hydrochloride (8.1 g, 19.01 in mmol) and triethylamine (13,2 ml, 95,05 mmol) in acetone (150 ml) and N2O (150 ml), cooled to 0° C, was added acetylchloride (5,4 ml, 76 mmol). The solution was stirred for 18 h at ambient temperature. The acetone evaporated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed N2O and dried over MgSO4. After concentration in vacuo received acetylated foam light yellow (9,24 g, quantitative yield).

Stage D: To a solution containing obtained in stage G acetylated (9,1 g, 20,33 mmol), N-methylmorpholin (6,7 ml, 61 mmol), 1-hydroxybenzotriazole (8.2 g, 60 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (4,85 g, 40 mmol) in N,N-dimethylformamide (40 ml), was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (11,65 g, 60 mmol). The resulting solution was stirred mortgage is e 20 h at ambient temperature. Then the solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3, KHSO4N2O and dried over MgSO4. After concentration in vacuo and chromatography (silica gel, ethyl acetate/hexane) received Tgp-amide in the form of a white foam (10 g, 89,7%).

Stage E: To a solution of 4h. HCl in dioxane (20 ml) was added to the solution obtained in stage D amide (5.0 g, 9.1 mmol) in methanol (5 ml) and dioxane (15 ml). This solution was stirred for 30 min at ambient temperature. After vacuum filtration of the white precipitate was obtained the hydrochloride of hydroxamate in a solid white color (3,3 g, 65%). Elemental analysis: calculated for C21H22N2O8S· HCl: 54,34; H 5,15; N 5,49; S to 6.43; found: 54,54; N 4,79; N 6,06; S 6,93. Msvr: calculated for C21H22N2O8S: 463,1175 found 463,118.

Example 38: Obtaining monohydrochloride 4-[[4-(3,4-dimethoxyphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: the Solution obtained in stage G of example 32 sulfone (10 g, 24 mmol) in ethyl acetate, cooled to 0° was barbotirovany gaseous HCl. After 4 h by vacuum filtration of the white precipitate was obtained amine hydrochloride in the form of a solid substance below the color (7,27 g, 86%).

Stage B: To a solution containing obtained on the stage And amine hydrochloride (5,98 g, 17 mmol) and powdered To2CO3(4.7 g, 34 mmol) in N,N-dimethylformamide (120 ml)was added at ambient temperature propylbromide (2,02 g, 17 mmol), then stirred for 4 h the Solution was diluted with ethyl acetate and washed with N2Oh, saturated NaCl solution and dried over MgSO4. After concentration in vacuo and chromatography (silica gel, ethyl acetate/hexane) received propargylamine in a solid white color (5,2 g, 86%).

Stage b: To a solution containing obtained in stage B propargylamine (8 g, 22,63 mmol) and powdered To2CO3(8.8 g, a 56.6 mmol) in N,N-dimethylformamide (150 ml)was added at ambient temperature 3,4-dimethoxyphenol (6,98 g, 45 mmol). The mixture was heated for 36 h to 90° C. the Solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed 1 N. solution Panso3N2O and dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received phenoxypropylamine in the form of a gel light yellow (10g, 90,9%).

Stage D: a Solution of NaOH (8,2 g, 200 mmol) in N2O (30 ml) was added via addition funnel at ambient temperature to a solution obtained at the stage In phenoxypropanol the Mina (10 g, of 20.5 mmol) in ethanol (15 ml) and tetrahydrofuran (15 ml). The resulting solution was heated for 48 h to 60° and kept for 48 h at ambient temperature. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with simple ether and acidified to pH 2. After vacuum filtration of the white precipitate was obtained acid in a solid white color (9.4 g, quantitative yield).

Stage D: To a solution containing obtained in stage g of the acid (9.4 g, 20,5 mmol), N-methylmorpholin (6.8 ml, 62 mmol), 1-hydroxybenzotriazole (of 8.3 g, 60 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (4.8 g, 40 mmol) in N,N-dimethylformamide (50 ml), was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (11,7 g, 60 mmol). Then the resulting solution was stirred for 20 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3N2O and dried over MgSO4. After concentration in vacuo and chromatography (silica gel, ethyl acetate/hexane) received Tgp-protected amide as white foam (10 g, 89,7%).

Stage E: To a solution of 4 N. HCl in dioxane (38 ml, 152 mmol) was added to the solution obtained in stage D amide (8.5 g, of 15.2 mmol) in methanol (8 ml) and dioxane (24 ml). Obrazovku the Xia and the mixture was stirred for 80 min at ambient temperature. After concentration in vacuo and trituration with simple ether there was obtained the hydrochloride of hydroxamate in a solid white color (7.7 g, quantitative yield). Msvr: calculated for C23H26N2O7S: 475,1461 found 475,1539.

Example 39: Receiving monohydrochloride 4-[[4-(3,5-dimethoxyphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To a solution containing obtained in stage B of example 38 propargylamine (2 g, 5.6 mmol) and powdered To2CO3(1.9 g, 13.7 mmol) in N,N-dimethylformamide (20 ml), was added at ambient temperature for 3.5-dimethoxyphenol (2,18 g, 13.7 mmol). The mixture was heated for 36 h to 90° C. the Solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed for 1H. solution Panso3N2O and dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received phenoxypropylamine in the form of a gel light yellow (2.76 g, quantitative yield).

Stage B: To the solution obtained in stage a of phenoxypropylamine (2,75 g, 5.6 mmol) in ethanol (5 ml) and tetrahydrofuran (5 ml) was added at ambient temperature NaOH (2.3 g, 56 mmol) in N2About (10 ml). Then the solution was heated for 18 h to 60° C. the Solution was concentrated in vacuum and diluted with water. The aqueous layer was extracted with simple ether and acidified to pH 2. After vacuum filtration of the white precipitate was obtained acid in a solid white color (2 g, 77.2 percent).

Stage b: To a solution containing obtained in stage B acid (2 g, 4.3 mmol), N-methylmorpholin (1.9 ml, and 17.2 mmol), 1-hydroxybenzotriazole (1,74 g, 13,2 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (1,02 g, 8.6 mmol) in N,N-dimethylformamide (20 ml), was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (2,47 g, 12.9 mmol). The resulting mixture was stirred for 20 h at ambient temperature. The solution was concentrated in high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3N2O and dried over MgSO4. After concentration in vacuo and chromatography (silica gel, ethyl acetate/hexane) received Tgp-amide in the form of a white foam (2.4 g, quantitative yield).

Stage G: To a solution of 4 N. HCl in dioxane (13 ml, 52 mmol) was added to the solution obtained at the stage In Tgp-protected amide (2,43 g, 4.35 mmol) in methanol (2 ml) and dioxane (6 ml) and the mixture was stirred for 80 min at ambient temperature. After vacuum filtration of the precipitate and washing with simple ether there was obtained the hydrochloride of hydroxamate in a solid white color (1,25 g, 56.3 per cent). Elemental analysis: RAS is Chicano for C 23H26N2O7S· 1,5HCl: 52,20; N 5,24; N of 5.29; found: 52,00; N. of 5.05; N5,17.

Example 40: Obtaining monohydrochloride 4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To a solution containing obtained in stage B of example 37 N-BOC-protected derivative of carboxylic acid (1.25 g, 2,47 mmol), N - methylmorpholin (1,00 g of 9.89 mmol) and the hydrate of 1-hydroxybenzotriazole (0.40 g, 2,96 mmol) in N,N-dimethylformamide (8 ml), was added at ambient temperature hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,616 g is 3.21 mmol). After 5 min the solution was added O-tetrahydro-2H-Piran-2-ipidacrine (0.39 g, of 3.33 mmol) in N,N-dimethylformamide (2 ml). After 2 days, the solution is light yellow concentrated in vacuum, obtaining a residue, which was dissolved in ethyl acetate and then washed with water (3x) and with brine and dried over magnesium sulfate. After concentrating the obtained residue, which was chromatographically on silica gel, elwira with ethyl acetate/hexane (20/80), with Tgp-protected hydroxamate in the form of oil (1.54 g, 100%).

Stage B: To the solution obtained at the stage And Tgp-protected hydroxamate (1,49 g of 2.46 mmol) in dioxane (9 ml) and methanol (3 ml) was added 4n. HCl in dioxane (10 ml, 40 mmol). After incubation for 1.5 h at tempera is ur environment, the suspension was treated with diethyl ether (15 ml) and filtered, receiving specified in the header of hydroxamate (1,00 g, 89%) as colorless powder. MS (CI) MH+: calculated for C19H20N2SO7: 421 detected 421. Elemental analysis: calculated for C19H20N2SO7·HCl: 49,95; N 4,63; N 6,13; Cl 7,76; S 7,02; found: 49,82; N 4,60; N 5,98; Cl 17,38; S 7,10.

Example 41: Obtaining monohydrochloride N-hydroxy-4-[[4-(3-methylphenoxy)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To a solution containing obtained in stage E of example 9 propargylamine (8.0 g, and 22.6 mmol) and K2CO3in N,N-dimethylformamide (30 ml), was added meta-cresol (3.5 g, to 33.9 mmol) and the solution was stirred for 18 h at 90° C. the Solution was diluted with N2O and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution and dried over MgSO4. After chromatography (silica gel, elwira a mixture of 10%ethyl acetate/hexane) received 3-methylphenethylamine derived in the form of a solid (10.3 g, 98%). MS: calculated for C24H28NSO5: 441,1688 found 442,1697.

Stage B: To the solution obtained in stage And 3-methylphenoxyacetic derived (10.3 g, 22,0 mmol) in tetrahydrofuran (50 ml) and ethanol (50 ml) was added NaOH (8,9 g, 22,3 mol) and the solution kept at a temperature of 65° C for 24 h Rast is the PR was concentrated in vacuo and the aqueous residue was acidified to pH 3. After vacuum filtration of the resulting precipitate got acid in a solid white color (9.0 g, 91%). MS: calculated for C22H24NSO5: 414,1375 found 414,1389.

Stage b: To the solution obtained in stage B acid (9.0 g, a 19.5 mmol) was added 1-hydroxybenzotriazole (3,24 g of 23.9 mmol), N-methylmorpholin (6,58 ml, was 59.9 mmol) and O-tetrahydro-2H-Piran-2-ispitatelny (3.5 g, and 29.9 mmol), and then the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (5.35 g of 27.9 mmol). Then the solution was stirred for 18 h at ambient temperature. The solution was diluted with N2O (400 ml) and was extracted with ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over MgSO4. After chromatography (silica gel, elwira a mixture of 40%ethyl acetate/hexane) required Tgp-protected hydroxamate in the form of a solid (6.9 g, 67%). Elemental analysis: calculated for C27H33N2SO6·0.1 n2About: With 62,92; N. Of 6.49; N 5,43; S 6,23; found: 62,69; N 6,47; N 5,57; S 6,33. MS: calculated for C27H33N2SO6: 513,2059 found 513,2071.

Stage G: To a solution obtained at the stage In Tgp-protected hydroxamate (6.4 g, 12.5 mmol) in dioxane (56 ml) and methanol (19 ml) was added to a mixture of 4 N. HCl/dioxane (40 ml). After stirring for 1 h at ambient temperature the solution is the end of what was tribali in vacuum. After trituration with diethyl ether there was obtained is listed in the title compound in the form of a solid white color (to 5.66 g, 97,4%). MS: calculated for C22H24N2SO5: 429,1484 found M+1: 429,1493.

Example 42: Obtain 4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-1-(methylsulphonyl)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 32 sulfone (25, g, to 67.3 mmol) in N,N-dimethylformamide was added potassium carbonate (23.3 g, 0,169 mol) and sesamol (23,2 g, 0,164 mol). The solution was placed in an oil bath at 90° and was stirred for 25 h To the solution was added ethyl acetate and the organic phase is washed with water, 1N. NaOH solution and water, dried over magnesium sulfate, filtered and concentrated in vacuum. After chromatography on silica with elution with a mixture of ethyl acetate/hexane (15/85) received compound, a complex of ethyl ether, in the form of oil (29.3 g, 82%).

Stage B: To the solution obtained in stage a complex ethyl ester (29.3 g, 54,93 mmol) in ethanol (60 ml) and tetrahydrofuran (60 ml) was added NaOH solution (21,9 g, 0,549 mol) in water (120 ml) and the solution was kept for 10 h at 65° C. the Solution was concentrated in vacuo and the aqueous residue was acidified to pH 3. The solution was extracted with ethyl acetate. The solution was dried over sulfate is magnesium, was filtered and concentrated in vacuum, obtaining the acid in the form of a yellow foam (25.6 g, 92.1 per cent).

Stage b: the Solution obtained in stage B acid (20,3 g, 40,15 mmol) in ethyl acetate was barbotirovany for 20 min at 0° With gaseous HCl. The solution was stirred for 1.5 h at 0° C. the precipitate was filtered and washed by a simple broadcast receiving amine hydrochloride in a solid white color (16.0 g, 93.5 per cent).

Stage G: To a solution obtained at the stage In amine hydrochloride (7.5 g, 17,0 mmol) in methylene chloride (200 ml) was added methanesulfonamide (2.0 g, 25,0 mol) and the solution was stirred for 18 h at ambient temperature. The solution was washed N2O and saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuum, obtaining the acid in a solid white color (6,97 g, 85%).

Stage D: To the solution obtained in stage G of the acid (7,37 g, 15.0 mmol) was added 1-hydroxybenzotriazole (2,43 g, 18.0 mmol), N-methylmorpholin (4,94 ml of 45.0 mmol), O-tetrahydro-2H-paradisiacally (2.65 g, to 22.5 mmol), and then the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (as 4.02 g, 21,0 mmol). The solution was stirred for 18 h at ambient temperature. The solution was diluted with N2O (400 ml) and was extracted with ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over MgSO . After chromatography (silica gel, elwira a mixture of 50%ethyl acetate/hexane) required Tgp-protected hydroxamate in a solid white color (rate of 7.54 g, 85%).

Stage E: To the solution obtained in stage D Tgp-protected hydroxamate (6,32 g to 10.8 mmol) in dioxane (75 ml) and methanol (25 ml) was added a mixture of 4h. HCl/dioxane (30 ml). After stirring for 1 h at ambient temperature the solution was concentrated in vacuum. After trituration with diethyl ether has been specified in the header connection. After chromatography (silica gel, elwira a mixture of 5%methanol/ethyl acetate) received hydroxamate in a solid white color (4,32 g, 80%). MS: calculated for C22H22N2S2O9+1: 499,0845 found: 499,0848.

Example 43: Obtaining monohydrochloride 4-[[4-(3,4-dimethylphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Phase A: a Mixture containing the obtained in stage E of example 9 fluorine compound (2.0 g, to 5.66 mmol), 3,4-dimethylphenol (2.0 g, 16.5 mmol) and potassium carbonate (2.3 g, 16.5 mmol) in N,N-dimethylformamide (15 ml)was kept overnight (approximately 18 hours) at 90° C in nitrogen atmosphere. Mix brown was concentrated in vacuo and was purified by chromatography (silica gel, ethyl acetate/hexane), Paul is the tea 3,4-dimethylbenzophenone derived in the form of a clear yellow oil (2.0 g, yield 79%). Elemental analysis: calculated for C25H29NO5S: 65,9; N, 6.42 Per; N 3.04 From; S? 7.04 baby mortality; found: 65,76; N 6,37; N 3,03; S 7,00.

Stage B: a Solution containing obtained on the stage And 3,4-dimethylbenzophenone derivative (2.0 g, is 4.93 mmol) and potassium hydroxide (1.7 g, 29.7 mmol) in ethanol (25 ml) and water (4 ml)was stirred for 4 h at the temperature of reflux distilled in a nitrogen atmosphere. The solution was cooled with an ice bath and then acidified with concentrated hydrochloric acid and concentrated, obtaining the crude residue. The mixture containing the crude residue, O-tetrahydro-2H-Piran-2-alhydrogel (0.88 g, 7,50 mmol), triethylamine (0,81 ml of 5.81 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in acetonitrile (24 ml), was stirred overnight at ambient temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution, water and saturated salt solution. After drying over magnesium sulfate, the filtrate, representing Tgp-protected hydroxamate, concentrated, receiving a yellow foam.

Stage b: Obtained in stage B Tgp-protected hydroxamate (920 mg, about 1.75 mmol) was dissolved in methanol (16 ml). Added acetylchloride (0,37 ml, 5.3 mmol). After 3 h by concentration and subsequent GHUR with reversed phase received is specified in the title compound in the form of solid white (611 mg, 79%). MS (ES) MN+: calculated for C23H26N2About5S: 443 detected 443.

Example 44: Obtaining monohydrochloride 4-[[4-(4-chlorophenyl)terfenol]sulfonyl]-1-(PROPYNYL)-4-piperidinecarboxylic acid and monohydrochloride-4-[[4-(4-chlorophenyl)terfenol]sulfonyl]-N-hydroxy-1-(PROPYNYL)-4-piperazinecarboxamide

Stage A:. The mixture containing the obtained in stage E of example 9 fluorine compound (2.0 g, to 5.66 mmol), 4-chlorothiophenol (1.0 g, 6,94 mmol) and potassium carbonate (1.1 g, 8.0 mmol) in N,N-dimethylformamide (12 ml)was stirred overnight (about 18 hours) at ambient temperature under nitrogen atmosphere. The mixture was concentrated in vacuum. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline rastvorom, dried over magnesium sulfate and concentrated in vacuum, obtaining a yellow oil. The oil was purified by chromatography (silica gel, ethyl acetate/hexane)to give 4-chlorophenylalanine derived in the form of a solid white color (2.0 g, 75%yield). Elemental analysis: calculated for C23H24NO4S2Cl: 57,791; N Is 5.06; N 2,93; S 13,42; Cl 7,42; found: 57,57; N 5,11; N 2,94; S 13,19; Cl 7,73.

Stage B: Obtained at the stage And chlorpheniramine derived (2,04 g, 4,27 mmol who) was diluted with ethanol (30 ml) and water (5 ml). Was added potassium hydroxide (1.55 g, 27.7 mmol) and the mixture was stirred for 3 h at the temperature of reflux distilled. After completion of the reaction the solution was cooled and acidified with concentrated HCl to a pH of 1-3. The solvent was removed on a rotary evaporator and the residue was dried to dryness in azeotropic conditions when re-adding acetonitrile. Then the acid chloride was subjected to further drying by vacuum installation, and then used in the reaction combinations without additional purification. It was assumed that the saponification is quantitative.

Stage b: Obtained at the previous stage, the acid chloride of carboxylic acid (4,27 mmol) suspended in acetonitrile (20 ml). Was added N-methylmorpholine (approximately 1.0 ml), and then O-tetrahydro-2H-Piran-2-alhydrogel (585 mg, 5 mmol). After 5 min was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC, 955 mg, 5 mmol). The mixture was stirred overnight (approximately 18 h), then the solvent was removed on a rotary evaporator, the residue was diluted with semi-saturated solution of NaHCO3(50 ml) and product was extracted with ethyl acetate (2× 100 ml). In this example, poorly reacts emulsion was complicated by the selection of the connection. The combined organic layers were dried over MgSO4was filtered through silica gel, concentrated and subjected to chromatography (exp is ECC-chromatography silica gel, ethyl acetate/hexane)to give after concentration specified in the header O-Tgp-protected hydroxamate (162 mg, 7%, of ester) in the form of foam. MS (ES) MN+: calculated for C21H22N2O4S2Cl: 450 discovered 450. Since the mass output was small, the filter cake from the silica was extracted with a mixture of methanol : ethyl acetate (1:1)to give monohydrochloride 4-[[4-(4-chlorophenyl)terfenol]sulfonyl]-1-(PROPYNYL)-4-piperidinecarboxylic acid (540 mg, 26%).

Stage D: Obtained at the stage In About-Tgp-protected hydroxamate (441 mg, 0.80 mmol) was dissolved in methanol (2 ml). Added acetylchloride (0.2 ml, 3 mmol). After 3 h by concentration and subsequent GHUR with reversed phase has been specified in the title compound, representing hydroxamate, in a solid pink color (162 mg, 44%). MS (ES) MN+: calculated for C21H22N2O4S2: 465 detected 465.

Example 45: Obtaining monohydrochloride 4-[[4-(cyclopentyl)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: Obtained in stage E of example 9 propargylamine (3,09 g, 8.5 mmol) was mixed with K2CO3(to 1.38 g, 10 mmol), N,N-dimethylformamide (6 ml) and cyclopentanemethanol (of 1.02 ml, 10 mmol). The mixture was heated for 4 h to 80� With and within 2.5 h to 95° With, monitoring the reaction by TLC. Water treatment was carried out by using water (10 ml) and ethyl acetate (2× 100 ml). The combined organic layers were dried over magnesium sulfate, concentrated and chromatographically (Express chromatography, eluent - ethyl acetate/hexane)to give cyclopentylpropionate derived in the form of an oil (3.2 g, 86%).

Stage B: Obtained at the stage And cyclopentylpropionate derived (3.12 g, 7,13 mmol) was diluted with ethanol (50 ml) and water (8 ml). Was added potassium hydroxide (2,59 g, and 46.3 mmol) and the mixture was stirred for 3.5 h at the temperature of reflux distilled. After completion of the reaction the solution was cooled and acidified with concentrated HCl to a pH of 1-3. The solvent was removed on a rotary evaporator and the residue was dried to dryness in azeotropic conditions when re-adding acetonitrile. The acid chloride of carboxylic acid was subjected to further drying by vacuum installation, and then used in the reaction combinations without additional purification. It was assumed that the saponification is quantitative.

Stage b: Obtained at stage B, the acid chloride of carboxylic acid (7,13 mmol) suspended in acetonitrile (50 ml). Was added N-methylmorpholine (approximately 2.0 ml), and then O-tetrahydro-2H-Piran-2-alhydrogel (1,05 g, 9 mmol). After 5 min was added EDC (1,72 g, 9 mm is eh). The mixture was stirred overnight (approximately 18 h), then the solvent was removed on a rotary evaporator, the residue was diluted polysystem solution of NaHCO3(50 ml) and product was extracted with ethyl acetate (2× 100 ml). The combined organic layers were dried over MgSO4was filtered through silica gel, concentrated and subjected to chromatography (rapid-chromatography on silica gel, ethyl acetate/hexane)to give after concentration of About-Tgp-protected hydroxamate (2.0 g, 51%, of ester) in the form of foam.

Stage D: Obtained at the stage In About-Tgp-protected hydroxamate (2.0 g, 3.95 mmol) was dissolved in methanol (16 ml). After 2 min was added acetylchloride (0,86 ml, 12 mmol). The reaction mixture was stirred for 4 h at ambient temperature, then was concentrated, re-adding chloroform and acetonitrile to effect the drying. Specified in the title compound was deposited in a solid white color (1.77 g, 98%). MS (ES) MN+: calculated for C20H26N2O4S2: 422 detected 422.

Example 47: Obtain 1-oxide N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide and N-hydroxy-4-[[4-(phenylsulfinyl)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

To a solution of N-hydrox the-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide (specified in the title compound, example 9) (215 mg, 0.5 mmol) in methanol (5 ml) was added at 0° meta-chloroperbenzoic acid (120 mg, 57-86%). The reaction mixture gave to slowly warm to ambient temperature and after 16 h the mixture was passed through a filter with a pore size of about microns and concentrated. Using GHUR with reversed phase (column type Delta Pak 50× 300 mm; 15 MK C18100 E; a method using a 30 minute gradient, since the ratio in the mixture, dilute HCl (0.5 ml/4 liters) : acetonitrile 80:20, and ending with a ratio of 50:50) were divided by 5 major components. After concentration of the first and second peak, buervenich from the column received 14 mg (6%) and 16 mg (7%) of the two compounds, which were identified on the basis of their NMR spectra as diastereoisomeric N-hydroxy-4-[[4-(phenylsulfinyl)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide. The third peak was not identified. The fourth peak on the basis of the NMR spectrum was identified as 1-oxide N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide (147 mg, 66%). MS (ES) MN+: calculated for C21H22N2O5S2: 447, found 447. The last peak contains 73 mg of the recovered 3-chlorbenzoyl acid.

Example 48: Obtain N-hydroxy-2,2-dimethyl-5-[(4-phenoxyphenyl)sulfonyl]-1,3-dioxane-4-carboxamide

Stage A: Prepare a fresh solution of sodium methoxide by slowly added at 0° washed With hexane granules of sodium (9.4 g, 410 mmol) to methanol (1.0 l). To this cooled solution was added 4-portifino (50.0 g, 390 mmol)and then methyl 2-CHLOROACETATE (42,3 g, 390 mmol). After heating to ambient temperature the reaction mixture was stirred overnight (about 18 hours). The methanol was removed in vacuo and the residue was dissolved in ethyl acetate (300 ml). The organic layer was washed with water (2× 200 ml) and dried over MgSO4. After concentration received the product, representing sulfide methyl ester, in the form of a clear oil (71,8 g, 92%).

Stage B: To the solution obtained at the stage And sulfide methyl ester (71,8 g, 358 mmol) in a mixture of 70%methanol/N2(1.0 l) was slowly added to Ohope™ (660 g of 1.08 mol). The mixture was stirred overnight (about 18 hours) at ambient temperature. The excess of Ohope™ was filtered and the methanol removed from the filtrate in vacuo. The remaining aqueous solution was extracted with ethyl acetate (3× 300 ml). The organic layers were washed with water (2× 300 ml) and dried over MgSO4. After concentration was received sulfon in the form of oil reddish brown (82 g, 98%).

Stage b: prepared suspension of potassium bicarbonate (1.0 g, 9.8 mmol) in 37%of rest the re formaldehyde was added obtained in stage B sulfon (28.6 g, 123 mmol). The reaction mixture was stirred for 1 h and then was added a saturated solution of sodium sulfate (20 ml). After stirring for 30 min the mixture was extracted with diethyl ether (4× 100 ml). The organic layers were dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received the product, representing sulfonyl, in the form of a clear oil (15.3 g, 42%).

Stage D: Obtained at the stage In sulfonyl (1.3 g, 4.5 mmol) was dissolved together with 2,2-dimethoxypropane (1.1 ml, 9.0 mmol) and the monohydrate para-toluensulfonate acid (0.03 mg, 0.14 mmol) in acetone (40 ml) and the resulting mixture was boiled under reflux for 6 hours After cooling, the mixture was neutralized with solid Na2CO3(pH~7), filtered and concentrated. The residue was dissolved in chloroform (50 ml) and washed with water (2× 30 ml). After drying over MgSO4and concentration received the product, representing dimethylacetal, in the form of a dark oil (1.4 g, 94%).

Stage D: To the solution obtained in stage G of dimethylketene (1.4 g, 4.2 mmol) in N,N-dimethylformamide (20 ml) was added phenol (0.6 g, 6.3 mmol) and cesium carbonate (2.0 g, 6.3 mmol). The mixture was stirred for 5 h at 90° C, was diluted with water (20 ml) and was extracted with ethyl acetate (4× 100 ml). The organic layers were washed with brine (g ml) and water (1× 10 ml). After concentration was obtained phenol-O-penultimately in the form of a dark brown oil (1.51 g, 88%).

Stage E: To the solution obtained in stage D phenol-O-fieldmetadata (1.5 g, 3.4 mmol) in tetrahydrofuran (10 ml) was added an aqueous solution of lithium hydroxide (0.34 g, of 14.8 mmol, in 5 ml of N2About). The reaction mixture was stirred for 2 h and then was diluted with water (15 ml) and acidified with 30%aqueous HCl solution to pH 3. The acidic solution was extracted with diethyl ether (3× 100 ml). After drying over MgSO4and concentration received the product, which represents a carboxylic acid, in the form of a brown oil (1.5 g, quantitative yield).

Stage G: To a solution containing obtained in stage E carboxylic acid (1.3 g, 3.3 mmol) and the hydrate of N-hydroxybenzotriazole (0.54 g, 4.0 mmol) in DMF (15 ml)was sequentially added 4-methylmorpholine (1,67 g, 16.5 mmol), O-tetrahydro-2H-Piran-2-alhydrogel (1.2 g, 10.2 mmol) and EDC (0.88 g, 4.6 mmol). After stirring over night DMF was removed in vacuo and the residue was dissolved in a mixture of ethyl acetate/water (1:1, 50 ml). The organic layer was washed with brine (1× 20 ml) and water (1× 20 ml) and dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received Tgp-protected hydroxylamine in the form of a solid white color (0.36 g, 22%), and dicarboxilic the cell by-product (0.27 g, 24%).

Stage C: the solution obtained in stage G Tgp-protected hydroxylamine (0.36 g, 0.73 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4 n HCl solution in dioxane (2 ml). The reaction mixture was stirred for 5 min and then the solvents were removed in vacuum. After chromatography (reversed phase, column C-18, acetonitrile/water) has been specified in the title compound in the form of solid white (0,13 g, 44%). MS (FAB) MH+: calculated for C19H21NO7S: 408 detected 408.

Example 49: Receiving tetrahydro-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

Stage A: To a solution of methyl 2-CHLOROACETATE (322 g, 2,96 mol) in N,N-dimethylacetamide (1.0 l) was added thiophenol (400 g, 3,12 mol) and potassium carbonate (408 mg, 2,96 mol). The reaction mixture was stirred overnight (about 18 hours) at ambient temperature. After dilution minimum amount of water (800 ml) the mixture was extracted with ethyl acetate (4× 1 l). The organic layers were washed with water (1× 800 ml), dried over MgSO4and concentrated, obtaining a product that is a sulfide, in the form of a clear oil (614 g, quantitative yield).

Stage B: To the solution obtained at the stage And sulfide (75,85 g, 0.38 mol) in methanol (1000 ml) was added at 20° With water (100 ml) and Ohope® (720 g, 1,17 supposedly is). Was exothermic reaction, in which the temperature was increased to 67° C. After 2 h the reaction mixture was filtered and the filter residue is thoroughly washed with methanol. The filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with brine, dried over MgSO4and concentrated in vacuum, obtaining sulfon in the form of a crystalline solid (82,74 g, 94%).

Stage b: To the solution obtained in stage B sulfone (60 g, 258 mmol) in DMA (350 ml) was added dibromodulcitol (76.9 g, 310 mmol)and then potassium carbonate (78,3 g, 568 mol). The mixture was stirred for 5 min, then was added a catalytic amount of 4-dimethylaminopyridine and tetrabutylammonium bromide. The reaction mixture was stirred overnight (about 18 hours), then poured with stirring into 10%aqueous HCl solution (2.5 liters). The precipitate was filtered and washed with hexane to remove excess tiefer. After drying in vacuum overnight (approximately 18 h) was obtained methyl ether thiopyran-Ph-p-F in the form of a yellow powder (76,1 g, 93%).

Stage G: To a solution obtained at the stage In methyl ester thiopyran-Ph-p-F (4.0 g, 12.6 mol) in N,N-dimethylacetamide (25 ml) was added cesium carbonate (6,1 g of 18.9 mmol) and thiophenol (2.1 g, to 18.9 mmol). The mixture was stirred for 2 h at 90° C. a Mixture of razbam the Yali water (30 ml) and was extracted with ethyl acetate (3× 100 ml). The organic layers were washed with brine (1× 75 ml) and water (1× 75 ml), then dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received were-S-phenyl ether in a solid yellowish (3.6 g, 71%).

Stage D: To the solution obtained in stage G were-C-phenyl ester (3.6 g, 8,8 mmol) in tetrahydrofuran (15 ml) was added trimethylsilyl potassium (1.24 g, 9.7 mmol). The mixture was stirred for 2-3 h at ambient temperature, or until, until it formed a solid residue. After completion of the hydrolysis was added N-methylmorpholine (2,9 ml of 26.4 mmol), and then Rougher (4.9 g, 10.6 mmol). The solution was stirred for 10 minutes was Added an aqueous solution of hydroxylamine (0.32 g, 9.7 mmol) and the mixture was stirred for 2 hours After completion of the reaction the solvent was removed in vacuum. After chromatography (reversed phase, column C-18, acetonitrile/water) residue has been specified in the title compound in the form of solids whitish (0,82 g, 23%). MS (FAB) MH+: calculated for C18H19NO4S3: 410 found 410.

Example 50: Obtain 4-[4-forfinal)sulfonyl]tetrahydro-N-[(tetrahydro-2H-Piran-2-yl)oxy]-2H-thiopyran-4-carboxamide

Stage A: To a solution of methyl 2-CHLOROACETATE (322 g, 2,96 mol) in N,N-DIMET is acetamide (1.0 l) was added thiophenol (400 g, 3,12 mol) and potassium carbonate (408 g, 2,96 mol). The reaction mixture was stirred overnight (about 18 hours) at ambient temperature. After dilution minimum amount of water (800 ml) the mixture was extracted with ethyl acetate (4× 1 l). The organic layers were washed with water (1× 800 ml), dried over MgSO4and concentrated, obtaining a product that is a sulfide, in the form of a clear oil (614 g, quantitative yield).

Stage B: To the solution obtained at the stage And sulfide (75,85 g, 0.38 mol) in methanol (1000 ml) was added at 20° With water (100 ml) and Ohope® (720 g of 1.17 mol). Was exothermic reaction, in which the temperature was increased to 67° C. After 2 h the reaction mixture was filtered and the filter cake was thoroughly washed with methanol. The filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with brine, dried over MgSO4, filtered and concentrated in vacuum, obtaining sulfon difficult methyl ester in the form of a crystalline solid (82,74 g, 94%).

Stage b: To the solution obtained in stage B sulfone difficult methyl ester (60,0 g, 258 mmol) in N,N-dimethylacetamide (350 ml) was added 2,2-dibromodulcitol (76.9 g, 310 mmol)and then potassium carbonate (78,3 g, 568 mol). The mixture was stirred for 5 min, then was added a catalytic amount the VA 4-dimethylaminopyridine and tetrabutylammonium bromide. The reaction mixture was stirred overnight (about 18 hours), then poured with stirring into 10%aqueous HCl solution (2.5 liters). The precipitate was filtered and washed with hexane to remove excess tiefer. After drying in vacuum overnight (approximately 18 h) was obtained methyl ether thiopyrano in the form of a yellow powder (76,1 g, 93%).

Stage G: To a solution obtained at the stage In methyl ester thiopyran (30.0 g, 94 mmol) in tetrahydrofuran (250 ml) was added trimethylsilyl potassium (28,9 g, 226 mmol). The mixture was stirred for 2-3 h at ambient temperature, or until, until it formed a solid residue. After completion of the hydrolysis, the solvent was removed in vacuum. Was added water (200 ml) and the mixture was washed with diethyl ether (1× 200 ml). The aqueous layer was cooled to 0° and was slowly added 10%aqueous HCl solution until until the formed precipitate. The solid was collected and dried under vacuum in the presence of phosphorus pentoxide, getting typerechargeable acid in a solid yellow color (17.8 g, 62%).

Stage D: To the solution obtained in stage G typerechargeable acid (17.8 g, 58,5 mmol) in N,N-dimethylformamide (100 ml) was added N-methylmorpholine (19.3 ml, 176 mmol), and then hydrate, N-hydroxybenzotriazole (9.5 g, to 70.2 mmol), O-tetrahydro-2H-Piran-2-alhydrogel (10.3 g, 7.8 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16,8 g, of 87.8 mol). The mixture was stirred for 3 h and then was diluted with water (100 ml). The mixture was extracted with ethyl acetate (4× 200 ml). The organic layers were washed with saturated aqueous solution of potassium carbonate (1× 200 ml), 1%aqueous solution of HCl and with brine (1× 200 ml). After drying over MgSO4and concentration in vacuum has been specified in the title compound in the form of solids whitish (30,8 g, quantitative yield). MS (FAB) MH+: calculated for C17H22FNO5S2: 404, found 404.

Example 51: Receiving tetrahydro-N-hydroxy-4-[[4-[4-methoxyphenyl)thio]phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

Stage A: To a solution specified in the header of example 50 compound (6.0 g, 14.9 mmol) in N,N-dimethylacetamide (25 ml) was added 4-methoxythiophene (2.5 g, of 17.8 ml)and then potassium carbonate (6.2 g, a 44.7 mmol). The reaction mixture was stirred for 3 h at 60° C. the Reaction mixture was diluted with water (25 ml) and was extracted with ethyl acetate (4× 100 ml). The organic layers were washed with water (2× 50 ml) and dried over MgSO4. After concentration in vacuo received Tgp-protected phenyl-S-para-phenyl-OMe-derived in the form of a solid yellowish (9,2 g, quantitative yield).

Stage B: To the solution obtained at the stage And Tgp-protected phenyl-S-para-Fe is Il-OMe-derived (9.2 grams, 14.9 mmol) in dioxane was slowly added 4n. a solution of HCl in dioxane (10 ml). After stirring overnight (approximately 18 h). the solvent was removed. After chromatography of the resulting residue (reversed phase, column C-18, acetonitrile/water) has been specified in the title compound in the form of solid white (1.84 g, 28.3 per cent). MS (FAB) MH+: calculated for C19H21About5S3: 440 detected 440.

Example 52: Obtaining 1,1-dioxide, tetrahydro-N-hydroxy-4-[[(4-(phenylthio)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

Stage A: To a solution specified in the header of example 50 compound (13,0 g, 24.5 mmol) in methylene chloride (100 ml), cooled to 0° C, was slowly added 50-60%meta-chloroperbenzoic acid (17.1 g, a 49.5 mmol). The mixture was stirred for 1 h at 0° and then for another 3 h, the temperature was raised to ambient temperature. Was added water (200 ml) and the mixture was neutralized 10%ammonium hydroxide solution (100 ml). The organic layer was washed with water (1× 200 ml) and dried over MgSO4. After concentration in vacuo received oil orange color (3.5 g, 33%). A solution of the product in a mixture of water/10%ammonium hydroxide saturated with sodium chloride and extracted with ethyl acetate (2× 400 ml). The organic layer was dried over MgSO4and to whom is centered, getting Tgp-protected sulfonterol-pair-F-derived foam orange (6,1 g, 57%).

Stage B: To the solution obtained at the stage And Tgp-protected sulfonterol-pair-F-derived (9.6 g, 22 mmol) in N,N-dimethylurea-MFA (120 ml) was added thiophenol (2.9 g of 26.4 ml)and then potassium carbonate (9.1 g, 66 mmol). The reaction mixture was stirred for 4 h at 60° C. the Reaction mixture was diluted with water (25 ml) and was extracted with ethyl acetate (4× 100 ml). The organic layers were washed with water (2× 50 ml) and dried over MgSO4. After chromatography (silica gel, ethyl acetate/hexane) received Tgp-protected phenyl-S-phenyl derivative in the form of an orange oil (5.1 g, 43%).

Stage b: To the solution obtained in stage B Tgp-protected phenyl-S-phenyl derivative (5,1 g, 9.4 mmol) in dioxane was slowly added 4n. a solution of HCl in dioxane (10 ml). After stirring overnight (approximately 18 h). the solvent was removed. After chromatography of the resulting residue (reversed phase, column C-18, acetonitrile/water) has been specified in the title compound in the form of solid pink (1.2 g, 29%). MS (FAB) MH+: calculated for C18H19NO6S3: 442 detected 442.

Example 53: Receiving monohydrochloride tetrahydro-N-hydroxy-4-[[4-[4-(1H-1,2,4-triazole-1-yl)phenoxy]phenyl]sulfonyl]-2H-thiopyran-4-to Roxane-1,1’-dioxide

Stage A: To a solution specified in the header of example 50 compound (13,0 g, 24.5 mmol) in methylene chloride (100 ml), cooled to 0° C, was slowly added 50-b%meta-chloroperbenzoic acid (17.1 g, a 49.5 mmol). The mixture was stirred for 1 h at 0° and then for another 3 h, the temperature was raised to ambient temperature. Was added water (200 ml) and the mixture was neutralized 10%ammonium hydroxide solution (100 ml). The organic layer was washed with water (1× 200 ml) and dried over MgSO4. After concentration in vacuo received oil orange color (3.5 g, 33%). A solution of the product in a mixture of water/10%ammonium hydroxide saturated with sodium chloride and extracted with ethyl acetate (2× 400 ml). The organic layer was dried over MgSO4and focused, getting Tgp-protected sulfonterol-pair-F-derived foam orange (6,1 g, 57%).

Stage B: To the solution obtained at the stage And Tgp-protected sulfonterol-pair-F-derived (6.0 g, of 13.8 mmol) in N,N-dimethylformamide (25 ml) was added 4-(1H-1,2,4-triazole-1-yl)phenol (4.4 g, 27.5 mmol), and then cesium carbonate (13,4 g, up 41.4 mmol). The reaction mixture was stirred for 5 h at 95° C. the Reaction mixture was diluted with water (25 ml) and was extracted with ethyl acetate (4× 100 ml). The organic layers were washed with water (2× 50 ml) and is sewed over MgSO 4. After concentration in vacuo received Tgp-protected phenyl-O-phenylthiazole derived in the form of a solid reddish-brown (9.7 g, quantitative yield).

Stage b: To the solution obtained in stage B of untreated Tgp-protected phenyl-O-phenylthiazole derived (8.0 g, of 13.8 mmol) in acetonitrile was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. The precipitate was collected, getting mentioned in the title compound in the form of a solid reddish-brown color (1.3 g, 18%). MS (FAB) MH+: calculated for C20H21ClN4O7S2: 493, found 493.

Example 54: Receiving monohydrochloride 4-[[4-[4-(2-amino-ethyl)phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-thiopyran-4-carboxamide-1,1’-dioxide

Stage A: To a solution specified in the header of example 50 compound (13,0 g, 24.5 mmol) in methylene chloride (100 ml), cooled to 0° C, was slowly added 50-60%meta-chloroperbenzoic acid (17.1 g, a 49.5 mmol). The mixture was stirred for 1 h at 0° and then for another 3 h, the temperature was raised to ambient temperature. Was added water (200 ml) and the mixture was neutralized 10%ammonium hydroxide solution (100 ml). The organic layer is washed with water (1× 200 ml) and dried over MgSO4. After concentration in vacuo received oil orange color (3.5 g, 33%). A solution of the product in a mixture of water/10%ammonium hydroxide saturated with sodium chloride and extracted with ethyl acetate (2× 400 ml). The organic layer was dried over MgSO4and focused, getting Tgp-protected sulfonterol-pair-P-derived foam orange (6,1 g, 57%).

Stage B: To the solution obtained at the stage And Tgp-protected sulfonterol-pair-F-derived (6.0 g, of 13.8 mmol) in N,N-dimethylacetamide (25 ml) was added tyramine (3.8 g, 28 mmol), and then cesium carbonate (13,6 g, 42 mmol). The reaction mixture was stirred for 5 h at 95° C. After removal of the N,N-dimethylacetamide in a vacuum received solid brown (20 g). After chromatography (reversed phase, column C-18, acetonitrile/water) received Tgp-protected tyramine in the form of oil is reddish-brown color (1.0 g, 13%).

Stage b: To the solution obtained in stage B of untreated Tgp-protected tiramina (1.0 g, 1.8 mmol) in acetonitrile was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. The precipitate was collected, getting mentioned in the title compound in the form of a solid reddish-brown color (0.9 g, 99%). MS (FAB) MH+: calculated for C 20H25CIN2O7S2: 469 detected 469.

Example 55: Obtain 4-[(4-forfinal)sulfonyl]tetrahydro-N-[(tetrahydro-2H-Piran-2-yl)oxy]-2H-Piran-4-carboxamide

To methanol (1000 ml)in a dry vessel was added in nitrogen atmosphere with 2° With metallic sodium (8,97 g, to 0.39 mol). The reaction mixture was stirred for 45 min at ambient temperature, during which time the sodium had dissolved. The solution was cooled to 5° and added para-portifino (41,55 ml to 0.39 mmol)and then methyl 2-CHLOROACETATE (34,2 ml to 0.39 mol). The reaction mixture was stirred for 4 h at ambient temperature, filtered and concentrated in vacuum, obtaining sulfide in the form of a clear colorless oil (75,85 g, 97%).

Stage B: To the solution obtained at the stage And sulfide (75,85 g, 0.38 mol) in methanol (1000 ml) was added at 20° With water (100 ml) and Ohope® (720 g of 1.17 mol). This was accompanied by an exothermic reaction in which the temperature was increased to 67° C. After 2 h the reaction mixture was filtered and the filter cake was thoroughly washed with methanol. The filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with brine, dried over MgSO4, filtered and concentrated in vacuum, obtaining sulfon in the form of a crystalline solid is wow substances (82,74 g, 94%).

Stage b: To the solution obtained in stage B sulfone (28.5 g, 0,123 mol) in N,N-dimethylacetamide (200 ml) was added potassium carbonate (37,3 g, 0.27 mol), easy-bis(2-bromatology) ether (19.3 ml, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol) and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction mixture was stirred overnight (about 18 hours) at ambient temperature. The reaction mixture was slowly poured into 1 n HCl solution (300 ml), was filtered, the resulting solid product and the filter cake was thoroughly washed with hexane. The solid is recrystallized from ethyl acetate/hexane, getting Piran in a solid beige color (28,74 g, 77%). MS (ES+) MN+: calculated for C13H15O5S1F1: 303, found 303.

Stage G: In a dry vessel under nitrogen atmosphere obtained at the stage In Piran (8.0 g, of 26.5 mmol) was dissolved in anhydrous tetrahydrofuran (250 ml) and at ambient temperature was added a solution of trimethylsilane potassium (10.2 g, 79.5 mmol) in anhydrous tetrahydrofuran (15 ml). After 90 min was added water (100 ml) and the solution was concentrated in vacuum. The residue was dissolved in water and was extracted with ethyl acetate to remove unreacted raw product. The aqueous solution was treated with 6N. a solution of HCl to reach pH 1. The suspension was extracted with ethyl acetate and merge the data extracts were washed with water, dried over Na2SO4, filtered and concentrated in vacuum. The residue was heated in diethyl ether, the solid product was filtered and dried, obtaining the carboxylic acid in the form of a crystalline solid (5,78 g, 76%). Msvr (ES-) M-N: calculated for C12H13O5S1F1: 287,04 found 287,04.

Stage D: Obtained in stage G of carboxylic acid (9.1 g, of 31.6 mmol) was dissolved in dry vessel under nitrogen atmosphere in anhydrous N,N-dimethylformamide (70 ml) and then to the solution was added to the other reagents in the following order: hydrate, N-hydroxybenzotriazole (5,1 g of 37.9 mmol), N-methylmorpholin (10.4 ml, or 94.8 mmol), O-tetrahydro-2H-Piran-2-alhydrogel (11,5 g, 98 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (8,48 g, a 44.2 mmol). After incubation for 3 h at ambient temperature the reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with water, 5%KHSO4, a saturated solution Panso3, saline solution, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) has been specified in the title compound as crystalline solid (9.7 g, 80%). Msvr (ES+) MN+: calculated for C17H22NO6S1F1: 388,12 found 388,12.

Example 56: N is the receiving 4-[[4-(3,4-divergence)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) was added 3,4-diferena (1.0 g, 7.7 mmol), and then cesium carbonate (6.6 g, a 20.2 mmol). The reaction mixture was stirred for 5 h at 95° C. After removal of the N,N-dimethylacetamide in a vacuum received solid brown (8,3 g, quantitative yield). After chromatography (reversed phase, column C-18, acetonitrile/water) received Tgp-protected diperolehi product in solution.

Stage B: To assembled obtained at the stage And Tgp-protected diversidade product in a mixture of acetonitrile/water (50 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (1,02 g, 48.6 per cent). MS (FAB) M+H: calculated for C18H17FNO6S: 414 detected 414.

Example 57: Receiving tetrahydro-N-hydroxy-4-[[4-(4-iodinase)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) was added 4-itfinal (1.7 g, 7.8 mmol), and then cesium carbonate (6.6 g, a 20.2 mmol). The reaction mixture in which he had laid down for 5 h at 95° C. After removal of the N,N-dimethylacetamide in a vacuum received solid brown (5.7 g, quantitative yield). After chromatography (reversed phase, column C-18, acetonitrile/water) received Tgp-protected iodine-containing product in solution.

Stage B: To the solution obtained at the stage And Tgp-protected iodine-containing product in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (2.6 g, 99%). MS (FAB) M+H: calculated for C18H18INO6S: 504 detected 504.

Example 58: Receiving tetrahydro-N-hydroxy-4-[[4-(2,4,5-tryptophanate)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) was added 2,4,5-tryptophanol (1.2 g, 7.8 mmol), and then cesium carbonate (10.1 g, was 31.0 mmol). The reaction mixture was stirred for 32 h at 95° C. After removal of the N,N-dimethylacetamide in a vacuum received solid brown (5.7 g, quantitative yield). After chromatography (reversed phase, column C-18, acetonitrile/water) received Tgp-protected phenol (1.2 g, 44%).

One hundred of the Oia B: To the solution obtained at the stage And untreated Tgp-protected phenol (1.2 g, 2.3 mmol) in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (0,79 g, 79%). MS (FAB) M-H: calculated for C18H16F3NO6S: 430 detected 430.

Example 59: Obtain 4-[[4-(3,5-dichlorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) was added 3,5-dichlorphenol (1.3 g, 7.8 mmol), and then cesium carbonate (6.6 g, a 20.2 mmol). The reaction mixture was stirred for 12 h at 95° C. After removal of the N,N-dimethylacetamide in a vacuum received solid brown (5.7 g, quantitative yield). The residue was dissolved in a mixture of acetonitrile/water (20 ml) and acidified to pH 6. Formed white precipitate, which was collected, receiving Tgp-protected substance in the form of sediment on the filter in white (1.8 g, 64%).

Stage B: To the solution obtained at the stage And Tgp-protected substance (1.8 g, 3.4 mmol) in a mixture of acetonitrile/water (20 ml) was slowly added 10%aqueous HCl solution (40 ml). After stirring overnight (approximately 18 h) acetonitrile delete the Lee. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (0.71 g, 47%). MS (FAB) M+H: calculated for C18H17Cl2NO6S: 447, found 447.

Example 59A: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-[[5-(trifluoromethyl)-2-pyridinyl]thio]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) was added 5-(trifluoromethyl)-2-pyridinethiol (1.4 g, 7.8 mmol)and then potassium carbonate (2.2 g, 15.6 mmol). The reaction mixture was stirred for 12 h at 65° C. After removal of the N,N-dimethylacetamide in a vacuum received solid brown (5,4 g, quantitative yield). After chromatography (reversed phase, column C-18, acetonitrile/water) received Tgp-protected substance in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected substance in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (40 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (0.20 g, 8%). MS (FAB) M+H: calculated for C18H17F3N2O5S2 : 463, found 463.

Example 60: Obtain 4-[[4-(3,4-dichlorophenyl)thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) was added 3,4-dichlorothiophene (1.4 g, 7.8 mmol)and then potassium carbonate (2.2 g, 15.6 mmol). The reaction mixture was stirred for 6 h at 70° C. After removal of the N,N-dimethylacetamide in a vacuum was obtained, the solid brown color (5.6 g, quantitative yield). After chromatography (reversed phase, column C-18, acetonitrile/water) received Tgp-protected substance in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected substance in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (40 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. Collected the sediment, getting mentioned in the title compound 6 as solid white (1.50 g, 62%). MS (FAB) M+H: calculated for C18H17Cl2NO5S: 463, found 463.

Example 61: Receiving monohydrochloride 4-[[4-[[2-amino-4-(trifluoromethyl)phenyl]thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header note the RA 55 compound (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) were added hydrochloride 2-amino-4-(trifluoromethyl)thiophenol (1.8 g, 7.8 mmol)and then potassium carbonate (3.6 g, 26 mmol). The reaction mixture was stirred for 8 h at 70° C. After removal of the N,N-dimethylacetamide in a vacuum received solid brown (14 g, quantitative yield). After chromatography (reversed phase, column C-18, acetonitrile/water) received Tgp-protected substance in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected substance in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (40 ml). After stirring overnight (approximately 18 h) acetonitrile was removed. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (1.3 g, 52%). MS (FAB) M+H: calculated for C18H17Cl2NO6S: 477, found 477.

Example 62: Getting monohydrochloride tetrahydro-4-[[4-(4-phenyl-1-piperidinyl)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To methanol (1000 ml)in a dry vessel was added in nitrogen atmosphere with 2° With metallic sodium (8,97 g, to 0.39 mol). The reaction mixture was stirred for 45 min at ambient temperature, during which time the sodium had dissolved. The solution of ohlord is whether to 5° With and added para-portifino (41,55 ml to 0.39 mmol)and then methyl 2-CHLOROACETATE (34,2 ml to 0.39 mol). The reaction mixture was stirred for 4 h at ambient temperature, filtered and concentrated in vacuum, obtaining sulfide in the form of a clear colorless oil (75,85 g, 97%).

Stage B: To the solution obtained at the stage And sulfide (75,85 g, 0.38 mol) in methanol (1000 ml) was added at 20° With water (100 ml) and Ohope® (720 g of 1.17 mol). This was accompanied by an exothermic reaction in which the temperature was increased to 67° C. After 2 h the reaction mixture was filtered and the filter cake was thoroughly washed with methanol. The filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with brine, dried over MgSO4, filtered and concentrated in vacuum, obtaining sulfon in the form of a crystalline solid (82,74 g, 94%).

Stage b: To the solution obtained in stage B sulfone (28.5 g, 0,123 mol) in N,N-dimethylacetamide (200 ml) was added potassium carbonate (37,3 g, 0.27 mol), easy-bis(2-bromatology) ether (19.3 ml, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol) and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction mixture was stirred overnight (about 18 hours) at ambient temperature. The reaction mixture was slowly poured into 1 n HCl solution (300 ml), filtered the resulting solid is already installed, and the filter cake was thoroughly washed with hexane. The solid is recrystallized from ethyl acetate/hexane, getting Piran in a solid beige color (28,74 g, 77%). MS (ES+) MN+: calculated for C13H15About5S1F1: 303, found 303.

Stage G: To a solution obtained at the stage In Piran (1,21 g, 4.0 mmol) in dimethyl sulfoxide (10 ml) was added cesium carbonate (3,26 g, 10 mmol) and 4-phenylpiperidine (0.64 g, 4.0 mmol) in methylsulfoxide (10 ml). The suspension was stirred for 2 h at 90° C. the Reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with 5%solution of KHSO4, a saturated solution of NaHCO3, saline solution, dried over Na2SO4, filtered and concentrated in vacuum. The resulting solid is suspended in diethyl ether, filtered and dried, obtaining N-substituted piperidine in the form of a solid white color (1.2 g, 67%). MS (FAB+) MN+: calculated for C24H29N1O5S1: 444, found 444.

Stage D: To a suspension containing obtained in stage G of N-substituted piperidine (815 g of 1.84 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml) was added 50%sodium hydroxide solution (3 ml). After incubation for 24 h at ambient temperature the reaction mixture was concentrated in vacuum. A suspension of p is bavlyali water (10 ml) was added 6 N. HCl to obtain pH 7. After vacuum filtration of the resulting precipitate got acid in a solid white color (705 mg, 89%). MS (FAB+) MN+: calculated for C23H27N1O5S1: 430 detected 430.

Stage E: Obtained in stage D carboxylic acid (620 mg, 1.44 mmol) suspended in dry vessel under nitrogen atmosphere in methylene chloride (10 ml) and N,N-dimethylformamide (3 ml) and then to the suspension was added to the other reagents in the following order: hexaphosphate bromo-Tris-pyrrolidinone (810 mg, at 1.73 mmol), N-methylmorpholine (0.5 ml, 4,34 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (190 mg, of 1.59 mmol) After incubation for 4 h at ambient temperature the reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with water, with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received Tgp-protected hydroxamate in a solid white color (630 mg, 83%). MS (FAB+) MN+: calculated for C28H22N2O6S1: 529 found 529.

Stage G: To the suspension obtained in stage E Tgp-protected hydroxamate (600 mg, to 1.14 mmol) in dioxane (1.5 ml) was added 4n. a solution of HCl in dioxane (1.5 ml) and methanol (1.5 ml). After wederive the I for 2 h at ambient temperature the reaction mixture was poured into diethyl ether (100 ml). After vacuum filtration of the resulting precipitate has been specified in the title compound in the form of solid light beige color (500 mg, 91%). MS (FAB+) M+Li: calculated for C23H28N2O5S1: 445, found 445.

Example 63: Obtaining monohydrochloride 4-[[4-[4-(1,3-benzodioxol-5-yloxy)-1-piperidinyl)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: In a dry vessel under nitrogen atmosphere was dissolved 4-hydroxypiperidine (20.2 g, 0.2 mol) in tetrahydrofuran (200 ml) and triethylamine (29 ml, 0.21 mol). Solution was added di-tert-BUTYLCARBAMATE (43,65 g, 0.2 mol) at such a speed that the temperature did not exceed 30° C. After stirring for 4 h at ambient temperature the reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with water, 5%solution of KHSO4, a saturated solution of NaHCO3, saline solution, dried over Na2SO4, filtered and concentrated in vacuum, obtaining the BOC-protected piperidine in the form of a solid white color (37,7 g, 94%).

Stage B: In a dry vessel under nitrogen atmosphere obtained at the stage AND the BOC-protected piperidine (5.0 g, 24,8 mmol)dissolved in anhydrous tetrahydrofuran (100 ml), cooled to 0° and added triphenylphosphine (9,77 g of 37.3 mmol). After PE is emiliania for 15 min at 0° To the reaction mixture were added sesamol (5,15 g of 37.3 mmol)and then dropwise diethylazodicarboxylate (by 5.87 ml, of 37.7 mmol). The reaction mixture was stirred for 30 min at 0° and then for 12 h at ambient temperature. The reaction mixture was concentrated in vacuum. The residue is suspended in diethyl ether, was filtered triphenylphosphine oxide and the filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received the substituted BOC-protected piperidine in the form of a solid white color (3,14 g, 39%).

Stage b: To a suspension obtained in stage B substituted BOC-protected piperidine (3,14 g, 9.8 mmol) in dioxane (15 ml) was added 4 n HCl solution in dioxane (15 ml). After incubation for 3 h at ambient temperature the reaction mixture was concentrated in vacuum. The residue is suspended in diethyl ether and after vacuum filtration of the resulting precipitate was received hydrochloride in a solid white color (2.3 g, 100%).

Stage G: To the suspension obtained in stage hydrochloride (0,93 g, 3.6 mmol) in N,N-dimethylformamide (10 ml) was added cesium carbonate (2,93 g, 9 mmol) and specified in the header of example 55 compound (1,16 g, 3.0 mmol). The suspension was stirred for 24 h at 90° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl is the Etat, washed with water, 5%solution of KHSO4, a saturated solution Panso3, saline solution, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in a solid white color (640 mg, 36%). MS (FAB+) MN+: calculated for C29H36N2O9S1: 589 found 589.

Stage D: To the suspension obtained in stage G Tgp-protected hydroxamate (600 mg, of 1.02 mmol) in dioxane (3 ml) was added 4n. a solution of HCl in dioxane (3 ml) and methanol (3 ml). After incubation for 1 h at ambient temperature the reaction mixture was poured into diethyl ether (100 ml). After vacuum filtration of the resulting precipitate has been specified in the title compound in the form of solid light beige color (440 mg, 80%). Msvr (ES+) MH+: calculated for C24H28N2O8S1: 505,16 found 505,16.

Example 64: Getting tetrahydro-N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (3,48 g, 9 mmol) in N,N-dimethylformamide (20 ml) was added cesium carbonate (8.8 g, 27 mmol) and para-methoxyphenol (2,23 g, 18 mmol). The suspension was stirred for 24 h at 95 C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a beige foam (3,82 g, 86%). MS (FAB+) MN+: calculated for C24H29N1O8S1: 492 detected 492.

Stage B: To a suspension obtained at the stage And Tgp-protected hydroxamate (3.6 g, 7,33 mmol) in dioxane (18 ml) was added 4n. a solution of HCl in dioxane (18 ml) and methanol (18 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuum. The product was recrystallized (acetone/hexane)to give specified in the title compound in the form of solid light beige color (2.1 g, 70%). Msvr (ES+) MH+: calculated for C19H21N1O7S1: 408,11 found 408,11.

Example 65: Getting tetrahydro-N-hydroxy-4-[[4-(4-methoxybenzylthio)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (3.1 g, 8 mmol) in N,N-dimethylformamide (20 ml) was added potassium carbonate (1,33 g, 9.6 mmol) is a pair-methoxybenzoyl (1.48 g, 12 mmol). The suspension was stirred for 24 h at 65° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (4.1 g, 100%). Msvr (ES+) M+NH

+
4
: calculated for C24H29N1O7S2: 525,17 found: 525,17.

Stage B: To a suspension obtained at the stage And Tgp-protected hydroxamate (4.0 g, 7.9 mmol) in dioxane (20 ml) was added 4n. a solution of HCl in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuum. The product was recrystallized (acetone/hexane)to give specified in the title compound in the form of solid white (of 2.21 g, 67%). Msvr (ES+) MH+: calculated for C19H21N1About6S2: 424,09 found: 424,09.

Example 66: Obtain 4-[(4-forfinal)sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a suspension specified in the header of example 55 compound (530 mg, 1.38 mmol) in dioxane (5 ml) was added 4 n HCl solution in dioxane (5 ml) and methanol (5 ml). After incubation for 15 min at ambient temperature the reaction mixture was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/water) has been specified in the title compound in the form of solid beige color (140 mg, 34%). Msvr (ES+) M+NH4+: calculated for C12H14N1O5S1F1: 321,09 found: 321,09.

Example 67: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-(4-piperidinyloxy)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: In a dry vessel under nitrogen atmosphere at 0° With 60%of the resultant solution of sodium hydride (210 mg, the 5.25 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added 4-hydroxy-N-tert-(butoxycarbonyl)piperidine (844 mg, 4.2 mmol). The suspension was stirred for 2 h at ambient temperature. At 5° With added specified in the header of example 55 compound (1.35 g, 3.5 mmol) and the reaction mixture was heated for 3 h to 50° C. the Reaction mixture was cooled, stopped the reaction by adding water and concentrated in vacuum. The residue was diluted with ethyl acetate, washed with brine, dried over PA2SO 4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (283 mg, 14%). MS (FAB+) MN+: calculated for C27H40N2O9S1: 569 detected: 569.

Stage B: To a suspension obtained at the stage And Tgp-protected hydroxamate (530 mg, of 0.93 mmol) in dioxane (5 ml) was added 4 n HCl solution in dioxane (5 ml) and methanol (5 ml). After incubation for 15 min at ambient temperature the reaction mixture was concentrated in vacuum. After chromatography with reversed phase (silica gel, mixture of acetonitrile/water, buffered with 0.01%HCl solution) has been specified in the title compound in the form of solids beige (240 mg, 62%). Msvr (ES+) MN+: calculated for C17H24N2About6S1: 385,14 found: 385,14.

Example 68: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-[(4-phenylmethyl)amino]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: In the vessel for the reaction in the solid phase to the resin II (obtained by the method described below 5.0 g, 4,55 mmol), melted in anhydrous 1-methyl-2-pyrrolidinone (40 ml), was added benzylamine (11,0 ml, 100 mmol). The reaction mixture was heated for 48 h to 100° With intensive strahija the AI. The resin was transferred to a Frit and washed 4 times N,N-dimethylformamide (30 ml), 4 times with methanol (30 ml), 4 times with methylene chloride (30 ml) and dried. The dried resin was transferred to a flask was added a mixture of 95% acetic acid/5% water (50 ml). The suspension was stirred for 1 h, filtered and the filter cake washed with methylene chloride. The combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate and was added saturated sodium bicarbonate solution to obtain pH 7. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. After chromatography with reversed phase (silica gel, mixture of acetonitrile/water, buffered with 0.01%HCl solution) has been specified in the title compound in the form of solids reddish color (1.01 g, 52%). Msvr (ES+) M+NH

+
4
: calculated for C19H22N2O5S1: 408,16 found: 408,16.

Example 69: Getting tetrahydro-N-hydroxy-4-[[4-(4-triptoreline)phenoxy)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 ml) was added cesium carbonate (8.8 g, 27 mmol) and para - (triptoreline phenol (2.1 ml, 16 mmol). The suspension was stirred for 19 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (4,2 g, 96%). Msvr (ES+) MN+: calculated for C24H26N1O8S1F3: 546,14 found: 546,14.

Stage B: To a suspension obtained at the stage And Tgp-protected hydroxamate (4.0 g, 7,3 mmol) in dioxane (20 ml) was added 4 n HCl solution in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate, washed with water, dried over PA2SO4, filtered and concentrated in vacuum. The product was recrystallized (acetone/hexane)to give specified in the title compound in the form of solid white (2.2 g, 65%). Msvr (ES+) M+NH

+
4
: calculated for C19H18N1About7S1F3: 479,11 found: 479,11.

Example 70: Obtain 4-[[4-(3,5-divergence)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide/p>

Stage A: To a solution specified in the header of example 55 compound (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 ml) was added cesium carbonate (8.8 g, 27 mmol) and 3,5-diferena (2.1 g, 16 mmol). The suspension was stirred for 48 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a beige foam (3,23 g, 81%). Msvr (ES+) MN+: calculated for C23H25N1O7S1F2: 498,14 found: 498,14.

Stage B: To a suspension obtained at the stage And Tgp-protected hydroxamate (3.2 g, 6.3 mmol) in dioxane (20 ml) was added 4n. a solution of HCl in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuum. The residue is suspended in diethyl ether and after vacuum filtration of the resulting precipitate has been specified in the title compound in the form of solid white (1.5 g, 57%). Msvr (ES+) M+NH

+
4
: calculated for C18H17N1O6S1F2: 431,11 found: 431,11.

Example 71: Obtain 4-[[4-(3,4-dichlorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 ml) was added cesium carbonate (8.8 g, 27 mmol) and 3,4-dichlorophenol (2,61 g, 16 mmol). The suspension was stirred for 41 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (4,17 g, 98%). Msvr (ES+) M+NH

+
4
: calculated for C23H25N1O7S1Cl2: 547,11 found: 547,10.

Stage B: To a suspension obtained at the stage And Tgp-protected hydroxamate (3.5 g, 6.6 mmol) in dioxane (20 ml) was added 4 n HCl solution in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted atilas what tatom, washed with water, dried over Na2SO4, filtered and concentrated in vacuum. The residue is suspended in diethyl ether and after vacuum filtration of the resulting precipitate has been specified in the title compound in the form of solid white (2,98 g, 100%). Msvr (ES+) M+NH

+
4
: calculated for C18H17N1About6S1Cl2: 463,05 found: 463,05.

Example 72: Getting tetrahydro-N-hydroxy-4-[[4-[4-[(phenylmethyl)oxy]phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (2.7 g, 7 mmol) in N,N-dimethylacetamide (20 ml) was added cesium carbonate (6,84 g, 21 mmol) and 4-(benzyloxy)phenol (2.8 g, 14 mmol). The suspension was stirred for 6 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (3.94 g, 99%). Msvr (ES+) M+NH

+
4
: calculated for C30H33N1O8S1:585,23 found: 585,23.

Stage B: To a suspension obtained at the stage And Tgp - protected hydroxamate (1.42 g, 2.5 mmol) in dioxane (6.3 ml) was added 4 n HCl solution in dioxane (6.3 ml) and methanol (6.3 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuum. The product was recrystallized (acetone/hexane)to give specified in the title compound in the form of solid white (0.56 g, 46%). Msvr (ES+) MH+: calculated for C25H25N1O7S1: 484,14 found: 484,14.

Example 73: Getting tetrahydro-N-hydroxy-4-[[4-[4-(triptoreline)phenylthio]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (3.1 g, 8 mmol) in N,N-dimethylformamide (20 ml) was added potassium carbonate (of 2.21 g, 16 mmol) and para-(triptoreline)sensation (2,33 g, 12 mmol). The suspension was stirred for 2 h at 70° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl the Etat/hexane) got replaced Tgp-protected hydroxamate in a solid white color (4.4 g, 98%). Msvr (ES+) M+NH

+
4
: calculated for C24H26N1O7S2F3: 579,14 found: 579,14.

Stage B: To a suspension obtained at the stage And Tgp-protected hydroxamate (4.15 g, 7.4 mmol) in dioxane (20 ml) was added 4n. a solution of HCl in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate, washed with water, dried over PA2SO4, filtered and concentrated in vacuum. The product was recrystallized (acetone/hexane)to give specified in the title compound in the form of solid white (3.0 g, 85%). Msvr (ES+) M+NH

+
4
: calculated for C19H18N1About6S2F3: 495,09 found: 495,09.

Example 74: Getting phenylmethyl-[4-[[2-(hydroxyamino)-2-oxoethyl]sulfanyl]phenyl]carbamate

Stage A: To a suspension of 2-(4-aminophenylthio) acetic acid (20,0 g, 0.11 mol) in methanol (100 ml), cooled to 0° C, was slowly added thionyl chloride (24,0 ml, 0.33 mol). Added additional portion of methanol (100 ml) and was removed in cooling the ban is. Then the resulting mixture was stirred for 2 h at the temperature of reflux distilled. Then the reaction mixture was cooled to ambient temperature and concentrated in vacuum. The residue was dissolved in N2O and neutralized with saturated solution of NaHCO3. The aqueous reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo received sulfide methyl ester in the form of butter dark purple color (22,75 g, quantitative yield).

Stage B: To the solution obtained at the stage And sulfide methyl ester (10.0 g, at 50.7 mmol) in dichloromethane (100 ml) was added N-methylmorpholine (11.2 ml of 101.4 mmol)and then N-(benzyloxycarbonyloxy)succinimide (12,6 g of 50.7 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature and then concentrated in vacuum. The residue was dissolved in ethyl acetate and then washed with N2Oh, a 5%solution of KHSO4, a saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo received sulfide benzyloxycarbonyl in the form of a dark oil (16.2 g, 96%).

Stage b: To a solution containing obtained in stage B sulfide benzyloxycarbonyl (16.2 g, of 48.7 mmol) in tetrahydrofuran (100 ml) and N2About (10 ml), was added to Ohope® (90.0 g, 146 mmol) and the resulting mixture was stirred for 16 h at ambient temperature. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with N2Oh, saturated NaCl and dried over Na2SO4. After concentration in vacuo received sulfon of benzyloxycarbonyl in the form of a solid reddish-brown (15.6 g, 88%).

Stage G: To a solution obtained at the stage In the sulfone of benzyloxycarbonyl (0.25 g, 0.69 mmol) in tetrahydrofuran (3 ml) was added 50%aqueous solution of hydroxylamine (1.5 ml). The resulting mixture was stirred for 24 h at ambient temperature. Then the mixture was diluted with ethyl acetate (30 ml), washed with H2Oh, saturated NaCl and dried over Na2SO4. After concentration in vacuum and subsequent washing with hot diethyl ether has been specified in the title compound in the form of solid light pink color (0.20 g, 80%). MS MN+: calculated for C16H17O6N2S: 365, found: 365.

Example 75: Obtain N-hydroxy-2-[[4-[[(phenylamino)carbonyl]amino]phenyl]sulfonyl]ndimethylacetamide

Stage A: Gaseous hydrogen was barbotirovany suspension containing obtained in stage b of example 74 sulfon of benzyloxycarbonyl (13,4 g, to 36.8 mmol), and 4%Pd/C in tetrahydrofuran (100 ml). After cessation of absorption of H 2the mixture was purged with N2and then filtered through a bed of Celite®, washing with tetrahydrofuran. The filtrate was concentrated in vacuum, obtaining aniline in the form of a solid brown color (8,1 g, 96%).

Stage B: To a suspension obtained at the stage And aniline (0.50 g, 2.2 mmol) in dichloromethane (4 ml) was added phenylisocyanate (0,36 ml, 3.3 mmol). The mixture was stirred at ambient temperature overnight (approximately 18 h) and then was diluted with dichloromethane (50 ml). The mixture is then washed with N2Oh, saturated NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received urea in a solid white color (0,59 g, 78%).

Stage b: To the solution obtained in stage B of urea (0.32 g, to 0.92 mmol) in tetrahydrofuran (3 ml) was added 50%aqueous solution of hydroxylamine (1.5 ml). The resulting mixture was stirred for 24 h at ambient temperature. Then the mixture was diluted with ethyl acetate (30 ml), washed with H2Oh, saturated NaCl and dried over Na2SO4. After concentration in vacuum and subsequent washing with hot diethyl ether has been specified in the title compound in the form of solid light pink color (0.24 g, 76%). MS MN+: calculated for C15H16O5N3S: 350, found: 350.

Example 78: ruchanie dihydrochloride 5-[4-(3,4-dimethylphenoxy)phenyl]sulfonyl-N 5-hydroxy-1,3-dimethylhexane-5-pyrimidinecarboxylic

Stage A: To a solution containing obtained in stage B of example 55 compound (2.00 g, 8,61 mmol) and 1,3,5-trimethylhexane-1,3,5-triazine (1,21 ml, 8,61 mmol) in benzene (20 ml), was slowly added triperoxonane acid (0,66 ml, 8,61 mmol). The resulting mixture was stirred at the temperature of reflux distilled for 1 h and then was cooled to ambient temperature. After that, the mixture was extracted with 2n. HCl. The aqueous layer was neutralized with saturated solution of NaHCO3and then was extracted with diethyl ether. The organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo received tetrahydropyrimidin in the form of a clear oil (2,31 g, 81%).

Stage B: To the solution obtained in stage a of tetrahydropyrimidine (1.26 g, 3,81 mmol) in N,N-dimethylformamide (5.0 ml) was added 3,4-dimethylphenol (0,559 g, 4,58 mmol) and Cs2CO3(and 3.72 g, 11,43 mmol). The resulting mixture was stirred at 90° C for 16 hours After cooling to ambient temperature the reaction mixture was diluted with H2O and was extracted with ethyl acetate. The organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate) received simple billowy e is R & d in the form of oil with a light amber color (1.40 g, 85%).

Stage b: To the solution obtained in stage B simple biryawaho ether (0,936 g of 2.16 mmol) in tetrahydrofuran (5.0 ml) was added trimethylsilanol potassium (0,360 g of 2.81 mmol). The resulting mixture was stirred for 48 h at ambient temperature and then solvent was removed. The resulting residue was dissolved in dichloromethane (5.0 ml), then was added N-methylmorpholine (0,712 ml, 6,48 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0,278 g of 2.38 mmol). After stirring for 10 min at ambient temperature was added Rougher® (1,21 g at 2.59 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature, then was diluted with dichloromethane (50 ml) and washed with H2The acting was Separated organic layer was washed with saturated solution of NaCl and dried over PA2SO4. After chromatography (silica gel, ethyl acetate) received hydroxamate in a solid white color (0,970 g, 87%).

Stage G: To a solution obtained at the stage At hydroxamate (0,667 g, 1,29 mmol) in dioxane (3.0 ml) and methanol (1.0 ml) was added a solution of 4 N. HCl in dioxane (3,22 ml, 12.9 mmol). After stirring for 30 min at ambient temperature the reaction mixture was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2O/triperoxonane KIS the PTA) has been specified in the title compound in the form of solid white (0,379 g, 58%). MS MN+: calculated for C21H28About5N3S: 434, found: 434.

Example 79: Getting monohydrochloride 4-[[4-(4-chloro-3-methylphenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To a suspension isonipecotic acid (50.0 g, to 0.39 mol) in methanol (300 ml), cooled to 0° slowly dropwise added thionyl chloride (85 ml of 1.16 mol). When you are finished adding remove the cooling bath and the mixture was stirred at the temperature of reflux distilled for 2 hours After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The formed solid particles suspended in ethyl acetate and then washed with saturated solution of NaHCO3. The aqueous layer was concentrated in vacuum and the resulting solids were dissolved in hot ethyl acetate and poured from a solution of salts. Then the organic layers were concentrated under vacuum, obtaining the methyl ester in the form of a solid white color (55,4 g, quantitative yield).

Stage B: To a solution of di-tert-BUTYLCARBAMATE (15.3 g, 70,0 mmol) in tetrahydrofuran (100 ml) was added obtained at the stage And methyl ester (10.0 g, 70,0 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature and then concentrated in vacuum. On the Le chromatography (on silica gel, the ethyl acetate/hexane) was obtained methyl ester BOC-protected piperidine in the form of oil is light yellow in color (10.1 g, 59%).

Stage b: To the solution obtained in stage B methyl ester BOC-protected piperidine (23,31 g 0,096 mol) in tetrahydrofuran (500 ml), cooled to -40° C, was slowly added diisopropylamide lithium (57,5 ml, 2.0 M in THF, 0,115 mol). The resulting mixture was stirred for 1 h at -40° and then for 30 min at 0° °C. Then the mixture was re-cooled to -40° and slowly added to the solution obtained in stage a of example 6 disulfide (24,37 g 0,096 mol) in tetrahydrofuran (60 ml). The resulting mixture was slowly heated overnight (approximately 18 hours) to ambient temperature, then was added N2O (200 ml). Then the mixture was concentrated in vacuo and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with 0.5 M NaOH solution, N2Oh, saturated NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received sulfide in the form of oil of amber (28,1 g, 79%).

Stage G: To a solution obtained at the stage In sulfide (28,2 g, 0,076 mol) in dichloromethane (250 ml), cooled to 0° With added meta-chloroperoxybenzoic acid (48 g, 0,152 mol). The resulting mixture was stirred for 1 h at 0° and then for 25 h at ambient temperature. After that, the mixture was diluted with H2Oh and 10%solution of NH4OH. The organic layer is washed with 10%solution of NH4OH, N2O and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received sulfon in a solid white color (24,7 g, 81%).

Stage D: To the solution obtained in stage G of the sulfone (3.00 g, 7,47 mmol) in N,N-dimethylformamide (15 ml) was added 4-chloro-3-METHYLPHENOL (1.28 g, 8,96 mmol) and Cs2CO3(7.30 g, are 22.42 mmol). The resulting mixture was stirred C. for 8 h at 80° C. the mixture is Then concentrated in vacuum and the residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received simple billowy ether as a clear oil (3,26 g, 83%).

Stage E: To the solution obtained in stage D simple biryawaho ether (3,17 g, 6.05 mmol) in tetrahydrofuran (30 ml) was added trimethylsilanol potassium (1.01 g, 7.87 mmol). The resulting mixture was stirred for 20 h at ambient temperature. Added additional portion of tetrahydrofuran (40 ml) and the mixture was stirred for 36 h at ambient temperature. Added additional portion trimethylsilanol potassium (0,233 g, 1.82 mmol) and the mixture was stirred for 3 h at ambient temperature. Remove the tetrahydrofuran and the resulting residue suspended in dichloromethane (30 ml). To the suspension was added N-methylmorpholine (2.00 ml, 18,15 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0,780 g of 6.66 mmol), and then Rougher® (3,38 g, 7,26 mmol). The mixture was stirred for 24 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed N2Oh, saturated NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received hydroxamate foam whitish (2,98 g, 81%).

Stage G: To a solution obtained in stage E of hydroxamate (2,98 g, 4,89 mmol) in dioxane (14 ml) and methanol (6 ml) was added a solution of 4 N. HCl in dioxane (10 ml). The resulting mixture was stirred for 3.5 h at ambient temperature, then added diethyl ether (40 ml) and the precipitate was collected by filtration, getting mentioned in the title compound in the form of solid light pink color (2.00 g, 88%). MS MN+: calculated for C19H22O5N2ClS: 425, found: 425.

Example 80: Getting monohydrochloride 4-[[4-(4-chloro-3-methylphenoxy)phenyl]sulfonyl]-4-(hydroxyamino)carbonyl]-1-piperidineacetic acid

Stage A: To a suspension specified in the header of the example is 79 connection (0,250 g, 0,542 mmol) in acetonitrile (4.0 ml) was added tert-butylbromide (0,088 ml, 0,542 mmol) and K2CO3(0,150 g at 1.08 mmol). The resulting mixture was stirred for 18 h at ambient temperature, then filtered through a bed of Celite®, washing with ethyl acetate. Then the filtrate was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2O/triperoxonane acid) received complex tert-butyl ether in a solid white color (0.156 g, 53%).

Stage B: Obtained at the stage And complex tert-butyl ester (0.156 g, 0,289 mmol) was treated with a solution of 4 N. HCl in dioxane (1.5 ml) and the resulting mixture was stirred for 3.5 h at ambient temperature, then added an additional portion dioxane (2 ml). After stirring for 8 h at ambient temperature the reaction mixture was concentrated in vacuum. The residue was again treated for 4 h at ambient temperature a solution of 4 N. HCl in dioxane (1.5 ml). To the reaction mixture were added diethyl ether and the precipitate was collected by filtration, getting mentioned in the title compound in the form of a solid whitish (0,111 g, 74%). MS MN+: calculated for C21H24O7N2SCl: 483, found: 483.

Example 81: Getting monohydrochloride 4-[[4-(4-chloro-3-methylphen the XI)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To a suspension specified in the header of example 79 connection (0,500 g at 1.08 mmol) in acetonitrile (8.0 ml) was added propargylamine (0,126 ml, 80%solution in toluene, 1.13 mmol) and K2CO3(0,300 g, 2,17 mmol). The resulting mixture was stirred for 24 h at ambient temperature, then filtered through a bed of Celite®, washing with methanol, and then the filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate) was obtained N-propargylglycine in the form of a solid reddish-brown (0,200 g, 40%).

Stage B: To the solution obtained at the stage And N-propargylglycine (0,200 g, 0,432 mmol) in acetonitrile (3.0 ml) and N2About (0.5 ml) was added concentrated HCl (0.05 ml). The resulting mixture was stirred for 5 min at ambient temperature and then concentrated in vacuum, obtaining mentioned in the title compound in a solid pink color (0,200 g, 93%). MS MN+: calculated for C22H24O5N2SCl: 463, found: 463.

Example 82: Getting monohydrochloride 4-[[4-(4-chloro-3-methylphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propenyl)-4-piperazinecarboxamide

Stage A: To a suspension specified in the header of example 79 connection (0,500 g at 1.08 mmol) in acetonitrile (8.0 ml) is obavljale allylbromide (0,093 ml, a 1.08 mmol) and K2CO3(0,300 g, 2,17 mmol). The resulting mixture was stirred for 22 h at ambient temperature. Added additional portion of allylbromide (0,054 ml, 1 M solution in acetonitrile, 0,054 mmol) and continued stirring for 6 h at ambient temperature. The resulting mixture was filtered through a bed of Celite®, washing with ethyl acetate, and then the filtrate was concentrated in vacuum. After chromatography (silica gel, methanol/ethyl acetate) was obtained N-arylhydroxamic in the form of a solid whitish (0,080 g, 15%).

Stage B: To the solution obtained at the stage And N-arylhydroxamic (0,080 g, 0,172 mmol) in acetonitrile (3.0 ml) and N2O (1.0 ml) was added concentrated HCl (0.05 ml). The resulting mixture was stirred for 10 min at ambient temperature and then concentrated in vacuum, obtaining mentioned in the title compound in the form of a solid white color (0,100 g, quantitative yield). MS MN+: calculated for C22H26About5N2SCl: 465, found: 465.

Example 83: Getting monohydrochloride 4-[[4-(4-fluoro-3-methylphenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 79 sulfone (5,00 g, 12,45 mmol) in tetrahydrofuran (100 ml) was added trim isranet potassium (4,79 g, 37,36 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature, diluted with H2O and diethyl ether (100 ml). The aqueous layer was extracted with diethyl ether and the combined organic layers were washed N2O. the Aqueous layers were combined, acidified 2 N. HCl (to pH 2) and then was extracted with ethyl acetate. The combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4getting acid in the form of a solid whitish (4.61 in g, 96%).

Stage B: To a suspension obtained at the stage And acid (0,830 g, 2.14 mmol) in dichloromethane (10 ml) was added N-methylmorpholine (0,706 ml, 6.42 per mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0,276 g of 2.35 mmol). After stirring for 5 min at ambient temperature was added Rougher® (1.20 g, 2.57 mmol) and the resulting mixture was stirred for 19 h at ambient temperature. The mixture was concentrated in vacuo and the residue was distributed between H2O and ethyl acetate. Then the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received para-feralfen in the form of a crystalline solid, white (0,993 g, 95%).

Stage b: To the solution obtained in stage B pairs is personphone (0,485 g, 0,996 mmol) in N,N-dimethylformamide (5 ml) was added 4-fluoro-3-METHYLPHENOL (of 0.133 ml, 1.20 mmol) and Cs2CO3(0,973 g, 2,99 mmol). The resulting mixture was stirred at 60° C for 17 hours Added an additional portion of 4-fluoro-3-METHYLPHENOL (by 0.055 ml, 0,498 mmol) and the temperature of the reaction mixture was raised to 80° C for 4 h and up to 100° C for 3 hours was Added an additional portion of 4-fluoro-3-METHYLPHENOL (of 0.133 ml, 1.20 mmol) and the reaction mixture was stirred for 7.5 hours at 100° C. was Added an additional portion of Cs2CO3and the mixture continued to stand at 100° C for 17 h, the Reaction mixture was cooled to ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of a solid whitish (0,490 g, 83%).

Stage G: To a solution obtained at the stage In protected hydroxamate (0,479 g, 0,808 mmol) in dioxane (3 ml) and methanol (1 ml) was added a solution of 4 N. HCl in dioxane (2,02 ml, 8,08 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature. Added diethyl ether (5 ml) and the precipitate was collected by filtration, receiving specified in the header connect the tion in the form of a solid whitish (0,323 g, 90%). MS MN+: calculated for C19H22About5N2SF: 409, found: 409.

Example 84: Getting monohydrochloride 4-[[4-(3-chloro-4-pertenece)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To the solution obtained in stage B of example 83 a pair of feralfen (0,485 g, 0,996 mmol) in N,N-dimethylformamide (5.0 ml) was added 4-fluoro-3-chlorophenol (0,176 g, 1.20 mmol) and Cs2CO3(0,973 g, 2,99 mmol). The resulting mixture was stirred for 17 h at 60° With, then added an additional portion of 4-fluoro-3-chlorophenol (0,073 g, 0,498 mmol) and the reaction mixture was stirred for 24 h at 80° and then the temperature was raised to 90° C. After incubation for 7 h at 90° With added an additional portion of 4-fluoro-3-chlorophenol (0,176 g, 1.20 mmol) and continued to stand at 90° in a period of 7.5 hours Added an additional portion of Cs2CO3(0,973 g, 2,99 mmol) and the mixture continued to stand at 90° within 24 hours After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of a solid substance be autogo color (0,550 g, 90%).

Stage B: To the solution obtained at the stage And secure hydroxamate (0,530 g, 0,864 mmol) in dioxane (3 ml) and methanol (1 ml) was added a solution of 4 N. HCl in dioxane (2.00 ml, of 8.00 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature. Added diethyl ether (5 ml) and the precipitate was collected by filtration, getting mentioned in the title compound in the form of a solid whitish (0,377 g, 94%). MS MN+: calculated for C19H19About5N2SFl: 429, found: 429.

Example 85: Getting monohydrochloride 4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 79 sulfone (4.53 in) to 11.28 mmol) in N,N-dimethylformamide (20 ml) was added 4-chlorophenol (to 4.41 g, 13,54 mmol) and Cs2CO3(11,03 g, 33,85 mmol). The resulting mixture was stirred for 5 h at 90° C. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received simple billowy ether in a solid white color (4,60 g, 78%).

Stage B: To the solution obtained is about at the stage And simple biryawaho ether (of 4.57 g, 8,96 mmol) in dioxane (10 ml) was added a solution of 4 N. HCl in dioxane (10 ml). The resulting mixture was stirred for 2.5 h at ambient temperature, then added an additional portion of dioxane (10 ml). After stirring for 1.5 h at ambient temperature the mixture was concentrated in vacuum. The resulting solid is suspended in dioxane (20 ml) and then treated with a solution of 4 N. HCl in dioxane (10 ml). The mixture was stirred for 1 h at ambient temperature, was added methanol (1 ml) and continued stirring at ambient temperature. After 1 h the mixture was concentrated in vacuum, obtaining the amine in the form of a solid white color (4.09 g, quantitative yield).

Stage b: To a suspension obtained in stage B Amin (4,00 g, 8,96 mmol) in acetonitrile (20 ml) was added propargylamine (1,05 ml, 80%solution in toluene, 9,41 mmol) and K2CO3(2,60 g, 18,82 mmol). The resulting mixture was stirred for 18 h at ambient temperature, filtered through a pad of Celite®, washing with ethyl acetate, and then the filtrate was concentrated in vacuum, obtaining N-propargylamine in the form of adhesive foam (4,14 g, quantitative yield).

Stage G: To the suspension obtained in stage N-propargylamine (4,14 g, 8,96 mmol) in tetrahydrofuran (20 ml) was added trimethylsilanol potassium (1.26 g, 9.8 mmol). The resulting mixture was stirred for 17 h at ambient temperature, then added an additional portion of tetrahydrofuran (5 ml) and trimethylsilanol potassium (0,350 g, 2,73 mmol). After stirring for 4 h at ambient temperature was added another portion of tetrahydrofuran (5 ml) and continued stirring at ambient temperature for 24 hours Then added another portion of trimethylsilanol potassium (0,115 g, 0,896 mmol) and the mixture was stirred for 24 h at ambient temperature, then added an additional portion trimethylsilanol potassium and the resulting mixture was stirred at ambient temperature for 24 hours tetrahydrofuran was Removed and the residue suspended in dichloromethane (20 ml).

Stage D: dichlormethane of the suspension was added N-methylmorpholine (2,96 ml, 26.9 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (1,15 g, 9,86 mmol), and then Rougher® (5,01 g of 10.75 mmol). The resulting mixture was stirred at ambient temperature overnight and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate foam whitish (3,29 g 69%).

Stage E: To the solution obtained in stage D secure hydroxamate (3,27 g, 6,13 mmol) in dioxane (21 ml) and methanol (7 ml) was added a solution of 4 N. HCl in dioxane (10 ml). The resulting mixture was stirred for 4 h at ambient temperature and then was added diethyl ether (75 ml). The solids were collected by filtration, washing with diethyl ether, resulting in the received specified in the title compound in the form of solids whitish (2,95 g, 99%). MS MN+: calculated for C21H22O5N2SCl: 449, found: 449.

Example 86: Getting monohydrochloride 4-[[4-(phenylthio)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To the solution obtained in stage G of example 79 sulfone (0,500 g, 1.25 mmol) in N,N-dimethylformamide (3.0 ml) was added thiophenol (0,154 ml, 1.50 mmol) and K2CO3(0.518 g, 3.75 mmol). The resulting mixture was stirred for 24 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received billowy tiefer in the form of a clear sticky oil (to 0.480 g, 78%).

Stage B: To the solution obtained in stage a of biari the new tiefer (2,01 g, 4.09 to mmol) in tetrahydrofuran (40 ml) was added trimethylsilanol potassium (0,682 g, 5,31 mmol). The resulting mixture was stirred for 23 h at ambient temperature and then concentrated in vacuum. Then the residue is suspended in dichloromethane (20 ml), then was added N-methylmorpholine (1.35 ml, 12,27 mmol) and 50%aqueous solution of hydroxylamine (0,265 ml, 4,50 mmol), and then Rougher® (to 2.29 g, 4,91 mmol). The resulting mixture was stirred for 16 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. The portion of the sample was subjected to chromatography with reversed phase (silica gel, acetonitrile/N2O/triperoxonane acid) receiving hydroxamate in the form of a solid whitish (0,190 g).

Stage b: To the solution obtained in stage a of hydroxamate (0,181 g, 0,367 mmol) in dioxane (5 ml) and methanol (1 ml) was added a solution of 4 N. HCl in dioxane (3 ml). The resulting mixture was stirred for 3 h at ambient temperature and then concentrated in vacuum, obtaining mentioned in the title compound in the form of a solid whitish (0,170 g, quantitative yield). MS MN+: calculated for C18H21O4N2S2: 393 detected is:393.

Example 87: Getting monohydrochloride 4-[(hydroxyamino)carbonyl]4-[[4-(phenylthio)phenyl]sulfonyl]-1-piperidineacetic acid

Stage A: To the solution obtained in example 86 connection (0,322 g, 0,751 mmol) in acetonitrile (4.0 ml) was added tert-butylbromide (0,121 ml, 0,751 mmol) and K2CO3(0,207 g, 1.50 mmol). The resulting mixture was stirred for 18 h at ambient temperature, filtered through a pad of Celite®, washed with ethyl acetate and the filtrate was concentrated in vacuum. After chromatography with reversed phase (silica gel, acetonitrile/N2O/triperoxonane acid) received complex tert-butyl ether in a solid whitish (0,150 g, 40%).

Stage B: Obtained at the stage And complex tert-butyl ether (0,145 g, 0,286 mmol) was treated with a solution of 4 N. HCl in dioxane (3.0 ml). The resulting mixture was stirred for 7 h at ambient temperature, was added diethyl ether and the precipitate was collected by filtration. After chromatography with reversed phase (silica gel, acetonitrile/N2O/Hcl) has been specified in the title compound in the form of solids whitish (to 0.060 g, 43%). MS MN+: calculated for C20H23O6N2S2:451, found: 451.

Example 88: Getting monohydrochloride 4-[[4-(4-chlorphenoxy)f the Nile]sulfonyl]-4-[(hydroxyamino)carbonyl]-1-piperidineacetic acid

Stage A: To a suspension hydrobromide 4-bromopyridine (40,0 g, 0.16 mol) in tetrahydrofuran (200 ml) was slowly added triethylamine (45,4 ml, 0.33 mol), and then di-tert-BUTYLCARBAMATE (or 37.4 g of 0.17 mol)which was added in several portions. The resulting mixture was stirred for 17 h at ambient temperature, then filtered and concentrated in vacuum. The solids were washed with hexane and then collected by filtration, receiving the BOC-protected piperidine derived in the form of oil of amber (with 45.8 g, >100%).

Stage B: To a solution of 4-terfenol (25,0 g, 0.20 mol) in acetone (150 ml), degassed with N2added Cs2CO3(79,7 g, 0.25 mol). After degassing for 5 min the mixture formed by N2added obtained at the stage And the BOC-protected piperidine derived (43,1 g, 0.16 mol). The resulting mixture was stirred for 22 h at ambient temperature and then filtered through a bed of Celite®, washing with acetone. The residue was washed with diethyl ether and the solids were collected by filtration, getting sulfide in the form of a yellow oil (47,6 g, 93%).

Stage b: To the solution obtained in stage B of sulfide (47,3 g, 0.15 mol) in dichloromethane (350 ml), cooled to 0° With added meta-chloroperoxybenzoic acid (80 g, 57-86%). D is balali an additional portion of dichloromethane (50 ml) and the mixture was stirred for 1 h at 0° With and then for 1.5 h at ambient temperature. The reaction mixture was diluted with H2Oh and added an aqueous solution of meta-bisulphite sodium (4.0 g in 50 ml). The mixture was concentrated in vacuo and then was extracted with diethyl ether and ethyl acetate. The combined organic layers washed with 10%solution of NH4OH, saturated NaCl and dried over Na2SO4. After recrystallization from ethyl acetate received sulfon in a solid white color (18,9 g, 36%).

Stage G: To a solution obtained at the stage In sulfone (8.00 g, 23,3 mol) in N,N-dimethylformamide (40 ml) was added 4-chlorophenol (3,59 g, 27,96 mmol) and K2CO3(22,77 g, 69,90 mmol). The resulting mixture was stirred for 4 h at 60° and then for 7 h raised the temperature to 80° C. the Reaction mixture was cooled to ambient temperature and then concentrated in vacuum. To the residue was added N2O (100 ml) and the solids were collected by filtration, getting simple billowy ether in a solid whitish (10.5 g, 99%).

Stage D: To the solution obtained in stage G simple biryawaho ether (5,00 g, 11.1 mmol) in tetrahydrofuran (50 ml), cooled to 0° C, was added bis (trimethylsilyl)amide lithium (13.3 ml, 1 M solution in tetrahydrofuran, 13.3 mmol) at such a speed that the temperature of the reaction of sesini never rose above 2° C. the Resulting mixture was stirred for 30 min at 0° With, then slowly added dimethylcarbonate (1,40 ml of 16.6 mmol) at such a speed that the temperature of the reaction mixture never rose above 2° C. After the reaction mixture gave medlenno to warm to ambient temperature.

After 17 h, the reaction mixture was re-cooled to 0° and added an additional portion of bis(trimethylsilyl)amide lithium (5.50 ml, 1 M solution in tetrahydrofuran, of 5.50 mmol) at such a speed that the temperature of the reaction mixture never rose above 2° C. After stirring for 30 min was added dimethylcarbonate (0,048 ml, 0,570 mmol) and continued stirring for 45 min at 0° C. was Slowly added an additional portion of bis(trimethylsilyl)amide lithium (0,500 ml, 1 M solution in tetrahydrofuran, 0,500 mmol)and after 1 h was added an additional portion of dimethylcarbonate (0,010 ml, 0,119 mmol). After stirring for 20 min at 0° C was added a saturated solution of NH4Cl and then the reaction mixture was concentrated in vacuum. The residue was diluted with H2O and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na2SO4. After recrystallization from methanol was obtained methyl ester as a crystalline solid substances is TBA white (of 3.56 g, 63%).

Stage E: obtained in stage D complex methyl ether (3.54 in) 6,94 mmol) in dioxane (18 ml) and methanol (6 ml) was added a solution of 4 N. HCl in dioxane (10.0 ml). The resulting mixture was stirred for 5 h at ambient temperature and then concentrated in vacuum, obtaining the amine in the form of a solid whitish (3,10 g, quantitative yield).

Stage G: To a solution obtained in stage E amine (1.50 g, to 3.36 mmol) in acetonitrile (15 ml) was added tert-butylbromide (0,570 ml of 3.53 mmol) and K2CO3(of 1.16 g of 8.40 mmol). The resulting mixture was stirred for 3 h at ambient temperature, then filtered through a bed of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuum, obtaining the complex tert-butyl ether in the form of oil is light yellow in color (1,83 g, >100%).

Stage C: the solution obtained in stage F complex tert-butyl ether (1,76 g, to 3.36 mmol) in tetrahydrofuran (15 ml) was added trimethylsilanol potassium (value (0.475) g, 3,70 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature, then added an additional portion of tetrahydrofuran (10 ml). After shuffle overnight (approximately 18 hours) at ambient temperature was added an additional portion trimethylsilanol potassium (value (0.475) g, 3,70 mmol). Education is asuza the mixture was stirred for 4 h at ambient temperature, then was diluted with H2O. the Reaction mixture was acidified (pH 7) using a 1H. HCl solution and then concentrated in vacuum. The solids were washed with diethyl ether and then H2Oh, getting acid in the form of a solid whitish (0,597 g, 32%).

Stage I: To the suspension obtained in stage C acid (0,597 g at 1.17 mmol) in dichloromethane (5 ml) was added N-methylmorpholine (0,386 ml, 3,51 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0,151 g, 1,29 mmol), and then Rougher® (0,655 g of 1.40 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of a white foam (0,510 g, 72%).

Stage: Obtained at the stage And secure hydroxamate (0,510 g, 0,837 mmol) was treated with 4 N. a solution of HCl in dioxane (10 ml). The resulting mixture was stirred for 24 h at ambient temperature, then added diethyl ether (20 ml) and the solids were collected by filtration, getting mentioned in the title compound in the form of a solid white color (0,370 g, 87%). MS MN+: calculated for C20H22O7 2SCl: 469, found: 469.

Example 89: obtain the dihydrochloride of 4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N-hydroxy-1-[2-(4-morpholinyl)ethyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage E of example 88 amine (1,00 g, 2,24 mmol) in acetonitrile (10 ml) was added 4-(2-chloroethyl)morpholine (0,438 g of 2.35 mol) and K2CO3(1.24 g, 8,96 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature, after which was added a catalytic amount of NaI and continued the stirring for 21 hours at ambient temperature. Then the temperature of the reaction mixture increased for 29 h to 60° C. After cooling to ambient temperature the reaction mixture was filtered through a bed of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuum, obtaining the ester in the form of oily solids (1,15 g, 98%).

Stage B: To the solution obtained in stage a of ester (1,15 g of 2.20 mmol) in tetrahydrofuran (10 ml) was added trimethylsilanol potassium (0,579 g, 4,51 mmol). The mixture was stirred for 4 h at ambient temperature, then added an additional portion of tetrahydrofuran (10 ml) and continued stirring overnight (about 18 hours) at ambient temperature. The reaction mixture was diluted with H2(10 is l) and acidified (to pH 7) with 1H. HCl solution. The precipitate was collected by filtration, getting acid in a solid gray color (0,753 g, 72%).

Stage b: To a suspension obtained in stage B acid (0,750 g of 1.47 mmol) in dichloromethane (7 ml) was added N-methylmorpholine (0,500 ml, 4,55 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0,198 g of 1.62 mmol), and then Rougher® (0,822 g of 1.76 mmol). The resulting mixture was stirred for 24 h at ambient temperature and then added additional portion of N-methylmorpholine (0,242 ml, 2.21 mmol) and O-tetrahydro-2H-Piran-2-ilyjocelyne (0,052 g, 0,441 mmol), and then Rougher® (0,343 g, 0,735 mmol). The resulting mixture was stirred for 23 h at ambient temperature and then added additional portion O-tetrahydro-2H-Piran-2-ilyjocelyne (0,017 g, 0,145 mmol) and Rougher® (0,073 g, of) 0.157 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over PA2SO4. After chromatography (silica gel, methanol/chloroform) received protected hydroxamate in the form of a solid whitish (0,750 g, 84%).

Stage D: Obtained at the stage In protected hydroxamate (at 0.730 g, 1.20 mmol) was treated with 4 N. races of the thief HCl in dioxane (10 ml) and methanol (10 ml). The resulting mixture was stirred for 1 h at ambient temperature, then added diethyl ether (20 ml) and the solids were collected by filtration, receiving specified in the header soedinenie in the form of a solid light-yellow color (0.625 g, 87%). MS MN+: calculated for C24H31O6N3SCl: 525 detected 525.

Example 90: Obtain 4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N-hydroxy-N-1-(methylethyl)-1,4-piperazinecarboxamide

Stage A: To a suspension obtained in stage E of example 88 amine (0,600 g of 1.34 mmol) in dichloromethane (5 ml) was added triethylamine (0,411 ml, 2,95 mmol) and isopropylidene (0,198 ml, a 2.01 mmol). The resulting mixture was stirred for 2 h at ambient temperature and then was diluted with dichloromethane (50 ml). The mixture was washed N2Oh, saturated NaCl and dried over Na2SO4receiving urea as solid whitish (0,670 g, >100%).

Stage B: To the solution obtained at the stage And urea (0,640 g, 1,29 mmol) in tetrahydrofuran (10 ml) was added trimethylsilanol potassium (0,199 g, 1.55 mmol). The resulting mixture was stirred for 17 h at ambient temperature, then added an additional portion trimethylsilanol potassium (0.015 g, 0,117 mmol). The resulting mixture was stirred for another 24 hours, then, tetrahydrofuran was removed by pulling the mixture of N2. To a suspension of the residue in dichloromethane (5 ml) was added N-methylmorpholine (0,426 ml, a 3.87 mmol) and O-tetrahydro-2H-Piran-2-alhydrogel (0,181 g, 1.55 mmol), and then Rougher® (0,902 g, 1.94 mmol).

The resulting mixture was stirred for 7 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of a solid whitish (0,330 g, 44%).

Stage b: To the solution obtained in stage B of protected hydroxamate (0,330 g, 0,569 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4 n HCl solution in dioxane (10 ml). The resulting mixture was stirred for 3.5 h at ambient temperature, then added diethyl ether. The solids were collected by filtration, receiving specified in the header of soedinenie in a solid white color (0,259 g, 92%). MS MN+: calculated for C22H27O6N3SCl: 496, found: 496.

Example 91: Getting monohydrochloride 4-[(4’-chloro[1,1’-biphenyl]-4-yl)sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To a solution of 4-bromothiophene is a (16,98 g, 89,80 mol) in acetone (200 ml), degassed with N2added To2CO3(12,41 g, 89,80 mol). After degassing the resulting mixture for 5 min with N2added obtained in stage a of example 88, the BOC-protected piperidine derived (21,57 g, 81,64 mol). The resulting mixture was stirred for 19 h at ambient temperature and then filtered through a bed of Celite®, washing with acetone. The residue was washed with diethyl ether and the solids were collected by filtration, getting sulfide in the form of oil green (31.7 g, >100%).

Stage B: To the solution obtained at the stage And sulfide (31,68 g, 81,64 mol) in dichloromethane (200 ml), cooled to 0° With added meta-chloroperoxybenzoic acid (56,35 g, 50-60%, 163,28 mmol). The resulting mixture became very thick, and added an additional portion of dichloromethane (100 ml). The mixture was stirred for 1.5 h at 0° and then for 1.5 h at ambient temperature. The reaction mixture was diluted with H2O (300 ml) was added an aqueous solution of meta-bisulphite sodium (8.0 g, 42,08 mmol in 50 ml of N2About). Dichloromethane was removed in vacuo and the aqueous reaction mixture was extracted with ethyl acetate. The combined organic layers washed with 10%solution of NH4OH, saturated NaCl and dried over Na2SO4. After kontsentrirovanie the vacuum received sulfon in the form of a yellow oil (33,42 g, >100%).

Stage b: To the solution obtained in stage B sulfone (7,80 g, 19,34 mol) in tetrahydrofuran (100 ml), cooled to 0° C, was added bis(trimethylsilyl)amide lithium (23,8 ml, 1 M solution in tetrahydrofuran, to 23.8 mmol) at such a speed that the temperature of the reaction mixture never rose above 2° C. After stirring for 30 min at 0° solution was added methylcarbamate (2.30 ml, to 29.8 mmol) in tetrahydrofuran (5 ml with such a speed that the temperature of the reaction mixture never rose above 2° C. After the reaction mixture gave to slowly warm to ambient temperature. Then the mixture was diluted with saturated solution of NH4Cl and the tetrahydrofuran was removed in vacuum. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received ester in the form of a solid yellow (6,33 g, 69%).

Stage G: To a solution obtained at the stage In a complex ether (4,74 g, 10,28 mmol) in dimethoxyethane (50 ml) was added 4-Chlorfenvinphos acid (1.77 g, 11,30 mmol), an aqueous solution of Cs2CO3(25 ml, 2.0 M, 50.0 mmol) and tetrakis(triphenylphosphine) palladium (0) (1 g). The resulting mixture was stirred for 3 days at ambient temperature. Reacciona the mixture was filtered through a bed of Celite®, washing with ethyl acetate, and the filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received biphenylene derived in the form of a solid whitish (4,16 g, 82%).

Stage D: To the solution obtained in stage G biphenylenes derived (1.50 g, 3.04 from mmol) in tetrahydrofuran (10 ml) was added trimethylsilanol potassium (0,468 g, 3.65 mmol). The resulting mixture was stirred for 1 h at ambient temperature, then added an additional portion of tetrahydrofuran (5 ml) and the reaction mixture was stirred overnight (about 18 hours) at ambient temperature. Added additional portion of tetrahydrofuran (15 ml) and the mixture was stirred for 26 h at ambient temperature. Added additional portion trimethylsilanol potassium (0,040 g, 0,304 mmol), the mixture was stirred overnight (about 18 hours) at ambient temperature and then the solvent was removed by pulling the reaction mixture of N2.

To a suspension of the residue in dichloromethane (20 ml) was added N-methylmorpholine (1,00 ml, 9,12 mmol) and O-tetrahydro-2H-Piran-2-ilyjocelyne (0,427 g, 3.65 mmol), and then Rougher® (2,13 g, 4,56 mmol). The resulting mixture was stirred for 24 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2 O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (1,25 g, 71%).

Stage E: To the solution obtained in stage D secure hydroxamate (1,25 g of 2.16 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4n. a solution of HCl in dioxane (10 ml). The resulting mixture was stirred for 3.5 h at ambient temperature, then added diethyl ether (20 ml). The solids were collected by filtration, getting mentioned in the title compound in the form of a solid white color (to 0.900 g, 97%). MS MN+: calculated for C18H20O4N2SCl: 395, found: 395.

Example 92: Getting monohydrochloride N-hydroxy-4-[[4-(methylpentylamino)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage b of example 91 of ester (1,00 g, 2,17 mmol) in toluene (4 ml) was added N-methylaniline (0,282 ml, 2,60 mmol), Cs2CO3(0,990 g, 3.04 from mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,018 g, 0.02 mmol) and (R)-(+)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP, 0,021 g 0,033 mmol). The resulting mixture was stirred for 20 h at 100° C. After cooling to ambient temperature was added Dyatlov the th ether, the mixture was filtered through a bed of Celite®, washing with diethyl ether, and the filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received aniline in the form of an adhesive resin yellow (0.930 g, 88%).

Stage B: To the solution obtained at the stage And aniline (0.930 g, 1,90 mmol) in tetrahydrofuran (10 ml) was added trimethylsilanol potassium (0,293 g, 2.28 mmol). The resulting mixture was stirred for 19 h at ambient temperature, then added an additional portion trimethylsilanol potassium (0,024 g, 0,190 mmol). After stirring at ambient temperature overnight (approximately 18 h). the solvent was removed by pulling the mixture of N2.

To a suspension of the residue in dichloromethane (10 ml) was added N-methylmorpholine (0,627 ml, 5,70 mmol) and O-tetrahydro-2H-Piran-2-ilyjocelyne (0,267 g, to 2.85 mmol), and then Rougher® (1,33 g, 2.28 mmol). The resulting mixture was stirred for 2 days at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (0,860 g, 79%).

Stage b: To the solution obtained in stage B is protected is hydroxamate (0,890 g, 1.55 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4 n HCl solution in dioxane (5 ml). The resulting mixture was stirred for 1 h at ambient temperature, then added diethyl ether (15 ml). The solids were collected by filtration, getting mentioned in the title compound in the form of a solid white color (0,529 g, 80%). MS MN+: calculated for C19H24O4N3S: 390, found: 390.

Example 93: Getting monohydrochloride 4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: To a suspension of resin I (to 4.98 g, by 5.87 mmol) in 1-methyl-2-pyrrolidinone (45 ml) of the peptide flask was added obtained in stage a of example 83 acid (4,55 g, 11,74 mmol), hexaflurophosphate benzotriazol-1-electroparadise (6.11 g, 11,74 mmol), N-methylmorpholin (2,58 ml, 23,48 mmol). The resulting mixture was stirred for 14 h at ambient temperature. Then the resin was collected by filtration, the filtrate was removed and set aside, the resin washed with N,N-dimethylformamide, N2Oh, N,N-dimethylformamide, methanol, dichloromethane and finally diethyl ether. The resin was dried in vacuum at ambient temperature, getting associated with a pair of resin-feralfen in a solid yellow color (6,72 g, 95%).

The filtrate was diluted with H2Oh and extra is Aravali with ethyl acetate. The aqueous layer was acidified (to pH 2.0) using 2n. HCl and then was extracted with ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over Na2SO4. The resulting residue was dissolved in 1-methyl-2-pyrrolidinone (40 ml), was added to the above resin, and then N-methylmorpholine (1.50 ml, 13,64 mmol) and hexaphosphate benzotriazol-1-electroparadise (3,05 g, 5,86 mmol). The resulting mixture was stirred for 3.5 h at ambient temperature. Then the resin was collected by filtration and the resin washed with N,N-dimethylformamide, N2Oh, N,N-dimethylformamide, methanol, dichloromethane and finally diethyl ether. The resin was dried in vacuum at ambient temperature, getting associated with a pair of resin-feralfen in the form of a solid light orange color (6,34 g, 89%). Download (component of 0.78 mmol/g) was determined by splitting a small portion associated with the pair of resin-feralfen using a mixture of 95%triperoxonane acid/N2O.

Stage B: To a suspension associated with the pair of resin-personphone (0,700 g, 0,546 mmol) in 1-methyl-2-pyrrolidinone (3 ml) was added para-chlorophenol (0,702 g, 5.46 mmol) and Cs2CO3(1.78 g, 5.46 mmol). The resulting mixture was heated for 13 h to 110° C. Then the resin was collected by filtration and then washed with N,N-dimethylformamide, N 2Oh, N,N-dimethylformamide, 2 N. HCl, N,N-dimethylformamide, methanol and dichloromethane. The resulting resin was re-subjected to the reaction for 3 h in the above conditions. After that, the resin was collected by filtration and then washed with N,N-dimethylformamide, N2Oh, N,N-dimethylformamide, 2 N. HCl, N,N-dimethylformamide, methanol and dichloromethane. The solid was dried in vacuum at ambient temperature, getting associated with the resin hydroxamate in a solid orange color (0,692 g, 91%).

Stage b: Obtained in stage B is associated with the resin hydroxamate (0,692 g, 0,540 mmol) were treated for 1 h at ambient temperature with a mixture of 95%triperoxonane acid/N2About (3 ml). The resin was filtered and washed with a mixture of 95%triperoxonane acid/N2About (3 ml)and then dichloromethane (2x3 ml). After that, the filtrate is evaporated. After chromatography with reversed phase (silica gel, acetonitrile/N2O/triperoxonane acid) received hydroxamate. The resulting solid was dissolved in acetonitrile (5 ml) and N2About (0.5 ml) and treated with concentrated HCl. The resulting mixture was stirred for 5 min at ambient temperature and then concentrated in vacuum, obtaining mentioned in the title compound in the form of a solid whitish (0,220 g, 1%). MS MN+: calculated for C18H20About5N2SCl: 411, found: 411.

Example 94: Getting tetrahydro-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 complex methyl ester (0.96 g, 3.2 mmol) in N,N-dimethylformamide (30 ml) under stirring was added phenol (0.3 g, 3.2 mmol), and then cesium carbonate (3.2 g, 10 mmol). The resulting composition was heated for 5 h to 70° C. the Solution was allowed to stand for 18 h at ambient temperature, then was diluted with H2O and was extracted with ethyl acetate. The organic layer was washed polysystem NaCl solution and dried over sodium sulfate. The solvent was removed on a rotary evaporator, obtaining the required phenoxypropane (1.1 g, 92%).

Stage B: To the solution obtained at the stage And phenoxypropanol (1.1 g, 2.9 mmol) in THF (10 ml) and ethanol (10 ml) was added sodium hydroxide (1 g, 25 mmol). The resulting solution was stirred for 1 h at ambient temperature. Then the solution was heated for 1 h to 80° C. the Solvent was removed on a rotary evaporator, the resulting sodium salt was acidified using 1 N. HCl (50 ml) and was extracted with ethyl acetate. The organic layer was dried over Na2SO4. The solvent was removed on a rotary IP is Ariele, getting the desired phenoxycarbonyl acid (1.1 g, 99%).

Stage b: To the solution obtained in stage B peroxycarbonates acid (1.1 g, 3 mmol) in DMF (7 ml) was added with stirring, N-hydroxybenzotriazole· N2On (0,623 g, 4.6 mmol), and then the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0,634 g, 3.3 mmol). After 10 min was added 50%aqueous solution of hydroxylamine (2 ml, 30 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed N2Oh, then polysystem NaCl, then dried over Na2SO4. After chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified in the title compound in the form of solid white (0,37 g, 33%). Msvr (ES+) MN+: calculated for C18H19NO6S: 378,1011 found: 378,0994.

Example 95: Getting tetrahydro-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 complex methyl ester (of 1.02 g, 3.4 mmol) in N,N-dimethylformamide (20 ml) under stirring in nitrogen atmosphere was added thiophenol (0,37 g, 3.4 mmol), and then cesium carbonate (3.3 g, 10.1 mmol) and the solution was heated in those who tell 17 h 70° C. the Solution was allowed to stand for 1 h at ambient temperature, then was diluted with H2O and was extracted with ethyl acetate. The organic layer was washed polysystem NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received S-phenyl derivative (0.6 g, 41%).

Stage B: To the solution obtained in stage a, S-phenyl derivative (0.6 g, 1.4 mmol) in THF (10 ml) and ethanol (10 ml) was added under stirring NaOH (0.8 g, 20 mmol). The solution was heated for 1 h to 80° C. the Solution was allowed to stand for 18 h at ambient temperature. The solvent was removed on a rotary evaporator, the resulting sodium salt was acidified using 1 N. HCl (25 ml), extracted with ethyl acetate and the organic layer was dried over sodium sulfate. The solvent was removed on a rotary evaporator, obtaining the desired S-phenylcarbamoyl acid (0.6 g, quantitative yield).

Stage b: To the solution obtained in stage B S-phenylcarbinol acid (0.6 g, 1.5 mmol) in DMF (6 ml) was added with stirring, N-hydroxybenzotriazole· N2On (0,30 g, 2.2 mmol), and then the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.32 g, 1.6 mmol). After 10 min was added 50%aqueous solution of hydroxylamine (1.5 ml, 22 mmol) and the solution was stirred for 42 h at ambient temperature. Rast is the PR was diluted with saturated sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed N2Oh, then polysystem NaCl, then dried over sodium sulfate. After chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified in the title compound in the form of solid white (0.15 g, 26%). Msvr (ES+) MN+: calculated for C18H19NO5S2392,0783 found: 394,0753.

Example 96: Obtain 4-[[4-(3,4-dimethylphenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 complex methyl ester (1.04 g, 3.3 mmol) in N,N-dimethylformamide (30 ml) under stirring was added 3,4-dimethylphenol (0.4 g, 3.3 mmol), and then cesium carbonate (3.2 g, 10 mmol). The resulting solution was heated for 5 h to 88° C. the Solution was concentrated on a rotary evaporator, diluted with H2O and was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed on a rotary evaporator, obtaining the required dimethylisoxazole (1.2 g, 91%).

Stage B: To the solution obtained at the stage And dimethylisoxazole (1.2 g, 3 mmol) in THF (10 ml) and ethanol (10 ml) was added NaOH (1 g, 25 mmol). The resulting solution was heated for 1 h to 80° C. the Solvent was removed on a rotary evaporator, obrazovavshuyusya the sodium salt was acidified using 1 N. HCl (50 ml) and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed on a rotary evaporator, obtaining the desired dimethylphenylcarbinol acid (1.2 g, quantitative yield).

Stage b: To the solution obtained in stage B dimethylphenylcarbinol acid (1.2 g, 3 mmol) in DMF (7 ml) was added with stirring, N-hydroxybenzotriazole, N2On (0,623 g, 4.6 mmol), and then the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0,634 g, 3.3 mmol). After 10 min was added 50%aqueous solution of hydroxylamine (2 ml, 30 mmol) and the solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed N2Oh, then polysystem NaCl, then dried over Na2SO4. After chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified in the title compound in the form of solid white (0.52 g, 43%). Msvr (ES+) MN+: calculated for C20H23NO6S: 406,1324 found: 406,1302.

Example 97: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-[(6-methyl-3-pyridinyl)oxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 complex is wow methyl ester (1,02 g, 3.4 mmol) in N,N-dimethylformamide (20 ml) under stirring was added 5-hydroxy-2-methylpyridine (0.54 g, 5 mmol), and then cesium carbonate (3.2 g, 10 mmol). The resulting solution was heated for 5 h to 70° C. the Solution was allowed to stand for 4 days at ambient temperature, then was diluted with H2O and was extracted with ethyl acetate. The organic layer was washed polysystem NaCl and dried over Na2SO4. The solvent was removed on a rotary evaporator, getting a thick oil, which in vacuum at ambient temperature have led to the desired methylpyridine derived white (1.2 g, 94%).

Stage B: To the solution obtained at the stage And methylpyridine derivative (1.2 g, 3.2 mmol) in THF (13 ml) was added trimethylsilanol potassium (0.5 g, 3.5 mmol). The resulting solution was stirred for 18 h at ambient temperature, resulting in the formed gel. The solvent was removed on a rotary evaporator, obtaining the desired methylphenylcarbinol acid (1.4 g, quantitative yield).

Stage b: To the solution obtained in stage B methylphenylcarbinol acid (1.4 g, 3.2 mmol) in methylene chloride (10 ml) was added with stirring hexaphosphate postreperfusion (1,79 g, 3.8 mmol), then 4-methylmorpholine (0,79 g, 9.6 mmol), and then O-tetrahydro-2H-Piran-2-hydroxylamine (0,41 g, 3.5 mmol) and the solution was stirred for 1.5 h at ambient temperature. The solution was filtered to remove the precipitate and the solvent was removed on a rotary evaporator. After chromatography (silica gel, ethyl acetate/hexane) received O-tetrahydropyrimidin in a solid white color (1.48 g, 97%).

Stage G: To a solution obtained at the stage In O-tetrahydropyrimidine (1.48 g, 3.1 mmol) in 4 BC HCl solution in dioxane (5 ml) was added under stirring methanol (3 ml). The solution was stirred for 3 h at ambient temperature and was poured into diethyl ether. The precipitate was collected by vacuum filtration. After chromatography with reversed phase (silica gel, acetonitrile/N2O/Hcl) has been specified in the title compound in the form of solid white (0.64 g, 53%). Msvr (ES+) MN+: calculated for C18H20N2O6S: 393,1120 found: 393,1110.

Example 98: Getting tetrahydro-N-hydroxy-4-[[4-[(6-methyl-2-pyridinyl)oxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 complex methyl ester (1.0 g, 3.3 mmol) in N,N-dimethylformamide (20 ml) under stirring was added 2-hydroxy-6-methylpyridin (0.54 g, 5 mmol), and then cesium carbonate (3.2 g, 10 mmol). The resulting solution n is gravely for 5 h to 70° C. the Solution was allowed to stand for 11 hours at ambient temperature, after which the solution under stirring was added an additional portion of 2-hydroxy-6-methylpyridin (0.3 g, 2.7 mmol) and the resulting solution was heated for 3 h to 70° C. the Solution was concentrated on a rotary evaporator, diluted with saturated solution of NaCl in H2O and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed on a rotary evaporator, and after chromatography (silica gel, ethyl acetate/methanol) received the required methylpyridin in a solid white color (0,63 g, 49%).

Stage B: To the solution obtained at the stage And methylpyridine (to 0.63 g, 1.6 mmol) in THF (13 ml) was added trimethylsilanol potassium (0.5 g, 3.5 mmol). The resulting solution was stirred for 18 h at ambient temperature. The precipitate was removed by filtration, washed with methylene chloride and dried in vacuum, obtaining the potassium salt of methylpyridin-carboxylic acid (0.4 g, 55%).

Stage b: To the solution obtained in stage B of potassium salt methylphenylcarbinol acid (0.4 g, 0.9 mmol) in N,N-dimethylformamide (5 ml) was added with stirring hexaphosphate postreperfusion (0.5 g, 1 mmol), then 4-methylmorpholine (0.27 g, 2.6 mmol), and then 50%aqueous solution of hydroxylamine (0.6 g, 9 mmol). Races the thief was stirred for 32 h at ambient temperature. The solution was concentrated on a rotary evaporator, and after chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified in the title compound in the form of solids, white (rate £ 0.162 g, 47%). Msvr (ES+) MN+: calculated for C18H20N2O6S: 393,1120 found: 393,1119.

Example 99: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-[4-(1H-imidazol-1-yl)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 Tgp-protected pyroprocessing (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 ml) was added 4-(1,3-imidazole) phenol (12.9 g, 33.3 mmol), and then cesium carbonate (32,5 g of 99.9 mmol). The reaction mixture was stirred for 12 h at 65° C. After removal of dimethylacetamide in a vacuum received a solid brown color. After chromatography with reversed phase (silica gel, acetonitrile/water) received Tgp-protected compound in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected compound in a mixture of acetonitrile/water (100 ml) was added aqueous 10%HCl solution (100 ml). After stirring overnight (approximately 18 h) remove the acetonitrile. Collected the sediment, getting mentioned in the title compound in the form of solid washes the VA brown (6.0 g, 41%). MS (FAB) M+N: calculated for C21H21N3O6S1: 444, found: 444.

Example 100: Obtain 4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 Tgp-protected pyroprocessing (2.9 g, 7.5 mmol) in N,N-dimethylformamide (15 ml) was added under stirring para-chlorophenol (1,93 g, 15 mmol)and then cesium carbonate (7,3 g of 22.5 mmol). The resulting mixture was heated for 1.5 h to 90° C. the Solution was kept under stirring for 18 h at ambient temperature, after which the solution was added with stirring dimethylformamide (20 ml), and then cesium carbonate (2 g, 6.2 mmol). The resulting mixture was heated for 3 hours to 95° C. Then the solution was kept for 20 h at ambient temperature, after which it was diluted N2O and was extracted with ethyl acetate. The organic layer was washed polysystem NaCl solution and dried over sodium sulfate. The solvent was removed on a rotary evaporator. After chromatography (silica gel, ethyl acetate/hexane) received para-chlorphenoxamine-Tgp-protected hydroxamate (2.9 g, 78%).

Stage B: To the solution obtained at the stage And steam-chlorphenoxamine-Tgp-protected hydroxamate (2.9 g, 5.7 mmol) in dioxane (5 ml) was added 4n. a solution of HCl in dioxane (5 ml, 20 mmol), and then methanol (7.5 ml). The resulting solution was stirred for 1 h at ambient temperature. The solvent was removed on a rotary evaporator. After chromatography with reversed phase (silica gel, ethyl acetate/hexane) has been specified in the title compound in the form of solid white (1.35 g, 58%). MS (FAB) M+H: calculated for C18H18NO6SCl: 412, found: 412.

Example 101: Obtain 4-[[4-(3-chlorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 Tgp-protected pyroprocessing (5.0 g, 13 mmol) in N,N-dimethylformamide (20 ml) was added under stirring para-chlorophenol (5 g, 39 mmol), and then cesium carbonate (17 g, 52 mmol). The resulting solution was heated for 7 h to 95° C. the Solution was kept under stirring for 7 h at ambient temperature, diluted with H2O and was extracted with ethyl acetate. The organic layer was washed polysystem NaCl solution and dried over sodium sulfate. The solution was concentrated on a rotary evaporator. After chromatography (silica gel, ethyl acetate/hexane) received meta-chlorphenoxamine-Tgp-protected hydroxamate (5,2 g, 82%).

Stage B: To the solution obtained at the stage And PA is the a-chlorphenoxamine-Tgp-protected hydroxamate (5,2 g, 10 mmol) in dioxane (5 ml) was added 4 n HCl solution in dioxane (5 ml, 20 mmol), and then methanol (10 ml). The resulting solution was stirred for 1 h at ambient temperature. The solvent was removed on a rotary evaporator, getting mentioned in the title compound in the form of a solid white color (3.4 g, 79%). Msvr (ES+) M+N+: calculated for C18H18NO6SCl: 429,0887 found: 429,0880.

Example 102: Obtain methyl 4-[4-[(tetrahydro-4-[(hydroxyamino)carbonyl]-2H-Piran-4-yl]sulfonyl]phenoxy]benzoylpropionate

Stage A: To the solution obtained in stage b of example 55 Tgp-protected paraformadehyde compound (5.0 g, 13 mmol) in N,N-dimethylformamide (45 ml) was added under stirring methyl-3-(4-hydroxyphenyl)propanoate (7 g, 39 mmol), and then cesium carbonate (17 g, 52 mmol). The resulting mixture was heated for 7 h to 95° C. Then the solution was kept for 7 h at ambient temperature. After that, the solution was diluted with N2O and was extracted with ethyl acetate. The organic layer was washed polysystem NaCl solution and dried over sodium sulfate. The solution was concentrated on a rotary evaporator. After chromatography (silica gel, ethyl acetate/hexane) received methylpropanesulfonic-Tgp-protected hydroxamate (5.6 g, 79%).

Stage B: Crestore obtained at the stage And methylpropanesulfonic-Tgp-protected hydroxamate (5.6 g, 10 mmol) in methanol (5 ml) was added 4 n HCl solution in dioxane (5 ml, 20 mmol). The resulting solution was stirred for 0.5 h at ambient temperature. The solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of methylene chloride/ethyl acetate and the compound precipitated with hexane. The precipitate was washed with hexane and dried in vacuum, obtaining mentioned in the title compound in the form of a solid white color (3.8 g, 80%). Msvr (ES+) M+: calculated for C22H25NO8S: 464,138 found: 464,135.

Example 103: Obtain 4-[[4-[(4-forfinal)thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 Tgp-protected pyroprocessing (2.9 g, 7.5 mmol) in N,N-dimethylformamide (25 ml) was added under stirring in nitrogen atmosphere cesium carbonate (4.9 g, 15 mmol)and then 4-portifino (1.9 g, 15 mmol). The resulting mixture was heated for 7 h to 95° C. After heating for 1 h was added cesium carbonate (1.2 g, 3.8 mmol), and then after 2 h, another portion of this connection. The solution after incubation for 9 h at ambient temperature then concentrated on a rotary evaporator, diluted with 30%aqueous saline solution and was extracted with ethyl acetate. The organic layer was washed of polonese the military NaCl solution and dried over sodium sulfate. The solution was concentrated on a rotary evaporator. After chromatography (silica gel, ethyl acetate/hexane) and subsequent chromatography with reversed phase (silica gel, acetonitrile/N2About) received para-formentini-S-phenyl-Tgp-protected hydroxamate (1,9 g, 55%).

Stage B: To the solution obtained at the stage And steam-forfinal-S-phenyl-Tgp-protected hydroxamate (1.9 g, 4 mmol) in methanol (5 ml) was added 4n. a solution of HCl in dioxane (5 ml, 20 mmol), and then methanol (10 ml). The resulting solution was stirred for 0.5 h at ambient temperature. The solvent was removed on a rotary evaporator, the residue was dissolved in methylene chloride and precipitated with hexane. Formed precipitate, which was dried in vacuum, obtaining specified in the title compound in the form of solid white (1.5 g, 89%). Msvr (ES+) M+NH

+
4
: calculated for C18H18NO5S2F: 429,0954 found: 429,0948.

Example 104: Receive monohydrochloride tetrahydro-N-hydroxy-4-[[4-(4-pyridylthio]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 Tgp-protected pyroprocessing (2.9 g, 7.5 mmol) in N,N-dimethylformamide (20 ml) was added to preparemessage potassium carbonate (2.6 g, 19 mmol)and then 4-mercaptopyridine (1.7 g, 15 mmol). The resulting mixture was heated for 5 h to 75° C. After heating for 1 h was added potassium carbonate (0.26 g, 1.9 mmol), and then after 2 h, another portion of this connection. The solution was allowed to stand for 14 hours at ambient temperature. The solution was concentrated on a rotary evaporator, diluted with 30%aqueous saline solution and was extracted with ethyl acetate. The organic layer was washed polysystem NaCl and dried over Na2SO4. The solution was concentrated on a rotary evaporator. After chromatography (silica gel, ethyl acetate/hexane) received mercaptopyridine-Tgp-protected hydroxamate (1.2 g, 33%).

Stage B: To the solution obtained at the stage And mercaptopyridine-Tgp-protected hydroxamate (1.2 g, 2.5 mmol) in acetonitrile (20 ml) was added 12,5h. a solution of HCl in dioxane (0.4 ml, 5 mmol), and then methanol (3 ml). The resulting solution was stirred for 1 h at ambient temperature. The precipitate was filtered, washed with methanol and then diethyl ether and dried in vacuum, obtaining mentioned in the title compound in the form of a solid white color (0,92 g, 86%). Msvr (ES+) M+NH

+
4
: calculated for C17H18 N2O5S2: 395,0735 found: 395,0734.

Example 105: Obtain 4-[4-[[tetrahydro-4-[(hydroxyamino)carbonyl]2H-Piran-4-yl]sulfonyl]phenoxy]benzoylpropionic acid

Stage A: To a solution specified in the header of example 102 compound (0.1 g, 0.2 mmol) in methanol (0.5 ml) was added with stirring a 1 M aqueous solution of Li(OH)2(of 0.43 ml, 0.43 mmol). After maturation for 24 h at ambient temperature the solution was boiled under reflux for 20 h the Solution liofilizirovanny dry and after chromatography with reversed phase has been specified in the title compound in the form of solids, white (9 mg, 9%). MS (FAB) M+Li+: calculated for C21H23NO8S: 456, found: 456.

Example 106: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-[[1-(2-PROPYNYL)-4-piperidinyl]oxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: In dried by heating three-neck flask under nitrogen atmosphere was added NaH (1,59 g, 60%, 40 mmol), suspended in N,N-dimethylformamide (50 ml). The suspension was cooled to 0° using an ice bath was added N-BOC-protected hydroxypiperidine (8 g, 40 mmol), and then washed with N,N-dimethylformamide (10 ml). The ice bath was removed and the solution was allowed to warm for 2 h at premarian and to the ambient temperature. The solution was again cooled with stirring to 0° and added obtained in stage b of example 55 methyl ester (10 g, 33 mmol)dissolved in N,N-dimethylformamide (40 ml). The ice bath was removed and the solution was stirred for 48 h at ambient temperature. The solution was concentrated on a rotary evaporator. The solution was diluted with N2O and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After chromatography (silica gel, ethyl acetate/hexane/methanol) of the crude N-Boc-protected methyl ester was treated with 1H. a solution of HCl in methanol. The solvent was removed on a rotary evaporator. Then the residue was dissolved in acetonitrile (21 ml)to which was added N2On (21 ml). After chromatography with reversed phase (silica gel, acetonitrile/N2Has received cleared hydrochloride complex piperidinemethanol ester (4.9 g, 35%).

Stage B: To a suspension obtained in stage a of the hydrochloride complex piperidinemethanol ether (1.8 g, 4 mmol) in acetonitrile (24 ml) was added potassium carbonate (1.8 g, 13 mmol), and then propylbromide (of 0.58 ml of 80%solution, 5.2 mmol). The mixture was stirred for 18 h at ambient temperature. The solution was concentrated on a rotary evaporator, diluted with H2O and was extracted with ethyl acetate. The organic layer was dried over Na2SO4

Stage b: To the solution obtained in stage B complex propargylamine-dimitrovova ester (1.1 g, 2.7 mmol) in THF (3 ml) was added trimethylsilanol potassium (0,57 g, 4 mmol). After 5 min was added THF (12 ml), and after 10 min was added to the second portion of THF (15 ml). The resulting solution was stirred for 18 h at ambient temperature, resulting in the formed gel. The solvent was removed on a rotary evaporator and the residue was diluted with H2O and washed with ethyl acetate. The aqueous layer was acidified and chromatographically (on silica gel, acetonitrile/N2About), getting after lyophilization the desired Propylenediamine acid (0.64 g, 59%).

Stage G: To a solution obtained at the stage In Propylenediamine acid (0.64 g, of 1.64 mmol) in N,N-dimethylformamide (5 ml) was added with stirring, 1-hydroxybenzotriazole (0.3 g, 2.3 mmol), then the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.33 g, 1.7 mmol), and then O-tetrahydro-2H-Piran-2-alhydrogel (0,57 g, 4.8 mmol). The solution was stirred for 42 h at ambient temperature, concentrated on a rotary evaporator, diluted with H2O and was extracted with ethyl acetate. The organic layer was washed nassen the m sodium bicarbonate solution, then with brine and dried over Na2SO4. The solution was concentrated on a rotary evaporator, and after chromatography with reversed phase (silica gel, acetonitrile/N2O) and subsequent lyophilization has been specified in the title compound in the form of a solid white color (0.2 g, 30%). Msvr (ES+) MH+: calculated for C20H26N2O6S: 423,159 found: 423,159.

Example 107: Obtain 4-[[4-[1-acetyl-4-piperidinyl)oxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a suspension obtained in stage a of example 106 hydrochloride complex piperidinemethanol ether (1.8 g, 4 mmol) in pyridine (2 ml) was added with stirring, acetic anhydride (1.7 g, 16 mmol). The mixture was stirred for 20 min at ambient temperature. The solution was concentrated on a rotary evaporator, and after chromatography (silica gel, ethyl acetate/methanol) received a connection representing a complex acetylpiperidine ether (1.5 g, 83%).

Stage B: To the solution obtained in stage B complex acetylpiperidine-methyl ester (1.5 g, 3.3 mmol) in THF (5 ml) was added trimethylsilanol potassium (0,86 g, 6 mmol). After 5 min was added THF (15 ml), and after 10 min was added to the second portion of THF (15 ml). The resulting solution was stirred during the s 18 h at ambient temperature. The precipitate was isolated by filtration, obtaining the desired acetylpiperidine acid (1.5 g, 98%).

Stage b: To the solution obtained in stage B acetylpiperidine acid (0.9 g, 2 mmol) in dimethylacetamide (5 ml) was added hexaphosphate postreperfusion (1 g, 2.3 mmol), then 4-methylmorpholine (0.6 g, 6 mmol), and then an aqueous solution of O-tetrahydro-2H-Piran-2-ilyjocelyne (1.5 g, 23 mmol) and the solution was stirred for 48 h at ambient temperature. After chromatography with reversed phase (silica gel, acetonitrile/N2Has been specified in the title compound in the form of a solid white color (0.1 g, 12%). MS (FAB) MH+: calculated for C19H26N2O7S: 427, found: 427.

Example 108: Obtain 4-[[4-(3-chloro-4-pertenece)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage b of example 55 pyroprocessing (3.2 g, 7.7 mmol) in N,N-dimethylacetamide (15 ml) was added with stirring 3-chloro-4-terfenol (1.7 ml, 12 mmol), and then cesium carbonate (5 g, of 15.5 mmol). The reaction mixture was stirred for 2 h at 95° C. was Added cesium carbonate (2.5 g, 8 mmol) and the reaction mixture was stirred for 6 h at 95° C. the Solution was allowed to stand for 8 h at ambient temperature with the food. Then the crude reaction mixture was filtered to remove cesium chloride and precipitated the product. The residue on the filter is suspended in N2O and acidified with HCl to pH 6. After cessation of foaming precipitate was removed by filtration, washed with N2Oh, was dissolved in a mixture of N2O/acetonitrile and chromatographically on the column for GHUR with reversed phase (H2O/acetonitrile)to give 3-chloro-4-pertenece-Tgp-protected hydroxamate (1.4 g, 35%).

Stage B: To the solution obtained in stage And 3-chloro-4-pertenece-Tgp-protected hydroxamate (1.4 g, 2.7 mmol) in acetonitrile (10 ml) was added 1N. an aqueous solution of HCl (10 ml). The solution was stirred for 1 h at ambient temperature. The acetonitrile is evaporated at ambient temperature in a constant stream of nitrogen until then, until they form a thick sludge. The precipitate was filtered and the filter cake washed with N2Oh, and then diethyl ether and dried in vacuum, obtaining mentioned in the title compound in the form of a solid white color (12.5 g, 96%). The compound was recrystallized from a mixture of acetone/hexane, obtaining crystals white (10,9 g, 86%). Msvr (ES) M+NH

+
4
: calculated for C18H19NO6SFCl: 447,079 found: 447,00.

Example 109: Getting tetrahydro-N-hydroxy-4-[[4-(4-phenoxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

Stage A: To the solution obtained in stage b of example 50 challenging methyl ester thiopyran (MM) (molecular weight) 318, 3 g, 1.0 EQ.) in N,N-dimethylacetamide (DMA, 40 ml) was added cesium carbonate (12 g, 1.5 EQ.) and phenol (1.5 g). The mixture was heated to 95° C for b hours After cooling the reaction mixture to ambient temperature, the reaction mixture was filtered and then deleted the N,N-dimethylacetamide at a rotary evaporator. The residue was dissolved in 10%aqueous HCl (100 ml) and was extracted twice with ethyl acetate. An ethyl acetate extract was dried over sodium sulfate and evaporated under reduced pressure, obtaining oil. The oil was purified on silica gel, receiving 2 g complex methyl ester. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: To the solution obtained in stage a complicated methyl ester (392 MM, 2 g) in THF (20 ml) was added trimethylsilanol potassium (128 MM, 1.6 g, 1.2 EQ.). The mixture was stirred for 2-3 h at ambient temperature until, until it formed a solid residue. After completion of the hydrolysis was added N-methylmorpholine (2 ml), and then Rougher (2.3 g, 1.2 EQ.). The solution was stirred for 10 min, then EXT is ulali aqueous solution of hydroxylamine and continued stirring for another 2 hours After completion of the reaction (2 h) the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of water/acetonitrile, acidified with TFA (to pH 2), then purified using preparative GHUR with reversed phase (GHURI), receiving 1 g specified in the connection header in the form of a solid white color. The results of the analysis using theIH-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+N: calculated for C18H19NO5S2: 393, found: 393.

Example 110: Getting tetrahydro-N-hydroxy-4-[[4-(4-fenac-si)phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in stage a of example 109 compound (2 g) in tetrahydrofuran (50 ml) was added water (50 ml). To this mixture with vigorous stirring was added Ohope® 8 g, 3 EQ.). The reaction was controlled by GHURAF. After 3 h was added water and the product was twice extracted with ethyl acetate (100 ml). An ethyl acetate layer was dried over sodium sulfate. After removal of the solvent under reduced pressure was obtained 1.8 g of complex Phenoxyethanol ether in a solid white color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: To the solution obtained in stage a complex Phenoxyethanol ether (M is 590, 2 g) in tetrahydrofuran (20 ml) was added trimethylsilanol potassium (128 MM, 1.2 g, 1.2 EQ.). The mixture was stirred for 2-3 h at ambient temperature until, until it formed a solid residue. After completion of the hydrolysis was added N-methylmorpholine (2 ml), and then Rougher (2.3 g, 1.2 EQ.). The solution was stirred for 10 min, then was added an aqueous solution of hydroxylamine and continued stirring for another 2 hours After completion of the reaction (2 h) the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of water/acetonitrile, acidified with TFA (to pH 2), then purified using preparative GHURAF, receiving 500 mg specified in the connection header in the form of a solid white color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C18H19NO7S2:425, found: 425.

Example 111: Getting tetrahydro-N-hydroxy-4-[[4-(4-fenac-si)phenyl]sulfonyl]-2H-sulfoximine-4-carboxamide

Stage A: To the solution obtained in stage a of example 109 methyl ester (2 g) in a mixture of acetic acid/water (25/5 ml) was added to it with hydrogen peroxide (2 ml, 30%solution). The reaction in this intensively mixed solution was controlled by GHURAF. After 3 h was added water and about the SPS was twice extracted with ethyl acetate (100 ml). An ethyl acetate layer was dried over sodium sulfate. After removal of the solvent under reduced pressure was obtained 2.1 g connection, which represents a methyl ester of selfaccelerating-O-phenyl, in a solid white color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: To the solution obtained in stage a complicated methyl ether selfaccelerating-O-phenyl (578 MM, 1.8 g) in tetrahydrofuran (25 ml) was added trimethylsilanol potassium (128 MM, 1.2 g, 1.2 EQ.). The mixture was stirred for 2-3 h until then, until it formed a solid residue. After completion of the hydrolysis was added N-methylmorpholine (2 ml), and then Rougher (2.3 g, 1.2 EQ.). The solution was stirred for 10 min, then was added an aqueous solution of hydroxylamine and continued stirring for another 2 hours After completion of the reaction (12 h). the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, receiving 500 mg specified in the connection header in the form of a solid white color. The results of the analysis using H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+N: calculated for C18H19NO6S2: 409 detected is: 409.

Example 112: Getting tetrahydro-N-hydroxy-4-[[4-(1-acetyl-4-(4-piperidinyloxy)phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: To the solution obtained in stage b of example 50 challenging methyl ester thiopyran (318 MM, 5 g, 1.0 EQ.) in N,N-dimethylacetamide (70 ml) was added cesium carbonate (MM 5.5 g, 1.5 EQ.), tetrahydroaluminate (2 ml, 2 M solution in THF) and 1-acetyl-4-(4-hydroxyphenyl)piperazine (4.9 g). The mixture was stirred and kept at 90° C for 6 hours, the Reaction mixture was filtered and then deleted the N,N-dimethylacetamide using a rotary evaporator. The residue was dissolved in water (100 ml) and was extracted twice with ethyl acetate. An ethyl acetate layer was dried over sodium sulfate and the ethyl acetate was removed under panigram pressure receiving oil. The oil was purified on silica gel, receiving 3 g complex methyl ester. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: To the solution obtained in stage a complicated methyl ester (433 MM, 3 g) in tetrahydrofuran (50 ml) was added trimethylsilanol potassium (128 MM, 0.9 g, 1.2 EQ.). The mixture was stirred for 2-3 h until then, until it formed a solid residue. After completion of the hydrolysis was added N-methylmorpholine (2 ml), and then Rougher (3.5 g, 1.2 EQ.). The solution was stirred for 10 min, then the school within 2 h was added with stirring an aqueous solution of hydroxylamine. After completion of the reaction (2 h) the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, receiving 1.2 g specified in the connection header in the form of a solid white color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C24H29N3O6S2: 519 detected: 519.

Example 113: Getting tetrahydro-N-hydroxy-4-[[4-(4-thiophenoxy)phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: To the solution obtained in stage b of example 50 challenging methyl ester thiopyran (5 g) in acetic acid (40 ml) was added a mixture of water/hydrogen peroxide (8 ml, 4 ml/4 ml, 30%solution). The reaction in this intensively mixed solution was controlled by GHURAF. After incubation at ambient temperature for 3 h was added water and the product was twice extracted with ethyl acetate (100 ml). An ethyl acetate layer was dried over sodium sulfate. After removal of the solvent under reduced pressure was obtained 4.5 g of complex methyl ester sulfoxide-Ph-pair-F in a solid white color. The results of the analysis using the1H-NMR, MS and GHUR a confirmation which was Eridani obtaining the desired connection.

Stage B: To the solution obtained in stage a complicated methyl ester sulfoxide-Ph-pair-F (318 MM, 5 g, 1.0 EQ.) in DMA (70 ml) was added cesium carbonate (MM 4.5 g, 1.1 EQ.) and thiophenol (1.5 g, of 1.05 EQ.). The mixture was stirred for 2 h at room temperature. The reaction mixture was filtered and then deleted the N,N-dimethylacetamide using a rotary evaporator. The residue was dissolved in water (100 ml) and was extracted twice with ethyl acetate. An ethyl acetate layer was dried over sodium sulfate and the ethyl acetate was removed under reduced pressure, obtaining oil. The oil was purified using GHURAF on silica gel, receiving 2 g complex methyl ether selfaccelerating-S-Ph. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage b: To the solution obtained in stage B complex methyl ether selfaccelerating-S-Ph (590 MM, 5 g) in tetrahydrofuran (100 ml) was added trimethylsilanol potassium (128 MM, 1.5 g, 2 EQ.). The mixture was stirred for 2-3 h at ambient temperature until, until it formed a solid residue. After completion of the hydrolysis was added N-methylmorpholine (6 ml), and then Rougher (4 g, 1.1 EQ.). The solution was stirred for 10 min, then for 2 h was added with stirring an aqueous solution of hydroxylamine. After completion of the reaction (12 h). the solvent was removed on a rotary IP is Ariele. The residue was dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, gaining 1.9 grams specified in the connection header in the form of a solid white color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C18H19NO5S3: 425, found: 425.

Example 114: Getting tetrahydro-N-hydroxy-4-[[4-[4-(4-hydroxyphenyl)thiophenoxy]phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: To a solution specified in the header of example 50 compound (402 MM, 5 g, 1.0 EQ.) in N,N-dimethylacetamide (70 ml) was added 4-hydrocity-phenol (126 MM, 1.6 g, 1.3 EQ.), and then potassium carbonate (138 MM, 5 g, 2.0 EQ.). The reaction mixture is kept at 65° C for 3 h, until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was filtered in vacuum, N,N-dimethylacetamide was removed under vacuum. The residue was dissolved in water (100 ml) and was extracted twice with ethyl acetate. An ethyl acetate layer was dried over sodium sulfate and the ethyl acetate was removed under reduced pressure, obtaining a pair of HE-thiophenecarbonitrile in the form of crude oil. The results of the analysis using thelH-NMR, MS and GHUR acknowledges the desired connection.

stage B: Obtained at the stage And a pair of HE-thiophenecarbonitrile, was stirred for 2 h in a mixture of HCl/dioxane (50 ml). The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 2.1 g specified in the connection header in a solid yellow color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+N: calculated for C18H19NO5S3: 425, found: 425.

Example 115: Getting tetrahydro-N-hydroxy-4-[[4-(4-AMINOPHENYL)thiophenoxy]phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: To a solution specified in the header of example 50 compound (402 MM, 5 g, 1.0 EQ.) in N,N-dimethylacetamide (70 ml) was added 4-aminothiophenol (126 MM, 1.6 g, 1.3 EQ.), and then potassium carbonate (138 MM, 5 g, 2.0 EQ.). The reaction mixture is kept at 65° C for 3 h until resulty analysis with GHUR showed that the reaction is complete. The reaction mixture was filtered and N,N-dimethylacetamide was removed under vacuum. The residue was dissolved in water (100 ml) and was extracted twice with ethyl acetate. An ethyl acetate layer was dried over sodium sulfate and the ethyl acetate was removed under panigram pressure receiving pair-NH2-thiophenecarbonitrile in the form of crude oil. The results of the analysis using the1/sup> H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: Obtained at the stage And steam-NH2-thiophenecarbonitrile was stirred for 2 h in a mixture of HCl/dioxane (50 ml). The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 2.1 g specified in the connection header in a solid yellow color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+N: calculated for C18H20N2O4S3·With2HF3About2: 538 detected: 538.

Example 116: Getting tetrahydro-N-hydroxy-4-[[4-(4-tyramine)phenoxy]phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: To a solution specified in the header of example 50 compound (402 MM, 5 g, 1.0 EQ.) in N,N-dimethylacetamide (50 ml) was added trippin (3 g, 2 equiv.) and then cesium carbonate (10 g, 2.0 EQ.). The reaction mixture is kept at 95° C for 5 h until the results of the analysis using GHUR showed that the reaction completed, the Reaction mixture was filtered and N,N-dimethylacetamide was removed under vacuum. The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triflorus the Noah acid (TFA, pH 2), then purified using preparative GHURAF, receiving 2.5 g of the crude complex methyl ester in the form of a solid yellow color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: Obtained at the stage And the crude methyl ester was stirred for 1 h in an aqueous solution of HCl (50 ml). The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 2.2 g of triptoreline specified in the title compound as yellow foam. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C20H24N2O5S2·C2HF3O2: 550, found: 550.

Example 117: Getting tetrahydro-N-hydroxy-4-[[4-(4-hydroxyphenyl-glycine)]phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: To a solution specified in the header of example 50 compound (402 MM, 5 g, 1.0 EQ.) in N,N-dimethylacetamide (50 ml) was added hydroxyphenyl-glycine (3 g, 2 equiv.) and then cesium carbonate (10 g, 2.0 EQ.). The reaction mixture is kept at 95° C for 5 h until the results of the analysis using GHUR have not shown that re is Ktsia completed. The reaction mixture was filtered and N,N-dimethylacetamide was removed under vacuum. The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 2.0 g of the crude complex methyl ester in the form of a solid reddish-corcavado color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: Obtained at the stage And the crude methyl ester was stirred for 1 h in an aqueous solution of HCl (50 ml). The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 2.2 g of triptoreline specified in the connection header in the form of foam/solid reddish-brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C20H22N2O7S2·With2HF3About2: 580 detected: 580.

Example 118: Getting tetrahydro-N-hydroxy-4-[[4-(4-hydroxyphenyl-glycine)]phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: the Solution is specified in the header of example 115 connection is in (518 MM, 2.5 g, 1.0 EQ.) in THF (25 ml) and N-BOC-protected N-hydroxysuccinimide (2.1 g, 2 equiv.) containing N-methylmorpholine (2 ml) and 4-dimethylaminopyridine (250 mg), was stirred for 12 hours After data analysis with GHURAF reaction was completed, the solvent was removed under reduced pressure, obtaining oil. Was added with stirring for a further 1-2 h 10%aqueous solution of hydrochloric acid. Then the solution was purified by using preparative GHURAF, receiving 1.2 g foam/solid white as trifenatate. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. The solid was dried under reduced pressure and then suspended in diethyl ether, after which was added a mixture of 4 N. HCl/dioxane (20 ml). Filtered hydrochloride and washed with diethyl ether, obtaining mentioned in the title compound in the form of a solid reddish-brown color (1.1 g). The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+N: calculated for C20H23N3O5s2·C2HF3o2: 595, found: 595.

Example 119: Getting monohydrochloride tetrahydro-N-hydroxy-4-[[4-(4-pyridylthio)]phenyl]sulfonyl-2H-thiopyran-4-carboxamide

Stage A: To rest the ru specified in the header of example 50 connections (MM 402, 5 g, 1.0 EQ.) in N,N-dimethylacetamide (50 ml) was added 4-dipyridine (3 g, 2 equiv.) and then cesium carbonate (10 g, 2.0 EQ.). The reaction mixture was stirred at 75° C for 5 h until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was filtered and N,N-dimethylacetamide was removed under vacuum. The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 2.0 g of crude S-pyridyl-Tgp-protected thiopyrano in a solid brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: Obtained at the stage And the crude S-pyridyl-Tgp-protected thiopyran was stirred for 1 h in an aqueous solution of HCl (50 ml). The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 1.8 g of triptoreline specified in the connection header in the form of foam/glass reddish-brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C17H18N2O4S3·HCl: 447, found: 447.

Example 120: Obtain 4-[[4-[(4-AMINOPHENYL)thio)]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (387 MM, 5 g, 1.0 EQ.) in N,N-dimethylacetamide (50 ml) was added 4-aminothiophenol (3 g, 2 equiv.) and then potassium carbonate (10 g, 2.0 EQ.). The reaction mixture was stirred at 60° C for 5 h until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was filtered and the DMA was removed in vacuum. The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 2.0 g of the crude compound, a 4-amino-S-RH-Tgp-protected thiopyran in a solid brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: Obtained at the stage And the crude 4-amino-S-RH-Tgp-protected thiopyran was stirred for 1 h in an aqueous solution of HCl (50 ml). The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, gaining 1.4 g of triptoreline specified in the connection header in VI is e foam/glass reddish-brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C18H20N2O5S2: 408, found: 408.

Example 121: Getting tetrahydro-N-hydroxy-4-[[4-[(2-methyl-5-benzothiazolyl)oxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (387 MM, 10 g, 1.0 EQ.) in DMA (50 ml) was added hydroxymethylbenzene (8 g, 1.5 EQ.), and then cesium carbonate (20 g, 2.0 EQ.). The reaction mixture was stirred at 90° C for 5 h until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was cooled, then filtered and threw N,N-dimethylacetamide. The filter cake was dissolved in 10%aqueous HCl and stirred for 30 min to remove salts of cesium. The desired solid was isolated from the solution in the form of a resin. This resin was dissolved in ethyl acetate (100 ml), washed with water and dried over sodium sulfate. The solvent was removed in vacuum, obtaining oil, which was dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, receiving 2-methyl-5-benzothiazolylsulfenamide. The results of the analysis using the1H-NMR, MS and GHUR confirmed received the e desired connection.

Stage B: Obtained at the stage And 2-methyl-5-benzothiazolylsulfenamide was stirred for 1 h in a mixture of aqueous HCl solution (20 ml)/acetonitrile (20 ml). The solvent was concentrated and separated solid was filtered, getting 6.5 g specified in the connection header. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C20H20N2O6S2:448, found: 448.

Example 122: Obtain 4-[[4-(4-chloro-3-pertenece)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (387 MM, 10 g, 1.0 EQ.) in N,N-dimethylacetamide (50 ml) was added 4-chloro-3-terfenol (7 g, 1.4 EQ.), and then cesium carbonate (20 g, 2.0 EQ.). The reaction mixture was stirred at 90° C for 5 h until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was cooled, then filtered and cast DMA. The filter cake was dissolved in 10%aqueous HCl and stirred for 30 min to remove salts of cesium. The desired 4-chloro-3-perteneciente was isolated from solution and was filtered. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: Obtained in the study is a 4-chloro-3-perteneciente (3.4 g), was stirred for 1 h in a mixture of aqueous HCl solution (20 ml) /acetonitrile (20 ml). The solvent was concentrated and spin-off

the solid was filtered, obtaining 2.0 g specified in the connection header. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C18H17ClFNO6S: 429, found: 429.

Example 123: Getting trifenatate 4-[[4-[4-(4-acetyl-1-piperazinil)phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (387 MM, 10 g, 1.0 EQ.) in DMA (50 ml) was added 1-acetyl-4-(4-hydroxyphenyl)piperazine (3 g, 2 equiv.) and then cesium carbonate (10 g, 2.0 EQ.). The reaction mixture was stirred at 90° C for 5 h until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was filtered and removed DMA in vacuum. The residue was dissolved in a mixture of water/acetonitrile, acidified with triperoxonane acid (to pH 2), then purified using preparative GHURAF, obtaining 3.1 g of crude 4-acetyl-1-piperazinecarboxamide. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: Obtained at the stage And 4-acetyl-1-piperazineethanesulfonic-the same was stirred for 1 h in an aqueous solution of HCl (50 ml). The solvent was removed and the residue was dissolved in a mixture of water/acetonitrile, acidified with TFA (to pH 2), then purified using preparative GHURAF, obtaining 2.0 g of triptoreline specified in the connection header in the form of foam reddish-brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C24H29N3O7S· C2HF3O2: 617 detected: 617.

Example 124: Getting trifenatate N,N-dimethyl-5-[4-[[tetrahydro-4-[(hydroxyamino)carbonyl]-2H-Piran-4-yl]sulfonyl]phenoxy]-1H-indole-2-carboxamide

Stage A: To a solution specified in the header of example 55 compound (387 MM, 5 g, 1.0 EQ.) in DMA (50 ml) was added 5-hydroxy-2-indolinecarboxylic (3 g, 2 equiv.) and then cesium carbonate (10 g, 2.0 EQ.). The reaction mixture was stirred at 90° C for 5 h until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was filtered and separated DMA in vacuum. The residue was dissolved in a mixture of water/acetonitrile, acidified with TFA (to pH 2), then purified using preparative GHURAF, obtaining 2.1 g of the crude Tgp-protected paragidroksi in a solid brown color. The results of the analysis using the1H-NMR, MS and GHUR confirmed the Ali obtaining the desired connection.

Stage B: Obtained at the stage And Tgp-protected pyramidologist was stirred for 1 h in an aqueous solution of HCl (50 ml). The solvent was removed, the residue was dried and dissolved in a mixture of water/acetonitrile, acidified with TFA (to pH 2), then purified using preparative GHURAF, receiving 1.5 g of triptoreline specified in the connection header in the form of a solid reddish-brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+N: calculated for C23H25N3O7S: 487, found: 487.

Example 125: Getting tetrahydro-N-hydroxy-4-[[4-[4-(1-methylethyl)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution specified in the header of example 55 compound (387 MM, 5 g, 1.0 EQ.) in DMA (50 ml) was added 4-isopropylphenol (3 g, 2 equiv.) and then cesium carbonate (10 g, 2.0 EQ.). The reaction mixture was stirred at 90° C for 8 h until the results of the analysis using GHUR showed that the reaction is complete. The reaction mixture was filtered and threw away the part that contains the DMA. The filter residue was dissolved in 10%aqueous HCl and stirred for 30 min to remove salts of cesium. Separated and was filtered solid (3.5 g), representing isopropylidenediphenol-Tgp-protected guide oximat. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection.

Stage B: To a solution containing an aqueous solution of HCl (20 ml) and acetonitrile (20 ml), was added under stirring obtained at the stage And the crude isopropylidenediphenol-Tgp-protected hydroxamate and the resulting mixture was stirred for 1-2 hours the Solvent was concentrated, passing a stream of nitrogen over the surface of the solution. The solid was filtered and dried, obtaining 2.2 g specified in the connection header in the form of a solid reddish-brown color. The results of the analysis using the1H-NMR, MS and GHUR acknowledges the desired connection. MS (CI) M+H: calculated for C21H25NO6S: 419, found: 419.

Example 126: Obtaining resin II

Stage 1: the Binding obtained in stage G of example 55 compound with resin I

In a round bottom flask with a volume of 500 ml was loaded resin I [Ployd and others, Tetrahedron Lett. 1996, 37, 8045-8048] (8,08 g, 9.7 mmol) and 1-methyl-2-pyrrolidinone (50 ml). Attach a magnetic stirrer and slowly stirred suspension of resin. To the suspension was added a separately prepared solution obtained in stage G of example 55 compound (5,58 g, and 19.4 mmol) in 1-methyl-2-pyrrolidinone (35 ml), and then in the form of one portion of hexaflurophosphate benzotriazol-1-electroparadise (10.1 g, and 19.4 mmol). Powerstorage of hexaflurophosphate was added dropwise 4-methylmorpholin (4.26 deaths ml, 39 mmol). The reaction suspension was stirred for 24 h at room temperature, then the resin was collected in a disk funnel from the melted glass and washed with N,N-dimethylformamide, methanol, methylene chloride and diethyl ether (3× 30 ml of each solvent). The resin was dried in vacuum, obtaining 10,99 g associated with the polymer hydroxamate in the form of polymer solids reddish-brown color. theoretical loading of the polymer was of 0.91 mmol/g Analysis using infrared spectroscopy with Fourier transform (ICFP) showed the presence of bands at 1693 and 3326 cm-1, which is the characteristic signs of the presence, respectively hydroxymethylbilane and nitrogen-hydrogen bonds.

Stage 2: obtain a resin III

Interaction resin II with nucleophiles

Resin II (50 mg, 0.046 mmol) were loaded into a glass vial and the vessel was added a 0.5m solution of the nucleophile in 1-methyl-2-pyrrolidone (1 ml). In the case of phenol and thiophenols of nucleophiles were added cesium carbonate (148 mg, 0.46 mmol), and in the case of substituted piperazinone of nucleophiles were added potassium carbonate (64 mg, 0.46 mmol). The vial was closed with a lid and heated in 24-48 hours before 70-155° C, then cooled to room temperature. The resin was decanted and washed with 1-methyl-2-pyrrolidone, a mixture of 1-methyl-2-pyrrolidon/water, water, a mixture of 10%acetic Islamabad, methanol and methylene chloride (3× 3 ml each solvent).

Stage 3: Removal of hydroxamic acids from polymeric substrate

Resin III were treated for 1 h at room temperature the mixture triperoxonane acid/water (19:1, 1 ml). During this time the resin has acquired a dark red color. After that, the resin was decanted and washed with a mixture triperoxonane acid/water (19:1) and methylene chloride (2× 1 ml of each solvent), collecting the combined filtrates in a volumetric flask. Volatile components were removed in vacuo, then the residue was added a mixture of toluene/methylene chloride (2 ml each). The mixture was again concentrated under vacuum. Characteristics of the product were determined using mass spectroscopy with ionization by electron impact MS (ES).

Following hydroxamic acids were synthesized from resin II using described for stage 2 conditions with the use of these nucleophiles, and then was separated from the polymer using the reaction conditions described for stage 3.

Example XX: large-Scale method of producing resin IIIa

In kiln dried three-neck round bottom flask, equipped with a temperature sensor, an air impeller stirrer and an inlet valve for nitrogen was loaded resin II (5 g, of 0.91 mmol). To the flask was added anhydrous 1-methyl-2-pyrrolidinone (35 ml), and then utilizedabated (7,0 ml of 45.5 mmol). Suspension resin was slowly mixed air stirrer and the mixture was heated for 65 h to 80° by means of a heating casing. After the flask was cooled to room temperature.

The resin was collected in a disk funnel from the melted glass and washed with N,N-dimethylformamide, methanol and methylene chloride (3× 30 ml of each solvent). The resin was dried in vacuum, obtaining 5,86 g resin IIIa in the form of tar balls whitish color. theoretical loading of the polymer was 0.81 mmol/g By cleavage with TFA 50 mg resin IIIa according to the method described for stage 3, received 10,4 mg solids whitish, indistinguishable by the spectroscopic method from the reaction product obtained in the example 211 using utilisedictated.

Example YY: large-Scale method of producing resin IIIb

Obtaining resin IIIb was carried out according to the method described for obtaining resin Ilia, except that instead of utilisedictated used utilipath After drying in vacuum was obtained resin IIIb in the form of resin beads light yellow color with output 5,77, theoretical loading of the polymer was 0.81 mmol/g By cleavage with TFA 50 mg resin IIIb according to the method described for stage 3, received 14,7 mg solids whitish, indistinguishable by the spectroscopic method from the reaction product obtained in example 212 using telnperature.

Stage 4: Hydrolysis associated with the polymer of ester

Obtaining resin IVa

In a three-neck round bottom flask, equipped with air vane stirrer, was loaded resin IIIa (5.8 g, 4.5 mmol). To the flask was added 1,4-dioxane and the suspension of the resin was stirred for 15 minutes and Then was added a 4 M solution of KOH (5 ml, 20 mmol) and the mixture was stirred for 44 hours After that, the resin was collected in a disk funnel from plavlenogo glass and washed with a mixture of dioxane/water (9:1), water, a mixture of 10%acetic acid/water, methanol and methylene chloride (3× 30 ml of each solvent). The resin was dried in vacuum, obtaining 5,64 g resin IVa in the form of polymer beads whitish color. Analysis using ICFP showed the presence of bands at 1732 and 1704 cm-1and a broad band at 2500-3500 cm-1. Theoretical loading associated with the polymer acid was 0.84 mmol/g

Obtaining resin IVb

Working according to the method described for stage 4, the resin IIIb (5,71 g, 4.5 mmol) was transformed into the resin IVb (5,61 g). Analysis using ICFP showed the presence of bands at 173 and 1705 cm -1and a broad band at 2500-3500 see Theoretical loading associated with the polymer acid was 0.84 mmol/g

Stage 5: the Formation of amide linkages: obtaining resin V is equipped with a Frit reactional vessel was loaded or resin IVa or resin IVb (50 mg, 0,042 mmol) and the vessel was closed with a lid in a nitrogen atmosphere. Added a 0.5 M solution of hydroxybenzotriazole in 1-methyl-2-pyrrolidinone (0.3 ml, 0.15 mmol), and then 0.5 M solution of diisopropylcarbodiimide 1-methyl-2-pyrrolidinone (0.3 ml, 0.15 mmol). The resin was stirred for 15 min using a mixer upper mount, then added 0.7 M solution of amine 1-methyl-2-pyrrolidinone (0.3 ml, 0.21 mmol). The reaction mixture was stirred for 6 h, then the resin was decanted and washed with 1-methyl-2-pyrrolidinone (3× 1 ml). The reaction was repeated using the above quantities of reagents. The reaction mixture was stirred for 16 h, then the resin was decanted and washed with 1-methyl-2-pyrrolidinone, methanol and methylene chloride (3× 1 ml of each solvent).

Following hydroxamic acids were synthesized using the specified associated with the polymer acid and the amine in the reaction conditions described for stage 5, with subsequent separation from the polymer in the reaction conditions described for stage 3.

Large-scale method of producing resin IIIc

In kiln dried three-neck round bottom flask, equipped with air vane stirrer, a temperature sensor and an intake valve for nitrogen was loaded resin II (3,01 g, is 2.74 mmol). Was added 1-methyl-2-pyrrolidinone (25 ml), and then piperazine (2,36 g, a 27.4 mmol) and cesium carbonate (8,93 g, a 27.4 mmol). Added an additional portion of 1-methyl-2-pyrrolidinone (10 ml) and the reaction mixture was heated to 100° and was stirred for 18 hours, the Flask was cooled to room temperature and collecting the resin in the disk funnel from the melted glass and washed with a mixture of N,N-diethylformamide/water (1:1), water, a mixture of 10%acetic acid/water, methanol and methylene chloride (3× 30 ml of each solvent). After drying in vacuum received 3,14 g resin IIb in the form of resin beads light yellow color. theoretical loading of the polymer was 0.86 mmol/g By cleavage with TFA 50 mg resin IIIb according to the method described for stage 3, received 21 mg solids whitish, not distinguishable by the spectroscopic method from the product described in example 209.

Article is Diya 6: the Formation of the amide bond with the resin IIIc: obtaining resin VI

In equipped with a Frit reactional vessel was loaded carboxylic acid (0,215 mmol) and 1-hydroxybenzotriazole (44 mg, 0,326 mmol). The vessel was closed with a lid in an atmosphere of nitrogen was added 1-methyl-2-pyrrolidinone, and then diisopropylcarbodiimide (0,034 ml, 0,215 mmol). The solution was stirred for 15 min using a mixer upper mount, then added in a single portion of the resin IIIc (50 mg, 0,043 mmol). The reaction mixture was stirred for 16 h, then the resin was decanted and washed with 1-methyl-2-pyrrolidinone, methanol and methylene chloride (3× 1 ml of each solvent). In the case of N-9-fluorenylmethoxycarbonyl-protected amino acid resin was further treated for 30 min with a solution of piperidine/N,N-dimethylformamide (1:4, 1 ml). The resin was decanted and washed with N,N-dimethylformamide, methanol and methylene chloride (3× 1 ml of each solvent).

Following hydroxamic acids were synthesized from resin IIIc according to the method described for stage 6, using the specified carboxylic acid and subsequent separation from the polymer in the reaction conditions described for stage 3.

Step 7: obtain a resin VII

Resin C (1.0 g, 0.86 mmol) was loaded into the kiln dried round bottom flask with a volume of 100 ml and was annexed magnetoimpedance and the membrane with a needle for injection of nitrogen. Added methylene chloride (10 ml) and the suspension resin was slowly stirred. Was added in one portion pair-nitrophenylphosphate (0,867 g, 4.3 mmol)and then dropwise added diisopropylethylamine (0.75 ml, 4.3 mmol). When adding a slight temperature increase. The reaction mixture was stirred for 18 h at room temperature, after which the resin was collected in a disk funnel from the melted glass and washed with methylene chloride, methanol and methylene chloride (3× 10 ml of each solvent).

Associated with the polymer product was dried in vacuum, obtaining a 1.25 g of resin VII in the form of tar balls brown. Analysis using ICFP microscopy showed the presence of bands in 1798, 1733, 1696 and 1210 cm-1. theoretical loading of the polymer amounted to 0.75 mmol/g

Stage 8: the Interaction of resin VII resin VIII. processed amines

In a bottle with a volume of 8 ml were loaded resin VII (50 mg, of 0.038 mmol), thereto was added a small magnetic stirrer was added a 0.5 M solution of amine 1-methyl-2-pyrrolidinone (1 ml). The vial was closed with a lid and heated to 50° C. Suspension resin was carefully stirred for 15 h, and then the vial was cooled to room temperature. The resin was collected into a reaction vessel with a Frit and washed with 1-methyl-2-pyrrolidinone, methanol and methylene chloride (3× 10 ml of each solvent).

PE is Chislennye following hydroxamic acids were synthesized from resin VII under reaction conditions, described for stage 8, using the specified amine with subsequent separation from the polymer in the reaction conditions described for stage 3.

Example XXX: Obtain 4-[(4-bromophenyl)sulfonyl]tetrahydro-2H-Piran-4-carboxylic acid

Stage A: Getting

In kiln dried three-neck round bottom flask with a volume of 500 ml was loaded into the chamber filled with nitrogen, 60%oil dispersion of sodium hydride (4.0 g, 0.1 mol) and the flask was attached inlet valve for nitrogen, a temperature sensor, an air impeller stirrer and a rubber membrane. To the flask was added anhydrous tetrahydrofuran (200 ml), then cooled in an ice bath. Was added dropwise 4-bromothiophene (18,91 g, 0.1 mol), keeping the temperature below 7° C. while adding observed intensive gas development. After complete addition, the mixture was stirred with cooling for 10 minutes and Then was added dropwise methylbromide (9,5 ml, 0.1 mol), keeping the temperature below 7° C. the Reaction mixture was stirred with cooling for 10 min, after which the ice bath was removed and the mixture was stirred for 30 minutes the Reaction was stopped by adding 5 ml of water, then p is storytell was removed on a rotary evaporator. The remainder in the form of oil was distributed between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with a mixture of 5%hydrochloric acid/water (1× 200 ml), saturated sodium bicarbonate solution (1× 200 ml) and with brine (1× 200 ml). The organic phase was dried over magnesium sulfate and concentrated, obtaining 24,53 g of product as yellow oil (94%). The results of the analysis using thelH-NMR confirmed that the substance had the desired structure. Analysis by mass spectroscopy showed that the value of m/z equal to 260 (M+H).

Stage B: Receive

Obtained above at the stage And the compound (24.5 g, 0,094 mmol) were loaded into a round bottom flask with a volume of 1.0 l, provided with an air vane stirrer and temperature probe, was then added to 550 ml of methanol, and then 55 ml of water, the resulting solution became slightly turbid. The flask was immersed in an ice bath and when the temperature dropped below 5°, was added in portions over 5 min Ohope® (144,5 g, 0,235 mol). Watched a small temperature increase up to 8° C. the Reaction mixture was stirred with cooling for 10 min, after which the ice bath was removed. After 4 h the analysis using liquid chromatography high-pressure reversed-phase showed the presence of one component with retention time of 13.6 minutes the Reaction to the offer was filtered and the solid was thoroughly washed with methanol. The combined filtrates were concentrated on a rotary evaporator and the residue was distributed between ethyl acetate (300 ml) and water (200 ml). The organic layer was washed with water (3× 200 ml), saturated sodium bicarbonate solution (1× 200 ml) and with brine (1× 200 ml)then the organic phase was dried over magnesium sulfate and concentrated, obtaining 25 g of the product in the form of a solid reddish-brown color. After trituration with hexane received 24,3 g of pure sulfone in the form of a solid whitish (88%). The results of the analysis using the1H-NMR confirmed that the substance had the desired structure.

Analysis by mass spectroscopy showed that the value of m/z equal to 293 (M+H).

Stage: Obtain

In kiln dried three-neck round bottom flask with a volume of 1.0 l were loaded into the chamber filled with nitrogen, 60%oil dispersion of sodium hydride (USD 5.76 g, 0.144 mol) and the flask was attached inlet valve for nitrogen, a temperature sensor, an air impeller stirrer and a rubber membrane. To the flask was added anhydrous N,N-dimethylformamide (250 ml), was begun mechanical stirring and the mixture was heated to 50° C. To a suspension of sodium hydride was added dropwise a solution containing obtained above in stage B connection (17,59 g, 0.06 mol) and simple dibromoethylene ester(14.5 g, 0.06 mol) in 40 ml of N,N-dimethylformamide, maintaining a temperature in the range of 50-55° while there was a steady evolution of hydrogen. After complete addition, the temperature of the reaction mixture was raised to 65° and the mixture was stirred for 2 hours Then the flask was cooled to room temperature and the flask was immersed in an ice bath. When the temperature dropped below 20° With added 0.5 l of ice water.

The mixture was transferred into a separating funnel displacement 4.0 l, was added to 1.0 l of water and the mixture was extracted with ethyl acetate (3× 200 ml). The combined organic layers were washed with a mixture of 5%hydrochloric acid/water (1× 200 ml), saturated solution of sodium carbonate (1× 200 ml) and with brine (1× 200 ml), dried over magnesium sulfate and concentrated in vacuum, obtaining of 18.2 g of the crude product in the form of a semi-solid substance is yellow. After recrystallization from a mixture of ethyl acetate/hexane received 6,53 g of pure product in the form of crystals reddish-brown (30%). The results of the analysis using the1H-NMR confirmed that the substance had the desired structure. Analysis by mass spectroscopy showed that the value of m/z 363 (M+H).

Stage G: Obtaining specified in the connection header

The solution obtained above at a stage In connections (of 4.57 g, 12.6 mmol) in 50 ml of anhydrous tetrahydrofuran, p is displaced in kiln dried round bottom flask with a volume of 100 ml, was stirred under nitrogen atmosphere at room temperature was added in one portion 4,84 g trimethylsilanol potassium (37,7 mmol). The mixture was stirred for 2 h, then was added dropwise 10 ml of water. Volatile components were removed in vacuum and the residue was distributed between 100 ml of diethyl ether and 100 ml of water. The aqueous layer was acidified to pH less 2 using concentrated hydrochloric acid, resulting precipitated sludge. This mixture was extracted with ethyl acetate (3× 75 ml), combined an ethyl acetate layers were dried over magnesium sulfate and concentrated in vacuum, obtaining 4.15 g of pure product in the form of a solid white (94%).1H-NMR (CDCl3/CD3OD) of 2.10 (m, 4H), of 3.28 (m, 2H), 3,90 (m, 2H), 7,60 (m, 4H). Analysis by mass spectroscopy showed that the value of m/z equal 349 (M+H).

Stage 9: the Binding resin I

Obtaining resin IX

Working according to the method described above for stage 1 were subjected to interaction of 3.13 g of the above in the header of the connection of 3.73 g of resin I, getting 5,19 g associated with the polymer hydroximate in the form of polymer solids reddish-brown color. theoretical loading of the polymer was 0.86 mmol/g Analysis using ICFP microscopy showed the presence of bands at 1693 and 3332 cm-1, which is the characteristic signs of the presence, respectively hydrox Maccarinelli and nitrogen-hydrogen bonds.

Stage 10: Catalyzed by palladium interaction IX resin with baronowie acids

Obtaining resin VII

In a glass vessel for solid-phase reaction volume of 8 ml were loaded resin IX (50 mg, 0,043 mmol). The resin was washed with anhydrous dimethoxyethane (2× 3 ml). To the vessel was added 0,017 M solution tetranitroaniline (0.6 ml, 0.01 mmol), and then 0.6 M solution Bronevoy acid in a mixture (1:1) dimethoxyethane/ethanol (0.6 ml, 0.36 mmol) and 2 M solution of potassium hydroxide in water (0.4 ml, 0.8 mmol). The vessel was supported by overpressure of argon and kept for 16 h at 90° C. the Vessel was cooled to room temperature, then the resin was decanted and washed with 1-methyl-2-pyrrolidinone, a mixture of 1-methyl-2-pyrrolidinone/water (1:1), water, a mixture of acetic acid/water (1:9), methanol and methylene chloride (3× 3 ml each solvent).

Following hydroxamic acids were synthesized from the IX resin in the reaction conditions described for stage 10, using the specified Bronevoy acid and subsequent separation from the polymer in the reaction conditions described for stage 3.

Example 233: Getting monoethanolamine salts: nanomeasurement N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-PROPYNYL)-4-piperidinecarboxylic the

The first way to obtain

Stage A: the Solution obtained in stage K of example 9 compound (2.1 g, 4.5 mmol) in warm N2O (200 ml) was mixed with Panso3when the ambient temperature. After stirring for 20 min the resulting solid white were isolated by filtration, washed with water and dried in a vacuum oven at 37° getting mentioned in the title compound in free base form in a solid white color (1.7 g, 86%). Elemental analysis: calculated for C21H22N2About4S2·3%N2About: 57,86; N 5,23; N To 6.43; S 14,71; found: 57,84; N 4,96; N 6,39; S 14,89.

Stage B: To the solution obtained in stage a of the free base (1.6 g, 3.7 mmol) in methanol (10 ml) was added at ambient temperature methansulfonate acid and 0.28 ml, 4.1 mmol). After 3 h the resulting solid was isolated by filtration, washed with methanol and dried in a vacuum oven at ambient temperature, getting mentioned in the title compound, representing nanomeasurement, in the form of a solid white color (1.6 g, 81%). Elemental analysis: calculated for C2lH22N2O4S2·CH4O3: C 48,51; H 5,18; N 5,14; S 17,66; found: 48,88; H 5,15; N 5,23; S 17,81.

The second way to obtain

<> Stage A: the Solution obtained at the stage And example 9 protected hydroxamate (6.0 g, 12 mmol) in methanol (37 ml) was added under nitrogen atmosphere methansulfonate acid (of 0.91 ml, 14 mmol). After 1 h the precipitate was isolated by filtration, washed with methanol and dried in a vacuum oven for 1 day at 40° getting mentioned in the title compound, represents methanesulfonate, in the form of a solid white (5.5 g, 89%)identical to the product obtained as described in example 233 first mode of receipt.

In the present description, methansulfonate other compounds representing cyclic amines can be obtained similarly by using the above two methods of obtaining.

Examples 234-280

Compounds of examples 234-280 was obtained by the method similar to the method of producing compounds of examples 129-199.

Example 281-288

Following hydroxamic acids were synthesized analogously to examples 213-232 from the IX resin according to the method described in stage 10, using the specified Bronevoy acid and subsequent separation from the of alimera method described in stage 3.

Examples 289-294

Stage 11: obtain a resin XI

Into a reaction vessel equipped with a Frit, loaded resin IIIc (50 mg, 0,043 mmol). Added 0,43 M solution of isocyanate in 1-methyl-2-pyrrolidinone (1 ml, 0.43 mmol), and then diisopropylethylamine (75 μl, 0.43 mmol). The vessel was closed with a lid in an atmosphere of nitrogen, was stirred on a shaker table and was heated for 48 h to 50° C. thereafter, the vessel was cooled to room temperature, the resin was decanted and washed with 1-methyl-2-pyrrolidinone, a mixture of 1-methyl-2-pyrrolidinone/water (1:1), water, a mixture of acetic acid/water (1:9), methanol and methylene chloride (31 ml each solvent).

Following hydroxamic acids were synthesized from resin IIIc according to the method described for stage 11, using the specified isocyanate and subsequent separation from the polymer in the reaction conditions described for stage 3.

Examples 295-300

Step 12: Synthesis of resin XII

Into a reaction vessel equipped with a Frit, loaded resin VII (50 mg, of 0.038 mmol) and cesium carbonate (122 mg, 0.38 mmol). Added 0,43 M phenol solution in 1-methyl-2-pyrrolidinone (1 ml, 0.43 mmol), then the vessel was closed with a lid in a nitrogen atmosphere. The reaction mixture was stirred on a shaker table and n is gravely within 48 h up to 50° C. After this, the vessel was cooled to room temperature, the resin was decanted and washed with 1-methyl-2-pyrrolidinone, a mixture of 1-methyl-2-pyrrolidinone/water (1:1), water, a mixture of acetic acid/water (1:9), methanol and methylene chloride (3× 1 ml of each solvent).

Following hydroxamic acids were synthesized from resin C according to the method described for stage 11, using the specified phenol and subsequent separation from the polymer in the reaction conditions described for stage 3.

Examples 301-323

Krupnomasshtabnoe obtaining resin Ha

Into a reaction vessel equipped with a Frit, downloaded the IX resin (1 g, 0.86 mmol) and 0.008 M solution of tetrakis(triphenylphosphine) palladium (0) in dimethyl ether of ethylene glycol (5 ml, 0.04 mmol). Added a 1M solution of 2-formylbenzeneboronic acid in a mixture (1:1) of ethanol and dimethyl ether of ethylene glycol (6 ml, 6 mmol)and then 1 M solution of cesium carbonate in water (2 ml, 2 mmol). The vessel was closed with a lid in an argon atmosphere and was heated for 16 h to 90° C. thereafter, the vessel was cooled to room temperature, the resin was decanted and washed with the following solvents: dimethylformamide, a mixture of dimethylformamide/water (1:1), dimethylformamide, water, methanol and methylene chloride (3× 5 ml of each solvent). The resin was dried in vacuum, n is the best 1,025 g of the product in the form of polymer solids reddish-brown color. theoretical loading of the polymer was 0.84 mmol/g By cleavage with TFA 35 mg Ha resin according to the method described for stage 3, got to 11.2 mg solid reddish-brown color.

Krupnomasshtabnoe obtaining resin b

Resin b was obtained similarly to the method of obtaining the resin Ha except that instead of 2-formylbenzeneboronic acid used 3-formylbenzeneboronic acid. After drying in vacuum, the yield of tar b in the form of tar balls reddish-brown color was 1,052, Theoretical loading of the polymer was 0.84 mmol/g By cleavage with TFA 20 mg resin b according to the method described for stage 3, received 6,5 mg solid reddish-brown color.

Krupnomasshtabnoe obtaining resin XC

Resin XC was obtained similarly to the method of obtaining the resin Ha except that instead of 2-formylbenzeneboronic acid used 4-formylbenzeneboronic acid. After drying in vacuum, the yield of tar Cholesterol in the form of tar balls reddish-brown color to 1.03, theoretical loading of the polymer was 0.84 mmol/g By cleavage with TFA 28 mg resin XC according to the method described for stage 3, received a 9.4 mg solid reddish-brown color.

Stage 13: Synthesis of resin XIII:

Into a reaction vessel equipped with a Frit, loaded resins is Ha, b or LDL (50 mg, 0,042 mmol). Added a 0.2m solution of amine in triethylorthoformate (1 ml, 0.2 mmol) and the vessel is then closed with a lid in an atmosphere of nitrogen. The reaction mixture was stirred on a shaker table for 3 hours Then the vessel was added a 0.5 M solution of triacetoxyborohydride sodium 1-methyl-2-pyrrolidinone (0.8 ml, 0.4 mmol) and the mixture was stirred for 40 hours then the resin was decanted and washed with solvents in the following order: 1-methyl-2-pyrrolidinone, methanol, water, methanol and methylene chloride (3× 1 ml of each solvent).

Following hydroxamic acids were synthesized using the specified linked with aldehyde resin and an amine according to the method described for stage 13, with subsequent separation from the polymer in the reaction conditions described for stage 3.

Krupnomasshtabnoe obtaining resin Xd

The Xd resin was obtained similarly to the method of obtaining the resin Ha, except that instead of 2-formylbenzeneboronic acid used 4-carboxybenzeneboronic acid. After drying in vacuum, the yield of tar Xd in the form of polymer solids reddish-brown color was 1,07, Theoretical loading of the polymer was 0.83 mmol/g P is the cleavage using TFA 23,5 mg resin Xd method, described for stage 3, received a 4.9 mg solid reddish-brown color.

Stage 14: Synthesis of resin XIV:

Into a reaction vessel equipped with a Frit, download Xd resin (50 mg, 0,042 mmol). The resin was washed for 1-methyl-2-pyrrolidinone (2× 3 ml), then was added a 1.0 M solution of hexaflurophosphate benzotriazol-1-yloxytris-pyrrolidinone 1-methyl-2-pyrrolidinone (0.2 ml, 0.2 mmol), and then 0.7 M solution of amine 1-methyl-2-pyrrolidinone (0.3 ml, 0.21 mmol) and 1.0 M solution of diisopropylethylamine 1-methyl-2-pyrrolidinone (0.4 ml, 0.4 mmol). The vessel was closed with a lid in a nitrogen atmosphere and the reaction mixture was stirred on a shaker table for 24 hours and Then the resin was decanted and washed with 1-methyl-2-pyrrolidinone (3× 1 ml). Again cooperated with the amine by adding 1.0 M solution of hexaflurophosphate benzotriazol-1-electroparadise 1-methyl-2-pyrrolidinone (0.2 ml, 0.2 mmol), 0.7 M solution of amine 1-methyl-2-pyrrolidinone (0.3 ml, 0.21 mmol) and 1.0 M solution of diisopropylethylamine 1-methyl-2-pyrrolidinone (0.4 ml, 0.4 mmol). The vessel was closed with a lid in a nitrogen atmosphere and the reaction mixture was stirred for another 8 hours After that, the resin was decanted and washed with solvents in the following order: 1-methyl-2-pyrrolidinone, a mixture of 1-methyl-2-pyrrolidinone/water (1:1), water, a mixture of acetic acid/water (1:9), meta is I, a methylene chloride (CH ml of each solvent).

Following hydroxamic acids were synthesized using resin Xd and the specified amine according to the method described for stage 14, with subsequent separation from the polymer in the reaction conditions described for stage 3.

Example 336: Obtain 4-[[4-[4-[[(N-fluoren-9 ylethoxy)carbonyl]amino]-1-piperidinyl]phenyl]sulfonyl]tetrahydro-2H-Piran-4-carboxylic acid

Stage A: To the solution obtained in stage B of example 11 product (10.0 g, to 34.7 mmol) in 1-methyl-2-pyrrolidinone (70 ml) was added 4-(N-tert-butoxycarbonylamino) piperidine (10,43 g of 52.1 mmol), and then diisopropylethylamine (6,0 ml of 34.7 mmol). The resulting mixture was heated for 24 h to 80° and then cooled to room temperature. The crude mixture was poured into 700 ml of water and turbid water layer was extracted with ethyl acetate (3× 150 ml). The combined organic layers were washed with 5%solution of potassium bisulfate (2× 150 ml) and with brine (2× 150 ml), dried over magnesium sulfate and concentrated in vacuum, obtaining the crude ester in the form of a foamy solid white (13,04 g, 78%).

Stage B: To the solution obtained in stage a of ester (5,74 g, to 11.9 mmol) in ethanol (80 ml) is tetrahydrofuran (40 ml) was added 2n. sodium hydroxide (60 ml, 120 mmol). The resulting solution was heated for 1 h to 60° and then cooled to room temperature. The solution was concentrated in vacuo and the residue was distributed between water (300 ml) and ethyl acetate (200 ml). The aqueous layer was separated and acidified with concentrated hydrochloric acid to pH 2. Formed white precipitate, which was collected by vacuum filtration and dried in vacuum, obtaining the carboxylic acid in the form of a solid white color (4,88 g, 88%).

Stage b: To a suspension obtained in stage B carboxylic acid (4,88 g, 10.4 mmol) in methylene chloride (35 ml) was added triperoxonane acid (35 ml), the result was the dissolution of solid substances. After incubation for 15 min at ambient temperature the solution was concentrated in vacuum. The product is triturated with diethyl ether, obtaining amino acid in a solid white color (4,92 g, 98%).

Stage G: the Suspension obtained at the stage In amino acids (4,92 g of 10.21 mmol) in a mixture containing 10%solution of potassium carbonate/water (35 ml), water (100 ml) and dioxane (100 ml), cooled in an ice bath. To the cooled suspension was added dropwise a solution of 9-fluorenylmethoxycarbonyl (3,79 g, 11,23 mmol) in dioxane (50 ml). After complete addition, the ice bath was removed and the mixture was heated to room temperatureis 1 h, the solution was concentrated in vacuo and the residue was distributed between water (300 ml) and ethyl acetate (200 ml). The aqueous layer was separated and acidified with concentrated hydrochloric acid to pH 2. Formed white precipitate, which was collected by vacuum filtration, washed with hexane and dried in vacuum, obtaining mentioned in the title compound in the form of a solid white color (5,46 g, 91%).

Stage 15: Obtaining resin XVI

Stage A: Working according to the method described above for stage 1 obtained in example 336 product (2.4 g, 4,06 mmol) was subjected to the interaction with the resin I (1.7 g, 2.03 mmol), receiving tar XV in the form of polymer solids reddish brown (2,82 g). theoretical loading of the polymer was 0.71 mmol/g

Stage B: Obtained above in stage And tar XV (2.76 g, a 1.96 mmol) suspended in equipped with a Frit reaction vessel solution (1:4) piperidine/dimethylformamide (20 ml) and stirred on a table shaker for 5 minutes the Resin was poured in the vessel was added an additional portion of the mixture (1:4) piperidine/dimethylformamide (20 ml). The suspension was stirred for 30 min at room temperature. After that, the resin was decanted and washed with dimethylformamide, methanol and methylene chloride (3× 20 ml of each solvent). After drying in vacuum has been specified resin in the form of polymer solids reddish brown (2.30 g).

Stage 16: Adriauna/sulfonylamine resin XVI In sabiendo what Frit reaction vessel resin XVI (50 mg, 0,043 mmol) were washed in 1-methyl-2-pyrrolidinone (2× 1 ml). Then the resin was added 0.22 M solution Alliluyeva or sulfonylurea reagent 1-methyl-2-pyrrolidinone (1 ml, 0.22 mmol), and then diisopropylethylamine (40 μl, 0.22 mmol). The vessel was closed with a lid in a nitrogen atmosphere and stirred on a table shaker for 16 h at room temperature. Then the resin was decanted and washed with 1-methyl-2-pyrrolidinone, water, a mixture of acetic acid/water (1:9), methanol and methylene chloride (3× 1 ml of each solvent).

Following hydroxamic acids were synthesized from resin XVI according to the method described for stage 16, using the specified Alliluyeva or sulfonylurea reagent with subsequent separation from the polymer in the reaction conditions described for stage 3.

Examples 365-371

Stage 17: Reductive alkylation resin XVI equipped with a Frit reaction vessel resin XVI (50 mg, 0,043 mmol) was washed with methylene chloride (2× 1 ml). Then the resin was added a 1 M solution of the aldehyde or ketone in methylene chloride (1 ml, 1 mmol). The vessel was closed with a lid in a nitrogen atmosphere and stirred on a table shaker for 3 h at room temperature. The resin was poured promyvali with methylene chloride (3× 1 ml). After that, the resin was re-treated with 1 M solution of the aldehyde or ketone in methylene chloride (1 ml, 1 mmol). The resin was decanted and washed with methylene chloride (3× 1 ml). Then the resin was added a 1M solution of triacetoxyborohydride sodium 1-methyl-2-pyrrolidinone (1 ml, 1 mmol) and the reaction mixture was stirred over night. After that, the resin was decanted and washed with 1-methyl-2-pyrrolidinone, methanol, water, a mixture of acetic acid/water (1:9), methanol and methylene chloride (3× 1 ml of each solvent).

Following hydroxamic acids were synthesized from resin XVI according to the method described for stage 17, using the indicated aldehyde or ketone, followed by the separation from the polymer in the reaction conditions described for stage 3.

Example 372: Obtain 4-[[4-(4-butoxyethoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (3.1 g, 8 mmol) in dimethylacetamide (20 ml) was added cesium carbonate (7,28 g, 24 mmol) and 4-butoxyphenol (2.66 g, 16 mmol). The suspension was stirred for 19 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over PA2SO4Phil is trevali and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate foam whitish (3,96 g, 93%). Msvr (ES+) M+NH

+
4
: calculated for C27H35N1O8S1F: 551,24 found: 551,24.

Stage B: To the solution obtained at the stage And Tgp-protected hydroxamate (3,9 g, 7,3 mmol) in 1,4-dioxane (20 ml) was added 4n. a solution of HCl in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solid white (2,75 g, 84%). Msvr (ES+) M+N+: calculated for C22H27N1O7S1:450,16 found: 450,16.

Example 373: Getting tetrahydro-N-hydroxy-4-[[4-[3-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (3.1 g, 8 mmol) in dimethylacetamide (20 ml) was added cesium carbonate (7,28 g, 24 mmol) and meta - (trifluoromethyl) phenol (1,95 ml, 16 mmol). Suspense which was stirred for 19 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (4.1 g, 97%). Msvr (ES+) M+N+: calculated for C24H26N1O7S1F3: 530,15 found: 530,14.

Stage B: To the solution obtained at the stage And Tgp-protected hydroxamate (3,9 g, 7.4 mmol) in 1,4-dioxane (20 ml) was added 4 n HCl solution in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solid white (1.9 g, 58%). Msvr (ES+) M+N+: calculated for C19H18N1O6S1F3: 446,09 found: 446,09.

Example 374: Getting tetrahydro-N-hydroxy-4-[[4-[4-(methylthio)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (3.1 g, 8 mmol) in dimethylacetamide (20 ml) was added ka is beat cesium (7,28 g, 24 mmol) and 4-(methylthio) phenol (2.24 g, 16 mmol). The suspension was stirred for 24 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (4.1 g, 100%). Msvr (ES+) M+N+: calculated for C24H29N1O7S2: 508,15 found: 508,14.

Stage B: To the solution obtained at the stage And Tgp-protected hydroxamate (4.0 g, 7.9 mmol) in 1,4-dioxane (20 ml) was added 4 n HCl solution in dioxane (20 ml) and methanol (20 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate and washed with water, dried over PA2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solid white (1.9 g, 57%). Msvr (ES+) M+N+: calculated for C19H21N1O6S2: 424,09 found: 424,09.

Example 375: Getting tetrahydro-N-hydroxy-4-[[4-[4-(phenylmethyl)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution obtained the CSOs in example 55 product (2.7 g, 7 mmol) in dimethylacetamide (15 ml) was added cesium carbonate (6,84 g, 21 mmol) and 4-hydroxydiphenylmethyl (2.8 g, 14 mmol). The suspension was stirred for 19 h at 90° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate foam light yellow (3.7 g, 96%). Msvr (ES+) M+N+: calculated for C30H33N1O7S1: 552,21 found: 552,21.

Stage B: To the solution obtained at the stage And Tgp-protected hydroxamate (3.5 g, 6.4 mmol) in 1,4-dioxane (16 ml) was added 4n. a solution of HCl in dioxane (16 ml) and methanol (16 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solid white (1,95 g, 67%). Msvr (ES+) M+N+: calculated for C25H25N1About6S1: 468,15 found: 468,15.

Example 376: Getting tetrahydro-N-hydroxy-4-[[4-(4-hydroxyphenoxy]phenyl]sulfonyl]-2H-Piran-4-Carbo is samida

Stage A: To the solution obtained in example 55 product (2.7 g, 7 mmol) in dimethylacetamide (20 ml) was added cesium carbonate (6,84 g, 21 mmol) and 4-(benzyloxy) phenol (2.8 g, 14 mmol). The suspension was stirred for 6 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam (3.94 g, 99%). Msvr (ES+) M+H+: calculated for C30H33N1About8S1: 585,23 found: 585,23.

Stage B: To the solution obtained at the stage And Tgp-protected hydroxamate (1.5 g, of 2.64 mmol) in glacial acetic acid (5 ml) was added concentrated HCl (5 ml) and the reaction mixture was heated for 20 minutes to 60° C. the Reaction mixture was cooled, diluted with water (100 ml) and was extracted with ethyl acetate. An ethyl acetate extract is washed three times with water, with brine, dried over Na2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solid white (810 mg, 78%). Msvr (ES+) M+NH4+: calculated for C18H 19N1O7S1: 468,15 found: 468,15.

Example 377: Getting tetrahydro-N-hydroxy-4-[[4-[4-[(1-methylethyl)thio]phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a suspension containing 4-hydroxythiophenol (5.0 g, 40 mmol) and potassium carbonate (8.0 g, 58 mmol) in dimethylformamide (70 ml), was added 2-jumprope (7.0 g, 41 mmol). The suspension was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed twice with water, 10%HCl solution, brine solution, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received a substituted phenol as a clear colorless oil (5.1 g, 76%).

Stage B: To the solution obtained in example 55 product (3.1 g, 8 mmol) in dimethylacetamide (20 ml) was added cesium carbonate (7,28 g, 24 mmol) and obtained at the stage And phenol (2.7 g, 16 mmol). The suspension was stirred for 15 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate in the form of a white foam is that (4.15 g, 97%). Msvr (ES+) M+H+: calculated for C26H33N1O7S2: 536,18 found: 536,17.

Stage b: To the solution obtained in stage B Tgp-protected hydroxamate (3,9 g, 7,3 mmol) in 1,4-dioxane (18 ml) was added 4n. a solution of HCl in dioxane (18 ml) and methanol (18 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solids whitish (2,32 g, 71%). Msvr (ES+) M+N+: calculated for C21H25N1O6S2: 452,12 found: 452,12.

Example 378: Getting tetrahydro-N-hydroxy-4-[[4-[4-(1-methylethoxy)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To a solution of 4-hydroxyphenylazo ester of benzoic acid (to 8.57 g, 40 mmol) in dimethylacetamide (65 ml) was added potassium carbonate (of 8.3 g, 60 mmol) and 2-jumprope (5 ml, 50 mmol). The suspension was stirred for 1 h at 65° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed three times with water, with brine, dried over Na2SO4, filtered and concentrated in vacuum, obtaining isopro the auxiproizvodnykh in the form of a solid light gray (9.7 g, 95%).

Stage B: To a suspension obtained at the stage And isopropoxypropylamine (9.7 g, 38 mmol) in 1,4-dioxane (20 ml) and water (20 ml) was added 2.5 n sodium hydroxide solution (26 ml, 65 mmol). The suspension was stirred for 4 h at 60° C. the Reaction mixture was cooled and was added 6N. a solution of hydrochloric acid to achieve a pH of 5. The reaction mixture was extracted with methylene chloride. The organic layer was washed 4 times with 5%ammonium hydroxide solution, water, saline solution, dried over Na2SO4, filtered and concentrated in vacuum, obtaining phenol in the form of oil of amber (5,4 g, 94%).

Stage b: To a suspension obtained in example 55 product (3.1 g, 8 mmol) in dimethylacetamide (20 ml) was added cesium carbonate (7,28 g, 24 mmol) and obtained in stage B phenol (2.4 g, 16 mmol). The suspension was stirred for 21 h at 95° C. the Reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed three times with water, with brine, dried over Na2SO4, filtered and concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) got replaced Tgp-protected hydroxamate foam whitish (3,65 g, 88%). Msvr (ES+) M+N+: calculated for C26H33N1About8S1: 520,20 found: 520,20.

Stage G: To a solution obtained on a hundred the AI In Tgp-protected hydroxamate (3.5 g, 6.7 mmol) in 1,4-dioxane (17 ml) was added 4 n HCl solution in dioxane (17 ml) and methanol (17 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solids whitish (2.2 g, 80%). Msvr (ES+) M+N+: calculated for C21H25N1O7S1: 436,14 found: 436,14.

Example 379: Getting tetrahydro-N-hydroxy-4-[[4-[4-[(trifluoromethyl]phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: In a dry vessel under nitrogen atmosphere at 0° to a solution of [4-(trifluoromethyl) phenoxy] phenol (50.0 g, 0,197 mol) in anhydrous dimethylformamide (150 ml) was added sodium hydride (60%dispersion in oil) (11,0 g, 0,275 mol). After 15 min the solution was added dimethylthiocarbamate (32 g, 0,259 mol) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred for 16 h at ambient temperature. The reaction mixture was poured into 10%aqueous HCl (1 l). After vacuum filtration of the resulting precipitate was received dinoprostone in a solid white color (67,0 g, 100%).

Stage B: Obtained at the stage And tionof otvagnoe (70 g, 0.2 mol) was heated using a protective screen for 30 min up to 317° C. the result of the exothermic reaction the temperature was increased to 330° C. Heating was stopped and the reaction mixture was cooled to ambient temperature, resulting in a received THIOCARBAMATE in a solid brown color (70 g, 100%).

Stage b: To the solution obtained in stage B of THIOCARBAMATE (65.0 g, to 0.19 mol) in methanol (510 ml) was added 2.5 n sodium hydroxide solution (160 ml, 0.4 mol), passing through the solution a stream of nitrogen. The suspension was stirred for 2 h at 74° C. the Reaction mixture was cooled and the methanol was removed in vacuum. The residue was diluted with water (100 ml) and 4 times was extracted with diethyl ether. After the aqueous solution was passed a stream of nitrogen was added sodium CHLOROACETATE (22,2 g at 0.19 mol). The reaction mixture was stirred at ambient temperature and after 30 min stopped the flow of nitrogen. After 12 h, the solution was cooled and was added 6 n hydrochloric acid to reach pH 1. Suspension 4 times were extracted with ethyl acetate. United an ethyl acetate extracts were washed 0,1N. hydrochloric acid, water, saline solution, dried over Na2SO4, was filtered and was dried in vacuum, obtaining tioxolone acid in the form of a solid reddish-brown (61,0 g, 98%).

Stage G: To a solution of the floor is obtained at the stage In teoksessa acid (54,45 g, 0,166 mol) in tetrahydrofuran (370 ml) was added at 20° With water (45 ml) and Ohope® (306 g, 0,498 mol). Watched the temperature rise due to exothermic reaction up to 42° C. After 2 h the reaction mixture was filtered and the filter cake was thoroughly washed with tetrahydrofuran, and then to the filtrate was added water (250 ml). The filtrate was concentrated in vacuum. Suspension 4 times were extracted with ethyl acetate. The combined extracts were washed three times with water, with brine, dried over MgSO4, filtered and concentrated in vacuum, obtaining sulfon in a solid beige color (60,0 g, 100%).

Stage D: a Solution containing obtained in stage G sulfon (119,52 g of 0.332 mol) in methanol (660 ml) and 4 n hydrochloric acid in dioxane (20 ml)was stirred for 12 h at ambient temperature. The reaction mixture was heated to boiling and slowly cooled to ambient temperature. The resulting crystals were filtered off, thoroughly washed with cold methanol and dried, obtaining the methyl ester in the form of a solid white color (89,4 g, 72%).

Stage E: To the solution obtained in stage D complex methyl ester (64,5 g, 0,180 mol) in dimethylacetamide (360 ml) was added potassium carbonate (66,8 g, 0.48 mol), easy-bis(2-bromatology)ether (40 ml, 0,305 mol), 4-dimethylaminopyridine (1.1 g, 9 mmol) and bromi the tetrabutylammonium (2.9 g, 9 mmol). The reaction mixture was stirred over night at ambient temperature. The reaction mixture was slowly poured into 1 N. HCl (500 ml). The precipitate was filtered, washed with water, then hexane. The solid is recrystallized from methanol, getting Piran in a solid white color (62.8 g, 79%). Msvr (ES+) M+NH

+
4
: calculated for C20H19About56S1F3: 462,12 found: 462,12.

Stage G: Obtained in stage E Piran (64,0 g, 0.144 mol) was dissolved in dry vessel under nitrogen atmosphere in anhydrous tetrahydrofuran (250 ml) was added at ambient temperature a solution trimethylsilanol potassium (55,9 g, 0,432 mol) in anhydrous tetrahydrofuran (40 ml). After 2 h was added water (200 ml) and the solution was concentrated in vacuum. The suspension was extracted with ethyl acetate to remove unreacted raw product. The aqueous solution was treated with 6 N. HCl to reach pH 1. The suspension was extracted with ethyl acetate and the combined extracts were washed with water, with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was heated in diethyl ether, the resulting solid was filtered and dried, obtaining the ka is oil acid in a solid white color (56,3 g, 91%). Msvr (ES+) M+NH

+
4
: calculated for C19H17About6S1F3: 448,10 found: 448,10.

Stage C: Obtained in stage G of carboxylic acid (49,0 g, 0,114 mol) was dissolved in dry vessel under nitrogen atmosphere in anhydrous dimethylformamide (280 ml), and then to the solution was added to the other reagents in the following order: hydrate, N-hydroxybenzotriazole (18.5 g, 0,137 mol), N-methylmorpholin (37.5 ml, 0,342 mol), O-tetrahydro-2H-Piran-2-alhydrogel (41,3 g, 0,353 mol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (30,6 g, 0,160 mol). After incubation for 4 h at ambient temperature the reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with water, 5%KHSO4, a saturated solution Panso3, saline solution, dried over Na2SO4, filtered and concentrated in vacuum, obtaining Tgp-protected hydroxamate in the form of a white foam (62,6 g, 100%). Msvr (ES+) M+NH

+
4
: calculated for C24H26NO7S1F3: 547,17 found: 547,17.

Stage I: To the solution obtained in stage 3 TBM-protected hydroxy the ATA (58.5 g, 0.11 mol) in 1,4-dioxane (280 ml) was added 4 n HCl solution in dioxane (280 ml) and methanol (280 ml). After incubation for 15 min at ambient temperature the reaction mixture was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated in vacuum. After recrystallization of the product (acetone/hexane) has been specified in the title compound in the form of solid white (42,79 g, 87%). Msvr (ES+) M+NH

+
4
: calculated for C19H18NO6S1F3: 463, found: 463.

Example 380: Obtain 4-[[4-([1,1’-biphenyl]-4-yloxy]phenyl)sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (2.0 g, 5.2 mmol) in dimethylacetamide (8 ml) was added 4-phenylphenol (company Aldrich, 1.3 g, 7.8 mmol), and then cesium carbonate (6.8 g, to 20.8 mmol). The reaction mixture was stirred for 5 h at 95° C. After evaporation of dimethylacetamide in a vacuum received solid brown (5,3 g, quantitative yield). After chromatography (reversed phase column type C-18, acetonitrile/water) received Tgp-protected biphenyl in solution.

Stage B: collected received on the stud and And Tgp-protected biphenyl in a mixture of acetonitrile/water (50 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (2.0 g, 83%). MS (FAB) M+H: calculated for C24H23NO6S: 454, found:454.

Example 381: Getting tetrahydro-N-hydroxy-4-[[4-[[4-(trifluoromethyl)phenyl]thio]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (2.0 g, 5.2 mmol) in dimethylacetamide (6 ml) was added 4-triptoreline (firm Maybridge, 2.0 g, and 11.2 mmol)and then potassium carbonate (2.9 g, to 20.8 mmol). The reaction mixture was stirred for 12 h at 65° C. After evaporation of dimethylacetamide in a vacuum received solid brown (6.5 g, quantitative yield). After chromatography (reversed phase column type C-18, acetonitrile/water) received Tgp-protected trifluoromethyl in solution.

Stage B: To a solution of the crude Tgp-protected trifloromethyl in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, getting mentioned in the title compound in the form of a solid reddish-brown (0.75 g, 31%). MS (FAB) M+H: RASSC the Eastern Europe and Caucasus for C 19H18F3NO5S2: 462 detected: 462.

Example 382: Getting tetrahydro-N-hydroxy-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (2.0 g, 5.2 mmol) in dimethylacetamide (6 ml) was added 4-(triptoreline)thiophenol (company Aldrich, 1.5 g, 7.8 mmol), and then cesium carbonate (6.8 g, to 20.8 mmol). After adding a catalytic amount of potassium fluoride, the reaction mixture was stirred for 12 h at 95° C. After evaporation of dimethylacetamide in a vacuum received solid brown (7.2 g, quantitative yield). After chromatography (reversed phase column type C-18, acetonitrile/water) received Tgp-protected triftormetilfosfinov in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected triftormetilfosfinov in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, getting mentioned in the title compound in the form of a solid reddish-brown (0,60 g, 24%). MS (FAB) M-N: calculated for C19H18F3NO6S2: 476, found: 476.

Example 383: Obtain 4-[4-[4-chloro-3-(trifluoromethyl)phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (2.0 g, 5.2 mmol) in dimethylacetamide (6 ml) was added 4-chloro-3-triptoreline (firm Avocado, 1.5 g, 7.8 mmol), and then cesium carbonate (6.8 g, to 20.8 mmol). The reaction mixture was stirred for 12 h at 95° C. After evaporation of dimethylacetamide in a vacuum received solid brown (7.6 g, quantitative yield). After chromatography (reversed phase column type C-18, acetonitrile/water) received Tgp-protected compound in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected compound in a mixture of acetonitrile/water (40 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, getting mentioned in the title compound in the form of a solid reddish-brown (0,92 g, 37%). MS (FAB) M+N: calculated for C19H17CIF3NO6S: 480 detected: 480 pixels.

Example 384: Obtain 4-[[4-[4-(1,1-dimethylethyl)phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (5.0 g, 12.9 mmol) in dimethylacetamide (25 ml) was added 4-tert-butylphenol (firm Avocado, 2.9 g, with 19.4 mmol), and then ka is beat cesium (20.4 g, 62.5 mmol). The reaction mixture was stirred for 12 h at 95° C. After evaporation of dimethylacetamide in a vacuum received solid brown (9.4 g, quantitative yield). After chromatography (reversed phase column type C-18, acetonitrile/water) received Tgp-protected compound in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected compound in a mixture of acetonitrile/water (60 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (0.28 g, 5%). MS (FAB) M+H: calculated for C22H27NO6S: 434, found: 434.

Example 385: Obtain 4-[[4-[3,5-bis(trifluoromethyl)phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (3.0 g, 7.7 mmol) in dimethylacetamide (15 ml) was added 3,5-dateformatter (2.9 g, with 19.4 mmol), and then cesium carbonate (20.4 g, 62.5 mmol). The reaction mixture was stirred for 12 h at 95° C. After evaporation of dimethylacetamide in a vacuum received solid brown (14,7 g, quantitative yield). After chromatography (reversed phase, the number of the NSV type C-18, acetonitrile/water) received Tgp-protected compound in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected compound in a mixture of acetonitrile/water (60 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, getting mentioned in the title compound in the form of a solid white color (1.2 g, 31%). MS (FAB) M+H: calculated for C20H17F6NO6S:514 detected: 514.

Example 386: Getting tetrahydro-N-hydroxy-4-[[4-[3-methyl-4-(1-methylethyl)phenoxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (4.0 g, or 10.3 mmol) in dimethylacetamide (20 ml) was added 4-isopropyl-3-METHYLPHENOL (company Aldrich, 2.3 g, a 15.5 mmol), and then cesium carbonate (16,8 g of 51.5 mmol). The reaction mixture was stirred for 12 h at 95° C. After evaporation of dimethylacetamide in a vacuum received solid brown (18,3 g, quantitative yield). After chromatography (reversed phase column type C-18, acetonitrile/water) received Tgp-protected compound in solution.

Stage B: To the solution obtained at the stage And untreated Tgp-protected compound in a mixture of acetonitrile/water (40 ml) was slowly added 1%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, getting mentioned in the title compound in the form of a solid reddish-brown color (1.8 g, 40%). MS (FAB) M-N: calculated for C22H27F3NO6S: 432, found: 432.

Example 387: Getting tetrahydro-N-hydroxy-4-[[4-[(2,2,3,3-titrator-2,3-dihydro-1,4-benzodioxin-6-yl)oxy]phenyl]sulfonyl]-2H-Piran-4-carboxamide

Stage A: To the solution obtained in example 55 product (5.0 g, 12.9 mmol) in dimethylacetamide (25 ml) was added 2,2,3,3-titrator-6-hydroxybenzoate (firm Oakwood, 4.3 g, and 19.4 mmol), and then cesium carbonate (21,0 g, and 64.5 mmol). The reaction mixture was stirred for 5 h at 95° C. After evaporation of dimethylacetamide in a vacuum received solid brown (11.3 g, quantitative yield). After chromatography (reversed phase column type C-18, acetonitrile/water) received Tgp-protected compound in solution.

Stage B: To assembled obtained at the stage And untreated Tgp-protected compound in a mixture of acetonitrile/water (50 ml) was slowly added 10%aqueous HCl solution (100 ml). After stirring overnight (approximately 18 h) acetonitrile evaporated. Collected the sediment, receiving specified in the header joint is in the form of solids, white (3.5 g, 54%). MS (FAB) M-N: calculated for C20H17F4NO8S: 506, found: 506.

Example 388: obtain the dihydrochloride of N-hydroxy-1-[2-(4-morpholinyl)ethyl]-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To a suspension hydrobromide 4-bromopyridine (107,0 g, 0,436 mol) in tetrahydrofuran (1 l) was slowly added triethylamine (122 ml, 0,872 mol), and then di-tert-BUTYLCARBAMATE (100 g, 0,458 mol)which was added in several portions. The resulting mixture was stirred for 22 h at ambient temperature, then was filtered and concentrated in vacuum. The solids were washed with hexane and then collected by filtration, receiving the BOC-protected piperidine in the form of oil of amber (124 g, >100%).

Stage B: To a solution of 4-terfenol (50.0 g, 0,390 mol) in acetone (400 ml), degassed with N2added Cs2CO3(159 g, 0,488 mol). After degassing the resulting mixture for 5 min with N2added obtained at the stage And the BOC-protected piperidine (85,9 g, 0,325 mol). The resulting mixture was stirred for 18 h at ambient temperature, then filtered through a bed of Celite®, washing with acetone. The filtrate was concentrated in vacuum, obtaining sulfide in the form of balance reddish brown (98,5 is, 97%).

Stage b: To the solution obtained in stage B of sulfide (8.00 g, of 25.7 mmol) in dichloromethane (90 ml) and methanol (15 ml) was added in two portions, the uranyl magnesium salt monoperoxyphthalic acid (19.1 g, and 38.6 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature and then filtered. The filtrate was washed with saturated solution of NaHCO3and then a saturated solution of NaCl. The combined aqueous layers were extracted with dichloromethane (100 ml). The combined organic layers were dried over Na2SO4and then concentrated in vacuum. The resulting solids were washed with hexane, then dissolved in dichloromethane and filtered through a bed of Celite®, rinsing with dichloromethane. The filtrate was concentrated in vacuo was recrystallized from ethyl acetate, getting sulfon in the form of a crystalline solid, white (4,45 g, 50%).

Stage G: To a solution obtained at the stage In sulfone (7,00 g of 20.4 mmol) in N,N-dimethylformamide (40 ml) was added Cs2CO3(19.9 g, to 61.2 mmol) and α ,α ,α -Cryptor-para-cresol (of 3.97 g, 24.5 mmol). The resulting mixture was stirred for 16 h at 80° C. After cooling to ambient temperature the reaction mixture was concentrated in vacuum. The resulting residue was treated with N2Oh and the solids were collected filtrazione this solids were washed with hexane, then with methanol, getting simple billowy ether in a solid reddish-brown color (at 8.60 g, 87%).

Stage D: To the solution obtained in stage G simple biryawaho ether (8,59 g of 17.7 mmol) in tetrahydrofuran (100 ml), cooled to 0° C, was slowly added bis(trimethylsilyl)amide lithium (22,0 ml, 1.0 M solution in tetrahydrofuran, to 22.0 mmol) at such a speed that the temperature of the reaction mixture never exceeded 1° C. the Resulting mixture was stirred for 1 h at 0° With, then slowly added to the solution of methylchloroform (2,05 ml, 26,6 mmol) in tetrahydrofuran (5.0 ml) at such a speed that the temperature of the reaction mixture never exceeded 4° C. After complete addition, the mixture was made to slowly warm to ambient temperature. Was added a saturated solution of NH4Cl (50 ml), after which the tetrahydrofuran was removed in vacuum. To the residue was added water (50 ml) and then extracted with ethyl acetate. The combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After recrystallization from methanol was obtained methyl ester in the form of a crystalline solid of light yellow color (7,66 g, 80%).

Stage E: To the solution obtained in stage D complex methyl ester (7,66 g, 14.1 mmol) in dioxane (30 ml) and methanol (10 ml) dobavlyali N. a solution of HCl in dioxane (10 ml, 40 mmol). After stirring for 2 h at ambient temperature was added an additional portion of 4 n HCl solution in dioxane (10 ml, 40 mmol). After stirring for 2.5 h at ambient temperature the reaction mixture was concentrated in vacuum, obtaining the amine in the form of a solid whitish (6,80 g, >100%).

Stage G: To the suspension obtained in stage E amine (3.00 g, and 6.25 mmol) in acetonitrile (20 ml) was added K2CO3(of 3.46 g of 25.0 mmol), hydrochloride of 4-(2-chloroethyl)of the research (1.22 g, 6,56 mol) and a catalytic amount of NaI. The resulting mixture was stirred for 22 h at the temperature of reflux distilled. After cooling to ambient temperature the reaction mixture was filtered through a bed of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuum, obtaining morpholinylmethyl in the form of a solid reddish-brown (3,45 g, >100%).

Stage C: the solution obtained in stage G of morpholinylmethyl (of 3.45 g of 6.25 mmol) in tetrahydrofuran (60 ml) was added trimethylsilanol potassium (1.60 g, 12,50 mmol). After stirring for 25 hours at ambient temperature was added N2O. Then the reaction mixture was neutralized (to pH 7) with 1 n HCl solution. The tetrahydrofuran was removed in vacuo and the precipitate was collected by filtration is washed with diethyl ether, receiving amino acid in a solid whitish (2,87 g, 85%).

Stage I: To the suspension obtained in stage 3 amino acids (2,87 g of 5.29 mmol) in dichloromethane (25 ml) was added N-methylmorpholine (1,74 ml, 15.9 mmol), O-(tetrahydropyranyl)hydroxylamine (0,682 g of 5.82 mmol) and Rougher® (2,96 g 6,35 mmol). After stirring for 19 h at ambient temperature was added an additional portion of N-methylmorpholine (0,872 ml, 7,94 mmol), O-(tetrahydropyranyl)hydroxylamine (0,310 g, to 2.65 mmol) and Rougher® (1.48 g, 3,17 mmol). The resulting mixture was stirred for 3 h at ambient temperature and then concentrated in vacuum. The residue was distributed between ethyl acetate and N2O. the Organic layer was washed with saturated solution of NaCl and dried over PA2SO4. After chromatography (silica gel, methanol/chloroform) received protected hydroxamate in the form of a solid whitish (2,62 g, 77%).

Stage: To the solution obtained at the stage And secure hydroxamate (2,62 g, 4,08 mmol) in dioxane (9 ml) and methanol (3 ml) was added 4 n HCl solution in dioxane (10 ml, 40.0 mmol). The resulting mixture was stirred for 2 h at ambient temperature, then added diethyl ether (20 ml). The resulting solids were collected by filtration, getting mentioned in the title compound in the form of a solid substance is elevatora color (2,31 g, 90%). MS MN+: calculated for C25H31O6N3SF3: 558 detected: 558.

Example 389: obtain the dihydrochloride of N-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To a suspension obtained in stage E of example 388 amine (1.50 g, of 3.13 mmol) in acetonitrile (10 ml) was added To a2CO3(1.73 g, 12.5 mmol) and the hydrochloride of 4-picolylamine (0.565 g, 3,44 mmol). After stirring for a period of 21.5 hours at a temperature of reflux distilled, the reaction mixture was filtered through a bed of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received picolylamine in the form of a transparent resin (1.44 g, 86%).

Stage B: To the solution obtained in stage a of picolylamine (1.44 g, 2,69 mmol) in tetrahydrofuran (20 ml) was added trimethylsilanol potassium (0,690 g, 5,38 mmol). The resulting mixture was stirred for 20 h at ambient temperature and then the tetrahydrofuran was removed by pulling N2through the reaction mixture. Added water and the reaction mixture was neutralized (to pH 7) with 2 n HCl solution. The precipitate was collected by filtration, obtaining amino acid in a solid white color (1.31 g, 94%).

Stage b: To a suspension obtained in stage B am is necessaty (1.31 g, 2,52 mmol) in N,N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0,408 g, to 3.02 mmol), N-methylmorpholin (0,832 ml, 7.56 mmol), O-(tetrahydropyranyl)hydroxylamine (0,443 g of 3.78 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0,676 g of 3.53 mmol). The resulting mixture was stirred for 3 days at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed with saturated solution of NaHCO3, a saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of a white foam (1.24 g, 79%).

Stage G: To a solution obtained at the stage In protected hydroxamate (1.24 g, 2.00 mmol) in dioxane (6 ml) and methanol (2 ml) was added 4 n HCl solution in dioxane (5,00 ml, 20.0 mmol). After stirring for 2.5 h at ambient temperature the reaction mixture was concentrated in vacuum. The resulting foam was again treated for 15 min 4 N. a solution of HCl in dioxane (3,00 ml)was then added diethyl ether and the precipitate was collected by filtration, getting mentioned in the title compound in the form of a solid whitish (1.04 g, 85%). MS MN+: calculated for C25H25O5N3SF3: 536 detected: 536

Example 390: obtain the dihydrochloride of N-hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To a suspension obtained in stage E of example 388 amine (1,00 g of 2.08 mmol) in acetonitrile (10 ml) was added To a2CO3(1,15 g of 8.33 mmol) and hydrochloride 3-picolylamine (0.375 g, to 2.29 mmol). After stirring for 12 h at the temperature of reflux distilled, the reaction mixture was filtered through a bed of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received picolylamine foam light yellow (0,740 g, 67%).

Stage B: To the solution obtained in stage a of picolylamine (0,740 g, 1.38 mmol) in tetrahydrofuran (10 ml) was added trimethylsilanol potassium (0,355 g, 2.77 mmol). The resulting mixture was stirred for 17 h at ambient temperature, then added an additional portion trimethylsilanol potassium (0,044 g, 0,343 mmol) and the resulting mixture was stirred for 2 h at ambient temperature. The tetrahydrofuran was removed by pulling N2through the reaction mixture. Was added water (5 ml) and the reaction mixture was neutralized (to pH 7) using a 2H. HCl solution. The precipitate was collected by filtration and was dried by concentration in vacuum and with what Econom, receiving amino acid in a solid whitish (0,700 g, 97%).

Stage b: To a suspension obtained in stage B of amino acids (0,700 g of 1.34 mmol) in N,N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0,218 g of 1.61 mol), N-methylmorpholin (0,442 ml, 4.02 mmol), O-(tetrahydropyranyl)hydroxylamine (0,235 g, a 2.01 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0,360 g, 1.88 mmol). The resulting mixture was stirred for 23 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed N2Oh, a saturated solution of NaHCO3, a saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate foam whitish (0,500 g, 60%).

Stage G: To a solution obtained at the stage In protected hydroxamate (0,500 g, 0,807 mmol) in dioxane (1.5 ml) and methanol (0.5 ml) was added 4 n HCl solution in dioxane (3,00 ml of 12.0 mmol). After stirring for 2 h at ambient temperature was added diethyl ether and the precipitate was collected by filtration, getting mentioned in the title compound in the form of a solid yellow (0,363 g, 74%). MS MN+: calculated for C25H25O5N3SF3: 536, about arozena: 536.

Example 391: obtain the dihydrochloride of N-hydroxy-1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To a suspension obtained in stage E of example 388 amine (1.26 g, 2,63 mmol) in acetonitrile (10 ml) was added To a2CO3(1.45 g, 10.5 mmol) and the hydrochloride of 2-picolylamine (value (0.475) g, 2.89 mol). After stirring for 12 h at the temperature of reflux distilled, the reaction mixture was filtered through a bed of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received picolylamine resin amber (1.40 g, 99%).

Stage B: To the solution obtained in stage a of picolylamine (1.40 g, 2,62 mmol) in tetrahydrofuran (20 ml) was added trimethylsilanol potassium (0,672 g of 5.24 mmol). The resulting mixture was stirred for 15 h at ambient temperature. The tetrahydrofuran was removed by pulling N2through the reaction mixture. Was added N2O (5 ml) and the reaction mixture was neutralized (to pH 7) with 2 n HCl solution. The precipitate was collected by filtration and was dried by concentration in vacuum with acetonitrile, receiving amino acid in a solid whitish color (1.07 g, 79%).

Stage b: To a suspension obtained in stage B amino acid (1.07 g, of 2.06 mmol) N,N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (of 0.333 g, 2,47 mol), N-methylmorpholin (0,679 ml, 6,18 mmol), O-(tetrahydropyranyl)hydroxylamine (0,362 g, to 3.09 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and (0,553 g is 2.88 mmol). The resulting mixture was stirred for 19 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed N2Oh, a saturated solution Panso3, a saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, methanol/dichloromethane) received protected hydroxamate in a solid white color (1,03 g, 81%).

Stage G: To a solution obtained at the stage In protected hydroxamate (1,03 g of 1.66 mmol) in dioxane (3.0 ml) and methanol (1.0 ml) was added 4 n HCl solution in dioxane (3,00 ml of 12.0 mmol). After stirring for 1.5 h at ambient temperature was added diethyl ether and the precipitate was collected by filtration, getting mentioned in the title compound in the form of solid light pink color (0,970 g, 96%). MS MN+: calculated for C25H25O5N3SF3:536 detected: 536.

Example 392: Getting monohydrochloride N-hydroxy-4-[[4-[(4-methoxyphenyl)amino]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the received n the steps In example 91 of ester (1,00 g, 2,17 mmol) was added Cs2CO3(0,990 g, 3.04 from mmol), BINAP (0,061 g, 0,098 mmol), Tris(dibenzylideneacetone)dipalladium(0) (to 0.060 g, 0.07 mol), para-anisidine (0,320 g, 2,60 mmol) and toluene (4 ml). The resulting mixture was heated for 22 h to 100° C. After cooling to ambient temperature was added diethyl ether and the mixture filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received aniline in the form of an orange foam (0.810 g, 74%).

Stage B: To the solution obtained at the stage And aniline (0,780 g, 1.55 mmol) in tetrahydrofuran (4.0 ml) was added trimethylsilanol potassium (0.238 g of 1.86 mmol). The resulting mixture was stirred for 17 h at ambient temperature and then added an additional portion trimethylsilanol potassium (0,020 g, 0,1955 mmol). After stirring for 24 h at ambient temperature was added an additional portion trimethylsilanol potassium (0,040 g, 0,310 mmol). After stirring for 26 h at ambient temperature the solvent was removed equalising N2through the mixture. To a suspension of the residue in dichloromethane (10 ml) was added N-methylmorpholine (0,511 ml and 4.65 mmol), O-(tetrahydropyranyl)hydroxylamine (0,218 g of 1.86 mmol), and then Rougher® (1.08 g, of 2.33 mmol). The resulting mixture was stirred for 2 is it at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in the form of a solid whitish (0,600 g, 66%).

Stage b: To the solution obtained in stage B of protected hydroxamate (0,580 g, 0,984 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4 n HCl solution in dioxane (2.5 ml, 10.0 mmol). The resulting mixture was stirred for 1 h at ambient temperature, then added diethyl ether (10 ml). The solids were collected by filtration, getting mentioned in the title compound in the form of a solid white color (0,437 g, 100%). MS MN+: calculated for C19H24O5N3S: 406, found: 406.

Example 393: Getting monohydrochloride N-hydroxy-4-[[4-[[4-(triptoreline)phenyl]amino]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage b of example 91 of ester (3,27 g, to 7.09 mmol) was added Cs2CO3(3,23 g, 9,92 mmol), BINAP (of 0.066 g, 0,107 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,065 g, 0,071 mol), 4-cryptomaterial (1,15 ml, 8,51 mmol) and toluene (14 ml). The resulting mixture was heated for 22 h to 100° C. After cooling to a temperature which s environmental amid the mixture was filtered through a bed of Celite®, washing with ethyl acetate, and the filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received aniline in the form of a solid reddish-brown (3,59 g, 91%).

Stage B: To the solution obtained at the stage And aniline (1,03 g of 1.84 mmol) in tetrahydrofuran (10 ml) was added trimethylsilanol potassium (0,331 g, 2.58 mmol). The resulting mixture was stirred for 24 h at ambient temperature and then added an additional portion trimethylsilanol potassium (amount of 0.118 g, 0,092 mmol). After stirring for 26 h at ambient temperature the solvent was removed equalising N2through the mixture. Was added N2Oh and the reaction mixture was acidified (to pH 3) using 1 n HCl solution. The aqueous reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo got acid in the form of a solid reddish-brown (1.01 g, 100%).

Stage b: To a suspension obtained in stage B acid (1,00 g of 1.84 mmol) in N,N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0,298 g, 2.21 mol), N-methylmorpholin (0,607 ml, 5,52 mmol), O-(tetrahydropyranyl)hydroxylamine (0,323 g, was 2.76 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0,494 g, 2.58 mmol). The resulting mixture is eremetical for 17 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed N2Oh, a saturated solution of NaHCO3, a saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (0,960 g, 81%).

Stage G: To a solution obtained at the stage In protected hydroxamate (0,960 g, 1,49 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4n. HCl in dioxane (4.0 ml, 16.0 mmol). The resulting mixture was stirred for 2.5 h at ambient temperature. The solvent is then removed by pulling N2through the reaction mixture. Added diethyl ether (20 ml) and the precipitate was collected by filtration, getting mentioned in the title compound in the form of solid light pink color (0,716 g, 100%). MS MN+: calculated for C19H21O5N3SF3: 460, found: 460.

Example 394: Getting monohydrochloride N-hydroxy-1-(2-methoxyethyl)-4-[[4-[[4-(triptoreline)phenyl]amino]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage a of example 392 aniline (2.55 g, of 4.57 mmol) in dioxane (9.0 ml) and methanol (3.0 ml) was added 4 n HCl solution in dioxane (10 ml, 40 mmol). After stirring for 2 h at the temperature of the environment and the surrounding environment, the reaction mixture was concentrated in vacuum, getting amine in the form of a solid reddish-brown (2,36 g, >100%).

Stage B: To a suspension obtained at the stage And amine (1.50 g, 3.03 mmol) in acetonitrile (12 ml) was added To a2CO3(1.26 g, 9.09 mmol) and easy-methyl-2-bromatology ether (0,313 ml of 3.33 mmol). After stirring for 23 hours at a temperature of reflux distilled was added Cs2CO3(2,96 g, 9.09 mmol). After incubation for 6 h at the temperature of reflux distilled, the reaction mixture was filtered through a bed of Celite®, rinsing with dichloromethane. The filtrate was concentrated in vacuum. After chromatography (silica gel, methanol/dichloromethane) received methoxyethylamine in the form of a solid reddish-brown (1.13 g, 72%).

Stage b: To the solution obtained in stage B of methoxyethylamine (1.13 g, are 2.19 mmol) in tetrahydrofuran (20 ml) was added trimethylsilanol potassium (0,561 g of 4.38 mmol). The resulting mixture was stirred for 18 h at ambient temperature and then added an additional portion trimethylsilanol potassium (0,140 g of 1.09 mmol). After stirring for 5 h at ambient temperature the solvent was removed equalising N2through the mixture. Was added water (8 ml) and the reaction mixture was neutralized (to pH 7) with 1 n HCl solution. The solids were collected by filtration and was dried by concentration in vacuum with AC is lonitrile, receiving amino acid in a solid off-white color (to 0.900 g, 82%).

Stage G: To a suspension obtained at the stage In amino acids (to 0.900 g, to 1.79 mmol) in N,N-dimethylformamide (8.0 ml) was added 1-hydroxybenzotriazole (0,290 g of 2.15 mol), N-methylmorpholin (0,590 ml, 5.37 mmol), O-(tetrahydropyranyl)hydroxylamine (0,315 g, 2,69 mmol) and the hydrochloride of 1-[3-(dimethylamino) propyl] -3-ethylcarbodiimide (to 0.480 g, 2.51 mmol). The resulting mixture was stirred for 16 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed N2Oh, a saturated solution Panso3, a saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, methanol/dichloromethane) received protected hydroxamate in the form of a solid whitish (0,870 g, 81%).

Stage D: To the solution obtained in stage G of protected hydroxamate (0,870 g, 1,45 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4 n HCl solution in dioxane (10.0 ml, 40.0 mmol). The resulting mixture was stirred for 2.0 hours at ambient temperature. The reaction mixture was concentrated in vacuo and then treated for 30 min 4 N. HCl solution (3 ml). The solvent is then removed by pulling N2through the reaction mixture. Added diethyl ether (30 ml) and the precipitate was collected by filtration, getting listed in the title compound in the form of solid light pink color (0,771 g, 96%). MS MN+: calculated for C22H27About6N3SF3: 518, found: 518.

Example 395: Getting monohydrochloride N-hydroxy-4-[[4-[[4-(tryptomer)phenyl]amino]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage b of example 91 of ester (3,16 g, 6,85 mmol) was added Cs2CO3(3.13 g, 9,59 mmol), BINAP (0,064 g, 0,103 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,063 g, 0,069 mol), α ,α ,α -triptorelin (of 1.03 ml, were 8.22 mmol) and toluene (14 ml). The resulting mixture was heated for 17 h to 100° C. After cooling to ambient temperature the mixture was filtered through a bed of Celite®, washing with dichloromethane, and the filtrate was concentrated in vacuum. After chromatography (silica gel, ethyl acetate/hexane) received aniline in the form of foam light orange color (is 3.08 g, 83%).

Stage B: To the solution obtained at the stage And aniline (1,00 g of 1.84 mmol) in tetrahydrofuran (10 ml) was added trimethylsilanol potassium (0,473 g of 3.69 mmol). The resulting mixture was stirred for 25 h at ambient temperature, then the solvent was removed equalising N2through the mixture. Added water and the reaction mixture was acidified (to pH 3) using 1 n HCl solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated solution of NaCl and dried over Na2SO4. After concentration in vacuo got acid in the form of an orange foam (1,00 g, >100%).

Stage b: To a suspension obtained in stage B acid (0,972 g of 1.84 mmol) in N,N-dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (0,298 g, 2.21 mol), N-methylmorpholin (0,607 ml, 5,52 mmol), O-(tetrahydropyranyl)hydroxylamine (0,323 g, was 2.76 mmol) and hydrochloride 1-13-(dimethylamino)propyl]-3-ethylcarbodiimide (0,494 g, 2.58 mmol). The resulting mixture was stirred for 18 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed N2Oh, a saturated solution of NaHCO3, a saturated solution of NaCl and dried over Na2SO4. After chromatography (silica gel, ethyl acetate/hexane) received protected hydroxamate in a solid white color (0,970 g, 84%).

Stage G: To a solution obtained at the stage In protected hydroxamate (0,950 g and 1.51 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4n. HCl in dioxane (4.0 ml, 16.0 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature. Added diethyl ether (20 ml) and the precipitate was collected by filtration, floor the tea mentioned in the title compound in the form of a solid white color (0,630 g, 87%). MS MN+: calculated for C19H21O4N3SF3: 444, found: 444.

Example 396: Getting monohydrochloride N-hydroxy-1-(2-methoxyethyl)-4-[[4-[[4-(trifluoromethyl)phenyl]amino]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage a of example 395 aniline (2,07 g is 3.82 mmol) in dioxane (9.0 ml) and methanol (3.0 ml) was added 4 n HCl solution in dioxane (10 ml, 40 mmol). After stirring for 2 h at ambient temperature the reaction mixture was concentrated in vacuum, obtaining the amine in the form of a solid yellow (1.89 g, >100%).

Stage B: To a suspension obtained at the stage And Amin (1,83 g is 3.82 mmol) in acetonitrile (20 ml) was added To a2CO3(1,58 g, 11,46 mmol) and methyl-2-bromatology ether (0,395 ml, 4.20 mmol). After stirring for 18 hours at a temperature of reflux distilled, the reaction mixture was filtered through a bed of Celite®, washing with dichloromethane and the filtrate was concentrated in vacuum. After chromatography (silica gel, methanol/dichloromethane) received methoxyethylamine in the form of a solid whitish (1,58 g, 83%).

Stage b: To the solution obtained in stage B of methoxyethylamine (1,58 g and 3.15 mmol) in tetrahydrofuran (30 ml) was added trimethylsilanol potassium (0.810 g, of 6.31 mmol). The resulting mixture was stirred for 3 is it at ambient temperature and then the solvent was removed, equalising N2through the mixture. Was added water (10 ml) and the reaction mixture was neutralized (to pH 7) with 1 n HCl solution. The solids were collected by filtration and was dried by concentration in vacuum with acetonitrile, receiving amino acid in a solid pink color (1,32 g, 86%).

Stage G: To a suspension obtained at the stage In amino acids (1,32 g, a 2.71 mmol) in N,N-dimethylformamide (12 ml) was added 1-hydroxybenzotriazole (0,439 g, 3.25 mol), N-methylmorpholin (0,894 ml, 8,13 mmol), O-(tetrahydropyranyl)hydroxylamine (0,476 g, 4.07 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0,727 g, with 3.79 mmol). The resulting mixture was stirred for 20 h at ambient temperature and then concentrated in vacuum. The residue was distributed between H2O and ethyl acetate. The combined organic layers were washed N2Oh, a saturated solution of NaHCO3saturated NaCl solution and dried over PA2SO4. After chromatography (silica gel, methanol/ethyl acetate) received protected hydroxamate in the form of a solid whitish (1.39 g, 88%).

Stage D: To the solution obtained in stage G of protected hydroxamate (1.40 g, 2,39 mmol) in dioxane (3 ml) and methanol (1 ml) was added 4 n HCl solution in dioxane (5,98 ml of 23.9 mmol). The resulting mixture was stirred for 2.5 h at ambient temperature. actionnow the mixture was concentrated almost to dryness, equalising N2through the reaction mixture. Added diethyl ether (25 ml) and the precipitate was collected by filtration. The resulting solid was dissolved in methanol (1 ml) and was treated with 4 N. a solution of HCl in dioxane (1.5 ml). After stirring for 1.5 h at ambient temperature the reaction mixture was slowly added to diethyl ether (50 ml). The precipitate was collected by filtration, getting mentioned in the title compound in the form of a solid whitish (1.08 g, 84%). MS MN+: calculated for C22H27O5N3SF3: 502, found: 502.

Example 397: Getting ethyl-1-(2-methoxyethyl)-3-phenylpropoxy)phenyl]sulfonyl]-4-piperidinecarboxylate

Phase A: a Mixture containing methoxyethylamine ethyl-4-[(4-perpenicular)]-1-(2-methoxyethyl)-4-piperidinecarboxylate (1.5 g, 4.0 mmol), 3-phenyl-1-propanol (2.2 ml, 16 mmol) and K2CO3(2.2 g, 16 mmol) in DMAC (6 ml), was kept for 1 day at 125° and for 3 days at 135° C. thereafter, the mixture was concentrated in vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and with brine, dried over magnesium sulfate and concentrated in vacuum, obtaining neojidannoe oil. Oil ociali Express chromatography (hexane/ethyl acetate 20:80)to give p Estoy ether in the form of a brown oil (1.35 g, 67%).

Phase B: a Mixture containing obtained on the stage And simple ester (1.3 g, 2.7 mmol) and 50%aqueous NaOH solution (2.1 g, 27 mmol) in THF (23 ml), tO (23 ml) and N2O (12 ml), was kept for 24 h at 60° C in nitrogen atmosphere. The product was concentrated in vacuo and triturated with diethyl ether, obtaining a solid substance. The solid was dissolved in water, cooled in an ice bath and acidified with concentrated hydrochloric acid. The precipitate was isolated by filtration, washed with cold water and dried in a vacuum oven for 3 days at ambient temperature, obtaining the crude acid.

The mixture containing the result of the above crude acid (1.1 g), N-hydroxybenzotriazole (0.36 g, 2.7 mmol), 4-methylmorpholine (0,74 ml, 6.7 mmol), O-tetrahydro-2H-Piran-2-alhydrogel (0.39 g, 3.3 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (of 0.60 g, 3.1 mmol) in DMF (11 ml)was stirred for 18 h at ambient temperature under nitrogen atmosphere. The mixture was concentrated in vacuo and dissolved in the solution containing a saturated solution of NaHCO3(90 ml), ethyl acetate (25 ml) and few drops of 2n. NaOH solution. The aqueous layer was extracted with an additional portion of ethyl acetate. United an ethyl acetate layers were washed with saturated solution of NaHCO3, water and salt solution. After drying over magnesium sulfate, the filtrate concentration is Aravali in vacuum, receiving the oil is dark yellow. The oil was purified Express chromatography (mixture of acetonitrile/toluene, 40:60)to give the protected hydroxamate in the form of a yellow oil (0.32 g, 25%). MS MN+: calculated for C29H40N2O7S: 561 detected: 561.

Stage b: To the solution obtained in stage B of protected hydroxamate (0.28 g, 0.50 mmol) in methanol (4.0 ml) was added acetylchloride (of 0.11 ml, 1.5 mmol) and the solution was stirred for 2.5 h at ambient temperature under nitrogen atmosphere. The solution was diluted with diethyl ether and concentrated. The solid is triturated with diethyl ether and dried in a vacuum oven at 40° receiving specified in the title compound in the form of solids whitish (0.15 g, 20%). MS MN+: calculated for C24H32N2O6S: 477, found: 477.

Example 398: Obtain monohydrochloride 1-cyclopropyl-N-hydroxy-4-[[4-(2-phenoxyethoxy)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: To the solution obtained in stage D of example 9 compound (14,36 g, 40 mmol) in methanol (50 ml) was added acetic acid (24.5 g, 400 mmol), portion (approximately 2 g), molecular sieves 4 Å, (1-amoxicilpin)axithromycin (from 25.8 ml, 148 mmol) and lambrogini sodium (7,05 g, 112 mmol). The solution was kept for 8 h at pace is the atur reflux distilled. Saducees solids were removed by filtration and the filtrate was concentrated in vacuum. The residue was diluted with H2O (400 ml) and was extracted with ethyl acetate. The organic layer was washed with saturated solution of NaCl and dried over MgSO4, filtered and concentrated in vacuum. The solid was filtered, washed with a mixture of N2O/diethyl ether, obtaining the required cyclopropylamine ethyl-4-[(4-perpenicular)]-1-cyclopropyl-4-piperidinecarboxylate in a solid white color (11,83 g, 81,5%). MS MN+: calculated for C17H22NO4SF: 356, found: 356.

Stage B: a Solution containing obtained on the stage And cyclopropylamine (2.0 g, 5.6 mmol), phenyl ether of ethylene glycol (2.8 ml, 23 mmol) and cesium carbonate (7,3 g, 23 mmol) in DMAC (10 ml), was kept for 18 h at 125-135 mA° C in nitrogen atmosphere. The mixture was concentrated in vacuum, diluted with water and extracted with ethyl acetate. United an ethyl acetate layers were washed with water and with brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, besieged as hydrochloride and dried in a vacuum oven at 40° C. the Solid was dissolved in a mixture of water, acetonitrile and ethanol and then the pH value was brought to 12 with 1 n NaOH solution. The mixture was concentrated in vacuo to remove ethanol and acetonitrile is. The solid was isolated by filtration, washed with water and dried in a vacuum oven at 50° receiving a simple ether in a solid white color (1.8 g, 68%). MS+: calculated for C25H31NO6S: 474, found: 474. Elemental analysis: calculated for C25H31NO6S: 63,40; N 6,60; N 2,96; S 6,77; found: 63,35; N 6,59; N 2,99; S 6,61.

Stage b: Mixture obtained in stage B simple ether (1.8 g, 3.7 mmol) and 50%aqueous NaOH solution (3.0 g, 37 mmol) in THF (32 ml), EtOH (32 ml) and N2O (16 ml), was kept for 24 at 60° C in nitrogen atmosphere. The product was concentrated in vacuo and triturated with diethyl ether, obtaining a solid substance. Solid reddish-brown color was dissolved in a mixture of water, ethanol and THF, besieged by bringing the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water and dried in a vacuum oven at 50° receiving the crude acid solids white (2.3 g).

The mixture containing the result of the above crude acid solids white (2.3 g), N-hydroxybenzotriazole (1.9 g, 14 mmol), 4-methylmorpholine (1.6 ml, 14 mmol), O-tetrahydro-2H-Piran-2-alhydrogel (1.1 g, 9.4 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (2.7 g, 14 mmol) in DMF (90 ml), was stirred for 2 days PR is the ambient temperature in the atmosphere of nitrogen. The mixture was concentrated in vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed 1 N. NaOH solution, water and saline solution, dried over magnesium sulfate, concentrated in vacuum and purified Express chromatography (mixture of ethyl acetate/toluene, from 20:80 to 40:60)to give the protected hydroxamate in a solid white color (0,43 g, 21%). MS MN+: calculated for C28H36N2O7S: 545 detected: 545. Elemental analysis: calculated for C28H36N2About7S: 61,74; N 6,66; N 5,14; S of 5.89; found: 61,72; N. Of 6.75; N Is 5.06; S 5,91.

An additional portion of the compound was isolated by acidification of the aqueous layer to pH 3, collect the solid by filtration and drying to obtain solid white (0,80 g).

Stage D: rsquore acetylchloride (0,31 ml, 4.4 mmol) in methanol (11 ml)at ambient temperature was added under nitrogen atmosphere obtained at the stage In protected hydroxamate (0,80 g, 1.5 mmol). After stirring for 2.5 h the precipitate was collected by filtration, washed with diethyl ether and dried in a vacuum oven at 45° receiving specified in the title compound in the form of solid white (0,58 g, 79%). MS MN+: calculated for C23H28N2O6S: 461, found: 461. Elemental analysis: calculated for C23H28 N2O6S· 1,5HCl: 53,62; N 5,77; N 5,44; S to 6.22; found: C 53.47 USD; N 5,79; N 5,41; S 6,16.

Example 399: Getting dihydrochloride hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-triptoreline)phenoxy]phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: a Solution containing obtained in example 410 amine hydrochloride (2.4 g, 4.6 mmol), 3-picolylamine (1.5 g, 8,8 mmol) and potassium carbonate (4.3 g, 31 mmol) in DMF (12 ml), was kept for 1 day at 50° C in nitrogen atmosphere. The mixture was concentrated in vacuo, dissolved in water and was extracted with ethyl acetate. The organic layers were washed with water and with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified Express chromatography (hexane/ethyl acetate 50:50)to give 3-picolylamine in the form of oil of amber (1.6 g, 60%). MS MN+: calculated for C27H27N2About6SF3: 565 detected: 565. Elemental analysis: calculated for C27H27N2O6SF3: 57,44; N 4,82; N 4,96; S of 5.68; found: 57,49; N 5,10; N 4,69; S 5,67.

Phase B: a Mixture containing obtained on the stage And picolylamine (1.5 g, 2.6 mmol) and 50%aqueous NaOH solution (2.1 g, 26 mmol) in THF (22 ml), EtOH (22 ml) and N2O (11 ml), was kept for 24 h at 65° C in nitrogen atmosphere. The product was concentrated in vacuo and triturated with diethyl ether, receiving TBE is the substance. Solid reddish-brown color was dissolved in water, was dissolved in water and the pH was brought to 1 with concentrated hydrochloric acid. The mixture was concentrated in vacuum and dried in a vacuum oven at 45° receiving the crude acid solids white (2.5 g). MS MN: calculated for C25H23N2About6SF3: 537 found: 537.

Stage b: Mixture obtained in stage B of the crude acid in white (2.5 g), N-hydroxybenzotriazole (1.0 g, 7.7 mmol), 4-methylmorpholine (of 0.64 ml, 7.7 mmol), O-tetrahydro-2H-Piran-2-alhydrogel (0,60 g, 5.1 mmol) and the hydrochloride of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide (1.5 g, 7.7 mmol) in DMF (40 ml)was stirred for 5 days at ambient temperature in the atmosphere of nitrogen. The mixture was concentrated in vacuum, diluted with ethyl acetate and washed with water and saline solution. The organic layer was dried over magnesium sulfate, concentrated in vacuum and purified Express chromatography (methanol/chloroform, 5:95)to give the protected hydroxamate in the form of a white foam (1.1 g, 66%). MS MN+: calculated for C30H32N3O7SF3: 636, found: 636.

Stage D: a Solution containing obtained on the stage In a protected hydroxamate (1.0 g, 1.6 mmol) and acetylchloride (0,34 ml, 4.7 mmol) in methanol (11 ml)under p and the ambient temperature, was stirred for 2.5 h under nitrogen atmosphere and then was poured into diethyl ether. The solid was isolated by filtration and dried in a vacuum oven at 46° getting mentioned in the title compound in the form of a solid white color of 0.85 g, 87%). Elemental analysis: calculated for C25H24N3About6SF3·2,2HCl: 47,53; N 4,18; N 6,65; S 5,08; found: 47,27; N 4,34; N 6,60; S of 5.29. MS MN+: calculated for C25H24N3About6SF3: 552 detected: 552.

Example 400: getting the dihydrochloride of N-hydroxy-4-[4-(4-methoxyphenoxy)phenyl]sulfonyl]-1-(2-pyridinylmethyl)-4-piperazinecarboxamide

Stage A: Hydrochloride ethyl-4-[(4-perpenicular)]-4-piperidinecarboxylate (2,02 g, USD 5.76 mmol) was combined with powdered potassium carbonate (2,48 g, 18 mmol) and N,N-dimethylformamide (12 ml).

Added hydrochloride 2-picoline (1.0 g, 6.1 mmol) and the mixture was stirred for 24 h at 40° C. the Reaction mixture was diluted with water (80 ml) and was extracted with ethyl acetate (3× 50 ml). The combined organic layers were dried over magnesium sulfate, concentrated and subjected to chromatography (ethyl acetate)to give the desired ester of pyridine in the form of oil (2.30 g, quantitative yield).

Stage B: Obtained at the stage And complex ethyl ester pyridine (2.30 g, USD 5.76 mmol) unite the Yali with powdered potassium carbonate (1.29 g, 9 mmol), 4-methoxyphenol (1.12 g, 9.0 mmol) and N,N-dimethylformamide (3 ml), and the mixture was stirred for 24 h at 75-80° C. was Added an additional portion of 4-methoxyphenol (300 mg) and potassium carbonate (350 mg) and the mixture was stirred for another 3 h at 90° C. the Mixture was diluted with water (50 ml) and was extracted with ethyl acetate (3× 50 ml). The combined organic layers were dried over magnesium sulfate, concentrated and chromatographically, getting the desired ester in the form of oil (2.85 g, quantitative yield).

Stage b: Obtained in stage B ester (2.85 g) was combined with ethanol (18 ml), water (6 ml) and potassium hydroxide (2.24 g, 40 mmol). The mixture was heated to the temperature of reflux distilled and kept over 4.5 hours, the Mixture was cooled to 0° and acidified with concentrated aqueous hydrochloric acid. The solvent was removed and the resulting solids were dried by azeotrope with acetonitrile. The product was kept under vacuum until reaching constant weight.

The crude acid chloride was stirred with N-methylmorpholine (1 ml), 1-hydroxybenzotriazole (0,945 g, 7 mmol), O-tetrahydropyranyloxy (0,82 g, 7 mmol) and N,N-dimethylformamide (21 ml). After 10 min was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (of 1.34 g, 7 mmol) and the mixture was stirred over night. Then the reaction mixture was diluted floor is saturated aqueous sodium bicarbonate 100 ml) and was extracted with ethyl acetate (200 ml, and then 50 ml). The combined organic layers were dried over magnesium sulfate, concentrated and chromatographically (ethyl acetate/hexane, 9:1)to give the desired O-tetrahydropyranyl protected hydroxamate in the form of a yellow oil (2,82 g, 88%).

Stage D: Obtained in stage B O-tetrahydropyranyl protected hydroxamate (2,82 g, 5 mmol) was diluted with methanol (20 ml). Within 2 min was added acetylchloride (2.1 ml, 30 mmol). The reaction mixture was stirred for 4 h at ambient temperature, then concentrated, receiving 2,59 g of the crude hydrochloride, which was recrystallized from a mixture of ethanol/water, receiving the first output of 525 mg (18%) specified in the header of hydroxamate. MS (ES) MN+: calculated for C25H27N3O6S: 498, found: 498.

Example 401: obtain the hydrochloride of N-hydroxy-4-[4-(4-cyclohexylthio)phenyl]sulfonyl]-1-(2-methoxyethyl)-4-piperazinecarboxamide

Stage A: Ethyl-4-[(4-perpenicular)]-1-(2-methoxyethyl)-4-piperidinecarboxylate (5.5 g, 14 mmol) was combined with powdered potassium carbonate (2.76 g, 20 mmol), N,N-dimethylformamide (7 ml) and cyclohexylmethanol (2.4 ml, 20 mmol) and was stirred for 2 days at ambient temperature. The temperature was raised to 45-50° and the stirring continued for another 24 h was Added on the additional portion of potassium carbonate (1.0 g) and cyclohexylaniline (1.0 ml) and the reaction mixture was heated for 16 hours The mixture was diluted with water (50 ml) and was extracted with ethyl acetate (100 ml, then 25 ml). The combined organic layers were dried, concentrated and chromatographically (ethyl acetate)to give the desired sulfide in the form of a yellow oil (3,59 g, 53%).

Stage B: Obtained at the stage And sulfide (3,59 g, 7.4 mmol) was converted into tetrahydropyranyl protected hydroxamate by saponification and subsequent combination with the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide according to the method described in stage b of example 401, receiving 2.16 g (54%) required tetrahydropyranyl-protected hydroxamate in the form of oil.

Stage b: Obtained in stage B tetrahydropyranyl protected hydroxamate (2.16 g, 4 mmol) was diluted with methanol (16 ml). Within 1 min was added acetylchloride (1.1 ml, 16 mmol). The reaction mixture was stirred for 4 h, then concentrated and subjected azeotrope with acetonitrile, getting 1,11 g of the crude product, which was recrystallized from absolute ethanol, receiving the first output 804 mg specified in the title compound (41%). MS (ES) MH+: calculated for C21H32N2About5S2: 457, found: 457.

Example 402: Receive N-hydroxyl-1-(2-methoxyethyl)-4-[[(phenylmethoxy)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: Ethyl-4-[(4-perpenicular)]-1-2-methoxyethyl)-4-piperidinecarboxylate (1,58 g, 4.5 mmol) was combined with powdered potassium carbonate (2,42 g, 18 mmol), N,N-dimethylacetamide (5 ml) and benzyl alcohol (1,94 ml, 18 mmol) and was stirred for 16 h at 140° C. the Mixture was diluted with water (50 ml) and was extracted with ethyl acetate (125 ml, then 25 ml). The combined organic layers were dried, concentrated and chromatographically (ethyl acetate)to give the desired complex ethyl ester in the form of oil (1,16 g, 56%).

Stage B: Obtained at the stage And complex ethyl ester (1,16 g, 2.5 mmol) was converted into tetrahydropyranyl protected hydroxamate by saponification and subsequent combination with the hydrochloride of 1-[3-(dimethylamino) propyl] -3-ethylcarbodiimide according to the method described in stage b of example 401, receiving 880 mg (80%) of the required tetrahydropyranyl-protected hydroxamate in the form of oil.

Stage b: Obtained in stage B tetrahydropyranyl protected hydroxamate (880 mg, 2.0 mmol) was diluted with methanol (8 ml). Within 1 min was added acetylchloride (0.68 ml, 10 mmol). The reaction mixture was stirred for 3 h, then concentrated and subjected azeotrope with acetonitrile, receiving the crude product, which was converted into the free base by adding saturated aqueous sodium bicarbonate solution (25 ml), sufficient to neutralize the hydrochloric acid, then was extracted with ethyl acetate (100 ml, then 50 m is). The organic phase was dried over magnesium sulfate, concentrated and chromatographically (dichloromethane/methanol, 9:1, 1%ammonium hydroxide)to give specified in the header of hydroxamate in the form of glass (327 mg, 36%). MS (ES) MN+: calculated for C22H28N2O6S: 447, found: 447.

Example 403: Obtaining N-hydroxyl-1-(1-methylethyl)-4-[[4-(2-phenylethane)phenyl]sulfonyl]-4-piperazinecarboxamide

Stage A: Ethyl-4-[(4-perpenicular)]-1-(1-methylethyl)-4-piperidinecarboxylate (2,75 g, 7.7 mmol) was combined with powdered potassium carbonate (2,62 g, 19 mmol), N,N-dimethylformamide (10 ml) and 2-phenylethanol (2 ml, 19 mmol) and was stirred for 24 h at 85° C. was Added an additional portion of potassium carbonate (1.3 g) and 2-phenylethanol and the temperature was increased within 48 h before 110° and then for 4 h to 135° C. the Mixture was diluted with water (100 ml) and was extracted with ethyl acetate (200 ml, then 25 ml). The combined organic layers were dried, concentrated and chromatographically (ethyl acetate)to give the desired complex ethyl ester in the form of oil (3,19 g, 90%).

Stage B: Obtained at the stage And complex ethyl ester (3,19 g, 6,9 mmol) was converted into tetrahydropyranyl protected hydroxamate by saponification and subsequent combination with the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide according to the person, described in stage b of example 401, receiving, and 2.27 g (64%) indicated in the title compound in the form of oil.

Stage b: Obtained in stage B tetrahydropyranyl protected hydroxamate of 2.27 g, 4.4 mmol) was diluted with methanol (16 ml). Within 1 min was added acetylchloride (0.68 ml, 10 mmol). The reaction mixture was stirred for 3 h, then concentrated and subjected azeotrope with acetonitrile, receiving the crude product, which was converted into the free base by adding saturated aqueous sodium bicarbonate solution (25 ml), sufficient to neutralize the hydrochloric acid, then was extracted with ethyl acetate (100 ml, then 50 ml). The organic phase was dried over magnesium sulfate, concentrated and chromatographically (dichloromethane/methanol, 9:1, 1%ammonium hydroxide)to give the required hydroxamate in the form of glass (812 mg, 42%). MS (ES) MH+: calculated for C23H30N2O5S: 449, found: 449.

Example 404: Receive phosphate N-hydroxy-4-[(4-phenylthiophene)sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: N-Hydroxy-4-[(4-phenylthiophene)sulfonyl]-1-(2-PROPYNYL)-4-piperidinecarboxylic (430 mg, 1.0 mmol) was dissolved in methanol (15 ml). Added concentrated phosphoric acid (67 ml) and then the solution was concentrated in vacuum. The remainder paracrystalline is Ali from methanol, were isolated by filtration and then again recrystallized from methanol/methyl tert-butyl ether, receiving specified in the header of the phosphate in the form of a solid (215 mg, 41%). Elemental analysis: calculated for C21H22N2O4·3H3PO4: 47,72; N. Of 4.77; N and 5.30; found: 47,63; N 5,04; N 4,82.

Example 405: steam-toluensulfonate N-hydroxy-4-[(4-phenylthiophene)sulfonyl]-1-(2-PROPYNYL)-4-piperazinecarboxamide

Stage A: N-Hydroxy-4-[(4-phenylthiophene)sulfonyl]-1-(2-PROPYNYL)-4-piperidinecarboxylic (516 mg, 1.0 mmol) was combined with monohydrate para-toluensulfonate acid (200 mg, 1.05 mmol) and the mixture was dissolved in methanol (3 ml). After 4 h, the resulting white precipitate was collected by filtration, getting 488 mg (81%) specified in the header tosilata, the characteristics of which were determined by spectroscopic means.

Example 406: Getting monohydrochloride 4-[[4-[(2,3-dihydro-1H-inden-2-yl)amino]Phenyl]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: a Solution containing obtained in stage G of example 9 product (0,979 g, 2.36 mmol), hydrochloride of 2-aminoindane (1,00 g of 5.89 mmol) and cesium carbonate (1.92 g, of 5.89 mmol) in N,N-dimethylformamide (8 ml), was heated for 22 h to 95° C. Then the reaction mixture was cooled, diluted those who acetate (50 ml) and washed three times with water and once with brine, then was dried over sodium sulfate. After concentrating the obtained residue, which was chromatographically on silica gel. After elution with a mixture of ethyl acetate/hexane (30/70) received the required 4-aminosulfonic derived (450 mg, 36%). MS (ES) MN+:calculated for C28H36N2About6S: 529 found: 529. Msvr M+: calculated for C28H36N2O6S: 528,2294 found: 528,2306.

Stage B: To the solution obtained in stage a complex ethyl ester (450 mg, 0.85 mmol) in ethanol (3 ml), water (2 ml) and tetrahydrofuran (3 ml) was added sodium hydroxide (340 mg, 8.5 mmol) and the solution was heated for 26 h to 60° C. the Solution was cooled, then diluted with water (10 ml) and then 10%aqueous solution of hydrochloric acid (3 ml), bringing the pH value to 2. The resulting solution was extracted with ethyl acetate. The organic extracts were combined and washed with water and with brine and dried over sodium sulfate, getting the desired carboxylic acid in the form of foam, light brown (376 mg, 88%). Elemental analysis: calculated for C26H32N2About6S: 62,38; N 6,44; N the ceiling of 5.60; S 6,40; found: 62,48; N 6,69; N 5,42; S 6,27.

Stage b: To a suspension obtained in stage B carboxylic acid (305 mg, 0,609 mmol) in N,N-dimethylformamide (2 ml) was added 4-methylmorpholine (247 mg, 2,44 mmol), N-hydroxybenzotriazole (99 mg,0.73 mol), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (152 g of 0.79 mmol), and then O-(tetrahydro-2H-Piran-2-yl)hydroxylamine (97 mg, 0.82 mmol). After stirring for 2 days at ambient temperature the solution was concentrated, obtaining oil. Added water and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and with brine and dried over sodium sulfate. After concentration was obtained a brown foam, which was chromatographically on silica gel. After elution with a mixture of ethyl acetate/hexane (40/60) received protected hydroxamate in the form of colourless glass (0,38 g, 100%). MS (ES) MH+:calculated for C31H41H3O7S: 600, found: 600.

Stage G: To a solution obtained at the stage In protected hydroxamate (350 mg, 0,584 mmol) in methanol (3 ml) and 1,4-dioxane (1.5 ml) was added to a mixture of 4 n HCl/1,4-dioxane (1.5 ml, 6 mmol) and the solution was stirred for 3 h at ambient temperature. After concentrating the obtained residue, which was triturated with diethyl ether, obtaining mentioned in the title compound in the form of a solid, which was filtered and dried for 40 hours at 51° (249 mg, 94%). Msvr (ESI) MN+: calculated for C21H25N3O4S: 416,1644 found: 416,1647.

Example 407: Getting monohydrochloride 4-[[4-(dimethylamino)dryer is l]sulfonyl]-N-hydroxy-4-piperazinecarboxamide

Stage A: a Solution containing obtained in stage G of example 9 product (0,979 g, 2.36 mmol), hydrochloride of 2-aminoindane (1,00 g of 5.89 mmol) and cesium carbonate (1.92 g, of 5.89 mmol) in N,N-dimethylformamide (8 ml), was heated for 22 h to 95° C. Then the reaction mixture was cooled, diluted with ethyl acetate (50 ml) and washed three times with water and once with brine, then dried over sodium sulfate. After concentrating the obtained residue, which was chromatographically on silica gel. After elution with a mixture of ethyl acetate/hexane (30/70) received the desired 4-N,N-diethylaminosulfur (590 mg, 57%), along with the product from example 406. MS (ES) MH+: calculated for C21H32N2O6S: 441, found: 441. Msvr: calculated for C21H32N2About6S: 440,1981 found: 440,1978.

Stage B: To the solution obtained in stage a complex ethyl ester (580 mg, 1.3 mmol) in ethanol (4 ml), water (3 ml) and tetrahydrofuran (4 ml